The pemphigoid disease epidermolysis bullosa acquisita (EBA) is an autoimmune blistering skin disease characterized by autoantibodies against type VII collagen (COL7), immune cell infiltrates at the dermal-epidermal junction and subepidermal blistering. Proteases, particularly granzyme B (GzmB), have been established as therapeutic targets for the treatment of EBA and other pemphigoid diseases. We investigated the impact of the novel GzmB inhibitor SNT-6935 on anti-COL7 IgG-induced subepidermal blistering in a well-established EBA ex vivo model. Our findings demonstrate that pharmacological targeting of GzmB with its selective inhibitor SNT-6935 significantly reduced autoantibody-induced dermal-epidermal separation in human skin cryosections. Interestingly, treatment of skin cryosections with recombinant human GzmB alone did not cause dermal-epidermal separation, suggesting that additional mechanisms alongside GzmB are required for tissue damage in EBA. In conclusion, our study highlights the significant contribution of GzmB to the pathogenesis of EBA and supports the notion of GzmB as a therapeutic target in EBA and other pemphigoid diseases.

UNASSIGNED: Epidermolysis bullosa acquisita (EBA) is a rare dermatosis of the mucous membrane and/or skin. Employing biologic treatment modalities, specifically rituximab (RTX), have become pivotal measure in treating patients with blistering diseases. This study aims to summarize the current evidence on the safety and efficacy of RTX in EBA.
UNASSIGNED: An extensive search was performed in MEDLINE/PubMed, Embase, Scopus, and Web of Science databases until the end of August 19th, 2023. Two independent reviewers screened the papers, and collected data. Two hundred thirty-three studies were screened using Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.
UNASSIGNED: Thirty-one studies were enrolled. The most common reason of RTX administration in patients with EBA was recalcitrant diseases. Clinical response and disease remission was recorded as 92.7 percent (63 patients) and 73.8 percent (45 patients) of the patients, respectively. A relapse rate of 39.5 percent (15 patients) in the mean follow-up of 23.0 months was reported in the studies. Of the patients, 28.2 percent (11 patients) experienced RTX-related side events, mostly mild and transient infusion reactions.
UNASSIGNED: The results of this systematic review demonstrated that RTX is safe and effective in patients with EBA. This biological treatment modality can be routinely used in managing EBA.

Az autoimmun betegségek az immuntolerancia károsodása következtében létrejövő kórállapotok, melyeknek szervspecifikus és szisztémás formáit különítjük el. Az autoimmun kórképek krónikus lefolyásuk, sokszor szervet vagy életet veszélyeztető megjelenésük, valamint növekvő incidenciájuk miatt komoly kihívást jelentenek mind a betegek, mind pedig az egészségügyi ellátórendszer számára. Mivel az alkalmazott terápiákra a betegek egy része nem vagy csak kevéssé reagál, az újabb potenciális gyógyszercélpontok feltérképezése és hatóanyagok kifejlesztése elengedhetetlen. Ehhez ugyanakkor jobban meg kell ismerni a betegségek hátterében álló folyamatokat. Jelen közleményünkben néhány autoimmun betegség példáján keresztül szeretnénk a teljesség igénye nélkül betekintést nyújtani abba, hogy milyen lehetőségek állnak rendelkezésre e kórképek patomechanizmusának részletesebb megismerésére. A kutatásban gyakran alkalmazunk az autoimmun betegségek vizsgálatára állatmodelleket vagy páciensek vér- és szövetmintáit, amelyek segítségével a patogenezis jobban feltárható, illetve a klinikumban még nem törzskönyvezett, célzott inhibitorok preklinikai vizsgálatai is elvégezhetők. Célunk, hogy rövid betekintést adjunk az autoimmun betegségek transzlációs szemléletű, izgalmas kutatási lehetőségeibe. Orv Hetil. 2024; 165(26): 983–996.

Epidermolysis bullosa acquisita (EBA) is a muco-cutaneous autoimmune disease characterized and caused by autoantibodies targeting type VII collagen (COL7). The treatment of EBA is notoriously difficult, with a median time to remission of 9 months. In preclinical EBA models, we previously discovered that depletion of regulatory T cells (Treg) enhances autoantibody-induced, neutrophil-mediated inflammation and blistering. Increased EBA severity in Treg-depleted mice was accompanied by an increased cutaneous expression of interferon gamma (IFN-γ). The functional relevance of IFN-γ in EBA pathogenesis had been unknown. Given that emapalumab, an anti-IFN-γ antibody, is approved for primary hemophagocytic lymphohistiocytosis patients, we sought to assess the therapeutic potential of IFN-γ inhibition in EBA. Specifically, we evaluated if IFN-γ inhibition has modulatory effects on skin inflammation in a pre-clinical EBA model, based on the transfer of COL7 antibodies into mice. Compared to isotype control antibody, anti-IFN-γ treatment significantly reduced clinical disease manifestation in experimental EBA. Clinical improvement was associated with a reduced dermal infiltrate, especially Ly6G+ neutrophils. On the molecular level, we noted few changes. Apart from reduced CXCL1 serum concentrations, which has been demonstrated to promote skin inflammation in EBA, the expression of cytokines was unaltered in the serum and skin following IFN-γ blockade. This validates IFN-γ as a potential therapeutic target in EBA, and possibly other diseases with a similar pathogenesis, such as bullous pemphigoid and mucous membrane pemphigoid.

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Epidermolysis bullosa acquisita (EBA) rarely develops in childhood. This study retrospectively recruited paediatric patients with EBA (age ≤ 16 years), diagnosed by clinical and histopathological features and results of immunofluorescence, immunoblotting and enzyme-linked immunosorbent assay (ELISA), and reviews their clinical manifestations, histopathology, immunological features, and responses to various treatments. All 7 included patients presented with inflammatory EBA. Among them, 3 had a bullous pemphigoid-like phenotype. Pathologically, in addition to dermal-epidermal blistering, in all patients, the distribution of neutrophils was superficial perivascular or interstitial, or in the dermal papilla. Mixed neutrophils and eosinophils were detected in 2 of the 3 patients with bullous pemphigoid-like phenotypes. In addition to treatment with glucocorticoids, dapsone was administered in 4 patients, while thalidomide and sulfasalazine were administered in 1 patient. All patients responded to the these therapies. Relapse was mainly due to reduction and cessation of glucocorticoids. In conclusion, EBA in childhood may be unique, and thus distinct from its adult counterpart. Specific treatment and follow-up protocols are required for therapy of this rare autoimmune skin disease in children.