SAT0614 New variant in the il1rn-gene associated with late onset and atypical presentation of dira
Authors: J.B. Kuemmerle-Deschner, K. Hoertnagel, S. Schlipf, S. Hansmann, A. Hospach, X. Liu, S.M. Benseler, A.N. Weber
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> Deficiency of the interleukin-1 receptor antagonist (DIRA) is an autoinflammatory disease characterised by severe systemic inflammation with bone and skin involvement present in the first days of life. <h3>Objectives</h3> We report a novel variant in the <i>IL1RN</i>-gene associated an atypical phenotype of DIRA. <h3>Methods</h3> A 3 year-old Caucasian boy presented with recurrent monthly episodes of fever and fatigue, associated with lymphadenopathy, pericarditis, pleuritis, pancreatitis, and arthritis involving sacroiliac, hip, knee and ankle joints in the absence of any skin involvement. Symptoms had started at age one and had progressed over time to life-threatening episodes requiring intensive care therapy. Throughout, inflammatory parameters including ESR, CRP, SAA, S100A8/9, leukocytes, and platelets were highly elevated. Treatment with colchicine and steroids improved symptoms, however did not prevent flares. Immune deficiencies were ruled out; genetic testing for FMF, CAPS, TRAPS, HIDS and DITRA did not reveal variants in the associated genes. <h3>Results</h3> Whole exome sequencing detected a novel homozygous stop variant c.62C&gt;G; p.Ser21* in the <i>ILRN</i> gene (NM_173842.2). Mother, father and brother are heterozygous for the same variant. In addition, three variants of unknown significance were identified in the patient's <i>PCGF5, CPA1</i> and <i>SPTA1</i> genes. Functional studies revealed only marginal secretion of IL-1RA in the patient's unstimulated leucocytes and after stimulation with IL-1β and LPS, confirming the disease-causing nature of the variant. Subsequently, IL-1 inhibition with anakinra at 2 mg/kg/d was started resulting in complete resolution of clinical symptoms, normal inflammatory markers and dramatically improved energy levels. Intolerance to daily subcutaneous injections prompted a switch to canakinumab at 4 mg/kg/4 weeks. However patient's and mothers assessment of disease activity was inferior on canakinumab compared to anakinra. After four months a flare appeared and lead to return to anakinra. <h3>Conclusions</h3> This is the first report of the novel c.62C&gt;G; p.Ser21* variant in the <i>IL1RN</i>-gene primarily causing severe serositis in a homozygous carrier, while heterozygous family members were completely symptom free. Skin disease, one of the most prominent features in other patients with DIRA was not observed in this patient, while Il-1 inhibition was likewise effective. Pathogenic variants in all reported DIRA patients so far affect all 4 isoforms of IL-1RA.<sup>1</sup> The different phenotype in the patient reported here, may be due to the selective loss of secreted IL1RN. <h3>Reference</h3> [1] Aksentijevich, et al. N Engl J Med2009;360:2426–2437. <h3>Disclosure of Interest</h3> J. Kuemmerle-Deschner Grant/research support from: Novartis, SOBI, Consultant for: Novartis, SOBI, K. Hoertnagel: None declared, S. Schlipf: None declared, S. Hansmann: None declared, A. Hospach: None declared, X. Liu: None declared, S. Benseler: None declared, A. Weber: None declared