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Helicobacter pylori infection in psoriasis: results of a clinical study and review of the literature Anna Campanati1*, MD, Giulia Ganzetti1*, MD, Emanuela Martina1, MD, Melania Giannoni1, MD, Rosaria Gesuita2, PhD, Emanuele Bendia3, MD, Katia Giuliodori1, MD, Lucia Sandroni1, PhD, and Annamaria Offidani1, MD
1 Dermatological Unit, Department of Clinical and Moleciular Sciences, Polytechnic Marche University, Ancona, Italy, 2Center of Epidemiology, Biostatistics and Medical Information Technology, Polytechnic Marche University, Ancona, Italy, and 3 Department of Gastroenterology, Polytechnic Marche University, Ancona, Italy
Correspondence Anna Campanati, MD Dermatological Clinic, Department of Clinical Medicine and Applied Biotechnologies Polytechnic Marche University Ancona Italy E-mail: [email protected]
Abstract Background Data from the literature concerning the role of Helicobacter pylori (H. pylori) infection in psoriasis are still conflicting. This study was carried out to evaluate prevalence of H. pylori in patients with mild to severe psoriasis, correlation between H. pylori infection and severity of psoriasis, and effect of H. pylori eradication on the clinical course of psoriasis. Methods Two hundred and ten patients with psoriasis and 150 healthy controls were screened for H. pylori through [13C] urea breath test at baseline (T0). All patients with psoriasis received standardized phototherapy treatment, and those infected by H. pylori were also treated with a 1-week triple therapy, then they were all re-evaluated four weeks later at the end of therapy (T5). Results The prevalence of H. pylori was not higher in psoriasis than in the control group (20.27 vs. 22%; P > 0.05). Patients infected by H. pylori showed more severe psoriasis than uninfected patients (psoriasis area and severity index score 17.9 7.1 vs. 13.7 6.9; P = 0.04), and patients who received successful eradication of H. pylori infection showed a greater improvement of psoriasis than the others (psoriasis area and
Conflicts of interest: None. *The authors equally contributed to the manuscript.
severity index score at T5 in patients infected by H. pylori was 8.36 3.76, in uninfected patients was 10.85 3.49; P = 0.006). Conclusions Patients with mild to severe psoriasis do not show a greater prevalence of H. pylori infection; however, H. pylori seems able to affect the clinical severity of psoriasis.
Introduction Psoriasis is an inflammatory, immune-mediated disease with a multifactorial physiopathology and a wide spectrum of clinical presentations.1–9 Some evidence suggests that infections can act as triggering factors for psoriasis. Several bacterial proteins with toxic-like action (named superantigens) can activate CD4+ T cells in an antigen independent manner, by binding the T-cell receptor and the molecules of a major histocompatibility system, expressed on the surface of antigen-presenting cells.9 This nonspecific link activates the inflammatory process causing cellular damage and stimulates the immune response through the uncontrolled release of interleukins.10,11 Starting from these data, some authors support the hypothesis that Helicobacter pylori (H. pylori) could worsen psoriasis by interfering and amplifying the immune response in genetically susceptible subjects.12–14 However, conflicting ª 2015 The International Society of Dermatology
results are reported in the literature, and both prevalence and the role of (H. pylori) infection in psoriasis are still discussed.15–22 The primary outcome of our study was to estimate the prevalence of H. pylori infection in a population of patients with mild to severe psoriasis; secondary outcomes were to evaluate the association between H. pylori infection and severity of psoriatic disease, and discuss the role of H. pylori eradication on the clinical course of psoriasis. Methods Population Among the 317 patients with psoriasis who had consecutively attended our dermatological department between December 2010 and January 2012, 210 had mild to severe psoriasis, and they met clinical criteria to be included in the study group. Patients were excluded from the study if they were affected by an erythrodermic or generalized pustular form of psoriasis, International Journal of Dermatology 2015, 54, e109–e114
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were pregnant or nursing women, had a previous infection of H. pylori, and had received any oral antibiotic in the last
PASI score derived from the mean of two scores calculated by two independent trained dermatologists both at baseline (T0)
12 weeks. A wash-out period of four weeks from conventional
and at the end of the study period (T5).
systemic treatments for psoriasis (cyclosporine, acitretin, methotrexate, etc.) and 12 weeks from tumor necrosis factor-alpha inhibitors were chosen. None of the enrolled
The DLQI was obtained through a self-administered and validated Italian version of the questionnaire. Patients were also asked to respond on the presence of
patients had received interleukin 12/23 inhibitor. During the
psoriasis-related symptoms (at least one among itch, burning
wash-out period, patients were allowed to use only mild
sensation, and pain).
topical corticosteroids. One hundred patients that had come to our attention for melanoma screening were used as the control group.
Study design This is an open-label clinical study approved by the Polytechnic Marche University Ethical Committee and conducted in accordance with the Declaration of Helsinski.23 At baseline (T0), both complete history and clinical examination were collected from each patient, focusing particularly on severity and extent of psoriasis, impact on patient’s quality of life, subjective symptoms (burning, itching), and presence of psoriatic arthritis. Both patients with psoriasis (study group) and controls underwent the [13C] urea breath test (13C-UBT) and were evaluated for H. pylori infection-related symptoms: epigastralgia; gastric pyrosis, dyspepsia; diarrhea; constipation; and weight loss. For each symptom, a severity score was assigned as follows: absent = 0; mild = 1; moderate = 2; severe = 3. Patients with psoriasis and controls were compared for prevalence of H. pylori infection at baseline (T0). All patients with psoriasis were then subdivided in two subgroups with respect to H. pylori infection: patients infected by H. pylori at T0 (H. pylori+T0) and patients not infected by H. pylori at T0 (H. pylori–T0); the two groups were then compared with each other for clinical expression of psoriasis at baseline (T0). H. pylori+T0 patients received eradication therapy for one week, and they were re-evaluated with 13C-UBT to ensure successful H. pylori eradication four weeks later (T5). Patients still positive for H. pylori infection at T5 were discontinued from the study. Eradicated patients (H. pylori–T5) and patients with psoriasis not affected by H. pylori infection at T0 (H. pylori–T0) were clinically reassessed at T5 for psoriasis severity (psoriasis area and severity index [PASI], dermatology life quality index [DLQI]) and compared to evaluate if eradication of H. pylori could exert an adjuvant therapeutic effect on psoriasis. To avoid any bias, all patients with psoriasis were simultaneously treated with the same psoralen+ultraviolet A (PUVA) protocol from baseline to the end of the study (5 weeks). Diagnosis of psoriasis and disease activity evaluation Psoriasis was clinically diagnosed by a trained dermatologist, and disease severity was evaluated by PASI, body surface area, and DLQI as reported in the literature.24,25 International Journal of Dermatology 2015, 54, e109–e114
Diagnosis of psoriatic arthritis Diagnosis of psoriatic arthritis was made by a trained rheumatologist and based on CASPAR criteria,26 whose sensitivity is 98.7% and specificity is 91.4%. Diagnosis of Helicobacter pylori infection The diagnosis of infection was made through the 13 C-UBT. H. pylori produces urease in the stomach, and the 13 C-UBT detects the activity of the urease. Fasting patients were asked to drink 200 ml of orange juice containing 75 mg of 13C-UBT urea. Breath samples at baseline and after 30 minutes were analyzed with a non-dispersive infrared spectrometer (Wagner Analysen Technik, Bremen, Germany). The results were considered positive when delta over baseline was 4%. Therapy for psoriasis All patients with psoriasis received the same standardized PUVA protocol from T0 to T5 as follows: UVA 2 J/cm2, with gradual increase of 0.5 J/cm2 per session, for 12 sessions in total, with an average frequency of three applications per week, preceded by the assumption of 8-methoxypsoralen at an average dose of 0.6–0.8 mg/kg, two hours before the session. Eradication therapy for Helicobacter pylori infection All H. pylori+T0 patients were treated according to the guidelines of the American Association of Gastroenterologists27 as follows: esomeprazole 40 mg two times per day, clarithromycin 500 mg two times daily, and amoxicillin 1 g two times per day (alternatively, in subjects allergic to penicillin, and metronidazole 500 mg two times per day) for seven days. Statistical analysis The percentage of H. pylori+ subjects was evaluated estimating the 95% confidence interval for a proportion, using a binomial distribution. The sample size was calculated through StatMate software. A non-parametric approach was followed, as variables were not normally distributed at the Shapiro test. Variables were summarized using absolute and percentage frequencies for qualitative variables and percentiles (median, 25th, and 75th) for quantitative variables. Differences in patients’ characteristics according to UBT result were evaluated using the chi-squared ª 2015 The International Society of Dermatology
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or Fisher exact test for qualitative variables and Wilcoxon rank sum test for quantitative variables.
