The clinical phenotype of anti-Th/To+ patients in systemic sclerosis: a case-control study within the European Scleroderma Trials and Research cohort.

Background: Systemic sclerosis (SSc) is a heterogeneous autoimmune disease, where autoantibody profiling plays a central role in defining disease subsets and guiding personalized management. Objectives: To investigate the clinical phenotype and long-term outcomes of anti-Th/To positive SSc patients in an international cohort, focusing on interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), malignancy association, organ damage accrual, and mortality within a precision medicine framework. Design: Multicenter case-control study. Methods: Data prospectively collected from 28 European Scleroderma Trial and Research centers were analyzed (CP144). For each anti-Th/To+ case, two anti-Th/To- controls were matched by sex, age at onset, and disease duration to enable detailed phenotypic comparisons. Results: A total of 102 anti-Th/To+ patients were compared to 204 anti-Th/To- matched controls. Anti-Th/To+ patients had a higher prevalence of concomitant anti-Ro52+, lower frequency of diffuse cutaneous involvement, digital ulcers, pitting scars, and telangiectasias. ILD on high-resolution computed tomography and ILD functional progression events were less frequent in anti-Th/To+ patients, and anti-Th/To positivity was not independently associated with ILD in multivariable analysis. Instead, ILD presence was significantly associated with anti-Topoisomerase-1 (anti-Topo1) and anti-Ro52 positivity, and lack of anticentromere antibodies. Similarly, myocarditis was less frequently observed in anti-Th/To+ cases, although myositis had a higher rate than in anti-centromere+ or other lcSSc patients. Other SSc manifestations, including PAH, and malignancies synchronous to SSc onset had similar frequencies between cases and controls. Anti-Th/To+ patients accrued mild organ damage during the disease course, with lower damage index scores than anti-Topo1+ matched controls. No SSc-related deaths occurred in anti-Th/To+ patients, who had survival curves slightly better, although not significantly different, than matched controls. Conclusion: Anti-Th/To+ SSc patients are characterized by low prevalence of major organ involvement, including ILD, when compared to matched controls, mild organ damage, and good survival. These results reinforce the ongoing use of autoantibody profiling-including rarer antibodies-in precision medicine for SSc.