Inhibition of interferon gamma impairs induction of experimental epidermolysis bullosa acquisita.

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.

Inhibition of Glucose Metabolism Abrogates the Effector Phase of Bullous Pemphigoid-Like Epidermolysis Bullosa Acquisita.

Bullous pemphigoid-like epidermolysis bullosa acquisita (EBA) is an autoantibody-driven, granulocyte-mediated skin disease. The role of cellular metabolism and its potential as a therapeutic target in EBA are unknown. We investigated the effect of 2-deoxy-D-glucose and metformin in the antibody transfer model of EBA. Both metformin and 2-deoxy-D-glucose attenuated disease in this model. Subsequently, we demonstrate that the stimulation of neutrophils by immune complexes increases the rate of aerobic glycolysis and that this increase is required to induce the release of leukotriene B4 and ROS critical for EBA. Accordingly, 2-deoxy-D-glucose as an inhibitor of the glycolytic enzymes hexokinase and phosphoglucose isomerase and heptelidic acid, an inhibitor of glyceraldehyde-3-phosphate dehydrogenase, blunted this neutrophil response. Decreasing oxidative phosphorylation, metformin also inhibited this neutrophil response but only when applied in suprapharmacological doses, rendering a direct effect of metformin on neutrophils in vivo unlikely. Considering that the oxidative phosphorylation inhibitor oligomycin likewise inhibits these neutrophil responses and that immune complex stimulation does not alter the rate of oxidative phosphorylation, these results, however, suggest that intact mitochondria are necessary for neutrophil responses. Collectively, we highlight 2-deoxy-D-glucose and metformin as potential drugs and both glycolysis and oxidative phosphorylation in neutrophils as promising therapeutic targets in EBA.

Diagnosis of autoimmune subepidermal bullous diseases with mucous membrane involvement based on laser-scanning confocal microscopy.

BACKGROUND: Mucosal involvement in autoimmune subepidermal blistering disorders (ASBD) may represent the only or predominant localization. Circulating autoantibodies are detected in 50% cases. OBJECTIVE: The aim of this study was to evaluate the usefulness of fluorescence overlay antigen mapping by laser-scanning confocal microscopy (FOAM-LSCM) to identify ASBD with mucosal involvement in oral mucosa specimens. MATERIALS & METHODS: Thirty-two ASBD patients, diagnosed based on direct immunofluorescence between 2006 and 2016, were enrolled. Localization of IgG deposits bound at the basement membrane zone, relative to laminin-332 and collagen IV localization, was assessed in vivo. RESULTS: FOAM-LSCM disclosed four different immunofluorescence patterns. IgG deposits were located above laminin-332, as in bullous pemphigoid (BP-type), in 19% cases and co-localized with laminin-332 (anti-laminin-332-type) in 6% cases. IgG deposits were found below laminin-332 and above collagen IV (mucous membrane pemphigoid-type) in 59% cases, and below collagen IV (epidermolysis bullosa acquisita-type) in 16%. Circulating antibodies were found in 56% cases. CONCLUSION: The FOAM-LSCM method should be used in order to obtain a definitive diagnosis of ASBD with mucosal involvement, particularly in the presence of negative circulating antibodies.

12/15-Lipoxygenase choreographs the resolution of IgG-mediated skin inflammation.

