Classification and Antigen Molecules of Autoimmune Bullous Diseases.

Autoimmune bullous diseases (AIBDs), which are a group of tissue-specific autoimmune diseases of the skin, present with various blistering lesions on the skin and mucous membranes, and show autoantibodies of IgG, IgA and IgM against epidermal cell surfaces and basement membrane zone. To date, AIBDs have been classified into a number of distinct subtypes by clinical and histopathological findings, and immunological characteristics. In addition, various biochemical and molecular biological studies have identified various novel autoantigens in AIBDs, which has resulted in proposals of new subtypes of AIBDs. In this article, we summarized various distinct AIBDs, and proposed the latest and most comprehensive classification of AIBDs with their autoantigen molecules.

Does SAPHO syndrome exist in dermatology?

In the late 1960s, palmoplantar pustulosis (PPP) with sternocostoclavicular arthropathy was first described in Japan, predominantly affecting women in the perimenopausal age. In the 1970s, the chronic non-bacterial osteomyelitis and chronic recurrent multifocal osteomyelitis were initially observed in paediatric patients with approximately 70% girls. Acne fulminans accompanied by polyarthralgia have been observed since early 1970s, which almost exclusively occurs in adolescent boys. Report on spondyloarthropathy associated with hidradenitis suppurativa can be traced back to 1982. The SAPHO syndrome was coined in 1987 to lump together synovitis, acne, pustulosis, hyperostosis and osteitis to conceptualize a group of inflammatory osteocutaneous diseases of unclear etiopathogenesis and ill-defined associations spanning disparate age and gender groups. From historical view, Sasaki syndrome is proposed to replace SAPHO syndrome to represent PPP with sternocostoclavicular arthropathy in the absence of other skin manifestations. Hidradenitis suppurativa is folliculitis in pathogenesis and no longer classified as acne. PPP accompanied by psoriasis vulgaris is more likely psoriasis pustulosa palmoplantaris in dermatological aspect, and the associated arthritis is part of psoriatic arthropathy. Pathophysiology of these disorders is incompletely understood. To echo the advancement of high-throughput sequencing, splitting but not lumping of clinical findings would be a better strategy to decipher these multigenic complex inflammatory disorders.

Estimated cut-off values for pemphigus severity classification according to pemphigus disease area index (PDAI), autoimmune bullous skin disorder intensity score (ABSIS), and anti-desmoglein 1 autoantibodies.

BACKGROUND: Pemphigus is a potentially fatal disease if left untreated. Valid scoring systems and defined cut-off values for classification of patients would help with better management through specified pharmaceutical and non-pharmaceutical treatments. METHODS: In this study, pemphigus patients who were receiving immunosuppressive treatments and had recent disease relapse were recruited for examination of pemphigus disease area index(PDAI), autoimmune bullous skin disorder intensity score (ABSIS), physician global assessment (PGA), autoimmune bullous disease quality of life (ABQoL), anti-desmoglein 1 (anti-Dsg1), and anti-Dsg3 autoantibody titers from December-2017 to February-2018. Cut-off values were estimated using model-based clustering classification and the 25th and 75th percentiles approach, performed separately for the exclusive cutaneous, exclusive mucosal, and mucocutaneous groups. RESULTS: In the 109 included patients, the 25th and 75th percentiles cut-offs were 6.2 and 27 for PDAI score, and 4 and 29.5 for ABSIS score. The model-based analysis resulted in two groups (cut-point:15) for PDAI score, and three groups (cut-points:6.4 and 31.5) for ABSIS score. The groups were significantly different for the PDAI, ABSIS, PGA, and ABQoL values. Based on anti-Dsg1 autoantibody values, the model-based analysis cut-point was 128 and the 25th and 75th percentiles cut-offs were 98 and 182. Anti-Dsg3 autoantibody values did not differentiate between pemphigus severity classes. CONCLUSIONS: Estimated cut-off values based on the anti-Dsg1 level, PDAI, and ABSIS scoring systems could be used to classify patients into different severity grades for better management and prognosis.

Review of autoimmune blistering diseases: the Pemphigoid diseases.

Autoimmune Blistering Diseases of the Pemphigoid type is characterised by sub-epidermal blisters (SEB) with circulating autoantibodies against components of the basement membrane zone (BMZ). The main disorders to date include bullous pemphigoid (BP), pemphigoid gestationis, mucous membrane pemphigoid (MMP), epidermolysis bullosa acquisita (EBA), linear IgA disease (LABD), dermatitis herpetiformis (DH), lichen planus pemphigoides and bullous lupus. This is in contrast to pemphigus and related disorders, which demonstrate intraepidermal acantholysis and a positive Nikolsky sign. The classification and management is based on clinical, histological and direct and indirect immunofluorescence findings. There are, however, overlapping clinical and histological features between the conditions and clinical heterogeneity within each disease.

