Growth Impairment in Juvenile Idiopathic Arthritis: An Overlooked Therapeutic Target Introduction

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children, defined by persistent arthritis of unknown origin beginning before 16 years of age and classified into seven subtypes under the ILAR criteria [1]. Growth impairment is one of the most visible long-term complications, affecting both final height and developmental outcomes. The degree of impairment differs by subtype: children with systemic JIA are most vulnerable due to early onset, systemic inflammation, and prolonged disease activity. Enthesitis-related arthritis often allows near-normal growth, whereas polyarticular and extended oligoarticular subtypes show intermediate outcomes. Psoriatic and undifferentiated JIA follow more heterogeneous patterns, influenced more by inflammatory activity than the subtype itself [2]. Growth restriction in JIA is not merely a cosmetic concern. Short stature and impaired pubertal progression reflect disease burden, treatment toxicity, and systemic inflammation. These consequences extend into adulthood, influencing musculoskeletal development, function, and psychosocial well-being. Nationwide cohort data from Taiwan further demonstrated that JIA patients continue to face substantial disease burden and adverse outcomes in adulthood [3]. This reflects a broader paradigm of genetic and inflammatory interactions underlying long-term outcomes. Growth impairment in JIA arises from complex interactions between chronic inflammation, treatment exposures, and nutritional status. Glucocorticoid exposure remains a central determinant. Cumulative dose and treatment duration correlate strongly with reduced height velocity and compromised adult stature [4]. Suppression of the GH–IGF-1 axis and direct skeletal toxicity explain much of this effect. Inflammatory cytokines, particularly IL-6, disrupt growth through IGF-1 suppression and effects on growth plates. The persistence of systemic inflammation in uncontrolled JIA amplifies these mechanisms. Biologic therapies have improved outcomes by reducing inflammation and reducing steroid dependence. Anti-TNF therapy increases height velocity in severe cases [5], while IL-6 blockade with tocilizumab has been associated with catch-up growth and normalization of IGF-1, particularly when glucocorticoids are tapered [6]. Endocrine interventions with recombinant GH have demonstrated limited efficacy, and benefits are blunted by ongoing inflammation or persistent steroid exposure. Taken together, minimizing glucocorticoids, controlling systemic inflammation, and appropriately timing endocrine therapy are the mainstay strategies. Importantly, a multidisciplinary approach encompassing rheumatology, endocrinology, and nutrition appears essential to safeguard long-term growth trajectories. Recent evidence has sharpened the epidemiological picture. A Taiwanese cohort demonstrated that early-onset JIA (< 6 years) and systemic JIA are strong predictors of markedly reduced adult height [7]. This finding provides clarity but also underscores an unmet need: growth preservation has never been studied as a primary therapeutic target in randomized trials. Current management focuses primarily on disease activity, relegating growth impairment to a secondary observation. Endocrine approaches such as GH supplementation provide only partial benefit and remain vulnerable to neutralization by inflammation and glucocorticoids. While anti-TNF agents have demonstrated improvement in growth velocity and partial catch-up [5], the impact of IL-1 and IL-6 inhibition on final adult stature remains insufficiently evaluated. Nutritional factors remain underexplored as modifiable risk factors. The broader implications of impaired growth—including orthopedic complications, altered body composition, reduced functional capacity, and diminished quality of life—reinforce the argument that height outcomes should be considered integral markers of disease impact. The field must now pivot from retrospective recognition toward prospective, mechanism-based intervention trials. Several key priorities emerge: Early evidence suggests that tocilizumab may improve IGF-1 signaling, and anti-TNF therapy increases growth velocity [5]. Future randomized studies should explicitly evaluate biologic–GH combination regimens, with growth parameters—height SDS, pubertal progression, and final adult stature—designated as prespecified endpoints. Altered body composition, lean mass deficits, and micronutrient insufficiencies are well described in JIA [8]. Structured nutritional programs should be systematically integrated into standard care, potentially amplifying the benefits of anti-inflammatory and endocrine therapies. Risk stratification based on predictors of reduced adult height may inform earlier orthopedic referral [7]. Early imaging, growth plate monitoring, and proactive orthopedic consultation should be incorporated to prevent irreversible skeletal deformities. Optimal care requires coordinated input from pediatric rheumatologists, endocrinologists, nutritionists, and orthopedic specialists. Growth should be formally incorporated into treat-to-target strategies, alongside disease remission and quality of life. Integration of cytokine profiles, IGF-1 levels, growth plate imaging, and genetic risk markers may allow risk stratification and individualized therapeutic planning. Such tools could identify children most likely to benefit from early combined biologic and GH therapy. Growth impairment in JIA has long been recognized but insufficiently addressed. While systemic inflammation and glucocorticoids remain central drivers, emerging biologic therapies and adjunctive endocrine strategies have opened new opportunities to preserve final height. However, without prospective, mechanism-driven trials, children at highest risk, particularly those with early-onset and systemic JIA remain without targeted solutions. It is time to elevate growth preservation from a secondary concern to a central therapeutic target. By integrating biologic therapies, endocrine interventions, nutritional strategies, and orthopedic monitoring into a coordinated framework, the pediatric rheumatology community can move beyond recognition of vulnerability to delivering durable, evidence-based strategies that safeguard not only survival and remission, but also the developmental potential of children living with JIA. Pin-Jiun Chen, Rou-Yi Chen: conceptualization; data curation; writing – original draft; Su-Boon Yong, Chia-Jung Li: project administration; resources; supervision; review and editing. The authors declare no conflicts of interest. The authors have nothing to report.