Autoimmune diseases are defined by an immune response against a specific autoantigen, driven by antigen-specific T cells or antibodies. While the mechanisms resolving brief episodes of acute inflammation elicited by microbial components or tissue injury are well understood, the mechanisms resolving tissue inflammation in autoimmune diseases are still largely elusive. We have, therefore, addressed the mechanisms of resolution in IgG-mediated autoimmune diseases using a mouse model of the pemphigoid disease "bullous pemphigoid-like epidermolysis bullosa acquisita" (BP-like EBA) as prototypical example. We found that 12/15-LO is induced in skin lesions of BP-like EBA and is predominantly expressed in eosinophils. Dependent on the expression of 12/15-LO, large amounts of proresolving lipid mediators, are biosynthesized in the skin by the point disease peaks. Their production is timely correlated to the gradual reversal of tissue inflammation. Genetic deficiency in Alox15, the gene encoding 12/15-LO, disrupts this process significantly protracting and aggravating disease. This protraction is associated reduced recruitment of regulatory T cells (Tregs) into lesional skin. Intriguingly, Alox15-/- mice also exhibit reduced recruitment of eosinophils into the skin, and the chemotaxis of cultured Alox15-/- eosinophils towards CCL11/eotaxin-1 is compromised. Finally, we demonstrate that 15-lipoxygenase-1, the human homologue of 12/15-LO is induced in granulocytes in lesional skin of patients suffering from a pemphigoid disease. Collectively, our result uncover key mechanisms resolving IgG-mediated skin inflammation. These mechanisms are orchestrated by 12/15-LO expressed in eosinophils promoting the recruitment of eosinophils and Tregs, which in turn inhibit neutrophils.

Propranolol Is an Effective Topical and Systemic Treatment Option for Experimental Epidermolysis Bullosa Acquisita.

Propranolol is an ADRB2 blocker that regulates heart muscle contractions, smooth muscle relaxation, and glycogenolysis. In addition, an increasing number of applications in dermatology have been described, most prominently, the use as a first-line treatment for infantile hemangiomas. We here show that propranolol enhances IL-8-induced neutrophil chemotaxis and reduces the release of ROS after immune complex stimulation. To obtain further molecular insights into the modulatory effects of propranolol in activated neutrophils, we performed RNA sequencing of immune complex-stimulated neutrophils in the absence and presence of the drug. We identified the transcriptomic signature of propranolol and demonstrated an ADR2-independent immunomodulatory effect. To determine if the anti-inflammatory transcriptomic signature of propranolol also translates into clinical effects, we next evaluated the impact of propranolol in a prototypical neutrophil-dependent skin disease, specifically, antibody transfer-induced epidermolysis bullosa acquisita in mice. To validate the identified propranolol gene signature obtained in human neutrophils, we analyzed a selection of genes by RT-PCR in mouse epidermolysis bullosa acquisita skin and confirmed TNF, among others, to be differentially regulated by propranolol treatment. Our data clearly indicate that, based on its molecular impact on immune complex-activated neutrophils, propranolol is a potential treatment option for neutrophil-mediated inflammatory skin diseases.

A Review Comparing International Guidelines for the Management of Bullous Pemphigoid, Pemphigoid Gestationis, Mucous Membrane Pemphigoid, and Epidermolysis Bullosa Acquisita.

Autoimmune blistering disease management can be challenging as treatment modalities vary greatly and no single standard of care exists. We consolidated the recommendations of international management guidelines in order to provide optimal management suggestions to physicians. A comprehensive literature search in PubMed/MEDLINE for published blistering disease management guidelines and consensus statements was conducted in November 2019. Search terms included "guideline or guidelines" or "consensus" and "pemphigoid" or "autoimmune blistering disease" or "epidermolysis bullosa acquisita". We included guidelines from established dermatologic societies and expert consensus groups. We excluded literature reviews, guidelines established by an association without dermatologists, or those specific to a single treatment. Guidelines in all languages were considered. Eleven guidelines from dermatologic associations and consensus groups meeting our inclusion criteria were selected. Several differences between recommendations, most notably when to introduce adjuvants for refractory disease, were found in bullous pemphigoid. In mucous membrane pemphigoid, treatment was directed to the sites involved and managed with systemic corticosteroids and immunosuppressants/biologics. There was no universal consensus on the first-line treatment for epidermolysis bullosa acquisita, but a combination of immunosuppressive, anti-inflammatory, and anti-neutrophil therapy was utilized. Comparison of the management guidelines revealed underrepresentation of guidelines from developing nations and key differences between the management styles among dermatologists from Europe and Asia. We attribute these discrepancies to the time elapsed between guidelines, regional differences, and demands of the local healthcare systems.