Utility of Direct Immunofluorescence Studies in Subclassification of Autoimmune Sub-Epidermal Bullous Diseases: A 2-Year Study in a Tertiary Care Hospital.

OBJECTIVE: Sub-epidermal bullous disorders belong to immunobullous diseases which develop as a result of autoantibody action against epidermal basement membrane proteins. Clinically, they are tense bullae and do not rupture easily. They are classified into various forms based on histopathology and direct immunofluorescence patterns. This study was undertaken to assess the incidence of various sub-epidermal bullous disorders and the utility of direct immunofluorescence in accurately classifying them, and to study the intensity and pattern of immunofluorescence in various sub-epidermal bullous disorders Material and Method: A 2-year study of 38 cases of sub-epidermal bullous disorders sent for direct immunofluorescence studies formed the study group. The specimens were processed as per standard protocols. The clinical details were obtained from case files and requisition sent for histopathological and direct immunofluorescence studies. RESULTS: Thirty-eight patients were diagnosed to have sub-epidermal bullous disorders over the period of 2 years. Twenty five cases of Bullous Pemphigoid, 5 cases of Dermatitis Herpetiformis, 3 cases of Linear IgA Bullous disorder, 2 cases of Bullous Systemic Lupus Erythematoses and 1 case each of Epidermolysis Bullosa Acquisita, Cicatricial Pemphigoid and Pemphigus Gestationis was diagnosed. Positive direct immunofluorescence was seen in 91.3% of the cases. CONCLUSION: Histopathology alone cannot classify sub-epidermal bullous disorders and direct immunofluorescence studies are mandatory in all of them. Bullous Pemphigoid needs to be distinguished from Epidermolysis Bullosa Acquisita which requires Salt split direct immunofluorescence studies. Dermatitis Herpetiformis, Bullous Systemic Lupus Erythematosus and Linear IgA Bullous disorder show more or less similar histological picture with neutrophilic microabscess. Direct immunofluorescence studies help in the majority of cases but further testing such as immunoblotting, immunoelectron microscopy or indirect immunofluorescence becomes essential in cases with overlapping features.

Summary of results of serological tests and diagnoses for 4774 cases of various autoimmune bullous diseases consulted to Kurume University.

BACKGROUND: Although many new disease entities of autoimmune bullous disease (AIBD) have recently been recognized, satisfactory immunological diagnostic methods and comprehensive classifications for various AIBDs have not been established. OBJECTIVES: To identify immunological diagnostics and comprehensive classifications for AIBDs. METHODS: We selected and examined 4774 patients with various AIBDs from our cohort of 5063 patients with difficult AIBDs, whose sera and information were sent for our diagnostic method from other institutes in either Japan or other countries over the last 19 years. We examined the sera by our immunological diagnostic methods including various immunofluorescence, immunoblotting and enzyme-linked immunosorbent assay tests to make final diagnoses. RESULTS: By our immunological diagnostic methods, we successfully made final diagnoses for approximately three-quarters of the difficult cases of AIBD, although the remaining cases could not be diagnosed. Using the results, we suggest the most extensive and newest classification of AIBDs, and also propose the most efficient algorithm of immunological tests for the diagnosis of various AIBDs. CONCLUSIONS: The results in this study of 4774 patients with various AIBDs indicate that our immunological diagnostic method is useful for making diagnoses for most patients with AIBD. However, we need further improvements including new immunological techniques to establish more satisfactory methods.

Eosinophilic pustular folliculitis: A published work-based comprehensive analysis of therapeutic responsiveness.

Eosinophilic pustular folliculitis (EPF) is a non-infectious inflammatory dermatosis of unknown etiology that principally affects the hair follicles. There are three variants of EPF: (i) classic EPF; (ii) immunosuppression-associated EPF, which is subdivided into HIV-associated (IS/HIV) and non-HIV-associated (IS/non-HIV); and (iii) infancy-associated EPF. Oral indomethacin is efficacious, especially for classic EPF. No comprehensive information on the efficacies of other medical management regimens is currently available. In this study, we surveyed regimens for EPF that were described in articles published between 1965 and 2013. In total, there were 1171 regimens; 874, 137, 45 and 115 of which were applied to classic, IS/HIV, IS/non-HIV and infancy-associated EPF, respectively. Classic EPF was preferentially treated with oral indomethacin with efficacy of 84% whereas topical steroids were preferred for IS/HIV, IS/non-HIV and infancy-associated EPF with efficacy of 47%, 73% and 82%, respectively. Other regimens such as oral Sairei-to (a Chinese-Japanese herbal medicine), diaminodiphenyl sulfone, cyclosporin and topical tacrolimus were effective for indomethacin-resistant cases. Although the preclusion of direct comparison among cases was one limitation, this study provides a dataset that is applicable to the construction of therapeutic algorithms for EPF.

