VBCR April, Vol 1, No 1 by Value-Based Cancer Care

Value-Based Care in Rheumatology

APRIL 2012 VOL 1 • NO 1

F R O M T H E P U B L I S H E R S O F A M E R I CA N H E A LT H & D R U G B E N E F I T S

www.ValueBasedRheumatology.com FROM THE EDITOR From Science to Medicine: Implications of Patient Centered Introducing the Inaugural Issue of Value-Based Care Outcomes Research for in Rheumatology Daily Practice

By Carolyn M. Clancy, MD Director, Agency for Healthcare Research and Quality, Rockville, MD

physician treating a child with juvenile arthritis has several intervention options at his or her disposal. These include conven-

tional treatments, such as nonsteroidal antiinflammatory drugs and corticosteroids, and several different kinds of disease-modifying antirheumatic drugs (DMARDs). Which should you prescribe for your patient? Like many clinical decisions, there is not necessarily one right answer. It may depend on age, sex, comorbidities, severity of illness, and other clinical and nonclinical factors. If we are truly putting the patient at the center of care, we have many questions: What treatment will work best for the patient in my office today? What are the drug compliance and drug–drug interaction issues that face my patient and his or her family? What are the side effects? Continued on page 6

Role of Dual-Energy CT Scan in Gout Defined Limit DECT use to longstanding disease to cut costs, improve diagnosis By Phoebe Starr Chicago, IL—Dual-energy computed tomography (DECT) scan should be used to identify gout crystal deposition in select patients suspected of

having gout but with undetectable disease on standard fluid aspiration. The technology is best used in

elcome to the inaugural issue of Value-Based Care in Rheumatology. In this journal, we will strive to provide a forum for physicians, payers, policymakers, and all those interested in providing optimum value-based, personalized care to patients with rheumatologic conditions. Value-Based Care in Rheumatology will strive to keep readers updated on key clinical developments from USbased and international rheumatology meetings and to scour the

rheumatology literature for emerging data that impact everyday clinical practice. Moreover, the journal will include expert commentaries and perspectives from key stakeholders involved in evaluating therapies and managing patients with rheumatic diseases, as well as from those responsible for paying for care. Ultimately, our goal is to present readers with a multidisciplinary vision of the rheumatology universe by providing perspectives on quality, cost, Continued on page 6

PERSONALIZED MEDICINE

A Novel Panel of Biomarkers Correlates with RA Disease Activity and Joint Damage, Predicting Response to Therapy By Wayne Kuznar Chicago, IL—A panel of 12-protein biomarkers blood test called Vectra DA has been receiving attention as a useful tool for assessing disease activity in patients with rheumatoid arthritis (RA). This multibiomarker signature has a number of potential roles in RA, including discriminating remission from low disease activity, said researchers at

the 2011 meeting of the American College of Rheumatology (ACR). A 12-Protein Biomarkers Panel Several presentations reviewed the utility of the biomarkers panel in identifying patients at risk for structural damage, despite remission suggested by the 28-joint Disease Continued on page 8

Continued on page 25

INSIDE PERSONALIZED MEDICINE in

Rheumatology

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A promising approach in RA CLINICAL PATHWAYS

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Nation’s first clinical pathways program for RA

On the cusp of major change in RA therapy

FIBROMYALGIA

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Pain scores increase when discontinuing milnacipran LUPUS

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Panel of biomarkers likely to emerge in SLE GOUT

VBCR PERSPECTIVE . . . . . . . . . . . . .

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Cost-comparison of 2 agents

Rheumatology PRACTICE MANAGEMENT™

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For the management of fibromyalgia

Savella relieves symptoms of fibromyalgia Delivers simultaneous improvements on 3 measures of fibromyalgia1 — Pain reduction — Improvement in patient global fibromyalgia assessment — Improvement in physical function Decrease in pain as early as week 1 of treatment with a stable dose in some patients who reported global improvement1 — Primary endpoint was assessed at week 15 Low potential for pharmacokinetic drug-drug interactions1 — Clinically important interactions may occur with MAOIs, serotonergic drugs (including other SSRIs, SNRIs, lithium, tryptophan, antipsychotics, and dopamine antagonists), triptans, catecholamines (epinephrine and norepinephrine), CNS-active drugs (including clomipramine), and select cardiovascular agents (digoxin and clonidine) A dual reuptake inhibitor that blocks the uptake of norepinephrine over serotonin with approximately 3 times greater potency in vitro1 — The clinical significance of in vitro data is unknown Widely available on managed care formularies2

IMPORTANT SAFETY INFORMATION Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior, especially during the initial few months of drug therapy or at times of dose changes, either increases or decreases. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella is not approved for use in pediatric patients. References: 1. Savella (milnacipran HCl) prescribing information. Forest Pharmaceuticals, Inc. St Louis, MO. 2. MediMedia Database as of April 2011 for Savella.

Contraindications Savella is contraindicated in patients taking monoamine oxidase inhibitors (MAOIs) concomitantly or within 14 days of discontinuing treatment with an MAOI. There have been reports of serious, sometimes fatal, reactions in patients started on an MAOI who were receiving or had recently discontinued a serotonin reuptake inhibitor. At least 5 days should be allowed after stopping Savella before starting an MAOI. Savella is contraindicated in patients with uncontrolled narrow-angle glaucoma and should be used with caution in patients with controlled narrow-angle glaucoma. In clinical trials, Savella was associated with an increased risk of mydriasis. Warnings and Precautions Prescriptions for Savella should be written for the smallest quantity of tablets, consistent with good patient management, in order to reduce the risk of overdose. Development of a potentially life-threatening serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions have been reported with SSRIs and SNRIs alone, including Savella, but particularly with concomitant use of serotonergic drugs (including triptans), drugs that impair metabolism of serotonin (including MAOIs), or antipsychotics or other dopamine antagonists. The management of these reactions should include immediate discontinuation of Savella and the concomitant agent and supportive symptomatic treatment. The concomitant use of Savella with serotonin precursors is not recommended. SNRIs, including Savella, have been associated with cardiovascular effects, including cases of elevated blood pressure, requiring immediate treatment. In clinical trials, sustained increases in systolic and diastolic blood pressure occurred more frequently in Savella-treated patients compared to placebo. Among patients who were non-hypertensive at baseline, approximately twice as many patients receiving Savella, vs placebo, became hypertensive at the end of the study. Clinically significant increases in pulse (≥20 bpm) occurred more frequently in Savella-treated than placebo-treated patients. Blood pressure and heart rate should be monitored prior to initiating treatment with Savella and periodically throughout treatment. Pre-existing hypertension, tachyarrhythmias, and other cardiac diseases should be treated before starting therapy with Savella. Savella should be used with caution in patients with significant hypertension or cardiac disease. Concomitant use of Savella with drugs that increase blood pressure and pulse has not been evaluated, and such combinations should be used with caution. For patients who experience a sustained increase in blood pressure or heart rate while receiving Savella, either dose reduction or discontinuation should be considered. Savella should be prescribed with caution in patients with a history of seizure disorder or mania.

Licensed from Pierre Fabre and Cypress Bioscience, Inc.

Savella has been associated with mild elevations of ALT and AST (1 to 3 times the upper limit of normal). Rarely, reports of serious liver injury, including fulminant hepatitis, have been reported in patients treated with milnacipran. Savella should be discontinued in patients who develop jaundice or other evidence of liver dysfunction and should not be resumed unless another cause can be established. As with other SNRIs and SSRIs, withdrawal symptoms have been observed following discontinuation of milnacipran. A gradual dose reduction is recommended. Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. Elderly patients may be at greater risk. Discontinuation should be considered for patients with symptomatic hyponatremia. SSRIs and SNRIs, including Savella, may increase the risk of bleeding events. Patients should be cautioned regarding the risk of bleeding associated with concomitant use of Savella and NSAIDs, aspirin, warfarin, or other drugs that affect coagulation. Savella can affect urethral resistance and micturition. Caution is advised in the use of Savella in patients with a history of dysuria, notably in male patients with a history of obstructive uropathies as these patients may experience higher rates of genitourinary adverse events. Savella should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. Use in Specific Populations There are no adequate and well-controlled studies in pregnant women. Savella should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Adverse Reactions In clinical trials, the most frequently occurring adverse reaction was nausea (37% vs 20% for placebo). The most commonly occurring adverse reactions (≥5% and greater than placebo) were headache (18% vs 14%), constipation (16% vs 4%), dizziness (10% vs 6%), insomnia (12% vs 10%), hot flush (12% vs 2%), hyperhidrosis (9% vs 2%), vomiting (7% vs 2%), palpitations (7% vs 2%), heart rate increased (6% vs 1%), dry mouth (5% vs 2%), and hypertension (5% vs 2%). Please see brief summary of Prescribing Information on the following pages. Please also see Full Prescribing Information at www.Savella.com.

SAVELLA® (milnacipran HCl) Tablets Brief Summary of Full Prescribing Information Initial U.S. Approval: 2009

Rx Only

WARNING: SUICIDALITY AND ANTIDEPRESSANT DRUGS Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Antidepressants increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders. Anyone considering the use of such drugs in a child, adolescent, or young adult must balance this risk with the clinical need. Short-term studies did not show an increase in the risk of suicidality with antidepressants compared to placebo in adults beyond age 24; there was a reduction in risk with antidepressants compared to placebo in adults aged 65 and older. Depression and certain other psychiatric disorders are themselves associated with increases in the risk of suicide. Patients of all ages who are started on Savella should be monitored appropriately and observed closely for clinical worsening, suicidality, or unusual changes in behavior. Families and caregivers should be advised of the need for close observation and communication with the prescriber. Savella is not approved for use in the treatment of major depressive disorder. Savella is not approved for use in pediatric patients [see Warnings and Precautions, Use in Specific Populations]. INDICATIONS AND USAGE: Savella is indicated for the management of fibromyalgia. Savella is not approved for use in pediatric patients [see Use in Specific Populations]. CONTRAINDICATIONS: Monoamine Oxidase Inhibitors-Concomitant use of Savella in patients taking monoamine oxidase inhibitors (MAOIs) is contraindicated. In patients receiving a serotonin reuptake inhibitor in combination with a monoamine oxidase inhibitor (MAOI), there have been reports of serious, sometimes fatal, reactions including hyperthermia, rigidity, myoclonus, autonomic instability with possible rapid fluctuations of vital signs, and mental status changes that include extreme agitation progressing to delirium and coma. These reactions have also been reported in patients who have recently discontinued serotonin reuptake inhibitors and have been started on an MAOI. Some cases presented with features resembling neuroleptic malignant syndrome. The effects of combined use of Savella and MAOIs have not been evaluated in humans. Therefore, it is recommended that Savella should not be used in combination with an MAOI, or within 14 days of discontinuing treatment with an MAOI. Similarly, at least 5 days should be allowed after stopping Savella before starting an MAOI [see Dosage and Administration, Warnings and Precautions]. Uncontrolled Narrow-Angle Glaucoma-In clinical trials, Savella was associated with an increased risk of mydriasis. Mydriasis has been reported with other dual reuptake inhibitors of norepinephrine and serotonin; therefore, do not use Savella in patients with uncontrolled narrow-angle glaucoma. WARNINGS AND PRECAUTIONS: Suicide Risk-Savella is a selective serotonin and norepinephrine reuptake inhibitor (SNRI), similar to some drugs used for the treatment of depression and other psychiatric disorders. Patients, both adult and pediatric, with depression or other psychiatric disorders may experience worsening of their depression and/or the emergence of suicidal ideation and behavior (suicidality) or unusual changes in behavior, whether or not they are taking these medications, and this risk may persist until significant remission occurs. Suicide is a known risk of depression and certain other psychiatric disorders, and these disorders themselves are the strongest predictors of suicide. There has been a long-standing concern, however, that antidepressants, including drugs that inhibit the reuptake of norepinephrine and/or serotonin, may have a role in inducing worsening of depression and the emergence of suicidality in certain patients during the early phases of treatment. In the placebo-controlled clinical trials of adults with fibromyalgia, among the patients who had a history of depression at treatment initiation, the incidence of suicidal ideation was 0.5% in patients treated with placebo, 0% in patients treated with Savella 100 mg/day, and 1.3% in patients treated with Savella 200 mg/day. No suicides occurred in the short-term or longer-term (up to 1 year) fibromyalgia trials. Pooled analyses of short-term placebo-controlled trials of drugs used to treat depression (SSRIs and others) showed that these drugs increase the risk of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults (ages 18-24) with major depressive disorder (MDD) and other psychiatric disorders. Short-term studies did not show an increase in the risk of suicidality with these drugs compared to placebo in adults beyond age 24; there was a reduction in suicidality risk with antidepressants compared to placebo in adults age 65 and older. The pooled analyses of placebo-controlled trials in children and adolescents with MDD, obsessive compulsive disorder (OCD), or other psychiatric disorders included a total of 24 short-term trials of 9 drugs used to treat depression in over 4400 patients. The pooled analyses of placebo-controlled trials in adults with MDD or other psychiatric disorders included a total of 295 short-term trials (median duration of 2 months) of 11 antidepressant drugs in over 77,000 patients. There was considerable variation in risk of suicidality among drugs, but a tendency toward an increase in the younger patients for almost all drugs studied. There were differences in absolute risk of suicidality across the different indications, with the highest incidence in MDD. The risk of differences (drug versus placebo), however, were relatively stable within age strata and across indications. These risk differences (drug-placebo difference in the number of cases of suicidality per 1000 patients treated) are provided in Table 1 of the full prescribing information. There were 14 additional cases reported in patients under the age of 18, while 5 additional cases were reported in patients between 18 and 24 years of age. Patients between 25 and 64 years of age reported 1 fewer case of suicidality, while patients 65 years of age and over reported 6 fewer cases. No suicides occurred in any of the pediatric trials. There were suicides in the adult trials, but the number was not sufficient to reach any conclusion about drug effect on suicide. It is unknown whether the suicidality risk extends to longer-term use, i.e., beyond several months. However, there is substantial evidence from placebo-controlled maintenance trials in adults with depression that the use of antidepressants can delay the recurrence of depression. All patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for any indication should be monitored appropriately and observed closely for clinical worsening, suicidality, and unusual changes in behavior, especially during the initial few months of a course of drug therapy, or at times of dose changes, either increases or decreases. The following symptoms, anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, mania, have been reported in adult and pediatric patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric. Although a causal link between the emergence of such symptoms and either the worsening of depression and/or the emergence of suicidal impulses has not been established, there is concern that such symptoms may represent precursors to emerging suicidality. Consideration should be given to changing the therapeutic regimen, including possibly discontinuing the medication, in patients who may experience worsening depressive symptoms, or who are experiencing emergent suicidality or symptoms that might be precursors to worsening depression or suicidality, especially if these symptoms are severe or abrupt in onset, or were not part of the patient’s presenting symptoms. If the decision has been made to discontinue treatment due to worsening depressive symptoms or emergent suicidality, medication should be tapered, as rapidly as is feasible, but with recognition that abrupt discontinuation can produce withdrawal symptoms [see Dosage and Administration and Warnings and Precautions]. Families and caregivers of patients being treated with drugs inhibiting the reuptake of norepinephrine and/or serotonin for major depressive disorder or other indications, both psychiatric and nonpsychiatric, should be alerted about the need to monitor patients for the emergence of agitation, irritability, unusual changes in behavior, and the other symptoms described above, as well as the emergence of suicidality, and to report such symptoms immediately to health care providers. Such monitoring should include daily observation by families and caregivers. Prescriptions for Savella should be written for the smallest quantity of tablets consistent with good patient management, in order to reduce the risk of overdose. Serotonin Syndrome or Neuroleptic Malignant Syndrome (NMS)-Like Reactions-The development of a potentially life-threatening serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)-like reactions have been reported with SNRIs and SSRIs alone, including Savella, but particularly with concomitant use of serotonergic drugs (including triptans), with drugs which impair metabolism of serotonin (including MAOIs) or with antipsychotics or other dopamine antagonists. Serotonin syndrome symptoms may include mental status changes (e.g., agitation, hallucinations, coma), autonomic instability (e.g., tachycardia, labile blood pressure, hyperthermia), neuromuscular aberrations (e.g., hyperreflexia, incoordination) and/or gastrointestinal symptoms (e.g., nausea, vomiting, diarrhea) [see Drug Interactions]. Serotonin syndrome, in its most severe form, can resemble neuroleptic malignant syndrome, which includes hyperthermia, muscle rigidity, autonomic instability with possible rapid fluctuation of vital signs, and mental status changes. Patients should be monitored for the emergence of serotonin syndrome or NMS-like signs and symptoms. The concomitant use of Savella with MAOIs is contraindicated [see Contraindications]. If concomitant treatment of Savella with a 5-hydroxytryptamine receptor agonist (triptan) is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Drug Interactions]. The concomitant use of Savella with serotonin precursors (such as tryptophan) is not recommended [see Drug Interactions]. Treatment with Savella and any concomitant serotonergic or antidopaminergic agents, including antipsychotics, should be discontinued immediately if the above events occur and supportive symptomatic treatment should be initiated. Effects on Blood Pressure-Inhibition of the reuptake of norepinephrine (NE) and serotonin (5-HT) can lead to cardiovascular effects. SNRIs, including Savella, have been associated with reports of increase in blood pressure. In a double-blind, placebo-controlled clinical pharmacology study in healthy subjects designed to evaluate the effects of milnacipran on various parameters, including blood pressure at supratherapeutic doses, there was evidence of mean increases in supine blood pressure at doses up to 300 mg twice daily (600 mg/day). At the highest 300 mg twice daily dose, the mean increase in systolic blood pressure was up to 8.1 mm Hg for the placebo group and up to 10.0 mm Hg for the Savella treated group over the 12 hour steady state dosing interval. The corresponding mean increase in diastolic blood pressure over this interval was up to 4.6 mm Hg for placebo and up to 11.5 mm Hg for the Savella treated group. In the 3-month placebo-controlled fibromyalgia clinical trials, Savella treatment was associated with mean increases of up to 3.1 mm Hg in systolic blood pressure (SBP) and diastolic blood pressure (DBP) [see Adverse Reactions]. In the placebo-controlled trials, among fibromyalgia patients who were non-hypertensive at baseline, approximately twice as many patients in the Savella treatment arms became hypertensive at the end of the study (SBP ≥ 140 mmHg or DBP ≥ 90 mmHg) compared with the placebo patients: 7.2% of patients in the placebo arm versus 19.5% of patients treated with Savella 100 mg/day and 16.6% of patients treated with Savella 200 mg/day. Among patients who met systolic criteria for pre-hypertension at baseline (SBP 120-139 mmHg), more patients became hypertensive at the end of the study in the Savella treatment arms than placebo: 9% of patients in the placebo arm versus 14% in both the Savella 100 mg/day and the Savella 200 mg/day treatment arms. Among fibromyalgia patients who were hypertensive at baseline, more patients in the Savella treatment arms had a >15 mmHg increase in SBP than placebo at the end of the study: 1% of patients in the placebo arm versus 7% in the Savella 100 mg/day and 2% in the Savella 200 mg/day treatment arms. Similarly, more patients who were hypertensive at baseline and were treated with Savella had DBP increases > 10 mmHg than placebo at the end of study: 3% of patients in the placebo arm versus 8% in the Savella 100 mg/day and 6% in the Savella 200 mg/day treatment arms. Sustained increases in SBP (increase of ≥ 15 mmHg on three consecutive post-baseline visits) occurred in 2% of placebo patients versus 9% of patients receiving Savella 100 mg/day and 6% of patients receiving Savella 200 mg/day. Sustained increases in DBP (increase of ≥ 10 mmHg on 3 consecutive post-baseline visits) occurred in 4% of patients receiving placebo versus 13% of patients receiving Savella 100 mg/day and 10% of patients receiving Savella 200 mg/day. Sustained increases in blood pressure could have adverse consequences. Cases of elevated blood pressure requiring immediate treatment have been reported. Concomitant use of Savella with drugs that increase blood pressure and pulse has not been evaluated and such combinations should be used with caution [see Drug Interactions]. Effects of Savella on blood pressure in patients with significant hypertension or cardiac disease have not been systematically evaluated. Savella should be used with caution in these patients. Blood pressure should be measured prior to initiating treatment and periodically measured throughout Savella treatment. Pre-existing hypertension and other cardiovascular disease should be treated before starting therapy with Savella. For patients who experience a sustained increase in blood pressure while receiving Savella, either dose reduction or discontinuation should be considered. Effects on Heart Rate-SNRIs have been associated with reports of increase in heart rate. In clinical trials, relative to placebo, Savella treatment was associated with mean increases in pulse rate of approximately 7 to 8 beats per minute [see Adverse Reactions]. Increases in pulse ≥ 20 bpm occurred more frequently in Savella-treated patients when compared to placebo: 0.3% in the placebo arm versus 8% in the Savella 100 mg/day and 8% in the 200 mg/day treatment arms. The effect of Savella on heart rate did not appear to increase with increasing dose. Savella has not been systematically evaluated in patients with a cardiac rhythm disorder. Heart rate should be measured prior to initiating treatment and periodically measured throughout Savella treatment. Pre-existing tachyarrhythmias and other cardiac disease should be treated before starting therapy with Savella. For patients who experience a sustained increase in heart rate while receiving Savella, either dose reduction or discontinuation should be considered. Seizures-Savella has not been systematically evaluated in patients with a seizure disorder. In clinical trials evaluating Savella in patients with fibromyalgia, seizures/convulsions have not been reported. However, seizures have been reported infrequently in patients treated with Savella for disorders other than fibromyalgia. Savella should be prescribed with care in patients with a history of a seizure disorder. Hepatotoxicity-In the placebo-controlled fibromyalgia trials, increases in the number of patients treated with Savella with mild elevations of ALT or AST (1-3 times the upper limit of normal, ULN) were observed. Increases in ALT were more frequently observed in the patients treated with Savella 100 mg/day (6%) and Savella 200 mg/day (7%), compared to the patients treated with placebo (3%). One patient receiving Savella 100 mg/day (0.2%) had an increase in ALT greater than 5 times the upper limit of normal but did not exceed 10 times the upper limit of normal. Increases in AST were more frequently observed in the patients treated with Savella 100 mg/day (3%) and Savella 200 mg/day (5%) compared to the patients treated with placebo (2%). The increases of bilirubin observed in the fibromyalgia clinical trials were not clinically significant. No case met the criteria of elevated ALT > 3x ULN and associated with an increase in bilirubin ≥ 2x ULN. There have been cases of increased liver enzymes and reports of severe liver injury, including fulminant hepatitis with milnacipran from foreign postmarketing experience. In the cases of severe liver injury, there were significant underlying clinical conditions and/or the use of multiple concomitant medications. Because of underreporting, it is impossible to provide an accurate estimate of the true incidence of these reactions. Savella should be discontinued in patients who develop jaundice or other evidence of liver dysfunction. Treatment with Savella should not be resumed unless another cause can be established. Savella should ordinarily not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. Discontinuation of Treatment with Savella-Withdrawal symptoms have been observed in clinical trials following discontinuation of milnacipran, as with other SNRIs and SSRIs. During marketing of milnacipran, and other SNRIs and SSRIs, there have been spontaneous reports of adverse events indicative of withdrawal and physical dependence occurring upon discontinuation of these drugs, particularly when discontinuation is abrupt. The adverse events include the following: dysphoric mood, irritability, agitation, dizziness, sensory disturbances (e.g., paresthesias such as electric shock sensations), anxiety, confusion, headache, lethargy, emotional lability, insomnia, hypomania, tinnitus, and seizures. Although these events are generally self-limiting, some have been reported to be severe. Patients should be monitored for these symptoms when discontinuing treatment with Savella. Savella should be tapered and not abruptly discontinued after extended use. If intolerable symptoms occur following a decrease in the dose or upon discontinuation of treatment, then resuming the previously prescribed dose may be considered. Subsequently, the physician may continue decreasing the dose but at a more gradual rate [see Dosage and Administration]. Hyponatremia-Hyponatremia may occur as a result of treatment with SSRIs and SNRIs, including Savella. In many cases, this hyponatremia appears to be the result of the syndrome of inappropriate antidiuretic hormone secretion (SIADH). Cases with serum sodium lower than 110 mmol/L have been reported. Elderly patients may be at greater risk of developing hyponatremia with SNRIs, SSRIs, or Savella. Also, patients taking diuretics or who are otherwise volume-depleted may be at greater risk [see Geriatric Use]. Discontinuation of Savella should be considered in patients with symptomatic hyponatremia. Signs and symptoms of hyponatremia include headache, difficulty concentrating, memory impairment, confusion, weakness, and unsteadiness, which may lead to falls. Signs and symptoms associated with more severe and/or acute cases have included hallucination, syncope, seizure, coma, respiratory arrest, and death. Abnormal Bleeding-SSRIs and SNRIs, including Savella, may increase the risk of bleeding events. Concomitant use of aspirin, nonsteroidal anti-inflamma-

