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A 75-year-old Japanese man presented with pruritic blisters and macules on his trunk and extremities. He had been on hemodialysis for 4 years because of chronic renal failure, and in recent months, a polymethylmethacrylate membrane had been used for dialysis. After a change in dialysis membrane to a cellulose triacetate membrane, pruritic tense blisters developed on the extremities in combination with marked blood eosinophilia. Physical examination showed erythematous macules and tense blisters on the trunk and extremities. A biopsy specimen of an erythematous macule showed subepidermal vesicles and eosinophils that attached to the dermal-epidermal junction. Serum level of eosinophilic cationic protein was elevated. From clinical, histological, and immunological findings, a diagnosis of bullous pemphigoid was made. New blisters continued to erupt during the period in which the patient used the cellulose triacetate membrane dialyzer, and even after the use of clobetasol propionate. It resolved only after the patient came back to the use of a synthetic membrane dialyzer. We discontinued the use of clobetasol propionate, and neither bullous eruptions nor blood eosinophilia recurred. These observations suggest that cellulose membrane may be involved in the development of bullous pemphigoid through activation of eosinophils in the blood and the skin lesion, as in the present case.

Background Drug-induced hypersensitivity syndrome (DIHS/DRESS) is a severe adverse systemic reaction. Reactivation of human herpesvirus (HHV) family members other than HHV-6 has been reported in patients with DIHS. Reactivation of HHV family members is generally characterized by increased serum antibody titers against the virus. By contrast, clinical symptoms caused by viral reactivation are relatively rare. Method We report a case of DIHS with intractable genital ulcers from reactivation of herpes simplex virus (HSV) in accordance with reactivation of HHV-6 and cytomegalovirus (CMV). Result Twenty-two days after the onset of the rash, the patient developed intractable genital ulcers that were resistant to treatment. Histological examination of the ulcers revealed necrotic degeneration in the epidermal cells, with giant cells containing inclusion bodies and marked lymphocytic infiltration in the upper dermis. Immunohistochemical staining with antibodies reactive to HSV or CMV showed that these giant cells were positive for HSV but negative for CMV. Conclusion Genital herpes is a common skin disease. However, our case was considered to be a DIHS-associated symptom, not an accidental complication, as the symptoms were severe and resistant to treatment.

Elevated serum levels of B-cell-activating factor belonging to the tumor necrosis factor family (BAFF) and/or a proliferation-inducing ligand (APRIL) are shown in autoimmune diseases. We determined serum levels of BAFF and APRIL, and clinical association in patients with atopic dermatitis (AD). Serum levels of BAFF and APRIL from 35 patients with AD, 25 patients with psoriasis vulgaris, 25 patients with systemic lupus erythematosus and 25 normal healthy subjects were examined by enzyme-linked immunosorbent assay. Serum levels of APRIL, but not BAFF, were significantly elevated in patients with AD than in healthy controls or patients with psoriasis vulgaris. Patients with severe AD exhibited significantly increased APRIL levels compared to patients with moderate AD and mild AD, and serum APRIL levels were significantly decreased after treatment compared with those before treatment. In addition, increased APRIL levels were significantly associated with serum immunoglobulin E levels and blood eosinophil numbers. These results suggest that elevated serum levels of APRIL are associated with disease severity and activity in AD, and APRIL may have an important role in the pathogenesis of AD.

Summary Background Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the hemidesmosomal proteins, BP180 and BP230. NC16A, a non-collagenous stretch of the BP180 ectodomain is the primary target of pathogenic IgG antibodies. Whereas IgG anti-BP180 autoantibodies play a primary role in the pathogenesis, there is a growing number of data regarding the potential pathogenic roles of IgE class autoantibodies in BP. Objectives To examine the levels of IgG and IgE autoantibodies against BP180 and BP230, and to investigate mutual association and clinical relevance. Methods Sera obtained from 67 BP patients and 36 healthy donors were subjected to ELISA assays to measure serum IgG and IgE levels of anti-BP180 and anti-BP230 antibodies. Results IgG anti-BP180 antibodies were positive in 63 (94%) of 67 BP patients. IgG anti-BP230, IgE anti-BP180, and IgE anti-BP230 antibodies were found in 48 (72%), 20 (30%) and 45 (67%), respectively. IgG anti-BP180 levels were correlated with the affected areas. IgG anti-BP230 antibodies tended to increase in proportion to elongation of disease duration. IgE anti-BP230 levels showed a strong association with local eosinophil accumulation, while the levels were reversely related with the affected areas in BP. Conclusions IgE autoantibodies to BP180 and BP230 are detected at high frequencies in BP. IgE anti-BP230 antibodies may have a role in attracting eosinophils to the skin lesions.

