Dysphagia 5:204-210 (1990)
Dysphagia g) S p r i n g e r - V e r l a g N e w Y o r k I nc. 19tJI)
Scleroderma Esophagus Sam R. Fulp, M.D. t and Donald O. Castell, M . D . 2 Bowman Gray School of Medicine, Winston-Salem, North Carolina, and 2 Thomas Jefferson University Philadelphia, Pennsylvania, USA
Abstract. Scleroderma (systemic sclerosis) is a connective tissue disorder characterized by thickening and fibrosis of the skin and visceral involvement that may include the heart, lungs, kidneys, and gastrointestinal tract. At least 40-50% of patients with scleroderma experience esophageal symptoms such as heartburn and dysphagia, while up to 90% of patients have esophageal dysfunction on objective testing at some point in their disease. The disease results in smooth muscle dysfunction that causes esophageal aperistalsis and reduced lower esophageal sphincter pressures. Gastroesophageal reflux with poor acid clearance results with an increased incidence of complications such as peptic stricture and Barrett's esophagus. Aggressive medical therapy is necessary to prevent these and other complications of gastroesophageal reflux. Key words: Deglutition disorders - Scleroderma - Systemic sclerosis - Sclerosis, esophagus Gastroesophageal reflux.
tinal tract is the third most common manifestation of scleroderma, following only sclerodermatous skin change and Raynaud's phenomenon [1]. The CREST syndrome is a form of systemic sclerosis in which there is relatively limited involvement of the skin, prominence of calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia. This subset of scleroderma is characterized by limited visceral involvement, an excellent prognosis, and a high incidence of positive anticentromere antibodies [7-9]. In a recent carefully matched comparison between patients with scleroderma and CREST, incidence of upper gastrointestinal involvement did not differ between patients in the two groups [10]. In this review, an illustrative case presentation will be followed by a summary of the clinical manifestations, pathophysiology, and treatment of esophageal scleroderma.
Case Report
Systemic sclerosis (scleroderma) is a generalized connective tissue disorder characterized by thickening and fibrosis of the skin and by distinctive forms of involvement in internal organs including the heart, lungs, kidneys, synovium, esophagus, and intestine [1]. The esophagus is involved in 55-90% of patients with scleroderma by manometric or radiographic criteria [2-5], while evidence of esophageal disease at autopsy has been found in up to 74% of those patients with typical skin manifestations [6]. Involvement of the gastrointesAddress reprint requests to. Donald O. Castell, M.D., Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA
A 51-year-old woman was referred for evaluation of dysphagia. Heartburn and regurgitation had been present for approximately 10 years. The patient had noted dysphagia to solids for the past 2 years, which had responded temporarily to bougie dilatation and treatment with histamine receptor antagonists. She admitted to intermittent joint stiffness and Raynaud's phenomenon for 2-3 years. Physical examination showed a healthy-appearing woman in no acute distress. She had mild cyanosis of the fingers, and the skin of the hands was tight and edematous. Joints were nontender with full range of motion. Physical examination was otherwise normal. Barium swallow showed a dilated, aperistaltic esophagus below the aortic arch and a distal esophageal stricture, Frcc reflux of barium was noted into the proximal esophagus (Fig. 1). Esophagoscopy showed distal ulcerative esophagitis (Fig. 2) and a stricture. A 60 Fr dilator was passed into the stomach with minimal resistance. Esophageal manometry showed aperistalsis and hypotensive lower esophageal spincter (Fig. 3). The esophageal findings were thought to be consistent
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Fig. I. A An air contrast barium radiograph of the esophagus. A stricture is seen (arrow) in the lower esophagus below a dilated segment of esophagus. B An upright radiograph of the esophagus taken after A. Refluxcd barium is seen along the full length of the esophagus, and the stricture is seen just proximal to a hiatal hernia.
with scleroderma. Rheumatoid factor was positive at 1 : 160 and antinuclear antibody was positive at 1:400 (speckled). Rheumatologic consultation confirmed the clinical diagnosis of systemic sclerosis with involvement of the skin and esophagus.
Symptoms The most common esophageal symptoms in patients with scleroderma are heartburn, regurgitation, and dysphagia. Dysphagia can result from either a peptic stricture or disturbed esophageal peristalsis [2]. Heartburn is a prominent symptom, described as a burning retrosternal pain radiating
toward the pharynx. This may be associated with sour or bitter regurgitation. Heartburn and regurgitation are due to gastroesophageai reflux [11]. Two large series found that esophageal symptoms are present at some point in 42-84% of patients with scleroderma [12, 13]. Raynaud's phenomenon is the clinical feature that correlates most closely with esophageal dysfunction in scleroderma [3]. Physical examination often shows typical skin findings of scleroderma, but none of the physical findings are specific for esophageal disease. Plain films of the chest can show evidence of esophageal involvement in scleroderma. Incompe-
206
S.R. Fulp and D.O, Castell: Scleroderma Esophagus
Fig. 2. Normal squamous esophageal mucosa to the left of the slide with an ulcer bed to the right, with overlying granulation tissue. Polymorphonuclear exudate can be seen in the lower right hand corner and in the granulation tissue. (Tissue obtained from endoscopic biopsy.)
tence of the lower esophageal sphincter (LES) can result in an air-filled esophagus that may be superimposed on a background of pulmonary fibrosis [14]. Barium swallow in patients with scleroderma may show mild to moderate degrees of dilatation, diminished or absent distal peristalsis, and a widely patulous gastroesophageal junction. Frequently esophagitis and/or an esophageal stricture can be seen [15]. Endoscopy is useful in the evaluation of mucosal changes that result from gastroesophageal reflux. These changes may include esophagitis or more complicated esophageal diseases such as peptic stricture, Barrett's epithelium, or carcinoma. Esophageal manometry shows evidence of esophageal dysfunction in up to 90% of patients with systemic sclerosis [5, 16]. The manometric abnormalities are often among the earliest findings in scleroderma [17, 18] and are more prevalent than symptoms of esophageal dysfunction. The two characteristic manometric abnormalities illustrate smooth muscle dysfunction: low-amplitude or absent esophageal contractions in the distal esophagus, and low to absent LES pressure [2]. These changes have been shown to be nonspecific, having been described in patients with systemic lupus er-
Fig. 3. A A slow pull-through of the lower esophageal sphincter. The lower esophageal sphincter has a very low pressure (4 mmHg) as measured at the pressure inversion point (PIP), which lies at the diaphragmatic hiatus. B Two wet swallows (WS) with the manometric catheter anchored 3 cm above the LES. In the top panel, normal pressures are generated by striated muscle 18 cm above the LES. A weak nonperistaltic response is seen distally in the smooth muscle portion of the esophagus.
