[Show abstract][Hide abstract] ABSTRACT: In our recent study, we revealed that the drug survival rate of adalimumab is shorter in Japanese patients than that in Euro-pean patients, raising the hypothesis that a low self-injection rate, which results in frequent hospital visits, may be related to the shorter drug survival rate. This prompted us to assess opinions among patients with psoriasis regarding biological agents and self-injection. Questionnaires were completed by 79 patients who visited the Department of Dermatology of Kurume University School of Medicine between January and April 2014. Sixty-one males and 18 females were enrolled, including 70 with psoriasis vulgaris, 1 with psoriatic arthritis, 6 with pustular psoriasis, and 2 with psoriatic erythroderma. Analysis of the study group revealed that 21 (26.6%) patients had gained more than 10 kg on average before the onset of psoriasis. Thirty-three (41.8%) patients were unaware of biological agents, whereas 22 (27.8%) had been treated with them. Nineteen of 22 patients were satisfied with the treatment, but 14 patients complained of high costs. Among 14 patients who were either on or had been treated with adalimumab, only 7 practiced self-injection. These 7 patients were satisfied with the decreased number of required hospital visits. When considering patients' satisfaction with fewer hospital visits afforded by self-injection of adalimumab, this practice seems to promote adherence to adalimumab. Eight patients declined the recommendation of biological agents by their doctors because of the high cost. Adequate information about biological agents, including marked efficacy and good reactions to comorbidities, may change patients' actions.
[Show abstract][Hide abstract] ABSTRACT: Liver injury caused by infliximab is rare. Only 2 cases have been reported, and both of them were successfully treated with etanercept after cessation of infliximab. No recurrence of liver injury during the treatment of etanercept was considered to be due to no cross reactivity with infliximab. We present a 36-year-old male with psoriasis developing liver injury with inf-liximab. Adalimumab has been suspected to recur liver injury because of similar mechanism of action to that of infliximab. However, our case was successfully treated with adalimumab without liver-function abnormalities. Adalimumab is a useful substitute for infliximab, suggesting toxicity or antigenicity of mouse/human chimera monoclonal antibody against TNF-α.
[Show abstract][Hide abstract] ABSTRACT: We report a 79-year-old Japanese man who developed subepidermal blistering skin disease after an 8-year history of psoriasis. Histology of a bullous lesion revealed a subepidermal blister with a mixed inflammatory cell infiltrate and fibrin nets. Indirect immunofluorescence using normal human skin sections revealed IgG and IgA autoantibodies in the patient serum, which bound to the epidermal side of 1M NaCl-split skin sections. Immunoblot analysis revealed that both IgA and IgG antibodies reacted with the BP180 NC16a domain and the 120-kDa LAD-1 and that IgG antibodies also reacted with the BP180 C-terminal domain and laminin gamma-1. These findings indicated that autoantibodies to laminin gamma-1 and multiple epitopes in BP180 ectodomain played a role in the pathogenesis of this unique autoimmune subepidermal blistering skin disease associated with psoriasis.
Indian Journal of Dermatology 09/2015; 60(5):521. DOI:10.4103/0019-5154.164433
[Show abstract][Hide abstract] ABSTRACT: Immunoreactants are found in the epidermal basement membrane in both lupus erythematosus and bullous pemphigoid (BP). To our knowledge, there are no comparative studies on direct immunofluorescence (DIF) of discoid lupus erythematosus (DLE) and BP. The authors studied DIF of lesional skins in 9 patients (2 males and 7 females) with DLE and 29 patients (11 males and 18 females) with BP to disclose the difference between these 2 diseases. IgG deposition was significantly more frequent at the epidermal basement membrane zone (BMZ) in the BP group than in the DLE group; however, IgA and IgM depositions were significantly more frequent at both the epidermal and follicular BMZs in the DLE group than in the BP group. In addition, the mean number of positive immunoreactants at both the epidermal and follicular BMZs was significantly larger in the DLE group than in the BP group. On an average, ≥3 immunoreactants were seen at the epidermal and follicular BMZs in DLE, whereas ≤2.5 immunoreactants were seen in BP. DIF may contribute to the differentiation between these 2 diseases.
