Helicobacter pylori infection and dermatologic diseases

ARTICLE

Auteur(s) : Ana C Hernando-Harder¹, Nina Booken², Sergij Goerdt², Manfred V Singer¹, Hermann Harder¹

¹Department of Medicine II (Gastroenterology, Hepatology and Infectious Diseases), University Hospital Mannheim, Mannheim, Germany
²Department of Dermatology, University Hospital Mannheim, Theodor-Kutzer-Ufer 1-3, D-68167 Mannheim, Germany

accepté le 3 Mai 2009

Two Australian researchers, Barry J. Marshall and Robin Warren, discovered the curved bacillus Campylobacter pyloridis, which was later named Helicobacter pylori (H. pylori) in 1982. For this discovery they were awarded the Nobel Prize of 2005 in Physiology or Medicine [1, 2]. They had rebutted a long-standing dogma in medical science that stress and lifestyle factors lead to gastritis and peptic ulcer disease. Their work and later work by others established an irrefutable link between the presence of the gram-negative, flagellate, and microaerophilic bacilli and peptic ulceration [1, 3], distal gastric adenocarcinoma [2, 4], and gastric lymphoma [5]. The clinical manifestations of infection with this bacillus were shown to depend on the host, environmental, and bacterial factors.

Since then, many reports have emerged describing the pathogenetic potential of H. pylori. Not only does this pathogen cause local tissue damage in the gastric mucosa, it also has been implicated in a variety of diseases that are sometimes not even related to the gastrointestinal tract. These include, but are not limited to: mucosa-associated lymphoid tissue lymphomas (MALT Lymphomas) [6-8], inflammation of the coronaries [9, 10], iron deficiency anemia [11], rheumatological conditions [12-14], dermatologic diseases [12, 15-36], as well as a variety of other disorders (table 1).

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 [39]. An increase in permeability of the gastric and intestinal mucosa in infected patients has also been demonstrated [41], 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 [37]. 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 [40]. It has been proposed that H. pylori induces a phenomenon similar to that seen in the molecular mimicry between hemolytic 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 [38]. 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.

This review aims to provide a brief introduction on the pathophysiology of gastric H. pylori infection and its diagnosis. It then reviews current knowledge on the role of H. pylori infection in the pathogenesis of dermatologic diseases taking into account the available medical literature between 1988 and 2008.

Gastric Helicobacter pylori infection

The pathogen is a gram-negative spiral shaped bacterium that has the unique ability to colonize the human gastric mucosa [1]. 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 [43]. 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/anti-apoptosis, and angiogenesis [44]. 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 [4, 45]. This response is related to the expression of proinflammatory cytokines, both on the surface epithelium and in macrophages/monocytes [46-49]. 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) [50]. In the last 19 years, Helicobacter-like organisms like Helicobacter mustelae and Helicobacter hepaticus have been also detected.
Table 1 Diseases with a proven or suspected pathophysiological role of Helicobacter pylori.

Diagnosis of Helicobacter pylori

Helicobacter pylori and chronic urticaria

A possible association between H. pylori infection and chronic urticaria has been proposed [56-61], and several mechanisms have been implicated. One proposed mechanism is that an increase in gastric vascular permeability during infection results in greater exposure of the host to alimentary allergens [62]. In support of this suggestion duodenal ulcer patients have a higher incidence of allergic manifestations than controls. IgE-containing cells in gastric and duodenal mucosa seem to be the culprits [63], although there is limited evidence for HP-specific IgE [64, 65]. Thus, the possibility that patients with urticaria develop specific IgE against H. pylori is an attractive pathogenic explanation that unfortunately has not been confirmed yet.

