Systemic sclerosis (SSc) is characterized by symptoms including internal organ dysfunction, most commonly involving the gastrointestinal (GI) tract. Any region of the GI tract may be affected in SSc; however, evidence indicates a disproportionate involvement of the upper tract. Studies have reported GI dysfunction in up to 90% of patients with SSc, symptoms of which may include esophageal or colonic dysmotility, gastroparesis, small intestinal bacterial overgrowth (SIBO), or fecal incontinence. Other study findings have showed that up to 70% of these patients receive medications to treat GI symptoms.1,2,3
Gastrointestinal manifestations represent a leading cause of death in SSc, with research suggesting that GI disease severity is a marker for worse outcomes in patients with scleroderma. Greater severity of GI disease in SSc has been linked to higher depression scores as well as pseudo-obstruction and malabsorption.1,3
In a 2018 review published in the Journal of Clinical Rheumatology, researchers at Johns Hopkins University School of Medicine, Baltimore, Maryland, and Stanford University, California, described the range of effects observed in various parts of the GI tract: Oropharyngeal symptoms including reduced oral aperture, salivary dysfunction (≤50% of patients), deglutition impairment, and mandibular changes; esophageal disorders including reflux esophagitis, stricture formation, Barrett esophagus, and adenocarcinoma collectively affect approximately 90% of patients and correlate with the severity of pulmonary disease in SSc; and gastroparesis symptoms including early satiety, postprandial nausea, distention, and abdominal pain in up to 80% of patients with scleroderma, and dysmotility in the small bowel in ≤60% to 80% of patients with SSc, with associated SIBO, related malabsorption and nutrient deficiencies, and pseudo-obstruction.1
We spoke with Eric Dein, MD, a researcher and rheumatology fellow at Johns Hopkins Hospital in Baltimore, Maryland, who offered further insight on GI dysfunction in SSc.
What is known about GI involvement in SSc?
Although many physicians associate scleroderma with external manifestations, such as skin thickening, the disease is often characterized by severe internal manifestations as well, most commonly GI involvement. Upper GI manifestations such as gastroesophageal reflux disease are most prevalent, but complications of scleroderma can occur at all levels of the gut from the esophagus to the anorectum.
Patients may present with acid reflux, nausea, vomiting, bloating, diarrhea, severe constipation, or even incontinence of stool. When [symptoms related to] GI motility are severe, patients may experience recurrent pseudo-obstruction and SIBO, and even require intravenous food for sustenance.
Multiple studies have been conducted to better understand which patients are at highest risk for severe lower GI disease. Factors that place patients at a higher risk for more severe GI manifestations include being men, muscle disease, and more extensive skin involvement (eg, diffuse scleroderma). Our research at [John’s] Hopkins has also shown that opioid exposure increases the risk for pseudo-obstruction in these patients.4
It is important for physicians to be aware of this problem, as GI complications can have a major effect on patient outcomes. Among patients with a history of pseudo-obstruction or malabsorption, mortality rates are 2 times higher and health-related quality of life is worse compared with other patients with scleroderma.5 In fact, patients with diffuse scleroderma and severe GI disease who experience recurrent pseudo-obstruction or malabsorption or require intravenous nutrition have an estimated 85% mortality at 9 years.6
What are believed to be the mechanisms driving GI dysfunction in SSc?
The mechanisms driving GI dysfunction in scleroderma are not clearly defined, although different hypotheses exist to explain its etiology. Gastrointestinal dysmotility in scleroderma has traditionally been thought of as a consequence of the mechanisms that contribute to the effects of the disease on other organs, such as progressive vasculopathy and fibrosis leading to organ dysfunction.
Nevertheless, in the last 2 decades, emerging data suggest that dysfunction of the autonomic and enteric nervous systems, possibly driven by autoantibodies that interfere with neurotransmission at the muscarinic-3 receptors, may also play a significant role in abnormal GI transit in scleroderma.1 A growing body of literature also suggests that changes within the microbiome of the GI tract in scleroderma may play a role in GI dysfunction and patient symptoms.7
How can clinicians address adverse GI events in patients with scleroderma?
All patients with scleroderma should be evaluated clinically for both upper and lower GI involvement, including fecal incontinence, which is often underrecognized. Patients with more extensive symptoms or refractory disease may benefit from objective motility testing to further characterize the extent and severity of GI involvement. Studies such as the smart pill and scintigraphy-based whole gut transit study can provide more comprehensive objective data on dysmotility and can also provide insight into the use of targeted promotility agents.8
Patients with severe GI dysmotility should minimize exposure to risks, including opioid use, which can predispose patients to pseudo-obstruction and SIBO. Mild gastroparesis may be treated with lifestyle and dietary modifications, but prokinetic therapy may be required in moderate to severe disease. Multiple prokinetic agents such as metoclopramide, prucalopride, and pyridostigmine have been described for off-label treatment of scleroderma-related dysmotility, but there are no established treatment guidelines that specifically guide the use of these medications.
What should be the focus of future research in this area?
Research is needed to understand disease mechanisms, identify biomarkers of disease activity, and determine the safest and most effective treatment options for dysmotility in scleroderma. We especially need to identify high-risk patients who might benefit from early targeted interventions to prevent complications.
1. Miller JB, Gandhi N, Clarke J, McMahan Z. Gastrointestinal involvement in systemic sclerosis: an update. J Clin Rheumatol. 2018;24(6):328-337.
2. Nagaraja V, McMahan ZH, Getzug T, Khanna D. Management of gastrointestinal involvement in scleroderma. Curr Treatm Opt Rheumatol. 2015;1(1):82-105.
3. Hoffman-Vold AM, Volkmann ER. Gastrointestinal involvement in systemic sclerosis: Effects on morbidity and mortality and new therapeutic approaches [published online December 20, 2019.] J Scleroderma Relat Disord. doi:10.1177/2397198319891282
5. Richard N, Hudson M, Wang M, et al. Severe gastrointestinal disease in very early systemic sclerosis is associated with early mortality. Rheumatology (Oxford). 2019;58(4):636-644.
6. Sallam H, McNearney TA, Chen JD. Systematic review: pathophysiology and management of gastrointestinal dysmotility in systemic sclerosis (scleroderma). Aliment Pharmacol Ther. 2006;23(6):691-712.
8. Maurer AH. Gastrointestinal motility, part 2: small-bowel and colon transit. J Nucl Med. 2015;56(9):1395-1400.