Shunsuke Takahagi

Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria

To cite this article: Takahagi S, Mihara S, Iwamoto K, Morioke S, Okabe T, Kameyoshi Y, Hide M. Coagulation/fibrinolysis and inflammation markers are associated with disease activity in patients with chronic urticaria. Allergy 2010; 65: 649–656.

Metastatic extramammary Paget's disease treated with paclitaxel and trastuzumab combination chemotherapy.

In the treatment of metastatic breast cancer, trastuzumab, a recombinant monoclonal antibody against human epidermal growth factor receptor 2 (HER2), is effective when tumor cells overexpress HER2 protein. Although some cases of extramammary Paget’s disease (EMPD) also express HER2 protein, no case of EMPD has been reported to be treated with trastuzumab. A 75‐year‐old man who suffered from EMPD of the scrotum and inguinal region underwent a local excision and lymph node dissection. Tumor cells invaded the dermis and lymph nodes. Although he was postoperatively treated with adjuvant chemotherapies, metastatic skin lesions appeared and spread over his left thigh, rapidly and widely. Tumor cells disseminated along lymph vessels in the dermis and overexpressed HER2 protein. We administered paclitaxel and trastuzumab according to a protocol for HER2‐positive metastatic breast cancers. The skin metastasis dramatically decreased during the regimen and a histopathological examination showed that most of HER2‐positive tumor cells diminished. Six months later, metastases were found in the central nervous system (CNS), but no other metastases were found in the skin, visceral organs or lymph nodes. Trastuzumab and paclitaxel‐combination with the assessment of central nervous system lesions should be considered as an option for the treatment of HER2‐positive EMPD.

Increase of coagulation potential in chronic spontaneous urticaria

To cite this article: Takeda T, Sakurai Y, Takahagi S, Kato J, Yoshida K, Yoshioka A, Hide M, Shima M. Increase of coagulation potential in chronic spontaneous urticaria. Allergy 2011; 66: 428–433.

Sweat antigen induces histamine release from basophils of patients with cholinergic urticaria associated with atopic diathesis

Background  We previously demonstrated that the semipurified human sweat antigen causes skin reactions and histamine release from basophils via specific IgE in patients with atopic dermatitis (AD). Patients with cholinergic urticaria (ChU) also develop skin reactions and histamine release of basophils in response to autologous sweat.

Increasing the dose of cetirizine may lead to better control of chronic idiopathic urticaria : an open study of 21 patients

SIR, Chronic idiopathic urticaria (CIU) is characterized by the occurrence of spontaneous pruritic weals on most days. It is common, but often disabling because of persistent clinical symptoms which negatively influence the quality of life. Antihistamines have been the mainstay of treatment and they produce a good response in most patients, but not in all. For those patients who derive only limited benefit from the initial treatment, therapeutic guidelines advocate the use of antihistamines above the licensed or manufacturers’ recommended doses. However, there is scant evidence regarding the effectiveness of dose increases of the same antihistamine in the patients who responded poorly to the first dosage of the agent. Cetirizine is a second-generation antihistamine effective in treating patients with CIU. The manufacturer’s recommended dosage is 10 mg daily and it is permissible to increase the dose up to 20 mg daily. As cetirizine inhibits histamine-induced weal and flare reactions dose-dependently, it is plausible that higher doses of the drug will be more effective in controlling urticarial symptoms. However, the clinical effect of such dose increases has not been evaluated in patients with CIU. In some previous studies, patients with CIU were initially treated with cetirizine 5 mg, and they were allowed to increase the dose to 10 or 20 mg if no benefit was obtained at the starting dose. However, neither urticarial activity at each dose nor clinical effects of the dose increase were assessed in these studies. In the present open study, we evaluated the effect of increasing the dose of cetirizine in order to control the disease activity in patients with CIU, who had derived only limited benefit from 10 mg daily of the same drug. Patients with CIU (> 1 month duration) were recruited from secondary care hospitals. Patients with physical urticaria, or urticaria caused by medications, foods or other known causes were excluded. Prior to the dose-increasing study, patients were treated with cetirizine 10 mg daily for 1 or 2 weeks as a screening period. Twenty-one patients who responded poorly to the treatment, i.e. the change of the total daily score of urticarial symptoms (see below) was less than 1, during the screening period, were enrolled in the study. Approximately one-third of patients who entered the screening period were eligible. At the beginning of the study, patients were randomly assigned to group A (11 patients) or group B (10 patients), after obtaining informed consent, and all patients were given an increased dose of cetirizine, 20 mg daily (10 mg twice daily), for 1 or 2 weeks (period 1). Thereafter, patients in group A continued the daily dosage of cetirizine 20 mg, whereas the patients in group B received the decreased dosage of 10 mg, for an additional 1 to 2 weeks (period 2). Patients were instructed to record daily urticarial activity scores throughout the study period including the screening period. The urticarial activity was assessed by using the scoring system as previously described. Namely, each of the number of weals, the duration of the weals, and the severity of itch, was scored from 0 to 3. The total daily score of the urticarial symptoms, therefore, ranged from 0 to 9. For the assessment of the clinical effect of increase ⁄decrease in the dosage, the data were analysed by the Friedman test and the Steel–Dwass test. There were no statistically significant differences between the two groups in age (42Æ5 ± 14Æ1 vs. 36Æ9 ± 16Æ7 years, mean ± SD, for groups A and B, respectively) or mean urticarial activity scores during the screening period [weal scores 1Æ09 ± 0Æ78 vs. 1Æ11 ± 0Æ64, itch scores 1Æ53 ± 0Æ89 vs.