Helicobacter pylori infection worsens psoriasis
Table 1 Demographic and clinical characteristics of psoriasis patients according to H. pylori infection at baseline Urea breath test at baseline
Results Two hundred and ten patients with psoriasis (study group) (109 men and 101 women, aged between 18 and 76 years, mean age: 49.75 years) and 100 patients that had come to our attention for melanoma screening were used as the control group (71 male and 79 female, aged between 19 and 71 years, mean age: 44.03 years) and were included in the study. The two groups were comparable for sex and age, and smoking, eating, and drinking habits. The educational level of all enrolled patients ranged from primary to secondary school. The percentage of H. pylori+ patients was similar between study and control group at baseline (19.6 vs. 22%, respectively; P = 0.831). All enrolled patients with psoriasis were subdivided into two subgroups according to the presence of H. pylori infection at baseline: H. pylori+T0 patients with psoriasis (n = 43) and H. pylori–T0 patients with psoriasis (n = 167). No significant differences were found between the two groups for age, gender, clinical presentation (plaque type, guttate, palmoplantar, pustular), pruritus, presence of arthritis, life quality, and for several gastrointestinal symptoms, i.e., dyspepsia, meteorism, diarrhea, constipation, and weight loss. However, H. pylori+T0 patients showed a significant higher PASI score compared with H. pylori–T0 patients (17.9 3.16 vs. 13.7 4.20 respectively; Table 1). Moreover, H. pylori+T0 patients were more frequently affected by epigastralgia and gastric pyrosis as expected (P = 0.046 and P = 0.037, respectively). With regard to H. pylori eradication, none of the patients reported any allergy to penicillin, thus they all received the same protocol for H. pylori eradication. No serious adverse events have occurred, thus all the patients concluded the therapeutic protocol, except for one patient of 167 H. pylori–T0, who failed to complete the PUVA treatment because she became pregnant. In the psoriasis group, three patients of 43 H. pylori+T0 were still positive at T5, and thus they were discontinued from the study. Fifteen of the 93 patients (16.12%) that had dyspepsia or epigastralgia or gastric pyrosis showed an initial worsening of symptoms during treatments, which disappeared within two weeks; 11 belonged to the H. pylori+ and four to the H. pylori– group. The main characteristics of the patients are reported in Table 1. At T5, the PASI score was significantly decreased in all patients; however, it was significantly lower in eradicated ª 2015 The International Society of Dermatology
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H. pylori+T0 (n = 43) Median (1st–3rd quartile) Age (years) 49 PASI score 17.9 DLQI score 9 n (%) Gender, male 25 Clinical variant Plaque type 32 Guttate type 4 Pustular type 3 Palmoplantar 1 Itching/burning 32 Arthritis 10 Epigastralgia 11 Gastric pyrosis 10 Dyspepsia 7 Meteorism 7 Diarrhea 3 Constipation 7 Weight loss 2
(39–59) (10.7–24.0) (5.75–17.0) (62.5) (80.0) (10.0) (7.5) (2.5) (73.1) (25.0) (27.5) (25.0) (17.5) (17.5) (7.5) (17.5) (5.0)
H. pylori–T0 (n = 167)
P
51 (43–60) 13.7 (9.8–17.6) 11 (6–15.0)
0.454a 0.047a 0.980a
96 (57.8) 115 23 14 5 94 53 23 18 24 17 18 23 13
(69.3) (13.8) (8.4) (3.0) (56.8) (31.9) (13.9) (10.8) (14.6) (10.7) (10.8) (13.9) (7.8)
0.719b 0.817c 0.763c 0.987c 0.956c 0.451c 0.508b 0.046b 0.037b 0.813c 0.269b 0.772c 0.616c 0.741c
H. pylori, Helicobacter pylori; H. pylori+T0, patients with psoriasis affected by H. pylori infection at baseline; H. pylori –T0, patients with psoriasis not affected by H. pylori infection at baseline. a Wilcoxon rank-sum test. b Chi-squared test. c Fisher exact test. Table 2 Psoriasis severity comparison between uninfected at T0 and patients eradicated at T5
patients
Urea breath test
PASI score DLQI score
H. pylori–T5 (n = 40)
H. pylori–T0 (n = 166)
P
8.36 (1.2–17.40) 9.7 (1–26)
10.85 (1–18.80) 9.13 (1–26)
0.006 0.912
DLQI, dermatology life quality index; H. pylori, Helicobacter pylori; H. pylori–T5, psoriatic eradicated patients; H. pylori–T0, patients with psoriasis not affected by H. pylori infection at baseline; PASI, psoriasis area and severity index.
