Subject: Ilaris (canakinumab) for Systemic Juvenile Original Effective Date: 4/24/2015 Idiopathic Arthritis (SJIA)

Policy Number: MCP-246 Revision Date(s):

Review Date(s): 12/15/2016; 6/22/2017

DISCLAIMER This Medical Policy is intended to facilitate the Utilization Management process. It expresses Molina's determination as to whether certain services or supplies are medically necessary, experimental, investigational, or cosmetic for purposes of determining appropriateness of payment. The conclusion that a particular service or supply is medically necessary does not constitute a representation or warranty that this service or supply is covered (i.e., will be paid for by Molina) for a particular member. The member's benefit plan determines coverage. Each benefit plan defines which services are covered, which are excluded, and which are subject to dollar caps or other limits. Members and their providers will need to consult the member's benefit plan to determine if there are any exclusion(s) or other benefit limitations applicable to this service or supply. If there is a discrepancy between this policy and a member's plan of benefits, the benefits plan will govern. In addition, coverage may be mandated by applicable legal requirements of a State, the Federal government or CMS for Medicare and Medicaid members. CMS's Coverage Database can be found on the CMS website. The coverage directive(s) and criteria from an existing National Coverage Determination (NCD) or Local Coverage Determination (LCD) will supersede the contents of this Molina medical coverage policy (MCP) document and provide the directive for all Medicare members.

SUMMARY This policy addresses the coverage of Ilaris (canakinumab) for the treatment of Systemic Juvenile Idiopathic Arthritis (SJIA) when appropriate criteria are met.

∑ PREFERRED AGENT for the treatment of Systemic Juvenile Idiopathic Arthritis (SJIA): Actemra (tocilizumab)

∑ Due to the lack of evidence regarding the safety and efficacy of Ilaris (canakinumab) in comparison to other biologic treatments for SJIA, the most cost-effective agent will be preferred: Actemra (tocilizumab)

∑ Consensus guidelines from the Childhood Arthritis Rheumatology and Research Alliance recommend the use of both Actemra (tocilizumab) and Kineret (anakinra) in the management of SJIA.A

‹ Actemra (tocilizumab) is a biologic agent that is also FDA-approved for the treatment of SJIA. It has also been shown to improve ACR 30 response in patients with SJIA.

‹ Kineret (anakinra) is a subcutaneously administered biologic medication used for the treatment of SJIA. It has also been shown to improve ACR 30 response. ‹ Based on the American College of Rheumatology guidelines for the treatment of systemic juvenile idiopathic arthritis,B anakinra is effective and is recommended as initial therapy2,3 or as adjunct therapy in children and adolescents with systemic juvenile idiopathic arthritis in whom an adequate trial of glucocorticoids and/or or nonsteroidal anti-inflammatory drugs (NSAIDs) has failed2,4; additional trials may be necessary to further define the role of anakinra in this condition.d

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∑ American College of Rheumatology: Recommendations for the Treatment of Juvenile Idiopathic Arthritis: Recommendations for the Medical Therapy of Children With Systemic Juvenile Idiopathic Arthritis and Tuberculosis Screening Among Children Receiving Biologic Medications

In September 2013, the ACR released updated guidelines for the treatment of systemic JIA, which included the medications canakinumab, rilonacept, and tocilizumab.B These guidelines include the following treatment recommendations:

‹ For systemic JIA with active systemic features and varying degrees of synovitis, initial treatment for most patients should consist of anakinra with systemic glucocorticoids

‹ For systemic JIA without active systemic features and with varying degrees of active synovitis, initial treatment should be methotrexate or leflunomide for an active joint count higher than 4, with a change to abatacept, anakinra, a tumor necrosis factor (TNF)-α inhibitor, or tocilizumab if disease activity continues after 3 months; for patients with 4 or fewer active joints, NSAID monotherapy or intra-articular glucocorticoid injections should be initial treatment

‹ For systemic JIA with features suggesting macrophage activation syndrome (MAS), initial treatment should include anakinra, a calcineurin inhibitor, or systemic glucocorticoid monotherapy for up to 2 weeks

FDA INDICATIONS

Systemic juvenile idiopathic arthritis: For the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients � 2 years and older. �

NOTE: Ilaris (canakinumab) for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS), including Familial � Cold Autoinflammatory Syndrome (FCAS) and Muckle-Wells Syndrome (MWS) is not addressed in the policy. Refer to � MCP-110. �

Available as: Ilaris 180mg vials (powder for subcutaneous injection) in a single-use 6 ml glass vial

FDA Approved: FCAS and MWS in June 2009; Systemic juvenile idiopathic arthritis in May 2013

Black Box Warnings: None at the time of this writing

CLASSIFICATION: Immune Modulator; Monoclonal Antibody; Interleukin-1B blocker

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RECOMMENDATIONS/COVERAGE CRITERIA

Ilaris (canakinumab) may be authorized for members who meet ALL of the following criteria [ALL]

1. � Prescriber specialty [ONE]

¶ Prescribed by, or in consultation with, a board-certified rheumatologist, pediatric rheumatologist or physician experienced in the management of systemic juvenile idiopathic arthritis (SJIA). Submit consultation notes if applicable.

2. � Diagnosis/Indication [ONE]

Clinical documented diagnosis of (includes clinical notes from the member’s medical records including any applicable labs and/or tests, supporting the diagnosis):

¶ Active systemic juvenile idiopathic arthritis (SJIA) with disease activity

3. � Age/Gender/Other restrictions [ALL]

¶ 2 years of age or older ‹ The safety and effectiveness of canakinumab in patients younger than 2 years have not been established.

¶ Tuberculin skin test (TST) or Centers for Disease Control (CDC)-recommended equivalent: Screening test must be negative. If test is positive, start treatment for TB prior to starting canakinumab. Documentation required. ‹ Screen all patients for TB prior to initiation and treat latent TB before starting Ilaris therapy.

4. � Step/Conservative Therapy/Other condition Requirements [ALL]

ß Member meets ONE (1) of the following: [A or B]

A. � New member to Molina Healthcare and stabilized on Ilaris (canakinumab) with a documented positive response or improvement as evaluated the member and Prescriber, such as: [ALL APPLICABLE] û Improvement in serum C reactive protein and signs and symptoms of SJIA (e.g., time between flare-ups and number of joints with active arthritis and limited range of motion) û Resolution of fevers; improvement in limitation of motion; less joint pain or tenderness; decreased duration of morning stiffness or fatigue û Improved function or activities of daily living û Reduced dosage of corticosteroids û Functional ability (Childhood Health Assessment Questionnaire – CHAQ)

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B. � Documentation of inadequate response, intolerance, or contraindication to the following: [ALL]

û At least ONE (1) oral systemic agent for SJIA [ONE] o Glucocorticoid (oral or IV) o Nonsteroidal anti-inflammatory drugs (NSAIDs) o Methotrexate, leflunomide, or sulfasalazine

‹ Ilaris (canakinumab) May be used alone or in combination with corticosteroids, methotrexate (MTX), or NSAIDs.

û Actemra (tocilizumab) ‹ FDA approved for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years and older.

¶ Member is NOT concurrently taking another biologic agent for an inflammatory condition, such as: [ANY] û Tumor Necrosis Factor [TNF] blocking agents [i.e. Cimzia (certolizumab pegol), Enbrel, Humira, Remicade (infliximab infusion), Simponi (golimumab), Simponi Aria (golimumab for IV infusion)] û IL-1 inhibitor , IL-6 inhibitor, IL-12/23: Kineret (anakinra), Actemra (tocilizumab), Stelara û Janus kinase inhibitors (i.e. Xeljanz [tofacitinib citrate]) û Other biologics: Orencia (abatacept), Rituxan

NOTE: Molina staff: Verify pharmacy claims data for drug names within the last 30 days, OR for new members to Molina Healthcare, confirm drug names in medical chart history