tory drugs, warfarin, and other anti-coagulants may add to this risk. Case reports and epidemiological studies (case-control and cohort design) have demonstrated an association between use of drugs that interfere with serotonin reuptake and the occurrence of gastrointestinal bleeding. Bleeding events related to SSRIs and SNRIs use have ranged from ecchymoses, hematomas, epistaxis, and petechiae to life-threatening hemorrhages. Patients should be cautioned about the risk of bleeding associated with the concomitant use of Savella and NSAIDs, aspirin, or other drugs that affect coagulation. Activation of Mania-No activation of mania or hypomania was reported in the clinical trials evaluating effects of Savella in patients with fibromyalgia. However those clinical trials excluded patients with current major depressive episode. Activation of mania and hypomania have been reported in patients with mood disorders who were treated with other similar drugs for major depressive disorder. As with these other agents, Savella should be used cautiously in patients with a history of mania. Patients with a History of Dysuria-Because of their noradrenergic effect, SNRIs including Savella, can affect urethral resistance and micturition. In the controlled fibromyalgia trials, dysuria occurred more frequently in patients treated with Savella (1%) than in placebo-treated patients (0.5%). Caution is advised in use of Savella in patients with a history of dysuria, notably in male patients with prostatic hypertrophy, prostatitis, and other lower urinary tract obstructive disorders. Male patients are more prone to genitourinary adverse effects, such as dysuria or urinary retention, and may experience testicular pain or ejaculation disorders. Controlled Narrow-Angle Glaucoma-Mydriasis has been reported in association with SNRIs and Savella; therefore, Savella should be used cautiously in patients with controlled narrow-angle glaucoma. Do not use Savella in patients with Uncontrolled Narrow-Angle Glaucoma [see Contraindications]. Concomitant Use with Alcohol-In clinical trials, more patients treated with Savella developed elevated transaminases than did placebo-treated patients [see Warnings and Precautions]. Because it is possible that milnacipran may aggravate preexisting liver disease, Savella should not be prescribed to patients with substantial alcohol use or evidence of chronic liver disease. ADVERSE REACTIONS: Clinical Trial Data Sources-Savella was evaluated in three double-blind placebo-controlled trials involving 2209 fibromyalgia patients (1557 patients treated with Savella and 652 patients treated with placebo) for a treatment period up to 29 weeks. The stated frequencies of adverse reactions represent the proportion of individuals who experienced, at least once, a treatment-emergent adverse reaction of the type listed. A reaction was considered treatment emergent if it occurred for the first time or worsened while receiving therapy following baseline evaluation. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Adverse Reactions Leading to Discontinuation-In placebo-controlled trials in patients with fibromyalgia, 23% of patients treated with Savella 100 mg/day, 26% of patients treated with Savella 200 mg/day discontinued prematurely due to adverse reactions, compared to 12% of patients treated with placebo. The adverse reactions that led to withdrawal in ≥ 1% of patients in the Savella treatment group and with an incidence rate greater than that in the placebo treatment group were nausea (milnacipran 6%, placebo 1%), palpitations (milnacipran 3%, placebo 1%), headache (milnacipran 2%, placebo 0%), constipation (milnacipran 1%, placebo 0%), heart rate increased (milnacipran 1%, placebo 0%), hyperhidrosis (milnacipran 1%, placebo 0%), vomiting (milnacipran 1%, placebo 0%), and dizziness (milnacipran 1% and placebo 0.5%). Discontinuation due to adverse reactions was generally more common among patients treated with Savella 200 mg/day compared to Savella 100 mg/day. Most Common Adverse Reactions-In the placebo-controlled fibromyalgia patient trials, the most frequently occurring adverse reaction in clinical trials was nausea. The most common adverse reactions (incidence ≥ 5% and twice placebo) in patients treated with Savella were constipation, hot flush, hyperhidrosis, vomiting, palpitations, heart rate increased, dry mouth, and hypertension. Table 2 lists all adverse reactions that occurred in at least 2% of patients treated with Savella at either 100 or 200 mg/day and at an incidence greater than that of placebo. Table 2 in the full PI shows the incidence of common adverse reactions that occurred in at least 2% of patients treated with Savella at either 100 or 200 mg/day and at an incidence greater than that of placebo. Savella 100 mg/day (n=632); Savella 200 mg/day (n=934); All Savella (n=1557); Placebo (n=652): Cardiac Disorders: Palpitations (8%; 7%; 7%; 2%); Tachycardia (3%; 2%; 2%; 1%); Eye Disorders: Vision blurred (1%; 2%; 2%; 1%); Gastrointestinal Disorders: Nausea (35%; 39%; 37%; 20%); Constipation (16%; 15%; 16%; 4%); Vomiting (6%; 7%; 7%; 2%); Dry mouth (5%; 5%; 5%; 2%); Abdominal pain (3%; 3%; 3%; 2%); General Disorders: Chest pain (3%; 2%; 2%; 2%); Chills (1%; 2%; 2%; 0%); Chest discomfort (2%; 1%; 1%; 1%); Infections: Upper respiratory tract infection (7%; 6%; 6%; 6%); Investigations: Heart rate increased (5%; 6%; 6%; 1%); Blood pressure increased (3%; 3%; 3%; 1%); Metabolism and Nutrition Disorders: Decreased appetite (1%; 2%; 2%; 0%); Nervous System Disorders: Headache (19%; 17%; 18%; 14%); Dizziness (11%; 10%; 10%; 6%); Migraine (6%; 4%; 5%; 3%); Paresthesia (2%; 3%; 2%; 2%); Tremor (2%; 2%; 2%; 1%); Hypoesthesia (1%; 2%; 1%; 1%); Tension headache (2%; 1%; 1%; 1%); Psychiatric Disorders: Insomnia (12%; 12%; 12%; 10%); Anxiety (5%; 3%; 4%; 4%); Respiratory Disorders: Dyspnea (2%; 2%; 2%; 1%); Skin Disorders: Hyperhidrosis (8%; 9%; 9%; 2%); Rash (3%; 4%; 3%; 2%); Pruritus (3%; 2%; 2%; 2%); Vascular Disorders: Hot flush (11%; 12%; 12%; 2%); Hypertension (7%; 4%; 5%; 2%); Flushing (2%; 3%; 3%; 1%). Weight Changes-In placebo-controlled fibromyalgia clinical trials, patients treated with Savella for up to 3 months experienced a mean weight loss of approximately 0.8 kg in both the Savella 100 mg/day and the Savella 200 mg/day treatment groups, compared with a mean weight loss of approximately 0.2 kg in placebo-treated patients. Genitourinary Adverse Reactions in Males-In the placebo-controlled fibromyalgia studies, the following treatmentemergent adverse reactions related to the genitourinary system were observed in at least 2% of male patients treated with Savella, and occurred at a rate greater than in placebo-treated male patients: dysuria, ejaculation disorder, erectile dysfunction, ejaculation failure, libido decreased, prostatitis, scrotal pain, testicular pain, testicular swelling, urinary hesitation, urinary retention, urethral pain, and urine flow decreased. Other Adverse Reactions Observed During Clinical Trials of Savella in Fibromyalgia-Following is a list of frequent (those occurring on one or more occasions in at least 1/100 patients) treatment-emergent adverse reactions reported from 1824 fibromyalgia patients treated with Savella for periods up to 68 weeks. The listing does not include those events already listed in Table 2, those events for which a drug cause was remote, those events which were so general as to be uninformative, and those events reported only once which did not have a substantial probability of being acutely life threatening. Adverse reactions are categorized by body system and listed in order of decreasing frequency. Adverse reactions of major clinical importance are described in the Warnings and Precautions section. Gastrointestinal Disorders – diarrhea, dyspepsia, gastroesophageal reflux disease, flatulence, abdominal distension; General Disorders – fatigue, peripheral edema, irritability, pyrexia; Infections – urinary tract infection, cystitis; Injury, Poisoning, and Procedural Complications – contusion, fall; Investigations – weight decreased or increased; Metabolism and Nutrition Disorders – hypercholesterolemia; Nervous System Disorders – somnolence, dysgeusia; Psychiatric Disorders – depression, stress; Skin Disorders – night sweats. Post-marketing Spontaneous Reports-The following additional adverse reactions have been identified from spontaneous reports of Savella received worldwide. These adverse reactions have been chosen for inclusion because of a combination of seriousness, frequency of reporting, or potential causal connection to Savella. However, because these adverse reactions were reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events include: Blood and Lymphatic System Disorders – leukopenia, neutropenia, thrombocytopenia; Cardiac Disorders – supraventricular tachycardia; Eye Disorders – accommodation disorder; Endocrine Disorders – hyperprolactinemia; Hepatobiliary Disorders – hepatitis; Metabolism and Nutrition Disorders – anorexia, hyponatremia; Musculoskeletal and Connective Tissue Disorders – rhabdomyolysis; Nervous System Disorders – convulsions (including grand mal), loss of consciousness, Parkinsonism; Psychiatric Disorders – delirium, hallucination; Renal and Urinary Disorders – acute renal failure; Reproductive System and Breast Disorders – galactorrhea; Skin Disorders – erythema multiforme, Stevens Johnson syndrome; Vascular Disorders – hypertensive crisis. DRUG INTERACTIONS: Milnacipran undergoes minimal CYP450 related metabolism, with the majority of the dose excreted unchanged in urine (55%), and has a low binding to plasma proteins (13%). In vitro and in vivo studies showed that Savella is unlikely to be involved in clinically significant pharmacokinetic drug interactions [see Pharmacokinetics in Special Populations]. Monoamine Oxidase Inhibitors - [See Contraindications] Serotonergic Drugs - Due to the mechanism of action of SNRIs and SSRIs, including Savella, and the potential for serotonin syndrome or Neuroleptic Malignant Syndrome (NMS)–like reactions, caution is advised when Savella is co-administered with other drugs that may affect the serotonergic neurotransmitter systems. This includes drugs such as triptans, lithium, tryptophan, antipsychotics and dopamine antagonists. Co-administration of Savella with other inhibitors of serotonin re-uptake may result in hypertension and coronary artery vasoconstriction, through additive serotonergic effects. Concomitant use of Savella with other SSRIs, SNRIs, or tryptophan is not recommended [see Warnings and Precautions]. Triptans - There have been rare postmarketing reports of serotonin syndrome with use of an SSRI and a triptan. If concomitant treatment of Savella with a triptan is clinically warranted, careful observation of the patient is advised, particularly during treatment initiation and dose increases [see Warnings and Precautions]. Catecholamines - Savella inhibits the reuptake of norepinephrine. Therefore concomitant use of Savella with epinephrine and norepinephrine may be associated with paroxysmal hypertension and possible arrhythmia [see Warnings and Precautions]. CNS-active drugs - Given the primary CNS effects of Savella, caution should be used when it is taken in combination with other centrally acting drugs, including those with a similar mechanism of action. Clomipramine: In a drug-drug interaction study, an increase in euphoria and postural hypotension was observed in patients who switched from clomipramine to Savella. Clinically Important Interactions with Select Cardiovascular Agents - Digoxin: Use of Savella concomitantly with digoxin may be associated with potentiation of adverse hemodynamic effects. Postural hypotension and tachycardia have been reported in combination therapy with intravenously administered digoxin (1 mg). Co-administration of Savella and intravenous digoxin should be avoided [see Warnings and Precautions]. Clonidine: Because Savella inhibits norepinephrine reuptake, co-administration with clonidine may inhibit clonidine’s anti-hypertensive effect. USE IN SPECIFIC POPULATIONS: Pregnancy-Pregnancy Category C. Milnacipran increased the incidence of dead fetuses in utero in rats at doses of 5 mg/kg/day (0.25 times the MRHD on a mg/m2 basis). Administration of milnacipran to mice and rabbits during the period of organogenesis did not result in embryotoxicity or teratogenicity at doses up to 125 mg/kg/day in mice (3 times the maximum recommended human dose [MRHD] of 200 mg/day on a mg/m2 basis) and up to 60 mg/kg/day in rabbits (6 times the MRHD of 200 mg/day on a mg/m2 basis). In rabbits, the incidence of the skeletal variation, extra single rib, was increased following administration of milnacipran at 15 mg/kg/day during the period of organogenesis. There are no adequate and well-controlled studies in pregnant women. Savella should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To provide information regarding the exposure to Savella during pregnancy, physicians are advised to recommend that pregnant patients taking Savella enroll in the Savella Pregnancy Registry. Enrollment is voluntary and may be initiated by pregnant patients or their healthcare providers by contacting the registry at 1-877-643-3010 or by email at registries@kendle.com. Data forms may also be downloaded from the registry website at www.savellapregnancyregistry.com. Nonteratogenic Effects; Neonates exposed to dual reuptake inhibitors of serotonin and norepinephrine, or selective serotonin reuptake inhibitors late in the third trimester have developed complications requiring prolonged hospitalization, respiratory support, and tube feeding. Such complications can arise immediately upon delivery. Reported clinical findings have included respiratory distress, cyanosis, apnea, seizures, temperature instability, feeding difficulty, vomiting, hypoglycemia, hypotonia, hypertonia, hyperreflexia, tremor, jitteriness, irritability, and constant crying. These features are consistent with either a direct toxic effect of these classes of drugs or, possibly, a drug discontinuation syndrome. It should be noted that, in some cases, the clinical picture is consistent with serotonin syndrome [see Warnings and Precautions]. In rats, a decrease in pup body weight and viability on postpartum day 4 were observed when milnacipran, at a dose of 5 mg/kg/day (approximately 0.2 times the MRHD on a mg/m2 basis), was administered orally to rats during late gestation. The no-effect dose for maternal and offspring toxicity was 2.5 mg/kg/day (approximately 0.1 times the MRHD on a mg/m2 basis). Labor and Delivery-The effect of milnacipran on labor and delivery is unknown. The use of Savella during labor and delivery is not recommended. Nursing Mothers-There are no adequate and well-controlled studies in nursing mothers. It is not known if milnacipran is excreted in human milk. Studies in animals have shown that milnacipran or its metabolites are excreted in breast milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from milnacipran, a decision should be made whether to discontinue the drug, taking into account the importance of the drug to the mother. Because the safety of Savella in infants is not known, nursing while on Savella is not recommended. Pediatric Use-Safety and effectiveness of Savella in a fibromyalgia pediatric population below the age of 17 have not been established [see Box Warning and Warnings and Precautions]. The use of Savella is not recommended in pediatric patients. Geriatric Use-In controlled clinical studies of Savella, 402 patients were 60 years or older, and no overall differences in safety and efficacy were observed between these patients and younger patients. In view of the predominant excretion of unchanged milnacipran via kidneys and the expected decrease in renal function with age, renal function should be considered prior to use of Savella in the elderly [see Dosage and Administration]. SNRIs, SSRIs, and Savella, have been associated with cases of clinically significant hyponatremia in elderly patients, who may be at greater risk for this adverse event [see Warnings and Precautions]. DRUG ABUSE AND DEPENDENCE: Controlled Substance-Milnacipran is not a controlled substance. Abuse-Milnacipran did not produce behavioral signs indicative of abuse potential in animal or human studies. Dependence-Milnacipran produces physical dependence, as evidenced by the emergence of withdrawal symptoms following drug discontinuation, similar to other SNRIs and SSRIs. These withdrawal symptoms can be severe. Thus, Savella should be tapered and not abruptly discontinued after extended use [see Warnings and Precautions]. OVERDOSAGE: There is limited clinical experience with Savella overdose in humans. In clinical trials, cases of acute ingestions up to 1000 mg, alone or in combination with other drugs, were reported with none being fatal. In postmarketing experience, fatal outcomes have been reported for acute overdoses primarily involving multiple drugs but also with Savella only. The most common signs and symptoms included increased blood pressure, cardio-respiratory arrest, changes in the level of consciousness (ranging from somnolence to coma), confusional state, dizziness, and increased hepatic enzymes. Management of Overdose-There is no specific antidote to Savella, but if serotonin syndrome ensues, specific treatment (such as with cyproheptadine and/or temperature control) may be considered. In case of acute overdose, treatment should consist of those general measures employed in the management of overdose with any drug. An adequate airway, oxygenation, and ventilation should be assured and cardiac rhythm and vital signs should be monitored. Induction of emesis is not recommended. Gastric lavage with a large-bore orogastric tube with appropriate airway protection, if needed, may be indicated if performed soon after ingestion or in symptomatic patients. Because there is no specific antidote for Savella, symptomatic care and treatment with gastric lavage and activated charcoal should be considered as soon as possible for patients who experience a Savella overdose. Due to the large volume of distribution of this drug, forced diuresis, dialysis, hemoperfusion, and exchange transfusion are unlikely to be beneficial. In managing overdose, the possibility of multiple drug involvement should be considered. The physician should consider contacting a poison control center for additional information on the treatment of any overdose. Telephone numbers for certified poison control centers are listed in the Physicians’ Desk Reference (PDR). Manufactured for: Manufactured by: Forest Pharmaceuticals, Inc. Forest Laboratories, Inc. Licensed from Pierre Fabre Medicament and Cypress Bioscience, Inc. Revised: November 2011 © 2011 Forest Laboratories, Inc. 043-12000147-B-RMC14503-NOV11 Please also see Full Prescribing Information at www.savella.com