The immunomodulatory role of H. pylori infection in CU is a subject of intensive debate. This immunomodulation is not only dependent on the virulence of H. pylori but also on host and environmental factors. An alternative possibility is that immunological stimulation by chronic infection may produce, through mediator release, a non-specific increase in sensitivity of the cutaneous vasculature to agents that enhance vascular permeability. Furthermore, IgG and IgA antibodies to 19-kDa H. pylori-associated lipoprotein were found to play role in the pathogenesis of CU [66, 67]. Moreover, H. pylori causes pronounced complement consumption due to H. pylori specific antibodies. This contributes further to the pathogenesis of CU [68, 69]. As recent studies have demonstrated, IgG autoantibodies against IgE and/or Fc εRi α can be found in the sera of one-third of patients with CU, and it is postulated that infection with H. pylori may induce production of pathogenetic antibodies possibly by molecular mimicry [70]. A growing body of evidence suggests that 30-50% of CU results from an autoimmune process involving functional histamine-releasing anti-Fc ε RI α autoantibodies or less commonly, anti-IgE-autoantibodies [71, 72]. Once this occurs, the production of antibodies might continue even after the eradication of H. pylori infection, explaining the lack of clinical improvement after eradication seen in some studies (table 4). Appelmelk et al. [70] first demonstrated the molecular mimicry between H. pylori and lipopolysaccharide (LPS) and anti-Lewis antibodies in autoimmune type-B gastritis. Further evidence was provided by the highly positive autologous serum skin test (ASST) results in chronic urticaria patients with H. pylori IgG antibodies [73].

Conflicting reports have been published. Some suggest that H. pylori eradication in patients with CU leads to an improvement in the symptoms of CU [60-74], while others showed no improvement (table 4).

The study by Magen et al. 2007, uses well-accepted standardized parameters to evaluate urticaria activity and found a significant decrease in urticaria activity score in HP-eradicated but not in non-eradicated CU patients [56].

Yadav et al. conducted a study to assess the prevalence of HP infection and effect of bacterium eradication on skin lesions in patients with chronic urticaria. In this study there was a high prevalence of HP infection, with 48 (70%) of the patients with CU and 46 (67%) of the controls testing positive for HP. The prevalence of HP in CU patients does not differ from that in patients without urticaria. But in infected patients there was a resolution of urticarial symptoms when HP eradication therapy was given. Patients of CU with HP-associated gastritis had a mean pretreatment CU-Q 2 oL score of 70.92 ± 12.59, mean post treatment score of 40.05 ± 10.35 (mean change 30.87 ± 12.19), which was statistically significant, P = 0.001, confidence interval at 5% level of significance [75].

Bakos et al. evaluated 56 patients with urticaria using gastroduodenoscopy. 33 patients had a positive urea breath test associated with mild gastritis on histology (score 1.3) [66]. Ojetti et al. studied 33 patients with CU. 57% CU patients and 64% controls (p > 0.05) were found to be infected with H. pylori. In all patients, endoscopic evaluation showed mild to moderate gastric hyperemia, and no evidence of peptic ulcer disease [76]. Wedi et al. assessed 100 patients with chronic urticaria. 47 of them had serologic evidence of H. pylori exposure. Twenty seven patients underwent endoscopic gastroduodenal examination. The presence of antral gastritis (100%) and corpus gastritis (46%) was confirmed histologically [25]. Thus these three groups found evidence of gastric inflammation in all patients with H. pylori positivity, but none had gastric or duodenal ulcers. Caig et al. studied 88 patients with CU. The 13C urea breath test was positive in 49 of them (56%). 20 patients underwent an upper endoscopy, but none had either gastrointestinal symptoms or endoscopic lesions [74]. To summarize, clinical trials including large numbers of patients are needed to establish a possible relationship between endoscopic gastrointestinal findings and CU.

To cure at least some patients from quality-of-life reducing CU, it seems worthwhile to eradicate H. pylori in all patients with CU and H. pylori infection. A positive effect is proposed for the eradication of H. pylori (grade C recommendation) [77].
Table 4 Studies on the frequency of H. pylori infection and the effect of eradication therapy in patients with chronic urticaria. Complete remission (> 90% improvement), partial remission (50-90% improvement), or no improvement (< 50% improvement). C: Clarithromycin; A: amoxicillin; M: metronidazole; L: lanzoprazol (Proton pump inhibitor); UBT: urea breath test.

