Mayumi Hatakeyama

Influence of neutralizing antibodies to adalimumab and infliximab on the treatment of psoriasis

Current treatment with biologics has produced dramatic therapeutic effects in patients with psoriasis, although these agents occasionally decrease in efficacy. One of the main factors responsible for this attenuation is attributed to the development of antidrug antibodies (ADAs).

IgG4-related skin manifestations in patients with IgG4-related disease

We describe two cases of IgG4-related disease associated with skin manifestations with IgG4-positive plasma cells. The first patient was a 52-year-old woman with a 3-year history of IgG4-related sialadenitis who presented with pruritic, indurated erythematous lesions on the auricle, postauricular and submandibular regions and neck. A skin biopsy showed infiltration of IgG4-positive plasma cells in the subcutaneous tissue. The second patient was a 53-year-old woman with IgG4-related lesions in the ocular adnexal tissues and nasal cavity who presented with pruritic, indurated erythema on the cheek and submandibular region. Histopathological examination of a skin biopsy revealed a dense, patchy infiltrate comprised of lymphocytes, IgG4-positive plasma cells and eosinophils around blood vessels and sweat glands in the entire dermis and subcutis. The skin lesions in these cases were considered to be skin manifestations of IgG4-related disease. The findings of these two cases together with the three reported cases of IgG4-related disease with skin manifestations in the literature suggest that IgG4-related skin lesions may appear on the scalp, face, neck, auricle and postauricular regions during the course of IgG4-related disease.

Anti-Inflammatory Role of Langerhans Cells and Apoptotic Keratinocytes in Ultraviolet-B–Induced Cutaneous Inflammation

UV radiation, particularly UVB, is the major risk factor for the induction of skin cancer, and it induces skin inflammation and immunosuppression. Although reports documented that Langerhans cells (LCs) play various roles in photobiology, little is known about whether they contribute to UVB-induced cutaneous inflammation. Recently, the anti-inflammatory effect of apoptotic cells was noted. This study focuses on the roles of LCs and apoptotic cells in UVB-induced cutaneous inflammation. We show that LCs are essential for resolution of UVB-induced cutaneous inflammation. Administration of quinolyl-valyl-O-methylaspartyl-[2,6-difluophenoxy]-methyl ketone, a broad-spectrum caspase inhibitor with potent antiapoptotic properties, inhibited the formation of UVB-induced apoptotic cells and aggravated UVB-induced cutaneous inflammation in wild-type mice. In contrast, exacerbation of UVB-induced cutaneous inflammation following quinolyl-valyl-O-methylaspartyl-[2,6-difluophenoxy]-methyl ketone administration was not observed in LC-depleted mice. These results suggest that the interaction between LCs and apoptotic cells is critical for resolution of UVB-induced cutaneous inflammation. Interestingly, UVB-induced apoptotic keratinocytes were increased in LC-depleted mice. In addition, we revealed that UVB-induced apoptotic keratinocytes were phagocytosed by LCs ex vivo and that prolongation of UVB-induced cutaneous inflammation following treatment with Cytochalasin D, an inhibitor of phagocytosis, was partially attenuated in LC-depleted mice. Collectively, our findings demonstrate that the interaction between LCs and apoptotic cells, possibly via LC-mediated phagocytosis of apoptotic keratinocytes, has an essential anti-inflammatory role in the resolution of UVB-induced cutaneous inflammation.

UVB Exposure Prevents Atherosclerosis by Regulating Immunoinflammatory Responses

Objective— UVB irradiation is an established treatment for immunoinflammatory cutaneous disorders and has been shown to suppress cutaneous and systemic inflammatory diseases through modulation of the adaptive immune response. However, it remains unknown whether UVB irradiation prevents an immunoinflammatory disease of arteries such as atherosclerosis. Approach and Results— Here, we show that UVB exposure inhibits the development and progression of atherosclerosis in atherosclerosis-prone mice by expanding and enhancing the functional capacity of CD4+ forkhead box P3+ regulatory T cells and regulating proatherogenic T-cell responses. Experimental studies in Langerhans cell–depleted mice revealed that epidermal Langerhans cells play a critical role in UVB-dependent induction of CD4+ forkhead box P3+ regulatory T cells, suppression of proatherogenic T-cell responses, and prevention of atherosclerotic plaque development. Conclusions— Our findings suggest the skin immune system as a novel therapeutic target for atherosclerosis and provide a novel strategy for the treatment and prevention of atherosclerosis.

