Prehistoria, Historia y Arte de la Reumatología, Gota y Espondilitis Anquilosante

PREHISTORIA, HISTORIA Y ARTE DE LA

REUMATOLOGÍA GOTA Y ESPONDILITIS ANQUILOSANTE

MIOCARDIOPATÍA HIPERTRÓFICA OBSTRUCTIVA

REHABILITACIÓN CARDIOVASCULAR MANEJO, EVALUACIÓN & RESULTADOS

RETO DIAGNÓSTICO ENTRE CROHN Y COLITIS SISTÉMICA

DIAGNÓSTICO INESPERADO EN PACIENTE CON SOSPECHA DE GIST INFILTRACIÓN GÁSTRICA POR MIELOMA MÚLTIPLE

FOR BIOLOGIC-NAIVE PATIENTS WITH ANKYLOSING SPONDYLITIS

Fast ASAS40 results at week 16; consistent through week 52

PATIENTS ACHIEVING RESPONSE, NRI (%)

COAST-V (BIOLOGIC-NAIVE): ASAS40 response rates

60

ASAS40 at week 16

40

48 36%‡

ASAS40 through week 52

53%

%†

*

20

18%

0 0

2

4

8

12

16

20

24

28

32

36

40

44

48

52

Extended Treatment Period

WEEK

Taltz 80 mg every 4 weeks (n=81)

Humira® (adalimumab) 40 mg every 2 weeks (n=90)

Placebo (n=87)

COAST-V was not designed to test the noninferiority or superiority of Taltz to Humira. Thus, these data should not be used to compare the efficacy between these products. *Nominal P value: Taltz P=.003, Humira P=.001 vs placebo. Not controlled for type-I error; therefore, no statistical conclusions can be made.

Results at week 2: Taltz=20%; Humira=21%; placebo=5%. † P<.0001 vs placebo at week 16. ‡ P=.0053 vs placebo at week 16.

Primary endpoint=ASAS40 at week 16.

ASAS scores measure degrees of spinal pain, function, inflammation, and patient global assessment.

Nonresponder imputation (NRI) of intent-to-treat population through weeks 16 and 52.

The extended treatment period of the study (weeks 16-52) has limitations (ie, no placebo comparison, patients remaining in the extension phase may be those more responsive to treatment).

ADDITIONAL WEEK 52 RESULTS FROM COAST-W TRIAL, NRI In COAST-W (TNFi-experienced) (Taltz 80 mg every 4 weeks n=114; placebo n=104), 25% of patients receiving Taltz achieved ASAS40 at week 16 vs 13% of patients receiving placebo. At week 52, 34% of patients receiving Taltz achieved ASAS40.

Taltz is the first and only approved AS treatment that has ASAS40 as a primary endpoint in its label.1-3

COAST-V AND COAST-W TRIAL DESIGN1 COAST-V (N=341) and COAST-W (N=316) were phase 3, multicenter, randomized, double-blind clinical trials designed to evaluate the efficacy and safety of Taltz compared with placebo in patients with active ankylosing spondylitis (AS). The primary efficacy endpoint for both trials was the proportion of patients achieving ASAS40 response at week 16. Patients in COAST-V were biologic-naive. Patients in COAST-W were TNFi-experienced, meaning they had an inadequate response or were intolerant to 1 or 2 tumor necrosis factor inhibitors (TNFis). All patients were ≥18 years of age, had a baseline Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score ≥4, and an established diagnosis of r-axSpA with sacroiliitis defined radiographically according to the mNY criteria. Patients had at least 1 spondyloarthritis (SpA) feature per ASAS criteria and were randomized to placebo or Taltz 80 mg or 160 mg at week 0, followed by Taltz 80 mg every 2 or 4 weeks. All patients had experienced back pain for at least 3 months, with onset before the age of 45. In COAST-V, an active reference arm of Humira 40 mg every 2 weeks was included. The approved AS dose for Taltz is 160 mg at week 0 followed by 80 mg every 4 weeks.

INDICATIONS AND IMPORTANT SAFETY INFORMATION Taltz is indicated for adult patients with active ankylosing spondylitis, for adult patients with active psoriatic arthritis (PsA), and for adult patients with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation. Taltz is also indicated for adult patients and pediatric patients aged 6 years or older with moderate-to-severe plaque psoriasis (PsO) who are candidates for systemic therapy or phototherapy.

CONTRAINDICATIONS Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients.

WARNINGS AND PRECAUTIONS Infections Taltz may increase the risk of infection. In clinical trials of adult patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%). A similar increase in risk of infection was seen in placebo-controlled trials of adult patients with psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and pediatric patients with plaque psoriasis. Serious infections have occurred. Instruct patients to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a serious infection develops, discontinue Taltz until the infection resolves.

Pre-Treatment Evaluation for Tuberculosis Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Closely monitor patients receiving Taltz for signs and symptoms of active TB during and after treatment.

Hypersensitivity Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in postmarketing use with Taltz. If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inflammatory Bowel Disease Patients treated with Taltz may be at an increased risk of inflammatory bowel disease. In clinical trials, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group than the placebo group. During Taltz treatment, monitor patients for onset or exacerbations of inflammatory bowel disease and if IBD occurs, discontinue Taltz and initiate appropriate medical management.

Immunizations Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz.

ADVERSE REACTIONS Most common adverse reactions (≥1%) associated with Taltz treatment are injection site reactions, upper respiratory tract infections, nausea, and tinea infections. Overall, the safety profiles observed in adult patients with psoriatic arthritis, ankylosing spondylitis, non-radiographic axial spondyloarthritis, and pediatric patients with plaque psoriasis were consistent with the safety profile in adult patients with plaque psoriasis, with the exception of influenza and conjunctivitis in psoriatic arthritis and conjunctivitis, influenza, and urticaria in pediatric psoriasis.

Please see Brief Summary of Prescribing Information on the following pages. Please see Instructions for Use included with the device.

IX HCP ISI 07MAY2020 References: 1. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2021. 2. van der Heijde D, ChengChung Wei J, Dougados M, et al. Ixekizumab, an interleukin-17A antagonist in the treatment of ankylosing spondylitis or radiographic axial spondyloarthritis in patients previously untreated with biological disease modifying anti-rheumatic drugs (COAST-V): 16 week results of a phase 3 randomised, double-blind, active-controlled and placebo-controlled trial. Lancet.

2018;392:2441-2451. 3. Data on file. Lilly USA, LLC. DOF-IX-US-0155.

ASAS20/40=Assessment of Spondyloarthritis International Society response criteria, ≥20%/≥40% improvement; mNY=modified New York; r-axSpA=radiographic axial spondyloarthritis.

Taltz® is a registered trademark owned or licensed by Eli Lilly and Company, its subsidiaries, and affiliates.

Humira® is a registered trademark of AbbVie Biotechnology Ltd. PP-IX-US-5202 12/2021 ©Lilly USA, LLC 2021. ALL RIGHTS RESERVED.

Hypothetical Patient

Taltz® (ixekizumab) injection Brief Summary: Consult the package insert for complete prescribing information.

INDICATIONS AND USAGE Plaque Psoriasis—Taltz is indicated for the treatment of patients aged 6 years and older with moderate-to-severe plaque psoriasis who are candidates for systemic therapy or phototherapy.

Psoriatic Arthritis—Taltz is indicated for the treatment of adult patients with active psoriatic arthritis.

Ankylosing Spondylitis—Taltz is indicated for the treatment of adult patients with active ankylosing spondylitis.

Non-radiographic Axial Spondyloarthritis—Taltz is indicated for the treatment of adult patients with active non-radiographic axial spondyloarthritis (nr-axSpA) with objective signs of inflammation.

CONTRAINDICATIONS Taltz is contraindicated in patients with a previous serious hypersensitivity reaction, such as anaphylaxis, to ixekizumab or to any of the excipients (Warnings and Precautions).

WARNINGS AND PRECAUTIONS Infections—Taltz may increase the risk of infection. In clinical trials in adult patients with plaque psoriasis, the Taltz group had a higher rate of infections than the placebo group (27% vs 23%).

Upper respiratory tract infections, oral candidiasis, conjunctivitis and tinea infections occurred more frequently in the Taltz group than in the placebo group. A similar increase in risk of infection was seen in placebo-controlled trials in patients with pediatric psoriasis, psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis (Adverse Reactions).

Instruct patients treated with Taltz to seek medical advice if signs or symptoms of clinically important chronic or acute infection occur. If a patient develops a serious infection or is not responding to standard therapy, monitor the patient closely and discontinue Taltz until the infection resolves.

Pre-treatment Evaluation for Tuberculosis—Evaluate patients for tuberculosis (TB) infection prior to initiating treatment with Taltz. Do not administer to patients with active TB infection. Initiate treatment of latent TB prior to administering Taltz. Consider anti-TB therapy prior to initiating Taltz in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed. Patients receiving Taltz should be monitored closely for signs and symptoms of active TB during and after treatment.

Hypersensitivity—Serious hypersensitivity reactions, including angioedema and urticaria (each ≤0.1%), occurred in the Taltz group in clinical trials. Anaphylaxis, including cases leading to hospitalization, has been reported in post-marketing use with Taltz (Adverse Reactions). If a serious hypersensitivity reaction occurs, discontinue Taltz immediately and initiate appropriate therapy.

Inflammatory Bowel Disease—Patients treated with Taltz may be at an increased risk of inflammatory bowel disease. In clinical trials, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the Taltz group than in the control group (Adverse Reactions). During Taltz treatment, monitor for onset or exacerbation of inflammatory bowel disease and if IBD occurs, discontinue Taltz and initiate appropriate medical management.

Immunizations—Prior to initiating therapy with Taltz, consider completion of all age-appropriate immunizations according to current immunization guidelines. Avoid use of live vaccines in patients treated with Taltz. No data are available on the response to live vaccines.

ADVERSE REACTIONS The following adverse drug reactions are discussed in greater detail in other sections of the label: • Infections (Warnings and Precautions) • Hypersensitivity Reactions (Contraindications and Warnings and Precautions) • Inflammatory Bowel Disease (Warnings and Precautions) Clinical Trials Experience—Because clinical trials are conducted under widely varying and controlled conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adult Plaque Psoriasis Weeks 0 to 12: Three placebo-controlled trials in subjects with plaque psoriasis were integrated to evaluate the safety of Taltz compared to placebo for up to 12 weeks. A total of 1167 subjects (mean age 45 years; 66% men; 94% White) with plaque psoriasis received Taltz (160 mg at Week 0, 80 mg every 2 weeks [Q2W] for 12 weeks) subcutaneously. In two of the trials, the safety of Taltz (use up to 12 weeks) was also compared with an active comparator, U.S. approved etanercept.

In the 12-week, placebo-controlled period, adverse events occurred in 58% of the Taltz Q2W group (2.5 per subject-year of follow-up) compared with 47% of the placebo group (2.1 per subject-year of follow-up). Serious adverse events occurred in 2% of the Taltz group (0.07 per subject-year of follow-up), and in 2% of the placebo group (0.07 per subject-year of follow-up).

Table 1 summarizes the adverse reactions that occurred at a rate of at least 1% and at a higher rate in the Taltz group than the placebo group during the 12-week placebo-controlled period of the pooled clinical trials.

Table 1: Adverse Reactions Occurring in ≥1% of the Taltz Group and More Frequently than in the Placebo Group in the Plaque Psoriasis Clinical Trials through Week 12 Placebo Adverse Reactions Taltz 80 mg Q2W Etanerceptb (N=287) (n%) (N=791) (n%) (N=1167) (n%) Injection site reactions 196 (17) 32 (11) 26 (3) Upper respiratory tract 163 (14) 23 (8) 101 (13) infectionsa Nausea 23 (2) 1 (<1) 5 (1) Tinea infections 17 (2) 0 1 (<1) a b

Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection.

U.S. approved etanercept.

Taltz® (ixekizumab) injection

Taltz, IX HCP BS 12MAR2021 - 7.5 x 10

IX HCP BS 12MAR2021

Adverse reactions that occurred at rates less than 1% in the Taltz group and more frequently than in the placebo group during the 12-week induction period included rhinitis, oral candidiasis, urticaria, influenza, conjunctivitis, inflammatory bowel disease, and angioedema.

Weeks 13 to 60: A total of 332 subjects received the recommended maintenance regimen of Taltz 80 mg dosed every 4 weeks. During the maintenance period (Weeks 13 to 60), adverse events occurred in 80% of subjects treated with Taltz (1.0 per subject-year of follow-up) compared to 58% of subjects treated with placebo (1.1 per subject-year of follow-up). Serious adverse events were reported in 4% of subjects treated with Taltz (0.05 per subject-year of follow-up) and none in the subjects treated with placebo.

Weeks 0 to 60: Over the entire treatment period (Weeks 0 to 60), adverse events were reported in 67% of subjects treated with Taltz (1.4 per subject-year of follow-up) compared to 48% of subjects treated with placebo (2.0 per subject-year of follow-up). Serious adverse events were reported in 3% of subjects treated with Taltz (0.06 per subject-year of follow-up), and in 2% of subjects treated with placebo (0.06 per subject-year of follow-up).

Specific Adverse Drug Reactions: Injection Site Reactions: The most frequent injection site reactions were erythema and pain.

Most injection site reactions were mild-to-moderate in severity and did not lead to discontinuation of Taltz.

Infections: In the 12-week, placebo-controlled period of the clinical trials in plaque psoriasis, infections occurred in 27% of subjects treated with Taltz (1.2 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.4% of subjects treated with Taltz (0.02 per subject-year of follow-up) and in 0.4% of subjects treated with placebo (0.02 per subject-year of follow-up) (Warnings and Precautions).

During the maintenance treatment period (Weeks 13 to 60), infections occurred in 57% of subjects treated with Taltz (0.70 per subject-year of follow-up) compared to 32% of subjects treated with placebo (0.61 per subject-year of follow-up). Serious infections occurred in 0.9% of subjects treated with Taltz (0.01 per subject-year of follow-up) and none in the subjects treated with placebo.

Over the entire treatment period (Weeks 0 to 60), infections were reported in 38% of subjects treated with Taltz (0.83 per subject-year of follow-up) compared to 23% of subjects treated with placebo (1.0 per subject-year of follow-up). Serious infections occurred in 0.7% of subjects treated with Taltz (0.02 per subject-year of follow-up), and in 0.4% of subject treated with placebo (0.02 per subject-year of follow-up).

Inflammatory Bowel Disease: In adult subjects with plaque psoriasis, Crohn’s disease and ulcerative colitis, including exacerbations, occurred at a greater frequency in the TALTZ 80 mg Q2W group (Crohn’s disease 0.1%, ulcerative colitis 0.2%) than the placebo group (0%) during the 12-week, placebo-controlled period in clinical trials (Warnings and Precautions).

Laboratory Assessment of Cytopenia: Neutropenia—Over the entire treatment period (Weeks 0 to 60), neutropenia occurred in 11% of subjects treated with Taltz (0.24 per subject-year of follow-up) compared to 3% of subjects treated with placebo (0.14 per subject-year of follow-up). In subjects treated with Taltz, the incidence rate of neutropenia during Weeks 13 to 60 was lower than the incidence rate during Weeks 0 to 12.

In the 12-week, placebo-controlled period, neutropenia ≥ Grade 3 (<1,000 cells/mm3) occurred in 0.2% of the Taltz group (0.007 per subject-year of follow-up) compared to 0.1% of the placebo group (0.006 per subject-year of follow-up). The majority of cases of neutropenia were either Grade 2 (2% for Taltz 80 mg Q2W versus 0.3% for placebo; ≥1,000 to <1,500 cells/mm3) or Grade 1 (7% for Taltz 80 mg Q2W versus 3% for placebo; ≥1,500 cells/mm3 to <2,000 cells/mm3).

Neutropenia in the Taltz group was not associated with an increased rate of infection compared to the placebo group.

Thrombocytopenia—Ninety eight percent of cases of thrombocytopenia were Grade 1 (3% for Taltz 80 mg Q2W versus 1% for placebo; ≥75,000 cells/mm3 to <150,000 cells/mm3).

Thrombocytopenia in subjects treated with Taltz was not associated with an increased rate of bleeding compared to subjects treated with placebo.

Active Comparator Trials: In the two clinical trials that included an active comparator, the rate of serious adverse events during weeks zero to twelve was 0.7% for U.S.-approved etanercept and 2% for Taltz 80 mg Q2W, and the rate of discontinuation from adverse events was 0.7% for U.S. approved etanercept and 2% for Taltz 80 mg Q2W. The incidence of infections was 18% for U.S. approved etanercept and 26% for Taltz 80 mg Q2W. The rate of serious infections was 0.3% for both Taltz 80 mg Q2W and U.S. approved etanercept.

Pediatric Plaque Psoriasis Taltz was evaluated in a placebo-controlled trial in pediatric subjects with moderate-to-severe psoriasis 6 to less than 18 years of age. A total of 171 subjects were studied (115 subjects on Taltz and 56 subjects on placebo). Overall, the safety profile observed in pediatric subjects with plaque psoriasis treated with Taltz every 4 weeks is consistent with the safety profile in adult subjects with plaque psoriasis with the exception of the frequencies of conjunctivitis (2.6%), influenza (1.7%), and urticaria (1.7%).

In this clinical trial, Crohn’s disease occurred at a greater frequency in the Taltz group (0.9%) than the placebo group (0%) during the 12-week, placebo-controlled period. Crohn’s disease occurred in a total of 4 Taltz treated subjects (2.0%) in the clinical trial (Warnings and Precautions).

Psoriatic Arthritis Taltz was studied in two placebo-controlled trials in patients with psoriatic arthritis. A total of 678 patients were studied (454 patients on Taltz and 224 on placebo). A total of 229 patients in these trials received Taltz 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with psoriatic arthritis treated with Taltz Q4W is consistent with the safety profile in adult patients with plaque psoriasis with the exception of the frequencies of influenza (1.3%) and conjunctivitis (1.3%).

Taltz® (ixekizumab) injection

IX HCP BS 12MAR2021

PRINTER VERSION 1 OF 2

Ankylosing Spondylitis Taltz was studied in two placebo-controlled trials in patients with ankylosing spondylitis. A total of 566 patients were studied (376 patients on Taltz and 190 on placebo). A total of 195 patients in these trials received Taltz 80 or 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W).

Overall, the safety profile observed in patients with ankylosing spondylitis treated with Taltz Q4W is consistent with the safety profile in adult patients with plaque psoriasis.

In adult patients with ankylosing spondylitis, Crohn’s disease and ulcerative colitis, including exacerbations, occurred in 2 patients (1.0%) and 1 patient (0.5%), respectively, in the Taltz 80 mg Q4W group and 1 patient (0.5%) and 0%, respectively, in the placebo group during the 16-week, placebo-controlled period in clinical trials. Of these patients, serious events occurred in 1 patient in the Taltz 80 mg Q4W group and 1 patient in the placebo group (Warnings and Precautions).

Non-radiographic Axial Spondyloarthritis Taltz was studied in a placebo-controlled trial in patients with non-radiographic axial spondyloarthritis. A total of 303 patients were studied (198 patients on Taltz and 105 on placebo).

A total of 96 patients in this trial received Taltz 80 or 160 mg at Week 0, followed by 80 mg every 4 weeks (Q4W). Overall, the safety profile observed in patients with non-radiographic axial spondyloarthritis treated with Taltz 80 mg Q4W up to Week 16 is consistent with the previous experience of Taltz in other indications.

Immunogenicity—As with all therapeutic proteins, there is the potential for immunogenicity with Taltz. The assay to test for neutralizing antibodies has limitations detecting neutralizing antibodies in the presence of ixekizumab; therefore, the incidence of neutralizing antibodies development could be underestimated.

Plaque Psoriasis Population

By Week 12, approximately 9% of adult subjects treated with Taltz every 2 weeks developed antibodies to ixekizumab. Approximately 22% of subjects treated with Taltz at the recommended dosing regimen developed antibodies to ixekizumab during the 60-week treatment period. The clinical effects of antibodies to ixekizumab are dependent on the antibody titer; higher antibody titers were associated with decreasing drug concentration and clinical response.

Of the adult subjects who developed antibodies to ixekizumab during the 60-week treatment period, approximately 10%, which equates to 2% of subjects treated with Taltz at the recommended dosing regimen, had antibodies that were classified as neutralizing. Neutralizing antibodies were associated with reduced drug concentrations and loss of efficacy.

In pediatric psoriasis subjects treated with ixekizumab at the recommended dosing regimen up to 12 weeks, 21 subjects (18%) developed anti-drug antibodies, 5 subjects (4%) had confirmed neutralizing antibodies associated with low drug concentrations. No conclusive evidence could be obtained on the potential association of neutralizing antibodies and clinical response and/or adverse events due to small number of pediatric subjects in the study.

Psoriatic Arthritis Population For subjects treated with Taltz 80 mg every 4 weeks for up to 52 weeks (PsA1), 11% developed anti-drug antibodies, and 8% had confirmed neutralizing antibodies.

In a pre- and post-natal development toxicity study, pregnant cynomolgus monkeys were administered weekly subcutaneous doses of ixekizumab up to 19 times the MRHD from the beginning of organogenesis to parturition. Neonatal deaths occurred in the offspring of two monkeys administered ixekizumab at 1.9 times the MRHD (on a mg/kg basis of 5 mg/kg/week) and two monkeys administered ixekizumab at 19 times the MRHD (on a mg/kg basis of 50 mg/kg/ week). These neonatal deaths were attributed to early delivery, trauma, or congenital defect. The clinical significance of these findings is unknown. No ixekizumab-related effects on functional or immunological development were observed in the infants from birth through 6 months of age.

Lactation Risk Summary—There are no data on the presence of ixekizumab in human milk, the effects on the breastfed infant, or the effects on milk production. Ixekizumab was detected in the milk of lactating cynomolgus monkeys. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Taltz and any potential adverse effects on the breastfed infant from Taltz or from the underlying maternal condition.

Pediatric Use—The safety and effectiveness of Taltz have been established in pediatric subjects aged 6 years to less than 18 years with moderate-to-severe plaque psoriasis. The safety and effectiveness of Taltz in other pediatric indications and for pediatric subjects less than 6 years of age have not been established.

Geriatric Use—Of the 4204 psoriasis subjects exposed to Taltz, a total of 301 were 65 years or older, and 36 subjects were 75 years or older. Although no differences in safety or efficacy were observed between older and younger subjects, the number of subjects aged 65 and over is not sufficient to determine whether they respond differently from younger subjects.

PATIENT COUNSELING INFORMATION—Advise the patient and/or caregiver to read the FDAapproved patient labeling (Medication Guide and Instructions for Use) before the patient starts using Taltz and each time the prescription is renewed, as there may be new information they need to know.

Instructions on Self-Administration: Provide guidance to patients and caregivers on proper subcutaneous injection technique, including aseptic technique, and how to use the autoinjector or prefilled syringe correctly (Instructions for Use).

Infection: Inform patients that Taltz may lower the ability of their immune system to fight infections.

Instruct patients of the importance of communicating any history of infections to the healthcare provider, and contacting their healthcare provider if they develop any symptoms of infection (Warnings and Precautions).

Allergic Reactions: Advise patients to seek immediate medical attention if they experience any symptoms of serious hypersensitivity reactions (Warnings and Precautions).

Additional information can be found at www.Taltz.com.

Ankylosing Spondylitis Population For patients treated with Taltz 80 mg every 4 weeks for up to 16 weeks (AS1, AS2), 5.2% developed anti-drug antibodies, and 1.5% had neutralizing antibodies.

Non-radiographic Axial Spondyloarthritis Population Of patients treated with Taltz 80 mg every 4 weeks for up to 52 weeks (nr-axSpA1), 8.9% developed anti-drug antibodies, all of which were low titer. No patient had neutralizing antibodies.

The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to Taltz across indications or with the incidences of antibodies to other products may be misleading.

Postmarketing Experience—The following adverse reactions have been identified during postapproval use of Taltz. Because the reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to Taltz exposure.

Immune system disorders: anaphylaxis (Contraindications and Warnings and Precautions) USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary—There are no available data on Taltz use in pregnant women to inform any drug associated risks. Human IgG is known to cross the placental barrier; therefore, Taltz may be transmitted from the mother to the developing fetus. An embryofetal development study conducted in pregnant monkeys at doses up to 19 times the maximum recommended human dose (MRHD) revealed no evidence of harm to the developing fetus. When dosing was continued until parturition, neonatal deaths were observed at 1.9 times the MRHD [see Data]. The clinical significance of these nonclinical findings is unknown.

The background risk of major birth defects and miscarriage for the indicated population is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Data Animal Data—An embryofetal development study was conducted in cynomolgus monkeys administered ixekizumab. No malformations or embryofetal toxicity were observed in fetuses from pregnant monkeys administered ixekizumab weekly by subcutaneous injection during organogenesis to near parturition at doses up to 19 times the MRHD (on a mg/kg basis of 50 mg/ kg/week). Ixekizumab crossed the placenta in monkeys.

Taltz® (ixekizumab) injection

Taltz, IX HCP BS 12MAR2021 - 7.5 x 10

IX HCP BS 12MAR2021

Marketed by: Lilly USA, LLC, Indianapolis, IN 46285, USA Copyright © 2016, 2017, 2019, 2020, 2021 Eli Lilly and Company. All rights reserved.

IX HCP BS 12MAR2021

Taltz® (ixekizumab) injection

IX HCP BS 12MAR2021

PRINTER VERSION 2 OF 2

CONTENIDO

RETO DIAGNÓSTICO ENTRE CROHN Y COLITIS SISTÉMICA

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PREHISTORIA, HISTORIA Y ARTE DE LA REUMATOLOGÍA GOTA Y ESPONDILITIS ANQUILOSANTE

MIOCARDIOPATÍA HIPERTRÓFICA OBSTRUCTIVA

REHABILITACIÓN CARDIOVASCULAR MANEJO, EVALUACIÓN & RESULTADOS

DIAGNÓSTICO INESPERADO EN PACIENTE CON SOSPECHA DE GIST: INFILTRACIÓN GÁSTRICA POR MIELOMA MÚLTIPLE

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Palabras clave Historia, Prehistoria, Arte, Gota, Espondilitis Anquilosante.

Keywords History, Prehistory, Art, Gout, Ankylosing Spondylitis.

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PREHISTORIA, HISTORIA y ARTE

DE LA REUMATOLOGÍA GOTA Y ESPONDILITIS ANQUILOSANTE

Antonio Iglesias-Gamarra1, Gerardo Quintana L.2, José Félix Restrepo Suárez3

1. Profesor Titular de Medicina Interna y Reumatología. Universidad Nacional de Colombia.

2. Internista-Reumatólogo. Estudiante de Maestría en Epidemiología. Universidad Nacional de Colombia.

3. Profesor Titular de Medicina Interna y Reumatología. Coordinador Unidad de Reumatología.

Universidad Nacional de Colombia.

RESUMEN En esta segunda parte analizamos los inicios y la evolución de la Gota y de la Espondilitis Anquilosante. Relatamos nuevamente la importancia del arte en el desarrollo del conocimiento de estas enfermedades reumáticas.

ABSTRACT En esta segunda parte analizaIn this second part, we analyzed the beginning and the evolution of the Gout and Ankylosing Spondylitis. We relate again the importance of art in the development of knowledge of this rheumatic diseases.

Historia de la gota La artritis gotosa es de las primeras enfermedades reconocidas en la historia de la medicina; al parecer fue identificada por los egipcios en el 2640 a. C., por las crisis de podagra que comprometían las primeras articulaciones metacarpofalángicas; posteriormente se le reconoce a Hipócrates en el siglo V a. C., en los aforismos (VI-28, VI-29, VI-30, VI-40, XI-55) publicados en el año 2500 a.

C. 214-215.

La palabra gota deriva del latín gutta y fue utilizada por los médicos a partir del siglo X de nuestra era, para designar la enfermedad causada por un humor viciado que fluía gota a gota especialmente en las articulaciones del pie. El término podagra (del griego podos: pie, y agreos: agarrar, atacar) es muchísimo más antiguo, puesto que aparece en escritos del siglo V a. C.183. En los aforismos, Hipócrates (469-377 a. C.)183, 214 cita lo siguiente, que al parecer, en nuestro criterio, hace referencias a la gota, pero que en algunos de ellos no se puede asegurar que esté relacionado con dicha enfermedad.

V-25: “Las afecciones de gota y las convulsiones se amortiguan y aun se calman y cesan de todo punto por la efusión de agua fría en abundancia”214.

VI-29: “Las mujeres no adolecen de gota

hasta que cesa la menstruación”.

VI-30: “Los jóvenes no adolecen de gota antes del uso de Venus”214.

VI-40: “En las afecciones causadas por la gota, la inflamación mejora a los 40 días”.

XI-55: “Los ataques de gota son más frecuentes por lo común en la primavera y el otoño”. 121 La palabra podagra se utilizaba para designar la enfermedad localizada en otras partes del cuerpo y no significaba gota. El Corpus hippocraticum utiliza varios nombres para el compromiso de las articulaciones como artritis, antritika, araron, pero no establece ninguna separación de las diferentes acepciones de las palabras mencionadas, ni separa el reumatismo de la gota. Por ello en algunos de sus libros como Le Corpus Hippocraticum, Des Affections, Epidèmie, Prorrhètique II y los Aforismos hipocráticos se utiliza la palabra gota9, 214, 216.

La percepción clínica de Hipócrates que se refleja en la descripción de los aforismos, en la misma clínica, que se describe en el día de hoy, también observó la relación entre el estilo de vida y la enfermedad, ya que él asociaba la podagra como “la artritis de los ricos” en contraposición al “reumatismo” que en los tiempos hipocráticos no sabemos a qué se refería, pero él lo relacionaba como “la artritis de los pobres”.

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Hipócrates fue el primero en utilizar purgantes como el Heleboro, costumbre que sobrepasó la edad media214.

Celso (25 a. C. - 50 d. C.)11 clasificó la gota, la artritis y el reumatismo como la misma enfermedad; recomendaba llevar una vida regular y evitar la obesidad.

Era tan frecuente la gota en la antigua Grecia que se hacían obras de teatro, dedicadas a este mal.

De una de estas obras deriva la palabra podagra (ataque de gota en el artejo grueso del pie), del término Trapopodagra, la diosa causante de la gota, que dañaba a los médicos que luchaban contra ella, pero dejaba tranquilos a los que no se metían con ella217.

El tratamiento siempre era a base de purgantes y consejos, pero en el siglo II, Pepagomenos218, uno de los famosos médicos, recomendaba la administración de renacuajos crudos y excremento humano.

Galeno (130-200 d. C.)125, 183, 217 describió los tofos. Galeno tuvo la percepción sobre el incremento de casos de gota, durante su generación, debido al hábito adquirido por los eunucos de glotonería y al hábito de emborracharse, a diferencia de la época de Hipócrates debido a la vida sobria y bien regulada. Desde esta época se asociaba la gota a la glotonería y al alcoholismo. Galeno219 reconoce que la gota es hereditaria, pero al parecer el famoso senador Romano Séneca, la había informado previamente de acuerdo a la información de Garrison en su libro “An Introduction to the History of Medicine”220. Séneca también fue el primero en observar que la gota puede afectar a las mujeres, durante el reinado de Nerón (5468) d. C.219, 220.

Aretaus, según algunos historiadores, fue el primero en descubrir un ataque agudo de gota como 10

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un dolor intenso del grueso artejo, que luego ataca al pie, el talón y el tobillo. Sugirió la posibilidad de la presencia de una sustancia tóxica en la sangre de individuos gotosos.

Paulus Aegineta (25-69 d. C.)130, el último de los grandes médicos de Bizancio, sostuvo que la enfermedad era causada por “la coincidencia de un humor preternatural y una debilidad de las partes”. El humor predominante, engendrado por exceso de alimento, indigestión, o falta de ejercicio, podía ser bilioso, sanguíneo o melancólico, pero la mayoría de las veces era pituitoso y crudo.

Durante el imperio Bizantino, durante los siglos VI y VII, vivieron dos de los últimos compiladores griegos; afortunadamente para la historia de la medicina, existieron estos dos personajes, quienes infirieron sobre el desarrollo de la teoría griega, sobre la patología humoral y explicaron a través de la teoría de los humores, el origen de la gota. El mérito de Alejandro de Tralles11, 124, 183, 221, quien describe la existencia de la Hermodactyl (dedo de Hermes) para el tratamiento de la gota, la cual es la misma colchicina. El uso de la colchicina al parecer fue fortuito, ya que se utilizó como un purgante, y posiblemente se empleó con este criterio imperante en la época, por el concepto relacionado por el exceso de flema. La colchicina ya se conocía y viene de colchicum autumnale, y el nombre viene de Colchis, distrito de la costa del mar Negro, región en donde se producía en abundancia y está descrita en el libro de Dioscórides122, De materia medica, en el siglo I; pero la colchicina se conocía como Hermodactyl y fue utilizada por Paulus Aegineta130.

La primera persona que utilizó la palabra gota para describir la podagra (gutta quam podagram vel artiticam vocant) fue el monje dominico Randol phusof Bocking, capellán del obispo de Chichester, que vivió entre los años de 1197 y 1258. El término, como lo ha-

bíamos mencionado, deriva del latín gutta (o gota), y se refiere a la creencia que existía en el medioevo, de un exceso de uno de los cuatro humores, los cuales se encuentran en equilibrio, para mantener la salud: bajo ciertas circunstancias fluye como una gota a través de una articulación, y causa dolor e inflamación.

Francis Adams130, 183 describe que los árabes Avicena183 y Rhazes183 utilizaron la colchicina; esta referencia también fue mencionada por Lanfrancus183. Pero la sobredosis generó efectos tóxicos y la colchicina fue “condenada” y no la utilizó en su época Sydenham54.

Fue redescubierta en 1763 por el barón Anton von Storch183, 216, 217, médico de la emperatriz María Teresa, y se conocía en esa época como Azafrán de las praderas o anima articulorum (alma de las articulaciones); el barón la utilizó como analgésico y diurético. El término “colchicum” probablemente se origina de un antiguo distrito en el Asia menor, denominado Colchis. Se menciona que en el papiro de Ebers (1500 a. C.) se hace referencia a un medicamento idéntico al colchicum autumnale, pero no se puede afirmar este dato; lo sorprendente es su utilización en el siglo XXI para la crisis aguda de gota217.

Paracelso (1493-1541)150 expuso su original teoría de las enfermedades del tártaro (Bitartrato de potasio), según la cual esta sustancia, encontrada en los barriles de vino, era resultado vital de la fermentación.

Paracelso150 confirma las observaciones de Galeno125. Fue el primero en relacionar la gota con la nefrolitiasis.

Thomas Sydenham Durante los siglos XVI y XVII se inició paulatinamente en el mundo occidental, el pensamiento patológico moderno; a través del razonamiento y el contacto directo con el paciente, se empiezan a construir los esquemas racionales

para explicar la enfermedad y dejar a un lado la patología polémica. Sydenham52, 222 vivió en sus primeros años la turbulencia política, durante el reinado de Carlos I222, para luego dedicarse de lleno a la medicina54.

La otra se refiere a Sir Han Sloane222, quien era el presidente del colegio de médicos y de la real sociedad; Sydenham le escribió una carta que aludía a su excelente preparación botánica y anatómica; Sloane le respondió: “no, joven: todo eso son fruslerías, debe ir junto al lecho del enfermo si quiere aprender lo que es la enfermedad”222. Tuvo la influencia y la amistad de Boyle y John Lock y especialmente de la escuela de Oxford222.

En esta escuela surge una nueva actitud y es la observación experimental. A través de una pléyade de investigadores de la talla de Wallis y Ward, Goddard, Petty, Wilkins, Wren, Wellington, Hooke, junto

con Robert Boyle, fundaron en 1660, la Royal Society; quienes adoptaron el método baconiano, cuyo lema es: “no hay que imaginar ni que resolver, sino descubrir lo que la naturaleza hace o produce”; por ello Sydenham describe el concepto de la especie morbosa y por medio de sus libros que son observaciones a través de sus pacientes logra describir en forma magistral la gota52, 222.

Escribe los siguientes textos: Methodus curandi febres, en 1666; Observation er medical, en 1676; Anatomie, en 1668 y De arte medica, en 1669222.

Los escritos de Sydenham52, 222 tuvieron gran repercusión en Europa durante el siglo XVII y fue tan importante su estudio sobre la gota, que toda enfermedad que tuviese dolor articular, la denominaban gota, incluso la tesis de Landrè-Beauvai42, 56 sobre artritis reumatoide, ya que la denominó “gota asthenica” en 1801.

Dos anécdotas son importantes en la vida de Sydenham: la primera está relacionada con una pregunta que le hizo Sydenham a Richard Blackmore, cuando le solicitaba cómo ser un buen práctico: “lea Don Quijote; es un libro muy bueno: yo no me canso de leerlo”.

Cómo se describe la gota El sabio médico inglés, el más importante del siglo XVII, Thomas Sydenham (16241689)52, 222, llamado el Hipócrates inglés, quien sufrió la gota durante 34 años, dio a conocer en 1683 su Tratado sobre la gota y las hidropesías; le escribía a su colega y amigo Thomas Short: “os envío un pequeño tratado sobre la gota y las hidropesías”. Este tratado es extraordinario en observaciones, es una descripción de las observaciones de este médico en la cual informa casi todo sobre la gota. Sostiene que la gota es más frecuente en los hombres de edad avanzada:después de “abusar de los buenos manjares, del vino, la mayoría tienen una constitución lujuriante (obesos), pero también ataca a flacos y enclenques”52; describe el paroxismo de las crisis y la gota crónica, de esta forma: “produce la deformación de uno o varios dedos, dándole un parecido a un manojo de raíces de nabo; inmovilizados poco a poco, dando origen, alrededor de los tejidos articulares, a concreciones tofáceas que rasgan la delgada piel, poniendo al descubierto tofos muy semejantes al yeso

o a los ojos del cangrejo, que deben ser extirpados con un estilete”; describe los periodos intercríticos de la siguiente manera: “antes de que el mal hubiera sufrido esta agravación, el gotoso no solamente gozaba de mayores remisiones entre los accesos, sino que durante los periodos de calma podía valerse de sus miembros al igual que el resto del cuerpo y todas las funciones del organismo se operaban como en estado normal”52. Describe la litiasis renal, y finalmente filosofa, cuando se consulta al saber que grandes reyes, príncipes, ilustres, generales y almirantes, filósofos y muchos otros, padecieron la enfermedad.

Antoni van Leeuwenhoek (1632-1723), el pionero de la microscopia, fue el primero en describir la aparición de los cristales de un tofo gotoso, aun cuando su composición química era desconocida para esa época223. En 1679 escribió lo siguiente: “I observed the solid matter which to our eyes resembles chalk, and saw to my great astonishment that I was mistaken in my opinion, for it consisted of nothing but long, transparent little particles, many pointed at both ende and about 4 ‘ayes’

of the globule in length223. Cincuenta y cinco años más tarde, el médico y anticuario William Stukeley en su libro Of the Gout publicado en 1734, quien padecía de gota, describe los cristales de una articulación llena de tofos224. Un descubrimiento trascendental fue realizado por el farmaceuta Kart Wilbelm Scheele (1742-1786)183, 216, 217, contenido en la comunicación a la Academia de Ciencias de Estocolmo en 1776: informó que los cálculos urinarios de los pacientes con gota al ser examinados por él, no eran calcáreos, sino que estaban conformados por un ácido orgánico desconocido. Este ácido se encontró también en la orina y lo denominó ácido Lítico, por encontrarse en los cálculos. En 1787, ya traducidos al inglés los trabajos de Scheele183, 216, 217, apareció el Tratado sobre Litiasis y gota de Murray Forbes, quien comprobó las afirmaciones del farmacéutico sueco; sugirió que la redundancia preternatural del ácido en la orina podría prevenir de la hiperproducción renal o excesiva producción sistémica y que cuando la redundancia era muy grande, podría precipitar-

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Dibujo en 3d de Gout en pies.

se dentro de los vasos sanguíneos interrumpiendo la circulación y causando la crisis de gota. Diez años después, William Hyde Wolleston183, 216, 217 presentó los trabajos filosóficos de la Real sociedad de Londres: al obtener material de un tofo de su oreja, demostró que estaba conformado por ácido Lítico y un mineral alcalino. Los estudios de Schelle y Wolleston183, 216, 217 demostraron que la materia mórbida estaba constituida por el ácido lítico. G. Pearson lo denominó “ouric” u “óxido úrico” y el francés Antoine de Fourcroy en 1779 lo denominó ácido úrico183, 216, 217 . Los trabajos de Wolleston y de Scheel permanecieron sin mayor aceptación, hasta que se conocieron las investigaciones del médico londinense Sir Alfred Baring Garrod (1819-1907)61, 190, 225, quien en 1848 demostró a través de estudios gravimétricos que la sangre de varios pacientes gotosos contenía ácido úrico, en forma de urato sódico, en concentraciones de 0,025 a 0,050 gramos por mililitro, e identificó masas de cristales de urato en concreciones gotosas de varias partes del cuerpo. También demostró que en las 12

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crisis de gota, se observaba una disminución de la concentración de ácido úrico en la orina, por lo que planteó que la gota podría depender de la pérdida temporal o definitiva del poder excretor de los riñones. Los depósitos tofáceos los interpretó Garrod como una sustitución del defecto excretor del ácido úrico61, 190, 225.

En 1779 Antoine de Fourcroy183, 216, 217 y William Hyde Wolleston183, 216, 217 informaron que la gota se producía por la acumulación de ácido úrico. La relación casual de ácido úrico y gota no fue definitivamente establecida hasta los estudios de Sir Alfred Baring Garrod.

En 1848 describió que la sangre del gotoso siempre contiene urato sódico en forma cristalina, lo cual demostró a través de la “prueba de la Pita”(String test). Esta prueba consiste en incubar un hilo con suero del paciente gotoso por sesenta horas, notándose la adherencia de cristales de urato monosódico al hilo. Garrod logra de manera definitiva separar la gota de la artritis reumatoide. Por estos descubrimientos es considerado el padre de la reumatología moderna.

Los soportes experimentales para

confirmar las hipótesis de Garrod226 están en Freudweiler227, quien en 1899 demostró que la artritis gotosa aguda podría ser precipitada por la inyección intro-articular de microcristales de urato sódico, His228 un año después demostró la formación de un tofo, a través de la inyección subcutánea de cristales de Urato. Sesenta y un año después McCarty y Hollander229 demostraron en un artículo seminal que los cristales del líquido sinovial de pacientes con gota estaban compuestos por urato monosódico, es decir, que McCarty y Hollander229 redescubrieron lo que Leeuwenhoek había hecho en 1679 con un microscopio rudimentario. McCarty y Hollander introducen la técnica de la microscopia con luz polarizada para el estudio de los cristales a nivel articular229.

Herencia y gota Séneca220 en el siglo I d. C. describe la herencia en la gota, pero fue en el siglo II que el distinguido médico Aretaeus de Cappadocian230 describe la herencia y la denomina diátesis gotosa. Solo hasta el siglo XVIII, William Cu-

llen215, 231 describe la herencia de la gota, a través de sus padres.

