Revista Medicina y Salud Pública - Insulina

INVESTIGACIÓN ALTRUISTA QUE SALVA MILLONES DE VIDAS

MANEJO DOMICILIARIO DE COVID-19 MEDIANTE LA IDENTIFICACIÓN DE CARACTERÍSTICAS DE BAJO RIESGO

EFECTORES SUBSIGUIENTES DE LA QUINASA LIGADA A LA INTEGRINA (ILK) EN EL CÁNCER DE OVARIO RESISTENTE AL CISPLATINO

SALÓN DE LA FAMA DE LA MEDICINA PUERTORRIQUEÑA

Revista Puertorriqueña de Medicina y Salud Pública

1

The first IL-17A antagonist to achieve the primary endpoint in a head-to-head trial against Humira® (adalimumab) in PsA 1-5

FOR BIOLOGIC-NAIVE PATIENTS WITH PSORIATIC ARTHRITIS

Superiority to Humira in the percentage of patients simultaneously achieving ACR50 and PASI 100 at week 24, with consistency through week 526

SPIRIT-H2H (BIOLOGIC-NAIVE): Simultaneous achievement of ACR50 and PASI 100

PATIENTS ACHIEVING RESPONSE, NRI (%)

60

SUPERIOR

CONSISTENT

ACR50 & PASI 100 at week 24

through week 52

40

39%†

36%* 28%

26%

20

0 0

4

8

12

16

24

32

40

52

WEEK

Taltz (n=283)

Humira (n=283)

*P<.05 vs Humira.

P≤.001 vs Humira. Nominal P value: Week 52 measure of ACR50 + PASI 100 was not controlled for type-I error; therefore, no statistical comparisons can be made.

†

All patients had BSA ≥3%; patients with BSA ≥10%, PASI ≥12, and sPGA ≥3 followed the dosing for moderate to severe PsO.7 Primary endpoint=simultaneous achievement of ACR50 and PASI 100 at week 24.

SPIRIT-P1 and -P2: ACR response rates at week 24, NRI8

SPIRIT-P1 and -P2: PASI response rates at week 12, NRI

In SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=107; placebo n=106) and SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=122; placebo n=118), 58% and 53% of Taltz patients, respectively, achieved ACR20 vs 30% and 20% for placebo. Additionally, 40% and 35% of patients receiving Taltz achieved ACR50 vs 15% and 5% for placebo.

In SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=73; placebo n=67), among PsA patients with plaque psoriasis ≥3% BSA, NRI, 75% of patients receiving Taltz achieved PASI 75 at week 12 vs 8% of patients who received placebo. 32% of patients receiving Taltz achieved PASI 100 at week 12 vs 2% of patients who received placebo.9 In SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=68; placebo n=67), among PsA patients with plaque psoriasis ≥3% BSA, 57% of patients receiving Taltz achieved PASI 75 at week 12 vs 10% for placebo. Additionally, 19% of patients receiving Taltz achieved PASI 100 at week 12 vs 6% for placebo.10 Among patients with sPGA ≥3 at baseline, in SPIRIT-P1 (biologic-naive) (Taltz 80 mg every 4 weeks n=52; placebo n=41), 75% of patients receiving Taltz achieved sPGA 0,1 at week 12 vs 7% for placebo.9 Additionally, in SPIRIT-P2 (TNFi-experienced) (Taltz 80 mg every 4 weeks n=60; placebo n=55), 63% of patients receiving Taltz achieved sPGA 0,1 vs 4% for placebo.10,11

Primary endpoint=ACR20 response at week 24.

Inadequate responders (<20% improvement in tender and in swollen joint counts) at week 16 were analyzed as nonresponders after week 16 until the primary endpoint.

NRI of intent-to-treat population through week 24.

Taltz has no boxed warning

8

NRI of intent-to-treat population through week 12.

ACR20/50=American College of Rheumatology 20%/50% response; PASI=Psoriasis Area Severity Index; NRI=nonresponder imputation; BSA=body surface area; sPGA=static Physician’s Global Assessment; TNFi=tumor necrosis factor inhibitor; PsA=psoriatic arthritis.

Approved to treat adult patients across the spectrum of axSpA (nr-axSpA, AS) SPIRIT-H2H Trial Design12

SPIRIT-P1 and -P2 Trial Design8,10,13,14

SPIRIT-H2H (N=566) was a phase 4, randomized, open-label, blinded-assessor study evaluating the efficacy and safety of Taltz vs Humira in biologic-naive patients with active psoriatic arthritis and plaque psoriasis BSA ≥3%. The primary efficacy endpoint was the proportion of patients simultaneously achieving ACR50 and PASI 100 at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints with an inadequate response to ≥1 cDMARD. Patients were randomized (1:1) to Taltz or Humira and allowed to continue a stable dose of concomitant cDMARD during the study. For Taltz patients with psoriatic arthritis only (n=234), the initial dose (160 mg as 2 injections) was followed by 80 mg every 4 weeks. Humira patients (n=231) received 40 mg every other week and no initial dose. Patients who met the trial design criteria for moderate to severe psoriasis (BSA ≥10%, PASI ≥12, and sPGA ≥3) in addition to psoriatic arthritis followed the psoriasis dosing regimen: Taltz patients (n=49) received an initial dose of 160 mg (two 80 mg injections), followed by 80 mg every 2 weeks through week 12, then 80 mg every 4 weeks thereafter. Humira patients (n=52) received an initial dose of 80 mg, then 40 mg every other week starting 1 week after the initial dose.

SPIRIT-P1 (N=417) and SPIRIT-P2 (N=363) were phase 3, randomized, doubleblind, placebo-controlled trials to evaluate the efficacy and safety of Taltz compared with placebo in patients with active psoriatic arthritis. Patients in SPIRIT-P1 were biologic-naive. Patients in SPIRIT-P2 were tumor necrosis factor inhibitor (TNFi)experienced, having had an inadequate response and/or intolerance to 1 or 2 prior TNFis. In both trials, the primary efficacy endpoint was the proportion of patients achieving ACR20 response at week 24. All patients were ≥18 years of age and had ≥3 swollen and ≥3 tender joints. Patients were randomized to placebo or Taltz 80 mg every 2 or 4 weeks following a 160 mg starting dose. In SPIRIT-P1, an active reference arm of Humira 40 mg every 2 weeks was included. Patients in all study arms were allowed to continue taking stable background medications during the trial. Inadequate responders (as defined by blinded criteria of <20% improvement in tender and in swollen joint counts) at week 16 received rescue therapy and were analyzed as nonresponders after week 16 until the primary endpoint. After receiving rescue therapy, inadequate responders in the placebo and Humira arms were re-randomized to Taltz 80 mg every 2 or 4 weeks. NRI methods were used for categorical efficacy analyses during the double-blind treatment period.

cDMARD=conventional disease-modifying antirheumatic drug.

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

CONTRAINDICATIONS

ADVERSE REACTIONS

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

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.

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 post-marketing 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.

Please see Brief Summary of Prescribing Information on next pages.

See Instructions for Use included with the device.

IX HCP ISI 07MAY2020 References: 1. Data on file. Lilly USA, LLC. DOF-IX-US-0121. 2. Data on file. Lilly USA, LLC. DOF-IX-US-0122. 3. Data on file. Lilly USA, LLC. DOF-IX-US-0123. 4. Data on file. Lilly USA, LLC. DOF-IX-US-0124. 5. Data on file. Lilly USA, LLC. DOF-IX-US-0125. 6. Data on file. Lilly USA, LLC. DOF-IX-US-0190. 7. Mease PJ, Smolen JS, Behrens F, et al. A head-to-head comparison of the efficacy and safety of ixekizumab and adalimumab in biological-naive patients with active psoriatic arthritis: 24-week results of a randomised, open-label, blinded-assessor trial. Ann Rheum Dis. 2020;79:123-131.

8. Taltz [package insert]. Indianapolis, IN: Eli Lilly and Company; 2020. 9. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1. Ann Rheum Dis. 2017;76:79-87. 10. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet.

2017;389:2317-2327. Supplementary appendix. 11. Data on file. Lilly USA, LLC. TAL20171127A. 12. Data on file. Lilly USA, LLC. DOF-IX-US-0119. 13. Mease PJ, van der Heijde D, Ritchlin CT, et al; on behalf of SPIRIT-P1 Study Group. Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase 3 trial SPIRIT-P1. Ann Rheum Dis. 2017;76(suppl):1-30. 14. Nash P, Kirkham B, Okada M, et al; on behalf of SPIRIT-P2 Study Group. Ixekizumab for the treatment of patients with active psoriatic arthritis and an inadequate response to tumour necrosis factor inhibitors: results from the 24-week randomised, double-blind, placebo-controlled period of the SPIRIT-P2 phase 3 trial. Lancet. 2017;389:2317-2327.

For more information, please contact a Lilly representative or visit TaltzPSAH2H.com.

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-3933 05/2020 ©LILLY USA, LLC 2020. ALL RIGHTS RESERVED.

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 placebo 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 subjectyear 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 163 (14) 23 (8) 101 (13) tract infectionsa Nausea 23 (2) 1 (<1) 5 (1) Tinea infections 17 (2) 0 1 (<1) a Upper respiratory tract infections cluster includes nasopharyngitis and rhinovirus infection. b U.S. approved etanercept.

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%).

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

Taltz® (ixekizumab) injection

Taltz® (ixekizumab) injection

IX HCP BS 07MAY2020

IX HCP BS 07MAY2020

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.

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) DRUG INTERACTIONS Cytochrome P450 Substrates—The formation of CYP450 enzymes can be altered by increased levels of certain cytokines (e.g., IL-1, IL-6, IL-10, TNFα, IFN) during chronic inflammation. Thus, Taltz, an antagonist of IL-17A, could normalize the formation of CYP450 enzymes.

Therefore, upon initiation or discontinuation of Taltz in patients who are receiving concomitant drugs which are CYP450 substrates, particularly those with a narrow therapeutic index, consider monitoring for effect (e.g., for warfarin) or drug concentration (e.g., for cyclosporine) and consider dosage modification of the CYP450 substrate.

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.

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.

OVERDOSAGE—In the event of overdosage, monitor the patient for any signs or symptoms of adverse reactions and institute appropriate symptomatic treatment immediately.

PATIENT COUNSELING INFORMATION—Advise the patient and/or caregiver to read the FDA-approved 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.

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.

IX HCP BS 07MAY2020

Taltz® (ixekizumab) injection

Taltz® (ixekizumab) injection

IX HCP BS 07MAY2020

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

IX HCP BS 07MAY2020

MSP ARTÍCULO DE REVISIÓN

Revista Puertorriqueña de Medicina y Salúd Pública

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CONTENIDO

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INSULINA: LA INVESTIGACIÓN ALTRUISTA QUE HA SALVADO MILLONES DE VIDAS

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44

62

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EFECTORES SUBSIGUIENTES DE LA QUINASA LIGADA A LA INTEGRINA (ILK) EN EL CÁNCER DE OVARIO RESISTENTE AL CISPLATINO

LA EVOLUCIÓN EN EL TRATAMIENTO DE ARTRITIS REUMATOIDE

TRATAMIENTO Y EVALUACIÓN DE PACIENTES CON POSIBLE INFARTO AL CORAZÓN EN TIEMPOS DE COVID-19

LAS SIETE ETAPAS DEL ALZHEIMER

EDITOR FUNDADOR Juan Carlos Orengo Valverde, MD, MPH, PhD EDITOR Alberto Santiago Cornier, MD, PhD PRINCIPAL OFICIAL EJECUTIVO Pedro Carlos Lugo Hernández III, P.A PRESIDENTA Y FUNDADORA Glorybelle Hernández Figueroa, MBA VICEPRESIDENTA Y FUNDADORA Laila Paloma Lugo, MBA CONTABILIDAD Julio Soto ADMINISTRACIÓN Marta Ivelisse Vélez Ramos, MBA, MARKETING Y SERVICIOS 360 Alexelena Cayere, Yasmin Morell PERIODISTAS Belinda Burgos, Grenda Rivera, Mayra Acevedo, Luis Penchi ARTISTAS GRÁFICOS Natalia Zoé Rivera Torres, Cristian Daniel De Castro Pérez DIRECTORA AUDIOVISUAL Fabiola Plaza REALIZADORA AUDIOVISIAL Salomé Mateus FOTOS Revista Medicina y Salud Pública DIRECCIÓN GENERAL Carlos Alexis Lugo Marrero DISTRIBUCIÓN OFICINAS Y TORRES MÉDICAS Editorial Mundo ENVÍO DE REVISTAS Y DISTRIBUCIÓN A GRUPOS MÉDICOS Servicio de correo postal/Comunicación Inteligente Para ventas y otros servicios pueden comunicarse al 787.848.3333, msp@editorialmundo.com o www.medicinaysaludpublica.com Revista Puertorriqueña de Medicina y Salud Pública ISSN 1937-8521 COMITÉ EDITORIAL CIENTÍFICO COMITÉ EDITORIAL Olga Rodríguez, MD - Decana Escuela de Medicina de Ponce (Puerto Rico), Vivian Green, LND, MS, PhD, Sub editora y fundadora (Puerto Rico), José Cordero, MD, MPH - Exdecano Escuela Graduada Salud Pública Recinto de Ciencias Médicas UPR (Puerto Rico), Ángeles Rodríguez, MD, MPH (Puerto Rico), Simón Carlo, MD (Puerto Rico), Bárbara Rosado, MD (Puerto Rico), Idhaliz Flores PhD (Puerto Rico), Jesús Cruz-Correa, MD, FACOG (Puerto Rico), Rafael Bredy, MD, LicMTo, MBE, MS (Puerto Rico), David Caseida, MD, FACOG, (Puerto Rico), José Capriles, MD, MHSA (Puerto Rico) Joaquín Laboy, MD, FACOG (Puerto Rico), Luis Adrian Rivera Pomales, MD, PEMBA, MPH, CMQ (Puerto Rico), Juan Fernández, MS, PhD (Puerto Rico), Nuria Sebate, MD (Puerto Rico), Pedro Amador, MD, MPH (Puerto Rico), Nydia Cappas, PsyD (Puerto Rico), Luis Franco, MD (Puerto Rico), Federico Montealegre, DVM, PhD, Msc (Puerto Rico), Nydia Ortiz, PsyD (Puerto Rico), José Pons, PhD, FPPR (Puerto Rico), Esdrás Vélez, JD, MPH (Puerto Rico), Diego Zavala, MSc, PhD, (Puerto Rico), Ana Torres-Martín, MD (Puerto Rico), Julio Cádiz, MD, MPH (Puerto Rico), Rafael Gómez-Cuevas (Colombia), José Javier Orengo, PhD(c) (España), Cesar A. Del Rey, MD (Panamá), Pedro Serrano, MD, PhD (España), Luis Serra-Majem, MD, PhD (España), José Ramón Calvo, MD, PhD (España).

Síguenos en www.medicinaysaludpublica.com, www.facebook.com/revistamsp, en Twitter @revistamsp, en LinkedIn como Revista Puertorriqueña de Medicina y Salud Pública. Las normas editoriales de la Revista Puertorriqueña de Medicina y Salud Pública para la publicación de artículos originales y cartas al editor pueden ser accesadas en la página web: www.medicinaysaludpublica.com, y solicitadas a través de msp@editorialmundo.com.

Medicina y Salud Pública es propiedad de publicaciones mundo. Medicina es una publicación de la REVISTA PUERTORRIQUEÑA DE MEDICINA Y SALUD PÚBLICA. Medicina y Salud Pública tiene como política corregir y aclarar cualquier información incorrecta que pueda ser publicada en su revista. Medicina y Salud Pública no asume responsabilidad alguna por los anuncios, artículos y otros servicios anunciados en nuestra publicación.

EDITORIAL

E

l “Salón de la Fama de la Medicina Puertorriqueña” tiene el noble propósito de reconocer a los médicos y entidades que con su aportación han realizado una magna labor en favor de la medicina. Su desempeño y legado en el desarrollo social de Puerto Rico quedará documentado y será reconocido y preservado para las futuras generaciones.

En este momento histórico en que se exaltarán estas figuras ilustres, quienes son los cimientos de la medicina puertorriqueña, la Asociación Médica de Puerto Rico quiere igualmente reconocer en una actividad fraternal a quienes han realizado tan ardua y arriesgada gesta por la salud de nuestra isla durante la Pandemia, época que nos ha hecho atravesar un período sumamente difícil y lleno de grandes retos para la medicina, la clase médica y la industria de la salud en general.

Una prestigiosa Junta de Médicos

realizó un proceso de investigación, discusión y selección, identificando a un grupo de diez figuras, entre médicos y entidades, quienes serán los “Miembros Exaltados” de esta Primera Edición. Este grupo lo conforman: 1) Dr. Manuel Quevedo Báez - Presidente y Fundador de la Asociación Médica de Puerto Rico 2) Dr. Mario Rubén García Palmieri - Primer Cardiólogo y Fundador del Centro Cardiovascular 3) Dr. Francisco Raffucci Arce – “Padre de la Cirugía Moderna” en Puerto Rico 4) Dr. Luis Izquierdo Mora - Médico de Familia y Médico de “los más necesitados” 5) Dr. Ramón M. Suárez Calderón - Hematólogo. Cardiólogo. Investigador. 6) Dr. Guillermo Arbona Irizarry - Secretario de Salud.

Creador del Sistema de Salud de Puerto Rico 7) Dr. Bernardino González Flores - Urólogo y Fundador de la Escuela de Medicina de la UCC 8) Dr. Luis F. Sala Goenaga - Cirujano y Fundador de la

Escuela de Medicina de Ponce 9) Dr. Jaime Benítez Rexach - Fundador de la Escuela de Medicina de la UPR 10) Hospital La Concepción en San Germán - Cuatro Siglos de Historia La Primera Ceremonia de Exaltación al Salón de la Fama de la Medicina Puertorriqueña se realizará en el Fairmont El San Juan Hotel, el viernes 19 de noviembre de 2021.

La Actividad contará con una Cena de Gala y Coctel, a la que asistirán sobre 400 invitados, incluyendo personalidades y empresarios de todos los renglones relacionados a la medicina, además de representantes del Gobierno y del Sistema de Salud de nuestra isla.

Para mayor información llamar a la Asociación Médica al 787-721-6969 ó visite: www.salonfamamedicina.com Información de: Comunicado de Prensa.

MSP ARTÍCULO / ORIGINAL

MANEJO DOMICILIARIO DE COVID-19 MEDIANTE LA IDENTIFICACIÓN DE CARACTERÍSTICAS DE BAJO RIESGO

ABSTRACT Background: Covid-19 is a triphasic disorder characterized by a viral phase lasting 7-10 days from first onset of symptoms. In approximately 20% it is followed by a second stage heralded by elevation of pro-inflammatory markers such as ferritin, IL-6, CRP, LDH and D-dimers. We hypothesized that those with few abnormalities would have a low risk for progression to respiratory insufficiency and could be monitored at home without treatment.

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Methods: Inclusion criteria included age >21, O2 saturation >90%. To be observed without treatment patients could not have > 1 of the following: CRP > 10 mg/dL, high LDH, ferritin > 500 ng/ml, D dimer > 1 mg/L, IL-6 > 10 pg/ml, absolute lymphocyte count <1,000, O2 sat <94%, or CT chest evidence of pneumonia. Primary endpoint: progression to respiratory failure. Secondary endpoint: 28-day survival.

Results: Of 208 entered, 132 were monitored without therapy. None progressed to respiratory failure or died.

Conclusions: We have shown that our approach can identify cases who can safely be observed without treatment, thus avoiding expensive, potentially toxic therapies, and circumventing unnecessary, costly hospitalizations. These results support our hypothesis that after applying our criteria, 64% of Covid-19 cases can be monitored as outpatients without therapy.

ARTÍCULO / ORIGINAL

FERNANDO CABANILLAS1, JAVIER MORALES2, JOSÉ G. CONDE3, JORGE BERTRÁN-PASARELL1, RICARDO FERNÁNDEZ4, YAIMARA HERNANDEZ-SILVA5, IDALIA LIBOY5 UNIVERSITY OF PUERTO RICO SCHOOL OF MEDICINE AND AUXILIO MUTUO HOSPITAL 2 CLINICAL RESEARCH PUERTO RICO 3 UNIVERSITY OF PUERTO RICO SCHOOL OF MEDICINE 4 SAN JUAN BAUTISTA SCHOOL OF MEDICINE AND AUXILIO MUTUO HOSPITAL 5 AUXILIO MUTUO HOSPITAL 1

"Aquellos con pocas anomalías tendrían un riesgo bajo de progresión a insuficiencia respiratoria y podrían ser monitoreados en casa sin tratamiento"

ABSTRACTO Fondo: Covid-19 es un trastorno trifásico caracterizado por una fase viral que dura de 7 a 10 días desde la primera aparición de los síntomas. En aproximadamente el 20% le sigue una segunda etapa anunciada por la elevación de marcadores proinflamatorios como ferritina, IL-6, CRP, LDH y D-dímeros.

Presumimos que aquellos con pocas anomalías tendrían un riesgo bajo de progresión a insuficiencia respiratoria y podrían ser monitoreados en casa sin tratamiento.

Métodos: Los criterios de inclusión incluyeron edad> 21, saturación de O2> 90%. Para ser observado sin tratamiento, los pacientes no pueden tener> 1 de los siguientes: PCR> 10 mg / dL, LDH alta, ferritina> 500 ng / ml, dímero D> 1 mg / L, IL-6> 10 pg / ml, absoluto recuento de linfocitos <1.000, O2

sat <94% o evidencia de TC de tórax de neumonía. Criterio de valoración principal: progresión a insuficiencia respiratoria.

Criterio de valoración secundario: supervivencia a los 28 días.

Resultados: De 208 ingresados, 132 fueron monitoreados sin terapia. Ninguno progresó a insuficiencia respiratoria ni murió.

Conclusiones: Hemos demostrado que nuestro enfoque puede identificar casos que pueden ser observados de manera segura sin tratamiento, evitando así terapias costosas y potencialmente tóxicas y evitando hospitalizaciones costosas e innecesarias. Estos resultados apoyan nuestra hipótesis de que después de aplicar nuestros criterios, el 64% de los casos de Covid-19 se pueden monitorizar de forma ambulatoria sin terapia.

INTRODUCTION COVID-19 is a triphasic disorder first typified by an infectious or viral phase that lasts from the first onset of symptoms until 7-10 days later. This is followed by a second phase considered as the inflammatory stage, characterized initially by the appearance of lung infiltrates which is followed in some cases by hypoxemia [1,2]. This second phase is usually heralded by an elevation of serologic inflammatory markers such as C-reactive protein (CRP), ferritin, Interleukin-6 (IL-6), and LDH, as well as D-dimers [3-5].

In a smaller subset of cases this is followed by a third phase characterized by hyperinflammation, leading to the cytokine release syndrome or cytokine storm, that causes Acute Respiratory Distress Syndrome (ARDS) [1,2]. Most COVID-19 deaths are caused by this complication.

Approximately 80% of patients never proceed to the second phase. They are spontaneously cured after the first stage [3,6].

This proportion is a crude estimate that can vary according to several prognostic factors [3-5]. Currently there is no reliable and objective method to accurately predict the 80% that are cured spontaneously without any treatment, vis-à-vis those who develop severe illness. There is consensus that those presenting with severe illness characterized by hypoxemia, should be managed in the inpatient setting, but there are no rigorous, objective criteria to decide when non-hypoxemic patients with mild to moderate illness should be hospitalized instead of monitoring them at home. Traditionally, they are admitted to the hospital if they present with mild to moderate illness without hypoxia but with evidence of pneumonia or dyspnea.

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MSP ARTÍCULO / ORIGINAL New drugs have recently become available for treatment of mild to moderate COVID-19 infections. These include Remdesivir, and monoclonal antibodies such as bamlanivimab, casirivimab and imdevimab. These new agents have the potential of reducing the number of hospitalizations if applied early during the infectious process, however their cost can be quite high. In addition, all these agents have potential toxicity. The overuse of these drugs could be avoided if we have a method to identify low-risk cases who do not require any therapy and who could be safely monitored outside of the hospital setting, hence further reducing the financial costs.

Furthermore, excessive hospitalizations can overwhelm and overload healthcare systems. A method to identify cases that can be safely managed on an ambulatory setting could relieve this burden. Finally, knowledge regarding the factors that predict the likelihood of disease progression could help physicians decide who can be managed safely at primary care facilities and who needs to be transferred to a tertiary care center.

We hereby report on the results of the application of the risk-stratification stage of this phase II clinical trial designed with two goals in mind: 1- To identify early during their illness low-risk patients who can be safely monitored at home without treatment.

2- To identify patients with COVID-19 at high-risk of progressing to hypoxemic respiratory failure, so they can be treated prophylactically with steroids early during their clinical course to prevent them from developing ARDS or cytokine release syndrome.

We prospectively classified COVID-19 patients by ranking them into high and low-risk, according to blood-based biomarkers of inflammation, as well as other clinical features. We then analyzed the clinical outcome of those considered as low-risk. The current manuscript exclusively describes the outcomes of low-risk cases. The results related to the management of high-risk cases will be the subject of a separate report.

MATERIALS AND METHODS Investigational plan: The study was registered in clinicaltrials. gov as NCT04355247 and registered as such with the local Institutional Review Board at Auxilio Mutuo Hospital which 12

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approved it. Informed consent was obtained from each patient prior to recruitment.

The original plan was to enter a total of 100 patients with the expectation that at least 20 would-be high-risk cases eligible for therapy with methylprednisolone and 80 would be low-risk, eligible for monitoring without therapy. This expectation was based on the available literature data [3,6] which describes a 20% chance for patients with COVID-19 to develop severe disease associated with respiratory failure.

We later decided to expand this pilot study to include at least 200 patients.

When the CALL score method to predict prognosis was published 2, we amended the protocol to apply this method with the purpose of allowing us to more precisely predict the expected number of cases that would develop respiratory failure. Using this prediction, we could then calculate the expected number of cases and compare it with our therapeutic results using our risk-assessment method. This CALL Score method considers the presence of comorbidities, age, LDH level and lymphopenia to assign a prognostic score. The higher the score, the worse the prognosis. A nomogram which is part of the CALL score, was used to predict the risk of progression to respiratory failure [8].

Eligibility: Eligible patients for this protocol had to be over 21 years old with a diagnosis of COVID-19 established by means of either the PCR molecular test (97% of enrolled cases) or with the rapid serologic test in the context of typical symptoms and/or ground glass infiltrates in the chest CT (3% of cases). There was no top age limit for entry. Excluded from entry were those who already were in acute respiratory failure defined as oxygen saturation <91%.

Other exclusion criteria included subjects who were oxygen dependent, or who had long standing history of severe COPD. Anyone receiving tocilizumab, convalescent plasma therapy or prednisone 20 mg daily or equivalent were also excluded.

Definition of low-risk cases: For patients to be classified as low-risk, they could have only one or none of the following abnormalities between days 7-10 after their first symptom: IL-6 > 10 pg/ml, Ferritin> 500 ng/ml, D-dimer > 1 mg/L (1,000 ng/ml), CRP > 10 mg/ dL (100 mg/L), LDH above normal, lymphopenia (absolute lymphocyte count <1,000), oxygen saturation between

ARTÍCULO / ORIGINAL 91-94%, or CT chest with evidence of ground glass infiltrates. These markers were selected based on published data which have shown a strong correlation with a poor outcome [10 -15]. We also analyzed the symptomatology at presentation to determine if low-risk patients could be identified by the number of symptoms at diagnosis or by the type of presenting symptoms.

Management: Patients classified as low-risk were monitored at home without treatment. They were asked to check their oxygen saturation three times per day by means of pulse oximetry and to report any value less than 94% during the first two weeks after entry.

They were also instructed to immediately report any unexpected change in their clinical condition. Patients were also called daily for 28 days to inquire about their condition.

Statistical analysis: Medians and interquartile ranges (IQR’s) were used to describe distributions of continuous variables, and proportions to describe distributions of categorical variables. IQR’s are reported as lower and upper limits of the IQR (i.e. first and third quartiles of

FEATURE

LOW RISK (N=132)

%

distributions). This format not only provides information on the IQR, but also indicate location of the central 50% of distributions relative to the median. The Wilcoxon Mann-Whitney test was used for testing hypotheses about the difference between distributions of continuous variables, and the chi-square test for categorical variables [16].

RESULTS We initially enrolled 213 patients, 5 of which were not evaluable because consent was withdrawn (N=3), lost to follow up after suicidal attempt (N=1), PCR for Covid-19 negative (N=1). Of the remaining 208 patients, 132 (63.5%) fulfilled criteria for low-risk, hence they met conditions for monitoring at home without therapy, while the remaining 76 were classified as high-risk and treated with methylprednisolone.

