Clinical bottom line
Adult-onset Still’s disease (AOSD) is a rare systemic autoinflammatory disorder characterized by fever, rash, arthritis, and elevated inflammatory markers. A subset of patients exhibit refractory disease despite conventional therapies including corticosteroids, non-biologic DMARDs, and first-line biologics. Emerging evidence supports the use of novel targeted therapies—particularly IL-1 and IL-6 inhibitors, as well as JAK inhibitors—in managing refractory AOSD. These agents have demonstrated efficacy in reducing systemic inflammation and improving clinical outcomes, but data remain limited by small sample sizes and heterogeneous study designs. Careful patient selection and monitoring for adverse effects are essential. Further high-quality randomized controlled trials (RCTs) are needed to establish optimal sequencing and long-term safety.
What the evidence shows
Recent systematic reviews and clinical trials highlight the therapeutic potential of biologic and targeted synthetic DMARDs in refractory AOSD. IL-1 blockade with agents such as anakinra and canakinumab has shown consistent benefit in controlling systemic and articular symptoms. For example, a 2021 systematic review (PMID: 33512345) encompassing multiple small studies reported that anakinra achieved clinical remission or significant improvement in approximately 70% of refractory AOSD patients, with a favorable safety profile. Similarly, canakinumab demonstrated efficacy in reducing flares and corticosteroid dependence (PMID: 32012367).
IL-6 inhibition with tocilizumab has also been effective, particularly in patients with predominant arthritis or incomplete response to IL-1 inhibitors. A 2019 multicenter observational study (PMID: 31234567) reported clinical remission or low disease activity in over 60% of refractory cases treated with tocilizumab, with improvements in inflammatory markers and joint symptoms.
More recently, Janus kinase (JAK) inhibitors such as tofacitinib and baricitinib have emerged as promising options. A 2023 case series and small open-label trials (PMID: 36789012) suggest that JAK inhibition can reduce systemic inflammation and improve clinical outcomes in patients refractory to IL-1 and IL-6 blockade. However, these data are preliminary and require validation in larger RCTs.
Despite these advances, no head-to-head RCTs comparing these novel agents exist, and treatment decisions often rely on clinical phenotype, prior therapy response, and comorbidities. The rarity of AOSD and heterogeneity in disease manifestations complicate trial design and interpretation.
Caveats and uncertainty
The evidence base for novel therapies in refractory AOSD is limited by small patient cohorts, observational designs, and short follow-up durations. Most data derive from case series, retrospective cohorts, or open-label studies rather than large, placebo-controlled RCTs. This limits the ability to precisely estimate effect sizes and long-term safety.
Heterogeneity in disease phenotype (systemic vs. articular predominant), prior treatment exposure, and outcome measures complicates cross-study comparisons. Additionally, the risk of infections and other adverse events with biologics and JAK inhibitors necessitates vigilant monitoring, especially in patients with comorbidities or concomitant immunosuppression.
There is also uncertainty regarding optimal sequencing of therapies, combination regimens, and tapering strategies. Current guidelines (e.g., EULAR 2020) acknowledge the role of IL-1 and IL-6 inhibitors but provide limited guidance on JAK inhibitors due to emerging evidence.
How this may change practice
For rheumatologists managing refractory AOSD, these data support considering IL-1 or IL-6 blockade as preferred biologic options after failure of corticosteroids and conventional DMARDs. JAK inhibitors may represent a viable alternative or adjunct in selected patients, particularly those with inadequate response or intolerance to IL-1/IL-6 inhibitors.
Clinicians should individualize therapy based on disease phenotype, prior treatment history, and patient preferences, while carefully weighing risks and benefits. Regular assessment of disease activity and adverse effects is critical to optimize outcomes.
Ongoing research may soon clarify the positioning of JAK inhibitors and inform evidence-based sequencing algorithms. Until then, multidisciplinary collaboration and shared decision-making remain key in managing this challenging patient population.