Gastrointestinal manifestations of systemic sclerosis (scleroderma)
- Stephanie A Kaye-Barrett, MD
Stephanie A Kaye-Barrett, MD
- Consultant and Honorary Lecturer in Rheumatology
- The Chelsea and Westminster Hospital
- Christopher P Denton, MD
Christopher P Denton, MD
- Professor of Experimental Rheumatology
- Royal Free Hospital, London
- Section Editors
- John S Axford, DSc, MD, FRCP, FRCPCH
John S Axford, DSc, MD, FRCP, FRCPCH
- Section Editor — Scleroderma
- Emeritus Professor of Rheumatology
- St George's University of London
- Nicholas J Talley, MD, PhD
Nicholas J Talley, MD, PhD
- Section Editor — Motility Disorders
- Professor of Medicine, University of Newcastle, Australia
- Adjunct Professor of Medicine and Epidemiology and Consultant, Mayo Clinic, Rochester, MN
- Adjunct Professor, University of North Carolina
The systemic manifestations of systemic sclerosis (SSc, scleroderma) are diverse. Most prominent are abnormalities of the circulation (most notably Raynaud phenomenon) and involvement of multiple organ systems, including the musculoskeletal, renal, pulmonary, cardiac, and gastrointestinal (GI) systems, with fibrotic and/or vascular complications. GI symptoms can cause significant morbidity [1,2].
This topic will review the pathogenesis, clinical manifestations, and diagnosis of GI disease in SSc. Management of GI disease in SSc is discussed separately. (See "Treatment of gastrointestinal disease in systemic sclerosis (scleroderma)".)
Nearly 90 percent of patients with systemic sclerosis (SSc) have some degree of gastrointestinal (GI) involvement, and approximately one-half are symptomatic [3,4]. Involvement of the gut occurs with equal frequency among patients with the diffuse and limited subtypes of SSc (dcSSc and lcSSc, respectively) . It is rare in localized scleroderma syndromes . (See "Overview and classification of scleroderma disorders", section on 'Localized scleroderma' and "Overview and classification of scleroderma disorders", section on 'Limited and diffuse cutaneous SSc'.)
Although the esophagus is the most frequently affected part of the GI tract, any part of the GI tract may be involved. The presence of malabsorption and esophageal dysfunction among patients with SSc is associated with an unfavorable prognosis [7-9]. In one study that included 264 patients with dcSSc, GI involvement was associated with poor survival. Among 131 deaths related to SSc during a mean follow-up of 5.2 years, 13 deaths were due to GI complications .
Systemic sclerosis (SSc) is associated with alterations of the microvasculature, the autonomic nervous system, and the immune system, leading to fibrosis [11-13]. Sjögren advanced the theory that SSc affects the gastrointestinal (GI) tract by an orderly series of steps that result in progressive dysfunction . According to this hypothesis, the disease begins with an initial neural disorder, progresses to muscle dysfunction, and ends with fibrosis. Early neural dysfunction may be a consequence of collagen deposits causing vascular derangement, compression of the nerves, or autoimmune-mediated injury [15-21]. The second stage of small bowel disease occurs with smooth muscle atrophy. Most patients present with symptoms at this stage. This is followed by the final stage of muscle fibrosis. At this point, the muscle is incapable of responding to stimuli and pharmacologic restoration of function is no longer possible. (See "Pathogenesis of systemic sclerosis (scleroderma)", section on 'Summary'.)
- Khanna D, Hays RD, Maranian P, et al. Reliability and validity of the University of California, Los Angeles Scleroderma Clinical Trial Consortium Gastrointestinal Tract Instrument. Arthritis Rheum 2009; 61:1257.
- Thoua NM, Bunce C, Brough G, et al. Assessment of gastrointestinal symptoms in patients with systemic sclerosis in a UK tertiary referral centre. Rheumatology (Oxford) 2010; 49:1770.
- Turner R, Lipshutz W, Miller W, et al. Esophageal dysfunction in collagen disease. Am J Med Sci 1973; 265:191.
