Performance of the UCLA Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 Instrument as a Clinical Decision Aid in the Routine Clinical Care of Patients With Systemic Sclerosis

Norina Zampatti; Alexandru Garaiman; Suzana Jordan; Rucsandra Dobrota; Mike Oliver Becker; Britta Maurer; Oliver Distler; Carina Mihai

Disclosures

Arthritis Res Ther. 2021;23(125)

Abstract and Introduction

Abstract

Background and Objectives: The University of California Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument 2.0 (UCLA GIT 2.0) is validated to capture gastrointestinal (GI) tract morbidity in patients with systemic sclerosis (SSc). The aims of this study were to determine in a large SSc cohort if the UCLA GIT 2.0 is able to discriminate patients for whom a rheumatologist with experience in SSc would recommend an esophago-gastro-duodenoscopy (EGD), and if it could identify patients with endoscopically proven esophagitis or with any pathologic finding on EGD.

Methods: We selected patients fulfilling the ACR/EULAR 2013 criteria for SSc from our EUSTAR center having completed at least once the UCLA GIT 2.0 questionnaire, and we collected data on gastrointestinal symptoms and EGD from their medical charts. We analyzed by general linear mixed effect models several parameters, including UCLA GIT 2.0, considered as potentially associated with the indication of EGD, as well as with endoscopic esophagitis and any pathologic finding on EGD.

Results: We identified 346 patients (82.7% female, median age 63 years, median disease duration 10 years, 23% diffuse cutaneous SSc) satisfying the inclusion criteria, who completed UCLA GIT 2.0 questionnaires at 940 visits. EGD was recommended at 169 visits. In multivariable analysis, UCLA GIT 2.0 and some of its subscales (reflux, distention/bloating, social functioning) were associated with the indication of EGD. In 177 EGD performed in 145 patients, neither the total ULCA GIT 2.0 score nor any of its subscales were associated with endoscopic esophagitis, nor with any pathologic EGD findings.

Conclusions: In a real-life setting, the UCLA GIT 2.0 and its reflux subscale were able to discriminate patients with SSc who had an indication for EGD, but did not correlate with findings in EGD. We conclude that, while using the UCLA GIT 2.0 in the routine care of patients with SSc may help the rheumatologist to better understand the burden of GI symptoms in the individual patient, it should not be used as a stand-alone instrument to identify an indication of EGD.

Introduction

In patients with systemic sclerosis (SSc), the gastrointestinal (GI) tract is the most common internal organ involvement, with over two thirds of patients reporting GI symptoms.^[1] SSc GI tract involvement is a major cause of serious morbidity, affecting health-related quality of life (HRQoL) and survival of these patients.^[2,3] The most prevalent GI manifestation is esophageal involvement due to hypomotility and gastroesophageal reflux, the latter often leading to esophagitis and in later stages to Barrett's esophagus.^[4] Another GI manifestation of SSc is gastric antral vascular ectasia (GAVE) which may cause severe anemia.^[5] To date, there are no recommendations or guidelines when to perform endoscopic and functional investigation of the upper GI tract in patients with SSc. Esophago-gastro-duodenoscopy (EGD) plays a major role in the diagnosis of reflux esophagitis, esophageal strictures, Barrett's esophagus, and adenocarcinoma of the esophagus.

The University of California at Los Angeles Scleroderma Clinical Trial Consortium GIT 2.0 instrument (UCLA GIT 2.0) is a patient-completed questionnaire validated to assess GI symptoms severity and related HRQoL in SSc.^[6] Originally developed in English, and with a minimal clinically important difference previously determined,^[6] it has been validated in different languages.^[7–11] Several clinical trials of GI treatments in patients with SSc already used this instrument as an outcome measurement.^[12–14] The UCLA GIT 2.0 is an excellent candidate to guide the need for further investigation of the GI tract by endoscopy and/or functional tests. Constructed to reflect the burden of GI symptoms including reflux, it is attractive to hypothesize that it is able to identify patients with endoscopic esophagitis or other clinically significant findings on EGD.

In this study, we aimed to determine, in an unselected, real-life cohort of patients with SSc, whether the UCLA GIT 2.0 could discriminate patients for whom a rheumatologist with experience in SSc would recommend an EGD, and if the UCLA GIT 2.0 could identify patients at risk for endoscopic esophagitis or other clinically significant EGD findings.