Posteriormente Sir Archibald Garrod (el hijo de Sir Alfred Garrod) sugirió que la gota podría incluirse entre las enfermedades que resultaban de los errores innatos del metabolismo. Pero la descripción de una deficiencia enzimática relacionada con el metabolismo de las purinas solo se describe en 1967 por Seegmiller, Rosenbloom y Kelley232.

Historia de las espondiloartropatías seronegativas Los diferentes estudios sobre paleopatología, especialmente en esqueletos petrificados de periodos geológicos remotos, el estudio de

esqueletos de dinosaurios, felinos, gorilas, aves, caballos, camellos, cocodrilos, en donde se han observado osificación del ligamento amarillo, y osificación y neoformación óseos, sugieren que puede tratarse de enfermedad articular degenerativa o de mecanismos óseos de defensa para proteger la columna25, 120, 233, 234.

Se ha documentado que las espondiloartropatías no sólo ocurren en humanos, sino que posiblemente tengan una evolución transmamaria en su naturaleza; por ello es importante entender la antigüedad y el origen de estas patologías en los diferentes mamíferos. Algunos estudios realizados por Bruce M. Rotschild y Robert S. Woods235-242 son muy interesantes, al conside-

rar 35 individuos de dieciséis poblaciones de la unión americana (Fontenac, Klunk Mound, Kodiak Island, Madisonville, Amelia Island, Yorem Mound, Pueblo Bonito, Pueblo San Cristóbal, Hardin Village, Kuava Mound, etc.). Los investigadores analizaron los esqueletos de acuerdo con la antigüedad, desde 3000 años a. C. hasta la población de Amelia Island, 500 años a. C.. Este estudio de población precolombina demostró que la frecuencia de espondiloartropatías en los años 2000 a 3000 a. C. es baja, pero a partir del 2000 a.

C. se empezaron a observar en las poblaciones indígenas de Norteamérica (como los pies negros, Watford y Cree) datos de espondiloartropatías. En el análisis de los

Se ha documentado que las espondiloartropatías no sólo ocurren en humanos, sino que posiblemente tengan una evolución transmamaria en su naturaleza; por ello es importante entender la antigüedad y el origen de estas patologías en los diferentes mamíferos. esqueletos se encontró una expresión fenotípica de la enfermedad tanto geográfica como cronológicamente. La frecuencia de la distribución articular y el carácter del compromiso articular se identificaron en todos los sitios. La anquilosis de columna y de articulaciones periféricas, al igual que la formación reactiva del hueso, son características de las espondiloartropatías y son totalmente diferentes a la artritis reumatoide. El compromiso pauci-articular y poli-articular se pudo advertir, así como también las erosiones y la anquilosis de articulaciones periféricas se observaron, siendo estas características más frecuentes en las espondiloartropatías242-243. Es posible que las malas condiciones sanitarias contribuyeran con algunos brotes epidémicos de agentes infecciosos que ocasionaron el síndrome de Reiter como una forma de espondiloartropatía.

Bruce Rothschild, Prothero y C. Rothschild estudiaron fósiles de mamíferos perisodáctilos de Nor-

teamérica y encontraron que las espondiloartropatías eran muy comunes en los fósiles estudiados. En las familias ya extinguidas, tales como los Brontotheridae y Chalicotherüdae, se encontró una alta frecuencia de espondiloartropatías, que también se han observado en los Equidae (equinos) y Rhinocerotidae. Es posible que este tipo de patología ósea, que se presentó en muchas de estas especies de mamíferos, se desarrollara como un “beneficio” para los mamíferos afectados235-242.

En un estudio reciente, Bruce Rothschild y cols.213 analizan una serie de esqueletos del oeste del río Tennessee en donde encontraron algunos con artritis reumatoide (AR) y analizan la importancia de la cuenca de los ríos y el papel de la tuberculosis en el desarrollo de la AR o de las espondiloartropatías. Los autores concluyen que tanto la tuberculosis como las espondiloartropatías ocurren simultáneamente alrededor de la cuenca

del río, pero les llama la atención la posibilidad de que la tuberculosis los proteja de la AR. Los autores plantean, además, que los dinucleótidos no metilados CpG que se encuentran en las micobacterias pueden activar el sistema inmunitario. De todas maneras los autores abren una caja de Pandora que posiblemente se va a dilucidar en el futuro.

En el capítulo de epidemiología del libro sobre espondiloartropatías, publicado por Andrei Calin244 en 1984, se menciona una frecuencia de sesenta casos por cada mil habitantes en los indígenas Pimas y una alta incidencia del HLA-B27 en los mismos. La mayoría de los estudios en los cuales se asocia las espondiloartropatías con el HLA-B27 dejan entrever que la enfermedad se encontraba en América durante la conquista, de acuerdo con los estudios de Rotschild; pero Gustavo Samano-Tirado245 en 1999 revisó los documentos y descripciones de los Pimas al con

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Dos hechos importantes contribuyeron a que la ARA liberara a las espondiloartropatías del grupo de la AR. tacto español, en la Colonia y después de la Independencia, y halló una evidencia contraria. Analizó los estudios de Francisco Eusebio Kino246 sobre una crónica de la Pimería Alta, escrito en 1708; los estudios de Juan de Esteyneffer247, en 1712; Juan Mateo Mange248, en 1723; Philip Segesser249, 250, en 1737; Juan Nentuig251, 252, entre 1762 y 1764, y el estudio de Ignacio Pfefferkorn253, 254, de 1795. En los diferentes textos antes mencionados se afirma que la salud de los Pimas era buena, ya que tenían excelentes sembradíos y acequias; además, no tenían incapacidades como lo narra Juan Mateo Mange248, ya que el trabajo de los indígenas era fundamental para el mantenimiento de las misiones y la falta de cumplimiento se castigaba con azotes.

Solo hasta 1895 Lumholtz233 detectó problemas de dolores en la espalda y de costado en los Pimas, al igual que el antropólogo Hrdlicka255, quien sin ser médico, realiza una descripción de las enfermedades de los Pimas en 1904 y de la distribución geográfica de los mismos, en donde los Pimas alto estaban en las reservaciones de los Estados Unidos. Según los estudios de Samano-Tirado245, se sugiere que la espondiloartropatía estuvo ausente en los Pimas durante la época de la colonia, pero con el mestizaje empezaron a aparecer los problemas de columna que describen Lumholtz y Hrdlicka.

Además de los estudios de Bruce Rothschild y cols., Manuel Martínez-Lavin, Mansila, Pineda y cols.256 informaron en 1995 el caso de un indígena del período posclásico (152-900 a. C.) que vivió en México y que padeció espondilitis anquilosante, lo cual sugiere 14

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la existencia de este padecimiento en América antes de la llegada de los españoles. Por ello hemos querido retomar la concepción histórica del extraordinario reumatólogo E.G.L. Bywaters257-259 sobre las espondiloartropatías, quien analiza en cinco etapas (etapa fósil, la descripción clínica y patológica, la radiología, la epidemiología y los estudios familiares); algunas de estas etapas las compartimos, pero haremos algunas modificaciones a esta concepción para que el análisis histórico sea más claro.

De acuerdo con la narración histórica de E. Collantes Estévez y B. Amor260 en el capítulo de espondiloartropatías en el Tratado Español de reumatología, en la década de 1950 en el mundo médico científico existían dos escuelas médicas en Europa y en la unión Americana: la agrupacionista y la separatista; por ellas la reumatología, que era una especialidad joven, no se podía abstraer de esta influencia.

La artritis reumatoide se consideraba un síndrome inespecífico que – se planteaba– era desencadenado por una serie de factores etiológicos, tales como psoriasis, uretritis o colitis ulcerosa.

En esa década no existía aún la clasificación y nomenclatura de las enfermedades reumáticas, y la artropatía psoriásica, la enfermedad de Reiter y la espondilitis anquilosante eran consideradas formas especiales atípicas de artritis reumatoide. En España la influencia de Marañón261 era muy grande por su libro Diecisiete lecciones sobre el reumatismo, editado en 1955. En el capítulo que realiza J. Gimena sobre reumatismos vertebrales se sostenía que la espondilitis anquilopoyética o anquilosante no es otra cosa que una artritis reumatoide de localización vertebral, lo que era un reflejo del pensamiento de esa época en España y, obviamente, en los países de Latinoamérica.

Por fortuna, para beneficio de la reumatología y de los pacientes, la teoría separatista triunfó y empezaron a cambiar los conceptos de acuerdo con uno de los primeros

artículos de esa época, escrito por McEwen, Zif, Carmel, Dilata y Tanner262 en 1958. Se confundía y se asociaba el síndrome de Reiter con la espondilitis anquilosante y esta con la enfermedad de Crohn.

En Europa, J. Forestier, F. Jacqueline y J. Rotes- Querol263 publicaron su libro la Spondylarthrite ankylosante en 1951, en donde hacían una descripción clínica, radiológica, anatomopatológica y del tratamiento de esta enfermedad como una entidad nosológica diferente.

Hace cuarenta años las enfermedades inflamatorias de tipo reumático se clasificaban de manera diferente en Europa y en Norteamérica264.

Mientras que en Europa se consideraba diferentes enfermedades a la artritis reumatoide, la espondiloartritis anquilosante, la enfermedad de Reiter y la artritis psoriásica265, en la unión Americana se consideraba que se trataba de una sola enfermedad: la artritis reumatoide; las demás eran simples variantes de la misma y todas estas tenían una causa única y un mismo mecanismo patológico, tal como se describe en el libro cumbre sobre artritis reumatoide, que fue considerado en su época (1957) como el trabajo importante en la reumatología americana descrito por Short, Bauer y Reynolds266; además estos conceptos eran mantenidos por la American Rheumatism Association (ARA).

Dos hechos importantes contribuyeron a que la ARA liberara a las espondiloartropatías del grupo de la AR. La descripción del factor reumatoide por Rose y Waaler, que resultaba negativo en estas enfermedades, por lo que se empezó a denominar poliartritis seronegativas a: las espondiloartritis, la artritis psoriásica, la enfermedad de Reiter, la colitis ulcerativa, la enfermedad de Crohn, la artritis crónica juvenil, la enfermedad de Whipple, el síndrome de Behçet y las artritis reactivas264-266. A pesar de que la ARA mantuvo esta concepción, el golpe contundente que revirtió el yugo de la AR sobre las espondiloartropatías fueron

los trabajos de dos extraordinarios ingleses: J.M.H. Moll, del General Infirmary de Leeds, y Verna Wright, del Royal Bath Hospital en Arrogate267, 268, quienes desde 1971 hasta 1974 escribieron diversos artículos donde definieron varios rasgos comunes en la espondiloartritis como se mencionó anteriormente: las artritis periféricas, las artritis axiales (sacroilitis con y sin espondilitis anquilosante), tendencia a las manifestaciones clínicas extraarticulares comunes, tendencia a la agrupación familiar y el factor reumatoide negativo. Moll y Wright267, 268 empezaron a utilizar el concepto de espondiloartropatía, de pathía que significa enfermedad de la columna y de las articulaciones, y le quitaron la terminación “itis”. A partir de 1974 el Vennumbrella de Wright267 se empezó a aceptar y de esta manera todas las enfermedades mencionadas anteriormente se entrelazaron con la columna (espondilitis), la entesitis y el B27.

Origen africano de las espondiloartropatías seronegativas Muchas de las enfermedades del hombre, que se han observado desde la antigüedad, han sido denominadas con otros nombres, al igual que muchas de las nuevas enfermedades que se están describiendo y que recibieron nuevos términos en muchas ocasiones originaron confusiones por la designación semántica, las cuales se han venido aclarando. Así ha ocurrido con las espondiloartropatías y la psoriasis233.

Las espondiloartropatías seronegativas son un grupo de enfermedades que han recibido varias denominaciones como espondilitis reumatoide, pelvoespondilitis osificante, espondilitis rizomélica, enfermedad de Marie-Strümpell, morbus de Bechterew y espondilitis anquilosante. Sobre esta enfermedad, aparentemente nueva, no se conocía su pasado hasta que los estudios de Ruffer y Rietti, y los estudios de Rogers, Watt y Dieppe25 empezaron a desentrañar el origen de esta intere-

sante enfermedad233.

Así como el hombre se originó en África, la espondilitis anquilosante (EA) también tiene posiblemente un origen africano, de acuerdo con los estudios citados. En 1907 el gobierno egipcio decidió analizar y estudiar los esqueletos de Nubia y otras poblaciones egipcias1-3, 233 . Las primeras observaciones las realizó Fouquet en 1889 al estudiar algunas tumbas egipcias y momias en una expedición a cargo de Sir Gaston Maspero, Flinders, Keatinge y Breccia, quienes estudiaron los mejores especímenes patológicos que se encontraban en las escuelas de medicina del Cairo, donde se estudiaron a nivel macroscópico y microscópico algunas enfermedades óseas, especialmente procedentes del norte de Egipto y Alejandría1-3, 233 . Uno de los esqueletos más antiguos es el de un hombre que se llamó Nefêrmaat, a quien se le diagnosticó una espondilitis deformans, artritis, y cuyo origen se remonta a la III dinastía, entre el 2980 y el 2900 a. C. Dentro de estos esqueletos se encontró uno en el que se observó la fusión total desde la cuarta vértebra cervical hasta el coxis; otro esqueleto de la dinastía XII con el mismo diagnóstico también fue informado por este grupo1-3, 233.

Elliot Smith y Jones269, 270 describen una momia de la dinastía XXI, 1090-1045 a. C., en la cual se observó sacroilitis izquierda y artrosis de las caderas. Además, se estudiaron esqueletos de la ocupación Persa en Egipto en los años 500 a. C., los esqueletos de los soldados de Alejandro el Grande y Ptolomeo en Chatby en los años 300 a. C. y algunos esqueletos de la influencia de Roma en Egipto en los años 200 a. C.1-3, 233, 269, 270. La ma yoría de las lesiones que se describieron en los esqueletos de Nubia y Alejandría, cerca de 3000 años a. C., tenían artritis y anquilosis en las articulaciones sacroilíacas y en los huesos largos de los miembros inferiores. En estos estudios casi no se informa del compromiso articular, excepto de los cambios en las manos por “osteoartritis”, pero

Muchas de las enfermedades del hombre, que se han observado desde la antigüedad, han sido denominadas con otros nombres, al igual que muchas de las nuevas enfermedades que se están describiendo y que recibieron nuevos términos sí llama la atención el compromiso de las fascias, las inserciones de los tendones (entesopatía) y llama la atención la descripción de procesos de osificación, especialmente en cuatro esqueletos de la III dinastía. Sobre la anquilosis parcial de las articulaciones sacroilíacas algunos de los investigadores de la época como Elliot Smith269, 270, Ruffer1-3 y Ferguson271 pensaban que eran producidos por algunos procesos “infecciosos crónicos”1-3, 233, 269, 270, 271 . De acuerdo con estos hallazgos paleopatológicos, si le aplicamos los criterios radiológicos de Nueva York de 1966272, Amor de 1990273 y los europeos de 1991274 en los que se describe la etapa II de la sacroilitis unilateral, la entesopatía y el origen infeccioso del síndrome de Reiter, estos pueden ser compatibles con el diagnóstico de espondiloartropatías.

En otro estudio paleopatológico dirigido por Sir Armand Ruffer1-3 sobre artritis deformans y espondilitis en el Egipto antiguo, se analizaron esqueletos y momias de la época predinástica de Egipto, especialmente en Faras (Nubia), el cementerio de Dabod, Merawi (Sudán), momias cópticas, esqueletos de soldados macedonios, griegos, egipcios y persas (también otros soldados turcos incorporados por los griegos: berberinos, herzegovinos, bosnios, búlgaros, servios y algunos sirios y judíos). En estos esqueletos se observó compromiso articular, especialmente en rodillas, húmero, caderas, manos, codos, en donde se aprecia sobre-cre-

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cimiento óseo, compromiso periarticular; pero, además, notaron coxavara, compromiso axial con los hallazgos de sobre-crecimiento óseo como osteofitos y anquilosis de sacroilíacas1-3, 18. El autor afirma que la espondilitis deformans existía en Nubia ocho siglos antes de la conquista de Egipto por los ejércitos griegos, macedonios y romanos, y un ejemplo claro es el caso del estudio del esqueleto de Nerfêrmaat descubierto por Wainwrigth en 1900, de la III dinastía Mastaba y Méydum (2000-1788 a. C.)1-3. En estas descripciones no es posible descartar la posibilidad de un raquitismo-osteomalacia y/o osteoartritis y el mal de Pott, en estos esqueletos. En cambio, la descripción de Elliot Smith y Jones269, 270 sobre el caso de una mujer llamada Nesi-Tet-Nabtaris, que es una momia

de la dinastía XXI, sí es clara, ya que describe una anquilosis completa de las articulaciones sacroilíacas, la entesitis del ligamento sacro-coxígeo de la tuberosidad isquiática, la fascia del obturador y las caderas. La otra momia descrita por Elliot Smith y Jones269, 270 también tenía las mismas características de Nesi-Tet-Nabtaris; es probable que esta momia sea el primer caso de espondilitis anquilosante en el mundo.

Ruffer empezó a utilizar el término de espondilitis deformans al utilizar la clasificación de Thomas Macrae, en sus artículos1-3 sobre las artritis deformans y las espondilitis en el antiguo Egipto, al observar artritis de las articulaciones de la columna; además, notó la presencia de proliferación ósea, atrofia del cartílago y su reemplazo por hueso, y cam-

bios óseos en los ligamentos1-3, 18.

Después de la ocupación griega en el 332 a. C., hasta los 300 d.

C., es decir, 600 años, y las ocupaciones de los romanos y de los soldados procedentes de Europa y Asia, la enfermedad a través de la mezcla genética entre las diferentes razas empezó su diseminación en Europa. Rogers, Watt y Dieppe25 analizaron 560 esqueletos intactos de los períodos de la XXI dinastía egipcia, y algunas momias, hasta algunos esqueletos del siglo XIX; los autores anotan que observaron compromiso asimétrico a nivel de la columna y compromiso de articulaciones periféricas que sugieren enfermedad de Reiter o espondilitis por psoriasis25. Los autores, además, infieren que los especímenes paleopatológicos informados como EA podrían ser ejemplo de hiperós-

Ruffer empezó a utilizar el término de espondilitis deformans al utilizar la clasificación de Thomas Macrae, en sus artículos1-3 sobre las artritis deformans y las espondilitis en el antiguo Egipto. tosis esquelética idiopática o enfermedad de Forestier u otras espondiloartropatías, pero estos autores no analizaron la anquilosis20 de las articulaciones sacroilíacas que fueron informadas por Ruffer1-3. En 1912 Raymond demostró la presencia de espondilitis en algunas momias de Egipto. Antes de la descripción de Connor275, Pausanias, durante el reinado de Pericles, cien años a.

C., describe el cuerpo de Protofanes, quien ganó una de las carreras olímpicas, y quien tenía casi una fusión de las costillas y los hombros; sería este el primer caso de EA en Europa276. Sin embargo, en la Biblia, en el capítulo XIII de San Lucas, en el versículo 11, en el pasaje de la higuera y la mujer encorvada, se narra la historia de una mujer que por espacio de dieciocho años padecía una enfermedad “causada por un maligno espíritu; y andaba encorvada, sin poder mirar poco ni mucho hacia arriba”; cuando la vio Jesús, la llamó y le dijo: “mujer, libre quedas de tu achaque. Puso sobre ella las manos y se enderezó al momento, y daba gracias y alabanza 16

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a Dios”; sería este el primer tratamiento para la EA233.

P. A. Sorba con la colaboración de George Simon18, quien transportó un equipo de rayos X portátil, pudieron revisar algunas de las momias estudiadas especialmente por Ruffer; estos investigadores no lograron demostrar datos compatibles con espondilitis anquilosante, en las radiografías de pelvis y columna dorso-lumbar, pero sí demostraron una leve osteoartritis en algunas de las radiografías estudiadas; llama la atención que una de las momias estudiadas, del periodo Romano (treinta años a.

C.), era compatible con una artropatía por alcaptonuria, al estudiar y tratar de analizar la etiología de algunas “artritis erosivas” en el noreste de África, especialmente en el norte del Sudán (área meriótica de la antigua Nubia), y en el norte de Malí (Hassi el Abiod) de una población que vivió aproximadamente 2000 años a. C. en las áreas antes mencionadas. Rothschild y cols.234 demuestran en seis esqueletos de la población de Nubia (meriótica), en

diez esqueletos cerca de la pirámide de la luz en Egipto y en la población de Hassi el Abiod en Malí, la fusión de las articulaciones zigomáticas, sindesmofitos, osificación de los anillos fibrosos, sacroilitis y cambios erosivos pero compatibles con espondiloartropatías, pero no encontraron datos que sugirieran artritis reumatoide en los esqueletos antiguos de Nubia y Egipto, corroborando el posible origen de la AR en el nuevo mundo y de las espondiloartropatías en el continente africano234.

Origen europeo de las espondiloartropatías No existen evidencias claras del papel de los soldados griegos, romanos, persas, turcos, judíos, herzegovinos, egipcios, ni de la posibilidad de una mezcla genética como el posible origen de las artritis reactivas en esta población y su paso a Europa.

En algunos estudios históricos se describe la espondilitis, como en el realizado por el gran maestro del London Hospital, E.G.L. Bywa-

ters257, 258, y por Baruch Blumberg y Charles Ragan277 de Columbian University del Presbiterian Hospital de Nueva York, quienes citan las descripciones de C.W. Buckley278, 279 , Golding280, Hart y cols.281-283, Jones284, Polley285, Rolleston286 y Van Swaay287, quienes afirman que el médico de origen irlandés, Bernard Connor u O’Connor, quien nació en County Kerry en 1666 y se educó en París, Montpelier y Rheims, publicó en 1691 en francés y en París, un esqueleto con espondilitis que encontró en un cementerio, del que se describe la fusión de la tercera vértebra dorsal hasta la pelvis, incluyendo las articulaciones sacroilíacas y las costillas. Por lo que se confirma en una pintura de esa época, no hay duda que se trata de un caso bien documentado de espondilitis anquilosante serone-

gativa; ya que las vértebras de la pelvis y las costillas se constituyen en un solo hueso continuo e inseparable275, 288-291. En 1694 Connor le envía una carta a Sir Charles Walgrave, que se publica en Transactions of the Royal Society, en la que describe y diagrama un esqueleto encontrado en una iglesia275, 288-291.

Un segundo esqueleto, con las características que describió Connor275, 288-291, fue encontrado por unos estudiantes en un jardín botánico, cerca de Coburg, el día en que celebraba el Goddes Flora257; el profesor de estos estudiantes, John Sebastián Albrecht292, publicó estos hechos en 1748. Cien años después de la descripción de Connor275, 288-291, en el museo de Anatomía de Leiden, E. Sandifort293 y su pupilo, van de Wynpersse294, 295, en 1793, describen otros cambios

a nivel de la columna compatible con espondilitis. En el museo Hunteriano de Londres hay un espécimen posiblemente observado por John Hunter296, quien no se dio cuenta de este compromiso, pero que Buess297, 298 y Koelbing299 describen muy bien en 1964.

En Alemania, especialmente en Frankfurt, en 1824, Carl Wenzel300 delinea muy bien un ejemplo de un caso de espondilitis y el diagnóstico diferencial de un esqueleto con espondilosis hiperostótica.

Estas descripciones prácticamente se realizaron en esqueletos de pacientes con espondilitis, ya que las evidencias fotográficas y las descripciones de algunos autores lo confirman. El mismo Wenzel300 en 1824 y Lyons301 en 1831 lograron diferenciar la miositis osificante de la espondilitis anquilosante y Ro-

Un segundo esqueleto, con las características que describió Connor275, 288-291 , fue encontrado por unos estudiantes en un jardín botánico, cerca de Coburg, el día en que celebraba el Goddes Flora. kitansky259, 302 en 1850 logró diferenciar la espondilitis anquilosante de la hiperóstosis. Por lo tanto, ya a comienzos del siglo XX, cuando se estudiaron los esqueletos y las momias de Ruffer1-3 en el antiguo Egipto, existía un conocimiento de estas patologías en Europa.

En España, D. Campillo ha demostrado una documentación de hallazgos procedentes de la época medieval, en la necrópolis situada en el subsuelo del Reinal Monestir de Sta. María en el Ripio (s. IX), y el más típico en el castillo de Calafell (Baix Penedes) de esqueletos con espondiloartropatías260.

Inicio de las descripciones clínicas A través de las descripciones clínicas de ingleses como Thomas Sydemhan233, Robert Willan233 y Thomas Bateman233, un médico del famoso Hospital St. Thomas, Benjamín Travers303, en 1824, describe un paciente de dieciséis años, fecha en que se inicia la enfermedad por rigidez de la columna, hasta comprometer la columna cervi-

cal a la edad de diecinueve años por “osificación de la sustancia intervertebral”, como la denominó Travers303. El segundo caso fue descrito en 1831 por Philip Moyle Lyons301 en Brighton, quien estudió al señor Ratcliffe, de treinta y seis años, cuya enfermedad tuvo un curso progresivo de quince meses de evolución, con anquilosis de las articulaciones periféricas y la columna. Al paciente lo remiten a Dublín donde muere y Houston reorganiza el caso clínico y lo describe en el museo del Trinity College, como lo menciona O’Connell en 1956257, 304. Lyons301, en 1832, distingue la EA de la miositis osificante que había sido descrita por Robert en 1741257, 305, obispo de Corke233, 257 . Así como Philip Lyons301 informó sobre el primer caso clínico en un varón, Wilson Baltimore, en 1856, describe el segundo caso en una mujer; si bien el primero es la momia de Elliot Smith269. Talvez una de las mejores descripciones clínicas, la realiza Sir Benjamín Brodie306 del hospital St. George de Londres en un famoso libro, Di-

seases of the Joints, en 1850, quien describe un paciente con rigidez y dolor de la columna, artritis de la rodilla e iritis; este autor también describe el absceso de Brodie (una forma de osteomielitis crónica).

Con este paciente se describe la artritis periférica y por primera vez el compromiso ocular306. Este autor diferencia la anquilosis angular del mal de Pott, enfermedad que se observó en los esqueletos egipcios del 3000 a. C. En Londres se realizan otras descripciones de casos por: Sir James Paget307 en 1877, W. Sturge308 en 1879, H. Clutton309 en 1883 y N. Davies-Colley310 en 1885. La primera correlación clínico-patológica la realiza Charles Fagge311, un médico del Guy Hospital, quien realiza la autopsia de su paciente con EA en 1877. El paciente había consultado por tos, y rigidez de la columna y las costillas fijas; además, tenía una respiración abdominal. Al practicársele la autopsia encontraron una anquilosis de los cuerpos vertebrales, articulaciones apofisiarias, costillas y la cadera dere Revista Puertorriqueña de Medicina y Salud Pública

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cha; se describen por primera vez la fibrosis pulmonar, las bronquiectasias y el compromiso de las válvulas cardiacas, aunque no es claro si es endocarditis o una arteritis311.

En la segunda mitad del siglo XIX se conocía la descripción de la enfermedad en esqueletos de París y de Londres y se habían realizado varias descripciones clínicas de la enfermedad; Fagge inició la correlación clínico-patológica311.

Al finalizar el siglo XIX, en pleno auge del positivismo, se realizaron las mejores descripciones clínicas y algunas correlaciones clínico-patológicas. Estas descripciones se inician en forma cronológica por Adolf Strümpell (1853-1925, de Leipzing), quien, en su libro publicado en 1884, informa sobre dos casos y describe posteriormente la clásica postura en zeta en 1897 y aparecen las primeras fotografías de pacientes con EA, en Leipzig (Alemania)312, 313. Cinco años después en San Petersburgo, V.M. Bechterew (1857-1917)314, quien era neurólogo, publica cinco casos, si bien pensaba que estaba describiendo una enfermedad neurológica que se caracterizaba por cifosis dorsal, rigidez de la columna y síntomas radiculares. Es posible que Bechterew por su formación neurológica estuviera describiendo el síndrome de la cauda equina ocasionada por la EA o alguna enfermedad en algunos de estos casos314, 315.

Al parecer esta descripción, como lo anota Dunham y Kautz316 en sus informes con veinte pacientes con EA, se confundió con la asociación de cifosis y una enfermedad articular degenerativa de la columna, especialmente en el anciano, que denominaban “espondilitis defor18

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mans”, que pudiesen ser pacientes con osteoporosis, osteoporomalacia y enfermedad de Forestier. Esta espondilitis deformans introdujo mucha confusión y produjo y demoró la separación de la EA como una entidad diferente, pero la observación de Strümpell312, 313 sobre el compromiso de la columna en la EA fue objetiva y contundente. En la última década del siglo XIX surgen las figuras de Pierre Marie (1853-1940)317, 318 en Salpétriére y Leri, quienes realizaron las mejores descripciones clínicas de la enfermedad. En el artículo “Sur la Spondylose rhizomelique” de Pierre Marie, publicado en Revue de Medecine en abril de 1898, se da la descripción más extraordinaria que se haya realizado hasta la fecha de la EA y además de forma clara utiliza algunas publicaciones que se habían realizado por esa época para los diagnósticos diferenciales.

Utiliza los términos espondilosis rizomélica317, 318.

Marie informa que M. Charcot, maestro de Marie, describe en 1886 un paciente que tenía compromiso severo y rigidez de la columna vertebral que, por la ignorancia en ese momento, pensaron que era una osteítis deformante de Paget, descrita en 1877 por Sir James Paget. En sus observaciones, Marie describe el compromiso articular de todo el esqueleto axial, el compromiso del tórax, la articulación escapulo-humeral, las articulaciones coxofemorales, las rodillas, es decir, el cuadro completo de la EA. En las otras observaciones informan el caso de R. Koehler320, y el de Beer. En la observación 6 realiza un resumen del compromiso articular; pero, además, utiliza el esqueleto 69 de la colección y del museo de Dupuytren, en el que aprecia claramente la anquilosis del esqueleto axial y la osificación de los ligamentos espinales.

Menciona el artículo Strümpell312 de la revista Deustche Zeits chr. f. Nervenheilkd, analiza en forma objetiva los diagnósticos diferenciales con la hiperóstosis, la atrofia muscular que ocasiona la enfermedad, la posición

del individuo en zeta, la marcha de los pacientes, la diferencia con el mal de Pott, la diferencia con la cifosis heredo-familiar, al publicar un caso con Astie321 en 1897; la diferencia del reumatismo crónico deformante, y finalmente analiza el artículo de Bricon322 sobre exostosis, hiperóstosis y sinostosis múltiple en los felinos. De esta manera, Marie describe317 dos casos completos en 1899, y describe la anquilosis de la columna, las costillas, las articulaciones sacroilíacas y el compromiso de las caderas en 1906319.

A raíz de estas descripciones se empieza a difundir el conocimiento de esta enfermedad y se publican otros artículos en algunos países, como los de Henri Forestier, el padre de Jacques Forestier323, en 1901. A raíz de las descripciones de Strümpell312, Bechterew314, Marie, Leri318 a finales del siglo XIX, y de los estudios de Ruffer1-3 en los esqueletos de Nubia y de Egipto, Thomas McCrae324 dividió la artritis deformans en tres grupos: 1. Un grupo, en el que los cambios se encuentran especialmente en los cartílagos y constituye la forma pedicular.

2. Otro grupo, en el que predomina la atrofia marcada de los huesos y cartílagos, lo que ocasiona cambios atróficos en los músculos y conforma la forma atrófica.

3. La forma hipertrófica, donde existe una proliferación ósea a nivel de la columna, articulaciones y ligamentos, como ocurre en la EA. En la página 1128 del libro de William Osler y Thomas McCrae324, The Principles and Practice of Medicine, novena edición publicada en 1920, en el capítulo sobre enfermedades del aparato locomotor y de la artritis deformans, este par de autores describen que la espondilitis se puede asociar o no a compromiso de las articulaciones periféricas y plantean dos tipos de espondilitis. La variedad de Bechterew314, 315 que solo compromete la columna, y el compromiso de las raíces nerviosas, ya que los

pacientes sienten dolor, anestesia y atrofia de los músculos con degeneración de los cordones ascendentes, posiblemente por una meningitis que compromete las raíces nerviosas y genera atrofia muscular; esta descripción es prácticamente la de una enfermedad neurológica. En el tipo Strümpell- Marie312, 318, hay compromiso de columna, caderas y hombros y pocos síntomas neurológicos, existe la verdadera EA o la espondilosis rizomeliza de Maire. Con las descripciones de Adolf Strümpell313, en 1897, y Pierre Maire317, en 1898, se descartó la idea prevaleciente de que la espondilitis era consecuencia de traumatismos, pero a pesar de las extraordinarias descripciones se obvió de una manera errónea la predisposición genética.

Osler y McCrae324, en 1920, creen

que estos dos tipos de artritis deformans, o la espondilitis deformans, son más frecuentes en el hombre y pueden ocasionar compromiso a nivel de la región lumbar y ciática, ocasionando dolor, parestesias y atrofia de los músculos. Es decir, en esta novena edición, publicada en 1920 en Nueva York y Londres, se realizó una descripción breve de la EA como una nueva entidad nosológica.

Hasta 1930 el compromiso de las articulaciones sacroilíacas casi no había sido informado, excepto en las narraciones ya citadas; de todas maneras el término espondilitis anquilosante se empezó a utilizar después de la descripción de Wladimir Bechterew, quien propuso el término “inflamación anquilosante de la columna y de las articulaciones

de los grandes miembros” entre los años 1927 y 1957, empezando así a generalizar el uso de la EA para describir la enfermedad.

Historia. A la zaga de la palabra reuma La prehistoria, la historia y el arte como predecesoras del conocimiento de la Reumatología son uncampo muy amplio, pero muy desconocido en el mundo actual. Con el descubrimiento y desarrollo de la imprenta por Johann Gutenberg en 1450, los primeros libros que se imprimieron hasta 1484 en Leipzip fueron las obras de los grandes médicos griegos, romanos y árabes como Hipócrates, Aristóteles, Galeno, Celsus y Avicena. Pero uno de los grandes médicos del renacimiento y desconocido por la historia es Sigismundo

Al parecer existe un escrito de un autor de la edad media llamado Magister Cristannus325 donde la palabra “rheumata” se describe como un exceso de fluido (o flegma) Albicus, quien fue el primer reumatólogo de la universidad de Carlos (fundada en 1348, en memoria de Carlos IV, rey de Baviera y Praga).

Albicus325 escribía que el español Arnaldus de Villanova, quien murió en 1311, era superior a los médicos antes mencionados, pero que su legado fue ignorado. Pero el legado de Albicus es necesario rescatarlo y difundirlo, ya que fue el primero en escribir un libro de Reumatología como el Régimen contra Reumata; se lo dedica al rey Wenceslao IV, hijo del rey Carlos IV, quien sufría de gota. Albicus fue el primero en recomendar una dieta adecuada y un modo de vida frugal, pero lo más importante del trabajo de Albicus325 es la frase: “la reuma como la madre de las enfermedades”, ya que Albicus no indujo a generar el concepto de reumatismo, como un grupo de enfermedades que comprometen órganos y tejidos, sino como el concepto de esa época, como un humor mórbido que fluye a través del cuerpo y causa una en-

fermedad. Este humor fluye a través de la gravedad, como un catarro de la cabeza al cuerpo, es decir, como el catarro de la influenza. Pero Albicus325 lo que describe con su frase, como es el origen del dolor ocular, los ruidos en los oídos, el dolor dental, el dolor toráxico, los cálculos renales, las enfermedades de la vejiga y otras enfermedades. Por ello se deriva la palabra Gota (del latín gutta o caída en las articulaciones de las manos (cheiragro y podagro). A pesar de que en algunos textos como De locis in homine de Hipócrates se menciona el concepto de fluido y el compromiso de varios órganos, y Galeno lo reafirma en su obra On the Natural Faculties, él solo describe que el cuerpo es capaz de recibir los fluidos, pero algunos de estos el organismo los recibe como nutrientes y otros los rechaza325. Al parecer existe un escrito de un autor de la edad media llamado Magister Cristannus (Christian ?)325 donde la palabra “rheumata” se describe como un exceso de fluido (o fleg-

ma). Albicus325 fue también uno de los primeros médicos que afirmaban que el clima podía reducir los dolores reumáticos; posteriormente Albicus325 escribe otro texto que se denomina Regimen contra reumata que data de 1462 en Klatovy y se encuentra en la librería universitaria de Praga. El texto en latín fue publicado por Ondxej Schrutz con un comentario en checo y publicado en la revista Czechoslovak Medical Journal en 1909325. La palabra “gutta”, que se empezó a utilizar en esa época, fue incorporada en el trabajo extenso que realizó ese extraordinario médico londinense Thomas Sydenham, en su libro A treatise of the gout and dropsy, quien se lo dedica al Dr. Thomas Short y analiza el cuadro clínico y la terminología de la enfermedad que denominó Gout (gota), cuya terminología se continúa utilizando en el siglo XXI; en este escrito, dedicado a las enfermedades agudas y crónicas, describe la artritis reumatoide, pero él no la diferencia de la gota53, 54.

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Antes de la descripción clásica de la enfermedad por Sydenham53, 54, la palabra reuma y gota se utilizó por otra serie de autores.

Albicus325 en su libro Régimen contra reumata, al parecer, es el que mejor describe la palabra reuma y fue el primero en utilizarla y no Guillaume de Bailou (Ballonius), un médico graduado en la universidad de París en 1570, información difundida por Robert S. Hormell182, 183 en su artículo “Notes on the History of Rheumatism and gout” publicado en el New England Journal of Medicine de noviembre 7 de 1940, página 755.

Benedek155 en su libro History of the rheumatic diseases menciona que el término reuma fue introducido en la primera centuria después de Cristo.

Pero llama la atención que Celsus, Galeno, Aretaus en Bizancio, los

compiladores como Alexander di Tralles221 y Paulus Aegina130, los médicos árabes como Rhazes y Avicena131 no utilizan la palabra reuma, pero sí el término gota; por ello, no es claro que la palabra reuma se hubiese utilizado en los primeros siglos después de Cristo.

La asociación entre reuma y artritis fue descrita en Londres por Andrew Boorde155 en 1547, y el concepto de reumatismo como enfermedad sistemática fue introducido por el médico parisino Guillaume de Baillou (15381616), conocido también como William de Baillou155, 182, a quien algunos llaman el padre de la reumatología, quien reconoció en 1611 el reumatismo como una aflicción de las articulaciones; sin embargo, su concepto solo se publicó en 1642 en París, en una edición póstuma de su libro Liber de

rheumatisme et pleuritide dorsali; en su sección “De arthritides”, como se dijo, De Baillou definió la gota como el compromiso de una articulación y el reumatismo como el compromiso de todo el cuerpo155, 182, 326.

La palabra reuma, como la describe Albicus325, significa “diarrea o descarga catarral” y se origina de la palabra griega pew o “flujo”; así la palabra gutta, de acuerdo con Alexander de Tralles, se utilizó en la sexta centuria en el sentido de enfermedad articular inflamatoria. Redulfe, citado por Pemberton y Osgood327, en su libro The medical and orthopaedia management of chronic artritis la utiliza en el siglo XIII, casi en la misma época en que Albicus325 utilizó la palabra reuma; al parecer Albicus se debe considerar como el primer reumatólogo y el padre de la reumato-

Otro caso es el de la familia real de Carlos V, pintado por Tiziano Vecellio, en un óleo sobre tela que se encuentra en el museo del Prado; este emperador coronado por el Papa Clemente VII fue pintado a los 33 años, cuando ya había padecido de varias crisis de gota. logía y no Baillou. Tanto la palabra gutta como reuma son derivadas de palabras diferentes pero con un significado similar y su aplicación al concepto de artritis como “inflamación” se utiliza siguiendo la teoría humoral de Hipócrates, Celsus, Galeno y Sydenham.

Es posible que la artritis reumatoide tenga su eclosión en el siglo XVI en Europa, pero específicamente a finales de ese siglo. El célebre Thomas Sydenham53,54,156- 157 (1624-1689) diferenció la gota de la artritis reumatoide y describió la deformación en cuello de cisne, en su libro Medical Observation53,54,156,157, publicado en 1676.

En Londres surgió otra figura de la medicina: William Heberden (17101801)328, quien también reconoció la artritis reumatoide y la diferenció de la gota, y describió, además, el compromiso de las rodillas y su discapacidad. En Islandia, Jón Petursson55 en 1782 describió una poliartritis destructiva en su práctica regular. En un texto publicado por Jonsson y Helga20

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son55, Petursson55 especificó que la artritis reumatoide en su práctica es más frecuente en la mujer alrededor de los cuarenta años. Sin embargo, la primera descripción clínica de la artritis reumatoide se le acredita a Augustin-Jacob Landres Beauvais56, 57.

Arte pictórica y gota La historia como una forma especializada de la medicina clínica aporta muchos conocimientos, ignorados por los médicos y las revistas; así, de esta manera, los tofos de la gota fueron pintados por primera vez, sin saberlo, por la genialidad de Rafael Sanzio (1483-1520)329 en su extraordinario cuadro La escuela de Atenas, que aparece en uno de los museos del Vaticano: la figura del extraordinario escultor y pintor de la Capilla Sixtina, demuestra claramente en el centro del cuadro la presencia de los tofos en las rodillas, especialmente la derecha. En este friso de la escuela de Atenas, se demuestra la importancia de Platón, el más grande maestro Aristóteles, el

sabio Sócrates, Pitágoras, Avicena, Ptolomeo y Euclides. Rafael describe a Miguel Ángel que para esa época era su enemigo, azotado por la gota, a la edad de 35 años. El mismo Miguel Ángel en su poema escrito entre 1546 y 1550 se lamenta de su enfermedad de la siguiente manera: “I’ ho’imparato conoce l’ orina”, lo que suponía la presencia de cálculos por su gota, la gonagra y sus tofos.

Otro caso es el de la familia real de Carlos V, pintado por Tiziano Vecellio, en un óleo sobre tela que se encuentra en el museo del Prado; este emperador coronado por el Papa Clemente VII fue pintado a los 33 años, cuando ya había padecido de varias crisis de gota; la patología de esta familia era de gotosos; como el abuelo de Carlos V, el emperador Maximiliano, su hijo Felipe II, su biznieto Felipe IV, todos estos reyes fueron pintados por pintores famosos, y todos fueron gotosos; además de su herencia, eran glotones famosos, con pésima masticación por su prognatis-

mo, dieta hiperproteica que ayudaba a ingerir con abundante cerveza. Cuando se retiró a Yuste sólo tenía 57 años y lo acompañaban dos médicos flamencos, Mathis y Comelius Balsdrog, y un maestro cervecero; en el cuadro de Tiziano se le muestra con la cabeza rapada por su cefalea, que se cubre con un gorro330, 331.

El arte pictórico y la Florencia del siglo XV Uno de los pintores de la Toscana del siglo XV es Domenico Veneziano, autor de la Virgen con el niño y cuadros santos; según Vasari, fue el que introdujo la pintura al óleo; además, inició una corriente de interés por el color, como sustitutivo de la línea en la perspectiva y la composición.

