- Email: [email protected]
Helicobacter pylori infection and systemic sclerosis–is there a link?
Joint Bone Spine 78 (2011) 337–340
Review
Helicobacter pylori infection and systemic sclerosis–is there a link? Mislav Radic´ a,∗ , Duˇsanka Martinovic´ Kaliterna a , Josipa Radic´ b a b
Department of Rheumatology, University Hospital, Split, Croatia Department of Nephrology, University Hospital, Split, Croatia
a r t i c l e
i n f o
Article history: Accepted 8 October 2010 Available online 8 December 2010 Keywords: Systemic sclerosis Helicobacter pylori Pathogenesis
a b s t r a c t Over the last 20 years, increasing evidence has accumulated to implicate infectious agents in the etiology of systemic sclerosis (SSc) and Raynaud’s phenomenon. Infection rates in patients with SSc compared with those in control populations do not provide clear support for any specific pathogen. However, increased antibody titers, a preponderance of specific strains in patients with SSc, and evidence of molecular mimicry inducing autoimmune responses suggest mechanisms by which infectious agents may contribute to the development and progression of SSc. Helicobacter pylori (H. pylori) has been associated with diseases such as autoimmune gastritis, Sjögren’s syndrome, atherosclerosis, immune thrombocytopenia purpura, inflammatory bowel diseases and autoimmune pancreatitis, in each of which it seems to play a pathogenetic, but it has also been suggested that it may help to protect against the development of autoimmune gastritis, multiple sclerosis, systemic lupus erythemathosus and inflammatory bowel diseases. A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and ACR/EULAR meeting abstracts. We hypotheses that H. pylori infection might play a critical role in the pathogenesis of SSc. Here we review studies examining the potential involvement of H. pylori infection in SSc. © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Systemic sclerosis (SSc) is a chronic multisystemic disease characterized by the excess deposition of connective tissue in the skin and internal organs, and is associated with microvasculature changes and immunologic abnormalities. SSc is a complex autoimmune disease characterized by three types of slow and frequently overlapping pathologic processes [1,2]. Immune/autoimmune pathologies are present, including perturbations in both cellular and humoral immunity. Cellular immunity in SSc is typified by an increase in the number of CD4+ T-helper and ␥/␦-TCR+ lymphocytes and a decrease in the number of CD8+ cytotoxic T lymphocytes. The humoral aspect of SSc pathology is characterized by the generation of self-reactive antibodies such as antiendothelial cell antibodies and antitopoisomerase, anticentromere, and antifibrillin-1 antibodies. In addition, there are fibrotic processes characterized by abnormal fibroblast/myofibroblast cell proliferation and the deposition of excessive extracellular matrix proteins in affected organs. Finally, there is vascular pathology, characterized by microvascular endothelial cell activation (increased expression of adhesion molecules such as E-selectin, P-selectin, and intracel-
lular adhesion molecule-1), and injury (endothelial cell apoptosis). The cause of SSc remains unclear. Increasing evidence suggests that there are many potential environmental triggers for SSc and that host factors determine susceptibility to disease in response to these triggers. Infectious agents, bacterial and viral, have long been suspected as a contributing factor in the development and progression of the pathologic features of SSc [3]. The infectious agents might have a role in SSc pathogenesis and expression, antibodies against cytomegalovirus, hepatitis B virus, and toxoplasmosis were detected more often in SSc patients [4]. The main question is: Where an infectious agent may impact on a patient to induce SSc? However, there are three main organs that may be the first entrance door: air (lung), direct contact (skin), meal (esophagus). Clearly, these three organs may be the target of a microorganism with a deleterious effect triggering the first local reaction. We performed a systematic literature review using the keywords “systemic sclerosis”, “Helicobacter pylori” and “pathogenesis”. A systematic literature search was carried out in MEDLINE; EMBASE; Cochrane Library and ACR/EULAR meeting abstracts. 2. Helicobacter pylori infection
∗ Corresponding author. Siˇ ˇ zgoriceva ´ 20, 21 000 Split, Croatia. Tel.: +00385 21 53 26 91/00385 91 89 41 421. ´ E-mail address: [email protected] (M. Radic).
Helicobacter pylori (H. pylori) is a gram negative, spiral shaped organism that colonizes the human gastric mucosa. H. pylori is one of the most common pathogens affecting humans, infecting
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2010.10.005
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approximately 50% of the world’s population. It is found more frequently in developing countries than in industrialized countries, presumably due to poor sanitary conditions [5]. The outcome of the infection depends on a combination of factors: bacterial virulence, host factors, and environmental factors [6]. Ulceration and carcinogenesis are mutually exclusive outcomes of this infection. H. pylori infection is a very persistent infection, and in areas of high prevalence, repeated infections are common [5,7]. The bacteria have been isolated from feces, saliva and dental plaques of infected patients, which suggest that the fecal-oral route is a possible transmission mode [8]. The pathogen is a gram-negative spiral shaped bacterium that has the unique ability to colonize the human gastric mucosa [9]. Some virulence factors such as urease and flagella are present in all strains and are necessary for the pathogenesis and colonization of the gastric mucosa. With its flagella, the bacterium moves through the gastric lumen and drills into the gastric mucosal layer. The presence of the flagella, and thus motility, is required for persistent gastric colonization [10]. The main bacterial factors associated with pathogenicity comprise outer membrane proteins, including the vacuolating cytotoxin VacA, and the products of CagA. An interaction between bacterial factors such as CagA and host signal transduction pathways seems to be critical for mediating cell transformation, cell proliferation, invasion, apoptosis/antiapoptosis, and angiogenesis [11]. The key pathophysiological event in H. pylori infection is initiation and continuance of an inflammatory response. Bacteria or their products trigger this inflammatory process the main mediators of which are cytokines [12,13]. This response is related to the expression of proinflammatory cytokines, both on the surface epithelium and in macrophages/monocytes [14–17]. Another putative virulence determinant is the neutrophil-activating protein (NapA) gene, a gene that was shown to be induced by contact with the epithelium (iceA1) [18].