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Arthritis Res Ther. 2021;23(125) © 2021 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Table 1. Baseline demographic and clinical characteristics of the study cohort
	N
Age (years): median (Q1–Q3)	346	63	(51–72)
Disease duration (years): median (Q1–Q3)	346	10	(7–17)
BMI (kg/m²): median (Q1–Q3)	310	23.4	(21–27)
Male sex: N (%)	346	60	(17.3)
Diffuse cutaneous subset: n (%)	283	65	(23)
Raynaud's phenomenon: n (%)	342	327	(95.6)
Digital ulcers ever: n (%)	335	114	(34.0)
mRSS: median (Q1–Q3)	337	3	(0–8)
Joint synovitis: n (%)	344	61	(17.7)
Joint contractures: n (%)	340	99	(29.1)
Esophageal symptoms (reflux, dysphagia): n (%)	344	185	(53.8)
Stomach symptoms (early satiety, vomiting): n (%)	341	102	(29.9)
Intestinal symptoms (diarrhea, bloating, constipation): n (%)	344	124	(36)
Malabsorption syndrome: n (%)	306	7	(2.3)
Intestinal pseudo-obstruction: n (%)	311	4	(1.3)
Barrett's esophagus	343	9	(2.6)
Pulmonary hypertension: n (%)	331	35	(10.6)
Thorax HRCT: lung fibrosis: n (%)	328	135	(41.2)
FVC: median (Q1–Q3)	339	97	(84–110)
Renal crisis: n (%)	343	6	(1.7)
ANA positive: n (%)	345	340	(98.6)
Anti-centromere positive: n (%)	327	155	(47.4)
Anti-topoisomerase I positive: n (%)	332	84	(25.3)
Anti-RNA polymerase III positive: n (%)	310	36	(11.6)
CRP (mg/dl): median (Q1–Q3)	312	1.6	(0.7–4)
ESR (mm/h): median (Q1–Q3)	329	12	(6–23.5)
Hb (g/dl): median (Q1–Q3)	310	13.2	(12.4–14.1)

BMI body mass index, mRSS modified Rodnan skin score, HRCT high-resolution computer tomography, FVC forced vital capacity, ANA anti-nuclear antibodies, CRP C-reactive protein, ESR erythrocyte sedimentation rate, Hb hemoglobin

Table 2. Gastrointestinal symptoms and scores of the UCLA GIT 2.0 and its subscales in all visits, N = 940
	n	%
Heartburn	323	(35.2)
Regurgitation	123	(13.4)
Dysphagia	184	(20.1)
Early satiety	106	(11.6)
Vomiting	34	(3.7)
Upper abdomen pain	26	(2.8)
Bloating	157	(17.1)
Diarrhea	84	(9.2)
Constipation	109	(11.9)
Fecal incontinence	58	(6.3)
UCLA GIT 2.0 subscales	Median	Q1, Q3	Range
Reflux	0.25	0.00, 0.63	(0–3)
Distention/bloating	0.50	0.00, 1.00	(0–3)
Fecal soilage	0.00	0.00, 0.00	(0–3)
Diarrhea	0.00	0.00, 0.50	(0–2)
Social functioning	0.00	0.00, 0.33	(0–2.5)
Emotional wellbeing	0.00	0.00, 0.22	(0–3)
Constipation	0.00	0.00, 0.50	(0–2.5)
Total score of UCLA GIT 2.0	0.22	0.07, 0.49	(0–2.4)

