Koichiro Nakamura

Japanese Guideline for Atopic Dermatitis 2014

Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and countermeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is a inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level. The basics of treatment discussed in this guideline are based on the Guidelines for the Treatment of Atopic Dermatitis 2008 prepared by the Health and Labour Sciences Research and the Guidelines for the Management of Atopic Dermatitis 2012 (ADGL2012) prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2013 together with those for other allergic diseases.Given the importance of appropriate diagnosis and appropriate assessment of cutaneous symptoms in treatment of atopic dermatitis, the basics of treatment in this guideline are composed of (1) investigation and coun- termeasures of causes and exacerbating factors, (2) correction of skin dysfunctions (skin care), and (3) pharmacotherapy, as three mainstays. These are based on the disease concept that atopic dermatitis is a inflammatory cutaneous disease with eczema by atopic diathesis, multi-factorial in onset and aggravation, and accompanied by skin dysfunctions. These three points are equally important and should be appropriately combined in accordance with the symptoms of each patient. In treatment, it is important to transmit the etiological, pathological, physiological, or therapeutic information to the patient to build a favorable partnership with the patient or his/her family so that they may fully understand the treatment. This guideline discusses chiefly the basic therapy in relation to the treatment of this disease. The goal of treatment is to enable patients to lead an uninterrupted social life and to control their cutaneous symptoms so that their quality of life (QOL) may meet a satisfactory level. The basics of treatment discussed in this guideline are based on the Guidelines for the Treatment of Atopic Dermatitis 2008 prepared by the Health and Labour Sciences Research and the Guidelines for the Management of Atopic Dermatitis 2012 (ADGL2012) prepared by the Atopic Dermatitis Guidelines Advisory Committee, Japanese Society of Allergology in principle. The guidelines for the treatment of atopic dermatitis are summarized in the Japanese Guideline for the Diagnosis and Treatment of Allergic Disease 2013 together with those for other allergic diseases.

Behçet's disease (Adamantiades-Behçet's disease).

Adamantiades-Behçets disease (ABD) is characterized by starting with oral aphthous ulceration and developing of the systemic involvements. The pathogenesis of ABD is closely correlated with the genetic factors and the triggering factors which acquire delayed-type hypersensitivity reaction against oral streptococci mediated by IL-12 cytokine family. HLA-B51 is associated in more than 60% of the patients and its restricted CD8+ T cell response is clearly correlated with the target tissues. Bes-1 gene encoded partial S. sanguinis genome which is highly homologous with retinal protein, and 65u2009kD heat shock protein (Hsp-65) released from streptococci is playing an important role with human Hsp-60 in the pathogenesis of ABD. Although Hsp-65/60 has homologies with the respective T cell epitope, it stimulates peripheral blood mononuclear cells (PBMCs) from ABD patients. On the other hand, some peptides of Hsp-65 were found to reduce IL-8 and IL-12 production from PBMCs of ABD patients in active stage.

A Randomized, Open-Label, Multicenter Trial of Topical Tacrolimus for the Treatment of Pruritis in Patients with Atopic Dermatitis

Background Pruritis caused by atopic dermatitis (AD) is not always well controlled by topical corticosteroid therapy, but use of tacrolimus often helps to soothe such intractable pruritis in clinical settings. Objective To determine the anti-pruritic efficacy of topical tacrolimus in treating AD in induction and maintenance therapy. Methods Prior to the study, patients were randomly allocated into two groups, induction therapy followed by tacrolimus monotherapy maintenance, and induction therapy followed by emollient-only maintenance. In the induction therapy, the patients were allowed to use topical tacrolimus and emollients in addition to a low dose (<10 g/week) of topical steroids. Patients showing relief from pruritis were allowed to proceed to maintenance therapy. Recurrence of pruritis in maintenance therapy was examined as a major endpoint. Results Two-thirds of patients (44/68; 64.7%) showed relief from pruritis after induction therapy. Pruritis recurred in 23.8% (5/21) of the tacrolimus monotherapy group and in 100% (21/21) of the emollient group during maintenance period, a difference that was statistically significant. Conclusion Use of topical tacrolimus is effective in controlling pruritis of AD compared to emollient.

