Adalimumab Versus JAK Inhibitors in Juvenile Idiopathic Arthritis

Abstract

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease that begins in childhood and is characterized by persistent joint inflammation. It includes a diverse and heterogeneous group of conditions categorized into seven subtypes based on clinical manifestations, genetic, and serological factors [1]. If left untreated, JIA can lead to a poor health-related quality of life (HRQoL), significant functional impairment, and disability. According to the American College of Rheumatology (ACR) guidelines, first-line treatment for JIA typically involves nonsteroidal anti-inflammatory drugs (NSAIDs), intra-articular glucocorticoids, and conventional synthetic disease-modifying antirheumatic drugs (csDMARDs). If the response is inadequate, biological DMARDs (bDMARDs), such as tumor necrosis factor inhibitors (TNFi), may be considered as a second-line treatment [2]. With ongoing advances in pharmacotherapy, Janus kinase inhibitors (JAKi) have also emerged as a treatment option.

TNFi effectively manages JIA by targeting and neutralizing TNF-α, a key cytokine driving inflammation in immune-mediated conditions. Currently, the TNFi available for treating JIA include adalimumab, etanercept, golimumab, and infliximab. A systematic review found limited evidence of differences in the efficacy and safety of TNFi across various JIA categories [3], although a 2017 review noted variable responses to biologics by JIA category and underrepresentation of specific categories in studies [4].

A randomized controlled trial (RCT) indicates that adalimumab, either alone or in combination with methotrexate, is an effective treatment for children with JIA. It significantly reduces joint inflammation and swelling [5]. Additional research has also evaluated the long-term safety and efficacy of adalimumab for JIA patients, finding that it is well tolerated and leads to significant clinical improvements. However, its retention rate is relatively low, mainly due to non-treatment-related factors [6]. Despite significant advancements in treatment over the past two decades, approximately one-quarter of patients with JIA remain resistant to these therapies [7]. This underscores the need to develop new medications explicitly targeting these challenging cases.

JAKi is a novel class of small-molecule medications. In contrast to the injectable options required for bDMARDs, their oral formulation may improve medication adherence. This is particularly beneficial for children, adolescents, and individuals with needle aversion. JAKi reduces inflammation and modulates immune responses by inhibiting Janus kinase activity, which blocks cytokine signaling—a key driver of various inflammatory processes. Different JAKis target distinct JAK enzymes, resulting in varied clinical applications in JIA subtypes. According to phase 3 clinical trials, tofacitinib is approved for polyarticular JIA (pJIA) and juvenile psoriatic arthritis (JPsA) in patients aged 2 years and older. In contrast, baricitinib is approved for pJIA, enthesitis-related arthritis (ERA), and JPsA [8, 9]. Recently, population pharmacokinetic modeling and simulation have led to the approval of upadacitinib for pediatric patients with pJIA and JPsA in the United States [10]. Completed RCTs involving adalimumab and JAKi in JIA patients are summarized in Table 1. Table 2 provides a comparative summary of their treatment characteristics.

Uveitis is the most common extra-articular manifestation of JIA and can lead to serious complications, including adhesions, cataracts, glaucoma, and vision loss. Current treatment guidelines recommend TNFi like adalimumab and infliximab, which have proven effective for refractory cases after methotrexate therapy [16]. However, some patients still experience treatment resistance even with these biologics, and JAKi is being evaluated as a promising alternative therapy for these challenging cases. A case series report involving four patients with a long history of JIA and severe associated uveitis showed that after treatment with JAKis—specifically baricitinib (three cases) and tofacitinib (one case)—all patients showed improvement in uveitis and good tolerability. However, the response in articular disease was not as favorable as that in uveitis [17]. An ongoing phase 3 trial is also evaluating the safety and efficacy of baricitinib compared to adalimumab in patients with JIA-associated uveitis (EudraCT 2019-000119-10; NCT04088409). These studies may offer insights into whether JAKi is a suitable treatment to address the unmet needs of patients who experience inadequate responses or intolerable side effects from current therapies.

