Mucocutaneous manifestations of Behçet's disease: Pathogenesis and management from perspectives of vasculitis.

Behçet's disease (BD) is a systemic inflammatory disorder characterized by vasculitis affecting blood vessels of any caliber or type. It can present with a wide spectrum of vasculitic lesions, including erythema nodosum-like lesions and retinal vasculitis, and may also lead to larger vessel diseases, such as aortic aneurysm and deep vein thrombosis. The full etiology of BD remains unclear, but it is considered a polygenetic disease with multiple genetic risk factors that promote immune dysregulation and thrombophilia. Inflammation can be triggered by environmental factors, such as bacteria or viruses, and the dysregulation of innate and adaptive immune cell subsets. Neutrophils and lymphocytes are the primary players involved in BD pathogenesis, with specific innate (i.e., neutrophil-derived reactive oxygen species and neutrophil extracellular traps) and adaptive (i.e., anti-endothelial cell antibodies) processes inducing endothelial cell activation and chemotaxis of inflammatory cells, leading to coagulation and vasculitis. These inflammation-induced vasculitic or vasculopathic features are observed in most mucocutaneous BD lesions, although vasculitis per se is often pathologically evident only during a brief period of the disease process. Due to the multifactorial nature of BD-associated inflammation, broad-spectrum anti-inflammatory medications, including glucocorticoids and immunosuppressive drugs, have been the mainstay for managing BD. In addition, inhibitors of interleukin (IL)-1, tumor necrosis factor (TNF)-α, and IL-17, which target innate and adaptive immune functions dysregulated in BD, have emerged as promising new therapeutics. In this review, we discuss the muco-cutaneous manifestations of BD by focusing on the underlying vasculitic components in their pathologies, as well as the current array of treatment options.

Guidelines for the treatment of skin and mucosal lesions in Behçet's disease: A secondary publication.

In the current study, we present guidelines for the diagnosis and treatment of the mucocutaneous lesions of Behçet's disease, which is a chronic inflammatory disease characterized by the involvement of various organs, including mucocutaneous, ocular, vascular, intestinal and central nervous system lesions. It is often identified in the Middle East Mediterranean to East Asia region. Skin manifestations include erythema nodosum, papulopustular lesions and thrombophlebitis, and mucosal manifestations include oral and genital ulcers. These mucocutaneous lesions are characteristically the first signs of Behçet's disease and are important to be recognized for the early diagnosis of the disease. Moreover, these manifestations also recur and persist over the long-term course of the disease. The management of mucocutaneous lesions is important to prevent recurrence. We developed consensus guidelines that provide recommendations for general practitioners and dermatologists and physicians on the management of the mucocutaneous lesions of Behçet's disease.

Mucocutaneous Manifestations of Behçet's Disease.

Behçet's disease (BD) is a chronic, relapsing, systemic inflammatory disease with clinical features showing mucocutaneous lesions involving the ocular, articular, and further miscellaneous organs. Mucocutaneous manifestations, one of the most characteristic signs of BD, have been most commonly observed upon onset or at any disease stage and are exceptionally important in its diagnosis. Given the lack of specific diagnostic laboratory tests for BD, diagnosis has been based on clinical findings. All diagnostic criteria published have thus far relied heavily on mucocutaneous manifestations, particularly oral ulcers (OU), genital ulcers (GU), cutaneous lesions, and pathergy test positivity. Worldwide, OU, GU, cutaneous lesions, and ocular and articular manifestations have been the most common symptoms, with erythema nodosum (EN)-like lesions and papulopustular lesions being the most prevalent cutaneous manifestations. While majority of the patients worldwide have reported OU as the most frequent symptom upon disease onset, GU, and EN-like lesions have also been identified upon onset. Considering that mucocutaneous symptoms precede severe organ involvement in most patients, familiarity with such symptoms is imperative for early diagnosis and prevention of potentially serious organ involvement through appropriate management.

Bronchoscopic Investigation of Atypical Drug-induced Hypersensitivity Syndrome Showing Viral Lung Involvement.

We herein report a case of atypical drug-induced hypersensitivity syndrome (DIHS) involving serological reactivation of cytomegalovirus induced by carbamazepine with pulmonary and skin manifestations. These lesions were not present on admission, but developed on virus reactivation as indicated by the presence of inclusion bodies and multinucleated giant cells in alveolar cells with CD8(+) T lymphocyte infiltration on a transbronchial lung biopsy. Although the precise mechanism of DIHS remains unknown, this case suggests the crucial role of viral reactivation in pulmonary lesions in DIHS.

