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High frequency of variants in genes associated with primary immunodeficiencies in patients with rheumatic diseases with secondary hypogammaglobulinaemia
  1. Georgios Sogkas,
  2. Natalia Dubrowinskaja,
  3. Ignatius Ryan Adriawan,
  4. Manfred Anim,
  5. Torsten Witte,
  6. Reinhold E Schmidt,
  7. Faranaz Atschekzei
  1. Rheumatology and Immunology, Hannover Medical University, Hannover, Germany
  1. Correspondence to Dr Georgios Sogkas, Rheumatology and Immunology, Hannover Medical School, Hannover, Germany; sogkas.georgios{at}mh-hannover.de

Abstract

Objectives Treatment of rheumatic diseases requires immunomodulatory agents which can compromise antibody production. However, even in case of agents directly targeting B cells, a minority of patients develop hypogammaglobulinaemia, suggesting a genetic predisposition, which has not been investigated so far. The phenotypic overlap between primary immunodeficiency disorders (PIDs) and rheumatic diseases suggests a shared genetic basis, especially in case of patients with rheumatic diseases with hypogammaglobulinaemia.

Methods 1008 patients with rheumatic diseases visiting the outpatient clinics of the Hannover University Hospital were screened for hypogammaglobulinaemia. Those with persistent hypogammaglobulinaemia and an equal number of patients without it underwent targeted next-generation sequencing, searching for variations in genes linked with hypogammaglobulinaemia in the context of PIDs.

Results We identified 33 predicted pathogenic variants in 30/64 (46.9%) patients with persistent secondary hypogammaglobulinaemia. All 33 variants were monoallelic and 10 of them in 10/64 (15.6%) patients were found in genes associated with autosomal dominant PIDs. 2/64 (3.1%) patients harboured variants which were previously reported to cause PIDs. In the group without hypogammaglobulinaemia we identified seven monoallelic variants in 7/64 (10.9%), including a variant in a gene associated with an autosomal dominant PID.

Conclusions Approximately half of patients with persistent secondary hypogammaglobulinaemia harboured at least a variant in a PID gene. Despite the fact that previous immunomodulatory treatment is an exclusion criterion in the diagnosis of PIDs, we identified genetic variants that can account for PID in patients with clear rheumatic phenotypes who developed hypogammaglobulinaemia after the introduction of immunomodulatory treatment. Our data suggest the common genetic causes of primary and secondary hypogammaglobulinaemia.

  • secondary hypogammaglobulinemia
  • primary immunodeficiency
  • common variable immunodeficiency
  • inborn errors of immunity
  • dmard

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Footnotes

  • Handling editor Josef S Smolen

  • Contributors GS and FA conceived and planned the study. GS took the lead in writing the manuscript. TW and RES significantly contributed to drafting and revision of the paper. GS and FA contributed substantially to data acquisition and interpretation, and performed the statistical analysis. ND, IRA and MA collected DNA samples and performed targeted NGS. All authors approved the final version.

  • Funding This project was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) under Germany’s Excellence Strategy—EXC 2155 'RESIST'—Project ID 39087428 and the German network for multi-organ autoimmune diseases (GAIN). GS receives funding from the Young Academy Clinician/Scientist program of Hannover Medical School, Germany and the Rosemarie-Germscheid foundation. IRA receives funding from the German Academic Exchange Service (DAAD), the Hannover Biomedical Research School (HBRS) and the Center for Infection Biology (ZIB). All authors and this project are supported by the German Center for Infection Research (DZIF TTU 07.801).

  • Competing interests None declared.

  • Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.

  • Patient consent for publication All studied patients signed an informed consent form.

  • Ethics approval This study was conducted in accordance with the Declaration of Helsinki and was also approved from the Ethical Committee of the Hannover Medical School (approval number: 8875).

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data availability statement Data are available upon reasonable request. Data are available for formal research purposes only upon request to the corresponding author.

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