In addition to efficacy, the potential adverse events of medications warrant careful attention to ensure patient safety. Adalimumab may increase the risk of infections and cause injection-site reactions, such as pain. Common adverse events in JIA and other pediatric indications include upper respiratory tract infections, nasopharyngitis, and headaches. In rare cases, severe allergic reactions can occur [11]. A 2008 trial of 171 patients receiving adalimumab (stratified into two groups, with or without methotrexate) reported severe adverse events, including neutropenia and infections (such as herpes simplex, shingles, urinary tract infections, pneumonia, and pharyngitis). No malignancy, tuberculosis, or lupus-like reactions were reported [5]. Regular medical monitoring is essential to evaluate the therapeutic response and potential adverse effects.

As a relatively novel class of therapies, JAKis are currently under investigation for their long-term safety. Commonly reported adverse events in children with JIA include upper respiratory tract infections, nasopharyngitis, headache, arthralgia, and JIA exacerbations. More serious concerns include severe infections, herpes zoster, tuberculosis, uveitis, and other opportunistic infections [8, 9, 14]. A study in rheumatoid arthritis indicates that tofacitinib is associated with a higher risk of infections compared to TNFi [18]. Cardiovascular events and malignancies have also been reported in adult JAKi users, primarily among patients aged ≥ 65 years, long-term smokers, or those with a history of atherosclerotic cardiovascular disease [15]. Although such risks have not been observed in the JIA population, caution is warranted in the use of JAKi until comprehensive long-term pediatric safety data become available.

A long-term extension study of tofacitinib, conducted in patients with JIA and encompassing over 700 patient-years and up to 105 months of follow-up, identified no new safety signals beyond those reported in the phase 3 trials. Laboratory abnormalities, including elevations in lipid levels and creatine kinase, have been observed during treatment [14]. Notably, in the phase 3 trial of baricitinib in patients with JIA, one case of pulmonary embolism was reported as a serious adverse event [9]. Given the involvement of the JAK–STAT pathway in growth hormone signaling, concerns have been raised regarding the possible effects of prolonged JAKi use on growth and development in children. The long-term safety profile of JAKi in children remains incompletely understood and warrants further investigation to assess their risk–benefit balance fully.

In addition to TNFi and emerging JAKi, biological therapies targeting different mechanisms are used to treat various types of JIA. Interleukin-1 inhibitors (e.g., Anakinra) and Interleukin-6 inhibitors (e.g., Tocilizumab) are commonly used for systemic JIA (sJIA), with Tocilizumab also approved for pJIA. Abatacept, which inhibits T-cell costimulation, is approved for pJIA as well. Although Rituximab, an anti-CD20 monoclonal antibody, is not yet approved for JIA, a cohort study suggests it may be effective for children who do not respond to TNFi [19]. A recent ongoing phase 3 multicenter trial (NCT06654882) compares the efficacy of a second TNFi (active control) with three alternative therapies—Tofacitinib (JAKi), Tocilizumab (Interleukin-6 inhibitors), and Abatacept (T-cell costimulation inhibitor)—in children aged 2 to 17 years with pJIA and inadequate response to the initial TNFi. The study aims to provide evidence for sequential medications for JIA patients who fail initial bDMARD treatment.

Adalimumab remains a well-established first-line treatment for patients with pJIA or enthesitis-related arthritis, and extensive clinical trial data supports its effectiveness in managing JIA-associated uveitis. Conversely, JAKi represents an emerging alternative treatment for patients who are unresponsive to, intolerant of, or prefer oral administration over TNFi. Although JAKi typically offers a lower-cost option than adalimumab or other biologics, it still burdens many patients, highlighting the need for biosimilars and more affordable alternatives.

Ongoing research is focused on optimizing treatment selection for various JIA subtypes, determining the best timing for drug initiation and discontinuation, understanding pediatric pharmacokinetics and dosing, and identifying accurate biomarkers for drug efficacy monitoring. Additionally, studies are exploring non-pharmacological interventions such as exercise and dietary modifications. While most data on JIA's safety and efficacy come from studies involving children and adolescents under 18, findings suggest that about 50% of those with JIA will continue to experience active disease into adulthood [20]. This highlights the need for further research into the transition from pediatric to adult care. Head-to-head comparisons of therapies for JIA remain a critical area for future research. Enhancing our understanding of these therapies is crucial for personalizing treatment, improving patient outcomes, and ensuring broader access to effective treatments.

Tsai-Yi Hung: conceptualization, writing – original draft preparation. Yung-Heng Lee: writing – review and editing. Brian Shiian Chen: writing – review and editing. Chen Dong: writing – review and editing. An-Ping Huo: conceptualization, writing – review and editing.

The authors declare no conflicts of interest.