Experience With Etanercept, Tocilizumab and Interleukin-1 Inhibitors in Systemic Onset Juvenile Idiopathic Arthritis Patients From the BIKER Registry

Gerd Horneff; Anna Carina Schulz; Jens Klotsche; Anton Hospach; Kirsten Minden; Ivan Foeldvari; Ralf Trauzeddel; Gerd Ganser; Frank Weller-Heinemann; Johannes Perter Haas


Arthritis Res Ther. 2017;19(256) 

In This Article


Severe, persistent systemic JIA still represents a major therapeutic challenge in pediatric rheumatology. We performed a systematic analysis of the German BIKeR register to evaluate and compare the effectiveness and safety of TOC, the IL-1i canakinumab and anakinra, and used ETA as a comparator. Both cohorts of patients receiving anakinra or canakinumab were pooled because of the small total numbers of patients receiving each medication compared to the other cohorts. No marked difference was observed between patients receiving one of these IL-1i.

Differences in baseline characteristics in regard to the ETA cohort as a comparator can be explained by the start of therapy at a different point of the pharmacological admission. Before the approval of ETA in 2000, no biological agent for the treatment of JIA was available. In contrast, 65% and 66%, respectively, of the cohorts of patients receiving TOC or one of the IL-1i were exposed to a biologic agent before. Patients in the IL-1i or TOC cohorts presented with more systemic disease activity, whereas active joints were the leading symptom in the ETA cohort, which makes direct comparison difficult. The low rate of active systemic features in the ETA cohort may be explained by the fact that ETA was approved in 2000 for treatment of polyarthritis in general. Patients with sJIA starting with systemic features during their course of the disease quite often have persistent articular disease with systemic features disappearing.[21] Thus, these patients were selected to receive a TNF inhibitor to treat articular manifestation of their disease. While a marked decrease in the mean JADAS was noted in all cohorts, the effectiveness of biologic treatment in patients with sJIA measured by the JADAS and JIA-ACR criteria resulted in higher response rates especially to IL-6 and IL-1i. The median JADAS decreased in the TOC cohort from 16.9 to 1.5 and in the IL-1i cohort from 13.0 to 0.6. ETA as the first biologic agent approved in the year 2000 for the treatment of JIA also led to a decrease of the JADAS from 20.8 to 6.2. The remarkable and significant difference in effectiveness between IL-1i and TOC compared to ETA were demonstrated in a larger proportion of patients reaching JADAS minimal disease activity or even JADAS remission under therapy.

Effectiveness in early disease upon either treatment with TOC or IL-1-inhibitiors was higher than in longer disease duration. This fits the observation that there has been a movement toward earlier treatment with biologics, probably because of a suggested "window of opportunity" that drives this trend, but still remains unproven. The influence of previous failure of a biologic was not pronounced. Failure to respond to ETA or an IL-1i seems not to predict response to TOC, whereas failure to respond to ETA or TOC has a numerical but not a statistically significant influence on the response to IL-1i. Only patients previously treated with anakinra had a markedly worse response to canakinumab, which is explained by their similar target but with a different mode of action. Since no patient switched from canakinumab to anakinra the opposite could not be analysed.

Adverse events (AE) and serious adverse events were significantly more frequent under therapy with TOC (RR 5.3, RR 2.5, respectively) and IL-inhibitors (RR 3.5., RR 2.9, respectively). The most frequently mentioned AE were infections. MAS was reported in all three cohorts. The occurrence of MAS with biologic therapy has been described before and biologics seem not to have a significant effect on risk of MAS or its clinical features in patients with systemic JIA.[22] Infections are the most common trigger, and MAS occurs even in patients whose systemic JIA is well-controlled with this treatment.

Neutropenia as a known side effect of TOC therapy was also observed in our population. In spite of the high rate of AEs under TOC or IL-1i, treatment discontinuation caused by intolerance was very rare within IL-1i (only one patient on canakinumab treatment who had MAS discontinued due to intolerance). However, biologic therapy was often discontinued due to remission of sJIA in the TOC and the IL-1i cohort.

Patients with JIA are already at greater risk of bacterial infections leading to hospitalization due to their chronic disease, the high disease burden and the high necessity for concomitant treatment with systemic corticosteroids. In summary, the safety profile regarding infections seems to be acceptable.

Previous clinical studies on TOC, canakinumab and anakinra demonstrated AE to occur more often in patients receiving a biological agent compared to their respective placebo group.[8–11] Especially, the rates of infections were reported to be higher in patients treated with TOC or canakinumab, as also seen in our analysis of data out of the clinical practice from the BIKeR register. Opportunistic infections were not reported although most of the patients had severe disease and were receiving combination therapies including biologics, immunosuppressants and moreover, corticosteroids. The pattern of AEs observed in this analysis of patients with sJIA is consistent with the known safety profile of biologics reported in other studies. They all were typical of those noted within other biological settings.

Clinical trials of TOC, canakinumab and anakinra in patients with sJIA have demonstrated the high efficacy of these biologic agents compared to placebos. These trials performed by De Benedetti et al.[9] and Yokota et al.[10] on the efficacy of TOC for treating sJIA show a large proportion of up to 90% of patients reaching JIA-ACR 30/50/70 response in week 6 and 12 of treatment. The same strength of efficacy was observed in two randomized clinical trials of canakinumab in patients with sJIA performed by Ruperto et al.[8] and in a clinical trial of anakinra.[9] For ETA no such trial has been performed for patients with sJIA, so a comparison with our results from the BiKeR register is not possible. Long-term observations of treatment with TOC, canakinumab and anakinra in patients with sJIA reveal similar results for efficacy assessment.[22–26]

In terms of the efficacy and safety of the here mentioned biologic treatments for sJIA, the effectiveness and safety profile can be assigned as similar to the other JIA categories. In the CLIPPER study, ETA treatment was effective and well-tolerated in paediatric subjects with extended oligoarticular JIA, enthesites-related arthritis and psoriasis arthritis, with no unexpected safety findings.[27] In a long-term observation of patients with polyarticular JIA, ETA offers an acceptable safety profile and provides significant improvement in disease manifestations.[28] A phase 3, randomised, double-blind withdrawal trial of TOC treatment for polyarticular JIA resulted in significant improvement of signs and symptoms and TOC has a known safety profile reported in other phase 3 studies. The most common mentioned AEs were infections and neutropenia.[29,30] The IL-1i canakinumab is not approved for JIA categories other than in systemic JIA, so a comparison of the efficacy and safety profile is not possible.

The comparison of effectiveness and safety between the ETA cohort and the IL-1i and TOC cohorts may be interpreted with caution and against the background of remarkably higher concomitant csDMARD and steroid use in the ETA cohort. It was not possible to adequately model this difference in a valid propensity score model; the differences remained after adjustments were made.

Beside this, there are a number of further limitations of our analysis. Data were gained from an observational study without any randomisation and a prolonged time period was necessary to gain larger numbers of patients. The decision to start and to stop treatment and the choice of the biologic was made by the responsible local physician with no predefined criteria. Nevertheless, this study provides the first indication for the comparison of different biologic agents in systemic JIA based on observational study data, with all their weaknesses, and demonstrates the need for well-controlled head-to-head studies for confirmation.