A Phenome-Wide Association Study of Drugs and Comorbidities Associated With Gastrointestinal Dysfunction in Systemic Sclerosis.

OBJECTIVE: To explore the causes of and contributors to gastrointestinal (GI) dysfunction in systemic sclerosis (SSc) in a phenome-wide association study (PheWAS), using real-world clinical records data. METHODS: Twelve thousand five hundred thirty-five documented clinical assessments of 2058 consenting individuals with SSc at the Royal Free Hospital (UK) were available for detailed phenotyping. Diagnoses and drugs were mapped to structured dictionaries of terms (Disease Ontology project and DrugBank Open Data, respectively). A PheWAS model was used to explore links between 6 important SSc-GI domains (constipation, diarrhea, dysmotility, incontinence, gastroesophageal reflux, and small intestinal bacterial overgrowth [SIBO]) and exposure to various comorbidities and drugs. "Hits" from the PheWAS model were confirmed and explored in a subcohort reporting quantitative GI symptom scores from the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract Instrument 2.0 (GIT 2.0) questionnaire. RESULTS: One thousand five hundred forty-six individuals were entered into the PheWAS analysis. Six hundred seventy-three distinct diagnoses and 634 distinct drugs were identified in the dataset, as well as SSc-specific phenotypes such as antinuclear antibodies (ANA). PheWAS analysis revealed associations between drugs, diagnoses, and ANAs with 6 important SSc-GI outcomes: constipation, diarrhea, dysmotility, incontinence, reflux, and SIBO. Subsequently, using GIT 2.0 symptom scores links with SSc-GI were confirmed for 22 drugs, 4 diagnoses, and 3 ANAs. CONCLUSION: Using a hypothesis-free PheWAS approach, we replicated known, and revealed potential novel, risk factors for SSc-GI dysfunction, including drug classes such as opioid, antimuscarinic, and endothelin receptor antagonist, and ANA subgroup.

Autoantibody predictors of gastrointestinal symptoms in systemic sclerosis.

OBJECTIVES: To assess the prevalence and burden of SSc-related gastrointestinal dysfunction (SSc-GI) and to evaluate associations with demographic, clinical and serological characteristics. METHODS: Patients completed the UCLA SCTC GIT 2.0 questionnaire for SSc-GI disease to assess the burden of GI disease across multiple functional and psychological domains. Questionnaire scores were assessed using non-parametric and quantile regression analyses. RESULTS: Our cohort included 526 patients with SSc, with a typical distribution of disease-associated autoantibodies (ACA, ARA, ATA, PM-Scl, U1RNP, U3RNP). We demonstrated associations between hallmark antibodies and the domain-specific burden of GI disease. In particular, ACA, ARA and ENA-negative demonstrated increased SSc-GI disease burden, while PM-Scl conferred relative protection. In a distributional analysis, associations with autoantibodies were particularly marked in those with the highest burden of GI disease. CONCLUSION: There is a significant burden of SSc-GI disease in patients with SSc; reflux and bloating symptoms are most prominent. SSc hallmark antibodies may predict increased risk of SSc-GI disease, in particular ACA and ARA, while PM-Scl may be protective.