3. Helicobacter pylori infection and systemic sclerosis The relationship between infection and autoimmunity has been increasingly defined over the last 20 years [19]. An increasing body of evidence suggests that there are many potential environmental triggers for SSc and that host factors determine the susceptibility of the host to disease in response to these triggers [20]. The hypothesis that infectious agents may cause SSc has been studied extensively. The rationale for this “infection hypothesis” is that many SSc-like symptoms are transiently elicited by infectious agents in otherwise healthy individuals. There are two general lines of evidence implicating bacterial infections in the pathogenesis of SSc. One is anecdotal evidence that antibiotic treatments relieve SSc symptoms in some people. The other is that graft-versus-host disease, which is recognized as having many similarities to SSc, cannot be induced in germ-free animals and is significantly reduced in children pretreated with antibiotics to eradicate their normal bacterial flora [21–23]. Recently performed study on the involvement of bacterial infections in the pathogenesis of SSc focuses on H. pylori, which has been implicated in other vascular diseases [24]. The influence of H. pylori infection on reflux esophagitis with SSc is still controversial [25–27]. According to previous reports, SSc patients have an accelerated frequency of H. pylori infection compared to the average incidence of gastric H. pylori in white, healthy, asymptomatic subjects [28–30]. Yazawa et al. showed that SSc patients have a higher incidence of IgG antibodies to H. pylori compared to the general population [31]. Although one study showed that H. pylori infection plays an important role in the prevalence of endoscopic reflux esophagitis associated with SSc in Japanese population [32]. Wipff et al. evaluated 110 SSc patients who were receiving long-term treatment with proton-pump inhibitors using
esophageal manometry and endoscopy [33]. In this study, the prevalence of Barrett’s esophagus was 12.7%, similar to the prevalence in patients with gastresophageal reflux disease. However, none of these patients with Barrett’s esophagus had esophageal adenocarcinoma [32]. Studies have investigated H. pylori infections for an association with Raynaud’s phenomenon, Sjögren syndrome, and SSc. In a study of patients with primary Raynaud’s phenomenon, eradication of H. pylori infection with a triple antibiotic regimen was associated with complete disappearance of Raynaud’s phenomenon episodes in 17% of those treated and a reduction in symptoms in an additional 72% of patients [33]. The possible bias of this study that it was not double blind, it is very interesting that Raynaud’s phenomenon symptoms were not improved in those patients in whom the treatment failed to eradicate the H. pylori infection. A more recent trial of similar design reported very similar results [34]. Attempts to associate H. pylori infection status and SSc have had some conflicting results. In 1999, Aragona et al. identified higher incidence rates of H. pylori infection in patients with rheumatic diseases, including SSc, as detected by serologic analysis [30]. In contrast to these results, three larger studies found no difference in H. pylori infection rates between patients with SSc with Raynaud’s phenomenon and healthy controls [35–38]. However, even if it is true that H. Pylori infection rates in these studies are not correlated with SSc, this does not necessarily rule out its involvement in the disease. Danese et al. confirmed that, although there is no difference in the H. pylori infection rate between control subjects and patients with SSc, 90% of patients with SSc were infected with the virulent CagA strain compared with 37% of infected control subjects [39]. Increased seroprevalence of H. pylori has been found in SSc (78%) [30]. Disturbed gastrointestinal motility in SSc patients may be linked to overlap with the occurrence of H. pylori that has been correlated to the risk of coronary heart disease and seems associated to Raynaud’s phenomenon [36]. It has been demonstrated that H. pylori sheds extracellular products that elicit local and systemic immune response that could be responsible for tissue damage. A 60 kDa protein, belonging to the heat shock proteins (hsp) seems to be involved: in fact, H. pylori associated, human hsp60 and mycobacterial hsp65 are members of the 60 kDa family of the hsp and they share high sequence homology [39]. These patients may elicit antibodies against these hsp. Therefore, confounding factors such as coinfections, differences in H. pylori strains, and immunologic and genetic host factors will have to be further identified and controlled for to understand the role of H. pylori in Raynaud’s phenomenon and SSc. The association between H. pylori infection and Raynaud’s syndrome [36,38] has been attributed to increased levels of cytokines and acute phase reactants, such as C-reactive protein and fibrinogen, resulting in vasospasm and platelet aggregation. Kalabay et al. [40], who found a high prevalence of H. pylori infection in SSc patients (78%) (n = 55), attempted to explain the preferential occurrence of H. pylori infection in SSc in two ways. First, an increased prevalence of H. pylori infection might be favoured by the disturbed gastrointestinal motility, a clinical phenomenon well known in SSc patients. The second explanation may be that H. pylori infection and the immunological mechanisms operative in the course of SSc may be related to each other. We recently performed a study aiming to evaluate the possible association between H. pylori infection with disease activity, biochemical and serological data [41]. Our preliminary results suggest that the H. pylori infection is implicated in activity of SSc, especially in skin involvement of this disease. This study may indicate the H. pylori infection as a possible cofactor in the development of SSc. Clinical trials are still necessary to define the pathogenesis and confirm the increase in association between H. pylori and SSc. Unfortunately, the experimental (animal) model which could be a
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relevant way to demonstrate the possible role of H. pylori in SSc is still missing. 4. Pathogenetic hypothesis Various mechanisms have been proposed in an attempt to explain the extra-intestinal manifestations of H. pylori infections. These include: molecular mimicry, endothelial cell damage, superatigens and microchimerism. Molecular mimicry is a mechanism that may explain the pathogenicity of antibodies against bacterial proteins in SSc. It is well known that the immunological response elicited by H. pylori is an important determinant of the amount of gastric mucosal damage. Thus the production of large amounts of various proinflammatory substances, such as cytokines, eicosanoids, and proteins of the acute phase, follows gastric colonisation by H. pylori [42]. This inflammatory response may lead to the development of antigen-antibody complexes or cross-reactive antibodies (by molecular mimicry) resulting in damage to other organs [6]. Endothelial injury represents one of the first steps in the pathogenesis of SSc. Raynaud’s phenomenon and diffuse microangiopathy suggests that endothelial cell injury is the event evolving in concert with excessive collagen production. It is unclear whether the collagen overproduction