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. Author manuscript; available in PMC: 2014 Nov 1.
Published in final edited form as: Curr Opin Rheumatol. 2013 Nov;25(6):10.1097/01.bor.0000434668.32150.e5. doi: 10.1097/01.bor.0000434668.32150.e5

Measuring Response in the Gastrointestinal Tract in systemic sclerosis

Dinesh Khanna 1, Vivek Nagaraja 1, Heather Gladue 1, William Chey 1, Mark Pimentel 2, Tracy Frech 3
PMCID: PMC3880116  NIHMSID: NIHMS541264  PMID: 24047604

Abstract

Purpose of review

Gastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication. This review discusses the outcome measures to measure GIT involvement in clinical care and trials.

Recent findings

Patient-reported outcome measures have been validated (UCLA SCTC GIT 2.0 and NIH PROMIS® scales) in SSc-GIT. Multiple objective measures are available to assess mucosal involvement and motility in GIT. However, these need to validated in SSc for trials.

Summary

GIT is a common cause of morbidity and has negative impact on quality of life in SSc. Recommendations are given for trial design and evaluation of GI involvement in SSc.

key words/phrases: systemic sclerosis, gastrointestinal involvement, UCLA SCTC GIT 2.0, outcome measures

Introduction

Gastrointestinal tract (GIT) involvement in systemic sclerosis (scleroderma, SSc) is the most common internal complication of this autoimmune disease characterized by progressive multi-organ vasculopathy and fibrosis (1). While the pathogenesis of SSc is not well understood, it has been proposed that akin to the cutaneous manifestations of this disease an early vascular lesion (vasculopathy) results in altered intestinal permeability, which is followed by neural dysfunction, fibrosis and loss of function (2). While circulating autoantibodies to myenteric neurons are reported in SSc (3, 4), it is unclear whether these autoantibodies are responsible for or a result of GIT dysfunction. Regardless of its etiology, progressive GIT vasculopathy and fibrosis results bothersome symptoms including esophageal reflux, bloating, distention, constipation, diarrhea, and fecal soilage. The symptoms of GIT dysfunction are challenging for the physician to assess since it may be the result of organ damage or secondary effects of therapeutics used for other disease manifestations, or poor motility, such as small intestine bacterial overgrowth. As such, understanding the etiology of GIT symptoms and measuring response of therapeutics requires a combination of patient reported outcomes and imaging modalities. This review discusses tools for measuring response in the GIT in SSc in clinical care and in clinical trials.

There are various tools available to assess the presence and severity of GI involvement in SSc (Table 1). In general, presence of GI-specific symptoms and abnormal finding on an objective test makes a diagnosis of GI involvement. However, there are little data available in SSc that longitudinally assesses response to therapy in SSc-associated GIT involvement.

Table 1.

Investigational modalities to assess gastrointestinal motility and mucosal involvement

Esophagus Stomach Small bowel Large bowel Anorectum
Motility Modified barium swallow Scintigraphy Manometry Radio-opaque markers Manometry
Manometry Antro-duodenal manometry Scintigraphy Scintigraphy Endo-sonography
Impedance monitoring Electro-gastrography Lactulose breath test Wireless motility capsule High resolution manometry
Combined impedance and manometry Gastric emptying breath test Wireless motility capsule MRI Surface electro-myography
Esophageal pH monitoring Single photon emission computerized tomography MRI and dynamic MRI Manometry Dynamic MRI
Scintigraphy Wireless pH monitoring Defecography
High resolution manometry Magnetic resonance imaging (MRI) Balloon expulsion test
Wireless pH monitoring
pH-impedancemetry
Mucosal involvement Endoscopy Endoscopy Enteroscopy (Balloon assisted and spiral) Colonoscopy Colonoscopy
Endoscopic ultrasound Endoscopic ultrasound Capsule Endoscopy
Capsule endoscopy Capsule endoscopy
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Not studied in SSc

Patient Reported Outcome Measures

There are validated patient reported outcome (PROs) measures for GIT involvement. This section will discuss PROs studied in patients with SSc. Later sections (recommendations) will also discuss other PROs.