The American Journal of dermatopathology 06/2015; DOI:10.1097/DAD.0000000000000387 · 1.39 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite established pathogenic role of anti-desmoglein (Dsg) antibodies in classical pemphigus, significance of autoantibodies to another desmosomal cadherin, desmocollin (Dsc), is at present unknown. No consistent immunoassay for IgG autoantibodies to Dscs has been developed.
The aim of this study was to develop reliable assays to detect anti-Dsc autoantibodies.
We expressed soluble recombinant proteins of human Dsc1-Dsc3 in mammalian cells and examined sera of various types of pemphigus, including 79 paraneoplastic pemphigus sera, by novel enzyme-linked immunosorbent assays (ELISAs) using the recombinant proteins. We also performed ELISAs of Dsc baculoproteins and cDNA transfection method, and compared the results with those of mammalian ELISAs.
By mammalian ELISAs, IgG autoantibodies to Dsc1, Dsc2 and Dsc3 were detected in 16.5%, 36.7% and 59.5% of paraneoplastic pemphigus sera, respectively, and considerable numbers of pemphigus herpetiformis and pemphigus vegetans sera strongly reacted with Dsc1 and Dsc3. Mammalian ELISAs were highly specific and more sensitive than baculoprotein ELISAs or cDNA transfection method. Several Dsc-positive sera, particularly pemphigus herpetiformis sera, showed no reactivity with Dsgs. Reactivity of a paraneoplastic pemhigus serum and a pemphigus vegetans serum with Dscs was not abolished by pre-absorption with Dsg receombinant proteins.
The results of these novel ELISAs indicated that IgG anti-Dsc autoantibodies were frequently detected and potentially pathogenic in non-classical pemphigus. This article is protected by copyright. All rights reserved.
This article is protected by copyright. All rights reserved.
British Journal of Dermatology 02/2015; 173(1). DOI:10.1111/bjd.13711 · 4.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Peroxisome proliferator-activated receptors (PPARs) are potentially useful for treatment of skin diseases, because they stimulate keratinocyte differentiation, exert anti-inflammatory effects and improve barrier function. We examined five PPAR-γ agonists, including four thiazolidinediones (ciglitazone, troglitazone, rosiglitazone and pioglitazone) and an angiotensin-II receptor blocker (telmisartan), for their ability to up-regulate filaggrin and loricrin expression at both mRNA and protein levels in cultured normal human keratinocytes (NHKs). Troglitazone, rosiglitazone, pioglitazone and telmisartan significantly increased filaggrin expression at both mRNA and protein levels in calcium-induced differentiated NHKs. Rosiglitazone and pioglitazone, but not troglitazone nor telmisartan, also significantly increased loricrin expression at both mRNA and protein levels in differentiated NHKs. These effects were not found in undifferentiated NHKs nor differentiated NHKs treated with ciglitazone. This study revealed differential effects of various PPAR-γ agonists on epidermal differentiation, and the most potent of those are rosiglitazone and pioglitazone.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Abstract Background: Adalimumab is an anti-tumor necrosis factor-? agent, and is widely used to treat moderate to severe psoriasis in Japan. The drug survival rate of adalimumab is shorter than that of other biological agents used for psoriatic patients in Europe. Objective: To study the long-term drug survival rate of adalimumab used for Japanese psoriatic patients. Methods: We studied 36 patients with moderate to severe psoriasis for whom adalimumab was administered between February 2010 and April 2013. Results: Thirty three patients had psoriasis vulgaris, and 3 patients had psoriatic arthritis. At the end of the observational period, 16 patients continued adalimumab therapy, while 20 patients discontinued. Six patients had adverse events, and 14 patients self-injected adalimumab. The mean probability of drug survival was 20.0 months (median, 18 months); it was shorter than the previously reported data from European countries. Gender, age, and the Psoriasis Area and Severity Index at baseline were not significant predictors of drug survival rates. Frequent visits for biweekly adalimumab injections were a burden for 40% of drop-out patients. Conclusion: The shorter drug survival rate of adalimumab in the present study may be attributed to the lower rate of self-injection than that in European patients.