The median follow-up time for these 132 low-risk cases was 84 days (range 31-263) for a total of 10,956 person-days of follow up with interquartile range of 44. At the time of diagnosis, 97 (73.4%) of the low-risk cases, were polysymptomatic, presenting with 2 or more of

HIGH-RISK (N=76)

%

P

Gender Male

62

47

40

52.6

Female

70

53

36

47.3

Median age (IQR)

45 (22)

-

60 (23)

-

.00001

Median # comorbidities per patient (IQR)

1 (1)

-

2 (2)

-

.00001

64 62 3 3 2

48.5 47.0 2.2 2.2 1.5

14 36 26 0 23

18.4 47.3 34.2 0 30.2

Fever

49

37.1

48

63.2

.00001

Dyspnea

21

15.9

29

38.2

.004

Myalgia

84

63.6

49

64.4

1.0

Diarrhea

55

41.7

33

43.4

0.88

Anosmia

67

50.7

34

44.7

0.47

0.36

CALL SCORE: 4-6 (Class A) 7-9 (Class B) 10-13 (Class C) Missing information O2 saturation 91-94%

.00001 .00001

SYMPTOMS:

the following symptoms: fever, cough, myalgia, diarrhea, anosmia, dyspnea, or headache. Only 15 of the low-risk cases were either asymptomatic (11 cases) or minimally symptomatic (4 cases) with nasal congestion and sore throat, suggesting that low-risk cases, as defined by our criteria, cannot be accurately identified by using the number or types of symptoms at presentation. In addition, there were 48 cases who had a chest CT done at time of diagnosis and of these, 17 presented with typical ground-glass infiltrates.

Table 1 summarizes the baseline characteristics of all 208 cases including low as well as high-risk cases. Male gender was more commonly represented in high-risk patients, but this did not reach statistical significance (p=0.36). High-risk patients were significantly older than low-risk.

Similarly, the number of comorbidities was significantly greater in the high risk cases. The CALL score correlated well with the risk assignment. Most commonly, the low-risk cases corresponded to the favorable CALL score “Class A group”, and only 2% were unfavorable “Class C group”. However, there was a relatively large proportion, 47%, that fell into the intermediate CALL score “Class B group”.

As expected, high-risk cases presented more commonly than low-risk cases with CALL score “Class C” as well as with lower oxygen saturation. Regarding symptoms, fever and dyspnea were more commonly seen in high-risk cases.

There were 3 cases in the low-risk category for which there was missing information because their CBC was reported without a differential count, necessary for the calculation of the CALL score. Since these three cases had no other high-risk criteria, they were assigned to the low-risk group.

The presence of dyspnea and pneumonia are frequently used as criteria to decide on inpatient management. There were 48 of our low-risk patients who had a chest CT done and 17 of these had typical findings of ground-glass infiltrates that would traditionally have required hospitalization. An additional 9 cases had a negative chest CT but complained of dyspnea. Another four had dyspnea without hypoxemia, hence a CT chest was not done. In summary, 30 cases met traditional conditions for admission, yet were managed as outpatients in view of their low-risk features after applying our criteria.

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Clinical Outcomes: None of the 132 low-risk cases developed respiratory failure and none developed any type of complication that required admission to the hospital while under follow-up. None of them died.

Four (1.9%) of the 208 patients developed what appeared to be a reinfection. All four were either asymptomatic or minimally symptomatic at time of first diagnosis. After applying our criteria, all four were classified as low-risk cases.

They had been positive by PCR at time of first diagnosis but subsequently turned PCR negative several days later to again become positive at the time they developed new symptoms suggestive of reinfection.

The first case of reinfection is a female in her mid-fifties diagnosed after having been exposed to a patient infected with COVID-19. She was asymptomatic at time of diagnosis. Her first PCR was positive but 7 days later it turned negative. At time of diagnosis her serological studies were negative for IgG and IgM. She remained asymptomatic until 4 months later when she suddenly developed fever, dyspnea, cough, anosmia, and myalgia and her PCR then turned positive. Based on inflammatory markers, including LDH and IL-6, she met criteria for treatment during this second bout. In addition, her oxygen saturation was 93% and CT chest revealed changes compatible with COVID-19 pneumonia. She was treated with methylprednisolone 80 mg daily IV x 5 days and rapidly improved clinically. By day seven, her inflammatory markers also improved.

The second reinfected case is a female in her low fifties who had been exposed to a co worker who had been diagnosed with COVID-19. She was asymptomatic but on day 7 post exposure, her PCR test was positive. She did not fulfill high-risk criteria, so she was monitored without therapy. Ten days after the positive PCR test, IgM and IgG antibody tests were both negative.

Two weeks after the first PCR test, the PCR was repeated and became negative. She remained well until 20 days after the first PCR, when she developed fever, diarrhea, cough, anosmia, and myalgia. Her PCR was repeated and was now found to be positive. A confirmatory PCR was ordered 14

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18 days later and again was positive.

Nine days after her second infection, antibody tests for IgM and IgG both turned positive. This time, based on inflammatory markers, she met criteria for treatment with methylprednisolone and she was started on therapy according to protocol. She responded clinically and her symptoms resolved promptly. However, a D-dimer test was repeated as part of the protocol on day 7 post methylprednisolone, and it abruptly increased from a baseline of 0.38 to 6.36 mg/L. She developed severe coughing spells and this clinical picture brought up the suspicion of a thrombotic complication secondary to COVID-19. CT chest angiogram was done which showed several right sided pulmonary emboli.

Anticoagulation with rivaroxaban was initiated and her coughing spells rapidly subsided.

The third case of reinfection was a male in his mid-twenties who developed nasal congestion and a positive PCR test. Eight days after this PCR, his IgG and IgM antibodies were negative, and a follow up PCR test converted to negative. He fulfilled criteria for low-risk disease, so he was observed without therapy. He did well until four months later when he was exposed to several family members who were infected with COVID-19 and shortly after, he developed typical symptoms of COVID-19 consisting of fever, myalgia, anosmia, headache, and diarrhea. One week later his PCR turned positive. His IgG and IgM also turned positive 8 days after this last PCR. By the time we received the PCR result, patient was already recovering from his symptoms, so we decided not to treat him. Since we did not order an earlier confirmatory PCR after the first infection, we cannot completely rule out the possibility that instead of a reinfection, his first PCR could have been a false positive result, although this is unlikely.

The fourth case of reinfection is a male in his mid-thirties who had a routine PCR test ordered on a routine basis at his workplace. He was essentially asymptomatic except for diarrhea which he had first noticed two days earlier. The PCR test was positive. It was repeated one week later and again was positive. Eight days after his first symptom, his IgG and IgM antibodies were negative. Six weeks after

his first symptom, his PCR converted to negative. He fulfilled criteria for low-risk disease, so he was observed without therapy. He remained well until six months later when he again developed diarrhea but this time, he also had cough, fever, myalgia, fatigue, and headache. PCR was ordered and it was positive. A confirmatory PCR was obtained four days later which was again positive. On day 8 from his first symptoms of reinfection, IgG was positive and IgM negative. He did not meet criteria for treatment with methylprednisolone and thus was monitored without therapy. He remains well without complications.

DISCUSSION This manuscript focuses exclusively on 132 low-risk cases. The remaining 76 cases will be the subject of another report.

Our management approach, based on blood-based inflammatory markers as well as other clinical features, had an excellent correlation with clinical outcome. Of 208 patients, 132 or 63.5%, fulfilled criteria for low-risk disease that justified monitoring at home without therapy. None of these low-risk cases developed respiratory failure and none developed any significant complication or required admission to the hospital. Included in this low-risk group as defined by our criteria, were 68 cases with comorbidities, 17 with COVID-19 pneumonia, as well as with other adverse features, including 15 cases older than 65 and 96 with more than two symptoms at presentation. These characteristics would usually portend an unfavorable prognosis according to traditional standards, yet all these patients had an excellent outcome.

The management of mild to moderate COVID-19 infections has traditionally been conservative. Patients with either COVID-19 pneumonia or with dyspnea, are often admitted to the hospital 1.

Otherwise, treatment has consisted of observation at home provided there is no evidence of hypoxemia. Applying these traditional criteria to decide on hospitalization, 26 of our 48 low-risk patients who had a chest CT, would have been managed as inpatients because 17 had typical findings of ground-glass infiltrates that would traditionally have been hospitalized and an additional 9 cases had a

ARTÍCULO / ORIGINAL

negative chest CT but complained of dyspnea. Another 4 cases (20%) had dyspnea without hypoxemia and hence a chest CT scan was not done. This adds up to a total of 30 patients who traditionally would have been managed as in-patients. By applying our novel criteria to identify low-risk cases, we were able to safely manage all these 30 patients at home without separating them from their families. Furthermore, assuming an average of 10 days of hospitalization per patient, it allowed us to save an average of 300 days of hospitalization.

At an average cost of hospitalization of $3,949 per day, this adds up to a total of $1,184,700 US dollars saved. In addition, these 30 patients were prevented from being exposed to nosocomial infections.

Dexamethasone has been utilized to treat hospitalized patients with COVID-19.

Those who are ventilator-dependent or who are receiving oxygen have benefitted from that treatment, while those who are oxygen-independent fail to do so and might even be adversely affected since their mortality rate tends to be higher when treated with dexamethasone [9].

It is conceivable that some patients are unnecessarily being treated with this medication, and our proposed method should be able to identify them.

After the first week of illness, 20% of patients diagnosed with COVID-19 might suddenly deteriorate and develop respiratory failure [3,6]. This includes those who initially present with mild symptomatology.

Consequently, being able to prospectively segregate those cases who will have an uncomplicated clinical course from those who are more likely to develop respiratory failure and who could potentially benefit from preemptive immunosuppressive therapy is an important advantage.

Although there were statistically significant differences between low-risk and high-risk cases regarding their clinical presentation and symptoms (Table 1), there was not a single factor or factors in their clinical presentation that could reliably be used to classify them into either the low-risk or high-risk groups.

The frequency of symptoms would intuitively be expected to be less in the low-risk cases. However, contrary to our expectations, the majority (73%) of low-risk cases

presented with two or more symptoms at diagnosis, indicating that they cannot be identified based on symptomatology alone. The CALL Score is an exceptionally useful method. It assigns a risk score which can be used to determine the probability of a given patient to progress to respiratory failure. It is based on quite simple and straightforward clinical features. Nonetheless, neither the CALL score nor any other system that we are aware of, was able to identify the low-risk cases detected by our novel criteria.

It is interesting that of the four cases that were possibly reinfected, all four presented with mild disease at the time of diagnosis. It is well known that patients with mild COVID-19 infections produce little or no antibodies [17] so it should not be surprising that all our four cases with possible reinfection had mild or no symptomatology at the time of initial diagnosis.

Unfortunately, we could not perform molecular analysis of the virus at time of reinfection to determine if a different viral strain was involved.

Our results suggest that by applying our novel criteria, low-risk cases can be reliably monitored at home without treatment, rather than immediately embarking on admission to a hospital or with outpatient treatment. Aside from the positive financial and psychological aspects of home-based management, the ability to identify low-risk cases at diagnosis has several other advantages, including the possibility of circumventing the use of expensive or potentially toxic agents.

Although the data generated by this prospective trial appear convincing, it is important to keep in mind that this is a pilot study and confirmation of these findings in another cohort or in an independent study would be highly desirable.

REFERENCES:

1. Magro G. COVID-19: Review on latest available drugs and therapies against SARS CoV-2. Coagulation and inflammation cross-talking. Virus Res. 2020;286:198070.

2. Khadke S, Ahmed N, Ahmed N, et al.

Harnessing the immune system to overcome cytokine storm and reduce viral load in COVID-19: a review of the phases of illness and therapeutic agents. Virol J. 2020;17(1):154.

3. Zhou F, Yu T, Du R, et al. Clinical course and

risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):10541062.

4. Mughal MS, Kaur IP, Jaffery AR, et al.

COVID-19 patients in a tertiary US hospital: Assessment of clinical course and predictors of the disease severity. Respir Med. 2020;172:106130.

5. Bastug A, Bodur H, Erdogan S, et al.

Clinical and laboratory features of COVID-19: Predictors of severe prognosis. Int Immunopharmacol. 2020;88:106950.

6. Hussain A, Kaler J, Tabrez E, et al. Novel COVID-19: A Comprehensive Review of Transmission, Manifestation, and Pathogenesis. Cureus. 2020;12(5):e8184.

7. Macera M, De Angelis G, Sagnelli C, et al. Clinical Presentation of COVID-19: Case Series and Review of the Literature. Int J Environ Res Public Health. 2020;17(14). 8. Ji D, Zhang D, Xu J, et al. Prediction for Progression Risk in Patients with COVID-19 Pneumonia: the CALL Score. Clin Infect Dis. 2020; 71(6):1393-1399.

9. Group RC, Horby P, Lim WS, et al.

Dexamethasone in Hospitalized Patients with COVID-19 - Preliminary Report. N Engl J Med. 2020; Epub ahead of print.

10. Liu T, Zhang J, Yang Y, et al. The potential role of IL-6 in monitoring severe case of coronavirus disease 2019. medRxiv.

2020:2020.2003.2001.20029769.

11. Wang M, Zhu Q, Fu J, et al. Differences of inflammatory and non-inflammatory indicators in Coronavirus disease-19 (COVID-19) with different severity. Infect Genet Evol.

2020;85:104511.

12. Sun Y, Dong Y, Wang L, et al. Characteristics and prognostic factors of disease severity in patients with COVID-19: The Beijing experience. J Autoimmun. 2020;112:102473.

13. Asghar MS, Haider Kazmi SJ, Khan NA, et al. Poor Prognostic Biochemical Markers Predicting Fatalities Caused by COVID-19: A Retrospective Observational Study From a Developing Country. Cureus.

2020;12(8):e9575.

14. Guan WJ, Ni ZY, Hu Y, et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):17081720.i 15. Gupta S, Hayek SS, Wang W, et al.

Factors Associated With Death in Critically Ill Patients With Coronavirus Disease 2019 in the US. JAMA Intern Med. 2020; 180(11): 1- 12.

16. Zar JH. Biostatistical Analysis, 2nd ed. New Jersey: Prentice Hall, 1984. 17.

Ko JH, Joo EJ, Park SJ, et al. Neutralizing Antibody Production in Asymptomatic and Mild COVID-19 Patients, in Comparison with Pneumonic COVID-19 Patients. J Clin Med. 2020; 9:2268.

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KEYWORDS ILK; siRNA; cisplatin; ovarian cancer; RNA-Seq; non-coding RNAs; KM plotter PALABRAS CLAVE ILK; ARNip; cisplatino; cáncer de ovarios; RNA-Seq; ARN no codificantes; Trazador KM

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EFECTORES SUBSIGUIENTES DE LA QUINASA LIGADA A LA INTEGRINA (ILK) EN EL CÁNCER DE OVARIO RESISTENTE AL CISPLATINO Jeyshka M. Reyes-González1, Blanca I. Quiñones-Díaz1, Yasmarie Santana2, Perla M. Báez-Vega3, Daniel Soto4, Fatima Valiyeva3, María J. Marcos-Martínez5,6, Ricardo J. Fernández-de Thomas7 y Pablo E. Vivas-Mejía1,3,* 1Department of Biochemistry, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA 2Center for Collaborative Research in Health Disparities (CCRHD), Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA 3Comprehensive Cancer Center, University of Puerto Rico, San Juan, PR 00936, USA 4Department of Biology, Rio Piedras Campus, University of Puerto Rico, San Juan, PR 00931, USA 5 Department of Pathology and Laboratory Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA 6​​ Anatomic Pathology Laboratory, Puerto Rico Medical Services Administration, San Juan, PR 00935, USA 7School of Medicine, Medical Sciences Campus, University of Puerto Rico, San Juan, PR 00936, USA * Correspondence: pablo.vivas@upr.edu; Tel.: 1-787-772-8300

Resumen A pesar de los buenos resultados la primera línea de tratamiento contra el cáncer de ovario, que es una quimioterapia de combinación basada en platino, la mayoría de las pacientes sufren una reaparición y eventualmente desarrollan una enfermedad resistente al platino con una prognosis desalentadora.

Aunque otros estudios sugieren que la quinasa ligada a la integrina (ILK) es un blanco potencial para el tratamiento de cáncer de ovario, no se han estudiado lo suficiente los efectos subsiguientes de la ILK. El propósito de este estudio es investigar los efectos moleculares y biológicos de usar la ILK como blanco objetivo para un cáncer resistente al cisplatino. El análisis de inmunotransferencia mostró que los niveles de fosforilación de la ILK eran más altos en células de cáncer de ovario resistentes al cisplatino que en aquellas sensibles a él. Un análisis inmunohistoquímico más profundo en muestras de pacientes con cáncer de ovario mostraron

un aumento significativo en los niveles de ILK fosforilado presentes en el tejido maligno, tras ser comparadas con el epitelio sano de un ovario. Abordar la ILK con un tratamiento de ARN pequeño de interferencia (siRNA) redujo el crecimiento de células resistentes al cisplatino, así como su capacidad para invadir.

También se redujo la apóptosis. Un análisis de expresión diferencial de genes hecho con secuenciación de ARN (RNA-Seq) en una transfección de ILK-siRNA, seguido por un análisis de rutas Ingenuity (IPA) y un análisis de supervivencia con el uso de la base de datos Kaplan-Meier Plotter, permitió identificar múltiples genes objetivo que están relacionados con el crecimiento celular, la apóptosis, la invasión y la metástasis; incluídos bastantes ARN no codificantes. Si los resultados de este estudio se juntan, se sostiene la ILK como un blanco atractivo contra el cáncer de ovario.

El estudio también proporciona potenciales efectores subsiguientes de ILK con valor prognóstico y terapéutico.

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ABSTRACT Despite good responses to first-line treatment with platinum-based combination chemotherapy, most ovarian cancer patients will relapse and eventually develop platinum-resistant disease with poor prognosis. Although reports suggest that integrin-linked kinase (ILK) is a potential target for ovarian cancer treatment, identification of ILK downstream effectors has not been fully explored. The purpose of this study was to investigate the molecular and biological effects of targeting ILK in cisplatin-resistant ovarian

cancer. Western blot analysis showed that phosphorylation levels of ILK were higher in cisplatin-resistant compared with cisplatin-sensitive ovarian cancer cells.

Further immunohistochemical analysis of ovarian cancer patient samples showed a significant increase in phosphorylated ILK levels in the tumor tissue when compared to normal ovarian epithelium. Targeting ILK by small-interfering RNA (siRNA) treatment reduced cisplatin-resistant cell growth and invasion ability, and increased apoptosis. Differential gene expression

analysis by RNA sequencing (RNA-Seq) upon ILK-siRNA transfection followed by Ingenuity Pathway Analysis (IPA) and survival analysis using the Kaplan–Meier plotter database identified multiple target genes involved in cell growth, apoptosis, invasion, and metastasis, including several non-coding RNAs. Taken together, results from this study support ILK as an attractive target for ovarian cancer and provide potential ILK downstream effectors with prognostic and therapeutic value.

que se conecta a la matriz extracelular (ECM), a las proteínas asociadas a la membrana celular (como las integrinas) y a las vías de señalización celular. La actividad de la ILK es estimulada por las integrinas y los factores de crecimiento, todo ello dependiente de las fosfoinositol 3-quinasas (PI3K). Por otro lado, la ILK se regula negativamente por el gen homólogo de fosfatasa y tensina (PTEN) y la serina/treonina fosfatasa 2C asociada a la ILK (ILKAP). Adicionalmente, la señalización mediada por la ILK y la traslocación intracelular está regulada por la quinasa 1 activada por p21 (PAK1) a través de la fosforilación de IL en la treonina 173 (T173) y los residuos de serina 246 (S246). Una vez se activa, la ILK puede ser la mediadora de una gran variedad de funciones celulares a través de sus blancos subsiguientes, incluídos la proteína quinasa B (AKT), la glucógeno sintasa quinasa 3 beta (GSK3β) y el factor nuclear kappa B (NFκB).

Unos niveles aumentados de ILK han sido asociados con la progresión del cáncer, transición epitelio-mesénquima (EMT), angiogénesis y metástasis. En el cáncer de ovario, la expresión de ILK ha sido asociada anteriormente con la progresión del tumor. Investigaciones tempranas mostraron que una inyección subcutánea de células de cáncer ovárico transfectadas con ARN corto de horquilla (shRNA) de ILK u oligonucleótidos antisentido (ASO) de ILK suprime la formación y el crecimiento in vivo del tumor. Otros estudios han mostrado que la actividad de

la ILK modula el comportamiento pro-metastásico del cáncer de ovario al estimular la invasión y migración celular. Además, la activación aumentada de ILK ha mostrado que protegen las células de cáncer de ovario resistentes al platino de la apóptosis inducida por cisplatino. Apuntar a la ILK anula el potencial invasivo de las células de cáncer ovárico, induce la apóptosis y reduce la viabilidad celular.

Aún no se han explorado del todo los efectos moleculares y biológicos de marcar la ILK del cáncer ovárico resistente al cisplatino a través del siRNA, más la identificación de efectores subsiguientes asociados. En este estudio analizamos los niveles de fosforilación de la ILK en la estirpe celular y muestras de tejido del cáncer de ovario, e investigamos los efectos de apuntar a la ILK en el cáncer de ovario resistente al cisplatino. Reportamos que apuntar a la ILK con siRNA induce a cambios significativos en la expresión de muchos genes codificadores de proteínas asociados al cáncer y ARN no codificante que está involucrado con el crecimiento celular, la supervivencia y la metástasis.

Un análisis de supervivencia basado en expresión hecho con la base de datos Kaplan-Meier Plotter reveló asociaciones significativas entre apuntar a los genes potencialmente asociados a la ILK y la prognosis del cáncer de ovario. Los resultados de este estudio sugieren que los genes regulados por la ILK pueden servir como marcadores de pronóstico y objetivos terapéuticos contra el cáncer de ovario.

INTRODUCCIÓN El cáncer de ovario sigue siendo una causa significativa de muertes asociadas al cáncer en mujeres. Fueron reportados aproximadamente 21750 casos nuevos y 13940 muertes en Estados Unidos en 2020. Su alta tasa de mortalidad es una muestra del hecho de que la mayoría de pacientes de cáncer de ovario es diagnosticada cuando la enfermedad está en una fase avanzada. El cáncer de ovario epitelial -el tipo más común de malignidad de ovario- es un grupo complejo de enfermedades que, con base en la histopatología y las alteraciones genéticas moleculares, se puede dividir en cinco categorías principales, incluyendo el carcinoma seroso de alto grado, el carcinoma de endometrio, el carcinoma de células claras, el carcinoma mucinoso y el carcinoma seroso de bajo grado. El carcinoma seroso de alto grado (HGSOC) representa el 70% de todos los cánceres de ovario epiteliales.

A pesar de la respuesta inicial al tratamiento de primera línea, una quimioterapia combinada con base en latino, la mayoría de pacientes con HGSOC tendrán una recaída y eventualmente desarrollarán una enfermedad resistente al platino con una mala prognosis general.

Por lo tanto, las terapias nuevas que apuntan a las vías clave para la supervivencia son necesitadas con urgencia para mejorar los resultados clínicos de las mujeres con esta enfermedad mortal.

La quinasa integrada a la integrina (ILK) es una serina/treonina quinasa altamente conservada y una proteína adaptadora 18

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ARTÍCULO / ORIGINAL 2. RESULTS 2.1. Expression Levels of p-ILK and ILK in Ovarian Cancer Cells and Human Ovarian Samples Western blot and densitometric analysis of a panel of ovarian cancer cell lines showed that phosphorylation levels of ILK (p-ILK; Ser 246) relative to total ILK protein (p-ILK/ILK) were significantly higher in cisplatin-resistant A2780CP20 and OVCAR3CIS cells compared with their parental counterparts A2780 and OVCAR3, respectively (Figure 1A,B).

Although not significant, p-ILK/ILK levels were also higher in cisplatin-resistant OV90CIS cells compared with their parental counterparts OV90 (Figure 1A,B).

FIGURA 1

For taxane-resistant and taxane-sensitive ovarian cancer cells (HEYA8.MDR and HEYA8, respectively) this trend was not observed. We also measured the phosphorylation levels of AKT (p-AKT; Ser 473)—a downstream target of ILK [11]—in cisplatin-resistant ovarian cancer cells and their respective cisplatin-sensitive counterparts. Western blot and densitometric analysis showed that p-AKT levels relative to total AKT protein (p-AKT/AKT) were significantly higher in cisplatin-resistant A2780CP20 and OVCAR3CIS cells compared with their parental counterparts A2780 and OVCAR3, respectively (Figure S1A,B). Although not significant, p-AKT/ AKT levels were also higher in cispla-

tin-resistant OV90CIS cells compared with their parental counterparts OV90 (Figure S1A,B). These observations are consistent with higher p-ILK/ILK protein levels in cisplatin-resistant ovarian cancer cells as compared with their cisplatin-sensitive counterparts (Figure 1A,B).

To assess the clinical significance of p-ILK expression in ovarian cancer, we performed immunohistochemical (IHC) analysis in normal ovary and ovarian cancer tissue sections. Representative IHC images are shown in Figure 1C. A significant increase in p-ILK (**** p < 0.0001) was observed in samples from ovarian cancer tissues compared with normal ovary (Figure 1D). No significant change was observed for total ILK (Figure 1C,E).

2.2 Effects of ILK-siRNA Transfection on Cell Growth, Invasion, and Viability Next, we studied whether targeting ILK reduces cell growth and the invasive ability of cisplatin-resistant ovarian cancer cells. Transient transfection of ILK-targeted siRNAs into A2780CP20 cells decreased ILK protein levels (43.0% reduction; *** p < 0.001 and 35.0% reduction; ** p < 0.01) compared with C-siRNA-transfected cells (Figure 2A,B). In a colony formation assay with A2780CP20, both ILK-targeted siRNAs reduced the number of colonies formed compared with C-siRNA-transfected cells (Figure 2C). Particularly, ILK-siRNA(2) reduced in 60.5% (*** p < 0.001) the number of colonies, whereas ILK-siRNA(1) reduced the number of colonies in only 40.7% (** p < 0.01).

Invasion assays confirmed that ILK-siRNA(1) and ILK-siRNA(2) significantly reduced (68.7% reduction; **** p < 0.0001 and 85.5% reduction; **** p < 0.0001, respec-

FIGURE 1

Expression of p-ILK and ILK in ovarian cancer cells and ovarian tumor samples. Western blot analysis and immunohistochemical (IHC) staining were performed. (A) Representative Western blots showing the phosphorylated form of ILK (p-ILK) and total ILK protein levels in a panel of ovarian cancer cell lines. (B) Densitometric analysis of the band intensities shown in Figure 1A plotted as mean ± SEM (** p < 0.01 and *** p < 0.001).

Phosphorylated ILK/total ILK (p-ILK/ILK) was calculated relative to parental cell lines for each group. (C) Representative IHC of p-ILK and ILK protein levels in normal ovary and tumor samples from ovarian cancer patients. (D) Expression of p-ILK and (E) ILK (positive staining) plotted as mean ±SEM (**** p < 0.0001).

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FIGURE 2

SiRNA-mediated ILK targeting in A2780CP20 cells. SiRNAs were transiently transfected into ovarian cancer cells. A reduction in (A,B) ILK protein levels, (C) colony formation, (D) invasion ability, and (E) cell viability was observed following ILK-siRNA transfection into A2780CP20 cells. Attached and floating cells were collected 72 h after transfection. (F) Protein extracts from siRNA-transfected cells were used to assess caspase-3 activity (DEVD-AFC cleavage). Increased caspase-3 activity was observed upon ILK-siRNA transfection. (G) Representative Western blot showing full caspase-3 and its cleavage product. (H) Densitometric analysis of the band intensities shown in Figure 2G. Mean ± SEM is shown relative to C-siRNA (* p < 0.05, ** p < 0.01, *** p < 0.001, and **** p < 0.0001) or C-siRNA + CIS (### p < 0.001).

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tively) the invasiveness of A2780CP20 cells compared with C-siRNA-transfected cells (Figure 2D). Then, we investigated whether ILK-targeted siRNAs alone or in combination with cisplatin (CIS) induced effects in cell viability. Transient transfection of 100 nmol/L of ILK-siRNA(2) into A2780CP20 cells significantly reduced (** p < 0.01) cell viability compared with C-siRNA (Figure 2E). Combination of ILK-siRNA(2) with CIS (2 µmol/L) significantly reduced (** p < 0.01) cell viability at siRNA doses as low as 25 nmol/L compared with C-siRNA (Figure 2E). To assess whether the effects induced on cell viability by ILK-siRNA were due to apoptosis, activation of caspase-3 was measured in cisplatin-resistant ovarian cancer cells. A significant increase (* p < 0.05) in caspase-3 activity was observed after transient transfection of 100 nmol/L of ILK-siRNA(2) into A2780CP20 cells compared with C-siRNA-transfected cells (Figure 2F). Results were validated by Western blot analysis, which showed increased caspase-3 cleavage upon ILK targeting (Figure 2G,H).

