Tofacitinib and esophageal-related manifestations in systemic sclerosis: a retrospective real-world cohort focused on lower esophageal sphincter pressure changes

Abstract Background Esophageal dysfunction represents one of the most prevalent, treatment-refractory visceral complications of systemic sclerosis (SSc). Janus kinase (JAK) inhibitors exhibit anti-inflammatory and antifibrotic effects against skin and interstitial lung lesions in SSc, yet evidence linking JAK inhibition to esophageal functional changes remains limited. This study aimed to analyze associations between add-on tofacitinib therapy and alterations in esophageal manometric parameters, gastrointestinal symptoms, and inflammatory biomarkers in SSc patients with esophageal involvement. Methods This single-centre retrospective controlled cohort enrolled 50 SSc patients with esophageal involvement treated for 24 weeks, split into two arms: tofacitinib added to stable conventional immunosuppressants ( n = 20) and conventional immunosuppressive therapy alone ( n = 30). The predefined primary endpoint was the 24-week change in resting lower esophageal sphincter pressure (ΔLESP), which was only analyzed in a subset of 26 participants with complete paired baseline and week-24 high-resolution manometry (HRM) data (12 in the tofacitinib group, 14 in the control group). Distal contractile integral (DCI), UCLA-GIT 2.0 score, modified Rodnan skin score (mRSS), inflammatory cytokines and infectious adverse events were defined as secondary exploratory outcomes. Multivariable linear regression and pre-planned subgroup analyses stratified by disease duration (< 5 years vs. ≥ 5 years) were performed to adjust for clinical confounders. Results Paired HRM analyses revealed a significant within-group elevation of resting LESP after 24 weeks in patients receiving tofacitinib (10.45 ± 3.97 mmHg at baseline vs. 14.07 ± 3.43 mmHg at week 24, P = 0.004), while LESP showed no statistically meaningful shift in the conventional therapy group (11.29 ± 6.68 vs. 11.56 ± 6.93 mmHg, P = 0.850). Comparison of ΔLESP values confirmed a substantially larger rise in the tofacitinib arm (3.62 ± 3.50 vs. 0.27 ± 2.56 mmHg, P = 0.013). After adjusting for disease duration, baseline LESP and concurrent prokinetic use, multivariable regression verified that add-on tofacitinib was independently correlated with greater LESP elevation (adjusted B = 3.545, 95%CI 1.418–5.672, P = 0.002). Subgroup stratification showed this favorable correlation was exclusive to patients with disease duration < 5 years. In contrast, DCI stayed stable over follow-up in both cohorts, with no significant intra- or inter-group differences detected at any time point. Unadjusted intergroup comparisons demonstrated larger reductions in mRSS, UCLA-GIT 2.0 score and serum IL-6 in the tofacitinib group ( P = 0.020, P = 0.028, P = 0.045), yet the gap in gastrointestinal symptom score disappeared following covariate adjustment. IL-6, IL-17 and ESR declined significantly within both groups, whereas CRP showed no intergroup discrepancy. The incidence of infectious adverse events was comparable between the two groups ( P = 0.720). Conclusions Within this retrospective non-randomized cohort, adjunctive tofacitinib was independently associated with more prominent improvements in lower esophageal sphincter pressure among SSc patients with esophageal involvement, with this correlation only evident in those with disease duration less than 5 years. No treatment-linked variation in esophageal body contractile function (DCI) was observed across all disease stages, and no independent benefit for patient-reported gastrointestinal symptoms existed after multivariable adjustment. These correlative findings derived from a small HRM subgroup cannot confirm causal therapeutic effects, and larger prospective multicentre trials with full esophageal functional monitoring are required for validation.