In This Issue

Value-Based Carein Rheumatology FROM THE PUBLISHERS OF AMERICAN HEALTH & DRUG BENEFITS

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editor Lara J. Lorton lara@engagehc.com 732-992-1892 Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Sales Assistant Zach Ceretelle Senior Production Manager Lynn Hamilton Quality Control Director Barbara Marino Business Manager Blanche Marchitto Mission Statement Value-Based Care in Rheumatology provides a forum for payers, providers, and the entire rheumatology team to consider the cost-value issues particular to rheumatology treatments. This unique focus is achieved through news coverage from major rheumatology meetings and the rheumatic diseases literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. Contact Information: For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@engagehc.com. Address all editorial queries to: editorial@engagehc.com Telephone: 732-992-1536 Fax: 732-992-1881 Value-Based Care in Rheumatology, ISSN applied, is published 6 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2012 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Care in Rheumatology is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Care in Rheumatology do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Care in Rheumatology should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Care in Rheumatology, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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OUTCOMES RESEARCH

FIBROMYALGIA

Implications of patient-centered research to daily practice

Milnacipran improves clinical outcomes compared with duloxetine

VALUE PROPOSITIONS

LUPUS

Growing use of biologics in rheumatology New studies charting a path for biomarkers More….

Panel of biomarkers likely to emerge in SLE

DRUG THERAPY Three TNF inhibitors equally cost-effective for ankylosing spondylitis Oral JAK inhibitor relieves RA symptoms after failure of TNF inhibition More….

PERSONALIZED MEDICINE in

Rheumatology

™

B-cell biomarkers may help guide rituximab use in RA Personalized therapy promising in RA More….

GOUT Cost comparison of monthly expenditures of 2 gout agents More….

CLINICAL PATHWAYS Nation’s first clinical pathways program for RA launched in 2011

Rheumatology PRACTICE

RHEUMATOLOGY UPDATE

MANAGEMENT™

Top-10 practice-changing topics in rheumatology

Navigating electronic health records and meaningful use rules

VBCR Advisory Editorial Board Editor-in-Chief Sy Schlager, MD, PhD President & Chief Medical Officer Therapeutic Window, LLC Southlake, TX Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield New York, NY Daniel Furst, MD Professor of Medicine, Rheumatology UCLA Health System Los Angeles, CA Allan Gibofsky, MD Professor of Medicine and Public Health Weill Medical College of Cornell University New York, NY Max Hamburger, MD National Medical Director International Rheumatology Network Melville, NY Gary L. Johnson, MD, MS, MBA Regional Medical Director Humana, Inc. Madison, WI

Atheer A. Kaddis, PharmD Vice President, Managed Markets Diplomat Specialty Pharmacy Swartz Creek, MI

Gary M. Owens, MD President Gary Owens Associates Philadelphia, PA

James T. Kenney, RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, MA

Kim A. Papp, MD, PhD Founder and President Probity Medical Research Waterloo, Ontario, Canada

Muhammad Asim Khan, MD Professor of Medicine Case Western Reserve University Cleveland, OH

Edmund J. Pezalla, MD, MPH National Medical Director for Pharmacy Policy and Strategy Aetna Hartford, CT

Randall Krakauer, MD, FACP, FACR National Medical Director, Medicare Aetna Princeton, NJ

Ronald van Vollenhoven, MD, PhD Associate Professor Karlinska University Hospital Solna Stockholm, Sweden

Alan Menter, MD Director Baylor Psoriasis Research Center Dallas, TX

F. Randy Vogenberg, RPh, PhD Principal Institute of Integrated Healthcare Sharon, MA

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth Murray, UT

Alvin Wells, MD Director, Rheumatology and Immunotherapy Center Franklin, WI

Lynn Nishida, RPh Director, Clinical Pharmacy Services RegenceRX Portland, OR

APRIL 2012

www.ValueBasedRheumatology.com

Outcomes Research

From Science to Medicine: Implications of Patient-Centered Outcomes... Continued from cover

We confront these issues every day. Further complicating matters is the overwhelming amount of new clinical information that constantly emerges. Keeping pace with the latest journal publications, evaluating the data, reading new reports of potential adverse effects of selected interventions, and working with patients to determine the best treatment option are daunting challenges. We struggle to translate scientific advances into actual clinical practice. We struggle to translate these advances into usable information both for ourselves as clinicians and for our patients. And we struggle to get it right the first time for our patients, because doing otherwise is both costly and potentially harmful to their health. One research endeavor—patientcentered outcomes research—shows great promise in helping us confront these issues. Patient-centered outcomes research has been much discussed lately thanks to recent legislation. The American Recovery and Reinvestment Act of 2009 directed an unprecedented $1.1 billion to this research, including $300 million directly to my agency, the Agency for Healthcare Research and Quality (AHRQ). The Patient Protection and Affordable Care Act of 2010 created the Patient-Centered Outcomes Research Institute (PCORI) to conduct research to provide information about the best available evidence to help patients and their healthcare providers make more informed decisions (for more information visit www.pcori.org). The PCORI is an independent, not-forprofit organization, and I am proud to serve on its Board of Governors.

Although the elevated profile of patient-centered outcomes research is new, the research itself is not. The AHRQ has been publishing comparative effectiveness research (a type of patient-centered outcomes research) reports since 2005 through its Effective Health Care Program, the federal government’s leading effort to compare the effectiveness and risks of different healthcare interventions. The Effective Health Care Program uses unbiased information to make head-to-head comparisons of treatment alternatives, including drugs. The program was created under the Medicare Prescription Drug, Improvement, and Modernization Act, in which Congress mandated the AHRQ to develop evidence about the effectiveness and comparative effectiveness of different treatments and clinical approaches to significant health problems, and to communicate its findings widely to a variety of audiences, including consumers.

Clinician research summaries sort through the science to arrive at a clinical “bottom line” to give us tools (but not rules) to get the most appropriate treatment to each patient. The Effective Health Care Program products include original research; comparative effectiveness reviews, which assess the state of the science to understand which interventions work

best under which conditions; and concise synopsis publications that summarize reports for clinicians, consumers, and policymakers. Clinician

nonopioid analgesics for osteoarthritis. Current projects of interest include a longitudinal study of the comparative effectiveness and safety of biolog-

The Effective Health Care Program has 14 priorities. Two of these priority areas are of special importance for readers of ValueBased Care in Rheumatology: arthritis and nontraumatic joint disorders, and functional limitations and disability. Carolyn M. Clancy, MD

research summaries sort through the science to arrive at a clinical “bottom line” to give us tools (but not rules) to get the most appropriate treatment to each patient. The Effective Health Care Program has 14 priorities—areas of special focus—because they affect a large number of Americans, and there is substantial variation in national clinical practices. Two of these priority areas are of special importance for readers of Value-Based Care in Rheumatology: arthritis and nontraumatic joint disorders, and functional limitations and disability. Accordingly, the Effective Health Care Program has recently produced several products of interest, including research summaries for clinicians on choosing medications for adults with rheumatoid arthritis (RA), the use of DMARDs in children with juvenile idiopathic arthritis, and choosing

ics in autoimmunity, and a medication research summary publication for vulnerable populations with RA. Patient-centered outcomes research is maturing as a discipline, thanks in part to increased funding and in part to the active participation of many stakeholders, including clinicians. Readers of this journal have a defined and important role to play. To submit a suggestion for research, comment on key questions and draft reports, and download evidence reports and clinician research summaries to learn valuable information that could affect your everyday practice, visit the Effective Health Care Program’s website at http://effective healthcare.gov. Your active participation in patient-centered outcomes research will ensure that the best information is used to make sure that the right patient gets the right treatment at the right time every time. ■

FROM THE EDITOR

Introducing the Inaugural Issue...

Sy Schlager, MD, PhD

and access to care, so that the interests of clinical, business, and regulatory stakeholders can be aligned in providing value-based care for patients. The motivation for Value-Based Care in Rheumatology is empowerment—empowerment of physicians to make knowledgeable, evidenceand value-based treatment decisions, and to have informed cost–value conversations with their patients, as well as empowerment of payers and policymakers to make educated coverage

VALUE-BASED CARE IN RHEUMATOLOGY

APRIL 2012

Continued from cover and reimbursement decisions. It is clear that the practice of medicine is moving toward personalized, valuebased care. This is especially true in rheumatology where treatment decisions frequently must consider the likelihood of an individual patient responding to one of several expensive therapeutic agents or treatment regimens. If we do our job right, Value-Based Care in Rheumatology will empower clinicians, payers, and policymakers to make informed decisions that will

ultimately benefit patients with rheumatic diseases. I welcome and encourage your input and feedback on Value-Based Care in Rheumatology. Please feel free to share your ideas, recommendations for topics, kudos, and criticisms with me. I hope that with each issue, we will succeed in positively impacting value-based care in rheumatology. ■ Sy Schlager, MD, PhD Editor-in-Chief sschlager@the-lynx-group.com

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Value Propositions Rheumatologists Continue to Prefer Biologics, Indicating Unmet Needs and Opportunities A recent study (presented at the 2011 American College of Rheumatology annual meeting) outlining treatment trends of US rheumatologists has shown that biologic agents remain the preferred treatments for patients with rheumatoid arthritis (RA) in the United States. Compared with 1 year ago, the use of biologics continues to increase, especially for patients with severe RA. Nevertheless, one third of patients across the disease severity scale are not achieving optimal response to current biologics, indicating an unmet need and an opportunity. Rheumatologists discontinue the use of a biologic for a variety of reasons, including safety or tolerability concerns and insufficient efficacy. When a patient is switched from one biologic to another, the main reasons are poor response and efficacy plateauing. Economic issues and out-of-pocket cost to the patient are also important factors in treatment discontinuation and switching decisions. The increasing use of the 3 key biologic agents with a unique mechanism of action is expected to continue to rise in the next 6 months; these include abatacept (Orencia SC), rituximab (Rituxan), and tocilizumab (Actemra). The increasing market share of these 3 agents is expected to be at the expense of the current market leaders—etanercept (Enbrel) and adalimumab (Humira). Until this change happens, etanercept and adalimumab continue to be used interchangeably as first- and second-line therapies. Awareness is also high among rheumatologists surveyed in this study with respect to new compounds for RA in late-stage development. Interest is highest for tofacitinib, an oral Janus kinase inhibitor currently under review by the US Food and Drug Administration (FDA). Overall, the most desired attributes for any new therapy for RA are long-term safety and sustained efficacy.

