Efficacy and safety of TNF inhibitors in the treatment of juvenile idiopathic arthritis: a systematic literature review

Juvenile idiopathic arthritis (JIA), the most common rheumatic disease observed in children, has been defined as “arthritis of unknown etiology that begins before the 16th birthday and persists for at least 6 weeks” by the International League of Associations for Rheumatology [1]. Overall, JIA has a reported incidence of 8 per 100,000 and 10–12 per 100,000 in Europe and the USA, respectively, while the corresponding prevalence is 70 per 100,000 and 45–58 per 100,000 [2‐4]. In childhood, JIA is a leading cause of short- and long-term disability due to progressive destruction of cartilage and bones within joints, as well as growth retardation [5‐8]. Approximately 50% of children who develop JIA continue to have active disease into adulthood, with ongoing physical disability and declining health-related quality of life (QoL) [8‐10], but adult patients with JIA may be underrepresented in clinical studies.

As recommended by the treatment guidelines published by the American College of Rheumatology (ACR) [11], first-line pharmacotherapy for JIA usually consists of a combination of nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular glucocorticoids, and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), with methotrexate being the most frequently used csDMARD. If a clinically inadequate outcome is achieved with this initial approach, treatment with a biologic DMARD (bDMARD), such as a tumor necrosis factor inhibitor (TNFi), may be considered as a second-line option. However, an International Task Force has proposed replacing this traditional sequential approach to JIA treatment with a treat-to-target strategy, in recognition that remission and low disease activity are currently achievable goals in most patients with JIA with recent therapeutic advances [12].

Two classes of recombinant TNFi are currently used in the treatment of JIA: TNF receptor fusion proteins (e.g., etanercept) and monoclonal anti-TNF antibodies (adalimumab, certolizumab pegol, golimumab, and infliximab), and some related biosimilars [13‐21]. Etanercept was the first bDMARD to be evaluated in JIA, followed by infliximab, adalimumab, tocilizumab, abatacept, golimumab, and secukinumab; certolizumab pegol is currently under investigation. To date, no head-to-head trials have compared outcomes with different bDMARDs, especially TNFis, in JIA. Several meta-analyses and systematic reviews of the efficacy and/or safety of these agents have been published [21‐27]. We conducted the current systematic literature review (SLR) to provide an update on previous reviews, including more recent literature, and to examine findings from pediatric and adult patients with JIA treated with a TNFi in the context of both clinical trials and large observational studies and registries, which afford experience with treatment in routine care settings. In the following article, we summarize the published data on the efficacy/effectiveness and safety of TNFis when used in clinical trials and observational studies of patients with JIA.

In this SLR, we identified many publications that assessed the use of TNFis in patients with JIA. The SLR included placebo-controlled randomized withdrawal trials and parallel-group trials, in addition to observational cohort studies. Efficacy estimates from these different designs are not comparable and should be viewed in light of the underlying study design. Overall, the data reported in these publications suggest that adalimumab, etanercept, golimumab, and infliximab are effective and well tolerated when used for the treatment of JIA. Because no publications describing studies of certolizumab pegol or TNFi biosimilars met the inclusion criteria of this SLR, the efficacy and safety of these agents in patients with JIA could not be examined. Most of the publications were of good quality, with a low risk of bias according to the RoB2 and NOS tools. However, of the RCTs identified, none were head-to-head studies of TNFis. In addition, most of the available evidence on TNFi treatment in JIA was derived from studies of etanercept (Table 1), reflecting in part the fact that this agent has the longest history of investigation in JIA.

Most of the studies that we identified included patient cohorts with multiple categories of JIA grouped under the functional concept of polyarticular-course JIA (namely, extended oligoarthritis, rheumatoid factor–positive or –negative polyarthritis, and/or systemic arthritis without active systemic symptoms in the prior 6 months). This JIA functional grouping was first introduced in the etanercept Phase 3 trial [13] and was adopted in subsequent TNFi Phase 3 trials by excluding patients with systemic onset JIA with recent systemic features. The approach, accepted by regulatory authorities such as the European Medicines Agency and U.S. Food and Drug Administration, was necessary because it was not feasible to conduct studies including patients with a single JIA category [48]. Studies that included populations with different categories of JIA provided little evidence of any difference in the efficacy and safety of TNFis when used in the different categories included within polyarticular-course JIA, although several reported reduced efficacy and increased discontinuation rates in patients with systemic JIA versus nonsystemic JIA. However, the latter differences should be interpreted with caution due to differences in disease severity/duration and treatment duration among the studies. A 2016 systematic review also provided some evidence of differences in responses to individual biologics by JIA category but noted the underrepresentation of some JIA categories in published studies [26].