Successful treatment with oral mizoribine in refractory ocular manifestation of mucosal pemphigus vulgaris: A unique response to different immunosuppressive drugs.

Pemphigus vulgaris (PV) is an acquired autoimmune disease in which the disease characteristic antibodies are directed against the desmosomal transmembrane glycoprotein, desmoglein 3 (Dsg 3), resulting in flaccid blisters and erosions of skin and mucous membrane. Among various affected sites, ocular involvement may often persist or relapse even after remission of other mucocutaneous lesions, and also represent a higher morbidity. We describe such an example case of mucosal PV, whose oral and ocular manifestations were responded specifically to oral cyclosporine and mizoribine, respectively. To our knowledge, this is the first case of the site-specific efficacy of mizoribine in PV.

One-Year Period Prevalence of Oral Aphthous Ulcers and Oral Health-Related Quality of Life in Patients with Behçet's Disease.

The aim of this study was to investigate the 1-year period prevalence of oral aphthous ulcers (OAUs) and their association with oral health-related quality of life (OHQOL) in patients with Behçet's disease (BD) and in the general population. In this cross-sectional study, 675 patients with Behçet's disease (BD group) and 1,097 males and females in the Japanese general population (control group) completed both questionnaires on their OAU status during the prior year and the General Oral Health Assessment Index (GOHAI). In the BD group, 84% of patients reported experiencing an OAU during the previous year, and the mean number of OAUs/year was 13. In the control group, 31% of individuals experienced an OAU during the previous year, and the mean number of OAUs/year was one. Multivariate analysis indicated that both BD patients (OR, 6.2; 95% CI, 4.8-8.0) and controls (OR, 2.6; 95% CI, 2.0-3.5) who had OAUs at least twice per year were more likely to have GOHAI scores below the norm than were controls who had fewer than two OAUs per year. The association between HLA-B∗51 and OAUs remains unknown. The presence of OAUs has a negative effect on the OHQOL of patients with BD.

A New Diagnostic Way for Behcet's Disease: Skin Prick with Self-Saliva.

Behcet's disease (BD) is a mysterious multisystemic disorder characterized by recurrent involvement of mucocutaneous (including recurrent aphthous stomatitis; RAS), ocular, intestinal, vascular, and/or nervous system organs. Previously, the positivity of "pathergy test", which is one of the diagnostic examinations, was reported to be related to the possession of HLA-B51 gene in BD patients, even though the positivity is low and different from the countries. Here, instead of the ordinal pathergy test, we would like to propose the prick with self-saliva as a new diagnostic way for patients with RAS of BD based on the genetic intrinsic factors including HLA-B51 and extrinsic triggering factors. BD patients are considered to acquire the hypersensitivity against oral streptococci through the innate immune mechanism in the oral cavity. Bes-1 gene and 65 kD of heat shock protein (HSP-65) derived from oral S. sanguinis are supposed to play important roles as extrinsic factors in BD pathogenesis. Although the prick positivity was not related to the possession of HLA-B51 gene, the method is suggested to be a significant way for BD diagnosis. The results also suggest that BD symptoms are due to the vascular immune responses by monocytes expressed oral streptococcal agents of the patients.

Skewed Helper T-Cell Responses to IL-12 Family Cytokines Produced by Antigen-Presenting Cells and the Genetic Background in Behcet's Disease.

Behcet's disease (BD) is a multisystemic inflammatory disease and is characterized by recurrent attacks on eyes, brain, skin, and gut. There is evidence that skewed T-cell responses contributed to its pathophysiology in patients with BD. Recently, we found that Th17 cells, a new helper T (Th) cell subset, were increased in patients with BD, and both Th type 1 (Th1) and Th17 cell differentiation signaling pathways were overactivated. Several researches revealed that genetic polymorphisms in Th1/Th17 cell differentiation signaling pathways were associated with the onset of BD. Here, we summarize current findings on the Th cell subsets, their contribution to the pathogenesis of BD and the genetic backgrounds, especially in view of IL-12 family cytokine production and pattern recognition receptors of macrophages/monocytes.

Cell-type-specific differentiation and molecular profiles in skin transplantation: implication of medical approach for genetic skin diseases.