5. � Contraindications/Exclusions/Discontinuations Authorization will not be granted if ANY of the following conditions apply [ANY] ¶ Non-FDA approved indications ¶ Hypersensitivity to canakinumab or any of the excipients ‹ Symptoms of underlying disease may mimic symptoms of hypersensitivity. ¶ Concurrent Biologic Therapy. Ilaris should not be administered in combination with another biologic agent for an inflammatory condition [e.g., tumor necrosis factor (TNF) blocking agents [e.g., Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), Remicade (infliximab), Simponi (golimumab), Simponi Aria (golimumab)], Kineret (anakinra), or Arcalyst ‹ May increase the risk of serious infections. ‹ Tumor necrosis factor (TNF) antagonist include adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi and Simponi Aria), and infliximab (Remicade) ¶ Concomitant use with live vaccines ‹ Adult and pediatric patients should be brought up to date with all immunizations prior to starting canakinumab therapy. ¶ Latent or active tuberculosis (TB) ‹ There is increased risk for developing new TB infection or reactivation of latent infection. ¶ Invasive fungal infection, or other active or chronic infection (e.g. tuberculosis, HIV, hepatitis B/C) or a history of recurrent infections ‹ There is an increased risk of developing serious infection when patient has preexisting, history of recurring infection, or underlying conditions predisposing them to infection. Exclusions [ANY] ¶ Tuberculin skin test (TST) or Centers for Disease Control (CDC)-recommended equivalent has not been performed to evaluate for latent tuberculosis

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6. Labs/Reports/Documentation required [ALL] All documentation for determination of medical necessity must be submitted for review. Prescriber to submit documentation as indicated in the criteria above, including but not limited to chart notes, applicable lab values and/or tests, adverse outcomes, treatment failures, or any other additional clinical information or clinical notes from the member’s medical records supporting the diagnosis. Letters of support and/or explanation are often useful, but are not sufficient documentation unless ALL specific information required by this MCP are included. NOTE: Additional documentation, rationale, and/or supporting evidence may be requested for review as deemed necessary or appropriate by Molina Medical/Pharmacy staff.

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CONTINUATION OF THERAPY Ilaris (canakinumab) may be authorized for continuation of therapy if meet ALL of the following criteria are met: [ALL]

1. � Initial Coverage Criteria

ß Member currently meets ALL initial coverage criteria

2. Compliance

ß Adherence to therapy at least 85% of the time as verified by Prescriber and member’s medication fill history (review Rx history for compliance), including: û Member is compliant in taking the medication as scheduled û Member tolerated the medication û Member did not experience any severe adverse reactions while taking the medication

NOTE: Therapy may be discontinued due to poor adherence upon recommendation of the Molina Medical Director when adherence < 85% has been demonstrated in at least two months during the course of therapy

ß History of non-compliance or non-adherence as verified by member’s medication fill history or prescription drug profile [MOLINA MEDICAL/PHARMACY REVIEWER TO VERIFY]

3. � Labs/Reports/Documentation required [ALL APPLICABLE]

¶ Documentation of positive response or improvement as evaluated the member and Prescriber, such as: [AT LEAST ONE] û improvement in serum C reactive protein and signs and symptoms of SJIA (e.g., time between flare- ups and number of joints with active arthritis and limited range of motion) û resolution of fevers; improvement in limitation of motion; less joint pain or tenderness; decreased duration of morning stiffness or fatigue û improved function or activities of daily living û reduced dosage of corticosteroids û functional ability (i.e. Childhood Health Assessment Questionnaire – CHAQ)

4. � Discontinuation of Treatment [ANY] Discontinue treatment if ANY of the following conditions applies: [ANY] ß Intolerable adverse effects or drug toxicity ß Persistent and uncorrectable problems with adherence to treatment ß Poor response to treatment as evidenced by physical findings and/or clinical symptoms ß Contraindications/Exclusions to therapy û Non-FDA approved indications û Hypersensitivity to canakinumab or any of the excipients ‹ Symptoms of underlying disease may mimic symptoms of hypersensitivity. û Concurrent Biologic Therapy. Ilaris should not be administered in combination with another biologic agent for an inflammatory condition [e.g., tumor necrosis factor (TNF) blocking agents [e.g., Cimzia (certolizumab pegol for SC injection), Enbrel, Humira, Remicade, Simponi (golimumab for SC injection), Simponi Aria (golimumab for IV infusion)], Kineret (anakinra), or Arcalyst ‹ May increase the risk of serious infections.

