Background/Purpose: Bruton’s tyrosine kinase (BTK), a TEC family non-receptor kinase, is expressed in B cells and myeloid cells. BTK relays signaling downstream of B cell receptor (BCR) and toll-like receptors (TLR) in B cells, whereas in myeloid cells, it mediates activating Fcg receptor and TLR signal transduction. Given the importance of these cell types in autoimmune pathogenesis, inhibition of BTK pathway is expected to provide an effective strategy for the treatment of rheumatoid arthritis (RA). However, the activity status of the BTK pathway in RA synovium and at various stages of RA disease progression has not been addressed.  

Methods: RNA-Seq expression profiling was used to examine the expression of BTK in synovial tissue samples from healthy, osteoarthritis (OA), seropositive arthralgia, early RA and established RA subjects. Immunohistochemistry was performed to determine the expression of BTK protein in healthy, OA and RA synovial tissue biopsies. BTK-responsive gene signatures were generated from vehicle or BTK inhibitor-treated and activated human B cells and monocytes. Gene Set Variation Analysis (GSVA) was employed to assess the status of BTK signaling by interrogating BTK in vitro B cell and monocyte gene signatures against expression profiles of synovial tissues from various stages of RA disease progression.

Results: We demonstrate that the expression of BTK was significantly increased in arthralgia, early RA and established RA, compared to healthy and OA synovial tissue samples. In addition, RA patients showed increased cytoplasmic BTK protein expression in the synovium when compared to their healthy and OA counterparts, and the protein was restricted to synovial immune cell infiltrates. GSVA revealed that anti-IgM-responsive genes in naïve B cells were significantly enriched in synovial tissues from various stages of RA disease progression, whereas immune complex (HSA and anti-HSA complex)-responsive genes in monocytes showed enrichment only in established RA synovial tissue samples, demonstrating differential involvement of B cells and monocytes in arthralgia and early disease vs., established RA. In accordance with these observations, BTK gene signatures from activated B cells showed enrichment in synovial tissue samples during RA disease progression, while BTK monocyte gene signatures showed enrichment only in established RA synovium.

Conclusion: Taken together, these data suggest that BTK pathway is active in synovium during RA disease progression, and BTK inhibitors may show efficacy not only for the treatment of RA but also in halting the progression of the disease to established RA.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/brutons-tyrosine-kinase-btk-pathway-is-active-in-synovium-at-various-stages-of-rheumatoid-arthritis-disease-progression/