Methotrexate in Still's Disease: An Updated Perspective on Efficacy and Safety

The EULAR/PreS and American College of Rheumatology (ACR) guidelines for Still's disease (SD) were recently published with new therapeutic management strategies to achieve therapeutic targets within a specified timeframe. The early use of interleukin (IL)-1 or IL-6 inhibitors associated with short-term corticosteroids is recommended. Methotrexate (MTX) is not recommended as initial monotherapy for the acute systemic phase and should not be considered an alternative to early cytokine-targeted therapy when biologic treatment is available. Nevertheless, observational and real-world studies retain clinical utility of MTX as a corticosteroid-sparing agent with a favorable safety profile particularly in adult patients with residual arthritis and preserved organ function. Beyond its well-known immunomodulatory effects, MTX has been hypothesized to influence IL-1-related inflammatory pathways; however, this hypothesis is extrapolated from other inflammatory diseases, and no SD-specific mechanistic study has directly demonstrated an IL-1-mediated therapeutic effect of MTX. Reported remission rates varied according to the therapeutic regimen and study definition and should therefore be interpreted cautiously. In settings where access to biologic agents is limited, MTX may also represent a pragmatic therapeutic option, although this use reflects healthcare constraints rather than evidence of equivalence to IL-1 or IL-6 inhibition. In children with SD, MTX is mainly used for residual arthritis or as a steroid-sparing agent after control of systemic inflammation. Moreover, combining MTX with biologic agents may provide additional benefit in selected patients with residual arthritis or corticosteroid dependence. This review provides an updated perspective on the efficacy and safety of MTX in SD, with particular emphasis on its complementary role within the current biologic-first therapeutic landscape.