Incidence of pemphigoid diseases in Northern Germany in 2016 - first data from the Schleswig-Holstein Registry of Autoimmune Bullous Diseases.

BACKGROUND: Autoimmune bullous diseases (AIBD) are rare disorders characterized by autoantibody formation against components of adhesion molecules; in pemphigoid diseases (PD), these are proteins of hemidesmosomes and basement membrane, important for cell-matrix adhesion in skin and/or mucous membranes. Incidences of these diseases vary considerably between different populations. OBJECTIVES: To establish a registry prospectively recruiting all AIBD patients in a geographically well-defined region in Northern Germany (Schleswig-Holstein). METHODS: Only patients with verified disease (by clinical presentation, histology, direct and/or indirect immunofluorescence and /or ELISA) living in Schleswig-Holstein were included. Incidences of PD were estimated based on the total number of inhabitants in Schleswig-Holstein, stratified by birth year and sex. RESULTS: Of 67 patients with PD [35 male, 32 female, mean age 75 (standard deviation 14.3 years)], 83% were patients with bullous pemphigoid [n = 56, 28 male, 28 female, mean age 78 (SD 9.9)]. The resulting crude incidences were 23.4 patients/million/year for all pemphigoid patients, 19.6 patients/million/year for bullous pemphigoid (age-standardized 16.9 patients/million/year) with a strong increase in bullous pemphigoid patients in the age group of 85-90 years with 262 patients/million/year. Incidences for bullous pemphigoid were higher in urban compared to rural areas. Other PD (mucous membrane pemphigoid, linear IgA disease, anti-p200 pemphigoid) were less frequent with crude incidences of 2.1, 1.0 and 0.7 patients/million/year, respectively. CONCLUSIONS: This study prospectively analyses the incidence of PD in a carefully defined geographical area. The highest incidence among PD patients was found for bullous pemphigoid. The incidence of bullous pemphigoid is considerably increased compared to previous reports and reveals regional differences. Further studies are needed in order to clarify these findings.

Prevalence and age distribution of pemphigus and pemphigoid diseases among paediatric patients in Germany.

BACKGROUND: Autoimmune bullous diseases are rare and mostly occur in adults. Several cases and small case series have been described in children, but no systematic study about the prevalence of autoimmune bullous diseases (AIBD) in children is available. PATIENTS AND METHODS: We analysed data of 1.7 million children insured in the largest German health insurance company based on the ICD-10-GM classification for the year 2015. Data were adjusted to the general German population based on the data of the Federal Statistical Office for the year 2015. RESULTS: The prevalence of AIBD was calculated to 101.1/million children in 2015, resulting in about 1351 patients below the age of 18 years in Germany. The highest prevalence of all AIBD was seen for pemphigus vulgaris (30.5/million children) followed by linear IgA disease (24.5/million children) and bullous pemphigoid (4.9/million children). CONCLUSION: Autoimmune bullous diseases in minors are scarce but should be taken into consideration in patients with pruritus and/or blisters and erosions on the skin and/or mucous membranes. Treatment is challenging, and due to the rarity of AIBD in minors, the management of these disorders in this patient population is best performed in specialized centres in a multidisciplinary approach, including paediatric dermatologists or dermatologists and paediatricians.

[Anti-p200 pemphigoid]. / Anti-p200-Pemphigoid.

Anti-p200 pemphigoid is a rare autoimmune blistering disease. It belongs to the group of pemphigoid diseases and was first described in 1996. The diagnostic gold standard is the combination of (1) linear deposits of immunoreactants at the dermal epidermal junction by direct immunofluorescence microscopy of a perilesional skin biopsy, (2) detection of circulating autoantibodies binding to the dermal side (blister floor) of human salt split skin by indirect immunofluorescence microscopy, and reactivity with a 200 kDa protein (p200) in extract of human dermis by immunoblotting. In 2009, laminin γ1 was described as an additional target antigen in 90% of anti-p200 pemphigoid patients. Since ex vivo and in vivo studies have shown no direct pathogenic relevance for laminin γ1 antibodies and the preadsorption of patient sera against laminin γ1 does not reduce their reactivity with p200, the molecular identity of p200 still remains to be elucidated. The clinical phenotype of the disease is heterogeneous; in most cases, however, it resembles bullous pemphigoid. Anti-p200 patients are younger and skin lesions more often appear on palms of the hands and soles of the feet than in bullous pemphigoid. Therapy consists of topical and systemic corticosteroids. In addition, the use of daspone and immunosuppressants has been reported.

A sensitive and specific assay for the serological diagnosis of antilaminin 332 mucous membrane pemphigoid.

BACKGROUND: Antilaminin 332 mucous membrane pemphigoid (MMP) is an autoimmune subepidermal blistering disease with predominant mucosal involvement and autoantibodies against laminin 332. Malignancies have been associated with this disease; however, no standardized detection system for antilaminin 332 serum antibodies is widely available. OBJECTIVES: Development of a sensitive and specific assay for the detection of antilaminin 332 antibodies. METHODS: An indirect immunofluorescence (IF) assay using recombinant laminin 332 was developed and probed with a large number of antilaminin 332 MMP patient sera (n = 93), as well as sera from patients with antilaminin 332-negative MMP (n = 153), bullous pemphigoid (n = 20), pemphigus vulgaris (n = 20) and noninflammatory dermatoses (n = 22), and healthy blood donors (n = 100). RESULTS: In the novel IF assay, sensitivities with the laminin 332 heterotrimer and the individual α3, ß3 and γ2 chains were 77%, 43%, 41% and 13%, respectively, with specificities of 100% for each substrate. The sensitivity for the heterotrimer increased when an anti-IgG4 enriched antitotal IgG conjugate was applied. Antilaminin 332 reactivity paralleled disease activity and was associated with malignancies in 25% of patients with antilaminin 332 MMP. CONCLUSIONS: The novel IF-based assay will facilitate the serological diagnosis of antilaminin 332 MMP and may help to identify patients at risk of a malignancy.

Prospective study in bullous pemphigoid: association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score.

BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone. OBJECTIVES: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera. METHODS: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality. RESULTS: Disease activity correlated with immunoglobulin (Ig)G anti-BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate. CONCLUSIONS: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease.

[Mucous membrane pemphigoid]. / Schleimhautpemphigoid.

Mucous membrane pemphigoid (MMP) is a pemphigoid disease defined by the presence of autoantibodies against the dermal-epidermal junction and predominant involvement of mucous membranes. Diagnosis is made by the clinical presentation and linear deposits of IgG and/or IgA and/or C3 at the dermal-epidermal junction by direct immunofluorescence microscopy of a perilesional biopsy. Circulating autoantibodies can be detected in most patients by indirect immunofluorescence microscopy on salt-split human skin as well as ELISA and immunoblotting with recombinant and cell-derived target antigens. For systemic treatment of MMP, corticosteroids, dapsone, mycophenolates, and azathioprine are applied. In severe cases and in cases with rapid disease progression cyclophosphamide, rituximab, high-dose intravenous immunoglobulins, and immunoadsorption are used. For the successful management of MMP patients, close cooperation with dentists, ophthalmologists, ENT specialists, gynecologists, and gastroenterologists is essential.