Responsiveness of the University of California Los Angeles Scleroderma Clinical Trial Consortium gastrointestinal tract 2.0 (UCLA-SCTC-GIT 2.0)to change in scleroderma patients

Abstract

Introduction:

Gastrointestinal tract involvement in systemic sclerosis is the most common internal organ involvement. Among the few validated patient-reported outcome measures for gastrointestinal involvement are the University of California Los Angeles Scleroderma Clinical Trial Consortium gastrointestinal tract 2.0 (UCLA-GIT 2.0) and the gastrointestinal problems’ visual analog scale (SHAQ-VAS). The latter is a component of the Scleroderma Health Assessment Questionnaire Disability Index. Our aim is to compare the responsiveness of the UCLA-GIT 2.0 total score, single domains, upper and lower gastrointestinal domains, and gastrointestinal problems’ visual analog scale of the scleroderma HAQ(SHAQ-GI-VAS) to change in gastrointestinal medication. In addition, we evaluated the correlation between the UCLA-GIT 2.0 and SHAQ-GI-VAS scale in our systemic sclerosis population.

Methods:

One hundred fifteen systemic sclerosis patients attending the University of California Los Angeles and Seattle outpatient clinics with two or more consecutive visits were enrolled in our study. The UCLA-GIT 2.0 and SHAQ_VAS were completed by all patients at both visits; any change in gastrointestinal medication at the baseline visit was reported. UCLA-GIT 2.0 asks about how the gastrointestinal tract affects the patient over the last week; It consists of 34 questions in seven domains (reflux, distension, soilage, diarrhea, social function, emotional wellbeing, and constipation). THE SHAQ-GI-VAS is a 100-mm horizontal VAS that asks the patient; “In the past week, how much did your gastrointestinal symptoms interfere with your function”. These measures were evaluated at two consecutive visits. Any change in gastrointestinal medication at baseline visit was reported. Percent change was calculated to evaluate the change in the values of the UCLA-GIT 2.0 and the SHAQ_GI-VAS, and we dichotomized the patients into two groups according to whether there was a change in gastrointestinal treatment or not. Pearson correlation was used to correlate both tests at baseline.

Results:

Ninety-eight (85%) of the systemic sclerosis patients were females, mean age: 52 years (standard deviation ± 12.9); median disease duration: 7 (range: 4–11 years), diffuse subtype: 57 patients (50%), median baseline gastrointestinal tract 2.0 was 0.3 (0.1–0.7) and median baseline SHAQ-GI-VAS was 0.8 (0–4.1). Out of the 115 patients, 41 (37.0%) patients needed a change in gastrointestinal medication at baseline visit (Group 1); they were compared to those not changing gastrointestinal medications (Group 2). Responsiveness to gastrointestinal medication treatment change in the form of percent change in total UCLA-GIT 2.0 was significantly more in Group 1 than in Group 2 (−6.6 (standard deviation = 20) in Group 1 vs +6.9 (standard deviation ± 18.8) in Group 2, p value < 0.001). On the contrary, there was no statistically significant difference between percent changes in SHAQ-GI-VAS from the in Group 1 versus Group 2 (59.5 (standard deviation ± 172) in Group 1 vs 51.9 (standard deviation ± 126.4) in Group 2, p value = 0.816). The correlation between the UCLA-GIT 2.0 and the SHAQ_GI-VAS was moderate (r = 0.6).

Conclusion:

The University of California Los Angeles Scleroderma Clinical Trial Consortium gastrointestinal tract 2.0 and gastrointestinal problems’ visual analog scale are utilized to measure gastrointestinal tract involvement in systemic sclerosis. Unlike the gastrointestinal problems’ visual analog scale, the gastrointestinal tract 2.0 was responsive to change in gastrointestinal medication while the SHAQ-GI-VAS was not. Hence, the UCLA-GIT 2.0 could be utilized in future trials and observational studies as a measure of systemic sclerosis gastrointestinal responsiveness.