Aspirin Augments IgE-Mediated Histamine Release from Human Peripheral Basophils via Syk Kinase Activation

BACKGROUND Non-steroidal anti-inflammatory drugs (NSAIDs), especially aspirin, and food additives (FAs) may exacerbate allergic symptoms in patients with chronic idiopathic urticaria and food-dependent exercise-induced anaphylaxis (FDEIA). Augmentation of histamine release from human mast cells and basophils by those substances is speculated to be the cause of exacerbated allergic symptoms. We sought to investigate the mechanism of action of aspirin on IgE-mediated histamine release. METHODS The effects of NSAIDs, FAs or cyclooxygenase (COX) inhibitors on histamine release from human basophils concentrated by gravity separation were evaluated. RESULTS Benzoate and tartrazine, which have no COX inhibitory activity, augmented histamine release from basophils similar to aspirin. In contrast, ibuprofen, meloxicam, FR122047 and NS-398, which have COX inhibitory activity, did not affect histamine release. These results indicate that the augmentation of histamine release by aspirin is not due to COX inhibition. It was observed that aspirin augmented histamine release from human basophils only when specifically activated by anti-IgE antibodies, but not by A23187 or formyl-methionyl-leucyl-phenylalanine. When the IgE receptor signaling pathway was activated, aspirin increased the phosphorylation of Syk. Moreover, patients with chronic urticaria and FDEIA tended to be more sensitive to aspirin as regards the augmentation of histamine release, compared with healthy controls. CONCLUSIONS Aspirin enhanced histamine release from basophils via increased Syk kinase activation, and that the augmentation of histamine release by NSAIDs or FAs may be one possible cause of worsening symptoms in patients with chronic urticaria and FDEIA.

Fucoidan suppresses IgE production in peripheral blood mononuclear cells from patients with atopic dermatitis.

We previously reported that fucoidan, a dietary fiber purified from seaweed, inhibited IgE production in B cells from mice spleen in vitro and ovalbumin-sensitized mice in vivo. In this study, we examined the effect of fucoidan on IgE production in human peripheral blood mononuclear cells (PBMC) in vitro. PBMC, obtained from healthy donors or patients with atopic dermatitis (AD) with high levels of serum IgE, were cultured with IL-4 and anti-CD40 antibody in the presence or absence of fucoidan. Fucoidan significantly reduced IgE production in PBMC without affecting cell proliferation and IFN-γ production. Fucoidan also inhibited immunoglobulin germline transcripts of B cells in PBMC, and decreased the number of IgE-secreting cells. The inhibitory effects of fucoidan were similarly observed for both PBMC from patients with AD and those with healthy donors. Our findings indicate that fucoidan suppresses IgE induction by inhibiting immunoglobulin class-switching to IgE in human B cells, even after the onset of AD.

Refractory Chronic Urticaria Treated Effectively with the Protease Inhibitors Nafamostat Mesilate and Camostat Mesilate

Chronic urticaria (CU) is characterized by the sponta-neous recurrent appearance of wheals and pruritus, which seriously impairs patients’ quality of life (QoL) (1, 2). Patients with refractory CU are treated with leukotriene receptor antagonists, glucocorticoids and/or other im-munomodulatory agents in addition to antihistamines (3, 4). Nevertheless, there remain a number of patients who are unsatisfactorily treated even with these medications, either due to insufficient efficacy or to the occurrence of side-effects. Nafamostat mesilate (NM) and camostat mesilate (CM) are newly synthesized protease inhibitors. They inhibit broad serine proteases, including trypsin, kallikrein, complements (C1r

Six cases of antihistamine-resistant dermographic urticaria treated with oral ciclosporin.

BACKGROUND Dermographic urticaria (DU) is characterized by strong itch and wheals induced by mechanical scratching. H(1)-receptor antagonists may reduce symptoms of DU to some extent, but other treatments being used for chronic spontaneous urticaria, such as H(2)-receptor antagonists and corticosteroids, are not usually effective for DU. CASE SUMMARY We here report six cases of antihistamine-resistant DU treated with oral ciclosporin. Four cases suffering from severe itches that spontaneously occurred before the appearance of wheals in response to scratching were substantially improved by use of ciclosporin for 21, 16, 32, and 8 months, and one of them reached complete remission. Two cases did not obtain a benefit from the treatment, because of insufficient effects and/or side effects. DISCUSSION Oral ciclosporin may be of value as a potential treatment of anti-histamine-resistant DU.

Chronic spontaneous urticaria and the extrinsic coagulation system

Chronic spontaneous urticaria (CSU) is a common skin disorder characterized by daily or almost daily recurring skin edema and flare with itch. Recently, the activation of the blood coagulation cascade has been suggested to be involved in CSU, but the trigger of the coagulation cascade remains unclear. In this article, we review recent understanding of the relationship between the pathogenesis of CSU and extrinsic coagulation reactions. In CSU, vascular endothelial cells and eosinophils may play a role as TF-expressing cells for activating the extrinsic coagulation pathway. Moreover, the expression of TF on endothelial cells is synergistically enhanced by the activation of Toll-like receptors and histamine H1 receptors. The activated coagulation factors may induce plasma extravasation followed by degranulation of skin mast cells and edema formation recognized as wheal in CSU. Molecules involved in this cascade could be a target for new and more effective treatments of urticaria.