Drug Development in Pemphigoid Diseases.

Pemphigoid diseases are organ-specific autoimmune diseases of the skin and/or mucous membranes. They are caused by autoantibodies targeting adhesion molecules located at the dermal-epidermal junction. While the diagnostics of pemphigoid diseases and insights into their pathogenesis have improved significantly, the development of novel treatments that are effective and safe remains an unmet medical need. However, numerous pre-clinical studies and early clinical trials have recently been launched. This review summarizes some pathways leading to drug development in pemphigoid diseases, namely: (i) hypothesis-driven drug development; (ii) omics-based drug development; (iii) drug repurposing; (iv) screening-based drug development; and (v) drug development based on careful clinical observations. Ultimately, it is hoped that this will lead to personalized and curative treatments.

Structural and biophysical characterization of the type VII collagen vWFA2 subdomain leads to identification of two binding sites.

Type VII collagen is an extracellular matrix protein, which is important for skin stability; however, detailed information at the molecular level is scarce. The second vWFA (von Willebrand factor type A) domain of type VII collagen mediates important interactions, and immunization of mice induces skin blistering in certain strains. To understand vWFA2 function and the pathophysiological mechanisms leading to skin blistering, we structurally characterized this domain by X-ray crystallography and NMR spectroscopy. Cell adhesion assays identified two new interactions: one with ß1 integrin via its RGD motif and one with laminin-332. The latter interaction was confirmed by surface plasmon resonance with a KD of about 1 mm. These data show that vWFA2 has additional functions in the extracellular matrix besides interacting with type I collagen.

Epidermal Damage Induces Th1 Polarization and Defines the Site of Inflammation in Murine Epidermolysis Bullosa Acquisita.

Epidermolysis bullosa acquisita is an autoimmune skin disease characterized by subepidermal blisters. The pathogenesis is mediated by deposits of autoantibodies directed against type VII collagen in the skin, but the sequence of events regulating the localization of skin blisters is not fully understood. In this study, using the immunization-induced mouse model of epidermolysis bullosa acquisita, we demonstrate that epidermal disruption induces not only an infiltration of CD4+ T cells but also a T helper type 1 phenotype as it has been described for delayed-type hypersensitivity reactions. This T helper type 1 reaction was not found when different antigens were applied. Deep T-cell receptor ß profiling revealed shifts in the V/J gene usage only in epidermolysis bullosa acquisita, suggesting an infiltration of autoantigen-specific T cells. To target these autoantigen-specific T cells, we established an approach with which skin inflammation could be prevented without impairing the functionality of autoantibodies. We conclude that T-cell involvement in skin blistering diseases such as epidermolysis bullosa acquisita relates not only to T-cell help for B cells that produce pathogenic autoantibodies but also to autoreactive T helper type 1 effector cells that migrate into injured skin sites, exacerbate inflammation through production of inflammatory cytokines such as IFNγ, and prevent wound healing.

Treatment Update of Autoimmune Blistering Diseases.

The treatment of refractory autoimmune blistering diseases (AIBDs) has always been a challenge. Because randomized controlled trials are lacking, treatment has been based on analysis of anecdotal data. The last 2 decades has seen the use of rituximab become a conventional treatment in the therapeutic armamentarium of AIBDs, leading to its Food and Drug Administration indication for pemphigus vulgaris in 2018. We review the current updated data on the use of rituximab including dosing, protocols, and its role in the algorithm of AIBDs. In addition, we discuss several promising novel emerging therapeutic agents for AIBDs.

Direct Immunofluorescence of Mechanobullous Epidermolysis Bullosa Acquisita, Porphyria Cutanea Tarda and Pseudoporphyria.

