Still’s disease exists in two closely related forms: systemic juvenile idiopathic arthritis, which begins in childhood, and adult-onset Still’s disease, which strikes later in life. Both are rare autoinflammatory disorders driven by an overactive innate immune system. Research over the past two decades has converged on a unified picture of the disease, in which the interleukin-1, interleukin-6, and interleukin-18 signaling pathways run amok, inflammasome activity surges, and neutrophils dominate the inflammatory landscape. In a subset of patients, the illness evolves into a chronic articular form that increasingly involves the adaptive immune system, resembling rheumatoid arthritis in its joint destruction.

This evolving understanding of disease biology has transformed treatment. Recently published recommendations from the European Alliance of Associations for Rheumatology together with the Paediatric Rheumatology European Society, and separately from the American College of Rheumatology, now emphasize early treatment with interleukin-1 or interleukin-6 inhibitors, paired with short courses of corticosteroids. The logic is compelling: blocking the driving cytokines quickly, within a therapeutic window of opportunity, appears to yield better outcomes, faster steroid tapering, and potentially drug-free remission. Against this backdrop, the reviewers argue, methotrexate should not be used as initial monotherapy for the acute systemic phase and should never delay biologic treatment when such agents are available.

Yet the evidence supporting methotrexate is far from negligible. The most comprehensive real-world dataset comes from the AIDA Network Still’s Disease Registry, which included 171 patients treated with the drug, mostly by subcutaneous injection at a mean weekly dose of about 15 milligrams over a median of 14 months. In that cohort, methotrexate significantly reduced systemic disease activity and C-reactive protein levels, with clinical remission achieved in roughly 39 percent of patients on monotherapy. When methotrexate was combined with a biologic agent, most often an interleukin-1 or interleukin-6 inhibitor, the remission rate climbed to nearly 70 percent, and concurrent biologic use was an independent predictor of remission.

The steroid-sparing effect may be methotrexate’s most clinically important attribute. In the AIDA registry, mean daily glucocorticoid doses fell from 25 milligrams to zero, and more than a third of methotrexate-treated patients stopped steroids entirely, a figure that rose above 58 percent with combination therapy. Earlier studies reinforce this pattern. A French multicenter study of 64 patients found that methotrexate produced a response in 88 percent of corticosteroid-resistant cases, with complete remission in 69 percent and prednisone doses reduced by more than two-thirds. A large Turkish multicenter cohort reported remission in 83 percent of patients treated with methotrexate plus corticosteroids. A Japanese retrospective series, by contrast, showed remission in about 62 percent of patients but also documented adverse effects including liver toxicity and one case of acute interstitial pneumonia, a reminder that tolerability varies.

The only randomized comparison between methotrexate-based therapy and biologic blockade comes from a small open-label trial in refractory adult-onset Still’s disease. Twenty-two corticosteroid-dependent patients were assigned to anakinra, an interleukin-1 receptor antagonist, or to conventional synthetic disease-modifying drugs, six of whom received methotrexate. Remission rates at weeks 4, 8, and 24 numerically favored anakinra but did not reach statistical significance, and both groups achieved comparable reductions of roughly 10 milligrams in daily prednisolone. A separate multicenter retrospective analysis of 141 patients treated with anakinra, 91 of whom also received methotrexate, found no consistent superiority of the biologic, though early anakinra use did resolve joint swelling faster. These findings suggest that in articular-dominant or less severe systemic phenotypes, conventional therapy can achieve comparable control in many patients.

In children, the picture is similarly constrained by limited evidence. No randomized controlled trials have specifically evaluated methotrexate in systemic juvenile idiopathic arthritis; the data derive from observational series and subgroup analyses of broader juvenile arthritis populations. The 2018 MARAJIA expert consensus endorsed methotrexate mainly for controlling the articular component of the disease, while the 2021 American College of Rheumatology guidelines strongly discourage conventional synthetic drugs as initial monotherapy for systemic features such as fever and rash. Pediatric dosing follows standard juvenile arthritis practice, at 10 to 15 milligrams per square meter of body surface area weekly, escalating to 20 milligrams per square meter if tolerated. Mild liver enzyme elevations, gastrointestinal symptoms, and cytopenia are the most common adverse events, and because systemic juvenile arthritis itself can impair liver function, careful hepatic monitoring is essential.

The safety profile of methotrexate in Still’s disease mirrors its long-established record elsewhere. Cytopenia and elevated transaminases are the most frequently reported problems, while hepatic fibrosis and myelosuppression are rare. Concomitant nonsteroidal anti-inflammatory drugs can amplify hepatotoxicity, and gastrointestinal disturbances such as nausea and mucositis sometimes force dose reduction. Pulmonary toxicity, manifesting as acute interstitial pneumonitis, is uncommon but serious, as illustrated by the Japanese case series. Folic acid supplementation mitigates many side effects, and structured monitoring, with blood counts, liver tests, and creatinine checked every two weeks for the first three months and then quarterly, allows early detection of toxicity. Because the drug is teratogenic, discontinuation is mandatory at least three months before conception in both men and women, and vaccination schedules should be kept current given the drug’s immunosuppressive action.

Mechanistically, methotrexate’s benefit in Still’s disease remains incompletely understood. Some evidence from rheumatoid arthritis suggests the drug may indirectly modulate interleukin-1 signaling, and this hypothesis has been extrapolated to Still’s disease, but no disease-specific mechanistic study has directly demonstrated an interleukin-1-mediated therapeutic effect. The reviewers are candid about the limitations of the evidence base: no randomized trials designed specifically for Still’s disease exist, remission definitions vary widely across studies, and most data come from retrospective cohorts vulnerable to selection bias and confounding by indication. Reported remission rates, ranging from about 39 percent with monotherapy to 83 percent with steroid combinations, should therefore be interpreted cautiously rather than compared across studies.

The practical takeaway is a stepwise, individualized algorithm. Early interleukin-1 or interleukin-6 inhibition remains the cornerstone for active systemic disease. Methotrexate, which takes roughly four weeks to show effect and three months to reach optimal efficacy, is positioned as a third-line option after failure of biologic inhibitors in patients with residual arthritis but no organ involvement or systemic features. Combination therapy with biologics may benefit selected patients with persistent joint disease or corticosteroid dependence. In regions where biologic access is limited by cost or infrastructure, methotrexate offers a pragmatic early option, though the reviewers stress this reflects healthcare constraints rather than proven equivalence to cytokine blockade. Future progress, they argue, depends on phenotype-stratified prospective trials and biomarker-driven stratification, such as interleukin-1 and interleukin-6 activity profiling, to identify which patients will truly benefit from this venerable but still imperfectly understood drug.

Subject of Research: The efficacy and safety of methotrexate in treating Still's disease within the current biologic-first therapeutic landscape

Article Title: Methotrexate in Still’s Disease: An Updated Perspective on Efficacy and Safety

Article References: Daghor-Abbaci, K., & Koker, O. (2026). Methotrexate in Still’s Disease: An Updated Perspective on Efficacy and Safety. Advances in Therapy. https://doi.org/10.1007/s12325-026-03823-w

Image Credits: AI Generated

DOI: 10.1007/s12325-026-03823-w

Keywords: Still's disease, methotrexate, adult-onset Still's disease, systemic juvenile idiopathic arthritis, interleukin-1 inhibitors, interleukin-6 inhibitors, biologics, corticosteroid-sparing, autoinflammatory disease, rheumatology, EULAR guidelines, drug safety