Steroid treatment can improve the impaired quality of life of patients with acquired idiopathic generalized anhidrosis

DEAR EDITOR, Acquired idiopathic generalized anhidrosis (AIGA) is characterized by systemic anhidrosis or hypohidrosis with no identified cause or other autonomic or neurological abnormalities. AIGA is sometimes accompanied by cholinergic urticaria with symptoms of tingling, unpleasant sensation and severe pruritus. Treatment options for AIGA are limited. Most reported cases responded to high-dose systemic corticosteroids including intravenous steroid pulse therapy. AIGA can lead to discomfort, hyperthermia and heat stroke, which may affect the quality of life (QoL) of patients. However, the relationship between the QoL of patients with AIGA and effectiveness of therapy has not been examined. The aim of this study was to examine the impact of AIGA on QoL and the relationship between therapeutic effectiveness and improvement in QoL. Eight male patients and one female patient with AIGA were enrolled in this study. The patient characteristics are described in Table 1. The diagnosis of anhidrosis and the treatment efficacy were assessed by a systemic thermoregulatory sweating test and local sweating test involving intradermal injection of acetylcholine and the starch–iodine test (Minor test). Other diseases with hypohidrosis such as Sj€ ogren syndrome and Fabry disease were excluded. Cholinergic urticaria was observed in seven patients. Histological findings revealed that morphological abnormalities of sweat glands and sweat ducts were absent in all patients, and slight infiltration of lymphocytes around the sweat glands was found in five patients. The mean interval between disease onset and treatment was 27 8 months. Histamine release test with the sweat or skin test using autologous sweat revealed sweat allergy in two of eight tested patients. One course of methylprednisolone pulse therapy (3 days, 1000 mg per day) was given to six patients, two courses were given to one patient and three courses were given to one patient. Sweating improved in all patients after therapy. Adverse effects and recurrence of symptoms were not observed for > 1 year after therapy. In the absence of therapy, anhidrosis remained unchanged in one patient who declined treatment. Skindex-16 inquires about the effect of skin conditions on QoL. Patients respond to questions by choosing one of seven possible response choices, which range from ‘never bothered’ to ‘always bothered’. Skindex responses are reported in three subscales (symptoms, emotions and functioning), which address three domains: symptoms, emotional effects, and effects on social and physical functioning. Scores vary from 0 (minimal effect on QoL) to 100 (significant effect on QoL). The mean Skindex-16 subscale scores before and after therapy are shown in Figure 1. Skindex-16 questions before therapy were carried out from spring to autumn (from May to November). Skindex-16 questions after therapy were performed in September (autumn in Japan). The average September temperature of our facility is 20–30 °C. Sweating tests were also performed alongside the Skindex-16 questionnaire before and after therapy.

Cholinergic urticaria: epidemiology, physiopathology, new categorization, and management

PurposeThe aim of this study was to review the evidence on the epidemiology, physiopathology, categorization, and management of cholinergic urticaria. We specifically focused on several subtypes of cholinergic urticaria and investigated the relationship between cholinergic urticaria and idiopathic anhidrosis.MethodsUsing an integrative approach, we reviewed publications addressing the epidemiology, clinical features, diagnostic approach, physiopathology, subtype classification, and therapeutic approach to cholinergic urticaria.ResultsMultiple mechanisms were found to contribute to the development of cholinergic urticaria. This disorder should be classified based on the pathogenesis and clinical characteristics of each subtype. Such a classification system would lead to better management of this resistant condition. In particular, sweating function should be given more attention when examining patients with cholinergic urticaria.ConclusionsBecause cholinergic urticaria is not a homogeneous disease, its subtype classification is essential for selection of the most suitable therapeutic method.

Addition of lafutidine can improve disease activity and lead to better quality of life in refractory cholinergic urticaria unresponsive to histamine H1 antagonists

Abbreviations: CU, cholinergic urticaria; H1RA, H1 receptor antagonists; H2RA, H2 receptor antagonists; QoL, quality of life; DLQI-J, Dermatology Life Quality Index. * Corresponding author at: Department of Dermatology, Kurume University School of Medicine, and Kurume University Institute of Cutaneous Cell Biology, 67 Asahimachi, Kurume, Fukuoka 8300011, Japan. Fax: +81 942 31 7853. E-mail address: hashimot@med.kurume-u.ac.jp (T. Hashimoto).

Aspirin-intolerant chronic urticaria exacerbated by cutaneous application of a ketoprofen poultice.