Esta pintura se realizó hacia 1445. Piero Della Francesca, discípulo de Veneziano, y un grupo de maestros florentinos, entre ellos Masaccio, Filippo Lippi, Uccello y los hermanos Antonio y Piero del Pollaivolo, le dieron al color de sus pinturas una vitalidad y se interesaron, además, por el estudio del paisaje y de la atmósfera, así como el de las formas anatómicas.

De este grupo de pintores florentinos surge la figura de Sandro Botticelli, quien tuvo la protección de Lorenzo di Pier Francesco de Médicis, primo segundo de Lorenzo el Magnífico, quien le encargó varios cuadros, cuya temática revela el interés por la filosofía platónica. Algunos de los cuadros de Botticelli son: La Fortaleza, la Anunciación, la Alegoría de la primavera, la Adoración de los Reyes, la virgen escribiendo el Magnificat, San Agustín en su estudio; todas estas obras se encuentran en la galería de los Uffizi332. Pero uno de los cuadros más bellos de Botticelli es El nacimiento de Venus, pintado en 1482, por encargo de Lorenzo de Pier Francesco para su Villa de Castelló. Este cuadro muestra a la diosa desnuda sobre una gran concha que flota graciosamente en las aguas de un mar verdoso. Además, se observa una figura femenina, ataviada por una ligera túnica floreada que acude solícita a arropar a Venus con un suntuoso manto. Se trata de una alegoría de la tierra o de la primavera; la Venus es de una belleza sin par, pero al observar detenidamente sus manos, se pueden apreciar cambios que sugieren AR y en sus pies aparece un hallux valgus que en su cua-

dro Alegoría de la Primavera se aprecia en una forma más objetiva, y es la misma Venus, en su forma de Venus genitrix, el vientre abultado por la fecundidad. Para esta misma época, en La Anunciación, del gran pintor Leonardo da Vinci, se observa que la mano derecha de la virgen tiene cambios que sugieren AR y no una postura para mantener las páginas del libro.

Estos cuadros sugieren la posibilidad de que la AR existiera y algunos pintores famosos lograran expresarla en sus cuadros; pero esto no se puede asegurar, sino sugerir, ya que en esa época los pintores exaltaban la belleza9, 3, 22.

La pintura flamenca y la artritis reumatoide Las enfermedades reumáticas son ancestrales. Lo que no podemos documentar estrictamente es el origen de ellas. No obstante existen estudios paleopatológicos sobre el origen de algunas patologías que están bien documentadas, como la osteoartritis, las espondiloartropatías, la gota; no podemos afirmar lo mismo con respecto a la artritis reumatoide, a pesar de algunas evidencias presentadas por los estudios de Rotchschild y cols.33-38, 40 sobre el origen americano de la AR, las evidencias sobre el inicio de la AR en Europa, es difícil documentarlo, sino hasta después del siglo XVII19, 26, 41-43, 55 como se discutió anteriormente. Además de los estudios ya revisados, la AR no aparece mencionada en la Biblia, los libros de Homero, o cualquier libro de los escritores griegos, romanos, hasta los trabajos de Shakespeare333, quien alude y describe algunos síndromes, y utiliza la palabra “rheumatic” en A Midsummer Night’s Dream, Henry IV, Venus y Adomis; “rheumatism”, en Venus y Adomis y la palabra “gout” en Venus y Adomis; es decir, que Shakespeare333 se refiere a la osteoartritis y a la gota, pero no a la artritis reumatoide. Solo a través de algunos pintores que tuvieron artritis reumatoide como Rubens, Renoir, o pacientes con artritis reumatoide que fueron pintados magistralmente por Van Gogh, quedaron plasmadas en los lienzos, las deformaciones ocasionadas por la artritis reumatoide9, 334.

Los pintores del renacimiento y de la edad media, por su fama, por el reconocimiento económico, no eran capaces

de pintar las deformaciones articulares u otros defectos de los nobles, o burgueses de la época; por ello es posible que algunos pacientes que tuviesen la enfermedad no fueron pintados, sino hasta que existió Pedro Pablo Rubens (1577-1640), famoso pintor flamenco que padeció posiblemente de artritis reumatoide (AR), enfermedad que se confundió con la gota; en los textos de pinturas, sobre la biografía de Rubens, siempre se menciona la gota335, 336 . Durante más de veinte años se logró analizar sus pinturas desde el inicio de su trabajo en este arte y casi hasta su muerte se puede analizar la incapacidad que le ocasiona la AR, ya que se puede vislumbrar un cambio de estilo de arte pictórico9, 335.

Utilizando la tesis de Word, “en la época en que la ausencia de una evidencia del pasado, no significa que una enfermedad no exista, solo se requiere una simple evidencia para probar la presencia de una enfermedad”. Con esta tesis, queremos analizar la importancia de las pinturas de origen flamenco (1400-1700), a partir de la primera exposición que realizó Jan Dequeker en la reunión anual de la “Heberden Society” realizada en Londres el 28 de noviembre de 1975. Este extraordinario profesor de la Universidad Católica analizó los diversos trabajos de pintores del renacimiento, especialmente

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Pedro Pablo Rubens, Colaboraba con sus ayudantes para ejecutar parte del primer boceto, ya que Rubens delineaba y daba las instrucciones y los retoques finales, lo que puede explicar la gran cantidad de pinturas que realizó, ya que en esa época tenía posiblemente una AR ya establecida. flamencos que pintaban portarretratos con escenas naturales; logró detectar algunos signos relacionados con enfermedades reumáticas y para ello analizó las obras pictóricas de muchos pintores como Breughel, Van Dyck, Rembrandt, Jerom Bosch, Rubens, Gossaert, Rombauts, Van Geant, Jordanes, Jan Stwwn; observó en muchos de los cuadros revisados cinco pinturas con lesiones en las manos parecidas a la artritis reumatoide, en las pinturas de los artistas flamencos, mas no en los pintores del renacimiento Italiano, y posiblemente los modelos utilizados en las pinturas tuviesen la enfermedad; por estos hallazgos Dequeker planteaba el origen reciente de la AR9, 17. Este trabajo seminal generó una línea de investigación, relacionada con el arte pictórico, para detectar algunas patologías de origen reumático.

Pedro Pablo Rubens Pedro Pablo Rubens vivió en el siglo XVII en los territorios que actualmente constituyen el estado de Bélgica, pero que en aquellos momentos ni eran independientes ni correspondían a los límites actuales.

Los territorios que entonces se llamaban países bajos, y también Flandes (los actuales Bélgica y Holanda y parte de la actual Francia), pertenecieron desde el siglo XV a la Borgoña, que a finales de ese siglo había pasado a depender del imperio de Austria, por el matrimonio de su titular, María de Borgoña, con el emperador Maximiliano, abuelo de Carlos I (conocido como Carlos V de España y descendiente de los Habsburgo)335, 336. Este los cedió después a su hijo Felipe II de España. Durante el reinado de este rey, y debi22

do a su política religiosa de lucha contra el protestantismo, que se había extendido a los países bajos, se produjeron varias sublevaciones y, de esta manera, los territorios del Norte, como Holanda, se independizaron del poder español, en vida de Rubens; mientras tanto las provincias del sur (la actual Bélgica) siguieron vinculadas al poder español, ya que Felipe II las asignó a su hija Isabel Clara Eugenia y a su esposo el archiduque Alberto, los cuales hicieron una política más autónoma y utilizaron a Rubens como embajador en diversas tareas diplomáticas, en varios países europeos, incluida España. Muertos los archiduques, la corona volvió a España, que las cedió al imperio Austro-Húngaro a principios del siglo XVIII. La vida de Rubens coincidió con los reinados de Felipe II, Felipe III y Felipe IV de España, y con los de Jacobo I y Carlos I de Inglaterra, y Enrique IV y Luis XIII de Francia. Rubens vivió en Amberes que era un puerto y centro cultural y enclave estratégico por el cruce de varios caminos para ingresar a Europa. Esta ciudad era frecuentada por marineros que retornaban del viejo mundo con cargamentos que revolucionaron los hábitos alimenticios, ya que la dieta del nuevo mundo era muy rica en carbohidratos como frutas, maíz, chocolate, plantas y hierbas, y un total desconocimiento de los aminoácidos y proteínas; también utilizaban plantas medicinales; se iniciaron, además, las mezclas genéticas entre europeos y población aborigen, el comercio basado en trueques, cambios en las condiciones de vida y de la ecología, posiblemente exposición de “agentes infecciosos” que encontraron un huésped genéticamente más susceptible al desarrollo de la AR en esta área de Europa, y que a través de los pintores de origen flamenco, se empezaron a plasmar en sus lienzos, como si fuese un “foco epidémico de artritis reumatoide”, es decir, que aparece como una enfermedad nueva en Europa337.

Pedro Pablo Rubens nace a finales del siglo XVI, en el esplendor de la pompa monárquica y el barroco, es decir, se resume en el gran esplendor del arte, la literatura y la escultura de Italia, España, Gran Bretaña, Francia, Flandes y Amberes; Rubens nace en Alemania en 1577, de padres flamencos; su padre Juan Rubens, hijo de

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un próspero farmacéutico de Amberes.

Rubens nace en el reinado del padre de Luis XIV (gestor de Versalles), Enrique IV y de la obra de Caravaggio, que marca el final del esplendor del renacimiento332.

Del espíritu renacentista se pasa al barroco y surge la nación-estado como modelo político (la romana, Florencia, Pisa, Génova, Venecia). Al regresar a Amberes, tras la muerte de su padre, Rubens se educa en la escuela de esta ciudad. Su madre le insiste que sea paje y aprendió a ser un buen cortesano; viaja a Italia en el año 1600, donde empezaba a pintar y se ganó el favor del duque de Mantua, al trasladarse este a Florencia. Presencia la boda de María de Médicis con Enrique IV; posteriormente Rubens pintó varios cuadros de esta familia, pinturas que se encuentran en el museo de Louvre, donde se puede apreciar la majestuosidad de la obra de este pintor, es decir, el barroco en todo su esplendor; Rubens se inclinó por la sobriedad, característica del clasicismo de la época332, 335, 336.

En Italia y Florencia estudió a todos los maestros de este estilo, como Miguel Ángel, Rafael Mantegna, Julio Romano y quizás conoció a Caravaggio. A los veintiséis años se convirtió en un diplomático avezado que pudo viajar a España y a Inglaterra.

España se encontraba en ese momento en la edad de oro de su arte y literatura con Calderón de la Barca, Tirso de Molina, El Greco, Ribero, Murillo, Velásquez y otros.

Después de estos viajes como diplomático, pero que a la vez le sirvieron para conocer profundamente a los maestros de la pintura universal, regresó a Amberes, donde estableció su propio taller y tuvo la posibilidad de crear su escuela. Colaboraba con sus ayudantes para ejecutar parte del primer boceto, ya que Rubens delineaba y daba las instrucciones y los retoques finales, lo que puede explicar la gran cantidad de pinturas que realizó, ya que en esa época tenía posiblemente una AR ya establecida.

Rubens se rodeó de más de setenta asistentes que le ayudaron en su trabajo artístico tan prolífico y tan extraordinario.

Por ello se ha logrado demostrar que Rubens se estableció en Flandes, donde siendo joven recibió la primera formación artística; pero que a partir de 1590 se estableció como aprendiz de un pintor. Emigró a Italia, la cuna del arte del renacimiento,

y trabajó como pintor con el duque de Mantua, no como retratista sino como plagiario de cuadros importantes para ornamentar el palacio de este duque y en Roma el joven pintor se italianizó, como lo muestran sus obras la Pietá y Susana, y el Retrato de un joven sabio; esta última obra que se encuentra en una colección privada de Nueva York, en la que precisamente de acuerdo con los críticos de arte, se observa una “mano defectuosamente dibujada” que podría ser el inicio de la AR de Rubens9, 32, 44, 46, 48, 49, 338 . Pero la importancia de la pintura y la relación con la artritis se inicia en un artículo publicado por J. Dequeker9, 32, 44, 46, 48 de la universidad de Leuven en Bélgica, quien analiza y estudia varias cuadros de famosos pintores flamencos entre 1400 y 1700. Entre las pinturas

y pintores que estudia Dequeker se encuentran los siguientes: Cristo apareciéndole a San Pedro de Jan Rambauts (museo Stedelijk, Leuven), en la que aparece Cristo, cuya mano derecha tiene deformaciones en cuello de cisne y boutonierre –este cuadro data del año 1500; el retrato de Federico de Montefeltre (palacio Urbino, Ducal) de Joos (Justus) van Gent, donde se observa una artritis de la interfalángica proximal del dedo índice y posteriormente del tercer dedo de la mano izquierda –en este caso sería especular decir qué clase de “artritis” es la que se describe9, 32.

En la pintura de Jan van Eyck, pintada en 1441, al padre Juan IV, duque de Brabante, quien fue uno de los fundadores de la universidad de Leuven, se le observan las deformaciones en cuello de cisne y

boutonierre de la mano derecha9, 32 . Este cuadro se encuentra en el museo Boymanns-Yan Beuningen en Rottendam9, 32. En el cuadro de Jacob Jordaens (La familia del pintor, en el museo del Prado, Madrid), en la institutriz se observa claramente el compromiso de las articulaciones metacarpofalángicas, interfalángicas proximales, la atrofia de los interóseos de sus manos, especialmente la derecha9, 32. En la pintura El donador de Jan Gossaert o Mabuse, cuadro que se encuentra en el museo nacional de Bruselas, se observan las deformaciones de las manos en una fase avanzada de la AR, especialmente en la mano izquierda; algunos autores piensan que deba tratarse de una contractura de Dupuytren9, 32.

Sus detalles en sus pinturas, especialmente en las manos y los pies, ausentes en las primeras obras, pero presentes en los últimos años por el progreso de la AR, establecen una marca o código de la presencia de su enfermedad.

Cómo se amplió este conocimiento Por las publicaciones de Dequeker sobre la AR de Rubens, en 1977, durante el verano de Amberes, se realizó una exposición Internacional de las obras de Rubens; para ello un grupo de expertos como Dequeker, Appelboom, Corine de Boel Paipe y Jena- Pierre Fammey de la universidad de Saint-Pierre de Bruselas y George Ehrlich del centro médico Albert Einstein de Filadelfia y otros especialistas, entre los que participaron reumatólogos, artistas, analizaron retrospectivamente y con criterio clínico y analítico la serie de cuadros, en busca de señales de artritis reumatoide en los personajes pintados por Rubens. Analizaron con mucha atención e interés las manos de los diferentes cuadros, ya que los diversos participantes conocían las manos que pintó Jean Renoir a finales del siglo XIX, y las notaron deformadas en las diversas pinturas (algunas ya mencionadas) y las distintas

señales que deja la AR a medida que la enfermedad iba avanzando en el cuerpo del propio artista. Después de seleccionar las diferentes pinturas donde son más notorios los efectos de la AR, estas pinturas fueron sometidas a una revisión minuciosa por los reumatólogos, médicos de otras especialidades y otros artistas. Solo cuando hubo un consenso entre los que conformaban el panel de expertos se concluyó que estas pinturas mostraban en las manos los signos característicos de la AR, además que Rubens no padecía de gota como se había afirmado durante más de trescientos treinta y siete años sino de AR y que sus obras no sólo lo colocaban en la cúspide de la pintura barroca europea sino que logra realizar un aporte a la historia de la medicina, como es la posible aparición de la AR en el continente europeo9, 32, 44, 48, 49, 32.

Sus detalles en sus pinturas, especialmente en las manos y los pies, ausentes en las primeras obras, pero

presentes en los últimos años por el progreso de la AR, establecen una marca o código de la presencia de su enfermedad. Durante la madurez, Rubens desarrolla dos actividades permanentes, como artista y como diplomático. En 1604 en su cuadro San Sebastián muestra unas rodillas hinchadas y un hallux valgus en los pies. En orden cronológico, Rubens en 1609 pinta su San Mateo (museo del Prado, Madrid), en el que muestra una inflamación en las articulaciones metacarpofalángicas de los dedos índice y mediano de la mano izquierda. En el Sátiro ebrio durmiendo (Gemäldegalerie der Akademie de Viena, 1610), y en Susana y los Ancianos (museo nacional de Estocolmo, 1614), se observa un engrosamiento sinovial de la muñeca, imágenes que repite en San Agustín entre Cristo y la Virgen (academia de San Fernando, Madrid, 1615), donde el pintor muestra el compromiso bilateral de las manos. A partir de 1620, su arte en el retrato de

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María de Médicis, viuda del rey Enrique IV de Francia, le permitió viajar a París para realizar una serie de cuadros sobre esta viuda y su familia. Las manos de MarÍa de Médicis denotan en forma muy sutil, el compromiso de la AR9, 32, 44, 46, 48, 49, 32, 335, 336 .

Para esta época la vida le cambió a Rubens, ya que además de fungir como un empresario talentoso, era un diplomático felizmente casado y dueño de una casa con un taller adecuado para continuar con su empresa pictórica. Su viaje a Italia le ayudó a encontrar su madurez artística, ya que aprendió de Tiziano, Tintoretto y el Verones los conceptos de temática, monumentalidad y cromatismo que aplicó en sus cuadros, especialmente en los cuerpos femeninos, como uno de los rasgos de la pintura flamenca. Por su vida diplomática, entre Flandes, París y Madrid, conoce a Felipe IV y lo convence para formalizar la alianza anglo-española. En esa época, amplía su cuadro la Adoración de los Magos que pintó en 1609, y le agregó su autorretrato al costado derecho, en el que se muestra una inflamación en las articulaciones interfalángicas y una atrofia del dorso de la mano, sugestiva de una AR en un estado avanzado, lo que indica que el autor de estos cuadros observaba como avanzaba su enfermedad y no los posibles modelos9, 32, 44, 46, 48, 49, 331, 335, 336.

En 1626 enviudó de su primera esposa Isabel Brand y se casó con Elena Fourment, hija de un próspero comerciante de sedas, con quien tuvo cinco hijos y estuvo muy enamorado, fue su modelo y su musa de inspiración, a quien el artista pintó varias veces.

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En su célebre cuadro Las tres Gracias, el pintor reúne a sus dos esposas, a Isabel Brant la coloca a la derecha y a Elena Fourment, a la izquierda, cuadro que se encuentra en el museo del Prado. En la musa que representa a Elena en su mano derecha, aparecen las características deformaciones en cuello de cisne y en boutonierre, características de una AR avanzada. En esta época (1638) Rubens estuvo en reposo por el compromiso activo de su enfermedad y empezó a utilizar un bastón para caminar, detalle que aparece marginalmente en su último autorretrato. Rubens ocultaba sus manos al pintar sus autorretratos; sólo en su último autorretrato, que se exhibe en el Museo Kunsthitorisches de Viena, se observa en la mano izquierda un engrosamiento sinovial y la rotura de los tendones extensores de los dedos tercero, cuarto, y quinto. A pesar de su enfermedad, Rubens siguió pintando, hasta que en 1640, él mismo en una carta describe su enfermedad y manifiesta que las manos “están paralizadas”, sin esperanza de que pueda mover el pincel y muere el 30 de mayo de ese año, cuando estaba por cumplir 63 años9, 32, 44, 46, 48, 49, 331, 335, 336.

Con la primera experiencia realizada en Amberes, la obstinación de Tierra Appelboom permitió realizar entre el 17 y el 19 de abril de 1986 en Bruselas un simposio patrocinado por Wyeth de Francia en el museo de Meaux-Art; para ello reunió a un grupo de personalidades que tenían los mismos intereses que Dequeker y Appelboom de explicar a través de la prehistoria, historia y arte el origen de las enfermedades reumáticas. En este simposio participaron M. F. Kanh, L. E. Shulman, P. Philippot, M. D. Grmek, Alan Cohen, Donato Alarcón-Segovia, Ramón de la Fuente, Jan Dequeker, P. H. Hermans, C. Preaux, J. Slovie, Y. Saudan, E. G. L. Bywaters, J. Dierkens, L. Beranek, M. Daudin, D.

Gourevitch, R. P. Wedeen, L. Rothfield, C. Rouffin, J. L. Van Herweghem, J. P. Vanden Branden, G. Ehrlich, J. N. Tamisier, P. Thomas, B. Duruy, G. V. Ball, J. A. López Ferez, S. L. Wallace, D. J. Ortner, B. M. Rothschild, T. F. Molleson, P. Dieppe, A. Heywood, J. Rogers, T. Waldron, I. Watt, H. Jesserer, K. Ammer, C. H. Krammar, R. Lagier, C. A. Baud, bajo la dirección de Tierra Appelboom. Cada una de estas ponencias se plasmaron en un extraordinario libro denominado Les Affections Rheumatis Males dan l’art et dans l’ historie, editado por René Malherbe en 1988 en la ciudad de Bruselas9.

Finalmente, en un artículo de Dequeker y Horacio Rico46, los autores analizan una pintura flamenca del museo Escorial, de un artista anónimo de los siglos XV y XVI, llamada La Tentación de San Antonio, en la que aparece claramente la subluxación de la muñeca derecha, la contractura de los dedos y la desviación cubital; esto hace pensar a Dequeker y a Rico46 que la AR existió en la edad media o antes y no después de 1800 con la descripción de Landre- Beauvais.

Comentario ¿Cómo pudo un pintor como Rubens, gestar tantas obras pictóricas, padeciendo una enfermedad como la AR? La explicación es la siguiente: Rubens gozaba de un gran prestigio y organizó una gran escuela, ya que recibió un sinnúmero de encargos; para ello organizó un sistema de trabajo y es que contrató a varios pintores destacados de su época, con cierta especialización como expertos en vestimentas, en fondos, en líneas, etc. y generó una línea de producción pictórica, que le permitía tener simultáneamente varias telas en ejecución. Cuando un cliente quería comprar un cuadro y visitaba su estudio, “Rubens despachaba a los pintores contratados; mientras el cliente lo ob-

De Europa y de Norteamérica podemos concluir que el origen de las enfermedades es bastante complejo de establecer, pero a través de este artículo queremos dejar una impronta de lo que la prehistoria, la historia y el arte nos pueden enseñar sobre el origen de algunas enfermedades reumáticas. servaba desde un balcón, Rubens trabajaba con increíble velocidad y energía un cuadro. El cliente se iba asombrado ante ese hombre prodigioso, capaz de pintar tantas obras maestras en tampoco tiempo”. De esta manera, Rubens se llevaba todos los laureles y la gran admiración y sus colaboradores no los conocía nadie y nunca les dio los créditos necesarios; aplicó la séptima ley del poder: “Logre que otros trabajen por usted, pero no deje nunca de llevarse los laureles” del libro Las 48 leyes del poder de Robert Greene. Es decir, a Rubens, no se le aplicó la ley de propiedad intelectual y de colaboración339.

Conclusiones Analizamos los diferentes artículos, relacionados con textos antiguos que citaron la palabra reuma, y buscamos las citas en diferentes publicaciones para estudiar las fuentes directas que se logran localizar.

Revisamos las diferentes publicaciones de paleopatología, en las cuales se lograron relacionar algunas enfermedades reumatológicas con figuras precolombinas; estudiamos los textos antiguos relacionados con reuma y los diferentes textos de Reumatología, en los que se describieron capítulos sobre historia de la Reumatología, y el origen de la palabra reuma. Se realizó una búsqueda sistemática de artículos en revistas indexadas y no indexadas sobre pinturas, pintores y enfermedades reumáticas.

Se revisaron varios catálogos, libros y reproducciones de pinturas y pintores que tuvieron alguna enfermedad reumática o que refle-

jaran en sus lienzos alguna enfermedad reumática, la colección de arte médica del mundo de arte de Filadelfia, y los cuadros de varios museos.

De Europa y de Norteamérica podemos concluir que el origen de las enfermedades es bastante complejo de establecer, pero a través de este artículo queremos dejar una impronta de lo que la prehistoria, la historia y el arte nos pueden enseñar sobre el origen de algunas enfermedades reumáticas.

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CASO CLÍNICO

RETO DIAGNÓSTICO ENTRE CROHN Y COLITIS SISTÉMICA Por: Dr. Ahmed Morales MD FACP, FACG, FASGE, AGAF Gastroenterólogo Miembro de la Junta de Editores de la Revista de Medicina y Salud Pública

Palabras clave

Crohn, colitis sistémica, evacuación, sangre

Keywords

Crohn’s, systemic colitis, evacuation, blood

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RESUMEN La colitis isquémica ocurre cuando se reduce temporalmente el flujo sanguíneo que va a una parte del intestino grueso (colon) y por lo general, debido a la constricción de los vasos sanguíneos que irrigan el colon o a la reducción del flujo de sangre a través de los vasos debido a presiones bajas.

La colitis isquémica se puede diagnosticar de forma errónea porque se puede confundir fácilmente con otros problemas digestivos.

E

Es posible que se necesiten medicamentos para tratar la colitis isquémica o prevenir una infección. Igualmente se pudiera requerir una cirugía si el colon se ha dañado. Sin embargo, la mayoría de las veces la colitis isquémica se cura por sí sola.

Entre sus principales síntomas destacan el dolor abdominal, diarreas, fiebre, pérdida de peso, hemorragia rectal, entre otros síntomas.

Mientras, la enfermedad de Crohn es una afectación inflamatoria de tipo crónico y autoinmune del tubo digestivo que evoluciona de modo recurrente con brotes. Puede afectar desde la boca hasta el ano. La localización más frecuente es el íleon terminal (porción más distal del intestino delgado).

La colitis ulcerativa provoca inflamación y úlceras en el tracto digestivo, que afecta el revestimiento más profundo del intestino grueso (colon) y el recto. Por lo general, los síntomas aparecen con el paso del tiempo.

Ambas condiciones guardan similitudes en su presentación, por lo que el cernimiento correcto en estos pacientes determinará el curso clínico idóneo para el paciente. Sin embargo, el no tener ambas enfermedades dentro de los diagnósticos diferenciales puede ser adverso para su salud.

ABSTRACT Ischemic colitis occurs when blood flow to part of the large intestine (colon) is temporarily reduced, usually due to constriction of the blood vessels supplying the colon or reduced blood flow through the intestines. vessels due to low pressures.

Ischemic colitis can be misdiagnosed because it can easily be confused with other digestive problems.

Medicines may be needed to treat ischemic colitis or prevent infection. Surgery may also be required if the colon has been damaged. However, most of the time ischemic colitis heals on its own.

Its main symptoms include abdominal pain, diarrhea, fever, weight loss, rectal bleeding, among other symptoms.

Meanwhile, Crohn’s disease is a chronic and autoimmune inflammatory affectation of the digestive tract that evolves recurrently with outbreaks. It can affect from the mouth to the anus.

The most common location is the terminal ileum (most distal portion of the small intestine).

Ulcerative colitis causes inflammation and ulcers in the digestive tract, affecting the deeper lining of the large intestine (colon) and the rectum. Symptoms usually appear over time.

Both conditions have similarities in their presentation, so the correct screening in these patients will determine the ideal clinical course for the patient.

However, not having both diseases within the differential diagnoses can be detrimental to your health.

RESUMEN Paciente de 53 años con dolor abdominal y evacuaciones con sangre. Un CT abdominal arrojó engrosamiento del lado izquierdo del colon. Se le hace colonoscopia con biopsias con evidencia de colitis isquémica. Este caso es uno relevante pues el cuadro clínico del paciente puede ser confundido con la enfermedad de Crohn y colitis ulcerativa y recibir un tratamiento incorrecto y adverso a su diagnóstico real.

CASO Paciente de 53 años con historial clínico de enfermedad coronariana, dia-

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Revista Puertorriqueña de Medicina y Salud Pública

betes e hipertensión, que se presentó a las salas de emergencias reportando dolor en el lado izquierdo abdominal dos días previos a su llegada.

Igualmente reportó episodios de diarreas con sangre. Al paciente se le realizaron laboratorios rutinarios y un estudio CT abdominal, que reflejó engrosamiento del lado izquierdo del colon.

Los médicos tomaron la decisión de realizar una colonoscopia que también reflejó la inflamación en el lado izquierdo del colon. No obstante, en las biopsias realizadas al tejido evaluado mediante colonoscopia, arrojó el diagnóstico de colitis isquémica, despejando así la posibilidad de una presentación de la enfermedad de Crohn.

Entre los tratamientos a estos pacientes se encuentran la administración de antibióticos e hidratación.

CONCLUSIÓN El diagnóstico de colitis sistémica provoca un escenario de inflamación en el colon que pudiera ser similar a aquella provocada por la enfermedad de Crohn y/o colitis ulcerativa. Es importante que los médicos estén conscientes de las presentaciones de ambas condiciones para poder administrar el tratamiento correcto, sobre todo en los hallazgos identificados en las colonoscopias.

REFERENCIAS: Colitis isquémica - Síntomas y causas - Mayo Clinic. (2021, July 29). Mayo Clinic. https://www.mayoclinic.org/ es-es/diseases-conditions/ischemic-colitis/symptoms-causes/syc-20374001 Clínica Universidad de Navarra. (2022). Enfermedad de Crohn: ¿Qué es? Síntomas y tratamiento. https://www.cun.es/enfermedades-tratamientos/enfermedades/enfermedad-crohn Colitis ulcerosa - Síntomas y causas - Mayo Clinic. (2021, February 23). Mayo Clinic. https://www.mayoclinic.org/es-es/ diseases-conditions/ulcerative-colitis/ symptoms-causes/syc-20353326#:%7E:text=La%20colitis%20ulcerosa%20 es%20una,tiempo%2C%20no%20se%20 presentan%20s%C3%BAbitamente.

ARRIBA El Dr. Ahmed Morales verifica sus equipos antes de iniciar la endoscopia.

ABAJO Plano detalle del equipo para realizar la endoscopia.

Este caso de un paciente de 53 años con dolor abdominal es uno relevante pues el cuadro clínico del paciente puede ser confundido y recibir un tratamiento incorrecto y adverso a su diagnóstico real.

Revista Puertorriqueña de Medicina y Salud Pública

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For moderate to severe ulcerative colitis (UC) in adult TNFi-IR patients1

DURABLE REMISSION. POWERFUL HEALING. IN A ONCE-DAILY PILL.1

PUT UC

With RINVOQ, UC remission isn’t temporary.

It can endure.1 See the 1-year data at RINVOQHCP.COM/UC U-ACHIEVE Induction (N=473) and U-ACCOMPLISH Induction (N=515) were Phase 3, randomized, double-blind, placebo-controlled studies to evaluate the efficacy and safety of RINVOQ (45 mg) vs placebo over 8 weeks in adult patients with moderate to severe UC who demonstrated prior treatment failure to conventional and/or biologic treatment.1 U-ACHIEVE Maintenance (N=451) was a Phase 3, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of RINVOQ (15 mg and 30 mg) vs placebo up to 52 weeks in patients who achieved clinical response during induction.1

INDICATION1 RINVOQ is indicated for the treatment of adults with moderately to severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers.

opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for ulcerative colitis, or with other potent immunosuppressants such as azathioprine and cyclosporine.

Mortality: A higher rate of all-cause mortality, including sudden cardiovascular (CV) death, was observed with a Janus kinase (JAK) inhibitor in a study comparing another JAK inhibitor with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years of age with at least one CV risk factor.

SAFETY CONSIDERATIONS1 Serious Infections: Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include tuberculosis (TB), invasive fungal, bacterial, viral, and other infections due to

Malignancies: Lymphoma and other malignancies have been observed in RINVOQ-treated patients. A higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]),

RAPID RELIEF

DURABLE REMISSION

Clinical response* of rectal bleeding and stool frequency subscores1,2

Clinical remission1† (Primary Endpoint)

POWERFUL HEALING Endoscopic improvement1‡

Histo-endoscopic mucosal improvement1§

100 80

60%

60

42% 40

50%

49% 35%

27%

20 0

62%

52%

14%

12% N=154

N=319

N=149 N=148

N=154

12% N=154

N=149 N=148

N=154

U-ACHIEVE Maintenance Week 52

U-ACHIEVE Induction Week 2 Placebo

N=149 N=148

RINVOQ 15 mg

RINVOQ 30 mg

RINVOQ 45 mg

P<0.001; RINVOQ vs Placebo

RECOMMENDED

MAINTENANCE DOSING

A dosage of 30 mg once daily may be considered for patients with refractory, severe, or extensive disease. Discontinue RINVOQ if an adequate therapeutic response is not achieved with the 30 mg dosage.1

Clinical Remission at Week 8 (Primary Endpoint)1: • U-ACHIEVE Induction – RINVOQ 45 mg 26% vs placebo 5% • U-ACCOMPLISH Induction – RINVOQ 45 mg 33% vs placebo 4%

Histo-endoscopic Mucosal Improvement at Week 81: • U-ACHIEVE Induction –­ RINVOQ 45 mg 30% vs placebo 7% • U-ACCOMPLISH Induction – RINVOQ 45 mg 37% vs placebo 6%

The relationship between histo-endoscopic mucosal improvement to disease progression and long-term outcomes was not evaluated.1 TNFi-IR=inadequate response to TNF inhibitors. * Clinical response per partial modified Mayo score is composed of Mayo stool frequency and rectal bleeding subscores (RBS), defined as a decrease in total score ≥30% and ≥1 point from baseline, and a decrease in RBS ≥1 or RBS of 0 or 1.1 Clinical remission is defined as stool frequency subscore ≤1 and not greater than baseline, RBS of 0, and endoscopic subscore (ES) ≤1 without friability.1

†

Endoscopic improvement was defined as Mayo ES of 0 or 1 without friability.1

‡

isto-endoscopic mucosal improvement was defined as an ES ≤1 without friability and Geboes score ≤3.1 (indicating neutrophil infiltration in <5% of crypts, no crypt H destruction, and no erosions, ulcerations, or granulation tissue).1

§

SAFETY CONSIDERATIONS1 (continued) lymphomas, and lung cancer (in current or past smokers) was observed with another JAK inhibitor when compared with TNF blockers in RA patients. Patients who are current or past smokers are at additional increased risk.

Major Adverse Cardiovascular Events: A higher rate of CV death, myocardial infarction, and stroke was observed with a JAK inhibitor in a study comparing another JAK inhibitor with TNF blockers in RA patients ≥50 years of age with at least one CV risk factor. Current or past smokers are at additional increased risk.

Thrombosis: Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions. A higher rate of thrombosis was observed with another JAK inhibitor when compared with TNF blockers in RA patients.

Hypersensitivity: RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients.

Other Serious Adverse Reactions: Hypersensitivity Reactions (anaphylaxis and angioedema), Gastrointestinal Perforations, Laboratory Abnormalities (neutropenia, lymphopenia, anemia, lipid elevations, liver enzyme elevations), and Embryo-Fetal Toxicity.

Please see additional Important Safety Information for RINVOQ, including BOXED WARNING on Serious Infections, Mortality, Malignancies, Major Adverse Cardiovascular Events, and Thrombosis, on the following page of this advertisement.

Please see Brief Summary of full Prescribing Information on adjacent pages of this advertisement.

IMPORTANT SAFETY INFORMATION1 SERIOUS INFECTIONS Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids. If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include: • Active tuberculosis (TB), which may present with pulmonary or extrapulmonary disease. Test patients for latent TB before RINVOQ use and during therapy. Consider treatment for latent TB infection prior to RINVOQ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

Carefully consider the risks and benefits of treatment with RINVOQ prior to initiating therapy in patients with chronic or recurrent infection.

Monitor patients closely for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy.

MORTALITY In a large, randomized, postmarketing safety study comparing another Janus kinase (JAK) inhibitor with tumor necrosis factor (TNF) blockers in rheumatoid arthritis (RA) patients ≥50 years old with at least one cardiovascular (CV) risk factor, a higher rate of all-cause mortality, including sudden CV death, was observed with the JAK inhibitor.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ. MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with RINVOQ. In a large, randomized, postmarketing safety study comparing another JAK inhibitor with TNF blockers in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer [NMSC]), lymphomas, and lung cancer (in current or past smokers) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk.

With RINVOQ, consider the benefits and risks for the individual patient prior to initiating or continuing therapy, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers. NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. Advise patients to limit sunlight exposure by wearing protective clothing and using sunscreen.

MAJOR ADVERSE CARDIOVASCULAR EVENTS In a large, randomized, postmarketing study comparing another JAK inhibitor with TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke) was observed with the JAK inhibitor. Patients who are current or past smokers are at additional increased risk. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other CV risk factors. Patients should be informed about the symptoms of serious CV events and the steps to take if they occur.

THROMBOSIS Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing study comparing another JAK inhibitor to TNF blockers in RA patients ≥50 years old with at least one CV risk factor, a higher rate of thrombosis was observed with the JAK inhibitor. Avoid RINVOQ in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ and be promptly evaluated.

HYPERSENSITIVITY RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients. Serious hypersensitivity reactions, such as anaphylaxis and angioedema, were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy.

GASTROINTESTINAL PERFORATIONS Gastrointestinal (GI) perforations have been reported in clinical trials with RINVOQ. Monitor RINVOQ-treated patients who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs). Promptly evaluate patients presenting with new onset abdominal pain for early identification of GI perforation.

LABORATORY ABNORMALITIES Neutropenia Treatment with RINVOQ was associated with an increased incidence of neutropenia (absolute neutrophil count [ANC] <1000 cells/mm3). Treatment with RINVOQ is not recommended in patients with an ANC <1000 cells/mm3.

Evaluate neutrophil counts at baseline and thereafter according to routine patient management.

Lymphopenia Absolute lymphocyte counts (ALC) <500 cells/mm3 were reported in RINVOQ-treated patients. Treatment with RINVOQ is not recommended in patients with an ALC <500 cells/mm3. Evaluate at baseline and thereafter according to routine patient management.

Anemia Decreases in hemoglobin levels to <8 g/dL were reported in RINVOQ-treated patients. Treatment should not be initiated or should be interrupted in patients with hemoglobin levels <8 g/dL. Evaluate at baseline and thereafter according to routine patient management.

Lipids Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Manage patients according to clinical guidelines for the management of hyperlipidemia. Evaluate patients 12 weeks after initiation of treatment and thereafter according to the clinical guidelines for hyperlipidemia.

Liver enzyme elevations Treatment with RINVOQ was associated with increased incidence of liver enzyme elevation compared to placebo. Evaluate at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury. If increases in aspartate aminotransferase (AST) or alanine aminotransferase (ALT) are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

EMBRYO-FETAL TOXICITY Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose. Verify pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ. VACCINATION Avoid use of live vaccines during, or immediately prior to, RINVOQ therapy.

Prior to initiating RINVOQ, patients should be brought up to date on all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.

LACTATION There are no data on the presence of RINVOQ in human milk, the effects on the breastfed infant, or the effects on milk production. Available data in animals have shown the excretion of RINVOQ in milk. Advise patients that breastfeeding is not recommended during treatment with RINVOQ and for 6 days after the last dose.

HEPATIC IMPAIRMENT RINVOQ is not recommended for use in patients with severe hepatic impairment.

ADVERSE REACTIONS The most common adverse reactions in RINVOQ clinical trials were upper respiratory tract infections, herpes zoster, herpes simplex, bronchitis, nausea, cough, pyrexia, acne, headache, increased blood creatine phosphokinase, hypersensitivity, folliculitis, abdominal pain, increased weight, influenza, fatigue, neutropenia, myalgia, influenza-like illness, elevated liver enzymes, and rash.

Inform patients that retinal detachment has been reported in clinical trials with RINVOQ. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving RINVOQ. Dosage Forms and Strengths: RINVOQ is available in 15 mg, 30 mg, and 45 mg extended-release tablets.

Please see Brief Summary of full Prescribing Information on adjacent pages of this advertisement.

References: 1. RINVOQ [package insert]. North Chicago, IL: AbbVie Inc. 2. Danese S, Vermeire S, Zhou W, et al. Efficacy and Safety of upadacitinib therapy in patients with moderately to severely active Ulcerative Colitis: results from the phase 3 U-ACHIEVE study.

Presented at: European Crohn’s and Colitis Organisation, 16th Congress of ECCO. July 2-3 & 8-10, 2021, Virtual.

© 2022 AbbVie. All rights reserved.

US-RNQG-210160 3/2022 Printed in U.S.A.

RINVOQ® (RIN-VOKE) (upadacitinib) extended-release tablets, for oral use WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS SERIOUS INFECTIONS Patients treated with RINVOQ are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions, Adverse Reactions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt RINVOQ until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before RINVOQ use and during therapy. Treatment for latent infection should be considered prior to RINVOQ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with RINVOQ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with RINVOQ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy [see Warnings and Precautions].

MORTALITY In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing another Janus kinase (JAK) inhibitor to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with the JAK inhibitor [see Warnings and Precautions].

MALIGNANCIES Lymphoma and other malignancies have been observed in patients treated with RINVOQ. In RA patients treated with another JAK inhibitor, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk [see Warnings and Precautions].

MAJOR ADVERSE CARDIOVASCULAR EVENTS In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), was observed when compared with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke [see Warnings and Precautions].

THROMBOSIS Thrombosis, including deep venous thrombosis, pulmonary embolism, and arterial thrombosis have occurred in patients treated with JAK inhibitors used to treat inflammatory conditions. Many of these adverse events were serious and some resulted in death. In RA patients 50 years of age and older with at least one cardiovascular risk factor treated with another JAK inhibitor, a higher rate of thrombosis was observed when compared with TNF blockers. Avoid RINVOQ in patients at risk. Patients with symptoms of thrombosis should discontinue RINVOQ and be promptly evaluated [see Warnings and Precautions].

INDICATIONS AND USAGE Rheumatoid Arthritis RINVOQ® is indicated for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of RINVOQ in combination with other JAK inhibitors, biologic disease-modifying antirheumatic drugs (DMARDs), or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.

Psoriatic Arthritis RINVOQ is indicated for the treatment of adults with active psoriatic arthritis who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of RINVOQ in combination with other JAK inhibitors, biologic DMARDs, or with potent immunosuppressants such as azathioprine and cyclosporine, is not recommended.

Atopic Dermatitis RINVOQ is indicated for the treatment of adults and pediatric patients 12 years of age and older with refractory, moderate to severe atopic dermatitis whose disease is not adequately controlled with other systemic drug products, including biologics, or when use of those therapies are inadvisable.

• Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biologic immunomodulators, or with other immunosuppressants.

Ulcerative Colitis RINVOQ is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: RINVOQ is not recommended for use in combination with other JAK inhibitors, biological therapies for ulcerative colitis, or with potent immunosuppressants such as azathioprine and cyclosporine.

CONTRAINDICATIONS RINVOQ is contraindicated in patients with known hypersensitivity to upadacitinib or any of its excipients [see Warnings and Precautions].

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections have been reported in patients receiving RINVOQ. The most frequent serious infections reported with RINVOQ included pneumonia and cellulitis [see Adverse Reactions]. Among opportunistic infections, tuberculosis, multidermatomal herpes zoster, oral/esophageal candidiasis, and cryptococcosis, were reported with RINVOQ. Avoid use of RINVOQ in patients with an active, serious infection, including localized infections. Consider the risks and benefits of treatment prior to initiating RINVOQ in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with RINVOQ. Interrupt RINVOQ if a patient develops a serious or opportunistic infection.