金沢大学医学部附属病院皮膚科, Objective: Our purpose was to determine the serum levels and frequency of antiphospholipid antibodies (aPLs) and confirm the clinical importance of these antibodies in patients with autoimmune blistering disease (ABD). Methods: IgG and IgM anticardiolipin antibodies (aCL), IgG anticardiolipin-β2 glycoprotein I complex antibody (aCL/β2GPI), and IgG antiphosphatidylserine-prothrombin complex antibody (aPS/PT) were examined with an enzyme-linked immunosorbent assay in 71 patients with ABD, including pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid. Results: The prevalence of IgG aCL, IgM aCL, aCL/β2GPI, and IgG aPS/PT was positive for 22.4%, 9.1%, 9.9%, and 25.4% of the ABD patients, respectively, whereas these antibodies were not detected in any of the normal control subjects. Ten of 20 patients with ABD who were attending our hospital in 2004 tested positive for aPLs, and thromboembolism was detected in 7 of 10 patients with aPLs. Limitations: Follow-up studies, especially with a large patient group, will be needed to clarify the clinical relevance of aPLs in ABD. Conclusion: aPLs are frequently detected in patients with ABD. Careful examination and follow-up for thromboembolism may be necessary in ABD patients with aPLs. © 2007 American Academy of Dermatology, Inc.

Serum levels of B-cell activating factor belonging to the tumor necrosis factor family (BAFF), a potent B-cell survival factor, are elevated in patients with systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis and systemic sclerosis (SSc). The objective of this study was to determine serum BAFF levels and relate the results to the clinical features in patients with organ-specific autoimmune diseases of the skin, such as localized scleroderma and autoimmune bullous diseases. Serum BAFF levels were examined by enzyme-linked immunosorbent assay in 44 patients with localized scleroderma, 20 with pemphigus vulgaris/pemphigus foliaceus, 20 with bullous pemphigoid and 30 healthy controls. Twenty patients with SSc and 20 with SLE were also examined as disease controls. Serum BAFF levels were elevated in localized scleroderma patients compared with healthy controls. Concerning localized scleroderma subgroups, patients with generalized morphea, the severest form of localized scleroderma, had higher serum BAFF levels than linear scleroderma or morphea patients. The BAFF levels of generalized morphea were comparable with those of SSc or SLE. Furthermore, serum BAFF levels correlated positively with antihistone antibody levels and the severity of skin lesion as well as the number of skin lesions. By contrast, serum BAFF levels were not significantly elevated in patients with pemphigus or pemphigoid. These results suggest that BAFF may be contributing to autoimmunity and disease development in localized scleroderma. © 2007 The Authors Journal compilation © 2007 Blackwell Munksgaard.