Introduction

Gastrointestinal (GI) involvement is the most common internal organ involvement in systemic sclerosis (SSc) patients, occurring in up to 90% of patients. It is a major cause of morbidity and mortality. Symptoms ranging from mild dysphagia and hyperacidity to marked dysmotility with small intestinal bacterial overgrowth (SIBO), malnutrition, and obstruction may occur from indolent to rapidly progressive disease.^1,2

Optimizing therapies to improve GI function in SSc patients is important, as GI involvement significantly impact patients’ quality of life. Thus, a validated measure of responsiveness to therapies is important. Unfortunately, there is no single objective investigation that can capture changes among the multiple levels of GI system involvement. Multiple tools have been suggested to detect the presence and assess severity of GI involvement in SSc. ³

A commonly utilized and validated GI patient-reported outcome (PRO) that could detect such abnormalities is of fundamental value. A 34-item scale, UCLA-GIT 2.0—to be designated as the GIT 2.0 in this article—is widely used, validated, reliable, and discriminates well among degrees of severity of GI involvement. Its domains include reflux, distension/bloating, diarrhea, fecal soilage, constipation, emotional wellbeing, and social functioning. ⁴ Another measurement for GI involvement is the intestinal visual analog scale (SHAQ-GI-VAS) which is a component of the Scleroderma Health Assessment Questionnaire (SHAQ). ⁵ It is very simple to use and has been validated and correlated with subjective and objective GI measures for degree of involvement.^5,6 SHAQ-GI-VAS is a 100-mm VAS that asks the patient; “In the past week, how much did your GI symptoms interfere with function”.

Given the multi-level involvement within the GI system (i.e. heterogeneous nature of the GI presentation), there has been some difficulty in measuring responsiveness to therapy by traditional investigations. Our primary aim was to evaluate the performance of UCLA-GIT 2.0 (total score, single domains, and upper and lower GI domains) and SHAQ-GI-VAS as measures of responsiveness to change in treatment and their relative sensitivity to change in medical treatment of SSc. As a secondary aim, we evaluated the correlation between UCLA-GIT 2.0 and SHAQ-GI-VAS in our patient population at one time point.

Patients and methods

Patients

Charts of 115 SSc patients attending the UCLA Scleroderma Clinic and the Seattle Rheumatology Associates Clinic were reviewed.

Inclusion criteria included adult patients (aged >18 years), SSc patients fulfilling the 2013 American College of Rheumatology (ACR) classification criteria for SSc and the presence of completed GIT 2.0 questionnaires on two or more consecutive visits, 2–12 months apart. A change in GI treatment at baseline visit was recorded and could include any one or a combination of proton pump inhibitors (PPIs), H2 blockers, Antacids, Antibiotics, Prokinetics, laxatives, and head elevation. Institutional review board (IRB) approval was obtained at the UCLA site, anonymized data were obtained from Seattle site. One hundred fifteen SSc patients had fully completed questionnaires at both visits. Patients were grouped into—Group 1: who had a change in GI treatment at baseline and Group 2 who did not change their GI therapy at the baseline visit. Change in GIT 2.0 (total score and separate domains) and SHAQ-GI-VAS scores were compared between those two groups at the two visits.

Questionnaires

GIT 2.0 and SHAQ-GI-VAS as a part of SHAQ were to be completed by each patient at both visits, and any change in GI medication at baseline visit was reported.

GIT 2.0 examines the previous week and includes 34 questions in seven domains (taking ⩽ 5 min to complete; reflux—eight questions; distension—four questions, soilage—one question, diarrhea—two questions, social function—six questions, emotional wellbeing—nine questions, and constipation—four questions). For convenience, the GIT 2.0 was divided into two general domains: the upper GI domain (reflux and distension) and the lower GI domain (soilage, diarrhea, constipation, and emotional).

GI-VAS is a 100-mm horizontal VAS with vertical end-points that asks the patient; “In the past week, how much did your GI symptoms interfere with your function.”

Clinical parameters and investigations (performed within 1 year of baseline visit) were collected per chart review. Skin fibrosis quantified by the modified Rodnan skin score, completed by an experienced scleroderma expert, pulmonary involvement assessed by pulmonary function tests (at least forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), and diffusing capacity of the lungs for carbon monoxide (DLCO)), and high-resolution computed tomography (HRCT) of the chest. Skin ulcers and joint involvement were documented by the clinician at baseline using a 66 Swollen Joint Count and 68 tender joint count. Cardiac and pulmonary artery pressures were evaluated by echocardiography (obtaining at least ejection fraction, volume of tricuspid regurgitation (VTR), and right ventricular systolic pressure (RVSP)) followed by right heart catheterization (for cardiac output, pulmonary capillary wedge pressure (PCWP), and pulmonary artery pressure (PAP)) as indicated.

Statistical analyses

All demographic, clinical, and investigational parameters routinely assessed were included in the descriptive analysis. T test was used to detect the responsiveness to change between the two visits in both GIT 2.0 (total score and individual domains) and GI-VAS of SSc patients among the two groups with compensation for repeated measures. Responsiveness to treatment change was calculated as percent change in total GIT 2.0 (as well as its separate domains) as follows (follow-up value − baseline value)/baseline value; the same equation was used to calculate percent change in GI-VAS. Effect size was calculated to assess the magnitude of change in both groups; Effect size = mean change between baseline and follow-up/standard deviation (SD).

