Assessment of Esophageal Dysmotility Disorder by High Resolution Manometry in Systemic Sclerosis: Association with Clinical Features

Keywords

High resolution esophageal manometry; Systemic sclerosis; Esophageal Dysmotility

Abstract

Aim of the Study: To find association between clinical features of systemic sclerosis and esophageal dysmotility disorder based on high resolution manometry (HRM) findings according to the 3rd version of Chicago classification.

Methods: In a cross-sectional study in Firozgar hospital we recruited 150 consecutive SSc patients. All patients fulfilled the 2013 ACR/EULAR classification for SSc criteria. We used water-perfused esophageal high resolution manometry (HRM) having 26-channel silicone-customized catheter.

Results: From all 150 SSc patients who were included in the study, forty-nine (46%) had dcSSc subset of disease with mean age (SD) 47.0 (12.1) years. According to the 3rd version of the Chicago classification, 135 (90%) patients had ineffective peristalsis [weak peristalsis in 24 (16.0%) and failed peristalsis in 111 (74.0%) of patients]. Hypotensive Esophagogastric junction pressure (hEGJP) presented in 47 (31.3%) patients. Two (1.3%) patients had achalasia in HRM. Age, gender, and duration of disease were not different in the above two groups of patients. In multivariate model FVC%, [OR (CI95%): 1.055(1.025-1.086), p<0.001] showed significant association with failed peristalsis.Comparison between average rank of FVC% in peristalsis status groups showed significant difference between average rank of FVC% in patients with failed peristalsis and weak peristalsis p=0.001, and average rank of FVC% in those with failed peristalsis and normal peristalsis p=0.020.

Conclusions: Our findings showed that esophageal dysmotility is a frequent finding in systemic sclerosis patients. The results demonstrated that FVC%, tendon friction rub kept significant concordance with failed peristalsis. Moreover, we noticed a concordance between HRM results and severity of FVC.

Citation

Poormoghim H, Dodangheh S, Yaseri HF, Jalali A and Andalib E. Assessment of Esophageal Dysmotility Disorder by High Resolution Manometry in Systemic Sclerosis: Association with Clinical Features. SM J Orthop. 2019; 5(1): 1067s.

Introduction

Systemic sclerosis, (SSc), is a chronic autoimmune systemic disease. Clinical features could be results of vascular obliteration, fibrosis in skin and different organs. The gastrointestinal tract (GIT) involvement is the most common visceral organ complication and has been reported in 90% in systemic sclerosis (SSc) [1,2].

Esophageal involvements may present as Gastro Esophageal Reflux Disease (GERD) symptoms (heart burn, substernal chest pain,dysphagea, chronic laryngitis, nocturnal cough,mouth ulcer and asthma) [3]. However, in some patients esophageal disordermanifestation may be asymptomatic [4]

It is postulated that pathologic mechanisms such as vascular injury, replacement of sub mucosal smooth muscle by collagen, smooth muscle atrophy andauto antibody (anti-muscarinic abs) production directed against enteric neuroncould lead to esophageal dysmotility in systemic sclerosis [2,5-8].

In systemic sclerosis High Resolution Manometry (HRM)considered as the most accurate tool. it is appliedto categorize esophageal motility disorders in patients with non-obstructive dysphagia and/or esophageal chest pain [9]. The characteristic HRM findings in SSc are failed peristalsis and hypotensive lower esophageal sphincter pressure [10,11].

Although there are a lot of studies that address associationbetween esophageal dysmotility andSSc disease manifestations, the results were inconsistent. In few studies patientswere enrolled based on ACR/EULAR 2013 classification criteria but usedthe 2nd version of Chicago classification for assessment of esophageal motility disorder [12-15].

The aims of this study were to find association between clinical features of systemic sclerosis, especially lung involvement and esophageal dysmotility disorder according to HRM findings.Moreover, we evaluated correlation between severity of pulmonary involvement and esophageal dysmotility.

Methods

In a cross-sectional study that we conducted in our hospital, 150 consecutive SSc patients were recruited into the study. The patients fulfilled the 2013 ACR/EULAR classification criteria [16]. According to skin involvement and its extension sub-classification of patients into limited cutaneous scleroderma (lcSSc), diffused cutaneous (dcSSc) [17] or sine scleroderma (sSSc) was performed. The study team conducted a throughout review of medical records for baseline and demographic data (age, duration of disease from time of diagnosis to the study) and auto-antibodies profiles through data bank. Besides, complete history, clinical examination, interview and esophageal manometry were performed in all participants. Pulmonary function tests and echocardiography data within three months to study were used. All patients completed a questionnaire on their symptoms which was adopted from study of Carla et al. [12] and UCLA-GIT 2 [3]. The interview includes clarifying questions on the followings: heart burn, dysphagia, bloating (to evaluate upper GIT symptoms and diarrhea), constipation and fecal soilage (to evaluate lower digestive symptoms).