is a sequel of endothelial injury or reflects an inherent abnormality of fibroblasts independent from vasculopathy and/or the immune alterations, and if it follows or precedes endothelial changes [42]. Endothelial cell may be infected by bacteria that may be instrumental in inducing vasculitis. Probably, the starting event is the internalization of bacterial agents by endothelial cell, or the infection of endothelial cell by microorganism which leads to leukocyte recruitment and adhesion to the vascular endothelium followed by inflammatory response [43]. Superantigens are proteins that are expressed endogenously in the organism or that are derived exogenously by bacteria [44]. Microbial superantigens could initiate an immediate T cell while it has been shown that B cell response may bind to microbial superantigens to surface class II MHC molecules and become a target of T-helper lymphocytes. The term microchimerism refers to one individual harbouring DNA or cells at a low level that derive from another individual. Microchimeric cells were found in 82.9% of peripheral blood and skin lesions SSc patients compared to 63.6% of controls [45]. Circulating levels of CD4+ and CD8+ T cells were found significantly higher in SSc patients than in controls. Furthermore, patients with diffuse SSc have significantly more CD4+ microchimeric T cells than controls [46]. In people with circulating microchimeric T cells, the endothelium represents an allotypic stimulus to those cells. This may mimic the same pathway transplanted T cells follow in graft-versus-host disease. Infections by any microorganism may trigger the intervention of ␥/␦ T cells (found in significant amount in SSc skin). The meeting of ␥/␦ T cells with microorganism shift from a Th2 tolerogenic to a Th1 cytotoxic pattern. The ␥/␦ T cells may encounter resident microchimeric cells inducing a cross-reaction against “nonself” cells igniting automatically a graft-versus-host disease-like reaction [47]. For all of these reasons, confounders like co-infections, differences between H. pylori strains, and host factors should be observed and controlled to understand possible role of H. pylori infection in SSc [48]. 5. Conclusion If H. pylori induces autoimmune disease, how does it do so? There are various mechanisms by which an infecting agent may induce autoimmunity, including molecular mimicry, polyclonal activation, epitope spread, bystander activation and superantigens. In any case, it is now almost universally accepted that microbial agents play a major role in the pathogenesis of many autoimmune
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diseases and it is clear that, in genetically susceptible subjects, a certain environmental factor (especially an infective agent) may induce or exacerbate them [48]. Various mechanisms have been proposed in an attempt to explain the extra-intestinal manifestations of H. pylori infections. These include: atrophic gastritis, an increase in gastric vascular permeability during infection, release of inflammatory mediators, molecular mimicry and systemic immune response. As an example, antigastric autoantibodies have been found in more than 30% of patients who are infected with H. pylori [5]. An increase in permeability of the gastric and intestinal mucosa in infected patients has also been demonstrated [7], and may result in increased exposure to alimentary antigens. Of note is that it is well known that the immunological response elicited by H. pylori is an important determinant of the amount of gastric mucosal damage. Thus the production of large amounts of various proinflammatory substances, such as cytokines, eicosanoids, and proteins of the acute phase, follows gastric colonisation by H. pylori [42]. This inflammatory response may lead to the development of antigen-antibody complexes or cross-reactive antibodies (by molecular mimicry) resulting in damage to other organs [6]. It has been proposed that H. pylori induces a phenomenon similar to that seen in the molecular mimicry between haemolytic streptococcus group A antigens and host proteins resulting in both humoral and cell mediated autoimmune reactions and ultimately causing rheumatic fever and rheumatic heart disease [49]. Based on these observations, investigators have examined the role of H. pylori as a pathogenic determinant for idiopathic extra intestinal diseases, in which immune dysregulation is implicated. A competing theory that is also being discussed is that an infection-induced immune response continues after the pathogen has been eradicated. This could explain why patients with confirmed eradication therapy failed to show improvement in short-term observations. H. pylori is frequently associated with various autoimmune diseases, although its precise role in many of them is still controversial [50]. Although several studies provide important information linking H. pylori to SSc, a direct association is still missing. Depending on factors such as genetic susceptibility, time of infection and disease type, it may act in different ways: it can be involved in pathogenesis and trigger the development of overt disease, or it may be protective. H. pylori components, urease in particular, may be among the environmental triggers that initiate SSc via producing autoreactive antibodies through the activation of B-1 cells, a subpopulation of B lymphocytes [51]. However, further studies are required in order to clarify its effects on autoimmunity. Very few infections are as rare as SSc. Therefore, development of SSc is unlikely to depend exclusively on an infectious agent. Instead, it likely occurs as a result of interactions between the infectious agent and a cascade of host-specific factors and events. This is not surprising because immune response to infection is highly individual. It is controlled by multiple genes, age, and the route of infection. It may even be different in the same individual from one day to the next owing to a number of factors, including coinfections, stress, and pregnancy. In addition, polymorphisms in genes unrelated to immunity may cause an infectious agent to induce disease through molecular mimicry in one person and not another. This hypothesis could be confirmed by the fact that that many SSc-like symptoms are provoked by infectious agents in healthy subjects [52]. Therefore, in a disease as varied, complex, and rare as SSc, infection prevalence alone should not be expected to provide sufficient evidence for or against a pathologic role in the disease. Alternatively, eradication and prevention of putative infectious triggers of SSc with drug prophylaxis may provide an answer in the long term. Conflict of interest statement None of the authors has any conflicts of interest to declare.
