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New therapeutic strategies are required in the management of adult-onset Still’s disease (AOSD) refractory to glucocorticoids, disease-modifying antirheumatic drugs (DMARDs) or anti-tumour necrosis factor α antagonists (anti-TNFs). It has been suggested that interleukin 1 (IL1) plays a key role in the maintenance of the chronic inflammatory diseases, providing a rationale for an IL1-blocking therapy.1 2 Anakinra, an IL1 receptor antagonist (IL1-RA) approved for the treatment of rheumatoid arthritis,3 has shown promising results in small cohorts of patients with AOSD.4 5 6 7 8 However, it is unclear whether these effects can be sustained over a long treatment period. We report rapid and long-lasting responses to anakinra in eight patients with AOSD refractory to glucocorticoids, DMARDs and/or anti-TNFs.
From December 2004, eight consecutive patients with refractory adult-onset Still’s disease diagnosed according to proposed criteria9 (7 women, 1 man, age 25–66 years, mean (SD) disease duration 5.7 (3.7) years) were treated with anakinra 100 mg/day subcutaneously (table 1). Before starting anakinra all patients received at least one DMARD including methotrexate (mean (SD) dose 15.8 (2.9) mg per week, range 10–20 mg per week) and 6 patients had been receiving anti-TNF therapy (6 patients on etanercept, 2 patients on adalimumab and 1 patient on infliximab) without a long-lasting effect. All patients were responsive to high-dose glucocorticoids, but disease flares reoccurred with reduction to moderate or low doses.
Sustained remission was achieved in all eight patients only after the introduction of anakinra (current treatment period 6–48 months). In all patients, clinical symptoms such as rash and arthritis significantly improved within a few hours after the first injection of anakinra. Inflammatory laboratory markers (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), neutrophils, ferritin) normalised within 1–4 weeks of starting treatment with anakinra, with the exception of patient 8 who showed a marked decrease in CRP and ferritin without reaching normal levels at the last follow-up (fig 1). Interestingly, in patient 8 fever and abnormal liver function markers relapsed 3 days after discontinuation of anakinra and improved again after reinstitution of anakinra.
In all patients, anakinra treatment allowed a rapid tapering of concomitant glucocorticoids to low doses (fig 1). At the same time, parallel treatment with DMARDs was only needed in four patients (table 1). In patient 1 methotrexate (15 mg per week) was reinstated at month 9 because of intermittent arthralgia; in patient 3 leflunomide was continued (20 mg per day); in patient 7 methotrexate (15 mg per week) was continued because of intermittent arthralgia; and in patient 8 ciclosporin was added at month 6 because of an episode of prolonged arthritis after transient interruption of anakinra. In four patients no further DMARD or anti-TNF therapy was necessary. This is of interest as anakinra is registered only in association with methotrexate. Phase III clinical trials10 and register data gave evidence for the efficacy and safety of anakinra monotherapy. In our cohort no severe adverse events due to anakinra were recorded during the follow-up period, apart from self-limiting erythema at the injection site in two patients.
This case series demonstrates for the first time a long-lasting remission of AOSD under IL1 blockade in patients who required high doses of glucocorticoids and who were non-responders to different DMARDs and anti-TNFα regimens. Anakinra therefore seems to be a promising treatment strategy in patients with refractory AOSD. In these patients, anakinra can induce clinical remission of disease activity with a remarkable glucocorticoid-sparing effect. The results clearly support the recommendation for randomised clinical trials on the effectiveness of IL1 receptor blockade in AOSD.
Competing interests None.
Provenance and Peer review Not commissioned; externally peer reviewed.