Compliance with Ethical Standards

All procedures performed in this study were in accordance with the ethical standards of the institutional committee and in accord with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Informed consent was obtained from all individual participants included in the study.

Definition of organ system

Interstitiallung disease (ILD) defined as fibrosis or ground glass in high resolutionchest CT scan (HRCT) and and/or abnormal pulmonary function Test (PFT), forced vital capacity (FVC) percentage 0.8). Advanced lung involvement defined based on Goh classification [18]. Medsger severity score was used for classifying of FVC% in patients [19]. Pericardial effusion and ejection fraction < 50% in echocardiography as cardiac involvement [19].

Esophageal high-resolution manometry

All esophageal manometries were performed by one gastroenterologist. Esophageal manometry was carried out after 12 hours overnight fasting, in left lateral position by water-perfused esophageal high-resolution manometry (HRM) having 26-channel silicone-customized catheter (manufactured by Mui Scientific, Ontario, CA). Recorded data were analyzed by MMS software. HRM was performed according to the 3rd version of Chicago classification. A normal esophageal contraction wasreported when the Distal Contractile Integral (DCI) was > 450 and < 8000 mmhg.s.cm. Ineffective dysmotility reported failed when DCI< 100, weak when DIC> 100 < 450 mmhg.s.cm.

If DIC was > 8000 mmhg.s.cm the report indicated a hyper contractile contraction. A contraction that occurred by delay latency (DL) less than 4.5 second was considered as premature contraction. Type I achalasia was defined as failed peristalsis and IRP>15 mmhg.s.cm. Hypotensive Esophagogastric Junction pressure (hEGJP) was defined if mean resting pressure was less than 10mmHg.

Autoantibody testing

In order to detect antinuclear antibodies (ANA) we carried indirect immune-fluorescence technique (IIF) and Enzyme Linked Immunosorbent Assay (ELISA) for detecting Anti centromere (ACA), Anti-TOPO I antibodies (ATA). We used line immunoassay (Euroline systemic sclerosis profile (IgG), Euroimmune, Lubeck, Germany)

Statistical analysis

Descriptive statistics were used to describe the basic features of the data and when measuring normality and drawing of box plot. Chi square or fisher’s exact tests were performed to compare binary outcome variables and strength of association with failed esophageal peristalsis reported by odds ratio (OR) and 95% confidence interval (CI). The Mann-Whitney test was used for comparison of continuous variable in the absence of normality assumption. Significance level was taken as p≤0.05. Inferences about means of FVC% among HRM groups were made by Kruskal-Wallis. Pair wise analysis was performed and significant values have been adjusted by Bonferroni correlation for multiple tests.

Logistic regression analysis using backward method was performed to find out dependent clinical or para-clinical factors associated with failed peristalsis. Factors that showed significant correlation, p<0.05, in univariate analysis entered in model. All statistical tests were performed applying SPSS V.23 statistical package.

Results

Out of a total 150 patients included in the study, 132 (88%) were female. Sixty-eight (46%) patients had dcSSc subset of disease. Patients mean age was (SD) 47.0 (12.1) years at the time of study with mean disease duration of 81.8 (72.6) months (Table 1).

Table 1: Baseline, demographic and clinical features in 150 SSc patients.

Results of high resolution manometry (HRM)

According to 3rd version of Chicago classification 135 (90%) patients had ineffective peristalsis [weak peristalsis in 24 (16.0%) and failed peristalsis in 111 (74.0%) patients]. Hypotensive Esophagogastric Junction pressure (hEGJP) was noticed in 47 (31.3%) patients. Two (1.3%) patients had achalasia in HRM.

The GIT Symptoms that were reported in our patients include: heart burn and non-cardiac chest pain in 103 (68.7%), Dyspepsia in 43 (28.7%), and bloating in 81(54.0%). Heart burn was the most frequent GIT symptoms in our patients and more prevalent with failed peristalsis. Dysphasic symptom however, was most prevalent in patients with failed peristalsis prevalence of upper GIT symptoms and esophageal junction pressure was shown in Table 2.