Mechanobullous epidermolysis bullosa acquisita (mEBA) can have a clinical presentation that is very similar to other blistering diseases, such as porphyria cutanea tarda (PCT) and pseudoporphyria. Direct immunofluorescence is an important feature in the diagnosis of mEBA, although features that overlap with PCT and pseudoporphyria have been reported. This retrospective observational study investigated whether direct immunofluorescence can discriminate mEBA from PCT and pseudoporphyria. Biopsies of 13 patients with mEBA, 10 with PCT and 10 with pseudoporphyria were included. In 7 cases of PCT and 4 of pseudoporphyria, direct immunofluorescence showed a pattern at the dermal-epidermal junction that appeared similar to the u-serrated pattern in mEBA. Vessel wall depositions were observed in all 3 diseases, but were more frequent and more intense in PCT and pseudoporphyria than in mEBA. Careful examination of direct immunofluorescence of mEBA vs. PCT and pseudoporphyria revealed different staining patterns, although overlapping features were present. Therefore, integrating all clinical and laboratory data is essential to differentiate between mEBA, PCT and pseudoporphyria.

Detection of anti-type VII collagen IgE antibodies in epidermolysis bullosa acquisita.

BACKGROUND: Epidermolysis bullosa acquisita (EBA) is a rare pemphigoid disease involving autoantibodies to type VII collagen (COL7), a major structural component of anchoring fibrils. IgE autoantibodies to type XVII collagen (BP180) have been identified in bullous pemphigoid (BP), the prototype of pemphigoid diseases. Although the pathogenic relevance of IgG anti-COL7 has been investigated, that of IgE in EBA remains unclear. OBJECTIVES: To reveal the presence and pathogenic relevance of IgE anti-COL7 in EBA. METHODS: We examined IgE antibodies in 109 patients with EBA by indirect immunofluorescence (IIF) and enzyme-linked immunosorbent assay (ELISA). RESULTS: IIF with normal human skin revealed IgE reactivity in the basement membrane zone in 29 (26·6%) cases. To verify whether the IgE antibodies were specific to COL7, we performed IIF with 21 clearly positive cases and the skin of a patient with dystrophic EBA, which does not involve COL7. All cases showed negative results, indicating that IgE antibodies were specific to COL7. In a modified IgG COL7 ELISA for IgE, 16 (14·7%) cases were positive (three and 13 cases were negative and positive on IIF, respectively). We compared anti-COL7 IgG and IgE, and found a weak but significant correlation (r = 0·459, P < 0·001). EBA is clinically divided into a mechanobullous (MB; noninflammatory) type and an inflammatory (INF) type resembling BP. Of the IIF-positive cases, 11 of 30 (37%) had INF and nine of 48 (19%) had MB. CONCLUSIONS: This study is the first to demonstrate the presence of circulating anti-COL7 IgE in patients with EBA, which may correlate with the clinical phenotype.

Fcγ Receptor IIB Controls Skin Inflammation in an Active Model of Epidermolysis Bullosa Acquisita.

Epidermolysis bullosa acquisita (EBA) is an autoimmune skin blistering disease characterized by IgG autoantibodies (aAb) against type VII collagen (COL7). The mechanisms controlling the formation of such aAbs and their effector functions in the skin tissue are incompletely understood. Here, we assessed whether the inhibitory IgG Fc receptor, FcγRIIB, controls the development of autoimmune skin blistering disease in an active model of EBA. For this purpose, we immunized congenic EBA-susceptible B6.SJL-H2s (B6.s) and B6.s-Fcgr2b-/- mice with the immunodominant vWFA2 region of COL7. B6.s-Fcgr2b-/- mice developed a strong clinical phenotype with 15 ± 3.3% of affected body surface area at week 4. In contrast, the body surface area in B6.s mice was affected to a maximum of 5% at week 6 with almost no disease signs at week 4. Surprisingly, we already found strong but similar COL7-specific serum IgG1 and IgG2b aAb production at week 2. Further, aAb and C3b deposition in the skin of B6.s and B6.s-Fcgr2b-/- mice increased between weeks 2 and 6 after vWFA2 immunization. Importantly, neutrophil skin infiltration and activation was much stronger in B6s-Fcgr2b-/- than in B6.s mice and already present at week 2. Also, the early aAb response in B6.s-Fcgr2b-/- mice was more diverse than in wt B6.s mice. Reactive oxygen species (ROS) release from infiltrating neutrophils play a crucial role as mediator of skin inflammation in EBA. In line, sera from B6.s and B6.s-Fcgr2b-/- mice induced strong ROS release from bone marrow-neutrophils in vitro. In contrast to the antibody-transfer-induced EBA model, individual targeting of FcγRIII or FcγRIV decreased ROS release to 50%. Combined FcγR blocking abrogated ROS release from BM neutrophils. Also, ROS release induced by COL7-specific serum IgG aAbs was significantly higher using BM neutrophils from B6.s-Fcgr2b-/- than from B6.s mice. Together, our findings identified FcγRIIB as a suppressor of skin inflammation in the active EBA model through inhibition of early epitope spreading, protection from strong early neutrophil infiltration to and activation of neutrophils in the skin and suppression of FcγRIII activation by IgG1 aAbs which drive strong ROS release from neutrophils leading to tissue destruction at the dermal-epidermal junction.