UCLA SCTC GIT 2.0 The UCLA Scleroderma Clinical Trial Consortium GIT 2.0 [UCLA SCTC 2.0](5, 6) includes 34 items and 7 multi-item scales (reflux, distention/bloating, diarrhea, fecal soilage, constipation, emotional well-being, and social functioning) and a total GIT score to assess HRQOL and GIT symptoms severity in SSc. All scales are scored from 0.00 (better HRQOL) to 3.00 (worse HRQOL) except the diarrhea and constipation (range from 0.00–2.00 and 0.00–2.50, respectively). The UCLA GIT 2.0 provides a total score of GIT severity and calculated by summation of all scales (except constipation) and ranges from 0.00–2.83. The GIT 2.0 takes 6–8 minutes to complete and was found to have acceptable feasibility, reliability (test-retest and internal consistency) and validity in different observational studies.(5, 7–14)

The severity for scales was calculated using 3 anchors (“In the past 1 week, how severe were your gastrointestinal (gut, GI) symptoms) overall/upper/lower symptoms?” with responses ranging from “No gut symptoms” to “Very severe” symptoms. These were assessed using original published data and data collected in a National Scleroderma Foundation online survey (Table 2). The patients have been classified as “None-to-Mild” symptoms, “Moderate” symptoms, and “Severe-to-Very Severe” symptoms.

Table 2.

Patient-reported GIT severity as assessed by the UCLA SCTC GIT 2.0

Scales None-to-Mild Moderate Severe-to Very Severe
Reflux 0.00–0.49 0.50–1.00 1.01–3.00
Distention/Bloating 0.00–1.00 1.01–1.60 1.61–3.00
Diarrhea 0.00–0.49 0.50–1.00 1.01–2.00
Constipation 0.00–0.49 0.50–1.00 1.01–3.00
Fecal Soilage 0.00–1.00 1.01–2.00 2.01–2.50
Emotional Weil-Being 0.00–0.49 0.50–1.00 1.01–3.00
Social Functioning 0.00–0.49 0.50–1.00 1.01–3.00
Total GIT score 0.00–0.49 0.50–1.00 1.01–3.00
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UCLA GIT 2.0 has been assessed in longitudinal studies and minimally important differences have been published(5). In an open-label study, 10 consecutive patients with SSc and a moderate-to- severe distention/bloating score but otherwise stable organ disease not requiring any medication adjustment such as change in calcium channel blocker dose, immunosuppression, initiation of a prokinetic or antibiotic, or any other clinical intervention. Subjects completed the UCLA SCTC GIT 2.0 assessment at baseline. Subjects were treated with daily probiotics and significant improvements were noted in the total score and the scale of reflux, bloating/distention, and emotional well-being scales after two months of daily probiotic use(15).

Malnutrition Universal Screening Tool

Malnutrition is common in SSc and may be associated with progressive GIT involvement (16, 17). All SSc patients should be screened for malnutrition, but this may prove challenging as malnutrition may be multifactorial in origin and not reflective in simple markers such as serum albumin (18, 19). The Malnutrition Universal Screening Tool (MUST) is a five-step screening tool designed to identify patients at risk of malnutrition across the whole range of health care settings has successfully detected malnutrition in SSc (20–22). However, while this tool is helpful for identifying its severity and facilitating a multidisciplinary approach for the management of malnutrition, it does not adequately assess the symptomatology contributing to its occurrence.

Subjective Global Assessment (SGA) is an assessment tool that uses aspects of the history (including, weight change, dietary intake, gastrointestinal symptoms, functionality) and physical exam (including wasting, edema, and ascites) to classify nutritional status (20, 23). In one small study of SSc, the soilage, social function and emotional subscores on the GIT 2.0 were associated with SGA nutritional status (20). It is feasible in the clinical setting, supplement the UCLA SCTC GIT 2.0 for assessing nutritional status, and captures aspects of loss of subcutaneous tissue, muscle wasting, and weight loss. However, it does not correlate with disease duration and may not be the best single tool for measuring the response of the GIT in SSc (20).

