doi: 10.1111/j.1346-8138.2010.01106.

Journal of Dermatology 2011; 38: 761766

ORIGINAL ARTICLE

Clinical study of the relationship between Helicobacter pylori and chronic urticaria and prurigo chronica multiformis: Effectiveness of eradication therapy for Helicobacter pylori
Rei AKASHI,1 Naoko ISHIGURO,1 Satoru SHIMIZU,2 Makoto KAWASHIMA1
1

Department of Dermatology, and 2Medical Research Institute, Tokyo Womens Medical University, Tokyo, Japan

ABSTRACT
Eighty two patients with chronic urticaria and 17 patients with prurigo chronica multiformis were referred to our department from October 2004 to February 2007 and were tested for Helicobacter pylori antigen using the polyclonal H. pylori stool antigen test (enzyme-linked immunosorbent assay method). H. pylori antigen was detected in 25 (30.5%) of the 82 patients with chronic urticaria and in 10 (58.8%) of the 17 patients with prurigo chronica multiformis. Those ndings were not signicantly higher than the positive rate for H. pylori stool antigen in healthy agematched controls. In patients positive for H. pylori antigen, seven of the 25 with chronic urticaria had complications of gastritis (six patients) or gastric ulcers (one patient). Three of the 10 patients with prurigo chronica multiformis had complications of gastritis (two patients) or gastric ulcers (one patient). We examined the therapeutic efcacy of antibacterial treatment for the 17 patients with chronic urticaria and the eight patients with prurigo chronica multiformis who were positive for H. pylori antigen and accepted the treatment based on informed consent. We evaluated the effectiveness of treatment by scoring the skin conditions and by using the Skindex-16, a measure of quality of life. The eradication therapy for H. pylori was more effective for treating prurigo chronica multiformis and the skin symptoms started to improve within 314 days after the therapy. However, that therapy was not always effective for treating chronic urticaria. We suggest that H. pylori may be an important pathogenetic factor, especially for prurigo chronica multiformis, and that eradication therapy should be considered to treat intractable cases. Key words: chronic urticaria, clinical study, eradication therapy, Helicobacter pylori, prurigo chronica multiformis.

INTRODUCTION
Helicobacter pylori is a spiral-shaped, microaerophilic, Gram-negative bacterium that colonizes the gastric mucosa, and is recognized as a cause of gastritis.1 Recently, it has been reported that H. pylori eradication is effective in treating some skin diseases, especially for chronic urticaria (CU), pruritus cutaneous, nummular dermatitis and prurigo chronica multiformis (PCM).2,3 Those studies reported that in chronic skin diseases, persistent infections with H. pylori may be an eruption trigger and may cause

deterioration of the disease into an intractable and chronic form.3 We have reported the effectiveness of eradication therapy for H. pylori in a small number of cases with CU or PCM.4 We now report an additional evaluation of the relationships between H. pylori, CU and PCM.

METHODS
Patients A total of 99 patients, including 82 patients (21 males 61 females) with CU and 17 patients

Correspondence: Naoko Ishiguro, M.D., Department of Dermatology, Tokyo Womens Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. Email: kasei@derm.twmu.ac.jp Received 3 August 2009; accepted 9 August 2010.

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(10 males seven females) with PCM, were entered into this study. The mean age of the patients with CU was 45.3 14.9 years, and for patients with PCM was 64.5 12.3 years. The mean length of disease was 32.4 52.8 months for CU and 40.5 47.8 months for PCM. They were referred to the Department of Dermatology in the Tokyo Womens Medical University from October 2004 to February 2007. The diagnoses of CU and PCM were based on clinical features. All 99 patients received medical interviews about past history and complications for gastritis, gastric ulcers or duodenal ulcers. A medical doctor in the Institute of Gastroenterology was consulted for patients with prominent gastrointestinal symptoms. Diagnosis of H. pylori infection and bacterial evaluation after eradication therapy Helicobacter pylori was detected using the polyclonal H. pylori stool antigen test, an enzyme-linked immunosorbent assay method.5,6 When patients were treated with eradication therapy, their antigen titers were checked again after 4 weeks of eradication therapy to determine if they had become negative or not. The stool hemoglobin was also checked if possible. Eradication therapy Helicobacter pylori eradication therapy was performed by the concomitant administration of two antibiotics, 750 mg amoxicillin and 400 mg clarithromycin, and a proton pump inhibitor, 30 mg lansoprazole, twice a day for 1 week. Evaluation of skin conditions Therapeutic efcacy was evaluated by assessing skin conditions and quality of life (QOL). We scored skin conditions into 47 grades for each parameter. Each parameter was assessed during the last 7 days before the visit date for CU patients, and on the day they arrived at our hospital for PCM patients. The skin conditions for CU patients consisted of four parameters (incidence of appearance during the last 7 days, distribution, type of eruption and level of pruritus), while those for PCM consisted of three parameters (distribution, type of eruption and level of pruritus) (Tables 1,2). QOL was evaluated by the Japanese version Skindex-16, which considers three parameters: symptoms, emotions and functioning.7,8 We checked skin conditions and Skindex-16 before the