The use of rituximab in treatment of epidermolysis bullosa acquisita: Three new cases and a review of the literature.

Epidermolysis bullosa acquisita (EBA) is a rare, subepidermal blistering disease affecting the skin and mucous membranes that often remains refractory to standard immunosuppressive therapy. We present three original cases and a review of the literature of 20 cases of refractory EBA treated with rituximab as monotherapy or in combination with other agents. Complete control (with or without therapy) and remission were seen in 56% of patients treated with rituximab monotherapy and 75% of patients treated with rituximab and immunoadsorption (IA). We conclude EBA refractory to standard immunosuppressive therapy may show a more favorable long-term response to the addition of rituximab; and rituximab in combination with intravenous immunoglobulin or IA may provide utility in terminating acute disease. Additional data are needed to evaluate the safety and long-term outcomes of rituximab-based treatment.

Specific Inhibition of Complement Activation Significantly Ameliorates Autoimmune Blistering Disease in Mice.

Epidermolysis bullosa acquisita (EBA) is an antibody-mediated blistering skin disease associated with tissue-bound and circulating autoantibodies to type VII collagen (COL7). Transfer of antibodies against COL7 into mice results in a subepidermal blistering phenotype, strictly depending on the complement component C5. Further, activation predominantly by the alternative pathway is required to induce experimental EBA, as blistering was delayed and significantly ameliorated only in factor B-/- mice. However, C5 deficiency not only blocked the activation of terminal complement components and assembly of the membrane attack complex (MAC) but also eliminated the formation of C5a. Therefore, in the present study, we first aimed to elucidate which molecules downstream of C5 are relevant for blister formation in this EBA model and could be subsequently pharmaceutically targeted. For this purpose, we injected mice deficient in C5a receptor 1 (C5aR1) or C6 with antibodies to murine COL7. Importantly, C5ar1-/- mice were significantly protected from experimental EBA, demonstrating that C5a-C5aR1 interactions are critical intermediates linking pathogenic antibodies to tissue damage in this experimental model of EBA. By contrast, C6-/- mice developed widespread blistering disease, suggesting that MAC is dispensable for blister formation in this model. In further experiments, we tested the therapeutic potential of inhibitors of complement components which were identified to play a key role in this experimental model. Complement components C5, factor B (fB), and C5aR1 were specifically targeted using complement inhibitors both prophylactically and in mice that had already developed disease. All complement inhibitors led to a significant improvement of the blistering phenotype when injected shortly before anti-COL7 antibodies. To simulate a therapeutic intervention, anti-fB treatment was first administered in full-blown EBA (day 5) and induced significant amelioration only in the final phase of disease evolution, suggesting that early intervention in disease development may be necessary to achieve higher efficacy. Anti-C5 treatment in incipient EBA (day 2) significantly ameliorated disease during the whole experiment. This finding is therapeutically relevant, since the humanized anti-C5 antibody eculizumab is already successfully used in patients. In conclusion, in this study, we have identified promising candidate molecules for complement-directed therapeutic intervention in EBA and similar autoantibody-mediated diseases.