A patient who develops a new infection during treatment with RINVOQ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, the patient should be closely monitored, and RINVOQ should be interrupted if the patient is not responding to antimicrobial therapy. RINVOQ may be resumed once the infection is controlled.

Tuberculosis Evaluate and test patients for latent and active tuberculosis (TB) infection prior to administration of RINVOQ. Patients with latent TB should be treated with standard antimycobacterial therapy before initiating RINVOQ. RINVOQ should not be given to patients with active TB. Consider anti-TB therapy prior to initiation of RINVOQ in patients with previously untreated latent TB or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but who have risk factors for TB infection.

Consultation with a physician with expertise in the treatment of TB is recommended to aid in the decision about whether initiating anti-TB therapy is appropriate for an individual patient.

During RINVOQ use, monitor patients for the development of signs and symptoms of TB, including patients who tested negative for latent TB infection prior to initiating therapy.

Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster) and hepatitis B virus reactivation, were reported in clinical trials with RINVOQ [see Adverse Reactions]. The risk of herpes zoster appears to be higher in patients treated with RINVOQ in Japan. If a patient develops herpes zoster, consider temporarily interrupting RINVOQ until the episode resolves.

Screening for viral hepatitis and monitoring for reactivation should be performed in accordance with clinical guidelines before starting and during therapy with RINVOQ. Patients who were positive for hepatitis C antibody and hepatitis C virus RNA, were excluded from clinical trials. Patients who were positive for hepatitis B surface antigen or hepatitis B virus DNA were excluded from clinical trials. However, cases of hepatitis B reactivation were still reported in patients enrolled in the Phase 3 trials of RINVOQ. If hepatitis B virus DNA is detected while receiving RINVOQ, a liver specialist should be consulted.

Mortality In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed in patients treated with the JAK inhibitor compared with TNF blockers.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ. Malignancy and Lymphoproliferative Disorders Malignancies, including lymphomas, were observed in clinical trials of RINVOQ [see Adverse Reactions].

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lymphomas was observed in patients treated with the JAK inhibitor compared to those treated with TNF blockers. A higher rate of lung cancers was observed in current or past smokers treated with the JAK inhibitor compared to those treated with TNF blockers. In this study, current or past smokers had an additional increased risk of overall malignancies.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy when on treatment, and patients who are current or past smokers.

Non-Melanoma Skin Cancer NMSCs have been reported in patients treated with RINVOQ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer.

Exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen.

Major Adverse Cardiovascular Events In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke was observed with the JAK inhibitor compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with RINVOQ, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue RINVOQ in patients that have experienced a myocardial infarction or stroke.

Thrombosis Thrombosis, including deep venous thrombosis (DVT), pulmonary embolism (PE), and arterial thrombosis, have occurred in patients treated for inflammatory conditions with JAK inhibitors, including RINVOQ. Many of these adverse events were serious and some resulted in death.

In a large, randomized, postmarketing safety study of another JAK inhibitor in RA patients 50 years of age and older with at least one cardiovascular risk factor, higher rates of overall thrombosis, DVT, and PE were observed compared to those treated with TNF blockers.

If symptoms of thrombosis occur, patients should discontinue RINVOQ and be evaluated promptly and treated appropriately. Avoid RINVOQ in patients that may be at increased risk of thrombosis.

Hypersensitivity Reactions Serious hypersensitivity reactions such as anaphylaxis and angioedema were reported in patients receiving RINVOQ in clinical trials. If a clinically significant hypersensitivity reaction occurs, discontinue RINVOQ and institute appropriate therapy [see Adverse Reactions].

Gastrointestinal Perforations Gastrointestinal perforations have been reported in clinical trials with RINVOQ. Monitor RINVOQ-treated patients who may be at risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).

Evaluate promptly patients presenting with new onset abdominal pain for early identification of gastrointestinal perforation.

Laboratory Abnormalities Neutropenia Treatment with RINVOQ was associated with an increased incidence of neutropenia (ANC less than 1000 cells/mm3).

Evaluate neutrophil counts at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation and interrupt RINVOQ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3).

Lymphopenia ALC less than 500 cells/mm3 were reported in RINVOQ-treated patients in clinical trials.

Evaluate lymphocyte counts at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation or interrupt RINVOQ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3).

Anemia Decreases in hemoglobin levels to less than 8 g/dL were reported in RINVOQ-treated patients in clinical trials.

Evaluate hemoglobin at baseline and thereafter according to routine patient management. Avoid RINVOQ initiation or interrupt RINVOQ treatment in patients with a low hemoglobin level (i.e., less than 8 g/dL).

Lipids Treatment with RINVOQ was associated with increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol [see Adverse Reactions].

Elevations in LDL cholesterol decreased to pre-treatment levels in response to statin therapy. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assess lipid parameters approximately 12 weeks after initiation of treatment, and thereafter according to the clinical guidelines for hyperlipidemia. Manage patients according to clinical guidelines for the management of hyperlipidemia.

Liver Enzyme Elevations Treatment with RINVOQ was associated with increased incidence of liver enzyme elevations compared to treatment with placebo.

Evaluate liver enzymes at baseline and thereafter according to routine patient management. Prompt investigation of the cause of liver enzyme elevation is recommended to identify potential cases of drug-induced liver injury.

If increases in ALT or AST are observed during routine patient management and drug-induced liver injury is suspected, RINVOQ should be interrupted until this diagnosis is excluded.

Embryo-Fetal Toxicity Based on findings in animal studies, RINVOQ may cause fetal harm when administered to a pregnant woman. Administration of upadacitinib to rats and rabbits during organogenesis caused increases in fetal malformations.

Verify the pregnancy status of patients of reproductive potential prior to starting treatment. Advise females of reproductive potential of the potential risk to the fetus and to use effective contraception during treatment with RINVOQ and for 4 weeks following completion of therapy [see Use in Specific Populations].

Vaccinations Avoid use of live vaccines during, or immediately prior to, RINVOQ therapy.

Prior to initiating RINVOQ, it is recommended that patients be brought up to date with all immunizations, including varicella zoster or prophylactic herpes zoster vaccinations, in agreement with current immunization guidelines.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections [see Warnings and Precautions] • Mortality [see Warnings and Precautions] • Malignancy and Lymphoproliferative Disorders [see Warnings and Precautions] • Major Adverse Cardiovascular Events [see Warnings and Precautions] • Thrombosis [see Warnings and Precautions] • Hypersensitivity Reactions [see Warnings and Precautions] • Gastrointestinal Perforations [see Warnings and Precautions] • Laboratory Abnormalities [see Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Adverse Reactions in Patients with Rheumatoid Arthritis A total of 3833 patients with rheumatoid arthritis were treated with upadacitinib in the Phase 3 clinical trials of whom 2806 were exposed for at least one year.

Patients could advance or switch to RINVOQ 15 mg from placebo, or be rescued to RINVOQ from active comparator or placebo from as early as Week 12 depending on the trial design.

A total of 2630 patients received at least 1 dose of RINVOQ 15 mg, of whom 1860 were exposed for at least one year. In trials RA-I, RA-II, RA-III and RA-V, 1213 patients received at least 1 dose of RINVOQ 15 mg, of which 986 patients were exposed for at least one year, and 1203 patients received at least 1 dose of upadacitinib 30 mg, of which 946 were exposed for at least one year.

Table 1: Adverse Reactions Reported in ≥ 1% of Rheumatoid Arthritis Patients Treated with RINVOQ 15 mg in Placebo-controlled Trials Placebo

RINVOQ 15 mg

Adverse Reaction n=1042 (%)

n=1035 (%)

Upper respiratory tract infection (URTI)*

9.5

13.5

Nausea

2.2

3.5

Cough

1.0

2.2

Pyrexia

0

1.2

*URTI includes: acute sinusitis, laryngitis, nasopharyngitis, oropharyngeal pain, pharyngitis, pharyngotonsillitis, rhinitis, sinusitis, tonsillitis, viral upper respiratory tract infection Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg group and at a higher rate than in the placebo group through Week 12 included pneumonia, herpes zoster, herpes simplex (includes oral herpes), and oral candidiasis.

Four integrated datasets are presented in the Specific Adverse Reaction section: Placebo-controlled Trials: Trials RA-III, RA-IV, and RA-V were integrated to represent safety through 12/14 weeks for placebo (n=1042) and RINVOQ 15 mg (n=1035). Trials RA-III and RA-V were integrated to represent safety through 12 weeks for placebo (n=390), RINVOQ 15 mg (n=385), and upadacitinib 30 mg (n=384). Trial RA-IV did not include the 30 mg dose and, therefore, safety data for upadacitinib 30 mg can only be compared with placebo and RINVOQ 15 mg rates from pooling trials RA-III and RA-V. MTX-controlled Trials: Trials RA-I and RA-II were integrated to represent safety through 12/14 weeks for MTX (n=530), RINVOQ 15 mg (n=534), and upadacitinib 30 mg (n=529).

12-Month Exposure Dataset: Trials RA-I, II, III, and V were integrated to represent the long-term safety of RINVOQ 15 mg (n=1213) and upadacitinib 30 mg (n=1203).

Exposure adjusted incidence rates were adjusted by trial for all the adverse events reported in this section.

Specific Adverse Reactions Infections Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, infections were reported in 218 patients (95.7 per 100 patient-years) treated with placebo and 284 patients (127.8 per 100 patient-years) treated with RINVOQ 15 mg.

In RA-III and RA-V, infections were reported in 99 patients (136.5 per 100 patient-years) treated with placebo, 118 patients (164.5 per 100 patient-years) treated with RINVOQ 15 mg, and 126 patients (180.3 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Trials: Infections were reported in 127 patients (119.5 per 100 patient-years) treated with MTX monotherapy, 104 patients (91.8 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 128 patients (115.1 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Infections were reported in 615 patients (83.8 per 100 patient-years) treated with RINVOQ 15 mg and 674 patients (99.7 per 100 patient-years) treated with upadacitinib 30 mg.

Serious Infections Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, serious infections were reported in 6 patients (2.3 per 100 patient-years) treated with placebo, and 12 patients (4.6 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, serious infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg, and 7 patients (8.2 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Trials: Serious infections were reported in 2 patients (1.6 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 8 patients (6.4 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Serious infections were reported in 38 patients (3.5 per 100 patient-years) treated with RINVOQ 15 mg and 59 patients (5.6 per 100 patient-years) treated with upadacitinib 30 mg.

The most frequently reported serious infections were pneumonia and cellulitis.

Tuberculosis Placebo-controlled Trials and MTX-controlled Trials: In the placebo-controlled period, there were no active cases of tuberculosis reported in the placebo, RINVOQ 15 mg, and upadacitinib 30 mg groups.

In the MTX-controlled period, there were no active cases of tuberculosis reported in the MTX monotherapy, RINVOQ 15 mg monotherapy, and upadacitinib 30 mg monotherapy groups.

12-Month Exposure Dataset: Active tuberculosis was reported for 2 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg.

Cases of extra-pulmonary tuberculosis were reported.

Opportunistic Infections (excluding tuberculosis) Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, opportunistic infections were reported in 3 patients (1.2 per 100 patient-years) treated with placebo, and 5 patients (1.9 per 100 patient-years) treated with RINVOQ 15 mg.

In RA-III and RA-V, opportunistic infections were reported in 1 patient (1.2 per 100 patient-years) treated with placebo, 2 patients (2.3 per 100 patient-years) treated with RINVOQ 15 mg, and 6 patients (7.1 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Trials: Opportunistic infections were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 0 patients treated with RINVOQ 15 mg monotherapy, and 4 patients (3.2 per 100 patient-years) treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Opportunistic infections were reported in 7 patients (0.6 per 100 patient-years) treated with RINVOQ 15 mg and 15 patients (1.4 per 100 patient-years) treated with upadacitinib 30 mg.

Malignancies Placebo-controlled Trials: In RA-III, RA-IV, and RA-V, malignancies excluding NMSC were reported in 1 patient (0.4 per 100 patient-years) treated with placebo, and 1 patient (0.4 per 100 patient-years) treated with RINVOQ 15 mg. In RA-III and RA-V, malignancies excluding NMSC were reported in 0 patients treated with placebo, 1 patient (1.1 per 100 patient-years) treated with RINVOQ 15 mg, and 3 patients (3.5 per 100 patient-years) treated with upadacitinib 30 mg.

MTX-controlled Trials: Malignancies excluding NMSC were reported in 1 patient (0.8 per 100 patient-years) treated with MTX monotherapy, 3 patients (2.4 per 100 patient-years) treated with RINVOQ 15 mg monotherapy, and 0 patients treated with upadacitinib 30 mg monotherapy.

12-Month Exposure Dataset: Malignancies excluding NMSC were reported in 13 patients (1.2 per 100 patient-years) treated with RINVOQ 15 mg and 14 patients (1.3 per 100 patient-years) treated with upadacitinib 30 mg.

Gastrointestinal Perforations Placebo-controlled Trials: There were no gastrointestinal perforations (based on medical review) reported in patients treated with placebo, RINVOQ 15 mg, and upadacitinib 30 mg.

MTX-controlled Trials: There were no cases of gastrointestinal perforations reported in the MTX and RINVOQ 15 mg group through 12/14 weeks. Two cases of gastrointestinal perforations were observed in the upadacitinib 30 mg group.

12-Month Exposure Dataset: Gastrointestinal perforations were reported in 1 patient treated with RINVOQ 15 mg and 4 patients treated with upadacitinib 30 mg.

Thrombosis Placebo-controlled Trials: In RA-IV, venous thrombosis (pulmonary embolism or deep vein thrombosis) was observed in 1 patient treated with placebo and 1 patient treated with RINVOQ 15 mg. In RA-V, venous thrombosis was observed in 1 patient treated with RINVOQ 15 mg. There were no observed cases of venous thrombosis reported in RA-III. No cases of arterial thrombosis were observed through 12/14 weeks.

MTX-controlled Trials: In RA-II, venous thrombosis was observed in 0 patients treated with MTX monotherapy, 1 patient treated with RINVOQ 15 mg monotherapy and 0 patients treated with upadacitinib 30 mg monotherapy through Week 14. In RA-II, no cases of arterial thrombosis were observed through 12/14 weeks. In RA-I, venous thrombosis was observed in 1 patient treated with MTX, 0 patients treated with RINVOQ 15 mg and 1 patient treated with upadacitinib 30 mg through Week 24. In RA-I, arterial thrombosis was observed in 1 patient treated with upadacitinib 30 mg through Week 24.

12-Month Exposure Dataset: Venous thrombosis events were reported in 5 patients (0.5 per 100 patient-years) treated with RINVOQ 15 mg and 4 patients (0.4 per 100 patient-years) treated with upadacitinib 30 mg. Arterial thrombosis events were reported in 0 patients treated with RINVOQ 15 mg and 2 patients (0.2 per 100 patient-years) treated with upadacitinib 30 mg.

Laboratory Abnormalities Hepatic Transaminase Elevations In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, alanine transaminase (ALT) and aspartate transaminase (AST) elevations ≥ 3 x upper limit of normal (ULN) in at least one measurement were observed in 2.1% and 1.5% of patients treated with RINVOQ 15 mg, and in 1.5% and 0.7% of patients treated with placebo, respectively. In RA-III and RA-V, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 1.0% of patients treated with RINVOQ 15 mg, 1.0% and 0% of patients treated with upadacitinib 30 mg and in 1.3% and 1.0% of patients treated with placebo, respectively.

In MTX-controlled trials, for up to 12/14 weeks, ALT and AST elevations ≥ 3 x ULN in at least one measurement were observed in 0.8% and 0.4% of patients treated with RINVOQ 15 mg, 1.7% and 1.3% of patients treated with upadacitinib 30 mg and in 1.9% and 0.9% of patients treated with MTX, respectively.

Lipid Elevations Upadacitinib treatment was associated with dose-related increases in total cholesterol, triglycerides and LDL cholesterol. Upadacitinib was also associated with increases in HDL cholesterol. Elevations in LDL and HDL cholesterol peaked by Week 8 and remained stable thereafter. In controlled trials, for up to 12/14 weeks, changes from baseline in lipid parameters in patients treated with RINVOQ 15 mg and upadacitinib 30 mg, respectively, are summarized below: • Mean LDL cholesterol increased by 14.81 mg/dL and 17.17 mg/dL. • Mean HDL cholesterol increased by 8.16 mg/dL and 9.01 mg/dL. • The mean LDL/HDL ratio remained stable.

• Mean triglycerides increased by 13.55 mg/dL and 14.44 mg/dL. Creatine Phosphokinase Elevations In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related increases in creatine phosphokinase (CPK) values were observed. CPK elevations > 5 x ULN were reported in 1.0%, and 0.3% of patients over 12/14 weeks in the RINVOQ 15 mg and placebo groups, respectively. Most elevations >5 x ULN were transient and did not require treatment discontinuation. In RA-III and RA-V, CPK elevations > 5 x ULN were observed in 0.3% of patients treated with placebo, 1.6% of patients treated with RINVOQ 15 mg, and none in patients treated with upadacitinib 30 mg.

Neutropenia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in neutrophil counts, below 1000 cells/mm3 in at least one measurement occurred in 1.1% and <0.1% of patients in the RINVOQ 15 mg and placebo groups, respectively. In RA-III and RA-V, decreases in neutrophil counts below 1000 cells/mm3 in at least one measurement occurred in 0.3% of patients treated with placebo, 1.3% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg. In clinical trials, treatment was interrupted in response to ANC less than 1000 cells/mm3.

Lymphopenia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, dose-related decreases in lymphocyte counts below 500 cells/mm3 in at least one measurement occurred in 0.9% and 0.7% of patients in the RINVOQ 15 mg and placebo groups, respectively.

In RA-III and RA-V, decreases in lymphocyte counts below 500 cells/mm3

in at least one measurement occurred in 0.5% of patients treated with placebo, 0.5% of patients treated with RINVOQ 15 mg, and 2.4% of patients treated with upadacitinib 30 mg.

Anemia In placebo-controlled trials (RA-III, RA-IV, and RA-V) with background DMARDs, for up to 12/14 weeks, hemoglobin decreases below 8 g/dL in at least one measurement occurred in <0.1% of patients in both the RINVOQ 15 mg and placebo groups. In RA-III and RA-V, hemoglobin decreases below 8 g/dL in at least one measurement were observed in 0.3% of patients treated with placebo, and none in patients treated with RINVOQ 15 mg and upadacitinib 30 mg.

Adverse Reactions in Patients with Psoriatic Arthritis A total of 1827 patients with psoriatic arthritis were treated with upadacitinib in clinical studies representing 1639.2 patient-years of exposure, of whom 722 were exposed to upadacitinib for at least one year. In the two Phase 3 studies, 907 patients received at least 1 dose of RINVOQ 15 mg, of whom 359 were exposed for at least one year.

Two placebo-controlled studies were integrated (640 patients on RINVOQ 15 mg once daily and 635 patients on placebo) to evaluate the safety of RINVOQ 15 mg in comparison to placebo for up to 24 weeks after treatment initiation.

Overall, the safety profile observed in patients with active psoriatic arthritis treated with RINVOQ 15 mg was consistent with the safety profile observed in patients with rheumatoid arthritis. During the 24-week placebo-controlled period, the frequencies of herpes zoster and herpes simplex were >1% (1.1% and 1.4%, respectively) with RINVOQ 15 mg and 0.8% and 1.3%, respectively with placebo. A higher incidence of acne and bronchitis was also observed in patients treated with RINVOQ 15 mg (1.3% and 3.9%, respectively) compared to placebo (0.3% and 2.7%, respectively).

Adverse Reactions in Patients with Atopic Dermatitis Three Phase 3 (AD-1, AD-2, and AD-3) and one Phase 2b (AD-4) randomized, double-blind, placebo-controlled, multicenter trials evaluated the safety of RINVOQ in patients with moderate-to-severe atopic dermatitis.

The majority of patients were White (68%) and male (57%). The mean age was 34 years (ranged from 12 to 75 years) and 13% of the patients were 12 to less than 18 years. In these 4 trials, 2612 patients were treated with RINVOQ 15 mg or 30 mg orally once daily, with or without concomitant topical corticosteroids (TCS).

In the Phase 3 clinical trials (AD-1, AD-2, and AD-3), a total of 1239 patients received RINVOQ 15 mg, of whom 791 were exposed for at least one year and 1246 patients received RINVOQ 30 mg, of whom 826 were exposed for at least one year.

Trials AD-1, AD-2, and AD-4 compared the safety of RINVOQ monotherapy to placebo through Week 16. Trial AD-3 compared the safety of RINVOQ + TCS to placebo + TCS through Week 16.

Weeks 0 to 16 (Trials AD-1 to AD-4) In RINVOQ trials with and without TCS (Trials AD-1, 2, 3 and 4) through Week 16, the proportion of patients who discontinued treatment because of adverse reactions in the RINVOQ 15 mg, 30 mg and placebo groups were 2.3%, 2.9% and 3.8%, respectively. Table 2 summarizes the adverse reactions that occurred at a rate of at least 1% in the RINVOQ 15 mg or 30 mg groups during the first 16 weeks of treatment.

Table 2: Adverse Reactions Reported in ≥ 1% of Patients with Atopic Dermatitis Treated with RINVOQ 15 mg or 30 mg Adverse Reaction

Placebo RINVOQ RINVOQ 15 mg 30 mg n=902 (%)

n=899 (%)

n=906 (%)

Upper respiratory tract infection (URTI)*

17

23

25

Acne**

2

10

16

Herpes simplex***

2

4

8

Headache

4

6

6

Increased blood creatine phosphokinase

2

5

6

Cough

1

3

3

Hypersensitivity****

2

2

3

Folliculitis

1

2

3

Nausea

1

3

3

Abdominal pain*****

1

3

2

Pyrexia

1

2

2

Increased Weight

1

2

2

Herpes zoster******

1

2

2

Influenza

<1

2

2

Fatigue

1

1

2

Neutropenia

<1

1

2

Myalgia

1

1

2

Influenza like illness

1

1

2

* Includes: laryngitis, laryngitis viral, nasopharyngitis, oropharyngeal pain, pharyngeal abscess, pharyngitis, pharyngitis streptococcal, pharyngotonsillitis, respiratory tract infection, respiratory tract infection viral, rhinitis, rhinolaryngitis, sinusitis, tonsillitis, tonsillitis bacterial, upper respiratory tract infection, viral pharyngitis, viral upper respiratory tract infection ** Includes: acne and dermatitis acneiform *** Includes: genital herpes, genital herpes simplex, herpes dermatitis, herpes ophthalmic, herpes simplex, nasal herpes, ophthalmic herpes simplex, herpes virus infection, oral herpes **** Includes anaphylactic reaction, anaphylactic shock, angioedema, dermatitis exfoliative generalized, drug hypersensitivity, eyelid oedema, face oedema, hypersensitivity, periorbital swelling, pharyngeal swelling, swelling face, toxic skin eruption, type I hypersensitivity, urticaria ***** Includes abdominal pain and abdominal pain upper ****** Includes herpes zoster and varicella Other adverse reactions reported in less than 1% of patients in the RINVOQ 15 mg and/or 30 mg group and at a higher rate than in the placebo group through Week 16 included anemia, oral candidiasis, pneumonia, and the adverse event of retinal detachment.

The safety profile of RINVOQ through Week 52 was generally consistent with the safety profile observed at Week 16.

Overall, the safety profile observed in patients with AD treated with RINVOQ was similar to the safety profile in patients with RA. Other specific adverse reactions that were reported in patients with AD included eczema herpeticum/Kaposi’s varicelliform eruption.

Eczema Herpeticum/Kaposi’s Varicelliform Eruption Placebo-controlled Period (16 weeks): Eczema herpeticum was reported in 4 patients (1.6 per 100 patient-years) treated with placebo, 6 patients (2.2 per 100 patient-years) treated with RINVOQ 15 mg and 7 patients (2.6 per 100 patient-years) treated with RINVOQ 30 mg.

12-Month Exposure (Weeks 0 to 52): Eczema herpeticum was reported in 18 patients (1.6 per 100 patient-years) treated with RINVOQ 15 mg and 17 patients (1.5 per 100 patient-years) treated with RINVOQ 30 mg.

Adverse Reactions in Patients with Ulcerative Colitis RINVOQ was studied up to 8 weeks in patients with moderately to severely active ulcerative colitis in two randomized, double-blind, placebo-controlled induction studies (UC-1, UC-2) and a randomized, double-blind, placebo controlled, dose-finding study (UC-4; NCT02819635). Long term safety up to 52-weeks was evaluated in patients who responded to induction therapy in a randomized, double-blind, placebo-controlled maintenance study (UC-3) and a long-term extension study.

In the two induction studies (UC-1, UC-2) and a dose finding study (UC-4), 1097 patients were enrolled of whom 719 patients received RINVOQ 45 mg once daily.

In the maintenance study (UC-3), 746 patients were enrolled of whom 250 patients received RINVOQ 15 mg once daily and 251 patients received RINVOQ 30 mg once daily.

Adverse reactions reported in ≥2% of patients in any treatment arm in the induction and maintenance studies are shown in Tables 3 and 4, respectively.

Table 3. Adverse Reactions Reported in ≥2% of Patients with Ulcerative Colitis Treated with RINVOQ 45 mg in Placebo-Controlled Induction Studies (UC-1, UC-2 and UC-4) Placebo

RINVOQ 45 mg Once Daily

N= 378 (%)

N = 719 (%)

Upper respiratory tract infection*

7

9

Acne*

1

6

Increased blood creatine phosphokinase

1

5

Neutropenia*

<1

5

Rash*

1

4

Elevated liver enzymes**

2

3

Lymphopenia*

1

3

Folliculitis

1

2

Herpes simplex*

<1

2

Adverse Reaction

* Composed of several similar terms ** Elevated liver enzymes composed of elevated ALT, AST, GGT, ALP, liver transaminases, hepatic enzymes, bilirubin, drug-induced liver injury and cholestasis.

Other adverse reactions reported in less than 2% of patients in the RINVOQ 45 mg group and at a higher rate than in the placebo group through Week 8 included herpes zoster and pneumonia.

Table 4. Adverse Reactions Reported in ≥2% of Patients with Ulcerative Colitis Treated with RINVOQ 15 mg or 30 mg in the Placebo-Controlled Maintenance Study (UC-3)1

Adverse Reaction

Placebo

RINVOQ RINVOQ 15 mg Once 30 mg Once Daily Daily

n = 245 (%)

n = 250 (%)

n = 251 (%)

Upper respiratory tract infection*

18

16

20

Increased blood creatine phosphokinase

2

6

8

Neutropenia*

2

3

6

Elevated liver enzymes**

1

6

4

Rash*

4

5

5

Herpes zoster

0

4

4

Folliculitis

2

2

4

Hypercholesterolemia*

1

2

4

Influenza

1

3

3

Herpes simplex*

1

2

3

Lymphopenia*

2

3

2

Hyperlipidemia*

0

2

2

1 Patients who were responders to 8 weeks induction therapy with RINVOQ 45 mg once daily * Composed of several similar terms ** Elevated liver enzymes composed of elevated ALT, AST, GGT, ALP, liver transaminases, hepatic enzymes, bilirubin, drug-induced liver injury, and cholestasis.

The safety profile of RINVOQ in the long-term extension study was similar to the safety profile observed in the placebo-controlled induction and maintenance periods.

Overall, the safety profile observed in patients with ulcerative colitis treated with RINVOQ was generally similar to the safety profile in patients with RA and AD.

Specific Adverse Reactions Serious Infections Induction Studies: In UC-1, UC-2, and UC-4, serious infections were reported in 5 patients (8.4 per 100 patient-years) treated with placebo and 9 patients (8.4 per 100 patient-years) treated with RINVOQ 45 mg through 8 weeks.

Placebo-controlled Maintenance Study: In UC-3, serious infections were reported in 8 patients (6.3 per 100 patient-years) treated with placebo, 8 patients (4.5 per 100 patient-years) treated with RINVOQ 15 mg, and 6 patients (3.1 per 100 patient-years) treated with RINVOQ 30 mg through 52 weeks.

Laboratory Abnormalities Hepatic Transaminase Elevations In studies UC-1, UC-2, and UC-4, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 1.5% of patients treated with RINVOQ 45 mg, and 0% of patients treated with placebo for 8 weeks. AST elevations to ≥ 3 x ULN occurred in 1.5% of patients treated with RINVOQ 45 mg, and 0.3% of patients treated with placebo. Elevations of ALT to ≥ 5 x ULN occurred in 0.4% of patients treated with RINVOQ 45 mg and 0% of patients treated with placebo.

In UC-3, elevations of ALT to ≥ 3 x ULN in at least one measurement were observed in 4% of patients treated with RINVOQ 30 mg, 2% of patients treated with RINVOQ 15 mg, and 0.8% of patients treated with placebo for 52 weeks. Elevations of AST to ≥ 3 x ULN in at least one measurement were observed in 2% of patients treated with RINVOQ 30 mg, 1.6% of patients treated with RINVOQ 15 mg and 0.4% of patients treated with placebo.

Elevations of ALT to ≥ 5 x ULN were observed in 0.8% of patients treated with 30 mg, 0.4% of patients treated with 15 mg, and 0.4% of patients treated with placebo.

Overall, laboratory abnormalities observed in patients with ulcerative colitis treated with RINVOQ were similar to those described in patients with RA. DRUG INTERACTIONS Strong CYP3A4 Inhibitors Upadacitinib exposure is increased when RINVOQ is co-administered with a strong CYP3A4 inhibitor (such as ketoconazole and clarithromycin), which may increase the risk of RINVOQ adverse reactions. Monitor patients closely for adverse reactions when co-administering RINVOQ 15 mg once daily with strong CYP3A4 inhibitors.

For patients with atopic dermatitis, coadministration of RINVOQ 30 mg once daily with strong CYP3A4 inhibitors is not recommended.

For patients with ulcerative colitis taking strong CYP3A4 inhibitors, reduce the RINVOQ induction dosage to 30 mg once daily. The recommended maintenance dosage is 15 mg once daily.

Strong CYP3A4 Inducers Upadacitinib exposure is decreased when RINVOQ is co-administered with strong CYP3A4 inducers (such as rifampin), which may lead to reduced therapeutic effect of RINVOQ. Coadministration of RINVOQ with strong CYP3A4 inducers is not recommended.

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary Available data from the pharmacovigilance safety database and postmarketing case reports on use of RINVOQ in pregnant women are not sufficient to evaluate a drug-associated risk for major birth defects or miscarriage. Based on animal studies, RINVOQ has the potential to adversely affect a developing fetus. Advise patients of reproductive potential and pregnant patients of the potential risk to the fetus.

In animal embryo-fetal development studies, oral upadacitinib administration to pregnant rats and rabbits at exposures equal to or greater than approximately 1.6 and 15 times the 15 mg dose, 0.8 and 7.6 times the 30 mg dose, and 0.6 and 5.6 times the maximum recommended human dose (MRHD) of 45 mg (on an AUC basis) resulted in dose-related increases in skeletal malformations (rats only), an increased incidence of cardiovascular malformations (rabbits only), increased post-implantation loss (rabbits only), and decreased fetal body weights in both rats and rabbits. No developmental toxicity was observed in pregnant rats and rabbits treated with oral upadacitinib during organogenesis at exposures approximately 0.29 and 2.2 times the 15 mg dose, 0.15 times and 1.1 times the 30 mg dose, and at 0.11 and 0.82 times the MHRD (on an AUC basis).

In a pre- and post-natal development study in pregnant female rats, oral upadacitinib administration at exposures approximately 3 times the 15 mg dose, 1.4 times the 30 mg dose, and the same as the MRHD (on an AUC basis) resulted in no maternal or developmental toxicity (see Data).

The background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriages are 2-4% and 15-20%, respectively.

Report pregnancies to the AbbVie Inc.’s Adverse Event reporting line at 1-888-633-9110, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data Animal Data In an oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 5, 25, and 75 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that consisted of misshapen humerus and bent scapula) at exposures equal to or greater than approximately 1.7 times the 15 mg dose, 0.9 times the 30 mg dose, and 0.6 times the MRHD (on an AUC basis at maternal oral doses of 5 mg/kg/day and higher). Additional skeletal malformations (bent forelimbs/hindlimbs and rib/vertebral defects) and decreased fetal body weights were observed in the absence of maternal toxicity at an exposure approximately 84 times the 15 mg dose, 43 times the 30 mg dose, and 31 times the MRHD (on an AUC basis at a maternal oral dose of 75 mg/kg/day).

In a second oral embryo-fetal development study, pregnant rats received upadacitinib at doses of 1.5 and 4 mg/kg/day during the period of organogenesis from gestation day 6 to 17. Upadacitinib was teratogenic (skeletal malformations that included bent humerus and scapula) at

exposures approximately 1.6 times the 15 mg dose, 0.8 times the 30 mg dose, and 0.6 times the MRHD (on an AUC basis at maternal oral doses of 4 mg/kg/day). No developmental toxicity was observed in rats at an exposure approximately 0.29 times the 15 mg dose, 0.15 times the 30 mg dose, and 0.11 times the MRHD (on an AUC basis at a maternal oral dose of 1.5 mg/kg/day).

In an oral embryo-fetal developmental study, pregnant rabbits received upadacitinib at doses of 2.5, 10, and 25 mg/kg/day during the period of organogenesis from gestation day 7 to 19. Embryolethality, decreased fetal body weights, and cardiovascular malformations were observed in the presence of maternal toxicity at an exposure approximately 15 times the 15 mg dose, 7.6 times the 30 mg dose, and 5.6 times the MRHD (on an AUC basis at a maternal oral dose of 25 mg/kg/day). Embryolethality consisted of increased post-implantation loss that was due to elevated incidences of both total and early resorptions. No developmental toxicity was observed in rabbits at an exposure approximately 2.2 times the 15 mg dose, 1.1 times the 30 mg dose, and 0.82 times the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

In an oral pre- and post-natal development study, pregnant female rats received upadacitinib at doses of 2.5, 5, and 10 mg/kg/day from gestation day 6 through lactation day 20. No maternal or developmental toxicity was observed in either mothers or offspring, respectively, at an exposure approximately 3 times the 15 mg dose, 1.4 times the 30 mg dose, and at approximately the same exposure as the MRHD (on an AUC basis at a maternal oral dose of 10 mg/kg/day).

Lactation Risk Summary There are no data on the presence of upadacitinib in human milk, the effects on the breastfed infant, or the effects on milk production. Available pharmacodynamic/toxicological data in animals have shown excretion of upadacitinib in milk (see Data). When a drug is present in animal milk, it is likely that the drug will be present in human milk. Because of the potential for serious adverse reactions in the breastfed infant, advise patients that breastfeeding is not recommended during treatment with RINVOQ, and for 6 days (approximately 10 half-lives) after the last dose.

Data A single oral dose of 10 mg/kg radiolabeled upadacitinib was administered to lactating female Sprague-Dawley rats on post-partum days 7-8. Drug exposure was approximately 30-fold greater in milk than in maternal plasma based on AUC0-t values. Approximately 97% of drug-related material in milk was parent drug.

Females and Males of Reproductive Potential Pregnancy Testing Verify the pregnancy status of females of reproductive potential prior to starting treatment with RINVOQ [see Use in Specific Populations].

Contraception Females Based on animal studies, upadacitinib may cause embryo-fetal harm when administered to pregnant women [see Use in Specific Populations]. Advise female patients of reproductive potential to use effective contraception during treatment with RINVOQ and for 4 weeks after the final dose.

Pediatric Use Juvenile Idiopathic Arthritis and Psoriatic Arthritis The safety and effectiveness of RINVOQ in pediatric patients with juvenile idiopathic arthritis and psoriatic arthritis have not been established.

Atopic Dermatitis The safety and effectiveness of RINVOQ in pediatric patients 12 years of age and older weighing at least 40 kg with atopic dermatitis have been established. A total of 344 pediatric patients aged 12 to 17 years with moderate to severe atopic dermatitis were randomized across three trials (AD-1, AD-2 and AD-3) to receive either RINVOQ 15 mg (N=114) or 30 mg (N=114) or matching placebo (N=116) in monotherapy or combination with topical corticosteroids. Efficacy was consistent between the pediatric patients and adults. The adverse reaction profile in the pediatric patients was similar to the adults [see Adverse Reactions].

The safety and effectiveness of RINVOQ in pediatric patients less than 12 years of age with atopic dermatitis have not been established.

Ulcerative Colitis The safety and effectiveness of RINVOQ in pediatric patients with ulcerative colitis have not been established.

Geriatric Use Rheumatoid Arthritis and Psoriatic Arthritis Of the 4381 patients treated in the five clinical studies, a total of 906 rheumatoid arthritis patients were 65 years of age or older, including 146 patients 75 years and older. Of the 1827 patients treated in the two psoriatic arthritis Phase 3 clinical studies, a total of 274 patients were 65 years of age or older, including 34 patients 75 years and older. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of overall adverse events, including serious infections, in patients 65 years of age and older.

Atopic Dermatitis Of the 2583 patients treated in the three Phase 3 clinical trials, a total of 120 patients with atopic dermatitis were 65 years of age or older, including 6 patients 75 years of age. No differences in effectiveness were observed between these patients and younger patients; however, there was a higher rate of serious infections and malignancies in those patients 65 years of age or older in the 30 mg dosing group in the long-term trials.

Ulcerative Colitis Of the 1097 patients treated in the controlled clinical trials, a total of 95 patients with ulcerative colitis were 65 years and older. Clinical studies of RINVOQ did not include sufficient numbers of patients 65 years of age and older with ulcerative colitis to determine whether they respond differently from younger adult patients.

Renal Impairment For patients with rheumatoid arthritis and psoriatic arthritis, no dosage adjustment is needed in patients with mild (eGFR 60 to < 90 mL/min/1.73 m2), moderate (eGFR 30 to < 60 mL/min/1.73 m2), or severe renal impairment (eGFR 15 to < 30 mL/min/1.73 m2).

For patients with atopic dermatitis, the maximum recommended dosage is 15 mg once daily for patients with severe renal impairment. No dosage adjustment is needed in patients with mild or moderate renal impairment.

For patients with ulcerative colitis, the recommended dosage for severe renal impairment is 30 mg once daily for induction and 15 mg once daily for maintenance. No dosage adjustment is needed in patients with mild or moderate renal impairment.

RINVOQ has not been studied in patients with end stage renal disease (eGFR <15 mL/min/1.73m2). Use in patients with atopic dermatitis or ulcerative colitis with end stage renal disease is not recommended.

Hepatic Impairment The use of RINVOQ has not been studied in patients with severe hepatic impairment (Child Pugh C), and therefore not recommended for use in patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis or ulcerative colitis.

For patients with rheumatoid arthritis, psoriatic arthritis, atopic dermatitis, no dosage adjustment is needed in patients with mild (Child Pugh A) or moderate (Child Pugh B) hepatic impairment.

For patients with ulcerative colitis, the recommended dosage for mild to moderate hepatic impairment is 30 mg once daily for induction and 15 mg once daily for maintenance.

PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Serious Infections Inform patients that they may be more likely to develop infections when taking RINVOQ. Instruct patients to contact their healthcare provider immediately during treatment if they develop any signs or symptoms of an infection [see Warnings and Precautions].

Advise patients that the risk of herpes zoster is increased in patients taking RINVOQ and in some cases can be serious [see Warnings and Precautions].

Malignancies Inform patients that RINVOQ may increase their risk of certain cancers and that periodic skin examinations should be performed while using RINVOQ. Advise patients that exposure to sunlight and UV light should be limited by wearing protective clothing and using a broad-spectrum sunscreen [see Warnings and Precautions].

Major Adverse Cardiovascular Events Inform patients that RINVOQ may increase their risk of major adverse cardiovascular events (MACE) including myocardial infarction, stroke, and cardiovascular death. Instruct all patients, especially current or past smokers or patients with other cardiovascular risk factors, to be alert for the development of signs and symptoms of cardiovascular events [see Warnings and Precautions].

Thrombosis Inform patients that events of deep venous thrombosis and pulmonary embolism have been reported in clinical trials with RINVOQ. Instruct patients to seek immediate medical attention if they develop any signs or symptoms of a DVT or PE [see Warnings and Precautions].

Hypersensitivity Reactions Advise patients to discontinue RINVOQ and seek immediate medical attention if they develop any signs and symptoms of allergic reactions [see Warnings and Precautions].

Gastrointestinal Perforations Inform patients that gastrointestinal perforations have been reported in clinical trials with RINVOQ and that risk factors include the use of NSAIDS or history of diverticulitis. Instruct patients to seek medical care immediately if they experience new onset of abdominal pain, fever, chills, nausea, or vomiting [see Warnings and Precautions].

Retinal Detachment Inform patients that retinal detachment has been reported in clinical trials with RINVOQ. Advise patients to immediately inform their healthcare provider if they develop any sudden changes in vision while receiving RINVOQ [see Adverse Reactions].

Laboratory Abnormalities Inform patients that RINVOQ may affect certain lab tests, and that blood tests are required before and during RINVOQ treatment [see Warnings and Precautions].

Vaccinations Advise patients to avoid use of live vaccines with RINVOQ. Instruct patients to inform their healthcare practitioner that they are taking RINVOQ prior to a potential vaccination [see Warnings and Precautions].

Embryo-Fetal Toxicity Advise pregnant women and females of reproductive potential that exposure to RINVOQ during pregnancy may result in fetal harm. Advise females to inform their healthcare provider of a known or suspected pregnancy [see Warnings and Precautions and Use in Specific Populations].

Advise females of reproductive potential that effective contraception should be used during treatment and for 4 weeks following the final dose of upadacitinib [see Use in Specific Populations].

Advise females patients who are exposed to RINVOQ during pregnancy to contact AbbVie Inc. at 1-800-633-9110 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Lactation Advise women not to breastfeed during treatment with RINVOQ and for 6 days after the last dose [see Use in Specific Populations].

Administration Advise patients not to chew, crush, or split RINVOQ tablets.

Manufactured by: AbbVie Ireland NL B.V., Sligo, Ireland Packed and Distributed by: AbbVie Inc., North Chicago, IL 60064 RINVOQ® is a registered trademark of AbbVie Biotechnology Ltd. ©2019-2022 AbbVie Inc. Ref: 20070589 Revised: March 2022 LAB-6843 MASTER

US-RNQG-210160

CASO CLÍNICO

MIOCARDIOPATÍA HIPERTRÓFICA OBSTRUCTIVA Running Head: Mitral Annular Calcification in HOCM Lara Gharibeh1,2,#,PhD, Kenza Rahmouni1,#,MD, Andrew M Crean3,MD, Javier Castillo4,MD, Juan B Grau1,5,*,MD 1Division of Cardiac Surgery, University of Ottawa Heart Institute, Ottawa, Canada. 2Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.

3Division of Cardiology, University of Ottawa Heart Institute, Ottawa, Canada.

4Hyspanic Valve Center, Puerto Rico, USA. 5Division of Cardiothoracic Surgery, The Valley Hospital, Ridgewood, NJ, USA. #Drs Gharibeh, Rahmouni and Grau contributed equally to this work.