Helicobacter pylori and rosacea

Recently, there have been several investigations suggesting a possible etiological role for H. pylori in rosacea [19, 26, 32, 67, 81-96]. Some of these investigations have shown that the prevalence of H. pylori infection in patients with rosacea is higher than that in control subjects [82] or average values, while others have reported that H. pylori eradication treatment reduces the severity of rosacea [63, 82-84, 91, 96, 97]. Additionally, it has been shown that H. pylori can increase serum or tissue levels of nitrous oxide (NO) [92], a free radical, which is important in a number of different physiological processes in the skin, including vasodilatation, inflammation, and immune modulation. Thus, it has been postulated that NO [92] produced by H. pylori might cause the flushing and erythema associated with rosacea, or that it may have a pathogenic role in the inflammation seen in rosacea. Increased ROS activity [98, 99] and decreased plasma antioxidant compounds, such as ascorbic acid, have been detected in H. pylori-infected patients. It has also been reported that the reduced circulating levels of vitamin C in H. pylori-infected subjects may contribute to the etiology of some diseases associated with antioxidant deficiency [100]. Inadequate antioxidant protection or excess production of ROS creates a condition known as oxidative stress, which is thought to play an important role in skin cancers, cutaneous aging, and many inflammatory skin diseases [80, 100].

Bonamigo et al. studied 62 patients with rosacea and 124 controls without rosacea. The data in this study show that: (i) patients with rosacea do not have a higher frequency of dyspeptic symptoms or a personal history of proven peptic disease; (ii) there do not appear to be differences in the frequency of exposure to H. pylori at different stages in the evolution of rosacea; and (iii) a weak association was found between exposure to H. pylori and rosacea, but stratified analysis showed that previous use of antibiotics modified the relationship between the factor studied and outcome [88].

Szlachcic and colleagues studied 60 subjects with skin lesions typical of rosacea. 53 (88.3%) had confirmed H. pylori infections as compared to only 39 (65%) of the non-ulcer disease controls. This interesting study showed a beneficial effect of H. pylori eradication in H. pylori-positive patients with acne rosacea, which led to a disappearance of the skin manifestations in 51 of 52 treated subjects [19]. The results led the authors to conclude that H. pylori eradication could be used in patients with rosacea that is unresponsive to conventional therapy. However, whether this effect is due to the eradication of H. pylori infection or is related to the cure of other concomitant infections is still unclear. In the endoscopic examination, 72% of the rosacea subjects had chronic active gastritis, predominantly antritis, 10% had chronic active multifocal inflammation of the stomach, and the remaining 18% had both antritis and chronic inflammation of the body of the stomach [19].

Boixeda de Miquel [96] and colleagues studied 44 patients diagnosed with rosacea. H. pylori infection was found in 84.1%. This supported a relationship between H. pylori and rosacea, and suggested that the presence of H. pylori infection should be ruled out in patients with rosacea because an appreciable percentage of these patients can benefit from eradication therapy, mainly patients with the papulopustular subtype. In this study, upper gastrointestinal endoscopy was performed in 37 patients. The findings in gastroduodenoscopy were: 5.4% duodenal ulcer; 5.4% erosive duodenitis; 18.9% chronic gastritis; 2.7% acute gastritis; and 67.6% of the cases had a normal examination.

Utaş et al. investigated the effect of H. pylori eradication therapy in 25 patients with rosacea and 87 healthy controls. The seroprevalence of H. pylori was similar in both groups. An upper gastrointestinal endoscopy and a rapid urease test were performed on the 13 patients with rosacea. There was no statistical difference in seropositivity between both groups. In H. pylori-positive rosacea patients there was a significant decrease in the severity of rosacea after eradication. These findings suggested that H. pylori may be involved in rosacea and that eradication may be beneficial [82].

However, further evidence from randomized clinical trials is required to confirm the effect of H. pylori eradication in patients with rosacea. A relationship between endoscopic gastrointestinal findings and rosacea could not be established yet. Prospective trials are necessary to confirm this association. At this time, and despite the promising data reviewed eradication of H. pylori in patients with rosacea is not generally recommended.

