The lack of controlled trials on the treatment of pemphigus and pemphigoid diseases limits an evidence-based therapy of these disorders.The aim of this survey was to assess the current treatment standards at German dermatological hospitals and the need for future therapeutic trials. A two-page questionnaire was sent to 42 German academic and non-academic dermatological hospitals and evaluated at the Department of Dermatology, University Medical Center, Freiburg. The response rate was 76%. Topical clobetasol propionate treatment was regarded as first line therapy of bullous pemphigoid in 27% of the hospitals. More than 50% used systemic corticosteroids at an initial dose of < or = 1 mg/kg prednisolone-equivalent in pemphigus and pemphigoid. Azathioprine is used as first line adjuvant in pemphigoid and pemphigus treatment in 69% and 81% of the hospitals, respectively. Dapsone and mycophenolate mofetil represent alternative options, as well as cyclophosphamide-dexamethasone-pulse therapy in pemphigus. Immunosuppressive treatment of pemphigoid and pemphigus is terminated by 58% and 46% of the hospitals 1-3 months after clinical remission, respectively, but the given time points appeared to be variable. The high response rate to this survey demonstrates the interest in this topic. The variability of the answers regarding initial doses of corticosteroids and time points for termination of therapy indicates the need for the establishment of guidelines and for controlled therapeutic trials.
Sir, Pemphigoid (herpes) gestationis (PG) is an autoimmune subepidermal blistering disease associated with pregnancy and characterized by linear deposition of C3 and, less frequently, of immunoglobulin (Ig)G along the dermal–epidermal junction (DEJ).1 Complement‐fixing circulating IgG autoantibodies to the DEJ in serum of PG patients are mainly directed to the 180‐kDa bullous pemphigoid antigen (BP180), a transmembrane hemidesmosomal glycoprotein.2 BP180 consists of an intracellular N‐terminal globular head, a transmembrane region, and a C‐terminal ectodomain. The extracellular domain of BP180 consists of 15 collagenous and 16 noncollagenous (NC) regions harbouring different antigenic sites recognized by autoantibodies from patients with various subepidermal blistering diseases.2 The ectodomain of BP180 may be shed from the surface of basal keratinocytes by cleavage within the NC16A domain resulting in a 120‐kDa fragment (LAD‐1) that lacks a short juxtamembranous portion of the extracellular domain of BP180 (Fig. 1).3, 4 In human skin, the cleavage of BP180 results in another antigenic fragment of 97 kDa (LABD97) that can be extracted from epidermis.5 Recent findings from our laboratory suggest that LAD‐1 and LABD97 have different N‐termini.6
This guideline has been initiated by the task force Autoimmune Blistering Diseases of the European Academy of Dermatology and Venereology, including physicians from all relevant disciplines and patient organizations. It is a S3 consensus-based guideline that systematically reviewed the literature on mucous membrane pemphigoid (MMP) in the MEDLINE and EMBASE databases until June 2019, with no limitations on language. While the first part of this guideline addressed methodology, as well as epidemiology, terminology, aetiology, clinical presentation and outcome measures in MMP, the second part presents the diagnostics and management of MMP. MMP should be suspected in cases with predominant mucosal lesions. Direct immunofluorescence microscopy to detect tissue-bound IgG, IgA and/or complement C3, combined with serological testing for circulating autoantibodies are recommended. In most patients, serum autoantibodies are present only in low levels and in variable proportions, depending on the clinical sites involved. Circulating autoantibodies are determined by indirect IF assays using tissue substrates, or ELISA using different recombinant forms of the target antigens or immunoblotting using different substrates. The major target antigen in MMP is type XVII collagen (BP180), although in 10-25% of patients laminin 332 is recognized. In 25-30% of MMP patients with anti-laminin 332 reactivity, malignancies have been associated. As first-line treatment of mild/moderate MMP, dapsone, methotrexate or tetracyclines and/or topical corticosteroids are recommended. For severe MMP, dapsone and oral or intravenous cyclophosphamide and/or oral corticosteroids are recommended as first-line regimens. Additional recommendations are given, tailored to treatment of single-site MMP such as oral, ocular, laryngeal, oesophageal and genital MMP, as well as the diagnosis of ocular MMP. Treatment recommendations are limited by the complete lack of high-quality randomized controlled trials.
