Background/Purpose: Deficiency of interleukin-1-receptor antagonist (DIRA) is a rare autoinflammatory disease caused by autosomal recessive loss of function mutations in IL1RN and characterized by early-onset generalized pustulosis, aseptic multifocal osteomyelitis, and elevation of acute-phase reactants. In a DIRA mouse model, aortitis can develop in a TNF-α dependent manner, no DIRA patients with large vessel vasculitis have previously been reported.

Methods: We performed clinical, genetic and radiographic evaluation of a patient with DIRA who developed an intra-cranial hemorrhage on anakinra treatment and had persistent low-grade elevation of acute phase reactants. We performed including whole exome sequencing and PET CT.

Results: A Puerto Rican patient previously reported with a homozygous 175-kb deletion and multiple comorbidities including severe bone deformities, developmental delay, generalized hypotonia at birth, pyoderma gangrenosum, developed a left intra-cranial hemorrhage at age 12. Follow-up work up of potential pathogenic causes revealed right-sided carotiditis and aortitis on PET CT images. Vascular findings were associated with carotid stenosis and an ascending aortic aneurism. Vascular abnormalities occurred while on optimal doses of anakinra (3.33 ±1.82 mg/kg/day) but persistently elevated inflammatory markers(CRP 5.41 ±3.08 mg/L and ESR 21.40 ±13.99 mm/hr). No other patient with DIRA was diagnosed with large vessel. vasculitis. While IL-1 receptor antagonist (Il-1ra) knock out (KO) murine models are prone to the development of vascular diseases, different genetic backgrounds modify vascular inflammation and injury. Il1ra KO on a C57BL/6J background is associated with intima damage and the development of atherosclerosis and Il1ra KO BALB/c mice develop aortitis that is responsive to TNF inhibition. Insights into the murine model suggested addition of TNF inhibitor after failure of increased doses of anakinra and steroids in achieving disease control. Acute phase reactants normalized after treatment with infliximab. Genetic analyses of rare variants that may contribute to the development af large vessel vasculitis are ongoing.

Conclusion: The development of large vessel vasculitis including carotitis and aortitis in a patient with DIRA who responds to combination therapy of IL-1 and TNF inhibition suggests a role of TNF in the development of large vessel vasculitis and may provide insights into pathways that may shed light on the pathogenesis of other forms of large vessel vasculitis. Strict monitoring of adverse events is required given the increased risk for opportunistic infections.

Funding for this study was provided in part by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/development-of-large-vessel-vasculitis-including-aortitis-in-a-patient-with-deficiency-of-the-il-1-receptor-antagonist-dira-points-to-converging-roles-of-il-1-and-tnf-in-vascular-pathogenesis-recapi/