Table 1. Evaluation of skin conditions for chronic urticaria

1. Incidence of appearance during the last 7 days No eruption (0), 1 day (1), 2 or 3 days (2), every other day (3), everyday (4) 2. Distribution No eruption (0), <25% of the whole body (1), 2549% (2), 5074% (3), 75100% (4) 3. Type of eruption No eruption (0), erythema (1), wheal with slight elevation (2), wheal with obvious elevation (3) 4. Level of pruritus No itch (0), mild itch without scratching (1), itch with some scratching (2), severe itch (3), unbearable itch (4)

Each parameter was estimated for the most serious condition 1 week before the visit day.

Table 2. Evaluation of skin conditions for prurigo chronica multiformis

1. Distribution No eruption (0), face, neck, trunk, upper extremities, lower extremities and other, total number of areas (16) 2. Type of eruption No eruption (0), mostly erythemas (1), mostly papules (2), almost the same number of erythemas and papules (3) 3. Level of pruritus No itch (0), mild itch without scratching (1), itch with some scratching (2), severe itch (3), unbearable itch (4)

Each parameter was estimated for the condition at the day of visiting our hospital.

treatment, at 1 month after the treatment, and at 24 months and or at 56 months after the treatment. Statistical analysis Statistical analyses were performed using the GLM procedure, SAS system ver. 9. P < 0.05 was considered statistically signicant. Ethical considerations The protocol for this study was approved by the Ethics Committee of Tokyo Womens Medical University. Informed consent was taken from all patients before the treatment.

RESULTS
Positive rates of H. pylori antigen and stool hemoglobin The positive rate for H. pylori antigen was 30.5% (25 82) for CU, and 58.8% (10 17) for PCM. Of the 80 patients examined, only one patient with CU was positive for stool hemoglobin.

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Past history and complication of gastritis, gastric ulcers and duodenal ulcers In the 25 CU patients positive for H. pylori antigen, 12 had a past history of gastritis (six patients), gastric ulcers (two patients) or duodenal ulcers (four patients), and seven of them had complications of gastritis (six patients) or gastric ulcers (one patient) during treatment. Out of the 10 patients with PCM, seven had a past history of gastritis (four patients), gastric ulcers (two patient) or duodenal ulcers (one patient), and three of them had complications of gastritis (two patients) or gastric ulcers (one patient) during treatment. Effectiveness of eradication therapy Of the 35 H. pylori antigen-positive patients, 17 with CU and eight with PCM, from whom written consent was obtained, were treated with the eradication therapy. In CU, all 17 cases had been treated with 13 kinds of H1-blockers and nine cases had also been prescribed a H2-blocker. In PCM, all eight cases had been treated with topical steroid and H1-blocker. Medications for CU and PCM were continued and H2-blockers were stopped during the course of eradication therapy. The mean length of disease was 23.3 32.9 months for 17 CU cases and 17.8 16.6 months for eight PCM cases. We evaluated the effectiveness for these intractable cases. CU The incidence of appearance, the distribution, the type of eruption and the level of pruritus of CU patients had a tendency to decrease after the eradication therapy, but the changes were not statistically signicant. In the Skindex-16, emotions were alleviated at a statistically signicant level (Fig. 1). Out of those 17, two cases were followed up only 1 month after the eradication. Fifteen of the cases were followed for more than 2 months at least, three cases underwent remission, three cases had improvement in all parameters of skin condition, two cases had improvement in two parameters, four cases were exacerbated in all parameters and three cases had no clear tendency. Out of the 15, 12 cases, except for three in remission, needed to continue treatment at 2 4 months and or at 56 months after the eradication.