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‹ Tumor necrosis factor (TNF) antagonist include adalimumab (Humira), certolizumab pegol (Cimzia), etanercept (Enbrel), golimumab (Simponi and Simponi Aria), and infliximab (Remicade) û Concomitant use with live vaccines ‹ Live vaccines should not be given concurrently with Ilaris. Prior to initiation of therapy with Ilaris, patients should receive all recommended vaccinations. In addition, because Ilaris may interfere with normal immune response to new antigens, vaccinations may not be effective in patients receiving Ilaris. û Latent or active tuberculosis (TB) ‹ There is increased risk for developing new TB infection or reactivation of latent infection. û Invasive fungal infection, or other active or chronic infection (e.g. tuberculosis, HIV, hepatitis B/C) or a history of recurrent infections ‹ There is an increased risk of developing serious infection when patient has preexisting, history of recurring infection, or underlying conditions predisposing them to infection.

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ADMINISTRATION, QUANTITY LIMITATIONS, AND AUTHORIZATION PERIOD

1. � Recommended Dosage [ALL] Systemic Juvenile Idiopathic Arthritis (SJIA)

¶ 4 mg/kg (with a maximum of 300 mg) for patients with a body weight greater than or equal to 7.5 kg. Administer subcutaneously every 4 weeks. ‹ There are no dosing recommendations for patients with body weight < 7.5 mg.

2. � Authorization Limit [ALL]

¶ Quantity limit: 300mg every 4 weeks

¶ Dispensing limit: Only a 1-month supply may be dispensed at a time: 2 vials (360 mg) per month [or 12 vials per 6 month period (up to 300mg per dose)]

¶ Duration of initial authorization: May be authorized up to 6 months

¶ Continuation of treatment: Re-authorization for continuation of treatment is required every 12 months to determine continued need based on documented positive clinical response

¶ Duration of continuation of treatment: May be authorized up to 12 months

3. � Route of Administration [ALL]

¶ Ilaris (canakinumab) is considered a provider-administered medication. Treatment should be initiated and supervised by a specialist physician experienced in the diagnosis and treatment of sJIA.

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COVERAGE EXCLUSIONS

This policy only addresses Ilaris (canakinumab) for the treatment of Systemic Juvenile Idiopathic Arthritis (SJIA) when appropriate criteria are met.

All other uses of Ilaris (canakinumab) that are not an FDA-approved indication or not included in the ‘Coverage Criteria’ section of this policy are considered experimental/investigational or not a covered benefit of this policy. This subject to change based on research and medical literature, or at the discretion of Molina Healthcare.

SUMMARY

Systemic onset Juvenile Idiopathic Arthritis (SJIA) is the most severe subtype of Juvenile Idiopathic Arthritis (JIA/JA/JRA/JCA). Juvenile Idiopathic Arthritis, is a general term used to describe inflammatory arthritis diagnosed in children 16 years of age or younger. SJIA is a unique type of childhood arthritis. It is classed as a subtype of juvenile idiopathic arthritis (JIA), and accounts for about 10% of JIA cases in Europe and North America, and about 30% in India and 50% in Japan.5

SJIA is heterogeneous in nature, and the disease course can vary from patient to patient in terms of severity and outcomes. sJIA begins in children aged 16 years or younger with a peak age of onset between 18 months and two years, although persistence of the disease into adulthood does occur. The arthritis is accompanied by a characteristic fever, skin rash, anaemia, enlargement of the liver and/or spleen and inflammation of the lining of the heart and/or lungs.5

The peak onset of sJIA is between the ages of 18 months and 2 years but may develop at any age. Patients are classified as having: • a monocyclic course, with remission within 2 to 4 years (about 42% of patients), • persistent disease with arthritis becoming more prominent on remission of the systemic features and lasting no more than 5 years (about 51%), or • a relapsing course characterized by flares of systemic features and mild arthritis (about 7%).

SJIA presents as recurrent systemic symptoms, including spiking fevers, rash, lymphadenopathy, hepatosplenomegaly and serositis. It is also associated with elevated erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), neutrophil and platelet counts from systemic inflammation, anemia, and elevated transaminases.6,7 Joint symptoms usually arise later and the clinical course of the disease is highly variable.

Based on the characteristic features and the severity of the disease, goals for SJIA management should include both systemic and arthritic symptom relief.B The end goal of treatment is to control symptoms and manage long-term problems, including pain relief, reduction of swelling, increasing joint mobility and strength, and prevention of joint damage and complications.