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RESUMEN El manejo de pacientes con miocardiopatía hipertrófica obstructiva (HOCM) y calcificación anular mitral severa puede ser un desafío. Nuestros casos resaltan la importancia de abordar todos los elementos que contribuyen a la obstrucción del tracto de salida del ventrículo izquierdo (TSVI) en casos de HOCM: tabique interventricular basal hipertrófico, músculos papilares anormales, movimiento anterior sistólico de la válvula mitral anterior.

Direccionamiento la reparación de la válvula mitral a través de la aortotomía, mediante la realización de una miectomía septal, realineamiento del músculo papilar y resección de cuerdas tendinosas aberrantes, permite corregir con éxito la obstrucción del TSVI y el movimiento sistólico anterior. El éxito de estos procedimientos dependía de las imágenes preoperatorias y la provocación intraoperatoria.

ABSTRACT Management of patients with hypertrophic obstructive cardiomyopathy (HOCM) and severe mitral annular calcification, can be challenging. Our cases highlight the importance of addressing all elements contributing to the left ventricular outflow tract (LVOT) obstruction in cases of HOCM: hypertrophic basal interventricular septum, abnormal papillary muscles, systolic anterior motion of the anterior mitral valve leaflet. Addressing the mitral valve repair through the aortotomy, by performing a septal myectomy, papillary muscle realignment, and a resection of aberrant chordae tendineae, allows LVOT obstruction and systolic anterior motion to be successfully corrected. The success of these procedures depended on pre-operative imaging and intra-operative provocation.

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FIGURE 1.

Pre-, intra- and post-operative imaging in patient_1.

Three-chamber MRI images in diastole (A) and systole (B) demonstrating normal appearances in diastole but high signal in the LVOT (black asterisk) together with SAM (arrow) in late systole. This view also shows low signal MAC (white asterisk). MAC (black asterisks) is more easily recognized on cardiac CT seen in short axis (C) and on volume-rendered images (D).

(E) Intra-operative transesophageal echocardiography image showing a long axis view of the LV, with high resting LVOT velocities (white arrow). The black arrow shows severe eccentric mitral regurgitation. (F) Post-operative cardiac CT in systole, notable for the lack of SAM (black arrow). Compared to the position of the leaflet in panel B, there is no longer any dynamic obstruction of the outflow tract. LA:Left atrium.

LV:Left ventricle. LVOT:Left ventricular outflow tract. MAC:Mitral annular calcification.

SAM:Systolic anterior motion.

Hypertrophic cardiomyopathy has a prevalence of 0.2%[1]. When left ventricular outflow tract (LVOT) obstruction occurs (gradient >30mmHg), the condition is known as hypertrophic obstructive cardiomyopathy (HOCM)[2]. When medical therapies fail, surgical intervention is indicated[3].

In HOCM patients, several elements, including the anterior leaflet of the mitral valve, the sub-valvular mitral val40

ve (MV) apparatus, and the hypertrophic septum, contribute to the LVOT obstruction[4].

Surgical management should address each one of them[5].

In rare cases, HOCM patients can present with concomitant Mitral Annular Calcification (MAC) presenting a significant challenge for the MV repair portion of this operation[6].

We present our experience in managing two HOCM patients with severe conco-

Revista Puertorriqueña de Medicina y Salud Pública

mitant MAC. A multidisciplinary HOCM heart team has proved to be invaluable in the pre-operative planning of these two cases.

CASE REPORTS Patient 1 Patient_1 was a 75-year-old female with pulmonary hypertension, hypothyroidism, and severe dyspnea. Pre-operative cardiac magnetic resonance imaging (MRI) and computed tomography (CT) demonstra-

ted a maximal septal thickness of 19mm and severe MAC(Fig.1). A pre-operative transesophageal echocardiogram (TEE) at rest demonstrated severe mitral insufficiency with a posteriorly directed jet, and severe LVOT obstruction caused by systolic anterior motion (SAM)(Fig.1). Her resting LVOT gradient was 95mmHg and 160mmHg during Valsalva.

After medical therapy failed, she was referred for surgical management.

AMVL Anterior Motion of CT HOCM LVOT MAC MR MRI MV SAM TEE TTE

the Anterior Valve Computed Tomography Hypertrophic Obstructive Cardiomyopathy Left Ventricular Outflow Tract Mitral Annular Calcification Mitral Regurgitation Magnetic Resonance Imaging Mitral Valve Systolic Anterior Motion Transesophageal Echocardiogram Transthoracic Echocardiogram

Patient 2 Patient_2 was a 73-year-old female with hypothyroidism and recurrent syncope.

A pre-operative transthoracic echocardiogram (TTE) revealed LVOT obstruction with a resting gradient of 34mmHg and 68mmHg with Valsalva. A subsequent stress TEE showed definite SAM with moderate eccentric mitral regurgitation (MR). Her maximum LVOT gradient during stress echo was 239mmHg. Cardiac CT and MRI both confirmed the diagnosis of HOCM with a maximal septal thickness of 17mm, and severe MAC(Fig.2). After failure of medical therapy, patient_2 was referred for surgical management.

Both patients underwent provocative measures intra-operatively(Fig. 1 and 2). Patient_1 underwent a 3-stage procedure with extended septal myectomy, resection of two ectopic chordae with anomalous insertion onto the body of the AMVL, and mobilization and realignment of the anterolateral papillary muscle group towards the posterior-medial group. Patient_1 required resection of 3 fibroelastomas from the aortic valve that were incidentally found on TEE(Video). A post-procedural TEE with isoproterenol and nitroglycerin provocation showed a peak LVOT gradient of 8mmHg (13mmHg with provocation) (Fig.1). Patient_2 had the same operation plus a resection of an anomalous papillary muscle(Fig.2). His post-procedural TEE showed a peak LVOT gradient of 10mmHg (20mmHg after provocation). In both cases, The MAC involved not only the mitral annulus but extended towards the posterior wall of the left ventricle. By approaching the MV repair through the aortic valve, we were able to completely avoid the area of the MAC. The degree of mitral insufficiency in both of these patients post-operatively was trace, with complete resolution of the SAM.

Patient_1 and Patient_2 had an uneventful hospital course with excellent results(Fig.1 and 2). In the past year, both patients have been followed in the HOCM clinic and remained in New York Heart association class I. COMMENT Patients with HOCM display a wide range of phenotypes[7]. Careful pre-operative evaluation by a multidisciplinary team addressing the septal thickness, AMVL motion, and papillary muscle position, using regular TTE, cine-CT scan, coronary angiography, and cardiac MRI, was essential for surgical planning. Intra-operative TEE and dynamic testing of these patients allowed us to measure the maximum LVOT gradient, and confirmed the presence of basal septal hypertrophy, torrential MR, and severe SAM with abnormal tethering of the AMVL. In all HOCM patients, the surgical procedure should appropriately address every element involved in the LVOT obstruction.

In these 2 cases, a basal hypertrophy was corrected by an extended myectomy. In addition, intervention on the MV apparatus was necessary as it was a crucial contributor in the mechanism of the LVOT obstruction[8]. The MV interventions were performed through the aortic valve and included a posterior realignment of the anterior-lateral papillary muscles, and a resection of aberrant chordae to the AMVL. Due to the presence of MAC, the anterior posterior diameter of the annulus was already fixed by the calcium and intervention at this level was not necessary to complete the MV repair portion of the operation.

In conclusion, we present two HOCM cases with severe MAC treated safely with septal myectomy, resection of accessory papillary muscles and papillary muscle realignment, in addition to a resection of aberrant chordae tendinea based on accurate pre-operative testing and intra-operative provocation maneuvers. Both patients had excellent short-term and 1-year post-operative outcomes.

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FIGURE 2.

Pre- and intra-operative imaging uncovering severe mitral regurgitation in patient_2. (A) Three-chamber MRI imaging demonstrating multi-level obstruction with jets arising at the LVOT (white asterisk) and the aortic valve (black asterisk).

Stationary tissue can be subtracted using phase contrast cine imaging (B) where the same jets can be appreciated.

Since the LVOT jet (white asterisk) is somewhat denser, this is the more dominant of the 2 levels of obstruction. Pre-operative CT imaging (C) demonstrates SAM (white arrow), and the secondary failure of coaptation of the mitral valve (black arrow). (D) Volume-rendered cardiac CT showing severe MAC (black asterisks).

(E) Resting intra-operative transesophageal echocardiogram image demonstrating significant LVOT flow acceleration (black asterisk). (F) Isoproterenol infusion is used to increase ventricular inotropy, worsening the degree of mitral regurgitation (white arrow), as the LVOT obstruction progresses. (G) At higher doses of isoproterenol, the mitral regurgitation (white arrow) becomes torrential.

LA:Left atrium. LVOT:Left ventricular outflow tract. SAM:Systolic anterior motion.

REFERENCES [1] Wang S, Cui H, Yu Q, Chen H, Zhu C, Wang J, et al. Excision of anomalous muscle bundles as an important addition to extended septal myectomy for treatment of left ventricular outflow tract obstruction. J Thorac Cardiovasc Surg 2016;152:461–8.

[2] Veselka J, Anavekar NS, Charron P. Hypertrophic obstructive cardiomyopathy. Lancet 2017;389:1253–67.

[3] Solomon Z, Breton C, 42

Rowin EJ, Maron BJ, Maron MS, Chen FY, et al. Surgical Approaches to Hypertrophic Obstructive Cardiomyopathy.

Semin Thorac Cardiovasc Surg 2018;30:125–8. [4] Ogunmuyiwa O, Rellecke P, Lichtenberg A, Assmann A. Muscular Mitral Chord Contribution to Left Ventricular Outflow Tract Obstruction in HOCM. Thorac Cardiovasc Surg Rep 2019;8:e18–9.

[5] Swistel DG, Sherrid MV. The surgical management of obstructive hypertrophic car-

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diomyopathy: the RPR procedure—resection, plication, release. Ann Cardiothorac Surg 2017;6:423–5.

[6] Patlolla Sri Harsha, Schaff Hartzell, Meghji Zahara, Geske Jeffrey, Dearani Joseph, Nishimura Rick A., et al. Impact of mitral annular calcification in patients with obstructive hypertrophic cardiomyopathy. Journal of the American College of Cardiology 2020;75:893– 893. [7] Kotkar KD, Said SM, Dearani JA, Schaff HV. Hyper-

trophic obstructive cardiomyopathy: the Mayo Clinic experience. Ann Cardiothorac Surg 2017;6:329–36.

[8] Song HK, Turner J, Macfie R, Kumar S, Mannello MJ, Smith D, et al. Routine Papillary Muscle Realignment and Septal Myectomy for Obstructive Hypertrophic Cardiomyopathy. Ann Thorac Surg 2018;106:670–5.

NOW APPROVED FOR

ADULTS WITH ACTIVE ANKYLOSING SPONDYLITIS (AS)1

XELJANZ IS THE FIRST AND ONLY ORAL JAKi APPROVED FOR 5 INDICATIONS: RA, PsA, UC, pcJIA, AND NOW FOR AS1,a a

Study pcJIA-I included patients with active polyarthritis, including RF negative, RF positive, extended oligoarthritis, systemic JIA without systemic manifestations, as well as jPsA and ERA patients.1

INDICATIONS Ankylosing Spondylitis • XELJANZ®/XELJANZ® XR (tofacitinib) is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Rheumatoid Arthritis • XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Psoriatic Arthritis • XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Ulcerative Colitis • XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Polyarticular Course Juvenile Idiopathic Arthritis • XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ Oral Solution in combination with biologic DMARDs or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

IMPORTANT SAFETY INFORMATION SERIOUS INFECTIONS Patients treated with XELJANZ* are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy. Treatment for latent infection should be initiated prior to XELJANZ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis.

Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis.

Avoid use of XELJANZ in patients with an active, serious infection, including localized infections.

In the UC population, XELJANZ 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection, or those who have lived or traveled in areas of endemic TB or mycoses. Viral reactivation including herpes virus and hepatitis B reactivation have been reported. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infection.

*Unless otherwise stated, “XELJANZ” in the Important Safety Information refers to XELJANZ, XELJANZ XR, and XELJANZ Oral Solution.

Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages or at XELJANZPI.com.

AFTER AN INADEQUATE RESPONSE OR INTOLERANCE TO TNF BLOCKERS IN ADULTS WITH ACTIVE AS,1 START WITH XELJANZ

Significant ASAS20 response at week 16 (primary endpoint) vs placebo with rapid response as early as week 21,2,b: – 56% of patients receiving XELJANZ 5 mg BID (N=133) vs 29% receiving placebo (N=136) at week 16 (P<0.0001)1,c – 29% of patients receiving XELJANZ 5 mg BID (N=133) vs 10% receiving placebo (N=136) at week 2 (P<0.0001)1,2,d

Significant ASAS40 response at week 16 (key secondary endpoint) vs placebo1,b: – 41% of patients receiving XELJANZ 5 mg BID (N=133) vs 13% receiving placebo (N=136) (P<0.0001)1,c

EXPERIENCE XELJANZ

– The first and only oral JAK inhibitor approved for 5 indications: RA, PsA, AS, UC, and pcJIA1

SAFETY

– XELJANZ contains a BOXED WARNING for Serious Infections, Mortality, Malignancies, Major Adverse Cardiovascular Events, and Thrombosis1 For all data, estimates are generated based on normal approximation adjusting for the stratification factor of treatment history via the CMH approach using on-treatment data, where missing responses were treated as nonresponses.2 c P≤0.05 vs placebo, according to the prespecified step-down testing procedure for type I error control.2 d P≤0.05 vs placebo, according to the prespecified step-down testing procedure for type I error control of ASAS response over time.2 ASAS consists of 4 domains (each scored from 0 to 10): patient global assessment of disease, total back pain, function, and inflammation.1,2 ASAS20 response was defined as ≥20% and ≥1 unit improvement in at least 3 domains on a scale of 0 to 10 and no worsening of ≥20% and ≥1 unit in the remaining domain.2 ASAS40 response was defined as ≥40% and ≥2 units improvement in at least 3 domains on a scale of 0 to 10 and no worsening in the remaining domain.2

b

IMPORTANT SAFETY INFORMATION (cont’d) MORTALITY In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular (CV) risk factor comparing XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden CV death, was observed with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

MALIGNANCIES Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day compared with TNF blockers.

Lymphoma and lung cancers were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. A XELJANZ 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. Other malignancies were observed in clinical studies and the postmarketing setting including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer. NMSCs have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. MAJOR ADVERSE CARDIOVASCULAR EVENTS (MACE) RA patients 50 years of age and older with at least one CV risk factor, treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily, had a higher rate

of MACE (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ in patients that have experienced a myocardial infarction or stroke.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients who are current or past smokers and patients with other CV risk factors. Inform patients about the symptoms of serious CV events. A XELJANZ 10 mg twice a day (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. THROMBOSIS Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one CV risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events. Avoid XELJANZ in patients at risk. Discontinue XELJANZ and promptly evaluate patients with symptoms of thrombosis.

A XELJANZ 10 mg twice daily (or XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. In a long-term extension study in UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer. For UC, use XELJANZ at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

GASTROINTESTINAL PERFORATIONS Gastrointestinal perforations have been reported in XELJANZ clinical trials, although the role of JAK inhibition is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). There was no discernible difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background

XELJANZ IS THE FIRST ORAL JAKi FDA-APPROVED FOR ACTIVE AS1

Study Design1-3

A randomized, double-blind, placebo-controlled, 48-week clinical trial in 269 adult patients with active AS who had an inadequate response (inadequate clinical response or intolerance) to ≥2 NSAIDs. Approximately 80% of the population were to be bDMARD-naïve, and approximately 20% were to have an IR to ≤2 TNF blockers or to have prior bDMARD (TNF blocker or non-TNF blocker) use without IR. XELJANZ is approved for use in patients with an inadequate response or intolerance to TNF blockers. Patients were randomized and treated with XELJANZ 5 mg BID or placebo for 16 weeks of blinded treatment and then all received treatment of XELJANZ 5 mg BID for additional 32 weeks. At baseline, 207 patients were bDMARD-naïve and 62 patients were TNF blocker-IR or bDMARD users (non-IR).

NSAIDs/COX-2 inhibitors, MTX, sulfasalazine, or oral corticosteroids were allowed if patients were on a stable dosage at baseline. Approximately 7% and 21% of patients used concomitant MTX or sulfasalazine, respectively from baseline to week 16. 22% of patients had an inadequate response to 1 or 2 TNF blockers. The mean age of patients in the trial was 41.1 years, and most patients were male (83.3%). Patients in the trial had a mean disease duration of 13.5 years since onset of AS symptoms, mean disease duration since diagnosis of 7.8 years, and a mean BASDAI score of 6.5 at baseline.

The primary endpoint was to evaluate the proportion of patients who achieved an ASAS20 response at week 16. To control for type I error at the 5% level for primary and certain secondary endpoints, 4 families of efficacy endpoints were tested in hierarchical sequences with a step-down approach. The first family, the global type I error–controlled endpoints at week 16, included: ASAS20 response; ASAS40 response; ∆ASDAS(CRP); ∆hsCRP; and ∆BASMI. Upon meeting statistical significance for ASAS20 response at week 16, the second family included ∆ASAS components at week 16, and included testing for ∆total back pain. The third family, ASAS20 response over time, and the fourth family, ASAS40 response over time, were each tested in the following sequence: weeks 16, 12, 8, 4, and 2. In each family, statistical significance could be declared only if the prior endpoint (or time point) in the sequence met the requirements for significance. Nonresponder imputation was applied to missing data for ASAS response rates.

IMPORTANT SAFETY INFORMATION (cont’d) GASTROINTESTINAL PERFORATIONS (cont’d) corticosteroids. XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).

HYPERSENSITIVITY Angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ and some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

LABORATORY ABNORMALITIES Lymphocyte Abnormalities: Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean lymphocyte counts. Avoid initiation of XELJANZ treatment in patients with a count less than 500 cells/mm3. In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ is not recommended. Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia: Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo. Avoid initiation of XELJANZ treatment in patients with an ANC less than 1000 cells/mm3. For patients who develop a persistent ANC of 500-1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended. Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia: Avoid initiation of XELJANZ treatment in patients with a hemoglobin level less than 9 g/dL. Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment. Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations: Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded. Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury.

Lipid Elevations: Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/ HDL cholesterol ratios. Manage patients with hyperlipidemia according to clinical guidelines. Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

VACCINATIONS Avoid use of live vaccines concurrently with XELJANZ. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents. Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

PATIENTS WITH GASTROINTESTINAL NARROWING Caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing. There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended-release formulation.

HEPATIC and RENAL IMPAIRMENT Use of XELJANZ in patients with severe hepatic impairment is not recommended.

For patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 5 mg twice daily or XELJANZ XR 11 mg once daily, reduce to XELJANZ 5 mg once daily. For UC patients with moderate hepatic impairment or with moderate or severe renal impairment taking XELJANZ 10 mg twice daily, reduce to XELJANZ 5 mg twice daily. If taking XELJANZ XR 22 mg once daily, reduce to XELJANZ XR 11 mg once daily.

ADVERSE REACTIONS The most common serious adverse reactions were serious infections. The most commonly reported adverse reactions during the first 3 months in controlled clinical trials in patients with RA with XELJANZ 5 mg twice daily and placebo, respectively, (occurring in greater than or equal to 2% of patients treated with XELJANZ with or without DMARDs) were upper respiratory tract infection, nasopharyngitis, diarrhea, headache, and hypertension. The safety profile observed in patients with active PsA treated with XELJANZ was consistent with the safety profile observed in RA patients.

Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials for UC were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

USE IN PREGNANCY Available data with XELJANZ use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy. In animal studies, tofacitinib at 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings.

The relevance of these findings to women of childbearing potential is uncertain.

Consider pregnancy planning and prevention for females of reproductive potential.

∆=change from baseline; AS=ankylosing spondylitis; ASAS=Assessment of SpondyloArthritis international Society; ASDAS(CRP)=Ankylosing Spondylitis Disease Activity Score based on C-reactive protein; BASDAI=Bath Ankylosing Spondylitis Disease Activity Index; BASMI=Bath Ankylosing Spondylitis Metrology Index; bDMARD=biologic disease-modifying antirheumatic drug; BID=twice daily; CMH=Cochrane-Mantel-Haenszel; COX-2=cyclooxygenase 2; CV=cardiovascular; DMARD=disease-modifying antirheumatic drug; ERA=enthesitis-related arthritis; hsCRP=high-sensitivity C-reactive protein; IR=inadequate response; JAK=Janus kinase; JAKi=Janus kinase inhibitor; JIA=juvenile idiopathic arthritis; jPsA=juvenile psoriatic arthritis; MTX=methotrexate; NSAID=nonsteroidal anti-inflammatory drug; pcJIA=polyarticular course juvenile idiopathic arthritis; PsA=psoriatic arthritis; RA=rheumatoid arthritis; RF=rheumatoid factor; TNF=tumor necrosis factor; UC=ulcerative colitis; XR=extended release.

References: 1. XELJANZ [prescribing information]. New York, NY: Pfizer Inc., January 2022. 2. Deodhar A, Sliwinska-Stanczyk P, Xu H, et al. Tofacitinib for the treatment of ankylosing spondylitis: a phase III, randomised, double-blind, placebo-controlled study. Ann Rheum Dis. 2021;80:1004-1013. doi:10.1136/annrheumdis-2020-219601 3. Data on file. Pfizer Inc., New York, NY.

Please see Brief Summary of full Prescribing Information, including BOXED WARNING, on the following pages or at XELJANZPI.com.

PP-XEL-USA-7543-01

© 2022 Pfizer Inc.

All rights reserved.

March 2022

XELJANZ® (tofacitinib)/XELJANZ XR/XELJANZ Oral Solution WARNING: SERIOUS INFECTIONS, MORTALITY, MALIGNANCY, MAJOR ADVERSE CARDIOVASCULAR EVENTS, AND THROMBOSIS SERIOUS INFECTIONS Patients treated with XELJANZ* are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids.

If a serious infection develops, interrupt XELJANZ until the infection is controlled.

Reported infections include: • Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before XELJANZ use and during therapy.Treatment for latent infection should be initiated prior to XELJANZ use.

• Invasive fungal infections, including cryptococcosis and pneumocystosis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.

• Bacterial, viral, including herpes zoster, and other infections due to opportunistic pathogens.

The risks and benefits of treatment with XELJANZ should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

MORTALITY In a large, randomized, postmarketing safety study in rheumatoid arthritis (RA) patients 50 years of age and older with at least one cardiovascular risk factor comparing XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day to tumor necrosis factor (TNF) blockers, a higher rate of all-cause mortality, including sudden cardiovascular death, was observed with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day. A XELJANZ/ XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. MALIGNANCIES Malignancies, including lymphomas and solid tumors, have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. In RA patients, a higher rate of malignancies (excluding NMSC) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day compared with TNF blockers.

Lymphomas and lung cancers were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day in RA patients compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk.

Epstein Barr Virus-associated post-transplant lymphoproliferative disorder has been observed at an increased rate in renal transplant patients treated with XELJANZ and concomitant immunosuppressive medications.

MAJOR ADVERSE CARDIOVASCULAR EVENTS RA patients 50 years of age and older with at least one cardiovascular risk factor, treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily, had a higher rate of major adverse cardiovascular events (MACE) (defined as cardiovascular death, myocardial infarction, and stroke), compared to those treated with TNF blockers. Patients who are current or past smokers are at additional increased risk. Discontinue XELJANZ in patients that have experienced a myocardial infarction or stroke.

THROMBOSIS Thrombosis, including pulmonary embolism, deep venous thrombosis, and arterial thrombosis have occurred in patients treated with XELJANZ and other Janus kinase inhibitors used to treat inflammatory conditions. Many of these events were serious and some resulted in death. RA patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily compared to TNF blockers had an observed increase in incidence of these events.

Avoid XELJANZ in patients at risk. Discontinue XELJANZ and promptly evaluate patients with symptoms of thrombosis.

INDICATIONS AND USAGE Rheumatoid Arthritis XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic disease-modifying antirheumatic drugs (DMARDs) or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Psoriatic Arthritis XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active psoriatic arthritis (PsA) who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Ankylosing Spondylitis XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with active ankylosing spondylitis (AS) who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Ulcerative Colitis XELJANZ/XELJANZ XR is indicated for the treatment of adult patients with moderately to severely active ulcerative colitis (UC), who have an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/XELJANZ XR in combination with biological therapies for UC or with potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

Polyarticular Course Juvenile Idiopathic Arthritis XELJANZ/XELJANZ Oral Solution is indicated for the treatment of active polyarticular course juvenile idiopathic arthritis (pcJIA) in patients 2 years of age and older who have had an inadequate response or intolerance to one or more TNF blockers.

• Limitations of Use: Use of XELJANZ/ XELJANZ Oral Solution in combination with biologic DMARDs or potent immunosuppressants such as azathioprine and cyclosporine is not recommended.

CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Serious Infections Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, or other opportunistic pathogens have been reported in patients receiving XELJANZ. The most common serious infections reported with XELJANZ included pneumonia, cellulitis, herpes zoster, urinary tract infection, diverticulitis, and appendicitis. Among opportunistic infections, tuberculosis and other mycobacterial infections, cryptococcosis, histoplasmosis, esophageal candidiasis, pneumocystosis, multidermatomal herpes zoster, cytomegalovirus infections, BK virus infection, and listeriosis were reported with XELJANZ. Some patients have presented with disseminated rather than localized disease, and were often taking concomitant immunomodulating agents such as methotrexate or corticosteroids.

In the UC population, XELJANZ treatment with 10 mg twice daily was associated with greater risk of serious infections compared to 5 mg twice daily. Additionally, opportunistic herpes zoster infections (including meningoencephalitis, ophthalmologic, and disseminated cutaneous) were seen in patients who were treated with XELJANZ 10 mg twice daily.

Other serious infections that were not reported in clinical studies may also occur (e.g., coccidioidomycosis).

Avoid use of XELJANZ in patients with an active, serious infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating XELJANZ in patients: • with chronic or recurrent infection • who have been exposed to tuberculosis • with a history of a serious or an opportunistic infection • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or • with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with XELJANZ. XELJANZ should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with XELJANZ should undergo prompt and complete diagnostic testing appropriate for an immunocompromised patient; appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Caution is also recommended in patients with a history of chronic lung disease, or in those who develop interstitial lung disease, as they may be more prone to infections.

Risk of infection may be higher with increasing degrees of lymphopenia and consideration should be given to lymphocyte counts when assessing individual patient risk of infection. Discontinuation and monitoring criteria for lymphopenia are recommended.

Tuberculosis Patients should be evaluated and tested for latent or active infection prior to and per applicable guidelines during administration of XELJANZ. Anti-tuberculosis therapy should also be considered prior to administration of XELJANZ in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but who have risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision about whether initiating antituberculosis therapy is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis, including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

*Unless otherwise stated, “XELJANZ” in the brief summary refers to XELJANZ, XELJANZ XR, and XELJANZ Oral Solution.

BRIEF SUMMARY OF PRESCRIBING INFORMATION. SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION.

Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before administering XELJANZ. Viral Reactivation Viral reactivation, including cases of herpes virus reactivation (e.g., herpes zoster), were observed in clinical studies with XELJANZ. Postmarketing cases of hepatitis B reactivation have been reported in patients treated with XELJANZ. The impact of XELJANZ on chronic viral hepatitis reactivation is unknown. Patients who screened positive for hepatitis B or C were excluded from clinical trials. Screening for viral hepatitis should be performed in accordance with clinical guidelines before starting therapy with XELJANZ. The risk of herpes zoster is increased in patients treated with XELJANZ and appears to be higher in patients treated with XELJANZ in Japan and Korea.

Mortality Rheumatoid arthritis patients 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day had a higher observed rate of all-cause mortality, including sudden cardiovascular death, compared to those treated with TNF blockers in a large, randomized, postmarketing safety study (RA Safety Study 1). The incidence rate of all-cause mortality per 100 patient-years was 0.88 for XELJANZ 5 mg twice a day, 1.23 for XELJANZ 10 mg twice a day, and 0.69 for TNF blockers. Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ. A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS. For the treatment of UC, use XELJANZ/XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Malignancy and Lymphoproliferative Disorders Malignancies, including lymphomas and solid cancers, were observed in clinical studies of XELJANZ. In RA Safety Study 1, a higher rate of malignancies (excluding non-melanoma skin cancer (NMSC)) was observed in patients treated with XELJANZ 5 mg twice a day or XELJANZ 10 mg twice a day as compared with TNF blockers. The incidence rate of malignancies (excluding NMSC) per 100 patient-years was 1.13 for XELJANZ 5 mg twice a day, 1.13 for XELJANZ 10 mg twice a day, and 0.77 for TNF blockers. Patients who are current or past smokers are at additional increased risk.

Lymphomas and lung cancers, which are a subset of all malignancies in RA Safety Study 1, were observed at a higher rate in patients treated with XELJANZ 5 mg twice a day and XELJANZ 10 mg twice a day compared to those treated with TNF blockers. The incidence rate of lymphomas per 100 patient-years was 0.07 for XELJANZ 5 mg twice a day, 0.11 for XELJANZ 10 mg twice a day, and 0.02 for TNF blockers. The incidence rate of lung cancers per 100 patient-years among current and past smokers was 0.48 for XELJANZ 5 mg twice a day, 0.59 for XELJANZ 10 mg twice a day, and 0.27 for TNF blockers.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients with a known malignancy (other than a successfully treated NMSC), patients who develop a malignancy while on treatment, and patients who are current or past smokers. A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA. In Phase 2B, controlled dose-ranging trials in de-novo renal transplant patients, all of whom received induction therapy with basiliximab, high-dose corticosteroids, and mycophenolic acid products, Epstein Barr Virus-associated post-transplant lymphoproliferative disorder was observed in 5 out of 218 patients treated with XELJANZ (2.3%) compared to 0 out of 111 patients treated with cyclosporine.

Other malignancies were observed in clinical studies and the postmarketing setting, including, but not limited to, lung cancer, breast cancer, melanoma, prostate cancer, and pancreatic cancer.

Non-Melanoma Skin Cancer Non-melanoma skin cancers (NMSCs) have been reported in patients treated with XELJANZ. Periodic skin examination is recommended for patients who are at increased risk for skin cancer. In the UC population, treatment with XELJANZ 10 mg twice daily was associated with greater risk of NMSC. Major Adverse Cardiovascular Events In RA Safety Study 1, RA patients who were 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ 5 mg twice daily or XELJANZ 10 mg twice daily had a higher rate of major adverse cardiovascular events (MACE) defined as cardiovascular death, non-fatal myocardial infarction (MI), and non-fatal stroke, compared to those treated withTNF blockers.

The incidence rate of MACE per 100 patient-years was 0.91 for XELJANZ 5 mg twice a day, 1.11 for XELJANZ 10 mg twice a day, and 0.79 forTNF blockers.The incidence rate of fatal or non-fatal myocardial infarction per 100 patient-years was 0.36 for XELJANZ 5 mg twice a day, 0.39 for XELJANZ 10 mg twice a day, and 0.20 for TNF blockers. Patients who are current or past smokers are at additional increased risk.

Consider the benefits and risks for the individual patient prior to initiating or continuing therapy with XELJANZ, particularly in patients who are current or past smokers and patients with other cardiovascular risk factors. Patients should be informed about the symptoms of serious cardiovascular events and the steps to take if they occur. Discontinue XELJANZ in patients that have experienced a myocardial infarction or stroke. A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA or PsA.

Thrombosis Thrombosis, including pulmonary embolism (PE), deep venous thrombosis (DVT), and arterial thrombosis, have occurred in patients treated with XELJANZ and other Janus kinase (JAK) inhibitors used to treat inflammatory conditions.

Many of these events were serious and some resulted in death.

Patients with rheumatoid arthritis 50 years of age and older with at least one cardiovascular risk factor treated with XELJANZ at both 5 mg or 10 mg twice daily compared to TNF blockers in RA Safety Study 1 had an observed increase in incidence of these events. The incidence rate of DVT per 100 patient-years was 0.22 for XELJANZ 5 mg twice a day, 0.28 for XELJANZ 10 mg twice a day, and 0.16 for TNF blockers. The incidence rate of PE per 100 patient-years was 0.18 for XELJANZ 5 mg twice a day, 0.49 for XELJANZ 10 mg twice a day, and 0.05 for TNF blockers.

A XELJANZ/XELJANZ Oral Solution 10 mg twice daily (or a XELJANZ XR 22 mg once daily) dosage is not recommended for the treatment of RA, PsA, or AS. In a long-term extension study in patients with UC, five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one death in a patient with advanced cancer.

Promptly evaluate patients with symptoms of thrombosis and discontinue XELJANZ in patients with symptoms of thrombosis.

Avoid XELJANZ in patients that may be at increased risk of thrombosis. For the treatment of UC, use XELJANZ/ XELJANZ XR at the lowest effective dose and for the shortest duration needed to achieve/maintain therapeutic response.

Gastrointestinal Perforations Events of gastrointestinal perforation have been reported in clinical studies with XELJANZ, although the role of JAK inhibition in these events is not known. In these studies, many patients with rheumatoid arthritis were receiving background therapy with Nonsteroidal Anti-Inflammatory Drugs (NSAIDs).

There was no discernable difference in frequency of gastrointestinal perforation between the placebo and the XELJANZ arms in clinical trials of patients with UC, and many of them were receiving background corticosteroids.

XELJANZ should be used with caution in patients who may be at increased risk for gastrointestinal perforation (e.g., patients with a history of diverticulitis or taking NSAIDs).

Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation.

Hypersensitivity Reactions such as angioedema and urticaria that may reflect drug hypersensitivity have been observed in patients receiving XELJANZ/XELJANZ XR. Some events were serious. If a serious hypersensitivity reaction occurs, promptly discontinue tofacitinib while evaluating the potential cause or causes of the reaction.

Laboratory Abnormalities Lymphocyte Abnormalities Treatment with XELJANZ was associated with initial lymphocytosis at one month of exposure followed by a gradual decrease in mean absolute lymphocyte counts below the baseline of approximately 10% during 12 months of therapy. Lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Avoid initiation of XELJANZ treatment in patients with a low lymphocyte count (i.e., less than 500 cells/mm3).

In patients who develop a confirmed absolute lymphocyte count less than 500 cells/mm3, treatment with XELJANZ is not recommended.

Monitor lymphocyte counts at baseline and every 3 months thereafter.

Neutropenia Treatment with XELJANZ was associated with an increased incidence of neutropenia (less than 2000 cells/mm3) compared to placebo.

Avoid initiation of XELJANZ treatment in patients with a low neutrophil count (i.e., ANC less than 1000 cells/mm3).

For patients who develop a persistent ANC of 500 to 1000 cells/mm3, interrupt XELJANZ dosing until ANC is greater than or equal to 1000 cells/mm3. In patients who develop an ANC less than 500 cells/mm3, treatment with XELJANZ is not recommended.

Monitor neutrophil counts at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Anemia Avoid initiation of XELJANZ treatment in patients with a low hemoglobin level (i.e., less than 9 g/dL). Treatment with XELJANZ should be interrupted in patients who develop hemoglobin levels less than 8 g/dL or whose hemoglobin level drops greater than 2 g/dL on treatment.

Monitor hemoglobin at baseline and after 4-8 weeks of treatment and every 3 months thereafter.

Liver Enzyme Elevations Treatment with XELJANZ was associated with an increased incidence of liver enzyme elevation compared to placebo. Most of these abnormalities occurred in studies with background DMARD (primarily methotrexate) therapy.

Routine monitoring of liver tests and prompt investigation of the causes of liver enzyme elevations is recommended to identify potential cases of drug-induced liver injury. If drug-induced liver injury is suspected, the administration of XELJANZ should be interrupted until this diagnosis has been excluded.

Lipid Elevations Treatment with XELJANZ was associated with dose-dependent increases in lipid parameters including total cholesterol, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. Maximum

effects were generally observed within 6 weeks. There were no clinically relevant changes in LDL/HDL cholesterol ratios. The effect of these lipid parameter elevations on cardiovascular morbidity and mortality has not been determined.

Assessment of lipid parameters should be performed approximately 4-8 weeks following initiation of XELJANZ therapy.

Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

Vaccinations Avoid use of live vaccines concurrently with XELJANZ. The interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

A patient experienced dissemination of the vaccine strain of varicella zoster virus, 16 days after vaccination with live attenuated (Zostavax) virus vaccine and 2 days after treatment start with tofacitinib 5 mg twice daily. The patient was varicella virus naïve, as evidenced by no previous history of varicella infection and no anti-varicella antibodies at baseline. Tofacitinib was discontinued and the patient recovered after treatment with standard doses of antiviral medication.

Update immunizations in agreement with current immunization guidelines prior to initiating XELJANZ therapy.

Risk of Gastrointestinal Obstruction with a Non-Deformable Extended-Release Formulation such as XELJANZ XR As with any other non-deformable material, caution should be used when administering XELJANZ XR to patients with pre-existing severe gastrointestinal narrowing (pathologic or iatrogenic). There have been rare reports of obstructive symptoms in patients with known strictures in association with the ingestion of other drugs utilizing a non-deformable extended release formulation.

ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: • Serious Infections • Mortality • Malignancy and Lymphoproliferative Disorders • Major Adverse Cardiovascular Events • Thrombosis • Gastrointestinal Perforations • Hypersensitivity • Laboratory Abnormalities Clinical Trials Experience Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Rheumatoid Arthritis The clinical studies described in the following sections were conducted using XELJANZ. Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily. The recommended dose for XELJANZ XR is 11 mg once daily. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not a recommended regimen for the treatment of rheumatoid arthritis. In RA Safety Study 1, 1455 patients were treated with XELJANZ 5 mg twice daily, 1456 patients were treated with 10 mg twice daily, and 1451 patients were treated with a TNF blocker for a median of 4.0 years.

The following data includes two Phase 2 and five Phase 3 double-blind, placebo-controlled, multicenter trials. In these trials, patients were randomized to doses of XELJANZ 5 mg twice daily (292 patients) and 10 mg twice daily (306 patients) monotherapy, XELJANZ 5 mg twice daily (1044 patients) and 10 mg twice daily (1043 patients) in combination with DMARDs (including methotrexate) and placebo (809 patients). All seven placebo-controlled protocols included provisions for patients taking placebo to receive treatment with XELJANZ at Month 3 or Month 6 either by patient response (based on uncontrolled disease activity) or by design, so that adverse events cannot always be unambiguously attributed to a given treatment. Therefore, some analyses that follow include patients who changed treatment by design or by patient response from placebo to XELJANZ in both the placebo and XELJANZ group of a given interval. Comparisons between placebo and XELJANZ were based on the first 3 months of exposure, and comparisons between XELJANZ 5 mg twice daily and XELJANZ 10 mg twice daily were based on the first 12 months of exposure.

The long-term safety population includes all patients who participated in a double-blind, placebo-controlled trial (including earlier development phase studies) and then participated in one of two long-term safety studies.The design of the long-term safety studies allowed for modification of XELJANZ doses according to clinical judgment.This limits the interpretation of the long-term safety data with respect to dose.

The most common serious adverse reactions were serious infections.

The proportion of patients who discontinued treatment due to any adverse reaction during the 0 to 3 months exposure in the double-blind, placebo-controlled trials was 4% for patients taking XELJANZ and 3% for placebo-treated patients.

Overall Infections In the seven placebo-controlled trials, during the 0 to 3 months exposure, the overall frequency of infections was 20% and 22% in the 5 mg twice daily and 10 mg twice daily groups, respectively, and 18% in the placebo group.

The most commonly reported infections with XELJANZ were upper respiratory tract infections, nasopharyngitis, and urinary tract infections (4%, 3%, and 2% of patients, respectively).

Serious Infections In the seven placebo-controlled trials, during the 0 to 3 months exposure, serious infections were reported in 1 patient (0.5 events per 100 patient-years) who received placebo and 11 patients (1.7 events per 100 patient-years) who received XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 1.1 (-0.4, 2.5) events per 100 patient-years for the combined 5 mg twice daily and 10 mg twice daily XELJANZ group minus placebo.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, serious infections were reported in 34 patients (2.7 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 33 patients (2.7 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was -0.1 (-1.3, 1.2) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The most common serious infections included pneumonia, cellulitis, herpes zoster, and urinary tract infection.

Tuberculosis In the seven placebo-controlled trials, during the 0 to 3 months exposure, tuberculosis was not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven placebo-controlled trials, during the 0 to 12 months exposure, tuberculosis was reported in 0 patients who received 5 mg twice daily of XELJANZ and 6 patients (0.5 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.5 (0.1, 0.9) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. Cases of disseminated tuberculosis were also reported. The median XELJANZ exposure prior to diagnosis of tuberculosis was 10 months (range from 152 to 960 days).

Opportunistic Infections (excluding tuberculosis) In the seven placebo-controlled trials, during the 0 to 3 months exposure, opportunistic infections were not reported in patients who received placebo, 5 mg twice daily of XELJANZ, or 10 mg twice daily of XELJANZ. In the seven placebo-controlled trials, during the 0 to 12 months exposure, opportunistic infections were reported in 4 patients (0.3 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 4 patients (0.3 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0 (-0.5, 0.5) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. The median XELJANZ exposure prior to diagnosis of an opportunistic infection was 8 months (range from 41 to 698 days).

Malignancy In the seven placebo-controlled trials, during the 0 to 3 months exposure, malignancies excluding NMSC were reported in 0 patients who received placebo and 2 patients (0.3 events per 100 patient-years) who received either XELJANZ 5 mg or 10 mg twice daily. The rate difference between treatment groups (and the corresponding 95% confidence interval) was 0.3 (-0.1, 0.7) events per 100 patient-years for the combined 5 mg and 10 mg twice daily XELJANZ group minus placebo.

In the seven placebo-controlled trials, during the 0 to 12 months exposure, malignancies excluding NMSC were reported in 5 patients (0.4 events per 100 patient-years) who received 5 mg twice daily of XELJANZ and 7 patients (0.6 events per 100 patient-years) who received 10 mg twice daily of XELJANZ. The rate difference between XELJANZ doses (and the corresponding 95% confidence interval) was 0.2 (-0.4, 0.7) events per 100 patient-years for 10 mg twice daily XELJANZ minus 5 mg twice daily XELJANZ. One of these malignancies was a case of lymphoma that occurred during the 0 to 12 month period in a patient treated with XELJANZ 10 mg twice daily.

The most common types of malignancy, including malignancies observed during the long-term extension, were lung and breast cancer, followed by gastric, colorectal, renal cell, prostate cancer, lymphoma, and malignant melanoma.

Laboratory Abnormalities Lymphopenia In the placebo-controlled clinical trials, confirmed decreases in absolute lymphocyte counts below 500 cells/mm3 occurred in 0.04% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

Confirmed lymphocyte counts less than 500 cells/mm3 were associated with an increased incidence of treated and serious infections.

Neutropenia In the placebo-controlled clinical trials, confirmed decreases in ANC below 1000 cells/mm3 occurred in 0.07% of patients for the 5 mg twice daily and 10 mg twice daily XELJANZ groups combined during the first 3 months of exposure.

There were no confirmed decreases in ANC below 500 cells/mm3 observed in any treatment group.

There was no clear relationship between neutropenia and the occurrence of serious infections.