Table 3. Comparison of patient data from visits in which EGD was recommended ( n = 169) vs. data from visits in which EGD was not recommended ( n = 740)
	Referral to EGD Median (Q1, Q3)	No referral to EGD Median (Q1, Q3)	p*
Age	63 (52, 70.5)	63 (53, 72)	0.759
Disease duration	11 (7, 20)	10 (6,16)	0.086
mRSS	3 (0, 8)	2 (0, 6)	0.009
FVC	98 (85, 109)	97 (85, 110)	0.813
BMI	23.7 (21.4–26.7)	23.4 (21, 27)	0.712
Hemoglobin	13.1 (12, 14.2)	13.3 (12.4, 14.1)	0.118
ESR	16 (9, 26)	12 (6, 22)	0.013
	n (%)	n (%)	p ^#
Subset of SSc	Diffuse 38 (24.4)Limited 118 (75.6)	Diffuse 156 (25.2)Limited 464 (74.8)	0.836
Heartburn	105 (60.7)	207 (29)	< 0.001
Regurgitation	41 (23.7)	78 (10.9)	< 0.001
Dysphagia	65 (38.5)	112 (15.6)	< 0.001
Vomiting	10 (5.9)	22 (3.1)	0.074
Esophageal symptoms	109 (72.2)	283 (43.5)	< 0.001
Stomach symptoms	66 (44.3)	139 (21.4)	< 0.001
Barrett's esophagus	17 (10.1)	5 (0.7)	< 0.001
PPI therapy	76 (62.3)	18 (81.8)	0.077
Digital ulcers	16 (16)	65 (15)	0.811
Joint contractures	46 (31.1)	226 (35.1)	0.354
UCLA GIT 2.0 subscales	Median (Q1, Q3)	Median (Q1, Q3)	p*
Reflux	0.50 (0.13, 0.88)	0.14 (0.00, 0.50)	< 0.001
Distention/bloating	0.75 (0.25, 1.46)	0.25 (0.00, 1.00)	< 0.001
Fecal soilage	0.00 (0.00, 1.00)	0.00 (0.00, 0.00)	0.067
Diarrhea	0.00 (0.00, 0.50)	0.00 (0.00, 0.50)	0.028
Social functioning	0.33 (0.00, 0.60)	0.00 (0.00, 0.33)	< 0.001
Emotional wellbeing	0.11 (0.00, 0.75)	0.00 (0.00, 0.22)	< 0.001
Constipation	0.25 (0.00, 0.75)	0.00 (0.00, 0.50)	0.004
Total score of UCLA GIT 2.0	0.35 (0.17, 0.70)	0.19 (0.05, 0.44)	< 0.001

Statistically significant results are highlighted in bold font
*Mann-Whitney U test, ^#Chi-square test
mRSS modified Rodnan skin score, FVC forced vital capacity, BMI body mass index, Hb hemoglobin, ESR erythrocyte sedimentation rate, PPI proton pump inhibitors

Table 4. Factors associated with referral to EGD (multivariable generalized linear mixed effects models, GLMM). Statistically significant results are highlighted in bold font
Multivariable GLMM
Parameters	Models*	OR	95% CI	p	AUC (95% CI)
Age	Model 1	0.99	0.97–1.01	0.269	0.75 (0.69–0.80)
Sex		0.66	0.33–1.33	0.242
Disease duration		1.00	0.98–1.02	0.926
SSc subset		1.27	0.67–2.40	0.471
mRSS		1.05	1.00–1.10	0.030
Hb		0.89	0.74–1.07	0.218
PPI		0.80	0.49–1.30	0.363
BMI		1.03	0.97–1.09	0.294
FVC		1.00	0.99–1.01	0.948
ESR		1.00	0.99–1.02	0.943
Barrett's esophagus		24.4	2.43–245.18	0.007
Heartburn	Model 2	2.23	1.35–3.69	0.002	0.71 (0.65–0.76)
Regurgitation		2.09	1.14–3.81	0.017
Dysphagia		3.01	1.79–5.05	< 0.001
Vomiting		1.98	0.62–6.25	0.247
Esophageal symptoms	Model 3	1.91	1.14–3.18	0.013	0.68 (0.62–0.74)
Stomach symptoms		2.12	1.24–3.61	0.006
Reflux subscale	Model 4	1.86	1.19–2.90	0.006	0.68 (0.62–0.74)
Distention/bloating subscale	Model 5	1.50	1.12–2.01	0.007	0.70 (0.65–0.76)
Social functioning	Model 6	2.57	1.56–4.23	< 0.001	0.65 (0.59–0.71)
Emotional wellbeing	Model 7	1.32	0.80–2.19	0.274	0.68 (0.62–0.74)
Total UCLA GIT 2.0 score	Model 8	2.16	1.21–3.83	0.009	0.64 (0.58–0.70)