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References [1] Kahaleh MB, LeRoy EC. Autoimmunity and vascular involvement in systemic sclerosis (SSc). Autoimmunity 1999;31:195–214. [2] Pandey JP, LeRoy EC. Human cytomegalovirus and the vasculopathies of autoimmune diseases (especially scleroderma), allograft rejection, and coronary restenosis. Arthritis Rheum 1998;41:10–5. [3] Namboodiri AM, Rocca KM, Kuwana M, et al. Antibodies to human cytomegalovirus protein UL83 in systemic sclerosis. Clin Exp Rheumatol 2006;24:176–8. [4] Arnson Y, Amital H, Guiducci S, et al. The role of infections in the immunopathogensis of systemic sclerosis–evidence from serological studies. Ann N Y Acad Sci 2009;1173:627–32. [5] Lehours P, Yilmaz O. Epidemiology of Helicobacter pylori infection. Helicobacter 2007;12(Suppl. 1):1–3. [6] Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:784–9. [7] Magalhaes Queiroz DM, Luzza F. Epidemiology of Helicobacter pylori infection. Helicobacter 2006;11(Suppl. 1):1–5. [8] Ndip RN, MacKay WG, Farthing MJ, et al. Culturing Helicobacter pylori from clinical specimens: review of microbiologic methods. J Pediatr Gastroenterol Nutr 2003;36:616–22. [9] Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:1311–5. [10] Andersen LP, Colonization. Infection by Helicobacter pylori in humans. Helicobacter 2007;12(Suppl. 2):12–5. [11] Maeda S, Mentis AF. Pathogenesis of Helicobacter pylori infection. Helicobacter 2007;12(Suppl. 1):10–4. [12] Palli D, Masala G, Del Giudice L, et al. CagA+ Helicobacter pylori infection and gastric cancer risk in the EPIC-EURGAST study. Int J Cancer 2007;120:859–67. [13] Basset C, Holton J, Gatta L, et al. Helicobacter pylori infection: anything new should we know? Aliment Pharmacol Ther 2004;20(Suppl. 2):31–41. [14] Zhang QB, Etolhi G, Dawodu JB, et al. Relationship between mucosal levels of interleukin 8 and toxinogenicity of Helicobacter pylori. Inflammopharmacology 1998;6:109–17. [15] Chan AO, Chu KM, Huang C, et al. Association between Helicobacter pylori infection and interleukin 1beta polymorphism predispose to CpG island methylation in gastric cancer. Gut 2007;56:595–7. [16] García-González MA, Lanas A, Quintero E, et al. Gastric cancer susceptibility is not linked to pro-and anti-inflammatory cytokine gene polymorphisms in whites: a Nationwide Multicenter Study in Spain. Am J Gastroenterol 2007;102:1878–92. [17] Obonyo M, Sabet M, Cole SP, et al. Deficiencies of myeloid differentiation factor 88, Toll-like receptor 2 (TLR2), or TLR4 produce specific defects in macrophage cytokine secretion induced by Helicobacter pylori. Infect Immun 2007;75:2408–14. [18] Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772–81. [19] Amital H, Govoni M, Maya R, et al. Role of infectious agents in systemic rheumatic diseases. Clin Exp Rheumatol 2008;26:27–32. [20] Ebert EC. Gastric and enteric involvement in progressive systemic sclerosis. J Clin Gastroenterol 2008;42:5–12. [21] Heidt PJ, Vossen JM. Experimental and clinical gnotobiotics: influence of the microflora on graft-versus-host disease after allogeneic bone marrow transplantation. J Med 1992;23:161–73. [22] Waer M, Ang KK, Van der Schueren E, et al. Allogeneic bone marrow transplantation in mice after total lymphoid irradiation: influence of breeding conditions and strain of recipient mice. J Immunol 1984;132:991–6. [23] Vossen JM, Heidt PJ, van den Berg H, et al. Prevention of infection and graftversus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation. Eur J Clin Microbiol Infect Dis 1990;9:14–23. [24] Ando T, Minami M, Ishiguro K, et al. Changes in biochemical parameters related to atherosclerosis after Helicobacter pylori eradication. Aliment Pharmacol Ther 2006;24(Suppl. 4):58–64. [25] McNamara D, O’Morain C. Gastro-oesophageal reflux disease and Helicobacter pylori: an intricate relation. Gut 1999;45(Suppl. 1):13–7. [26] Voutilainen M, Sipponen P, Mecklin JP, et al. Gastroesophageal reflux disease: prevalence, clinical, endoscopic and histopathological findings in 1,128 consec-
[27]
[28]
[29]
[30]
[31]
[32] [33] [34] [35] [36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44] [45] [46]
[47] [48] [49]
[50]
[51]
[52]
utive patients referred for endoscopy due to dyspeptic and reflux symptoms. Digestion 2000;61:6–13. Wu JC, Sung JJ, Chan FK, et al. Helicobacter pylori infection is associated with milder gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000;14:427–32. Reinauer S, Goerz G, Ruzicka T, 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. Graham DY, Malaty HM, Evans DG, et al. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Effect of age, race, and socioeconomic status. Gastroenterology 1991;100:1495–501. Aragona P, Magazzu G, Macchia G, et al. Presence of antibodies against Helicobacter pylori and its heat-shock protein 60 in the serum of patients with Sjogren’s syndrome. J Rheumatol 1999;26:1306–11. Yazawa N, Fujimoto M, Kikuchi K, et al. High seroprevalence of Helicobacter pylori infection in patients with systemic sclerosis: association with esophageal involvement. J Rheumatol 1998;25:650–3. Yamaguchi K, Iwakiri R, Hara M, et al. Reflux esophagitis and Helicobacter pylori infection in patients with scleroderma. Intern Med 2008;47:1555–9. Wipff J, Allanore Y, Soussi F, et al. Prevalence of Barrett’s esophagus in systemic sclerosis. Arthritis Rheum 2005;52:2882–8. Gasbarrini A, Massari I, Serricchio M, et al. Helicobacter pylori eradication ameliorates primary Raynaud’s phenomenon. Dig Dis Sci 1998;43:1641–5. Csiki Z, Gál I, Sebesi J, et al. Raynaud syndrome and eradication of Helicobacter pylori. Orv Hetil 2000;141:2827–9. Savarino V, Sulli A, Zentilin P, et al. No evidence of an association between Helicobacter pylori infection and Raynaud phenomenon. Scand J Gastroenterol 2000;35:1251–4. Sulli A, Seriolo B, Savarino V, et al. Lack of correlation between gastric Helicobacter pylori infection and primary or secondary Raynaud’s phenomenon in patients with systemic sclerosis. J Rheumatol 2000;27:1820–1. Hervé F, Cailleux N, Benhamou Y, et al. Helicobacter pylori prevalence in Raynaud’s disease. Rev Med Interne 2006;27: 736–41. Danese S, Zoli A, Cremonini F, et al. High prevalence of Helicobacter pylori type I virulent strains in patients with systemic sclerosis. J Rheumatol 2000;27:1568–9. Kalabay L, Fekete B, Czirják L, et al. Helicobacter pylori infection in connective tissue disorders is associated with levels of antibodies to mycobacterial hsp65 but not to human hsp60. Helicobacter 2002;7:250–8. Radic´ M, Martinovic´ Kaliterna M, Bonacin D, et al. Correlation between Helicobacter pylori infection and systemic sclerosis activity. Rheumatology (Oxford) 2010;49:1784–5. Negrini R, Savio A, Poiesi C, et al. Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology 1996;111:655–65. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical and serological features and survival in 1012 Italian patients. Medicine 2002;81:139. Randone SB, Guiducci S, Cerinic MM. Systemic sclerosis and infections. Autoimmun Rev 2008;8:36–40. Lobo-Yeo A, Lamb JR. Superantigens as immunogens and tolerogens. Clin Exp Rheumatol 1993;11:17–21. Rak JM, Pagni PP, Tiev K, et al. Male microchimerism and HLA compatibility in French women with sclerodema: a different profile in limited and diffuse subset. Rheumatology (Oxford) 2009;48:363–6. Gilliam AC. Scleroderma. Curr Dir Autoimmun 2008;10:258–79. Mora GF. Systemic sclerosis: environmental factors. J Rheumatol 2009;36:2383–96. Giacomelli R, Cipriani P, Fulminis A, et al. Gamma/delta T cells in placenta and skin: their different functions may support the paradigm of microchimerism in systemic sclerosis. Clin Exp Rheumatol 2004;22:28–30. Macchia G, Massone A, Burroni D, et al. The hsp60 protein of Helicobacter pylori: structure and immune response in patients with gastrointestinal diseases. Mol Microbiol 1993;3:645–52. Yamanishi S, Iizumi T, Watanabe E, et al. Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pylori urease. Infect Immun 2006;74:248–56. Hamamdzic D, Kasman L, LeRoy C. Role of infectious agents in the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 2002;14:694–8.
