The prevalence, clinical relevance and origin of autoantibodies in patients with Common variable immunodeficiency on regular immunoglobulin replacement therapy

Background: Common variable immunodeficiency (CVID) is an inborn error of immunity characterized by disturbed immunoglobulin production. Despite of the terrain with severe antibody deficiency, autoantibody-mediated autoimmune phenomena belong to the most frequent autoimmune manifestation. However, many unresolved issues such as prevalence, clinical relevance and origin of autoantibodies detected in CVID patients receiving immunoglobulin replacement therapy (IRT) make the diagnostics of autoimmune complications difficult. Methods: A prospective observational study evaluating the spectrum of 38 different autoantibodies in 38 CVID patients receiving IRT, and in the immunoglobulin solutions used for IRT. Results: The study reveals a high prevalence of anti-GAD (55.3%) and anti-TPO (68.4%) autoantibodes in the cohort of 38 CVID patients on regular IRT. However, the titers of anti-GAD (3.22 vs. 22 kU/L, p≤0.0001) and anti-TPO (109.7 vs. 713 kU/L, p≤0.0001) were significantly lower compared to the newly diagnosed T1D and AIT patients. Moreover, none of the CVID patients with detectable antibodies manifested with T1D and only three patients became suspected of having AIT. A high quantity of anti-GAD (3.24-24.48 kU/L) and anti-TPO (123.6-156.55 kU/L) autoantibodies was found in immunoglobulin solutions for IRT. Conclusions: The study finds a very high prevalence of anti-GAD and anti-TPO autoantibodies in CVID patients receiving regular IRT. Nevertheless, the presence of anti-GAD and anti-TPO is not associated with the manifestation of the respective autoimmune disease. As the high titers of both anti-GAD and anti-TPO were also found in the therapeutics used for IRT, we suggest that the therapeutic immunoglobulins are the source of this false positivity.