patients (H. pylori–T5) than in uninfected patients at baseline (H. pylori–T0) (8.36 vs. 10.85 respectively; P = 0.006) (Table 2, Fig. 1). The DLQI score was decreased in a non-statistically significant way after treatment, and no difference was detected between previously uninfected patients and those who received eradication therapy (Table 2). International Journal of Dermatology 2015, 54, e109–e114
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Figure 1 Absolute value of PASI score at T5. PASI, psoriasis area and severity index
Discussion It has already been demonstrated that H. pylori infection may cause worsening in several dermatological diseases such as acne rosacea,28 chronic idiopathic urticaria,29 Behcßet, and other autoimmune diseases.30 Moreover, several studies support the possible relationship between H. pylori and several immune-mediated inflammatory diseases.31,32 However, only few and conflicting studies, aimed at investigating the worsening role of H. pylori in psoriasis, have been reported in the literature. The first analysis conducted on a wide sample was published in 2000 by Dauden et al.,15 and they recruited 145 patients (84 with psoriasis and 61 with lichen planus) who underwent 13C-UBT and were compared with healthy controls; 73.8% of patients with psoriasis and 75.4% of patients with lichen planus were UBT+, while the prevalence of UBT+ in controls was 80.2% and 74.1%, respectively. The authors failed to demonstrate a significant higher prevalence of UBT+ test in patients with psoriasis than in controls. Among the patients with psoriasis that were UBT+, 11 were receiving cyclosporine and six acitretin; the authors conclude that cyclosporine could encourage a gastric colonization by H. pylori, and the interaction between retinoids and specific receptors placed on the mucosa could modify the gastric microenvironment.15 Among the UBT+ patients, only 10 received specific eradication treatment, and in only eight patients, the eradication was confirmed by UBT repetition; however, the authors concluded that eradication did not influence the clinical course of psoriasis. Epidemiological studies on H. pylori infection prevalence in psoriasis are exiguous and inconclusive. However, an Italian analysis on H. pylori infection prevalence in psoriasis was conducted by Fabrizi et al. in 2001 on a pediatric population aged between 5 and 18 (20 patients with psoriasis and 29 healthy controls).16 All the subjects recruited for the study underwent the UBT test: two patients with International Journal of Dermatology 2015, 54, e109–e114
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psoriasis (10%) with a positive history of dyspeptic symptoms and five controls (29%) were infected with H. pylori. The main limits of this study are its sample size and the low sensibility and specificity of the 13C-UBT in childhood.16 Qayoom and Ahmad17 in 2002 showed that the prevalence of H. pylori seropositivity in Indian patients with psoriasis (20 of 50; 40% of cases) was significantly higher than in healthy people (five of 50; 10% of cases). The unexpected low prevalence of infection in the analyzed samples was probably dependent on the authors’ decision to exclude subjects with gastrointestinal symptoms from the study. In 2004, a prospective case–control study by Dauden et al. investigated the seroprevalence of cytotoxin-associated gene A (cagA) in patients with psoriasis with H. pylori infection. Among the 11 patients, six were positive for the serotype cagA (54.5%), whereas 15 of 22 controls were positive (68.1%). The authors concluded that the cagA status was not related to the disease’s duration, clinical presentation, severity, and presence of psoriatic arthritis.18 In the literature, two case reports described the complete remission of psoriasis after the eradication of H. pylori in subjects positive to the UBT test. The first one, reported by S aez-Rodrıguez et al.,19 described a 38-year-old woman affected by palmoplantar pustular psoriasis unresponsive to topical and systemic corticosteroids, dapsone, and colchicine; the patient also had a history of dyspepsia unresponsive to omeprazole and ranitidine, and the worsening of cutaneous lesions was preceded by exacerbation of gastrointestinal symptoms. The patient had a 13C-UBT with positive results, and she received the diagnosis of chronic atrophic gastritis; after eradication of the H. pylori, the psoriatic lesions completely disappeared without any clinical relapse after four years of follow-up. H€ ubner and Tenbaum20 in 2008 reported another case of palmoplantar pustular psoriasis in a 35-year-old woman that was clinically improved after H. pylori eradication. The patient was affected by dyspeptic syndrome and psoriasis unresponsive to corticosteroid and calcipotriol application. Six weeks after H. pylori eradication, a gradual improvement of cutaneous lesions started to appear, and three years later, the patient was completely free from psoriasis. Ali and Whitehead in 2008 reported a case of a woman affected by a severe form of psoriasis in which a great improvement of cutaneous lesions was obtained after H. pylori eradication.21 The 48-year-old woman affected by epigastralgia was treated with triple therapy after the presence of H. pylori was assessed. The patients had not received any dermatological care. Four months after eradication, the patient showed a ª 2015 The International Society of Dermatology
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clear improvement of psoriasis with persistence of hyperpigmented post-lesional areas. Owing to the lack of specific therapy for psoriasis, the authors justified the improvement with the eradication of the gastric infective focus. Onsun et al.22 in 2012 reported an association between psoriasis severity and H. pylori infection, and they focused on the role of eradication therapy in improving psoriasis. However, the authors used the stool antigen test, whose reliability to detect H. pylori colonization in Italian adults is still debated.33 As announced, the studies conducted until now cannot contribute to form a unique opinion about the role of H. pylori infection in psoriasis. As most of the reported studies show several methodological limits, it may not be confirmed unambiguously from the data available in the literature that H. pylori worsens psoriasis. First, the prevalence of H. pylori infection, particularly in some Italian geographic areas, makes the wide recruitment of patients mandatory to perform a reliable investigation.34 Studies based on serological tests provide information about the patient’s immunological status against the bacterium, but they fail to demonstrate active infection by H. pylori. In some other reports, patients were not standardized to receive the same therapy for psoriasis during the study, thus it becomes almost impossible to understand the contribution played by eradication in improving the disease course. Finally, some authors reported the clinical improvement of psoriasis without using validated and reproducible severity scales. The aim of this study was to add a further clinical experience to what was reported in literature, trying to overcome the limits of previously reported analyses. Therefore, we designed a sample size appropriate to the proposed outcomes, disease severity was estimated through validated scales, patients received a standardized treatment for psoriasis for the period of the study, and finally we used the 13C-UBT, which is the gold standard among the non-invasive methods to detect H. pylori infection. Our results demonstrated that the prevalence of H. pylori infection among patients with psoriasis is no higher than that reported in a dermatological setting or for the general Italian population. The prevalence of H. pylori infection in central and southern Italy ranges from 9.5% to 21.3%.34–36 H. pylori infection seems able to aggravate the clinical expression of psoriasis, although it could also be postulated that patients with psoriasis with higher PASI often need systemic therapy that might increase the risk of H. pylori infections. We cannot exclude that eradication could exert an adjuvant therapeutic role in the short-term control of psoª 2015 The International Society of Dermatology