Review
Helicobacter pylori infection and systemic sclerosis–is there a link? Mislav Radic´ a,∗ , Duˇsanka Martinovic´ Kaliterna a , Josipa Radic´ b a b
Department of Rheumatology, University Hospital, Split, Croatia Department of Nephrology, University Hospital, Split, Croatia
a r t i c l e
i n f o
Article history: Accepted 8 October 2010 Available online 8 December 2010 Keywords: Systemic sclerosis Helicobacter pylori Pathogenesis
a b s t r a c t Over the last 20 years, increasing evidence has accumulated to implicate infectious agents in the etiology of systemic sclerosis (SSc) and Raynaud’s phenomenon. Infection rates in patients with SSc compared with those in control populations do not provide clear support for any specific pathogen. However, increased antibody titers, a preponderance of specific strains in patients with SSc, and evidence of molecular mimicry inducing autoimmune responses suggest mechanisms by which infectious agents may contribute to the development and progression of SSc. Helicobacter pylori (H. pylori) has been associated with diseases such as autoimmune gastritis, Sjögren’s syndrome, atherosclerosis, immune thrombocytopenia purpura, inflammatory bowel diseases and autoimmune pancreatitis, in each of which it seems to play a pathogenetic, but it has also been suggested that it may help to protect against the development of autoimmune gastritis, multiple sclerosis, systemic lupus erythemathosus and inflammatory bowel diseases. A systematic literature search was carried out in MEDLINE, EMBASE, Cochrane Library and ACR/EULAR meeting abstracts. We hypotheses that H. pylori infection might play a critical role in the pathogenesis of SSc. Here we review studies examining the potential involvement of H. pylori infection in SSc. © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Systemic sclerosis (SSc) is a chronic multisystemic disease characterized by the excess deposition of connective tissue in the skin and internal organs, and is associated with microvasculature changes and immunologic abnormalities. SSc is a complex autoimmune disease characterized by three types of slow and frequently overlapping pathologic processes [1,2]. Immune/autoimmune pathologies are present, including perturbations in both cellular and humoral immunity. Cellular immunity in SSc is typified by an increase in the number of CD4+ T-helper and ␥/␦-TCR+ lymphocytes and a decrease in the number of CD8+ cytotoxic T lymphocytes. The humoral aspect of SSc pathology is characterized by the generation of self-reactive antibodies such as antiendothelial cell antibodies and antitopoisomerase, anticentromere, and antifibrillin-1 antibodies. In addition, there are fibrotic processes characterized by abnormal fibroblast/myofibroblast cell proliferation and the deposition of excessive extracellular matrix proteins in affected organs. Finally, there is vascular pathology, characterized by microvascular endothelial cell activation (increased expression of adhesion molecules such as E-selectin, P-selectin, and intracel-
lular adhesion molecule-1), and injury (endothelial cell apoptosis). The cause of SSc remains unclear. Increasing evidence suggests that there are many potential environmental triggers for SSc and that host factors determine susceptibility to disease in response to these triggers. Infectious agents, bacterial and viral, have long been suspected as a contributing factor in the development and progression of the pathologic features of SSc [3]. The infectious agents might have a role in SSc pathogenesis and expression, antibodies against cytomegalovirus, hepatitis B virus, and toxoplasmosis were detected more often in SSc patients [4]. The main question is: Where an infectious agent may impact on a patient to induce SSc? However, there are three main organs that may be the first entrance door: air (lung), direct contact (skin), meal (esophagus). Clearly, these three organs may be the target of a microorganism with a deleterious effect triggering the first local reaction. We performed a systematic literature review using the keywords “systemic sclerosis”, “Helicobacter pylori” and “pathogenesis”. A systematic literature search was carried out in MEDLINE; EMBASE; Cochrane Library and ACR/EULAR meeting abstracts. 2. Helicobacter pylori infection
∗ Corresponding author. Siˇ ˇ zgoriceva ´ 20, 21 000 Split, Croatia. Tel.: +00385 21 53 26 91/00385 91 89 41 421. ´ E-mail address: [email protected] (M. Radic).
Helicobacter pylori (H. pylori) is a gram negative, spiral shaped organism that colonizes the human gastric mucosa. H. pylori is one of the most common pathogens affecting humans, infecting
1297-319X/$ – see front matter © 2010 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved. doi:10.1016/j.jbspin.2010.10.005
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approximately 50% of the world’s population. It is found more frequently in developing countries than in industrialized countries, presumably due to poor sanitary conditions [5]. The outcome of the infection depends on a combination of factors: bacterial virulence, host factors, and environmental factors [6]. Ulceration and carcinogenesis are mutually exclusive outcomes of this infection. H. pylori infection is a very persistent infection, and in areas of high prevalence, repeated infections are common [5,7]. The bacteria have been isolated from feces, saliva and dental plaques of infected patients, which suggest that the fecal-oral route is a possible transmission mode [8]. The pathogen is a gram-negative spiral shaped bacterium that has the unique ability to colonize the human gastric mucosa [9]. Some virulence factors such as urease and flagella are present in all strains and are necessary for the pathogenesis and colonization of the gastric mucosa. With its flagella, the bacterium moves through the gastric lumen and drills into the gastric mucosal layer. The presence of the flagella, and thus motility, is required for persistent gastric colonization [10]. The main bacterial factors associated with pathogenicity comprise outer membrane proteins, including the vacuolating cytotoxin VacA, and the products of CagA. An interaction between bacterial factors such as CagA and host signal transduction pathways seems to be critical for mediating cell transformation, cell proliferation, invasion, apoptosis/antiapoptosis, and angiogenesis [11]. The key pathophysiological event in H. pylori infection is initiation and continuance of an inflammatory response. Bacteria or their products trigger this inflammatory process the main mediators of which are cytokines [12,13]. This response is related to the expression of proinflammatory cytokines, both on the surface epithelium and in macrophages/monocytes [14–17]. Another putative virulence determinant is the neutrophil-activating protein (NapA) gene, a gene that was shown to be induced by contact with the epithelium (iceA1) [18].