ythematosus, polymyositis, dermatomyositis, rheumatoid arthritis, psoriatic arthritis, polyarteritis nodosa, Raynaud's disease, and mixed connective tissue disease [3, 19, 20]. The typical manometric changes have also been reported in patients who had no sign of rheumatic disease [21]. Radionuclide esophageal scintigraphy is not generally utilized in the evaluation of esophageal
S.R. Fulp and D.O. Castell: Scleroderma Esophagus
dysfunction in patients with scleroderma. However, scintigraphy has been shown to be as sensitive as manometry in detecting esophageal dysfunction in a prospective study of 11 patients [22]. Delayed esophageal emptying is seen in scleroderma, but this is a nonspecific finding. Proponents of scintigraphy point out its superior sensitivity compared to radiography and its superior patient acceptance compared to manometry.
Diagnosis Although systemic sclerosis is a clinical diagnosis, the American Rheumatism Association has proposed preliminary criteria for the classification of systemic sclerosis based on a multicenter study of 797 patients. The criteria have been useful in ensuring uniformity of clinical research, and the diagnosis requires the finding of either the sole major criterion or two of the minor criteria. The major criterion is proximal scleroderma (tightness, thickening, and nonpitting induration of the skin proximal to the metacarpophalangeal or metatarsophalangeal joints). Minor criteria include sclerodactyly, digital pitting scars of fingertips or loss of substance of the distal finger pad, and bilateral basilar pulmonary fibrosis. Notably absent from this list is esophageal dysfunction because of its lack of specificity [23]. However, the presence of typical esophageal changes on barium swallow or manometry may be very helpful in leading to a clinical diagnosis of systemic sclerosis, as it did in our case.
Complications Complications of esophageal disease associated with systemic sclerosis includes peptic stricture, Barrett's epithelium, and ulcerative esophagitis. Pulmonary aspiration and esophageal candidiasis may also occur. Peptic stricture in systemic sclerosis may be heralded by dysphagia to solid food, This may occur in the presence or absence of reflux symptoms [2]. Benign peptic stricture has been seen in up to 40% of patients with scleroderma [24], while only 11% of patients with gastroesophageal reflux disease (without scleroderma) in one series had a peptic stricture [25]. Barrett's esophagus in scleroderma has only recently been described. It was reported first by Cameron and Payne [26] in 1978, and there have been several reports since then [27 35]. Halpert and colleagues reported esophageal adenocarcinoma in
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three patients with Barrett's epithelium and scleroderma in 1983 [27]. Since then there have been several reports of esophageal adenocarcinomas arising in Barrett's epithelium in patients with scleroderma [28 30]. The prevalence of Barrett's esophagus in scleroderma is unknown, but a large series of symptomatic patients with scleroderma who underwent endoscopy showed that 37% of the patients had biopsy-proven Barrett's esophagus, with 20% of those patients with Barrett's also having adenocarcinoma [28]. Ulcerative esophagitis is another example of complicated esophageal disease due to gastroesophageal reflux from scleroderma. This may coexist with Barrett's epithelium, as first reported by Cameron and Payne in 1978 [26] and later reported by others [31-35]. Ulcerative esophagitis may also occur without Barrett's epithelium as seen in our illustrative case. Chronic pulmonary aspiration of gastroesophageal contents due to reflux has been suggested as a contributing cause of pulmonary disease in scleroderma. In a recent study [36] of 13 patients with scleroderma, 85% had proximal esophagitis, 92% had laryngeal changes suggestive of aspiration, and 15% had a positive "aspiration scan." A positive "aspiration scan" consisted of delayed radioisotope activity over the lateral thoracic area following an oral meal containing [99mTC]suifur colloid. Esophageal candidiasis has been noted to be a common occurrence in patients with scleroderma [11, 37]. In a recent controlled study of 48 consecutive patients with scleroderma, 44% had candidiasis diagnosed by esophageal mucosal brushing, a higher rate than patients without scleroderma with and without reflux in the same study [38].
Pathophysiology The pathogenesis of esophageal dysfunction in systemic sclerosis is incompletely understood, The prominent lesion at autopsy is atrophy of the smooth muscle in the muscularis propria and one or both muscle layers. Also noted is mildly increased fibrosis and collagen deposition in the lamina propria and submucosa, and thinning or erosion of the mucosa. However, the myenteric plexus and skeletal muscle appear normal [6, 18, 39]. In early scleroderma, motility studies have shown altered esophageal motility in the presence of normal esophageal smooth muscle at autopsy [39]. Some patients with scleroderma have a preserved re-
208 sponse to muscle stimulants but not to agents requiting intact cholinergic innervation, suggesting a primary neuronal defect early in the disease course [17]. While motility studies suggest that disordered neural function precedes smooth muscle atrophy, ultrastructural and light microscopic studies have failed to give morphologic supporting evidence [18, 40]. Recent work with esophageal electromyography suggests that disordered myoelectric hyperactivity occurs early in scleroderma, while a marked decrease in myoelectric activity may occur later in scleroderma [41]. It has been suggested that impaired perfusion from the nutritive vasculature and microvascular disruption contribute to the pathogenesis, first as disordered myoelectric function and later as smooth muscle atrophy [1]. These aforementioned pathologic changes produce decreased or absent lower esophageal peristalsis with lower esophageal sphincter incompetence. These defects in smooth muscle function lead to reflux of gastric contents into the esophagus with impaired acid clearance. With these pathogenetic factors being important, 60% of patients develop erosive esophagitis [37] and other complications. Treatment
