Background/Purpose: The development of disease-modifying anti-rheumatic drugs (DMARDs) has reduced disease activity in patients living with rheumatic diseases. Despite this, there is continued unmet need for safe and effective agents with improved convenience. TNF-like protein 1A (TL1A) is a pro-inflammatory and pro-fibrotic cytokine. TL1A inhibition has shown proof-of-concept in inflammatory bowel disease (IBD) and is under investigation in additional autoimmune conditions. Spyre Therapeutics is developing half-life extended antibodies targeting TL1A for the treatment of patients with IBD and rheumatic diseases. Animal model and translational data are needed to support the development of TL1A inhibitors in rheumatic diseases.

Methods: Gene expression data from published rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA) studies deposited in NCBI GEO were merged and queried to assess TL1A expression in controls and those with rheumatic diseases. To further characterize the role of TL1A in arthritis, the rat collagen-induced arthritis (CIA) model was used to assess the impact of TL1A inhibition on arthritic endpoints. Female Wistar rats were injected with a bovine type II collagen emulsion on days 0 and 7. Antibody treatments were injected (IV) once weekly. Etanercept was injected (IP) every 3 days. Body weight, hind paw volume and arthritis scores were measured twice per week. At study conclusion, X-ray images of the hind paws were taken and scored. Decalcified hind paw sections were scored by a blinded pathologist for cell infiltration, pannus severity, cartilage lesion severity, and bone resorption. RNA sequencing was performed on knee synovium.

Results: TL1A gene expression is upregulated in the blood of RA and axSpA patients and in skin lesions of PsA patients compared to healthy controls. In the rat CIA model, initiating treatment prior to symptom onset resulted in significantly improved disease activity score and hind paw volume with anti-TL1A antibodies compared to etanercept. Treatment with either anti-TL1A or etanercept improved hind paw X-ray scores relative to control groups with the magnitude of improvement being greater for animals treated with anti-TL1A than with etanercept. Anti-TL1A treatment, but not etanercept treatment, resulted in improvement across all histopathology scores compared to the vehicle control group. When initiated after the development of symptoms, treatment with anti-TL1A and etanercept showed comparable improvements in disease activity score, hind paw volume, and hind paw X-ray score relative to vehicle controls.

Conclusion: TL1A gene expression is increased in the blood of RA and axSpA patients and in skin lesions of PsA patients compared to healthy controls. Anti-TL1A antibody treatment reduced disease symptoms and pathology scores in the rat model of CIA. In this model, anti-TL1A treatment resulted in superior efficacy relative to etanercept when initiated prior to symptom onset and had comparable efficacy to etanercept when initiated at the start of symptom onset. These data support the clinical development of anti-TL1A therapy in rheumatic diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/tl1a-expression-is-upregulated-in-rheumatic-diseases-and-anti-tl1a-antibody-reduces-disease-symptoms-and-pathological-changes-in-rat-collagen-induced-arthritis/