3. Helicobacter pylori infection and systemic sclerosis The relationship between infection and autoimmunity has been increasingly defined over the last 20 years [19]. An increasing body of evidence suggests that there are many potential environmental triggers for SSc and that host factors determine the susceptibility of the host to disease in response to these triggers [20]. The hypothesis that infectious agents may cause SSc has been studied extensively. The rationale for this “infection hypothesis” is that many SSc-like symptoms are transiently elicited by infectious agents in otherwise healthy individuals. There are two general lines of evidence implicating bacterial infections in the pathogenesis of SSc. One is anecdotal evidence that antibiotic treatments relieve SSc symptoms in some people. The other is that graft-versus-host disease, which is recognized as having many similarities to SSc, cannot be induced in germ-free animals and is significantly reduced in children pretreated with antibiotics to eradicate their normal bacterial flora [21–23]. Recently performed study on the involvement of bacterial infections in the pathogenesis of SSc focuses on H. pylori, which has been implicated in other vascular diseases [24]. The influence of H. pylori infection on reflux esophagitis with SSc is still controversial [25–27]. According to previous reports, SSc patients have an accelerated frequency of H. pylori infection compared to the average incidence of gastric H. pylori in white, healthy, asymptomatic subjects [28–30]. Yazawa et al. showed that SSc patients have a higher incidence of IgG antibodies to H. pylori compared to the general population [31]. Although one study showed that H. pylori infection plays an important role in the prevalence of endoscopic reflux esophagitis associated with SSc in Japanese population [32]. Wipff et al. evaluated 110 SSc patients who were receiving long-term treatment with proton-pump inhibitors using
esophageal manometry and endoscopy [33]. In this study, the prevalence of Barrett’s esophagus was 12.7%, similar to the prevalence in patients with gastresophageal reflux disease. However, none of these patients with Barrett’s esophagus had esophageal adenocarcinoma [32]. Studies have investigated H. pylori infections for an association with Raynaud’s phenomenon, Sjögren syndrome, and SSc. In a study of patients with primary Raynaud’s phenomenon, eradication of H. pylori infection with a triple antibiotic regimen was associated with complete disappearance of Raynaud’s phenomenon episodes in 17% of those treated and a reduction in symptoms in an additional 72% of patients [33]. The possible bias of this study that it was not double blind, it is very interesting that Raynaud’s phenomenon symptoms were not improved in those patients in whom the treatment failed to eradicate the H. pylori infection. A more recent trial of similar design reported very similar results [34]. Attempts to associate H. pylori infection status and SSc have had some conflicting results. In 1999, Aragona et al. identified higher incidence rates of H. pylori infection in patients with rheumatic diseases, including SSc, as detected by serologic analysis [30]. In contrast to these results, three larger studies found no difference in H. pylori infection rates between patients with SSc with Raynaud’s phenomenon and healthy controls [35–38]. However, even if it is true that H. Pylori infection rates in these studies are not correlated with SSc, this does not necessarily rule out its involvement in the disease. Danese et al. confirmed that, although there is no difference in the H. pylori infection rate between control subjects and patients with SSc, 90% of patients with SSc were infected with the virulent CagA strain compared with 37% of infected control subjects [39]. Increased seroprevalence of H. pylori has been found in SSc (78%) [30]. Disturbed gastrointestinal motility in SSc patients may be linked to overlap with the occurrence of H. pylori that has been correlated to the risk of coronary heart disease and seems associated to Raynaud’s phenomenon [36]. It has been demonstrated that H. pylori sheds extracellular products that elicit local and systemic immune response that could be responsible for tissue damage. A 60 kDa protein, belonging to the heat shock proteins (hsp) seems to be involved: in fact, H. pylori associated, human hsp60 and mycobacterial hsp65 are members of the 60 kDa family of the hsp and they share high sequence homology [39]. These patients may elicit antibodies against these hsp. Therefore, confounding factors such as coinfections, differences in H. pylori strains, and immunologic and genetic host factors will have to be further identified and controlled for to understand the role of H. pylori in Raynaud’s phenomenon and SSc. The association between H. pylori infection and Raynaud’s syndrome [36,38] has been attributed to increased levels of cytokines and acute phase reactants, such as C-reactive protein and fibrinogen, resulting in vasospasm and platelet aggregation. Kalabay et al. [40], who found a high prevalence of H. pylori infection in SSc patients (78%) (n = 55), attempted to explain the preferential occurrence of H. pylori infection in SSc in two ways. First, an increased prevalence of H. pylori infection might be favoured by the disturbed gastrointestinal motility, a clinical phenomenon well known in SSc patients. The second explanation may be that H. pylori infection and the immunological mechanisms operative in the course of SSc may be related to each other. We recently performed a study aiming to evaluate the possible association between H. pylori infection with disease activity, biochemical and serological data [41]. Our preliminary results suggest that the H. pylori infection is implicated in activity of SSc, especially in skin involvement of this disease. This study may indicate the H. pylori infection as a possible cofactor in the development of SSc. Clinical trials are still necessary to define the pathogenesis and confirm the increase in association between H. pylori and SSc. Unfortunately, the experimental (animal) model which could be a
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relevant way to demonstrate the possible role of H. pylori in SSc is still missing. 4. Pathogenetic hypothesis Various mechanisms have been proposed in an attempt to explain the extra-intestinal manifestations of H. pylori infections. These include: molecular mimicry, endothelial cell damage, superatigens and microchimerism. Molecular mimicry is a mechanism that may explain the pathogenicity of antibodies against bacterial proteins in SSc. It is well known that the immunological response elicited by H. pylori is an important determinant of the amount of gastric mucosal damage. Thus the production of large amounts of various proinflammatory substances, such as cytokines, eicosanoids, and proteins of the acute phase, follows gastric colonisation by H. pylori [42]. This inflammatory response may lead to the development of antigen-antibody complexes or cross-reactive antibodies (by molecular mimicry) resulting in damage to other organs [6]. Endothelial injury represents one of the first steps in the pathogenesis of SSc. Raynaud’s phenomenon and diffuse microangiopathy suggests that endothelial cell injury is the event evolving in concert with excessive collagen production. It is unclear whether the collagen overproduction is a sequel of endothelial injury or reflects an inherent abnormality of fibroblasts independent from vasculopathy and/or the