The National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS®) roadmap initiative is a cooperative research program designed to develop, evaluate, and standardize item banks to measure PROs across different medical conditions as well as the US population (www.nihpromis.org)(24). It has comprehensive items banks that assess physical, mental, and social well-being. The GIT Symptoms Item Bank assesses eight domains of GI symptoms: (1) GI Pain; (2) Bloat/Gas; (3) Diarrhea; (4) Constipation; (5) Bowel Incontinence/Soilage; (6) Gastroesophageal Reflux; (7) Nausea/Vomiting; and (8) Disrupted Swallowing. The scale has been tested in patients with SSc and GIT involvement in a longitudinal study and will be published in near future.

Imaging modalities

This section discusses the imaging modalities used to assess mucosal involvement and motility in patients with GIT disorders.

Esophageal and Stomach

The choice of an imaging modality in assessment of SSc GIT disease may be assisted by use of a patient reported outcome, which quantifies severity of symptoms or response to therapeutics. However, esophageal manifestations of SSc may not always be symptomatic (25). Nonetheless, early diagnosis of esophageal involvement remains important as a delay may increase the risk of complications, such as Barrett’s or interstitial lung disease (2, 26). Diagnostic tools used to identify esophageal pathology in SSc may include modified barium swallow study (MBSS), manometry, impedance, endoscopy, and endoscopic ultrasound (EUS). Once identified, response to therapeutics may be identified on repeat imaging.

A MBSS can clarify abnormalities of both oropharyngeal and esophageal swallow function. As such the functional interrelationship between abnormalities of oropharyngeal and esophageal swallowing as well as impaired clearance of the esophagus can be identified with this test (27). MBSS is usually the first test ordered for evaluation of dysphagia. While it does not characterize refluxate and is not sufficiently sensitive to determine response to reflux treatment, it is helpful for identification of aspiration and stricture (28).

Reflux may occur due to abnormalities in the relaxation of the lower esophageal sphincter (LES), inhibition of the diaphragmatic crural sling, or change in the positive pressure gradient present between the stomach and the gastroesophageal junction (29).

Esophageal manometry allows the study of esophageal motility by measuring pressure profiles in the esophagus. The recent development of high-resolution esophageal manometry has further enhanced the ability to study motility in much greater detail by providing pressure measurements at more levels along the esophagus (30). The most significant limitation of pH-metry is its poor capacity to detect episodes of alkaline reflux, it cannot determine the characteristics of the refluxate, the height reached by the refluxate in the esophagus, or the mechanism of its clearance (31). Nonetheless, the use of manometry in addition to 24-hour combined pH-impedance monitoring may reveal esophageal motility disorders that can predispose to chronic respiratory symptoms and allow detection of reflux regardless of pH (32, 33).

Endoscopy can be used to evaluate the condition of the esophagus in SSc and to evaluate for erosive lesions, gastric antral vascular ectasia (GAVE; “watermelon stomach”) and can monitor the clinical course of Barrett’s esophagus. EUS can accurately demonstrate the layers of the esophageal wall (34). Capsule endoscopy may also be used to evaluate the esophagus, small bowel, and colon (35), with possible identification of occult gastrointestinal bleeding from GAVE possibly its most important indication in SSc.

Computed tomography and magnetic resonance imaging may have features of SSc, such as dilation of the esophagus, but are not diagnostic (36). Lastly, (18)F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) provides robust and reproducible data for early metabolic response assessment in various malignancies (37), it has not yet been used for assessment of GIT disease in SSc.

Small Bowel

The entire small bowel can be visualized in a noninvasive manner by CE, but both visualization and therapeutic management can be performed with deep enteroscopy (ileocolonoscopy) techniques, including balloon-assisted and spiral enteroscopy (38). CT enterography is another modality for the evaluation of small bowel disease, which has the potential additional advantages of detecting extraluminal complications, but is not the standard of care in SSc (39).