Pearson correlation was used to correlate tests at baseline. P values less than 0.05 were considered significant.

Minimally important differences (MIDs) identified in a previous study ⁷ were used to further examine our results; a change of 0.2 (as calculated from total GIT 2.0 of visit 2 − total GIT 2.0 of visit 1) was considered to be a meaningful change.

Results

Ninety-eight (85%) of 115 SSc patients were females, mean age: 52 years (SD ± 12.9); median disease duration: 7 (4–11) years defined by the first non-Raynaud sign or symptom typical of SSc, 55 patients (47%) diffuse subtype (Table 1). Out of the 115 patients, 41 patients needed a change in GI medication at the baseline visit.

Table 1.

Demographics of systemic sclerosis patients.

Variable	Mean (SD), number (%)
Age	52 (12.9)
Females	98 (85%)
Diffuse subtype	55 (47%)
Body mass index	24.1 (5.7)
Disease duration	7 (4–11)
Intestinal VAS (GI-VAS)	0.8 (0–9.5)
UCLA-GIT 2.0	0.3 (0.1–2.15)
Interstitial lung disease	66 (57%)
Pulmonary artery hypertension	19 (16%)
Modified Rodnan skin score	7 (7.2)

SD: standard deviation; GI-VAS: gastrointestinal problems’ visual analog scale; UCLA: University of California Los Angeles; GIT: gastrointestinal tract.

Mean baseline GIT 2.0 values were significantly higher in Group 1 (who needed a change in GI therapy) than in Group 2 (who did not require new GI therapies), which supported their need for adding new medications or adjusting the dosage of GI treatment (0.7 (0.5) in Group 1 vs 0.4 (0.4) in Group 2 with p value < 0.001). Mean baseline SHAQ-GI-VAS values were higher in Group 1 than in Group 2 but did not reach statistical significance level (2.7 (2.9) in Group 1 vs 1.9 (2.7) in Group 2, p value = 0.159).

There were baseline differences among four single domains of the GIT 2.0 comparing Group 1 and Group 2 (Table 2). The baseline differences were in reflux, distension, social function, and emotional wellbeing. There were no differences at baseline in the other three domains.

Table 2.

Baseline and percent change differences in GIT 2.0 (total and single domains) and SHAQ-GI-VAS between two groups of patients (negative values indicates improvement) (Group (1) change in GI treatment and Group (2) who did not change their GI therapy at baseline visit).

	Group 1 Mean (SD)	Group 2 Mean (SD)	p value
GIT 2.0 (total) baseline	0.7 (0.5)	0.4 (0.4)	< 0.001
GIT 2.0 (total) percent change (follow-up − baseline)/baseline	−6.6 (20)	6.9 (18.8)	0.001
Effect size (follow-up − baseline)/SD	0.4	0	N/A
Reflux (baseline)	0.8 (0.6)	0.5 (0.5)	0.004
Reflux percent change (follow-up − baseline)/baseline	−5.2 (23.7)	13.4 (39.3)	0.007
Distension (baseline)	1.4 (0.9)	0.7 (0.7)	<0.001
Distension_bloating percent change (follow-up − baseline)/baseline	2.4 (53.7)	−9.9 (47)	0.211
Soilage (baseline)	0.4 (0.8)	0.2 (0.6)	0.08
Soilage percent change (follow-up − baseline)/baseline	−2.1 (31.8)	8.3 (37.2)	0.143
Diarrhea (baseline)	0.6 (0.7)	0.4 (0.6)	0.057
Diarrhea percent change (follow-up − baseline)/baseline	−4.8 (31)	13.2 (47.6)	0.033
Constipation (baseline)	0.4 (0.5)	0.3 (0.4)	0.064
Constipation percent change (follow-up − baseline)/baseline	1.8 (23.6)	14.2 (57.5)	0.188
Social function (baseline)	0.5 (0.6)	0.2 (0.5)	0.002
Social_function percent change (follow-up − baseline)/baseline	−6.9 (21.5)	7.8 (25.1)	0.002
Emotional_well_being (baseline)	0.5 (0.7)	0.2 (0.5)	0.014
Emotional_well_being percent change (follow-up − baseline)/baseline	0.5 (21.3)	6.1 (24.7)	0.229
GI-VAS baseline	2.7 (2.9)	1.9 (2.7)	0.159
GI-VAS percent change (follow-up − baseline)/baseline	59.5 (172.9)	51.9 (126.4)	0.816

SD: standard deviation; GIT: gastrointestinal tract; GI-VAS: gastrointestinal problems’ visual analog scale.

