Anti-muscarinic 3 antibodies associate with a severe clinical phenotype in patients with systemic sclerosis

OBJECTIVES: Functional antibodies play a role in SSc gastrointestinal (GI) disease, but their clinical relevance is unclear. We examined GI and extraintestinal features associated with anti-muscarinic-3 receptor (M3R) antibodies in SSc patients. METHODS: In a cohort enriched for GI symptoms, SSc patients were tested for anti-M3R antibodies using an ELISA. High-titres were defined a priori based on the top quartile of anti-M3R titres to enhance specificity. Clinical features, including high GI severity (Medsger GI Severity Score of ≥2), whole-gut transit study data and UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 (UCLA GIT 2.0) scores, were compared between patients with and without high-titre anti-M3R antibodies. RESULTS: In 132 patients, 52 (39.4%) tested positive for anti-M3R antibodies and 33 (25%) had high-titre anti-M3R antibodies. Compared with patients without high titres, high-titre patients were more likely to have diffuse disease (43.8% vs 22.9%, P = 0.023), high GI severity (90.9% vs 69.7%, P = 0.019), and anti-RNPC3 (18.2% vs 6.1%, P = 0.036) and anti-U1RNP antibodies (21.2 vs 2.0%, P = 0.001). Whole-gut transit studies and UCLA GIT 2.0 scores were not different between the groups. In multivariable logistic regression analysis, high GI severity odds ratio: 4.50 (95% CI: 1.11, 18.18), P = 0.035 and anti-U1RNP antibodies odds ratio: 20.36 (95% CI: 3.16, 131.14), P = 0.002 remained associated with high-titre anti-M3R antibodies. CONCLUSION: Anti-M3R antibodies are associated with a more severe GI phenotype and distinct extraintestinal and serological features in SSc patients. Utilizing these features may optimize risk stratification in clinical practice and identify those likely to have progressive GI disease for clinical trials.