Table 2: Prevalence of upper GI symptoms with results of high resolution manometry (HRM).

Association of clinical featuresand serological finding with failed peristalsis on HRM

Modified RodnanSkin Score (MRSS) was significantly higher in patients with failed peristalsis 10.84±8.45 than patients without failed peristalsis 7.28±7.58, [OR0.94, CI (0.89-0.99), p=0.03].

Patients with failed peristalsis had lower DLCO% 67.07±26.71 compared with those without failed peristalsis 80.49±20.76, [OR1.02, CI (1.01-1.04); p=0.007]. In the same way, FVC% was significantly lower in group with failed peristalsis 76.96±19.71compared to those without failed peristalsis 95.95±17.32, [OR1.05, CI (1.03-1.07); p=0.001].

No differences were found between age, gender, disease subsets, vascular and GIT symptoms, renal and cardiac system involvements or used medications between the two groups. ATA positivity and ACA negativity were also associated with failed peristalsis [respectively, OR 2.46, CI (1.10-5.49), p-0.02 and OR 3.38, (CI 1.12-10.1); p=0.03] (Table 3).

Table 3: Association of clinical features and failed peristalsis on HRM in 150 SSc patients.

In a multivariate study Variables entered on model included duration of diagnose of disease, Rodnan skin score, FVC%, DLCO%, digital ulcer-gangren, Dysphagia-symptom, advance fibrosis on chest HRCT, ACA positivity, anti-scl positivity, friction rub. The results showed only FVC%, and friction rub kept significant association with failed peristalsis.

Comparison of FVC% and peristalsis findings on HRM study

Mean rank of FVC% showed significant differences among 4 groups of patients based on esophageal motility study results (p=0.001). Mean rank of FVC% in patients with failed peristalsis was 65.6, significantly lower than in patients with diagnose of normal (mean rank:103.1), weak peristalsis (mean rank:101.8) or achalasia (mean rank:125.5) in manometry study. Comparison between average rank of FVC% in peristalsis status groups showed significant difference between average rank of FVC% in patients with failed peristalsis and weak peristalsis p=0.001, and average rank of FVC% in those with failed peristalsis and normal peristalsis p=0.020 (Figure 1).

Graph 1: A) Box Plot shows median and the interquartile range of Force Vital Capacity (FVC %) of 150 scleroderma patients with High Resolution Manometry (HRM) findings. B) pairwise comparison of peristalsis status with FVC% in 150 SSc patients and different HRM finding by the Kruskal-Wallis test

Discussion

In this cross-sectional study, we enrolled patients based on ACR/EULAR classification criteria for SSc disease and esophageal manometry findings that were characterized by using 3rd version of Chicago classification. We found that most of SSc patients had failed peristalsis and one third had hypotensive esophagogastric junction pressure (hEGJP). Failed peristalsis and LEJP is accepted as a typical sign for esophageal involvement in scleroderma [15,20,21]. Additionally, we found associations between failed peristalsis and duration of disease, modified skin score, tendon friction rub and pulmonary manifestations of disease.

Previously published studies which had used HRMs in scleroderma patient (3rd version of Chicago classification CC), reportedfailed peristalsis and achalasiain 55.6-82% [12,20], and 2.7 4% of their patients [12,21,22]. To compare, our findings shows 74% of patients had failed peristalsisand 1.3% achalasia

Association between disease subsets, skin score assessment by MRSS and esophageal manometry are variable among patients. Similar to other studies we did not found significant difference between association of skin involvement and conventional manometry results [12,14,23-25].

Association between MRSS and failed peristalsis in current study is similar to data from Kimme et al. [15] and Vischio et al. results [26]. It seems that patientswith higher skin score and diffuse subtype of SSc show more correlation with severity of internal organ involvements [27-30)].

Raynaud’s phenomenon (RP) was reported in 93.3% of our patients which similar to reported prevalence rate of 94-100% [6,12,15,31]. Moreover, we found high prevalence of esophageal dysmotility. Concomitant high prevalence may be explained by vasculopathy as a common underlying pathologic process. Although pathogenesis of esophageal dysfunction is not clear, vasculopathy resulting in ischemia and neuromuscular degeneration and eventually, smooth muscle atrophy and fibrotic tissue replacement could be speculated as an underlying cause. [2,6,8,32]. In the study of Adrews et al. gender was not associated with esophageal dysmotility, but men more likely had hypotensive LESP [33]. Our results are similar to the results from Carlanet al. that shows no relationship between age, gender and failed peristalsis [12].