*Model 1 contains the covariates age, sex, disease duration, PPI therapy, mRSS, ESR, Hb, FVC, Barrett's esophagus, BMI, and a subset of SSc. All other models contain, in addition to the covariates of model 1, the following covariates: model 2: heartburn, regurgitation, dysphagia, and vomiting; model 3: the symptom clusters "esophageal symptoms" and "stomach symptoms" as per expert opinion; and models 4–8: one of the mentioned subscales of UCLA GIT 2.0, respectively the total UCLA GIT 2.0 score
mRSS modified Rodnan skin score, Hb hemoglobin, ESR erythrocyte sedimentation rate, PPI proton pump inhibitors, FVC forced vital capacity, BMI body mass index

Table 5. Comparison of patient data from visits in which EGD detected esophagitis ( n = 52), respectively did not detect esophagitis ( n = 125)
	Esophagitis Median (Q1, Q3)	No esophagitis Median (Q1, Q3)	p*
Age	62 (51, 69.5)	64 (56, 72)	0.086
Disease duration	10 (6, 19)	12 (7, 19)	0.487
mRSS	5 (0, 11.75)	2 (0, 6)	0.002
FVC	93.5 (76.5, 110.8)	99 (84, 108)	0.528
BMI	23.2 (21.6, 25.9)	23.8 (21.1, 28.1)	0.407
Hb	13.6 (12.4, 14.6)	12.9 (11.6, 13.7)	0.006
ESR	18 (8, 28)	16 (10, 28)	0.888
	n (%)	n (%)	p ^#
Subset of SSc	Diffuse 13 (26.5) Limited 36 (73.5)	Diffuse 24 (22) Limited 85 (78)	0.536
Barrett's esophagus	9 (17.3)	15 (12)	0.347
Heartburn	32 (64)	62 (50.4)	0.104
Regurgitation	13 (26)	25 (20.3)	0.414
Dysphagia	18 (36)	46 (37.4)	0.863
Vomiting	5 (10)	5 (4.1)	0.129
Esophageal symptoms	40 (81.6)	67 (60.4)	0.008
Stomach symptoms	22 (46.8)	39 (35.5)	0.163
PPI therapy	30 (57.7)	89 (72.4)	0.057
Digital ulcers	9 (27.3)	11 (15.7)	0.217
Joint contractures	16 (33.3)	32 (29.1)	0.594
UCLA GIT 2.0 subscales	Median (Q1, Q3)	Median (Q1, Q3)	p*
Reflux	0.50 (0.25, 0.84)	0.38 (0.13, 0.88)	0.534
Distention/bloating	0.50 (0.06, 1.00)	0.75 (0.25, 1.50)	0.069
Fecal soilage	0.00 (0.00, 0.00)	0.00 (0.00, 1.00)	0.535
Diarrhea	0.00 (0.00, 0.50)	0.00 (0.00, 0.50)	0.708
Social functioning	0.17 (0.00, 0.50)	0.17 (0.00, 0.50)	0.283
Emotional wellbeing	0.00 (0.00, 0.33)	0.11 (0.00, 0.44)	0.337
Constipation	0.00 (0.00, 0.50)	0.25 (0.00, 0.75)	0.404
Total score of UCLA GIT 2.0	0.27 (0.16, 0.61)	0.37 (0.13, 0.74)	0.452

Statistically significant results are highlighted in bold font. *Mann-Whitney U test, ^#Chi-square test
mRSS modified Rodnan skin score, FVC forced vital capacity, BMI body mass index;, Hb hemoglobin, ESR erythrocyte sedimentation rate, PPI proton pump inhibitors