Large Bowel and Rectum

Endoscopy directly visualizes the large bowel and rectum, but it does not provide diagnostic motility information. Plain radiograph, rectal barium study, and CT may be used to rule out large bowel obstruction (LBO) as a complication of SSc (40). Defecography is helpful to evaluate the anorectal area. In this procedure, a radiopaque substance which is the consistency of normal stools, is introduced into the rectum and the patient is then seated on a specially designed seat which measures movements induced by evacuation of the rectum(41). In the setting of SSc this procedure can be used to evaluate rectal outlet obstruction (obstructed defecation) symptoms, suspected conditions such as internal rectal intussusception, pelvic floor dysynergia, rectocele or sigmoidocele. Another possible complication of SSc, pneumatosis intestinalis is characterized by the appearance of intramural clusters of gas in the small and large bowel wall on X-ray or computed tomography and often is accompanied by free air in the peritoneal cavity (42).

Recommendations for validating outcome measures in SSc-GIT involvement

These recommendations are based on the Scleroderma Clinical Trial Consortium GI Working Group meeting at the last Annual American College of Rheumatology meeting held in November 2012 at Washington D.C. There are separate ongoing efforts to develop recommendations for clinical trials in SSc and will be published elsewhere. For the each of the symptoms below, the data should be evaluated for feasibility, reliability (including test-retest and internal consistency), and validity (including sensitivity to change).(11, 12) A feasible measure is accessible, easily interpretable, and associated with low cost. Reliability (precision) is extent to which a measure yields the same score each time it is administered if underlying health condition has not changed. A reliability coefficient of 0.90 or higher (means that 90% of the score is accurate while the remaining 10% denotes error) is considered satisfactory for individual comparisons and 0.70 or higher is considered satisfactory for group comparisons. Validity is the extent to which the score a health measure yields accurately reflects the health concept and includes face (sensible), content (comprehensive), construct (measures or correlates with a theorized health construct), and criterion validity (predicts or correlates with ‘gold standard’). Sensitivity to change, an aspect of construct validity, assesses if an instrument score changes in the right direction when underlying health construct changes; the ability of an instrument to detect clinically important change is crucial to their usefulness as an outcome measure in a clinical trial.

The outcome measures are chosen based on review of GIT literature and expert opinion. The group agreed on further evaluating outcome measures in patients with signs and symptoms of gastroesophageal reflux disease, gastroparesis, small bowel bacterial overgrowth, constipation, and rectal incontinence.

Gastroesophageal Reflux Disease (GERD)

Although heartburn is the most common symptom of GERD, other symptoms may include odonophagia, mouth ulcers, substernal chest pain, chronic laryngitis, chronic nocturnal cough, and asthma(43).

Proposed inclusion criteria for GERD involvement

  1. Symptoms of GERD present for at least 3 of last 7 days

  2. Abnormal 24 pH probe, pH impedance study, barium swallow (showing spontaneous reflux) or upper gastrointestinal endoscopy

  3. Plan to initiate GERD-specific therapy (H2 blockers/proton pump inhibitor) to assess sensitivity to change over time

Outcome measures administered at baseline and 4 weeks

Reflux Disease Questionnaire(44), UCLA SCTC GIT 2.0(5), Quality of Life in Reflux and Dyspepsia (QOLRAD)(45).

The Reflux Disease questionnaire consists of six symptom items that has a 4-point scale (0–3) for both frequency and intensity, 0 =absent symptoms and 3 =present daily or severe symptoms(44). QOLRAD is a validated scale using 25 items with 5 dimensions (physical/social functioning, emotional distress, sleep disturbance, diet problems and vitality). Responses are based upon a 7- point Likert scale that is used to assess the amount of patients’ distress, with 1 being the most distress. The total score is calculated as a mean of each dimension (45). The QOLRAD and Reflux Disease Questionnaire have been assessed for reliability and validity in multiple clinical trials(46–50).

Gastroparesis

Patients with SSc develop clinical symptoms of gastroparesis, including bloating, nausea and vomiting, abdominal pain, and excessive flatulence; these symptoms may contribute to significant weight loss.