Although in our study one third of patients had esophagogastric junction pressure (EGJ) of less than 10 mmHg, and most were on proton pump inhibitors (PPIs), but pyrosis was reported by about two- third of patients. The reason of discrepancy may be role of factors other than abnormal relaxation of lower esophageal sphincter, such as peristalsis or autonomic dysfunction and/or presence of hiatal hernia, in pyrosis [6].

Dysphagia was reported in one third of patients enrolled in the current study. It was not associated with failed peristalsis. However, in comparison to other GIT symptoms it may reflect stronger association with esophageal body dysmotility. In a study conducted by Katz et al. dysphagia, in the absence of obstruction, was the most frequent symptom that was associated with manometric abnormality [34].

We did not found association between upper GI symptoms and EGJ pressure and Esophageal body dysfunction, in other words, the upper GI symptoms in SSc patients were not discriminative between esophageal dysmotility findings. Similar to other studies our results showed lack of association between esophageal symptoms and manometry dysfunction [35,36].

We found relation between esophageal motility and advanced lung fibrosis and lower FVC%, and DLCO% in a univariate analysis. Moreover, there was association between severity score of FVC% in spirometry and the results of esophageal dysmotility tests. We show that FVC% was and dependent factor of failed peristalsis. Causality between esophageal dysmotility and lung involvement is a controversial matter. Carlen et al. showed association of lung fibrosis with manometry abnormality [12]. In prospective study of Marie et al. patients with systemic sclerosis during first evaluation have had median of DLCO% 68% vs. 94% vs. 104 in those with sever, moderate and normal motility disorder and higher prevalence of ILD on HRCT scan. At 2 years in follow up, in group of patients with severe esophageal dysmotility compared to those without motility abnormality show more prevalent ILD and faster deterioration of DLCO% [23]. In addition, there are some reports that PFTs was related to GERD in manometry. It is speculated that more severe lung f ibrosis may result in higher intra thoracic pressure swing during respiration, which may promote GERD [37].

Previous studies have reported variable association between esophageal dysfunction and anti-Scl70 and anti-centromereabs. Some found esophageal abnormalities were more frequent in anti Scl70 positive patients [38-40] as oppose to a study by Carlan et al. which demonstrated that failed peristalsis was more frequently seen in anti-ACA positive patients [12]. Although in univariate analysis we found association between ATA positivity and ACA negativity with failed peristalsis status, in multivariate analysis specific scleroderma auto antibodies did not showed correlation with failed peristalsis.

There are conflicting reports about influence of PPI on esophageal motility. While the results of Smythe et al. study [41]. suggested no influence of PPI and other antisecretory agents on esophageal motility. In study that conducted by Carlan et al.found PPI therapy to be more frequent in patients with failed peristalsis but they did not found association between failed peristalsis and using Nifedipine and Sildenafil [12]. In current study we did not found association between failed peristalsis and using Nifedipine and Sildenafil.

One of the limitations of this study was lack of endoscopic results in some patients that did not let us evaluate the role of esophageallesion. Another limitation could be counted as the study being conducted as cross sectional and prevalence of symptoms may be affected by prescribed medicine and it is impossible to study their causality. The strength of the current study includes use a large sample size of patients, use of new ACR/EULAR classification set for enrolling patients and evaluating, for the first time, the association between the severities of FVC% in spirometry with failed esophageal body dysmotility.

In this study we found high prevalence of the esophageal dysmotility that had no association with age, gender, duration of disease. There was no association between use of calcium blocker or 5-phosphodiasteres inhibitors and esophageal manometry abnormality. Additionally, we found no association between prednisolone, cyclophosphamide and manometric findings.

Not finding an association between the use of nifedipine and esophageal manometric abnormalities warrants future studies. The patients with failed peristalsis had lower FVC than patients with weak or normal motility on HRM.

Our results showed FVC%, tendon friction rub dependently associated with failed esophageal body dysmotility.

References

1. Lock G, Zeuner M, Lang B, Hein R, Scholmerich J, Holstege A. Anorectal function in systemic sclerosis: correlation with esophageal dysfunction? Dis Colon Rectum. 1997; 40: 1328-1335.