Skin is highly accessible and valuable organ, which holds promise to accelerate the understanding of future medical innovation in association with skin transplantation, engineering, and wound healing. In skin transplantation biology, multistage and multifocal damages occur in both grafted donor and perilesional host skin and need to be repaired properly for the engraftment and maintenance of characteristic skin architecture. These local events are more unlikely to be regulated by the host immunity, because human skin transplantation has accomplished the donor skin engraftment onto the immunocompromised or immunosuppressive animals. Recent studies have emerged the importance of α-smooth muscle actin- (SMA-) positive myofibroblasts, via stage- and cell-specific contribution of TGFß, PDGF, ET-1, CCN-2 signalling pathways, and mastocyte-derived mediators (e.g., histamine and tryptase), for the functional reorganisation of the grafted skin. Moreover, particular cell lineages from bone marrow (BM) cells have been shown to harbour the diferentiation capacity into multiple skin cell phenotypes, including epidermal keratinocytes and dermal endothelial cells and pericytes, undercontrolled by chemokines or cytokines. From a dermatological viewpoint, we review the recent update of cell-type- and molecular-specific action associated with reconstitution of the grafted skin and also focus on the novel application of BM transplantation medicine in genetic skin diseases.

Analysis of psoriasis patients registered with the Japanese Society for Psoriasis Research from 2002-2008.

A survey of psoriasis patients from 1982-2001 has been reported by the Japanese Society for Psoriasis Research. The aim of this study is to analyze psoriasis patients in Japan registered from 2002-2008. A total of 11 631 cases were registered from 152 dermatological institutions in Japan. Males (7738 cases, 66.5%) were predominant over females (3893 cases, 33.5%). The clinical types of psoriasis were psoriasis vulgaris (88.5%), guttate psoriasis (3.9%), psoriasis arthropathica (3.3%), generalized pustular psoriasis (1.3%), psoriatic erythroderma (1.2%), localized pustular psoriasis (0.9%) and infantile psoriasis (0.1%). Topical corticosteroids (85.4%) and vitamin D(3) (59.7%) products were the main previous topical agents. Previous systemic treatments included etretinate (8.8%), cyclosporin (8.3%) and methotrexate (2.0%). Use of topical vitamin D(3) and systemic cyclosporin therapies has been increasing during the past 7 years. Topical psoralen and ultraviolet A therapy (PUVA) (7.6%) was the predominant phototherapy followed by UV-B (7.3%) and systemic PUVA (4.7%). Use of UV-B phototherapy has been increasing during the past 5 years. The survey of Japanese psoriasis patients during 2002-2008 disclosed that psoriasis arthropathica is more prevalent (1%) than that of the previous survey during 1982-2001. Use of topical vitamin D(3) and systemic cyclosporin has been increasing during the past 7 years.

English version of the interim report published in 1998 by the members of the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

The Japanese Dermatological Association established an advisory committee in 1995 to set up severity scoring systems for atopic dermatitis (AD). Its interim report was published in Japanese in the Japanese Journal of Dermatology (108: 1491-1496, 1998) by Chairman Hikotaro Yoshida. Because of the strong demand for an English version, we have decided to publish the report in English. This prospective study was designed to evaluate the status of 259 AD patients using Method 1, which involves a simple global evaluation of disease severity; Method 2, which involves global evaluation by summing severity scores obtained from five body regions (i.e. the head and neck, anterior and posterior trunks, and upper and lower limbs); Method 3, which consists of both assessment of the extent of involved areas at each of the five body regions and that of the severity scores of each eruption component observed in the most severely affected body region; and Method 4, which consists of the evaluation of only subjective components (daytime pruritus and sleep disturbance). Employing the results obtained with Method 1 as a tentative benchmark, we analyzed its correlation with those of Methods 2, 3 and 4 to statistically assess the validity and reliability of these methods. Method 2, Method 3 and the portion of Method 4 involving evaluation of only the subjective symptom of daytime pruritus but not the sleep disturbance were considered useful in evaluating AD severity.

