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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 12  |  Issue : 4  |  Page : 204-208

Helicobacter Pylori infection in systemic sclerosis and its association with upper gastrointestinal dysfunction


Institute of Rheumatology, Madras Medical College and RGGGH, Chennai, Tamil Nadu, India

Date of Web Publication16-Nov-2017

Correspondence Address:
Chilukuri Balaji
1/3B Sai Lakshmi Enclave Patel Street, West Mambalam, Chennai - 600 033, Tamil Nadu
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_62_17

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  Abstract 


Background: Immune dysregulation triggered by environmental events (including microbes) have been implicated in the etiopathogenesis of systemic sclerosis (SSc). Helicobacter pylori (H. pylori) a pathogen well known to cause gastric ulcers and has been associated with several autoimmune diseases. However, the role of H. pylori in SSc has not been widely reported. The objective of the study was to estimate the prevalence of H. pylori infection in SSc patients and analyze its clinical associations.
Methods: This study comprised 55 patients who satisfied ACR/EULAR 2013 classification criteria for SSc and 25 age and sex-matched healthy controls. Demographic, clinical, laboratory, and immunological parameters were recorded. Upper gastrointestinal (GI) endoscopy was done. Anti-H. pylori IgG levels (RU/ml) were estimated by ELISA and results analyzed by SPSS.
Results: Baseline characteristics were comparable in both groups. Prevalence of H. pylori infection was high in SSc patients in comparison to controls (61.8% vs. 24%). Anti-H. pylori IgG levels were high in SSc patients in comparison to controls (mean 65 RU/ml vs. 25.3RU/ml; P = 0.003). SSc patients with symptomatic GI involvement had higher anti-H. pylori IgG levels than asymptomatic patients (mean 118.3 RU/ml vs. 20.7 RU/ml; P < 0.001). Anti-H. pylori IgG levels were not significantly different between diffuse cutaneous SSc and limited cutaneous SSc (mean 72.9 RU/ml vs. 54.1RU/ml; P = 0.289). Anti-H. pylori IgG antibody levels showed no correlation with disease duration, erythrocyte sedimentation rate, C-reactive protein, interstitial lung disease, and modified Rodnan Skin Score.
Conclusion: SSc patients have high seropositivity for anti-H. pylori IgG antibodies. High anti-H. pylori IgG antibody titers are associated with symptomatic upper GI dysfunction.

Keywords: Autoimmune, esophagitis, infections, pathogenesis, scleroderma


How to cite this article:
Balaji C, Bhuvanesh M, Saranya C, Ramesh R, Saravanan M, Rajeswari S. Helicobacter Pylori infection in systemic sclerosis and its association with upper gastrointestinal dysfunction. Indian J Rheumatol 2017;12:204-8

How to cite this URL:
Balaji C, Bhuvanesh M, Saranya C, Ramesh R, Saravanan M, Rajeswari S. Helicobacter Pylori infection in systemic sclerosis and its association with upper gastrointestinal dysfunction. Indian J Rheumatol [serial online] 2017 [cited 2019 Oct 22];12:204-8. Available from: http://www.indianjrheumatol.com/text.asp?2017/12/4/204/216793



Introduction

Systemic sclerosis (SSc) is an autoimmune connective tissue disorder. The pathogenesis of SSc is complex and is characterized by fibrosis, vasculopathy, and autoimmunity. It occurs in genetically susceptible individuals whose immune system is dysregulated by environmental triggers. Environmental agents such organic solvents, chemicals, silica, drugs, and viruses such as cytomegalovirus and human parvovirus B19 have been implicated as triggers of immune dysregulation in SSc.[1],[2]

Helicobacter pylori (H. pylori) is a Gram-negative, spiral-shaped bacteria detected intracellularly on luminal side of the gastric mucosal epithelial cells.[3]H. pylori lipopolysaccharide is less potent in promoting a pro-inflammatory response that is mediated by toll-like receptor 4 signaling. Flagellin of H. pylori escapes recognition by toll-like receptor 5 signaling. H. pylori also escapes activation of acquired immune system through cytotoxin A which blocks the proliferation of CD4 + T helper lymphocytes.[4] High antibody titers against H. pylori are usually present in infected individuals. However, unlike other antimicrobial antibodies, anti-H. pylori antibodies promote the presence of bacteria. An elevated IgG antibody titer is a marker of chronic infection. H. pylori infection is more prevalent in developing countries. Persistence of H. pylori in gastric mucosa leads to chronic immune stimulation, cytokine production, gastric mucosal infiltration of inflammatory cells-neutrophils, macrophages, and lymphocytes.