Treatment trial of multicentric reticulohistiocytosis with a combination of predonisolone, methotrexate and alendronate

Dear Editor, Multicentric reticulohistiocytosis (MRH), which was first described by Goltz and Lyamon in 1954, is a rare multisystem disorder classified under nonLangerhans cell histiocytosis. It affects various tissues and organs, most commonly the skin and joints. The symptoms are characterized by cutaneous papulonodular eruptions, mainly on the extremities, and destructive polyarthritis. Histologically, cutaneous and synovial lesions compose the infiltrate of histiocyte-like cells and multinucleated giant cells of monocyte/macrophage origin. The pathogenesis of MRH has not been clarified, however, Gorman et al. implicated tumor necrosis factor (TNF)-α as playing important roles in the development and progression of the disease. Although some cases may resolve spontaneously, others often tend to wax and wane over many years, ultimately extending into rheumatoid arthritis-like contracture and disfiguring appearance of the affected joints. Therefore, MRH represents a morbidity, and is also of potential importance in looking into therapeutic intervention in individual subjects. Different kinds of treatments, including predonisolone (PSL), hydroxychloroquine, methotrexate (MTX), cyclophosphamide and azathioprine, have been used with no consensus and often resulted in minimal or disappointing effects. We herein report a Japanese patient who successfully responded to oral administration of PSL, MTX and alendronate, an aminobisphosphonate compound. A 25-year-old Japanese female presented with a 10-month history of skin-colored, asymptomatic papulonodular eruptions on the face, dorsal hands and knees (Fig. 1a). She also complained of severe bilateral arthralgia, which was not articular swelling, on the proximal and distal interphalangeal joints, wrists, elbows, shoulders, knees and ankles. There were no mucous membrane lesions. The osteocutaneous symptoms developed simultaneously 2 months after surgical excision of an ovarian carcinoma (diagnosed histologically as a primitive neuroectodermal tumor), and gradually progressed during the adjuvant chemotherapy (i.e. vincristine, doxorubicin, cyclophosphamide, ifosfamide, etoposide [VDC-IE]) that was repeated for three courses over 4 months postoperation. She received non-steroidal anti-inflammatory drugs (NSAIDs) orally together with morphine (90 mg/day) for joint pain relief, but without obvious effects. She was otherwise clinically healthy with no recurrence of ovarian carcinoma and had no relevant familial history of rheumatic disease and malignancy. Laboratory tests including peripheral blood count, biochemistry, serum lipids and complement profile were normal. The erythrocyte sedimentation rate and C-reactive protein were not elevated. Testing for rheumatoid factor yielded a negative result, but was slightly positive (×160) for antinuclear antibodies without detection of diseasespecific autoantibodies such as anti-SSA, anti-SSB or anti-dsDNA antibodies. Radiography of the hands showed marginal erosions in multiple joints. Skin biopsy from the nodule on the dorsal hand showed the dermal infiltrate of numerous histiocyte-like cells and multinucleated giant cells exhibiting abundant eosinophilic periodic acid-Schiff-positive cytoplasm with “ground glass” appearance. Immunohistochemical staining revealed that histiocytic cells and giant cells were positive for CD68 and lysozyme, but negative for CD1a, S100 protein, CD34 and FactorXIIIa (Fig. 2), suggesting a macrophage cell lineage. Based on these findings, a diagnosis of MRH was established. Investigation for malignancy, such

Serum thymic stromal lymphopoietin levels are not elevated in patients with atopic dermatitis.

Dear Editor, Thymic stromal lymphopoietin (TSLP) is an interleukin (IL)-7-like cytokine produced by epidermal keratinocytes (KC). TSLP induces CCL17/thymus and activation regulated chemokine (TARC) production by dendritic cells (DC) and it also activates epidermal Langerhans cells. A high level of immunoreactivity for TSLP is detected on the lesional KC in patients with atopic dermatitis (AD). Keratin 14 driven TSLP transgenic mice showed inflammatory eruptions showing a pathology similar to that of AD. TSLP is thus considered to play an important role in the regulation of T-helper (Th)2-type cytokine production in the pathogenesis of AD. With regard to serum levels of cytokines and chemokines in AD, we have previously revealed that high levels of both serum CCL17 and CCL22 were detected in AD patients, and that these reflect disease activity of AD. Thus, it is speculated that serum levels of TSLP may also reflect disease activity of AD. However, little is known about the serum levels of TSLP in AD patients. We herein examined the serum levels of TSLP in 46 patients of AD (average age, 26.5 years old; 19 men and 27 women) and 32 healthy controls (HC; average age, 29.7 years; 16 men and 16 women) using an enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, MN, USA). The diagnosis of AD was determined according to the criteria by Hanifin and Rajka. As a result, the serum levels of TSLP in the AD patients were 192.2 ± 54.1 pg/mL (mean + standard deviation), while those with HC were 112.6 ± 52.6 pg/mL. No significant difference in the serum TSLP levels were detected between these two groups (P = 0.139). There were no significant differences in the serum TSLP levels among the different severities of AD patients. The serum TSLP levels in mild cases (n = 18) were 183.9 ± 105.0 pg/mL, 224.8 ± 66.0 pg/mL in moderate cases (n = 16) and 178.7 ± 95.4 pg/mL in severe cases (n = 12), individually. There were no significant differences between serum immunoglobulin E levels, serum CCL17 levels or peripheral eosinophil numbers and serum TSLP levels among the different severities of AD patients. Thus, our results suggest that the function of TSLP may be different from that of Th2-chemokines such as CCL17 in the point that TSLP does not mainly enter the blood circulation in AD patients. TSLP is produced by epidermal KC, and this induces DC to produce CCL17, attracting Th2-type CCR4 T cells in the lesional skin of AD. Another report also has revealed that TSLP induces dendritic cells to induce Th2 cell response through OX40 ligand. Furthermore, TSLP activates CD4 T cells to secrete IL-4. These data suggest that TSLP may exert its effects directly in the inflammatory skin in patients with AD. However, it is reported that