Responsiveness to treatment: change in the total GIT 2.0 was significantly higher in Group 1 than in Group 2 ((mean (SD)) (−6.6 (20) in Group 1 vs +6.9 (18.8) in Group 2, p < 0.001). In contrast, there was no statistically significant difference between percent changes of SHAQ- GI-VAS in Group 1 versus Group 2 (59.5 (172) in Group 1 vs 51.9 (126.4) in Group 2, p < 0.816). Effect size of total UCLA-GIT 2.0 in Group 1 was 0.4 (medium) versus no measurable effect in Group 2 (effect size = 0).

Responsiveness to treatment among separate GI domains of the GIT 2.0: reflux, diarrhea, and social function percent changes were significantly different in Group 1 than Group 2 (−5.2, −4.8, and −6.9 in Group 1 vs +13.4, +13.2, and +7.8 in Group 2, p = 0.007, 0.033, and 0.002, respectively). Distension, soilage, constipation, and emotional wellbeing percent changes were not significantly different in either groups (see Table 2). Effect size of single domains was medium for reflux, distension, and diarrhea (0.4,0.33, and 0.3, respectively) while small to no effect was noted in soilage, constipation, social function, and emotional wellbeing (0.13, 0, 0.1, and 0, respectively).

Upper GI domains of the GIT 2.0 (i.e. reflux and distension) assessed separately: at baseline (reflux + distension baseline), mean Group 1 values were significantly higher than Group 2 (+1.1 (SD: 0.7) in Group 1 vs +0.6 (SD: 0.6), p < 0.001). Responsiveness of the upper GI domains to treatment (percent change) was calculated with the following equation (reflux + distension percent change) ((follow-up − baseline)/baseline). Percent change was significantly higher in Group 1 than in Group 2 (−5.6 (SD: 30.8) in Group 1 vs +10.6 (SD: 37.9) in Group 2, p = 0.024).

Lower GI domains of the GIT 2.0 (i.e. distension, diarrhea, soilage, and emotional) were also evaluated separately; at baseline (distension + diarrhea + soilage + emotional baseline), mean Group 1 values were significantly higher than Group 2 (0.7 (SD: 0.6) in Group 1 vs 0.4 (SD: 0.5) for Group 2, p < 0.001). Responsiveness of lower GI domains to treatment in the form of percent change was calculated with the following equation: distension + diarrhea + soilage + emotional ((follow-up − baseline)/baseline). Percent change was significantly higher in Group 1 than in Group 2 (−5.7 (SD: 23.8) in Group 1 vs 5.5 (SD: 22.5) in Group 2, p value = 0.017).

MID estimates of total GIT 2.0 were met in patients from Group 1 (GI treatment change): a value change of −0.2 or less was considered clinically meaningful improvement in total GIT 2.0 according to the work done by Khanna et al. ⁷ and it was evidenced in 21 patients of Group 1 who needed a change in their GI medication.

Correlation between SHAQ-GI-VAS and GIT 2.0 (total and individual domains) were noted at baseline and follow-up visits: GIT 2.0 total score and SHAQ-GIT-VAS showed a moderate correlation (r = 0.6) at baseline as well as at follow-up visits (Table 3).

Table 3.

Correlation between UCLA-GIT 2.0 (total and individual domain) and GI-VAS at each of baseline and follow-up visits.

UCLA-GIT 2.0	Total	Reflux	Distension	Soilage	Constipation	Social	Emotional
GI-VAS (baseline)	0.65	0.61	0.56	0.54	0.32	0.33	0.58
GI-VAS (follow-up)	0.61	0.56	0.54	0.32	0.33	0.58	0.49

UCLA: University of California Los Angeles; GIT: gastrointestinal tract; GI-VAS: gastrointestinal problems’ visual analog scale.

Discussion

Measuring response to treatment in SSc GI involvement is of great significance; since GI is the most common internal organ complication in SSc. In SSc clinical trials, various objective measures were utilized to assess GI involvement in SSc. In our study, we assessed 115 SSc patients with various degrees of GI involvement at two time points and dichotomized them into two groups: Group 1 (41) who had changed any GI medication at baseline visit and Group 2 who had no change in medication at baseline visit. Our results demonstrated that GIT 2.0 total score was significantly responsive to change in medical treatment, while SHAQ-GI-VAS did not change significantly between the two visits. Specific separate domains of GIT 2.0 (i.e. reflux, diarrhea, and social function) showed significantly more change in Group 1 than Group 2, while other domains (i.e. distension, soilage, constipation, and emotional wellbeing) did not show any significant change at the two time points. The SHAQ- GI-VAS did not show change when medications were changed. In addition, we evaluated the correlation between GIT 2.0 and SHAQ-GI-VAS at baseline and found that there was only moderate agreement between the two tests.