H. pylori has unique characteristics such as its ubiquitous presence worldwide, prolonged survival, and proven association with immune system.[5] Link between H. pylori and several rheumatic diseases such as rheumatoid arthritis, systemic lupus erythematosus, Sjogrens syndrome, vasculitis, and fibromyalgia have been reported.[6] Studies linking the presence of H. pylori in various autoimmune diseases found mixed results. H. pylori infection and its associations have not been widely reported in SSc.

The objective of this study was to estimate the prevalence of H. pylori infection in patients with SSc and analyze its possible correlation with organ involvement, namely, gastrointestinal (GI), lung involvement (interstitial lung disease [ILD]), and skin involvement.


  Methods Top


Study design

This was a cross-sectional study done between January 2016 and April 2016. Patients with SSc who satisfied American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) 2013 classification criteria were included after informed consent.[7] Patients with overlap syndrome, mixed connective tissue disease, undifferentiated connective tissue disease with SSc-like features, juvenile SSc, and pregnant women were excluded from this study.

They were enquired for history of dysphagia, dyspepsia, regurgitation of food, early satiety, and bloating sensation. Patients were subjected to baseline investigations; erythrocyte sedimentation rate (ESR) by Westergen method, C-reactive protein (CRP) by latex agglutination method, and antinuclear antibodies (ANA) by indirect immunofluorescence (IIF)-Human Epithelial cell HEp-2000.

Lung involvement was assessed by pulmonary function tests and followed by high-resolution computed tomography (HRCT) chest if the patient had low FVC or was symptomatic with dyspnea. All patients underwent upper GI endoscopy (UGIE). The endoscopy was performed on patients after overnight fast; endoscopic studies were done by gastroenterologist. Findings of UGIE endoscopy noted were specifically for the presence or absence of esophagitis, esophageal candidiasis, esophageal ulcers, gastric ulcers, and gastric mucosal erosions. Disease severity of the skin was assessed with modified Rodnan Skin Score (mRSS).[8],[9]

Healthy control participants were age and sex matched, recruited from among healthy individuals attending the outpatient master health checkup clinics.

Five milliliters venous blood sample was collected from all patients and controls. Sera were separated and sample stored at −80°C till analysis. Sera for anti-H. pylori IgG levels were estimated by indirect ELISA using commercial ELISA kits (EUROIMMUN, Germany) in all cases and controls. Anti-H. Pylori IgG levels <16 RU/ml was taken as negative, 16–25 RU/ml was considered borderline, and >25 RU/ml was taken as positive. This kit showed 100% correlation with Helicobacter urease test and 100% specificity and sensitivity (as per EUROIMMUNE ELISA kit manufacturer).

Statistical analysis

All statistical analyses were performed using the Statistical Package for the Social Sciences (SPSS) version 22 (Armonk, NY, IBM Corp). Proportions were computed for discrete data. Mean and standard deviation were used for continuous data. Student's t-test was used for independent samples. Linear correlations were calculated by Pearson's correlation coefficient. For all statistical evaluations, P < 0.05 was considered statistically significant. For purpose of analysis, patients were classified into those with GI symptoms and those without GI symptoms.

Ethical approval

The study was approved by the ethics committee of the institute. Informed written consent was obtained from all patients prior to their enrollment in this study.


