Arthritis in Two Patients With Partial Recombination Activating Gene Deficiency

Abstract

Autoimmunity is becoming an increasingly recognized complication in patients with primary immunodeficiencies (PIDs), including a variety of combined immune deficiencies such as Recombination Activating Gene (RAG) defects. The approach to treating autoimmunity in PID patients is complex, requiring a balance between immunosuppression and susceptibility to infection. Inflammatory arthritis is a feature of immune dysregulation in many PIDs, and the optimal treatment may differ from first line therapies that usually consist of disease-modifying anti rheumatic drugs (DMARDs). An example of mechanism-based therapy of arthritis in PID uses blockade of IL-6 signaling with tocilizumab for patients with STAT 3 gain-of-function (GOF) mutation and augmented IL-6 pathway. Herein, we describe two PID cases with arthritis who were found to have defects in RAG. One patient with refractory inflammatory arthritis experienced remarkable improvement in symptoms with tocilizumab therapy. Arthritis can be a clinical feature of immune dysregulation in RAG deficiency, and tocilizumab therapy has been suggested to have utility in treatment of arthritis in RAG deficiency.

The Clinical and Genetic Spectrum of 82 Patients With RAG Deficiency Including a c.256_257delAA Founder Variant in Slavic Countries

“…This phenotype was first described by Schuetz C. et al in 2008, which they named "atypical/leaky SCID." During the last 10 years, there is growing awareness of these patients (2,4,7,9,13,19,20,22,30). Distinct clinical features include inflammatory and/or autoimmune complications.…”

“…We retrospectively collected and studied 82 patients with RAG deficiency from 67 families in 12 countries, born in the period of 1992-2018. Thirty-five of 82 (43%) patients were reported previously (9)(10)(11)(12)(13)(19)(20)(21)(22)(23). Distribution was even between males (n = 40, 49%) and females (n = 42, 51%).…”

Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells

“…Patients manifesting with late-onset phenotype of pRD with immune dysregulation, termed ‘combined immune deficiency with granuloma/autoimmunity’ (CID-G/AI) 12 are present with multiorgan autoimmune disease with high titers of serum autoantibodies, including those targeting cytokines 5 . The remnant recombinase activity only partially correlates with the clinical phenotype 13 , 14 and the same RAG genetic variant, even within the same family, can result in a spectrum from asymptomatic to variable autoimmunity 15 , 16 , which may worsen with age and exposure to environmental antigens 3 , 5 , 17 – 22 . Accordingly, chronic Toll-like receptor (TLR) stimulation mimicking viral infection in a mouse model resulted in a broadening autoantibody profile 5 .…”

Autoimmunity as a continuum in primary immunodeficiency

“…In the first case, the infant developed autoimmune thrombocytopenia (ITP) after varicella infection prompted the clinicians to screen for immunological biomarkers and genetic cause for presumed P-CID [14]. The second case describes a child with history of Kawasaki-like disease, arthritis, and alopecia followed by infections [15]. Both cases highlighted the importance of immune evaluation and biomarkers, to promote early genetic diagnosis in children who have early-onset autoimmune disease [14,15].…”

“…The second case describes a child with history of Kawasaki-like disease, arthritis, and alopecia followed by infections [15]. Both cases highlighted the importance of immune evaluation and biomarkers, to promote early genetic diagnosis in children who have early-onset autoimmune disease [14,15].…”