Pharmacologic Agents/Conventional Therapy Optimal care of patients with juvenile idiopathic arthritis (JIA) requires an integrated approach of nonpharmacologic and pharmacologic therapies. Classes of medications used include disease-modifying antirheumatic drugs (DMARDs), biologicals, NSAIDs, and corticosteroids

Ilaris (canakinumab) Canakinumab is a recombinant fully human anti-interleukin-1beta (anti-IL-1β) monoclonal antibody. It selectively blocks the action of IL-1β without affecting other interleukin-1 (IL-1) types. IL-1β is a key proinflammatory cytokine. It mediates local and systemic responses to infection and tissue injury. When activated, it induces multiple effects that include fever, sensitization to pain, and destruction of bone and cartilage.

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By binding to human IL-1B, canakinumab blocks the IL-1 receptor interaction and neutralizes overactive IL-1B activity which is present in disorders such as Cryopyrin-Associated Periodic Syndromes (CAPS) and systemic juvenile idiopathic arthritis (SJIA). Canakinumab does not bind IL-1 alpha or IL-1 receptor antagonist (IL-ra).

Hayes At the time of this writing, there was no Hayes Directory report or Hayes Rating available addressing canakinumab in the treatment of SJIA.

Pivotal Trials The efficacy of ILARIS for the treatment of active SJIA was assessed in two phase 3 studies (SJIA Study 1 and SJIA Study 2). Patients enrolled were aged 2 to less than 20 years (mean age at baseline: 8.5 years) with a confirmed diagnosis of SJIA at least 2 months before enrollment (mean disease duration at baseline: 3.5 years). Patients had active disease defined as greater than or equal to 2 joints with active arthritis (mean number of active joints at baseline: 15.4), documented spiking, intermittent fever (body temperature greater than 38°C) for at least 1 day within 1 week before study drug administration, and CRP greater than 30 mg/L (normal range less than 10 mg/L) (mean CRP at baseline: 200.5mg/L). Patients were allowed to continue their stable dose of methotrexate, corticosteroids, and/or NSAIDs without change, except for tapering of the corticosteroid dose as per study design in SJIA Study 2.

∑ Ruperto and colleagues (2012a) randomly assigned 84 children aged 2 to 19 years with SJIA (2.3 years, median disease duration) with active systemic features and arthritis (including fever with intermittently spiking temperatures, ≥ 2 active joints, and CRP level of greater than 30 mg per liter) to a single dose of canakinumab (n=43) (4 mg/kg subcutaneously) or placebo (n=41). Concomitant treatment with another biologic agent or DMARD was not allowed, but those on background therapy with glucocorticoids (such as prednisone), stable doses of NSAIDs, and/or MTX were allowed to enroll. More than two-thirds of the participants had previously received biologic agents prior to study enrollment. The primary outcome, the proportion of participants with an adapted JIA American College of Rheumatology 30 (ACR30) response, was reported as a significant difference between the canakinumab group (84%, n=36) and the placebo group (10%, n=4), which was sustained at Day 29 (p<0.001). Two serious adverse events were reported in each group, including varicella and macrophage activation syndrome (MAS) in the canakinumab group and MAS and gastroenteritis in the placebo group.

∑ The second trial used a two-part withdrawal design. The first part was an open-label phase and the second part was a randomized withdrawal phase. In the second part, 100 participants who had a sustained adapted JIA ACR30 response or better and who were not on glucocorticoids or had been tapered to a stable glucocorticoid dose were randomized 1:1 in a double-blind design to either continue on canakinumab or receive placebo. The rate of flares was significantly lower in the canakinumab group compared with the placebo group (26% versus 75%, respectively; median time to flare, 236 days). In addition, inactive disease rates were higher at the end of the withdrawal phase in the canakinumab group compared with placebo (62% versus 34%). Four cases of MAS were reported in the open-label phase, and 1 in the placebo group in the withdrawal phase. Two participants with MAS died, 1 in the open-label phase and 1 in the placebo group in the withdrawal phase. There was no difference in the rate of serious adverse events between the 2 groups in the withdrawal phase (Ruperto, 2012a).