English version of the concluding report published in 2001 by the Advisory Committee on Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

The Japanese Dermatological Association established an advisory committee in 1995 to develop a severity scoring system for atopic dermatitis (AD). Its interim and concluding reports were published in Japanese in the Japanese Journal of Dermatology (108: 1491-1496, 1998 and 111: 2023-2033, 2001). Because of the strong demand for an English version, we have decided to publish the reports in English. This manuscript is the English version of the concluding report. The interim report suggested that eruption components such as erythema, papule, erosion, crust, excoriation and lichenification with extent of involved areas in five body regions, including the head and neck, anterior and posterior trunks, and upper and lower limbs, were important items for assessing AD severity. Additionally, it was recommended that streamlining of eruption components was mandatory for improving the statistical validity and reliability. The committee members subsequently concentrated their efforts on this task, and finally proposed an Atopic Dermatitis Severity Classification Criteria of the Japanese Dermatological Association.

Skin prick test with self-saliva in patients with oral aphthoses: a diagnostic pathergy for Behcet's disease and recurrent aphthosis.

There may be some difficulties to differentiate Behcet's disease (BD), recurrent aphthosis (RA), and herpetic aphthous ulceration, from other mimicking oral disorders. Despite of unexpected sensitivity and responsiveness, the skin pathergy test regarding a non specific hypersensitivity has long been thought as one of auxiliary diagnostic benefits for BD. To determine the potential usefulness and disease specificity of the prick reaction with saliva, a skin prick test with neat and filter-sterilized saliva was performed on the forearm skin of 26 individuals; 10 patients with BD (8 incomplete type without uveitis, 1 complete type, and 1 neurological type), 5 with RA, 3 with herpetic oral aphthosis, 2 with erythema nodosum alone, and 6 healthy controls. We assessed the skin reaction at 48 hours after pricking, and the pricked skin lesions were biopsied and analyzed immunohistologically. Nine of 10 BD patients (90 %) exhibited an indurative erythema at the skin site pricked with self-saliva, whereas 3 of 5 RA patients (60%) were relatively weak reaction. Pricking with filter-sterilized saliva failed to recapitulate any of positive skin reactions, albeit a faint erythematous dot appeared in a few BD patients, implicating the involvement of causative microorganism(s) in oral bacterial flora. Culture of saliva from 3 randomly chosen BD patients revealed numerous streptococcal colonies on Mitis-Salivarius agar. Histology of the pricked skin sites showed perivascular inflammatory infiltrates, composed of CD4+ T cells and CD68+ monocyte/macrophage lineage, a feature consistent with a delayed type hypersensitive reaction. Our results suggested that skin prick test using self-saliva (a new diagnostic pathergy) can be a simple and valuable in vivo diagnostic approach for differentiating BD and RA from other mimicking mucocutaneous diseases. The positive skin prick may be triggered by resident intra-oral microflora, particularly streptococci, and may in part address the underlying immunopathology in BD.

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

Adamantiades-Behçet's 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 65 kD 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 double-blind trial of intravenous immunoglobulin for pemphigus.

BACKGROUND: Pemphigus is a rare life-threatening intractable autoimmune blistering disease caused by IgG autoantibodies to desmogleins. It has been difficult to conduct a double-blind clinical study for pemphigus partly because, in a placebo group, appropriate treatment often must be provided when the disease flares. OBJECTIVE: A multicenter, randomized, placebo-controlled, double-blind trial was conducted to investigate the therapeutic effect of a single cycle of high-dose intravenous immunoglobulin (400, 200, or 0 mg/kg/d) administered over 5 consecutive days in patients relatively resistant to systemic steroids. METHODS: We evaluated efficacy with time to escape from the protocol as a novel primary end point, and pemphigus activity score, antidesmoglein enzyme-linked immunosorbent assay scores, and safety as secondary end points. RESULTS: We enrolled 61 patients with pemphigus vulgaris or pemphigus foliaceus who did not respond to prednisolone (> or =20 mg/d). Time to escape from the protocol was significantly prolonged in the 400-mg group compared with the placebo group (P < .001), and a dose-response relationship among the 3 treatment groups was observed (P < .001). Disease activity and enzyme-linked immunosorbent assay scores were significantly lower in the 400-mg group than in the other groups (P < .05 on day 43, P < .01 on day 85). There was no significant difference in the safety end point among the 3 treatment groups. LIMITATION: Prednisolone at 20 mg/d or more may not be high enough to define steroid resistance. CONCLUSION: Intravenous immunoglobulin (400 mg/kg/d for 5 d) in a single cycle is an effective and safe treatment for patients with pemphigus who are relatively resistant to systemic steroids. Time to escape from the protocol is a useful indicator for evaluation in randomized, placebo-controlled, double-blind studies of rare and serious diseases.