The importance of transitional care for children with JIA has been demonstrated by findings that approximately 50% will continue to have active disease into adulthood, with further declines in physical health-related QoL and potential long-term disability [8‐10]. In patients with JIA who continue to experience flares into adulthood, flares may preferentially impact previously inflamed joints, but patients are also at sustained risk for new joint accumulation [49]. A multifaceted clinical approach and optimal treatment are needed during the transition period. It should be emphasized that most data on the efficacy and safety of TNFis in the treatment of JIA were only available from children and adolescents. In fact, none of the publications of RCTs or nRCTs identified in the SLR included patients with JIA who were aged ≥ 18 years, and only 11 observational studies included such patients. Unfortunately, few of the latter observational studies reported evidence or discussed requirements relating to the transition from pediatric to adult care. Studies that include post-adolescent patients with long-term JIA are necessary to gain insight into the safety and effectiveness of TNFis when these agents are used through the transition from childhood to adulthood, including through periods of treatment discontinuation and/or switches. The challenges associated with patient follow-up through this transition period may explain, at least in part, the small number of studies that include such patients.

In addition to the absence of findings on treatment outcomes during the transition from pediatric to adult JIA care, several other important evidence gaps were identified in this SLR. Clinical evidence is lacking from TNFi RCTs, especially from head-to-head comparative studies. Additional data on clinical outcomes achieved with each TNFi across the different JIA categories would facilitate development of more specific treatment guidance, with the potential for improving outcomes. Most available evidence is derived from observational studies based on large patient registries, which have contributed essential information about the real-world safety, effectiveness, and tolerability of TNFi treatments developed within the context of clinical trials. For example, current evidence from observational studies indicates that infections are the most common adverse events and SAEs reported with the use of TNFis and other bDMARDs [50, 51]. Finally, in this SLR, we also found a considerable difference in the quantity of evidence available for each TNFi, with the more recently studied agents having the least information on their use. This gap is primarily attributable to differences in the development timelines of the TNFis included for review.

Only one infliximab study, which evaluated doses of 3 or 6 mg/kg, reported JIA-ACR response rates. For some indications, patients may benefit from higher doses of infliximab (e.g., up to 10 mg/kg every 8 weeks), and higher doses are sometimes used in clinical practice [52, 53]. However, no studies included in this SLR evaluated efficacy of doses of infliximab > 6 mg/kg.

This study builds on the findings of several prior systematic reviews and meta-analyses of efficacy and/or safety of bDMARDs in JIA that have been published between 2013 and 2020 [21‐27]. For example, a 2016 meta-analysis of randomized withdrawal trials of biological agents in polyarticular JIA reported that the included biologics (abatacept, adalimumab, anakinra, etanercept, and tocilizumab) were similarly effective and safe compared with placebo [23]. The results of a 2020 meta-analysis of randomized controlled trials of biological agents in JIA also supported a net benefit in favor of biologic agents in the short term [27]. Given the need for long-term effectiveness data [22], it is important to continue to review emerging data from registries and long-term extension studies.

The present analysis has some specific limitations beyond those generally associated with the conduct of an SLR, such as the restriction to English-language publications and specific congresses and databases included in the search. The main limitation was the heterogeneity of the studies described in the publications identified, which prevents direct comparisons (such as meta-analysis) of evidence from clinical trials or observational studies. This heterogeneity arises largely from differences in the following features: 1) study design/methodology (e.g., outcomes, time of assessment/follow-up); 2) treatment arms (e.g., dosing, concomitant medications, treatment duration); and 3) patient populations (e.g., JIA of varying categories, duration, and severity; DMARD/biologic/TNFi-naïve, -intolerant, or -refractory). Another limitation of our analysis is the lack of a formal comparison of the patient populations across the different studies in terms of baseline disease severity. In addition, the exclusion of treatment arms containing fewer than 30 patients, implemented to increase the robustness of the data, is also considered a limitation. Moreover, a detailed description of SAEs reported in the included studies was beyond the scope of our SLR but may be worthy of additional analysis in future research. Finally, we note that the SLR was conducted according to PRISMA 2009 guidelines [28], which were current at the time the literature searches were conducted; however, updated PRISMA recommendations have recently been published [54].

In conclusion, the published evidence suggests that adalimumab, etanercept, golimumab, and infliximab are effective and well-tolerated treatments for JIA. This SLR could serve as the basis for a dedicated meta-analysis of the efficacy and safety of TNFis in JIA, as well as a future SLR dedicated to functional and QoL outcomes that would provide more precise guidance for the optimal use of TNFis in JIA.