Helicobacter pylori and psoriasis

It has been suggested that H. pylori infection of gastric mucosa may be one of the organisms capable of triggering psoriasis [16, 28, 103], but to date this remains controversial. In an uncontrolled study of 33 patients with psoriasis and without any history of chronic gastrointestinal tract complaints, the seroprevalence of H. pylori infection was 27% [24]. Three patients were treated for H. pylori infection without apparent improvement in their psoriasis. Daudén et al. studied the CagA seroprevalence patients with psoriasis and concluded that the more virulent CagA positive strains of H. pylori did not seem to be strongly associated with psoriasis [34]. Recently, in another study in 50 psoriatic patients, the prevalence of H. pylori sero-positivity was significantly higher than in the control group [29]. There are contradicting reports on the benefits of H. pylori eradication in patients with chronic psoriasis [28, 36]. Prospective trials are needed to confirm this association.

Helicobacter pylori and Sjögren’s syndrome

The possible relationship between H. pylori and autoimmune diseases (including Sjögren’s syndrome) has been made particularly intriguing by a series of studies reporting an autoimmune reaction in bacterial-induced gastritis [106, 107]. A number of different autoantibodies in H. pylori infection have been described in the last few years. Among these, the anticanalicular autoantibodies seem to be directed against H+K+-ATPase and to correspond, in part, to the classic antiparietal cell antibodies of autoimmune gastritis (type A), whereas the antifoveolar antibodies appear to have less clinical relevance. Patients with anticanalicular autoantibodies against H+K+-ATPase could develop corpus atrophy with decreased acid secretion, [108, 109] subsequent loss of H. pylori and transition to classic autoimmune gastritis/pernicious anemia [110, 111]. It is not clear whether the gastritis associated with autoimmunity represents a truly different type of H. pylori gastritis or whether there are transitions between one type and the other. What seems likely is that the autoimmune reaction induced by H. pylori occurs in susceptible individuals [112]. Susceptibility to develop an autoimmune reaction following a microbial infection could be linked to the particular immune background of the host such as that of patients with Sjögren’s syndrome.

In a Japanese study the mean titers of anti-H. pylori antibodies was significantly higher (P < 0.05) in 7 patients with Sjögren syndrome than in 24 age-matched controls with chronic pulmonary disease [104]. In Finland, Collin et al. [113] studied 32 consecutive patients with primary Sjögren syndrome and 64 age- and sex-matched controls using upper endoscopy. Although atrophic gastritis of the antrum was found more frequently in the patients with Sjögren syndrome (25% vs. 4%; P < 0.01), there was no significant difference in the prevalence of H. pylori infection (31% vs. 39%; P > 0.05). In a study by Sorrentino et al. [114] H. pylori infection was equally prevalent among dyspeptic Sjögren’s syndrome patients (185 cases) and dyspeptic controls. Likewise, there were no differences regarding anti CagA prevalence or antigastric autoantibodies between the two groups. Similarly, Theander et al. [115] could not find higher H. pylori seropositivity in 164 Swedish patients with primary SS compared to controls. Thus good evidence is lacking for an association between H. pylori infection and Sjögren syndrome.

Helicobacter pylori and Schoenlein-Henoch purpura

Helicobacter pylori and alopecia areata

Helicobacter pylori and atopic dermatitis

A positive association between H. pylori antibodies and food allergy presenting with gastrointestinal symptoms has recently been reported. A subset of a H. pylori strain possesses an antigen, CagA, as a virulence factor. Anti H. pylori and anti-CagA IgG titer have been determined in children with atopic dermatitis as the sole clinical manifestation of food allergy. Corrado et al. demonstrated a positive association between H. pylori antibodies and food allergy in 30 children with gastrointestinal symptoms [128]. Recently, Galadari et al. studied 20 patients with atopic dermatitis. The prevalence of H. pylori infection was significantly higher (p < 0.05) compared to controls. Murakami et al. reported a case of AD and H. pylori infection in a 14-year-old girl: AD was successfully treated by eradication of H. pylori without any treatment for the skin lesions [129]. Some data seem to suggest that the increase in H. pylori antibodies may occur prior to AD. H. pylori, by damaging gastric mucosa, may trigger a food allergy reaction [130]. Later, an increase in IgE serum levels induces the synthesis and release of cytokines, sustaining chronic allergic inflammation, such as that seen AD. Moreover, it has been stressed that Staphylococcus aureus may promote AD by an IgE mediated immune response [131]. It is tempting to hypothesize that H. pylori may also induce a similar immunological event. Clinical trials are necessary to confirm these promising preliminary results.