Background: Fractalkine expressed on endothelial cells mediates activation and adhesion of leucocytes expressing its receptor, CX3CR1. Soluble fractalkine exhibits chemotactic activity for leucocytes expressing CX3CR1. Objective: To determine the role of fractalkine and its receptor in systemic sclerosis (SSc) by assessing their expression levels in patients with this disease. Methods: The expression of fractalkine and CX3CR1 in the skin and lung tissues was immunohistochemically examined. Circulating soluble fractalkine levels were examined by enzyme linked immunosorbent assay (ELISA). Blood samples from patients with SSc were stained for CX3CR1 with flow cytometric analysis. Results: CX3CR1 levels on peripheral monocytes/macrophages and T cells were found to be raised in patients with diffuse cutaneous SSc. The numbers of cells expressing CX3CR1, including monocytes/macrophages, were increased in the lesional skin and lung tissues from patients with diffuse cutaneous SSc. Fractalkine was strongly expressed on endothelial cells in the affected skin and lung tissues. Soluble fractalkine levels were significantly raised in sera and were associated with raised erythrocyte sedimentation rates, digital ischaemia, and severity of pulmonary fibrosis. Conclusions: Up regulated expression of fractalkine and CX3CR1 cooperatively augments the recruitment of mononuclear cells expressing CX3CR1 into the affected tissue of SSc, leading to inflammation and vascular injury.

Dermatomyositis (DM) is a heterogeneous disease with varying degrees and time courses of skin eruptions, myositis and internal organ involvement.1 Increasing evidence has demonstrated that myositis-specific autoantibodies (MSAs) are closely associated with distinct clinical subsets.2 Recently, Betteridge et al 3 ,4 reported a novel MSA against small ubiquitin-like modifier activating enzyme (SAE) in DM patients. In this study, we detected this autoantibody in a Japanese DM cohort and assessed its clinical correlations. We screened 456 consecutive Japanese patients with DM (11 children, 445 adults); 373 fulfilled the criteria of Bohan and Peter5 ,6 and the remaining 83 fulfilled Sontheimer's criteria for clinically amyopathic DM (CADM).7 Controls included 62 patients with polymyositis, 108 with systemic lupus erythematosus, 433 with systemic sclerosis and 124 with interstitial lung disease (ILD) alone. The institutional review board approved the study protocol. Immunoprecipitation assays were performed as described.8 Protein A-agarose beads preincubated with sera were incubated with 35S-methionine-labelled or unlabelled K562 cell extracts. Immunoprecipitants were fractionated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis, followed by autoradiography or …

副腎皮質ホルモン剤内服に問題のあった水泡性類天泡瘡患者4名にテトラサイクリンとニコチン酸アミドの併用内服療法(TC/NA療法)を行い有効であった。症例1: 70歳女性。水痕性類天泡瘡に対するプレドニゾロン内服の減量時に再燃した。DDSやアザチオプリンの併用は無効で, TC1000mgとNA1500mgの併用により皮疹は消退した。症例2: 99歳女性。水疱性類天疱瘡に対するベタメタゾン内服治療中に副腎皮質ホルモン剤によるせん妄が出現した。オキサゾラム内服でせん妄はコントロールされたが,水疱性類天疱瘡の再燃時に副腎皮質ホルモン剤を増量したところせん妄が増悪した。TC1000mgとNA600mgを併用して副腎皮質ホルモン剤を減量することによりせん妄は軽減した。症例3: 91歳女性。水疱性類天疱瘡の再燃時にプレドニゾロンを増量したところ,消化管出血を起こしDICの状態に陥った。副腎皮質ホルモン剤を中止し,メシル酸ガベキサート点滴などの治療で全身状態は回復した。その後水疱が再発したが,TCとNAの内服で消退した。症例4: 75歳女性。脳梗塞の既往のため副腎皮質ホルモン剤は投与せず,TCとNAの内服を行い皮疹は消退した。過去の報告および自験例の経過よりTC/NA療法は中等症以下の水疱性類天疱瘡に対して有用と考えられた。また,副腎皮質ホルモン剤内服によるコントロール不良の水疱性類天疱瘡の場合,TCとNAの併用により副腎皮質ホルモン剤の減量を試みることも有用と思われた。