[Show abstract][Hide abstract] ABSTRACT: Background: Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are two blistering skin diseases mediated by antibodies to desmoglein 3 (Dsg3) and/or Dsg1. Phenotypic transition from PV to PF is rarely reported. Objectives: To determine the immune response to extracellular (EC) domains of Dsgs during this transition. Materials and Methods: We report two PV patients who subsequently developed a PF phenotype. To map the conformational epitopes in these cases, we examined the reactivity of the sera of two patients by immunoprecipitation-immunoblotting analysis, using five Dsg1/Dsg3 domain-swapped molecules on a backbone of Dsg2. Results: Reactivity exclusively with the EC1 domain of Dsg1 was maintained in both PV and PF stages. No reactivity to Dsg3 in the PF stage was found in patient 1. Various changes in immunoreactivity to Dsg3 were found and the EC1 and EC2 domains of Dsg3 reacted weakly to serum taken at remission and PF stages in patient 2. Conclusions: Our findings suggest that amino-terminal pathogenic antibodies to the EC domain of Dsg1 were retained, while considerable epitope changes occurred in response to Dsg3 during the shift from PV to PF, with an absolute or significant decrease in pathogenic antibodies to the EC1 domain of Dsg3.
[Show abstract][Hide abstract] ABSTRACT: We investigated protein expression and in situ activity of transglutaminases (TGs) in normal skin and various epidermal neoplasms. In normal skin, TG1 protein expression and TG activity were found at keratinocyte cell membranes in upper epidermis and granular layer, respectively. In seborrheic keratosis, TG1 protein was expressed evenly throughout tumors, while TG activity increased in gradient fashion from lower tumor area to cornified layer. In squamous cell carcinoma, TG1 protein was expressed at inner side of cell membranes, whereas TG activity was found in cytoplasm predominantly at horn pearls. In basal cell carcinoma, weak TG activity was found in cytoplasm of all tumor cells without the presence of TG1 protein. Immunoblotting and in situ activity assays using specific substrate peptides confirmed that TG2, but not TG1, contributed to the TG activity. These results suggested that different expression and activation of TGs may contribute to characteristics of the skin tumors.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: B-cell activating factor (BAFF), an important immune regulatory cytokine, is involved in development of autoimmune diseases. Although BAFF is expressed in various cells, including dendritic cells and monocytes, BAFF expression on B-cells has not been well documented. In the present study, BAFF molecules on dendritic cells and naïve and memory B-cells in autoimmune bullous diseases, including pemphigus vulgaris, pemphigus foliaceus and bullous pemphigoid, were analyzed by flow cytometry. Compared to healthy controls, BAFF expression on naïve and memory B-cells increased significantly in bullous pemphigoid. No difference in BAFF receptor expression in naïve and memory B-cells was shown among all study groups. Furthermore, BAFF expression in both naïve and memory B-cells of bullous pemphigoid, but not healthy controls, was detected by confocal microscopic analysis. These results implied that BAFF expressed by B-cells may play a pathogenic role in autoimmune bullous diseases, particularly bullous pemphigoid.This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract] ABSTRACT: Drug-induced pemphigus (DIP) shows clinical, histopathological and immunological features of pemphigus. However, little is known about immunological profiles in DIP.
To characterize clinical and immunological profiles in DIP patients.
We studied 17 Japanese DIP patients who were treated in Kurume University Hospital or consulted from other hospitals between 1997 and 2012. Complicated diseases, clinical and histopathological manifestations, responsible drugs and findings in immunofluorescence (IF), enzyme-linked immunosorbent assays (ELISAs), immunoblotting (IB) and prognosis were analyzed.
Eight of the 17 DIP patients showed pemphigus foliaceus-like appearance, three showed pemphigus herpetiformis-like appearance, and six showed atypical bullous lesions. Responsible drugs were thiol-containing drugs in 16 patients (bucillamine in 9 cases, d-penicillamine in 4 case, and cetapril, thiopronine and captopril in one case each.), and non-thiol drug, azalfidine in one patient. By ELISAs and/or IB analyses, 9 patients reacted only with desmoglein 1 (Dsg1), four reacted with Dsg1 and Dsg3, and four showed no specific reactivity. By IB of normal human epidermal extracts, in addition to positive reactivity with Dsg1, 4 patients with no detectable malignancy showed paraneoplastic pemphigus-like reactivity with the 210 kDa envoplakin and the 190 kDa periplakin. Four cases showed anti-Dsg3 antibodies without mucosal lesions. While 11 cases recovered by discontinuation of the causative drugs, six patients had very protracted or intractable disease course, who might develop true pemphigus.