2. Sjogren RW. Gastrointestinal motility disorders in scleroderma. Arthritis Rheum. 1994; 37:1265-1282.

3. Khanna D, Nagaraja V, Gladue H, Chey W, Pimentel M, Frech T. Measuring Response in the Gastrointestinal Tract in systemic sclerosis. Curr Opin Rheumatol. 2013; 25: 700-706.

4. Forbes A, Marie I. Gastrointestinal complications: the most frequent internal complications of systemic sclerosis. Rheumatology (Oxford). 2009; 48: iii36 iii39.

5. Goldblatt F, Gordon T P, Waterman SA. Antibody-mediated gastrointestinal dysmotility in scleroderma. Gastroenterology. 2002; 123: 1144-1150.

6. Ebert EC. Esophageal disease in scleroderma. J Clin Gastroenterol. 2006; 40: 769-775.

7. Treacy WL, Baggenstoss AH, Slocumb CH, Code CF. Scleroderma of the esophagus. A correlation of histologic and physiologic findings. Ann Intern Med. 1963; 59: 351-356.

8. Roberts CG, Hummers LK, Ravich WJ, Wigley FM, Hutchins GM. A case control study of the pathology of oesophageal disease in systemic sclerosis (scleroderma). Gut. 2006; 55: 1697-1703.

9. Kahrilas PJ, Bredenoord AJ, Fox M, Gyawali CP, Roman S, Smout AJ, et al. The Chicago Classification of esophageal motility disorders, v3.0. Neurogastroenterol Motil. 2015; 27: 160-174.

10. Saladin TA, French AB, Zarafonetis CJ, Pollard HM. Esophageal motor abnormalities in scleroderma and related diseases. Am J Dig Dis. 1966; 11: 522-535.

11. Yarze JC, Varga J, Stampfl D, Castell DO, Jimenez SA. Esophageal function in systemic sclerosis: a prospective evaluation of motility and acid reflux in 36 patients. Am J Gastroenterol. 1993; 88: 870-876.

12. Carlen M ,LescottA, Brochard C, CoiffierG, Cazalets C, Ropert A, et al. Association between clinical manifestations of systemic sclerosis and esophageal dysmotility assessed by high-resolution manometry. JSRD. 2017; 2: 50-56.

13. Carlson DA, Crowell MD, Kimmel JN, Patel A, Gyawal CP, Hinchcliff M, et al. Loss of Peristaltic Reserve, Determined by Multiple Rapid Swallows, Is the Most Frequent Esophageal Motility abnormality in Patients with Systemic Sclerosis. Clin Gastroenterol Hepatol. 2016; 14: 1502-1506.

14. Roman S, Hot A, Fabien N, Cordier JF, Miossec P, Ninet J, et al. Esophageal dysmotility associated with systemic sclerosis: a high-resolution manometry study. Dis Esophagus. 2011; 24: 299-304.

15. Kimme JK L, Carlson DA, Hinchcliff M, Carns M. A, Aren KA, Lee J, et al. The association between systemic sclerosis disease manifestations and esophageal high-resolution manometry parameters. Neurogastroenterol Motil. 2016; 28: 1157-1165.

16. van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A. Classification criteria for systemic sclerosis. An American college of rheumatology/European league against rheumatism collaborative initiative. Arthritis Rheum. 2013; 65: 2737-2747.

17. LeRoy EC, Black C, Fleischmajer R, Jablonska S, Krieg T, Medsger TA Jr, et al. Scleroderma (systemic sclerosis): classification, subsets and pathogenesis. J Rheumatol. 1988; 15: 202-205.

18. Goh NS, Desai SR, Veeraraghavan S, Hansell DM, Copley SJ, Maher TM, et al. Interstitial lung disease in systemic sclerosis: a simple staging system. Am J Respir Crit Care Med. 2008; 177: 1248-1254.

19. Medsger TA, Bombardieri S, Czirjak L, Scorza R, Della Rossa A, BencivelliW. Assessment of disease severity and prognosis. Clin Exp Rheumatol. 2003; 21: S42-S46.

20. Calderaro DC, de Carvalho MA, Moretzsohn LD. Esophageal manometry in 28 systemic sclerosis Brazilian patients: findings and correlations. Dis Esophagus. 2009; 22: 700-704.

21. Marie I, Levesque H, Ducrotté P, Denis P, Benichou J, Hellot MF, et al. Manometry of the upper intestinal tract in patients with systemic sclerosis: a prospective study. Arthritis Rheum. 1998; 41: 1874-1883.