- Akesson A, Wollheim FA. Organ manifestations in 100 patients with progressive systemic sclerosis: a comparison between the CREST syndrome and diffuse scleroderma. Br J Rheumatol 1989; 28:281.
- Furst DE, Clements PJ, Saab M, et al. Clinical and serological comparison of 17 chronic progressive systemic sclerosis (PSS) and 17 CREST syndrome patients matched for sex, age, and disease duration. Ann Rheum Dis 1984; 43:794.
- Zaninotto G, Peserico A, Costantini M, et al. Oesophageal motility and lower oesophageal sphincter competence in progressive systemic sclerosis and localized scleroderma. Scand J Gastroenterol 1989; 24:95.
- Montesi A, Pesaresi A, Cavalli ML, et al. Oropharyngeal and esophageal function in scleroderma. Dysphagia 1991; 6:219.
- Bharadwaj S, Tandon P, Gohel T, et al. Gastrointestinal Manifestations, Malnutrition, and Role of Enteral and Parenteral Nutrition in Patients With Scleroderma. J Clin Gastroenterol 2015; 49:559.
- Domsic RT, Nihtyanova SI, Wisniewski SR, et al. Derivation and validation of a prediction rule for two-year mortality in early diffuse cutaneous systemic sclerosis. Arthritis Rheumatol 2014; 66:1616.
- Altman RD, Medsger TA Jr, Bloch DA, Michel BA. Predictors of survival in systemic sclerosis (scleroderma). Arthritis Rheum 1991; 34:403.
- Russell ML, Friesen D, Henderson RD, Hanna WM. Ultrastructure of the esophagus in scleroderma. Arthritis Rheum 1982; 25:1117.
- Dessein PH, Joffe BI, Metz RM, et al. Autonomic dysfunction in systemic sclerosis: sympathetic overactivity and instability. Am J Med 1992; 93:143.
- Silver RM. Clinical aspects of systemic sclerosis (scleroderma). Ann Rheum Dis 1991; 50 Suppl 4:854.
- Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum 1994; 37:1265.
- Willerson JT, Thompson RH, Hookman P, et al. Reserpine in Raynaud's disease and phenomenon. Short-term response to intra-arterial injection. Ann Intern Med 1970; 72:17.
- TREACY WL, BAGGENSTOSS AH, SLOCUMB CH, CODE CF. SCLERODERMA OF THE ESOPHAGUS. A CORRELATION OF HISTOLOGIC AND PHYSIOLOGIC FINDINGS. Ann Intern Med 1963; 59:351.
- Di Trapani G, Pocchiari M, Masullo C, et al. Peripheral neuropathy in the course of progressive systemic sclerosis: light and ultrastructural study. Ital J Neurol Sci 1982; 3:341.
- Howe S, Eaker EY, Sallustio JE, et al. Antimyenteric neuronal antibodies in scleroderma. J Clin Invest 1994; 94:761.
- Manetti M, Neumann E, Müller A, et al. Endothelial/lymphocyte activation leads to prominent CD4+ T cell infiltration in the gastric mucosa of patients with systemic sclerosis. Arthritis Rheum 2008; 58:2866.
- Raja J, Nihtyanova SI, Murray CD, et al. Sustained benefit from intravenous immunoglobulin therapy for gastrointestinal involvement in systemic sclerosis. Rheumatology (Oxford) 2016; 55:115.
- Thoua NM, Derrett-Smith EC, Khan K, et al. Gut fibrosis with altered colonic contractility in a mouse model of scleroderma. Rheumatology (Oxford) 2012; 51:1989.
- Kahn IJ, Jeffries GH, Sleisenger MH. Malabsorption in intestinal scleroderma. Correction by antibiotics. N Engl J Med 1966; 274:1339.
- HORSWELL RR, HARGROVE MD Jr, PEETE WP, RUFFIN JM. Scleroderma presenting as the malabsorption syndrome. A case report. Gastroenterology 1961; 40:580.
- Schuffler MD, Kaplan LR, Johnson L. Small-intestinal mucosa in pseudoobstruction syndromes. Am J Dig Dis 1978; 23:821.