Value-Based Care in Rheumatology: Balancing Economic and Pharmacotherapy Considerations As a result of many studies conducted across the globe over the past few decades, data supporting the basis for pharmacoeconomic studies in rheumatic diseases have been well established. This is particularly true in the case of RA. It has been clearly established that RA is a chronic progressive autoimmune disease that has a tremendous impact on affected patients. The joint destruction and attendant functional disability characteristic of RA are associated with substantial morbidity and accelerated mortality. The severe sequelae of untreated or inadequately treated RA result directly in sizable economic costs, not only to patients with RA and their families but also to society. Although the costs of RA have been clearly delineated through rigorous observational studies and in-depth analyses, only recently have the implications of these costs gained significant attention. This increasing interest has been driven primarily by the introduction of newer therapeutic agents. Progress in understanding the immunopathogenesis of RA, combined with advances in biotechnology, has allowed the development of novel therapeutic agents that target specific components of the dysregulated immune system. These biologic agents, particularly inhibitors of the key proinflammatory cytokine tumor necrosis factor (TNF)-alpha, have proved highly effective not only in improving the signs and symptoms of disease but also in inhibiting the progression of joint damage, improving patients’ quality of life, and preserving their functional status. The introduction of TNF inhibitors has resulted in dramatic changes in the therapeutic approach and treatment paradigms for patients with RA. The ability to meaningfully improve clinical outcomes has led to growing treatment goals. Therefore, remission is now considered not only highly desirable but also an achievable goal for patients with RA. In addition to their efficacy in RA, biologic agents have been shown to have impressive benefits in other systemic inflammatory diseases, including psoriatic arthritis, ankylosing spondylitis, psoriasis, and inflammatory bowel disease. Biologics are under study for a number of other autoimmune conditions as well.

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The relatively high acquisition cost of these newer biologics is a key concern, with direct impact on the ability of clinicians to use these medications. In 2006, the average wholesale price (AWP) for 1 year of therapy with standard RA dosages of etanercept or adalimumab in the United States was approximately $16,000. The exact cost of the TNF inhibitor infliximab (Remicade) is harder to determine, because it is administered intravenously; however, its cost is comparable with that of the other TNF inhibitors. Although costs that are slightly lower than the AWP may be available for the TNF inhibitors, the costs of the currently available agents still far exceed those of older therapeutic agents. For example, the AWP for 1 year of treatment with generic methotrexate, at a dose of 17.5 mg weekly, is approximately $500. Although methotrexate is certainly cheaper than other RA treatments, recent trials using all anti-TNF agents have shown that combinations of methotrexate and anti-TNFs are clearly more effective than methotrexate alone in improving signs and symptoms, optimizing quality of life, and slowing or preventing the progressive joint destruction that is characteristic of severe RA. The extent to which the greater clinical outcomes achievable with the use of newer medications are “worth” their higher costs is the most pressing value-based question in rheumatology. With healthcare costs rising globally, and with newer therapeutics consuming a greater portion of healthcare budgets, there has been increased attention to pharmacoeconomic analyses as a means to justify therapy with newer, more expensive agents.

New Studies Charting New Path for Biomarkers in Rheumatology There is widespread recognition of the value of biomarkers in different clinical areas, but no biomarkers are yet available in rheumatology. To date, no FDA-approved proteomic tests are available for arthritis. There is little doubt that such tests could help the diagnosis and treatment of RA, but such biologic tests present a major clinical and financial challenge to develop, validate, and market. Robust validation data, including evidence of sensitivity, specificity, and correlation to the existing limited set of clinical or laboratory criteria, are necessary to support clinical utility. The measurement of specific proteins that flag a particular patient’s status could add objectivity in circumstances where the clinician currently relies on clinical judgment alone. Multiple studies are currently under way to address 3 key areas that could provide solid evidence for potential tests in terms of their clinical utility, cost-effectiveness, and commercial viability; these areas include (1) limiting bias in study design, (2) thorough protein isoform verification, and (3) modes of orthogonal and targeted validation. If successful, the results of these studies will provide guidance for value-based care of rheumatic disorders in the near future.

Online Genetic Testing Registry a New Tool from NIH An online tool launched by the National Institutes of Health (NIH) will help patients, providers, and researchers navigate the rapidly growing landscape of genetic testing. The Genetic Testing Registry (GTR) is available at www.ncbi.nlm.nih.gov/gtr/ and can be accessed by the public. “It is a tremendous resource for all who are struggling to make sense of the complex world of genetic testing,” said NIH Director Francis S. Collins, MD, PhD. The GTR will be updated frequently, using data submitted by genetic test providers. The GTR can be searched by a test, condition, gene, genetic mutation, or laboratory; it will also have links to practice guidelines and a variety of genetic and literature resources through the National Library of Medicine. NIH News, National Institutes of Health; February 29, 2012.

APRIL 2012

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Personalized Medicine in Rheumatology

™

See also page 8

By Wayne Kuznar Chicago, IL—The explosion of genetic data and the rapidly improving methods for genotyping that produce faster results at lower costs are 2 major reasons for optimism for the future of personalized medicine in rheumatoid arthritis (RA), said S. Louis Bridges, Jr, MD, PhD, Professor of Medicine and Director, Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham at the 2011 meeting of the American College of Rheumatology. Role of Pharmacogenomics in RA Once highly reliable predictive algorithms emerge, physicians and third-party payers will take notice of pharmacogenomics and pharmacogenetics, Dr Bridges said. Payer willingness to reimburse for genetic tests and treatments will ultimately determine the pace of integration of personalized medicine into clinical practice. RA is an especially suitable disease for the advancement of personalized medicine because many treatments are available, the efficacy and toxicity for each is variable, the cost differs between treatment approaches, and

at a glance ➤ Personalized medicine is particularly appropriate for RA, because of its chronic nature and the variability in efficacy and toxicity of each treatment ➤ The explosion in genetic information and the rapidly improving methods for genotyping that accelerates results at lower costs are fertile ground for personalized medicine in rheumatic diseases ➤ Payer willingness to reimburse for genetic tests in addition to treatment will determine the pace of integration of personalized medicine into RA clinical practice ➤ An ideal test to predict treatment response must be robust and predictable, with proved clinical value and relatively low cost ➤ Larger, publicly available, standardized data sets are needed to identify patients likely to respond to treatment

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RA is a relatively common, chronic, and potentially disabling disease. It is, however, a complex disease that involves many genes and pathways. The use of surrogate tissue (blood) rather than affected tissue drives the search for biomarkers of treatment response, Dr Bridges said. The challenges in pharmacogenomics are many. One challenge is defining candidate genes and drug responses. Identifying genetic variants (eg, single nucleotide polymorphisms [SNPs], insertions/deletions) through genome-wide association studies (GWAS) or candidate gene studies is one approach to discovering biomarkers of treatment response. With the candidate gene approach, quantitative real-time polymerase chain reaction can be used to analyze the expression of individual genes. “How much RNA is present is a marker for how much that gene is turned on or not turned on,” said Dr Bridges. A GWAS involves rapidly scanning markers across the complete sets of DNA or genomes of patients to find genetic variations associated with a particular disease. “A GWAS is an agnostic approach; we do not have to have a hypothesis of what gene is involved. It is discovery-based,” he said. “One of the messages that we take from GWAS is that you have to look for biological plausibility,” said Dr Bridges. Genetic Testing to Predict Response Once a candidate gene is discovered, the next step is to determine if it is clinically useful and relevant. “This is where some of our colleagues in other fields are ahead of us,” he said, citing the example of choosing a warfarin (Coumadin) dosage based on the results of genotyping for the VKORC1 and CYP2C9 genetic variants of the cytochrome P450 enzyme. Several anticancer drugs are currently approved by the US Food and Drug Administration with a companion genetic test. “Our friends in oncology are showing us what possibly can be done to target therapy more effectively,” said Dr Bridges. Pharmacogenetic studies in RA are not new. In 1984, human leukocyte antigen (HLA-A3) positivity and HLA-DR4 negativity were suggested as predictors of response to gold therapy. “We are light years ahead of where we were in 1984, but not as far

“Our friends in oncology are showing us what possibly can be done to target therapy more effectively. We are light years ahead of where we were in 1984, but not as far ahead as we would like to be.” —S. Louis Bridges, Jr, MD, PhD ahead as we would like to be,” commented Dr Bridges. An ideal test to predict treatment response must be robust and predictable, with proved clinical value and relatively low cost and/or paid for by insurance companies, he said. It must also be accurate, reliable, precise, generalizable, noninvasive, easily interpretable, and have rapid turnaround time. “It is a high hurdle to hit, but that is what we should aim for,” Dr Bridges said. Thiopurine S-Methyltransferase In 1998, thiopurine S-methyltransferase (TPMT) activity was identified as a prototypical monogenic (autosomal dominant) pharmacogenetic trait for thiopurine drugs. Although 2 copies of the variant delays metabolism and can cause bone marrow toxicity, 2 copies of the wild-type TPMT alleles inactivate azathioprine. Because the white blood cell count is an alternate marker of bone marrow toxicity, TPMT genotyping has not penetrated the market as a test for potential azathioprine toxicity, he said. Polymorphism at PTPRC In 2010, 31 SNPs associated with the risk of RA were genotyped and tested for an association with treatment response in 9 different cohorts of patients with RA, with a finding that an SNP at the PTPRC (also referred

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to as CD45) gene locus predicted a European League Against Rheumatism (EULAR) good response (vs no response) to anti–tumor necrosis factor-alpha therapy (Arthritis Rheum. 2010;62:1849-1861). The G allele predicted a favorable response on the 28-joint Disease Activity Score (DAS28) as well. “If you have the G allele in the PTPRC, you are more likely to respond, except in one study [conducted in the Netherlands], in which the A allele was associated with a favorable response,” said Dr Bridges. “So the test might be problematic for people in the Netherlands, but if combined across all populations, it looks like the G allele is associated with a EULAR good response and also DAS28.” Methotrexate Polyglutamate Concentrations Concentrations of red blood cell (RBC) methotrexate (Rhuematrex, Trexall) polyglutamate have been found to be a measure of disease activity in RA. Recently, among a series of patients switched from oral to subcutaneous methotrexate, a decrease in DAS28 was found to be associated with increasing concentrations of RBC methotrexate Glu(5) and RBC methotrexate Glu(3-5) over 24 weeks. Large Data Sets Needed Larger data sets will be needed to identify the types of patients likely to respond to a treatment. Ideal data sets would be large enough to have adequate statistical power, be publicly available, standardize the collection of data with respect to response and therapy and toxicity, and contain data on concomitant collection of biologic samples, said Dr Bridges. Also, new platforms must be developed to interrogate very large numbers of polymorphisms in large numbers of patients. The Treatment and Efficacy and Toxicity in RA Database and Repository is a collaborative network of leading academic investigators to harmonize efforts to collect treatment response data and biologic samples in patients with RA who are starting therapy with methotrexate or biologic agents. A key aim is to create a database to allow a better understanding of the molecular basis of treatment and rapidly accelerate translational research in RA. ■

www.ValueBasedRheumatology.com

Clinical Pathways

CareFirst BlueCross BlueShield, Cardinal Health Specialty Solutions Introduce Nation’s First Clinical Pathways Program for RA New management approach for improving quality, reducing cost of RA care By Winston Wong, PharmD, and Roshan Girglani Dr Wong is Associate Vice President, CareFirst BlueCross BlueShield Pharmacy Management, and Mr Girglani is Vice President and General Manager of Rheumatology, Cardinal Health Specialty Solutions

fter successfully launching the nation’s first clinical pathways program for oncology in 2008, CareFirst BlueCross BlueShield (CareFirst) and Cardinal Health Specialty Solutions launched the nation’s first clinical pathways program for rheumatoid arthritis (RA) at the end of 2011. The goal of the new program is to foster collaboration between CareFirst and its in-network physicians to develop evidence-based clinical protocols, or pathways, to improve the way care is delivered to patients. Since launching the program in December 2011, more than 70 rheumatology practices and more than 100 rheumatologists have joined this initiative. Central to the program’s structure is a new treat-to-target approach to care, where participating physicians are encouraged to test different treatment options until a patient’s symptoms are in remission. The program leverages patient Clinical Disease

at a glance ➤ This new treat-to-target approach to RA care encourages physicians to test different treatment options until symptoms are in remission ➤ Because pathways can never take into account 100% of patient characteristics or circumstances, the program does not demand 100% compliance with the pathway ➤ Physicians have the opportunity to pilot a new electronic tool to help them measure patient CDAI scores by monitoring disease progression and therapy effectiveness ➤ As this program evolves, we plan to track broad-based patient outcome metrics to ensure that the program is directly impacting the quality of RA care

Winston Wong, PharmD

When CDAI scores indicate that patients have not favorably responded to a therapy after 3 months, the program provides guidance to help rheumatologists determine the next, most appropriate treatment option.

Activity Index (CDAI) scores to standardize the way physicians treat patients. When CDAI scores indicate that patients have not favorably responded to a therapy after 3 months, the program provides guidance to help rheumatologists determine the next, most appropriate treatment option. Participating physicians have the opportunity to pilot a new electronic tool that will help them measure patient CDAI scores by monitoring disease progression and the effectiveness of therapy. This tool, the first of its kind, leverages touch-screen technology to increase accessibility for patients with limited dexterity, and helps physicians determine when medication regimens need to be modified. We firmly believe that for pathways programs to be credible and

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successful, they must be brandagnostic, and local physicians must be involved in developing the clinical protocols they will be expected to follow. Toward that end, a steering committee comprised of rheumatologists throughout the CareFirst network worked together to develop brandagnostic clinical pathways. The steering committee is moderated by Norman B. Gaylis, MD, FACP, FACR, Managing Partner of Arthritis and Rheumatic Disease Specialties in Aventura, FL. It is also chaired by Herbert S.B. Baraf, MD, FACP, FACR, and Alan K. Matsumoto, MD, FACR, who are Managing Director and Senior Partner of Arthritis and Rheumatism Associates in Wheaton, MD, respectively. The steering committee now meets regularly, and at least quarterly, to update the pathways as new clinical evidence is available. Because we also recognize the importance of physician autonomy when it comes to patient care decisions, this program is designed to acknowledge that pathways are not a substitute for physician judgment and decision-making. Because pathways can never take into account 100% of patient characteristics or circumstances, we do not

already tracking toward their year 1 compliance goals. To make it as easy and time-efficient as possible for physicians, we are also providing proprietary technology, tools, educational programs, and training to help participating physicians implement and monitor use of the clinical pathways. These tools will also capture clinical results and track cost-savings of the program, without additional administrative work for physicians. We recognize the tremendous value of the cognitive care services that rheumatologists provide to patients, and are also working toward identifying new ways to compensate physicians for taking proved steps to improve the quality and cost-efficiency of RA care. As this program evolves, we also plan to track broad-based patient outcome metrics, because we believe this is an important step in ensuring that the program is directly impacting the quality of care. We also look forward to developing similar pathways programs for other chronic illnesses that are treated with the same biologics as those used to treat RA, including Crohn’s disease, psoriatic arthritis, and ankylosing spondylitis. We believe that innovative pro-

We recognize the tremendous value of the cognitive care services that rheumatologists provide to patients, and are also working toward identifying new ways to compensate physicians for taking proved steps to improve the quality and cost-efficiency of RA care.

expect or demand 100% compliance. Participating physicians are expected to comply with their pathways 70% of the time during the first year and 80% of the time in year 2, giving them the necessary flexibility to treat a patient who would respond better to a treatment regimen outside of the pathway. In just its first few months of operation, most participating physicians are

grams such as this are creating a new paradigm for enabling payers and physicians to work together to improve the quality and cost of care. Our ultimate goal is to work collaboratively to ensure patients continue to have access to quality, personalized care in the community practice setting, where care is proved to be most convenient and cost-effective. ■

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Rheumatology Update

Top 10 Practice-Changing Data in Rheumatology Released in 2011 By Sy Schlager, MD, PhD, Editor-in Chief, Value-Based Care in Rheumatology

he year 2011 was a banner year for the release of data with the potential for changing the clinical practice of rheumatology. Based on a review of the literature, a survey of topics presented at the 2011 American College of Rheumatology (ACR) meetings, and consultation with our editorial board and other leaders in rheumatology, here is our top 10 list of that data.