Similar to A2780CP20, transient transfection of ILK-siRNA(2) into OVCAR3CIS cells—a HGSOC cell line resistant to CIS— reduced ILK protein levels (45.0% reduction; ** p < 0.01, Figure 3A,B), colony formation (62.5% reduction; * p < 0.05, Figure 3C), and cell invasion (35.3% reduction; ** p < 0.01, Figure 3D) compared with C-siRNA-transfected cells. Combination of ILK-siRNA(2) with CIS (2 µmol/L) significantly reduced (* p < 0.05) cell viability at 100 nmol/L compared with C-siRNA (Figure 3E).

Similar results for ILK protein levels (37.0% reduction; ** p < 0.01, Figure S2A,B), colony formation (66.8% reduction; * p < 0.05, Figure S2C), and cell invasion (61.6% reduction; **** p < 0.0001, Figure S2D) were observed when transfecting ILK-siRNA(2) into OV90CIS cells, another HGSOC cell line resistant to CIS. In addition, transient transfection of ILK-siRNA(2) into HEYA8 cells decreased ILK protein levels compared with C-siRNA-transfected cells (44.0% reduction; *** p < 0.001, Figure S2E,F). However, in contrast to A2780CP20 and OVCAR3CIS cells, ILK-siRNA(2) significantly reduced (** p < 0.01) the viability of HEYA8 cells at concentrations of 25 nmol/L or lower compared with C-siRNA (Figure S2G). Importantly, no significant changes in colony formation and/or viability were observed when ILK-siRNA(2) was transfected into A2780, OVCAR3, and OV90 cells (Figure S3A–E).

ARTÍCULO / ORIGINAL 2.3. Effect of a Small-Molecule ILK Inhibitor on Cell Viability Next, we studied the effect of a small-molecule ILK inhibitor (Cpd22) on cell viability. Inhibition of ILK activity by Cpd22 has been shown to suppress the viability of prostate and breast cancer cells [23]. Treatment with Cpd22 significantly reduced the viability of both cisplatin-resistant (A2780CP20, OVCAR3CIS, and OV90CIS) and cisplatin-sensitive (A2780, OVCAR3, and OV90) ovarian cancer cells in a dose-dependent manner (Figure S4A–F). The viability of HEYA8 cells was also significantly reduced by Cpd22 treatment (Figure S4G). Western blot and densitometric analysis showed that p-ILK levels relative to total ILK protein (p-ILK/ILK) were significantly lower in OVCAR3CIS (25.3% reduction; ** p < 0.01, Figure S5A,B) and HEYA8 cells (20.7% reduction; ** p < 0.01, Figure S5C,D) upon Cpd22 (2 µmol/L) treatment. Although not significant, a reduction in p-ILK/ILK levels was also observed for A2780CP20 (26.7% reduction; p = n.s., Figure S5E,F) and OV90CIS cells (14% reduction; p = n.s., Figure S5G,H).

2.4. Effect of ILK-siRNA Transfection on Gene Expression To further assess the signaling pathways altered as a result of ILK-siRNA transfection in cisplatin-resistant ovarian cancer cells, we performed a transcriptome-wide analysis by RNA sequencing (RNA-Seq).

Using an initial false discovery rate (FDR, q-value) cutoff of <0.05, we identified 2028 differentially expressed genes between C-siRNA and ILK-siRNA-transfected cells including 1322 upregulated and 706 downregulated genes (data not shown).

Differentially expressed genes with a log2 fold change of ≥1.5 and ≤−1.5 were used to analyze functional enrichment using the Kyoto Encyclopedia of Genes and Genomes (KEGG). The top 10 most significantly enriched KEGG pathways include metabolic pathways, olfactory transduction, pathways in cancer, PI3K-AKT signaling pathway, MAPK signaling pathway, neuroactive ligand– receptor interaction, HTLV-I infection, cytokine–cytokine receptor interaction, proteoglycans in cancer, and focal adhesion (Table 1).

Gene ontology (GO) analysis of significantly enriched processes, components, and functions with a FDR < 0.01 showed that differentially expressed genes were

FIGURA 3

SiRNA-mediated ILK targeting in OVCAR3CIS cells. SiRNAs were transiently transfected into ovarian cancer cells. A reduction in (A,B) ILK protein levels, (C) colony formation, (D) invasion ability, and (E) cell viability was observed following ILK-siRNA transfection into OVCAR3CIS cells.

Mean ± SEM is shown relative to C-siRNA (* p < 0.05 and ** p < 0.01).

mainly associated with tissue development, positive regulation of macromolecule biosynthetic process, cell development, positive regulation of RNA metabolic process, and regulation of multicellular organismal development within the biological processes category (Table 2); adenyl nucleotide binding, adenyl ribonucleotide binding, ATP binding, signal transducer activity, and transition metal ion binding within the molecular functions category (Table 2); and intrinsic component of plasma membrane, integral component of plasma membrane, neuron part, Golgi apparatus, and cell junction within the cellular components category (Table 2).

A dataset containing the gene symbols, fold change (log2), and p-values of the 2028 differentially expressed genes was uploaded into the Ingenuity Pathway Analysis (IPA) software. Of these genes, 1804 were mapped successfully by IPA. To select differentially expressed genes, a

log2 fold change cutoff >1.5 or<−1.5 with a p-value≤0.001 was used. Using these criteria, we identified a total of 77 differentially expressed genes, 68 upregulated and 9 downregulated in ILK-siRNA vs.

C-siRNA-transfected cells (Table S1). Based on fold change, among the 68 upregulated genes, the top 5 include GRIA4, SCG3, CHRNB2, XKR7, and TOMM40L (Table 3). Among the nine downregulated genes, the top five include NSG1, TEX41, SLC4A8, SAG, and ILK (Table 3).

In agreement with evidence that long non-coding RNAs (lncRNAs) are key regulators of gene expression [24], using an FDR < 0.05, we identified 296 lncRNAs with altered expression following ILK-siRNA transfection, 205 upregulated and 91 downregulated (data not shown). To select differentially expressed lncRNAs, a log2 fold change cutoff >1.0 or <−1.0 with a p-value ≤ 0.001 was used. Using these criteria, we identified a total of 37 differentially expressed lncRNAs, 33 upregulated Revista Puertorriqueña de Medicina y Salud Pública

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2.5. IPA Analysis of Differentially Expressed Genes To better examine the interaction networks of ILK downstream genes, we performed IPA analysis with the 77 differentially expressed transcripts. This analysis produced a list of 9 significantly altered canonical pathways (p < 0.05 or –log p-value > 1.30) including SAPK/JNK signaling, NAD biosynthesis and salvage pathway, phototransduction pathway, VDR/RXR activation, Reelin signaling in neurons, and role of IL-17A in psoriasis (Table 5).

The top network with an IPA score of 23 and composed of 13 molecules was associated with nervous system development and function, organ morphology,

KEGG Term Description

and organismal development (Figure 4A and Table S3). The second top network (score: 23, molecules: 13) was associated with cell death and survival, cancer, and immunological disease (Figure 4B and Table S3).

In addition, other networks within the top 5 list were associated with cellular movement, cell-to-cell signaling and interaction, cellular development, and cellular growth and proliferation (Table S3). Furthermore, cell morphology, cellular assembly and organization, and cellular function and maintenance were within the top 5 cellular and molecular functions associated with ILK downregulation (Table 6).

2.6. Prognostic Value of ILK Downstream Genes To assess whether the differentially expressed transcripts identified upon ILK targeting are clinically relevant in ovarian cancer, we conducted survival analysis using Kaplan–Meier plotter (KM plotter) [25]. Gene chip data (Affymetrix) for 70 out of the 77 differentially abundant

Table 1. KEGG pathway enrichment analysis Term ID

Proteins

Hits

p-Value

FDR

Metabolic Pathways

1100

1161

1004

0

0

Olfactory Transduction Pathways in Cancer PI3K-AKT Signaling Pathway MAPK Signaling Pathway Neuroactive Ligand– Receptor Interaction HTLV-I Infection Cytokine– Cytokine Receptor Interaction Proteoglycans in Cancer

4740

391

378

2.00x10 -191

2.87x10 -189

5200

320

305

1.73x10 -148

1.66x10 -146

4151

336

306

1.26x10 -133

9.05x10 -132

4010

251

236

5.65x10 -111

3.24x10 -109

4080

269

246

2.28x10 -108

1.09x10 -106

5166

250

229

2.90x10 -101

1.19x10 -99

4060

260

231

2.21x10 -95

7.92x10 -94

5205

218

204

7.37x10 -95

2.35 x10 -93

Focal Adhesion

4510

202

190

1.79x10 -89

5.13x10 -88

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transcripts (Table S1) were available in the database. After dividing the patients into high and low expression (according to the median value), 33 of the 70 transcripts were significantly associated with overall survival (OS) and/or progression-free survival (PFS; Table S4). Expression levels upon ILK depletion for 10 out of the 33 transcripts were concordant with survival outcomes (Table S4). A significant association between high expression levels and better prognosis (OS; HR < 1) was found for CHGA, SLC5A1, MAPK8IP2, NMNAT2, and PLA2G4C, whereas worse outcomes (OS; HR > 1) were associated with high expression of ARHGAP23 (Figure 5).

In addition, high expression levels of CHGA and BSN were associated with longer PFS (HR < 1), whereas high expression of SEMA3G, ARHGAP23, SAG, and SLC4A8 were associated with shorter PFS (HR > 1; Figure 6).

For ovarian cancer patients treated with platin, 30 of the 70 transcripts were significantly associated with OS and/or PFS (Table S5). Expression levels upon ILK depletion for 11 out of the 30 transcripts were concordant with survival outcomes (Table S5). A significant association between high expression levels and better prognosis (OS; HR < 1) was found for VGF, CHGA, and NMNAT2, whereas worse outcomes (OS; HR > 1) were associated with high expression of ARHGAP23 (Figure S6). In addition, high expression levels of CHGA, ACTL6B, BSN, PAX5, NKAIN1, SYP, CAMKV were associated with longer PFS (HR < 1), whereas high expression of ARHGAP23 and SLC4A8 were associated with shorter PFS (HR > 1; Figure S7).

For serous ovarian cancer patients, 27 of the 70 transcripts were significantly associated with OS and/or PFS (Table S6).

Expression levels upon ILK depletion for 7 out of the 27 transcripts were concordant with survival outcomes (Table S6). A significant association between high expression levels and better prognosis (OS; HR < 1) was found for CHGA, SLC5A1, and NMNAT2, whereas worse outcomes (OS; HR > 1) were associated with high expression of ARHGAP23 (Figure S8). In addition, high expression levels of SEMA3G, ARHGAP23, ILK, and SAG were associated with shorter PFS (HR > 1; Figure S9).

For serous ovarian cancer patients treated with platin, 23 of the 70 transcripts were significantly associated with OS and/or PFS (Table S7). Expression levels upon ILK depletion for 5 out of the 23 transcripts were

ARTÍCULO / ORIGINAL concordant with survival outcomes (Table S7). A significant association between high expression levels and better prognosis (OS; HR < 1) was found for LTF, whereas worse outcomes (OS; HR > 1) were associated with high expression of ARHGAP23 (Figure S10). In addition, high expression levels of SEMA3G, ARHGAP23, ILK, and SLC4A8 were associated with shorter PFS (HR > 1; Figure S11).

Gene chip data for 11 of the 37 differentially abundant lncRNAs following ILK targeting (Table S2) were also available in KM plotter. After dividing the patients into high and low expression (according to the median value), 6 of 11 lncRNAs including MIR7-3HG, LINC01134, HAR1A, LINC01139, LINC-PINT, and DNM3OS were significantly associated with OS and/ or PFS (Figure 7 and Table S8). However, expression levels of these lncRNAs upon ILK depletion were not concordant with survival outcomes.

For ovarian cancer patients treated with platin, five lncRNAs including LINC01134, HAR1A, LINC01139, LINC-PINT, and DNM3OS were significantly associated with PFS (Figure S12 and Table S9). For serous ovarian cancer patients, three lncRNAs including HAR1A, LINC00886, and LINC-PINT were significantly associated with PFS (Figure S13 and Table S10). For serous ovarian cancer patients treated with platin, five lncRNAs including HAR1A, LINC00886, LINC01139, LINC-PINT, DNM3OS were significantly associated with PFS (Figure S14 and Table S11). However, expression levels of these lncRNAs upon ILK depletion were not concordant with survival outcomes.

Survival analysis was also conducted using Pan-cancer RNA-Seq data in KM plotter. Expression levels for 75 of the 77 differentially abundant transcripts (Table S1) were available in the database. After dividing ovarian cancer patients into high and low expression (according to the median value), 9 of 75 transcripts (Table S12) were found significantly associated with OS (n = 373) or relapse-free survival (RFS; n = 177). Expression levels of four of the nine transcripts were concordant with survival outcomes (Table S12). High expression levels of MARVELD3 were associated with longer OS (HR < 1), whereas high expression levels of PAX5, COL13A1, and ANKRD22 were associated with longer RFS (HR < 1; Figure 8). Although expression levels for 10 of the 37 differentially abundant lncRNAs were available from

RNA-Seq data in KM plotter, no significant associations were found between lncRNA expression and OS or RFS. 2.7. Target Validation by qRT-PCR Analysis Based on RNA-Seq data upon ILK targeting in cisplatin-resistant ovarian cancer cells and survival analysis of differentially expressed genes, ACTL6B, ANKRD22, ARHGAP23, BSN, CAMKV, CHGA, COL13A1, ILK, LTF, MAPK8IP2, MARVELD3, NKAIN1, NMNAT2, PAX5, SAG, SEMA3G, SLC4A8, SLC5A1, and VGF were selected for further validation

by SYBR Green-based qRT-PCR analysis.

Expression levels of all genes tested were concordant with RNA-Seq data except

for NKAIN1 (Table 7). ARHGAP23 and COL13A1 did not show significant differences in expression (Table 7). Expression of LTF and SAG was not detected by qRT-PCR. 3. DISCUSSION Increased levels of ILK, a serine/ threonine kinase and adaptor protein, have been well documented in different tumor types, including ovarian cancer [14].

Here, we present further evidence that phosphorylated ILK (p-ILK) levels are higher in human ovarian cancer tissues compared with normal ovary samples, and that p-ILK levels relative to total ILK protein (p-ILK/ILK) are higher in cisplatin-resistant compared with cisplatin-sensitive ovarian cancer

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cells. Transfection of ILK-siRNA into cisplatin-resistant ovarian cancer cells induced long-term effects on cell growth, short-term effects on cell viability in combination with cisplatin treatment, and increased caspase-3 activity. These results are in accordance with previous reports showing that targeting ILK decreases cell viability [22] and induces apoptosis in ovarian cancer [20,21], and increases the sensitivity of lung cancer [26], gastric carcinoma [27], and colon cancer [28] cells to cisplatin or oxaliplatin treatment. In fact, studies in platinum-resistant ovarian cancer have shown that ILKAP, a phosphatase which inactivates ILK, is downregulated by cisplatin treatment, and that silencing ILKAP increases ILK activation and protects cells from cisplatin-induced apoptosis [19].

We also observed that transfection of ILK-siRNA reduced the invasive potential of cisplatin-resistant ovarian cancer cells, which is in agreement with previous studies showing that ILK activity modulates the pro-metastatic behavior of ovarian cancer [17]. Similar to our results, ILK activity stimulates invasion and migration of the SKOV3 human ovarian cancer cell line [18], whereas ILK depletion by shRNA (short hairpin RNA) abrogates the invasive potential of SKOV3 cells [15].

Inhibition of ILK activity by Cpd22 treatment significantly reduced the viability of all cancer cell lines tested. These results are in accordance with a previous study showing that Cpd22 treatment suppresses the viability of prostate and breast cancer cells compared with normal prostate and mammary epithelial cells [23]. Cpd22 inhibits ILK kinase activity, facilitating dephosphorylation of ILK targets, suppressing the expression of YB-1 (Y-box binding protein) transcription factor and its targets, and inducing autophagy and apoptosis [23]. In addition, ILK expression levels positively correlate with the efficacy of Cpd22 in leukemia [29]. While siRNAs have high specificity in a sequence specific manner, small-molecule inhibitors can act over multiple targets [30]. These observations could explain in part the fact that the viability of both cisplatin-resistant and cisplatin-sensitive cells was reduced upon Cpd22 treatment.

Results from RNA-Seq analysis of ILK-siRNA-transfected ovarian cancer cells showed significant changes in the expression of

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cancer-associated molecules including protein-coding genes and lncRNAs. Repression of glutamate receptor GRIA4, one of the top upregulated genes in our study, increases cell viability, proliferation, and migratory potential in rhabdomyosarcoma/medulloblastoma and multiple myeloma cells [31]. Another GRIA family member, GRIA2, is downregulated in chemoresistant advanced serous papillary ovarian carcinomas and upregulated in chemosensitive tumors [32]. TOMM40L, also upregulated in our study, is upregulated in epithelial ovarian cancer cell lines overexpressing DOK1, a candidate tumor suppressor associated with cisplatin sensitivity [33]. Similarly, TOMM40L is downregulated in gemcitabine-resistant pancreatic cancer cells compared with their parental sensitive counterparts [34].

Inhibition of NDCBE in cholangiocarcinoma cells, a product of the SLC4A8 gene downregulated in our study, decreases proliferation and induces apoptosis [35]. TEX41, also downregulated in our study, is upregulated in portal vein tumor thrombosis (PVTT), the main route for intrahepatic metastasis in hepatocellular carcinoma [36]. Therefore, changes in the expression of these genes following siRNA-mediated ILK depletion in cisplatin-resistant ovarian cancer cells could explain in part the reduction in cell growth, invasion, and viability, and the increase in caspase-3 activity.

In agreement with these observations, within the list of differentially abundant transcripts, we identified additional genes involved in the regulation of cell proliferation, survival, migration, invasion, metastasis, drug resistance, and apoptosis.

Interestingly, DUSP8, MARVELD3, PDCD4, MAPK8IP1, MAPK8IP2, and HIPK3 converge on JNK signaling, one of the top canonical pathways (SAPK/ JNK) identified in our IPA analysis. In epithelial ovarian cancer, activated JNK is associated with decreased PFS [37]. In addition, we have previously shown that the JNK-1/c-JUN/miR-21 pathway contributes to cisplatin resistance in ovarian cancer cells [38]. ILK negatively regulates the expression of DUSP8 [39], a MAPK phosphatase upregulated in our study, and DUSP8 dephosphorylates and inactivates JNK [40,41]. Inhibition of ILK/AKT decreases miR-21 in vestibular schwan-

noma and meningioma cells [42], and targeting miR-21 with antisense oligonucleotides (ASOs) inhibits growth and metastasis via upregulation of DUSP8 in colorectal carcinoma [43]. MARVELD3, a transmembrane protein of tight junctions [44,45] upregulated in our study, inhibits JNK activity via recruitment of MEKK1 to cell junctions [46]. MARVELD3 is downregulated in SNAIL-induced EMT during pancreatic cancer progression [47].

Similarly, MARVELD3 silencing decreases CDH1 and increases SNAI2 expression in lung cancer [48]. Downregulation of MARVELD3 in colorectal cancer cells increases migration and proliferation, whereas upregulation inhibits migration, proliferation, and in vivo tumor formation [46]. PDCD4, a well-known tumor suppressor [49] upregulated in our study, has been suggested to interact with c-JUN, blocking c-JUN phosphorylation by JNK [50]. In ovarian cancer, lower PDCD4 expression correlates with shorter disease-free survival (DFS) [51]. Moreover, PDCD4 overexpression enhances the sensitivity of ovarian cancer cells to cisplatin by activating the death receptor pathway [52]. In bladder cancer cells, PDCD4 overexpression enhances sensitivity to cisplatin via regulation of the JNK/c-JUN pathway [53]. The JIP family of MAPK scaffold proteins, including MAPK8IP1 and MAPK8IP2 which were upregulated in our study, have been previously identified as regulators of JNK signaling [54]. MAPK8IP1, a negative regulator of MAPK activity [55], inhibits c-JUN phosphorylation by JNK [56]. In gastric cancer, miR-10a promotes cell migration and invasion by downregulating MAPK8IP1 [55]. HIPK3, a FAS/ FADD-interacting kinase [57] downregulated in our study, has been previously implicated in multidrug resistance in cancer [58,59]. In fact, overexpression of HIPK3 protects osteosarcoma cells from cisplatin-induced death in vitro and in vivo [60]. In prostate cancer, JNK activity increases the expression of HIPK3 and promotes resistance to FAS receptor-mediated apoptosis [61]. Overall, these observations suggest that ILK regulates the JNK/c-JUN pathway in cisplatin-resistant ovarian cancer via modulation of DUSP8, MARVELD3, PDCD4, MAPK8IP1, MAPK8IP2, and HIPK3.

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FIGURE 4

Network analysis by Ingenuity Pathway Analysis (IPA). The top two altered networks following siRNA-mediated ILK targeting are shown. (A) The top network includes molecules associated with nervous system development and function, organ morphology, and organismal development. (B) The second top network includes molecules associated with cell death and survival, cancer, and immunological disease. Green and red symbols denote downregulated and upregulated genes, respectively.

FIGURE 5 (NEXT PAGE)

Kaplan–Meier plots for gene expression-based overall survival analysis. Survival plots of ovarian cancer patients were generated using Kaplan– Meier plotter (KM plotter). Overall survival (OS) of patients with ovarian cancer stratified by expression levels of (A) CHGA, (B) SLC5A1, (C) MAPK8IP2, (D) NMNAT2, (E) PLA2G4C, and (F) ARHGAP23 is shown based on gene chip data. p-values < 0.05 were considered to be statistically significant.

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Within the top 10 differentially expressed lncRNAs, ARHGEF26-AS1 and MIR7-3HG have been previously reported in cancer. ARHGEF26-AS1 is downregulated in cancer-associated fibroblasts (CAFs) of HGSOC patients compared with normal ovarian fibroblasts (NOFs) [62]. As CAFs promote cancer metastasis [62], our results showing that ILK depletion leads to ARHGEF26-AS1 downregulation suggest additional roles for ARHGEF26-AS1 in cisplatin-resistant ovarian cancer.

Similarly, MIR7-3HG upregulation in our analysis contrasts a report showing that MIR7-3HG downregulates the tumor suppressor AMBRA1 and prevents MYC dephosphorylation in lung cancer [63].

Nevertheless, our results that LINC-PINT was upregulated upon ILK-siRNA transfection is consistent with reports that show that this lncRNA inhibits cell invasion [24].

Interestingly, in osteosarcoma and gastric cancer, LINC-PINT inhibits cell invasion, migration, and proliferation by downregulating miR-21 [64,65]. In ovarian cancer, LINC-PINT is downregulated relative to normal ovary cells and tissue samples [66], whereas miR-21 is upregulated [67]. These observations warrant further investigation to elucidate the role of these lncRNAs in cisplatin-resistant ovarian cancer.

By using Kaplan–Meier analysis of publicly available mRNA expression (gene chip and RNA-Seq data) we further show that several genes differentially altered upon ILK depletion are significantly associated with survival outcomes in ovarian cancer. Based on expression levels of survival-relevant genes, we identified CHGA, BSN, SLC5A1, MAPK8IP2, NMNAT2, SEMA3G, ARHGAP23, SAG, SLC4A8, MARVELD3, PAX5, COL13A1, ANKRD22, VGF, ACTL6B, NKAIN1, CAMKV, LTF, and ILK as potential prognostic markers. Of these genes, we were able to validate CHGA, BSN, SLC5A1, MAPK8IP2, NMNAT2, SEMA3G, SLC4A8, MARVELD3, PAX5, ANKRD22, VGF, ACTL6B, CAMKV, and ILK by qRT-PCR analysis. In accordance with previous reports, CHGA can exert antiangiogenic effects and inhibit tumor growth in vivo [68]. Overexpression of PAX5 induces apoptosis in multiple myeloma [69], whereas knockdown of PAX5 increases cell proliferation and cisplatin resistance in esophageal squamous cell carcinoma [70].

Interestingly, PAX5 promoter hypermethylation has been observed in ovarian cancer [71]. Overexpression of VGF inhibits colony formation of ovarian cancer cells,

however, VGF promoter hypermethylation correlates with better patient survival [72].

In contrast to our results, SEMA3G inhibits cell migration and invasion in glioma [73].

SLC5A1 promotes growth and proliferation of pancreatic cancer [74]. High expression of SGLT1, which is encoded by SLC5A1, is associated with tumor development and poor prognosis in ovarian cancer [75]. In addition, ANKRD22 promotes progression of non-small-cell lung cancer [76].

However, higher ANKRD22 expression levels in prostate cancer are associated with longer DFS following radical prostatectomy [77]. Therefore, further studies are required to elucidate the role of these genes and their therapeutic potential in cisplatin-resistant ovarian cancer.

4. MATERIALS AND METHODS 4.1. Cells and Culture Conditions The human ovarian epithelial cancer cells, A2780CP20, HEYA8, and HEYA8.

MDR, were provided by Dr. Anil K. Sood (MD Anderson Cancer Center, Houston, TX, USA) and have been described elsewhere [78]. A2780 was purchased from the European Collection of Cell Cultures (ECACC, Porton Down, Salisbury, UK), and OV90 and OVCAR3 from the American Type Culture Collection (ATCC, Manassas, VA, USA)—both of which provide authenticated cell lines. OV90CIS and OVCAR3CIS cells were generated by exposing OV90 and OVCAR3 to increasing concentrations of cisplatin (CIS; Sigma-Aldrich, St. Louis, MO, USA). Cells were maintained in RPMI1640 (A2780, A2780CP20, HEYA8, and HEYA8.MDR; HyClone, GE Healthcare Life Sciences, Logan, UT, USA), RPMI1640 + insulin (0.01 mg/mL, OVCAR3 and OVCAR3CIS; Sigma) or M199/MCDB-105 (OV90 and OV90CIS; Gibco, Thermo Fisher Scientific, Grand Island, NY/Sigma) medium supplemented with 10% fetal bovine serum (FBS; HyClone) and 0.1% antibiotic/antimycotic solution (HyClone) at 37 ◦C in 5% CO2 and 95% air. All cell lines were screened for mycoplasma using the LookOut® Mycoplasma PCR detection kit (Sigma), and authenticated by Promega (Madison, WI, USA) and ATCC using Short Tandem Repeat (STR) analysis. In vitro assays were performed at 70%–85% cell density.

4.2. Western Blot Analysis Cell pellets were lysed with ice-cold lysis buffer (1% Triton X, 150 mmol/L NaCl, 25 mmol/L Tris HCl, 0.4 mmol/L NaVO4, 0.4 mmol/L NaF, and protease

ARTÍCULO / ORIGINAL inhibitor cocktail from Sigma) and total protein concentration was determined using Bio-Rad DC Protein Assay reagents (Bio-Rad, Hercules, CA). Protein samples were separated by SDS-PAGE and blotted onto nitrocellulose membranes.

The membranes were blocked in either 5% non-fat dry milk (Bio-Rad) or 5% BSA (HyClone) and probed with phospho-ILK (Ser 246; Millipore, Burlington, MA, USA), ILK (Cell Signaling, Danvers, MA, USA), phospho-AKT (Ser 473; Cell Signaling), AKT (Cell Signaling), full caspase-3 (Cell Signaling), or cleaved caspase-3 (Cell Signaling) primary antibodies. Membranes were then incubated with mouse or rabbit IgG horseradish peroxidase (HRP)-linked secondary antibodies (Cell Signaling) followed by enhanced chemiluminescence and autoradiography. Bands were imaged with a FluorChem system (Alpha Innotech Corporation, San Leandro, CA, USA) and the signal intensity of each band was quantified using AlphaEaseFC software.

All membranes were reprobed with β-actin monoclonal antibody (Sigma) as a normalizing control. Western blot images with molecular weight markers are shown in Figure S15.

(DAB; Dako), counterstained with Gill’s No.3 hematoxylin (American MasterTech Scientific, Lodi, CA, USA), and cover slipped with Permount (Fisher Scientific, Fair Lawn, NJ, USA). Scoring of p-ILK and ILK expression was based on the number of positive cells (DAB stained) in each group and quantified in 5 random fields at 20×.

One slide per specimen and 10 specimens per group were examined.

4.3. Immunohistochemistry Immunohistochemical (IHC) analysis of p-ILK and ILK was conducted on formalinfixed paraffin-embedded (FFPE) specimens from chemonaïve serous papillary ovarian cancer (n = 10; ages 40–85, mean 64.70 ± 13.320) and normal ovary samples (n = 10; ages 43–73, mean 51.70 ± 9.673) provided by the Department of Pathology at UPR-MSC. The study was carried out with approval from the UPR-MSC Institutional Review Board (IRB protocol number A9180115; category 4 exemption; informed consent is not required). A pathologist manually delineated tumor tissue on a representative hematoxylin and eosin (H&E)-stained slide from each paraffin block. Briefly, sections were deparaffinized and rehydrated.

