Background: Despite progress in the treatment of patients with rheumatic diseases such as rheumatoid arthritis (RA), psoriatic arthritis (PsA), and axial spondyloarthritis (axSpA), many patients do not achieve remission or significant improvement in disease activity with currently available advanced therapeutic disease modifying anti-rheumatic drugs (DMARDs). Thus, new therapeutics are needed to address the unmet need in these diseases. TL1A (TNF-like cytokine 1A), produced by antigen presenting cells, signals via its receptor, DR3, on T cells to promote Th1 (TNFα), Th17 (IL17A/F) responses and IL6 expression. Tulisokibart, a monoclonal TL1A blocking antibody, has shown efficacy in ulcerative colitis and Crohn’s disease and reduces Th1, Th17 and activated fibroblast pathways in intestinal tissue. Intestinal bowel disease and spondyloarthropathy (SpA) are interrelated and can present as coexisting clinical manifestations and previous studies have shown that inhibition of the TL1A-DR3 pathway prevents arthritis in pre-clinical models. However, it is unknown if the TL1A-DR3 pathway is expressed in human tissue from these rheumatic diseases.

Objectives: Determine if TL1A expression and TL1A driven pathways are upregulated in RA synovial, PsA skin and axSpA synovial tissue. Identify the specific cell subsets that express the gene encoding TL1A, TNFSF15 , and the gene encoding DR3, TNFRSF25 , in single cell data from RA and PsA synovial tissue. Determine if blockade of TL1A protects against collagen-induced arthritis and ear inflammation in the imiquimod-induced skin psoriasis mouse models.

Methods: Bulk and single cell transcriptomic public data from RA, PsA, axSpA and control tissue were analyzed for gene expression. TL1A and DR3 protein expression were assessed in RA tissue by immunohistochemistry. The Accelerating Medicines Partnership® (AMP®) RA single-cell RNA sequencing dataset from RA and OA synovial tissue were interrogated for TNFSF15 (TL1A) and TNFRSF25 (DR3) gene expression. Male DBA/1 mice were administered type II collagen in CFA on days 0 and 21. Anti-TL1A or isotype control were administered starting on day 13, every two days. Histopathology and anti-collagen antibody were analyzed on day 36. In a skin psoriasis model, imiquimod (IMQ) was applied topically for 5 days. Anti-TL1A was administered starting on day -1, daily. Ear thickness was measured daily. Ear thickness and ear cytokines were analyzed on day 6.

Results: In bulk transcriptomic datasets, the gene encoding TL1A, TNFSF15 , was significantly upregulated in three out of five datasets in RA compared to control synovium. TL1A driven Th1 pathways were also increased in three out of five datasets in RA compared to control synovial tissue. In single cell analysis of RA synovial tissue, TNFSF15 was expressed by macrophages and fibroblasts. TNFRSF25 was highly expressed by T cells, whereas there was a lower percentage of gene expression by fibroblasts, endothelial, B cells and myeloid cells. TL1A positive cells were detected within the intima and subintima of RA synovium, while DR3 positive cells were detected within the subintima. TL1A blockade prevented arthritis in the collagen-induced arthritis mouse model and significantly reduced paw inflammation and cartilage destruction. In bulk transcriptomic datasets, TL1A pathways were elevated in PsA lesional skin compared to control skin tissue and in axSpA synovium compared to control tissue. In single cell analysis of PsA synovial fluid, T cells expressed TNFRSF25, and TNFRSF25 was co-expressed with IFNG and TNFA . TL1A blockade ameliorated IMQ-induced ear inflammation and cytokine expression levels in the psoriasis mouse model.

Conclusions: TL1A expression and pathway analysis suggests that TL1A may modulate immune pathways in RA, PsA and axSpA tissue. Anti-TL1A prevented inflammation in an arthritis model and skin inflammation in a psoriatic mouse model. Data supports targeting TL1A as a potential effective therapy in RA, PsA and axSpA.

REFERENCES: NIL.

Acknowledgments: NIL.

Disclosure of Interests: Heather Llewellyn Merck & Co., Inc., Merck & Co., Inc., In Sock Jang Merck & Co., Inc., Merck & Co., Inc., Arjun Baghela Merck & Co., Inc., Merck & Co., Inc., Albert Jeon Merck & Co., Inc., Marc Sze Merck & Co., Inc., Merck & Co., Inc., Su-Yang Liu Merck & Co., Inc., Merck & Co., Inc., Laxminarayan Hegde Merck & Co., Inc., Merck & Co., Inc., Mingxin Tang Merck & Co., Inc., Janice Woodhouse Merck & Co., Inc., Ernesto Munoz Merck & Co., Inc., Merck & Co., Inc.