There are n o pharmacologic treatments of proven value in the management of systemic sclerosis [I]. Therapy cannot reverse the motor findings in scleroderma and should be directed toward preventing and treating reflux esophagitis and its complications [42]. Histamine receptor antagonists have been found to be useful in treating the manifestations of gastroesophageal reflux associated with scleroderma. Cimetidine has been shown to be significantly more effective than antacids in relieving heartburn and healing endoscopically documented esophagitis [43]. However, prolonged therapy with 1200 mg/day may be required to maintain improvement in some patients [37]. Ranitidine has also been shown to improve symptoms and heal endoscopically proven esophagitis, but chronic therapy must be utilized to maintain improvement [44]. However, neither drug improved motility or altered stricture size. Omeprazole, a hydrogen/potassium ATPase blocker in the parietal cell was approved by the Food and Drug Administration in 1989 for use in the short-term (less than 2 months) treatment of reflux esophagitis. Omeprazole has been consistently superior to placebo and conventional doses of histamine antagonists
S.R. Fulp and D.O. Castell: SclerodermaEsophagus in relieving reflux symptoms and in healing endoscopic esophagitis [45, 46]. Since omeprazole is extremely effective in treating reflux esophagitis, it will presumably be helpful in treating reflux esophagitis associated with scleroderma. It would be reasonable to recommend omeprazole in the shortterm treatment of reflux disease associated with scleroderma not controlled by histamine antagonists. Occasionally patients with scleroderma may benefit from the motility-enhancing effects of metoclopramide [47]. Lifestyle modifications should be tried such as elevation of the head of the bed, and avoidance of cigarette smoking, fatty foods, chocolate, and large meals shortly before bedtime. Dysphagia can be minimized by careful mastication of small quantities of food [1]. Refractory dysphagia is suggestive of a peptic stricture that requires mechanical dilatation. Once formed, a peptic stricture may require repeated bougie dilatation. For patients in whom medical therapy is not successful, antireflux surgery must be carefully considered. Fundoplication can exacerbate dysphagia significantly, so it is generally discouraged. Good results have been reported with antireflux procedures in scleroderma by Henderson and Pearson [48] as well as by Orringer and associates [49]. However, follow-up was relatively short, averaging 131/2 and 47 months, respectively. Orringer recommended a loose fundoplication around a 46 Fr bougie. Good results have also been reported with esophageal resection and bowel replacement [50-52]. In a recent surgical series with endoscopic follow-up of up to 12 years following surgery, there was a 100% rate of recurrence of endoscopic esophagitis following antireflux procedures, but good results were noted in three patients who underwent partial esophagectomy and short-segment colon interposition for severe stricture [52]. Barrett's esophagus in scleroderma requires surveillance for possible dysplasia and esophageal adenocarcinoma. Conclusions
This article has described the clinical, radiographic, and manometric manifestations of esophageal scleroderma. In addition, the diagnosis, complications, pathophysiology, and treatment of scleroderma (systemic sclerosis) are discussed. Esophageal dysfunction occurs in up to 90% of patients with scleroderma. The primary defect is smooth muscle dysfunction, eventually causing aperistalsis and an incompetent lower esophageal sphincter. This results in gastroesophageal reflux
S.R. Fulp and D.O. Castell: Scleroderma Esophagus
with a high incidence of severe esophagitis, stricture, and Barrett's esophagus. However, these findings are not specific for systemic sclerosis and are found in many other collagen vascular diseases. Treatment is largely medical and should be directed at prevention of complications of gastroesophageal reflux. Surgical therapy is generally reserved for severe symptomatic or complicated reflux esophagitis. Acknowledgments. The authors wish to thank Wain White, M.D., for the photomicrograph, David Ott, M.D., for the radiographs, and Christine Dalton, P.A.-C., for the manometric tracings.
References 1. Seibold JR: Scleroderma. In Kelly WN, Harris ED, Ruddy S, Sledge CB (eds): Textbook ofRheumatology, 3rd ed. Philadelphia: WB Saunders, 1989, pp 1215-1244 2. Turner R, Lipshutz W, Miller W, Rittenberg G, Schumaker HR, Cohen S: Esophageal dysfunction in collagen disease. Am J Med Sci 265:191-199, 1973 3. Stevens MB, Hookman P, Siegel CI, Esterly JR, Shulman LE, Hendrix TR: Aperistalsis of the esphagus in patients with connective tissue disorders and Raynaud's phenomenon. N Engl J Med 270:1218-1222, 1964 4. Clements PJ, Kadell B, Ippoliti A, Ross M" Esophageal motility in progressive systemic sclerosis (PSS). Comparison of cine-radiographic and manometric evaluation. Dig Dis Sci 24:639-644, 1979 5. Poirier TJ, Rankin GB: Gastrointestinal manifestations of progressive systemic scleroderma based on a review of 364 cases. Am J Gastroentero158 : 30-44, 1972 6. D'Angelo WA, Fries J, Masi AT, Shulman LE: Pathologic observations in systemic sclerosis (scleroderma). Am J Med 46:428-440, 1969 7. Rodnan GP, Medsger TA, Buckingham RB." Progressive systemic sclerosis-crest syndrome: observations on natural history and late complications in 90 patients. Arthritis Rheum 18:423, 1975 (abstract) 8. Carr RD, Heisel EB, Stevenson TD: CREST syndrome. A benign variant of scleroderma. Arch Dermatol 92: 519-525, 1965 9. Fritzler M J, Kinsella TD, Garbutt E: The CREST syndrome: a distinct serologic entity with anticentromere antibodies. Am J Med 69: 520-526, 1980 10. Furst DE, Clements PJ, Saab M, Sterz MG, Paulus HE: 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 43:794-801, 1984 I I. Cohen S, Laufer I, Snape WJ, Shiau YF, Levine GM, Jimenez S: The gastrointestinal manifestations of scleroderma: pathogenesis and management. Gastroenterology 79:155-166, 1980 12. Tuffanelli DL, Winkelmann RK: Systemic scleroderma. A clinical sutdy of 727 cases. Arch Dermato184: 359-371, 1961 13. Henderson RD: Esophageal motor disorders. Surg Clin North Am 67:455--474, 1987 14. Dinsmore RE, Goodman D, Dreyfuss JR: The air esophagram: a sign of scleroderma involving the esophagus. Radiology 87: 348-349, 1966 15. Lorber SH, Zarafonetis CJD: Esophageal transit studies in scleroderma. Am J Med Sci 245: 654-667, 1963