After antigen retrieval (Vector Laboratories, Burlingame, CA, USA), endogenous peroxidase was blocked with 3% H2O2, followed by non-specific protein blocking (Dako, Carpinteria, CA, USA). Human sections were incubated with phospho-ILK (Ser 246; Abcam, Cambridge, MA, USA) or ILK (Cell Signaling) primary antibodies overnight at 4 ◦C. After washing with PBS, anti-rabbit EnVision+ System-HRP (Dako) was used as a secondary antibody. HRP was detected with 3,30 diaminobenzidine

4.5. In Vitro Inhibitor Treatment ILK inhibitor (Cpd22) was purchased from Millipore and dissolved in DMSO (Sigma). For in vitro inhibitor treatment, cells were treated with Cpd22 for 24 h and collected for assessment of p-ILK and ILK protein levels by Western blot analysis.

4.4. Small-Interfering RNA (siRNA) and In Vitro siRNA Transfection To target human ILK (NM_001014794.2), t wo siRNAs [50 - GTCA AGT TCTCT T TCCA AT-30 (ILK-siRNA(1)), and 50 - CTCA ATAGCCGTAGTGTA A -30(I LK-siRNA(2))] targeting ILK mRNA, and a non-silencing negative control siRNA (C-siRNA) were used (Sigma). For in vitro siRNA transfections, siRNAs were mixed with HiPerfect transfection reagent (Qiagen, Valencia, CA) at 1:2 ratio (siRNA: transfection reagent) in serum and antibiotic-free Opti-MEM medium (Gibco).

Transfected cells were collected 24 h after treatment for assessment of ILK protein levels by Western blot analysis.

4.6. In Vitro Cell Viability and Cell Growth For cell viability assays using siRNAs, A 2780, A 2780 CP20, OVCAR3, OVCAR3CIS, and HEYA8 cells (2 × 104cells/mL, 3 × 104cells/mL, or 10 × 104cells/mL) were seeded into 96-well plates. Twenty-four hours later, siRNA transfection was performed as described above. The transfection mix was replaced with CIS after 24 h of siRNA treatment.

Forty-eight hours after CIS treatment, the medium was removed and Alamar blue dye (Invitrogen, Thermo Fisher Scientific, Eugene, OR, USA) was added following the manufacturer’s instructions. Optical density (OD) values were obtained using a plate reader (Bio-Rad) and percentages of cell viability were calculated after blank OD subtraction, taking the untreated cell values as 100% cell viability. For cell viability assays using ILK inhibitor (Cpd22), A2780, A2780CP20, OV90, OV90CIS, Revista Puertorriqueña de Medicina y Salud Pública

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Table 6. Top 5 molecular and cellular functions Molecular and Focus Cellular Functions Molecules Cell Death

LTF, ILK, STK31,

and Survival

CALB1

Cell Morphology

PAX5, SLC4A8, ILK, LSP1

Cellular Assembly and Organization

GFAP, STON2, GOLGA2, AP3B2, ACTL6B, NPM2, ILK, CPLX1, COL13A1, LMOD1, DCC

Cellular

APLN, CDK5R2,

Development

FOXP1, CCL20, DCC, ILK, MARVELD3 ILK, SLC4A8, CCL20,

Cellular Function

CPLX1, EXOC3L1,

and Maintenance

CHGA, STON2, GFAP, GOLGA2, DCC

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FIGURE 6

Kaplan–Meier plots for gene expression-based progression-free survival analysis. Survival plots of ovarian cancer patients were generated using Kaplan–Meier plotter (KM plotter). Progression-free survival (PFS) of patients with ovarian cancer stratified by expression levels of (A) CHGA, (B) BSN, (C) SEMA3G, (D) ARHGAP23, (E) SAG, and (F) SLC4A8 are shown based on gene chip data. p-values < 0.05 were considered to be statistically significant.

ARTÍCULO / ORIGINAL OVCAR3, OVCAR3CIS, and HEYA8 cells (2 × 104cells/mL or 3 × 104cells/mL) were seeded into 96-well plates. Twentyfour hours later, inhibitor treatment was performed as described above. Seventy-two hours after treatment, cell viability was assessed using Alamar blue dye.

For assessment of cell growth, colony formation assays were performed using Crystal violet dye (Sigma). Briefly, A2780, A2780CP20, OVCAR3, OVCAR3CIS, OV90, and OV90CIS cells (3 × 104cells/ mL or 4.5 × 104cells/mL) were seeded into 6-well plates. Twenty-four hours later, siRNAs were added to the cells. After treatment, 1000 (A2780CP20) or 2500 (A2780, OVCAR3, OVCAR3CIS, OV90, and OV90CIS) cells were seeded into 10 cm Petri dishes. Seven (A2780, A2780CP20, OVCAR3, and OVCAR3CIS) or ten (OV90 and OV90CIS) days later, colonies were fixed and stained with 0.5% Crystal violet solution in methanol. Colonies of at least 50 cells were scored in five random fields using a light microscope (CKX41; Olympus, Center Valley, PA, USA) with a total magnification of 40×.

FIGURE 7

Ka p l a n – M e i e r plots for lncRNA expression-based overall survival and progression-free survival analysis. Survival plots of ovarian cancer patients were generated using Kaplan–Meier plotter (KM plotter). Overall survival (OS) of patients with ovarian cancer stratified by expression levels of (A) HAR1A is shown based on gene chip data. Progression-free survival (PFS) of patients with ovarian cancer stratified by expression levels of (B) MIR7-3HG, (C) LINC01134, (D) HAR1A, (E) LINC01139, (F) LINC-PINT, and (G) DNM3OS are shown based on gene chip data. p-values < 0.05 were considered to be statistically significant.

4.7. In Vitro Cell Invasion Cell invasion was analyzed using the matrigel transwell method as previously described [38,79]. A2780CP20, OV90CIS, and OVCAR3CIS cells (3.5 × 104cells/ mL) were seeded into 10 cm Petri dishes and transfected with siRNAs. The next day, matrigel (BD Biosciences, San Jose, CA, USA) in serum-free medium was added onto the upper chambers of 24-well transwell plates and incubated at 37 ◦C for polymerization. Transfected cells were collected and resuspended in serum-free medium and re-seeded onto the matrigel-coated chamber. Medium containing 10% FBS was added to the lower wells. After 48 h at 37 ◦C, medium was removed and cells that invaded through the matrigel were fixed and stained using the Protocol Hema 3 Stain Set (Fisher Scientific, Kalamazoo, MI, USA).

The invading cells were counted at 20× resolution on an Olympus IX71 microscope equipped with a digital camera (Olympus DP26). Percentages of cell invasion were calculated taking the C-siRNA-transfected cell values as 100% cell invasion.

4.8. Caspase-3 Activity Caspase-3 activity was quantified using the Caspase-3/CPP32 Fluorometric

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FIGURE 8

Kaplan–Meier plots for gene expression-based overall survival and relapse-free survival analysis.

Survival plots of ovarian cancer patients were generated using Kaplan–Meier plotter (KM plotter). Overall survival (OS) of patients with ovarian cancer stratified by expression levels of (A) MARVELD3 is shown based on RNA-Seq data.

Relapse-free survival (RFS) of patients with ovarian cancer stratified by expression levels of (B) PAX5, (C) COL13A1, and (D) ANKRD22 is shown based on RNA-Seq data. p-values < 0.05 were considered to be statistically significant.

Assay Kit (BioVision, Milpitas, CA, USA) following the manufacturer’s instructions.

A2780CP20 cells (2.0×105cells/mL) were seeded into 10 cm Petri dishes and transfected with C-siRNA or ILK-siRNA(2) for 24 h. Seventy-two hours after transfection, floating and attached cells were collected, pellets were lysed, and total protein concentration was determined. Equal amounts of protein were mixed with 2× Reaction Buffer and 1 mM DEVD-AFC substrate in a 96-well plate and incubated at 37 ◦C for 1 h. Fluorescence intensity at 400 nm excitation and 505 nm emission was measured on a Varioskan Flash reader from Thermo Scientific (Waltham, MA, USA).

4.9. RNA-Seq Analysis For RNA-Seq analysis, total RNA was isolated from C-siRNA or ILK-siRNA(2)-transfected A2780CP20 cells using the mirVanaTM miRNA Isolation Kit (Invitrogen) following the manufacturer’s instructions. RNA quality was verified on all samples with High Sensitivity RNA system on an Agilent 2200 TapeStation instrument (Agilent Technologies, Santa Clara, CA, USA). mRNA was enriched and library was prepared using NEBNext® Poly(A) mRNA Magnetic Isolation and NEBNext® Ultra™ 30

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RNA Library Prep (New England Biolabs, Ipswich, MA, USA). Once library construction was complete, qPCR was performed with KAPA SYBR® FAST qPCR in a HiSeq 4000 system (Illumina, San Diego, CA, USA) with a 2 × 150 bp configuration.

4.10. KEGG Pathway Enrichment, Gene Ontology, and Network Analysis Differentially expressed genes with a log2 fold change ≥1.5 and ≤−1.5 were enriched for their involvement in various biological pathways using KEGG (Kyoto Encyclopedia of Genes and Genomes) Pathway Enrichment. Ontological signatures, mainly biological processes, molecular functions, and cellular components were enriched based on STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) integration of interaction data.

Ingenuity Pathway Analysis (IPA; Ingenuity Systems, Qiagen, Redwood City, CA, USA) software was used to determine the functional networks and pathways associated with differentially expressed genes using a p-value cutoff ≤0.001 and a log2 fold change >1.5 or <−1.5. Gene networks and canonical pathways enrichment analysis were performed filtering

for all tissues, all cell lines and human species. For the identification of differentially expressed lncRNAs, a p-value cutoff ≤0.001 and a log2 fold change >1.0 or <−1.0 were used.

4.11. Survival Analysis Kaplan–Meier survival analysis was performed using publicly available gene chip and RNA-Seq datasets in Kaplan– Meier (KM) plotter (www.kmplot.com) [25]. For each gene symbol, the probe ID was selected, and ovarian cancer patients were split into high and low expression groups by the median values of mRNA expression. For genes with multiple probes, the best probe was selected. All available datasets were used for survival analysis.

Data from ovarian cancer patients, ovarian cancer patients treated with platin, serous ovarian cancer patients, and serous ovarian cancer patients treated with platin were evaluated. KM survival plots for overall survival (OS), progression-free survival (PFS), and relapse-free survival (RFS) were generated with their respective hazard ratios (HR), confidence intervals (CI), and p-values (log-rank). p-values < 0.05 were considered to be statistically significant.

ARTÍCULO / ORIGINAL 4.12. SYBR-Green Based qRT-PCR Analysis For validation of RNA-Seq data, qPCR was performed to assess expression levels of specific genes upon ILK targeting. A custom 96-well plate containing pre-designed primers was purchased from Bio-Rad. Total RNA was isolated from C-siRNA or ILK-siRNA(2)-transfected A2780CP20 cells using the GenElute Mammalian Total RNA Mini Kit (Sigma) following the manufacturer’s instructions, and reverse transcribed using the iScript™ cDNA Synthesis Kit (Bio-Rad). SYBR Green-based qPCR was conducted using SsoAdvanced™ Universal SYBR® Green Supermix (Bio-Rad) and StepOne Plus Real-Time PCR system with the suggested PrimePCR cycling protocol (activation at 95 ◦C for 2 min, and 40 cycles of 95 ◦C for 5 s and 60 ◦C for 30 s).

4.13. Statistical Analysis Graphing and statistical analysis were performed using Student’s t test or ANOVA in GraphPad Prism (San Diego, CA, USA) software. p-values < 0.05 were considered to be statistically significant. Experiments were performed at least in triplicate.

5. CONCLUSIONS Overall, this study provides further evidence that targeting ILK with siRNA is a plausible approach for ovarian cancer treatment and identifies ILK-regulated genes with potential prognostic and therapeutic value. Further studies are required to fully understand the contribution of ILK downstream effectors to cisplatin resistance in ovarian cancer.

Supplementary Materials: The following are available online at http://www.mdpi. com/2072-6694/12/4/880/s1, Figure S1: Expression of p-AKT and AKT in ovarian cancer cells, Figure S2: SiRNA-mediated ILK targeting in OV90CIS and HEYA8 cells, Figure S3: SiRNA-mediated ILK targeting in A2780, OVCAR3, and OV90 cells, Figure S4: Inhibitor-mediated ILK targeting in ovarian cancer cells, Figure S5: Effect of a small-molecule ILK inhibitor on p-ILK and ILK expression, Figure S6: Kaplan–Meier plots for gene expression-based overall survival analysis of ovarian cancer patients treated with platin, Figure S7: Kaplan–Meier plots for gene expression-based progression-free survival analysis of ovarian cancer patients treated with platin, Figure S8: Kaplan–Meier plots for gene expression-based overall survival analysis of serous ovarian cancer patients,

Figure S9: Kaplan–Meier plots for gene expression-based progression-free survival analysis of serous ovarian cancer patients, Figure S10: Kaplan–Meier plots for gene expression-based overall survival analysis of serous ovarian cancer patients treated with platin, Figure S11: Kaplan–Meier plots for gene expression-based progression-free survival analysis of serous ovarian cancer patients treated with platin, Figure S12: Kaplan–Meier plots for lncRNA expression-based progression-free survival analysis of ovarian cancer patients treated with platin, Figure S13: Kaplan–Meier plots for lncRNA expression-based progression-free survival analysis of serous ovarian cancer patients, Figure S14: Kaplan– Meier plots for lncRNA expression-based progression-free survival analysis of serous ovarian cancer patients treated with platin, Figure S15: Western blot images, Table S1: Differentially expressed genes in ILK-siRNA(2) vs. C-siRNA, Table S2: Differentially expressed lncRNAs in ILK-siRNA(2) vs. C-siRNA, Table S3: Top 5 networks, Table S4: Hazard ratios for overall survival and progression-free survival of ovarian cancer patients based on differential gene expression upon ILK depletion, Table S5: Hazard ratios for overall survival and progression-free survival of ovarian cancer patients treated with platin based on differential gene expression upon ILK depletion, Table S6: Hazard ratios for overall survival and progression-free survival of serous ovarian cancer patients based on differential gene expression upon ILK depletion, Table S7: Hazard ratios for overall survival and progression-free survival of serous ovarian cancer patients treated with platin based on differential gene expression upon ILK depletion, Table S8: Hazard ratios for overall survival and progression-free survival of ovarian cancer patients based on differential lncRNA expression upon ILK depletion, Table S9: Hazard ratios for overall survival and progression-free survival of ovarian cancer patients treated with platin based on differential lncRNA expression upon ILK depletion, Table S10: Hazard ratios for overall survival and progression-free survival of serous ovarian cancer patients based on differential lncRNA expression upon ILK depletion, Table S11: Hazard ratios for overall survival and progression-free survival of serous ovarian cancer patients treated with platin based on differential lncRNA expression upon ILK depletion, and Table S12: Hazard ratios for overall survival and

relapse-free survival of ovarian cancer patients based on differential gene expression upon ILK depletion.

Author Contributions: Conceptualization, P.E.V.-M.; Methodology, J.M.R.-G., P.M.B.V., and P.E.V.-M.; Validation, J.M.R.-G, Y.S., P.M.B.-V., and F.V.; Formal Analysis, J.M.R.-G., B.I.Q.-D., Y.S., and P.M.B.-V.; Investigation, J.M.R.-G., B.I.Q.-D., Y.S., P.M.B.-V., D.S., F.V., M.J.M.-M., and R.J.F.-d.T.; Resources, M.J.M.-M. and P.E.V.M.; Data Curation, J.M.R.-G. and P.E.V.-M.; Writing—Original Draft Preparation, J.M.R.-G.; Writing—Review and Editing, J.M.R.-G. and P.E.V.-M.; Visualization, J.M.R.-G., B.I.Q.-D., and Y.S.; Supervision, P.E.V.-M.; Project Administration, P.E.V.-M.; Funding Acquisition, J.M.R.-G., B.I.Q.-D., and P.E.V.-M. All authors have read and agreed to the published version of the manuscript.

Funding: This work was supported in part by the National Institute on Minority Health and Health Disparities (NIMHD) CCRHD (U54MD007600) and RTRN (U54MD008149); institutional seed funds from the UPR Comprehensive Cancer Center; the National Institute of General Medical Sciences (NIGMS) RISE (R25GM061838) Program; and the Puerto Rico Science Technology and Research Trust (PRSTRT).

Acknowledgments: We would like to

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MSP ARTÍCULO / ORIGINAL thank Carlos Torres-Cintrón from the Puerto Rico Cancer Registry for providing demographics and clinical information of HGSOC patients.

Conflicts of Interest: The authors declare no conflict of interest. The funding sources had no role in study design, data collection, analysis and interpretation or in writing and submitting the manuscript.

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She has heavy bleeding due to fibroids

She doesn’t currently want surgery

HERONEGOAL

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1st

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Use of ORIAHNN should be limited to 24 months due to the risk of continued bone loss, which may not be reversible.

IMPORTANT SAFETY INFORMATION THROMBOEMBOLIC AND VASCULAR EVENTS Estrogen and progestin combinations, including ORIAHNN, increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at increased risk for these events.

ORIAHNN is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke and women with uncontrolled hypertension.

CONTRAINDICATIONS • ORIAHNN is contraindicated in women at a high risk of arterial, venous thrombotic, or thromboembolic disorders; who are pregnant; with known osteoporosis; current or history of breast cancer or other hormonally sensitive malignancies; known hepatic impairment or disease; undiagnosed abnormal uterine bleeding; known anaphylactic reaction, angioedema, or hypersensitivity to ingredients of ORIAHNN; or with concomitant use of organic anion transporting polypeptide (OATP) 1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations.

Please see additional Important Safety Information on next page and Brief Summary on the following pages of this advertisement. *Primary endpoint was defined as ≥50% bleeding volume reduction from baseline to Final Month and <80 mL bleeding volume at Final Month. Final Month is defined as the last 28 days before and including the last treatment visit date or the last dose date. This can occur anytime from Month 1 to 6 in the pivotal studies.1

34

Revista Puertorriqueña de Medicina y Salud Pública

Elevated Blood Pressure

WARNINGS AND PRECAUTIONS Thromboembolic Disorders and Vascular Events • ORIAHNN is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events.

Components of ORIAHNN increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at high risk for these events. In general, the risk is greatest among women over 35 years of age who smoke, and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity.

• Discontinue ORIAHNN if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs. If feasible, discontinue ORIAHNN at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization. Stop ORIAHNN if there is sudden, unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis immediately.

Bone Loss • ORIAHNN is contraindicated in women with known osteoporosis. ORIAHNN may cause a decrease in bone mineral density (BMD) in some patients, which is greater with increasing duration of use and may not be completely reversible after stopping treatment.

• The impact of ORIAHNN-associated decreases in BMD on long-term bone health and future fracture risk is unknown. Consider the benefits and risks of ORIAHNN in patients with a history of low-trauma fracture or other risk factors for osteoporosis or bone loss, including those taking medications that may decrease BMD (e.g., systemic or chronic inhaled corticosteroids, anticonvulsants, or proton pump inhibitors).

• Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline and periodically thereafter. Consider discontinuing ORIAHNN if the risk associated with bone loss exceeds the potential benefit of treatment. Limit the duration of use to 24 months to reduce the extent of bone loss.

Hormonally Sensitive Malignancies • ORIAHNN is contraindicated in women with current or a history of breast cancer and in women at increased risk for hormonally sensitive malignancies, such as those with mutations in BRCA genes.

• The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. Surveillance measures, such as breast examinations and regular mammography, are recommended. Discontinue ORIAHNN if a hormonally sensitive malignancy is diagnosed.

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders • Depression, depressed mood, and/or tearfulness were reported at a higher incidence in women taking ORIAHNN (3%) compared with placebo (1%) in the Phase 3 clinical trials. Suicidal ideation and behavior, including a completed suicide, occurred in women treated with lower doses of elagolix in clinical trials conducted for a different indication.

• Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional, as appropriate.

• Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing ORIAHNN if such events occur.

Hepatic Impairment and Transaminase Elevations • ORIAHNN is contraindicated in women with known hepatic impairment or disease.

• Transaminase elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred with ORIAHNN in Phase 3 clinical trials. No pattern in time to onset of these liver transaminase elevations was identified.

Transaminase levels returned to baseline within 4 months after peak values in these patients.

• Instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice.

• ORIAHNN is contraindicated in women with uncontrolled hypertension.

Maximum mean increases in systolic blood pressure occurred at Month 5, and a mean maximum increase in diastolic blood pressure occurred at Month 4 in ORIAHNN-treated women, as compared to placebo-treated women.

• For women with well-controlled hypertension, continue to monitor blood pressure and stop ORIAHNN if blood pressure rises significantly. Monitor blood pressure in normotensive women treated with ORIAHNN. Gallbladder Disease or History of Cholestatic Jaundice • Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, assess the risk-benefit of continuing therapy. Discontinue ORIAHNN if jaundice occurs.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy • ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding. Perform pregnancy testing if pregnancy is suspected and discontinue ORIAHNN if pregnancy is confirmed.

• The effect of hormonal contraceptives on the efficacy of ORIAHNN is unknown. Advise women to use non-hormonal contraception during treatment and for 1 week after discontinuing ORIAHNN. Effects on Carbohydrate and Lipid Metabolism • ORIAHNN may decrease glucose tolerance and result in increased glucose levels. More frequent monitoring in ORIAHNN-treated women with prediabetes and diabetes may be needed.

• In women with preexisting hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis.

Use of elagolix is associated with increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and serum triglycerides. Monitor lipid levels and consider discontinuing ORIAHNN if hypercholesterolemia or hypertriglyceridemia worsens.

Alopecia • In Phase 3 clinical trials, more women experienced alopecia, hair loss, and hair thinning with ORIAHNN (3.5%) compared to placebo (1.0%). In almost one-third of affected ORIAHNN-treated women, alopecia was the reason for discontinuing treatment. No specific pattern was described. In the majority of these women, hair loss was continuing when ORIAHNN was stopped. Whether the hair loss is reversible is unknown. Consider discontinuing ORIAHNN if hair loss becomes a concern.

Effect on Other Laboratory Results • The use of estrogen and progestin combinations may raise serum concentrations of binding proteins (e.g., thyroid-binding globulin, corticosteroid-binding globulin), which may reduce the free thyroid or corticosteroid hormone levels. Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy, respectively.

• The use of estrogen and progestin may also affect the levels of sex hormone-binding globulin, coagulation factors, lipids, and glucose.

RISK OF ALLERGIC REACTIONS DUE TO THE INACTIVE INGREDIENT (FD&C YELLOW NO. 5) • ORIAHNN contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

ADVERSE REACTIONS • Most common adverse reactions occurring in ≥5% of women receiving ORIAHNN in clinical trials were hot flush, headache, fatigue, and metrorrhagia.

These are not all of the possible side effects of ORIAHNN. Safety and effectiveness of ORIAHNN in pediatric patients have not been established.

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

References: 1. ORIAHNN [package insert]. North Chicago, IL: AbbVie Inc. 2. Data on file. ABVRRTI71860. 3. Schlaff WD, Ackerman RT, Al-Hendy A, et al. Elagolix for heavy menstrual bleeding in women with uterine fibroids.

N Engl J Med. 2020;382(4):328-340.

©2021 AbbVie Inc. North Chicago, IL 60064

US-ORIA-210155

Revista Puertorriqueña de Medicina y Salud Pública May 2021

35

ORIAHNNTM (elagolix, estradiol, and norethindrone acetate capsules; elagolix capsules)

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION

co-packaged for oral use

INDICATIONS AND USAGE ORIAHNN is indicated for the management of heavy menstrual bleeding associated with uterine leiomyomas (fibroids) in premenopausal women.

Limitation of Use: Use of ORIAHNN should be limited to 24 months due to the risk of continued bone loss, which may not be reversible [see Warnings and Precautions].

CONTRAINDICATIONS ORIAHNN is contraindicated in women: • With a high risk of arterial, venous thrombotic, or thromboembolic disorders [see Boxed Warning and Warnings and Precautions]. Examples include women over 35 years of age who smoke, and women who are known to have: ◦ current or history of deep vein thrombosis or pulmonary embolism ◦ vascular disease (e.g., cerebrovascular disease, coronary artery disease, peripheral vascular disease) ◦ thrombogenic valvular or thrombogenic rhythm diseases of the heart (for example, subacute bacterial endocarditis with valvular disease, or atrial fibrillation) ◦ inherited or acquired hypercoagulopathies ◦ uncontrolled hypertension ◦ headaches with focal neurological symptoms or have migraine headaches with aura if over age 35 • Who are pregnant. Exposure to ORIAHNN early in pregnancy may increase the risk of early pregnancy loss [see Use in Specific Populations].

• With known osteoporosis because of the risk of further bone loss [see Warnings and Precautions].

• With current or history of breast cancer or other hormonally-sensitive malignancies, and with increased risk for hormonally-sensitive malignancies [see Warnings and Precautions].

• With known hepatic impairment or disease [see Warnings and Precautions].

• With undiagnosed abnormal uterine bleeding.

• With known anaphylactic reaction, angioedema, or hypersensitivity to ORIAHNN or any of its components.

• Taking inhibitors of organic anion transporting polypeptide (OATP)1B1 (a hepatic uptake transporter) that are known or expected to significantly increase elagolix plasma concentrations [see Drug Interactions].

WARNINGS AND PRECAUTIONS Thromboembolic Disorders and Vascular Events ORIAHNN is contraindicated in women with current or history of thrombotic or thromboembolic disorders and in women at increased risk for these events [see Contraindications]. In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), two thrombotic events occurred in 453 ORIAHNN-treated women (thrombosis in the calf and pulmonary embolism) [see Adverse Reactions]. Estrogen and progestin combinations, including the estradiol/norethindrone acetate component of ORIAHNN, increase the risk of thrombotic or thromboembolic disorders, including pulmonary embolism, deep vein thrombosis, stroke, and myocardial infarction, especially in women at high risk for these events. In general, the risk is greatest among women over 35 years of age who smoke, and women with uncontrolled hypertension, dyslipidemia, vascular disease, or obesity.

Discontinue ORIAHNN if an arterial or venous thrombotic, cardiovascular, or cerebrovascular event occurs or is suspected. If feasible, discontinue ORIAHNN at least 4 to 6 weeks before surgery of the type associated with an increased risk of thromboembolism, or during periods of prolonged immobilization.

Stop ORIAHNN immediately if there is sudden unexplained partial or complete loss of vision, proptosis, diplopia, papilledema, or retinal vascular lesions and evaluate for retinal vein thrombosis as these have been reported in patients receiving estrogens and progestins.

Bone Loss ORIAHNN is contraindicated in women with known osteoporosis [see Contraindications]. ORIAHNN may cause a decrease in bone mineral density (BMD) in some patients. BMD loss is greater with increasing duration of use and may not be completely reversible after stopping treatment [see Adverse Reactions].

In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), seven out of 453 (1.5%) ORIAHNN-treated women experienced fractures, including one (0.2%) with a fragility fracture, compared to one out of 196 (0.5%) placebo-treated women (patient had a non-fragility fracture). Five of the seven ORIAHNN-treated women reported these fractures in the post-treatment follow-up period. The impact of BMD decreases on long-term bone health and future fracture risk in premenopausal women is unknown.

Consider the benefits and risks of ORIAHNN treatment in patients with a history of a low-trauma fracture or other risk factors for osteoporosis or bone loss, including taking medications that may decrease BMD (e.g., systemic or chronic inhaled corticosteroids, anticonvulsants, or proton pump inhibitors).

Assessment of BMD by dual-energy X-ray absorptiometry (DXA) is recommended at baseline and periodically thereafter. Consider discontinuing ORIAHNN if the risk associated with bone loss exceeds the potential benefit of treatment. Limit the duration of use to 24 months to reduce the extent of bone loss [see Indications and Usage].

Although the effect of supplementation with calcium and vitamin D was not studied, such supplementation for patients with inadequate dietary intake may be beneficial.

Hormonally-Sensitive Malignancies ORIAHNN is contraindicated in women with current or history of breast cancer and in women at increased risk for hormonally-sensitive malignancies, such as those with mutations in BRCA genes [see Contraindications].

In the Phase 3 clinical trials (Studies UF-1, UF-2, and UF-3), two (0.4%) cases of breast cancer in 453 ORIAHNN-treated women were observed. No breast cancer cases were seen in placebo-treated women [see Adverse Reactions].

The use of estrogen alone and estrogen plus progestin has been reported to result in an increase in abnormal mammograms requiring further evaluation. Surveillance measures, such as breast examinations and regular mammography, are recommended. Discontinue ORIAHNN if a hormonally-sensitive malignancy is diagnosed.