DEFINITIONS

Macrophage Activation Syndrome (MAS) is a life-threatening disorder that may develop in patients with rheumatic conditions, in particular SJIA, and should be aggressively treated. Physicians should be attentive to symptoms of infection or worsening of SJIA, as these are known triggers for MAS. Eleven cases of MAS were observed in 201 SJIA patients treated with canakinumab in clinical trials. Based on the clinical trial experience, Ilaris does not appear to increase the incidence of MAS in SJIA patients, but no definitive conclusion can be made.

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APPENDIX

N/A �

CODING INFORMATION: THE CODES LISTED IN THIS POLICY ARE FOR REFERENCE PURPOSES ONLY. LISTING OF A SERVICE OR DEVICE CODE IN THIS POLICY DOES NOT IMPLY THAT THE SERVICE DESCRIBED BY THIS CODE IS A COVERED OR NON-COVERED. COVERAGE IS DETERMINED BY THE BENEFIT DOCUMENT. THIS LIST OF CODES MAY NOT BE ALL INCLUSIVE. CPT Description NA

HCPCS Description J0638 Injection, canakinumab, 1 mg

ICD-9 Description 714.30- Juvenile arthritis range of codes 714.33

ICD-10 Description M08.0- Juvenile arthritis range of codes M08.99

REFERENCES

Package Insert, FDA, Drug Compendia a. � Ilaris (canakinumab) [product monograph]. Dorval, Quebec, Canada: Novartis Pharmaceuticals Canada Inc; December 2013 b. � American Hospital Formulary Service (AHFS). Drug Information 2015. [STAT!Ref Web site]. Available at: http://online.statref.com. [via subscription only]. c. � Micromedex Healthcare Series. DrugDex. [Micromedex Web site]. Available at: http://www.thomsonhc.com/micromedex2/librarian [via subscription only]. d. � Drug Facts and Comparisons. Drug Facts and Comparisons 4.0 [online]. 2015. Available from Wolters Kluwer Health, Inc. e. � Clinical Pharmacology [database online]. Tampa, FL: Gold Standard, Inc.; 2015. URL: http://www.clinicalpharmacology.com. f. � Actemra [package insert]. South San Francisco, CA: Genentech Inc; October 2013.

Clinical Trials, Definitions, Peer-Reviewed Publications 1. � Ruperto N, Brunner HI, Quartier P, et al. Two randomized trials of canakinumab in systemic juvenile idiopathic arthritis. N Engl J Med. 2012a; 367(25):2396-2406. 2. � Hedrich CM, Bruck N, Fiebig B, Gahr M. Anakinra: a safe and effective first-line treatment in systemic onset juvenile idiopathic arthritis (SoJIA). Rheumatol Int. 2012;32(11):3525-3530. PubMed 3. � Quartier P, Allantaz, Cimaz R, et al. A multicenter, randomized, double-blind, placebo-controlled trial with the interleukin-1 receptor antagonist anakinra in patients with systemic-onset juvenile idiopathic arthritis (ANAJIS trial). Ann Rheum Dis. 2011;70(5):747-754. 4. � Gurion R, Lehman TJA, Moorthy LN (2012). Systemic arthritis in children. A review of clinical presentation and treatment. Int J Inflammation: article 271569; 2012:1-16. 5. � Woo, P. Systemic juvenile rheumatoid arthritis: diagnosis, management, and outcome. Nature Clinical Practice: Rheumatology. 2006. 2:1

Government Agencies, Professional Societies, and Other Authoritative Publications

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A. � DeWitt EM, Kimura Y, Beukelman T, et al; Juvenile Idiopathic Arthritis Disease-specific Research Committee of Childhood Arthritis Rheumatology and Research Alliance. Consensus treatment plans for new-onset systemic juvenile idiopathic arthritis. Arthritis Care Res (Hoboken). 2012 Jul;64(7):1001-10. doi: 10.1002/acr.21625. PubMed PMID: 22290637; PubMed Central PMCID: PMC3368104. B. � Ringold S, Weiss PF, Beukelman T, et al; American College of Rheumatology. 2013 update of the 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: recommendations for the medical therapy of children with systemic juvenile idiopathic arthritis and tuberculosis screening among children receiving biologic medications. Arthritis Rheum. 2013;65(10):2499-2512.

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