Challenging the Paradigm: Severe Rheumatoid Arthritis and Anti-TNF Failure in an X-Linked Agammaglobulinemia Patient

Background X-linked agammaglobulinemia (XLA) is a rare inherited immunodeficiency disorder caused by a mutation of the Bruton tyrosine kinase (BTK) gene on the X chromosome. It is characterized by absent B cells and recurrent infections. Autoimmune manifestations in XLA, such as rheumatoid arthritis (RA), are uncommon and poorly understood [1, 2]. Case Presentation We report a case of a 56-year-old male with XLA, diagnosed at age 5, and chronic seronegative erosive polyarthritis who failed anti-TNF therapy with adalimumab (Hadlima), despite the absence of circulating B cells. He fulfills the 2010 ACR/EULAR classification criteria for RA with ongoing disease activity in small and large joints. After treatment failure with adalimumab, he was switched to upadacitinib (JAK1 inhibitor) with significant improvement and resolution of his synovitis. Investigations A primary immunodeficiency gene panel was performed, and the results were consistent with an XLA diagnosis, revealing a likely pathogenic mutation on the BTK gene (c.1932C>G and p.Phe644Leu). The investigations concord with agammaglobulinemia, including absent circulating B cells on flow cytometry (Figure 1, Tables 4, 6). Additionally, a rheumatologic workup was conducted and showed results supportive of seronegative arthritis (Table 7). Figure 1. Flow cytometry. Table 1. Naïve and memory T cell subsets (% and cells/cu mm). Table 2. T cell subsets (% and cells/cu mm). Table 3. T cell activation markers. Table 4. Memory B cells. Table 5. Genetic investigations. Table 6. Laboratory investigations. Table 7. Rheumatology workup. Discussion The failure of an anti-TNF inhibitor is unusual in this case, as this patient’s XLA results in no circulating B cells. It is unexpected for a patient with no functioning B cells to develop autoimmunity and anti-TNF treatment failure, as it is most often due to antibody development. Furthermore, although the role of T cells is not fully established with regard to RA, it is thought that they are involved in chronic inflammatory responses [3, 4]. There have been some recorded cases in the literature of RA in XLA patients, although the sample size of XLA patients is too small to draw a definitive conclusion [3]. Conclusion This case raises questions about the mechanisms underlying treatment resistance in B cell–deficient patients and highlights a rare and complex presentation of autoimmune RA and anti-TNF treatment failure in a patient with XLA. These findings underline the need for further investigation into immune dysregulation in XLA and the implications for autoimmune disease development and treatment response [3].