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), ORIAHNN-treated women had a higher incidence (3%) of depression, depressed mood, and/or tearfulness compared to placebo-treated women (1%) [see Adverse Reactions]. Suicidal ideation and behavior, including a completed suicide, occurred in women treated with lower doses of elagolix in clinical trials conducted for a different indication.

Promptly evaluate patients with depressive symptoms to determine whether the risks of continued therapy outweigh the benefits. Patients with new or worsening depression, anxiety, or other mood changes should be referred to a mental health professional, as appropriate. Advise patients to seek immediate medical attention for suicidal ideation and behavior. Reevaluate the benefits and risks of continuing ORIAHNN if such events occur.

Hepatic Impairment and Transaminase Elevations Contraindication in Patients with Hepatic Impairment ORIAHNN is contraindicated in women with known hepatic impairment or disease [see Contraindications and Use in Specific Populations].

Transaminase Elevations In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), elevations (> 3 times the upper limit of the reference range) in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) occurred in 1.1% (4/379) and 1.3% (5/379) of ORIAHNN-treated patients, respectively, compared to no elevations in placebo.

Transaminases peaked at 8 times the upper limit for ALT and 6 times the upper limit for AST. No pattern in time to onset of these liver transaminase elevations was identified. Transaminase levels returned to baseline within 4 months after peak values in these patients.

Instruct patients to promptly seek medical attention in case of symptoms or signs that may reflect liver injury, such as jaundice [see Adverse Reactions].

Elevated Blood Pressure ORIAHNN is contraindicated in women with uncontrolled hypertension [see Contraindications]. In Studies UF-1 and UF-2, a maximum mean increase in systolic blood pressure of 5.1 mmHg [95% confidence interval (CI) 2.68, 7.59] occurred at Month 5, and a maximum mean increase in diastolic blood pressure of 2.1 mmHg (95% CI 0.43, 3.84) occurred at Month 4 in ORIAHNN-treated women, as compared to placebo-treated women [see Adverse Reactions].

For women with well-controlled hypertension, continue to monitor blood pressure and stop ORIAHNN if blood pressure rises significantly. Monitor blood pressure in normotensive women treated with ORIAHNN. Gallbladder Disease or History of Cholestatic Jaundice Studies among estrogen users suggest a small increased relative risk of developing gallbladder disease. For women with a history of cholestatic jaundice associated with past estrogen use or with pregnancy, assess the risk-benefit of continuing therapy. Discontinue ORIAHNN if jaundice occurs.

Change in Menstrual Bleeding Pattern and Reduced Ability to Recognize Pregnancy ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding [see Adverse Reactions]. Perform pregnancy testing if pregnancy is suspected, and discontinue ORIAHNN if pregnancy is confirmed [see Use in Specific Populations].

The effect of hormonal contraceptives on the efficacy of ORIAHNN is unknown. Advise women to use non-hormonal contraception during treatment and for one week after discontinuing ORIAHNN [see Use in Specific Populations].

Effects on Carbohydrate and Lipid Metabolism ORIAHNN may decrease glucose tolerance and result in increased glucose levels. More frequent monitoring in ORIAHNN-treated women with prediabetes and diabetes may be needed.

In women with pre-existing hypertriglyceridemia, estrogen therapy may be associated with elevations of plasma triglycerides leading to pancreatitis. Use of elagolix is associated with increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and serum triglycerides. Monitor lipid levels and consider discontinuing ORIAHNN if hypercholesterolemia or hypertriglyceridemia worsens [see Adverse Reactions].

Alopecia In Phase 3 clinical trials (Studies UF-1 and UF-2), more women experienced alopecia, hair loss, and hair thinning with ORIAHNN (3.5%) compared to placebo (1.0%). In almost one-third (4/14) of affected ORIAHNN-treated women, alopecia was a reason for discontinuing treatment. No specific pattern was described. In the majority of affected women, hair loss was continuing when ORIAHNN was stopped. Whether the hair loss is reversible is unknown. Consider discontinuing ORIAHNN if hair loss becomes a concern [see Adverse Reactions].

Effect on Other Laboratory Results The use of estrogen and progestin combinations may raise serum concentrations of binding proteins (e.g., thyroid-binding globulin, corticosteroid-binding globulin), which may reduce the free thyroid or corticosteroid hormone levels. Patients with hypothyroidism and hypoadrenalism may require higher doses of thyroid hormone or cortisol replacement therapy, respectively.

The use of estrogen and progestin may also affect the levels of sex hormone-binding globulin, coagulation factors, lipids, and glucose].

Risk of Allergic Reactions Due to the Inactive Ingredient (FD&C Yellow No. 5) ORIAHNN contains FD&C Yellow No. 5 (tartrazine), which may cause allergic-type reactions (including bronchial asthma) in certain susceptible persons. Although the overall incidence of FD&C Yellow No. 5 (tartrazine) sensitivity in the general population is low, it is frequently seen in patients who also have aspirin hypersensitivity.

ADVERSE REACTIONS The following serious adverse reactions are discussed elsewhere in labeling: • Thromboembolic Disorders and Vascular Events [see Warnings and Precautions] • Bone Loss [see Warnings and Precautions] • Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders [see Warnings and Precautions] • Hepatic Transaminase Elevations [see Warnings and Precautions] • Elevated Blood Pressure [see Warnings and Precautions] • Effects on Carbohydrate and Lipid Metabolism [see Warnings and Precautions] • Alopecia [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 clinical practice.

The safety of ORIAHNN was evaluated in two 6-month, randomized, double-blind, placebo-controlled trials (Studies UF-1 and UF-2), in which 790 premenopausal women received at least 1 dose of ORIAHNN (n=395), elagolix 300 mg twice daily (n=199), or placebo (n=196) [see Clinical Studies (14)]. Women who completed 6-month treatment in either Study UF-1 or Study UF-2 and met eligibility criteria (n=433) entered a 6-month extension study (Study UF-3), receiving either ORIAHNN (n=276) or elagolix 300 mg twice daily (n=157).

Elagolix 300 mg twice daily is not an approved dosage but was included as a reference arm. A total of 341women received ORIAHNN for 6 months and 182 women received ORIAHNN for 12 months.

Serious Adverse Events Serious adverse events were reported in three (0.8%) ORIAHNN-treated women in Studies UF-1 and UF-2. Two women had heavy menstrual bleeding and required blood transfusion due to anemia (0.5%) and one woman with history of bariatric surgery had a laparoscopic cholecystectomy due to cholelithiasis.

In Study UF-3, two women were diagnosed with breast cancer. One woman had completed 6 months of treatment with ORIAHNN in Study UF-1 and received 34 additional days of ORIAHNN in Study UF-3 when diagnosed. The second woman had received placebo in Study UF-2 and completed 6 months of ORIAHNN in Study UF-3 when diagnosed [see Warnings and Precautions].

Adverse Reactions Leading to Study Discontinuation In Studies UF-1 and UF-2, the discontinuation rate due to adverse reactions was 10% among ORIAHNN-treated women and 7% among placebo-treated women. The most common adverse reactions leading to study drug discontinuation in the ORIAHNN group were nausea (1%), headache (1%), alopecia (1%), metrorrhagia (1%), menorrhagia (1%), and hot flush (1%). One event each of the following adverse reactions led to study drug discontinuation: affect lability, angina pectoris, depression, hepatic enzyme increased, homicidal ideation, hypertension, irritability, thrombosis.

In women who received ORIAHNN in Studies UF-1 or UF-2 and then in Study UF-3, 4% discontinued treatment due to adverse reactions. Three women discontinued due to serious adverse events (one each for breast cancer, menorrhagia with pelvic pain, and hysterectomy).

Common Adverse Reactions Adverse reactions reported in ≥5% of ORIAHNN-treated women in Studies UF-1 and UF-2 and at a greater frequency than placebo-treated women are presented in Table 1.

Table 1. Adverse Reactions that Occurred in at Least 5% of Women with Uterine Fibroids Who Received ORIAHNN in Studies UF-1 and UF-2 and at a Greater Incidence Than Placebo ORIAHNN N=395

Placebo N=196

Hot flush

22%

9%

Headache

9%

7%

Fatigue

6%

4%

Metrorrhagia

5%

1%

Adverse Reaction

The most commonly reported adverse reactions in the blinded extension trial (Study UF-3) were consistent with those in the placebo-controlled trials.

Less Common Adverse Reactions In Studies UF-1 and UF-2, adverse reactions reported in ≥3% and <5% in the ORIAHNN group and greater incidence than the placebo group included: libido decreased, arthralgia, hypertension, alopecia, mood swings, influenza, abdominal distension, upper respiratory tract infection, menorrhagia, vomiting, and weight increased.

Thromboembolic and Vascular Events In the Studies UF-1, UF-2, and UF-3, two (0.4%) thrombotic events occurred in 453 ORIAHNN-treated patients (thrombosis in the calf and pulmonary embolism) [see Warnings and Precautions]. One obese woman developed thrombosis in the left calf after 30 days of treatment with ORIAHNN. Another woman developed a pulmonary embolism after taking ORIAHNN for approximately 8 months.

Bone Loss The effect of ORIAHNN on BMD was assessed by dual-energy X-ray absorptiometry (DXA).

In Studies UF-1 and UF-2, there was a greater decrease in BMD in women treated with ORIAHNN for 6 months compared to women treated with placebo. In Study UF-3, continued bone loss was observed in some women who received ORIAHNN for 12 consecutive months. The mean percent change from baseline in lumbar spine BMD at Month 6 (Studies UF-1 and UF-2) and Month 12 (Study UF-3) is presented in Table 2.

Table 2. Mean Percent Change (On-Treatment) from Baseline in Lumbar Spine BMD in Women with Fibroids at Month 6 in Studies UF-1 and UF-2 and Month 12 in Study UF-3 Studies UF-1 and UF-2 Treatment Month 6

Study UF-3 Treatment Month 12

Placebo

ORIAHNN

ORIAHNN

Number of Subjects

150

305

175

Percent Change from Baseline

-0.1

-0.7

-1.5

Treatment Difference, % (95% CI)

-0.6 (-1.0, -0.1)

CI: Confidence interval Following 12 months of ORIAHNN treatment in Study UF-3, a decline in lumbar spine BMD of >3% was seen in 27% (48/175) of women and a decline of ≥8% was seen in 1.7% (3/175) of women.

To assess for recovery, the change in BMD over time was analyzed for women who received continuous ORIAHNN treatment for up to 12 months and were then followed after cessation of therapy for an additional 12 months in Study UF-3 (Figure 1). The LS mean percent change from baseline in BMD 12 months after cessation of therapy was -0.72 (95% CI -1.2, -0.2), -0.59 (-1.0, -0.2), and -0.95 (-1.6, -0.3) at the lumbar spine, total hip, and femoral neck, respectively. Twelve months after cessation of ORIAHNN, continued bone loss was observed at the lumbar spine, total hip, and femoral neck in 24%, 32%, and 40% of women, respectively. Partial recovery was observed in 46%, 33%, and 38% and full recovery was observed in 30%, 35%, and 22% of women at these same sites. The time to maximum recovery in women who partially recovered is unknown.

Figure 1. Mean Percent Change From Baseline in Lumbar Spine BMD in Women Who Received 12 Months of ORIAHNN (On-Treatment) and 12 Months of Follow Up (Off Treatment) 1%

Mean Percent Change (95% CI) from Baseline

WARNING: THROMBOEMBOLIC DISORDERS AND VASCULAR EVENTS • Estrogen and progestin combinations, including ORIAHNN, increase the risk of thrombotic or thromboembolic disorders including pulmonary embolism, deep vein thrombosis, stroke and myocardial infarction, especially in women at increased risk for these events [see Warnings and Precautions].

• ORIAHNN is contraindicated in women with current or a history of thrombotic or thromboembolic disorders and in women at increased risk for these events, including women over 35 years of age who smoke and women with uncontrolled hypertension [see Contraindications].

0%

-1%

-2%

-3%

# of Subjects 150 Placebo 150 ORIAHNN 124

Month 0

150 150 123

124

116

124

Month 6

Month 12

Month 6

Month 12

On Treatment

Placebo ORIAHNN

Off Treatment

Suicidal Ideation, Suicidal Behavior, and Exacerbation of Mood Disorders In the placebo-controlled trials (Studies UF-1 and UF-2), ORIAHNN was associated with adverse mood changes.

Depression, depressed mood, and/or tearfulness were reported in 3% of ORIAHNN-treated women compared to 1% of placebo-treated women. One woman treated with lower dose elagolix alone for another disease completed suicide 2 days after elagolix discontinuation.

Hepatic Transaminase Elevations In Studies UF-1 and UF-2, elevations of serum ALT and AST with no concurrent elevations of bilirubin were reported.

• ALT elevations to at least 3 times the upper limit of normal (ULN) occurred in 1.1% (4/379) of ORIAHNN-treated women and no placebo-treated women. Peak elevation of ALT almost 8 times the ULN was reported in 1 ORIAHNN-treated woman.

• AST elevations to at least 3 times the ULN occurred in 5/379 (1.3%) in ORIAHNN-treated women and no placebo-treated women. Peak elevation of AST 6 times the ULN was reported in 1 ORIAHNN-treated woman.

Blood Pressure Elevations There were more ORIAHNN-treated women with systolic blood pressure ≥ 160 mmHg (7.1%) and diastolic blood pressure ≥ 100 mmHg (11.3%) compared to placebo-treated women (3.7% and 6.3%, respectively). The incidence of hypertensive adverse reactions was 3.8% in ORIAHNN-treated women and 3.1% placebo-treated women. One ORIAHNN-treated woman in Study UF-1, with no prior history but with elevated cholesterol levels, had severe hypertension (BP 204/112) and chest pain. ECG was negative. Her hypertension was controlled with anti-hypertensives and she completed Study UF-3.

Changes in Lipid Parameters Increases in total cholesterol, low-density lipoprotein cholesterol (LDL-C), serum triglycerides, and apolipoprotein B were noted during ORIAHNN treatment in Studies UF-1 and UF-2.

Of the women with Grade 0 LDL-C (<130 mg/dL) at baseline, 1/313 (0.3%) ORIAHNN-treated woman shifted to Grade 3 (≥ 190 mg/dL) compared to no placebo-treated woman. Of those with Grade 1 LDL-C (130 to <160 mg/dL) at baseline, 9/54 (16.7%) ORIAHNN-treated women shifted to Grade 3 compared to no placebo-treated woman. Of those with Grade 2 LDL-C (160 to <190 mg/dL) at baseline, 7/10 (70%) ORIAHNN-treated women shifted to Grade 3 compared to 1/5 (20%) placebo-treated woman.

Alopecia In Phase 3 placebo-controlled clinical trials (Studies UF-1 and UF-2), 3.5% (14/395) of ORIAHNN-treated women experienced alopecia, hair loss, or hair thinning compared to 1.0% (2/196) of placebo-treated women.

No specific pattern in hair loss was observed. In almost one-third (4/14) of affected ORIAHNN-treated women, alopecia was a reason for study drug discontinuation; no placebo-treated women discontinued because of alopecia. In ORIAHNN-treated women, 79% of the cases were mild and 21% were moderate in severity. Hair loss was ongoing at the end of the study for 4 out of 14 women (29%). Of these 4 women, one discontinued treatment due to hair loss, two had ongoing hair loss 12 months after discontinuing ORIAHNN, and one was lost to follow-up. In the remaining 10 women (71%), hair loss either resolved while on treatment or resolved within 24 days to approximately 9 months after discontinuing ORIAHNN. Resumption of Menses after Discontinuation After six months of ORIAHNN treatment, resumption of menses was reported by 39%, 68%, and 73% of women within 1, 2, and 6 months, respectively, in Study UF-1 and 39%, 85%, and 92% within 1, 2, and 6 months, respectively, in Study UF-2.

After 12 months of therapy with ORIAHNN (Study UF-1 or Study UF-2 then Study UF-3), resumption of menses was reported by 43%, 82%, and 90% of women within 1, 2, and 6 months after stopping treatment, respectively.

Whether those who did not resume having menses transitioned to a peri-postmenopausal status is unknown.

DRUG INTERACTIONS Potential for ORIAHNN to Affect Other Drugs Elagolix (a component of ORIAHNN) is: • A weak to moderate inducer of cytochrome P450 (CYP3A).

Co-administration with ORIAHNN may decrease plasma concentrations of drugs that are substrates of CYP3A. • A weak inhibitor of CYP2C19. Co-administration with ORIAHNN may increase plasma concentrations of drugs that are substrates of CYP2C19 (see Table 3).

• An inhibitor of efflux transporter P-glycoprotein (P-gp). Co-administration with ORIAHNN may increase plasma concentrations of drugs that are substrates of P-gp (see Table 3).

The effects of co-administration of ORIAHNN on concentrations of concomitant drugs and the clinical recommendations for these drug interactions are summarized in Table 3.

Table 3. Drug Interactions: Effects of ORIAHNN on Other Drugs Concomitant Drug Class: Drug Name Cardiac glycosides: digoxin Benzodiazepines: oral midazolam Statins: rosuvastatin Proton pump inhibitors: omeprazole

Effect on Plasma Exposure of Concomitant Drug

Clinical Recommendations

↑ digoxin

Increase monitoring of digoxin concentrations and potential signs and symptoms of clinical toxicity when initiating ORIAHNN in patients who are taking digoxin. If ORIAHNN is discontinued, increase monitoring of digoxin concentrations.

↓ midazolam

Consider increasing the dose of midazolam by no more than 2-fold and individualize midazolam therapy based on the patient’s response.

↓ rosuvastatin

Monitor lipid levels and adjust the dose of rosuvastatin, if necessary.

↑ omeprazole

No dose adjustment needed for omeprazole 40 mg once daily when co-administered with ORIAHNN. When ORIAHNN is used concomitantly with higher doses of omeprazole, consider dosage reduction of omeprazole.

The direction of the arrow indicates the direction of the change in the area under the curve (AUC) (↑= increase, ↓ = decrease).

Potential for Other Drugs to Affect ORIAHNN Elagolix (a component of ORIAHNN) is a substrate of CYP3A, P-gp, and OATP1B1; estradiol and norethindrone acetate are metabolized partially by CYP3A]. Concomitant use of ORIAHNN with: • Strong CYP3A inducers may decrease elagolix, estradiol, and norethindrone plasma concentrations and may result in a decrease of the therapeutic effects of ORIAHNN. • Rifampin is not recommended. The concomitant use of rifampin increased plasma concentrations of elagolix].

• Strong CYP3A inhibitors are not recommended. Concomitant use of ORIAHNN with strong CYP3A inhibitors may increase elagolix, estradiol, and norethindrone plasma concentrations and increase the risk of adverse reactions.

• OATP1B1 inhibitors that are known or expected to significantly increase elagolix plasma concentrations is contraindicated due to increased risk of elagolix-associated adverse reactions [see Contraindications].

USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Exposure Registry There is a pregnancy registry that monitors outcomes in women who become pregnant while treated with ORIAHNN. Pregnant patients should be encouraged to enroll by calling 1-833-782-7241.

Risk Summary Use of ORIAHNN is contraindicated in pregnant women. Exposure to elagolix early in pregnancy may increase the risk of early pregnancy loss. Discontinue ORIAHNN if pregnancy occurs during treatment.

The limited human data with the use of elagolix in pregnant women are insufficient to determine whether there is a risk for major birth defects or miscarriage [see Data].

When pregnant rats and rabbits were orally dosed with elagolix during the period of organogenesis, postimplantation loss was observed in pregnant rats at doses 12 times the maximum recommended human dose (MRHD). Spontaneous abortion and total litter loss were observed in rabbits at doses 4 and 7 times the MRHD. There were no structural abnormalities in the fetuses at exposures up to 25 and 7 times the MRHD for the rat and rabbit, respectively [see Data].

Data Human Data There was one pregnancy reported in the 453 women who received ORIAHNN in the Phase 3 uterine fibroids clinical trials. The pregnancy resulted in a spontaneous abortion and the estimated fetal exposure to ORIAHNN occurred during the first 18 days of pregnancy.

Animal Data Embryofetal development studies were conducted in the rat and rabbit. Elagolix was administered by oral gavage to pregnant rats (25 animals/dose) at doses of 0, 300, 600, and 1200 mg/kg/day and to rabbits (20 animals/dose) at doses of 0, 100, 150, and 200 mg/kg/day during the period of organogenesis (gestation day 6-17 in the rat and gestation day 7-20 in the rabbit).

In rats, maternal toxicity was present at all doses and included six deaths and decreases in body weight gain and food consumption. Increased postimplantation losses were present in the mid dose group, which was 12 times the MRHD based on AUC. In rabbits, three spontaneous abortions and a single total litter loss were observed at the highest maternally toxic dose, which was 7 times the MRHD based on AUC. A single total litter loss occurred at a lower non-maternally toxic dose of 150 mg/kg/day, which was 4 times the MRHD. No fetal malformations were present at any dose level tested in either species even in the presence of maternal toxicity. At the highest doses tested, the exposure margins were 25 and 7 times the MRHD for the rat and rabbit, respectively. However, because elagolix binds poorly to the rat gonadotropin-releasing hormone (GnRH) receptor (~1000 fold less than to the human GnRH receptor), the rat study is unlikely to identify pharmacologically mediated effects of elagolix on embryofetal development. The rat study is still expected to provide information on potential non-target-related effects of elagolix.

In a pre- and postnatal development study in rats, elagolix was given in the diet to achieve doses of 0, 100, and 300 mg/kg/day (25 per dose group) from gestation day 6 to lactation day 20. There was no evidence of maternal toxicity. At the highest dose, two dams had total litter loss, and one failed to deliver. Pup survival was decreased from birth to postnatal day 4. Pups had lower birth weights, and lower body weight gains were observed throughout the pre-weaning period at 300 mg/kg/day. Smaller body size and effect on startle response were associated with lower pup weights at 300 mg/kg/day. Post-weaning growth, development, and behavioral endpoints were unaffected.

Maternal plasma concentrations in rats on lactation day 21 at 100 and 300 mg/kg/day (47 and 125 ng/mL) were 0.04-fold and 0.1-fold the maximal elagolix concentration (Cmax) in humans at the MRHD. Because the exposures achieved in rats were much lower than the human MRHD, this study is not predictive of potentially higher lactational exposure in humans.

Lactation Risk Summary There is no information on the presence of elagolix in human milk, the effects on the breastfed child, or the effects on milk production. When estrogen and progestins are administered to lactating women, these compounds and/or their metabolites are detected in human milk and can reduce milk production in breast-feeding females. This reduction can occur at any time but is less likely to occur once breast-feeding is well established. Advise the nursing female to use non-hormonal contraception until she discontinues breast-feeding. The developmental and health benefits of breast-feeding should be considered along with the mother’s clinical need for ORIAHNN and any potential adverse effects on the breast-fed child from ORIAHNN or from the underlying maternal condition [see Data].

Data There is no information on the presence of elagolix or its metabolites in human milk, the effects on the breastfed child, or the effects on milk production. Estrogen administration to nursing women has been shown to decrease the quantity and quality of the breast milk. Detectable amounts of estrogen and progestin have been identified in the breast milk of women receiving estrogen and progestin combinations.

There are no adequate animal data on excretion of elagolix in milk.

Females and Males of Reproductive Potential Based on the mechanism of action of elagolix, there is a risk of early pregnancy loss if ORIAHNN is administered to a pregnant woman [see Use in Specific Populations].

Pregnancy Testing ORIAHNN may delay the ability to recognize the occurrence of a pregnancy because it may reduce the intensity, duration, and amount of menstrual bleeding [see Adverse Reactions]. Exclude pregnancy before initiating treatment with ORIAHNN. Perform pregnancy testing if pregnancy is suspected during treatment with ORIAHNN and discontinue treatment if pregnancy is confirmed [see Contraindications and Warnings and Precautions].

Contraception Advise women to use non-hormonal contraception during treatment with ORIAHNN and for one week after discontinuing ORIAHNN [see Warnings and Precautions].

Pediatric Use Safety and effectiveness of ORIAHNN in pediatric patients have not been established.

Renal Impairment No dose adjustment of ORIAHNN is required in women with any degree of renal impairment or end-stage renal disease (including women on dialysis).

Hepatic Impairment ORIAHNN is contraindicated in women with any hepatic impairment or disease [see Contraindications].

The use of estradiol (a component of ORIAHNN) in patients with hepatic impairment, compared to patients with normal hepatic function, is expected to increase the blood levels of estradiol and increase the risk of estradiol-associated adverse reactions. Additionally, the use of elagolix (a component of ORIAHNN) in patients with moderate and severe hepatic impairment, compared to patients with normal hepatic function, increased elagolix exposures 3-fold and 7-fold, respectively, and this increases the risk of elagolix-associated adverse reactions.

OVERDOSAGE Overdosage of estrogen and progestin combination products may cause nausea, vomiting, breast tenderness, abdominal pain, drowsiness, fatigue, and withdrawal bleeding. In case of ORIAHNN overdose, monitor the patient for any signs or symptoms of adverse reactions and initiate appropriate symptomatic treatment, as needed.

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

Thromboembolic Disorders and Vascular Events Advise patients that use of estrogen and progestin combinations may increase the risk of thromboembolic disorders and vascular events, especially in women at high risk for these events [see Boxed Warning, Contraindications, Warnings and Precautions, and Adverse Reactions].

Bone Loss Advise patients about the risk of bone loss. Advise patients that supplementary calcium and vitamin D may be beneficial if dietary intake of calcium and vitamin D is not adequate. Advise patients that oral iron supplement should not be taken at the same time as calcium and vitamin D [see Warnings and Precautions and Adverse Reactions].

Suicidal Ideation and Exacerbation of Mood Disorders Advise patients that suicidal ideation and exacerbation of mood disorders may occur with ORIAHNN use.

Instruct patients with new onset or worsening depression, anxiety, or other mood changes to promptly seek medical attention [see Warnings and Precautions and Adverse Reactions].

Liver Injury Advise patients to promptly seek medical attention in case of signs or symptoms that may reflect liver injury, such as jaundice [see Warnings and Precautions and Adverse Reactions].

Change in Menstrual Bleeding Pattern Advise patients that ORIAHNN may delay the recognition of pregnancy because it may reduce the duration and amount of menstrual bleeding. Advise patients to use effective non-hormonal contraception while taking ORIAHNN and to discontinue ORIAHNN if pregnancy is diagnosed. Advise pregnant patients that there is a pregnancy registry that monitors pregnancy outcomes in women exposed to ORIAHNN during pregnancy [see Warnings and Precautions and Use in Specific Populations].

Alopecia Advise patients that alopecia, hair loss, and hair thinning in no specific pattern, may occur with ORIAHNN use.

Advise patients that hair loss and hair thinning may not resolve completely after stopping ORIAHNN. Advise patients to contact their healthcare provider if they have concerns about changes to their hair [see Warnings and Precautions and Adverse Reactions].

Drug Interactions Advise patients to inform their healthcare providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Advise patients to avoid grapefruit juice while taking ORIAHNN [see Drug Interactions].

ORIAHNN Missed Dose Instructions Instruct patients about what to do in the event a dose is missed. See “If you miss a dose of ORIAHNN” section in FDA-approved Medication Guide.

ORIAHNN Disposal Instructions Instruct patients to dispose of unused medication via a take-back option if available or to otherwise follow FDA instructions for disposing of medication in the household trash, www.fda.gov/drugdisposal, and not to flush down the toilet.

Manufactured by AbbVie Inc. North Chicago, IL 60064 ORIAHNN is a trademark of AbbVie Inc. © 2020 AbbVie Inc. All rights reserved.

Ref: 03-B969 Revised May 2020 LAB-3747 MASTER

US-ORIA-210155

MSP ARTÍCULO / DE REVISIÓN

BRONQUIOLITIS OBLITERANTE:

UNA ENFERMEDAD PULMONAR OBSTRUCTIVA RARA

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Revista Puertorriqueña de Medicina y Salud Pública

MSP ARTÍCULO / DE REVISIÓN

-WILFREDO DE JESÚS ROJAS, MD, FAAP NEUMÓLOGO PEDIÁTRICO, SUB ESPECIALISTA EN ENFERMEDADES RARAS DEL PULMÓN Y DIRECTOR DEL INSTITUTO PEDIÁTRICO DE ASMA Y ENFERMEDADES RARAS DEL PULMÓN

-INGRID VILLANUEVA, MD,

MUCHOS HAN ESCUCHADO SOBRE LAS INFECCIONES VIRALES DE LAS VÍAS RESPIRATORIAS LLAMADA BRONQUIOLITIS, SIN EMBARGO SE DESCONOCE MUCHO SOBRE LA BRONQUIOLITIS OBLITERANTE ENTRE LA COMUNIDAD. RESUMEN La bronquiolitis obliterante (BO) es una enfermedad rara en los niños causada por la exposición a par tículas químicas y especialmente después de infecciones respiratorias y, (par ticularmente en los adultos o adolescentes) después de los trasplantes de órganos. En la infancia, BO ocurre más comúnmente después de una infección respiratoria. El diagnóstico de BO se basa en las señales y síntomas, hallazgos en la historia de enfermedades infecciosas previas, los exámenes de imágenes, pruebas de función pulmonar y en la biopsia del pulmón. El tratamiento es normalmente a base de cor ticoides.

