Patients with juvenile idiopathic arthritis (JIA) with active systemic disease receiving canakinumab demonstrated sustained improvements without new safety concerns that were associated with glucocorticoid dose reduction or discontinuation, according to data from a long-term extension study reported in Annals of the Rheumatic Diseases.
Interleukin-1 (IL-1) plays a major role in the pathogenesis of systemic JIA, and blockade of its activity is effective in treating the disease. The safety and efficacy of the monoclonal antibody canakinumab, which works by selectively inhibiting IL-1β, has been supported in shorter trials. Investigators sought to provide evidence of continued efficacy and safety of the drug in a long-term extension trial continued up to 5 years.
Pediatric patients (aged 2 to 19 years) from two phase 3 trials were enrolled in a combined long-term extension study for up to 5 years. Between July 2009 and December 2014, canakinumab 4 mg/kg was administered subcutaneously every 4 weeks, with the possibility of tapering to 2 mg/kg in patients who had discontinued glucocorticoids. Efficacy assessments — including the Juvenile Arthritis Disease Activity Score (JADAS), adapted JIA American College of Rheumatology (JIA-ACR) criteria, and the ACR clinical remission on medication criteria — were conducted every 3 months. Tolerability and safety were reported in terms of adverse events and serious adverse events, as well as laboratory and clinical measures.
Of the 177 patients involved in the 2 initial studies, 144 patients (81%) entered the extension study (55% women; mean age, 9.0 years; mean disease duration, 2.3 years; mean JADAS, 7.85), with 43.8% receiving glucocorticoids at baseline. Of the total 177 participants, 42% completed the entire trial and 58% ended participation at some point. Discontinuation was mainly due to inefficacy (62%), with late responders discontinuing at a much higher rate than early responders.
After 2 years of follow-up, the response rates for 50%, 70%, and 90% improvement in adapted JIA-ACR criteria were 62%, 61%, and 54%, respectively. In addition, ACR clinical remission on medication criteria were met in 20% of patients at 6 months and 32% at 2 years. A total of 49% of participants achieved a low disease activity score using JADAS after 2 years, with efficacy sustained through 5 years. Early responders (n=96; 54.2%) fared better over the long-term compared with late responders (n=48; 27.1%; P < .01), offering a potentially useful clinical predictor of therapeutic success.
At baseline, 128/177 of patients (72.3%) were taking glucocorticoids. Of these, 20 (15.6%) and 28 (22%) were able to discontinue and significantly taper these medications to 0.150 mg/kg/d, respectively. Another 7 individuals (5.5%) achieved clinical remission and were able to discontinue canakinumab completely during the extension study. There were 72 individuals (56%) still taking steroids at 5 years.
The safety profile of canakinumab was consistent with previous reports and expectations, with no new findings observed. Macrophage activation syndrome occurred in 13 cases (3 reported previously), with no additional mortality beyond the previously reported deaths. The incidence rates of adverse events and serious adverse events were 796.69 and 40.68 per 100 patient-years, respectively. Infections and infestations accounted for the majority of adverse events, while JIA flares and macrophage activation syndrome accounted for most serious adverse events.
Study limitations included a low retention rate (58% discontinuation rate at 5 years) and high variability in canakinumab therapy duration in participants.
“There was a marked, rapid improvement of sJIA activity at 6 months, which was maintained
for up to 5 years and allowed for the marked reduction or even discontinuation of glucocorticoids in the majority of patients,” noted the authors, adding, “Exploratory analysis suggested that early response to canakinumab leads to a better long-term favourable outcome.”
This study was funded by Novartis Pharma. Please see original article for conflicts of interest.
Ruperto N, Brunner HI, Quartier P, et al. Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials [published September 29, 2018]. Ann Rheum Dis. doi:10.1136/annrheumdis-2018-213150