Hirohito Kotani

Systemic sclerosis is an autoimmune disease characterized by vasculopathy, fibrosis, and immune dysregulation. Anti‐SS‐A antibodies (anti‐SSA) have been reported to confer severe clinical manifestations in some Western and Japanese cohorts. We aimed to determine whether anti‐SSA seropositivity affects clinical outcomes in Japanese patients. We retrospectively analyzed 307 Japanese patients with systemic sclerosis who underwent initial evaluation between January 2011 and March 2020 in our clinic. “Isolated” anti‐SSA seropositivity was defined as positivity for anti‐SSA in the absence of anti‐topoisomerase I, anti‐centromere, anti‐RNA polymerase III, and anti‐U1 ribonucleoprotein antibodies. Overall survival was defined as time to all‐cause mortality, and progression‐free survival was defined as time to disease progression necessitating intensified therapy. Cox proportional hazards models were employed to estimate hazard ratios and 95% confidence intervals. For patients with “isolated” anti‐SSA seropositivity, further investigation for SSc‐related autoantibodies was conducted utilizing Autoantibody Array Assay (A‐Cube). Anti‐SSA were detected in 31.3% of patients. Although anti‐SSA seropositivity overall correlated with interstitial lung disease, it was not independently associated with overall survival or progression‐free survival. In contrast, “isolated” anti‐SSA seropositivity emerged as an independent risk factor for both shorter overall survival (hazard ratio 21.7, 95% confidence interval 5.57–84.8) and progression‐free survival (hazard ratio 4.18, 95% confidence interval 1.05–16.7). Expanded serologic testing revealed additional autoantibodies implicated in severe SSc phenotypes. These findings underscore the importance of routinely assessing anti‐SSA and highlight the need for autoantibody screening in depth in this subpopulation.

Objective: Epitope spreading (ES), involving autoantibodies, plays a crucial role in the development and persistence of autoimmune reactions in various autoimmune diseases. This study aimed to investigate the relationship between ES of anti–RNA polymerase III (RNAP III) antibodies (ARAs) and the clinical manifestations of systemic sclerosis (SSc).Methods: We investigated whether intermolecular ES occurs in the subunits of the RNAP III complex and whether intramolecular ES targets the major antigen, RNA polymerase III subunit A (RPC1), in patients with SSc. To achieve this, we synthesized 17 full‐length subunit proteins of the RNAP III complex and 5 truncated forms of RPC1 in vitro using a wheat germ cell‐free translation system. Subsequently, we prepared antigen‐binding plates and measured autoantibodies in the serum of patients with SSc.Results: Autoantibodies against different RNAP III complex subunits were found in patients who were ARA‐positive with SSc. The intermolecular ES indicators significantly correlated with the modified Rodnan skin thickness score (mRSS) and surfactant protein‐D, a biomarker of interstitial lung disease. However, the extent of disease on high‐resolution computed tomography or pulmonary function tests did not show any significant correlation. Intramolecular ES indicator against RPC1 were significantly correlated with mRSS and renal crisis. Furthermore, longitudinal assessment of ES in RNAP III complex subunits correlated with mRSS and exhibited potential as a disease activity biomarker.Conclusion: Our findings indicate a correlation between ES levels and the severity of skin sclerosis or the risk of other complications in SSc. This study suggests that measuring ES in SSc serves as a novel biomarker for disease activity. image