© 2010 The Authors. doi: 10.2340/00015555-0901 Journal Compilation

Drug fever due to S‐carboxymethyl‐L‐cystein: Demonstration of a causative agent with patch tests

Dear Editor, Drug fever is a febrile response to a drug without skin manifestations and happens temporally following administration of the causative drug and disappears after discontinuation of the drug. The most frequent mechanism of drug fever is a hypersensitivity reaction. However, its exact pathogenesis remains poorly understood. S-carboxymethyl-L-cystein (SCMC) has been used worldwide for many years as an expectorant to treat chronic obstructive airway disease and bronchitis, and reported adverse reactions to that agent are rare. Here, we report a first case of drug fever caused by SCMC. A 67-year-old woman developed a fever of 39.5 C without any eruptions after an intake of SCMC and dextromethorphan hydrobromide hydrate and after an administration of SCMC and clarithromycin in August 2009 as cold medicine. Physical examinations causing a fever and laboratory tests revealed no abnormalities. She also had experienced an episode of febrile response after taking SCMC in 2002. After stopping an administration of drugs including SCMC, these episodes of febrile responses disappeared. These clinical histories suggested the possible diagnosis of drug fever due to SCMC. It was considered that the recurrence of fever after rechallenge with the suspected drug strengthens the definitive diagnosis of drug fever but the risks and benefits of rechallenge should be weighed. Because the patient wanted an exact diagnosis and a cause of episodic fever, rechallenge with the suspected drug was performed in the hospital after obtaining informed consent. Fifty milligrams of SCMC (1 ⁄ 10th the normal dose) was administrated at 13.00 and 19.00 hours and on the following day 500 mg SCMC was further administrated at 09.00 and 13.00 hours, resulting in no fervescence. However, the administration of 500 mg SCMC at 20.00 hours induced a definite fever of 37.4 C 5–12-h later with an ‘‘inappropriately well’’ condition but without any eruptions (Fig. 1). An increase in C-reactive protein (4.05 mg ⁄ dL) occurred the following day after the intake of 500 mg SCMC at night. Due to these examinations, this patient was diagnosed as having drug fever due to SCMC. Because administration of SCMC at night but not in the daytime induced fever and thiodiglycolic acid (TDA), its night-time metabolite, was suggested to be the causative agent of fixed drug eruptions induced by SCMC, we hypothesized that this timedependent febrile reaction induced by SCMC was due to its night-time metabolism. Because a common mechanism for the development of drug fever is thought to be a T-cell-mediated hypersensitivity reaction, patch tests using SCMC and its metabolites (S-methyl-L-cystein [SMC] and TDA [Sigma-Aldrich, St Louis, MO, USA]) were performed to confirm the causative agent. A patch test with 10% concentration of TDA was positive at day 2 and day 3 but 10% SCMC itself or SMC was not according to the International Contact Dermatitis Research Group criteria (Fig. 2). Five healthy volunteers had no positive reactions at those concentrations to the three chemicals. Taken together, these data strongly suggest that TDA is the probable causative agent that induces drug fever due to SCMC in this patient. The diagnosis of drug fever is often difficult and a careful review of a patient’s clinical presentation as well as the drug history can lead to an exact diagnosis. In this patient, the exact diagnosis of drug fever due to SCMC could be made by a rechallenge test. No case of drug fever due to the widely-used SCMC has been reported so far. An administration of SCMC at night but not in the daytime Figure 1. A febrile reaction during a rechallenge test with S-carboxymethyl-L-cystein (SCMC). Administration of SCMC at night but not in the daytime induced a febrile reaction.

Management of Inducible Urticarias

AbstractPurpose of review This review aims to update the information and latest advances in chronic inducible urticarias. Recent findings In contrast to chronic spontaneous/idiopathic uriticarias, chronic inducible urticarias are associated with a specific trigger and factor. One must accurately identify and characterize the specific trigger for distinguishing chronic spontaneous/idiopathic uriticaria and chronic inducible urticarias. The latter are diagnosed based on patient history and results of provocation testing which contribute to confirm the exact diagnosis, assess the threshold, and determine the severity of the disease. The general management of chronic inducible urticarias includes the identification and avoidance of the specific trigger, and symptomatic treatment with the goal of reaching complete symptom control. Symptomatic treatment for chronic inducible urticarias targets the blocking of mast-cell mediators (H1-antihistamines, H2-antihistamies, leukotriene antagonists) and inhibition of mast-cell activation (omalizumab, cyclosporine, phototherapy). H1-antihistamines are fundamental treatments for chronic inducible urticarias, but H1-antihistamine-resistant cases are not rare and additional treatment is often necessary. Also, therapeutic reactivity varies according to each subtype and patient. Summary Notably, some subtypes of chronic inducible urticaria can be treated by desensitization and/or tolerance induction to triggers. In contrast, the underlying pathogenesis of chronic inducible urticaria is not known and further studies are needed to better clarify its etiology.