Background: Interleukin-6 (IL-6) is a key proinflammatory cytokine regulating the humoral immune response by inducing B lymphocyte differentiation into plasma cells and stimulating antibody production. The principal intracellular signaling cascade mediated by IL-6 is the JAK/STAT pathway. In clinical practice, we observed severe hypogammaglobulinemia in some patients treated with IL-6 blockers; however, this potential association remains insufficiently studied.

Objectives: Our study aims to analyze the frequency of hypogammaglobulinemia in patients with rheumatoid arthritis (RA), giant cell arteritis (GCA) or spondyloarthritis (SpA) treated with IL-6 receptor inhibitors (IL6Ri) or janus kinase inhibitors (JAKi).

Methods: This study is an observational, retrospective chart review that included adult patients clinically diagnosed with RA, GCA, or SpA, and treated with tocilizumab, sarilumab, or JAKi at an academic rheumatology unit. Patients with a treatment duration of less than 3 months, those without post-treatment immunoglobulin determination, and those with immunoglobulin assessments conducted before 3 months of treatment or after more than 3 years were excluded. The primary endpoint was the occurrence of hypogammaglobulinemia, defined as IgG levels below 750 mg/dL ^[1,2] with its 95% confidence interval (CI). Additionally, we compared the frequency of hypogammaglobulinemia between IL-6Ri and JAKi. Secondary endpoint included frequency of severe hypogammaglobulinemia (IgG <450 mg/dL) ^[1,2] and severe infection (which required hospital admission or intravenous treatment). We present a descriptive report.

Results: Out of 237 initially selected patients, 181 were excluded: 160 due to unavailable post-treatment immunoglobulin determination, 8 for immunoglobulin assessments conducted before 3 months or more than 3 years after treatment initiation, and finally, 5 for a deemed too-short treatment duration.

The final study sample comprised 56 patients with a mean age of 62.3 years (SD ±12 years), and 78.6% of them were women. The most prevalent disease was RA (71.4%), followed by GCA (23.2%) and SpA (5.4%). Among the patients, 31 received IL6Ri treatment (25 with tocilizumab and 6 with sarilumab). Additionally, 25 patients received JAKi treatment, with baricitinib being the most frequently prescribed (15 out of 25). The median post-treatment immunoglobulin determination time was 8.18 months (IQR 4.5-14.8 months). Hypogammaglobulinemia was observed in 20 out of the 56 included patients, 35,71% of the sample (95% CI 24-49%). Furthermore, hypogammaglobulinemia occurred in 13 out of 31 patients treated with IL6Ri (41.94%, 95% CI 26-59%), and in 7 out of 25 patients treated with JAKi (28%, 95% CI 14-48%); with no significant difference between the two groups.

Patients with hypogammaglobulinemia comprised 17 females and 3 males, with a mean age of 67.9 years (SD ±10.6 years). Hypogammaglobulinemia occurred in 14 cases with RA and 6 with GCA, with no cases observed in SpA. At treatment initiation, 13 patients received concomitant corticosteroids, and 9 patients received conventional synthetic disease-modifying antirheumatic drugs (DMARDs). Among these patients, 35% (7/20) had baseline hypogammaglobulinemia; three of them had prior rituximab treatment. Severe hypogammaglobulinemia was observed in 5 cases, with one patient requiring immunoglobulin replacement therapy. Additionally, 5 cases of severe infection were noted. 8 cases exhibited decreased IgA levels, while 6 cases showed decreased IgM levels. Notably, no decrease in lymphocyte counts was observed in any case.

Conclusion: The determination of immunoglobulins in patients treated with IL6Ri and JAKi is not integrated into clinical practice. Hypogammaglobulinemia was common in our dataset and remains unexplored in the literature. Moreover, our data strongly support the need for new prospective studies to thoroughly analyze this potentially harmful association.

REFERENCES: [1] PMID: 17994123.

[2] PMID: 23919557.

Acknowledgements: Special thanks to my Rheumatology colleagues for their invaluable support and assistance in completing this work.

Disclosure of Interests: None declared.