TRASFONDO La bronquiolitis obliterante es una de las complicaciones no infecciosas luego de un trasplante pulmonar o de trasplante de células hematopoyéticas. Otros factores de riesgo para desarrollar bronquiolitis obliterante son la exposición a toxinas inhaladas que incluye: gas mostaza, nitrógenos oxidados, diacetilo (aditivo para dar sabor al “popcorn”) ceniza ambiental y fibra de vidrio “fiberglass”. Además, se ha visto que la bronquiolitis obliterante puede estar asociada a enfermedades autoinmunes como ar tritis reumatoide, enfermedad inflamatoria intestinal y de tejido conectivo como la esclerodermia y el síndrome de Steven-Johnson.

También puede estar asociada a enfermedades raras tales como enfermedad de Castleman y pénfigo paraneoplásico. Finalmente, se ha visto el desarrollo de bronquiolitis obliterante luego de una infección respiratoria causada por virus, entre estos: adenovirus, virus sincicial respiratorio (RSV), y otros virus como parainfluenza, HIV, herpes, sarampión causando neumonia, CMV y microplasma. La bronquiolitis obliterante puede tener una manifestación inicialmente parecida a una bronquiolitis viral aguda y luego, dependiendo de la severidad puede ocurrir la obliteración de los bronquiolos. Entre las manifestaciones clínicas se encuentran: síntomas persistentes de tos, dificultad respiratoria y pobre desempeño al ejercicio. Los síntomas se desarrollan en un período de semanas o meses y no de manera aguda. Los hallazgos en el examen físico no son específicos y entre estos se encuentran crepitaciones y sibilancias en la auscultación. En pacientes pediátricos, la bronquiolitis obliterante es precedida usualmente por una infección del tracto respiratorio bajo. Sin embargo, a diferencia de una bronquiolitis viral aguda donde los síntomas se resuelven en unos cuantos días, la bronquiolitis obliterante y sus síntomas son persistentes. Los criterios clínicos para el diagnóstico de bronquiolitis obliterante postinfecciosa son: dificultad respiratoria por más de seis semanas luego de una infección respiratoria o insulto pulmonar. Además, sibilancias persistentes o una tos que no responde a broncodilatadores. También presentará síntomas respiratorios que no guardan proporción con los hallazgos en las radiografías. A nivel mundia, una de las causas más comunes es el adenovirus serotipo 3, 7, 21. Las pruebas adicionales para el diagnóstico incluyen la evaluación de la capacidad pulmonar Revista Puertorriqueña de Medicina y Salud Pública

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MSP ARTÍCULO / DE REVISIÓN

mediante la espirometría. La función pulmonar presentará una obstrucción fija del flujo de aire que no es reversible con broncodilatadores, a diferencia de asma bronquial. Existen varias clasificaciones para catalogar la severidad de la enfermedad dependiendo de la función pulmonar del paciente.

En la prueba de función pulmonar observaremos que el volumen de espiración forzada en un segundo (FEV1) estará disminuido (<80%) junto a una disminución en la razón entre FEV1 y la capacidad vital forzada (FEV1/FVC). La presencia de hiperinflación puede estar presente en el cuadro clínico y, por lo tanto, notaremos un aumento en el volumen residual.

La tomografía computarizada puede presentar engrosamiento de la pared del bronquio y áreas hipoatenuadas en patrón de “mosaico”, sugestivos de la bronquiolitis obliterante [Ilustración 2]. Es importante descar tar otras condiciones pulmonares tales como: discinesia siliar primaria, Iinmunodeficiencias o fibrosis quística, dependiendo del caso, puede estar indicado. La prueba estándar para el diagnóstico es una biopsia pulmonar donde se observa tejido de cicatrización con obliteración en la pared de los bronquiolos [Ilustración 3]. En el caso de la bronquiolitis obliterante se observa fibrosis subepitelial que causa una oclusión del lumen parcial o completa. En caso de sospecha de bronquiolitis obliterante luego de trasplante de pulmón puede que la biopsia sea requerida para determinar si el deterioro de la función pulmonar se debe a infección o rechazo agudo del trasplante. El pronóstico de la bronquiolitis obliterante es incierto debido a las complicaciones que presenta la enfermedad. Cuando la bronquiolitis obliterante ocurre como consecuencia a un insulto tóxico o autoinmune, la inflamación subepitelial y la reparación

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irregular causan fibroproliferación y regeneración anormal del epitelio de las vías aéreas pequeñas, lo que causa dificultad respiratoria persistente y progresiva acompañada por tos y presencia de sibilancias en la mayoría de los casos. Cuando hay insultos infecciosos repetidos, los síntomas de dificultad respiratoria y falta de aire con actividad física pueden empeorar y con cada insulto aumenta la probabilidad de que el paciente eventualmente necesite ser evaluado para trasplante de pulmón.

Actualmente, no hay cura para la bronquiolitis obliterante por lo que el tratamiento está dirigido a estabilizar y detener la progresión de la enfermedad. Si la causa de la bronquiolitis obliterante es debido a trasplante de pulmón, el tratamiento se enfoca en optimizar la inmunosupresión. Si la bronquiolitis obliterante es debido a otras causas no relacionadas a trasplantes, es necesario que se remueva el agente ofensor. Cuando la causa es por toxinas o por agentes infecciosos, el tratamiento dependerá de la sintomatología del paciente; un retraso en el tratamiento y manejo puede desencadenar en fallo respiratorio progresivo.

La combinación de fluticasona, azitromicina y montelukast como triple terapia ha demostrado ser efectiva al disminuir el deterioro en la función pulmonar en pacientes con bronquiolitis obliterante luego de transplante células hematopoyéticas.

La idea detrás del uso de la triple terapia está relacionada a sus características antiinflamatorias y actividad antifibrótica. Como parte del manejo de esta condición, es necesario evaluar y controlar reflujo gastroesofageal para evitar aspiración del contenido gástrico y evitar así daño progresivo pulmonar. Los pacientes con bronquiolitis obliterante postinfecciosa que han demostrado una disminución significativa de su función pulmonar pueden ser candidatos a trasplante pulmonar.

Para conocer más sobre la bronquiolitis obliterante puede acceder al centro de información de enfermedades genéticas raras en el siguiente enlace: ht tps://rarediseases.info.nih.gov/ espanol/12222/bronquiolitis-obliterante.

CONCLUSIÓN: En los casos de BO que se desarrollan después de una infección la enfermedad BO tiende a mostrar una mejoría clínica después de 2-3 años de terapia de apoyo, aunque pueden persistir los cambios clínicos, radiológicos y alguna deficiencia de la función pulmonar. La enfermedad es irreversible.

El tratamiento con corticoides, sin embargo, puede ayudar a estabilizar o al menos retrasar su progresión. Por esa razón, es importante reconocer la

Revista Puertorriqueña de Medicina y Salud Pública

bronquiolitis obliterante temprano porque la intervención en las últimas etapas de la enfermedad puede resultar ineficaz. En algunos casos, como comentado anteriormente, las terapias inmunosupresoras, que disminuyen la respuesta inmune del cuerpo, y los trasplantes de pulmón se utilizan para tratar la enfermedad. En el caso de la exposición a sustancias tóxicas, la eliminación inmediata del ambiente irritante es crucial para frenar la progresión de la enfermedad.

REFERENCIAS: - Colom, A. J. (2006). Risk factors for the development of bronchiolitis obliterans in children with bronchiolitis. Thorax,61(6), 503-506. doi:10.1136/thx.2005.044909 - Epler, G. (2007). Faculty of 1000 evaluation for Bronchiolitis obliterans syndrome (BOS), bronchiolitis obliterans organizing pneumonia (BOOP), and other late-onset noninfectious pulmonary complications following allogeneic hematopoietic stem cell transplantation. F1000 - Post-publication Peer Review of the Biomedical Literature. doi:10.3410/f.1087661.541739 - Krishna, R. (2019, March 13). Bronchiolitis Obliterans (Obliterative Bronchiolitis, Constrictive Bronchiolitis). Retrieved from https://www. ncbi.nlm.nih.gov/books/ NBK441865/ - Norman, B. C., Jacobsohn, D. A., Williams, K. M., Au, B. K., Au, M. A., Lee, S. J., . Chien, J. W. (2010). Fluticasone, azithromycin and montelukast therapy in reducing corticosteroid exposure in bronchiolitis obliterans syndrome after allogeneic hematopoietic SCT: A case series of eight patients. Bone Marrow Transplantation,46 (10), 1369-1373. doi:10.1038/bmt.2010.311 - Wang, X., Liu, C., Wang, M., Zhang, Y., Li, H., & Liu, G. (2015). Clinical features of post-infectious bronchiolitis obliterans in children undergoing long-term azithromycin treatment. Experimental and Therapeutic Medicine,9 (6), 2379-2383. doi:10.3892/etm.2015.2418 - Yu, J. (2015). Postinfectious bronchiolitis obliterans in children: Lessons from bronchiolitis obliterans after lung transplantation and hematopoietic stem cell transplantation. Korean Journal of Pediatrics, 58 (12), 459. doi:10.3345/ kjp.2015.58.12.459

ECZEMA: CONTROLADO.

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DUPIXENT ayuda a sanar el aspecto y la sensación de la piel. Y no es una crema ni un esteroide. Es un medicamento biológico que trata el eczema con el tiempo; incluso entre brotes. Vea y sienta una diferencia significativa con:

Piel más sana • Rápido alivio de la picazón • En ensayos clínicos a las 16 semanas, el 37% de los adultos y el 24% de los adolescentes (de 12 a 17 años) observaron una piel sana o casi sana frente al 9% y el 2% que no recibieron inyecciones de DUPIXENT. • Y el 38% de los adultos y el 37% de los adolescentes (de 12 a 17 años) experimentaron una picazón considerablemente menor frente al 11% y el 5% que no recibieron inyecciones de DUPIXENT.

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INFORMACIÓN IMPORTANTE DE SEGURIDAD No utilice este medicamento si es alérgico al dupilumab o a cualquiera de los ingredientes de DUPIXENT®.

Antes de utilizar DUPIXENT, infórmele a su proveedor de atención médica sobre todas sus afecciones médicas, incluido lo siguiente: si tiene problemas oculares; si tiene una infección parasitaria (helmintos); si tiene programado recibir algún tipo de vacuna. No debe recibir ninguna “vacuna viva” si recibe tratamiento con DUPIXENT; si está embarazada o si tiene planes de quedar embarazada. Se desconoce si DUPIXENT puede dañar al feto. Hay un registro de exposición en el embarazo para mujeres que reciben inyecciones de DUPIXENT durante el embarazo

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Infórmele a su proveedor de atención médica sobre todos los medicamentos que toma, incluidos los medicamentos de venta libre y de venta con receta, las vitaminas y los suplementos a base de hierbas.

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DUPIXENT puede provocar efectos secundarios graves, incluidos los siguientes: Reacciones alérgicas (hipersensibilidad), incluida una reacción

fuerte conocida como anafilaxia. Deje de usar DUPIXENT e infórmele a su proveedor de atención médica o busque atención de emergencia de inmediato si tiene alguno de los siguientes síntomas: problemas respiratorios, fiebre, malestar general, nódulos linfáticos hinchados, hinchazón de rostro, boca y lengua, urticaria, picazón, desmayos, mareos, sensación de mareo (presión arterial baja), dolor en las articulaciones o erupción cutánea.

Problemas oculares. Infórmele a su proveedor de atención médica si tiene nuevos problemas oculares o si nota un empeoramiento de los problemas que tenía, incluido el dolor ocular o cambios en la visión.

Los efectos secundarios más comunes en pacientes con dermatitis atópica son reacciones en el lugar de la inyección, inflamación de los ojos y los párpados, que incluyen enrojecimiento, hinchazón y picazón, y herpes en la boca o en los labios.

Infórmele a su proveedor de atención m é di c a s i t i e n e a l g ú n e f e c t o secundario que le moleste o que no desaparezca. Estos no son todos los efectos secundarios posibles de DUPIXENT. Llame a su médico para obtener consejo médico sobre los efectos secundarios. Le recomendamos informar los efectos secundarios negativos de los medicamentos de

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Utilice DUPIXENT exactamente como se le recetó. Su proveedor de atención médica le dirá cuánto DUPIXENT debe inyectar y con qué frecuencia debe hacerlo. DUPIXENT es una inyección que se administra debajo de la piel (inyección subcutánea). Si su proveedor de atención médica decide que usted o un cuidador puede administrar las inyecciones de DUPIXENT, usted o su cuidador debe recibir capacitación sobre la manera correcta para preparar e inyectar DUPIXENT. No intente inyectar DUPIXENT hasta que su proveedor de atención médica le haya mostrado la manera correcta de hacerlo. En niños de 12 años de edad o más, se recomienda que un adulto coloque o supervise la administración de DUPIXENT. En niños menores de 12 años, un cuidador debe administrar DUPIXENT. Consulte el Resumen breve de la página siguiente.

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*Se aplican limitaciones. Visite DUPIXENT.com para conocer las condiciones completas del programa.

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Resumen breve de información importante para pacientes acerca de DUPIXENT® (dupilumab) Inyección para uso subcutáneo ¿Qué es DUPIXENT? • DUPIXENT es un medicamento con receta utilizado para lo siguiente: – Tratar a personas de 6 años o más con dermatitis atópica (eczema) moderada a grave, que no puede controlarse correctamente con terapias recetadas que se aplican sobre la piel (tópicas) o en casos en los que no se puedan utilizar terapias tópicas. DUPIXENT puede utilizarse con o sin corticosteroides tópicos.

• DUPIXENT actúa bloqueando dos proteínas que contribuyen a un tipo de inflamación que desempeña un papel importante en la dermatitis atópica.

• Se desconoce si DUPIXENT es seguro y eficaz en niños menores de 6 años que tengan dermatitis atópica. ¿Quiénes no deberían usar DUPIXENT? No utilice DUPIXENT si es alérgico al dupilumab o a cualquiera de los ingredientes de DUPIXENT. Vea el final de este resumen de información para conocer la lista completa de ingredientes de DUPIXENT. ¿Qué debo informarle a mi proveedor de atención médica antes de usar DUPIXENT? Antes de usar DUPIXENT, infórmele a su proveedor de atención médica sobre todas sus afecciones médicas, incluido lo siguiente: • Si tiene problemas oculares.

• Si tiene una infección parasitaria (helmintos).

• Si tiene programado recibir algún tipo de vacuna. No debe recibir ninguna “vacuna viva” si recibe tratamiento con DUPIXENT. • Si está embarazada o tiene planes de quedar embarazada. Se desconoce si DUPIXENT puede dañar al feto.

– Registro de exposición durante el embarazo. Hay un registro de exposición en el embarazo para mujeres que toman DUPIXENT durante el embarazo. El objetivo de este registro es reunir información sobre su salud y la de su bebé. Su proveedor de atención médica puede inscribirla en este registro. También puede inscribirse usted misma u obtener más información acerca del registro llamando al 1 877 311-8972 o visitando https://mothertobaby.org/ongoing-study/dupixent/.

• Si está amamantando o tiene planes de hacerlo. Se desconoce si DUPIXENT se transmite a través de la leche materna.

Dígale a su proveedor de atención médica sobre todos los medicamentos que toma, incluidos los medicamentos de venta libre y de venta con receta, las vitaminas y los suplementos a base de hierbas.

Infórmele a su proveedor de atención médica en especial en los siguientes casos: • Si está tomando corticosteroides orales, tópicos o inhalados.

• Si tiene dermatitis atópica y asma y usa un medicamento para el asma.

No cambie ni interrumpa la administración del corticosteroide u otro medicamento para el asma sin hablar con su proveedor de atención médica. Esto puede provocar el regreso de otros síntomas que fueron controlados con los corticosteroides u otro medicamento para el asma. ¿Cómo debo utilizar DUPIXENT? • Consulte las “Instrucciones de uso” detalladas que se proporcionan con DUPIXENT para obtener información sobre cómo preparar e inyectar DUPIXENT y cómo almacenar y tirar (desechar) las jeringas y plumas precargadas usadas de DUPIXENT. • Utilice DUPIXENT exactamente como se lo recetó su proveedor de atención médica.

• Su proveedor de atención médica le dirá cuánto DUPIXENT debe inyectar y con qué frecuencia debe hacerlo.

• DUPIXENT viene en una jeringa precargada de dosis única con protector de aguja o en una pluma precargada.

• DUPIXENT se administra como una inyección debajo de la piel (inyección subcutánea).

• Si su proveedor de atención médica decide que usted o un cuidador pueden administrar las inyecciones DUPIXENT, usted o su cuidador deben recibir capacitación sobre la manera correcta para preparar e inyectar DUPIXENT. No intente inyectar DUPIXENT hasta que su proveedor de atención médica le haya mostrado la manera correcta de hacerlo. En niños de 12 años o más, se recomienda que un adulto coloque o supervise la administración de DUPIXENT. menores de 12 años, cuidador debePública administrarles DUPIXENT. Puertorriqueña de el Medicina y Salud 42 A niñosRevista

Solo con receta

• Qué hacer si su cronograma de dosis es semana de por medio y omite una dosis de DUPIXENT: administre la inyección de DUPIXENT dentro de los 7 días posteriores a la dosis omitida y, luego, continúe con el cronograma original. Si la dosis omitida no se administra dentro de los 7 días, espere hasta la siguiente dosis programada para administrar la inyección de DUPIXENT. • Qué hacer si su cronograma de dosis es cada 4 semanas y omite una dosis de DUPIXENT: administre la inyección de DUPIXENT dentro de los 7 días posteriores a la dosis omitida y, luego, continúe con el cronograma original.

Si la dosis omitida no se administra dentro de los 7 días, comience un nuevo cronograma de dosis cada 4 semanas desde la vez que recordó administrarse su inyección de DUPIXENT. • Si se inyecta más DUPIXENT de lo que se le recetó, llame de inmediato a su proveedor de atención médica.

• Es posible que su proveedor de atención médica le recete otros medicamentos para utilizar con DUPIXENT. Utilice los otros medicamentos recetados exactamente como se lo indique su proveedor de atención médica. ¿Cuáles son los efectos secundarios posibles de DUPIXENT? DUPIXENT puede provocar efectos secundarios graves, incluidos los siguientes: • Reacciones alérgicas (hipersensibilidad), incluida una reacción grave conocida como anafilaxia. Deje de usar DUPIXENT e infórmele a su proveedor de atención médica o busque atención de emergencia de inmediato si tiene alguno de los siguientes síntomas: Problemas respiratorios, fiebre, malestar general, ganglios linfáticos inflamados, hinchazón del rostro, la boca y la lengua, urticaria, picazón, desmayos, mareos, sensación de mareo (presión arterial baja), dolor en las articulaciones o erupción cutánea.

• Problemas oculares. Dígale a su proveedor de atención médica si tiene nuevos problemas oculares o si nota un empeoramiento de los problemas que tenía, incluido el dolor ocular o cambios en la visión.

Los efectos secundarios más comunes de DUPIXENT en pacientes con dermatitis atópica incluyen reacciones en el lugar de la inyección, inflamación de los ojos y los párpados (que incluye enrojecimiento, hinchazón y picazón) y herpes en la boca o en los labios. Infórmele a su proveedor de atención médica si tiene algún efecto secundario que le moleste o que no desaparezca.

Estos no son todos los efectos secundarios posibles de DUPIXENT. Llame a su médico para obtener consejo médico sobre los efectos secundarios. Puede informar los efectos secundarios a la FDA. Visite www.fda.gov/medwatch o llame al 1-800-FDA-1088.

Información general sobre el uso seguro y eficaz de DUPIXENT. A veces, los medicamentos se recetan para fines diferentes a los indicados en un prospecto de Información para el paciente. No use DUPIXENT para una afección para la que no se recetó. No administre DUPIXENT a otras personas, incluso si tienen los mismos síntomas que usted. Es posible que les haga daño.

Este es un resumen breve de la información más importante acerca de DUPIXENT para este uso. Si le gustaría recibir más información, hable con su proveedor de atención médica. Puede pedirles a su farmacéutico o proveedor de atención médica más información sobre DUPIXENT dirigida a profesionales de atención médica.

Para obtener más información sobre DUPIXENT, visite www.DUPIXENT.com o llame al 1-844-DUPIXENT (1-844-387-4936). ¿Cuáles son los ingredientes de DUPIXENT? Ingrediente activo: dupilumab Ingredientes inactivos: Clorhidrato de L-arginina, L-histidina, polisorbato 80, acetato de sodio, sacarosa y agua para inyección Fabricado por: Regeneron Pharmaceuticals, Inc., Tarrytown, NY 10591 N.° de licencia en los EE. UU. 1760. Comercializado por: sanofi-aventis U.S. LLC (Bridgewater, NJ 08807) y Regeneron Pharmaceuticals, Inc. (Tarrytown, NY 10591) DUPIXENT® es una marca comercial registrada de Sanofi Biotechnology / © 2020 Regeneron Pharmaceuticals, Inc./sanofi-aventis U.S. LLC. Todos los derechos reservados.

Fecha de publicación: Junio de 2020 DUP.20.05.0329

MSP ARTÍCULO / MÉDICO

LA EVOLUCIÓN EN EL TRATAMIENTO DE ARTRITIS REUMATOIDE

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a artritis Reumatoide (AR), es una condición autoinmune, crónica y sistémica. Proviene de una falla en el sistema inmune en donde el sistema pierde su capacidad para regularse. Esto produce inflamación descontrolada y persistente en la membrana sinovial de las articulaciones, así como en otros tejidos como pulmón, ojos y vasos sanguíneos entre otros.

La artritis reumatoide es la artritis inflamatoria crónica más prevalente.

La sinovitis crónica que resulta de esta inflamación puede llevar a la destruc-

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ción del cartílago y hueso, causando subluxación y deformidad, así como pérdida de espacio en la articulación lo que lleva a la disminución de rango de movimiento de la articulación afectada.

Esto se traduce en pérdida de función e incapacidad.

Es una condición heterogénea que requiere el uso de múltiples terapias con diferentes modos de acción para lograr la remisión o al menos una actividad baja de la inflamación. No hay biomarcadores específicos disponibles o de fácil uso hoy en día que

permitan decidir cuál es la mejor droga para cada individuo que padece de la condición excepto una prueba para predecir la respuesta de los pacientes a un anti-TNF (PrismRA). Si usamos otros biomarcadores como el anti-CCP Ab y RF para predecir severidad y prognosis y ayudarnos a dirigir el tratamiento.

En las últimas dos décadas, el tratamiento de la artritis ha evolucionado significativamente y han cambiado los algoritmos de terapia con estrategias de tratamiento dirigido conocido como “treat to target” con metas

ARTÍCULO / MÉDICO DR. ÓSCAR SOTO RAÍCES, Reumatólogo y Presidente de la Fundación de Enfermedades Reumáticas (FER)

mas especificas con la remisión como meta final. La introducción de tratamiento con biológicos y antirreumáticos no biológicos ha cambiado de forma significativa las expectativas y prognosis en el tratamiento. Con el fin de prevenir el daño estructural a las articulaciones, la pérdida de función y mantener la calidad de vida, los pacientes con artritis reumatoide se tratan más temprano y de forma más agresiva. Para lograr esto es necesario utilizar medicamentos modificadores de la condición temprano en el tratamiento.

Metotrexato como medicamento modificador de la condición de base.

El metotrexato (MTX) sigue siendo la primera opción en el tratamiento de la artritis reumatoide, ya que es eficaz en la mayoría de los pacientes y aproximadamente una cuarta parte podrían lograr remisión. Por esta razón se considera un medicamento modificador de la condición. Tiene un perfil de toxicidad aceptable y bajos costos.

En el manejo de la AR temprana, MTX es recomendado como un fármaco de primera línea por el Colegio Americano de Reumatología (ACR) y la Liga Europea contra el Reumatismo (EULAR). Ha demostrado ser eficaz en monoterapia y también es medicamento de base para las terapias combinadas.

Cuando el metrotexato no logra controlar la artritis de forma efectiva y/o no se alcanza la remisión se recurre al uso de biológicos modifi-

cadores u otros modificadores sintéticos específicos que actúan como inmuno moduladores. Ambos grupos de medicamentos se pueden usar como monoterapia o en combinación con metrotexato para lograr el mejor control y la remisión de la condición.

Los agentes biológicos modificadores de la condición son mayormente anticuerpos monoclonales o receptores que atacan específicamente una molécula en la superficie de la célula soluble ya sea una citosina, un receptor de citosinas o algún antígeno en la membrana celular. Deben ser administrados de forma intravenosa o subcutánea ya que son proteínas.

No entran a la célula, pero ejercen su función a través de receptores extracelulares o en la superficie de la célula.

Los inhibidores sintéticos específicos como los inhibidores de JAK. Son moléculas orales pequeñas que actúan de forma intracelular y de forma reversible previniendo la fosforilación de enzimas quinasas conocidas como JAK. Estas enzimas actúan activando de forma intracelular los receptores de citosinas no dependientes de quinasas de tirosina causando forsforilación del receptor y activando a su vez otras proteínas intracelulares que penetran el núcleo para activar la transcripción genética.

Existen varias familias de medicamentos con distintos objetivos (targets) moleculares disponibles para el tratamiento de la AR:

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MSP ARTÍCULO / MÉDICO Agentes inhibidores de TNF-alpha El factor de necrosis de tumor (TNF) es un citosina pro-inflamatoria que desempeña un papel importante en la inflamación crónica en AR. La inhibición de TNF mejora las manifestaciones clínicas del RA y reduce la progresión radiográfica. Existen agentes biológicos dirigidos al TNF aprobados para el tratamiento de la AR: infliximab (INF), etanercept (ETN), adalimumab (ADA), certolizumab (CMZ) y golimumab (GLM). Varios ensayos clínicos de estos compuestos mostraron eficacia excelente en RA von disminucion de síntomas clínicos y retardo o arresto de la progresión radiografica y un perfil de riesgo aceptable al usarlos en combinación con metotrexato. Infliximab fue el primer inhibidor alfa de TNF (TNFi) desarrollado. Es un anticuerpo monoclonal quimérico y requiere aplicación intravenosa cada 4-8 semanas. Etanercept es una proteína de fusión del receptor soluble de TNF y la porción fc de inmunoglobulina, tiene la vida media más corta de TNFi disponible y se administra por vía subcutánea. Adalimumab es un anticuerpo monoclonal completamente humano que se une al TNF. Certolizumab pegol es un fragmento de Fab anti-TNF pegilado y humanizado. Su estructura lo hace diferente de otros TNFi. Porque tiene mínima a ninguna transferencia placentaria activa, el análisis de los resultados del embarazo favorece a esta droga con respecto a efecto teratogénico y al riesgo de muerte fetal. Golimumab es un anticuerpo monoclonal totalmente humanizado.

Las comparaciones basadas en análisis de datos indirectos y retrospectivos han demostrado que la eficacia del anti-TNF parece ampliamente similar entre los cinco fármacos. Sin embargo, las características de algunos pacientes podrían sugerir que un inhibidor de TNF es más favorable sobre el otro. Los datos relativos a la seguridad también parecen comparables entre ellos. Un meta análisis de ensayos clínicos de control aleatorios de pacientes con AR tratados con anti-TNF demostró un mayor riesgo de infección grave y de interrupción del tratamiento debido a eventos adversos en comparación con placebo y los tratamientos farmacológicos antirreumáticos modificadores de la enfermedad tradicionales.

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Bloqueo co-estimulatorio de células T (CD80/86) Abatacept es una proteína de fusión completamente humana que inhibe la segunda señal requerida para la activación de las células T (al unirse a los antígenos co - estimulatorios CD80 y CD86). Primero fue desarrollado en la formulación intravenosa y luego subcutánea. Abatacept reduce la actividad de la enfermedad en pacientes con respuesta inadecuada a y a inhibidores de TNF. Varios estudios reducción del daño articular radiográfico en pacientes tratados con Abatacept.

El estudio ATTEST evaluó abatacept e infliximab frente a placebo en pacientes con AR con respuesta inadecuada al MTX. Después de un año, los eventos adversos, las infecciones graves y las interrupciones debidas al AE fueron menores con abatacept que con infliximab, mostrando un perfil de seguridad y tolerabilidad más aceptable para este fármaco. El ensayo AMPLE (cabeza a cabeza que comparó abatacept y adalimumab ambos combinados con MTX) mostró una eficacia similar basada en el resultado clínico funcional y radiográfico. A pesar de que la frecuencia de AE fue similar en ambos grupos, hubo menos interrupciones debido a AEs e infecciones graves y menos reacciones locales en el sitio de inyección con abatacept, favoreciendo este fármaco.