In the long-term safety population, the pattern and incidence of confirmed decreases in ANC remained consistent with what was seen in the placebo-controlled clinical trials.

Liver Enzyme Elevations Confirmed increases in liver enzymes greater than 3 times the upper limit of normal (3x ULN) were observed in patients treated with XELJANZ. In patients experiencing liver enzyme elevation,

modification of treatment regimen, such as reduction in the dose of concomitant DMARD, interruption of XELJANZ, or reduction in XELJANZ dose, resulted in decrease or normalization of liver enzymes.

In the placebo-controlled monotherapy trials (0-3 months), no differences in the incidence of ALT or AST elevations were observed between the placebo, and XELJANZ 5 mg, and 10 mg twice daily groups.

In the placebo-controlled background DMARD trials (0-3 months), ALT elevations greater than 3x ULN were observed in 1.0%, 1.3% and 1.2% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively. In these trials, AST elevations greater than 3x ULN were observed in 0.6%, 0.5% and 0.4% of patients receiving placebo, 5 mg, and 10 mg twice daily, respectively.

One case of drug-induced liver injury was reported in a patient treated with XELJANZ 10 mg twice daily for approximately 2.5 months. The patient developed symptomatic elevations of AST and ALT greater than 3x ULN and bilirubin elevations greater than 2x ULN, which required hospitalizations and a liver biopsy.

Lipid Elevations In the placebo-controlled clinical trials, dose-related elevations in lipid parameters (total cholesterol, LDL cholesterol, HDL cholesterol, triglycerides) were observed at one month of exposure and remained stable thereafter. Changes in lipid parameters during the first 3 months of exposure in the placebo-controlled clinical trials are summarized below: • Mean LDL cholesterol increased by 15% in the XELJANZ 5 mg twice daily arm and 19% in the XELJANZ 10 mg twice daily arm.

• Mean HDL cholesterol increased by 10% in the XELJANZ 5 mg twice daily arm and 12% in the XELJANZ 10 mg twice daily arm.

• Mean LDL/HDL ratios were essentially unchanged in XELJANZ-treated patients.

In a placebo-controlled clinical trial, elevations in LDL cholesterol and ApoB decreased to pretreatment levels in response to statin therapy.

In the long-term safety population, elevations in lipid parameters remained consistent with what was seen in the placebo-controlled clinical trials.

Serum Creatinine Elevations In the placebo-controlled clinical trials, dose-related elevations in serum creatinine were observed with XELJANZ treatment. The mean increase in serum creatinine was <0.1 mg/dL in the 12-month pooled safety analysis; however with increasing duration of exposure in the long-term extensions, up to 2% of patients were discontinued from XELJANZ treatment due to the protocol-specified discontinuation criterion of an increase in creatinine by more than 50% of baseline. The clinical significance of the observed serum creatinine elevations is unknown.

Other Adverse Reactions Adverse reactions occurring in 2% or more of patients on 5 mg twice daily or 10 mg twice daily XELJANZ and at least 1% greater than that observed in patients on placebo with or without DMARD are summarized in the following table.

Common Adverse Reactions* in Clinical Trials of XELJANZ for the Treatment of Rheumatoid Arthritis With or Without Concomitant DMARDs (0-3 Months)

Preferred Term Upper respiratory tract infection

XELJANZ 5 mg Twice Daily

XELJANZ 10 mg Twice Daily**

Placebo

N = 1336 (%)

N = 1349 (%)

N = 809 (%)

4

4

3

Nasopharyngitis

4

3

3

Diarrhea

4

3

2

Headache

4

3

2

Hypertension

2

2

1

N reflects randomized and treated patients from the seven placebo-controlled clinical trials. * reported in ≥2% of patients treated with either dose of XELJANZ and ≥1% greater than that reported for placebo. ** the recommended dose of XELJANZ for the treatment of rheumatoid arthritis is 5 mg twice daily.

Other adverse reactions occurring in placebo-controlled and open-label extension studies included: Blood and lymphatic system disorders: Anemia Infections and infestations: Diverticulitis Metabolism and nutrition disorders: Dehydration Psychiatric disorders: Insomnia Nervous system disorders: Paresthesia Respiratory, thoracic and mediastinal disorders: Dyspnea, cough, sinus congestion, interstitial lung disease (cases were limited to patients with rheumatoid arthritis and some were fatal) Gastrointestinal disorders: Abdominal pain, dyspepsia, vomiting, gastritis, nausea Hepatobiliary disorders: Hepatic steatosis Skin and subcutaneous tissue disorders: Rash, erythema, pruritus Musculoskeletal, connective tissue and bone disorders: Musculoskeletal pain, arthralgia, tendonitis, joint swelling Neoplasms benign, malignant and unspecified (including cysts and polyps): Non-melanoma skin cancers

General disorders and administration site conditions: Pyrexia, fatigue, peripheral edema Clinical Experience in Methotrexate-Naïve Patients Study RA-VI was an active-controlled clinical trial in methotrexate-naïve patients. The safety experience in these patients was consistent with Studies RA-I through V. Psoriatic Arthritis XELJANZ 5 mg twice daily and 10 mg twice daily were studied in 2 double-blind Phase 3 clinical trials in patients with active psoriatic arthritis (PsA). Although other doses of XELJANZ have been studied, the recommended dose of XELJANZ is 5 mg twice daily.

The recommended dose for XELJANZ XR is 11 mg once daily. A dosage of XELJANZ 10 mg twice daily or XELJANZ XR 22 mg once daily is not recommended for the treatment of PsA. Study PsA-I (NCT01877668) had a duration of 12 months and enrolled patients who had an inadequate response to a nonbiologic DMARD and who were naïve to treatment with a TNF blocker. Study PsA-I included a 3-month placebocontrolled period and also included adalimumab 40 mg subcutaneously once every 2 weeks for 12 months.

Study PsA-II (NCT01882439) had a duration of 6 months and enrolled patients who had an inadequate response to at least one approved TNF blocker. This clinical trial included a 3-month placebo-controlled period.

In these combined Phase 3 clinical trials, 238 patients were randomized and treated with XELJANZ 5 mg twice daily and 236 patients were randomized and treated with XELJANZ 10 mg twice daily. All patients in the clinical trials were required to receive treatment with a stable dose of a nonbiologic DMARD [the majority (79%) received methotrexate]. The study population randomized and treated with XELJANZ (474 patients) included 45 (9.5%) patients aged 65 years or older and 66 (13.9%) patients with diabetes at baseline.

During the 2 PsA controlled clinical trials, there were 3 malignancies (excluding NMSC) in 474 patients receiving XELJANZ plus non-biologic DMARD (6 to 12 months exposure) compared with 0 malignancies in 236 patients in the placebo plus non-biologic DMARD group (3 months exposure) and 0 malignancies in 106 patients in the adalimumab plus non-biologic DMARD group (12 months exposure). No lymphomas were reported. Malignancies have also been observed in the long-term extension study in psoriatic arthritis patients treated with XELJANZ. The safety profile observed in patients with active psoriatic arthritis treated with XELJANZ was consistent with the safety profile observed in rheumatoid arthritis patients.

Ankylosing Spondylitis XELJANZ 5 mg twice daily was studied in patients with active ankylosing spondylitis (AS) in a confirmatory double blind placebo-controlled Phase 3 clinical trial (Study AS-I) and in a dose ranging Phase 2 clinical trial (Study AS-II).

Study AS-I (NCT03502616) had a duration of 48 weeks and enrolled patients who had an inadequate response to at least 2 NSAIDs. Study AS I included a 16-week double-blind period in which patients received XELJANZ 5 mg or placebo twice daily and a 32-week open-label treatment period in which all patients received XELJANZ 5 mg twice daily.

Study AS-II (NCT01786668) had a duration of 16 weeks and enrolled patients who had an inadequate response to at least 2 NSAIDs. This clinical trial included a 12-week treatment period in which patients received either XELJANZ 2 mg, 5 mg, 10 mg, or placebo twice daily.

In the combined Phase 2 and Phase 3 clinical trials, a total of 420 patients were treated with either XELJANZ 2 mg, 5 mg, or 10 mg twice daily. Of these, 316 patients were treated with XELJANZ 5 mg twice daily for up to 48 weeks. In the combined double-blind period, 185 patients were randomized to and treated with XELJANZ 5 mg twice daily and 187 to placebo for up to 16 weeks. Concomitant treatment with stable doses of nonbiologic DMARDs, NSAIDs, or corticosteroids (≤10 mg/day) was permitted. The study population randomized and treated with XELJANZ included 13 (3.1%) patients aged 65 years or older and 18 (4.3%) patients with diabetes at baseline.

The safety profile observed in patients with AS treated with XELJANZ was consistent with the safety profile observed in RA and PsA patients.

Ulcerative Colitis XELJANZ has been studied in patients with moderately to severely active UC in 4 randomized, double-blind, placebo-controlled trials (UC-I, UC-II, UC-III, and dose-ranging UC-V) and an open-label long-term extension study (UC-IV).

Adverse reactions reported in ≥5% of patients treated with either 5 mg or 10 mg twice daily of XELJANZ and ≥1% greater than reported in patients receiving placebo in either the induction or maintenance clinical trials were: nasopharyngitis, elevated cholesterol levels, headache, upper respiratory tract infection, increased blood creatine phosphokinase, rash, diarrhea, and herpes zoster.

Induction Trials (Study UC-I, UC-II, and UC-V): Common adverse reactions reported in ≥2% of patients treated with XELJANZ 10 mg twice daily and ≥1% greater than that reported in patients receiving placebo in the 3 induction trials were: headache, nasopharyngitis, elevated cholesterol levels, acne, increased blood creatine phosphokinase, and pyrexia.

Maintenance Trial (Study UC-III) Common adverse reactions reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported in patients receiving placebo are shown in the following table.

Common Adverse Reactions* in -UC Patients during the MaintenanceTrial (Study UC-III) XELJANZ XELJANZ 5 mg 10 mg Twice Daily Twice Daily

Placebo

Preferred Term

N = 198 (%)

N = 196 (%)

N = 198 (%)

Nasopharyngitis

10

14

6

Elevated cholesterol levels**

5

9

1

Headache

9

3

6

Upper respiratory tract infection

7

6

4

Increased blood creatine phosphokinase

3

7

2

Rash

3

6

4

Diarrhea

2

5

3

Herpes zoster

1

5

1

Gastroenteritis

3

4

3

Anemia

4

2

2

Nausea

1

4

3

* reported in ≥4% of patients treated with either dose of XELJANZ and ≥1% greater than reported for placebo. ** includes hypercholesterolemia, hyperlipidemia, blood cholesterol increased, dyslipidemia, blood triglycerides increased, low density lipoprotein increased, low density lipoprotein abnormal, or lipids increased.

Dose-dependent adverse reactions seen in patients treated with XELJANZ 10 mg twice daily, in comparison to 5 mg twice daily, include the following: herpes zoster infections, serious infections, and NMSC. During the UC controlled clinical studies (8-week induction and 52-week maintenance studies), which included 1220 patients, 0 cases of solid cancer or lymphoma were observed in XELJANZ-treated patients.

In the long-term extension study, malignancies (including solid cancers, lymphomas and NMSC) were observed in patients treated with XELJANZ 5 mg and 10 mg twice daily.

Five cases of pulmonary embolism were reported in patients taking XELJANZ 10 mg twice daily, including one fatality in a patient with advanced cancer.

Polyarticular Course Juvenile Idiopathic Arthritis XELJANZ/XELJANZ Oral Solution 5 mg twice daily or weight-based equivalent twice daily was studied in 225 patients from 2 years to 17 years of age in Study pcJIA-I and one open-label extension study. The total patient exposure (defined as patients who received at least one dose of XELJANZ/XELJANZ Oral Solution) was 351 patient-years.

In general, the types of adverse drug reactions in patients with pcJIA were consistent with those seen in adult RA patients.

Postmarketing Experience The following adverse reactions have been identified during post-approval use of XELJANZ/XELJANZ XR. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Immune system disorders: Drug hypersensitivity (events such as angioedema and urticaria have been observed).

DRUG INTERACTIONS The table below includes drugs with clinically important drug interactions when administered concomitantly with XELJANZ and instructions for preventing or managing them.

Clinically Relevant Interactions Affecting XELJANZ When Coadministered with Other Drugs Strong CYP3A4 Inhibitors (e.g., ketoconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ is recommended

Moderate CYP3A4 Inhibitors Coadministered with Strong CYP2C19 Inhibitors (e.g., fluconazole) Clinical Impact

Increased exposure to tofacitinib

Intervention

Dosage adjustment of XELJANZ is recommended

Strong CYP3A4 Inducers (e.g., rifampin) Clinical Impact

Decreased exposure to tofacitinib and may result in loss of or reduced clinical response

Intervention

Coadministration with XELJANZ is not recommended

Immunosuppressive Drugs (e.g., azathioprine, tacrolimus, cyclosporine) Clinical Impact

Risk of added immunosuppression; coadministration with biologic DMARDs or potent immunosuppressants has not been studied in patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, UC, or pcJIA.

Intervention

Coadministration with XELJANZ is not recommended

USE IN SPECIFIC POPULATIONS All information provided in this section is applicable to XELJANZ as all contain the same active ingredient (tofacitinib).

Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to XELJANZ during pregnancy. Patients should be encouraged to enroll in the XELJANZ pregnancy registry if they become pregnant.To enroll or obtain information from the registry, patients can call the toll free number 1-877-311-8972.

Risk Summary Available data with XELJANZ use in pregnant women are insufficient to establish a drug associated risk of major birth defects, miscarriage or adverse maternal or fetal outcomes. There are risks to the mother and the fetus associated with rheumatoid arthritis and UC in pregnancy. In animal reproduction studies, fetocidal and teratogenic effects were noted when pregnant rats and rabbits received tofacitinib during the period of organogenesis at exposures multiples of 73-times and 6.3-times the maximum recommended dose of 10 mg twice daily, respectively.

Further, in a peri- and post-natal study in rats, tofacitinib resulted in reductions in live litter size, postnatal survival, and pup body weights at exposure multiples of approximately 73-times the recommended dose of 5 mg twice daily and approximately 36 times the maximum recommended dose of 10 mg twice daily, respectively.

The estimated background risks of major birth defects and miscarriage for the indicated populations are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. The background risks in the U.S. general population of major birth defects and miscarriages are 2 to 4% and 15 to 20% of clinically recognized pregnancies, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Published data suggest that increased disease activity is associated with the risk of developing adverse pregnancy outcomes in women with rheumatoid arthritis or ulcerative colitis. Adverse pregnancy outcomes include preterm delivery (before 37 weeks of gestation), low birth weight (less than 2500 g) infants, and small for gestational age at birth.

Data Animal Data In a rat embryofetal developmental study, in which pregnant rats received tofacitinib during organogenesis, tofacitinib was teratogenic at exposure levels approximately 146 times the recommended dose of 5 mg twice daily, and approximately 73 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 100 mg/kg/day in rats).

Teratogenic effects consisted of external and soft tissue malformations of anasarca and membranous ventricular septal defects, respectively; and skeletal malformations or variations (absent cervical arch; bent femur, fibula, humerus, radius, scapula, tibia, and ulna; sternoschisis; absent rib; misshapen femur; branched rib; fused rib; fused sternebra; and hemicentric thoracic centrum). In addition, there was an increase in post-implantation loss, consisting of early and late resorptions, resulting in a reduced number of viable fetuses. Mean fetal body weight was reduced. No developmental toxicity was observed in rats at exposure levels approximately 58 times the recommended dose of 5 mg twice daily, and approximately 29 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in pregnant rats).

In a rabbit embryofetal developmental study in which pregnant rabbits received tofacitinib during the period of organogenesis, tofacitinib was teratogenic at exposure levels approximately 13 times the recommended dose of 5 mg twice daily, and approximately 6.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 30 mg/kg/day in rabbits) in the absence of signs of maternal toxicity. Teratogenic effects included thoracogastroschisis, omphalocele, membranous ventricular septal defects, and cranial/skeletal malformations (microstomia, microphthalmia), mid-line and tail defects. In addition, there was an increase in post-implantation loss associated with late resorptions. No developmental toxicity was observed in rabbits at exposure levels approximately 3 times the recommended dose of 5 mg twice daily, and approximately 1.5 times the

maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in pregnant rabbits).

In a peri- and postnatal development study in pregnant rats that received tofacitinib from gestation day 6 through day 20 of lactation, there were reductions in live litter size, postnatal survival, and pup body weights at exposure levels approximately 73 times the recommended dose of 5 mg twice daily, and approximately 36 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 50 mg/kg/day in rats). There was no effect on behavioral and learning assessments, sexual maturation or the ability of the F1 generation rats to mate and produce viable F2 generation fetuses in rats at exposure levels approximately 17 times the recommended dose of 5 mg twice daily, and approximately 8.3 times the maximum recommended dose of 10 mg twice daily (on an AUC basis at oral doses of 10 mg/kg/day in rats).

Lactation Risk Summary There are no data on the presence of tofacitinib in human milk, the effects on a breastfed infant, or the effects on milk production. Tofacitinib is present in the milk of lactating rats. When a drug is present in animal milk, it is likely that the drug will be present in human milk. Given the serious adverse reactions seen in patients treated with XELJANZ, such as increased risk of serious infections, advise patients that breastfeeding is not recommended during treatment and for at least 18 hours after the last dose of XELJANZ/XELJANZ Oral Solution or 36 hours after the last dose of XELJANZ XR (approximately 6 elimination half-lives).

Data Following administration of tofacitinib to lactating rats, concentrations of tofacitinib in milk over time paralleled those in serum, and were approximately 2 times higher in milk relative to maternal serum at all time points measured.

Females and Males of Reproductive Potential Contraception Females In an animal reproduction study, tofacitinib at AUC multiples of 13 times the recommended dose of 5 mg twice daily and 6.3 times the maximum recommended dose of 10 mg twice daily demonstrated adverse embryo-fetal findings. However, there is uncertainty as to how these animal findings relate to females of reproductive potential treated with the recommended clinical dose. Consider pregnancy planning and prevention for females of reproductive potential.

Infertility Females Based on findings in rats, treatment with XELJANZ may result in reduced fertility in females of reproductive potential. It is not known if this effect is reversible.

Pediatric Use The safety and effectiveness of XELJANZ/ XELJANZ Oral Solution for the treatment of active pcJIA have been established in patients 2 years to 17 years of age. Use of XELJANZ/XELJANZ Oral Solution for the treatment of pediatric patients with active pcJIA in this age group is supported by evidence from adequate and well-controlled studies of XELJANZ in adult RA patients with additional data from a clinical trial of XELJANZ/XELJANZ Oral Solution in pediatric patients (2 years to 17 years of age) with active pcJIA consisting of an 18-week, open label, run-in period followed by a 26-week placebo-controlled, randomized withdrawal period.The safety and effectiveness of XELJANZ/ XELJANZ Oral Solution have not been established in pcJIA patients less than 2 years of age.

Adverse reactions observed in pediatric patients receiving XELJANZ/XELJANZ Oral Solution were consistent with those reported in RA patients.

Safety and efficacy of XELJANZ/XELJANZ Oral Solution in pediatric patients for indications other than pcJIA have not been established.

The safety and effectiveness of XELJANZ XR in pediatric patients have not been established.

Geriatric Use Of the 3315 patients who enrolled in rheumatoid arthritis Studies I to V, a total of 505 rheumatoid arthritis patients were 65 years of age and older, including 71 patients 75 years and older.The frequency of serious infection among XELJANZ-

treated subjects 65 years of age and older was higher than among those under the age of 65.

Of the 1156 XELJANZ-treated patients in the UC program, a total of 77 patients (7%) were 65 years of age or older. The number of patients aged 65 years and older was not sufficient to determine whether they responded differently from younger patients.

As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Use in Diabetics As there is a higher incidence of infection in diabetic population in general, caution should be used when treating patients with diabetes.

Renal Impairment Moderate and Severe Impairment XELJANZ-treated patients with moderate or severe renal impairment had greater tofacitinib blood concentrations than XELJANZ-treated patients with normal renal function.

Therefore, dosage adjustment of XELJANZ is recommended in patients with moderate or severe renal impairment (including but not limited to those with severe insufficiency who are undergoing hemodialysis).

Mild impairment No dosage adjustment is required in patients with mild renal impairment.

Hepatic Impairment Severe Impairment XELJANZ has not been studied in patients with severe hepatic impairment; therefore, use of XELJANZ in patients with severe hepatic impairment is not recommended.

Moderate Impairment XELJANZ-treated patients with moderate hepatic impairment had greater tofacitinib blood concentration than XELJANZ-treated patients with normal hepatic function.

Higher blood concentrations may increase the risk of some adverse reactions. Therefore, dosage adjustment of XELJANZ is recommended in patients with moderate hepatic impairment.

Mild Impairment No dosage adjustment of XELJANZ is required in patients with mild hepatic impairment.

Hepatitis B or C Serology The safety and efficacy of XELJANZ have not been studied in patients with positive hepatitis B virus or hepatitis C virus serology.

OVERDOSAGE There is no specific antidote for overdose with XELJANZ. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions.

In a study in subjects with end stage renal disease (ESRD) undergoing hemodialysis, plasma tofacitinib concentrations declined more rapidly during the period of hemodialysis and dialyzer efficiency, calculated as dialyzer clearance/blood flow entering the dialyzer, was high [mean (SD) = 0.73 (0.15)]. However, due to the significant non-renal clearance of tofacitinib, the fraction of total elimination occurring by hemodialysis was small, and thus limits the value of hemodialysis for treatment of overdose with XELJANZ. This brief summary is based on XELJANZ® (tofacitinib) Prescribing Information LAB-0445-23.0 Issued: December 2021 See XELJANZ full Prescribing Information at XELJANZPI.com © 2022 Pfizer Inc.All rights reserved. January 2022

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REHABILITACIÓN CARDIOVASCULAR

MANEJO, EVALUACIÓN & RESULTADOS

Por: Odrick R. Rosas-Virella, MD. PhD.1, Jose R. Vives-Alvarado MD.2, & William A. Ramos-Guasp3

Attending Medicina Física y Rehabilitacíon- Sub-Especialista Medicina Deportiva, Terapia Fisica del Toa/Servicio Integral de la Montaña (SIM), Toa Alta/Naranjito, Puerto Rico.

2 Assistance Professor of Physical Medicine and Rehabilitation- Spinal Cord Injury Medicine Sub-Specialist at University of Miami Miller School of Medicine- Christine E. Lynn Rehabilitation Center for the Miami Project to Cure Paralysis 1611 NW 12th Avenue, Miami, Florida.

3 Médico Residente, Departamento de Medicina Física y Rehabilitación, Universidad de Puerto Rico-Escuela de Medicina, San Juan, Puerto Rico.

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Palabras clave

Rehabilitación cardiovascular, ejercicio, aterosclerosis, calidad de vida, aptitud física.

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Revista Puertorriqueña de Medicina y Salud Pública

Keywords

Cardiovascular rehabilitation, exercise, atherosclerosis, quality of life, physical fitness.

Odrick R. RosasVirella, MD. PhD.

Jose R. VivesAlvarado MD.

William A. Ramos-Guasp

Las enfermedades cardiovasculares son la causa número uno de muerte en los Estados Unidos, afectando tanto hombres como mujeres por igual.

La rehabilitación cardíaca es una herramienta importante en la prevención secundaria de enfermedades cardiovasculares.

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RESUMEN Las enfermedades cardiovasculares son la causa número uno de muerte en los Estados Unidos, afectando tanto hombres como mujeres por igual. La rehabilitación cardíaca es una herramienta importante en la prevención secundaria de enfermedades cardiovasculares. Los beneficios de la rehabilitacion cardiaca han demostrado una reducción en riesgos cardiovasculares, un aumento en la tolerancia al ejercicio, mejora en el bienestar, reduccion en peso, control de lípidos, y manejo de comorbilidades del paciente. Una prescripción de ejercicios básica es diseñada a las necesidades del individuo, comorbilidades y metas de aptitud física. La prescripción de ejercicios esta compuesta de varios componentes: frecuencia, duración, tipo e intensidad. La rehabilitación cardiovascular se divide en cuatro fases, que van del 1-4 dependiendo de la condición física y cuanta observación requiere su enfermedad. La recomendación de comenzar actividad física o un programa de rehabilitación cardiaca no es solo para mejorar la aptitud física, también se puede utilizar para promocionar la actividad sexual, reducir la depresión y ansiedad, y reducir riesgo de diabetes tipo 2.

ABSTRACT: Cardiovascular diseases are the number one cause of death in the United States, affecting both men and women alike. Cardiac rehabilitation is an important tool in the secondary prevention of cardiovascular diseases. The benefits of cardiac rehabilitation have demonstrated a reduction in cardiovascular risks, an increase in exercise tolerance, improve well-being, reduce weight, control lipids and manage patient comorbidities. A prescription for basic exercises is design for the individual’s needs, comorbidities and fitness goals.

The prescription of exercises is composed of several components, such as: frequency, duration, type and intensity. Cardiovascular rehabilitation is divided into four phases, ranging from 1 to 4 depending of the patient physical condition and diseases. The recommendation to start physical activity or a cardiac rehabilitation program is not only to improve physical fitness, it can also be used to promote sexual activity, reduce depression-anxiety and risk of diabetes mellitus type II.

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INTRODUCCIÓN: Rehabilitación cardiaca es el proceso por el cual los individuos con condiciones cardiovasculares son reestablecidos a su estado óptimo tanto en el área fisiológica, psicológica, social, vocacional y emocional. La Asociación Americana del Corazón (AHA), enfatiza en que la rehabilitación cardiaca es designada a optimizar las funciones vocacionales, sociales, fisiológicas y psicológicas mientras se revierte o desacelera el proceso de enfermedad coronario vascular. Adicional, los programas de rehabilitación cardiaca proveen manejo en nutrición, cesación de fumar, manejo de presión y regulación de los lípidos (www.heart.org).

La educación al paciente y la reducción en los factores de riesgo es una de las metas primarias del médico rehabilitador. Los factores de riego para enfermedad de arteria coronaria se pueden dividir en irreversibles y reversibles como se desglosan en la tabla 1 (Wilson, Castelli, & Kannel, 1987). Las metas para los pacientes aptos para trabajar que sostienen una condición cardiaca es regresar al trabajo lo más pronto posible y mantener o mejorar su estado físico. Para aquellos que no tiene la capacidad de regresar a trabajo, la meta es mantener un estilo de vida activa y establecer nuevas áreas de interés para mejorar la calidad de vida.

Las enfermedades cardiovasculares son la causa número uno de muerte en los Estados Unidos, alrededor de 610, 000 personas mueren por año, afectando tanto hombres como mujeres por igual. La condición cardiaca más común es la enfermedad de arteria coronaria, matando alrededor de 370,000 personas al año. Además, enfermedades cardiacas son la causa principal de muerte en la mayoría de los grupos sociales, incluyendo afroamericanos, hispanos y blancos (www.heart.org).

PATOFISIOLOGÍA / EVALUACIÓN Y FASES: Patofisiología: La visión actual de la patogénesis de la aterosclerosis se basa en la hipótesis de la respuesta a un insulto. Este modelo considera la aterosclerosis como una respuesta inflamatoria crónica de la pared arterial a un insulto al endotelio vascular. La progresión de la lesión envuelve la interacción de lipoproteínas modificadas, macrófagos derivados de monocitos, linfocitos T y los constituyentes celulares de la pared arterial. Según este modelo, la aterosclerosis es el resultado de los siguientes eventos patológicos (Ahmadi, Argulian, Leipsic, Newby, & Narula, 2019): Lesión de células endoteliales – y la disfunción endotelial resultante – que conduce a una mayor permeabilidad, adhesión de leucocitos, y trombosis.

Acumulación de lipoproteínas (principalmente LDL oxidada y cristales de colesterol) en la pared del vaso sanguíneo Adhesión plaquetaria Adhesión de monocitos al endotelio, migración a la íntima y diferenciación en macrófagos y células espumosas La acumulación de lípidos dentro de los macrófagos, que responden liberando citoquinas inflamatorias.

Reclutamiento de células de músculo liso debido en respuesta a liberados por las plaquetas activadas, los macrófagos y las células de la pared vascular.

Proliferación de células musculares lisas y producción de matriz extracelular.

Evaluación y Fases: La rehabilitación cardiovascular se divide en cuatro fases, que van del 1-4 dependiendo de la condición física y cuanta observación requiere su enfermedad. La Fase I o “Intrahospitalario” requiere evaluación por médico rehabilitador, movilización temprana, educación de factores de riesgo y un plan de alta - dura de 1 a 14 días. Fase II o “Seguimiento en clínicas” requiere de un programa de ejercicios individualizado, reducción y estratificación de

factores de riesgo, mejorar calidad de vida y crear confianza – duración máxima de 3 a 6 meses. Fase III o “Periodo Intermedio” requiere de menos observación o supervisión, se mantiene en un programa de ejercicios para mejorar resistencia y cambio en estilo de vida. Por último, Fase IV o “Mantenimiento”- una vez el paciente cumplió con las metas, requiere poca o ninguna supervisión (Rj., n.d.).

EJERCICIO COMO TRATAMIENTO: La rehabilitación cardíaca es una herramienta importante en la prevención secundaria de enfermedades cardiovasculares. Su objetivo es ayudar a los participantes a llevar una vida plena y saludable, reduciendo al mismo tiempo la probabilidad de sufrir incidentes cardíacos posteriores. Los programas de ejercicios tienen como objetivo aumentar la aptitud cardiorrespiratoria y la fuerza muscular de los participantes.

El entrenamiento con ejercicio es de alta importancia en la rehabilitación cardíaca, sin embargo, todavía hay controversia con respecto al modo y la intensidad del ejercicio que puede producir efectos beneficiosos óptimos en pacientes con CAD. Se ha demostrado que la capacidad aeróbica es inversamente proporcional a la mortalidad cardiovascular y la morbilidad. Esto se debe a que, por cada mejoría en el equivalente metabólico en la resistencia cardiorrespiratoria, hay una reducción de 11% en “toda causa mortalidad” en pacientes de CHF (McMahon, Ades, & Thompson, 2017) (O’Connor et al., 2009).

Prescripción de ejercicios: Una prescripción de ejercicios básica es diseñada a las necesidades del individuo, comorbilidades y metas de aptitud física. La prescripción de ejercicios esta compuesta de varios componentes (Garber et al., 2011), tales como: Frecuencia: (numero de días por semana) Numero recomendado 3-5 días/semana Intensidad: utilizando el ritmo cardiaco máximo estimado (220 – ritmo cardiaco), entrenas a un 60%, 70% u 80% del numero estimado para determinar la intensidad.

Duración: 30 min/ día x 5 días/semana, o un total de 150 min/semana (mínimo recomendado).

Tipo: isotónico, rítmico y aeróbico, evitando ejercicios isométricos.

Ejercicio en intervalo en alta intensidad (HIIT por sus siglas en ingles) en Rehabilitación Cardiaca: El entrenamiento con intervalos de alta intensidad implica alternar cargas de ejercicio breves de intensidad alta e intensidad moderada a lo largo de una sesión de ejercicio. Tradicionalmente se utiliza para entrenar a los atletas que requieren altos niveles de aptitud aeróbica y anaeróbica, sin embardo los beneficios del entrenamiento a intervalos de alta intensidad en pacientes con enfermedad de las arterias coronarias se han investigado desde 1981. Cada vez hay más evidencia de que el entrenamiento a intervalos de alta

El entrenamiento con ejercicio es de alta importancia en la rehabilitación cardíaca, sin embargo, todavía hay controversia con respecto al modo y la intensidad del ejercicio que puede producir efectos beneficiosos óptimos en pacientes con CAD.

Tabla 1. Factores de Riesgo para enfermedad de arteria coronaria.

IRREVERSIBLE

REVERSIBLE

Age

Cigarette

Male Gender

HTN

Family History of Premature CAD (Before age 55 in sibling or parents)

Low HDL Cholesterol

Past History of CAD

Hypercholesterolemia

Past History of Occlusive Peripheral Vascular Disease

High Lipoprotein A

Past History of Cerebrovascular Disease

Abdominal Obesity Hypertriglyceridemia Diabetes Mellitus, Hyperinsulinemia Sedentary Lifestyle

intensidad parece ser más eficaz que el entrenamiento continuo de intensidad moderada para mejorar la aptitud cardiorrespiratoria dentro de la población cardíaca.

El entrenamiento con ejercicio de alta intensidad mejora la capacidad de ejercicio, lo cual está estrechamente relacionado con la supervivencia a largo plazo en pacientes cardíacos. Varias revisiones sistemáticas han informan sobre los efectos positivos, incluyendo cambio en el consumo máximo de oxígeno en pacientes con CAD comparando el entrenamiento con intervalos de alta intensidad (HIIT) y el entrenamiento tradicional de intensidad moderada continuo (MICT por sus siglas en ingles) (Hannan et al., 2018). En pacientes con CAD, HIIT ha demostrado mejorar significativamente el umbral ventilatorio, el tamaño y la función del ventrículo izquierdo, la función contráctil, el diámetro diastólico del ventrículo izquierdo, el volumen diastólico, el engrosamiento de la pared posterior, el acortamiento fraccional y el producto de presión de velocidad, la resistencia cardiorrespiratoria, la fracción de eyección y la función endotelial mejor que el MICT. Esto muestra resultados positivos para la función cardíaca (Pattyn, Coeckelberghs, Buys, Cornelissen, & Vanhees, 2014).

Además, estudios han demostrado evidencia de HIIT para mejorar la biogénesis mitocondrial, la sensibilidad la insulina y la regulación de la glucosa, el colesterol HDL, presión arterial, y grasa abdominal profunda mejor que el MICT, todos los cuales son importantes para los pacientes con CHD (Hannan et al., 2018). El riesgo de un evento cardiovascular es bajo después de ejercicio de alta intensidad y de intensidad moderada en un entorno de rehabilitación cardiovascular.

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R

RESULTADOS: Los beneficios de la rehabilitacion cardiaca han demostrado una reducción en riesgos cardiovasculares, un aumento en la tolerancia al ejercicio, mejora el bienestar, reduce peso, controla los lípidos, y maneja las comorbilidades del paciente (McMahon et al., 2017). En este repaso de la literatura se hablaran dos temas de suma importancia en la rehabilitacion cardiaca mas preguntados por los pacientes: Salud mental: Eventos cardiovasculares generan niveles altos de estrés, ansiedad y depresión (Chauvet-Gelinier & Bonin, 2017). Las situaciones estresantes generan una cascada de eventos a nivel de sistema nervioso central, que a su vez aumentan el eje Hipotálamo- Pituitaria- Adrenal y la respuesta del sistema nervioso autonómico afectando la homeostasis de la presión sanguínea, niveles de cortisol y reduciendo la eficacia del sistema inmunológico (Chauvet-Gelinier & Bonin, 2017). Hipercortisolemia pudiera estar relacionado a arterosclerosis que a su vez se relaciona con eventos cardiovasculares.

La rehabilitación cardiaca reduce la depresión y ansiedad, y aumenta la calidad de vida de los pacientes con condiciones cardiacas. Utilizando un cuestionario validado se observó que pacientes que completaron un programa de rehabilitación cardiaca le disminuye la razón de depresión de un 17% en entrada al programa a 6% una vez culminado (McMahon et al., 2017).

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Actividad sexual: La recomendación de comenzar actividad física no es solo para mejorar la aptitud física, también se puede utilizar para promocionar la actividad sexual. Si el paciente puede realizar actividad física que conlleve a un nivel equivalente metabólico de la tarea (MET por sus siglas en ingles) de 3 a 5, pueda subir dos tramos de escaleras o pueda caminar a 3 a 4 millas por hora sin fatigarse, entonces el paciente esta listo para comenzar su actividad sexual (Steinke & Jaarsma, 2015).

La actividad sexual en el estado pre-orgásmico requiere de una carga de trabajo de alrededor de 2 a 3 METs y en la fase del orgasmo se requiere de una carga de trabajo de 3 a 4 METs. La evidencia en la literatura sugiere que el paciente sostenga relaciones sexuales con personas familiares para disminuir el estrés cardiaco relacionado a la actividad sexual, debido a que la mayoría de las muertes ocurren durante relaciones sexuales extramaritales (Steinke & Jaarsma, 2015). Se recomienda que el paciente asuma la posición de misionero en la parte de abajo porque requiere un gasto energético menor y se debe evitar el sexo anal debido a la estimulación vagal (Steinke & Jaarsma, 2015).

REFERENCIAS: Ahmadi, A., Argulian, E., Leipsic, J., Newby, D. E., & Narula, J. (2019). From Subclinical Atherosclerosis to Plaque Progression and Acute Coronary Events: JACC State-of-the-Art Review. Journal of the American College of Cardiology. https://doi.org/10.1016/j.jacc.2019.08.012 Chauvet-Gelinier, J. C., & Bonin, B. (2017). Stress, anxiety and depression in heart disease patients: A major challenge for cardiac rehabilitation. Annals of Physical and Rehabilitation Medicine, 60(1), 6–12. https://doi.org/10.1016/j. rehab.2016.09.002 Garber, C. E., Blissmer, B., Deschenes, M. R., Franklin, B. A., Lamonte, M. J., Lee, I. M., … Swain, D. P. (2011). Quantity and quality of exercise for developing and

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maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: Guidance for prescribing exercise. Medicine and Science in Sports and Exercise, 43(7), 1334–1359. https://doi.org/10.1249/MSS.0b013e318213fefb Hannan, A., Hing, W., Simas, V., Climstein, M., Coombes, J., Jayasinghe, R., … Furness, J. (2018). High-intensity interval training versus moderate-intensity continuous training within cardiac rehabilitation: a systematic review and meta-analysis. Open Access Journal of Sports Medicine, Volume 9, 1–17. https:// doi.org/10.2147/oajsm.s150596 McMahon, S. R., Ades, P. A., & Thompson, P. D. (2017). The role of cardiac rehabilitation in patients with heart disease.

Trends in Cardiovascular Medicine, 27(6), 420–425. https://doi.org/10.1016/j. tcm.2017.02.005 O’Connor, C. M., Whellan, D. J., Lee, K. L., Keteyian, S. J., Cooper, L. S., Ellis, S. J., … Piña, I. L. (2009). Efficacy and safety of exercise training in patients with chronic heart failure HF-ACTION randomized controlled trial. JAMA - Journal of the American Medical Association. https:// doi.org/10.1001/jama.2009.454 Pattyn, N., Coeckelberghs, E., Buys, R., Cornelissen, V. A., & Vanhees, L. (2014).

Aerobic interval training vs. Moderate continuous training in coronary artery disease patients: A systematic review and meta-analysis. Sports Medicine, 44(5), 687–700. https://doi.org/10.1007/ s40279-014-0158-x Rj., T. (n.d.). doi_10.1016 _ j. jacc.2007.04.033 _ Elsevier Enhanced Reader.pdf.

Steinke, E. E., & Jaarsma, T. (2015). Sexual counseling and cardiovascular disease: Practical approaches. Asian Journal of Andrology, 17(1), 32–39. https://doi. org/10.4103/1008-682X.135982 Wilson, P. W. F., Castelli, W. P., & Kannel, W. B. (1987). Coronary risk prediction in adults (The Framingham Heart Study). The American Journal of Cardiology. https:// doi.org/10.1016/0002-9149(87)90165-2

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IMPORTANT SAFETY INFORMATION WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO® INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA

A. Premature discontinuation of XARELTO® increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO®, increases the risk of thrombotic events. If anticoagulation with XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO® who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks

CONTRAINDICATIONS • Active pathological bleeding • Severe hypersensitivity reaction to XARELTO® (eg, anaphylactic reactions)

WARNINGS AND PRECAUTIONS • Increased Risk of Thrombotic Events after Premature Discontinuation: Premature discontinuation of any oral anticoagulant, including XARELTO®, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO® to warfarin in clinical trials in atrial fibrillation patients. If XARELTO® is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant.

• Risk of Bleeding: XARELTO® increases the risk of bleeding and can cause serious or fatal bleeding. Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue in patients with active pathological hemorrhage.

– An agent to reverse the anti-factor Xa activity of rivaroxaban is available. Because of high plasma protein binding, rivaroxaban is not dialyzable.

– Concomitant use of other drugs that impair hemostasis increases risk of bleeding.

These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, NSAIDs, selective serotonin reuptake inhibitors (SSRIs), and serotonin norepinephrine reuptake inhibitors (SNRIs).

– Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding: Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO® for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage; active cancer (ie, undergoing acute, in-hospital cancer treatment); active gastroduodenal ulcer or history of bleeding in the three months prior to treatment; or dual antiplatelet therapy. XARELTO® is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.

• Spinal/Epidural Anesthesia or Puncture: When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma, which can result in longterm or permanent paralysis. To reduce the potential risk of bleeding associated with concurrent use of XARELTO® and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO®. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO® is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known. An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (ie, 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO®. The next dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO® for 24 hours. Monitor frequently to detect signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), or bowel and/or bladder dysfunction. Instruct patients to immediately report any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

• Use in Patients with Renal Impairment: – Nonvalvular Atrial Fibrillation: Periodically assess renal function as clinically indicated (ie, more frequently in situations in which renal function may decline) and adjust therapy accordingly. Consider dose adjustment or discontinuation in patients who develop acute renal failure while on XARELTO®. Clinical efficacy and safety studies with XARELTO® did not enroll patients with CrCl <30 mL/min or end-stage renal disease (ESRD) on dialysis.

– Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patientswho develop acute renal failure while on treatment.

– Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate signs or symptoms of blood loss in

when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • Use of indwelling epidural catheters • Concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants, see Drug Interactions • A history of traumatic or repeated epidural or spinal punctures • A history of spinal deformity or spinal surgery • Optimal timing between the administration of XARELTO® and neuraxial procedures is not known Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary.

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis. these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patients who develop acute renal failure while on treatment.

– Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding: In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO® in these patients. Discontinue XARELTO® in patients who develop acute renal failure while on treatment.

– Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients after Recent Lower Extremity Revascularization Due to Symptomatic PAD: For patients with CrCl <15 mL/min, no data are available, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg XARELTO® twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min), whose efficacy and safety outcomes were similar to those with preserved renal function. Clinical efficacy and safety studies with XARELTO® did not enroll patients with end-stage renal disease (ESRD) on dialysis.

– Pediatric Patients: There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m²); therefore, avoid use of XARELTO® in these patients.

There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO® in these patients.

• Use in Patients with Hepatic Impairment: No clinical data are available for adult patients with severe hepatic impairment. Avoid use in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy, since drug exposure and bleeding risk may be increased. No clinical data are available in pediatric patients with hepatic impairment.

• Use with P-gp and Strong CYP3A Inhibitors or Inducers: Avoid concomitant use of XARELTO® with known combined P-gp and strong CYP3A inhibitors or inducers.

• Risk of Pregnancy-Related Hemorrhage: In pregnant women, XARELTO® should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO® dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO® cannot be monitored with standard laboratory testing. Promptly evaluate signs or symptoms suggesting blood loss (eg, a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress).

