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OBJECTIVES: The gastrointestinal tract (GIT) is the most commonly affected internal organ in systemic sclerosis (SSc). We sought to determine the prevalence and impact of GIT symptoms on survival and patient-reported outcomes. METHODS: 907 consecutive patients from the Australian Scleroderma Cohort Study (ASCS) who had prospectively completed the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 questionnaire (UCLA GIT) between 2015 and 2021 were included. The association between UCLA GIT scores and physical function (SHAQ), QoL (SF-36), mood (PROMIS anxiety and depression domains), fatigue (FACIT-fatigue score) and employment was investigated using multivariable population-averaged panel models using Generalized Estimating Equations (GEE). Kaplan-Meier curves and multivariable Cox proportional hazard regression model were used to evaluate survival according to total UCLA GIT scores. RESULTS: GIT symptoms were reported in 87% of participants with 46-52% reporting moderate to very severe symptoms of reflux, distension, diarrhoea and constipation. Higher total UCLA GIT scores were associated with worse QoL, physical function, fatigue, anxiety and depression (p<0.001). In multivariable GEE analysis, moderate and severe to very severe total scores, reflux and distension scores were associated with worse physical function, QoL, fatigue, anxiety and depression compared to those with mild scores (p<0.05). Patients with severe total scores and diarrhoea scores were more likely to be unemployed compared to those with mild scores (p<0.05). UCLA GIT total scores were not independently associated with mortality in our cohort. CONCLUSION: GIT manifestations are common in SSc and negatively impact QoL, physical function and employment but are not directly associated with increased mortality.

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BACKGROUND: To determine the relationship between gastroesophageal reflux disease (GORD) and its treatment and interstitial lung disease in patients with systemic sclerosis (SSc). METHODS: SSc patients from the Australian Scleroderma Cohort Study (ASCS) were included. GORD was defined as self-reported GORD symptoms, therapy with a proton pump inhibitor (PPI) or histamine 2 receptor antagonist (H2RA) and/or the presence of reflux oesophagitis diagnosed endoscopically. The impact of GORD and its treatment on ILD features (including severity and time to ILD development) and survival was evaluated. RESULTS: GORD was a common manifestation affecting 1539/1632 (94%) of SSc patients. GORD affected 450/469 (96%) of those with SSc-ILD cohort. In SSc-ILD, there was no relationship between the presence of GORD or its treatment and time to ILD development or ILD severity. However, GORD treatment was associated with improved survival in those with ILD (p = 0.002). Combination therapy with both a PPI and a H2RA was associated with a greater survival benefit than single agent therapy with PPI alone (HR 0.3 vs 0.5 p < 0.050 respectively). CONCLUSION: GORD is a common SSc disease manifestation. While the presence or treatment of GORD does not influence the development or severity of ILD, aggressive GORD treatment, in particular with a combination of PPI and H2RA, is associated with improved survival in those with SSc-ILD.

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BACKGROUND: Primary chronic intestinal pseudo-obstruction (CIPO) is a rare, potentially life-threatening disorder characterized by severely impaired gastrointestinal motility. The objective of this study was to examine the contribution of ACTG2, LMOD1, MYH11, and MYLK mutations in an Australasian cohort of patients with a diagnosis of primary CIPO associated with visceral myopathy. METHODS: Pediatric and adult patients with primary CIPO and suspected visceral myopathy were recruited from across Australia and New Zealand. Sanger sequencing of the genes encoding enteric gamma-actin (ACTG2) and smooth muscle leiomodin (LMOD1) was performed on DNA from patients, and their relatives, where available. MYH11 and MYLK were screened by next-generation sequencing. KEY RESULTS: We identified heterozygous missense variants in ACTG2 in 7 of 17 families (~41%) diagnosed with CIPO and its associated conditions. We also identified a previously unpublished missense mutation (c.443C>T, p.Arg148Leu) in one family. One case presented with megacystis-microcolon-intestinal hypoperistalsis syndrome in utero with subsequent termination of pregnancy at 28 weeks' gestation. All of the substitutions identified occurred at arginine residues. No likely pathogenic variants in LMOD1, MYH11, or MYLK were identified within our cohort. CONCLUSIONS AND INFERENCES: ACTG2 mutations represent a significant underlying cause of primary CIPO with visceral myopathy and associated phenotypes in Australasian patients. Thus, ACTG2 sequencing should be considered in cases presenting with hypoperistalsis phenotypes with suspected visceral myopathy. It is likely that variants in other genes encoding enteric smooth muscle contractile proteins will contribute further to the genetic heterogeneity of hypoperistalsis phenotypes.

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