209 16. Weihrauch TR, Korting GW, Ewe K, Vogt G: Esophageal dysfunction and its pathogenesis in progressive systemic sclerosis. Klin Wochenschr 56:963-968, 1978 17. Cohen S, Fisher R, Lipshutz W, Turner R, Myers A, Schumacher R: The pathogenesis of esophageal dysfunction in scleroderma and Raynaud's disease. J Clin Invest 51 : 2663-2668, 1972 18. Atkinson M, Summerling MD: Oesophageal changes in systemic sclerosis. Gut 7:402-408, 1966 19. DeMerieux P, Verity A, Clements PJ, Paulus HE: Esophageal abnormalities and dysphagia in polymyositis and dermatomyositis. Clinical, radiologic, and pathologic features. Arthritis Rheum 26:961-968, 1983 20. Gutierrez F, Valenzuela dE, Ehresmann GR, Quismorio FP, Kitridou RC: Esophageal dysfunction in patients with mixed connective tissue diseases and systemic lupus erythematosus. Dig Dis Sci 27:592-597, 1982 21. Schneider HA, Yonger RA, Longley S, Katz P, Mathias J, Panush RS: Scleroderma esophagus: a non-specific entity. Ann lntern Med 100:848-850, 1984 22. Drane WE, Karvelis K, Johnson DA, Curran JJ, Silverman ED: Progressive systemic sclerosis: radionuclide esophageal scintigraphy and manometry. Radiology 160: 73-76, 1986 23. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23: 581-590, 1980 24. Cohen S: Motor disorders of the esophagus. N Engl J Med 301:184-192, 1979 25. Palmer ED: Subacute erosive ("peptic") esophagitis. Clinical study of one hundred cases. Arch Intern Med 94: 364-374, 1954 26. Cameron AJ, Payne W$: Barrett's esophagus occurring as a complication of scleroderma. Mayo Clin Proc 53:612-615, 1978 27. Halpert RD, Laufer I, Thomspon JJ, Feczko PJ : Adenocarcinoma of the esophagus in patients with scleroderma. AJR 140:927-930, 1983 28. Recht MP, Levine MS, Katzka DA, Reynolds JC, Sail SH : Barrett's esophagus in scleroderma: increased prevalence and radiographic findings. Gastrointest Radiol 13:1-5, 1988 29. Niv Y, Abu-Avid S, Yelin A, Liberman Y" Barrett's epithelium and esophageal adenocarcinoma in scleroderma. Am J Gastroentero183: 792-793, 1988 30. McKinley M, Sherlock P: Barrett's esophagus with adenocarcinoma in scleroderma. Am .I Gastroenterol 79: 438--439, 1984 31. Dill dE: Barrett's epithelium in scleroderma. Gastrointest Endosc 29:296-297, 1983 32. Sprung D J, Gibb SP: Dysplastic Barrett's esophagus in scleroderma. Am J Gastroenter o180 : 518-522, 1985 33. Agha FP, Dabich L: Barrett's esophagus complicating scleroderma. Gastrointest Radiol 10: 325-329, 1985 34. Anderson M, Seymour EQ: Association of Barrett's esophagus and scleroderma. South Med J 80: 764-765, 1987 35. Katzka DA, Reynolds JC, Saul SH: Barrett's metaplasia and adenocarcinoma of the esophagus in scleroderma. Am J Med 82:46-52, 1987 36. Johnson DA, Drane WE, Curran J, et al.: Pulmonary disease in progressive systemic sclerosis. A complication of gastroesophageal reflux and occult aspiration? Arch Intern Med 149:589-593, 1989 37. Zamost BJ, Hirschberg J, Ippoliti AF, et al.: Esophagitis in scleroderma - prevalence and risk factors. Gastroenterology 92:421-428, 1987
210 38. Hendel L, Svejgaard E, Walsoe I, Kieffer M, Stenderup A: Esophageal candidosis in progressive systemic sclerosis: occurrence, significance, and treatment with flueonazole. Scand J Gastroentero123 :1182-1186, 1988 39. Treacy WL, Baggenstoss AH, Slocumb CH, Code CF'. Scleroderma of the esophagus. A correlation of histologic and physiologic findings. Ann lntern Med 59:351-356, 1963 40. Russell ML, Friesen D, Henderson RD, Hanna WM : Ultrastructure of the esophagus in scleroderma. Arthritis Rheum 25:1117-1123, 1982 41. Bortolotti M, Pinotti R, Sarti P, Barbara L: Esophageal electromyography in scleroderma patients with functional dysphagia. Am J Gastroentero184 :1497-1502 42. Clouse RE: Esophageal diseases caused by infection, systemic illness, and trauma. In Sleisenger MH, Fordtran JS (eds): Gastrointestinal Disease. Pathophysiology, Diagnosis, Management, 4th ed. Philadelphia: WB Saunders, 1989, pp 640-651 43. Petrokubi R J, Jeffries GH: Cimetidine versus antacid in scleroderma with reflux esophagitis. A randomized doubleblind controlled study. Gastroenderology 77: 691-695, 1979 44. Hendel L, Aggestrup S, Stentoft P: Long-term ranitidine in progressive systemic sclerosis (scleroderma) with gastroesophageal reflux. Scand J Gastroentero121 : 799-805, 1986
S.R. Fulp and D.O. Castell: Scleroderma Esophagus 45. Hetzel D J, Dent J, Reed WD, et al: Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 95: 903-912, 1988 46. Klinkenberg-Knol EC, Jansen JMBJ, Festen HPM, Meuwissen SGM, Lamers CBHW: Double blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux esophagitis. Lancet !: 349-351, 1987 47. Ramirez-Mata M, Ibanez G, Alarcon-Segovia D: Stimulatory effect of metoclopramide on the esophagus and lower esophageal sphincter of patients with PSS. Arthritis Rheum 20:30-34, 1977 48. Henderson RD, Pearson FG: Surgical management of esophageal scleroderma. J Thorac Cardiovasc Surg 66:686-692, 1973 49. Orringer MB: Surgical management of scleroderma reflux esophgitis. Surg Clin North Am 63:859-867, 1983 50. Brain RHF. Surgical management of hiatal herniae and oesophageal strictures in systemic sclerosis. Thorax 28: 515-520, 1973 51. McLaughlin JS, Roig R, Woodruff MFA: Surgical treatment of strictures of the esophagus in patients with scleroderma. J Thorac Cardiooasc Surg 61:641-645, 1971 52. Mansour KA, Malone CE: Surgery for scleroderma of the esophagus: a 12-year experience. Ann Thorac Surg 46:513-514, 1988
Dysphagia g) S p r i n g e r - V e r l a g N e w Y o r k I nc. 19tJI)
Scleroderma Esophagus Sam R. Fulp, M.D. t and Donald O. Castell, M . D . 2 Bowman Gray School of Medicine, Winston-Salem, North Carolina, and 2 Thomas Jefferson University Philadelphia, Pennsylvania, USA
Abstract. Scleroderma (systemic sclerosis) is a connective tissue disorder characterized by thickening and fibrosis of the skin and visceral involvement that may include the heart, lungs, kidneys, and gastrointestinal tract. At least 40-50% of patients with scleroderma experience esophageal symptoms such as heartburn and dysphagia, while up to 90% of patients have esophageal dysfunction on objective testing at some point in their disease. The disease results in smooth muscle dysfunction that causes esophageal aperistalsis and reduced lower esophageal sphincter pressures. Gastroesophageal reflux with poor acid clearance results with an increased incidence of complications such as peptic stricture and Barrett's esophagus. Aggressive medical therapy is necessary to prevent these and other complications of gastroesophageal reflux. Key words: Deglutition disorders - Scleroderma - Systemic sclerosis - Sclerosis, esophagus Gastroesophageal reflux.