immune alterations, and if it follows or precedes endothelial changes [42]. Endothelial cell may be infected by bacteria that may be instrumental in inducing vasculitis. Probably, the starting event is the internalization of bacterial agents by endothelial cell, or the infection of endothelial cell by microorganism which leads to leukocyte recruitment and adhesion to the vascular endothelium followed by inflammatory response [43]. Superantigens are proteins that are expressed endogenously in the organism or that are derived exogenously by bacteria [44]. Microbial superantigens could initiate an immediate T cell while it has been shown that B cell response may bind to microbial superantigens to surface class II MHC molecules and become a target of T-helper lymphocytes. The term microchimerism refers to one individual harbouring DNA or cells at a low level that derive from another individual. Microchimeric cells were found in 82.9% of peripheral blood and skin lesions SSc patients compared to 63.6% of controls [45]. Circulating levels of CD4+ and CD8+ T cells were found significantly higher in SSc patients than in controls. Furthermore, patients with diffuse SSc have significantly more CD4+ microchimeric T cells than controls [46]. In people with circulating microchimeric T cells, the endothelium represents an allotypic stimulus to those cells. This may mimic the same pathway transplanted T cells follow in graft-versus-host disease. Infections by any microorganism may trigger the intervention of ␥/␦ T cells (found in significant amount in SSc skin). The meeting of ␥/␦ T cells with microorganism shift from a Th2 tolerogenic to a Th1 cytotoxic pattern. The ␥/␦ T cells may encounter resident microchimeric cells inducing a cross-reaction against “nonself” cells igniting automatically a graft-versus-host disease-like reaction [47]. For all of these reasons, confounders like co-infections, differences between H. pylori strains, and host factors should be observed and controlled to understand possible role of H. pylori infection in SSc [48]. 5. Conclusion If H. pylori induces autoimmune disease, how does it do so? There are various mechanisms by which an infecting agent may induce autoimmunity, including molecular mimicry, polyclonal activation, epitope spread, bystander activation and superantigens. In any case, it is now almost universally accepted that microbial agents play a major role in the pathogenesis of many autoimmune
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diseases and it is clear that, in genetically susceptible subjects, a certain environmental factor (especially an infective agent) may induce or exacerbate them [48]. Various mechanisms have been proposed in an attempt to explain the extra-intestinal manifestations of H. pylori infections. These include: atrophic gastritis, an increase in gastric vascular permeability during infection, release of inflammatory mediators, molecular mimicry and systemic immune response. As an example, antigastric autoantibodies have been found in more than 30% of patients who are infected with H. pylori [5]. An increase in permeability of the gastric and intestinal mucosa in infected patients has also been demonstrated [7], and may result in increased exposure to alimentary antigens. Of note is that it is well known that the immunological response elicited by H. pylori is an important determinant of the amount of gastric mucosal damage. Thus the production of large amounts of various proinflammatory substances, such as cytokines, eicosanoids, and proteins of the acute phase, follows gastric colonisation by H. pylori [42]. This inflammatory response may lead to the development of antigen-antibody complexes or cross-reactive antibodies (by molecular mimicry) resulting in damage to other organs [6]. It has been proposed that H. pylori induces a phenomenon similar to that seen in the molecular mimicry between haemolytic streptococcus group A antigens and host proteins resulting in both humoral and cell mediated autoimmune reactions and ultimately causing rheumatic fever and rheumatic heart disease [49]. Based on these observations, investigators have examined the role of H. pylori as a pathogenic determinant for idiopathic extra intestinal diseases, in which immune dysregulation is implicated. A competing theory that is also being discussed is that an infection-induced immune response continues after the pathogen has been eradicated. This could explain why patients with confirmed eradication therapy failed to show improvement in short-term observations. H. pylori is frequently associated with various autoimmune diseases, although its precise role in many of them is still controversial [50]. Although several studies provide important information linking H. pylori to SSc, a direct association is still missing. Depending on factors such as genetic susceptibility, time of infection and disease type, it may act in different ways: it can be involved in pathogenesis and trigger the development of overt disease, or it may be protective. H. pylori components, urease in particular, may be among the environmental triggers that initiate SSc via producing autoreactive antibodies through the activation of B-1 cells, a subpopulation of B lymphocytes [51]. However, further studies are required in order to clarify its effects on autoimmunity. Very few infections are as rare as SSc. Therefore, development of SSc is unlikely to depend exclusively on an infectious agent. Instead, it likely occurs as a result of interactions between the infectious agent and a cascade of host-specific factors and events. This is not surprising because immune response to infection is highly individual. It is controlled by multiple genes, age, and the route of infection. It may even be different in the same individual from one day to the next owing to a number of factors, including coinfections, stress, and pregnancy. In addition, polymorphisms in genes unrelated to immunity may cause an infectious agent to induce disease through molecular mimicry in one person and not another. This hypothesis could be confirmed by the fact that that many SSc-like symptoms are provoked by infectious agents in healthy subjects [52]. Therefore, in a disease as varied, complex, and rare as SSc, infection prevalence alone should not be expected to provide sufficient evidence for or against a pathologic role in the disease. Alternatively, eradication and prevention of putative infectious triggers of SSc with drug prophylaxis may provide an answer in the long term. Conflict of interest statement None of the authors has any conflicts of interest to declare.