- Marguerie C, Kaye S, Vyse T, et al. Malabsorption caused by coeliac disease in patients who have scleroderma. Br J Rheumatol 1995; 34:858.
- McBrien DJ, Mummery HE. Steatorrhoea in Progressive Systemic Sclerosis (Scleroderma). Br Med J 1962; 2:1653.
- ROSSON RS, YESNER R. PERORAL DUODENAL BIOPSY IN PROGRESSIVE SYSTEMIC SCLEROSIS. N Engl J Med 1965; 272:391.
- Stafford-Brady FJ, Kahn HJ, Ross TM, Russell ML. Advanced scleroderma bowel: complications and management. J Rheumatol 1988; 15:869.
- D'Angelo WA, Fries JF, Masi AT, Shulman LE. Pathologic observations in systemic sclerosis (scleroderma). A study of fifty-eight autopsy cases and fifty-eight matched controls. Am J Med 1969; 46:428.
- Rajapakse CN, Bancewicz J, Jones CJ, Jayson MI. Pharyngo-oesophageal dysphagia in systemic sclerosis. Ann Rheum Dis 1981; 40:612.
- Poirier TJ, Rankin GB. Gastrointestinal manifestations of progressive systemic scleroderma based on a review of 364 cases. Am J Gastroenterol 1972; 58:30.
- Lock G, Holstege A, Lang B, Schölmerich J. Gastrointestinal manifestations of progressive systemic sclerosis. Am J Gastroenterol 1997; 92:763.
- Cohen S, Fisher R, Lipshutz W, et al. The pathogenesis of esophageal dysfunction in scleroderma and Raynaud's disease. J Clin Invest 1972; 51:2663.
- Belch JJ, Land D, Park RH, et al. Decreased oesophageal blood flow in patients with Raynaud's phenomenon. Br J Rheumatol 1988; 27:426.
- Segel MC, Campbell WL, Medsger TA Jr, Roumm AD. Systemic sclerosis (scleroderma) and esophageal adenocarcinoma: Is increased patient screening necessary? Gastroenterology 1985; 89:485.
- Lahcene M, Oumnia N, Matougui N, et al. Esophageal involvement in scleroderma: clinical, endoscopic, and manometric features. ISRN Rheumatol 2011; 2011:325826.
- Geirsson AJ, Akesson A, Gustafson T, et al. Cineradiography identifies esophageal candidiasis in progressive systemic sclerosis. Clin Exp Rheumatol 1989; 7:43.
- ASGE Standards of Practice Committee, Pasha SF, Acosta RD, et al. The role of endoscopy in the evaluation and management of dysphagia. Gastrointest Endosc 2014; 79:191.
- Katzka DA, Reynolds JC, Saul SH, et al. Barrett's metaplasia and adenocarcinoma of the esophagus in scleroderma. Am J Med 1987; 82:46.
- Kirby DF, Chatterjee S. Evaluation and management of gastrointestinal manifestations in scleroderma. Curr Opin Rheumatol 2014; 26:621.
- Parrado RH, Lemus HN, Coral-Alvarado PX, Quintana López G. Gastric Antral Vascular Ectasia in Systemic Sclerosis: Current Concepts. Int J Rheumatol 2015; 2015:762546.
- Watson M, Hally RJ, McCue PA, et al. Gastric antral vascular ectasia (watermelon stomach) in patients with systemic sclerosis. Arthritis Rheum 1996; 39:341.
- Maddern GJ, Horowitz M, Jamieson GG, et al. Abnormalities of esophageal and gastric emptying in progressive systemic sclerosis. Gastroenterology 1984; 87:922.
- Blackwell JN, Hannan WJ, Adam RD, Heading RC. Radionuclide transit studies in the detection of oesophageal dysmotility. Gut 1983; 24:421.
- Marie I, Ducrotte P, Antonietti M, et al. Watermelon stomach in systemic sclerosis: its incidence and management. Aliment Pharmacol Ther 2008; 28:412.