  Results Top


Twenty-three patients had limited cutaneous SSc and 32 had diffuse cutaneous SSc. The baseline characteristics of the patients as given in [Table 1] show that most patients were females, predominantly in reproductive age group. The mean disease duration was short which indicated recent onset SSc. Mean mRSS was high indicating high severity. Mean ESR and CRP were modestly elevated.
Table 1: Baseline characteristics of systemic sclerosis cases and controls

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Nonspecific interstitial pneumonia pattern of ILD was the most common ILD pattern detected by HRCT chest. Most common ANA pattern detected by IIF in HEp 2000 was (nucleus–nucleolar) Scl-70 pattern (anti-topoisomerase I) followed by nucleolar and centromere pattern which reflected the higher number of patients with diffuse cutaneous SSc in this study.

Upper GI endoscopic findings in the SSc patients were esophagitis, esophageal candidiasis, esophageal ulcers, gastric ulcers, and gastric mucosal erosions. The most common findings were esophagitis seen in 46 (83.6%) and gastric ulcers seen in 9 (16%) patients. Other findings noted were esophageal candidiasis seen in 5 (9%), esophageal ulcers seen in 4 (7%), and gastric mucosal erosions seen in 6 (10.9%).

Anti-Helicobacter pylori IgG antibodies

Thirty-four of 55 (61.8%) patients (n = 34) were positive for anti-H. pylori IgG antibodies whereas 6 out of 25 (24%) healthy controls were seropositive for anti-H. pylori IgG antibodies.

We compared the anti-H.pylori IgG levels between patients and controls, and as shown in [Table 2], anti-H. pylori IgG levels were significantly higher in SSc compared to controls (mean 65.0 ± 64.1 versus 25.3 ± 21.2 RU/ml; P = 0.003). SSc patients with GI symptoms had higher anti-H. pylori IgG levels than patients who did not have GI symptoms (mean 118.3 ± 57.6 vs. 20.7 ± 20.7 RU/ml; P < 0.001).
Table 2: Comparison of anti-Helicobacter pylori IgG levels in study subgroups

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The mean levels of anti-H. pylori IgG antibodies were significantly higher in those with gastric ulcers compared to those with esophagitis (mean 135.3 ± 57.8 vs. 57.4 ± 61 RU/ml; P = 0.013). There was no difference in the anti-H. pylori IgG levels between diffuse SSc and limited SSc (mean 72.9 ± 63.8 vs. 54.1 ± 64.3 RU/ml; P = 0.289). Furthermore, there was no difference in the anti-H. pylori IgG levels between patients with or without ILD (mean 67.5 ± 63.4 vs. 63.07 ± 65.7 RU/ml; P = 0.080). There was also no correlation of anti-H. pylori IgG levels with disease duration, ESR, CRP, and mRSS [Table 3].
Table 3: Correlation analysis between anti-Helicobacter pylori IgG and modified Rodnan Skin Score, erythrocyte sedimentation rate, C-reactive protein, and disease duration

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  Discussion Top


In our study, 61.8% of patients with SSc were seropositive for anti-H. pylori IgG antibodies. Similar to our findings, studies done in Japanese cohort of SSc patients by Yazawa et al. (55.6%) and Yamaguchi et al. (57.8%) also reported high seropositivity for anti-H. pylori IgG antibodies.[10],[11] Even in European SSc cohorts, 42% were found to be positive for H. pylori infection.[12] This high prevalence of H. pylori infection among SSc patients might to be due to defective peristalsis which is a troublesome upper GI manifestation of SSc, which may have contributed to the increased H. pylori colonization in SSc compared to control population. Similarly, some other studies have also reported higher prevalence of H. pylori infection in SSc patients in comparison to controls.[13],[14]

In contrast to our findings, Danese et al. did not find any difference in the prevalence of the H. pylori infection between SSc patients and controls, but they reported that 90% of the H. pylori-positive SSc patients had virulent CagA strain in comparison to 37% of the non-CagA seropositive controls.[15] There are other studies too that have also failed to find an increased prevalence of H. pylori seropositivity compared to control groups indicating the lack of conclusive data suggesting that the role of H. pylori in SSc is still not clear.