A 75-year-old Japanese man presented with pruritic blisters and macules on his trunk and extremities. He had been on hemodialysis for 4 years because of chronic renal failure, and in recent months, a polymethylmethacrylate membrane had been used for dialysis. After a change in dialysis membrane to a cellulose triacetate membrane, pruritic tense blisters developed on the extremities in combination with marked blood eosinophilia. Physical examination showed erythematous macules and tense blisters on the trunk and extremities. A biopsy specimen of an erythematous macule showed subepidermal vesicles and eosinophils that attached to the dermal-epidermal junction. Serum level of eosinophilic cationic protein was elevated. From clinical, histological, and immunological findings, a diagnosis of bullous pemphigoid was made. New blisters continued to erupt during the period in which the patient used the cellulose triacetate membrane dialyzer, and even after the use of clobetasol propionate. It resolved only after the patient came back to the use of a synthetic membrane dialyzer. We discontinued the use of clobetasol propionate, and neither bullous eruptions nor blood eosinophilia recurred. These observations suggest that cellulose membrane may be involved in the development of bullous pemphigoid through activation of eosinophils in the blood and the skin lesion, as in the present case.

We describe the case of a patient with anticentriole antibody-positive scleroderma spectrum disorder (SSD) who developed pulmonary hypertension. A 54-year-old woman had noticed Raynaud's phenomenon and digital ulcers during the winter for the past 10 years. Although sclerodactyly was not present, digital ulcers, swelling of her hands, and phalangeal contracture were observed. An indirect immunofluorescence test revealed anticentriole antibody. Other SSc-specific antoantibodies were negative. An echocardiogram demonstrated that the estimated right ventricular systolic pressure was increased to 51 mmHg. She was diagnosed as SSD with pulmonary hypertension. This is the first case of SSD with anticentriole antibody to develop pulmonary hypertension.

A 38-year-old woman had noticed sclerodactylia and Raynaud's phenomenon 10 months before consultation. She was diagnosed as having systemic sclerosis (SSc) based on the skin sclerosis of her arms, chest, and face. Antinuclear antibody (ANA) level was 1:1280 with a speckled pattern, but specific autoantibodies were negative. Following the treatment with oral prednisolone and D-penicillamine, her skin sclerosis gradually improved. Three months after initiation of prednisolone, she presented Pneumocystis carinii pneumonia. About 1 year after the first admission, the pattern of indirect immunofluorescence staining changed from the speckled pattern to the discrete speckled pattern, and simultaneously anticentromere antibody (ACA) was detected by enzyme-linked immunosorbent assay. Her skin sclerosis rapidly and remarkably improved after appearance of ACA. It is generally considered that once certain SSc-specific autoantibody occurs, it does not disappear and change into other specificity of autoantibody thereafter. This case suggests that the presence of ACA closely correlates with clinical features and also suggests that clinical features may change during the clinical course with the appearance of another specific ANA. This case is very rare because such a case was not reported previously.

Drug-induced hypersensitivity syndrome (DIHS/DRESS) is a severe adverse systemic reaction. Reactivation of human herpesvirus (HHV) family members other than HHV-6 has been reported in patients with DIHS. Reactivation of HHV family members is generally characterized by increased serum antibody titers against the virus. By contrast, clinical symptoms caused by viral reactivation are relatively rare.We report a case of DIHS with intractable genital ulcers from reactivation of herpes simplex virus (HSV) in accordance with reactivation of HHV-6 and cytomegalovirus (CMV).Twenty-two days after the onset of the rash, the patient developed intractable genital ulcers that were resistant to treatment. Histological examination of the ulcers revealed necrotic degeneration in the epidermal cells, with giant cells containing inclusion bodies and marked lymphocytic infiltration in the upper dermis. Immunohistochemical staining with antibodies reactive to HSV or CMV showed that these giant cells were positive for HSV but negative for CMV.Genital herpes is a common skin disease. However, our case was considered to be a DIHS-associated symptom, not an accidental complication, as the symptoms were severe and resistant to treatment.