Treating Rheumatoid Arthritis to Target An international task force of expert rheumatologists conducted a systematic review of the rheumatoid arthritis (RA) literature and developed a set of 10 recommendations that change the paradigm of RA therapy. The treat-to-target (T2T) recommendations are designed to inform rheumatologists, patients, and other stakeholders about strategies to reach optimal outcomes in RA. The recommendations include redefining the primary target in RA to be clinical remission or at least low disease activity; defining clinical remission in measurable terms; urging frequent adjustments of drug therapy (every 3 months based on predefined, validated composite measures of disease activity, as well as structural changes and functional impairment); and appropriate physician–patient interactions to discuss T2T strategies and educate patients on their disease. A separate version of the recommendations that can be easily understood by patients has been published (Ann Rheum Dis. 2011;70:891-895). A New Definition of Remission in RA Although the T2T task force urged remission as a target in RA, the definition of what remission means has varied significantly between clinical studies. An ACR/EULAR (European League Against Rheumatism) committee has now issued uniform definitions of remission that can be used across clinical studies (Arthritis Rheum. 2011;63:573-586). Further studies are needed to determine how these new definitions will be useful in the realworld management of patients with RA. A New Agent for Lupus Belimumab (Benlysta), a fully human monoclonal antibody that inhibits B-lymphocyte stimulator, was shown to be effective in improving the

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clinical response of patients with active, autoantibody-positive systemic lupus erythematosus (SLE). Belimumab is administered as an infusion at 10 mg/kg every 2 weeks for 1 month and then every 4 weeks thereafter. This is the first new agent approved by the US Food and Drug Administration (FDA) for SLE since the 1950s (Lancet. 2011;377:721-731).

matic activity, results in an improved reduction in these toxicities compared with careful hematologic monitoring during therapy. Therefore, at this time, assessing TPMT does not appear to improve outcomes in patients with inflammatory diseases who are treated with AZA or 6-MP, and careful surveillance of hematologic parameters in these patients remains the standard of care (Ann Intern Med. 2011;154:814-823).

Belimumab was shown to be effective in improving the clinical response of patients with active, autoantibodypositive systemic lupus erythematosus.

Development of Antidrug Antibodies in RA Short-term data on the immunogenicity of anti-TNF monoclonal antibodies have demonstrated the association of development of antidrug antibodies and diminished treatment response. In the first study examining the long-term effects of antidrug antibodies, after 3-year therapy with the fully human anti-TNF monoclonal antibody adalimumab (Humira), the development of antiadalimumab antibodies, which occurred in 28% of the 272 patients studied, was associated with lower adalimumab serum concentrations and a lower likelihood of clinical remission or minimal disease activity (JAMA. 2011;305:1460-1468).

A New Option in Psoriatic Arthritis In a 6-month, randomized, placebocontrolled study, abatacept (Orencia) 10 mg/kg, given on days 1, 15, 29, and then every 28 days, has been shown to be an effective treatment option for psoriatic arthritis in patients who had previously taken oral disease-modifying antirheumatic drugs or tumor necrosis factor (TNF) antagonists. Abatacept significantly improved the ACR 20% criteria for improvement (ACR20) response rates, as well as magnetic resonance imaging (MRI), Health Assessment Questionnaire, Short Form-36, psoriasis target lesion, and Psoriasis Area and Severity Index scores. The FDA has not yet granted approval for this indication (Arthritis Rheum. 2011;63:939-948). Genotyping for Thiopurine S-Methyl Transferase The evidence in favor of testing for thiopurine S-methyl transferase (TPMT) enzymatic activity or for genotype before starting therapy with thiopurine-based drugs—such as azathiopurine (AZA, Imuran) or 6-mercaptopurine (6-MP)—for a variety of rheumatic diseases has been unclear. A systematic review of the sensitivity and specificity of genotyping for TPMT genotyping to reduce toxicities (leukopenia or myelotoxicity) associated with thiopurine drugs demonstrated that there is insufficient evidence to show that pretesting for TPMT activity, either by genetic testing or direct measurement of enzy-

A New Treatment for Refractory Gout Gout continues to cause significant morbidity, with increasing impact on healthcare dollars. Although several drugs are available for lowering uric acid levels, these agents are not always effective or well tolerated. In a new study, pegloticase (Krystexxa), a

Gout continues to cause significant morbidity, with increasing impact on healthcare dollars. In a new study, pegloticase significantly lowered uric acid levels and rapidly reduced the size of gouty tophi. recombinant uricase infused at 8 mg every 2 weeks, significantly lowered uric acid levels and rapidly reduced the size of gouty tophi. This new agent may be useful in patients who have failed other thera-

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pies for gout, although allergic reactions to the drug, loss of efficacy over time, and cost are significant concerns (JAMA. 2011;306:711-720; Bull NYU Hosp Jt Dis. 2011;69:257-263). A Standard of Care for Lupus Nephritis Lupus nephritis (LN) occurs in up to 60% of patients with SLE and significantly impacts their survival. For more than 30 years, the National Institutes of Health (NIH) regimen of high-dose cyclophosphamide (Cytoxan) plus steroids was the standard of care for LN but was associated with serious side effects, including severe infection and premature ovarian failure. Two new therapeutic approaches have been proposed—mycophenolate mofetil (MMF, Cellcept), or shortterm, low-dose cyclophosphamide, followed by long-term immunosuppression with AZA. Both of these newer regimens have been shown to be as effective as the older NIH regimen; however, a recent study showed that MMF was superior to AZA as long-term maintenance therapy for maintaining a renal response to treatment and preventing relapse for up to 36 months. Significantly fewer renal flares were observed with MMF, and the rate of withdrawal because of adverse events was significantly lower with MMF than with AZA. This and other studies have demonstrated that at least 2 drugs are appropriate for long-term use in patients with LN, with reasonable efficacy and acceptable toxicity profiles. It is also possible that patients who fail therapy with one immunosuppressant could be successfully rescued by switching to the other agent, although this was not specifically tested in any of the trials (N Engl J Med. 2011;365:1886-1895). New Targets for RA We are well into the age of biologic therapy in RA, in which monoclonal antibodies or other large proteinbased molecules are used to block specific target cytokines and cellsurface molecules, but rheumatology is now entering a new phase of development of new classes of small, organic molecules for RA. Of these, a number of oral agents, with unique molecular targets (inhibitors of signaling pathways involved in the specific Continued on page 14

www.ValueBasedRheumatology.com

VBCR Perspective

On the Cusp of Major Change in Rheumatoid Arthritis Treatment By Atheer A. Kaddis, PharmD Vice President, Managed Markets, Diplomat Specialty Pharmacy

he shift to oral treatment options for chronic, complex specialty disease states continues to expand. With more than 600 drugs currently in the pharmaceutical pipeline—in phase 2 or phase 3 clinical trials—nearly half of these new medications are being developed for oral administration. During the past 14 months we have experienced the impact of new oral therapies for the treatment of specialty disease states, such as multiple sclerosis, hepatitis C, and metastatic prostate cancer. These are all disease states for which only injectable treatment options were available before the most recent oral therapies received approval from the US Food and Drug Administration. The new oral therapies are offering not only additional treatment options but, in fact, the availability of new oral protease inhibitors for hepatitis C has produced a new standard of care for the treatment of genotype 1 hepatitis C viral infection.1 It is expected that the treatment of rheumatoid arthritis (RA) will also go through a similar significant transformation within the next 12 months. Today, the treatment of RA is dominated by injectable medications,

It is important to understand the value equation for these new drugs and develop strategies for a major change in the treatment of RA. Value-Based Care in Rheumatology is a valuable resource that will help guide these strategies. namely, etanercept (Enbrel), adalimumab (Humira), and infliximab (Remicade). Etanercept and adalimumab are covered primarily under

the pharmacy benefit by health plans. Infliximab is covered primarily under the medical benefit by health plans. These 3 medications may enter the list of the top 10 best-selling drugs in the United States by the end of 2012.2 We are, nevertheless, on the cusp of significant change in the way RA is treated, and the oral therapies are leading the way toward this change. During the next 12 months, oral medications for the treatment of RA are expected to enter the US market. These medications work by targeting different pathways, for example, by blocking the Janus kinase (ie, JAK inhibitors) and phosphodiesterase-4 (ie, PDE-4 inhibitors) pathways, among others, to assist in treating pain and joint malformations associated with RA. These medications may also play a role in the treatment of other immune-mediated diseases, such as psoriasis and Crohn’s disease. Although these new oral medications are not expected to replace the currently available injectable treatment options for RA, they are expected to provide an alternative to current therapy and may even have a role in combination therapy for RA. One thing is sure: based on recent experience, the new oral medications

will be priced similar to or higher than injectable options, and combination therapy will significantly increase the cost of managing the patient with RA. It remains to be seen whether the additional drug costs will be offset by better overall patient outcomes. Because oral therapies are covered under the pharmacy benefit by payers, we can also expect that utilization management strategies, formulary strategies, and out-of-pocket costs for patients will play a role in the uptake of the new oral therapies for RA. It is important to track the development of the new oral therapies for RA, determine their place in therapy, understand the value equation for these new drugs, and develop strategies now for a major change in the treatment of RA. Value-Based Care in Rheumatology is a valuable resource that will help guide these strategies. ■ References 1. Ghany MG, Nelson DR, Strader DB, et al. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54:1433-1444. Epub 2011 Sep 26. 2. Bartholow M. Top 200 prescription drugs of 2009. Pharmacy Times. May 11, 2010. www.pharmacytimes. com/issue/pharmacy/2010/May2010/RxFocusTop Drugs-0510. Accessed October 8, 2010.

Rheumatology Update

Top Ten Practice-Changing Data in Rheumatology... types of inflammation associated with RA), have caused the most excitement. Fostamatinib, an inhibitor of spleen tyrosine kinase, was tested in 219 patients with active RA in whom treatment with biologic agents had failed. In a 3-month randomized, double-blind, placebo-controlled study of oral fostamatinib 100 mg twice daily, ACR20/50/70 response rates with fostamatinib were no better than with placebo, but the drug was associated with significantly increased rates of normalization of C-reactive protein and improvements in synovitis scores on MRI (Arthritis Rheum. 2011;63:337-345). Similarly, atacicept, a recombinant fusion protein of the binding sites for B-lymphocyte stimulator and a pro-

liferation-inducing ligand and the constant region of immunoglobulin, which blocks the maturation, proliferation, and survival of B-cells, was tested in 311 patients with RA who had failed methotrexate therapy. The efficacy of atacicept was modest at best and inferior to an anti-TNF comparator (adalimumab). However, this is a new agent with unique properties—unlike the anti-CD20 monoclonal antibodies used in RA, such as rituximab (Rituxan)—in that it affects the entire lineage of B-cells, including plasma cells, and biologic activity consistent with its proposed mechanism of action was observed in patients using it. Because atacicept has an acceptable safety profile, further study of its effi-

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cacy in RA and other rheumatic diseases may reveal its potential as a new therapeutic agent (Arthritis Rheum. 2011;63:1782-1792). The third class of promising compounds in RA is the Janus kinase inhibitors, which is reviewed in a separate article in this publication (see page 24). Anti-TNF Agents and Cancer Outcomes There have been many investigations of cancer risk in patients with RA treated with biologic agents. Overall, it appears that there is no significantly increased risk for most cancers in patients with RA treated with biologics compared with matched patients with RA not treated with biologics.

Continued from page 13

However, a recent large Swedish observational study of 300 patients who had both RA and cancer and were taking anti-TNF agents showed that during routine care, cancers that occur after anti-TNF therapy are not characterized by any markedly altered stage at presentation or by altered postcancer survival rates. Therefore, antiTNF agents do not appear to worsen cancer outcomes in patients with RA. A significant limitation of this study is that anti-TNF therapy was stopped in most patients once a cancer developed; therefore, this study does not address the question of whether it is safe to continue long-term anti-TNF therapy in a patient with RA who develops cancer (Arthritis Rheum. 2011;63:1812-1822). ■

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Help manage

MANY THREATS: Rheumatoid Arthritis. Psoriatic Arthritis. Ankylosing Spondylitis.

Indications1 Moderate to severe rheumatoid arthritis: HUMIRA is indicated, alone or in combination with methotrexate or other non-biologic DMARDs, for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. Psoriatic arthritis: HUMIRA is indicated, alone or in combination with non-biologic DMARDs, for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. Ankylosing spondylitis: HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis.

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

ONE

40 mg every other week. Some patients with RA not receiving methotrexate may benefit from increasing the frequency to 40 mg every week.

Safety Considerations1 Serious Infections: Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. These infections include active tuberculosis (TB), reactivation of latent TB, invasive fungal infections, and bacterial, viral, and other infections due to opportunistic pathogens. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. Malignancies: Lymphoma, including a rare type of T-cell lymphoma, and other malignancies, some fatal, have been reported in patients treated with TNF blockers, including HUMIRA. Other Serious Adverse Reactions: Patients treated with HUMIRA also may be at risk for other serious adverse reactions, including anaphylaxis, hepatitis B virus reactivation, demyelinating disease, cytopenias, pancytopenia, heart failure, and a lupus-like syndrome. Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

Please see Important Safety Information, including BOXED WARNING on Serious Infections and Malignancy, on the following page.

