Outcomes and Treatment Strategies for Autoimmunity and Hyperinflammation in Patients with RAG Deficiency

Abstract

Background: While autoimmunity and hyperinflammation secondary to recombinase activating gene (RAG) deficiency have been associated with delayed diagnosis and even death, our current understanding is limited primarily to small case series. Objective: Understand the frequency, severity, and treatment responsiveness of autoimmunity and hyperinflammation in RAG deficiency. Methods: In reviewing the literature and our own database, we identified 85 patients with RAG deficiency, reported between 2001 and 2016, and compiled the largest case series to date of 63 patients with prominent autoimmune and/or hyperinflammatory pathology. Results: Diagnosis of RAG deficiency was delayed a median of 5 years from the first clinical signs of immune dysregulation. The majority of patients (55.6%) presented with more than one autoimmune or hyperinflammatory complication, with the most common etiologies being cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%). Infections, including live viral vaccinations, closely preceded the onset of autoimmunity in 28.6% of cases. Autoimmune cytopenias had early onset (median 1.9, 2.1, and 2.6 years for autoimmune hemolytic anemia (AIHA), immune thrombocytopenia (ITP) and autoimmune neutropenia (AN), respectively) and were refractory to intravenous immunoglobulin, steroids, and rituximab in the majority of cases (64.7%, 73.7%, and 71.4% for AIHA, ITP, and AN, respectively). Evans syndrome specifically was associated with lack of response to first-line therapy. Treatment-refractory autoimmunity/hyperinflammation prompted hematopoietic stem cell transplantation in 20 patients. Conclusions: Autoimmunity/hyperinflammation can be a presenting sign of RAG deficiency and should prompt further evaluation. Multi-lineage cytopenias are often refractory to immunosuppressive treatment and may require hematopoietic cell transplantation for definitive management.

Asymptomatic Infant With Atypical SCID and Novel Hypomorphic RAG Variant Identified by Newborn Screening: A Diagnostic and Treatment Dilemma

“…Patients with partial RAG deficiency including atypical SCID and CID phenotype are increasingly recognized in young children and adults after severe infections (13,14,21). As with SCID, multiple classification systems for primary CID disorders exist, complicating diagnostic and management decisions.…”

“…Our patient had a unconventional immune phenotype with overlap between atypical SCID and CID that influenced the decision and design of the conditioning and transplant process. It is well-established that symptomatic patients with infectious and autoimmune complications, and CID immune phenotype secondary to RAG deficiency, do not respond well to immune modulation and ultimately require HSCT (13). However, there are no case studies nor established guidelines available on how to proceed with an asymptomatic infant with extreme TCL but normal T cell proliferation, and mostly normal humoral immunity.…”

The five dimensions of B cell tolerance

“…[97][98][99] These observations might be taken to suggest, iconoclastically, that if the mechanisms that censor the BCR repertoire to avoid auto-reactivity functioned too well or too completely, autotoxicus would ensue. While aberrant primary development of "forbidden clones" or excessive signaling of B cells and/or T cells may cause autoimmunity and autoimmune disease, as often as not the inception of autoimmunity and immunopathology appears connected with immunodeficiency and hypogammaglobulinemia.…”

“…While aberrant primary development of "forbidden clones" or excessive signaling of B cells and/or T cells may cause autoimmunity and autoimmune disease, as often as not the inception of autoimmunity and immunopathology appears connected with immunodeficiency and hypogammaglobulinemia. [97][98][99] These observations might be taken to suggest, iconoclastically, that if the mechanisms that censor the BCR repertoire to avoid auto-reactivity functioned too well or too completely, autotoxicus would ensue.…”

Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency

“…Hypomorphic variants with more preserved relative recombinase activity (in average 5-30%), compared to OS and LS, result in a broader spectrum of distinct phenotypes, including, combined immunodeficiency with granuloma and/or autoimmunity (CID-G/A) (5, 6), primary antibody deficiencies (7-9), idiopathic CD4 + T cell lymphopenia (10), hyper-IgM syndrome (11), and sterile chronic multifocal osteomyelitis (12). This highly vulnerable patient population presents with a variety of autoimmune and hyperinflammatory complications including refractory cytopenias (84.1%), granulomas (23.8%), and inflammatory skin disorders (19.0%) (13).…”