Exertional leg pain (ELP) is a common but frequently underrecognized symptom in children with familial Mediterranean fever (FMF). This study aimed to evaluate the clinical characteristics of ELP, its relationship with disease severity, and its potential impact on treatment modifications in a large pediatric cohort. This study evaluated pediatric FMF patients (2013-2024) fulfilling the 2019 Eurofever/PRINTO criteria. Demographic, clinical, genetic, and treatment data were analyzed. Disease severity was assessed using the International Severity Score for FMF (ISSF). Among 1290 patients, 464 (36.0%) experienced ELP. Patients with ELP were diagnosed at a younger age and had a longer follow-up duration (p = 0.005 and p < 0.001). ELP was significantly associated with arthralgia (p < 0.001), arthritis (p = 0.003) and erysipelas-like erythema (p = 0.01). According to the ISSF, patients with ELP had higher disease severity scores and a higher frequency of moderate-to-severe disease (p = 0.007). Homozygous M694V mutations and colchicine resistance were more frequent in the ELP group (both p < 0.001) and multivariate analysis identified M694V homozygosity, longer follow-up duration, and higher disease severity as independent predictors of ELP. Treatment modifications were required in 68 (14.6%) patients with ELP, most commonly involving colchicine dose escalation or nonsteroidal anti-inflammatory drugs. Further evaluation revealed sacroiliitis in 6 (1.3%) patients and chronic nonbacterial osteomyelitis (CNO) in 2 (0.4%) patients. CONCLUSION: ELP is associated with increased disease severity and colchicine resistance in pediatric FMF and may influence treatment decisions, particularly in patients with conditions like sacroiliitis or CNO. Systematic assessment of ELP provides insight into disease characteristics and helps identify patients with a more challenging disease course. WHAT IS KNOWN: • Exertional leg pain is a recognized musculoskeletal manifestation of familial Mediterranean fever. • It has been associated with arthritis, enthesopathy, and a more severe disease phenotype. WHAT IS NEW: • In a large pediatric cohort, exertional leg pain was associated with increased disease severity, colchicine resistance, homozygous M694V mutations, and was more frequent in patients with erysipelas-like erythema and lower-extremity arthritis. • Recognition of exertional leg pain influenced treatment decisions and occasionally prompted evaluation for sacroiliitis or chronic nonbacterial osteomyelitis.
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