tinal tract is the third most common manifestation of scleroderma, following only sclerodermatous skin change and Raynaud's phenomenon [1]. The CREST syndrome is a form of systemic sclerosis in which there is relatively limited involvement of the skin, prominence of calcinosis, Raynaud's phenomenon, esophageal dysfunction, sclerodactyly, and telangiectasia. This subset of scleroderma is characterized by limited visceral involvement, an excellent prognosis, and a high incidence of positive anticentromere antibodies [7-9]. In a recent carefully matched comparison between patients with scleroderma and CREST, incidence of upper gastrointestinal involvement did not differ between patients in the two groups [10]. In this review, an illustrative case presentation will be followed by a summary of the clinical manifestations, pathophysiology, and treatment of esophageal scleroderma.
Case Report
Systemic sclerosis (scleroderma) is a generalized connective tissue disorder characterized by thickening and fibrosis of the skin and by distinctive forms of involvement in internal organs including the heart, lungs, kidneys, synovium, esophagus, and intestine [1]. The esophagus is involved in 55-90% of patients with scleroderma by manometric or radiographic criteria [2-5], while evidence of esophageal disease at autopsy has been found in up to 74% of those patients with typical skin manifestations [6]. Involvement of the gastrointesAddress reprint requests to. Donald O. Castell, M.D., Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA
A 51-year-old woman was referred for evaluation of dysphagia. Heartburn and regurgitation had been present for approximately 10 years. The patient had noted dysphagia to solids for the past 2 years, which had responded temporarily to bougie dilatation and treatment with histamine receptor antagonists. She admitted to intermittent joint stiffness and Raynaud's phenomenon for 2-3 years. Physical examination showed a healthy-appearing woman in no acute distress. She had mild cyanosis of the fingers, and the skin of the hands was tight and edematous. Joints were nontender with full range of motion. Physical examination was otherwise normal. Barium swallow showed a dilated, aperistaltic esophagus below the aortic arch and a distal esophageal stricture, Frcc reflux of barium was noted into the proximal esophagus (Fig. 1). Esophagoscopy showed distal ulcerative esophagitis (Fig. 2) and a stricture. A 60 Fr dilator was passed into the stomach with minimal resistance. Esophageal manometry showed aperistalsis and hypotensive lower esophageal spincter (Fig. 3). The esophageal findings were thought to be consistent
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Fig. I. A An air contrast barium radiograph of the esophagus. A stricture is seen (arrow) in the lower esophagus below a dilated segment of esophagus. B An upright radiograph of the esophagus taken after A. Refluxcd barium is seen along the full length of the esophagus, and the stricture is seen just proximal to a hiatal hernia.
with scleroderma. Rheumatoid factor was positive at 1 : 160 and antinuclear antibody was positive at 1:400 (speckled). Rheumatologic consultation confirmed the clinical diagnosis of systemic sclerosis with involvement of the skin and esophagus.
Symptoms The most common esophageal symptoms in patients with scleroderma are heartburn, regurgitation, and dysphagia. Dysphagia can result from either a peptic stricture or disturbed esophageal peristalsis [2]. Heartburn is a prominent symptom, described as a burning retrosternal pain radiating
toward the pharynx. This may be associated with sour or bitter regurgitation. Heartburn and regurgitation are due to gastroesophageai reflux [11]. Two large series found that esophageal symptoms are present at some point in 42-84% of patients with scleroderma [12, 13]. Raynaud's phenomenon is the clinical feature that correlates most closely with esophageal dysfunction in scleroderma [3]. Physical examination often shows typical skin findings of scleroderma, but none of the physical findings are specific for esophageal disease. Plain films of the chest can show evidence of esophageal involvement in scleroderma. Incompe-
206
S.R. Fulp and D.O, Castell: Scleroderma Esophagus
Fig. 2. Normal squamous esophageal mucosa to the left of the slide with an ulcer bed to the right, with overlying granulation tissue. Polymorphonuclear exudate can be seen in the lower right hand corner and in the granulation tissue. (Tissue obtained from endoscopic biopsy.)
tence of the lower esophageal sphincter (LES) can result in an air-filled esophagus that may be superimposed on a background of pulmonary fibrosis [14]. Barium swallow in patients with scleroderma may show mild to moderate degrees of dilatation, diminished or absent distal peristalsis, and a widely patulous gastroesophageal junction. Frequently esophagitis and/or an esophageal stricture can be seen [15]. Endoscopy is useful in the evaluation of mucosal changes that result from gastroesophageal reflux. These changes may include esophagitis or more complicated esophageal diseases such as peptic stricture, Barrett's epithelium, or carcinoma. Esophageal manometry shows evidence of esophageal dysfunction in up to 90% of patients with systemic sclerosis [5, 16]. The manometric abnormalities are often among the earliest findings in scleroderma [17, 18] and are more prevalent than symptoms of esophageal dysfunction. The two characteristic manometric abnormalities illustrate smooth muscle dysfunction: low-amplitude or absent esophageal contractions in the distal esophagus, and low to absent LES pressure [2]. These changes have been shown to be nonspecific, having been described in patients with systemic lupus er-
Fig. 3. A A slow pull-through of the lower esophageal sphincter. The lower esophageal sphincter has a very low pressure (4 mmHg) as measured at the pressure inversion point (PIP), which lies at the diaphragmatic hiatus. B Two wet swallows (WS) with the manometric catheter anchored 3 cm above the LES. In the top panel, normal pressures are generated by striated muscle 18 cm above the LES. A weak nonperistaltic response is seen distally in the smooth muscle portion of the esophagus.
