Outcomes and treatment strategies for autoimmunity and hyperinflammation in patients with RAG deficiency

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

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

Primary Immune Deficiency Treatment Consortium (PIDTC) report

The Primary Immune Deficiency Treatment Consortium (PIDTC) is a network of 33 centers in North America that study the treatment of rare and severe primary immunodeficiency diseases. Current protocols address the natural history of patients treated for severe combined immunodeficiency (SCID), Wiskott-Aldrich syndrome, and chronic granulomatous disease through retrospective, prospective, and cross-sectional studies. The PIDTC additionally seeks to encourage training of junior investigators, establish partnerships with European and other International colleagues, work with patient advocacy groups to promote community awareness, and conduct pilot demonstration projects. Future goals include the conduct of prospective treatment studies to determine optimal therapies for primary immunodeficiency diseases. To date, the PIDTC has funded 2 pilot projects: newborn screening for SCID in Navajo Native Americans and B-cell reconstitution in patients with SCID after hematopoietic stem cell transplantation. Ten junior investigators have received grant awards. The PIDTC Annual Scientific Workshop has brought together consortium members, outside speakers, patient advocacy groups, and young investigators and trainees to report progress of the protocols and discuss common interests and goals, including new scientific developments and future directions of clinical research. Here we report the progress of the PIDTC to date, highlights of the first 2 PIDTC workshops, and consideration of future consortium objectives