Eosinophilic pustular folliculitis: the transition in sex differences and interracial characteristics between 1965 and 2013.

Eosinophilic pustular folliculitis (EPF) is characterized by a non-infectious infiltration of eosinophils in the hair follicles. It has three variants: (i) classic EPF; (ii) immunosuppression-associated EPF, which herein is subdivided into HIV-associated (IS/HIV) and non-HIV-associated (IS/non-HIV); and (iii) infancy-associated EPF (I-EPF). The rarity of EPF has hindered our understanding of this entity. To examine the characteristics of EPF, with respect to age, sex, race, and chronology, published in case reports to date, we queried PubMed using the following terms: ("eosinophilic pustular folliculitis" [All Fields] OR "eosinophilic folliculitis" [All Fields]) AND ("1965/1/1" [PDAT]: "2013/12/31" [PDAT]). Additional Japanese cases were collected from Igaku Chuo Zasshi through Ichushi-Web, JDream III, and secondhand quotations from domestic periodicals published in Japan. Proceedings were excluded. The PubMed search produced 275 citations containing 358 cases of EPF (224 men, 132 women, and two of unspecified sex); these cases involved classic EPF (101 Japanese and 81 non-Japanese), IS/HIV (4 Japanese and 85 non-Japanese), IS/non-HIV (4 Japanese and 20 non-Japanese), and I-EPF (4 Japanese and 59 non-Japanese). Ichushi generated an additional 148 citations containing 207 cases of Japanese (148 men and 59 women), which included cases of classic EPF (181 cases), IS/HIV (14 cases), IS/non-HIV (9 cases), and I-EPF (3 cases). There was no sex difference in the classic EPF cases reported between 2003 and 2013, whereas IS/HIV, IS/non-HIV, and I-EPF were predominated by men. There is room for reconsideration of sex differences, particularly with regard to classic EPF. The rarity and specificity of I-EPF in Japan may reflect a state of uncertainty about this entity.

Eosinophilic pustular folliculitis: a review of the Japanese published works.

Eosinophilic pustular folliculitis (EPF), also known as Ofuji's disease, is an inflammatory dermatosis that was first described in Japan in 1970. More than 300 cases have been reported so far, and 113 Japanese cases have been reported in Japan since 1980. To comprehend the characteristics of Japanese EPF cases, we classified these cases into three types: classic, immunosuppression-associated (IS-EPF), and infancy-associated (I-EPF). Trends in age of onset and in distribution and characterization of eruptions differed between the types. We found 91 cases of classic EPF (mean age, 39.7 years), consisting of 66 males (73%) and 25 females (27%), in most of which eruptions primarily affected the face; 18 cases of IS-EPF (44.2 years), consisting of 15 males (83%) and three females (17%), in which eruptions affected the face less predominantly; and four cases of I-EPF (7.0 years), consisting of two males (50%) and two females (50%), primarily affecting the scalp. The number of IS-EPF cases has increased since the late 1990s, reflecting the increasing number of HIV-positive patients in Japan. Systemic non-steroidal anti-inflammatory drugs were effective in more than 70% of cases. Dimethyl diphenyl sulfone, antibiotics including minocycline, psoralen plus ultraviolet A therapy and ultraviolet B treatments worked in some cases. Topical steroids and tacrolimus were also effective in some cases of EPF, while topical indomethacin was less effective.

Severity score indexes for blistering diseases.

Scoring systems are used to assess the severity of a disease and the response to treatment. The main severity scoring indexes are the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS) and the Pemphigus Disease Area Index (PDAI). They have been validated and are already used in the evaluation of pemphigus and in clinical trials. They quantify disease severity by performing a global assessment of all lesions. In recent years, other severity scoring systems have been developed for pemphigus and other autoimmune blistering diseases.

Shape and configuration of skin lesions: targetoid lesions.