ythematosus, polymyositis, dermatomyositis, rheumatoid arthritis, psoriatic arthritis, polyarteritis nodosa, Raynaud's disease, and mixed connective tissue disease [3, 19, 20]. The typical manometric changes have also been reported in patients who had no sign of rheumatic disease [21]. Radionuclide esophageal scintigraphy is not generally utilized in the evaluation of esophageal
S.R. Fulp and D.O. Castell: Scleroderma Esophagus
dysfunction in patients with scleroderma. However, scintigraphy has been shown to be as sensitive as manometry in detecting esophageal dysfunction in a prospective study of 11 patients [22]. Delayed esophageal emptying is seen in scleroderma, but this is a nonspecific finding. Proponents of scintigraphy point out its superior sensitivity compared to radiography and its superior patient acceptance compared to manometry.
Diagnosis Although systemic sclerosis is a clinical diagnosis, the American Rheumatism Association has proposed preliminary criteria for the classification of systemic sclerosis based on a multicenter study of 797 patients. The criteria have been useful in ensuring uniformity of clinical research, and the diagnosis requires the finding of either the sole major criterion or two of the minor criteria. The major criterion is proximal scleroderma (tightness, thickening, and nonpitting induration of the skin proximal to the metacarpophalangeal or metatarsophalangeal joints). Minor criteria include sclerodactyly, digital pitting scars of fingertips or loss of substance of the distal finger pad, and bilateral basilar pulmonary fibrosis. Notably absent from this list is esophageal dysfunction because of its lack of specificity [23]. However, the presence of typical esophageal changes on barium swallow or manometry may be very helpful in leading to a clinical diagnosis of systemic sclerosis, as it did in our case.
Complications Complications of esophageal disease associated with systemic sclerosis includes peptic stricture, Barrett's epithelium, and ulcerative esophagitis. Pulmonary aspiration and esophageal candidiasis may also occur. Peptic stricture in systemic sclerosis may be heralded by dysphagia to solid food, This may occur in the presence or absence of reflux symptoms [2]. Benign peptic stricture has been seen in up to 40% of patients with scleroderma [24], while only 11% of patients with gastroesophageal reflux disease (without scleroderma) in one series had a peptic stricture [25]. Barrett's esophagus in scleroderma has only recently been described. It was reported first by Cameron and Payne [26] in 1978, and there have been several reports since then [27 35]. Halpert and colleagues reported esophageal adenocarcinoma in
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three patients with Barrett's epithelium and scleroderma in 1983 [27]. Since then there have been several reports of esophageal adenocarcinomas arising in Barrett's epithelium in patients with scleroderma [28 30]. The prevalence of Barrett's esophagus in scleroderma is unknown, but a large series of symptomatic patients with scleroderma who underwent endoscopy showed that 37% of the patients had biopsy-proven Barrett's esophagus, with 20% of those patients with Barrett's also having adenocarcinoma [28]. Ulcerative esophagitis is another example of complicated esophageal disease due to gastroesophageal reflux from scleroderma. This may coexist with Barrett's epithelium, as first reported by Cameron and Payne in 1978 [26] and later reported by others [31-35]. Ulcerative esophagitis may also occur without Barrett's epithelium as seen in our illustrative case. Chronic pulmonary aspiration of gastroesophageal contents due to reflux has been suggested as a contributing cause of pulmonary disease in scleroderma. In a recent study [36] of 13 patients with scleroderma, 85% had proximal esophagitis, 92% had laryngeal changes suggestive of aspiration, and 15% had a positive "aspiration scan." A positive "aspiration scan" consisted of delayed radioisotope activity over the lateral thoracic area following an oral meal containing [99mTC]suifur colloid. Esophageal candidiasis has been noted to be a common occurrence in patients with scleroderma [11, 37]. In a recent controlled study of 48 consecutive patients with scleroderma, 44% had candidiasis diagnosed by esophageal mucosal brushing, a higher rate than patients without scleroderma with and without reflux in the same study [38].
Pathophysiology The pathogenesis of esophageal dysfunction in systemic sclerosis is incompletely understood, The prominent lesion at autopsy is atrophy of the smooth muscle in the muscularis propria and one or both muscle layers. Also noted is mildly increased fibrosis and collagen deposition in the lamina propria and submucosa, and thinning or erosion of the mucosa. However, the myenteric plexus and skeletal muscle appear normal [6, 18, 39]. In early scleroderma, motility studies have shown altered esophageal motility in the presence of normal esophageal smooth muscle at autopsy [39]. Some patients with scleroderma have a preserved re-
208 sponse to muscle stimulants but not to agents requiting intact cholinergic innervation, suggesting a primary neuronal defect early in the disease course [17]. While motility studies suggest that disordered neural function precedes smooth muscle atrophy, ultrastructural and light microscopic studies have failed to give morphologic supporting evidence [18, 40]. Recent work with esophageal electromyography suggests that disordered myoelectric hyperactivity occurs early in scleroderma, while a marked decrease in myoelectric activity may occur later in scleroderma [41]. It has been suggested that impaired perfusion from the nutritive vasculature and microvascular disruption contribute to the pathogenesis, first as disordered myoelectric function and later as smooth muscle atrophy [1]. These aforementioned pathologic changes produce decreased or absent lower esophageal peristalsis with lower esophageal sphincter incompetence. These defects in smooth muscle function lead to reflux of gastric contents into the esophagus with impaired acid clearance. With these pathogenetic factors being important, 60% of patients develop erosive esophagitis [37] and other complications. Treatment