Figure 1. Transition of skin conditions and Skindex-16 depending on eradication for chronic urticaria.

The H. pylori stool antigen test was negative for 14 of 17 cases 1 month after the eradication therapy. Out of the three cases who remained positive, one underwent remission, one improved in all parameters and the other case was exacerbated. Among the six cases that improved (three in remission and three improved in all parameters), two cases had gastric symptoms before the eradication therapy. One had improved after the therapy. The other had remission, although the H. pylori stool antigen test remained positive. PCM The distribution, the type of eruption and the level of pruritus of PCM patients was lower after the eradication therapy. In particular, the type of eruption and the level of pruritus improved at a statistically signicant level. In the Skindex-16, emotions were also alleviated at a statistically signicant level (Fig. 2). Six of the eight cases had complete improvement, although one of the six cases relapsed at 6 months, and

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DISCUSSION
Helicobacter pylori was rst isolated from the gastric mucosa in 1983.1 It has been known as a factor involved in gastritis and gastric ulcers, and it is also an important factor in the pathogenesis of gastric cancers and low-grade B-cell lymphomas of mucosa-associated lymphoid tissue.911 Even in the dermatological area, some reports have shown a relationship between H. pylori and some skin diseases, rosacea,12 prurigo nodularis,13 prurigo pigmentosa14 and erythema elevatum diutinum.15 Since the 1990s, several studies of H. pylori eradication therapy have been reported for CU, the results of which were not necessarily denitive.2,1619 In Japan, Furukawa and Sakurane reported the effectiveness of eradication therapy for patients with some intractable skin diseases (CU, pruritus cutaneous, nummular dermatitis and PCM) who had serum immunoglobulin (Ig)G antibodies against H. pylori and had H. pylori infections observed by gastroscopic examination. They proposed that in chronic skin diseases, a persistent infection with H. pylori may be a trigger of the eruptions and may cause the deterioration of the disease into an intractable and chronic form.3,20 However, there have been few reports about eradication therapy especially on PCM patients after that. We assessed H. pylori stool antigen in patients with CU and PCM who had been referred to our Department from October 2004 to February 2007. The positive rates were 30.5% (25 82) for CU and 58.8% (10 17) for PCM. H. pylori stool antigen in 92 healthy Japanese was examined and the mean positive rate was 59.8% in all cases, approximately 54% in the 3549-year-olds, approximately 55% in the 5059year-olds and 69% in the 6074-year-olds.21 H. pylori stool antigen in 994 Japanese healthy adults was examined in a farming area and the mean positive rate was 56.4% in all cases, 36.4% in those under 49 years old, 55.1% for those aged 5160 years and 66.7% in those aged 6170 years.22 The stool antigen positive rates in our study were not necessarily higher than that of a healthy control. Along with establishment of eradication therapy, the diagnosis for H. pylori infection is important. It is common to check serum IgG antibodies against H. pylori and to look for the bacteria by gastroscopy. The sensitivity and specicity of the serum IgG

Figure 2. Transition of skin conditions and Skindex-16 depending on eradication for prurigo chronica multiformis.

another was not able to be followed 56 months after the treatment. One of the eight cases had mild improvement and one had no change. The cured cases began to improve 314 days after the therapy nished. H. pylori stool antigens were negative for the seven cases except for one case with no change. Out of eight PCM cases, three cases, which improved with eradication therapy, had gastric symptoms before the therapy. Those symptoms improved in two cases after the therapy. Side-effects of treatment Ten cases had side-effects, including soft stools or diarrhea in seven cases, dysgeusia in two, and glossitis, angular cheilitis, mild stomach ache, constipation or skin rash in one patient each. All symptoms were mild, and were alleviated relatively quickly after the eradication treatment.