22. Crowel MD, Umar SB, Griffing WL, DiBaise JK, Lacy BE, Vela MF. Esophageal Motor Abnormalities in Patients with Scleroderma: Heterogeneity, Risk Factors, and Effects on Quality of Life. Clin Gastroenterol Hepatol. 2017; 15: 207-213.

23. Marie I, Dominique S, Levesque H, Ducrotte P, Denis P, Hellot MF, et al. Esophageal involvement and pulmonary manifestations in systemic sclerosis. Arthritis Rheum. 2001; 45: 346-354.

24. Savarino E, Mei F, Parodi A, Ghio M, Furnari M, Gentile A, et al. Gastrointestinal motility disorder assessment in systemic sclerosis. Rheumatology (Oxford). 2013; 52: 1095-1100.

25. Clements P, Lachenbruch P, Siebold J, White B, Weine S, Martin R, et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol. 1995; 22: 1281-1285.

26. Vischio J, Saeed F, Karimeddini M, Mubashir A, Feinn R, Caldito G, et al. Progression of esophageal dysmotility in systemic sclerosis. J Rheumatol. 2012; 39: 986- 991.

27. Steen VD, Medsger TA Jr. Severe organ involvement in systemic sclerosis with diffuse scleroderma. Arthritis Rheum. 2000; 43: 2437-2444.

28. Verrecchia F, Laboureau J, Verola O, RoosN, Porcher R, Bruneval P, et al. Skin involvement in scleroderma–where histological and clinical scores meet. Rheumatology (Oxford). 2007; 46: 833-841.

29. Clements PJ, Hurwitz EL, Wong WK, Seibold JR, Mayes M, White B, et al. Skin thickness score as a predictor and correlate of outcome in systemic sclerosis: highdose versus low-dose penicillamine trial. Arthritis Rheum. 2000; 43: 2445-2454.

30. Shand L, Lunt M, Nihtyanova S, Hoseini M, Silman A, Black CM, et al. Relationship between change in skin score and disease outcome in diffuse cutaneous systemic sclerosis: application of a latent linear trajectory model. Arthritis Rheum. 2007; 56: 2422-2431.

31. Belch JJ, Land D, Park RH, McKillop JH, MacKenzie JF. Decreased oesophageal blood flow in patients with Raynaud’s phenomenon. Rheumatol. 1988; 27: 426-430

32. Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009; 360: 1989-2003.

33. Andrews J M, Heddle R, Hebbard G S, Checklin H, Besanko L, Fraser R J. Age and gender affect likely manometric diagnosis: audit of a tertiary referral hospital clinical esophageal manometry service. J Gastroenterol Hepatol. 2009; 24: 125-128.

34. Katz PO, Menin RA, Gideon RM. Utility and standards in esophageal manometry. J Clin Gastroentrol. 2008; 42: 620-626.

35. Lahcene M, Oumnia N, Matougu N, Boudjella M, Tebaibia A, Touchene B. Esophageal Involvement in Scleroderma: Clinical, Endoscopic, and Manometric Features. ISRN Rheumatol. 2011; 2011: 325826.

36. Arana-Guajardo AC, Barrera-Torres G, Villarreal-Alarcón MÁ, Vega-Morales D, Esquivel-Valerio JA. Esophageal symptoms and their lack of association with high-resolution manometry in systemic sclerosis. Reumatol Clin. 2017; S1699-258X: 30243-30247.

37. Beaumont H, Boeckxstaens G. Recent developments in esophageal motor disorders. Curr Opin Gastroenterol. 2007; 23: 416-421.

38. Stacher G, Merio R, Budka C, Schneider C, Smolen J, Tappeiner G. Cardiovascular autonomic function, autoantibodies, and esophageal motor activity and mixed connective tissue disease. J Rheumatol. 2000; 27: 692-697.

39. Savas N, Dagli U, Ertugrul E, Kuran S, Sahin B . Autoantibody profile in systemic sclerosis as a marker for esophageal and other organ involvement in Turkish populations. Dig Dis Sci. 2007; 52: 3081-3086.

40. Kinuya K, Nakajima K, Kinuya S, Michigishi T, Tonami N, Takehara K. Esophageal hypomotility in systemic sclerosis: close relationship with pulmonary involvement. Ann Nucl Med. 2001; 15: 97-101.

41. Smythe A, Troy GP, Ackroyd R, Bird NC. Proton pump inhibitor influence on reflux in Barrett’s oesophagus. Eur J Gastroenterol Hepatol. 2008; 20: 881-887