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Acta Medica Mediterranea, 2015, 31: 1127 HELICOBACTER PYLORI INFECTION IN MULTIPLE FORMS OF DERMATOSIS Emine Colgecen1, Seyhan Karacavus2, Cigdem Kader3, Kemal Ozyurt4, Mehmet Celikbilek5 1 Bozok University Medical Faculty, Department of Dermatology, Yozgat - 2Bozok University Medical Faculty, Department of Nuclear Medicine, Yozgat - 3Bozok University Medical Faculty, Department of Infection Diseases and Clinical Microbiology, Yozgat - 4Kayseri Training and Research Hospital, Department of Dermatology, Kayseri - 5Bozok University Medical Faculty, Department of Gastroenterology, Yozgat, Turkey ABSTRACT Introduction: Chronic spontaneous urticaria (CSU), idiopathic generalized pruritus (IGP), and rosacea are significant dermatological diseases of unknown etiology that adversely affect patients’ quality of life. The aim of this study was to determine the frequency of Helicobacter pylori (HP) infection in patients with CSU, IGP, and rosacea and to establish whether signs of dermatological disease improve with anti-HP eradication treatment in HP-positive patients. Materials and methods: Sixty patients (22 CSU, 17 IGP, and 21 rosacea) and 30 healthy individuals were enrolled. The 14Curea breath test (14C-UBT) was administered for diagnosis of HP. Patients with positive 14C-UBT results were administered amoxicillin 1 g, clarithromycin 500 mg and lansoprazole 30 mg twice daily for 2 weeks. At the end of this treatment, lansoprazole was maintained alone for another 2 weeks. Patients were examined for signs of clinical improvement at the 2nd week and the 1st, 3rd, and 6th months after this treatment. Results: Nineteen (86.4%) patients with CSU, 13 (76.5%) patients with IGP, and 16 (76.2%) patients with rosacea tested positive for HP on the basis of 14C-UBT. Fourteen (46.7%) individuals in the control group tested positive for HP on the basis of 14 C-UBT. Statistical analysis revealed greater HP positivity in the patient group compared to the control group (p < 0.05). Almost complete improvement of clinical signs was observed after eradication treatment for HP in 3 (15.8%) patients with CSU, 3 (23.1%) with IGP and 6 (15.8%) with rosacea. Conclusion: HP may play a role in the etiopathogenesis of CSU, IGP, and rosacea. In selected cases, HP eradication may have beneficial effects on the course of the disease. Key words: Chronic spontaneous urticaria, Helicobacter pylori, idiopathic generalized pruritus, rosacea. Received April 27, 2015; Accepted October 14, 2015 Introduction Helicobacter pylori (HP) is a gram negative microaerophilic bacterium found in the mucosal lining covering the gastric epithelium. Human to human contact via the fecal-oral route is the primary mode of transmission, making it one of the most widespread bacterial pathogens worldwide. HP infection occurs across a broad range of demographic characteristics of populations (such as age, socioeconomic status and race) and geographical areas worldwide. The prevalence is higher in developing countries, where levels as high as 70% have been reported. The prevalence in developed countries is approximately 40%. Colonization of HP infection begins in childhood, and unless eradication treatment is administered this persists throughout the patient’s entire life. HP plays a significant role in the etiology of gastritis, peptic ulcer, gastric carcinoma, and gastric lymphoma(1, 2). In recent years, HP has been associated with various diseases outside the gastrointestinal system possibly including some hematologic, cardiovascu- 1128 lar and dermatological diseases. Various theories have been proposed to account for extraintestinal findings associated with HP infection. These include atrophic gastritis, increased gastric vascular permeability, released inflammatory mediators, molecular mimicry and systemic immune response(3-5). Reports have suggested that HP may trigger lesions in chronic skin diseases, may be a cause of deterioration in disease, and/or may lead to increased resistance and chronic manifestation(1, 4, 5). In terms of dermatological diseases, HP has been reported to be associated with recurrent aphthous stomatitis, rosacea, chronic urticaria (CU), pruritus, Behcet’s disease, lichen planus, Sjögren syndrome, Henoch-Schönlein purpura, and alopecia areata(2, 5-9). The aim of this study was (I) to