MADRID—For patients with significant gastrointestinal (GI) manifestations of scleroderma, the effect on quality of life and longevity itself can be dramatic. A recent study of two multi-center cohorts of patients with scleroderma who demonstrated features of severe GI involvement showed these patients have worse physical and mental health-related quality of life and a greater than twofold increase in the risk of death compared with those without severe GI disease. In the study, severe GI involvement was defined as malabsorption, hyperalimentation, pseudo-obstruction and/or ≥10% weight loss in association with the use of antibiotics for bacterial overgrowth or esophageal stricture.1
With this in mind, the 2019 European Congress of Rheumatology (EULAR), June 12–15, featured a Challenges in Clinical Practice session titled, Lights at the Ends of Both Tunnels? Advances in GI Involvement in Systemic Sclerosis. The session provided insights from patient cases, and the expert presentations helped shed light on this important subject.
The Big Picture
Carina Mihai, MD, PhD, senior rheumatologist at the department of rheumatology at Zurich University Hospital, Switzerland, provided an overview of the spectrum of GI tract involvement in scleroderma. In describing the pathogenesis of these issues, she noted the combination of progressive fibrotic changes in the GI tract along with neuromuscular dysfunction create what can be thought of as a traffic jam in the gut with resulting dysmotility, dilation of the intestine, malabsorption and, in some cases, malnutrition.
Esophageal hypoperistalsis can manifest as dysphagia or regurgitation, and nearly every patient with scleroderma will describe some degree of gastroesophageal reflux symptoms. In cases of delayed stomach emptying, patients may note bloating, early satiety, nausea and vomiting. Small intestinal hypomotility can also lead to bloating and constipation. Some patients will have features of intestinal pseudo-obstruction and possible small intestinal bacterial overgrowth, which may actually manifest with diarrhea. Likewise, colon hypomotility can result in constipation, while anorectal dysfunction can lead to incontinence, a symptom patients may be hesitant to discuss with clinicians unless directly questioned about it.
To assess for GI tract involvement in scleroderma patients, Dr. Mihai advocated for the use of the UCLA Scleroderma Clinical Trial Consortium Gastrointestinal Tract 2.0 (SCTC GIT 2.0) questionnaire. This 34-item questionnaire has seven multi-item scales that include reflux, distension/bloating, diarrhea, fecal soilage, constipation, emotional wellbeing, social functioning and a total GIT score. Dr. Mihai noted this tool provides a thorough and comprehensive assessment of patient symptoms and also helps capture an overview of the nature and severity of these symptoms.
This questionnaire has been validated in multiple languages and in numerous countries outside the U.S., and work has been performed demonstrating a correlation of its results with objective measures of GI dysfunction in patients with scleroderma. In one study of 40 scleroderma patients who were administered the UCLA SCTC GIT 2.0 and underwent esophageal high-resolution manometry, it was shown that decreased distal esophageal amplitude encountered as hypoperistalsis or even aperistalsis was associated with increased reflux and GIT scores.2
Dr. Mihai cited a review article she often refers to that is helpful for understanding the spectrum of treatments available for the management of GI involvement in scleroderma. In this article, the authors provide a summary of the myriad medications now available or under study in the management of GI dysmotility, such as prucalopride, intravenous immunoglobulin, pyridostigmine, linaclotide and relamorelin. They note these drugs may improve symptoms and quality of life in scleroderma patients and that combination therapies are currently under investigation. Further, the authors write that electroacupuncture, dietary intervention (e.g. medical nutrition therapy, low FODMAP diet), and medical cannabis may also play a role in alleviating patient symptoms, but more data are needed to evaluate the true efficacy of these interventions.3
Treatment Options
In the second portion of the session, Christopher Denton, MD, PhD, FRCP, professor of experimental rheumatology at University College London (UCL) Medical School and consultant rheumatologist and joint director of the Centre for Rheumatology, Royal Free Hospital, London, discussed the rationale for when to treat GI involvement in scleroderma with antibiotics and when to use immunosuppressive therapy. Dr. Denton explained that small intestinal bacterial overgrowth is common in these patients due to altered motility, proton pump inhibitor use, immunosuppression and structural abnormalities. The diagnosis of small intestinal bacterial overgrowth can be made with hydrogen breath testing or jejunal aspirate analysis.
