IL-1 and IL-6 blockade emerged as the strongest pharmacologic signal in Still’s disease
A large systematic review prepared to inform the EULAR/PReS recommendations for Still’s disease places IL-1 inhibitors and IL-6 receptor inhibitors at the center of current therapeutic evidence. The review assembled 128 full texts spanning randomized trials, controlled studies, observational cohorts, and systematic reviews, giving a broad view of how clinicians have treated Still’s disease and the related emergency of macrophage activation syndrome (MAS). Across that mixed evidence base, the same signal kept returning: cytokine-directed therapy outperformed older empiric approaches when the goal was meaningful disease control.
Still’s disease is driven by innate immune activation, and the biology matches the treatment effect. Blocking IL-1 or IL-6 interrupts downstream inflammatory amplification, which helps explain why these agents repeatedly produced higher response rates than nonspecific anti-inflammatory strategies. The review does not claim a single answer for every patient, but it does show where the strongest clinical momentum lies.
Response rates favored biologic cytokine inhibition over broader anti-inflammatory treatment
Two meta-analyses of randomized trials were especially influential. For achievement of an ARC50 response rate, the odds ratio reached 6.02 (95% CI 2.24 to 21.36) for IL-1 inhibitors and 8.08 (95% CI 1.89 to 34.57) for IL-6 receptor inhibitors. Those are large effect estimates, even allowing for the width of the confidence intervals and the expected heterogeneity of a rare disease literature.
Retrospective cohorts reinforced the same direction of travel. Early initiation of IL-1 or IL-6 inhibition was associated with high rates of clinically inactive disease, suggesting that prompt cytokine blockade may matter before inflammatory cascades become entrenched. In practical terms, early suppression of the IL-1/IL-6 axis may reduce fever burden, systemic inflammation, and cumulative steroid exposure, which is especially relevant in a disease where prolonged glucocorticoid dependence can become its own source of harm.
A clear clinical pattern is hard to miss here. The best-supported drugs were not the broadest drugs; they were the ones aimed at the dominant inflammatory circuitry.
MAS remained a steroid-first emergency, with biologic rescue layered on top
The evidence for MAS looked different because the syndrome itself is different. MAS represents a hyperinflammatory escalation, often requiring immediate treatment before there is time for a stepwise outpatient strategy. In the reviewed studies, glucocorticoids were used in all patients, typically combined with ciclosporin and/or anakinra. Complete response rates ranged from 53% to 100%, a wide spread that reflects both the severity of MAS and the uneven design of the available studies.
This is one of the few areas where the pathophysiology and the bedside response line up with striking clarity. High-dose glucocorticoids suppress the explosive cytokine surge, while IL-1 inhibition can blunt the inflammatory feed-forward loop that drives fever, cytopenias, ferritin elevation, and organ dysfunction. Ciclosporin likely contributes through T-cell suppression, but the literature assembled here places the practical treatment backbone on steroids plus targeted immunomodulation rather than on any single salvage agent.
The data do not support a leisurely approach. MAS is the kind of complication in which delayed immune suppression can quickly translate into ICU-level illness.
Emapalumab produced the most striking single-study signal in MAS
Among the therapies studied for MAS, emapalumab stood out because it was the only drug tested in a controlled clinical trial. In that controlled setting, complete response reached 93%. Emapalumab targets interferon-γ, a cytokine deeply implicated in MAS biology, and the result is consistent with the idea that this syndrome is not merely severe arthritis but a distinct hyperinflammatory state with a recognizable cytokine signature.
The controlled-trial signal is clinically important because MAS evidence is otherwise dominated by observational experience. A 93% complete response rate in a controlled study does not by itself define the standard of care, but it does establish interferon-γ blockade as a serious mechanistic and therapeutic candidate when conventional steroid-based management is insufficient.
The evidence base was broad, but not equally strong across all study types
The review included 25 randomized trials, 1 controlled clinical trial, 11 systematic reviews published after 2013, and 91 longitudinal observational studies, both retrospective and prospective. That mix matters because rare inflammatory diseases often rely on observational data long before large confirmatory trials are feasible. Still, the hierarchy of evidence remained uneven, and the authors assessed risk of bias using Cochrane methods for trials and AMSTAR-2 for systematic reviews.
In Still’s disease, IL-1 and IL-6 inhibitors were the most studied therapies by far, which makes the consistency of the treatment signal more persuasive. In MAS, the evidence was thinner and more heterogeneous, but the therapeutic pattern was recognizable: glucocorticoids first, with ciclosporin, anakinra, or emapalumab layered in depending on severity and availability. The practical consequence is a treatment framework built on biologic plausibility and repeated clinical observation rather than on many large head-to-head trials.
What the review means for clinicians treating Still’s disease now
For active Still’s disease, the review supports a cytokine-targeted strategy centered on IL-1 inhibition and IL-6 receptor inhibition. For MAS, it supports urgent high-dose glucocorticoids with consideration of IL-1 or interferon-γ blockade, often alongside ciclosporin. The review does not erase uncertainty about sequencing, optimal duration, or comparative safety across agents, but it does narrow the field of credible options.
The clinical challenge now is not whether these pathways matter. It is how best to position them in real patients who present at different stages of systemic inflammation, with different organ involvement, and with different tolerance for steroid toxicity. Observational data strongly favor early biologic use in Still’s disease, while MAS still demands rapid suppression of the cytokine storm with whatever effective agents can be deployed quickly.
Longer-term comparative trials are still needed to define whether one biologic should be preferred over another in specific phenotypes, and whether controlled interferon-γ blockade can move beyond rescue treatment into earlier MAS management. For now, the review leaves clinicians with a clear therapeutic hierarchy rooted in the biology of the disease: target IL-1 and IL-6 in Still’s disease, and treat MAS as a high-risk hyperinflammatory emergency built on steroids and rapid cytokine inhibition.