Important Safety Information1 SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: s !CTIVE TUBERCULOSIS 4" INCLUDING REACTIVATION OF LATENT 4" 0ATIENTS WITH 4" HAVE FREQUENTLY PRESENTED WITH DISSEMINATED OR EXTRAPULMONARY DISEASE 0ATIENTS SHOULD BE TESTED FOR LATENT 4" BEFORE (5-)2! USE AND DURING THERAPY 4REATMENT FOR LATENT 4" SHOULD BE INITIATED PRIOR TO (5-)2! USE s )NVASIVE FUNGAL INFECTIONS INCLUDING HISTOPLASMOSIS COCCIDIOIDOMYCOSIS CANDIDIASIS ASPERGILLOSIS BLASTOMYCOSIS AND PNEUMOCYSTOSIS 0ATIENTS WITH HISTOPLASMOSIS OR OTHER INVASIVE FUNGAL INFECTIONS MAY PRESENT WITH DISSEMINATED RATHER THAN LOCALIZED DISEASE !NTIGEN AND ANTIBODY TESTING FOR HISTOPLASMOSIS MAY BE NEGATIVE IN SOME patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. s "ACTERIAL VIRAL AND OTHER INFECTIONS DUE TO OPPORTUNISTIC PATHOGENS INCLUDING ,EGIONELLA AND ,ISTERIA The risks and benefits of treatment with HUMIRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be CLOSELY MONITORED FOR THE DEVELOPMENT OF SIGNS AND SYMPTOMS OF INFECTION DURING AND AFTER TREATMENT WITH (5-)2! INCLUDING THE POSSIBLE DEVELOPMENT OF 4" IN PATIENTS WHO TESTED NEGATIVE FOR LATENT 4" INFECTION PRIOR TO INITIATING THERAPY s $O NOT START (5-)2! IN PATIENTS WITH AN ACTIVE INFECTION INCLUDING LOCALIZED INFECTIONS s 0ATIENTS OLDER THAN YEARS PATIENTS WITH CO MORBID CONDITIONS AND OR PATIENTS TAKING CONCOMITANT IMMUNOSUPPRESSANTS MAY BE AT GREATER RISK OF INFECTION s %XERCISE CAUTION IN PATIENTS WITH CHRONIC OR RECURRENT INFECTION OR WITH UNDERLYING CONDITIONS WHICH MAY PREDISPOSE THEM TO INFECTION PATIENTS WHO HAVE BEEN EXPOSED TO 4" PATIENTS WITH A HISTORY OF OPPORTUNISTIC INFECTION OR PATIENTS WHO HAVE RESIDED OR TRAVELED IN REGIONS WHERE 4" OR MYCOSES ARE ENDEMIC s 0ATIENTS WHO DEVELOP A NEW INFECTION SHOULD UNDERGO A PROMPT AND COMPLETE DIAGNOSTIC WORKUP AND APPROPRIATE ANTIMICROBIAL THERAPY SHOULD BE INITIATED s $RUG INTERACTIONS WITH BIOLOGIC PRODUCTS #ONCURRENT USE OF ANAKINRA OR ABATACEPT WITH (5-)2! IS NOT RECOMMENDED AS THE COMBINATION OF ANAKINRA OR ABATACEPT WITH 4.& BLOCKERS HAS BEEN ASSOCIATED WITH AN INCREASED RISK OF SERIOUS INFECTIONS 4HIS RISK HAS ALSO BEEN OBSERVED WITH RHEUMATOID ARTHRITIS PATIENTS TREATED WITH RITUXIMAB WHO RECEIVED SUBSEQUENT TREATMENT WITH A 4.& BLOCKER -!,)'.!.#9 ,YMPHOMA AND OTHER MALIGNANCIES SOME FATAL HAVE BEEN REPORTED IN CHILDREN AND ADOLESCENT PATIENTS TREATED WITH 4.& BLOCKERS OF WHICH (5-)2! IS A MEMBER 0OSTMARKETING CASES OF HEPATOSPLENIC 4 CELL LYMPHOMA (34#, A RARE TYPE OF 4 CELL LYMPHOMA HAVE BEEN REPORTED IN PATIENTS TREATED WITH 4.& BLOCKERS INCLUDING HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or MERCAPTOPURINE CONCOMITANTLY WITH A 4.& BLOCKER AT OR PRIOR TO DIAGNOSIS )T IS UNCERTAIN WHETHER THE OCCURRENCE OF (34#, IS RELATED TO USE OF A 4.& BLOCKER OR A 4.& blocker in combination with these other immunosuppressants. s 4HE RISKS AND BENElTS OF (5-)2! TREATMENT SHOULD BE CONSIDERED PRIOR TO INITIATING OR CONTINUING THERAPY IN A PATIENT WITH KNOWN MALIGNANCY s -ORE CASES OF MALIGNANCIES WERE OBSERVED AMONG (5-)2! TREATED PATIENTS COMPARED TO CONTROL PATIENTS IN CLINICAL TRIALS s .ON MELANOMA SKIN CANCER .-3# HAS BEEN REPORTED DURING CLINICAL TRIALS FOR (5-)2! TREATED PATIENTS !LL PATIENTS PARTICULARLY THOSE WITH HISTORY OF PROLONGED IMMUNOSUPPRESSANT OR 056! THERAPY SHOULD BE EXAMINED FOR THE PRESENCE OF .-3# PRIOR TO AND DURING TREATMENT WITH (5-)2! s )N (5-)2! CLINICAL TRIALS THERE WAS AN APPROXIMATE FOLD HIGHER RATE OF LYMPHOMA THAN EXPECTED IN THE GENERAL 5 3 POPULATION 0ATIENTS WITH CHRONIC INmAMMATORY DISEASES PARTICULARLY WITH HIGHLY ACTIVE DISEASE AND OR CHRONIC EXPOSURE TO IMMUNOSUPPRESSANT THERAPIES MAY BE AT HIGHER RISK OF LYMPHOMA THAN THE GENERAL POPULATION EVEN IN THE ABSENCE OF 4.& BLOCKERS s 0OSTMARKETING CASES OF ACUTE AND CHRONIC LEUKEMIA WERE REPORTED WITH 4.& BLOCKER USE s !PPROXIMATELY HALF OF THE POSTMARKETING CASES OF MALIGNANCIES IN CHILDREN ADOLESCENTS AND YOUNG ADULTS RECEIVING 4.& BLOCKERS WERE LYMPHOMAS OTHER CASES INCLUDED RARE MALIGNANCIES ASSOCIATED WITH IMMUNOSUPPRESSION AND MALIGNANCIES NOT USUALLY OBSERVED IN CHILDREN AND ADOLESCENTS (90%23%.3)4)6)49 s !NAPHYLAXIS AND ANGIONEUROTIC EDEMA HAVE BEEN REPORTED RARELY FOLLOWING (5-)2! ADMINISTRATION s )F A SERIOUS ALLERGIC REACTION OCCURS STOP (5-)2! AND INSTITUTE APPROPRIATE THERAPY (%0!4)4)3 " 6)253 2%!#4)6!4)/. s 5SE OF 4.& BLOCKERS INCLUDING (5-)2! MAY INCREASE THE RISK OF REACTIVATION OF HEPATITIS " VIRUS ("6 IN PATIENTS WHO ARE CHRONIC CARRIERS 3OME CASES HAVE BEEN FATAL s 0ATIENTS AT RISK FOR ("6 INFECTION SHOULD BE EVALUATED FOR PRIOR EVIDENCE OF ("6 INFECTION BEFORE INITIATING 4.& BLOCKER THERAPY s %XERCISE CAUTION IN PATIENTS WHO ARE CARRIERS OF ("6 AND MONITOR THEM DURING AND AFTER TREATMENT WITH (5-)2! s $ISCONTINUE (5-)2! AND BEGIN ANTIVIRAL THERAPY IN PATIENTS WHO DEVELOP ("6 REACTIVATION s %XERCISE CAUTION WHEN CONSIDERING RESUMPTION OF (5-)2! THERAPY AFTER APPROPRIATE TREATMENT FOR ("6 .%52/,/')# 2%!#4)/.3 s 4.& BLOCKERS INCLUDING (5-)2! HAVE BEEN ASSOCIATED IN RARE CASES WITH NEW ONSET OR EXACERBATION OF CENTRAL NERVOUS SYSTEM AND PERIPHERAL DEMYELINATING DISEASES INCLUDING MULTIPLE SCLEROSIS OPTIC NEURITIS AND 'UILLAIN "ARRÏ SYNDROME s %XERCISE CAUTION WHEN CONSIDERING (5-)2! FOR PATIENTS WITH THESE DISORDERS (%-!4/,/')# 2%!#4)/.3 s 2ARE REPORTS OF PANCYTOPENIA INCLUDING APLASTIC ANEMIA HAVE BEEN REPORTED WITH 4.& BLOCKERS -EDICALLY SIGNIlCANT CYTOPENIA E G THROMBOCYTOPENIA LEUKOPENIA HAS BEEN INFREQUENTLY REPORTED WITH (5-)2! s #ONSIDER STOPPING (5-)2! IN PATIENTS WITH SIGNIlCANT HEMATOLOGIC ABNORMALITIES #/.'%34)6% (%!24 &!),52% s 7ORSENING OR NEW ONSET CONGESTIVE HEART FAILURE #(& MAY OCCUR s %XERCISE CAUTION IN PATIENTS WITH #(& AND MONITOR THEM CAREFULLY !54/)--5.)49 s 4REATMENT WITH (5-)2! MAY RESULT IN THE FORMATION OF AUTOANTIBODIES AND RARELY IN DEVELOPMENT OF A LUPUS LIKE SYNDROME s $ISCONTINUE TREATMENT IF SYMPTOMS OF A LUPUS LIKE SYNDROME DEVELOP IMMUNIZATIONS s 0ATIENTS ON (5-)2! SHOULD NOT RECEIVE LIVE VACCINES s )T IS RECOMMENDED THAT JUVENILE IDIOPATHIC ARTHRITIS PATIENTS IF POSSIBLE BE BROUGHT UP TO DATE WITH ALL IMMUNIZATIONS IN AGREEMENT WITH CURRENT IMMUNIZATION GUIDELINES PRIOR TO INITIATING (5-)2! THERAPY !$6%23% 2%!#4)/.3 s 4HE MOST COMMON ADVERSE REACTIONS IN (5-)2! CLINICAL TRIALS INCIDENCE WERE INFECTIONS E G UPPER RESPIRATORY SINUSITIS INJECTION SITE REACTIONS HEADACHE AND RASH Reference: 1. HUMIRA Injection [package insert]. North Chicago, IL: Abbott Laboratories.

0LEASE SEE "RIEF 3UMMARY OF FULL 0RESCRIBING )NFORMATION on the following pages of this advertisement. ©2011 Abbott Laboratories Abbott Park, IL 60064 64C-759105 ©2012 64C-xxxxxx March January 2011 2012 Printed Printed in U.S.A. in U.S.A.

HUMIRA® (adalimumab) WARNINGS: SERIOUS INFECTIONS AND MALIGNANCY SERIOUS INFECTIONS Patients treated with HUMIRA are at increased risk for developing serious infections that may lead to hospitalization or death [see Warnings and Precautions]. Most patients who developed these infections were taking concomitant immunosuppressants such as methotrexate or corticosteroids. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. Reported infections include: • Active tuberculosis (TB), including reactivation of latent TB. Patients with TB have frequently presented with disseminated or extrapulmonary disease. Patients should be tested for latent TB before HUMIRA use and during therapy. Treatment for latent TB should be initiated prior to HUMIRA use. • Invasive fungal infections, including histoplasmosis, coccidioidomycosis, candidiasis, aspergillosis, blastomycosis, and pneumocystosis. Patients with histoplasmosis or other invasive fungal infections may present with disseminated, rather than localized, disease. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. Empiric anti-fungal therapy should be considered in patients at risk for invasive fungal infections who develop severe systemic illness. • Bacterial, viral and other infections due to opportunistic pathogens, including Legionella and Listeria. The risks and benefits of treatment with HUMIRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection. Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the possible development of TB in patients who tested negative for latent TB infection prior to initiating therapy. [See Warnings and Precautions and Adverse Reactions] MALIGNANCY Lymphoma and other malignancies, some fatal, have been reported in children and adolescent patients treated with TNF blockers, of which HUMIRA is a member. [See Warnings and Precautions] Post-marketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all these patients had received treatment with azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. INDICATIONS AND USAGE Rheumatoid Arthritis HUMIRA is indicated for reducing signs and symptoms, inducing major clinical response, inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active rheumatoid arthritis. HUMIRA can be used alone or in combination with methotrexate or other non-biologic disease-modifying anti-rheumatic drugs (DMARDs). Juvenile Idiopathic Arthritis HUMIRA is indicated for reducing signs and symptoms of moderately to severely active polyarticular juvenile idiopathic arthritis in pediatric patients 4 years of age and older. HUMIRA can be used alone or in combination with methotrexate. Psoriatic Arthritis HUMIRA is indicated for reducing signs and symptoms, inhibiting the progression of structural damage, and improving physical function in adult patients with active psoriatic arthritis. HUMIRA can be used alone or in combination with non-biologic DMARDs. Ankylosing Spondylitis HUMIRA is indicated for reducing signs and symptoms in adult patients with active ankylosing spondylitis. Crohn’s Disease HUMIRA is indicated for reducing signs and symptoms and inducing and maintaining clinical remission in adult patients with moderately to severely active Crohn’s disease who have had an inadequate response to conventional therapy. HUMIRA is indicated for reducing signs and symptoms and inducing clinical remission in these patients if they have also lost response to or are intolerant to infliximab. Plaque Psoriasis HUMIRA is indicated for the treatment of adult patients with moderate to severe chronic plaque psoriasis who are candidates for systemic therapy or phototherapy, and when other systemic therapies are medically less appropriate. HUMIRA should only be administered to patients who will be closely monitored and have regular follow-up visits with a physician [see Boxed Warnings and Warnings and Precautions]. CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS (see also Boxed WARNINGS) Serious Infections Patients treated with HUMIRA are at increased risk for developing serious infections involving various organ systems and sites that may lead to hospitalization or death. Opportunistic infections due to bacterial, mycobacterial, invasive fungal, viral, parasitic, or other opportunistic pathogens including aspergillosis, blastomycosis, candidiasis, coccidioidomycosis, histoplasmosis, legionellosis, listeriosis, pneumocystosis and tuberculosis have been reported with TNF blockers. Patients have frequently presented with disseminated rather than localized disease. The concomitant use of a TNF blocker and abatacept or anakinra was associated with a higher risk of serious infections in patients with rheumatoid arthritis (RA); therefore, the concomitant use of HUMIRA and these biologic products is not recommended in the treatment of patients with RA [see Warnings and Precautions and Drug Interactions]. Treatment with HUMIRA should not be initiated in patients with an active infection, including localized infections. Patients greater than 65 years of age, patients with co-morbid conditions and/or patients taking concomitant immunosuppressants (such as corticosteroids or methotrexate), may be at greater risk of infection. The risks and benefits of treatment should be considered prior to initiating therapy in patients: • with chronic or recurrent infection; • who have been exposed to tuberculosis; • with a history of an opportunistic infection; • who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, such as histoplasmosis, coccidioidomycosis, or blastomycosis; or • with underlying conditions that may predispose them to infection. Tuberculosis Cases of reactivation of tuberculosis or new tuberculosis infections have been observed in patients receiving HUMIRA, including patients who have previously received treatment for latent or active tuberculosis. Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating HUMIRA and periodically during therapy. Treatment of latent tuberculosis infection prior to therapy with TNF blocking agents has been shown to reduce the risk of tuberculosis reactivation during therapy. Anti-tuberculosis therapy should also be considered prior to initiation of HUMIRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Tuberculosis should be strongly considered in patients who develop a new infection during HUMIRA treatment, especially in patients who have previously or recently traveled to countries with a high prevalence of tuberculosis, or who have had close contact with a person with active tuberculosis. Monitoring Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with HUMIRA, including the development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy. Tests for latent tuberculosis infection may also be falsely negative while on therapy with HUMIRA. HUMIRA should be discontinued if a patient develops a serious infection or sepsis. A patient who develops a new infection during treatment with HUMIRA should be closely monitored, undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, and appropriate antimicrobial therapy should be initiated. Invasive Fungal Infections For patients who reside or travel in regions where mycoses are endemic, invasive fungal infection should be suspected if they develop a serious systemic illness. Appropriate empiric antifungal therapy should be considered while a diagnostic workup is being performed. Antigen and antibody testing for histoplasmosis may be negative in some patients with active infection. When feasible, the decision to administer empiric antifungal therapy in these patients should be made in consultation with a physician with expertise in the diagnosis and treatment of invasive fungal infections and should take into account both the risk for severe fungal infection and the risks of antifungal therapy. Malignancies The risks and benefits of TNF-blocker treatment including HUMIRA should be considered prior to initiating therapy in patients with a known malignancy other than a successfully treated non-melanoma skin cancer (NMSC) or when considering continuing a TNF blocker in patients who develop a malignancy. Malignancies in Adults In the controlled portions of clinical trials of some TNF-blockers, including HUMIRA, more cases of malignancies have been observed among TNF-blocker-treated adult patients compared to control-treated adult patients. During the controlled portions of 32 global HUMIRA clinical trials in adult patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), ankylosing spondylitis (AS), Crohn’s disease (CD), and plaque psoriasis (Ps), malignancies, other than non-melanoma (basal cell and squamous cell) skin cancer, were observed at a rate (95% confidence interval) of 0.6 (0.38, 0.93) per 100 patient-years among 6694 HUMIRA-treated patients

PROFESSIONAL BRIEF SUMMARY CONSULT PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION versus a rate of 0.5 (0.28, 1.05) per 100 patient-years among 3749 control-treated patients (median duration of treatment of 4 months for HUMIRA-treated patients and 4 months for control-treated patients). In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps, the most frequently observed malignancies, other than lymphoma and NMSC, were breast, colon, prostate, lung, and melanoma. The malignancies in HUMIRA-treated patients in the controlled and uncontrolled portions of the studies were similar in type and number to what would be expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). In controlled trials of other TNF blockers in adult patients at higher risk for malignancies (i.e., patients with COPD with a significant smoking history and cyclophosphamide-treated patients with Wegener’s granulomatosis), a greater portion of malignancies occurred in the TNF blocker group compared to the control group. Non-Melanoma Skin Cancer During the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, the rate (95% confidence interval) of NMSC was 0.7 (0.50, 1.11) per 100 patient-years among HUMIRA-treated patients and 0.2 (0.06, 0.56) per 100 patient-years among control-treated patients. All patients, and in particular patients with a medical history of prior prolonged immunosuppressant therapy or psoriasis patients with a history of PUVA treatment should be examined for the presence of NMSC prior to and during treatment with HUMIRA. Lymphoma and Leukemia In the controlled portions of clinical trials of all the TNF-blockers in adults, more cases of lymphoma have been observed among TNF blocker-treated patients compared to control-treated patients. In the controlled portions of 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD, and Ps, 3 lymphomas occurred among 6694 HUMIRA-treated patients versus 1 among 3749 control-treated patients. In 45 global controlled and uncontrolled clinical trials of HUMIRA in adult patients with RA, PsA, AS, CD and Ps with a median duration of approximately 0.6 years, including 22,026 patients and over 32,000 patient-years of HUMIRA, the observed rate of lymphomas was approximately 0.11 per 100 patient-years. This is approximately 3-fold higher than expected in the general U.S. population according to the SEER database (adjusted for age, gender, and race). Rates of lymphoma in clinical trials of HUMIRA cannot be compared to rates of lymphoma in clinical trials of other TNF blockers and may not predict the rates observed in a broader patient population. Patients with RA and other chronic inflammatory diseases, particularly those with highly active disease and/or chronic exposure to immunosuppressant therapies, may be at a higher risk (up to several fold) than the general population for the development of lymphoma, even in the absence of TNF blockers. Post-marketing cases of acute and chronic leukemia have been reported in association with TNF-blocker use in RA and other indications. Even in the absence of TNF-blocker therapy, patients with RA may be at a higher risk (approximately 2-fold) than the general population for the development of leukemia. Malignancies in Pediatric Patients and Young Adults Malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers (initiation of therapy Ū 18 years of age), of which HUMIRA is a member. Approximately half the cases were lymphomas, including Hodgkin’s and non-Hodgkin’s lymphoma. The other cases represented a variety of different malignancies and included rare malignancies usually associated with immunosuppression and malignancies that are not usually observed in children and adolescents. The malignancies occurred after a median of 30 months of therapy (range 1 to 84 months). Most of the patients were receiving concomitant immunosuppressants. These cases were reported post-marketing and are derived from a variety of sources including registries and spontaneous postmarketing reports. Postmarketing cases of hepatosplenic T-cell lymphoma (HSTCL), a rare type of T-cell lymphoma, have been reported in patients treated with TNF blockers including HUMIRA. These cases have had a very aggressive disease course and have been fatal. The majority of reported TNF blocker cases has occurred in patients with Crohn’s disease or ulcerative colitis and the majority were in adolescent and young adult males. Almost all of these patients had received treatment with the immunosuppressants azathioprine or 6-mercaptopurine concomitantly with a TNF blocker at or prior to diagnosis. It is uncertain whether the occurrence of HSTCL is related to use of a TNF blocker or a TNF blocker in combination with these other immunosuppressants. Hypersensitivity Reactions In postmarketing experience, anaphylaxis and angioneurotic edema have been reported rarely following HUMIRA administration. If an anaphylactic or other serious allergic reaction occurs, administration of HUMIRA should be discontinued immediately and appropriate therapy instituted. In clinical trials of HUMIRA in adults, allergic reactions overall (e.g., allergic rash, anaphylactoid reaction, fixed drug reaction, non-specified drug reaction, urticaria) have been observed in approximately 1% of patients. Hepatitis B Virus Reactivation Use of TNF blockers, including HUMIRA, may increase the risk of reactivation of hepatitis B virus (HBV) in patients who are chronic carriers of this virus. In some instances, HBV reactivation occurring in conjunction with TNF blocker therapy has been fatal. The majority of these reports have occurred in patients concomitantly receiving other medications that suppress the immune system, which may also contribute to HBV reactivation. Patients at risk for HBV infection should be evaluated for prior evidence of HBV infection before initiating TNF blocker therapy. Prescribers should exercise caution in prescribing TNF blockers for patients identified as carriers of HBV. Adequate data are not available on the safety or efficacy of treating patients who are carriers of HBV with anti-viral therapy in conjunction with TNF blocker therapy to prevent HBV reactivation. In patients who develop HBV reactivation, HUMIRA should be stopped and effective anti-viral therapy with appropriate supportive treatment should be initiated. The safety of resuming TNF blocker therapy after HBV reactivation is controlled is not known. Neurologic Reactions Use of TNF blocking agents, including HUMIRA, has been associated with rare cases of new onset or exacerbation of clinical symptoms and/or radiographic evidence of central nervous system demyelinating disease, including multiple sclerosis (MS) and optic neuritis, and peripheral demyelinating disease, including Guillain-Barré syndrome. Prescribers should exercise caution in considering the use of HUMIRA in patients with preexisting or recent-onset central or peripheral nervous system demyelinating disorders. Hematological Reactions Rare reports of pancytopenia including aplastic anemia have been reported with TNF blocking agents. Adverse reactions of the hematologic system, including medically significant cytopenia (e.g., thrombocytopenia, leukopenia) have been infrequently reported with HUMIRA. The causal relationship of these reports to HUMIRA remains unclear. All patients should be advised to seek immediate medical attention if they develop signs and symptoms suggestive of blood dyscrasias or infection (e.g., persistent fever, bruising, bleeding, pallor) while on HUMIRA. Discontinuation of HUMIRA therapy should be considered in patients with confirmed significant hematologic abnormalities. Use with Anakinra Concurrent use of anakinra (an interleukin-1 antagonist) and another TNF-blocker, was associated with a greater proportion of serious infections and neutropenia and no added benefit compared with the TNF-blocker alone in patients with RA. Therefore, the combination of HUMIRA and anakinra is not recommended [see Drug Interactions]. Heart Failure Cases of worsening congestive heart failure (CHF) and new onset CHF have been reported with TNF blockers. Cases of worsening CHF have also been observed with HUMIRA. Physicians should exercise caution when using HUMIRA in patients who have heart failure and monitor them carefully. Autoimmunity Treatment with HUMIRA may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. If a patient develops symptoms suggestive of a lupus-like syndrome following treatment with HUMIRA, treatment should be discontinued [see Adverse Reactions]. Immunizations In a placebo-controlled clinical trial of patients with rheumatoid arthritis, no difference was detected in anti-pneumococcal antibody response between HUMIRA and placebo treatment groups when the pneumococcal polysaccharide vaccine and influenza vaccine were administered concurrently with HUMIRA. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. No data are available on the secondary transmission of infection by live vaccines in patients receiving HUMIRA. It is recommended that juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating HUMIRA therapy. Patients on HUMIRA may receive concurrent vaccinations, except for live vaccines. Use with Abatacept In controlled trials, the concurrent administration of TNF-blockers and abatacept was associated with a greater proportion of serious infections than the use of a TNF-blocker alone; the combination therapy, compared to the use of a TNF-blocker alone, has not demonstrated improved clinical benefit in the treatment of RA. Therefore, the combination of abatacept with TNF-blockers including HUMIRA is not recommended [see Drug Interactions]. ADVERSE REACTIONS Clinical Studies Experience The most serious adverse reactions were: • Serious Infections [see Warnings and Precautions] • Malignancies [see Warnings and Precautions] The most common adverse reaction with HUMIRA was injection site reactions. In placebo-controlled trials, 20% of patients treated with HUMIRA developed injection site reactions (erythema and/or itching, hemorrhage, pain or swelling), compared to 14% of patients receiving placebo. Most injection site reactions were described as mild and generally did not necessitate drug discontinuation. The proportion of patients who discontinued treatment due to adverse reactions during the double-blind, placebo-controlled portion of Studies RA-I, RA-II, RA-III and RA-IV was 7% for patients taking HUMIRA and 4% for placebo-treated patients. The most common adverse reactions leading to discontinuation of HUMIRA were clinical flare reaction (0.7%), rash (0.3%) and pneumonia (0.3%). Infections In the controlled portions of the 32 global HUMIRA clinical trials in adult patients with RA, PsA, AS, CD and Ps, the rate of serious infections was 4.7 per 100 patient-years in 6694 HUMIRA-treated patients versus a rate of 2.7 per 100 patient-years in 3749 control-treated patients. Serious infections observed included pneumonia, septic arthritis, prosthetic and post-surgical infections, erysipelas, cellulitis, diverticulitis, and pyelonephritis [see Warnings and Precautions]. Tuberculosis and Opportunistic Infections In 45 global controlled and uncontrolled clinical trials in RA, PsA, AS, CD and Ps that included 22,026 HUMIRA-treated patients, the rate of reported active tuberculosis was 0.22 per 100 patient-years and the rate of positive PPD conversion was 0.07 per 100 patient-years. In a subgroup of 8940 U.S. and Canadian HUMIRAtreated patients, the rate of reported active TB was 0.07 per 100 patient-years and the rate of positive PPD