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riasis. However, the clinical improvement of psoriasis after eradication could also be related to the resolution of undiagnosed infectious processes other than H. pylori. The major limit of this study is the lack of an internal control group in the subset of patients with psoriasis with no eradication for H. pylori infection, to make a comparison on PASI variations between patients with eradicated and non-eradicated psoriasis. However, our ethical committee had judged this control group as unethical, and the three patients who had failed the eradication were too few to form an internal group for comparison. For this reason, currently, we cannot recommend the routine use of eradication therapy for psoriasis with psoriasis infected by H. pylori until further controlled studies are performed with an internal group of patients with non-eradicated psoriasis. References 1 Orciani M, Campanati A, Salvolini E, et al. The mesenchymal stem cell profile in psoriasis. Br J Dermatol 2011; 165: 585–592. 2 Campanati A, Orciani M, Gorbi S, et al. Effect of biologic therapies targeting tumour necrosis factor-a on cutaneous mesenchymal stem cells in psoriasis. Br J Dermatol 2012; 167: 68–76. 3 Potenza C, Bernardini N, Nicolucci F, et al. Severe psoriasis with positive TB-gold test in treatment with Etanercept: case report. Cutis 2012; 90: 120–122. 4 Campanati A, Moroncini G, Ganzetti G, et al. Adalimumab modulates angiogenesis in psoriatic skin. Eur J Inflamm 2013; 11: 489–498. 5 De Simone C, Amerio P, Amoruso G, et al. Immunogenicity of anti-TNFa therapy in psoriasis: a clinical issue? Expert Opin Biol Ther 2013; 13: 1673– 1682. 6 Rigopoulos D, Gregoriou S, Katrinaki A, et al. Characteristic of psoriasis in Greece: an epidemiological study of a population in a sunny Mediterranean climate. Eur J Dermatol 2010; 24: 530–534. 7 Bardazzi F, Antonucci VA, Tengattini V, et al. A 36-week retrospective open trial comparing the efficacy of biological therapies in nail psoriasis. J Dtsch Dermatol Ges 2013; 11: 1065–1070. 8 Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis 2005; 64: 30–36. 9 Campanati A, Ganzetti G, Di Sario A, et al. Insulin resistance, serum insulin and HOMA-R. J Gastroenterol 2013; 48: 673. 10 Hernando-Harder AC, Booken N, Goerdt S, et al. Helicobacter pylori infection and dermatologic diseases. Eur J Dermatol 2009; 19: 431–444. 11 Ganzetti G, Campanati A, Offidani A. Alopecia areata: a possible extraintestinal manifestation of Crohns disease. J Crohns Colitis 2012; 6: 962–963. International Journal of Dermatology 2015, 54, e109–e114
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12 Correa P, Piazuelo MB. Natural history of Helicobacter pylori infection. Dig Liver Dis 2008; 40: 490–496. 13 Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 2006; 19: 449–490. 14 Pellicano R, Rizzetto M. Extragastric manifestations of Helicobacter species infection. Do these bacteria act as triggers? Minerva Gastroenterol Dietol 2002; 48: 179–187. 15 Dauden E, V azquez-Carrasco MA, Pe~ nas PF, et al. Association of Helicobacter pylori infection with psoriasis and lichen planus: prevalence and effect of eradication therapy. Arch Dermatol 2000; 136: 1275–1276. 16 Fabrizi G, Carbone A, Lippi ME, et al. Lack of evidence of relationship between Helicobacter pylori infection and psoriasis in childhood. Arch Dermatol 2001; 137: 1529. 17 Qayoom S, Ahmad QM. Psoriasis and Helicobacter pylori. Indian J Dermatol Venereol Leprol 2003; 69: 133–134. 18 Dauden E, Cabrera MM, O~ nate MJ, et al. CagA seropositivity in Helicobacter pylori positive patients with psoriasis. J Eur Acad Dermatol Venereol 2004; 18: 116– 117. 19 Saez-Rodrıguez M, Noda-Cabrera A, Garcıa-Bustınduy M, et al. Palmoplantar pustulosis associated with gastric Helicobacter pylori infection. Clin Exp Dermatol 2002; 27: 720. 20 H€ ubner AM, Tenbaum SP. Complete remission of palmoplantar psoriasis through Helicobacter pylori eradication: a case report. Clin Exp Dermatol 2008; 33: 339–340. 21 Ali M, Whitehead M. Clearance of chronic psoriasis after eradication therapy for Helicobacter pylori infection. J Eur Acad Dermatol Venereol 2008; 22: 753–754. 22 Onsun N, Arda Ulusal H, Su O, et al. Impact of Helicobacter pylori infection on severity of psoriasis and response to treatment. Eur J Dermatol 2012; 22: 117–120. 23 World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Patients. Adopted by the 18th WMA General Assembly 1964 and amended by the 29th, 35th, 41st and 48th WMA General Assemblies. 24 Campanati A, Ganzetti G, Di Sario A, et al. The effect of etanercept on hepatic fibrosis risk in patients with nonalcoholic fatty liver disease, metabolic syndrome, and psoriasis. J Gastroenterol 2013; 48: 839–846.
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25 Campanati A, Giuliodori K, Ganzetti G, et al. A patient with psoriasis and vitiligo treated with etanercept. Am J Clin Dermatol 2010; 11(Suppl. 1): 46–48. 26 Coates LC, Conaghan PG, Emery P, et al. Sensitivity and specificity of the classification of psoriatic arthritis criteria in early psoriatic arthritis. Arthritis Rheum 2012; 64: 3150–3155. 27 Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007; 102: 1808–1825. 28 T€ uz€ un Y, Keskin S, Kote E. The role of Helicobacter pylori infection in skin diseases: facts and controversies. Clin Dermatol 2010; 28: 478–482. 29 Campanati A, Gesuita R, Giannoni M, et al. Role of small intestinal bacterial overgrowth and Helicobacter pylori infection in chronic spontaneous urticaria: a prospective analysis. Acta Derm Venereol 2013; 93: 161– 164. 30 Guarneri F, Guarneri C, Benvenga S. Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? J Cell Mol Med 2005; 9: 741– 744. 31 Suzuki H, Franceschi F, Nishizawa T, et al. Extragastric manifestations of Helicobacter pylori infection. Helicobacter 2011; 16(Suppl. 1): 65–69. 32 Figura N, Franceschi F, Santucci A, et al. Extragastric manifestations of Helicobacter pylori infection. Helicobacter 2010; 15(Suppl. 1): 60–68. 33 Bilardi C, Biagini R, Dulbecco P, et al. Stool antigen assay (SA) is less reliable than urea breath test for posttreatment diagnosis of Helicobacter pylori infection. Aliment Pharmacol Ther 2002; 16: 1733–1738. 34 Straffolini T, Rosmini F, Ferrigno L, et al. Prevalence of Helicobacter pylori infection in a cohort of Italian military students. Epidemiol Infect 1998; 120: 151–155. 35 Ponzetto A, Pellicano R, Morgando A, et al. Seroprevalence of Helicobacter pylori infection among blood donors in Torino, Italy. Minerva Gastroenterol Dietol 2001; 47: 3–7. 36 Bazzoli F, Palli D, Zagari RM, et al. The LoianoMonghidoro population-based study of Helicobacter pylori infection: prevalence by 13C-urea breath test and associated factors. Aliment Pharmacol Ther 2001; 15: 1001–1007.