The present study indicated that the majority of the DIP cases studied showed pemphigus foliaceus-type phenotype with anti-Dsg1 autoantibodies, caused by thiol-containing drugs. This article is protected by copyright. All rights reserved.
British Journal of Dermatology 03/2014; 171(3). DOI:10.1111/bjd.12925 · 4.28 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In this study, we report on the efficacy of combination therapy of second-generation antihistamine antagonist, fexofenadine hydrochloride, and leukotriene receptor inhibitor, montelukast sodium, for the treatment of 15 prurigo nodularis or pemphigoid nodularis patients, in whom conventional therapy was ineffective. All patients received 10 mg montelukast once a day and 240 mg fexofenadine twice a day for 4 weeks in addition to other medications they had been taking. We assessed the manifestations of the lesions and itching intensity before and after the therapy, and we evaluated each patient as (i) markedly improved, (ii) improved, (iii) slightly improved, (iv) no change, (v) worse. Two patients (13.3%) were evaluated as markedly improved, and the lesions of one patient completely disappeared. Three patients (20.0%) were evaluated as improved, and six patients (40.0%) as slightly improved. Thus, 11 of 15 cases (73.3%) improved by combination therapy of fexofenadine and montelukast, in which nine cases (75.0%) of prurigo nodularis and two cases (66.7%) of pemphigoid nodularis were involved. No patients revealed any side effects. This study revealed that combination therapy of fexofenadine and montelukast was effective for some patients with conventional therapy-resistant prurigo nodularis and pemphigoid nodularis.
[Show abstract][Hide abstract] ABSTRACT: Importance:
Pemphigus vegetans shows clinically vegetating and/or pustular skin lesions mainly on the intertriginous areas and histopathologically neutrophilic and eosinophilic pustules in the epidermis. Pemphigus vegetans shows IgG reactivity mainly with desmoglein (Dsg) 3, but also with other autoantigens, including Dsg1 and desmocollins (Dscs).
We examined antigen profiles in 2 cases of pemphigus vegetans. (1) A women in her 80s presented with typical vegetating skin lesions on the right inguinal region with typical histopathological features. Immunoblotting using normal human epidermal extracts detected IgG antibodies to Dsg1 and Dscs. Enzyme-linked immunosorbent assays (ELISAs) revealed IgG antibodies to Dsg1 but not to Dsg3. Complementary DNA (cDNA) transfection method to COS-7 cells and novel ELISAs using eukaryotic recombinant proteins of human Dsc1, Dsc2, and Dsc3 confirmed specific IgG reactivity with Dsc3. (2) A women in her 70s presented with pustular skin lesions on the left fingers with typical histopathological features. Immunoblotting and ELISAs did not detect antibodies to either Dsg1 or Dsg3. Conversely, immunoblotting detected IgG antibodies to Dscs, cDNA transfection method revealed IgG reactivity only with Dsc3, and findings from ELISAs showed that IgG reacted weakly with Dsc2 and strongly with Dsc3.
Conclusions and relevance:
Autoantibodies to Dscs, particularly to Dsc3, may play a pathogenic role in some cases of pemphigus vegetans.
[Show abstract][Hide abstract] ABSTRACT: Pemphigus is an autoimmune bullous disease showing intraepidermal blisters and IgG autoantibodies to desmogleins (Dsgs).(1) Dsg1 and Dsg3 are autoantigens for pemphigus foliaceus and mucosal-dominant type pemphigus vulgaris, respectively.(1) In addition, antibodies to desmocollins (Dscs), another group of desmosomal cadherin, are rarely detected in variants of pemphigus.(2-5) Dsc1 is autoantigen for subcorneal pustular dermatosis-type IgA pemphigus.(2) In addition, anti-Dsc antibodies were detected in some pemphigus cases with or without anti-Dsg autoantibodies.(3-5) This article is protected by copyright. All rights reserved.
British Journal of Dermatology 04/2013; 169(3). DOI:10.1111/bjd.12398 · 4.28 Impact Factor