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.
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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