The frequency of esophageal involvement in patients with mixed connective tissue disease.
Dysphagia is one of the symptoms in patients with connective tissue diseases (CTDs), although it is not directly fatal and is a frequent complication. The frequency of esophageal dysmotility is 46-92%, 30-88%, 21-72%, and 50% in patients with systemic sclerosis (SSc), mixed connective tissue disease (MCTD), systemic lupus erythematosis (SLE), and polymyositis/dermatomyositis (PM/DM), respectively [1-8]. While the cause of esophageal dysfunction in patients with CTDs has been unclear, there are some reports that suggest the accumulation of extracellular matrix, neuropathy, and autoantibody as the cause of esophageal dysfunction in patients with SSc [9-11]. On the other hand, there are few reports relating to the cause of esophageal dysfunction in MCTD patients, despite its frequency. Therefore, we examined the histopathological characteristics of esophageal lesions in MCTD patients using 27 autopsy cases in Japan .
2. Histopathological analysis of esophagus in MCTD patients
2.1. Comparison between changes in the upper, middle, and lower portion of the esophagus.
To date, there have been studies demonstrating a high frequency of esophageal symptoms in patients with MCTD [1-7,13] (Table 1). In our study, evidence of histological changes was found in 25 of the 27 cases examined (91%). The differences may be due to differences in the method of measurement. Esophageal dysmotility in MCTD patients is sometimes associated with the dilatation of the distal esophagus (Figure 1). The main sites of esophageal change were generally different between CTDs . In patients with SSc and MCTD, the lower portion of the esophagus changes histologically. Therefore, we examined 3 different regions of the esophagus, which we defined as follows: 1) upper, at the height of the ring around the cartilage of the trachea; 2) middle, at the height of the bifurcation of the trachea; and 3) lower, just above the esophago-cardiac junction. We compared histological changes for each portion. Of 12 cases examined, 9 showed slight to severe changes in the lower portion, 3 showed slight to severe changes in the middle portion, and none showed histopathological changes in the upper portion. According to these results, the lower portion was involved in many cases of MCTD.
||8/17 (47.1%)||Bennett (1980) |
||11/17 (64.7 %)||Gutierrez (1982) |
|• Heartburn||10/17 (58.8%)|
|• Regurgitation||6/17 (35.3%)|
|• Dysphagia||1/17 (5.9%)|
||Dantas (1985) |
|• Dysphagia||6/12 (50%)|
||Marshall (1990) |
|• Heartburn or regurgitation||29/61 (47.5%)|
|• Dysphagia||23/61 (37.7%)|
||14/21 (66.6%)||Doria (1991) |
|• Heartburn||5/21 (23.8%)|
|• Regurgitation||5/21 (23.8%)|
||15/17 (88.2%)||Lapadula (1994) |
||10/18 (55.6%)||Rayes (2002) |
||Calerio (2006) |
|• Heartburn||9/24 (37.5%)|
|• Dysphagia||18/24 (75%)|
2.2. Comparison between changes in the inner circular muscular layer and outer longitudinal muscular layer of the esophagus
As regards histological changes in the muscular layers, the inner circular muscular layer (IM) exhibited more severe changes than the outer longitudinal muscular layer (OM) in 17 of 27 cases (63%). Eight cases (30%) showed similar changes. Two cases (7%) showed no pathological changes in either IM or OM, and no cases (0%) showed more severe involvement of OM than IM. Muscular dynamisms of IM and OM in esophageal motility are different. The IM is fairly active and subject to greater stress than the OM . Furthermore, esophageal regurgitation often occurs and exerts direct effects on the IM, particularly in the lower esophagus. Thus the IM in the lower portion may carry a larger physical stress than the OM. Therefore, more severe histological changes may occur in the IM of the lower portion than in the OM.
2.3. Cellular and tissue change
In our study, the most striking change of the esophagus in MCTD was severe atrophy and occasional disappearance of muscular fibers followed by fibrosis in muscular layer (Figure 2). In contrast to smooth muscle, however, striated muscle of the upper esophageal portion exhibited no marked changes. Similar histopathological changes occur in SSc [15,16]. In SSc patients, histological features are also characterized by degeneration and disappearance of smooth muscle cells with fibrosis, especially in the IM of the lower portion . In our study, ganglionic cells had not decreased in number and were not particularly atrophic except in severely fibrotic areas. Vascular changes were also not overly severe in non-fibrotic regions, although slight intimal thickening of small vessels was sporadically found in the fibrotic area. The vein wall was injured and smooth muscle cell disruption and inflammatory cell invasion were observed (Figure 3).
