This study demonstrated that Infliximab is effective and safe in the treatment of JoSpA. The primary endpoint, namely the number of active joints, was significantly lower in patients on infliximab compared to placebo. Moreover, most secondary outcomes, including composite scores and response criteria, showed improvements in favour of Infliximab. The repeated mixed model analyses showed sustained efficacy of infliximab on the primary and most secondary outcomes during the open label phase. AEs were mild and mostly related to infections and infusion reactions.
Although the incidence of JoSpA in Paediatric Rheumatology clinics is relatively low, the disease seems more active and severe than other JIA and adult-onset SpA (28, 29). The risk of developing r-axSpA within 10 years from onset is higher in HLA-B27 boys who are ≥8 years old and present with foot arthritis, enthesitis along with hip, sacroiliac, and spinal involvement at onset (30–33). Before the use of bDMARDs, disease remission occurred in only 20% of patients with JoSpA five years after onset. At 15-year follow-up, disease remained active in 50% of the cases, and disease activity at baseline predicted functional impairment at 10 years in 60% of the patients (32, 34, 35). Moreover, patients with JoSpA score higher in the CHAQ (31, 36) and bodily pain (37, 38) than other JIA categories.
Up to date, the efficacy of bDMARDs in children with JoSpA has not been established well in RCTs. The documented efficacy of bDMARDs in patients with a polyarticular JIA and adults with axSpA has contributed to justify their use in children and adolescents with JoSpA and enthesitis-related arthritis (ERA). JIA categories differ from each other regarding prevalence, clinical features, outcome measures, and management. Considering ethical constraints related with conducting RCTs in children, the use of a controlled withdrawal design RCT has become the standard for clinical trials in JIA, eventhough the appropriateness of this standard has been questioned (39–41). Therefore, most of the clinical trials on the use of TNFi in JoSpA utilized a controlled withdrawal desing and only one has utilized a standard RCT design (15), which we implemented in the present study.
Two open-label studies on the efficacy of bDMARDS in the JoSpA population have been published. One open-label study on Etanercept for 24 weeks clearly showed an effect of the TNFi to prevent disease flares (42). Similarly, the open-label CLinical Study in Paediatric Patients of Etanercept for treatment of ERA, PsA, and extended oligoarthritis (CLIPPER)(14, 15, 43) showed efficacy of the biologic to achieve the ACR Pedi 30 response at 12 weeks. This study utilized two historical groups for comparison with the treatment group (14, 17).
Two other RCTs evaluated the efficacy of the bDMARD Adalimumab in the JoSpA population (16, 17). Our trial contributes to reduce the existing gap in the literature with only few placebo-controlled RCTs conducted (40). Conducting placebo-controlled RCTs in the JoSpA population has several advantages. One of the mentioned Adalimumab RCTs included 32 patients with Juvenile-onset Ankylosing Spondylitis (JoAS) and found no statistically significant differences between adalimumab and placebo in the achievement of ASAS 40 response as their primary endpoint (17). The other RCT on Adalimumab included 46 patients with ERA and found a clear positive effect of the TNFi on the percentual change from baseline in the number of active joints in comparison to placebo (16). Utilizing the “percentual change from baseline” to attribute intervention causality in RCTs has been shown ineffective due to this strategy’s high sensitivity to changes in variance, reducing its power to detect true differences (28). Additionally, in our study we opted for ANCOVA adjusting for baseline outcomes for the between group comparison of means at the end of the RCT as a more appropriate manner to assess between group differences.
Moreover, even though we selected the same RCT design as the Adalimumab studies previously referred, we implemented more stringent criteria to select patients with higher disease activity. We believe that our disease activity parameters are more in line with what is currently used to identify children with JoSpA/ERA who require bDMARDs. Inclusion criteria of other studies have been typically more permissive including a wider range of disease activity, which could go from two active joints in CLIPPER (14) to a combination of sacroiliac, spinal, oligoarthritis, and imaging studies in the JoAS trial (17).
With respect to our primary outcome selection, the ACR Pedi 30 response criteria has been the primary endpoint of RCT withdrawal trials, which included the ACR criteria for flare (42). The Adalimumab trials included ASAS40 response as a primary outcome (16, 17). We selected the number of active joints as our primary outcome, due to its clinical implications, which strongly indicates the disease severity in this population. In addition, our results demonstrate that this outcome is sensitive to change, and clinically important differences can be found even in small samples.
There were no SAEs reported in this study. However, more patients on Infliximab had infectious and infusion-related reactions compared with placebo. In contrast, a trial of Infliximab in 122 patients with polyarticular-course juvenile rheumatoid arthritis randomised to 3 mg/kg or 6 mg/kg yielded AEs in 95% of the patients (18, 19), including serious AEs in 32% of infliximab users. The Pharmachild (n = 2022; all licensed bDMARDs) and Biker (n = 1697; all licensed bDMARDs) registries barely mention the use of Infliximab suggesting low utilization of this TNFi in the paediatric population in some countries (44–48). Interestingly, few AEs have been reported with the use of high doses of Infliximab in refractory cases of JIA extra musculoskeletal manifestations such as uveitis (49, 50).
The limitations of our study could be related with potential comparability with future studies, particularly the fact that we did not use composite measures as our primary outcome. Some of the newest composite measures, such as the AS Disease Activity index (51, 52), the juvenile SpA Disease Activity index (53), and the Juvenile Arthritis Disease Activity Index (JADAS) (54) were not available when we designed the study, and have since been developed to improve the assessment of patients with JoSpA and can be used in future clinical trials. Another limitation was related with the sample size calculation, as by the time we planned the study there were no clinical trials on the use of TNFi for JoSpA in the literature. Therefore, the power of our study was determined by experts’ opinion on the significant difference expected among groups. The fact that our sample size was enough to detect significant differences between groups on our primary outcome, makes this limitation less relevant for the conclusions that emerge from our findings.