Best Evidence Analyses and Commentary
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New treatment available for systemic juvenile idiopathic arthritis
Kevin Olivieri, PharmD Candidate; Michael Mueller, PhD

Until recently, no FDA approved treatment was available for systemic juvenile idiopathic arthritis (sJIA), a disease from which an estimated 250,000 children suffer in the US alone.1  On May 10, 2013 the biologic interleukin-1 beta antagonist Ilaris®, (canakinumab) was approved for the treatment of sJIA in children aged 2 years and older.  Canakinumab has been on the market since 2009 when it was approved for the treatment of Cryopyrin-Associated Periodic Syndromes (CAPS) in adults and children older than 4 years.2,3

Interleukin-1 beta is a cytokine and a potent mediator of response to infection and injury.  It is produced mainly by monocytes and macrophages, and induces various inflammatory and immune responses.4  Blocking this inflammatory pathway reduces the amount of pro-inflammatory mediators in the blood stream, decreasing the likelihood of fever, arthritis and rash.

sJIA is characterized by an evanescent erythematous skin rash, and a fever > 39° C for longer than 2 weeks that appears either once or twice a day at approximately the same time each day.  Diagnosis requires at least one of the following: lymphad-enopathy, pericarditis, pleuritis, or hepatosplenomegaly, in children aged 16 years or younger.  The etiology of sJIA is unknown. There are no specific lab tests for sJIA, but patterns of abnormalities have been identified including high C-reactive protein, high erythrocyte sedimentation rates, neutrophilia, thrombocytosis, and a hypochromic, microcytic anemia.5

Previously treatment was 24-hour non-steroidal anti-inflammatory drugs (NSAIDs) coverage for mild sJIA, and corticosteroids in severe cases, Minimal efficacy has been demonstrated with disease modifying drugs, such as methotrexate and etanercept.6,7 

Canakinumab was approved for sJIA based on two clinical trials.  Eligible patients had a diagnosis of sJIA and were between the ages 2 to 19 years.  Patients taking up to 1mg/kg/day of prednisone and stable doses of NSAIDs were included in the study.  Exclusion criteria included use of another biologic agent or of a disease-modifying drug without the proper washout period of 5 half-lives.  Other exclusion factors included active tuberculosis infection, live-virus activation within 3 months before enrollment, active or recurrent bacterial, fungal or viral infection, and diagnosis of macrophage activation syndrome.  Patients who did not have a fever were also excluded from the trials.5,8

Trial 1 was a 29-day, single-dose, randomized double-blind, placebo-controlled study, with 84 participants.  Patients who had a response to canakinumab at day 15 were automatically enrolled in trial 2 at day 29.  Clinical responses were assessed according to an adaptation of the JIA American College of Rheumatology 30 response, which is defined as absence of fever plus 30% improvements in three or more of the JIA core set with no more than one variable worsening.  Assessment was based on the number of participants whose condition improved more than 30% and had an absence of fever.5 All patients treated with canakinumab were fever free at Day 3 compared to 87% of patients treated with the placebo.  No patients discontinued the study due to an adverse event.2,5

Trial 2 was a randomized, double-blind, placebo controlled, withdrawal study of flare prevention.  The first part was an open-label phase in which eligible patients were treated with canakinumab every 4 weeks for 12 to 32 weeks.  The objective of the withdrawal phase of the trial was to observe the median time to flare event, comparing placebo and canakinumab.  74% of patients in the canikinumab group had no flare, compared to 25% of patients in the placebo group. The second part of this study was to determine whether patients previously using glucocorticoids could be tapered down by at least 25%.  45% of patients were able to taper steroid use from 0.24 mg/kg/day to 0.05 mg/kg/day, and 33% of patients were able to discontinue glucocorticoid use completely.5  Overall six patients withdrew from the placebo group due adverse events, three due to serious immunologic events; three due to less severe side effects (vomiting, rash and uveitis).5

Careful consideration should be used before prescribing canakinumab to patients at an increased risk of infection. Patients should be counseled not to use any other Interleukin-1 blocking drug, or anti-tissue necrosis factor drug while taking canakinumab.  Patients who have chronic or active infection, including HIV, hepatitis B or hepatitis C, were excluded from the trials and patients should be screened for tuberculosis infection before beginning canakinumab.  Any patient considering canakinumab should consult their physician regarding their vaccination history.  Patients should be informed of signs and symptoms of macrophage activation syndrome (MAS), which is a life-threatening disorder that must be aggressively treated.  Eleven of the 201 sJIA patients in the trials who were treated with canakinumab experienced MAS.2,5,8

Most common side effects reported in phase three trials were abdominal pain, cough, headache, nasopharyngitis, pyrexia, upper respiratory tract infection, and vomiting.6 No drug-drug interaction studies have been conducted on canakinumab, nor has any pregnancy data been reported.2 To date, canakinumab is the only approved sJIA treatment with efficacy data from large scale clinical trials in this patient population.  



1.     Pascual, Virginia, Florence Allantaz, Edsel Arce, Marilynn Punaro, and Jacques Banchereau. "Abstract." National Center for Biotechnology Information. 05 Feb. 2005. U.S. National Library of Medicine. 13 June 2013 <>.

2.     Highlights of Prescribing Information. May 2013. Novartis. 13 June 2013 <>.

3.     Novartis drug Ilaris® approved by FDA to treat active systemic juvenile idiopathic arthritis, a serious form of childhood arthritis. Novartis drug Ilaris® approved by FDA to treat active systemic juvenile idiopathic arthritis, a serious form of childhood arthritis. 10 May 2013. Novartis. 13 June 2013 <>. 

4.     Li, Limei, and Et. Al. "Functional imaging of interleukin 1 beta expression in inflammatory process using bioluminescence imaging in transgenic mice." BioMed Central Immunology 9 (2009). BMC Immunology. 2013. Springer. 14 June 2013 <>. 

5.     Ruperto N, Brunner HI, Quartier P, et al. Two Randomized Trials of Canakinumab in Systemic Juvenile Idiopathic Arthritis. The New England Journal of Medicine 367 (2012): 2396-406. 

6.     Woo, Patricia. Systemic juvenile idiopathic arthritis: Diagnosis, management, and outcome. Nature Clinical Practice 2 (2006): 28-34

7.     Juvenile idiopathic arthritis (juvenile rheumatoid arthritis). Juvenile Idiopathic Arthritis. Boston Children's Hospital/Harvard Medical Center. 20 June 2013 <>. 

8.     Flare Prevention Study of Canakinumab in Patients With Active Systemic Juvenile Idiopathic Arthritis (SJIA) (?-SPECIFIC 2). 11 June 2013. National Institute of Health. 13 June 2013 <>.

9.     Rosebraugh, Curtis J. BLA Approval. 17 June 2009. Department of Health and Human Services. 13 June 2013 <>.

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