Anti-Ro/SSA and rheumatoid factor antibodies are associated with more severe lung involvement in patients with systemic sclerosis: a study from the EUSTAR database

BACKGROUND: As precision medicine is needed in systemic sclerosis (SSc) and SSc-associated interstitial lung disease (ILD), SSc non-specific antibodies might improve the risk stratification in this population. RESEARCH QUESTION: To evaluate the prevalence and characterize the disease phenotype of SSc patients positive for anti-Ro/SSA alone or in combination with RF antibodies in the largest cohort of SSc patients, focusing on lung involvement. METHODS: Patients from the EUSTAR database with available data on anti-Ro/SSA and RF antibodies were included. Clinical characteristics of patients with or without anti-Ro/SSA and RF antibodies were compared at baseline. Multivariable logistic regression models were built to identify factors associated with ILD. In patients with ILD at baseline, multivariable mixed-effects models for longitudinal FVC and DLCO were built to assess the impact of anti-Ro/SSA and RF. Prognostic factors for the ILD progression and death during follow-up were tested by multivariable Cox proportional hazards regression. RESULTS: Among the 4,221 patients fulfilling the inclusion criteria, 641 (15.2%) had anti-Ro/SSA antibodies. These patients exhibited a higher prevalence of muscular involvement (p < 0.01), pulmonary hypertension (p = 0.06), and ILD (p < 0.01) at baseline. Over 14,066 follow-up visits, anti-Ro/SSA independently predicted the presence of ILD (OR 1.24 [1.07-1.43], p < 0.01). Among anti-Ro/SSA+/RF+ patients, who represented 4.1% of the cohort, ILD was more prevalent as compared to single positive or negative anti-Ro/SSA and RF patients. Anti-Ro/SSA+/RF+ double-positive patients had a more severe ILD, with lower FVC% (R -4.12 [-7.85;-0.40]; p = 0.03) and lower DLCO% (R -5.4[-9.05;-1.74]; p < 0.01). INTERPRETATION: In the large EUSTAR cohort, anti-Ro/SSA antibodies are detected in 15% of SSc patients and represent an independent risk factor for the presence and severity of ILD, particularly for cases with anti-Ro/SSA+/RF+ double positivity. These data support the inclusion of anti-Ro/SSA and RF antibodies in routine clinical practice to improve the risk stratification of SSc patients.