- Duchini A, Sessoms SL. Gastrointestinal hemorrhage in patients with systemic sclerosis and CREST syndrome. Am J Gastroenterol 1998; 93:1453.
- Ingraham KM, O'Brien MS, Shenin M, et al. Gastric antral vascular ectasia in systemic sclerosis: demographics and disease predictors. J Rheumatol 2010; 37:603.
- Marie I. [Gastrointestinal involvement in systemic sclerosis]. Presse Med 2006; 35:1952.
- Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum 2000; 43:2437.
- REINHARDT JF, BARRY WF Jr. Scleroderma of the small bowel. Am J Roentgenol Radium Ther Nucl Med 1962; 88:687.
- DiMarino AJ, Carlson G, Myers A, et al. Duodenal myoelectric activity in scleroderma. Abnormal responses to mechanical and hormonal stimuli. N Engl J Med 1973; 289:1220.
- Rees WD, Leigh RJ, Christofides ND, et al. Interdigestive motor activity in patients with systemic sclerosis. Gastroenterology 1982; 83:575.
- Greydanus MP, Camilleri M. Abnormal postcibal antral and small bowel motility due to neuropathy or myopathy in systemic sclerosis. Gastroenterology 1989; 96:110.
- Greenberger NJ, Dobbins WO 3rd, Ruppert RD, Jesseph JE. Intestinal atony in progressive systemic sclerosis (scleroderma). Am J Med 1968; 45:301.
- Kaye SA, Lim SG, Taylor M, et al. Small bowel bacterial overgrowth in systemic sclerosis: detection using direct and indirect methods and treatment outcome. Br J Rheumatol 1995; 34:265.
- Wegener M, Adamek RJ, Wedmann B, et al. Gastrointestinal transit through esophagus, stomach, small and large intestine in patients with progressive systemic sclerosis. Dig Dis Sci 1994; 39:2209.
- Horowitz AL, Meyers MA. The "hide-bound" small bowel of scleroderma: characteristic mucosal fold pattern. Am J Roentgenol Radium Ther Nucl Med 1973; 119:332.
- Miercort RD, Merrill FG. Pneumatosis and pseudo-obstruction in scleroderma. Radiology 1969; 92:359.
- Baron M, Hudson M, Steele R, Canadian Scleroderma Research Group. Malnutrition is common in systemic sclerosis: results from the Canadian scleroderma research group database. J Rheumatol 2009; 36:2737.
- Caporali R, Caccialanza R, Bonino C, et al. Disease-related malnutrition in outpatients with systemic sclerosis. Clin Nutr 2012; 31:666.
- Harrison E, Herrick AL, McLaughlin JT, Lal S. Malnutrition in systemic sclerosis. Rheumatology (Oxford) 2012; 51:1747.
- Hansi N, Thoua N, Carulli M, et al. Consensus best practice pathway of the UK scleroderma study group: gastrointestinal manifestations of systemic sclerosis. Clin Exp Rheumatol 2014; 32:S.
- Bae S, Allanore Y, Furst DE, et al. Associations between a scleroderma-specific gastrointestinal instrument and objective tests of upper gastrointestinal involvements in systemic sclerosis. Clin Exp Rheumatol 2013; 31:57.
- Jayson MI, Salmon PR, Gough J, et al. Spontaneous bowel perforation in intestinal scleroderma: first report of a non-fatal case. Postgrad Med J 1972; 48:56.
- Battle WM, McLean GK, Brooks JJ, et al. Spontaneous perforation of the small intestine due to scleroderma. Dig Dis Sci 1979; 24:80.
- Meihoff WE, Hirschfield JS, Kern F Jr. Small intestinal scleroderma with malabsorption and pneumatosis cystoides intestinalis. Report of three cases. JAMA 1968; 204:854.
- Hendy MS, Torrance HB, Warnes TW. Small-bowel volvulus in association with progressive systemic sclerosis. Br Med J 1979; 1:1051.
- MESZAROS WT. The colon in systemic sclerosis (scleroderma). Am J Roentgenol Radium Ther Nucl Med 1959; 82:100.