Because of the morbidity and limited therapeutic options of autoimmune diseases, there is a high, and thus far, unmet medical need for development of novel treatments. Pemphigoid diseases, such as epidermolysis bullosa acquisita (EBA), are prototypical autoimmune diseases that are caused by autoantibodies targeting structural proteins of the skin, leading to inflammation, mediated by myeloid cells. To identify novel treatment targets, we performed cutaneous genome-wide mRNA expression profiling in 190 outbred mice after EBA induction. Comparison of genome-wide mRNA expression profiles in diseased and healthy mice, and construction of a co-expression network identified Sykb (spleen tyrosine kinase, SYK) as a major hub gene. Aligned, pharmacological SYK inhibition protected mice from experimental EBA. Using lineage-specific SYK-deficient mice, we identified SYK expression on myeloid cells to be required to induce EBA. Within the predicted co-expression network, interactions of Sykb with several partners (e.g., Tlr13, Jdp2, and Nfkbid) were validated by curated databases. Additionally, novel gene interaction partners of SYK were experimentally validated. Collectively, our results identify SYK expression in myeloid cells as a requirement to promote inflammation in autoantibody-driven pathologies. This should encourage exploitation of SYK and SYK-regulated genes as potential therapeutic targets for EBA and potentially other autoantibody-mediated diseases.
Summary Autoimmune bullous skin disorders are induced by autoantibodies against distinct adhesion complexes of the epidermal and dermal‐epidermal junction. Since most of these disorders are characterized by a severe, potentially lethal course,they require long‐term immunosuppressive treatment to reduce the de novo synthesis of pathogenic autoantibodies by B lymphocytes. Rituximab, a chimeric monoclonal antibody against CD20 on B lymphocytes, has shown promise in several case reports or cohort studies in the treatment of paraneo‐plastic pemphigus,refractory cases of pemphigus vulgaris and foliaceus and in other autoimmune bullous disorders.Treatment with rituximab leads to depletion of pathogenic B‐cells which may last up to 12 months resulting in a reduction of plasma cells secreting pathogenic autoantibodies.Rituximab is usually administered in an adjuvant setting at a dose of 375 mg/m 2 i.v.in weekly intervals for four consecutive weeks in addition to the standard immunosuppressive treatment.The present consensus statement of German‐speaking derma‐tologists,rheumatologists and oncologists summarizes and evaluates the current evidence for the use and mode of application of rituximab in autoimmune bullous skin disorders.
Epidermolysis bullosa acquisita (EBA) is a subepidermal blistering disorder associated with tissue-bound and circulating autoantibodies specific to type VII collagen, a major constituent of the dermal-epidermal junction. Previous attempts to transfer the disease by injection of patient autoantibodies into mice have been unsuccessful. To study the pathogenic relevance of antibodies specific to type VII collagen in vivo, we generated and characterized rabbit antibodies specific to a murine form of this antigen and passively transferred them into adult nude, BALB/c, and C57BL/6 mice. Immune rabbit IgG bound to the lamina densa of murine skin and immunoblotted type VII collagen. Mice injected with purified IgG specific to type VII collagen, in contrast to control mice, developed subepidermal skin blisters, reproducing the human disease at the clinical, histological, electron microscopical, and immunopathological levels. Titers of rabbit IgG in the serum of mice correlated with the extent of the disease. F(ab′)2 fragments of rabbit IgG specific to type VII collagen were not pathogenic. When injected into C5-deficient mice, antibodies specific to type VII collagen failed to induce the disease, whereas C5-sufficient mice were susceptible to blister induction. This animal model for EBA should facilitate further dissection of the pathogenesis of this disease and development of new therapeutic strategies.
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