Table 6. Factors associated with esophagitis on EGD (multivariable linear mixed effects models, GLMM)
Multivariable GLMM
Parameters	Models*	OR	95% CI	p	AUC (95%CI)
Age	Model 1	0.98	0.96–1.01	0.289	0.69 (0.60–0.79)
Sex		0.89	0.34–2.31	0.803
Disease duration		1.00	0.96–1.03	0.925
PPI		0.50	0.21–1.23	0.133
mRSS	Model 2	1.11	1.04–1.18	0.003	0.76 (0.67–0.84)
Hb	Model 3	1.33	1.00–1.77	0.051	0.89 (0.83–0.95
Heartburn	Model 4	1.71	0.76–3.83	0.193	0.64 (0.55–0.73)
Regurgitation		1.43	0.59–3.46	0.433
Dysphagia		1.01	0.46–2.18	0.987
Esophageal symptoms	Model 5	3.25	1.00–10.54	0.049	0.61 (0.52–0.71)
Stomach symptoms		1.43	0.57–3.60	0.443
Reflux subscale	Model 6	1.17	0.60–2.26	0.644	0.60 (0.51–0.69)
Distention/bloating subscale	Model 7	0.69	0.43–1.12	0.135	0.66 (0.58–0.75)
Social functioning	Model 8	0.70	0.33–1.50	0.362	0.59 (0.50–0.68)
Emotional wellbeing	Model 9	0.91	0.43–1.95	0.810	0.64 (0.55–0.73)
Total UCLA GIT 2.0 score	Model 10	0.82	0.33–2.02	0.659	0.68 (0.59–0.77)

General linear mixed models. Statistically significant results are highlighted in bold font
*Model 1 contains the covariates age, sex, disease duration and PPI therapy. All other models contain, in addition to the covariates of model 1, the following covariates: model 2: mRSS; model 3: hemoglobin; model 4: the symptoms heartburn, regurgitation, dysphagia, and vomiting; model 5: the symptom clusters "esophageal symptoms" and "stomach symptoms" as per expert opinion; models 6–10: one of the mentioned subscales of UCLA GIT 2.0, respectively the total UCLA GIT 2.0 score
PPI proton pump inhibitors, Hb hemoglobin, mRSS modified Rodnan skin score

Authors and Disclosures

Norina Zampatti¹, Alexandru Garaiman¹, Suzana Jordan¹, Rucsandra Dobrota¹, Mike Oliver Becker¹, Britta Maurer^1,2, Oliver Distler¹ and Carina Mihai^1,3*

¹Department of Rheumatology, University Hospital Zurich, University of Zurich, Gloriastrasse 25, 8091 Zurich, Switzerland. ²Department of Rheumatology and Immunology, University Hospital Bern, University of Bern, Bern, Switzerland. ³Department of Internal Medicine and Rheumatology, Cantacuzino Hospital, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania.

*Correspondence
Carmen-Marina.Mihai@usz.ch; carmenmarinamihai@yahoo.com; carinamihai@gmail.com

Authors' contributions
NZ, OD, and CM designed the study and wrote the manuscript, NZ and AG performed the statistical analysis. RD, SJ, MB, BM, OD, and CM contributed to data collection. All authors discussed the results and revised the manuscript. The authors read and approved the final manuscript.

Competing interests
Norina Zampatti, Alexandru Garaiman, and Suzana Jordan: nothing to
disclose.
Rucsandra Dobrota has received grants/research support from Actelion and Pfizer, outside the submitted work.
Mike Oliver Becker has received consultancy fees from Bayer and Amgen, outside the submitted work.
Britta Maurer had grant/research support from AbbVie, Protagen, Novartis, congress support from Pfizer, Roche, Actelion, and MSD, and received consultancy fees from Boehringer Ingelheim, outside the submitted work. In addition, B. Maurer has a patent mir-29 for the treatment of systemic sclerosis registered.
Oliver Distler has received consultancy fees from Acceleron Pharma, Amgen, AnaMar, Arxx Therapeutics, Bayer, Baecon Discovery, Blade Therapeutics, Boehringer Ingelheim, Corbus Pharmacheuticals, ChemomAb, CSL Behring, Galapagos NV, Glenmark Pharmaceuticals, GSK, Horizon Pharmaceuticals, Inventiva, Italfarmaco, iQvia, Kymera Therapeutics, Lilly, Medac, Medscape, MSD, Novartis, Pfizer, Roche, Roivant Sciences, Sanofi, Serodapharm, Topadur, Target Bioscience and UCB, in the area of potential treatments of scleroderma and its complications, outside the submitted work. In addition, Prof. Distler had a project scoring fee from Abbvie and grants/research support from Kymera and Mitsubishi Tanabe Pharma. He also holds the issued Patent on mir-29 for the treatment of systemic sclerosis (US8247389, EP2331143).
Carina Mihai has received congress support from Actelion and Roche, and personal fees from Boehringer Ingelheim, Mepha, and MEDtalks Switzerland, outside the submitted work.