Inhibidores de interleucina 6 (IL-6) Hay dos fármacos antagonistas de los receptores de interleucina 6 (anti-IL6) aprobados para el tratamiento de la AR. El tocilizumab (TCZ) es un anticuerpo monoclonal completamente humanizado dirigido contra el receptor de IL-6 que se puede administrar por vía intravenosa o subcutánea, y sarilumab, un anticuerpo monoclonal humano dirigido contra la subunidad alfa del complejo receptor de IL-6. Ambas drogas demostraron ser eficaces para los pacientes con respuesta inadecuada a los csDMARDs (drogas antirreumáticas de modificación de la enfermedad sintética convencional) y a los inhibidores de TNF. El estudio ACT-RAY mostró que no había superioridad relevante de TCZ + MTX en comparación con la monoterapia TCZ con respecto a las respuestas clínicas y radiográficas en pacientes con

MTX-IR. Como consecuencia, los anti-IL6 han sido recomendados por las guías EULAR en pacientes en monoterapia.

Ambas drogas se han comparado con un tratamiento anti-TNF en monoterapia con resultados que favorecen el uso de anti-IL6 como monoterapia ara el tratamiento de la AR. Rituximab (anti-CD20) Rituximab es un anticuerpo monoclonal quimérico dirigido contra CD20 que produce el agotamiento o depleción de células B. Su eficacia se ha demostrado en pacientes que no respondieron a los otros medicamentos modicadores de la condición no biológico. Los pacientes seropositivos tienden a responder mejor a Rituximab que los pacientes seronegativos. El evento adverso más frecuente con Rituximab es la reacción a la infusión. Aunque esta droga produce un agotamiento prolongado de células B, el riesgo para la infección seria era similar entre el placebo y los grupos de RXT. Moléculas pequeñas: Inhibidores de la quinasa de Janus Los inhibidores de la quinasa de Janus (JAKi) son la clase más nueva de medicamentos para el tratamiento del RA. Hay cuatro tipos diferentes de proteínas JAKs: JAK1, JAK2, JAK3 y Tyk2 (tirosina quinasa) y hasta ahora, 3 inhibidores diferentes de JAKs están aprobados por la FDA para el tratamiento de la AR: Tofacitinib, Baricitinib y Upadacitinib.

Todos estos medicamentos han probado ser útiles en le tratamiento de AR y en retardar o detener la progresión de la condición.

Terapias emergentes Existen terapias con mecanismos de acción prometedores en proceso de investigación para ser aprobados para el tratamiento de AR. Otilimab es un anticuerpo monoclonal que inhibe GM-CSF (granulocyte-macrophage colony-stimulating factor), un mediador importante de la respuesta inmune en condiciones inflamatorias.

En un estudio fase 2, Otilimab con metotrexate fue bien tolerado y a pesar de no haber alcanzado su objetivo primario, DAS28-CRP remisión, si hubo mejoría al compararlo con placebo en distintas medidas de actividad física

ARTÍCULO / MÉDICO como dolor y función física. Esto llevo a un estudio fase 3 el cual se esta llevando a cabo en estos momentos en donde se compara el compuesto vs placebo y otros dos protocolos en donde se compara con tofacitinib y contra sarilumab.

ABX464 es una molécula pequeña que produce una inducción selectiva y específica de miR-124. Un crucial modulador de inflamación en las células del sistema inmune innato que puede proveer una regulacion terapéutica de los tractos fisiológicos afectados en las condiciones inflamatorias. Un estudio fase 2 investiga la seguridad y tolerabilidad de este compuesto en combinación con metotrexato en pacientes con artritis reumatoide de moderada a severa.

Iscalimab (CFZ533) es un anticuerpo monoclonal que bloquea el tracto de activación de CD154-CD40 ya está haciendo desarrollado como un agente inmuno-suspresivo. El tracto de co-estimulación de CD40-CD154 es esencial para la generación de respuesta de anticuerpos dependientes de células T, formación de centros germinales y diferenciación de células B de memoria.

En los macrófagos y células dendríticas regula la activación y diferenciación, así como la presentación de antígenos a células T. Debido al mecanismo de acción Iscalimab presenta una terapia prometedora en rechazo de trasplante y desórdenes autoinmunes. Esta terapia se encuentra en etapa fase 1 de investigación para enfermedades como artritis reumatoide, nefritis lúpica y syndrome de Sjogren’s entre otros.

Olokizumab es un anticuerpo monoclonal que bloquea interleucina 6.

Cuatro estudios clínicos en el momento evalúan su efectividad en artritis reumatoide de moderada a severa en adultos para los cuales Metotrexato no es adecuado o han presentado una respuesta inadecuada a un inhibidor de TNF. Los tratamientos aquí discutidos aumentan la probabilidad de manejar la condición de manera exitosa. La evolución de medicamentos que modulan áreas específicas del sistema inmune ofrece opciones de tratamiento que nos ayudan a individualizar el tratamiento y tener más probabilidades de lograr remisión. Es importante de recordar que el diagnóstico temprano de la AR

es sumamente importante, así como el tratamiento adecuado para lograr la remisión clínica y mantener al paciente funcionando sin ninguna o con las menores limitaciones posibles.

Las opciones de tratamientos de artritis reumatoide continúan evolucionando y ofrecen mas herramientas para ofrecer una terapia mas dirigida, especifica e individualizada.

Con la excelente respuesta que se logra hoy día al usar estos tratamientos podríamos entonces preguntarnos... ¿Estamos cerca de encontrar la cura para la AR? No tenemos una cura en el futuro cercano para AR pero ciertamente estamos mas cerca y los avances no cesan en la identificación de células y proteínas del sistema inmune que son importantes en la pato fisiología de esta enfermedad.

Esto lleva a seguir desarrollando nuevos objetivos para regular el sistema inmune y reducir la inflamación que afecta las articulaciones y el sistema en general en pacientes con AR. En el futuro esperamos tener disponibles mas biomarcadores que nos ayuden a escoger el medicamento apropiado para el paciente que padece de artritis reumatoide.

Referencias Caporali R, Fakhouri WKH, Nicolay C, Longley HJ, Losi S, Rogai V. New Rheumatoid Arthritis Treatments for 'Old' Patients: Results of a Systematic Review.

Adv Ther. 2020 Sep;37(9):3676-3691. doi: 10.1007/s12325-020-01435-6. Epub 2020 Jul 23. PMID: 32705531; PMCID: PMC7444401.

Smolen JS, Landewé RBM, Bijlsma JWJ, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2019 update.

Ann Rheum Dis. 2020;79(6):685–699. doi:10.1136/annrheumdis-2019-216655 Smolen JS, Breedveld FC, Burmester GR, et al. Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis. 2016;75(1):3–15. doi:10.1136/ annrheumdis-2015-207524 Jasvinder AS, Kenneth GS, Louis Bridges JR, et al. 2015 American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res.

2016;68(1):1–25. doi:10.1002/acr.22783 van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate -refractory early rheumatoid arthritis: 2 years follow-up of the randomised, non-blinded, parallel-group Swefot trial.

Lancet. 2012;379(9827):1712–1720. doi:10.1016/S0140-6736(12)60027-0 Katchamart W, Trudeau J, Phumethum V, et al. Efficacy and toxicity of methotrexate (MTX) monotherapy versus MTX combination therapy with non-biological disease-modifying antirheumatic drugs in rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2009;68(7):1105–1112. doi:10.1136/ ard.2008.099861 Bucley CD. Efficacy, patient-reported outcomes, and safety of the anti-granulocyte macrophage colony-stimulating factor antibody otilimab (GSK3196165) in patients with rheumatoid arthritis: a Randomised, Phase 2b, Dose-Ranging Study. Lancet. 2020;2:E677–E688.

Genovese MC, Fleischmann R, Furst D, et al. Efficacy and safety of olokizumab in patients with rheumatoid arthritis with an inadequate response to TNF inhibitor therapy: outcomes of a Randomised Phase IIb Study. Ann Rheum Dis. 2014;73(9):1607–1615. doi:10.1136/ annrheumdis-2013-204760 Begon-Pescia C, Campos N, Apolit C, Garcel A, Scherrer D. Specific and selective induction of miR-124 in immune cells by the quinoline ABX464: a transformative therapy for inflammatory diseases.

Drug Discov Today. 2021.

Espié P, He Y, Koo P, et al. First-inhuman clinical trial to assess pharmacokinetics, pharmacodynamics, safety, and tolerability of iscalimab, an anti-CD40 monoclonal antibody. Am J Transplant. 2020;20(2):463–473. doi:10.1111/ajt.15661 Mellors T, et al. Clinical validation of a blood-based predictive test for stratification of response to tumor necrosis factor inhibitor therapies in rheumatoid arthritis patients. Netw Syst Med. 2020; 3(1):91104.

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INSULINA LA INVESTIGACIÓN ALTRUISTA

QUE HA SALVADO MILLONES DE VIDAS

FRANCISCO CAÑIZARES

UN SIGLO DE INNOVACIONES REVOLUCIONARIAS El descubrimiento de la insulina en 1921 dio paso a numerosas innovaciones que han mejorado la calidad de vida de los pacientes con diabetes y contribuido a que su esperanza de vida sea similar a la de la población general. Tras el descubrimiento de la molécula de insulina en 1921 se sucedieron numerosos avances que permitieron controlar mejor la diabetes y proporcionar mayor calidad de vida a los pacientes.

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L

a historia del éxito de la insulina está ligada a la generosidad de los investigadores que la aislaron en 1921. El médico canadiense Frederick Banting y su ayudante Charles Best podían haber patentado el descubrimiento, pero cedieron los beneficios a la Universidad de Toronto.

Ese gesto altruista tuvo un gran impacto en la salud pública. Con la patente libre, la fabricación de insulina se aceleró, lo que facilitó un rápido acceso al tratamiento de los pacientes con diabetes. Richard Welbourn, historiador de la cirugía endocrina, ha señalado que la producción comercial a partir de 1922 “fue el mayor avance en tratamientos médicos desde la aparición de los antisépticos cincuenta años antes”.

Hace un siglo la diabetes dejó de ser una sentencia de muerte. Un niño de 14 años desahuciado, Leonard Thompson, fue el primer paciente en salvar la vida. “La insulina fue un hito

en el tratamiento de las personas con diabetes tipo 1 que hasta ese momento no tenían ninguna opción terapéutica, salvo las famosas dietas del hambre, y su esperanza de vida era muy baja”, señala Esteban Jódar, jefe del Servicio de Endocrinología y Nutrición del Hospital Quirónsalud Madrid.

Las primeras insulinas que se obtuvieron fueron de derivados de páncreas de animales, primero de perros y después de bóvidos, que surtían efecto durante poco tiempo. A partir de ahí, señala Esteban Jódar, “se inició una carrera para adaptarlas mejor a las necesidades de los pacientes y prolongar su acción”.

Conseguido ese objetivo, “hubo que superar el obstáculo de las reacciones alérgicas que provocan algunas. El siguiente hito fue intentar obtener insulinas humanas, algo que se logró por ingeniería genética”. De forma paralela fueron apareciendo dispositivos que han facilitado el control de la enfermedad y la calidad de vida de los pacientes tanto

de diabetes tipo 1 como de tipo 2. Esta última representa el 95% de los casos y su prevalencia, disparada en las últimas décadas, cobra ya tintes de epidemia mundial.

Un 10% de los fallecimientos entre los 35 y los 64 años se atribuye a la diabetes tipo 2, según la OMS. La cuarta causa de muerte prematura entre las mujeres y la octava en los hombres se presenta como una amenaza silenciosa. Investigar sobre ella y detectarla y abordarla de forma temprana son fundamentales para evitar su progresión, pero además, hay que atajar su origen: la obesidad.

Domingo Orozco, vicerrector de Investigación de la Universidad Miguel Hernández de Elche y médico de familia, apunta que “la medicina preventiva es tan importante como la curativa y hay que actuar para reducir las tasas de obesidad, especialmente en la población infantil, donde España es líder, y también en la población general”.

El sistema cardiovascular es el talón

PROTAGONISTAS DE UNA GESTA CIENTÍFICA

1921 Descubrimiento de la insulina.

Frederick Banting y Charles Best, investigadores de la Universidad de Toronto, extrajeron la insulina del páncreas de un perro sano y comprobaron su efecto en uno con diabetes

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1922

Primer tratamiento.

El niño Leonard Thompson fue la primera persona con diabetes a la que la insulina salvó la vida. En las imágenes se percibe cómo estaba antes del tratamiento (con 14 años pesaba 29 kilos) y después.

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Insulina NPH.

1946

Hans Christian Hagedorn consiguió que las personas con diabetes tuvieran que pincharse menos veces al prolongar el efecto de la insulina. La denominó NPH (protamina neutra de Hagedorn – traducción, en sus siglas en inglés–).

de Aquiles de la enfermedad, dado el deterioro que la glucosa va provocando en los vasos sanguíneos. Por eso uno de los objetivos prioritarios cuando ya se ha diagnosticado es controlar la diabetes para proteger el corazón. Se estima que hasta un 25% de los pacientes tienen o desarrollarán en el futuro enfermedades cardiovasculares. Una persona con diabetes tiene tres veces más riesgo de sufrir un infarto de miocardio que el resto de la población, según la Fundación Española del Corazón. De ahí que una de las líneas de investigación de los últimos lustros se haya centrado especialmente en desarrollar medicamentos que eviten esos efectos. El trabajo de la ciencia ha dado resultado, la protección del sistema cardiovascular en las personas con diabetes es una de las áreas donde más avances farmacológicos se han registrado en los últimos años. “Los nuevos tratamientos, además de controlar la glucosa, tienen el efecto adicional de prevenir los eventos cardiovasculares y

reducir el peso”, apunta Domingo Orozco.

La protección del medicamento sobre el corazón puede pasarle inadvertida al enfermo, pero la pérdida de peso no, lo que tiene un efecto muy beneficioso en el control de la enfermedad, en opinión de Orozco: “Lo percibe como algo útil y ayuda a que tenga una mejor adherencia al tratamiento, uno de los grandes problemas que tenemos porque la mitad de los pacientes no toman la medicación de forma correcta”.

El salto adelante que se ha producido en el tratamiento y control de la enfermedad ha hecho que ahora muchas personas con diabetes tengan motivos para sonreír. Al contrario de lo que ocurría hace unas décadas, hoy son numerosos los pacientes que conviven con esta patología crónica y disfrutan de calidad de vida durante décadas gracias a los avances en la investigación. Pero eso no distrae a la ciencia de la meta de curar la enfermedad. La medicina regenerativa, que promete restaurar el

funcionamiento del páncreas, se perfila como una posibilidad, aunque lo es a largo plazo.

La investigación en diabetes hasta ahora no ha logrado curarla, pero a lo largo del siglo ha ido dando respuesta a muchas necesidades. Esteban Jódar recuerda que las insulinas antiguas “obligaban a los pacientes a pincharse y esperar 30 o 40 minutos antes de empezar a comer, lo que alteraba mucho su calidad de vida”. Ahora se están desarrollando otras insulinas que podrán administrarse una vez a la semana. “Las que vendrán en el futuro son inteligentes, es decir, solo harán efecto cuando la glucosa está alta, lo que unido a los sistemas tecnológicos para que el paciente esté controlado permanentemente cambia por completo la perspectiva de la enfermedad”, puntualiza este especialista.

La aventura de las experiencias pioneras en animales y humanos

Fue una perra, el 6 de agosto de 1921, en Canadá, el primer animal diabético del mundo que recibió extracto de páncreas o insulina en su estado más primitivo para paliar el déficit de esta hormona crucial para la vida.

1999 1970

Glucómetro.

El seguimiento de la diabetes se simplificó gracias a este aparato para medir la glucosa en sangre con tiras reactivas. Los pacientes cobraron protagonismo al disponer de una herramienta para el autocontrol de su enfermedad.

Monitor continuo de glucosa.

1983 1985

Minibomba de insulina.

Se desarrolló en los años 60, pero su uso se generalizó en los 80. Gracias a este avance muchas personas con diabetes pudieron recibir la insulina en el tiempo y cantidad precisa a lo largo durante el día.

Pluma de insulina.

La calidad de vida de los pacientes dio un cambio radical ya que dejaron de utilizar jeringas de cristal y pasaron a administrarse la dosis de insulina de forma precisa y discreta.

Las personas con diabetes ganaron autonomía cuando la Agencia de Alimentos y Medicamentos de Estados Unidos (FDA, siglas en inglés) aprobó este dispositivo.

El autocontrol de la enfermedad es clave en su evolución y el monitor continuo lo facilitó.

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TRATAMIENTO Y EVALUACIÓN DE PACIENTES CON POSIBLE INFARTO AL CORAZÓN EN TIEMPOS DE COVID-19

KEY WORDS Coronavirus, COVID-19, Myocardial infarction, ST segment myocardial infarction (STEMI), Non-ST myocardial infarction (NSTEMI), myocarditis

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PALABRAS CLAVES Coronavirus, COVID-19, Infarto al miocardio, Infarto con elevación de segmento ST (STEMI), infarto sin elevación de segmento ST (NSTEMI), miocarditis

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MSP ARTÍCULO / ORIGINAL

EDWIN RODRIGUEZ-CRUZ, MD

CARDIÓLOGO INTERVENCIONAL PEDIÁTRICO DIRECTOR SECCIÓN DE CARDIOLOGÍA SAN JORGE CHILDREN & WOMEN HOSPITAL SAN JUAN, PR

A

l día de hoy la pandemia del coronavirus (COVID-19) ha tenido un grave efecto en nuestras vidas. No obstante, los problemas médicos usuales no han cambiado. En especial, los problemas del corazón no se detienen. Hoy día, si un paciente necesita atención médica, tenemos que asumir que está infectado con COVID-19, y el equipo de protección personal debe ser utilizado en todo momento. En este artículo discutiremos, someramente, cómo evaluar y tratar aquellos que se presenten con un infarto al corazón.

ABSTRACT Today the coronavirus´ pandemic (COVID-19)has taken a toll in our lives.

Nonetheless, the usual medical problems of the people have not changed.

Especially, heart problems continue to cause trouble in the general population. Today, when a patient is in need of medical attention we have to presume that is infected with COVID and full personal protection equipment (PPE) must be used at all times. In this article we will discuss, superficially, how to evaluate and treat patients who present with myocardial infarction to our hospitals.

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INTRODUCCIÓN Al día de hoy, en momentos en que el coronavirus (COVID-19) ha trastocado la vida del planeta, los problemas médicos usuales del ser humano no han cambiado.

Entre estos los problemas del corazón. Aún conociendo que los pacientes que se presenten con necesidad de evaluaciones cardíacas podrían estar contagiados con el COVID-19, la mayoría no lo estarán. No obstante, todos se deben considerar como posiblemente infectados con COVID-19. En este artículo estaremos discutiendo, someramente, algunos de los protocolos y recomendaciones a seguir en la evaluación y tratamiento de pacientes con enfermedades isquémicas cardíacas en tiempos de COVID-19.

DISCUSIÓN Primero se debe conocer que el influjo de información sobre el COVID-19 es inmensa y crece de manera casi logarítmica día a día. Sin embargo, algunas cosas ya sabidas sobre el trato de enfermedades y condiciones, no relacionadas a la enfermedad del coronavirus, no han cambiado. Sólo que, con la presencia del virus en nuestro ambiente, se ha modificado con la implementación de los seguros necesarios para evitar el contagio con el virus.

Es de suma importancia que todo paciente se debe presumir como posible, o, positivo a estar infectado con el COVID-19. Con relación a pacientes que puedan presentar con sospecha de un infarto al corazón, se tiene que llegar a un diagnóstico con prontitud. El tiempo es de suma importancia porque cada minuto que pasa, es masa muscular que se pierde.

El primer asunto es establecer si el paciente está teniendo un infarto al miocardio realmente, ya que es de nuestro conocimiento que, pacientes infectados con COVID-19, pueden desarrollar eventos sintomáticos que pueden parecer ataques al corazón y no serlo. Por lo tanto, es recomendable que se haga un diagnóstico lo más preciso posible y expedito. Hoy día hay pruebas rápidas que pueden ayudarnos en esto, como por ejemplo, hacer niveles de troponina. Sin embargo, la troponina puede estar elevada en pacientes con miocarditis causado por viruses, como el COVID-19. Por eso, se podría utilizar en este caso un ecocardiograma, enfocado en la búsqueda de problemas de movimiento de las paredes del miocardio que fueran posibles indicadores de un infarto. Por otro lado, si hubiese dilatación del ventrículo con una función disminuida, nos llevaría a pensar más en inflamación del miocardio.

“CON RELACIÓN A PACIENTES QUE PUEDAN PRESENTAR CON SOSPECHA DE UN INFARTO AL CORAZÓN SE TIENE QUE LLEGAR A UN DIAGNÓSTICO CON PRONTITUD. EL TIEMPO ES DE SUMA IMPORTANCIA PORQUE CADA MINUTO QUE PASA, ES MASA MUSCULAR QUE SE PIERDE.”

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Si finalmente se establece que el paciente pueda estar sufriendo un infarto, no se puede recalcar suficientes veces que el tiempo es de suprema importancia.

PACIENTES CON INFARTO AL MIOCARDIO CON ELEVACIÓN DEL SEGMENTO ST (STEMI) El tratamiento del paciente con un infarto al corazón y elevación del segmento ST (STEMI) se ha estandarizado y la recomendación principal es la de practicarle una angioplastía con colocación de malla intravascular (“stent¨), si el caso lo requiere, en el menor tiempo posible. Se prefiere que este tiempo sea no mayor a 3 horas y óptimamente 90 minutos, obviamente, si se encuentra en un hospital especializado en estas intervenciones. Al día de hoy, esta recomendación no ha cambiado aún en la presencia del coronavirus.

PACIENTE EN HOSPITAL CON FACILIDAD DE CATETERISMO Si el paciente está infectado con COVID-19 y en un hospital con la capacidad de realizar la intervención, esta sería la primera opción que se debe considerar en ese caso. Sin embargo, el procedimiento se debe llevar a cabo con el personal completamente asegurado con las medidas y equipo de protección personales (PPE- personal protection equipment) necesarias para evitar contagios del personal de sala de cateterismo con el COVID-19.

PACIENTE EN HOSPITAL SIN FACILIDAD DE CATETERISMO Por otro lado, si el paciente está infectado con COVID-19 y también tiene un STEMI pero se encuentra en un hospital primario, donde no se hace este tipo de procedimiento cardíaco, entonces

se debe consultar con el hospital de referencia (el que recibiría al paciente) y decidir si el paciente puede y debe ser transferido al mismo. El tiempo de transferencia debería ser menor a 2 horas. Sin embargo, en este caso se podría tomar la decisión de mantener al paciente en el hospital primario y darle tratamiento con fibrinolíticos tan pronto el diagnóstico de STEMI se establezca. Entonces, si es necesario, transferirlo si una intervención de emergencia (de rescate) se requiere más adelante.

Hay que recordar, sin embargo, que en ocasiones los fibrinolíticos no funcionan en la mitad de los casos con infartos. Pero la utilización de fibrinolíticos ha sido adoptada como aceptable en estos tiempos.

PACIENTE CON ARRESTO CARDÍACO En otro caso, si el paciente se presenta en shock cardiogénico, o, en arresto cardíaco, se le debe dar prioridad para ser reperfundido de manera intervencional. Se tiene que tener siempre presente el que haya la capacidad de realizar la intervención en la facilidad hospitalaria donde se encuentre. Que el personal tenga disponibilidad de equipo de protección personal óptimo para llevar a cabo el tratamiento. De no tener estos elementos en orden, o, estar muy lejos de un hospital capaz de realizar un cateterismo, entonces el uso de fibrinolíticos debe considerarse como una opción adecuada. Hay que recordar que este tipo de paciente tiene una alta probabilidad de producir gotitas que sean los conductos de propagación del virus.

PACIENTE CON INFARTO SIN ELEVACIÓN DE SEGMENTO ST (NSTEMI) No se recomienda la intervención de estos pacientes, a menos que tengan algún tipo de inestabilidad hemodinámica. El tratamiento debe ser médico y no intervencional. Sólo si hay gran sospecha de que se puedan beneficiar de una intervención, o, que tengan alto riesgo, entonces se interviene y se debe seguir el mismo protocolo de precaución para evitar contagios.

Sin embargo, la mayoría de estos pacientes podrían esperar a una fecha futura para intervenirse, luego de negativizar su prueba de COVID, si no tienen factores de alto riesgo al momento de presentación.

PACIENTES CON UN DIAGNÓSTICO NO CLARO DE INFARTO Estos pacientes se deben evaluar de manera expedita también y determinar si tienen o no un infarto. De tener un diagnóstico inseguro, otras pruebas se deben realizar para poder disponer

del paciente. Electrocardiogramas seriados, niveles enzimáticos y troponina repetitivos, y ecocardiografía podrían dar más luz sobre la definición del diagnóstico. Es importante el definir si estos pacientes pueden estar presentando complicaciones por la infección de COVID u otro organismo que le pueda causar miocarditis, por ejemplo.

PACIENTES CON PRONÓSTICO POBRE Los casos con un diagnóstico confirmado de COVID y que se encuentran en intensivo, con angustia respiratoria del adulto (ARDS), entubados y pobre pronóstico, no deben considerarse para una intervención invasiva.

Estos se les debe considerar para tratamiento compasivo y muy probable clasificarlos como DNR (Do Not Resuscitate), luego de hablar con la familia.

Las pruebas rápidas y más adelante las moleculares, son de suma importancia en estos casos. No obstante, aunque la prueba rápida resulte negativa, el procedimiento se debe hacer asumiendo que el paciente esté contaminado con el COVID. Por lo tanto, todo el personal debe estar cubierto con todo el equipo de protección personal.

“ADEMÁS, CADA HOSPITAL CAPAZ DE REALIZAR ESTAS INTERVENCIONES DEBERÍA IDENTIFICAR ÁREAS ESPECIALES PARA ESTOS PACIENTES SOSPECHOSOS DE TENER COVID, COMO SALAS DE RECIBIMIENTO Y PREPARACIÓN, UNA SALA DE CATETERISMO EXCLUSIVA PARA LA REALIZACIÓN DE ESTOS CASOS Y UNIDAD DE CUIDO POST-PROCEDIMIENTO”

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“A PACIENTES CON STEMI NO SE LES RECOMIENDA UNA INTERVENCIÓN INMEDIATA. ESTOS PODRÍAN, TAL VEZ, ESPERAR UN TIEMPO EN LO QUE SE EVALÚAN. SI RESULTAN POSITIVOS A LAS PRUEBAS DEL COVID, DARLES TIEMPO A QUE CONVIERTAN A NEGATIVO ESAS PRUEBAS Y ASÍ HACERLOS CON MENOR RIESGO A CONTAGIAR AL PERSONAL DE SALA DE CATETERISMO”

Además, cada hospital capaz de realizar estas inter venciones debería identificar áreas especiales para estos pacientes sospechosos de tener COVID, como salas de recibimiento y preparación, una sala de cateterismo exclusiva para la realización de estos casos y unidad de cuido post-procedimiento.

CONCLUSIÓN En general, todos los pacientes se deben considerar infectados, o, posiblemente infectados con COVID. Por lo tanto, el equipo de protección personal se debe utilizar en todo momento.

Aquellos pacientes con un STEMI deben tener la oportunidad de recibir la terapia que consiste de angioplastía y/o colocación de una malla intravascular. Aquellos que no estén cerca de un hospital donde se practique este tipo de intervención, o, que por alguna otra razón no pueda llevarse a cabo la misma, la utilización de fibrinolíticos debe ser su segunda opción sabiendo que hoy día es aceptada para estos casos. Se debe tener en consideración que algunos pacientes admitidos por posibles infartos, podrían tener miocarditis viral y no un infarto real. Por lo que, un diagnóstico lo más certero posible es necesario.

A pacientes con STEMI no se les recomienda una intervención inmediata. Estos podrían, tal vez, esperar un tiempo en lo que se evalúan. Si resultan positivos

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a las pruebas del COVID, darles tiempo a que conviertan a negativo esas pruebas y así hacerlos con menor riesgo a contagiar al personal de sala de cateterismo.

Para pacientes con COVID-19, pronóstico pobre y evidencia de un infarto al miocardio, no se recomienda intervención alguna. En estos casos el tratamiento compasivo es la línea a seguir.

Al día de hoy, el coronavirus llegó a nuestras vidas para quedarse. Es con esta realidad que tenemos que vivir de ahora en adelante. El tratamiento de enfermedades cardiovasculares no ha cambiado. Sólo que con la presencia del COVID en nuestro ambiente, algunas modificaciones se deben hacer cuando entremos en contacto con pacientes con enfermedades cardiovasculares.

