Elevated circulating levels of decoy receptor 3 (DcR3) were associated with systemic sclerosis-associated interstitial lung disease (SSc-ILD), greater systemic inflammation, and disease progression over 2 years, according to a recent study published in Clinical Rheumatology. The findings suggest that circulating DcR3 may have potential as a biomarker for identifying patients with systemic sclerosis (SSc) who are at greater risk of pulmonary involvement and disease progression.
Systemic sclerosis is a complex autoimmune disease characterised by vascular abnormalities, immune dysregulation, and progressive fibrosis affecting the skin and internal organs. Interstitial lung disease is one of the major organ manifestations of SSc and can contribute substantially to morbidity and mortality. Identifying circulating biomarkers that reflect disease activity or predict progression could therefore help improve risk stratification and clinical monitoring.
Tumour necrosis factor-like cytokine 1A (TL1A), encoded by TNFSF15, is a member of the tumour necrosis factor superfamily with proinflammatory and profibrotic properties. Experimental studies have implicated TL1A-mediated signalling in inflammatory and fibrotic processes associated with interstitial lung disease. DcR3 is a soluble member of the tumour necrosis factor receptor superfamily that can bind TL1A and other ligands. It also acts as a decoy receptor for Fas ligand (FasL), potentially inhibiting FasL-mediated apoptosis. In addition, previous experimental evidence has suggested that DcR3 may promote T-cell activation through costimulatory mechanisms, raising the possibility that it contributes to immune dysregulation in autoimmune diseases.
Against this background, researchers investigated the clinical relevance of circulating TL1A and DcR3 in patients with SSc. The study included 41 consecutive, unselected patients with SSc, 52 individuals with primary Raynaud’s phenomenon (pRP), and 49 apparently healthy individuals. Serum TL1A and DcR3 concentrations were measured using enzyme-linked immunosorbent assays.
Both biomarkers showed differences between the study groups. Serum TL1A levels were significantly higher in patients with SSc than in healthy individuals. DcR3 levels were also significantly elevated in patients with SSc compared with both individuals with pRP and healthy controls, with all reported comparisons reaching statistical significance at P < 0.001.
The investigators subsequently examined whether circulating levels of the two biomarkers were associated with clinical characteristics and subsequent disease progression. Clinical features, pulmonary function tests, and treatment information were assessed at baseline and annually for 2 consecutive years. Disease progression was evaluated using the MINIMISE endpoint, which incorporates mortality and morbidity outcomes.
Baseline DcR3 levels showed a significant association with subsequent SSc progression. Receiver operating characteristic analysis demonstrated that serum DcR3, but not TL1A, had predictive value for progression over the 2-year follow-up period, with an area under the curve of 0.684 (P = 0.04). Although the magnitude of discrimination was moderate, the finding supported further investigation of DcR3 as a potential prognostic biomarker.
The association between elevated DcR3 and pulmonary involvement was particularly notable. Patients whose DcR3 concentrations exceeded the ROC-defined cut-off had higher erythrocyte sedimentation rates, indicating greater systemic inflammation. They also had a higher prevalence of ILD confirmed by high-resolution computed tomography of the chest. In addition, these patients had lower diffusing capacity for carbon monoxide, suggesting greater impairment of pulmonary gas transfer.
In contrast, the study did not identify significant associations between circulating TL1A levels and the assessed clinical disease characteristics. These findings indicated that although both TL1A and DcR3 were elevated in patients with SSc, DcR3 showed a closer relationship with clinically relevant disease manifestations and subsequent progression.
The researchers noted that the findings may have implications for understanding the biological pathways involved in SSc. The association between DcR3, systemic inflammation, ILD, and disease progression supports the possibility that DcR3 reflects aspects of the immune and fibrotic processes underlying SSc. However, the study was relatively small, and the findings require validation in larger and independent patient cohorts.
Further research is also needed to determine whether DcR3 provides prognostic information beyond established clinical, serological, and pulmonary function measures. Studies involving larger and clinically defined SSc subgroups could help establish whether DcR3 is particularly useful in patients at risk of developing ILD or those with established pulmonary disease.
The study identified circulating DcR3 as a potential biomarker associated with ILD, systemic inflammation, and disease progression in SSc. While the results do not yet establish its role in routine clinical practice, they provide a basis for further investigation of DcR3 in risk stratification and longitudinal monitoring of patients with systemic sclerosis.
References
- Poulia V, Vlachogiannis NI, Avdi AP, Bournia VK, Bamias G, Tektonidou MG, Sfikakis PP, Panopoulos S. Circulating levels of TL1A and its decoy receptor DcR3 in systemic sclerosis. Clin Rheumatol. 2026 Oct;45(10):6181-6187.
- Lee CS, Hu CY, Tsai HF, Wu CS, Hsieh SL, Liu LC, Hsu PN. Elevated serum decoy receptor 3 with enhanced T cell activation in systemic lupus erythematosus. Clin Exp Immunol. 2008 Mar;151(3):383-90.