Helicobacter pylori and Sweet syndrome

Helicobacter pylori and progressive systemic sclerosis

The most recent research on the involvement of bacterial infections in the pathogenesis of PSS focuses on H. pylori, which has been implicated in other vascular diseases [10]. Studies have investigated H. pylori infections for an association with Raynaud’s phenomenon, Sjögren syndrome, and PSS. In a study of patients with primary Raynaud’s phenomenon, eradication of H. pylori infection was associated with complete disappearance of the episodes of Raynaud’s phenomenon in 17% of treated patients and a reduction in symptoms in an additional 72% [136]. Although this study was not double blinded, it is intriguing that symptoms of Raynaud’s phenomenon did not improve in those patients in whom eradication of H. pylori failed. A more recent trial of comparable design reported very similar results [137]. One study identified higher incidence rates of serological evidence of H. pylori infection in patients with rheumatological diseases, including PSS [138]. In contrast, three larger studies found no difference in H. pylori infection rates between patients with PSS with Raynaud’s phenomenon compared to healthy controls [139-141]. However, even if it were true that H. pylori infection rates do not correlate with PSS, this does not necessarily rule out its involvement in PSS. A recent study [142] indicated that, despite the absence of a difference in H. pylori infection rates between PSS patients and control subjects, 90% of patients with PSS were infected with the virulent CagA strain compared with only 37% of the infected control subjects. Therefore, confounding factors such as co-infections, differences in H. pylori strains, and immunological and genetic host factors will have to be further identified and controlled in order to understand the role of H. pylori in Raynaud’s phenomenon, PSS, and other vascular phenomena. The association between H. pylori infection and Raynaud’s syndrome [140, 142] 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. [143], who found a high prevalence of H. pylori infection in patients with systemic sclerosis (78%) (n = 55), attempted to explain the preferential occurrence of H. pylori infection in PSS 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 patients with PSS. The second explanation may be that H. pylori infection and the immunological mechanisms operative in the course of PSS may be related to each other. Clinical trials are still necessary to define the pathogenesis and confirm the increase in association between H. pylori and PSS.

Helicobacter pylori and Behçet’s disease

Helicobacter pylori and cutaneous pruritus

In a study by Kandyil et al. [148] 10 patients with severe pruritus, unresponsive to conventional therapy, were evaluated for H. pylori infection. Eight had evidence of an active infection. Of these 88% had some pruritus relief after eradication. It therefore can be concluded that patients having an H. pylori infection may experience refractory pruritus that resolves after eradication of H. pylori (table 6). The evidence for a causal role of H. pylori in pruritus cutaneous needs further evaluation, however.
Table 6 The improvement rate in cutaneous pruritus after H. pylori eradication expressed as Nr. of patients and percent (%). Complete remission (> 90% improvement), partial remission (50-90% improvement) or no improvement (< 50% improvement). C: Clarithromycin; A: amoxicillin; M: metronidazole; L: lanzoprazol; UBT: urea breath test.

Chronic prurigo multiformis

Helicobacter pylori and nodular prurigo

Helicobacter pylori and immune thrombocytopenic purpura

Since the publication of Gasbarrini et al. in 1998 [150], several investigators, mostly in Japan and Italy, have studied the efficacy of H. pylori eradication in increasing the platelet count in ITP patients with evidence of H. pylori infection. In contrast to the findings by Gasbarrini et al., studies from the United States [151, 152] have refuted a clinical benefit from eradication suggesting a geographical difference in the efficacy of H. pylori eradication on ITP management. The value of H. pylori detection and eradication in managing ITP patients has therefore not received universal acceptance. Due to the fact that most studies demonstrated remarkable therapeutic benefits (i.e., bacterial eradication rate, platelet response rate, and durability of response) of antibiotics plus proton-pump inhibitors for adult patients with chronic ITP and active H. pylori infection [150, 153-171] (table 8), the European Helicobacter Study Group consensus 2007 [50] has recommended the eradication of H. pylori infection in patients with chronic idiopathic thrombocytopenic purpura. However, due to intrinsic limits in the design of the studies analysed, further evidence from randomized clinical trials is required to confirm the effect of eradication treatment on platelet count.

