Abstract
BackgroundThe tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). However, the relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear.MethodsWe measured soluble TL1A in synovial fluid (SF), serum, or plasma from RA first-degree relatives (FDRs) and in early RA and established disease. We measured the effects of anti-TNF and methotrexate (MTX) therapy on circulating TL1A from multiple independent RA treatment trials. We also determined the ability of a blocking anti-TL1A antibody to inhibit clinical disease and articular bone destruction in the murine collagen-induced arthritis (CIA) model of human RA.ResultsSoluble TL1A was specifically elevated in the blood and SF of patients with RA compared to patients with other diseases and was elevated early in disease and in at-risk anti-cyclic citrullinated peptide (CCP) (+) first-degree relatives (FDRs). Therapeutic TNF inhibition reduced serum TL1A in both responders and non-responders, whereas TL1A declined following MTX treatment only in responders. In murine CIA, TL1A blockade was clinically efficacious and reduced bone erosions.ConclusionsTL1A is specifically elevated in RA from early in the disease course and in at-risk FDRs. The decline in TL1A after TNF blockade suggests that TL1A levels may be a useful biomarker for TNF activity in RA. These results support the further investigation of the relationship between TL1A and TNF and TL1A blockade as a potential therapeutic strategy in RA.
Highlights
Therapies that block tumor necrosis factor (TNF) have dramatically improved patient outcomes in several autoimmune diseases, rheumatoid arthritis (RA)
Fc receptor (FcR) crosslinking induced higher levels of TNF-like protein 1A (TL1A) that were detectable at 18 h, whereas LPSinduced TL1A was only detectable at 48 h, with TL1A production approximately 10-fold lower with optimal doses of LPS than with FcR crosslinking (Fig. 1b)
To determine which of these signaling pathways are important in induction of TL1A expression, we stimulated human monocytes with a panel of TLR ligands specific for each receptor
Summary
Therapies that block tumor necrosis factor (TNF) have dramatically improved patient outcomes in several autoimmune diseases, rheumatoid arthritis (RA). Other members of the TNF superfamily of cytokines, especially those that costimulate B or T cell activation, may be potential candidates for therapeutic blockade in RA [3]. Among these is TNF-like ligand 1A (TL1A, TNFSF15), a TNF-family cytokine expressed by immune and endothelial cells in response to a number of proinflammatory stimuli. The tumor necrosis factor (TNF) superfamily cytokine TNF-like protein 1A (TL1A) and its receptor DR3 are essential for diverse animal models of autoimmune disease and may be pathogenic in rheumatoid arthritis (RA). The relationship of TL1A to disease duration, activity, and response to anti-TNF and other therapies in RA is not clear
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