In our study, high anti-H. pylori IgG levels did not correlate with skin involvement (diffuse cutaneous vs. limited cutaneous) or severity of skin involvement as assessed by mRSS. However, in contrast to our findings, Radić et al. noted that seropositivity for anti-H. pylori IgG antibodies was associated with extensive skin involvement.[16] We also did not find any relationship of ESR, CRP, ILD, disease duration, and autoantibody profile with levels of anti-H. pylori which was similar to the observations made by Radić et al.[16]

As might have been expected, we observed that high anti-H. pylori IgG levels were associated with symptomatic upper GI dysfunction. The most common upper GI endoscopic abnormalities in our patients with SSc were esophagitis and gastric ulcers. Japanese SSc cohort also made similar observation of higher prevalence of reflux esophagitis in anti-H. pylori IgG antibody seropositive patients compared to anti-H. pylori IgG-negative patients.[11] Wipff et al. have reported that SSc patients with Barrett's esophagus are less likely to be seropositive for anti H. pylori IgG compared to SSc patients without Barrett's esophagus (10% vs. 42.5%).[17]

Based on our and other aforementioned studies, it appears that environmental factors such as H. pylori may play a major role in pathogenesis of SSc than genetics.[18] Mechanisms by which H. pylori could possibly trigger the immune system are molecular mimicry, epitope spreading, and bystander effect. H. pylori antigens cross-react with T-cells in autoimmune gastritis.[19]H. pylori components such as urease are known to activate B-cells to produce autoantibodies.[20]H. pylori can also be a source of chronic antigenic stimulation.[21]

On the other hand, SSc patients are susceptible to severe H. pylori infection by virtue of high prevalence of abnormal GI motility in these patients. As we and other studies show that high titers of anti-H. pylori IgG antibodies are associated with symptomatic GI dysfunction.

Some studies have observed improvement in Raynaud's phenomenon in patients with SSc treated with H. pylori eradication regimens.[22],[23] Radic et al. reported that SSc patients who received H. pylori eradication therapy differed significantly from patients without H. pylori eradication in terms of improvement of skin, muscle, and peripheral vascular involvement.[17] Furthermore, acute phase reactants and autoantibody titers were also found to be low in H. pylori eradicated patients.

Arnold et al. reported that eradication of H. pylori leads to increase in platelet counts in patients with idiopathic thrombocytopenic purpura.[24]H. pylori eradication may alter microbiome status of the seropositive individuals, possibly by downgrading the chronic stimulation of immune system. H. pylori eradication regimens are cheap and easily available in our country. These studies suggest the importance of identification and eradication of H. pylori, which may improve troublesome upper GI symptoms which are so common in SSc.

The limitation of our study was that we could not get a biopsy confirmation of H. pylori infection. We conclude that H. pylori infection is common in Indian patients with SSc. High anti-H. pylori IgG antibodies are associated with symptomatic upper GI dysfunction. Further studies are needed to assess if H. pylori eradication regimens alter the disease course or not.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Kettaneh A, Al Moufti O, Tiev KP, Chayet C, Tolédano C, Fabre B, et al. Occupational exposure to solvents and gender-related risk of systemic sclerosis: A metaanalysis of case-control studies. J Rheumatol 2007;34:97-103.  Back to cited text no. 1
    
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Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:1311-5.  Back to cited text no. 3
    
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van den Hoogen F, Khanna D, Fransen J, Johnson SR, Baron M, Tyndall A, et al. 2013 classification criteria for systemic sclerosis: An American college of rheumatology/European league against rheumatism collaborative initiative. Ann Rheum Dis 2013;72:1747-55.  Back to cited text no. 7
    
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Clements P, Lachenbruch P, Siebold J, White B, Weiner S, Martin R, et al. Inter and intraobserver variability of total skin thickness score (modified Rodnan TSS) in systemic sclerosis. J Rheumatol 1995;22:1281-5.  Back to cited text no. 8
    
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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: High-dose versus low-dose penicillamine trial. Arthritis Rheum 2000;43:2445-54.  Back to cited text no. 9
    