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Helicobacter pylori infection in psoriasis: results of a clinical study and review of the literature Anna Campanati1*, MD, Giulia Ganzetti1*, MD, Emanuela Martina1, MD, Melania Giannoni1, MD, Rosaria Gesuita2, PhD, Emanuele Bendia3, MD, Katia Giuliodori1, MD, Lucia Sandroni1, PhD, and Annamaria Offidani1, MD
1 Dermatological Unit, Department of Clinical and Moleciular Sciences, Polytechnic Marche University, Ancona, Italy, 2Center of Epidemiology, Biostatistics and Medical Information Technology, Polytechnic Marche University, Ancona, Italy, and 3 Department of Gastroenterology, Polytechnic Marche University, Ancona, Italy
Correspondence Anna Campanati, MD Dermatological Clinic, Department of Clinical Medicine and Applied Biotechnologies Polytechnic Marche University Ancona Italy E-mail: [email protected]
Abstract Background Data from the literature concerning the role of Helicobacter pylori (H. pylori) infection in psoriasis are still conflicting. This study was carried out to evaluate prevalence of H. pylori in patients with mild to severe psoriasis, correlation between H. pylori infection and severity of psoriasis, and effect of H. pylori eradication on the clinical course of psoriasis. Methods Two hundred and ten patients with psoriasis and 150 healthy controls were screened for H. pylori through [13C] urea breath test at baseline (T0). All patients with psoriasis received standardized phototherapy treatment, and those infected by H. pylori were also treated with a 1-week triple therapy, then they were all re-evaluated four weeks later at the end of therapy (T5). Results The prevalence of H. pylori was not higher in psoriasis than in the control group (20.27 vs. 22%; P > 0.05). Patients infected by H. pylori showed more severe psoriasis than uninfected patients (psoriasis area and severity index score 17.9 7.1 vs. 13.7 6.9; P = 0.04), and patients who received successful eradication of H. pylori infection showed a greater improvement of psoriasis than the others (psoriasis area and
Conflicts of interest: None. *The authors equally contributed to the manuscript.
severity index score at T5 in patients infected by H. pylori was 8.36 3.76, in uninfected patients was 10.85 3.49; P = 0.006). Conclusions Patients with mild to severe psoriasis do not show a greater prevalence of H. pylori infection; however, H. pylori seems able to affect the clinical severity of psoriasis.
Introduction Psoriasis is an inflammatory, immune-mediated disease with a multifactorial physiopathology and a wide spectrum of clinical presentations.1–9 Some evidence suggests that infections can act as triggering factors for psoriasis. Several bacterial proteins with toxic-like action (named superantigens) can activate CD4+ T cells in an antigen independent manner, by binding the T-cell receptor and the molecules of a major histocompatibility system, expressed on the surface of antigen-presenting cells.9 This nonspecific link activates the inflammatory process causing cellular damage and stimulates the immune response through the uncontrolled release of interleukins.10,11 Starting from these data, some authors support the hypothesis that Helicobacter pylori (H. pylori) could worsen psoriasis by interfering and amplifying the immune response in genetically susceptible subjects.12–14 However, conflicting ª 2015 The International Society of Dermatology
results are reported in the literature, and both prevalence and the role of (H. pylori) infection in psoriasis are still discussed.15–22 The primary outcome of our study was to estimate the prevalence of H. pylori infection in a population of patients with mild to severe psoriasis; secondary outcomes were to evaluate the association between H. pylori infection and severity of psoriatic disease, and discuss the role of H. pylori eradication on the clinical course of psoriasis. Methods Population Among the 317 patients with psoriasis who had consecutively attended our dermatological department between December 2010 and January 2012, 210 had mild to severe psoriasis, and they met clinical criteria to be included in the study group. Patients were excluded from the study if they were affected by an erythrodermic or generalized pustular form of psoriasis, International Journal of Dermatology 2015, 54, e109–e114
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were pregnant or nursing women, had a previous infection of H. pylori, and had received any oral antibiotic in the last
PASI score derived from the mean of two scores calculated by two independent trained dermatologists both at baseline (T0)
12 weeks. A wash-out period of four weeks from conventional
and at the end of the study period (T5).
systemic treatments for psoriasis (cyclosporine, acitretin, methotrexate, etc.) and 12 weeks from tumor necrosis factor-alpha inhibitors were chosen. None of the enrolled
The DLQI was obtained through a self-administered and validated Italian version of the questionnaire. Patients were also asked to respond on the presence of
patients had received interleukin 12/23 inhibitor. During the
psoriasis-related symptoms (at least one among itch, burning
wash-out period, patients were allowed to use only mild
sensation, and pain).
topical corticosteroids. One hundred patients that had come to our attention for melanoma screening were used as the control group.
Study design This is an open-label clinical study approved by the Polytechnic Marche University Ethical Committee and conducted in accordance with the Declaration of Helsinski.23 At baseline (T0), both complete history and clinical examination were collected from each patient, focusing particularly on severity and extent of psoriasis, impact on patient’s quality of life, subjective symptoms (burning, itching), and presence of psoriatic arthritis. Both patients with psoriasis (study group) and controls underwent the [13C] urea breath test (13C-UBT) and were evaluated for H. pylori infection-related symptoms: epigastralgia; gastric pyrosis, dyspepsia; diarrhea; constipation; and weight loss. For each symptom, a severity score was assigned as follows: absent = 0; mild = 1; moderate = 2; severe = 3. Patients with psoriasis and controls were compared for prevalence of H. pylori infection at baseline (T0). All patients with psoriasis were then subdivided in two subgroups with respect to H. pylori infection: patients infected by H. pylori at T0 (H. pylori+T0) and patients not infected by H. pylori at T0 (H. pylori–T0); the two groups were then compared with each other for clinical expression of psoriasis at baseline (T0). H. pylori+T0 patients received eradication therapy for one week, and they were re-evaluated with 13C-UBT to ensure successful H. pylori eradication four weeks later (T5). Patients still positive for H. pylori infection at T5 were discontinued from the study. Eradicated patients (H. pylori–T5) and patients with psoriasis not affected by H. pylori infection at T0 (H. pylori–T0) were clinically reassessed at T5 for psoriasis severity (psoriasis area and severity index [PASI], dermatology life quality index [DLQI]) and compared to evaluate if eradication of H. pylori could exert an adjuvant therapeutic effect on psoriasis. To avoid any bias, all patients with psoriasis were simultaneously treated with the same psoralen+ultraviolet A (PUVA) protocol from baseline to the end of the study (5 weeks). Diagnosis of psoriasis and disease activity evaluation Psoriasis was clinically diagnosed by a trained dermatologist, and disease severity was evaluated by PASI, body surface area, and DLQI as reported in the literature.24,25 International Journal of Dermatology 2015, 54, e109–e114
Diagnosis of psoriatic arthritis Diagnosis of psoriatic arthritis was made by a trained rheumatologist and based on CASPAR criteria,26 whose sensitivity is 98.7% and specificity is 91.4%. Diagnosis of Helicobacter pylori infection The diagnosis of infection was made through the 13 C-UBT. H. pylori produces urease in the stomach, and the 13 C-UBT detects the activity of the urease. Fasting patients were asked to drink 200 ml of orange juice containing 75 mg of 13C-UBT urea. Breath samples at baseline and after 30 minutes were analyzed with a non-dispersive infrared spectrometer (Wagner Analysen Technik, Bremen, Germany). The results were considered positive when delta over baseline was 4%. Therapy for psoriasis All patients with psoriasis received the same standardized PUVA protocol from T0 to T5 as follows: UVA 2 J/cm2, with gradual increase of 0.5 J/cm2 per session, for 12 sessions in total, with an average frequency of three applications per week, preceded by the assumption of 8-methoxypsoralen at an average dose of 0.6–0.8 mg/kg, two hours before the session. Eradication therapy for Helicobacter pylori infection All H. pylori+T0 patients were treated according to the guidelines of the American Association of Gastroenterologists27 as follows: esomeprazole 40 mg two times per day, clarithromycin 500 mg two times daily, and amoxicillin 1 g two times per day (alternatively, in subjects allergic to penicillin, and metronidazole 500 mg two times per day) for seven days. Statistical analysis The percentage of H. pylori+ subjects was evaluated estimating the 95% confidence interval for a proportion, using a binomial distribution. The sample size was calculated through StatMate software. A non-parametric approach was followed, as variables were not normally distributed at the Shapiro test. Variables were summarized using absolute and percentage frequencies for qualitative variables and percentiles (median, 25th, and 75th) for quantitative variables. Differences in patients’ characteristics according to UBT result were evaluated using the chi-squared ª 2015 The International Society of Dermatology
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or Fisher exact test for qualitative variables and Wilcoxon rank sum test for quantitative variables.