conversion was 0.06 per 100 patient-years. These trials included reports of miliary, lymphatic, peritoneal, and pulmonary TB. Most of the TB cases occurred within the first eight months after initiation of therapy and may reflect recrudescence of latent disease. In these global clinical trials, cases of serious opportunistic infections have been reported at an overall rate of 0.07 per 100 patient-years. Some cases of serious opportunistic infections and TB have been fatal[see Warnings and Precautions]. Autoantibodies In the rheumatoid arthritis controlled trials, 12% of patients treated with HUMIRA and 7% of placebo-treated patients that had negative baseline ANA titers developed positive titers at week 24. Two patients out of 3046 treated with HUMIRA developed clinical signs suggestive of new-onset lupus-like syndrome. The patients improved following discontinuation of therapy. No patients developed lupus nephritis or central nervous system symptoms. The impact of long-term treatment with HUMIRA on the development of autoimmune diseases is unknown. Liver Enzyme Elevations There have been reports of severe hepatic reactions including acute liver failure in patients receiving TNF-blockers. In controlled Phase 3 trials of HUMIRA (40 mg SC every other week) in patients with RA, PsA, and AS with control period duration ranging from 4 to 104 weeks, ALT elevations ū 3 x ULN occurred in 3.5% of HUMIRA-treated patients and 1.5% of control-treated patients. Since many of these patients in these trials were also taking medications that cause liver enzyme elevations (e.g., NSAIDS, MTX), the relationship between HUMIRA and the liver enzyme elevations is not clear. In controlled Phase 3 trials of HUMIRA (initial doses of 160 mg and 80 mg, or 80 mg and 40 mg on Days 1 and 15, respectively, followed by 40 mg every other week) in patients with Crohn’s disease with control period duration ranging from 4 to 52 weeks, ALT elevations ū 3 x ULN occurred in 0.9% of HUMIRA-treated patients and 0.9% of control-treated patients. In controlled Phase 3 trials of HUMIRA (initial dose of 80 mg then 40 mg every other week) in patients with plaque psoriasis with control period duration ranging from 12 to 24 weeks, ALT elevations ū 3 x ULN occurred in 1.8% of HUMIRA-treated patients and 1.8% of control-treated patients. Immunogenicity Patients in Studies RA-I, RA-II, and RA-III were tested at multiple time points for antibodies to adalimumab during the 6- to 12-month period. Approximately 5% (58 of 1062) of adult rheumatoid arthritis patients receiving HUMIRA developed low-titer antibodies to adalimumab at least once during treatment, which were neutralizing in vitro. Patients treated with concomitant methotrexate had a lower rate of antibody development than patients on HUMIRA monotherapy (1% versus 12%). No apparent correlation of antibody development to adverse reactions was observed. With monotherapy, patients receiving every other week dosing may develop antibodies more frequently than those receiving weekly dosing. In patients receiving the recommended dosage of 40 mg every other week as monotherapy, the ACR 20 response was lower among antibody-positive patients than among antibody-negative patients. The long-term immunogenicity of HUMIRA is unknown. In patients with juvenile idiopathic arthritis, adalimumab antibodies were identified in 16% of HUMIRA-treated patients. In patients receiving concomitant methotrexate, the incidence was 6% compared to 26% with HUMIRA monotherapy. In patients with ankylosing spondylitis, the rate of development of antibodies to adalimumab in HUMIRAtreated patients was comparable to patients with rheumatoid arthritis. In patients with psoriatic arthritis, the rate of antibody development in patients receiving HUMIRA monotherapy was comparable to patients with rheumatoid arthritis; however, in patients receiving concomitant methotrexate the rate was 7% compared to 1% in rheumatoid arthritis. In patients with Crohn’s disease, the rate of antibody development was 3%. In patients with plaque psoriasis, the rate of antibody development with HUMIRA monotherapy was 8%. However, due to the limitation of the assay conditions, antibodies to adalimumab could be detected only when serum adalimumab levels were < 2 ug/ml. Among the patients whose serum adalimumab levels were < 2 ug/ml (approximately 40% of total patients studied), the immunogenicity rate was 20.7%. In plaque psoriasis patients who were on HUMIRA monotherapy and subsequently withdrawn from the treatment, the rate of antibodies to adalimumab after retreatment was similar to the rate observed prior to withdrawal. Other Adverse Reactions The data described below reflect exposure to HUMIRA in 2468 patients, including 2073 exposed for 6 months, 1497 exposed for greater than one year and 1380 in adequate and well-controlled studies (Studies RA-I, RA-II, RA-III, and RA-IV). HUMIRA was studied primarily in placebo-controlled trials and in long-term follow up studies for up to 36 months duration. The population had a mean age of 54 years, 77% were female, 91% were Caucasian and had moderately to severely active rheumatoid arthritis. Most patients received 40 mg HUMIRA every other week. Table 1 summarizes reactions reported at a rate of at least 5% in patients treated with HUMIRA 40 mg every other week compared to placebo and with an incidence higher than placebo. In Study RA-III, the types and frequencies of adverse reactions in the second year open-label extension were similar to those observed in the one-year double-blind portion. Table 1. Adverse Reactions Reported by Ű5% of Patients Treated with HUMIRA During Placebo-Controlled Period of Rheumatoid Arthritis Studies b HUMIRA 40 mg subcutaneous Every Other Week b (N=705) Adverse Reaction (Preferred Term) b b bbRespiratory 17% bbbbbUpper respiratory infection bbbbbSinusitis 11% 7% bbbbbFlu syndrome Gastrointestinal b bbbbbNausea 9% 7% bbbbbAbdominal pain Laboratory Tests* b bbbbbLaboratory test abnormal 8% bbbbbHypercholesterolemia 6% bbbbbHyperlipidemia 7% bbbbbHematuria 5% bbbbbAlkaline phosphatase increased 5% Other b bbbbbHeadache 12% bbbbbRash 12% bbbbbAccidental injury 10% bbbbbInjection site reaction ** 8% bbbbbBack pain 6% bbbbbUrinary tract infection 8% bbbbbHypertension 5% * bLaboratory test abnormalities were reported as adverse reactions in European trials ** Does not include injection site erythema, itching, hemorrhage, pain or swelling

Placebo (N=690) b b 13% 9% 6% b 8% 4% b 7% 4% 5% 4% 3% b 8% 6% 8% 1% 4% 5% 3%

Juvenile Idiopathic Arthritis Clinical Studies In general, the adverse reactions in the HUMIRA-treated pediatric patients in the juvenile idiopathic arthritis (JIA) trial were similar in frequency and type to those seen in adult patients [see Warnings and Precautions, Adverse Reactions]. Important findings and differences from adults are discussed in the following paragraphs. HUMIRA was studied in 171 pediatric patients, 4 to 17 years of age, with polyarticular JIA. Severe adverse reactions reported in the study included neutropenia, streptococcal pharyngitis, increased aminotransferases, herpes zoster, myositis, metrorrhagia, appendicitis. Serious infections were observed in 4% of patients within approximately 2 years of initiation of treatment with HUMIRA and included cases of herpes simplex, pneumonia, urinary tract infection, pharyngitis, and herpes zoster. A total of 45% of children experienced an infection while receiving HUMIRA with or without concomitant MTX in the first 16 weeks of treatment. The types of infections reported in HUMIRA-treated patients were generally similar to those commonly seen in JIA patients who are not treated with TNF blockers. Upon initiation of treatment, the most common adverse reactions occurring in the pediatric population treated with HUMIRA were injection site pain and injection site reaction (19% and 16%, respectively). A less commonly reported adverse event in children receiving HUMIRA was granuloma annulare which did not lead to discontinuation of HUMIRA treatment. In the first 48 weeks of treatment, non-serious hypersensitivity reactions were seen in approximately 6% of children and included primarily localized allergic hypersensitivity reactions and allergic rash. Isolated mild to moderate elevations of liver aminotransferases (ALT more common than AST) were observed in children with JIA exposed to HUMIRA alone; liver enzyme test elevations were more frequent among those treated with the combination of HUMIRA and MTX than those treated with HUMIRA alone. In general, these elevations did not lead to discontinuation of HUMIRA treatment. In the JIA trial, 10% of patients treated with HUMIRA who had negative baseline anti-dsDNA antibodies developed positive titers after 48 weeks of treatment. No patient developed clinical signs of autoimmunity during the clinical trial. Approximately 15% of children treated with HUMIRA developed mild-to-moderate elevations of creatine phosphokinase (CPK). Elevations exceeding 5 times the upper limit of normal were observed in several patients. CPK levels decreased or returned to normal in all patients. Most patients were able to continue HUMIRA without interruption. Psoriatic Arthritis and Ankylosing Spondylitis Clinical Studies HUMIRA has been studied in 395 patients with psoriatic arthritis (PsA) in two placebo-controlled trials and in an open label study and in 393 patients with ankylosing spondylitis (AS) in two placebo-controlled studies. The safety profile for patients with PsA and AS treated with HUMIRA 40 mg every other week was similar to the safety profile seen in patients with RA, HUMIRA Studies RA-I through IV.

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Crohn’s Disease Clinical Studies HUMIRA has been studied in 1478 patients with Crohn’s disease in four placebo-controlled and two open-label extension studies. The safety profile for patients with Crohn’s disease treated with HUMIRA was similar to the safety profile seen in patients with RA. Plaque Psoriasis Clinical Studies HUMIRA has been studied in 1696 patients with plaque psoriasis in placebo-controlled and open-label extension studies. The safety profile for patients with plaque psoriasis treated with HUMIRA was similar to the safety profile seen in patients with RA with the following exceptions. In the placebo-controlled portions of the clinical trials in plaque psoriasis patients, HUMIRA-treated patients had a higher incidence of arthralgia when compared to controls (3% vs. 1%). Postmarketing Experience Adverse reactions have been reported during post-approval use of HUMIRA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to HUMIRA exposure. Gastrointestinal disorders: Diverticulitis, large bowel perforations including perforations associated with diverticulitis and appendiceal perforations associated with appendicitis, pancreatitis Respiratory disorders: Interstitial lung disease, including pulmonary fibrosis Skin reactions: Stevens Johnson Syndrome, cutaneous vasculitis, erythema multiforme, new or worsening psoriasis (all sub-types including pustular and palmoplantar) Vascular disorders: Systemic vasculitis DRUG INTERACTIONS Methotrexate Although methotrexate (MTX) reduces the apparent adalimumab clearance, the data do not suggest the need for dose adjustment of either HUMIRA or MTX. Biologic Products In clinical studies in patients with RA, an increased risk of serious infections has been seen with the combination of TNF blockers with anakinra or abatacept, with no added benefit; therefore, use of HUMIRA with abatacept or anakinra is not recommended in patients with RA [see Warnings and Precautions]. A higher rate of serious infections has also been observed in patients with RA treated with rituximab who received subsequent treatment with a TNF blocker. There is insufficient information to provide recommendations regarding the concomitant use of HUMIRA and other biologic products for the treatment of RA, PsA, AS, Crohn’s Disease, and plaque psoriasis. Live Vaccines Live vaccines should not be given concurrently with HUMIRA [see Warnings and Precautions]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category B - There are no adequate and well-controlled studies in pregnant women. Because animal reproduction and developmental studies are not always predictive of human response, HUMIRA should be used during pregnancy only if clearly needed.

Pregnancy Registry: To monitor outcomes of pregnant women exposed to HUMIRA, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 1-877-311-8972. Nursing Mothers It is not known whether adalimumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs and immunoglobulins are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from HUMIRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use Safety and efficacy of HUMIRA in pediatric patients for uses other than juvenile idiopathic arthritis (JIA) have not been established. Juvenile Idiopathic Arthritis In the JIA trial, HUMIRA was shown to reduce signs and symptoms of active polyarticular JIA in patients 4 to 17 years of age. HUMIRA has not been studied in children less than 4 years of age, and there are limited data on HUMIRA treatment in children with weight <15 kg. The safety of HUMIRA in pediatric patients in the JIA trial was generally similar to that observed in adults with certain exceptions [see Adverse Reactions]. Post-marketing cases of malignancies, some fatal, have been reported among children, adolescents, and young adults who received treatment with TNF-blockers including HUMIRA [see Warnings and Precautions]. Geriatric Use A total of 519 rheumatoid arthritis patients 65 years of age and older, including 107 patients 75 years of age and older, received HUMIRA in clinical studies RA-I through IV. No overall difference in effectiveness was observed between these subjects and younger subjects. The frequency of serious infection and malignancy among HUMIRA treated subjects over 65 years of age was higher than for those under 65 years of age. Because there is a higher incidence of infections and malignancies in the elderly population in general, caution should be used when treating the elderly. OVERDOSAGE Doses up to 10 mg/kg have been administered to patients in clinical trials without evidence of dose-limiting toxicities. In case of overdosage, it is recommended that the patient be monitored for any signs or symptoms of adverse reactions or effects and appropriate symptomatic treatment instituted immediately. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies of HUMIRA have not been conducted to evaluate the carcinogenic potential or its effect on fertility. No clastogenic or mutagenic effects of HUMIRA were observed in the in vivo mouse micronucleus test or the Salmonella-Escherichia coli (Ames) assay, respectively. PATIENT COUNSELING INFORMATION Patients or their caregivers should be provided the HUMIRA “Medication Guide” and provided an opportunity to read it and ask questions prior to initiation of therapy. The healthcare provider should ask the patient questions to determine any risk factors for treatment. Patients developing signs and symptoms of infection should seek medical evaluation immediately.