2.4. Pathogenesis of esophageal lesions
The factors that seem to be associated with esophageal dysfunction have been reported in some studies, and include extracellular matrix degradation, disorder of blood circulation, and autoantibodies [10,18-20]. Our hypothesis was that autoantibodies are associated with the pathogenesis of esophageal lesions. In immunohistochemical studies, anti-human IgG and anti-C3 antibodies reacted positively with muscle tissues showing a myolytic appearance accompanied by edema and inflammatory cell infiltration in MCTD autopsy case (Figures 4). No IgM deposition was found (Figure 4). The reactivity of IgG extracted from sera of MCTD patients against normal esophageal tissues was then assessed. Esophageal tissues used here were non-cancerous parts taken intraoperatively from esophageal cancer patients without specific immunological disorder. The IgG reacted with smooth muscle cells in the muscularis mucosa, muscular layer and venous wall, the ganglion cells in Auerbach’s plexus, and squamous epithelium of the esophagus (Figure 5), but did not react with striated muscle in upper portion (Figure 5 A,B). IgG from MCTD patients also reacted with primary-cultured smooth muscle cells prepared from surgical specimens of esophagus (unpublished data) (Figure 6). These results suggested that antibodies in the serum of patients with MCTD attack smooth muscle tissues as well as other tissues of the esophagus.
Histopathological features of the esophagus in SSc and MCTD patients are similar, but muscular change in SSc is more progressive than in MCTD patients in our study. It has been suggested that there is no association between manometric abnormality and cutaneous symptoms in MCTD patients, and the characteristics of SSc are not always linked to esophageal dysfunction . The pathological mechanism of esophageal dysfunction in MCTD may be similar but not always identical to that in SSc.
In patients with CTDs, autoimmune inflammation occurs in systemic organs such as kidney, lung, skin and blood vessels, and so on. The gastrointestinal tract is also involved though the histological features and grades are different from disease to disease even in the same CTD.
In CTDs, many kinds of autoantibodies may play an important role in causing the various symptoms and diseases, whether they are fatal or not. These differ from disease to disease and from tissue to tissue. We showed that IgG from MCTD patients reacts to various tissues such as kidney and lung (unpublished data) (Figure 7). It is well known that pulmonary hypertension is the fatal cause of MCTD. Anti-endothelial cell antibody (AECA) was identified in the serum of MCTD patients, and was especially high in patients with pulmonary hypertension . We now examine the antigen of AECA in endothelial cells of small pulmonary vascular vessels . As for the autoantibody of MCTD against esophagus, our study revealed that IgG extracted from MCTD patients showed a positive immunohistochemical reaction not only for the smooth muscle cells of esophagus, but also for the ganglion cells in Auerbach’s plexus, the vascular walls in esophageal muscular tissues, and squamous epithelium of the esophagus. Dysphagia in MCTD and SSc patients may be one of the symptoms often occurring as an autoimmune reaction.
The reason why the inner layer of the lower portion incurs more severe damage than other portions has not been clarified. Esophageal manometry shows that this portion sustains more intense mechanical stress in peristalsis than the outer layer or upper portions. Thus autoantibodies, mechanical stress and regurgitation may induce the severe dysphagia in MCTD and other CTDs.
Motility dysfunction is not a direct cause of death, but a strong association between esophageal dysmotility and interstitial lung disease in patients with MCTD is indicated . Therefore, care must be taken with diagnosis.
This research was partly supported by a Grant-in-Aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan.
Bennett RM, O'Connell DJ. Mixed connective tissue disease: a clinicopathologic study of 20 cases. Semin Arthritis Rheum. 1980;10(1):25-51.
Gutierrez F, Valenzuela JE, Ehresmann GR, Quismorio FP, Kitridou RC. Esophageal dysfunction in patients with mixed connective tissue diseases and systemic lupus erythematosus. Dig Dis Sci. 1982;27(7):592-7.
Dantas RO, Villanova MG, de Godoy RA. Esophageal dysfunction in patients with progressive systemic sclerosis and mixed connective tissue diseases. Arq Gastroenterol. 1985;22(3):122-6.
Marshall JB, Kretschmar JM, Gerhardt DC, Winship DH, Winn D, Treadwell EL, et al. Gastrointestinal manifestations of mixed connective tissue disease. Gastroenterology. 1990;98(5 Pt 1):1232-8.
Doria A, Bonavina L, Anselmino M, Ruffatti A, Favaretto M, Gambari P, et al. Esophageal involvement in mixed connective tissue disease. J Rheumatol. 1991;18(5):685-90.