Helicobacter pylori infection worsens psoriasis
Table 1 Demographic and clinical characteristics of psoriasis patients according to H. pylori infection at baseline Urea breath test at baseline
Results Two hundred and ten patients with psoriasis (study group) (109 men and 101 women, aged between 18 and 76 years, mean age: 49.75 years) and 100 patients that had come to our attention for melanoma screening were used as the control group (71 male and 79 female, aged between 19 and 71 years, mean age: 44.03 years) and were included in the study. The two groups were comparable for sex and age, and smoking, eating, and drinking habits. The educational level of all enrolled patients ranged from primary to secondary school. The percentage of H. pylori+ patients was similar between study and control group at baseline (19.6 vs. 22%, respectively; P = 0.831). All enrolled patients with psoriasis were subdivided into two subgroups according to the presence of H. pylori infection at baseline: H. pylori+T0 patients with psoriasis (n = 43) and H. pylori–T0 patients with psoriasis (n = 167). No significant differences were found between the two groups for age, gender, clinical presentation (plaque type, guttate, palmoplantar, pustular), pruritus, presence of arthritis, life quality, and for several gastrointestinal symptoms, i.e., dyspepsia, meteorism, diarrhea, constipation, and weight loss. However, H. pylori+T0 patients showed a significant higher PASI score compared with H. pylori–T0 patients (17.9 3.16 vs. 13.7 4.20 respectively; Table 1). Moreover, H. pylori+T0 patients were more frequently affected by epigastralgia and gastric pyrosis as expected (P = 0.046 and P = 0.037, respectively). With regard to H. pylori eradication, none of the patients reported any allergy to penicillin, thus they all received the same protocol for H. pylori eradication. No serious adverse events have occurred, thus all the patients concluded the therapeutic protocol, except for one patient of 167 H. pylori–T0, who failed to complete the PUVA treatment because she became pregnant. In the psoriasis group, three patients of 43 H. pylori+T0 were still positive at T5, and thus they were discontinued from the study. Fifteen of the 93 patients (16.12%) that had dyspepsia or epigastralgia or gastric pyrosis showed an initial worsening of symptoms during treatments, which disappeared within two weeks; 11 belonged to the H. pylori+ and four to the H. pylori– group. The main characteristics of the patients are reported in Table 1. At T5, the PASI score was significantly decreased in all patients; however, it was significantly lower in eradicated ª 2015 The International Society of Dermatology
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H. pylori+T0 (n = 43) Median (1st–3rd quartile) Age (years) 49 PASI score 17.9 DLQI score 9 n (%) Gender, male 25 Clinical variant Plaque type 32 Guttate type 4 Pustular type 3 Palmoplantar 1 Itching/burning 32 Arthritis 10 Epigastralgia 11 Gastric pyrosis 10 Dyspepsia 7 Meteorism 7 Diarrhea 3 Constipation 7 Weight loss 2
(39–59) (10.7–24.0) (5.75–17.0) (62.5) (80.0) (10.0) (7.5) (2.5) (73.1) (25.0) (27.5) (25.0) (17.5) (17.5) (7.5) (17.5) (5.0)
H. pylori–T0 (n = 167)
P
51 (43–60) 13.7 (9.8–17.6) 11 (6–15.0)
0.454a 0.047a 0.980a
96 (57.8) 115 23 14 5 94 53 23 18 24 17 18 23 13
(69.3) (13.8) (8.4) (3.0) (56.8) (31.9) (13.9) (10.8) (14.6) (10.7) (10.8) (13.9) (7.8)
0.719b 0.817c 0.763c 0.987c 0.956c 0.451c 0.508b 0.046b 0.037b 0.813c 0.269b 0.772c 0.616c 0.741c
H. pylori, Helicobacter pylori; H. pylori+T0, patients with psoriasis affected by H. pylori infection at baseline; H. pylori –T0, patients with psoriasis not affected by H. pylori infection at baseline. a Wilcoxon rank-sum test. b Chi-squared test. c Fisher exact test. Table 2 Psoriasis severity comparison between uninfected at T0 and patients eradicated at T5
patients
Urea breath test
PASI score DLQI score
H. pylori–T5 (n = 40)
H. pylori–T0 (n = 166)
P
8.36 (1.2–17.40) 9.7 (1–26)
10.85 (1–18.80) 9.13 (1–26)
0.006 0.912
DLQI, dermatology life quality index; H. pylori, Helicobacter pylori; H. pylori–T5, psoriatic eradicated patients; H. pylori–T0, patients with psoriasis not affected by H. pylori infection at baseline; PASI, psoriasis area and severity index.