determine the frequency of HP infection in patients with chronic spontaneous urticaria (CSU), idiopathic generalized pruritus (IGP), and rosacea using 14C-urea breath test (14C-UBT); and (II) to evaluate whether dermatological disease signs improve with anti-HP eradication treatment in HP-positive patients. Materials and methods Patients Sixty patients over the age of 18 admitted to the Bozok University Faculty of Medicine Dermatology Clinic and 30 age-matched healthy individuals with similar sociocultural demographics to those of the patient group were enrolled. The patient group consisted of 22 patients with CSU, 17 with IGP and 21 with rosacea. Local ethics committee approval was obtained before the study began. Sex, age, drug use history, food anamnesis, presence of systemic and dermatological diseases, and the presence of gastrointestinal complaints were investigated and recorded for all individuals in the patient and control groups. Individuals who had been using antibiotics and proton pump inhibitors during the previous four weeks were excluded. HP infection assessment and treatment All patients swallowed 37 kBq (1μCi) of an encapsulated form of 14C-urea/citric acid composition (HelicapTMNoster System, Stockholm, Sweden) in 25 mL water after overnight fasting. Breath samples were collected using a special dry cartridge system (HeliprobeTMBreathCardTM; Noster System) after 10 min. Patients exhaled gently into the cartridge mouthpiece until the indicator membrane changed colour from orange to yellow. Emine Colgecen, Seyhan Karacavus et Al Activity was measured on a Geiger-Müller counter (HeliprobeTM Analyzer; Noster System) for 250 s. Results were expressed both as counts per min (cpm) and as grade (0= not infected, <25 cpm; 1= equivocal, 25-50 cpm; 2= infected,>50 cpm), as recommended by the manufacturer depending on the counts obtained from the cartridges. Patients with positive 14C-UBT results were administered amoxicillin 1 g, clarithromycin 500 mg, and lansoprazole 30 mg twice daily over 2 weeks. At the end of this treatment, lansoprazole was maintained alone for a further 2 weeks. Patients were examined for signs of clinical improvement at the 2nd week and at the 1st, 3rd, and 6th months after this treatment. Statistical analysis All analyses were performed using Statistical Package for the Social Sciences (SPSS) 15.0 software (SPSS Inc., Chicago, IL, USA). Results were reported as mean ± standard deviation (SD) or percentages. The Chi-square test was performed to compare categorical variables. Student’s t-test was used to determine significance at comparison of means of continuous variables in the two groups. A p-value of less than 0.05 was considered statistically significant. Results Of the 22 patients with CSU, 16 were female and 6 male, with a mean age of 41.7 ± 11.2. Nineteen (86.4%) patients with CSU tested positive for HP based on 14C-UBT. Of the 17 patients with IGP, 10 were female and 7 female, with a mean age of 44.6 ± 12.6. Thirteen (76.5%) patients with IGP tested positive for HP based on 14C-UBT. Of the 21 patients with rosacea, 19 were female and 2 male, with a mean age of 45.3 ± 10.8. Twelve of the patients with rosacea had papulopustular rosacea (PPR) and 9 had erythematotelangiectatic rosacea (ETR). Sixteen (76.2%) of these patients tested positive for HP based on 14C-UBT. All the patients had gastric symptoms. The control group consisted of 30 subjects, 16 female and 14 male, with a mean age of 44.3 ± 13.6. No gastric symptoms were observed in the control group. Fourteen (46.7%) individuals in the control group tested positive for HP based on 14C-UBT. Mean ages and sex distribution in the patient and control groups are given in Table 1. Table 2 shows HP positivity in the patient groups (CSU, IGP, Helicobacter pylori infection in multiple forms of dermatosis 1129 and rosacea) and the control group based on 14CUBT. Statistical analysis revealed greater HP positivity in the patient group compared to the control group (p < 0.05). Chronic spontaneous urticaria Idiopathic generalized pruritus Rosacea Control N 22 17 21 30 Age 19-69 18-64 26-72 18-72 Mean age 41.7 ± 11.2 44.6 ± 12.6 Signs of rosacea disappeared almost entirely at the end of the 1st month in 5 patients, whereas one patient exhibited recurrence of PPR lesions at 6th month check-up. One patient with ETR exhibited significant improvement in erythema at the 1st month after eradication treatment although severe relapse was observed at 3rd month check-up (Table 3). 