Proposed inclusion criteria for gastroparesis

  1. Symptoms of distention/bloating AND/OR nausea/vomiting present for at least 3 of last 7 days

  2. Abnormal solid phase gastric emptying study

  3. Plan to initiate promotility agents to assess sensitivity to change

Outcome measures administered at baseline and 4 weeks

Gastroparesis Cardinal Symptom Index(51), UCLA SCTC GIT 2.0(5)

The Gastroparesis Cardinal Symptom Index is based on post-prandial fullness/early satiety (4 items), nausea/vomiting (3 items), and bloating (2 items). All three subscales are given a score from 0 to 5 with the higher scores reflecting greater symptom severity(51). Reliability and validity has been assessed in multiple trials(52–54).

Small bowel bacterial overgrowth

The symptoms include bloating, nausea, vomiting, abdominal pain, diarrhea (with pale, greasy, voluminous, foul-smelling stools), excessive flatulence, and inability to gain or maintain body weight with good oral intake; the symptoms overlap with that of gastroparesis.

Proposed inclusion criteria for small bowel bacterial overgrowth

  1. Symptoms of distention/bloating with or without diarrhea present for at least 3 of last 7 days

  2. Abnormal glucose breath test

  3. Plan to initiate antibiotics to assess sensitivity to change

Outcome measures administered at baseline and 4 weeks

Daily rating on Likert scale (55) for abdominal pain, distention, and diarrhea with 0 indicating not at all; 1, hardly; 2, somewhat; 3, moderately; 4, a good deal; 5, a great deal; and 6, a very great deal and the UCLA SCTC GIT 2.0(5). Daily rating scale was shown to be feasible, valid, and sensitivity to change in a recent large RCT (55).

Constipation

Colonic contractions are usually reduced or absent in patients with SSc, resulting in prolonged colonic transit (56) and symptoms of constipation.

Proposed inclusion criteria for constipation

  1. Symptoms of constipation (having a bowel movement fewer than three times per week with usually hard, dry, small stools AND/OR painful bowel movement with straining during bowel movement) present for at least 3 of 7 last days

  2. Slow transit constipation using Smart Pill® or radio opaque markers

  3. Plan to initiate laxatives and/or fibers to assess sensitivity to change

Outcome measures administered at baseline and 12 weeks

Proportion of 3 or more complete spontaneous bowel movements (CSBMs) per week and an increase of one or more CSBMs from baseline during at least 9 of the 12 weeks(57); UCLA SCTC GIT 2.0(5)

Rectal incontinence

The patients present with chronic diarrhea, fecal incontinence and rectal prolapse.

Proposed inclusion criteria for rectal incontinence

  1. Symptoms of bowel incontinence in 3 of last 7 days

  2. Abnormal anorectal manometry showing impaired internal sphincter function

  3. Plan for intervention such as surgery, sacral nerve stimulation to assess sensitivity to change

Outcome measures administered at baseline and 12 weeks

Fecal Incontinence Quality of Life scale (FIQL)(35); UCLA SCTC GIT 2.0(5) Fecal incontinence quality of life scale includes 29 items and 4 multi-item scales (lifestyle, coping/behavior, depression/self perception, embarrassment). All scales are scored from 1 to 4, with 1 indicating a lower functional status of quality of life. Scales are the mean to all items in the scale(58). The fecal incontinence quality of life scale has been found to have acceptable reliability and validity in various studies(59–62).

Conclusions

This review discusses the available modalities to measure response to therapeutics in SSc-GIT. Identification of the etiology of GIT symptomatology in SSc can be aided by the use of patient reported outcomes and malnutrition assessments, which may guide the ordering of imaging.

3–5 key points.

  • GIT is a common cause of morbidity and has negative impact on quality of life in SSc.

  • There is dearth of clinical trials in SSc-GIT due to lack of feasible outcome measures.

  • Recent evidence supports feasibility, reliability, and validity of UCLA SCTC GIT 2.0 in SSc-GIT as an outcome measure.

  • Recommendations are provided to validate outcome measures in GIT-associated gastro-esophageal reflux disease, gastroparesis, small bowel bacterial overgrowth, constipation, and rectal incontinence.

Acknowledgments

Dr. Khanna was supported by the NIH/NIAMS K24 AR063120

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