Background Systemic autoinflammatory disorders (SAIDs) are a rare group of disorders featuring seemingly unprovoked chronic sterile inflammation with raised inflammatory markers1. Although many causative genes have now been identified, ∼50% SAIDs have no identified genetic cause and thus no definitive treatment2. Excess interleukin 1 (IL-1) production is an established features of many SAIDs of known genetic cause, and IL-1 antagonists are clinical efficacious in such patients2.
Objectives To evaluate the diagnostic and therapeutic value use of IL-1 antagonist anakinra for SAID of unknown genetic cause (UGC).
Methods Retrospective case series of 8 patients (4 male, 4 female) presenting to Leeds Teaching Hospital Trust Immunology department 2008-2014 with SAID of UGC, treated with anakinra.
Results All patients presented with periodic fever and pyrexia (38-41°C) with variable fatigue, arthralgia, myalgia, synovitis, arthritis, rash, aphthous ulceration, headaches, gastrointestinal disturbance, sore throat and pericardial symptoms. Median age of symptom onset was 33.5 years (24-76 years). Average time between presentation and referral to immunology department was 2.4 years. Prior to being given a diagnosis of SAID of UGC, patients were subject to extensive investigation including computerised tomography (CT) (6/8), positron emission tomography (PET) CT (5/8), magnetic resonance imaging (2/8), bone marrow biopsy (2/8) and skin biopsy (2/8). All of the patients were negative for known SAID genes, although one patient had an NLRP3 variant of unknown significance (table 1). 7/8 patients had failed DMARD trial(s). Of the 7/8 patients trialled on steroids, 5/7 were steroid dependent, 2/7 were steroid refractory and 3/7 developed side effects from chronic steroid use (glaucoma, intolerable weight gain, buffalo hump/ cushingoid appearance). Moreover, 6/8 patients had required hospital admission for management of symptoms, one patient being admitted on 6 separate occasions. Trial of 100mg daily subcutaneous anakinra successfully controlled symptoms in 5/8 patients significantly improving quality of life and enabling cessation of steroid and/or disease-modifying anti-rheumatic drug (DMARD) treatment. 1/8 patients also showed partial response (table 1). Non-response to anakinra was evident within 4-6 weeks enabling rapid termination of treatment in non-responders, avoiding the side effects and costs associated with unnecessary treatment.
Conclusions Response to anakinra stratified SAID of UGC into two groups based on response and non-response, implicating Il-1 dysregulation in the aetiopathogenesis of SAID in responders. In these patients, anakinra completely controlled symptoms otherwise unresponsive to steroid and/or DMARDs. Response to anakinra was evident within 4-6 weeks; therefore anakinra provides a rapid and effective diagnostic tool for SAID of UGC that minimizes the cost and side effects associated with unnecessary treatment.
Savic S, Dickie LJ, Battellino M, McDermott MF. Familial mediterranean fever and related periodic fever syndromes/autoinflammatory diseases. Curr Opin Rheumatol. 2012;24(1):103-12.
Savic S, Dickie LJ, Wittmann M, McDermott MF. Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives”. Best Pract Res Clin Rheumatol. 2012;26(4):505-33.
Disclosure of Interest S. Harrison: None declared, D. McGonagle Grant/research support from: Received an honorarium for a lecture sponsored by SOBI, M. McDermott: None declared, S. Savic Grant/research support from: Received educational grant and participated on advisory board meeting for SOBI
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