Patient Counseling Patients should be advised of the potential benefits and risks of HUMIRA. Physicians should instruct their patients to read the Medication Guide before starting HUMIRA therapy and to reread each time the prescription is renewed. • Infections Inform patients that HUMIRA may lower the ability of their immune system to fight infections. Instruct patients of the importance of contacting their doctor if they develop any symptoms of infection, including tuberculosis, invasive fungal infections, and reactivation of hepatitis B virus infections. • Malignancies Patients should be counseled about the risk of malignancies while receiving HUMIRA. • Allergic Reactions Patients should be advised to seek immediate medical attention if they experience any symptoms of severe allergic reactions. Advise latex-sensitive patients that the needle cap of the prefilled syringe contains latex. • Other Medical Conditions Advise patients to report any signs of new or worsening medical conditions such as congestive heart failure, neurological disease, autoimmune disorders, or cytopenias. Advise patients to report any symptoms suggestive of a cytopenia such as bruising, bleeding, or persistent fever. Revised: December, 2011 Ref: 03-A569-R27 Abbott Laboratories North Chicago, IL 60064, U.S.A. 64C-757903 MASTER

64C-759105

Fibromyalgia

Fibromyalgia Pain Scores Increase When Discontinuing Milnacipran Improved outcomes seen in nonresponders to duloxetine who switched to milnacipran By Wayne Kuznar Chicago, IL—Two separate studies involving patients with fibromyalgia show loss of therapeutic response in patients who discontinued therapy with milnacipran (Savella), and improvements in several pain and function domains in patients who switched to this drug after an inadequate response to duloxetine (Cymbalta). The studies were presented at the poster session during the 2011 meeting of the American College of Rheumatology. Multicenter Study Investigators at the University of Michigan, Ann Arbor, and the Swedish Medical Center and University of Washington, Seattle, studied 151 patients with fibromyalgia who completed a 3.25-year openlabel study of milnacipran. After 4 weeks of continued milnacipran therapy (50-200 mg/day), patients who achieved at least a 50% reduction in pain on the visual analog scale (VAS) were randomized in a 2:1 ratio to dou-

ble-blind treatment with milnacipran or to placebo for 12 weeks. At baseline, the mean VAS pain score was 17.5, representing a 73% reduction from the mean score pretreatment.

The higher loss of response rates in the placebo group support the long-term efficacy of milnacipran. The primary end point was loss of therapeutic response, defined as an increase in the VAS pain score to <30% reduction from premilnacipran exposure or a worsening of fibromyalgia that required an alternative treatment. The median time to loss of therapeutic response was 56 days in the placebo group and could not be calculated for patients who continued to use milnacipran. Of the placebo group, 64% had a loss of therapeutic response at the end of double-blind treatment compared

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with 35% of the milnacipran group. The investigators note that the higher loss of response rates in the placebo group support the long-term efficacy of milnacipran. Second Study The second study included 107 patients with fibromyalgia who had a 1-week recall VAS pain score of ≥40 while being treated with a stable dosage of duloxetine. The patients were randomized in a 4:1 ratio to doubleblind milnacipran 100 mg daily or to placebo for 10 weeks. Outcome measures were fatigue, physical function, satisfaction with discretionary social activity, and wake disturbance on Patient Reported Outcomes Measurement Information System (PROMIS) computer adaptive testing (CAT). Patients switched from duloxetine to milnacipran had significant improvement in fatigue and wake disturbance as measured by PROMISCAT and trends toward improvement in discretionary social activity and

at a glance ➤ The median time to loss of therapeutic response was 56 days in the placebo group and could not be calculated for patients who continued using milnacipran ➤ In the placebo group, 64% of patients had a loss of therapeutic response compared with 35% of those in the milnacipran group ➤ Patients who switched from duloxetine to milnacipran had significant improvement in fatigue and wake disturbance ➤ There was no suggestion of change in any domain in patients who switched from duloxetine to placebo physical function scores. There was no suggestion of change in any domain in patients switched from duloxetine to placebo. ■

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ACR/ARHP Key Abstracts

Rheumatology Roundup Corrals Most Salient Studies Presented at 2011 ACR/ARHP Discussed by Co-Chairs John J. Cush, MD, and Arthur F. Kavanaugh, MD By Richard Hyer Chicago, IL—More than 1700 abstracts were presented at the 2011 meeting of the American College of Rheumatology/Association of Rheumatology Health Professionals (ACR/ ARHP); of these, 26 were selected for discussion at this year’s Rheumatology Roundup. Co-chairs John J. Cush, MD, Director, Clinical Rheumatology, Baylor Research Institute, and Arthur F. Kavanaugh, MD, Professor of Medicine, University of California San Diego (UCSD) School of Medicine and Director, Center for Innovative Therapy, UCSD Division of Rheumatology, Allergy, and Immunology, emphasized that these were the year’s abstracts of special interest. This review highlights some of the most salient studies discussed by Dr Cush and Dr Kavanaugh. Additional abstracts will be discussed in the May issue. Cardiovascular Risk Reduced with Methotrexate and TNF Inhibitors In what may be the first-ever study of the duration effect of therapy on cardiovascular (CV) risk in patients with rheumatoid arthritis (RA), investigators found that the risk is reduced with methotrexate and tumor necrosis factor (TNF) inhibitors. Dr Cush complimented this study for its clinical implications. This study by Rasa BozaiteGluosniene, MD, Geisinger Medical Center, Danville, PA, and colleagues, examined the effects of TNF inhibitors and methotrexate on CV risk in a cohort of 1829 patients with RA and without preexisting coronary artery disease. The investigators compared the CV effects among users and nonusers of methotrexate or any TNF inhibitor. Dr Bozaite-Gluosniene and colleagues further subdivided data between patients who had never used methotrexate and those who used it for less than or more than 24 months. Hazard ratios for CV events were significantly decreased by both drugs and dropped even further with increasing length of use, suggesting that duration of therapy had an added effect on CV outcome. “I think we know that these drugs further lessen cardiovascular events, including myocardial infarction,” said Dr Cush. “There is a lot of good evi-

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dence of that. But this is a first for duration effect of therapy,” he said, declaring it a “good, solid outcome.”

“We know that these drugs further lessen cardiovascular events, including myocardial infarction. There is a lot of good evidence of that. But this is a first for duration effect of therapy.” —John J. Cush, MD Indocyanine Green Shows Inflammation, Treatment Response The sensitivity and specificity of indocyanine green–enhanced optical imaging (Xiralite) compares favorably to magnetic resonance imaging and ultrasonography and is useful in monitoring treatment response, according to a pair of abstracts presented by Stephanie G. Werner, MD, Rheumatology, Immunology, Osteology Center, Düsseldorf, Germany, and colleagues. Indocyanine green fluorescent dye was injected into the hands of patients with RA. “It is kind of like a bone scan,” said Dr Kavanaugh. “You inject it, and then watch how quickly the uptake is into the area of the inflamed joints, how long it stays there, and how long it takes to wash away. And, similar to the bone scan, how fast it gets there and the longer it stays there is an indicator of inflammation.” The procedure is currently performed only in Europe, using a special device to read the dye in the patient’s hand. Dr Cush asked whether it would be practical to incorporate this into current practice. Dr Kavanaugh replied that, “It still has a ways to go.”

Interpreting the data requires specialized skills. However, according to Dr Kavanaugh, “molecular imaging is really going to be the way forward in terms of imaging.” First Study of Abatacept in Patients with RA and Hepatitis B A retrospective study of 8 patients with RA and a history of hepatitis B virus (HBV) infection who were receiving abatacept caught Dr Cush’s interest, in part because no other studies have previously been conducted on the use of this drug in this patient population. The study was conducted by Paul S. Kim, MD, of the University of California, Irvine, and colleagues, who investigated the safety and efficacy of abatacept in patients with RA who were diagnosed with chronic HBV infection. HBV infection was confirmed by positive serology for hepatitis B surface antigen. Four of the 8 patients had received antiviral prophylaxis, and 4 patients had not. “The interesting thing about this study was that those who were hepatitis B surface antigen–positive, who had received prophylaxis, were able to safely receive abatacept, without any consequence, and they did very well as far as arthritis. There was no reactivation or worsening with hepatitis B,” Dr Cush said. However, the 4 patients who did not receive antiviral prophylaxis had worsening of HBV infection, as measured by polymerase chain reaction and viral DNA load. “That’s obviously the take home message,” Dr Cush pointed out. “I have learned from Len Calabrese [of the Cleveland Clinic Foundation] that you need to look for active infection in patients who have [hepatitis] B surface antigen positivity. They are the ones you really want to avoid. If you have to go there, you must prophylaxe them; if you are going to use a drug, a biologic, especially a TNF inhibitor. But now even abatacept falls under the same rules,” Dr Cush said. Should You Withdraw Therapy for Stable Patients Who Are Doing Well? According to Dr Cush, one of the 2011 ACR/ARHP meeting’s more interesting ideas was withdrawing

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therapy in patients who are stable and doing well. This was particularly emphasized in a late-breaking abstract by Josef Smolen, Chairman of the Department of Rheumatology, Medical University of Vienna, and colleagues, which discussed the PRESERVE trial. PRESERVE is a 2-period multicenter trial of patients with moderately active RA who achieved low disease activity on the 28-joint Disease Activity Score (DAS28) or clinical remission, while receiving the combination of etanercept (Enbrel) plus methotrexate (Rheumatrex, Trexal) in period 1, and were then randomized to continue to receive the combination of etanercept plus methotrexate or methotrexate alone in period 2.

“You inject it, and then watch how quickly the uptake is into the area of the inflamed joints, how long it stays there, and how long it takes to wash away…. Molecular imaging is really going to be the way forward in terms of imaging.” —Arthur F. Kavanaugh, MD

The results of the second period showed that the percentage of patients who maintained low disease activity on the DAS28 or those who achieved clinical remission at week 88 was significantly higher in patients who received etanercept plus methotrexate than in those receiving methotrexate alone. Dr Cush said that this trial was interesting, because it involved paContinued on page 22

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Lupus

Panel of Biomarkers, Not Single Marker, Likely to Emerge in Systemic Lupus Erythematosus By Wayne Kuznar Chicago, IL—Consistent with the heterogeneity of systemic lupus erythematosus (SLE), a panel of biomarkers to predict flares, prognosis, and response to therapy is more likely to emerge than a single biomarker, said Jill Buyon, MD, Professor of Medicine and Vice Chair of Rheumatology, New York University, New York City, at the 2011 meeting of the American College of Rheumatology. The diversity of clinical expression and severity of SLE is reflected by the large number of biomarkers that have been analyzed. Outcomes of interest with the use of biomarkers include disease activity, severity of flares, and response to therapy. What a biomarker is intended to predict “makes a huge difference in how you define it,” said Dr Buyon. For defining disease activity, scores of 6, 8, 10, or >12 on the SLE disease activity index have been proposed, complicating the use of biomarkers. As well, the definitions chosen for mild, moderate, and severe flares would make a difference. For predicting disease susceptibility, acuity, and organ involvement, biomarkers including chemokines, cytokines, serum and cell surface proteins, circulating proteins, and urinary proteins have been assessed. For predicting flares, the analytes C3, C4, CH50, anti–double-stranded

(ds) DNA, and C3a are specific but lack sensitivity. “An absence of an abnormal analyte does not equate with clinical stability, but its presence may be predictive of flares,” she said.

“An absence of an abnormal analyte does not equate with clinical stability, but its presence may be predictive of flares….Paradoxical mEPCR response may represent a thwarted attempt at endothelial protection.” —Jill Buyon, MD Short-term corticosteroid treatment was found to avert severe flares in clinically stable patients with SLE and elevations of plasma C3a, accompanied by rising anti-ds DNA titers. However, fluctuations in or absolute levels of anti-DNA and/or complement proteins did not predict flares in a later study of serologically active clinically quiescent patients. “Although [it is] appreciated that tissue injury in SLE arises in part from the deposition of immune complexes, anti-DNA antibodies and standard measurement of complement proteins

Rheumatology Roundup...Continued from page 21 tients with established RA for 6 to 7 years who were given the combination of methotrexate plus etanercept in this study. Those who achieved a DAS28 of <3.2 (ie, low disease activity) were randomized to changes in therapy. A total of 604 patients either continued the usual dose of 50 mg of etanercept weekly (group 1) or had that dose lowered to 25 mg weekly, while continuing methotrexate (group 2). In the third group, etanercept was withdrawn and replaced by placebo injections, and patients received a stable dose of methotrexate. “Not surprising, the patients who remained on etanercept at either dose—the usual dose or the half dose—continued to do well as far as maintenance of low disease activity state,” said Dr Cush. “The number of

remissions was still no different between the groups. However, the patients who had the etanercept withdrawn did not do as well clinically, with almost half the responses dropping. So, withdrawing therapy may be risky,” he said. “The question is, can you withdraw therapy, and should you withdraw the TNF inhibitor, as they did in this case, or should you withdraw the methotrexate, which is done in other trials?” Dr Cush said. Dr Kavanaugh said that this was “very exciting,” especially in view of related research involving infliximab, adalimumab, and the Study of the Optimal Protocol for Methotrexate and Adalimumab Combination Therapy in Early Rheumatoid Arthritis (OPTIMA) and the BeSt (Behandel-Strategieën) study. ■

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have often fallen short of expectations as biomarkers when rigorously studied,” said Dr Buyon. Cell-bound complement activation products (ie, erythrocyte coded with C3d [EC3d] or C4d [EC4d]) have been shown to track disease activity, but they have fallen short as predictive and prognostic biomarkers. However, platelet-coated C4d, which is highly specific for SLE, was found to be associated with cardiovascular events and all-cause mortality. A panel of complement activation products—antinuclear antibody, antimutated citrullinated vimentin, antiDNA, EC4d, and BC4d—was highly sensitive and specific for SLE. Dysregulated Interferon Alpha Pathway Expression profiling has found that type-1 interferon-alpha–regulated genes are overexpressed in the peripheral blood of patients with SLE, but “interferon alpha as a predictive biomarker is not iron clad,” she said. Although it is clear that the interferon alpha pathway is dysregulated in SLE, overexpression of interferoninducible genes in whole blood appears to be associated with initial pathogenesis rather than clinical disease manifestations. Dr Buyon concluded that the usefulness of exploiting interferon alpha as a direct predictive, prognostic, or pharmaco-

at a glance ➤ The diversity of clinical expression and severity of SLE is reflected by the large number of potential biomarkers ➤ Anti-DNA antibodies and standard measurement of complement proteins have often fallen short of expectations as biomarkers ➤ Although interferon alpha pathway is dysregulated in SLE, overexpression of interferoninducible genes may only be associated with initial pathogenesis and no clinical manifestations ➤ A panel of biomarkers that can help in the diagnosis of SLE, prediction of flare, and therapy selection is most likely to emerge

logic biomarker to assure drug coverage in evaluating efficacy still needs to be established. A truer biomarker may be downstream of interferon alpha, she said. Overexpression of type-1 interferonalpha–regulated chemokines is associated with a greater likelihood of flares, and neutrophil gene expression and circulating endothelial cells correlate with disease activity. Predicting Renal Flares Traditional urinary markers, such as proteinuria and normalization of C3 and C4, and the low-molecular-weight antibacterial protein neutrophil gelatinase–associated lipocalin (NGAL), may predict kidney-specific disease and outcomes, Dr Buyon stated. Anti-C1q antibodies may predict renal flares; anti-C1q levels are higher during episodes of renal activity than in episodes without renal activity. NGAL is a predictive urinary biomarker; in experimental acute kidney injury, NGAL protects renal tubules. Urinary NGAL is a sensitive and specific forecaster of renal flare in adult patients with a history of lupus nephritis. In the Aspreva Lupus Management Study, early predictors of response to induction therapy for lupus nephritis were a reduction in proteinuria and normalization of C3 and C4. In the maintenance phase, treatment failure is less likely with a reduction in antids DNA. Patients with lower C4 levels and higher anti-ds DNA after induction treatment may be at higher risk of relapse, Dr Buyon said. In the Euro-Lupus trial, an early improvement in proteinuria predicted favorable renal outcome at 10 years of follow-up. Membrane endothelial protein C receptor (mEPCR) is considered an antithrombotic and antiinflammatory protein. An mEPCR score of >2 predicted poor renal response at 6 and 12 months. “Paradoxical mEPCR response may represent a thwarted attempt at endothelial protection,” she added. Index of Biomarkers Likely A panel of biomarkers that can be compiled into an index that provides a level of certainty in an individual with respect to diagnosis, prediction of flare, choice of therapy and the response to therapy, and overall prognosis is most likely to emerge, concluded Dr Buyon. ■

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Drug Therapy

Biologics Confer Similar Efficacy in the Treatment of Rheumatoid Arthritis