Neutrophil Adhesion Is a Prerequisite for Antibody-Mediated Proteolytic Tissue Damage in Experimental Models of Epidermolysis Bullosa Acquisita.

Although uncontrolled proteolytic activity mediated by activated neutrophils is a major reason for tissue damage, therapeutic approaches using protease inhibitors are inefficient. Here, we investigated the role of the immune complex-induced neutrophil adhesion and protease release in tissue damage. We show both in vitro and in vivo that immune complex-mediated neutrophil adhesion to the target tissue depends on ß2 integrins. Without affecting elastase or reactive oxygen species release, blocking of adhesion drastically inhibited tissue damage in an experimental model of autoantibody-mediated skin blistering disease. By using a cell-bound fluorescent resonance energy transfer-based elastase sensor, we detected elastase enzyme activity on the surface of adherent cells resistant to protease inhibitors. Inhibitor resistance was lost by CD18 blockade or deficiency in vitro and in vivo. Immune complex-induced neutrophil adhesion created an enclosed protected space between the cell and its target structure where proteinases and reactive oxygen species can execute their tissue-damaging effect. Because immune complex-induced neutrophil adhesion represents an indispensable step for tissue damage of many diseases, our findings may facilitate the development of strategies for the treatment of such disorders.

Whole-Genome Expression Profiling in Skin Reveals SYK As a Key Regulator of Inflammation in Experimental Epidermolysis Bullosa Acquisita.

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.

Effectiveness and Safety of Rituximab in Recalcitrant Pemphigoid Diseases.

Introduction: Rituximab (RTX) is a monoclonal antibody targeting CD20, a transmembrane protein expressed on B cells, causing B cell depletion. RTX has shown great efficacy in studies of pemphigus vulgaris, but data of pemphigoid diseases are limited. Objective: To assess the effectiveness and safety of RTX in pemphigoid diseases. Methods: The medical records of 28 patients with pemphigoid diseases that were treated with RTX were reviewed retrospectively. Early and late endpoints, defined according to international consensus, were disease control (DC), partial remission (PR), complete remission (CR), and relapses. Safety was measured by reported adverse events. Results: Patients with bullous pemphigoid (n = 8), mucous membrane pemphigoid (n = 14), epidermolysis bullosa acquisita (n = 5), and linear IgA disease (n = 1) were included. Treatment with 500 mg RTX (n = 6) or 1,000 mg RTX (n = 22) was administered on days 1 and 15. Eight patients received additional 500 mg RTX at months 6 and 12. Overall, DC was achieved in 67.9%, PR in 57.1%, and CR in 21.4% of the cases. During follow-up, 66.7% patients relapsed. Repeated treatment with RTX led to remission (PR or CR) in 85.7% of the retreated cases. No significant difference in response between pemphigoid subtypes was found. IgA-dominant cases (n = 5) achieved less DC (20 vs. 81.3%; p = 0.007), less PR (20 vs. 62.5%; p = 0.149), and less CR (0 vs. 18.8%; p = 0.549) compared to IgG-dominant cases (n = 16). Five severe adverse events and three deaths were reported. One death was possibly related to RTX and one death was disease related. Conclusion: RTX can be effective in recalcitrant IgG-dominant pemphigoid diseases, however not in those where IgA is dominant.

Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita.

Type VII collagen (COL7), a major component of anchoring fibrils in the epidermal basement membrane zone, has been characterized as a defective protein in dystrophic epidermolysis bullosa and as an autoantigen in epidermolysis bullosa acquisita. Although COL7 is produced and secreted by both epidermal keratinocytes and dermal fibroblasts, the role of COL7 with regard to the epidermis is rarely discussed. This review focuses on COL7 physiology and pathology as it pertains to epidermal keratinocytes. We summarize the current knowledge of COL7 production and trafficking, its involvement in keratinocyte dynamics, and epidermal carcinogenesis in COL7 deficiency and propose possible solutions to unsolved issues in this field.