There are n o pharmacologic treatments of proven value in the management of systemic sclerosis [I]. Therapy cannot reverse the motor findings in scleroderma and should be directed toward preventing and treating reflux esophagitis and its complications [42]. Histamine receptor antagonists have been found to be useful in treating the manifestations of gastroesophageal reflux associated with scleroderma. Cimetidine has been shown to be significantly more effective than antacids in relieving heartburn and healing endoscopically documented esophagitis [43]. However, prolonged therapy with 1200 mg/day may be required to maintain improvement in some patients [37]. Ranitidine has also been shown to improve symptoms and heal endoscopically proven esophagitis, but chronic therapy must be utilized to maintain improvement [44]. However, neither drug improved motility or altered stricture size. Omeprazole, a hydrogen/potassium ATPase blocker in the parietal cell was approved by the Food and Drug Administration in 1989 for use in the short-term (less than 2 months) treatment of reflux esophagitis. Omeprazole has been consistently superior to placebo and conventional doses of histamine antagonists
S.R. Fulp and D.O. Castell: SclerodermaEsophagus in relieving reflux symptoms and in healing endoscopic esophagitis [45, 46]. Since omeprazole is extremely effective in treating reflux esophagitis, it will presumably be helpful in treating reflux esophagitis associated with scleroderma. It would be reasonable to recommend omeprazole in the shortterm treatment of reflux disease associated with scleroderma not controlled by histamine antagonists. Occasionally patients with scleroderma may benefit from the motility-enhancing effects of metoclopramide [47]. Lifestyle modifications should be tried such as elevation of the head of the bed, and avoidance of cigarette smoking, fatty foods, chocolate, and large meals shortly before bedtime. Dysphagia can be minimized by careful mastication of small quantities of food [1]. Refractory dysphagia is suggestive of a peptic stricture that requires mechanical dilatation. Once formed, a peptic stricture may require repeated bougie dilatation. For patients in whom medical therapy is not successful, antireflux surgery must be carefully considered. Fundoplication can exacerbate dysphagia significantly, so it is generally discouraged. Good results have been reported with antireflux procedures in scleroderma by Henderson and Pearson [48] as well as by Orringer and associates [49]. However, follow-up was relatively short, averaging 131/2 and 47 months, respectively. Orringer recommended a loose fundoplication around a 46 Fr bougie. Good results have also been reported with esophageal resection and bowel replacement [50-52]. In a recent surgical series with endoscopic follow-up of up to 12 years following surgery, there was a 100% rate of recurrence of endoscopic esophagitis following antireflux procedures, but good results were noted in three patients who underwent partial esophagectomy and short-segment colon interposition for severe stricture [52]. Barrett's esophagus in scleroderma requires surveillance for possible dysplasia and esophageal adenocarcinoma. Conclusions
This article has described the clinical, radiographic, and manometric manifestations of esophageal scleroderma. In addition, the diagnosis, complications, pathophysiology, and treatment of scleroderma (systemic sclerosis) are discussed. Esophageal dysfunction occurs in up to 90% of patients with scleroderma. The primary defect is smooth muscle dysfunction, eventually causing aperistalsis and an incompetent lower esophageal sphincter. This results in gastroesophageal reflux
S.R. Fulp and D.O. Castell: Scleroderma Esophagus
with a high incidence of severe esophagitis, stricture, and Barrett's esophagus. However, these findings are not specific for systemic sclerosis and are found in many other collagen vascular diseases. Treatment is largely medical and should be directed at prevention of complications of gastroesophageal reflux. Surgical therapy is generally reserved for severe symptomatic or complicated reflux esophagitis. Acknowledgments. The authors wish to thank Wain White, M.D., for the photomicrograph, David Ott, M.D., for the radiographs, and Christine Dalton, P.A.-C., for the manometric tracings.
References 1. Seibold JR: Scleroderma. In Kelly WN, Harris ED, Ruddy S, Sledge CB (eds): Textbook ofRheumatology, 3rd ed. Philadelphia: WB Saunders, 1989, pp 1215-1244 2. Turner R, Lipshutz W, Miller W, Rittenberg G, Schumaker HR, Cohen S: Esophageal dysfunction in collagen disease. Am J Med Sci 265:191-199, 1973 3. Stevens MB, Hookman P, Siegel CI, Esterly JR, Shulman LE, Hendrix TR: Aperistalsis of the esphagus in patients with connective tissue disorders and Raynaud's phenomenon. N Engl J Med 270:1218-1222, 1964 4. Clements PJ, Kadell B, Ippoliti A, Ross M" Esophageal motility in progressive systemic sclerosis (PSS). Comparison of cine-radiographic and manometric evaluation. Dig Dis Sci 24:639-644, 1979 5. Poirier TJ, Rankin GB: Gastrointestinal manifestations of progressive systemic scleroderma based on a review of 364 cases. Am J Gastroentero158 : 30-44, 1972 6. D'Angelo WA, Fries J, Masi AT, Shulman LE: Pathologic observations in systemic sclerosis (scleroderma). Am J Med 46:428-440, 1969 7. Rodnan GP, Medsger TA, Buckingham RB." Progressive systemic sclerosis-crest syndrome: observations on natural history and late complications in 90 patients. Arthritis Rheum 18:423, 1975 (abstract) 8. Carr RD, Heisel EB, Stevenson TD: CREST syndrome. A benign variant of scleroderma. Arch Dermatol 92: 519-525, 1965 9. Fritzler M J, Kinsella TD, Garbutt E: The CREST syndrome: a distinct serologic entity with anticentromere antibodies. Am J Med 69: 520-526, 1980 10. Furst DE, Clements PJ, Saab M, Sterz MG, Paulus HE: 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 43:794-801, 1984 I I. Cohen S, Laufer I, Snape WJ, Shiau YF, Levine GM, Jimenez S: The gastrointestinal manifestations of scleroderma: pathogenesis and management. Gastroenterology 79:155-166, 1980 12. Tuffanelli DL, Winkelmann RK: Systemic scleroderma. A clinical sutdy of 727 cases. Arch Dermato184: 359-371, 1961 13. Henderson RD: Esophageal motor disorders. Surg Clin North Am 67:455--474, 1987 14. Dinsmore RE, Goodman D, Dreyfuss JR: The air esophagram: a sign of scleroderma involving the esophagus. Radiology 87: 348-349, 1966 15. Lorber SH, Zarafonetis CJD: Esophageal transit studies in scleroderma. Am J Med Sci 245: 654-667, 1963