We believe the GIT 2.0 is preferable to the SHAQ- GI-VAS when examining responsiveness. This does not imply the SHAQ-GI-VAS should not be used as it is a simple, single response and very easy to use. Also, there is sufficient disagreement between the two measures to suggest that they reflect different aspects of GI involvement and that they should be considered separately in the clinical GI evaluation of SSc patients.

We report significantly higher baseline scores of GI domains (reflux distension, soilage constipation social, and emotional) in Group 1 which justified a change in treatment at the initial baseline visit. Due to the multi-level involvement of the GI system in SSc, we divided responsiveness of the GI system into upper, lower, and social/emotional subgroups but included distension in both upper and lower GI subgroupings. This latter overlap resulted from the fact that distension may represent either dysmotility in the upper GI tract or be a manifestation of SIBO or hypomotility from any cause in the small intestine. Since distension may result from change in more than one part of the GI tract, it is quite possible that there is some degree of opposing interactions thus explaining the apparent lack of change in distension.

When we considered the domains of the GIT 2.0 separately, a significant change in reflux and diarrhea was detected after treatment in Group 1. Other domains like distension, soilage, and constipation did not show any significant change which may be due to the multifactorial pathogenic mechanisms driving those symptoms (fibrosis, dysmotility, vasculopathy, and autoimmunity) or the absence of drugs targeting those manifestations/mechanisms effectively.

It is worth noting that negative values in the GIT 2.0 indicates improvement while positive values denote worsening, for example, the percent change of −6.6 in the second row of Table 2 indicates a 6.6% improvement.

Our results regarding the reflux domain are consonant with an earlier study on the correlation between the reflux and distension domains of the GIT 2.0 and objective testing of upper GI-SSc. ⁶ That study reported a high correlation of both reflux and distension domains with endoscopy and manometric measures (r = 0.4, p = 0.01), confirming their sensitivity as measures of internal gastroesophageal involvement. ⁸ However, they did not report the scores on a second follow-up visit to evaluate their responsiveness to treatment.

In addition, a study tested the efficacy of probiotics in a small group of SSc patients (n = 10 patients) with moderate-to-severe bloating using GIT 2.0 as a measure of responsiveness. ⁹ They demonstrated significant improvement after 2 month of treatment in total GIT 2.0 and in single domains (reflux, distension, and emotional scales), which is in alignment with our results.

In an attempt to identify MIDs in the GIT 2.0, Khanna et al. ⁷ showed correlations among the seven GIT 2.0 domains with subjective patient-reported anchors at two time points. However, the majority of patients in this study did not change their GI medications, so it was not possible to examine responsiveness to treatment. However, when we used their MID value for the total GIT 2.0 score change, we identified 21 patients in our study who showed a MID after modifying their GI medication.

We also examined the effect size according to Cohen et al. ¹⁰ The effect sizes were calculated to define whether large differences occurred. Hence, large effect size defines the large differences between groups and so shows that fewer patients are needed to test a hypothesis. Group 1 (GI-treated) showed an effect size of 0.4 (medium effect) in comparison to Group 2 which showed an effect size of zero denoting no meaningful effect.

Our study has several strong points. There was no ceioing effect in our study, so this did not limit our results. We reported the responsiveness on a large sample size, at two time points, with PROs completed at both visits. Also about 40% of the patients changed their GI treatments, allowing us to examine responsiveness to treatment compared to a non-treated control group. Furthermore, the patients were carefully examined for other visceral involvement, allowing comparison between the two groups and showing relative comparability. Finally, these patients represent real life patients in a routine clinical environment.

Our data have some limitations; we did not uniformly carry out objective measures of GI involvement as this was routine clinical practice, so we could not correlate our results with objective measures. This has been done previously so was not necessary (see above). Our patients had generally low GI scores and were not using uniform therapy, as our study represents real-life practice. Finally, this is not a prospective, controlled clinical trial but, rather, is a retrospective evaluation of prospectively gathered data. We consider our study as preliminary and it should be confirmed with larger prospective cohorts or clinical trials.

In conclusion, we provide evidence of responsiveness to change in the GIT 2.0 total and some of its single domains. These data support its utilization in future randomized controlled trials (RCTs) and observational studies of SSc GI involvement.