What is probably the first description of targetoid or iris lesions, as they appear in erythema multiforme (EM), can be found in Thomas Bateman's 1836 textbook "Practical Synopsis of Cutaneous Diseases According to the Arrangement of Dr. Willan." EM was initially described by Bateman and later by von Hebra as an acute self-limiting skin disease, symmetrically distributed on the extremities with typical concentric "targetoid" or "iris" lesions, and often recurrent. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) were added to this syndrome later. A newer classification has created two disease spectra: EM consisting of EM minor and EM major (or bullous EM), and SJS and TEN. EM minor and EM major are often recurrent, postinfectious (especially after herpes and mycoplasma) disorders with low morbidity and almost no mortality. SJS and TEN are usually severe drug-induced reactions with high morbidity and poor prognosis. The target lesions found in each form of the disease are described and defined. Although the term "target lesion" originated from the description of EM and despite its being the dominant lesion in this disease, it is not pathognomonic for EM, and these lesions can sometimes appear in other diseases. Short descriptions of these other diseases are presented.

Linear IgA bullous dermatosis: the more frequent bullous dermatosis of children.

BACKGROUND: Linear IgA bullous dermatosis (LAD) of children is relatively frequent in Africa. We undertook this study to evaluate the frequency of this disease among autoimmune bullous diseases (AIBD) in Tunisian children. METHODS: We present a 32-year retrospective study (January 1976 to December 2007). Children with chronic acquired bullous diseases seen at the Charles Nicolle Hospital of Tunis and for whom direct immunofluorescence (DIF) of the perilesional skin demonstrated linear IgA immunoglobulin deposits were included in the study population. RESULTS: Thirty-one children with LAD were collected representing 65.9 percent of all AIBD of children collected in the same period, with a mean age of 5.5 years and a sex ratio M/F of 2.4. Most of the children had a generalized eruption (28/31) but more profuse on the face, pelvic region, buttocks, and limbs. Mucosal lesions were present in only 4 children (12.9%). The mean duration of the disease was 14 months. Direct immunofluorescence demonstrated predominantly linear IgA deposits along the dermal-epidermal junction in all patients. Faint IgG, IgM, and complement were also seen (20/31). Indirect immunofluorescence was negative in 67 percent of cases. Eight patients responded to Dapsone, but prednisone had to be added in 7 children and erythromycin in 4 others to control the disease. A long term remission period (34 months) was achieved in 61.9 percent of patients. CONCLUSION: This study confirms that LAD is the most common AIBD in children in Tunisia and it frequently occurs in preschool-aged males. Independently of the medication chosen for treatment, a long term remission is frequently observed.

[Optimizing therapy in patients with severe autoimmune blistering skin diseases]. / Therapieoptimierung bei schweren bullösen Autoimmundermatosen.

Autoimmune bullous diseases are a heterogeneous group of disorders that can be subdivided according to the level of split formation in the intraepidermal blistering pemphigus diseases and subepidermal bullous disorders, latter including pemphigoid diseases, epidermolysis bullosa acquisita (EBA), and dermatitis herpetiformis. In the majority of autoimmune bullous disorders, disease activity can be sufficiently controlled by systemic corticosteroids in combination with further immunsuppressants/-modulants such as dapsone, doxycycline, azathioprine, mycophenolate mofetil, or methotrexate. In contrast, in pemphigus, mucous membrane pemphigoid, and EBA, treatment is challenging and conventional immunosuppressive therapy induces clinical remission only in a minority of patients. Until recently, only cyclosphosphamide and high-dose intravenous immunoglobulin (IVIG) were available as potent second-line therapies. Meanwhile, immunoadsorption and the monoclonal anti-CD20 antibody rituximab have been established as further therapeutic options. The present review focuses on efficacy, adverse events, treatment protocols, and mechanisms of action of IVIG, immunoadsorption, and rituximab in the treatment of severe and/or refractory patients with bullous autoimmune diseases.

[Kindler syndrome. A new bullous dermatosis]. / Kindler-Syndrom. Eine neue bullöse Dermatose.

The Kindler syndrome is a new form of inherited epidermolysis bullosa and the first genodermatosis caused by a defect of the focal adhesions. Kindlin-1, the deficient protein, plays an essential role in integrin activation and in the adhesion of keratinocytes to the extracellular matrix. The adhesion defect leads to skin blistering which begins at birth and ameliorates with age, and to mucosal fragility which leads to scarring and stricture formation. Skin atrophy and poikiloderma develop progressively. Photosensitivity is rather mild, but squamous cell carcinomas develop on sun-exposed areas mainly after the age of 40 years. The most important differential diagnoses are epidermolysis bullosa with mottled pigmentation and dystrophic epidermolysis bullosa. Management aims to treat the symptoms and prevent complications.