209 16. Weihrauch TR, Korting GW, Ewe K, Vogt G: Esophageal dysfunction and its pathogenesis in progressive systemic sclerosis. Klin Wochenschr 56:963-968, 1978 17. Cohen S, Fisher R, Lipshutz W, Turner R, Myers A, Schumacher R: The pathogenesis of esophageal dysfunction in scleroderma and Raynaud's disease. J Clin Invest 51 : 2663-2668, 1972 18. Atkinson M, Summerling MD: Oesophageal changes in systemic sclerosis. Gut 7:402-408, 1966 19. DeMerieux P, Verity A, Clements PJ, Paulus HE: Esophageal abnormalities and dysphagia in polymyositis and dermatomyositis. Clinical, radiologic, and pathologic features. Arthritis Rheum 26:961-968, 1983 20. Gutierrez F, Valenzuela dE, Ehresmann GR, Quismorio FP, Kitridou RC: Esophageal dysfunction in patients with mixed connective tissue diseases and systemic lupus erythematosus. Dig Dis Sci 27:592-597, 1982 21. Schneider HA, Yonger RA, Longley S, Katz P, Mathias J, Panush RS: Scleroderma esophagus: a non-specific entity. Ann lntern Med 100:848-850, 1984 22. Drane WE, Karvelis K, Johnson DA, Curran JJ, Silverman ED: Progressive systemic sclerosis: radionuclide esophageal scintigraphy and manometry. Radiology 160: 73-76, 1986 23. Subcommittee for Scleroderma Criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee: Preliminary criteria for the classification of systemic sclerosis (scleroderma). Arthritis Rheum 23: 581-590, 1980 24. Cohen S: Motor disorders of the esophagus. N Engl J Med 301:184-192, 1979 25. Palmer ED: Subacute erosive ("peptic") esophagitis. Clinical study of one hundred cases. Arch Intern Med 94: 364-374, 1954 26. Cameron AJ, Payne W$: Barrett's esophagus occurring as a complication of scleroderma. Mayo Clin Proc 53:612-615, 1978 27. Halpert RD, Laufer I, Thomspon JJ, Feczko PJ : Adenocarcinoma of the esophagus in patients with scleroderma. AJR 140:927-930, 1983 28. Recht MP, Levine MS, Katzka DA, Reynolds JC, Sail SH : Barrett's esophagus in scleroderma: increased prevalence and radiographic findings. Gastrointest Radiol 13:1-5, 1988 29. Niv Y, Abu-Avid S, Yelin A, Liberman Y" Barrett's epithelium and esophageal adenocarcinoma in scleroderma. Am J Gastroentero183: 792-793, 1988 30. McKinley M, Sherlock P: Barrett's esophagus with adenocarcinoma in scleroderma. Am .I Gastroenterol 79: 438--439, 1984 31. Dill dE: Barrett's epithelium in scleroderma. Gastrointest Endosc 29:296-297, 1983 32. Sprung D J, Gibb SP: Dysplastic Barrett's esophagus in scleroderma. Am J Gastroenter o180 : 518-522, 1985 33. Agha FP, Dabich L: Barrett's esophagus complicating scleroderma. Gastrointest Radiol 10: 325-329, 1985 34. Anderson M, Seymour EQ: Association of Barrett's esophagus and scleroderma. South Med J 80: 764-765, 1987 35. Katzka DA, Reynolds JC, Saul SH: Barrett's metaplasia and adenocarcinoma of the esophagus in scleroderma. Am J Med 82:46-52, 1987 36. Johnson DA, Drane WE, Curran J, et al.: Pulmonary disease in progressive systemic sclerosis. A complication of gastroesophageal reflux and occult aspiration? Arch Intern Med 149:589-593, 1989 37. Zamost BJ, Hirschberg J, Ippoliti AF, et al.: Esophagitis in scleroderma - prevalence and risk factors. Gastroenterology 92:421-428, 1987
210 38. Hendel L, Svejgaard E, Walsoe I, Kieffer M, Stenderup A: Esophageal candidosis in progressive systemic sclerosis: occurrence, significance, and treatment with flueonazole. Scand J Gastroentero123 :1182-1186, 1988 39. Treacy WL, Baggenstoss AH, Slocumb CH, Code CF'. Scleroderma of the esophagus. A correlation of histologic and physiologic findings. Ann lntern Med 59:351-356, 1963 40. Russell ML, Friesen D, Henderson RD, Hanna WM : Ultrastructure of the esophagus in scleroderma. Arthritis Rheum 25:1117-1123, 1982 41. Bortolotti M, Pinotti R, Sarti P, Barbara L: Esophageal electromyography in scleroderma patients with functional dysphagia. Am J Gastroentero184 :1497-1502 42. Clouse RE: Esophageal diseases caused by infection, systemic illness, and trauma. In Sleisenger MH, Fordtran JS (eds): Gastrointestinal Disease. Pathophysiology, Diagnosis, Management, 4th ed. Philadelphia: WB Saunders, 1989, pp 640-651 43. Petrokubi R J, Jeffries GH: Cimetidine versus antacid in scleroderma with reflux esophagitis. A randomized doubleblind controlled study. Gastroenderology 77: 691-695, 1979 44. Hendel L, Aggestrup S, Stentoft P: Long-term ranitidine in progressive systemic sclerosis (scleroderma) with gastroesophageal reflux. Scand J Gastroentero121 : 799-805, 1986
S.R. Fulp and D.O. Castell: Scleroderma Esophagus 45. Hetzel D J, Dent J, Reed WD, et al: Healing and relapse of severe peptic esophagitis after treatment with omeprazole. Gastroenterology 95: 903-912, 1988 46. Klinkenberg-Knol EC, Jansen JMBJ, Festen HPM, Meuwissen SGM, Lamers CBHW: Double blind multicentre comparison of omeprazole and ranitidine in the treatment of reflux esophagitis. Lancet !: 349-351, 1987 47. Ramirez-Mata M, Ibanez G, Alarcon-Segovia D: Stimulatory effect of metoclopramide on the esophagus and lower esophageal sphincter of patients with PSS. Arthritis Rheum 20:30-34, 1977 48. Henderson RD, Pearson FG: Surgical management of esophageal scleroderma. J Thorac Cardiovasc Surg 66:686-692, 1973 49. Orringer MB: Surgical management of scleroderma reflux esophgitis. Surg Clin North Am 63:859-867, 1983 50. Brain RHF. Surgical management of hiatal herniae and oesophageal strictures in systemic sclerosis. Thorax 28: 515-520, 1973 51. McLaughlin JS, Roig R, Woodruff MFA: Surgical treatment of strictures of the esophagus in patients with scleroderma. J Thorac Cardiooasc Surg 61:641-645, 1971 52. Mansour KA, Malone CE: Surgery for scleroderma of the esophagus: a 12-year experience. Ann Thorac Surg 46:513-514, 1988
