From the Journals

Drug-free inactive disease a feasible goal in JIA



Recent recommendations from an international task force advocating that patients with juvenile idiopathic arthritis (JIA) be treated to a target of clinical remission have been backed up by research that finds the goal is a feasible one.

Published online in the Annals of the Rheumatic Diseases, the investigator-initiated, multicenter, randomized BEST for Kids study found that, regardless of initial specific treatments, after 24 months of treatment to target aimed at drug-free inactive disease, 71% of recent-onset patients with JIA had inactive disease (at a median onset of 9 months), and 39% were drug free.

The investigators, led by Petra Hissink Muller, MD, department of pediatrics, Leiden (the Netherlands) University Medical Center said previous studies of JIA supported the “window of opportunity” hypothesis in which disease optimally responds to treatment.

“In JIA, continuous treatment-to-target therapy in a tight control setting, with treatment adjustments based on frequent evaluations of disease activity, has not yet been studied. Recent recommendations agree that treatment to target should be implemented in daily practice,” they wrote.

The aim of the BEST for Kids study was to investigate which of three frequently used treatment-to-target strategies was most effective and safe.

Overall, 94 children (67% girls) with a median age of 9.1 years with new-onset (oligoarticular, juvenile psoriatic arthritis, or rheumatoid factor–negative polyarticular) JIA, without previous disease-modifying antirheumatic drug (DMARD) therapy and symptom duration of less than 18 months were enrolled in the study.

Median symptom duration was 7.5 months and median duration between diagnosis and inclusion in the study was 6 weeks. The investigators noted that two patients left the study during follow-up because of a revised diagnosis.

All study participants were randomized into three strategy arms:

  • Initial treatment with conventional synthetic DMARD monotherapy (methotrexate [MTX] or sulfasalazine if preferred by treating physician), n = 32.
  • Initial treatment with MTX and 6 weeks of tapered prednisolone (‘bridging therapy), n = 32).
  • Initial treatment with MTX and etanercept, n = 30.

In case of inactive disease for at least 3 (oligoarticular disease) or 6 (polyarticular disease) consecutive months, DMARDs were tapered and stopped in all three arms. For combination therapy, etanercept was tapered to once every 2 weeks, followed by a 50% dose reduction, then halted. The dose of MTX or sulfasalazine was reduced by 25% per week to zero.

In case of a disease flare, the last discontinued drug and/or the last effective dose was reintroduced. The protocol did not allow prednisolone to be restarted, whereas etanercept could be restarted but not discontinued for a second time.

The primary outcome of the trial was time to inactive disease and time to flare (defined as the time between first moment of drug-free inactive disease (DFID) and the first arthritis flare as judged by the treating physician) after tapering and stopping all DMARD therapy. Secondary outcomes were adapted ACR Pediatric (ACR Pedi) 30/50/70/90 scores, functional ability, and adverse events.

Results showed that after 24 months inactive disease was achieved by more than 70% of the patients (71%, arm 1; 70%, arm 2; and 72%, arm 3).

Furthermore, drug-free inactive disease (DFID) was achieved by 59% of the cohort (54 of 92 patients; 45% of arm 1, 31% of arm 2, and 41% of arm 3), although the authors noted that early flares did occur in 14 patients and were successfully retreated, resulting in 39% of the patients in DFID at the 2-year study endpoint.

In the treatment of JIA,“we showed that tapering and discontinuation of treatment is a realistic goal. On the other hand, treatment to target resulted in a relatively high use of [biologic] DMARDs, greater than 50% of patients in all arms,” the investigators wrote.

Median time to inactive disease was 9 months in all arms (P = .30), and time to flare was also not significantly different among the groups (overall 3 months [3.0-6.8]; P = .7). The investigators noted that while overall flare rates (26%) were lower than the 37%-60% mentioned in previous cohorts, this finding could be a result of the limited follow-up time.

After 3 months of treatment, more patients who started with MTX and etanercept (arm 3) had achieved rapid improvement as determined by ACR Pedi 70 scores. However, the investigators noted that, because of treatment adjustments in cases of active disease, which were needed more often in arms 1 and 2 than in arm 3, ACR Pedi improvement scores were met in similar percentages of patients over time across the arms.

Adverse events were similar across treatment arms and were generally mild, involving mostly gastrointestinal complaints, upper respiratory tract and other infections, and general malaise.

Overall, the investigators concluded that DFID was a “feasible goal” in the treatment of children with JIA.

Limitations of the study included breaches of treatment protocol by physicians in patients across the three arms.“The physicians did not follow protocol for various reasons, mainly reluctance to intensify therapy based on shared decision making,” they wrote.

Another limitation was the small sample size, which the investigators said could obscure differences between groups that in a larger population might have become clear.

“Long-term follow-up of the BEST for Kids cohort, including radiology results, is initiated to investigate possible lasting positive results of treatment to target in JIA,” they said.

SOURCE: Hissink Muller P et al. Ann Rheum Dis. Oct 12. doi: 10.1136/annrheumdis-2018-213902.

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