Methods and Patients
Study Population
For this observational, post hoc analysis of prospectively collected data from the SSc cohort of the University Hospital Zurich, we selected patients who were included in the European Scleroderma Trials and Research Group (EUSTAR) database, fulfilled the ACR/EULAR 2013 criteria for the classification of SSc, and completed at least one UCLA GIT 2.0 questionnaire. Our center is following the EUSTAR recommendations for a detailed annual assessment, based on a standardized clinical approach and work-up.[1] Patients also complete additional questionnaires at their annual visits as part of that routine assessment, including the UCLA GIT 2.0. Investigations of the GI tract, such as EGD, are not included in the routine assessment and are selectively recommended by the expert rheumatologist, after taking the history, performing the clinical examination of the patients, and evaluating their same-day work-up results (laboratory, lung function tests, lung imaging, electrocardiogram, and power-Doppler echocardiography). There was no regular use of the UCLA GIT 2.0 questionnaire to decide further GI investigation, although the rheumatologist could have access to the patient self-reported data, at least in part of the cases.
Data were retrieved from the prospectively collected EUSTAR registry for our center. In the EUSTAR database, information on gastrointestinal involvement is recorded by 3 items: esophageal symptoms (reflux and/or dysphagia), stomach symptoms (early satiety and/or vomiting), and intestinal symptoms (diarrhea, bloating, and/or constipation). To collect more detailed data on upper GI symptoms, presence of EGD, and treatment with proton pump inhibitors (PPI), we additionally reviewed retrospectively the electronic medical records (EMR) of the selected patients (see details in the online supplement). We also recorded the attending rheumatologist's indication to perform an EGD from each visit of the patient. As some patients had more than one EGD, we selected for further analysis the EGD performed within a period of up to 3 months before or after the corresponding EUSTAR assessment visit and, if more than one EGD, the one closest to the corresponding visit. Reflux esophagitis was graded according to the Los Angeles classification.[15] Patients with concomitant acute GI bleeding or a history of cancer in the upper GI tract were excluded from this study. The study has been performed in accordance with the Declaration of Helsinki Ethical Principles and with GCP guidelines. Ethical approval for this data collection and analysis was issued by the cantonal ethics (BASEC Nr. PB2016–01515 and 2018–02165).
UCLA GIT 2.0 Questionnaire and Study Outcomes
The UCLA GIT 2.0 questionnaire contains 34 items, organized into seven subscales: reflux, distention/bloating, diarrhea, fecal soilage, constipation, emotional wellbeing, and social functioning. The subscales are scored from 0 to 3, higher scores indicating more severe symptomatology and worse HRQoL. Scoring of the diarrhea and constipation scales is different, ranging from 0 to 2 and 0 to 2.5, respectively. The total UCLA GIT 2.0 score is calculated by averaging all subscales, except the one for constipation, and ranges from 0 to 2.83.[6,7]
We defined three study outcomes: first, the recommendation to perform EGD by the SSc-specialized rheumatologist; second, macroscopic esophagitis identified on EGD (based on the EGD report and mentioning the Los Angeles grade of esophagitis), further referred to as "endoscopic esophagitis"; and third, any significant pathologic finding on EGD, further referred to as "pathologic EGD." The latter included endoscopic esophagitis, mycotic esophagitis, esophageal strictures, Barrett's esophagus, gastric antral vascular ectasia (GAVE), peptic ulcers, and tumors.
Statistical Analysis
For statistical calculations, we used the statistic software IBM SPSS 25.0 and R language 3.6 (lme4 package).[16] A p value < 0.05 was considered statistically significant. Numeric variables are described as median and inter-quartile range (Q1, Q3), while categorical variables are described as n and percentage. Comparisons between groups were performed with the chi-squared test for categorical variables and with the Mann-Whitney U test for numeric variables.
The parameters of interest for all three study outcomes were the UCLA GIT 2.0 total score and its reflux, distention/bloating, social functioning, and emotional wellbeing subscales. We analyzed their association with each of the three dichotomous outcomes of the study using multivariable generalized linear mixed effects models (GLMM) adjusted for random effects of subjects and fixed effects for all other candidate parameters mentioned. For the first outcome (recommendation to perform EGD), we excluded patients who had performed EGD during the last 3 months before their visit to our center, considering that in most of these patients a new EGD would not be recommended again at the assessment.
The following parameters, which potentially influence the study outcomes (further referred as "covariates") were selected by the authors based on clinical experience and evidence from published literature: age, sex, disease duration, cutaneous subset of SSc (diffuse vs. any other subset),[17] modified Rodnan skin score (mRSS), body mass index (BMI), hemoglobin (Hb), erythrocyte sedimentation rate (ESR), forced vital capacity (FVC), PPI therapy, gastro-esophageal symptoms as retrieved from the charts of the patients (heartburn, regurgitation, dysphagia, and vomiting), "esophageal symptoms" as recorded in the EUSTAR database (reflux and/or dysphagia), and "stomach symptoms" as recorded in the EUSTAR database (early satiety and/or vomiting).
For the outcome "recommendation to perform EGD," we performed the following GLMM models using as covariates: 1. age, sex, disease duration, mRSS, SSc subset, BMI, Hb, ESR, FVC, and PPI therapy, which were included in all the other models; 2. gastro-esophageal symptoms, as collected from the patient charts (heartburn, regurgitation, dysphagia, vomiting); 3. "esophageal symptoms" and "stomach symptoms" as recorded in EUSTAR database; and in models 4 to 8, one of the selected subscales of UCLA GIT 2.0 (reflux, distention/bloating, social functioning, emotional wellbeing) or the UCLA GIT 2.0 total score, respectively.
For the outcomes "endoscopic esophagitis" and "pathologic EGD," anticipating that the number of EGD will be less than one third than the number of visits with a completed UCLA GIT 2.0 questionnaire, we reduced, by clinical judgment, the number of covariates included in the multivariable analysis. Consequently, all GLMM models for these outcomes included only four independent variables, selected by clinical judgment: age, sex, disease duration, and PPI therapy. Further GLMM models included these four parameters and one of the following parameters, or group of parameters: mRSS (model 2), Hb (model 3), gastroesophageal symptoms reported by the patient: heartburn, regurgitation, and dysphagia, as collected from EMR (model 4), "esophageal symptoms" and "stomach symptoms" (model 5), and one of the selected subscales of UCLA GIT 2.0 or the UCLA GIT 2.0 total score, respectively (models 6 to 10).
We further identified by receiver operating characteristic (ROC) curve analysis, selecting the values with the largest area under the curve (AUC) and significant 95% confidence intervals (95% CI), cutoffs for the reflux, and total UCLA GIT 2.0 score discriminating best between patients with recommendation to perform EGD and those without. Based on the AUC, the accuracy of the prediction model can be considered excellent (0.9–1.0), good (0.8–0.9), fair (0.7–0.8), or poor (0.6–0.7).
Arthritis Res Ther. 2021;23(125) © 2021 BioMed Central, Ltd.
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