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antibodies are reported as 99%, and 81.8% or 86.4%.23 However, the serum IgG antibody is not suitable to evaluate the treatment because it takes 1 year or more to decrease the titer by 50% after the eradication therapy. On the other hand, the 13C-urea breath test and the polyclonal H. pylori stool antigen test also have high sensitivity and specicity, the sensitivity being 98.3% and the specicity being 95% in the latter.23 These were recommended as methods for the diagnosis of infection and evaluation of eradication in the Guidelines in the Management of H. pylori Infection in Japan 2003.24 We suggest that the H. pylori stool antigen test is more accurate and should be used in a widespread manner because it does not require administration of any drug (compared with the 13C-urea breath test which requires ingestion of 13C-urea), does not depend on an immune response and is easy to use, even for young children and unconscious patients.5,6 In the intractable cases with CU, only three cases underwent remission. H. pylori stool antigens were still positive after the eradication therapy in three cases, one underwent remission, one improved in all parameters, and the other one was exacerbated. At this time, it is difcult to determine the effectiveness of eradication therapy for CU, although H. pylori may be one of causes for some cases with CU. It was reported that there is insufcient evidence for the effectiveness of eradication therapy, although CU was included as one of the indications of eradication therapy in the Guidelines in the Management of H. pylori Infection in Japan 2009.25 Further examination will be needed to reach a conclusion on this. On the other hand, in the intractable cases with PCM, the type of eruption and the level of pruritus were improved at a statistically signicant level. Six out of eight cases underwent remission and the skin conditions started to improve within 314 days after the therapy was completed. After 6 months, four of the six cases did not relapse, and we consider that H. pylori may play an important role in the onset of PCM. We believe that the improvement was caused by the eradication because our eradication term was just 1 week, although we cannot rule out that the improvement by eradication therapy might be due to anti-inammatory effects of the macrolide, clarithromycin, and we should examine strictly whether 1 week therapy with clarithromycin is effective or not

for the group negative for H. pylori antigen. Furthermore, we do not think that eight cases with PCM were enough to evaluate the role of H. pylori. The mechanisms by which H. pylori causes chronic gastritis and gastric ulcers have been investigated as follows.20,2628 H. pylori expresses several proteins, including 20 (HpaA), 196 and 63 kDa, which are related to the adherence to the gastric mucosal epithelium. It also has high urease activity, by which urea is degraded to generate NH3 and NH 4 , lipopolysaccharide (LPS) and cholesteryl glucoside that cause mucosal injury. A subclass of H. pylori secretes vacuolating cytotoxin A (VacA) which mediates cellular degeneration (apoptosis), and cytotoxin-associated gene A protein (CagA). Further, H. pylori-neutrophil activating protein (HP-NAP)1 and N-formyl-methionylleucyl-phenylalanine (FMLP) from H. pylori are involved in neutrophil migration, activation and adhesion to the angioendothelium, and in macrophage activation. Remarkable neutrophil and lymphocyte inltrations are observed in the gastric mucosa histologically. Activating neutrophils and macrophages produce interleukin (IL)-1, IL-6 and tumor necrosis factor (TNF)-a, which are involved with various immune responses. IL-8, which is mainly produced in gastric epithelial cells stimulated by H. pylori directly, plays an important role, accelerating neutrophil adherence to the angioendothelium, migration and activity. On the other hand, levels of TNF-a and interferon (IFN)-c are increased in affected mucosal lesions which suggests that T-helper cell (Th)1-type effector immune responses are evoked. Human leukocyte antigen (HLA) class II antigens are expressed by infected gastric mucosal epithelia which may stimulate the immune system. However, it is thought that the inammation persists without the removal of H. pylori. Such immune reaction elicited by H. pylori might even cause various diseases including PCM, however, details of that are unknown at this time. We believe that H. pylori itself may be a trigger of inammation for PCM, because our cases rapidly improved after the eradication therapy. However, we should examine this in more cases. We hope that the pathogenetic mechanism will be elucidated in the near future. We suggest that H. pylori may be an important pathogenetic factor, especially for PCM, and that eradication therapy should be considered for intractable cases of PCM.

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ACKNOWLEDGMENTS
This study was nancially supported in part by a grant from the Grant of Takako SATAKE, Tokyo Womens Medical University.

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