• Patients with Prosthetic Heart Valves: Use of XARELTO® is not recommended in patients who have had transcatheter aortic valve replacement (TAVR), based on the results of the GALILEO study, which reported higher rates of death and bleeding in patients randomized to XARELTO® compared to those randomized to an antiplatelet regimen. Safety and efficacy of XARELTO® have not been studied in patients with other prosthetic heart valves or other valve procedures. Use of XARELTO® is not recommended in patients with prosthetic heart valves.

• Acute PE in Hemodynamically Unstable Patients/Patients Who Require Thrombolysis or Pulmonary Embolectomy: Initiation of XARELTO® is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

• Increased Risk of Thrombosis in Patients with Antiphospholipid Syndrome: Direct-acting oral anticoagulants (DOACs), including XARELTO®, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

DRUG INTERACTIONS

• Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase risk of bleeding.

• Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase risk of thromboembolic events.

• XARELTO® should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (eg, erythromycin) unless the potential benefit justifies the potential risk.

Please read accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS for XARELTO®.

(continued on next page)

NVAF

Reduce stroke risk

CAD PAD

VTE Prophylaxis Acutely ill medical patients

DVT/PE

Initial treatment

DVT/PE

Extended treatment

LER = lower extremity revascularization.

PAD = peripheral artery disease.

INDICATIONS

XARELTO® (rivaroxaban) is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation (AF).

There are limited data on the relative effectiveness of XARELTO® and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well controlled.

XARELTO® is indicated for the treatment of deep vein thrombosis (DVT). XARELTO® is indicated for the treatment of pulmonary embolism (PE). XARELTO® is indicated for the reduction in the risk of recurrence of DVT and/or PE in adult patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

XARELTO® is indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery.

XARELTO® is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE-related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic

IMPORTANT SAFETY INFORMATION (cont’d) DRUG INTERACTIONS (cont'd)

The XARELTO® vascular dose* is the FIRST and ONLY treatment approach indicated to help reduce the risks of major thrombotic vascular events† in patients with PAD, including patients after recent LER due to symptomatic PAD.2,3

Reduce the risk of major thrombotic vascular events

DVT Prophylaxis

After hip/knee replacement surgery

XARELTO® 2.5 mg twice daily plus aspirin 75 mg to 100 mg once daily. † Reduction of a composite of acute limb ischemia, major amputation of vascular etiology, myocardial infarction, ischemic stroke, or CV death. *

complications due to moderate or severe restricted mobility and other risk factors for VTE, and not at high risk of bleeding.

XARELTO®, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease (CAD).

XARELTO®, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with peripheral artery disease (PAD), including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD XARELTO® is indicated for the treatment of venous thromboembolism (VTE) and reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment.

XARELTO® is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

• Coadministration of enoxaparin, warfarin, aspirin, clopidogrel, and chronic NSAID use may increase risk of bleeding.

were less than 37 weeks of gestation at birth, had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg.

• Avoid concurrent use of XARELTO® with other anticoagulants due to increased bleeding risk, unless benefit outweighs risk. Promptly evaluate signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs.

Clinical studies that evaluated safety, efficacy, and pharmacokinetic/ pharmacodynamic data support the use of XARELTO® 10-mg, 15-mg, and 20-mg tablets in pediatric patients. For the XARELTO® 2.5-mg tablets, there are no safety, efficacy, and pharmacokinetic/pharmacodynamic data to support the use in pediatric patients. Therefore, XARELTO® 2.5-mg tablets are not recommended for use in pediatric patients.

USE IN SPECIFIC POPULATIONS • Pregnancy: The limited available data on XARELTO® in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO® with caution in pregnant patients because of the potential for pregnancy-related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO® cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO® for the mother and possible risks to the fetus when prescribing to a pregnant woman.

– Fetal/Neonatal adverse reactions: Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

– Labor or delivery: The risk of bleeding should be balanced with the risk of thrombotic events when considering use in this setting.

– There are no adequate or well-controlled studies of XARELTO® in pregnant women, and dosing for pregnant women has not been established. Postmarketing experience is currently insufficient to determine a rivaroxabanassociated risk for major birth defects or miscarriage.

• Lactation: Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Consider the developmental and health benefits of breastfeeding along with the mother’s clinical need for XARELTO® and any potential adverse effects on the breastfed infant from XARELTO® or from the underlying maternal condition.

• Females and Males of Reproductive Potential: Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants, including XARELTO®, should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

• Pediatric Use: XARELTO® was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who XARELTO® is licensed from Bayer HealthCare AG, 51368 Leverkusen, Germany. © Janssen Pharmaceuticals, Inc. 2022 02/22 cp-237997v2

Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

• Geriatric Use: In clinical trials the efficacy of XARELTO® in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients.

OVERDOSAGE • Overdose of XARELTO® may lead to hemorrhage. Discontinue XARELTO® and initiate appropriate therapy if bleeding complications associated with overdosage occur. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

ADVERSE REACTIONS • Most common adverse reactions in adult patients with XARELTO® were bleeding complications.

• Most common adverse reactions in pediatric patients were bleeding, cough, vomiting, and gastroenteritis.

Please read accompanying Brief Summary of full Prescribing Information, including Boxed WARNINGS for XARELTO®.

REFERENCES: 1. Gerhard-Herman MD, Gornik HL, Barret C, et al. 2016 AHA/ACC Guideline on the management of patients with lower extremity peripheral artery disease: Executive summary.

Circulation. 2016;135:e686-e725. 2. XARELTO® [prescribing information]. Titusville, NJ: Janssen Pharmaceuticals, Inc. 3. Bonaca MP, Bauersachs RM, Anand SS, et al. Rivaroxaban in peripheral artery disease after revascularization [article and supplementary appendix]. N Engl J Med. 2020;382(21):1994-2004.

cp-62551v9

Patients with PAD are complex.1 Helping protect them against thrombosis doesn’t have to be.

Reduce the risk of major CV events

Brief Summary of Prescribing Information for XARELTO® (rivaroxaban) XARELTO (rivaroxaban) tablets, for oral use XARELTO (rivaroxaban) for oral suspension See package insert for Full Prescribing Information WARNING: (A) PREMATURE DISCONTINUATION OF XARELTO INCREASES THE RISK OF THROMBOTIC EVENTS, (B) SPINAL/EPIDURAL HEMATOMA A. Premature discontinuation of XARELTO increases the risk of thrombotic events Premature discontinuation of any oral anticoagulant, including XARELTO, increases the risk of thrombotic events. If anticoagulation with XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4) in Full Prescribing Information, Warnings and Precautions, and Clinical Studies (14.1) in Full Prescribing Information].

B. Spinal/epidural hematoma Epidural or spinal hematomas have occurred in patients treated with XARELTO who are receiving neuraxial anesthesia or undergoing spinal puncture. These hematomas may result in long-term or permanent paralysis. Consider these risks when scheduling patients for spinal procedures. Factors that can increase the risk of developing epidural or spinal hematomas in these patients include: • use of indwelling epidural catheters • concomitant use of other drugs that affect hemostasis, such as non-steroidal anti-inflammatory drugs (NSAIDs), platelet inhibitors, other anticoagulants • a history of traumatic or repeated epidural or spinal punctures • a history of spinal deformity or spinal surgery • optimal timing between the administration of XARELTO and neuraxial procedures is not known [see Warnings and Precautions and Adverse Reactions].

Monitor patients frequently for signs and symptoms of neurological impairment. If neurological compromise is noted, urgent treatment is necessary [see Warnings and Precautions].

Consider the benefits and risks before neuraxial intervention in patients anticoagulated or to be anticoagulated for thromboprophylaxis [see Warnings and Precautions].

INDICATIONS AND USAGE Reduction of Risk of Stroke and Systemic Embolism in Nonvalvular Atrial Fibrillation XARELTO is indicated to reduce the risk of stroke and systemic embolism in adult patients with nonvalvular atrial fibrillation.

There are limited data on the relative effectiveness of XARELTO and warfarin in reducing the risk of stroke and systemic embolism when warfarin therapy is well-controlled [see Clinical Studies (14.1) in Full Prescribing Information].

Treatment of Deep Vein Thrombosis XARELTO is indicated for the treatment of deep vein thrombosis (DVT).

Treatment of Pulmonary Embolism XARELTO is indicated for the treatment of pulmonary embolism (PE).

Reduction in the Risk of Recurrence of Deep Vein Thrombosis and/or Pulmonary Embolism XARELTO is indicated for the reduction in the risk of recurrence of DVT and/or PE in adult patients at continued risk for recurrent DVT and/or PE after completion of initial treatment lasting at least 6 months.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery XARELTO is indicated for the prophylaxis of DVT, which may lead to PE in adult patients undergoing knee or hip replacement surgery.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding XARELTO is indicated for the prophylaxis of venous thromboembolism (VTE) and VTE related death during hospitalization and post hospital discharge in adult patients admitted for an acute medical illness who are at risk for thromboembolic complications due to moderate or severe restricted mobility and other risk factors for VTE and not at high risk of bleeding [see Warnings and Precautions and Clinical Studies (14.5) in Full Prescribing Information].

Reduction of Risk of Major Cardiovascular Events in Patients with Coronary Artery Disease (CAD) XARELTO, in combination with aspirin, is indicated to reduce the risk of major cardiovascular events (cardiovascular death, myocardial infarction, and stroke) in adult patients with coronary artery disease.

Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD XARELTO, in combination with aspirin, is indicated to reduce the risk of major thrombotic vascular events (myocardial infarction, ischemic stroke, acute limb ischemia, and major amputation of a vascular etiology) in adult patients with PAD, including patients who have recently undergone a lower extremity revascularization procedure due to symptomatic PAD. Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients XARELTO is indicated for the treatment of venous thromboembolism (VTE) and the reduction in the risk of recurrent VTE in pediatric patients from birth to less than 18 years after at least 5 days of initial parenteral anticoagulant treatment.

Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease after the Fontan Procedure XARELTO is indicated for thromboprophylaxis in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure.

CONTRAINDICATIONS XARELTO is contraindicated in patients with: • active pathological bleeding [see Warnings and Precautions] • severe hypersensitivity reaction to XARELTO (e.g., anaphylactic reactions) [see Adverse Reactions] WARNINGS AND PRECAUTIONS Increased Risk of Thrombotic Events after Premature Discontinuation Premature discontinuation of any oral anticoagulant, including XARELTO, in the absence of adequate alternative anticoagulation increases the risk of thrombotic events. An increased rate of stroke was observed during the transition from XARELTO to warfarin in clinical trials in atrial

XARELTO® (rivaroxaban)

XARELTO® (rivaroxaban)

fibrillation patients. If XARELTO is discontinued for a reason other than pathological bleeding or completion of a course of therapy, consider coverage with another anticoagulant [see Dosage and Administration (2.3, 2.4) and Clinical Studies (14.1) in Full Prescribing Information].

Risk of Bleeding XARELTO increases the risk of bleeding and can cause serious or fatal bleeding. In deciding whether to prescribe XARELTO to patients at increased risk of bleeding, the risk of thrombotic events should be weighed against the risk of bleeding.

Promptly evaluate any signs or symptoms of blood loss and consider the need for blood replacement. Discontinue XARELTO in patients with active pathological hemorrhage. The terminal elimination half-life of rivaroxaban is 5 to 9 hours in healthy subjects aged 20 to 45 years.

Concomitant use of other drugs that impair hemostasis increases the risk of bleeding. These include aspirin, P2Y12 platelet inhibitors, dual antiplatelet therapy, other antithrombotic agents, fibrinolytic therapy, non-steroidal anti-inflammatory drugs (NSAIDs) [see Drug Interactions], selective serotonin reuptake inhibitors, and serotonin norepinephrine reuptake inhibitors.

Concomitant use of drugs that are known combined P-gp and strong CYP3A inhibitors increases rivaroxaban exposure and may increase bleeding risk [see Drug Interactions].

Risk of Hemorrhage in Acutely Ill Medical Patients at High Risk of Bleeding Acutely ill medical patients with the following conditions are at increased risk of bleeding with the use of XARELTO for primary VTE prophylaxis: history of bronchiectasis, pulmonary cavitation, or pulmonary hemorrhage, active cancer (i.e., undergoing acute, in-hospital cancer treatment), active gastroduodenal ulcer in the three months prior to treatment, history of bleeding in the three months prior to treatment, or dual antiplatelet therapy.

XARELTO is not for use for primary VTE prophylaxis in these hospitalized, acutely ill medical patients at high risk of bleeding.

Reversal of Anticoagulant Effect An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Because of high plasma protein binding, rivaroxaban is not dialyzable [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Protamine sulfate and vitamin K are not expected to affect the anticoagulant activity of rivaroxaban. Use of procoagulant reversal agents, such as prothrombin complex concentrate (PCC), activated prothrombin complex concentrate or recombinant factor VIIa, may be considered but has not been evaluated in clinical efficacy and safety studies. Monitoring for the anticoagulation effect of rivaroxaban using a clotting test (PT, INR or aPTT) or anti-factor Xa (FXa) activity is not recommended.

Spinal/Epidural Anesthesia or Puncture When neuraxial anesthesia (spinal/epidural anesthesia) or spinal puncture is employed, patients treated with anticoagulant agents for prevention of thromboembolic complications are at risk of developing an epidural or spinal hematoma which can result in long-term or permanent paralysis [see Boxed Warning].

To reduce the potential risk of bleeding associated with the concurrent use of XARELTO and epidural or spinal anesthesia/analgesia or spinal puncture, consider the pharmacokinetic profile of XARELTO [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Placement or removal of an epidural catheter or lumbar puncture is best performed when the anticoagulant effect of XARELTO is low; however, the exact timing to reach a sufficiently low anticoagulant effect in each patient is not known.

An indwelling epidural or intrathecal catheter should not be removed before at least 2 half-lives have elapsed (i.e., 18 hours in young patients aged 20 to 45 years and 26 hours in elderly patients aged 60 to 76 years), after the last administration of XARELTO [see Clinical Pharmacology (12.3) in Full Prescribing Information]. The next XARELTO dose should not be administered earlier than 6 hours after the removal of the catheter. If traumatic puncture occurs, delay the administration of XARELTO for 24 hours.

Should the physician decide to administer anticoagulation in the context of epidural or spinal anesthesia/analgesia or lumbar puncture, monitor frequently to detect any signs or symptoms of neurological impairment, such as midline back pain, sensory and motor deficits (numbness, tingling, or weakness in lower limbs), bowel and/or bladder dysfunction. Instruct patients to immediately report if they experience any of the above signs or symptoms. If signs or symptoms of spinal hematoma are suspected, initiate urgent diagnosis and treatment including consideration for spinal cord decompression even though such treatment may not prevent or reverse neurological sequelae.

Use in Patients with Renal Impairment Nonvalvular Atrial Fibrillation Periodically assess renal function as clinically indicated (i.e., more frequently in situations in which renal function may decline) and adjust therapy accordingly [see Dosage and Administration (2.1) in Full Prescribing Information]. Consider dose adjustment or discontinuation of XARELTO in patients who develop acute renal failure while on XARELTO [see Use in Specific Populations].

Treatment of Deep Vein Thrombosis (DVT), Pulmonary Embolism (PE), and Reduction in the Risk of Recurrence of DVT and of PE In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations].

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations].

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In patients with CrCl <30 mL/min, rivaroxaban exposure and pharmacodynamic effects are increased compared to patients with normal

renal function. There are limited clinical data in patients with CrCl 15 to <30 mL/min; therefore, observe closely and promptly evaluate any signs or symptoms of blood loss in these patients. There are no clinical data in patients with CrCl <15 mL/min (including patients on dialysis); therefore, avoid the use of XARELTO in these patients.

Discontinue XARELTO in patients who develop acute renal failure while on treatment [see Use in Specific Populations].

Pediatric Patients There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid the use of XARELTO in these patients.

There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO in these patients [see Dosage and Administration (2.2) in Full Prescribing Information and Use in Specific Populations].

Use in Patients with Hepatic Impairment No clinical data are available for adult patients with severe hepatic impairment.

Avoid use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy since drug exposure and bleeding risk may be increased [see Use in Specific Populations].

No clinical data are available in pediatric patients with hepatic impairment.

Use with P-gp and Strong CYP3A Inhibitors or Inducers Avoid concomitant use of XARELTO with known combined P-gp and strong CYP3A inhibitors [see Drug Interactions].

Avoid concomitant use of XARELTO with drugs that are known combined P-gp and strong CYP3A inducers [see Drug Interactions].

Risk of Pregnancy-Related Hemorrhage In pregnant women, XARELTO should be used only if the potential benefit justifies the potential risk to the mother and fetus. XARELTO dosing in pregnancy has not been studied. The anticoagulant effect of XARELTO cannot be monitored with standard laboratory testing.

Promptly evaluate any signs or symptoms suggesting blood loss (e.g., a drop in hemoglobin and/or hematocrit, hypotension, or fetal distress) [see Warnings and Precautions and Use in Specific Populations].

Patients with Prosthetic Heart Valves On the basis of the GALILEO study, use of XARELTO is not recommended in patients who have had transcatheter aortic valve replacement (TAVR) because patients randomized to XARELTO experienced higher rates of death and bleeding compared to those randomized to an anti-platelet regimen. The safety and efficacy of XARELTO have not been studied in patients with other prosthetic heart valves or other valve procedures.

Use of XARELTO is not recommended in patients with prosthetic heart valves.

Acute PE in Hemodynamically Unstable Patients or Patients Who Require Thrombolysis or Pulmonary Embolectomy Initiation of XARELTO is not recommended acutely as an alternative to unfractionated heparin in patients with pulmonary embolism who present with hemodynamic instability or who may receive thrombolysis or pulmonary embolectomy.

Increased Risk of Thrombosis in Patients with Triple Positive Antiphospholipid Syndrome Direct-acting oral anticoagulants (DOACs), including XARELTO, are not recommended for use in patients with triple-positive antiphospholipid syndrome (APS). For patients with APS (especially those who are triple positive [positive for lupus anticoagulant, anticardiolipin, and anti-beta 2-glycoprotein I antibodies]), treatment with DOACs has been associated with increased rates of recurrent thrombotic events compared with vitamin K antagonist therapy.

ADVERSE REACTIONS The following clinically significant adverse reactions are also discussed in other sections of the labeling: • Increased Risk of Stroke After Discontinuation in Nonvalvular Atrial Fibrillation [see Boxed Warning and Warnings and Precautions] • Bleeding Risk [see Warnings and Precautions] • Spinal/Epidural Hematoma [see Boxed Warning and Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

During clinical development for the approved indications, 34,947 adult patients were exposed to XARELTO. Hemorrhage The most common adverse reactions with XARELTO were bleeding complications [see Warnings and Precautions].

Nonvalvular Atrial Fibrillation In the ROCKET AF trial, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 4.3% for XARELTO vs. 3.1% for warfarin. The incidence of discontinuations for non-bleeding adverse events was similar in both treatment groups.

Table 1 shows the number of patients experiencing various types of bleeding events in the ROCKET AF trial.

Table 1: Bleeding Events in ROCKET AF*- On Treatment Plus 2 Days Parameter Major Bleeding† Intracranial Hemorrhage (ICH)‡ Hemorrhagic Stroke§ Other ICH Gastrointestinal (GI)¶ Fatal Bleeding# ICH Non-intracranial

XARELTO Warfarin XARELTO vs. Warfarin HR N=7125 N=7111 (95% CI) n (%/year) n (%/year) 395 (3.6) 386 (3.5) 1.04 (0.90, 1.20) 55 (0.5)

84 (0.7)

0.67 (0.47, 0.93)

36 (0.3)

58 (0.5)

0.63 (0.42, 0.96)

19 (0.2) 221 (2.0) 27 (0.2) 24 (0.2) 3 (0.0)

26 (0.2) 140 (1.2) 55 (0.5) 42 (0.4) 13 (0.1)

0.74 (0.41, 1.34) 1.61 (1.30, 1.99) 0.50 (0.31, 0.79) 0.58 (0.35, 0.96) 0.23 (0.07, 0.82)

XARELTO® (rivaroxaban)

XARELTO® (rivaroxaban)

XARELTO® (rivaroxaban)

Abbreviations: HR = Hazard Ratio, CI = Confidence interval, CRNM = Clinically Relevant Non-Major. * Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. ‡ Intracranial bleeding events included intraparenchymal, intraventricular, subdural, subarachnoid and/or epidural hematoma. § Hemorrhagic stroke in this table specifically refers to non-traumatic intraparenchymal and/or intraventricular hematoma in patients on treatment plus 2 days. ¶ Gastrointestinal bleeding events included upper GI, lower GI, and rectal bleeding. # Fatal bleeding is adjudicated death with the primary cause of death from bleeding.

Table 3: Bleeding Events* in EINSTEIN CHOICE

Table 5: Bleeding Events in MAGELLAN* Study–Safety Analysis Set - On Treatment Plus 2 Days MAGELLAN Study¶ XARELTO 10 mg Enoxaparin 40 mg / placebo N=3218 N=3229 n (%) n (%) ‡† Major bleeding 22 (0.7) 15 (0.5) Critical site bleeding 7 (0.2) 4 (0.1) 3 (<0.1) 1 (<0.1) Fatal bleeding§ Clinically relevant non-major 93 (2.9) 34 (1.1) bleeding events (CRNM) * Patients at high risk of bleeding (i.e. bronchiectasis/pulmonary cavitation, active cancer, dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months) were excluded. † Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment. ‡ Defined as clinically overt bleeding associated with a drop in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. § Fatal bleeding is adjudicated death with the primary cause of death from bleeding. ¶ Patients received either XARELTO or placebo once daily for 35 ±4 days starting in hospital and continuing post hospital discharge or received enoxaparin or placebo once daily for 10 ±4 days in the hospital.

Figure 1 shows the risk of major bleeding events across major subgroups.

Figure 1: Risk of Major Bleeding Events by Baseline Characteristics in ROCKET AF – On Treatment Plus 2 Days

XARELTO† Acetylsalicylic Acid (aspirin)† 100 mg 10 mg N=1127 N=1131 n (%) n (%) 5 (0.4) 3 (0.3) 0 1 (<0.1) 2 (0.2) 1 (<0.1) 3 (0.3) 1 (<0.1)

Parameter Major bleeding event Fatal bleeding Non-fatal critical organ bleeding Non-fatal non-critical organ bleeding‡ 22 (2.0) 20 (1.8) Clinically relevant non-major (CRNM) bleeding§ Any bleeding 151 (13.4) 138 (12.2) * Bleeding event occurred after the first dose and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule: XARELTO 10 mg once daily or aspirin 100 mg once daily. ‡ Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells. § Bleeding which was clinically overt, did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

In the EINSTEIN CHOICE study, there was an increased incidence of bleeding, including major and CRNM bleeding in the XARELTO 20 mg group compared to the XARELTO 10 mg or aspirin 100 mg groups.

Prophylaxis of Deep Vein Thrombosis Following Hip or Knee Replacement Surgery In the RECORD clinical trials, the overall incidence rate of adverse reactions leading to permanent treatment discontinuation was 3.7% with XARELTO. The rates of major bleeding events and any bleeding events observed in patients in the RECORD clinical trials are shown in Table 4.

Table 4: Bleeding Events* in Patients Undergoing Hip or Knee Replacement Surgeries (RECORD 1-3)

Note: The figure above presents effects in various subgroups all of which are baseline characteristics and all of which were pre-specified (diabetic status was not pre-specified in the subgroup but was a criterion for the CHADS2 score). The 95% confidence limits that are shown do not take into account how many comparisons were made, nor do they reflect the effect of a particular factor after adjustment for all other factors. Apparent homogeneity or heterogeneity among groups should not be over-interpreted.

Treatment of Deep Vein Thrombosis (DVT) and/or Pulmonary Embolism (PE) EINSTEIN DVT and EINSTEIN PE Studies In the pooled analysis of the EINSTEIN DVT and EINSTEIN PE clinical studies, the most frequent adverse reactions leading to permanent drug discontinuation were bleeding events, with XARELTO vs. enoxaparin/ Vitamin K antagonist (VKA) incidence rates of 1.7% vs. 1.5%, respectively. The mean duration of treatment was 208 days for XARELTO-treated patients and 204 days for enoxaparin/VKA-treated patients.

Table 2 shows the number of patients experiencing major bleeding events in the pooled analysis of the EINSTEIN DVT and EINSTEIN PE studies.

Table 2: Bleeding Events* in the Pooled Analysis of EINSTEIN DVT and EINSTEIN PE Studies Enoxaparin/ VKA† XARELTO† N=4130 N=4116 Parameter n (%) n (%) Major bleeding event 40 (1.0) 72 (1.7) Fatal bleeding 3 (<0.1) 8 (0.2) Intracranial 2 (<0.1) 4 (<0.1) Non-fatal critical organ bleeding 10 (0.2) 29 (0.7) Intracranial‡ 3 (<0.1) 10 (0.2) 1 (<0.1) 8 (0.2) Retroperitoneal‡ Intraocular‡ 3 (<0.1) 2 (<0.1) 0 4 (<0.1) Intra-articular‡ 27 (0.7) 37 (0.9) Non-fatal non-critical organ bleeding§ Decrease in Hb ≥ 2 g/dL 28 (0.7) 42 (1.0) Transfusion of ≥2 units of whole blood 18 (0.4) 25 (0.6) or packed red blood cells Clinically relevant non-major bleeding 357 (8.6) 357 (8.7) Any bleeding 1169 (28.3) 1153 (28.0) * Bleeding event occurred after randomization and up to 2 days after the last dose of study drug. Although a patient may have had 2 or more events, the patient is counted only once in a category. † Treatment schedule in EINSTEIN DVT and EINSTEIN PE studies: XARELTO 15 mg twice daily for 3 weeks followed by 20 mg once daily; enoxaparin/VKA [enoxaparin: 1 mg/kg twice daily, VKA: individually titrated doses to achieve a target INR of 2.5 (range: 2.0-3.0)] ‡ Treatment-emergent major bleeding events with at least >2 subjects in any pooled treatment group § Major bleeding which is not fatal or in a critical organ, but resulting in a decrease in Hb ≥ 2 g/dL and/or transfusion of ≥ 2 units of whole blood or packed red blood cells Reduction in the Risk of Recurrence of DVT and/or PE EINSTEIN CHOICE Study In the EINSTEIN CHOICE clinical study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 1% for XARELTO 10 mg, 2% for XARELTO 20 mg, and 1% for acetylsalicylic acid (aspirin) 100 mg. The mean duration of treatment was 293 days for XARELTO 10 mg-treated patients and 286 days for aspirin 100 mg-treated patients.

Table 3 shows the number of patients experiencing bleeding events in the EINSTEIN CHOICE study.

Total treated patients Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event‡ Hip Surgery Studies Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event‡ Knee Surgery Study Major bleeding event Fatal bleeding Bleeding into a critical organ Bleeding that required re-operation Extra-surgical site bleeding requiring transfusion of >2 units of whole blood or packed cells Any bleeding event‡

XARELTO 10 mg N=4487 n (%) 14 (0.3) 1 (<0.1) 2 (<0.1) 7 (0.2) 4 (0.1)

Enoxaparin†

261 (5.8) N=3281 n (%) 7 (0.2) 1 (<0.1) 1 (<0.1) 2 (0.1) 3 (0.1)

251 (5.6) N=3298 n (%) 3 (0.1) 0 1 (<0.1) 1 (<0.1) 1 (<0.1)

201 (6.1) N=1206 n (%) 7 (0.6) 0 1 (0.1) 5 (0.4) 1 (0.1)

191 (5.8) N=1226 n (%) 6 (0.5) 0 2 (0.2) 4 (0.3) 0

60 (5.0)

60 (4.9)

N=4524 n (%) 9 (0.2) 0 3 (0.1) 5 (0.1) 1 (<0.1)

* Bleeding events occurring any time following the first dose of doubleblind study medication (which may have been prior to administration of active drug) until two days after the last dose of double-blind study medication. Patients may have more than one event. † Includes the placebo-controlled period for RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) ‡ Includes major bleeding events Following XARELTO treatment, the majority of major bleeding complications (≥60%) occurred during the first week after surgery.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding In the MAGELLAN study, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events.

Cases of pulmonary hemorrhage and pulmonary hemorrhage with bronchiectasis were observed. Patients with bronchiectasis/pulmonary cavitation, active cancer (i.e., undergoing acute, in-hospital cancer treatment), dual antiplatelet therapy or active gastroduodenal ulcer or any bleeding in the previous three months all had an excess of bleeding with XARELTO compared with enoxaparin/placebo and are excluded from all MAGELLAN data presented in Table 5. The incidence of bleeding leading to drug discontinuation was 2.5% for XARELTO vs. 1.4% for enoxaparin/placebo.

Table 5 shows the number of patients experiencing various types of bleeding events in the MAGELLAN study.

Reduction of Risk of Major Cardiovascular Events in Patients with CAD In the COMPASS trial overall, the most frequent adverse reactions associated with permanent drug discontinuation were bleeding events, with incidence rates of 2.7% for XARELTO 2.5 mg twice daily vs. 1.2% for placebo on background therapy for all patients with aspirin 100 mg once daily. The incidences of important bleeding events in the CAD and PAD populations in COMPASS were similar.

Table 6 shows the number of patients experiencing various types of major bleeding events in the COMPASS trial.

Table 6: Major Bleeding Events in COMPASS - On Treatment Plus 2 Days*

Parameter Modified ISTH Major Bleeding‡ - Fatal bleeding event Intracranial hemorrhage (ICH) Non-intracranial - Symptomatic bleeding in critical organ (non-fatal) - ICH (fatal and non-fatal) Hemorrhagic Stroke Other ICH - Bleeding into the surgical site requiring reoperation (non-fatal, not in critical organ) - Bleeding leading to hospitalization (non-fatal, not in critical organ, not requiring reoperation) Major GI bleeding

XARELTO† N=9134 n (%/year) 263 (1.6) 12 (<0.1)

Placebo† XARELTO vs.

Placebo N=9107 n (%/year) HR (95 % CI) 144 (0.9) 1.8 (1.5, 2.3) 1.5 (0.6, 3.7) 8 (<0.1)

6 (<0.1) 6 (<0.1)

3 (<0.1) 5 (<0.1)

2.0 (0.5, 8.0) 1.2 (0.4, 4.0)

58 (0.3) 23 (0.1) 18 (0.1) 6 (<0.1) 7 (<0.1)

43 (0.3) 21 (0.1) 13 (<0.1) 9 (<0.1) 6 (<0.1)

1.4 (0.9, 2.0) 1.1 (0.6, 2.0) 1.4 (0.7, 2.8) 0.7 (0.2, 1.9) 1.2 (0.4, 3.5)

188 (1.1)

91 (0.5)

2.1 (1.6, 2.7)

117 (0.7)

49 (0.3)

2.4 (1.7, 3.4)

* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. These events occurred during treatment or within 2 days of stopping treatment in the safety analysis set in COMPASS patients. † Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily. ‡ Defined as i) fatal bleeding, or ii) symptomatic bleeding in a critical area or organ, such as intraarticular, intramuscular with compartment syndrome, intraspinal, intracranial, intraocular, respiratory, pericardial, liver, pancreas, retroperitoneal, adrenal gland or kidney; or iii) bleeding into the surgical site requiring reoperation, or iv) bleeding leading to hospitalization.

CI: confidence interval; HR: hazard ratio; ISTH: International Society on Thrombosis and Hemostasis Reduction of Risk of Major Thrombotic Vascular Events in Patients with Peripheral Artery Disease (PAD), Including Patients after Lower Extremity Revascularization due to Symptomatic PAD The incidence of premature permanent discontinuation due to bleeding events for XARELTO 2.5 mg twice daily vs. placebo on background therapy with aspirin 100 mg once daily in VOYAGER was 4.1% vs. 1.6% and in COMPASS PAD was 2.7% vs. 1.3%, respectively.

Table 7 shows the number of patients experiencing various types of TIMI (Thrombolysis in Myocardial Infarction) major bleeding events in the VOYAGER trial. The most common site of bleeding was gastrointestinal.

Table 7: Major Bleeding Events* in VOYAGER- On Treatment Plus 2 Days

Parameter TIMI Major Bleeding (CABG/non-CABG) Fatal bleeding Intracranial bleeding Clinically overt signs of hemorrhage associated with a drop in hemoglobin of ≥5 g/dL or drop in hematocrit of ≥15%

XARELTO† Placebo† XARELTO vs.

N=3256 N=3248 Placebo n (%) Event n (%) Event HR (95 % CI) rate rate %/year %/year 62 (1.9) 0.96 44 (1.4) 0.67 1.4 (1.0, 2.1) 6 (0.2) 13 (0.4)

0.09 0.20

6 (0.2) 17 (0.5)

0.09 0.26

1.0 (0.3, 3.2) 0.8 (0.4, 1.6)

46 (1.4)

0.71

24 (0.7)

0.36

1.9 (1.2, 3.2)

XARELTO® (rivaroxaban)

XARELTO® (rivaroxaban)

* Major bleeding events within each subcategory were counted once per patient, but patients may have contributed events to multiple subcategories. † Treatment schedule: XARELTO 2.5 mg twice daily or placebo. All patients received background therapy with aspirin 100 mg once daily.

CABG: Coronary artery bypass graft; CI: confidence interval; HR: hazard ratio; TIMI: Thrombolysis in Myocardial Infarction Bleeding Criteria

†

Other Adverse Reactions Non-hemorrhagic adverse reactions reported in ≥1% of XARELTO-treated patients in the EINSTEIN DVT and EINSTEIN PE studies are shown in Table 8.

¶

Table 8: Other Adverse Reactions* Reported by ≥1% of XARELTO-Treated Patients in EINSTEIN DVT and EINSTEIN PE Studies Body System Adverse Reaction XARELTO 20 mg Enoxaparin/VKA EINSTEIN DVT Study N=1718 N=1711 n (%) n (%) Gastrointestinal disorders Abdominal pain 46 (2.7) 25 (1.5) General disorders and administration site conditions Fatigue 24 (1.4) 15 (0.9) Musculoskeletal and connective tissue disorders Back pain 50 (2.9) 31 (1.8) Muscle spasm 23 (1.3) 13 (0.8) Nervous system disorders Dizziness 38 (2.2) 22 (1.3) Psychiatric disorders Anxiety 24 (1.4) 11 (0.6) Depression 20 (1.2) 10 (0.6) Insomnia 28 (1.6) 18 (1.1) XARELTO 20 mg Enoxaparin/VKA EINSTEIN PE Study N=2412 N=2405 n (%) n (%) Skin and subcutaneous tissue disorders Pruritus 53 (2.2) 27 (1.1)

‡ §

XARELTO® (rivaroxaban)

Treatment schedule: body weight-adjusted doses of XARELTO; randomized 2:1 (XARELTO: Comparator).

Unfractionated heparin (UFH), low molecular weight heparin (LMWH), fondaparinux or VKA. Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome.

Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 11.

Table 11: Other Adverse Reactions* Reported in XARELTO-Treated Patients by ≥5% in EINSTEIN Junior Study

Adverse Reaction

XARELTO N=329 n (%)

Comparator Group N=162 n (%)

Pain in extremity

23 (7)

7 (4.3)

Fatigue†

23 (7)

7 (4.3)

* Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator. † The following terms were combined: fatigue, asthenia.

* Adverse reaction with Relative Risk >1.5 for XARELTO versus comparator

A clinically relevant adverse reaction in XARELTO-treated patients was vomiting (10.6% in the XARELTO group vs 8% in the comparator group).

Thromboprophylaxis in Pediatric Patients with Congenital Heart Disease (CHD) after the Fontan Procedure The data below are based on Part B of the UNIVERSE study which was designed to evaluate the safety and efficacy of XARELTO for thromboprophylaxis in 98 children with CHD after the Fontan procedure who took at least one dose of study drug. Patients in Part B were randomized 2:1 to receive either body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg).

Discontinuation due to bleeding events occurred in 1 (1.6%) patient in the XARELTO group and no patients in the aspirin group.

Table 12 shows the number of patients experiencing bleeding events in the UNIVERSE study.

Non-hemorrhagic adverse reactions reported in ≥1% of XARELTOtreated patients in RECORD 1-3 studies are shown in Table 9.

Table 12: Bleeding Events in UNIVERSE Study - Safety Analysis Set On Treatment Plus 2 Days

Table 9: Other Adverse Drug Reactions* Reported by ≥1% of XARELTOTreated Patients in RECORD 1-3 Studies XARELTO 10 mg Enoxaparin† Body System N=4524 N=4487 Adverse Reaction n (%) n (%) Injury, poisoning and procedural complications Wound secretion 125 (2.8) 89 (2.0) Musculoskeletal and connective tissue disorders Pain in extremity 74 (1.7) 55 (1.2) Muscle spasm 52 (1.2) 32 (0.7) Nervous system disorders Syncope 55 (1.2) 32 (0.7) Skin and subcutaneous tissue disorders Pruritus 96 (2.1) 79 (1.8) Blister 63 (1.4) 40 (0.9) * Adverse reaction occurring any time following the first dose of doubleblind medication, which may have been prior to administration of active drug, until two days after the last dose of double-blind study medication † Includes the placebo-controlled period of RECORD 2, enoxaparin dosing was 40 mg once daily (RECORD 1-3) Pediatric Patients Treatment of Venous Thromboembolism and Reduction in Risk of Recurrent Venous Thromboembolism in Pediatric Patients The safety assessment is based on data from the EINSTEIN Junior Phase 3 study in 491 patients from birth to less than 18 years of age.

Patients were randomized 2:1 to receive body weight-adjusted doses of XARELTO or comparator (unfractionated heparin, low molecular weight heparin, fondaparinux or VKA).

Discontinuation due to bleeding events occurred in 6 (1.8%) patients in the XARELTO group and 3 (1.9%) patients in the comparator group.

Table 10 shows the number of patients experiencing bleeding events in the EINSTEIN Junior study. In female patients who had experienced menarche, ages 12 to <18 years of age, menorrhagia occurred in 23 (27%) female patients in the XARELTO group and 5 (10%) female patients in the comparator group.

Table 10: Bleeding Events in EINSTEIN Junior Study – Safety Analysis Set - Main Treatment Period*

Parameter Major bleeding§

Comparator Group‡ N=162 n (%)

0

2 (1.2)

10 (3.0)

1 (0.6)

Trivial bleeding

113 (34.3)

44 (27.2)

Any bleeding

119 (36.2)

45 (27.8)

Clinically relevant non-major bleeding¶

*

XARELTO† N=329 n (%)

These events occurred after randomization until 3 months of treatment (1 month for patients <2 years with central venous catheter-related VTE (CVC-VTE). Patients may have more than one event.

Parameter Major Bleeding† Epistaxis leading to transfusion

XARELTO* N=64 n (%)

Aspirin* N=34 n (%)

1 (1.6)

0

1 (1.6)

0

4 (6.3)

3 (8.8)

Trivial bleeding

21 (32.8)

12 (35.3)

Any bleeding

23 (35.9)

14 (41.2)

Clinically relevant non-major (CRNM) bleeding§

Treatment schedule: body weight-adjusted doses of XARELTO or aspirin (approximately 5 mg/kg); randomized 2:1 (XARELTO: Aspirin). † Defined as clinically overt bleeding associated with a decrease in hemoglobin of ≥2 g/dL, a transfusion of the equivalent of ≥2 units of packed red blood cells or whole blood, bleeding at a critical site, or with a fatal outcome. § Defined as clinically overt bleeding, which did not meet the criteria for major bleeding, but was associated with medical intervention, unscheduled contact with a physician, temporary cessation of treatment, discomfort for the patient, or impairment of activities of daily life.

Non-bleeding adverse reactions reported in ≥5% of XARELTO-treated patients are shown in Table 13.

Table 13: Other Adverse Reactions* Reported by ≥5% of XARELTOTreated Patients in UNIVERSE Study (Part B) *

XARELTO N=64 n (%)

Aspirin N=34 n (%)

Cough

10 (15.6)

3 (8.8)

Vomiting

9 (14.1)

3 (8.8)

Gastroenteritis†

8 (12.5)

1 (2.9)

Rash†

6 (9.4)

2 (5.9)

Adverse Reaction

* †

Adverse reaction with Relative Risk >1.5 for XARELTO versus aspirin.

The following terms were combined: Gastroenteritis: gastroenteritis, gastroenteritis viral Rash: rash, rash maculo-papular, viral rash

Postmarketing Experience The following adverse reactions have been identified during postapproval use of XARELTO. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Blood and lymphatic system disorders: agranulocytosis, thrombocytopenia Hepatobiliary disorders: jaundice, cholestasis, hepatitis (including hepatocellular injury) Immune system disorders: hypersensitivity, anaphylactic reaction, anaphylactic shock, angioedema Nervous system disorders: hemiparesis Skin and subcutaneous tissue disorders: Stevens-Johnson syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS)

DRUG INTERACTIONS General Inhibition and Induction Properties Rivaroxaban is a substrate of CYP3A4/5, CYP2J2, and the P-gp and ATPbinding cassette G2 (ABCG2) transporters. Combined P-gp and strong CYP3A inhibitors increase exposure to rivaroxaban and may increase the risk of bleeding. Combined P-gp and strong CYP3A inducers decrease exposure to rivaroxaban and may increase the risk of thromboembolic events.

Drugs that Inhibit Cytochrome P450 3A Enzymes and Drug Transport Systems Interaction with Combined P-gp and Strong CYP3A Inhibitors Avoid concomitant administration of XARELTO with known combined P-gp and strong CYP3A inhibitors (e.g., ketoconazole and ritonavir) [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Although clarithromycin is a combined P-gp and strong CYP3A inhibitor, pharmacokinetic data suggests that no precautions are necessary with concomitant administration with XARELTO as the change in exposure is unlikely to affect the bleeding risk [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Interaction with Combined P-gp and Moderate CYP3A Inhibitors in Patients with Renal Impairment XARELTO should not be used in patients with CrCl 15 to <80 mL/min who are receiving concomitant combined P-gp and moderate CYP3A inhibitors (e.g., erythromycin) unless the potential benefit justifies the potential risk [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Drugs that Induce Cytochrome P450 3A Enzymes and Drug Transport Systems Avoid concomitant use of XARELTO with drugs that are combined P-gp and strong CYP3A inducers (e.g., carbamazepine, phenytoin, rifampin, St. John’s wort) [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information].

Anticoagulants and NSAIDs/Aspirin Coadministration of enoxaparin, warfarin, aspirin, clopidogrel and chronic NSAID use may increase the risk of bleeding [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Avoid concurrent use of XARELTO with other anticoagulants due to increased bleeding risk unless benefit outweighs risk. Promptly evaluate any signs or symptoms of blood loss if patients are treated concomitantly with aspirin, other platelet aggregation inhibitors, or NSAIDs [see Warnings and Precautions].

USE IN SPECIFIC POPULATIONS Pregnancy Risk Summary The limited available data on XARELTO in pregnant women are insufficient to inform a drug-associated risk of adverse developmental outcomes. Use XARELTO with caution in pregnant patients because of the potential for pregnancy related hemorrhage and/or emergent delivery. The anticoagulant effect of XARELTO cannot be reliably monitored with standard laboratory testing. Consider the benefits and risks of XARELTO for the mother and possible risks to the fetus when prescribing XARELTO to a pregnant woman [see Warnings and Precautions].

Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. The estimated background risk of major birth defects and miscarriage for the indicated populations is unknown. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2–4% and 15–20%, respectively.

Clinical Considerations Disease-Associated Maternal and/or Embryo/Fetal Risk Pregnancy is a risk factor for venous thromboembolism and that risk is increased in women with inherited or acquired thrombophilias. Pregnant women with thromboembolic disease have an increased risk of maternal complications including pre-eclampsia. Maternal thromboembolic disease increases the risk for intrauterine growth restriction, placental abruption and early and late pregnancy loss.

Fetal/Neonatal Adverse Reactions Based on the pharmacologic activity of Factor Xa inhibitors and the potential to cross the placenta, bleeding may occur at any site in the fetus and/or neonate.

Labor or Delivery All patients receiving anticoagulants, including pregnant women, are at risk for bleeding and this risk may be increased during labor or delivery [see Warnings and Precautions]. The risk of bleeding should be balanced with the risk of thrombotic events when considering the use of XARELTO in this setting.

Data Human Data There are no adequate or well-controlled studies of XARELTO in pregnant women, and dosing for pregnant women has not been established. Post-marketing experience is currently insufficient to determine a rivaroxaban-associated risk for major birth defects or miscarriage. In an in vitro placenta perfusion model, unbound rivaroxaban was rapidly transferred across the human placenta.

Animal Data Rivaroxaban crosses the placenta in animals. Rivaroxaban increased fetal toxicity (increased resorptions, decreased number of live fetuses, and decreased fetal body weight) when pregnant rabbits were given oral doses of ≥10 mg/kg rivaroxaban during the period of organogenesis. This dose corresponds to about 4 times the human exposure of unbound drug, based on AUC comparisons at the highest recommended human dose of 20 mg/day. Fetal body weights decreased when pregnant rats were given oral doses of 120 mg/kg during the period of organogenesis. This dose corresponds to about 14 times the human exposure of unbound drug. In rats, peripartal maternal bleeding and maternal and fetal death occurred at the rivaroxaban dose of 40 mg/kg (about 6 times maximum human exposure of the unbound drug at the human dose of 20 mg/day).

XARELTO® (rivaroxaban)

XARELTO® (rivaroxaban)

Lactation Risk Summary Rivaroxaban has been detected in human milk. There are insufficient data to determine the effects of rivaroxaban on the breastfed child or on milk production. Rivaroxaban and/or its metabolites were present in the milk of rats. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for XARELTO and any potential adverse effects on the breastfed infant from XARELTO or from the underlying maternal condition (see Data).

Data Animal Data Following a single oral administration of 3 mg/kg of radioactive [14C]-rivaroxaban to lactating rats between Day 8 to 10 postpartum, the concentration of total radioactivity was determined in milk samples collected up to 32 hours post-dose. The estimated amount of radioactivity excreted with milk within 32 hours after administration was 2.1% of the maternal dose.

Females and Males of Reproductive Potential Females of reproductive potential requiring anticoagulation should discuss pregnancy planning with their physician.

The risk of clinically significant uterine bleeding, potentially requiring gynecological surgical interventions, identified with oral anticoagulants including XARELTO should be assessed in females of reproductive potential and those with abnormal uterine bleeding.

Pediatric Use The safety and effectiveness of XARELTO have been established in pediatric patients from birth to less than 18 years for the treatment of VTE and the reduction in risk of recurrent VTE. Use of XARELTO is supported in these age groups by evidence from adequate and wellcontrolled studies of XARELTO in adults with additional pharmacokinetic, safety and efficacy data from a multicenter, prospective, open-label, active-controlled randomized study in 500 pediatric patients from birth to less than 18 years of age. XARELTO was not studied and therefore dosing cannot be reliably determined or recommended in children less than 6 months who were less than 37 weeks of gestation at birth; had less than 10 days of oral feeding, or had a body weight of less than 2.6 kg [see Dosage and Administration (2.2) in Full Prescribing Information, Adverse Reactions, Clinical Pharmacology (12.3) and Clinical Studies (14.8) in Full Prescribing Information].

The safety and effectiveness of XARELTO have been established for use in pediatric patients aged 2 years and older with congenital heart disease who have undergone the Fontan procedure. Use of XARELTO is supported in these age groups by evidence from adequate and wellcontrolled studies of XARELTO in adults with additional data from a multicenter, prospective, open-label, active controlled study in 112 pediatric patients to evaluate the single- and multiple-dose pharmacokinetic properties of XARELTO and the safety and efficacy of XARELTO when used for thromboprophylaxis for 12 months in children with single ventricle physiology who had the Fontan procedure [see Dosage and Administration (2.2) in Full Prescribing Information, Adverse Reactions, Clinical Pharmacology (12.3) and Clinical Studies (14.9) in Full Prescribing Information].

Clinical studies that evaluated safety, efficacy, pharmacokinetic and pharmacodynamic data support the use of XARELTO 10 mg, 15 mg, and 20 mg tablets in pediatric patients. For the XARELTO 2.5 mg tablets, there are no safety, efficacy, pharmacokinetic and pharmacodynamic data to support the use in pediatric patients. Therefore, XARELTO 2.5 mg tablets are not recommended for use in pediatric patients.

Although not all adverse reactions identified in the adult population have been observed in clinical trials of children and adolescent patients, the same warnings and precautions for adults should be considered for children and adolescents.

those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.

Geriatric Use Of the total number of adult patients in clinical trials for the approved indications of XARELTO (N=64,943 patients), 64 percent were 65 years and over, with 27 percent 75 years and over. In clinical trials the efficacy of XARELTO in the elderly (65 years or older) was similar to that seen in patients younger than 65 years. Both thrombotic and bleeding event rates were higher in these older patients [see Clinical Pharmacology (12.3) and Clinical Studies (14) in Full Prescribing Information].

Renal Impairment In pharmacokinetic studies, compared to healthy adult subjects with normal creatinine clearance, rivaroxaban exposure increased by approximately 44 to 64% in adult subjects with renal impairment. Increases in pharmacodynamic effects were also observed [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Nonvalvular Atrial Fibrillation Patients with Chronic Kidney Disease not on Dialysis In the ROCKET AF trial, patients with CrCl 30 to 50 mL/min were administered XARELTO 15 mg once daily resulting in serum concentrations of rivaroxaban and clinical outcomes similar to those in patients with better renal function administered XARELTO 20 mg once daily. Patients with CrCl <30 mL/min were not studied, but administration of XARELTO 15 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Patients with End-Stage Renal Disease on Dialysis Clinical efficacy and safety studies with XARELTO did not enroll patients with end-stage renal disease (ESRD) on dialysis. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 15 mg once daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in the ROCKET AF study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar stroke reduction and bleeding risk in patients with ESRD on dialysis as was seen in ROCKET AF. Treatment of DVT and/or PE and Reduction in the Risk of Recurrence of DVT and/or PE In the EINSTEIN trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO is expected to result in serum concentrations of rivaroxaban similar to

Prophylaxis of DVT Following Hip or Knee Replacement Surgery The combined analysis of the RECORD 1-3 clinical efficacy studies did not show an increase in bleeding risk for patients with CrCl 30 to 50 mL/min and reported a possible increase in total venous thromboemboli in this population. In the RECORD 1-3 trials, patients with CrCl values <30 mL/min at screening were excluded from the studies, but administration of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid the use of XARELTO in patients with CrCl <15 mL/min.

Prophylaxis of Venous Thromboembolism in Acutely Ill Medical Patients at Risk for Thromboembolic Complications Not at High Risk of Bleeding Patients with CrCl values <30 mL/min at screening were excluded from the MAGELLAN study. In patients with CrCl <30 mL/min a dose of XARELTO 10 mg once daily is expected to result in serum concentrations of rivaroxaban similar to those in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Observe closely and promptly evaluate any signs or symptoms of blood loss in patients with CrCl 15 to <30 mL/min. Avoid use of XARELTO in patients with CrCl <15 mL/min.

Reduction of Risk of Major Cardiovascular Events in Patients with CAD and Reduction of Risk of Major Thrombotic Vascular Events in Patients with PAD, Including Patients After Recent Lower Extremity Revascularization due to Symptomatic PAD Patients with Chronic Kidney Disease not on Dialysis Patients with a CrCl <15 mL/min at screening were excluded from COMPASS and VOYAGER, and limited data are available for patients with a CrCl of 15 to 30 mL/min. In patients with CrCl <30 mL/min, a dose of 2.5 mg XARELTO twice daily is expected to give an exposure similar to that in patients with moderate renal impairment (CrCl 30 to <50 mL/min) [see Clinical Pharmacology (12.3) in Full Prescribing Information], whose efficacy and safety outcomes were similar to those with preserved renal function.

Patients with End-Stage Renal Disease on Dialysis No clinical outcome data is available for the use of XARELTO with aspirin in patients with ESRD on dialysis since these patients were not enrolled in COMPASS or VOYAGER. In patients with ESRD maintained on intermittent hemodialysis, administration of XARELTO 2.5 mg twice daily will result in concentrations of rivaroxaban and pharmacodynamic activity similar to those observed in moderate renal impaired patients in the COMPASS study [see Clinical Pharmacology (12.2, 12.3) in Full Prescribing Information]. It is not known whether these concentrations will lead to similar CV risk reduction and bleeding risk in patients with ESRD on dialysis as was seen in COMPASS. Pediatric Use No dosage adjustment is required in patients 1 year of age or older with mild renal impairment (eGFR 50 to ≤ 80 mL/min/1.73 m2). There are limited clinical data in pediatric patients 1 year or older with moderate or severe renal impairment (eGFR <50 mL/min/1.73 m2); therefore, avoid the use of XARELTO in these patients.

There are no clinical data in pediatric patients younger than 1 year with serum creatinine results above 97.5th percentile; therefore, avoid the use of XARELTO in these patients [see Dosage and Administration (2.2) in Full Prescribing Information].

Hepatic Impairment In a pharmacokinetic study, compared to healthy adult subjects with normal liver function, AUC increases of 127% were observed in adult subjects with moderate hepatic impairment (Child-Pugh B).

The safety or PK of XARELTO in patients with severe hepatic impairment (Child-Pugh C) has not been evaluated [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Avoid the use of XARELTO in patients with moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment or with any hepatic disease associated with coagulopathy.

No clinical data are available in pediatric patients with hepatic impairment.

OVERDOSAGE Overdose of XARELTO may lead to hemorrhage. Discontinue XARELTO and initiate appropriate therapy if bleeding complications associated with overdosage occur. Rivaroxaban systemic exposure is not further increased at single doses >50 mg due to limited absorption. The use of activated charcoal to reduce absorption in case of XARELTO overdose may be considered. Due to the high plasma protein binding, rivaroxaban is not dialyzable [see Warnings and Precautions and Clinical Pharmacology (12.3) in Full Prescribing Information]. Partial reversal of laboratory anticoagulation parameters may be achieved with use of plasma products. An agent to reverse the anti-factor Xa activity of rivaroxaban is available.

Active Ingredient Made in Germany Manufactured for: Janssen Pharmaceuticals, Inc. Titusville, NJ 08560 Licensed from: Bayer HealthCare AG 51368 Leverkusen, Germany © 2011-2021 Janssen Pharmaceutical Companies cp-62545v11

Por: Laura Martí-Gelonch*, José I. Asensio-Gallego, Emma Eizaguirre-Letamendia, Francisco J. Murgoitio-Lazkano, Íñigo Arana-Iñiguez, José M. Enríquez-Navascués Servicio de Cirugía General y Digestiva, Sección de Cirugía Esofagogástrica y Obesidad, Hospital Universitario Donostia, San Sebastián, España

DIAGNÓSTICO INESPERADO EN PACIENTE CON SOSPECHA DE GIST:

INFILTRACIÓN GÁSTRICA POR MIELOMA MÚLTIPLE RESUMEN El mieloma múltiple se caracteriza por la proliferación neoplásica medular de células plasmáticas productoras de inmunoglobulina monoclonal. Un porcentaje pequeño de pacientes presenta compromiso extramedular en forma de plasmocitoma, siendo la localización más habitual las vías respiratorias altas. La afectación gastrointestinal es rara y la clínica asociada dependerá de la localización, la extensión y el mecanismo de infiltración. La afectación gástrica en forma de tumoración tiene un aspecto y una sintomatología similares a los de otras lesiones, por lo que es necesario realizar un diagnóstico histológico para un adecuado tratamiento.

A continuación se presenta el caso de un mieloma múltiple con afectación gástrica.

Palabras clave Estómago. GIST. Hemorragia. Mieloma.

Keywords Stomach. GIST. Hemorrhage. Mieloma.

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ABSTRACT Multiple myeloma is characterized by medullary neoplastic proliferation of plasma cells producing monoclonal immunoglobulin. A small percentage of patients have extramedullary involvement in form of plasmacytoma, the most common location being the upper respiratory tract. Gastrointestinal involvement is rare and the associated symptoms will depend on the location, extent and mechanism of infiltration. Gastric involvement presents an appearance and symptoms similar to other lesions, so a histological diagnosis is necessary for proper treatment. This article presents the case of multiple myeloma with gastric involvement.

CASO CLÍNICO INTRODUCCIÓN El mieloma múltiple se caracteriza por la proliferación neoplásica de células plasmáticas productoras de inmunoglobulina (Ig) monoclonal. Aunque la mayoría de los pacientes presentan únicamente compromiso intramedular, hasta en un 20% puede haber compromiso extramedular en forma de plasmocitoma, siendo la localización más habitual las vías respiratorias altas (orofaringe, nasofaringe, senos paranasales y laringe)1. La afectación del tracto digestivo es rara; representa menos del 5% de los plasmocitomas y menos del 1% de los casos de mieloma múltiple2. La localización gastrointestinal más habitual es el intestino delgado, seguido del estómago, el colon y el esófago1. La mayoría de los pacientes con afectación gastrointestinal son diagnosticados durante el seguimiento de la enfermedad o en recidivas, siendo excepcional su diagnóstico como primera manifestación. A continuación se presenta el caso de un plasmocitoma gástrico que debuta con hemorragia digestiva, y se realiza una revisión de la literatura.

CASO CLÍNICO Mujer de 76 años con antecedentes de hipertensión y diabetes tipo 2, diagnosticada de mieloma múltiple IgG-kappa en febrero de 2018, en estadio IIIA ISS-3, con afectación únicamente intramedular con múltiples lesiones óseas y tratada con nueve ciclos de bortezomib-ciclofosfamida-dexametasona (VCD) con muy buena respuesta parcial en diciembre de 2018.

En seguimiento en consultas de hematología, en el último control, en diciembre de 2019, presenta estabilidad clínica pero con una lenta progresión de la gammapatía, por lo que se plantea reiniciar el tratamiento antimieloma.

Previo al inicio del tratamiento, ingresa en el servicio de digestivo en enero de 2020 por melenas junto con anemización hasta una hemoglobina de 7,9, sin presentar clínica digestiva ni repercusión hemodinámica. Se inicia el estudio realizando una gastroscopia preferente (Fig. 1), con hallazgo de una lesión de aspecto submucoso en la curvatura mayor de unos 50 mm de diámetro, con gran úlcera central

que sugiere tumoración del estroma gastrointestinal (GIST, gastrointestinal stromal tumor); se realizan biopsias de la lesión.

Se completa el estudio con tomografía computarizada toracoabdominopélvica (Fig. 2), en la que se objetiva, además de la masa en el fundus gástrico de 7 × 2,6 cm, un nódulo sólido paravertebral izquierdo de 2,4 cm y múltiples lesiones óseas líticas. Se realiza también una resonancia magnética de cuerpo entero solicitada por el servicio de hematología, y se objetivan los mismos hallazgos que en la tomografía computarizada.

Figura 1. Imagen endoscópica de la lesión.

Figura 2. Imagen de tomografía computarizada de la lesión.

Se presenta el caso en el comité de tumores y se decide realizar cirugía resectiva de la lesión gástrica, sospechosa de GIST, por hemorragia digestiva, a pesar de no tener los resultados de anatomía patológica y previo a reiniciar el tratamiento del mieloma. Antes de la fecha programada para la intervención, la paciente reingresa por melenas y anemización hasta una hemoglobina de 4,8, por lo que se decide realizar una cirugía preferente.

Se interviene a principios de febrero de 2020 mediante abordaje laparoscópico, que muestra una tumoración de gran ta-

maño en el cuerpo gástrico, cara posterior, de unos 12 cm de diámetro máximo, umbilicada y muy friable. Presenta adenopatías aumentadas de tamaño en el tronco celíaco. Dado que se desconoce todavía la naturaleza de la lesión, y ante los hallazgos intraoperatorios sospechosos de malignidad, se decide realizar una gastrectomía total con linfadenectomía D2 y reconstrucción en Y de Roux.

El posoperatorio transcurre sin incidencias y se reinicia la dieta oral al séptimo día, tras realizar un estudio baritado que no objetivaba fugas. Al décimo día de posoperatorio presenta fiebre y dolor en el hipocondiro derecho secundario a un hematoma intraabdominal infectado que requiere drenaje percutáneo, con mejoría posterior. La paciente es dada de alta en el día 21 de posoperatorio.

El estudio anatomopatológico de la pieza reveló una tumoración de 12, 5 × 9 cm correspondiente a una proliferación neoplásica de células plasmáticas con restricción de cadenas ligeras Kappa. Cinco ganglios linfáticos del grupo 1 presentaban proliferación de células plasmáticas; el resto eran reactivos. Se hallaron además tres implantes en el tejido adiposo del tronco celíaco. Las biopsias realizadas preoperatoriamente también mostraban infiltración gástrica por mieloma de células plasmáticas kappa.

Actualmente la paciente se encuentra a la espera de iniciar el tratamiento antimieloma.

DISCUSIÓN El plasmocitoma extramedular es poco frecuente, puede aparecer de forma solitaria o asociado a mieloma múltiple, representando una progresión extramedular de la enfermedad3. La localización más habitual es las vías aéreas altas, y la afectación gastrointestinal rara. En un estudio publicado por Talamo, et al.2 en el que se revisaban 2584 casos de mieloma múltiple, solo 24 (0,9%) presentaban afectación gastrointestinal. Además, se observó que la afectación gástrica al manifestarse la enfermedad es mucho más infrecuente que cuando se presenta en el curso de una enfermedad avanzada o en progresión, como en nuestra paciente, asocián-

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Endoscópicamente se presentan como múltiples ulceraciones mucosas o bien como una masa única ulcerada, similar a otro tipo de tumores con los cuales debe hacerse un diagnóstico diferencial. dose en estos casos a mal pronóstico.

La sintomatología asociada a la afectación gastrointestinal depende de la extensión y se produce por tres mecanismos: invasión directa de un órgano, efecto masa o ascitis mielomatosa2. Cuando afecta al estómago, el mecanismo suele ser por invasión directa y los síntomas son anorexia, pérdida de peso, náuseas, vómitos, sangrado digestivo oculto y rara vez sangrado activo1,3-6. En nuestra paciente destacaban la importante anemización y la hemorragia digestiva en forma de melenas, sin presentar inestabilidad hemodinámica que requiriese realizar una intervención de urgencia.

Endoscópicamente se presentan como múltiples ulceraciones mucosas o bien como una masa única ulcerada, similar a otro tipo de tumores con los cuales debe hacerse un diagnóstico diferencial.

Dentro de los diagnósticos hay que considerar el adenocarcinoma, los GIST, los tumores neuroendocrinos, los linfomas (en particular el linfoma MALT [mucosa associated lymphoid tissue]) y la amiloidosis gastrointestinal, por lo que la realización de biopsias para el estudio anatomopatológico e inmunohistoquímico es crucial3,4,7.

Desde el punto de vista inmunológico, un 27% expresan IgG, un 33% IgA y un 40% IgM1. En cuanto a su estudio histológico, es importante diferenciarlo del linfoma de células B de bajo grado asociado a las mucosas (linfoma MALT), ya que el estómago es su localización más habitual1,4.

Cuando se manifiesta como plasmocitoma solitario, tanto la cirugía o exéresis endoscópica como la radioterapia se han descrito como opciones terapéuticas3,6,7.

En ocasiones, cuando no es posible conseguir márgenes libres de tumor, se puede asociar radioterapia. La única excepción serían los plasmocitomas solitarios localizados en la cabeza y el cuello. En estos casos, la radioterapia es el tratamiento de elección6. Cuando se manifiesta asociado a mieloma múltiple se han descrito diversas opciones terapéuticas según su forma de presentación. Si se presentan en forma de hemorragia digestiva se puede realizar una endoscopia terapéutica (habitualmente con malos resultados y resangrado por tratarse de un tejido tumoral) 66

o radioterapia local. Siddique, et al.8 reportan un caso de plasmocitoma duodenal tratado mediante embolización de la arteria gastroduodenal en un paciente con hemorragia digestiva recurrente y alto riesgo quirúrgico. La cirugía se suele indicar en los pacientes que presentan un sangrado incontrolable o recurrente, como en nuestro caso, y en aquellos que presentan clínica obstructiva3. La quimioterapia con esquemas como bortezomib + dexametasona se suele reservar para los casos más avanzados; es bien tolerada, con pocos efectos adversos y consigue remisiones completas, además de evitar los efectos adversos de la radiación abdominal9.

En nuestro caso, las biopsias preoperatorias confirmaban el diagnóstico definitivo, pero su resultado no se obtuvo hasta después de la intervención. Nuestra paciente presentaba un sangrado persistente, por lo que la cirugía resectiva estaba indicada. El conocimiento de la naturaleza de la lesión preoperatoriamente podría haber modificado la técnica quirúrgica y haber realizado un procedimiento menos agresivo, por lo que creemos importante realizar un diagnóstico histológico.

Conflicto de intereses Los autores declaran que no existe conflicto de intereses.

Financiamiento Los autores declaran que no existen fuentes de financiación.

Responsabilidades éticas Protección de personas y animales. Los autores declaran que para esta investigación no se han realizado experimentos en seres humanos ni en animales.

Confidencialidad de los datos. Los autores declaran que han seguido los protocolos de su centro de trabajo sobre la publicación de datos de pacientes.

Derecho a la privacidad y consentimiento informado. Los autores han obtenido el consentimiento informado de los pacientes y/o sujetos referidos en el artículo. Este documento obra en poder del autor de correspondencia.

Revista Puertorriqueña de Medicina y Salud Pública

Bibliografía 1. Chim CS, Wong WM, Nicholls J, Chung LP, Liang R. Extramedullary sites of involvement in hematologic malignancies:case 3. Hemorrhagic gastric plasmacytoma as the primary presentation in multiple myeloma. J Clin Oncol. 2002;20:344-7.

2. Talamo G, Cavallo F, Zangari M, Barlogie B, Lee CK, Pineda-Roman M, et al.

Clinical and biological features of multiple myeloma involving the gastrointestinal system. Haematologica. 2006;91:964-7.

3. Telakis E, Tsironi E, Tavoularis G, Papatheodorou K, Tzaida O, Nikolaou A. Gastrointestinal involvement in a patient with multiple myeloma:a case report. Ann Gastroenterol. 2009;22:287-90.

4. Vicuña Arregui M, Borobio Aguilar E, Vila Costas JJ, Cruz Viguria Alegría M, Arrechea Irigoyen M, Borda Celaya F, et al. Plasmocitoma gástrico como causa infrecuente de hemorragia digestiva alta.

Gastroenterol Hepatol. 2008;31:217-20.

5. Comba IY, Torres Luna NE, Cooper C, Crespo MW, Carilli A. A rare case of extramedullary plasmacytoma presenting as massive upper gastrointestinal bleeding.

Cureus. 2019;11:e3993.

6. Honkisz BJ. Multiple myeloma with the primary gastric manifestation. J Clin Case Rep. 2015;05(04). (COnsultado el 24 de marzo de 2020.) Disponible en:http://www.omicsgroup.org/journals/ multiple-myeloma-with-the-primary-gastric-manifestation-2165-7920-1000525. php?aid=55637 7. Park CH, Lee SM, Kim TO, Kim DU, Jung WJ, Kim GH, et al. Treatment of solitary extramedullary plasmacytoma of the stomach with endoscopic submucosal dissection. Gut Liver. 2009;3:334-7.

8. Siddique I, Papadakis KA, Weber DM, Glober G. Recurrent bleeding from a duodenal plasmacytoma treated successfully with embolization of the gastroduodenal artery. Am J Gastroenterol.

1999;94:1691-2.

9. Katodritou E, Kartsios C, Gastari V, Verrou E, Mihou D, Banti A, et al. Successful treatment of extramedullary gastric plasmacytoma with the combination of bortezomib and dexamethasone:first reported case. Leuk Res. 2008;32:339-41.

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PROTÉGETE CONTRA EL CÁNCER DE PIEL -Una condición prevenible que puede afectar a cualquieraPor: Anabelle Carrión, BSHE, MPHE Vicepresidenta Auxiliar de Promoción y Bienestar de la Salud de MCS

L

as estadísticas son claras. El cáncer de la piel es el tipo de cáncer más común en Estados Unidos según la revista de la Biblioteca Nacional de Medicina de los Estados Unidos, MedlinePlus. De hecho, el Registro Central de Cáncer de Puerto Rico indica que ha habido un aumento en el cáncer de piel en la Isla en los últimos 10 años.

Esta enfermedad provocada por el exceso de exposición a los rayos ultravioleta (UV) del sol y de equipos y camas de bronceado, altera la piel formando células cancerosas. Esto en conjunto con la falta de protección adecuada y el desconocer el efecto acumulativo que tiene la exposición diaria al sol en el órgano más grande del cuerpo, la piel.

FACTORES DE RIESGO: • Historial familiar de cáncer de piel.

• Piel clara, ojos y cabello claro, pero a cualquiera puede afectarle.

• Exposición al sol por años sin protección.

La buena noticia es que es prevenible.

A continuación, algunas recomendaciones generales para prevenir el daño a la piel causado por el sol.

• Protección de la piel: o Usar ropa apropiada en la playa, el parque y hasta en el patio, por ejemplo, camisas de manga larga con protección contra rayos UV. o Usar gorra o sombrero de ala ancha. o Usar gafas para evitar condiciones de la vista en el futuro.

• Bloqueador solar: o Escoger un bloqueador solar de al menos 30 SPF, que filtra aproximadamente el 97% de los rayos UV; si es de 50 es un 98%. Su clasificación conocida como factor de protección solar o SPF, comienza en 15 indicando que a la piel le tomará 15 veces más tiempo quemarse que si no lo tuvieses aplicado; 30 veces más en el caso de un SPF 30 y así sucesivamente. o Aplicarlo al menos 20 minutos antes de la exposición al sol. o Replicarlo cada dos horas o luego de nadar, sudar o usar la toalla. Este paso es el más i mportante. o Para el rostro de acuerdo con el tipo

de piel. Hoy día las casas de cosméticos están incluyendo filtro solar en algunos productos como las bases.

• Vigilar el horario y clima: o Evitar la exposición excesiva entre 10:00 a.m. y 4:00 p.m. A mediodía los rayos UV son más fuertes. o En días nublados o en el auto, los rayos UV también afectan. o Protegerse no sólo en verano, sino todo el año.

• Observar la piel: oVigila las manchas, heridas que no cicatrizan y lunares nuevos. oUsa la guía del ABCDE para saber cuándo debes consultar al médico relacionado a un lunar o mancha en la piel: • Asimetría: Su forma no es pareja.

• Bordes irregulares y el color se puede extender a la piel que lo rodea.

• Color disparejo; puede haber variedad de tonos hasta negro, con partes rojas, blancas o azules.

• Diámetro: El tamaño va aumentando.

Los melanomas pueden ser muy pequeños, pero generalmente miden más de 1/4 de pulgada de ancho.

• Evolución: Se nota cómo va cambiando.

Además, procura siempre: • Mantenerte bajo la sombra.

• Usar sombrilla de playa o toldo, y para eventos al aire libre, o un paraguas.

• Salir al patio antes de las 10:00 a.m. o luego de las 4 p.m.

• Mantenerte hidratado • Usar filtro solar diariamente y antes del maquillaje.

La exposición prolongada por años al sol no tan solo aumenta el riesgo de sufrir de esta condición, sino que provoca la aparición de manchas, resequedad y arrugas que no pueden ser revertidas. Al estar consciente de la importancia y el cuidado que merece el órgano más grande del cuerpo, es posible prevenir y disfrutar de una verdadera salud completa.

REFERENCIAS: https://magazine.medlineplus.gov/es/art%C3%ADculo/ deteccion-del-cancer-de-piel-consejos-delinstituto-nacional-del-cancer/ https://www.cancer.org/es/noticias-recientes/escoja-el-protector-solar-adecuado. html#:~:text=El%20n%C3%BAmero%20 SPF%20(o%20FPS,n%C3%BAmero%2C%20menor%20es%20la%20 diferencia. https://wwwnc.cdc.gov/travel/page/ sun-exposure https://www.cancer.org/es/cancer/ cancer-de-piel-tipo-melanoma/acerca/ estadisticas-clave.html https://bvirtualogp.pr.gov/ogp/Bvirtual/ leyesreferencia/PDF/11-2021.pdf

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Revista Puertorriqueña de Medicina y Salud Pública

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Presentado por:

MSP lanza campaña educativa junto a Danilo Beauchamp para educar sobre la

PSORIASIS en Puerto Rico

Danilo Beauchamp

Actor, Comediante y Vocero de la campaña “Sin Miedo a la Psoriasis”. Foto: Revista de Medicina y Salud Pública. Natalia Rivera.

SINMIEDOALAPSORIASIS.COM

Debido a la necesidad de fortalecer la educación sobre la enfermedad de la psoriasis, la importancia de diagnosticarla a tiempo y, sobre todo, la necesidad de una pronta atención médica, la Revista de Medicina y Salud Pública (MSP) lanzó hoy una campaña educativa en alianza con el comediante Danilo Beauchamp, titulada “Sin Miedo a la Psoriasis”.

Cabe destacar que el también productor anunció en exclusiva su diagnóstico de psoriasis durante el mes de octubre del año 2021, a través de un simposio educativo producido por la revista MSP junto al Recinto de Ciencias Médicas y la Sociedad Dermatológica de Puerto Rico.

“Agradezco a la revista de Medicina y Salud Pública por esta oportunidad de ser la voz de la campaña de orientación sobre la psoriasis. Estoy confiado que a través de esta campaña continuaremos educando sobre esta enfermedad que tiene forma de combatirse si la diagnosticamos y atendemos a tiempo”, expresó Danilo Beauchamp.

De igual manera, concordó con el reumatólogo y consejero editorial de la revista MSP, el doctor Oscar Soto Raíces, la necesidad de educación que existe 76

para con esta enfermedad autoinmune.

El reumatólogo y consejero editorial de la revista MSP, el doctor Oscar Soto Raíces, reconoció la necesidad de este tipo de campañas educativas, debido a que esta condición crónica no es contagiosa y el paciente puede tener la tranquilidad de compartir y hacer su vida normal sin temor al rechazo.

“Recordemos que cuando esta condición dermatológica es detectada a tiempo, las oportunidades son más amplias para el paciente a nivel corporal y psicosocial, lo que impacta de manera positiva en su vida y su entorno. La psoriasis no es contagiosa y los pacientes con el tratamiento adecuado van a tener una vida normal”, enfatizó.

La opinión del especialista no solo favorece al paciente, sino que destaca el valor de esta campaña que busca educar a las personas que conocen a un paciente con esta condición, quienes necesitan información que les confirme que su amigo o familiar necesita de su apoyo.

La campaña educativa recobrará mayor impacto para el mes de octubre de este año, donde se celebra el Día Mundial de la Psoriasis.

Revista Puertorriqueña de Medicina y Salud Pública

“La psoriasis es una condición de la piel que afecta al paciente en el aspecto físico y emocional. Si no se le educa y no se le empodera en torno a los cuidados personales necesarios como complemento a la medicina, pudiera resultar en serias consecuencias. Por ello la importancia de visitar a un especialista de la piel para un tratamiento efectivo que lleve a un nivel de estabilidad dentro de la enfermedad”, destacó en entrevistas previas la Dra. Damaris Torres- Paoli, presidenta de la Sociedad Dermatológica de Puerto Rico, asociación de especialistas en dermatología que han indicado que, en el caso particular de Puerto Rico, existen aproximadamente de 35.000 a 100.000 personas que padecen de psoriasis.

Te invitamos hoy a convertirte en un agente de educación y prevención de la psoriasis, visitando www.sinmiedoalapsoriasis.com y compartiendo nuestros contenidos especiales a través de todas nuestras redes sociales, @revistamsp @ revistaginecologia @pediatriayfamilia @saludycardiologia @artritisyreuma @ revistadiabetesPR @saludoncologia @ ElForodePuertoRico

MSP SERVICIO PÚBLICO IMPACTO ECONÓMICO DE LA INDUSTRIA BIOFARMACÉUTICA EN LA ISLA Leslie Adames, director de la División de Análisis y Política Económica de Estudios Técnicos, Inc y el Licenciado Carlos Bonilla, retirado de la Industria y miembro de la Junta de Fundación. Foto: Suministrada a la Revista de Medicina y Salud Pública.

la Asociación de la Industria Farmacéutica de Puerto Rico (PIA) informó el impacto económico de la industria biofarmacéutica en la Isla, en donde indicaron que los aportes serían de más de $3,000 millones en contribuciones al fisco, lo que representa cerca del 37% de los ingresos que recauda el Gobierno de Puerto Rico, así lo destacó el licenciado Carlos Bonilla, retirado de la Industria y miembro de la Junta de Fundación.

Por su parte, el economista Leslie Adames, director de la División de Análisis y Política Económica de Estudios Técnicos, Inc., indicó que la industria biofarmacéutica aporta el 18% del Producto Interno Bruto (GDP por sus siglas en inglés) y genera más de 87,400 empleos directos e indirectos en la

Isla. Esto incluye 18,000 empleos directos en diferentes compañías farmacéuticas que operan localmente y cuyos empleados aportan más de $150 millones en contribuciones anuales.

“Puer to Rico tiene conocimientos acumulados de muchas décadas, y por otro un capital humano altamente diestro que se puede alinerar con los requisitos tecnológicos que se dan dentro de esta industria. Hay otro elemento, es el pleno conocimiento de cuáles son las reglamentaciones y los requisitos de cumplimiento de Ley y todo eso, obviamente, aporta a que Puerto Rico tenga importancia en la industria”, explicó Adames.

Ambos indicaron que se estima que el salario promedio de los empleados de la

industria es de $80,000 y se paga una nómina de sobre $1,400 millones. La industria adquiere productos y servicios locales que se valoran en más de $750 millones, todo esto al año.

“Puerto Rico produce 4 de los 20 medicamentos principales que se consumen globalmente. En total 11 de las 20 compañías principales biofarmacéuticas del mundo tienen operaciones de manufactura en Puerto Rico, específicamente en 11 municipios donde generan empleos, actividad económica, pagan patentes e invierten en programas comunitarios y educativos”, destacó Bonilla.

EQUIDAD Y PODER: LA MUJER COMO FIGURA DE APORTE A LA SALUD DE LOS PUERTORRIQUEÑOS Dra. Marelli Colon Emeric, psiquiatra de niños y adolescentes con práctica privada en Puerto Rico. Dra. Marcia Cruz Correa, directora ejecutiva del centro comprensivo de cáncer de la universidad de Puerto Rico. Dra. Marietta Vázquez, profesora de pediatría en la escuela de medicina de Yale. Foto: Revista de Medicina y Salud Pública. Belinda Burgos.

Durante el panel, Charlando con ellas, las doctoras puertorriqueñas destacaron sus proyectos de vida, desde familia, medicina, ciencia y la investigación. Cada una desde su especialidad compartió con los asistentes esas vivencias que hoy por hoy las tienen en los espacios de liderazgo que ocupan, siendo el ejemplo profesional de muchas estudiantes y mujeres médicas.

“El número de mujeres en el c-suit es bajo, probablemente el 10 % o 20 % de estos roles son ejecutados por mujeres. A nivel nacional hay 113 centros de cáncer en EE.UU. y de esa cantidad solo hay 7 mujeres a cargo”, señala La Dra. Marcia Cruz Correa, gastroenteróloga, oncóloga, quién desarrolla investigaciones en cáncer y es directora ejecutiva del centro comprensivo de cáncer

de la universidad de Puerto Rico.

Enfatizando en el poder que tienen las mujeres, “que la capacidad intelectual es idéntica, que la capacidad de completar tareas difíciles y complejas, es igual en el hombre y la mujer; las médicas tienen todas las capacidades para llegar a estos roles de liderazgo”.

La Dra. Marietta Vázquez, es profesora de pediatría en la Escuela de Medicina de Yale, y funge como la primera profesora puertorriqueña de la academia. Por otra parte, fue la primera decana en la historia de Yale, siendo una mujer latina.

“La mujer puertorriqueña se destaca dentro y fuera de la Isla; tenemos una responsabilidad de quienes vienen detrás de nosotros, hacerles entender que tenemos el mismo nivel

de excelencia que las personas que no son latinas y que los hombres”, afirma la Dra. Vázquez y extiende el llamado a todas las mujeres que actualmente están cursando su carrera de medicina o están en el desarrollo de un proyecto de vida vinculado a la salud.

Por su parte, la Dra. Marelli Colon Emeric, psiquiatra de niños y adolescentes con práctica privada en Puerto Rico; resalto sus esfuerzos en establecer para todos la relación de la salud física y mental como un factor determinante para mejorar todos los aspectos de la vida de los pacientes. Haciendo una invitación a médicos y profesionales de salud a ser integrales y cumplir con su vocación de servicio, pensando siempre primero en su salud propia.

Revista Puertorriqueña de Medicina y Salud Pública

77

MSP SERVICIO PÚBLICO

LA FDA APRUEBA MAVACAMTEN PARA LA MIOCARDIOPATÍA HIPERTRÓFICA OBSTRUCTIVA Camzyos es el primer y único inhibidor de la miosina cardíaca aprobado por la FDA que se dirige específicamente a la fuente de la MCH obstructiva.

“La aprobación de Camzyos representa un hito importante p ara l os p a cie nt e s c o n MCH obstructiva sintomática adecuada y sus familias, que han esperado durante mucho tiempo

una nueva opción de tratamiento para esta enfermedad crónica y progresiva”, así lo indicó Anjali T. Owens, directora médica del Centro de enfermedades cardíacas hereditarias y profesor asistente de medicina de la Facultad de medicina Perelman de la Universidad de Pensilvania, en Filadelfia, en un comunicado de prensa.

JARDIANCE® FASE III EMPA-KIDNEY SE DETENDRÁ ANTES DE TIEMPO DEBIDO A LA CLARA EFICACIA POSITIVA EN PERSONAS CON ENFERMEDAD RENAL CRONICA The EMPA-KIDNEY trial, evaluating the effect of Jardiance® (empagliflozin) in adults with chronic kidney disease (CKD), will stop early based on a recommendation from the trial’s Independent Data Monitoring Committee. This follows a formal interim assessment that met prespecified criteria for positive efficacy, announced the Medical Research Council (MRC) Population Health Research Unit at the University of Oxford, Boehringer Ingelheim and Eli Lilly and Company (NYSE: LLY).

As the largest SGLT2 inhibitor trial in CKD to date, EMPA-KIDNEY

78

is evaluating the efficacy and safety of Jardiance in adults with CKD who are frequently seen in clinical practice but who have been under-represented in previous SGLT2 inhibitor trials, therefore addressing a critical unmet need.

The trial includes people: • with mildly to severely reduced eGFR (a measure of kidney function); • with normal and increased levels of albumin (a type of protein present in the urine); • with and without diabetes; • with CKD attributable to a wide range of underlying causes.

Revista Puertorriqueña de Medicina y Salud Pública

FDA APRUEBA UPADACITINIB COMO TRATAMIENTO ORAL PARA ADULTOS CON ESPONDILITIS ANQUILOSANTE “La espondilitis anquilosante es una enfermedad debilitante que, a menudo, afecta a los adultos más jóvenes y, con el tiempo, puede causar daño estructural duradero que puede tener un efecto emocional en la vida del paciente”, explicó Thomas Hudson, vicepresidente sénior,

investigación y desarrollo, oficial científico principal de AbbVie. “Esta última aprobación demuestra otro paso adelante importante en nuestra misión para adelantar las normas de atención respecto a las enfermedades reumáticas”, indicó en el comunicado.

LA FDA APRUEBA DOS TERAPIAS CON VONOPRAZAN PARA LA ERRADICACIÓN DEL HELICOBÁCTER PYLORI La Administración de Drogas y Alimentos de los Estados Unidos (FDA) ha aprobado dos tratamientos a base de vonoprazan para la infección por Helicobacter pylori, el cuál cumple como bloqueador oral de ácido que compite con el potasio y “el primer supresor de ácido innovador de una nueva clase de fármacos aprobado en los EE. UU. en más de 30 años”, dijo la compañía en un comunicado de prensa anunciando la aprobación.

“La aprobación de los regímenes de tratamiento de Voquezna ofrece a los médicos y pacientes dos opciones terapéuticas que mostraron tasas de erradicación superiores en comparación con la terapia triple de lansoprazol basada en inhibidores de la bomba de protones (IBP) en la población general de pacientes en un ensayo fundamental”, Terrie Curran, presidenta y directora ejecutiva de Phathom Pharmaceuticals, dijo en el comunicado.

DR. HIRAM RUIZ

AL SERVICIO DE LA PIEL DE LOS PUERTORRIQUEÑOS

DR. HIRAM RUIZ Dermatólogo Especialista en Cirugía de Mohs

80

Revista Puertorriqueña de Medicina y Salud Pública

El Dr. Hiram Ruiz, no solo eligió cuidar el órgano más grande del cuerpo, la piel, sino que también decidió ir más allá y convertirse en cirujano de Mohs, una especialidad que solo comparte con una colega más en toda la Isla.

Entre sus principales pacientes se encuentran aquellos que han enfrentado el agresivo cáncer de piel: el melanoma.

Muchas son las historias de pacientes que han sucumbido ante la enfermedad y el poder de este tipo de cáncer, pero hay otros que son testimonio de vida, precisamente porque un cirujano de Mohs removió la lesión a tiempo, como testifica el Dr. Ruiz.

El especialista ha enfatizado en que ningún bronceado es seguro y

los daños son irreversibles en la piel, por ello ha destacado que entre más rápido se diagnostica la enfermedad, mejor pronóstico tendrá el paciente.

“Dependiendo de la magnitud del tumor y sus características se desprende la tasa de supervivencia, es por eso que es necesario y muy importante un diagnóstico temprano”, ha enfatizado siempre el Dr. Ruiz, hijo, quien estudió en el Recinto de Ciencias Médicas, y su Sub-especialidad Mohs Micrographic Surgery: DermSurgery Associates, Houston, Texas.

Con miras en el futuro, el Dr. Ruiz es fiel creyente de continuar dando lo mejor de sí en beneficio de los pacientes, quienes cuenta con su pasión, profesionalismo y calidad humana.

Dr. Eric Adler

Dr. Álvarez Romagosa

Cirujano Plástico Facial

Ginecólogo/Obstetra

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