Development of bullous pemphigoid after change of dialysis membrane.

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.

Intractable genital ulcers from herpes simplex virus reactivation in drug-induced hypersensitivity syndrome caused by allopurinol.

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.

Serum levels of IgE anti-BP180 and anti-BP230 autoantibodies in patients with bullous pemphigoid.

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 67BP 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 67BP 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.

Elevated serum levels of APRIL, but not BAFF, in patients with atopic dermatitis.

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.

Antiphospholipid antibodies in patients with autoimmune blistering disease.

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-beta(2) glycoprotein I complex antibody (aCL/beta(2)GPI), 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/beta(2)GPI, 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.

Elevated serum BAFF levels in patients with localized scleroderma in contrast to other organ-specific autoimmune diseases.

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.

Decreased expression levels of CD22 and L-selectin on peripheral blood B lymphocytes from patients with bullous pemphigoid.

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.

Both Th1 and Th2 chemokines are elevated in sera of patients with autoimmune blistering diseases.

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.

Sentinel lymph node biopsy in patients with extramammary Paget's disease.

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.

Improvement of skin sclerosis after occurrence of anticentromere antibody in a patient with diffuse cutaneous systemic sclerosis.

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.

Expression of fractalkine and its receptor, CX3CR1, in atopic dermatitis: possible contribution to skin inflammation.

BACKGROUND: Fractalkine (FKN) induces activation and adhesion of leukocytes expressing its receptor, CX(3)CR1. FKN is released from the cell surface through proteolytic cleavage as soluble FKN (sFKN). OBJECTIVE: We sought to assess FKN and CX(3)CR1 expression in the skin, serum sFKN levels, and CX(3)CR1 expression on blood leukocytes in patients with atopic dermatitis (AD). METHODS: FKN and CX(3)CR1 expression in the skin was examined immunohistochemically. mRNA expression of FKN, thymus and activation-regulated chemokine, and macrophage-derived chemokine in the skin was assessed by means of real-time RT-PCR. Serum sFKN levels were assessed by using ELISA. Blood leukocytes were stained for CX(3)CR1 by means of flow cytometric analysis. RESULTS: FKN was strongly expressed on endothelial cells in skin lesions of patients with AD and psoriasis but not in normal skin. FKN mRNA levels in AD lesional skin increased to a similar extent to thymus and activation-regulated chemokine and macrophage-derived chemokine mRNA levels. CX(3)CR1-expressing cells in the affected skin of patients with AD or psoriasis increased compared with those in normal skin. Serum sFKN levels were increased in patients with AD but not in patients with psoriasis relative to levels in healthy control subjects. Serum sFKN levels were associated with the disease severity and decreased with the improvement of skin lesions in patients with AD. CX(3)CR1(+) cell frequencies and CX(3)CR1 expression levels were decreased in CD8(+) T cells, monocytes, and natural killer cells from patients with AD, but this was not observed in patients with psoriasis. CONCLUSIONS: These results suggest that through functions in both membrane-bound and soluble forms, FKN plays an important role in the trafficking of CX(3)CR1(+) leukocytes during the inflammation caused by AD.

A case of scleroderma spectrum disorder with anticentriole antibody and pulmonary hypertension.

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.