Homozygous C2 Deficiency with Hyper IgE Discovered in Adulthood After Persistently Low CH50

IntroductionComplement C2 deficiency is a classical pathway defect associated with recurrent infections and autoimmunity. This case demonstrates the need for increased awareness amongst rheumatologists for the indications to suspect complement deficiency and also presents a unique presentation of C2 deficiency with hyper IgE.CaseA 34-year-old woman with systemic lupus erythematosus and rheumatoid arthritis diagnosed in adolescence presented with lifelong recurrent infections. Her history included meningitis in infancy, recurrent otitis media and sinusitis during childhood, and multiple pneumonias requiring hospitalization in adulthood with the development of bronchiectasis. Complement testing demonstrated a CH50 less than 13 U/mL with normal AH50, low C4, and normal C3. Complement studies were repeated by a rheumatologist and noted that CH50 was persistently low despite optimal autoimmunity control with anifrolumab and hydroxychloroquine, so she was referred to immunology.Immunologic testing showed IgE above 10,000 kU/L, IgM below 5 mg/dL, IgA 33 mg/dL, normal IgG with preserved subclasses except for low IgG4, and normal absolute eosinophil count. Absolute CD19 B cells were reduced at 58 cells/μL. Pneumococcal antibody titers were protective to only 8 of 23 serotypes above 1.3 mcg/L, while tetanus and diphtheria responses were intact. Serum protein electrophoresis was normal. Patient is not very atopic, with only slightly positive aeroallergen sensitization.Commercial genetic testing using a 574-gene inborn errors of immunity panel identified homozygous known pathogenic variants in C2 (c.841_849+19del in the splice site). Management includes optimizing vaccines, antibiotic prophylaxis, and consideration of immunoglobulin replacement.DiscussionThis case demonstrates a unique finding of hyper-IgE in C2 deficiency. We do not know if the two findings are related, and we also cannot rule out that her hyper IgE is an immunologic consequence of anifrolumab targeting interferon, causing a downstream Th2 phenotype. This case also demonstrates that rheumatologists should always refer autoimmune patients with infectious histories and that persistently low CH50 is concerning for complement deficiency. Earlier identification of complement deficiencies may prevent diagnostic delays and improve clinical outcomes.Tabular data are included as downloadable supplement files.