Lapadula G, Muolo P, Semeraro F, Covelli M, Brindicci D, Cuccorese G, et al. Esophageal motility disorders in the rheumatic diseases: a review of 150 patients. Clin Exp Rheumatol. 1994 Sep-Oct;12(5):515-21.
Rayes HA, Al-Sheikh A, Al Dalaan A, Al Saleh S. Mixed connective tissue disease: the King Faisal Specialist Hospital experience. Ann Saudi Med. 2002;22(1-2):43-6.
Sheehan NJ. Dysphagia and other manifestations of oesophageal involvement in the musculoskeletal diseases. Rheumatology (Oxford). 2008;47(6):746-52.
Hendel L, Ammitzbøll T, Dirksen K, Petri M. Collagen in the esophageal mucosa of patients with progressive systemic sclerosis (PSS). Acta Derm Venereol. 1984;64(6):480-4.
Stacher G, Merio R, Budka C, Schneider C, Smolen J, Tappeiner G. Cardiovascular autonomic function, autoantibodies, and esophageal motor activity in patients with systemic sclerosis and mixed connective tissue disease. J Rheumatol. 2000 Mar;27(3):692-7.
Zuber-Jerger I, Müller A, Kullmann F, Gelbmann CM, Endlicher E, Müller-Ladner U, et al. Gastrointestinal manifestation of systemic sclerosis--thickening of the upper gastrointestinal wall detected by endoscopic ultrasound is a valid sign. Rheumatology (Oxford). 2010;49(2):368-72.
Uzuki M, Kamataki A, Watanabe M, Sasaki N, Miura Y, Sawai T. Histological analysis of esophageal muscular layers from 27 autopsy cases with mixed connective tissue disease (MCTD). Pathol Res Pract. 2011;207(6):383-90.
Caleiro MT, Lage LV, Navarro-Rodriguez T, Bresser A, da Costa PA, Yoshinari NH. Radionuclide imaging for the assessment of esophageal motility disorders in mixed connective tissue disease patients: relation to pulmonary impairment. Dis Esophagus. 2006;19(5):394-400.
Bansal A, Kahrilas PJ. Has high-resolution manometry changed the approach to esophageal motility disorders? Curr Opin Gastroenterol. 2010;26(4):344-51.
Reynolds TB, Denison EK, Frankl HD, Lieberman FL, Peters RL. Primary biliary cirrhosis with scleroderma, Raynaud's phenomenon and telangiectasia. New syndrome. Am J Med. 1971;50(3):302-12.
Rohrmann CA Jr, Ricci MT, Krishnamurthy S, Schuffler MD. Radiologic and histologic differentiation of neuromuscular disorders of the gastrointestinal tract: visceral myopathies, visceral neuropathies, and progressive systemic sclerosis. AJR Am J Roentgenol. 1984;143(5):933-41.
Schneider HA, Yonker RA, Longley S, Katz P, Mathias J, Panush RS. Scleroderma esophagus: a nonspecific entity. Ann Intern Med. 1984;100(6):848-50.
Jinnin M, Ihn H, Yamane K, Asano Y, Yazawa N, Tamaki K. Serum levels of tissue inhibitor of metalloproteinases in patients with mixed connective tissue disease. Clin Exp Rheumatol. 2002;20(4):539-42.
Flick JA, Boyle JT, Tuchman DN, Athreya BH, Doughty RA. Esophageal motor abnormalities in children and adolescents with scleroderma and mixed connective tissue disease. Pediatrics. 1988;82(1):107-11
Takeda Y, Wang GS, Wang RJ, Anderson SK, Pettersson I, Amaki S, et al. Enzyme-linked immunosorbent assay using isolated (U) small nuclear ribonucleoprotein polypeptides as antigens to investigate the clinical significance of autoantibodies to these polypeptides. Clin Immunol Immunopathol. 1989;50(2):213-30.
Sasaki N, Kurose A, Inoue H, Sawai T. A possible role of anti-endothelial cell antibody in the sera of MCTD patients on pulmonary vascular damage relating to pulmonary hypertension. Ryumachi. 2002;42(6):885-94.
Kamataki A, Sasaki N, Hatakeyama A, Sawai T. Analysis of the serum reactivity against possible target proteins for anti-endotheial cell antibodies from sera of mixed connective tissue disease patients with pulmonary hypertension. Arth Rheum. 2007;56(9): S643
Fagundes MN, Caleiro MT, Navarro-Rodriguez T, Baldi BG, Kavakama J, Salge JM, et al. Esophageal involvement and interstitial lung disease in mixed connective tissue disease. Respir Med. 2009;103(6):854-60.