Gastrointestinal Involvement in Systemic Sclerosis

Diagnosis and Management

Zsuzsanna H. McMahan; Laura K. Hummers


Curr Opin Rheumatol. 2018;30(6):533-540. 

In This Article


While data on targeted therapies for gastrointestinal dysmotility specifically in SSc is somewhat lacking, data evaluating novel therapeutic targets from other gastrointestinal dysmotility disorders may help physicians manage these patients. A list of possibly beneficial prokinetic therapies and the level of available data in SSc are listed in Table 1. In this section, new data on therapies will be examined in detail and divided by gastrointestinal regions.

Gastroesophageal Reflux Disease

Gastroesophageal reflux disease, in patients with or without SSc, is often initially managed with lifestyle modification, proton pump inhibitors (PPI), and H2 blockers. However, data related to the best first-line agent and the efficacy of combination therapies in SSc are limited. The efficacy of combination therapy for GERD was recently studied in a double-blind randomized multicenter clinical trial in non-SSc patients with esophageal reflux disease. Investigators sought to determine whether esomeprazole single therapy or esomeprazole and mosapride (gastroprokinetic agent that increases decreases gastric emptying time and decreases esophageal reflux) combination therapy was more effective.[44] Combination therapy improved upper abdominal pain, belching, and contributed to more rapid improvement in GERD symptom scores.

In a SSc population, a randomized placebo-controlled trial was recently completed, in which SSc patients with GERD who partially responded to PPI were randomly assigned to add domperidone or algycon (a medication for indigestion/heartburn made of alginic acid, aluminum hydroxide, and magnesium carbonate) therapy. Domperidone and algycon were equally effective treatments in combination with omeprazole, though approximately 20% of patients were nonresponders in each group.[22]

Esophageal Dysmotility

Esophageal dysmotility is often associated with symptoms of regurgitation, heartburn, dysphagia, and chest discomfort. Treating these symptoms can significantly improve quality of life. An open-label trial was used to evaluate the effects of 20 mg daily buspirone on esophageal motor function and symptoms in SSc patients. Of the 22 patients who tolerated the drug, lower esophageal sphincter pressure increased from 7.7 ± 3.9 to 12.2 ± 4.6 mmHg (P = 0.00002) after buspirone administration in the absence of change in other manometric parameters. Improvements in heartburn and regurgitation were noted over the 4-week follow-up period.[23]


Gastroparesis can be mild, and such cases may be managed by lifestyle/dietary modification. Patients with more significant symptoms, however, often require prokinetic agents, such as metoclopramide or domperidone, to decrease gastric emptying time; however, the tolerability and adverse effects (e.g. tarditive dyskinesia, long QT interval) associated with these medications can limit their use. Novel therapies, under study in the gastroparesis population, aim to control symptoms and limit toxicity.

Studies suggest that intravenous immunoglobulin (IVIG) may benefit patients with gastroparesis.[45] Both an open-label study and a retrospective chart review determined that IVIG may improve gastroparesis symptoms refractory to standard treatments. Although there was no placebo group in the open-label trial, significant improvement was noted in nausea, vomiting, early satiety, and abdominal pain symptom scores.[24,25,46] The application of IVIG therapy in gastrointestinal dysmotility is particularly interesting in the context of functional antimuscarinic 3 receptor (M3R) antibodies, which are reported in scleroderma, and known to have negative effects on gastrointestinal motility.

Other novel approaches in the management of gastroparesis are also under study. Selective 5HT4 receptor agonists, such as prucalopride, have a higher affinity for the 5HT4 receptor, and are therefore thought to be less cardiotoxic than prior versions such as cisapride. These drugs decrease gastric emptying time,[47] and improve motility in other parts of the gut (e.g. colon).[47–52] However, trials with revexepride (M0003 or R149402) – a different 5HT4 receptor agonist – demonstrated no significant improvement in symptoms or gastric emptying in non-SSc patients with gastroparesis.[53] In addition, while prucalopride demonstrated efficacy in chronic constipation, data showing benefit in gastroparesis are lacking.[54] In summary, these data suggest that selective 5HT4 receptor agonists have a role in the management of refractory constipation; there may not be a significant role from them in the management of gastroparesis.

Relamorelin is a synthetic peptide and selective agonist of the ghrelin/growth hormone secretogogue receptor.[55,56] It increases growth hormone levels and accelerates human gastric emptying time. In phase IIB studies, it decreased nausea, fullness, bloating, and abdominal pain associated with diabetic gastroparesis. Cardiac and neurological side effects were not reported.[55] At present, it is under investigation in phase III studies, but is unstudied in SSc. Relamorelin may also play a role in the management of constipation as it can stimulate defecation and improve lower gastrointestinal transit.[57,58]

Small Bowel

Small bowel involvement associated with distention, diarrhea, and bloating can be severe is SSc and result in malabsorption, recurrent pseudoobstruction, hospitalization, and unintentional weight loss. A range of therapeutic approaches is often integrated in the management of such patients, including dietary modification,[59] antibiotics for suspected bacterial overgrowth, and promotility agents.

A systematic review and meta-analysis recently evaluated the evidence related to the efficacy and safety of rifaximin for the eradication of SIBO in adults.[60] Thirty-two studies and 1331 patients were included. The overall eradication rate was 70.8%, whereas the overall rate of adverse events was 4.6%. Improvement or resolution of symptoms occurred in 67.7% of patients with eradicated SIBO, though this subset analysis only included 10 studies. Overall, it was determined that rifaximin therapy is well tolerated and effective for SIBO, though RCTs need to confirm these findings and define the optimal regimen.

