Sequential occurrence of primary cutaneous indeterminate cell histiocytosis after oesophageal cancer and subsequent bullous pemphigoid: a case report.

Aims/Background Indeterminate cell histiocytosis is a rare proliferative histiocytic disease with an unknown aetiology, which shares immunophenotypic features of both Langerhans cells and macrophages. There is a relationship between indeterminate cell histiocytosis and cancer, while there are no reports about indeterminate cell histiocytosis and bullous pemphigoid. In this study, we reported the rare case of a patient with primary cutaneous indeterminate cell histiocytosis who had been diagnosed with oesophagal cancer and later developed bullous pemphigoid. The objective of this clinical case report is to analyse the association between solid tumours and indeterminate cell histiocytosis and focus on the coexistence of indeterminate cell histiocytosis and bullous pemphigoid in a patient with cancer. Case Presentation This study presented the case of a 75-year-old man who exhibited annular erythema lesions of variable size and papules scattered over his chest, abdomen, and limbs, along with four bullae on his thigh, persisting for 1.5 months. The patient also had a 9-month history of oesophageal cancer treated with radical radiotherapy. Histopathology and immunohistochemistry confirmed cutaneous indeterminate cell histiocytosis. Bullae and blisters developed on the lower limbs 38 days after treatment. A diagnosis of bullous pemphigoid was established based on clinical and histopathological features and results of direct immunofluorescence and enzyme-linked immunosorbent assay. Results Histopathological examination of the abdominal lesion revealed an accumulation of mononuclear cells in the dermis, with infiltration of eosinophils and lymphocytes in the superficial dermal layer. The histology of the blister on the thigh indicated the formation of an old subepidermal blister, with slurry and eosinophils present within the blister, and infiltration of eosinophils, lymphocytes, as well as histiocytoid cells in the superficial dermal layer. Immunohistochemical staining was positive for CD1a, S100, and CD68, and negative for CD207. Histopathological examination of blisters and bullae on the lower limbs revealed a subepidermal blister with infiltration of a large number of eosinophils within the blister and the dermis beneath it. Direct immunofluorescence showed that immunoglobulin Gs (IgGs) were linearly deposited in the basal membrane zone. Conclusion The coexistence of oesophageal carcinoma, indeterminate cell histiocytosis, and bullous pemphigoid in a single patient represents a rare case that warrants consideration of possible underlying mechanisms.

A case report of bullous pemphigoid following secukinumab therapy for a patient with psoriasis.

Aim: Bullous pemphigoid induced by secukinumab in treatment of psoriasis is rare.Methods: We report a 49-year-old man with psoriasis who developed bullous pemphigoid during treatment with secukinumab.Results: Scattered tense vesicles with itching appeared all over the body after the fourth treatment. Bullous pemphigoid was confirmed by pathological examination and direct immunofluorescence. The patient was treated with topical corticosteroids, oral nicotinamide and minocycline hydrochloride. The lesions of bullous pemphigoid improved significantly after 7 days of treatment.Conclusions: Bullous pemphigoid is a rare adverse event following administration of secukinumab.

Single-cell sequencing reveals distinct immune cell features in cutaneous lesions of pemphigus vulgaris and bullous pemphigoid.

Bullous pemphigoid (BP) and pemphigus vulgaris (PV) are two common subtypes of autoimmune bullous disease (AIBD). The key role of circulating autoreactive immune cells contributing to skin damage of AIBD has been widely recognized. Nevertheless, the immune characteristics in cutaneous lesions remain unclear. Here, we performed single-cell RNA sequencing (scRNA-seq) and single-cell VDJ sequencing (scRNA-seq) to generate transcriptional profiles for cells and T/B cell clonetype in skin lesions of BP and PV. We found that the proportions of NK&T, macrophages/ dendritic cells, B cells, and mast cells increased in BP and PV lesions. Then, BP and PV cells constituted over 75% of all myeloid cell subtypes, CD4+ T cell subtypes and CD8+ T cell subtypes. Strikingly, CD8+ Trm was identified to be expanded in PV, and located in the intermediate state of the pseudotime trajectory from CD8+ Tm to CD8+ Tem. Interestingly, CD8+ Tem and CD4+ Treg highly expressed exhaustion-related genes, especially in BP lesions. Moreover, the enhanced cell communication between stromal cells and immune cells like B cells and macrophages/ dendritic cells was also identified in BP and PV lesions. Finally, clone expansion was observed in T cells of BP and PV compared with HC, while CD8+ Trm represented the highest ratio of hyperexpanded TCR clones among all T cell subtypes. Our study generally depicts a large and comprehensive single-cell landscape of cutaneous lesions and highlights immune cell features in BP and PV. This offers potential research targets for further investigation.

