JIA, Today and Tomorrow

Unexplained arthritis with symptoms lasting more than 6 weeks and onset before the age of 16 is categorized as juvenile idiopathic arthritis (JIA). This condition is the most prevalent chronic inflammatory rheumatic disease affecting children [1]. The seven different categories of JIA defined by the International League Against Rheumatism (ILAR) are based on the symptoms and signs that emerge in the first 6 months of disease. Although the prognosis of JIA has improved significantly, some children continue to experience inadequate responses to treatment. JIA has an impact on every aspect of the lives of children and their families, prompting researchers to focus on enhancing the health-related quality of life for those impacted by the condition. In this editorial, we focus on some new insights in the field of JIA treatment. Studies carried out by the Pediatric Rheumatology International Trials Organization (PRINTO) have enrolled more than 45 000 patients across 70 countries in 300 hospitals. This high number of cases demonstrates the significant increase in the clinical trials that have been completed since 2000 [2]. These trials do offer various different options for treating JIA. In particular, the final innovation is somewhat linked to Janus kinase (JAK) inhibitors [3].

In 2022, the American College of Rheumatology published its latest JIA guidelines. The escalation strategies for the three JIA phenotypes are as follows: (1) systemic JIA with and without macrophage activation syndrome (MAS), (2) oligoarthritis, and (3) temporomandibular joint (TML) arthritis [4]. A step-up strategy is considered to be the traditional JIA therapeutic approach. According to this method, the drug level is increased from first-line nonsteroidal anti-inflammatory drugs (NSAIDs) to conventional second-line synthetic disease-modifying antirheumatic drugs (cDMARDs), to progression biologic DMARDs (bDMARDs). This strategy is used to treat the various functional forms of JIA, including arthritis with fever (systemic JIA), JIA involving four or fewer joints (JIA with oligoarticular involvement), and JIA involving five or more joints (polyarticular course JIA) [1].

Articular injection of glucocorticoids is the gold standard of treatment for oligoarthritis. Scheduled NSAID is recommended as part of the initial therapy for active disease. bDMARDs are introduced for polyarticular course JIA, including anti-IL-6, anti-CTLA4, anti-TNF, and JAK inhibitors. These treatments are used when methotrexate fails to achieve disease remission, thereby significantly altering JIA treatment. NSAIDs and systemic glucocorticoids have long dominated treatment of systemic JIA; however, the current bDMARDs (IL-1 and IL-6 inhibitors) are conditionally recommended as the first monotherapy for systemic JIA in the absence of MAS [1]. IL-1 and IL-6 inhibitors have been rapidly adopted in clinical practice due to their effectiveness and well-tolerated treatments for systemic JIA [5-8]. Furthermore, a treatment-to-target strategy has been proposed, emphasizing that the focus should not solely be on a single therapy but rather on a comprehensive approach aimed at achieving clinical remission as the primary objective [9]. In patients with long-term disease at least minimal (or low) disease activity should be achieved if the primary target cannot produce clinical remission. Consequently, this method is personalized according to an assessment of disease activity. Based on each patient's characteristics, the target should be set, tools should be defined, and therapeutic decisions should be made in keeping with the individual's and parents' agreement [9].

Among the new strategies for the treatment of JIA, small molecules offer an important alternative biological therapy for inflammatory diseases. Small molecule drugs known to be JAK inhibitors have the distinct advantage of oral administration for pediatricians. An essential role in cell signal transduction is played by multidomain nonreceptor tyrosine kinases (JAKs). Different JAKs are targeted by first-generation drugs and specific JAK types are targeted by the second-generation drugs. Tofacitinib was the first JAK inhibitor commercially approved for the treatment of rheumatoid arthritis. The compound has undergone the classic process of drug development.

To evaluate the treatment of several autoimmune inflammatory diseases, phase III trials have begun [10, 11]. A multicenter phase I study evaluated the safety and pharmacokinetics of tofacitinib [12]. This open-label study assessed the dosing regimens of tofacitinib for pediatric patients with polyarticular JIA. Phase III studies have evaluated the safety and efficacy of a pediatric development program for tofacitinib. The taste of tofacitinib was acceptable and treatment was well tolerated [12]. Another randomized phase III trial included a double-blind and placebo-controlled withdrawal of tofacitinib to treat JIA. According to the results, treatment with tofacitinib produced a fast and sustained clinical improvement in the activity of polyarticular course JIA disease. No new safety risks were identified, suggesting an appropriate balance between risk and benefit for the use of oral tofacitinib in patients with polyarticular JIA [13].

In an international phase III trial, baricitinib (another JAK1/2 inhibitor) was evaluated. This randomized safety trial was a double-blind, placebo-controlled, withdrawal, and efficacy study. Baricitinib improved patient-reported outcomes and clinical measures compared with placebo, demonstrating a favorable balance between risks and benefits for the treatment of JIA. Patients who received baricitinib had a much higher frequency of JIA flare than those who received the placebo during the double-blind study's withdrawal period. Baricitinib also demonstrated more favorable secondary efficacy end points for disease activity, quality of life, and functional ability than the placebo showed. The established profile of indications for baricitinib to treat adults aligned with the safety profile of baricitinib to treat children and adolescents with JIA [14].

Options remain limited to treat patients who have enthesitis-related arthritis (ERA) and juvenile psoriatic arthritis (JPsA), both subtypes of JIA. Therapy for spinal arthritis, represented by anti-IL-17, is crucial. The complete human monoclonal antibody secukinumab can inhibit IL-17A directly. In a randomized phase III trial of secukinumab in patients who had JIA and ERA, nearly 90% showed a response to the double-blind placebo-controlled study during treatment withdrawal. In ERA and JPsA, secukinumab also proved to be safe and demonstrated efficacy [15].

These are study designs of several completed or ongoing multicenter trials (see Table 1 and Figure 1) in which small molecule therapies for JIA have made significant progress and have changed patient outcomes to some extent, but achieving and maintaining drug-free remission remains suboptimal. The future direction lies in patient-specific precision medicine, a strategic pharmacological approach based on the clinical, biochemical, genetic and psychosocial factors of the disease [16]. Sustained international collaboration, high-quality study design, and extensive patient and public participation are the trends [17]. Furthermore, if these new JAK inhibitors prove effective, they may provide a cheaper and more convenient option for the numerous subtypes and clinical complications of JIA, placing higher requirements on the evaluation of treatment-to-target strategy. Simultaneously, JAK and other inhibitors targeting the cytokine signaling pathway may become the research direction of new drugs. Future improvements in response rates will also require more innovative trials and collaborative studies of new medications in children and adolescents to further understand drug effectiveness and optimal use strategies. Research to treat JIA has continued to advance with the objective of achieving clinical remission or at least inactive disease. The goal was to produce limited adverse effects as well as to rapidly improve quality of life in patients with JIA to match their healthy peers. Increasingly effective and safe biologics are being introduced in clinical treatment to provide even better options to treat JIA. These personalized treatments are making it possible to recommend individual options for each child. Significant research, however, is still needed despite these developments.

Wenbo Zhang, Huihua Yuan, and Xing Lv drafted the manuscript and managed the submission. Huihua Yuan, Xing Lv, Chunlin Huang, Haisheng Zeng, Dexin Liu, and Nicola Ruperto provided editorial support. Huasong Zeng reviewed the manuscript several times.

The authors declare no conflicts of interest.