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Yazawa N, Fujimoto M, Kikuchi K, Kubo M, Ihn H, Sato S, et al. High seroprevalence of Helicobacter pylori infection in patients with systemic sclerosis: Association with esophageal involvement. J Rheumatol 1998;25:650-3.  Back to cited text no. 10
    
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Yamaguchi K, Iwakiri R, Hara M, Kikkawa A, Fujise T, Ootani H, et al. Reflux esophagitis and Helicobacter pylori infection in patients with scleroderma. Intern Med 2008;47:1555-9.  Back to cited text no. 11
    
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Reinauer S, Goerz G, Ruzicka T, Susanto F, Humfeld S, Reinauer H, et al. Helicobacter pylori in patients with systemic sclerosis: Detection with the 13C-urea breath test and eradication. Acta Derm Venereol 1994;74:361-3.  Back to cited text no. 12
    
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Farina G, Rosato E, Francia C, Proietti M, Donato G, Ammendolea C, et al. High incidence of helicobacter pylori infection in patients with systemic sclerosis: Association with Sicca Syndrome. Int J Immunopathol Pharmacol 2001;14:81-5.  Back to cited text no. 13
    
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Kountouras J, Zavos C, Gavalas E, Deretzi G, Katsinelos P, Boura P, et al. Helicobacter pylori may be a common denominator associated with systemic and multiple sclerosis. Joint Bone Spine 2011;78:222-3.  Back to cited text no. 14
    
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Danese S, Zoli A, Cremonini F, Gasbarrini A. High prevalence of helicobacter pylori type I virulent strains in patients with systemic sclerosis. J Rheumatol 2000;27:1568-9.  Back to cited text no. 15
    
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Radić M, Kaliterna DM, Bonacin D, Vergles JM, Radić J, Fabijanić D, et al. Is helicobacter pylori infection a risk factor for disease severity in systemic sclerosis? Rheumatol Int 2013;33:2943-8.  Back to cited text no. 16
    
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Wipff J, Allanore Y, Soussi F, Terris B, Abitbol V, Raymond J, et al. Prevalence of Barrett's esophagus in systemic sclerosis. Arthritis Rheum 2005;52:2882-8.  Back to cited text no. 17
    
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Bogdanos DP, Smyk DS, Rigopoulou EI, Mytilinaiou MG, Heneghan MA, Selmi C, et al. Twin studies in autoimmune disease: Genetics, gender and environment. J Autoimmun 2012;38:J156-69.  Back to cited text no. 18
    
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Amedei A, Bergman MP, Appelmelk BJ, Azzurri A, Benagiano M, Tamburini C, et al. Molecular mimicry between helicobacter pylori antigens and H+, K+ – Adenosine triphosphatase in human gastric autoimmunity. J Exp Med 2003;198:1147-56.  Back to cited text no. 19
    
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Jackson L, Britton J, Lewis SA, McKeever TM, Atherton J, Fullerton D, et al. A population-based epidemiologic study of Helicobacter pylori infection and its association with systemic inflammation. Helicobacter 2009;14:108-13.  Back to cited text no. 20
    
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Yamanishi S, Iizumi T, Watanabe E, Shimizu M, Kamiya S, Nagata K, et al. Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pylori urease. Infect Immun 2006;74:248-56.  Back to cited text no. 21
    
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Gasbarrini A, Massari I, Serricchio M, Tondi P, De Luca A, Franceschi F, et al. Helicobacter pylori eradication ameliorates primary Raynaud's phenomenon. Dig Dis Sci 1998;43:1641-5.  Back to cited text no. 22
    
23.
Csiki Z, Gál I, Sebesi J, Szegedi G. Raynaud syndrome and eradication of Helicobacter pylori. Orv Hetil 2000;141:2827-9.  Back to cited text no. 23
    
24.
Arnold DM, Bernotas A, Nazi I, Stasi R, Kuwana M, Liu Y, et al. Platelet count response to H. Pylori treatment in patients with immune thrombocytopenic purpura with and without H. Pylori infection: A systematic review. Haematologica 2009;94:850-6.  Back to cited text no. 24
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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