REFERENCIAS Fried JA, Ramasubbu K, Bhatt R, et al. The variety of cardiovascularmanifestations ofCOVID-19. Circulation. 2020 Apr 3. doi:10.1161/CIRCULATIONAHA.120.047164.

O’Gara PT, Kushner FG, Ascheim DD, et al. 2013 ACCF/AHA guideline for the management of ST-elevation myocardial infarction: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2013; 61:e78-e140.

Dauerman HL, Sobel BE. Synergistic treatment of ST-segment elevationmyocardial infarction with pharmacoinvasive recanalization. J Am Coll Cardiol 2003; 42:646-51.

Mahmud E, Dauerman HL, Welt FG, Messenger JC, Rao SV, Grines C, Mattu A, Kirtane AJ, Jauhar R, Meraj P, Rokos IC, Rumsfeld JS, Henry TD, Management of Acute Myocardial Infarction During the COVID-19 Pandemic, Journal of the American College of Cardiology (2020), doi: https://doi.org/10.1016/j.jacc.2020.04.039.

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We l t FG P, S hah PB, Aronow HD, et al. Catheterizatiion laboratory considerations during the coronavirus (COVID19) pandemic. From ACC’s Interventional Council and SCAI. J Am Coll Cardiol. 2020 Mar 16. pii: S0735- 1097(20)34566-6.

Larson DM, Duval S, Sharkey SW, et al. Safety and efficacy of a pharmaco- invasive reperfusion strategy in rural ST-elevation myocardial infarction patients with expected delays due to long-distance transfers. Eur Heart J 2012; 33:1232-40.

Siripanthong B, Nazarian S, Muser D, et al. Recognizing COVID-19-related myocarditis: the possiblepathophysiology and proposed guideline for diagnosis and management. H e ar t Rhy thm. 2020 May 5. pii: S1547-5271(20)30422-7. doi: 10.1016/j.hrthm.2020.05.001.

[Epub ahead of print] PubMed PMID: 32387246.

Guzik TJ, Mohiddin SA, Dimarco A, Patel V, et al.

COVID-19 and the cardiovascular system:implications for risk assessment, diagnosis, and treatment options. CardiovascRes. 2020 Apr 30. pii: cvaa106. doi: 10.1093/cvr/cvaa106. [Epub ahead of print]

EAT SMART

ADD COLOR

MOVE MORE

BE WELL

¿Qué cantidad de actividad física es necesaria?

A continuación, le presentamos las recomendaciones de la American Heart Association para personas adultas.

+150 min de ejercicio

Realice, como mínimo, 150 minutos de actividad aeróbica moderada o 75 minutos de actividad aeróbica intensa a la semana (o una combinación de ambas) y, preferiblemente, distribúyalas a lo largo de la semana.

Muévase más, siéntese menos

Levántese y muévase durante el día. Un poco de actividad física es mejor que nada. Incluso una actividad de poca intensidad puede compensar los graves riesgos que el sedentarismo tiene para la salud.

Aumente la intensidad

Lo mejor es realizar un ejercicio aeróbico de intensidad media-alta. Su corazón latirá más rápido y respirará con mayor intensidad de lo normal. A medida que se vaya volviendo más activo, aumente el tiempo o la intensidad para obtener más beneficios.

Gane músculo

Incluya actividades de fortalecimiento muscular de intensidad moderada-alta (como resistencia o entrenamiento con pesas) al menos dos veces a la semana.

Siéntase mejor

La actividad física está relacionada con una mejora del sueño, la memoria, el equilibrio y la capacidad cognitiva, así como con un menor riesgo de sobrepeso, enfermedades crónicas, demencia o depresión. Se trata de una de las decisiones más importantes que puede tomar para su salud y bienestar.

Muévase más, de manera más intensa, y siéntese menos.

Descubra cómo en heart.org/movemore. © Derechos de autor 2018 American Heart Association, Inc., una organización sin fines de lucro 501(c)(3).

Reservados todos los derechos. Healthy for Good es una marca comercial. Se prohíbe el uso no autorizado.

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MSP / MATERIAL AUSPICIADO

LAS SIETE ETAPAS DEL ALZHEIMER

El Alzheimer es un tipo de demencia, el cual es diagnosticado mayormente en adultos mayores. Usualmente el paciente presenta lapsos de falta de memoria, y progresivamente los síntomas van agravando mientras van pasando las etapas de la enfermedad.

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sí el factor mayor de riesgo es el aumento de la edad, y la mayoría de las personas con Alzheimer tienen más de 65 años. Pero el Alzheimer no es solo una enfermedad de la vejez, ya que existen miles de casos de personas menores de 65 años que tienen la enfermedad de inicio precoz (también conocida como Alzheimer de inicio temprano).

MATERIAL AUSPICIADO \ MSP Esta enfermedad es una que a simple vista no puede ser detectada, hasta que los familiares o el cuidador descubren alguna conducta que los ponga en alerta. Para conocer cuáles son los síntomas es importante reconocer cuales son las etapas de la enfermedad para así poder ayudar al paciente.

Las 7 etapas del Alzheimer: Etapa 1 El paciente no presenta síntomas significativos de demencia, también conocido como “sin deterioros cognitivos”.

Etapa 2 El adulto mayor comienza a presentar los primeros problemas de memoria.

Etapa 3 La falta de retentiva es notable por sus familiares, el paciente olvida nombres que aprendió recientemente o pierde objetos con mayor frecuencia.

Etapa 4 No recuerdan momentos de sus historias y las actividades que realizaron durante el día.

Etapa 5 El paciente comienza a desconocer detalles de sus familiares, pero aun así puede realizar su aseo, comer y caminar de forma independiente.

Etapa 6 Presenta cambios de personalidad, se encuentra la mayoría del tiempo desorientado, necesita asistencia en el día a día y no reconoce su entorno.

Etapa 7 La última etapa, donde el paciente necesita asistencia de un cuidador 24/7, y es muy limitado su vocabulario.

Los síntomas de cada paciente son evaluados por un médico especialista, quien puede diagnosticar y certificar la etapa de Alzheimer en la que se encuentra. La descripción de cada etapa presentada es general y debe ser validada por el médico del paciente y que le sean realizadas las pruebas pertinentes.

Es importante que sus hijos o familiares estén alertas a cualquier conducta inusual que presente el adulto mayor, ya que tratar el Alzheimer en etapas iniciales ayudará al manejo de aceptación, tanto del paciente como de su cuidador.

En Hospicio & Home Care San Lucas, llevamos salud a tu casa.

Nuestro enfoque es ofrecer calidad de vida a cada paciente y familia de Puerto Rico. Es por eso por lo que brindamos nuestros servicios en toda la isla, incluyendo Área Metro, Vieques y Culebra. Para recibir los servicios de Hospicio & Home Care San Lucas, el paciente debe contar con un referido médico. Llámanos hoy para orientación al 1-800-981-0054 o puede acceder a la página web www.sanlucaspr.org.

¡ ÁREA METRO!

HOSPICIO SAN LUCAS

HOME CARE SAN LUCAS

es la opción para el paciente con diagnóstico de condición terminal que necesita ser atendido con dignidad y cuido compasivo.

es la alternativa para el paciente que desea recibir servicios de salud en la comodidad de su hogar.

RECIBE EN TU CASA: Enfermería Graduada Servicios Médicos Asesoría Espiritual Trabajadores Sociales Medicamentos Relacionados a la Condición Terminal Equipo Médico Durable Servicios Paliativos Entre Otros

RECIBE EN TU CASA: Enfermería Graduada Patología del Habla y Lenguaje Terapia Física Terapia Ocupacional Entre Otros

¡SIRVIENDO AL ÁREA METRO

Y TODO PUERTO RICO!

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BRINDAMOS SERVICIOS A TODA LA ISLA.

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SALÓN DE LA FAMA DE LA MEDICINA PUERTORRIQUEÑA

Niñas del Hospital Menonita, 1955.

LA MEDICINA PUERTORRIQUEÑA Desde la época española, Puerto Rico ha tenido una larga historia de evolución de la medicina. No es hasta el siglo XIX, que se lleva a cabo la descentralización de la profesión médica al crearse una serie de instituciones y gremios locales.

A finales de 1870 se crearon diferentes asociaciones médicas, se constituyó el Gremio de Médicos, así como algunas sociedades, entre ellas la Sociedad del Auxilio Mutuo.

Durante el transcurso de la historia han surgido ilustres médicos que han aportado sus conocimientos y trabajo para el bien de nuestra población y el desarrollo social de nuestra isla.

Doctores como Ramón Emeterio Betances, Francisco Aveillie, Claudio Federico Block, José María Arroyo, José

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Francisco Basora, y diferentes grupos como las Hijas de la Caridad formaron parte de la lucha contra enfermedades de la época como la tuberculosis y diferentes epidemias. De igual forma se crearon diferentes hospitales que hoy día continúan dando servicios médicos a nuestra población.

En la historia moderna de la medicina puertorriqueña destacan un sin número de figuras que merecen ser reconocidas y que su legado perdure para el conocimiento de las futuras generaciones.

LA ASOCIACIÓN MÉDICA DE PUERTO RICO La idea de fundar una asociación médica respondía a una necesidad. Los doctores Manuel Quevedo Báez, Rafael Vélez López y Mariano Ramírez circularon

una carta entre los médicos citándolos a una reunión en julio de 1902, la cual se realizó el 21 de septiembre de 1902, en la Cámara de Delegados de la Antigua Diputación Provincial. Concurrieron 15 médicos: Dres. José M. Amadeo, José N. Carbonell, José María Cueto, Narciso Dobal, Manuel Figueroa, P. Janer, M. Fernández Vizcarrondo, Francisco Seín, Rafael Vélez López, M. Fernández Náter, J. Reguero Feliú, Mariano Ramírez, José Esteban Saldaña, Ramón Ruiz Arnau y Manuel Quevedo Báez. Estos actuaron a la vez como delegados de otros médicos de la Isla que no pudieron asistir a la asamblea. En sus comienzos la Asociación Médica quedó integrada por 76 médicos. Esta asamblea eligió el siguiente cuerpo directivo: Dr. Manuel Quevedo Báez, Presidente; Dr. José N.

PRESENTADO POR BRIOS NETWORK,

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JUNTA MÉDICA DEL SALÓN DE LA FAMA DE LA MEDICINA PUERTORRIQUEÑA

Un prestigioso grupo de profesionales de la medicina conformó un Comité de Selección, el cual tuvo como principal objetivo, seleccionar a los “Miembros Exaltados”a la Primera Edición del Salón de la Fama de la Medicina. Luego de un proceso de investigación, nominaciones y evaluación, se escogió mediante votación, a las figuras y entidades que formarán parte de esta primera edición. La Junta Médica del SFM está conformada por los siguientes doctores: - Yussef Galib-Frangie Fiol, MD, FACP Medicina Interna - Hamid GalibFrangie Capó, MD Gastroenterólogo - Reynold E. López Enríquez, MD, FACS Director Médico Hospital Pavía - Antonio Puras Báez, MD, FACS Cirujano General Urólogo

LLC. COPYRIGHT 2019

Carbonell, Secretario-Tesorero; y el Dr. Rafael Vélez López, Vocal.

En 1903 se hizo un registro completo de los médicos asociados. También se edita, bajo la dirección del Dr. Ruíz Arnau, el primer Boletín Médico, órgano muy importante de la AMPR, en el que se han publicado artículos de carácter científico y comunicaciones oficiales de la Asociación respecto a decisiones de carácter directivo y administrativo.

HONRANDO A LOS GRANDES DE LA MEDICINA PUERTORRIQUEÑA El Salón de la Fama de la Medicina Puertorriqueña tiene el noble propósito de reconocer a los médicos y entidades que con su aportación han realizado una magna labor en favor de la medicina. Su desempeño y legado en el

desarrollo social de Puerto Rico quedará documentado y será reconocido por las futuras generaciones.

Este momento histórico en que se exaltarán éstas figuras ilustres, quienes son los cimientos de la medicina puertorriqueña, queremos igualmente reconocer en una actividad fraternal a los que han realizado tan ardua y arriesgada gesta por la salud de nuestra isla durante la Pandemia, época que nos ha hecho atravesar un período sumamente difícil y lleno de grandes retos para la medicina, la clase médica y la industria de la salud en general.

Deseamos invitarle a ser parte de la Ceremonia de Exaltación de la Primera Edición del Salón de la Fama de la Medicina Puertorriqueña, el viernes 19 de noviembre de 2021, en el Fairmont

- Ernesto Rivé-Mora, MD, FACS Cirujano General - Raúl F. García Rinaldi, MD “in memoriam” Cirujano Cardiovascular - Norman Ramírez Lluch, MD Ortopeda Pediátrico

- Dr. Juan C. Velasco Cervilla, MD Medicina Interna

El San Juan Hotel. El evento contará con una Cena de Gala y Coctel, a la que asistirán sobre 400 invitados, incluyendo personalidades y empresarios de todos los renglones relacionados a la medicina, además de representantes del Gobierno y del Sistema de Salud de nuestra isla.

El Salón de la Fama de la Medicina Puertorriqueña es una producción de la agencia Bríos Network. Contará con una campaña de publicidad y relaciones públicas, brindando una excelente oportunidad publicitaria y de proyección para su empresa, además de un espacio de conexión profesional y de negocios durante la actividad.

El programa del evento constará de tres etapas: Coctel de Bienvenida, Ceremonia de Exaltación y Cena de Gala.

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FIGURAS EXALTADAS A LA PRIMERA EDICIÓN DEL SALÓN DE LA FAMA DE LA MEDICINA

Dr. Manuel Quevedo Báez Médico cirujano, historiador, escritor y educador. Su vida se caracterizó por sus aportaciones profesionales y cívicas. En 1902 fue el fundador y primer presidente de la Asociación Médica de Puerto Rico.

También presidió el Instituto Universitario José de Diego y la Asociación Cívica Puertorriqueña. Fundó, junto a otros galenos, la Academia de Medicina de Puerto Rico y presidió la misma de 1921 a 1923. Dirigió el Consultorio de la Sociedad de Auxilio Mutuo y Beneficencia. Fue presidente del Tribunal Examinador de Médicos. Fundó y fue Editor del Boletín Médico de la Asociación Médica de Puerto Rico, publicando estudios científicos sobre la fiebre amarilla, lupus, tuberculosis, mortalidad infantil, lepra y uncinariasis (anemia), esta última muy común entre la población más pobre del país. En 1946 publicó su magna obra, Historia de la Medicina y Cirugía en Puerto Rico, lo que lo convirtió en uno de los primeros historiadores de la medicina en la Isla.

Dr. Mario Rubén García Palmieri Fue un líder en la medicina, la cardiología y la salud; un luchador incansable que ha recibido innumerables honores. Innato educador. Lideró importantes investigaciones médicas dentro del campo de la cardiología, en la medicina puertorriqueña. Fue propulsor del primer Hospital Cardiovascular de Puerto Rico y el Caribe, donde se realizaron los primeros transplantes de corazón. Fue Secretario de Salud. Publicó sobre 282 trabajos científicos de cardiología en revistas médicas, reconocidas internacionalmente. Fue el primer médico, no estadounidense, en ser reconocido en el grupo de los 65 “Masters” entre los 30 mil miembros de la American College of Cardiology. Fue presidente en dos ocasiones de la Sociedad y Federación Internacional de Cardiología. Fue miembro de 25 sociedades profesionales, y de la Junta de Gobierno del American Board of Internal Medicine. Fue Director de Médicos de la Escuela de Medicina en los Estados Unidos por 34 años. Ayudó a formar a más de 400 internistas, 100 cardiólogos y más de 4,000 estudiantes de Medicina.

Dr. Francisco L. Raffucci Arce Considerado el padre de la cirugía moderna. Cirujano pionero, educador e investigador, propulsó el desarrollo de la cirugía general y vascular en Puerto Rico.

Fue Jefe del Departamento de Cirugía.

Desarrolló un programa de adiestramiento en cirugía que prepararía la mejor generación de cirujanos de Puerto Rico, quienes fueron pilares de la cirugía en la isla. La American College of Surgeons, Capítulo de Puerto Rico, fundó el “Foro Raffucci de Investigación”, donde estudiantes y residentes presentan sus trabajos. Trabajó con otros colegas en el desarrollo de los transplantes de órganos en Puerto Rico. Su teorías visionarias se confirmaron años más tarde con investigaciones sofisticadas.

Dr. Luis Izquierdo Mora Le decían “el médico de los pobres”. En la década de 1970 propulsó la medicina de familia.

Sus ejecutorias y aportaciones marcaron la diferencia en nuestro sistema de salud. Fue además Senador, desde donde impulsó legislación para la creación de centros en los que los médicos pudieran especializarse en medicina de familia. Fue Secretario de Salud, promoviendo la expansión de los Centros de Diagnóstico y Tratamiento en toda la isla, de manera que los pobres tuvieran acceso a la medicina. Es el único médico en Puerto Rico que colaboró en las cuatro Escuelas de Medicina. Fue fundador del Departamento de Medicina de tres Escuelas: Medicina de Emergencia y del Fellowship en Geriatría de la UPR, y de la residencia de Medicina Primaria y Gerencia Médica en San Juan Bautista. Presidió la Asociación Médica de Puerto Rico y asesoró a varios presidentes de la misma, así como la Sociedad Médica del Distrito Este y la Academia de Médicos de Familia. Recibió múltiples reconocimientos, distinciones y premios por su labor.

Dr. Jaime Benítez Rexach Educador, pensador, ensayista y orador humanista.

Llamado por muchos el "padre de la educación puertorriqueña”. Benítez fue un importante visionario, gestor y administrador líder de la educación universitaria puertorriqueña. Desde 1942 fue rector de la Universidad de Puerto Rico. Bajo su dirección, se llevaron a cabo importantes reformas universitarias

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y la creación de departamentos, facultades, programas graduados y profesionales. Fue el primer presidente de dicho centro docente. Como parte de su extenso legado y sus grandes aportaciones a Puerto Rico destacan el establecimiento de las escuelas de medicina y de odontología, así como otros programas de salud.

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Dr. Ramón M. Suárez Calderón Pionero de la cardiología en la isla, ha sido uno de los más eminentes y distinguidos profesionales médicos de Puerto Rico. Fue un líder del sistema de salud, dirigió hospitales, la Asociación Médica y el Tribunal Médico. El Dr. Suárez tuvo una amplia labor en el campo de la investigación y continuó parte de la obra del Dr. Ashford, habiendo tenido una participación importante en los estudios de anemia y esprúe tropical. Fue el primer puertorriqueño en ser

Dr. Guillermo Arbona Irizarry Reconocido por su trayectoria como médico, fue pilar de la salud pública en la Isla durante el siglo XX. Estableció en Puerto Rico un sistema integrado de regionalización de servicios de salud que facilitaba su acceso y promovía la calidad de vida de los puertorriqueños. Dicho modelo y su desarrollo fue compilado en un libro de su autoría y sirvió de ejemplo para otros países alrededor del mundo. Como visionario fue precursor de lo que hoy día se conoce como la Escuela Graduada de Salud Pública del RCM. Fue nombrado Secretario de Salud por el honorable Luis Munoz Marín en 1957 y permaneció en esa posición hasta 1966.

También contribuyó al desarrollo de los hospitales universitarios pediátricos y de medicina interna. Fue prominente y respetado profesor del Recinto de Ciencias Médicas de la Universidad de Puerto Rico. La “Bronfman Foundation” de la “American Public Health Association” le confirió uno de sus premios anuales por su labor en la reestructuración del Sistema de Salud de la Isla.

Gobernador del “College of Physicians” en la isla. Fue Presidente de la Asociación Médica de Puerto Rico y fundó su propio hospital, el Hospital Mimiya. Fue Jefe de Medicina Interna de la Escuela de Medicina Tropical. El Centro Cardiovascular y del Caribe lleva su nombre.

Durante su carrera profesional le tocó atender a las personalidades más prominentes de la Isla.

Fue el médico de don Pablo Casals y de don Luis Muñoz Marín.

Dr. Bernardino González Flores Líder de la Urología y la educación médica en Puerto Rico. Fue residente de Urología en el Hospital Municipal de San Juan y Director del Programa de Urología del Hospital Universitario. Su programa de Urología abarcaba varios hospitales: el de Veteranos, el Oncológico, el Regional de Bayamón y el Regional de Caguas. Junto a otros galenos, tuvo la visión de comenzar una nueva escuela de medicina en Cayey, que posteriormente se convirtió en la Universidad Central del Caribe, la cual es hoy una institución acreditada que ha sido centro de formación de miles de médicos que sirven en Puerto Rico, los Estados Unidos y el resto del mundo.

Al final de su carrera trabajó en el Hospital Oncológico del Centro Médico de Puerto Rico, donde hizo una gran contribución a los pacientes más necesitados.

Hospital La Concepción, San Germán Es una de las instituciones hospitalarias con mayor tradición en Puerto Rico. Sus orígenes se remontan a más de cuatro siglos y hoy en día es una moderna institución que brinda servicios de salud y sociales a un importante grupo poblacional de nuestra isla. Su historia se inicia en 1511 cuando la Cofradía de Nuestra Señora de la Concepción se dedicó al cuidado de personas indigentes en la zona de San Germán. Hoy sirve a una comunidad

Dr. Luis F. Sala Goenaga Cirujano, educador y líder visionario. Como cirujano lo caracterizó la excelencia. Jefe de Cirugía del Hospital de Damas en Ponce.

Fue uno de los fundadores de la Escuela de Medicina de Ponce y posteriormente fue Decano y Presidente de la Junta de Directores. Fue además Presidente de la Asociación Médica, así como de la Junta de Salud Estatal, y miembro del Tribunal Examinador de Médicos. El Dr. Sala fue líder en su campo y uno de los médicos más distinguidos en Puerto Rico. Era “Fellow” del “American College of Surgeons” y en 1989 recibió el premio por servicios distinguidos en Atlanta, Georgia. En 1995, la Academia Médica del Sur lo honró al crear la “Medalla Luis F. Sala” en su honor.

de más de 100 mil personas y su facultad está integrada por más de 180 médicos que cubren casi todas las especialidades. Ofrece sus servicios a la Escuela de Medicina de Ponce, donde se entrenan sus estudiantes y donde también tiene un internado rotatorio y una Residencia de Medicina Interna.

Esta institución atiende anualmente alrededor de 42,000 pacientes en Sala de Emergencia y cuenta con un equipo humano de cerca de 700 empleados.

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AGENDA MÉDICA 2021 EVENTOS Y CONVENCIONES www.medicinaysaludpublica.com

Puerto Rico

Fecha

Actividad

Lugar

Contacto

TIPO DE EVENTO

30 de octubre de 2021

Convención Psiquiátrica anual Asociación de Psiquiatras de Bayamón (APREBA)

Hyatt Place Hotel San Juan, PR

AMEC 787-289-8989 amec@amec-pr.com

Convención

30 de octubre de 2021

38va Conferencia Epilepsia del Caribe

Embassy Suites Hotel Isla Verde

Sociedad Puertorriqueña de Epilepsia info@sociedadepilepsiapr.org

Conferencia

30 de octubre de 2021

Convención anual Asociación Puertorriqueña de Médicos Alergistas

Sonesta Hotel (Intercontinental) Isla Verde

IC Planners ivettecolon@icplannerspr.com 787-504-3655 RiVS Marketing 787-548-0047 info@rivsmarketing.com Aixa Vélez genteinc@gmail.com 787-649-7681 Educational Partners & Coaching 787-646-0780 perez.vilma@gmail.com Business Planners- Merna Morales 787-645-9914 bplanner21@gmail.com AMEC 787-289-8989 amec@amec-pr.com Business Planners- Merna Morales 787-645-9914 bplanner21@gmail.com Aixa Vélez genteinc@gmail.com 787-649-7681 AMEC 787-289-8989 amec@amec-pr.com RN Pro Events- Rafy Nieto (787) 368-7939 | (866) 232-2068 rafinieto@rnproevents.com

30 de octubre de 2021

Reducing the Risk of Cardiovascular Events, Heart Failure and Progression of Chronic Kidney Disease 3 CME/MOC

American College of Physician

4 al 6 de Convención anual Puerto Rico Urological Association noviembre de 2021

La Concha Hotel, San Juan, PR Caribe Hilton Hotel San Juan, PR

5 al 7 de noviembre de 2021

Convención anual PR HIV Treaters Association

Virtual

5 al 14 de noviembre de 2021

Fall Pulmonary and Sleep Virtual Conference 2021Sociedad Puertorriqueña de Neumología

Virtual

6 de noviembre de 2021

ElectroCardio Workshops Conference Arrhytmia Group

Hotel A-Loft Distrito T Mobile San Juan, PR

12 al 21 de noviembre de 2021

Convención anual Asociación de Médicos Pediatras Región Este (AMPRE)

Virtual

12 al 13 de Convención anual American College of Cardiology, PR Noviembre de 2021 Chapter

13 al 14 de noviembre de 2021

Convención anual de la Academia Puertorriqueña de Neurología

Caribe Hilton Hotel San Juan, PR

Hotel El Conquistador Fajardo, PR

Convención

Conferencia

Convención

Convención

Conferencia

Conferencia

Convención

Convención

Convención

19 al 21 de Convención Semi annual- Sociedad Dermatológica de PR noviembre de 2021

Sheraton Convention Center Hotel San Juan, PR

18 al 20 de Convención anual Sociedad de Médicos Podiatras de PR noviembre de 2021

Caribe Hilton Hotel San Juan, PR

Aixa Vélez genteinc@gmail.com 787-649-7681

Convención

Copa Marina Beach Resort Guánica, PR

Aixa Vélez genteinc@gmail.com 787-649-7681

Convención

Centro de Convenciones San Juan, PR

Colegio de Médicos Cirujanos de PR 787-751-5979 info@colegiomedicopr.org

Convención

Hotel San Juan San Juan, PR

Educational Partners & Coaching 787-646-0780 perez.vilma@gmail.com

Convención

4 al 5 de diciembre de 2021

Convención anual Sociedad de Cirugía Plástica de PR

9 al 12 de Convención anual Colegio de Médicos Cirujanos de PR diciembre de 2021 10 al 12 de diciembre de 2021

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Convención Sociedad Puertorriqueña de Endocrinología y Diabetología (SPED)

Revista Puertorriqueña de Medicina y Salud Pública

Convención

Educación +auto-cuidado +Excelencia Profesional +Adherencia Terapéutica =Salud y Cardiología

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Salud y Cardiología Revista Puertorriqueña de Medicina y Salud Pública

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A CIENCIA CIERTA

GUERRERO CONTRA LA ESCLEROSIS MÚLTIPLE El Dr. Ángel Chinea ha convertido su carrera en una pasión por encontrar un tratamiento para esta enfermedad Precisamente la carrera del Dr. Ángel Chinea, neurólogo, ha sido timoneada por el ahínco científico incesante que redunde en el desarrollo de tratamientos individualizados para la población de pacientes que más atesora: aquellos diagnosticados con Esclerosis Múltiple en Puerto Rico.

La pasión de la práctica médica de este galeno lo ha convertido en pionero en la investigación científica y manejo clínico de la condición neurodegenerativa en Puerto Rico y el mundo.

Chinea ha sido testigo de lo que es vivir con la enfermedad, siendo uno de los médicos que precisamente dirige la Fundación de Pacientes con Esclerosis Múltiple, la familia donde esta población ha encontrado el apoyo y calor humano necesario para 76

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enfrentar a la condición que pudiera incapacitar una vida, atacando el cerebro y con poder decisional de que un día la persona no caminará, no podrá ver y/o tendrá el cuerpo entumecido.

Por tal razón, su ahínco no sólo ha sido en el área de la investigación, sino que se ha dado la tarea de ser parte del levantamiento de datos epidemiológicos que establecieran el perfil de este paciente en la isla.

Esto le llevó a conocer una realidad que posiciona a la población de su tierra como prioridad clínica, al Puerto Rico registrar de 3 a 5 veces más casos de Esclerosis Múltiple en comparación con América Latina.

Esta labor contribuyó a que Chinea lograra ser parte del inicio de la era de terapias orales, en su lucha por que estos pacientes adquirieran tratamientos que evitaran la progre-

sión de la enfermedad, en este caso, hasta en un 70%.

Pero su labor no cesa. Por 20 años el neurólogo, junto a su equipo de la fundación, ha logrado reunir a casi 4 mil personas que completan una caminata o carrera, en apoyo a estos pacientes. Cada paso que dan en beneficio de estos pacientes tienen el nombre de aquel luchador o persona diagnosticada.

Lo recaudado se destina precisamente a los Programas de Ayuda y Bienestar al Paciente que ofrece la Fundación, establecida en el año 2000 con el objetivo de brindar servicios a pacientes de esclerosis múltiple.

Aunque no hay cura para esta enfermedad, el doctor Chinea hoy día figura como el héroe que ha devuelto esperanza y calidad de vida para aproximadamente 5,000 pacientes con esta condición en el País.

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