45.3 ± 10.8 44.3 ± 13.6 Sex Discussion HP is the one of the most common infectious agents worldwide(10). In addition to causing local Male n (%) 6 (27.3) 7 (41.2) 2 (9.5) 14 (46.7) tissue damage in the gastric mucosa, HP has also been shown to be involved in various diseases that Table 1: Mean age and gender distribution in the patient and are not directly related to the gastrointestinal syscontrol groups. tem. Several major dermatological diseases have been reported to be associated with HP. Testing for C-urea breath C-urea breath test positive test negative p HP is frequently performed with non-invasive methn (%) n (%) ods such as 13 or 14C-UBT, stool antigen tests, and seroChronic spontaneous 19 (86.4) 3 (13.6) 0.003 logical tests. Histological examination and the urease urticaria test have higher diagnostic value, but are invasive Idiopathic generalized 13 (76.5) 4 (23.5) 0.017 techniques(1, 4, 5, 11). pruritus In approximately 75-80% of cases of urticaria, Rosacea 16 (76.2) 5 (23.8) 0.035 the disease takes the form of CU. This is more comControl 14 (46.7) 16 (53.3) mon in middle-aged women, and no etiological agent (12) Table 2: Comparison of 14C-urea breath test positivity is identified in two-thirds of patients . A relationship between HP infection and CSU has been docubetween the patient and control groups. mented in recent studies, and various mechanisms Improvement Recurrence have been proposed as the underlying cause(13-17). Cases Cases Following colonization of HP, increased gastric vasChronic spontaneous urticaria 3 0 cular permeability during infection results in increased exposure to allergens ingested through Idiopathic generalized pruritus 3 1 food consumption. More frequent allergic conditions Rosacea 6 2 may therefore be expected in patients with duodenal Papulopustular 5 1 ulcer. There are also studies suggesting that HP-speErythematotelangiectatic 1 1 cific immunoglobulin (Ig) E levels may increase in Total 12 3 the gastric and duodenal mucosa and may thus be involved in the pathogenesis of urticaria(4, 18). It has Table 3: Dermatological responses after eradication in the also been suggested that HP may trigger the producpatient groups. tion of autoantibodies targeted against circulating Three (15.8%) patients with CSU were IgE and/or the IgE receptor FcεRI through molecular observed to be free of signs of urticaria following mimicry(19). Nonetheless, the role of HP infection in eradication treatment, 2 in the 1st month and one in CU is still uncertain. Chronic infection can also the 3rd month. These were still healthy at 6th month result in immunological stimulation through the follow-up. Three (23.1%) patients with IGP respondrelease of various mediators, and in increased noned well to eradication treatment. Improvement specific cutaneous vascular permeability. In addition st occurred in the 1 month after treatment in each of to the virulence of HP, host-related and environmenthese cases. However, relapse was observed in one tal factors are also implicated(5, 20). Some researchers th case at 6 month follow-up. Six (15.8%) (5 PPR and have suggested that HP eradication may result in 1 ETR) patients with rosacea exhibited almost comimprovement in CU symptoms(15-17), while others plete improvement of clinical signs after treatment. have suggested the opposite(21-23). Female n (%) 16 (72.7) 10 (58.8) 14 19 (90.5) 14 16 (53.3) 1130 A recent study by Magen et al.(15) demonstrated that CU patients were resistant to antihistamines. Those authors reported HP positivity of 63.0% based on 13C-UBT and a 27.8% succession rate with HP eradication. In our study, 86.4% of patients with CSU were HP positive. Signs of urticaria resolved completely after eradication treatment for HP in 15.8% of patients. Idiopathic pruritus refers to conditions that cannot be explained in terms of dermatological or systemic diseases, and that generally cause no skin damage or that exhibit lower levels of secondary itching lesions. IGP constitutes nearly 30.0% of all itchiness. It is observed in both sexes, although the level is slightly higher in females(24). Previous reports have identified an association between HP and other dermatological diseases, including chronic pruritus, prurigo nodularis, and prurigo pigmentosa(9, 25, 26). Sakurane M. et al.