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References [1] Kahaleh MB, LeRoy EC. Autoimmunity and vascular involvement in systemic sclerosis (SSc). Autoimmunity 1999;31:195–214. [2] Pandey JP, LeRoy EC. Human cytomegalovirus and the vasculopathies of autoimmune diseases (especially scleroderma), allograft rejection, and coronary restenosis. Arthritis Rheum 1998;41:10–5. [3] Namboodiri AM, Rocca KM, Kuwana M, et al. Antibodies to human cytomegalovirus protein UL83 in systemic sclerosis. Clin Exp Rheumatol 2006;24:176–8. [4] Arnson Y, Amital H, Guiducci S, et al. The role of infections in the immunopathogensis of systemic sclerosis–evidence from serological studies. Ann N Y Acad Sci 2009;1173:627–32. [5] Lehours P, Yilmaz O. Epidemiology of Helicobacter pylori infection. Helicobacter 2007;12(Suppl. 1):1–3. [6] Uemura N, Okamoto S, Yamamoto S, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 2001;345:784–9. [7] Magalhaes Queiroz DM, Luzza F. Epidemiology of Helicobacter pylori infection. Helicobacter 2006;11(Suppl. 1):1–5. [8] Ndip RN, MacKay WG, Farthing MJ, et al. Culturing Helicobacter pylori from clinical specimens: review of microbiologic methods. J Pediatr Gastroenterol Nutr 2003;36:616–22. [9] Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984;1:1311–5. [10] Andersen LP, Colonization. Infection by Helicobacter pylori in humans. Helicobacter 2007;12(Suppl. 2):12–5. [11] Maeda S, Mentis AF. Pathogenesis of Helicobacter pylori infection. Helicobacter 2007;12(Suppl. 1):10–4. [12] Palli D, Masala G, Del Giudice L, et al. CagA+ Helicobacter pylori infection and gastric cancer risk in the EPIC-EURGAST study. Int J Cancer 2007;120:859–67. [13] Basset C, Holton J, Gatta L, et al. Helicobacter pylori infection: anything new should we know? Aliment Pharmacol Ther 2004;20(Suppl. 2):31–41. [14] Zhang QB, Etolhi G, Dawodu JB, et al. Relationship between mucosal levels of interleukin 8 and toxinogenicity of Helicobacter pylori. Inflammopharmacology 1998;6:109–17. [15] Chan AO, Chu KM, Huang C, et al. Association between Helicobacter pylori infection and interleukin 1beta polymorphism predispose to CpG island methylation in gastric cancer. Gut 2007;56:595–7. [16] García-González MA, Lanas A, Quintero E, et al. Gastric cancer susceptibility is not linked to pro-and anti-inflammatory cytokine gene polymorphisms in whites: a Nationwide Multicenter Study in Spain. Am J Gastroenterol 2007;102:1878–92. [17] Obonyo M, Sabet M, Cole SP, et al. Deficiencies of myeloid differentiation factor 88, Toll-like receptor 2 (TLR2), or TLR4 produce specific defects in macrophage cytokine secretion induced by Helicobacter pylori. Infect Immun 2007;75:2408–14. [18] Malfertheiner P, Megraud F, O’Morain C, et al. Current concepts in the management of Helicobacter pylori infection: the Maastricht III Consensus Report. Gut 2007;56:772–81. [19] Amital H, Govoni M, Maya R, et al. Role of infectious agents in systemic rheumatic diseases. Clin Exp Rheumatol 2008;26:27–32. [20] Ebert EC. Gastric and enteric involvement in progressive systemic sclerosis. J Clin Gastroenterol 2008;42:5–12. [21] Heidt PJ, Vossen JM. Experimental and clinical gnotobiotics: influence of the microflora on graft-versus-host disease after allogeneic bone marrow transplantation. J Med 1992;23:161–73. [22] Waer M, Ang KK, Van der Schueren E, et al. Allogeneic bone marrow transplantation in mice after total lymphoid irradiation: influence of breeding conditions and strain of recipient mice. J Immunol 1984;132:991–6. [23] Vossen JM, Heidt PJ, van den Berg H, et al. Prevention of infection and graftversus-host disease by suppression of intestinal microflora in children treated with allogeneic bone marrow transplantation. Eur J Clin Microbiol Infect Dis 1990;9:14–23. [24] Ando T, Minami M, Ishiguro K, et al. Changes in biochemical parameters related to atherosclerosis after Helicobacter pylori eradication. Aliment Pharmacol Ther 2006;24(Suppl. 4):58–64. [25] McNamara D, O’Morain C. Gastro-oesophageal reflux disease and Helicobacter pylori: an intricate relation. Gut 1999;45(Suppl. 1):13–7. [26] Voutilainen M, Sipponen P, Mecklin JP, et al. Gastroesophageal reflux disease: prevalence, clinical, endoscopic and histopathological findings in 1,128 consec-
[27]
[28]
[29]
[30]
[31]
[32] [33] [34] [35] [36]
[37]
[38]
[39]
[40]
[41]
[42]
[43]
[44] [45] [46]
[47] [48] [49]
[50]
[51]
[52]
utive patients referred for endoscopy due to dyspeptic and reflux symptoms. Digestion 2000;61:6–13. Wu JC, Sung JJ, Chan FK, et al. Helicobacter pylori infection is associated with milder gastro-oesophageal reflux disease. Aliment Pharmacol Ther 2000;14:427–32. Reinauer S, Goerz G, Ruzicka T, 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. Graham DY, Malaty HM, Evans DG, et al. Epidemiology of Helicobacter pylori in an asymptomatic population in the United States. Effect of age, race, and socioeconomic status. Gastroenterology 1991;100:1495–501. Aragona P, Magazzu G, Macchia G, et al. Presence of antibodies against Helicobacter pylori and its heat-shock protein 60 in the serum of patients with Sjogren’s syndrome. J Rheumatol 1999;26:1306–11. Yazawa N, Fujimoto M, Kikuchi K, et al. High seroprevalence of Helicobacter pylori infection in patients with systemic sclerosis: association with esophageal involvement. J Rheumatol 1998;25:650–3. Yamaguchi K, Iwakiri R, Hara M, et al. Reflux esophagitis and Helicobacter pylori infection in patients with scleroderma. Intern Med 2008;47:1555–9. Wipff J, Allanore Y, Soussi F, et al. Prevalence of Barrett’s esophagus in systemic sclerosis. Arthritis Rheum 2005;52:2882–8. Gasbarrini A, Massari I, Serricchio M, et al. Helicobacter pylori eradication ameliorates primary Raynaud’s phenomenon. Dig Dis Sci 1998;43:1641–5. Csiki Z, Gál I, Sebesi J, et al. Raynaud syndrome and eradication of Helicobacter pylori. Orv Hetil 2000;141:2827–9. Savarino V, Sulli A, Zentilin P, et al. No evidence of an association between Helicobacter pylori infection and Raynaud phenomenon. Scand J Gastroenterol 2000;35:1251–4. Sulli A, Seriolo B, Savarino V, et al. Lack of correlation between gastric Helicobacter pylori infection and primary or secondary Raynaud’s phenomenon in patients with systemic sclerosis. J Rheumatol 2000;27:1820–1. Hervé F, Cailleux N, Benhamou Y, et al. Helicobacter pylori prevalence in Raynaud’s disease. Rev Med Interne 2006;27: 736–41. Danese S, Zoli A, Cremonini F, et al. High prevalence of Helicobacter pylori type I virulent strains in patients with systemic sclerosis. J Rheumatol 2000;27:1568–9. Kalabay L, Fekete B, Czirják L, et al. Helicobacter pylori infection in connective tissue disorders is associated with levels of antibodies to mycobacterial hsp65 but not to human hsp60. Helicobacter 2002;7:250–8. Radic´ M, Martinovic´ Kaliterna M, Bonacin D, et al. Correlation between Helicobacter pylori infection and systemic sclerosis activity. Rheumatology (Oxford) 2010;49:1784–5. Negrini R, Savio A, Poiesi C, et al. Antigenic mimicry between Helicobacter pylori and gastric mucosa in the pathogenesis of body atrophic gastritis. Gastroenterology 1996;111:655–65. Ferri C, Valentini G, Cozzi F, et al. Systemic sclerosis: demographic, clinical and serological features and survival in 1012 Italian patients. Medicine 2002;81:139. Randone SB, Guiducci S, Cerinic MM. Systemic sclerosis and infections. Autoimmun Rev 2008;8:36–40. Lobo-Yeo A, Lamb JR. Superantigens as immunogens and tolerogens. Clin Exp Rheumatol 1993;11:17–21. Rak JM, Pagni PP, Tiev K, et al. Male microchimerism and HLA compatibility in French women with sclerodema: a different profile in limited and diffuse subset. Rheumatology (Oxford) 2009;48:363–6. Gilliam AC. Scleroderma. Curr Dir Autoimmun 2008;10:258–79. Mora GF. Systemic sclerosis: environmental factors. J Rheumatol 2009;36:2383–96. Giacomelli R, Cipriani P, Fulminis A, et al. Gamma/delta T cells in placenta and skin: their different functions may support the paradigm of microchimerism in systemic sclerosis. Clin Exp Rheumatol 2004;22:28–30. Macchia G, Massone A, Burroni D, et al. The hsp60 protein of Helicobacter pylori: structure and immune response in patients with gastrointestinal diseases. Mol Microbiol 1993;3:645–52. Yamanishi S, Iizumi T, Watanabe E, et al. Implications for induction of autoimmunity via activation of B-1 cells by Helicobacter pylori urease. Infect Immun 2006;74:248–56. Hamamdzic D, Kasman L, LeRoy C. Role of infectious agents in the pathogenesis of systemic sclerosis. Curr Opin Rheumatol 2002;14:694–8.