patients (H. pylori–T5) than in uninfected patients at baseline (H. pylori–T0) (8.36 vs. 10.85 respectively; P = 0.006) (Table 2, Fig. 1). The DLQI score was decreased in a non-statistically significant way after treatment, and no difference was detected between previously uninfected patients and those who received eradication therapy (Table 2). International Journal of Dermatology 2015, 54, e109–e114
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Figure 1 Absolute value of PASI score at T5. PASI, psoriasis area and severity index
Discussion It has already been demonstrated that H. pylori infection may cause worsening in several dermatological diseases such as acne rosacea,28 chronic idiopathic urticaria,29 Behcßet, and other autoimmune diseases.30 Moreover, several studies support the possible relationship between H. pylori and several immune-mediated inflammatory diseases.31,32 However, only few and conflicting studies, aimed at investigating the worsening role of H. pylori in psoriasis, have been reported in the literature. The first analysis conducted on a wide sample was published in 2000 by Dauden et al.,15 and they recruited 145 patients (84 with psoriasis and 61 with lichen planus) who underwent 13C-UBT and were compared with healthy controls; 73.8% of patients with psoriasis and 75.4% of patients with lichen planus were UBT+, while the prevalence of UBT+ in controls was 80.2% and 74.1%, respectively. The authors failed to demonstrate a significant higher prevalence of UBT+ test in patients with psoriasis than in controls. Among the patients with psoriasis that were UBT+, 11 were receiving cyclosporine and six acitretin; the authors conclude that cyclosporine could encourage a gastric colonization by H. pylori, and the interaction between retinoids and specific receptors placed on the mucosa could modify the gastric microenvironment.15 Among the UBT+ patients, only 10 received specific eradication treatment, and in only eight patients, the eradication was confirmed by UBT repetition; however, the authors concluded that eradication did not influence the clinical course of psoriasis. Epidemiological studies on H. pylori infection prevalence in psoriasis are exiguous and inconclusive. However, an Italian analysis on H. pylori infection prevalence in psoriasis was conducted by Fabrizi et al. in 2001 on a pediatric population aged between 5 and 18 (20 patients with psoriasis and 29 healthy controls).16 All the subjects recruited for the study underwent the UBT test: two patients with International Journal of Dermatology 2015, 54, e109–e114
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psoriasis (10%) with a positive history of dyspeptic symptoms and five controls (29%) were infected with H. pylori. The main limits of this study are its sample size and the low sensibility and specificity of the 13C-UBT in childhood.16 Qayoom and Ahmad17 in 2002 showed that the prevalence of H. pylori seropositivity in Indian patients with psoriasis (20 of 50; 40% of cases) was significantly higher than in healthy people (five of 50; 10% of cases). The unexpected low prevalence of infection in the analyzed samples was probably dependent on the authors’ decision to exclude subjects with gastrointestinal symptoms from the study. In 2004, a prospective case–control study by Dauden et al. investigated the seroprevalence of cytotoxin-associated gene A (cagA) in patients with psoriasis with H. pylori infection. Among the 11 patients, six were positive for the serotype cagA (54.5%), whereas 15 of 22 controls were positive (68.1%). The authors concluded that the cagA status was not related to the disease’s duration, clinical presentation, severity, and presence of psoriatic arthritis.18 In the literature, two case reports described the complete remission of psoriasis after the eradication of H. pylori in subjects positive to the UBT test. The first one, reported by S aez-Rodrıguez et al.,19 described a 38-year-old woman affected by palmoplantar pustular psoriasis unresponsive to topical and systemic corticosteroids, dapsone, and colchicine; the patient also had a history of dyspepsia unresponsive to omeprazole and ranitidine, and the worsening of cutaneous lesions was preceded by exacerbation of gastrointestinal symptoms. The patient had a 13C-UBT with positive results, and she received the diagnosis of chronic atrophic gastritis; after eradication of the H. pylori, the psoriatic lesions completely disappeared without any clinical relapse after four years of follow-up. H€ ubner and Tenbaum20 in 2008 reported another case of palmoplantar pustular psoriasis in a 35-year-old woman that was clinically improved after H. pylori eradication. The patient was affected by dyspeptic syndrome and psoriasis unresponsive to corticosteroid and calcipotriol application. Six weeks after H. pylori eradication, a gradual improvement of cutaneous lesions started to appear, and three years later, the patient was completely free from psoriasis. Ali and Whitehead in 2008 reported a case of a woman affected by a severe form of psoriasis in which a great improvement of cutaneous lesions was obtained after H. pylori eradication.21 The 48-year-old woman affected by epigastralgia was treated with triple therapy after the presence of H. pylori was assessed. The patients had not received any dermatological care. Four months after eradication, the patient showed a ª 2015 The International Society of Dermatology
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clear improvement of psoriasis with persistence of hyperpigmented post-lesional areas. Owing to the lack of specific therapy for psoriasis, the authors justified the improvement with the eradication of the gastric infective focus. Onsun et al.22 in 2012 reported an association between psoriasis severity and H. pylori infection, and they focused on the role of eradication therapy in improving psoriasis. However, the authors used the stool antigen test, whose reliability to detect H. pylori colonization in Italian adults is still debated.33 As announced, the studies conducted until now cannot contribute to form a unique opinion about the role of H. pylori infection in psoriasis. As most of the reported studies show several methodological limits, it may not be confirmed unambiguously from the data available in the literature that H. pylori worsens psoriasis. First, the prevalence of H. pylori infection, particularly in some Italian geographic areas, makes the wide recruitment of patients mandatory to perform a reliable investigation.34 Studies based on serological tests provide information about the patient’s immunological status against the bacterium, but they fail to demonstrate active infection by H. pylori. In some other reports, patients were not standardized to receive the same therapy for psoriasis during the study, thus it becomes almost impossible to understand the contribution played by eradication in improving the disease course. Finally, some authors reported the clinical improvement of psoriasis without using validated and reproducible severity scales. The aim of this study was to add a further clinical experience to what was reported in literature, trying to overcome the limits of previously reported analyses. Therefore, we designed a sample size appropriate to the proposed outcomes, disease severity was estimated through validated scales, patients received a standardized treatment for psoriasis for the period of the study, and finally we used the 13C-UBT, which is the gold standard among the non-invasive methods to detect H. pylori infection. Our results demonstrated that the prevalence of H. pylori infection among patients with psoriasis is no higher than that reported in a dermatological setting or for the general Italian population. The prevalence of H. pylori infection in central and southern Italy ranges from 9.5% to 21.3%.34–36 H. pylori infection seems able to aggravate the clinical expression of psoriasis, although it could also be postulated that patients with psoriasis with higher PASI often need systemic therapy that might increase the risk of H. pylori infections. We cannot exclude that eradication could exert an adjuvant therapeutic role in the short-term control of psoª 2015 The International Society of Dermatology