Bullous pemphigoid (BP), an autoimmune subepidermal-blistering disease of the elderly, is caused by antibodies against BP antigens at the epidermal basement membrane zone (BMZ). CD22 is a B lymphocyte specific response regulator, which is down-regulated after B-cell activation. Old CD22-deficient mice produce class-switched autoantibodies. To assess the role of CD22 in the pathogenesis of BP, we examined CD22 expression on B cells from BP patients and correlated its expression with clinical parameters. B cell expression of CD22 was 20% lower in BP patients when compared to healthy control subjects. In addition, B cells from BP patients showed decreased expression of L-selectin, which is an indicator of leukocyte activation, and CD22 expression levels were correlated with L-selectin expression. These results suggest that the decreased CD22 expression may be associated with the activation of B cells in BP. CD22 expression levels in BP patients did not correlate with the levels of anti-epidermal BMZ antibodies, and old CD22-deficient mice did not develop the anti-epidermal BMZ antibody. These results suggest that a decrease in CD22 expression may not be associated with BP-specific antibody production.

Although chemokines are critical elements for the selective attraction and activation of various leukocyte subsets in the inflammatory process, there are few findings concerning T helper (Th) 1 or Th2 chemokines in autoimmune blistering disease (ABD). To determine whether serum levels of chemokines that are preferentially chemotactic for Th1 (monokine induced by IFN-gamma (MIG/CXCL9)) and Th2 (thymus and activation regulated chemokine (TARC/CCL17) and macrophage derived chemokine (MDC/CCL22)) cells were elevated and whether they correlated with the clinical features in patients with ABD. Serum chemokine levels were examined using ELISA in patients with pemphigus vulgaris (PV, n=19), pemphigus foliaceous (PF, n=14), or bullous pemphigoid (BP, n=27) and normal controls (n=20). Serum MIG levels were significantly higher in patients with PV, PF, or BP than those in the control subjects. Serum levels of TARC and MDC were also significantly elevated in patients with PV, PF, or BP relative to the normal controls. Among the ABD subgroups, the levels of each chemokine tended to be higher in BP patients than in PV patients. Furthermore, serum TARC levels correlated positively with serum IgE levels in patients with ABD. Levels of TARC, MDC, and MIG were significantly decreased after treatment when the skin lesions disappeared in these patients. Furthermore, serum MIG levels correlated positively with serum levels of TARC and MDC in the ABD patients. These results suggest that both a Th1 chemoattractant MIG and Th2 chemoattractants, TARC and MDC, cooperatively play a role in the development of ABD.

Background. Patients with invasive extramammary Paget's disease appear to have a risk of regional lymph node metastasis. Despite the poor prognosis for patients with lymph node metastasis, management of extramammary Paget's disease without clinical evidence of involved nodes is controversial. Objective. To evaluate the usefulness of sentinel lymph node biopsy, patients with extramammary Paget's disease underwent sentinel lymph node biopsy using preoperative lymphoscintigraphy and intraoperative patent blue dye injection with a handheld gamma-detecting probe. Methods. Thirteen patients with primary genital extramammary Paget's disease were included in the study. Sentinel nodes identified were excised and examined by hematoxylin and eosin staining. All sentinel lymph nodes were also subjected to immunohistochemical staining for carcinoembryonic antigen, MUC1, cytokeratin 7, and gross cystic disease fluid protein-15. Results. A total of 23 nodes were removed successfully. Tumor cells were detected in 4 nodes from four patients by hematoxylin and eosin staining. No additional lymph nodes were positive by immunohistochemistry. Three of the four sentinel-node-positive patients developed distant metastases. All nine patients without node involvement were free from disease during the follow-up period. Conclusion. Sentinel lymph node biopsy was safe and feasible method and may have an important role in the management of extramammary Paget's disease with clinically N0 status. To establish the optimal management of inguinal lymph nodes in extramammary Paget's disease, additional studies in large number of patients are needed.

A 68-year-old woman who had been diagnosed with sarcoidosis presented with acral lentiginous melanoma (Breslow's tumour thickness, 2.6 mm; Clark's level IV) on her right heel. She underwent surgery for excision of the primary tumour and sentinel lymph node biopsy. The two sentinel lymph nodes revealed numerous sarcoidal granulomas and small nests of metastatic melanoma cells in the subcapuslar lesions. She subsequently underwent ilio-inguinal lymph node dissection. Surprisingly, all of the nine dissected nodes were mostly replaced by sarcoidal granulomas and contained melanoma micrometastases.