Another systematic review assessed the evidence for the efficacy of probiotics in preventing or treating SIBO.[61] Fourteen full-text articles and eight abstracts were included. Probiotics did not prevent SIBO, but contributed to decontaminating SIBO, decreasing H2 concentration and relieving abdominal pain.

Recent studies examined the prevalence of lactose malabsorption and correlation between lactose malabsorption and SSc gastrointestinal disease. Lactose malabsorption was more prevalent in SSc patients than in controls, and the presence of lactose malabsorption correlated strongly with severe esophageal and small intestinal motor disorders.[59] A trial of lactose elimination in such patients may improve quality of life and reduce the need for extensive motility testing and promotility medications.

Studies using animal models and human engineered tissue have identified potentially novel therapies for patients with small bowel dysmotility.[62,63] Electroacupuncture at the L11 stimulation point promoted jejunal motility through the parasympathetic pathway in rats,[63] and the implantation of neural crest cells restored enteric nervous system function in human tissue engineered small intestine.[64] Further studies are needed to determine the efficacy and safety of such interventions in patients.

A case series involving five SSc patients treated successfully with Abatacept in the treatment of chronic intestinal pseudo-obstruction (CIPO) was also recently described. Improvement in symptoms and a reduction in the episodes of pseudoobstruction suggested that further studies might be important.[65] A multicentered clinical trial evaluating the effects of abatacept in patients with diffuse SSc is underway, and will hopefully provide additional data in this area.

Colonic Hypomotility

Mild to moderate colonic hypomotility is often managed with dietary modification, stool softeners and laxatives; however, these interventions are inadequate in more severe disease. Prior studies demonstrated that serotonin receptor agonists are effective promotility agents; however, cardiotoxicity resulted in their removal from the market. Recently, in both the SSc and general gastrointestinal literature, several studies evaluated the safety and efficacy of prucalopride for refractory constipation.[47–52] Vigone and Beretta[26]reported the results of an open-label crossover study (PROGASS) evaluating the safety and efficacy of prucalopride in SSc patients' gastrointestinal disease. Patients on prucalopride had a higher number of complete bowel movements, and reductions in reflux and bloating, as determined by the UCLA GIT 2.0. In the non-SSc population, prucalopride reduced abdominal symptoms in patients with functional bowel disorders.[66] Prucalopride had a favorable safety and tolerability profile in an analysis of six randomized controlled clinical trials.[67] It is a promising drug for the management of SSc gastrointestinal dysmotility.

Pyridostigmine – an acetylcholinesterase inhibitor – may also be applied in the context of gastrointestinal dysmotility.[68–71] Most recently, a retrospective series evaluated 31 symptomatic SSc patients who were treated for at least 4 weeks with at least 30 mg three times daily pyridostigmine. Constipation was the most commonly improved symptom.[27] Symptom improvement from pyridostigmine was also reported in prior case series focused on non-SSc patients with autoimmune gastrointestinal dysmotility.[69,72,73] In our experience, pyridostigmine generally has a milder effect on the colon, relative to linaclotide or lubiprostone, and is a good option for patients who do not tolerate the intensity of these drugs.

Guanylyl cyclase agonists, such as sildenafil, increase cGMP levels in the intestinal epithelium to promote secretion and may normalize bowel transit in preclinical models.[74] Further clinical studies in humans are needed to define the potential benefit of cGMP agonists in the management of refractory constipation.

An expert panel in functional digestive disorders convened to review the efficacy and safety of linaclotide and to develop an updated consensus report for the treatment of patients with constipation-predominant irritable bowel syndrome (CP-IBS).[7] The panel recommended linaclotide for the treatment of moderate to severe CP-IBS in adults. They recommended that patients take it continuously, and that tachyphylaxis is unlikely to occur based on existing data. While this drug has not yet been studied in SSc, it could be considered in patients with refractory constipation.

Fecal Incontinence

The management of fecal incontinence can be challenging in SSc. Importantly, women with SSc have an increased prevalence of lower gastrointestinal and pelvic floor symptoms than what is observed in the general population.[75] A recent study evaluated whether anorectal feedback improves symptoms of fecal incontinence in SSc compared to patients with functional fecal incontinence.[76] Both groups of patients benefitted equally from biofeedback therapy as measured by Fecal Incontinence Severity Index (FISI) scores, feelings of control over bowel movements, and quality of life. Anorectal feedback is a noninvasive intervention that should be considered early in the management of SSc-associated fecal incontinence.

Other Therapies Under Investigation

Medical cannabis is gaining increased attention in the literature for the management of autoimmune and gastrointestinal diseases.[77] In the context of gastrointestinal motility, endocannabinoids exert marked antipropulsive effects, mainly mediated by the reduction in acetylcholine release through the activation of presynaptic cannabinoid receptor-1 (CB1). Collectively, the evidence suggests that endocannabinoids significantly reduce smooth muscle contractility though the binding of CB1.[78,79] Further studies in humans with SSc will be important in determining the role of endocannabinoids in the management of SSc gastrointestinal symptoms and further defining their effects on gastrointestinal dysmotility.

Dietary Modification

Medical nutrition therapy was evaluated in eighteen SSc patients with gastrointestinal involvement and unintentional weight loss were consented and recruited for a 6-week intervention. Individually tailored medical nutrition therapy improved symptom burden and appendicular lean height (a measure of sarcopenia) in this population.[80] Specific diets, such as the low FODmap diet, may benefit IBS patients and should be evaluated in SSc.[81]