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Report
riasis. However, the clinical improvement of psoriasis after eradication could also be related to the resolution of undiagnosed infectious processes other than H. pylori. The major limit of this study is the lack of an internal control group in the subset of patients with psoriasis with no eradication for H. pylori infection, to make a comparison on PASI variations between patients with eradicated and non-eradicated psoriasis. However, our ethical committee had judged this control group as unethical, and the three patients who had failed the eradication were too few to form an internal group for comparison. For this reason, currently, we cannot recommend the routine use of eradication therapy for psoriasis with psoriasis infected by H. pylori until further controlled studies are performed with an internal group of patients with non-eradicated psoriasis. References 1 Orciani M, Campanati A, Salvolini E, et al. The mesenchymal stem cell profile in psoriasis. Br J Dermatol 2011; 165: 585–592. 2 Campanati A, Orciani M, Gorbi S, et al. Effect of biologic therapies targeting tumour necrosis factor-a on cutaneous mesenchymal stem cells in psoriasis. Br J Dermatol 2012; 167: 68–76. 3 Potenza C, Bernardini N, Nicolucci F, et al. Severe psoriasis with positive TB-gold test in treatment with Etanercept: case report. Cutis 2012; 90: 120–122. 4 Campanati A, Moroncini G, Ganzetti G, et al. Adalimumab modulates angiogenesis in psoriatic skin. Eur J Inflamm 2013; 11: 489–498. 5 De Simone C, Amerio P, Amoruso G, et al. Immunogenicity of anti-TNFa therapy in psoriasis: a clinical issue? Expert Opin Biol Ther 2013; 13: 1673– 1682. 6 Rigopoulos D, Gregoriou S, Katrinaki A, et al. Characteristic of psoriasis in Greece: an epidemiological study of a population in a sunny Mediterranean climate. Eur J Dermatol 2010; 24: 530–534. 7 Bardazzi F, Antonucci VA, Tengattini V, et al. A 36-week retrospective open trial comparing the efficacy of biological therapies in nail psoriasis. J Dtsch Dermatol Ges 2013; 11: 1065–1070. 8 Krueger JG, Bowcock A. Psoriasis pathophysiology: current concepts of pathogenesis. Ann Rheum Dis 2005; 64: 30–36. 9 Campanati A, Ganzetti G, Di Sario A, et al. Insulin resistance, serum insulin and HOMA-R. J Gastroenterol 2013; 48: 673. 10 Hernando-Harder AC, Booken N, Goerdt S, et al. Helicobacter pylori infection and dermatologic diseases. Eur J Dermatol 2009; 19: 431–444. 11 Ganzetti G, Campanati A, Offidani A. Alopecia areata: a possible extraintestinal manifestation of Crohns disease. J Crohns Colitis 2012; 6: 962–963. International Journal of Dermatology 2015, 54, e109–e114
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12 Correa P, Piazuelo MB. Natural history of Helicobacter pylori infection. Dig Liver Dis 2008; 40: 490–496. 13 Kusters JG, van Vliet AH, Kuipers EJ. Pathogenesis of Helicobacter pylori infection. Clin Microbiol Rev 2006; 19: 449–490. 14 Pellicano R, Rizzetto M. Extragastric manifestations of Helicobacter species infection. Do these bacteria act as triggers? Minerva Gastroenterol Dietol 2002; 48: 179–187. 15 Dauden E, V azquez-Carrasco MA, Pe~ nas PF, et al. Association of Helicobacter pylori infection with psoriasis and lichen planus: prevalence and effect of eradication therapy. Arch Dermatol 2000; 136: 1275–1276. 16 Fabrizi G, Carbone A, Lippi ME, et al. Lack of evidence of relationship between Helicobacter pylori infection and psoriasis in childhood. Arch Dermatol 2001; 137: 1529. 17 Qayoom S, Ahmad QM. Psoriasis and Helicobacter pylori. Indian J Dermatol Venereol Leprol 2003; 69: 133–134. 18 Dauden E, Cabrera MM, O~ nate MJ, et al. CagA seropositivity in Helicobacter pylori positive patients with psoriasis. J Eur Acad Dermatol Venereol 2004; 18: 116– 117. 19 Saez-Rodrıguez M, Noda-Cabrera A, Garcıa-Bustınduy M, et al. Palmoplantar pustulosis associated with gastric Helicobacter pylori infection. Clin Exp Dermatol 2002; 27: 720. 20 H€ ubner AM, Tenbaum SP. Complete remission of palmoplantar psoriasis through Helicobacter pylori eradication: a case report. Clin Exp Dermatol 2008; 33: 339–340. 21 Ali M, Whitehead M. Clearance of chronic psoriasis after eradication therapy for Helicobacter pylori infection. J Eur Acad Dermatol Venereol 2008; 22: 753–754. 22 Onsun N, Arda Ulusal H, Su O, et al. Impact of Helicobacter pylori infection on severity of psoriasis and response to treatment. Eur J Dermatol 2012; 22: 117–120. 23 World Medical Association Declaration of Helsinki: Ethical Principles for Medical Research Involving Human Patients. Adopted by the 18th WMA General Assembly 1964 and amended by the 29th, 35th, 41st and 48th WMA General Assemblies. 24 Campanati A, Ganzetti G, Di Sario A, et al. The effect of etanercept on hepatic fibrosis risk in patients with nonalcoholic fatty liver disease, metabolic syndrome, and psoriasis. J Gastroenterol 2013; 48: 839–846.
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25 Campanati A, Giuliodori K, Ganzetti G, et al. A patient with psoriasis and vitiligo treated with etanercept. Am J Clin Dermatol 2010; 11(Suppl. 1): 46–48. 26 Coates LC, Conaghan PG, Emery P, et al. Sensitivity and specificity of the classification of psoriatic arthritis criteria in early psoriatic arthritis. Arthritis Rheum 2012; 64: 3150–3155. 27 Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol 2007; 102: 1808–1825. 28 T€ uz€ un Y, Keskin S, Kote E. The role of Helicobacter pylori infection in skin diseases: facts and controversies. Clin Dermatol 2010; 28: 478–482. 29 Campanati A, Gesuita R, Giannoni M, et al. Role of small intestinal bacterial overgrowth and Helicobacter pylori infection in chronic spontaneous urticaria: a prospective analysis. Acta Derm Venereol 2013; 93: 161– 164. 30 Guarneri F, Guarneri C, Benvenga S. Helicobacter pylori and autoimmune pancreatitis: role of carbonic anhydrase via molecular mimicry? J Cell Mol Med 2005; 9: 741– 744. 31 Suzuki H, Franceschi F, Nishizawa T, et al. Extragastric manifestations of Helicobacter pylori infection. Helicobacter 2011; 16(Suppl. 1): 65–69. 32 Figura N, Franceschi F, Santucci A, et al. Extragastric manifestations of Helicobacter pylori infection. Helicobacter 2010; 15(Suppl. 1): 60–68. 33 Bilardi C, Biagini R, Dulbecco P, et al. Stool antigen assay (SA) is less reliable than urea breath test for posttreatment diagnosis of Helicobacter pylori infection. Aliment Pharmacol Ther 2002; 16: 1733–1738. 34 Straffolini T, Rosmini F, Ferrigno L, et al. Prevalence of Helicobacter pylori infection in a cohort of Italian military students. Epidemiol Infect 1998; 120: 151–155. 35 Ponzetto A, Pellicano R, Morgando A, et al. Seroprevalence of Helicobacter pylori infection among blood donors in Torino, Italy. Minerva Gastroenterol Dietol 2001; 47: 3–7. 36 Bazzoli F, Palli D, Zagari RM, et al. The LoianoMonghidoro population-based study of Helicobacter pylori infection: prevalence by 13C-urea breath test and associated factors. Aliment Pharmacol Ther 2001; 15: 1001–1007.
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