Only few studies in patients with ITP and H. pylori infection carried out endoscopic evaluations. Although demonstration of H. pylori in gastric biopsies is the gold standard of H pylori detection, many authors preferred blood antibody detection and/or the urea breath test due to the fact that upper endoscopy may result in unexpected bleeding in thrombocytopenic patients, especially in those whose platelet counts were less than 50 × 10⁹/L [152, 158, 161, 162, 164-167, 170-172]. Some investigators who performed endoscopic evaluation on ITP patients did not show the data [159, 168]. Emilia et al. studied 10 patients with ITP and H. pylori infection with gastroduodenoscopy. All (100%) had chronic and/or atrophic gastritis [169]. In a study by Ando et al., H. pylori infection was found in 17/20 ITP patients (85%). All of these patients had atrophic gastritis by endoscopic evaluation [158]. Further studies are needed to establish a relationship between ITP, H. pylori and endoscopic findings. Neverthelss, in patients with immune thrombocytopenic purpura and H. pylori infection, the recommendation for eradication is commonly accepted.
Table 8 Summary of literature published since 2004 on the efficacy of H. pylori eradication therapy on idiopathic thrombocytopenic purpura. HP, Helicobacter pylori; ITP, idiopathic thrombocytopenic purpura; Plt, platelet; NA, data not available.

Helicobacter pylori and lichen planus

A case-control study was conducted in 78 patients with LP. The prevalence of H. pylori infection in patients with chronic/refractory LP and transient LP was not significantly different from that in patients with other skin diseases [173]. Dauden et al. [27] found that eradication of H. pylori in 10 patients resulted in partial remission in three patients, no change in four patients and aggravation in the remaining three patients. Later, Dauden et al. investigated the seroprevalence of CagA in 14 patients with LP and evidence of H. pylori infection, but could not find a strong association between CagA and LP [174]. In conclusion, there is no clear evidence of a causal association between H. pylori infection and LP and further studies are needed.
Table 9 Prevalence of H. pylori in patients with lichen planus expressed as Nr. of patients and percent (%). C: Clarithromycin; A: amoxicillin; O: omeprazol.

Helicobacter pylori and aphthous stomatitis

Several issues led investigators to study the association between RAS and H. pylori infection. These include the association of both with MALT (mucosa-associated lymphoid tissue), the histological similarities between RAS and peptic ulcers [177], and the response of RAS to the broad-spectrum antibiotics such as tetracycline used to eradicate H. pylori infection. Therefore, a possible role for H. pylori in the development of RAS lesions has been proposed [50, 178], and the oral environment has been suggested to be one of the many potential routes for transmission. The studies of Elsheikh and colleagues [179] of 146 patients with recurrent multiple aphthous ulcers of the oral cavity and pharynx, support a possible causative role for H. pylori in recurrent aphthous ulcerations with a characteristic distribution and affinity to mucosa-associated lymphoid tissues (MALT) of the pharynx. Mansour-Ghanaei et al. [175] studied 50 patients with RAS. Twenty-six patients (52%) had evidence of H. pylori infection by serological IgG antibody tests, but H. pylori DNA could only be identified in one patient (2%). This suggests that this pathogen is not involved in recurrent oral aphthous ulcers.

Conclusion

The diagnosis of H. pylori infection was predominantly carried out using evidence of the presence of circulating antibodies by serological tests and/or urea breath tests. In the limited number of studies in which endoscopic evaluation was followed by subsequent H. pylori tests, the description of the findings was incomplete at best. A relationship between dermatological diseases, H. pylori infection and endoscopic findings in the upper gastrointestinal tract cannot be definitively confirmed, and further studies are necessary. No data are available evaluating differences between developing and developed countries in the prevalence of H. pylori in skin diseases, which could be a key issue and seems to be an interesting topic for future trials.

Acknowledgments

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