(27) demonstrated that eradication therapy was effective in several intractable skin diseases (such as CU, pruritus cutaneous, nummular dermatitis and prurigo chronica multiformis (PCM)) in patients exhibiting HP positivity through gastroscopic examination. That study suggested that chronic HP infection may perpetuate eruptions and result in disease deterioration as well as in the manifestation and persistence of skin diseases(27). Akashi et al.(8) observed HP positivity in patients with CU (30.5%) and in patients with PCM (58.8%), and administered eradication treatment. That study further confirmed HP as an important pathogenic factor and underlined the use of eradication therapy for the treatment of intractable skin diseases, including PCM(8). We determined HP positivity in 76.5% of patients with IGP. Following eradication treatment for HP, we observed complete recovery from itching in 23.1% of patients. Rosacea is a chronic inflammatory dermatosis characterized by papules and pustules over an erythematous and a telangiectasic base in the mid face area. Both rosacea and peptic ulcer exhibit seasonal variation, and some antibiotics used in the treatment of HP cause remission of symptoms of patients with rosacea. An association between HP and rosacea has therefore been posited. Various mechanisms have been proposed to explain the contribution of HP to rosacea development. Nitric oxide production is induced by HP, and increased concentrations of nitric oxide in patient serum and tissues result in vasodilation, inflammation, and immunomodulation. This condition is thought to be responsible for the flushing and erythema observed in patients with rosacea(28-30). Emine Colgecen, Seyhan Karacavus et Al In addition to research observing HP positivity in patients with rosacea, some studies have also reported significant remission in rosacea symptoms following eradication treatment for HP (6, 31-35) . However, other studies have reported no relation between HP and rosacea(36, 37). The prevalence of HP in patients with rosacea in this study was 76.2%. This is comparable to the rate reported in a recent study involving Egyptian patients(6). In addition, we observed that HP was present at a very high level in patients with PPR (83.3%), higher than that in patients with ETR (66.7%). We therefore think there may be a relation between subtypes of rosacea and HP infection, which is consistent with the previous research reported by Diaz et al.(33). HP eradication significantly improved PPR lesions and reduced relapse rates in our study, but did not affect ETR lesions in the rosacea patient group. Boixeda et al.(34) reported higher rates of improvement in PPR lesions (83.3%) after eradication of the microorganism compared to ETR lesions (36.5%). We suggest that these results represent evidence for a positive cause and effect relationship between inflammatory rosacea and HP infection, especially in cases with gastritis and dyspeptic symptoms. There are a number of limitations to our study. Most importantly, the patient cohort was small. Additionally we did not employ histological examination and the urease test, although these are of greater diagnostic value for the detection of HP, due to their invasive nature(1, 4, 5, 11). The specificity and sensitivity of UBT for the detection of HP infection are close to 100%(11). In addition, this study did not investigate the potential underlying mechanisms of HP eradication in the pathophysiology of CSU, IGP, and rosacea. Conclusion CSU, IGP, and rosacea are important dermatological diseases that adversely affect patients’ quality of life. HP may be involved in the etiopathogenesis of these diseases. In selected cases, HP eradication may have beneficial effects on the course of the disease. Whether these treatment programs have any effect on remission rates in these patients should now be clarified with further prospective studies involving larger patient series. Helicobacter pylori infection in multiple forms of dermatosis References 1) 2) 3) 4) 5) 6) 7) 8) 9) 10) 11) 12) 13) 14) 15) 16) 17) Tüzün Y, Keskin S, Kote E. The role of Helicobacter pylori infection in skin diseases: facts and controversies. Clin Dermatol 2010; 28: 478-82. 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