- Hamel-Roy J, Devroede G, Arhan P, et al. Comparative esophageal and anorectal motility in scleroderma. Gastroenterology 1985; 88:1.
- Gyger G, Baron M. Systemic Sclerosis: Gastrointestinal Disease and Its Management. Rheum Dis Clin North Am 2015; 41:459.
- Cohen S. The gastrointestinal manifestations of scleroderma: pathogenesis and management. Gastroenterology 1980; 79:155.
- Leighton JA, Valdovinos MA, Pemberton JH, et al. Anorectal dysfunction and rectal prolapse in progressive systemic sclerosis. Dis Colon Rectum 1993; 36:182.
- Thoua NM, Abdel-Halim M, Forbes A, et al. Fecal incontinence in systemic sclerosis is secondary to neuropathy. Am J Gastroenterol 2012; 107:597.
- Thoua NM, Schizas A, Forbes A, et al. Internal anal sphincter atrophy in patients with systemic sclerosis. Rheumatology (Oxford) 2011; 50:1596.
- Chiou AW, Lin JK, Wang FM. Anorectal abnormalities in progressive systemic sclerosis. Dis Colon Rectum 1989; 32:417.
- Peachey RD, Creamer B, Pierce JW. Sclerodermatous involvement of the stomach and the small and large bowel. Gut 1969; 10:285.
- deSouza NM, Williams AD, Wilson HJ, et al. Fecal incontinence in scleroderma: assessment of the anal sphincter with thin-section endoanal MR imaging. Radiology 1998; 208:529.
- Jacobsen S, Halberg P, Ullman S, et al. Clinical features and serum antinuclear antibodies in 230 Danish patients with systemic sclerosis. Br J Rheumatol 1998; 37:39.
- Assassi S, Fritzler MJ, Arnett FC, et al. Primary biliary cirrhosis (PBC), PBC autoantibodies, and hepatic parameter abnormalities in a large population of systemic sclerosis patients. J Rheumatol 2009; 36:2250.
- Reynolds TB, Denison EK, Frankl HD, et al. Primary biliary cirrhosis with scleroderma, Raynaud's phenomenon and telangiectasia. New syndrome. Am J Med 1971; 50:302.
- Rigamonti C, Shand LM, Feudjo M, et al. Clinical features and prognosis of primary biliary cirrhosis associated with systemic sclerosis. Gut 2006; 55:388.
- Worman HJ, Courvalin JC. Antinuclear antibodies specific for primary biliary cirrhosis. Autoimmun Rev 2003; 2:211.
- Hu SL, Zhao FR, Hu Q, Chen WX. Meta-analysis assessment of GP210 and SP100 for the diagnosis of primary biliary cirrhosis. PLoS One 2014; 9:e101916.
- Cobden I, Axon AT, Rowell NR. Pancreatic exocrine function in systemic sclerosis. Br J Dermatol 1981; 105:189.
- Shawis TN, Chaloner C, Herrick AL, Jayson MI. Pancreatic function in systemic sclerosis. Br J Rheumatol 1996; 35:298.
- Hastier P, Buckley MJ, Le Gall P, et al. First report of association of chronic pancreatitis, primary biliary cirrhosis, and systemic sclerosis. Dig Dis Sci 1998; 43:2426.
- Gastrointestinal histopathology
- OROPHARYNGEAL INVOLVEMENT
- Oropharyngeal dysphagia
- ESOPHAGEAL INVOLVEMENT
- Esophageal motility disorder and gastroesophageal reflux
- GASTRIC INVOLVEMENT
- Gastric antral vascular ectasia
- SMALL INTESTINAL INVOLVEMENT
- Small intestinal bacterial overgrowth
- Hypomotility and intestinal pseudo-obstruction
- COLON AND ANORECTAL INVOLVEMENT
- Colonic inertia
- Diarrhea and fecal incontinence
- LIVER AND BILIARY TREE INVOLVEMENT
- Primary biliary cholangitis overlap
- PANCREATIC INVOLVEMENT
- Pancreatic exocrine insufficiency
- SUMMARY AND RECOMMENDATIONS