Inhibitory effect of a histamine 4 receptor antagonist on CCL17 and CCL22 production by monocyte‐derived Langerhans cells in patients with atopic dermatitis

We examined the inhibitory effect of a histamine 4 receptor (H4R) antagonist (JNJ7777120) on CCL17 and CCL22 chemokine production by human monocyte‐derived Langerhans cells (MoLC) in patients with atopic dermatitis (AD) and healthy controls (HC). We confirmed the significantly higher production of both CCL17 and CCL22 in the MoLC of AD patients compared with HC. The H4R antagonist significantly inhibited the production of both CCL17 and CCL22 in the MoLC of AD patients. With regard to TLR2‐signaled enhancement, peptidoglycan (PGN)‐enhanced production of CCL17 and CCL22 by MoLC was inhibited by the H4R. Immunoblotting analysis demonstrated that phosphorylated p38 mitogen‐activated protein kinase was induced by PGN and that this enhancement was attenuated by the application of the H4R antagonist. These data indicate that H4 signaling modulates the production of T‐helper 2 chemokine in MoLC and contributes to chronic inflammation in AD patients. Our data suggest a possible novel therapeutic approach using a H4R antagonist in the treatment of patients with AD.

Eosinophilic pustular folliculitis with extensive distribution: correlation of serum TARC levels and peripheral blood eosinophil numbers

A 62-year-old man noted an itchy eruption on his palms and soles, which gradually expanded to the face, extremities, and trunk, during May 2009. He presented at our hospital in July 2009. The eruption was apparent on the patient’s scalp, face, trunk, extremities, and palms and soles (Fig. 1). Clinical examination revealed slightly increased levels of peripheral blood eosinophils. The patient’s serological human immunodeficiency virus (HIV) titer was negative. Histological examination of the pustular follicular erythema on the subject’s face showed numerous eosinophils infiltrating the hair follicles and the destruction of hair walls (Fig. 2). The numerous eosinophils also infiltrated the sebaceous gland. Histological examination of the erythematous macules with pustules on the patient’s lower leg showed intraepidermal pustules with neutrophil and eosinophil infiltration. Eosinophilic pustular folliculitis was diagnosed according to clinical and histological findings. The patient was treated with oral indomethacin and minocycline. However, the minocycline was ineffective and, because of the occurrence of itchiness, indomethacin was stopped for two weeks (Fig. 3). The subject was treated with oral prednisolone at 15 mg/d along with topical corticosteroid ointment (difluprednate ointment and clobetasol ointment) from September 2009. The erythematous macules gradually improved and oral prednisolone was gradually decreased and withdrawn in May 2011 after two years of treatment. Peripheral blood eosinophil numbers showed maximum levels and then gradually decreased to within normal ranges. Serum TARC (thymus and activation-regulated chemokine, CCL17) levels were also examined. Serum TARC reached a maximum level in October 2009 and then gradually decreased in parallel with peripheral blood eosinophils.

Cysteinyl leukotriene receptor 2 gene polymorphism ‐1220 A/C is not associated with atopic dermatitis or psoriasis vulgaris in Japanese patients

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Distinct phenotype of epidermolysis bullosa simplex with infantile migratory circinate erythema due to frameshift mutations in the V2 domain of KRT5.

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Interleukin-17A gene polymorphism with the susceptibility of intestinal symptoms in patients with Behçet's disease.

been used worldwide, all nine eruption cases were discovered in Japan. Recently, the relationships between genetic background and immediate type allergic reaction or aspirin intolerance has attracted considerable attention. For example, gene variants of human leukocyte antigen (HLA)-DRA and the HLA-DRA–HLA-DRB5 interregion has been observed in penicillin-induced immediate allergic reaction by genome-wide association study. Whereas, in the case of aspirin-intolerant urticaria, HLA-DB1*0609 has been identified as a possible genetic marker. According to these observations, which suggest that certain HLA alleles could be genetic markers for certain immediate type drug eruptions, it is possible to speculate that genetic differences may contribute to a distinctive BU hypersensitivity rate. Further investigations would be needed to determine whether this speculation is accurate.