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Adult-onset Still’s disease (AOSD) is an autoinflammatory disease characterised by spiking fever, rash, polyarthralgia, sore throat and even life-threatening complications, such as macrophage activation syndrome and fulminant hepatitis. Excessive and inappropriate production of cytokines is a cornerstone in AOSD pathogenesis.1 Unlike anakinra and tocilizumab, Janus kinases (JAK) inhibitors block the proinflammatory effect of a wide range of cytokines. This range of activity could be beneficial in AOSD patients who are refractory to or intolerant of treatment with biologicals. Anti-interleukin 1 (IL-1) agents are not available in mainland China. Tofacitinib, a JAK1/3 inhibitor, has been proven efficacious in several inflammatory diseases, such as rheumatoid arthritis, systemic lupus erythematosus and psoriasis arthritis.2 To our interest, a case report observed that tofacitinib could ameliorate arthritis in a 13-year-old girl with recalcitrant systemic juvenile idiopathic arthritis,3 which is the juvenile counterpart of AOSD.4 Moreover, a JAK1/2 inhibitor, baricitinib has been reported effective in a 43-year-old patient with refractory AOSD.5 Therefore, JAK inhibitors may be a novel therapeutic approach for refractory AOSD.
In our study, we aim to describe, to our knowledge for the first time, the efficacy of tofacitinib in 14 patients with refractory AOSD. All patients fulfilled Yamaguchi’s criteria and were classified as refractory AOSD as defined previously.6 They were followed up for the shortest of 1 month and the longest for 24 months by the same medical team. The evaluation of tofacitinib treatment was conducted at each visit, including clinical manifestations, laboratory tests, including white cell count (WBC) count, neutrophil per cent, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and ferritin, as well as glucocorticoids dosage adjustment. The AOSD disease activity was measured by a modified Pouchot’s systemic score,7 and adverse events were also recorded. The effectiveness of treatment was defined previously8: effective treatment was considered when all initial clinical manifestations and abnormal laboratory tests had resolved, meaning achieving complete remission; partially effective treatment was considered when all but one initial clinical manifestation or abnormal laboratory test had resolved, meaning achieving partial remission; ineffective treatment was considered when two or more clinical manifestations or abnormal laboratory tests persisted.
The demographic data and clinical characteristics of the 14 patients are detailed in table 1. Seven of 14 (50%) AOSD patients achieved complete remission with decreased prednisone, six patients achieved partial remission and one relapsed when reduced the dosage of prednisone to 2.5 mg/day (table 1). Totally, four patients terminated tofacitinib: two patients were for partial remission, one for menometrorrhagia and one for relapse. Two patients reduced the dosage of tofacitinib to 5 mg/day and no relapses were observed after the adjustment. After application of tofacitinib for 1 month, seven patients quickly achieved complete resolution of fever and rashes, eight of polyarthritis. The systemic score was quickly reduced after 1 month, and completely improved at month 9 (figure 1A). WBC, neutrophil per cent, ESR, CRP and ferritin were decreased (figure 1B–F). The average dose of prednisone was significantly decreased from 37.3 mg/day to 5.0 mg/day at month 12 (figure 1G). Adverse events occurred in two patients. One had diarrhoea and increased heart rate and the other had menometrorrhagia. The first one continued the therapy, and the second stopped tofacitinib when achieved complete remission.
The cytokine storm activated by neutrophils and macrophages is strongly implicated in AOSD pathogenesis.1 Tofacitibib inhibits the effect of IL-6, IL-10, IFN-γ, INF-α and granulocyte macrophage-colony stimulating factor (GM-CSF), thus suppressing neutrophils NOD-like receptor family pyrin domain-containing 3 (NLRP3) activation and IL-1β production.9 Tofacitinib also suppresses macrophage activation and function.10 It provides some experimental evidence to use tofacitinib in refractory AOSD.
In conclusion, application of tofacitinib in refractory AOSD patients contributes to disease remission/revolution and sparing corticosteroid dosage, especially these with polyarthritis.
Handling editor Josef S Smolen
QH and MW contributed equally.
Contributors QH participated in follow-up, provided the figure and wrote the manuscript. MW performed statistical analysis. JJ and JT collected the clinical data at baseline. HC,TL and HL helped to prepared the table. XC, JY and Yutong Su accessed the disease activity of AOSD patients. Yue Sun, ZZ and LW analysed the data and revised the manuscript. ZW and FW helped to follow-up. HS designed, participated in follow-up and performed statistical analysis. CY designed the study, contributed to the discussion and edited the manuscript. All authors read and approved the final manuscript.
Funding This work was supported by the National Natural Science Foundation of China (81671589, 81871272, 81801602).
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design or conduct or reporting or dissemination plans of this research.
Patient consent for publication Obtained.
Ethics approval The study was performed in accordance with the Declaration of Helsinki and the principles of Good Clinical Practice. Information on demographic and clinical data were obtained under a protocol approved by the Institutional Research Ethics Committee of Ruijin Hospital (ID: 2016-62), Shanghai, China. All subjects signed written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.