The U.K. Scleroderma Study Group has issued best practices that suggest an empiric trial of antibiotics, such as monotherapy with ciprofloxacin or a similar antimicrobial for one to three weeks. Courses can be repeated every 6–12 weeks as needed. When refractory, rotational courses of multiple antibiotics may be needed for symptom amelioration.4 Given that rifaximin has been successfully used the general population to eradicate small intestinal bacterial overgrowth, Dr. Denton also noted that it could be used at high doses of 800 mg twice per day.
Dr. Denton explained that immunosuppressive therapy may have a role in the treatment of GI involvement of scleroderma as a means of disease modification before damage becomes irreversible and as a way to modulate antibody mediated GI pathology. With respect to the former category, Dr. Denton cited numerous studies that have shown how immunosuppressive treatment may have improved or completely resolved gastric antral vascular ectasia (GAVE) in patients with scleroderma. One article cited by Dr. Denton describes improvement in GAVE in three patients treated with cyclophosphamide (200 mg/kg) and antithymocyte globulin (40 mg/kg) conditioning followed by infusion of unmanipulated autologous stem cells.5
More work is needed to understand the role immunosuppression may have in treating GI involvement in scleroderma. This is timely and relevant in light of the recent SCOT trial.6 In this study, scleroderma patients treated with myeloablative autologous stem-cell transplantation experienced significantly higher rates of disease-free survival at 52 months post-treatment compared with those treated with cyclophosphamide. Although treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, compared with 0% in the cyclophosphamide group, this study has thrust myeloablative autologous stem cell transplantation into the spotlight. This attention has resulted in many providers and patients wondering in which scenarios it may be reasonable to pursue this course of treatment.
With much work remaining to better understand diagnosis and treatment of GI disease in patients with scleroderma, the presenters closed their remarks with hope for a future in which many questions are answered through research and clinical experience. Indeed, it is more than a gut feeling that such a future is important for the many patients dealing with the daily symptoms created by GI involvement in scleroderma.
Jason Liebowitz, MD, recently completed his fellowship in rheumatology at Johns Hopkins University, Baltimore, where he also earned his MD. He is currently in practice with Arthritis, Rheumatic, and Back Disease Associates, New Jersey.
References
- Richard N, Hudson M, Wang M, et al. Severe gastrointestinal disease in very early systemic sclerosis is associated with early mortality. Rheumatology (Oxford). 2019 Apr 1;58(4):636–644.
- Abozaid HSM, Imam HMK, Abdelaziz MM, et al. High-resolution manometry compared with the University of California, Los Angeles Scleroderma Clinical Trials Consortium GIT 2.0 in systemic sclerosis. Semin Arthritis Rheum. 2017 Dec;47(3):40–408.
- McMahan ZH, Hummers LK. Gastrointestinal involvement in systemic sclerosis: Diagnosis and management. Curr Opin Rheumatol. 2018 Nov;30(6):533–540.
- Hansi N, Thoua N, Carulli M, et al. Consensus best practice pathway of the U.K. scleroderma study group: Gastrointestinal manifestations of systemic sclerosis. Clin Exp Rheumatol. 2014 Nov-Dec;32(6 Suppl 86):S-214-21.
- Bhattacharyya A, Sahhar J, Milliken S, et al. Autologous hematopoietic stem cell transplant for systemic sclerosis improves anemia from gastricantral vascular ectasia. J Rheumatol. 2015 Mar;42(3):554-555.
- Sullivan KM, Goldmuntz EA, Keyes-Elstein L, et al. Myeloablative autologous stem-cell transplantation for severe scleroderma. N Engl J Med. 2018 Jan 4;378(1):35–47.