Lichen planus pemphigoides with predominant mucous membrane involvement: a series of 12 patients and a literature review.

Background: Lichen planus pemphigoides (LPP), an association between lichen planus and bullous pemphigoid lesions, is a rare subepithelial autoimmune bullous disease. Mucous membrane involvement has been reported previously; however, it has never been specifically studied. Methods: We report on 12 cases of LPP with predominant or exclusive mucous membrane involvement. The diagnosis of LPP was based on the presence of lichenoid infiltrates in histology and immune deposits in the basement membrane zone in direct immunofluorescence and/or immunoelectron microscopy. Our systematic review of the literature, performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, highlights the clinical and immunological characteristics of LPP, with or without mucous membrane involvement. Results: Corticosteroids are the most frequently used treatment, with better outcomes in LPP with skin involvement alone than in that with mucous membrane involvement. Our results suggest that immunomodulators represent an alternative first-line treatment for patients with predominant mucous membrane involvement.

Targeting antibody-mediated complement-independent mechanism in bullous pemphigoid with diacerein.

BACKGROUND: Bullous pemphigoid (BP) is an antibody-mediated blistering disease predominantly affecting the elderly. The pathogenesis involves both complement-dependent and complement-independent mechanisms. The therapeutic potential of targeting complement-independent mechanism has not yet been determined. The mainstay of treatment, corticosteroid, has many side effects, indicating the needs of better treatments. OBJECTIVE: We tempted to establish an in vitro model of BP which resembles complement-independent mechanism and to examine the therapeutic potential of a novel anti-inflammatory agent, diacerein. METHODS: Cultured HaCaT cells were treated with purified antibodies from BP patients, with or without diacerein to measure the cell interface presence of BP180, protein kinase C, and the production of proinflammatory cytokines. An open-label, randomized, phase 2 trial was conducted to compare topical diacerein and clobetasol ointments in patients with mild-to-moderate BP (NCT03286582). RESULTS: The reduced presentation of BP180 at cell interface after treating with BP autoantibodies was noticed in immunofluorescence and western blotting studies. The phenomenon was restored by diacerein. Diacerein also reduced the autoantibody-induced increase of pro-inflammatory cytokines. Reciprocal changes of BP180 and protein kinase C at the cell interface were found after treating with BP autoantibodies. This phenomenon was also reversed by diacerein in a dose-dependent manner. The phase 2 trial showed that topical diacerein reduced the clinical symptoms which were comparable to those of topical clobetasol. CONCLUSION: Diacerein inhibited BP autoantibody-induced reduction of BP180 and production of proinflammatory cytokines in vitro and showed therapeutic potential in patients with BP. It is a novel drug worthy of further investigations.

Low pH condition impairs BP-IgG binding to the basement membrane zone.

Bullous pemphigoid (BP), an autoimmune subepidermal blistering disease, shows tense blisters associated with urticarial erythema. Tissue-bound Immunoglobulin G (IgG) at the basement membrane zone (BMZ) detected by direct immunofluorescence (DIF) is strong evidence for a diagnosis of BP. The sensitivity of DIF is higher in complement component 3 (C3) than in IgG, but the reason for this different sensitivity is not fully understood. In this study, we performed several ex vivo studies to investigate the possible mechanism of IgG negativity and C3 positivity at the BMZ by DIF in some BP cases. First, sera from BP patients showing IgG negativity by DIF were found to clearly react to the BMZ in their own DIF skin samples. Next, indirect immunofluorescence (IIF) was performed using sera diluted with different pH phosphate-buffered saline (PBS), pH 7.4, 6.0, and 3.0. Patients' sera diluted with pH 7.4 PBS showed linear staining at the BMZ, but sera diluted with pH 6.0 PBS and pH 3.0 PBS showed lower fluorescence intensities. Finally, sections of skin from BP patients were pre-incubated with different pH PBS (pH 3.0, 6.0, and 7.4), followed by staining with anti-human IgG and C3. The fluorescence intensities were notably lower for IgG and C3 that had been pre-incubated with pH 3.0 PBS and pH 6.0 PBS than for IgG and C3 that had been pre-incubated with pH 7.4 PBS. These results suggest that a low pH condition hinders the binding of autoantibodies to the BMZ, that is, the drop in tissue pH induced by inflammation inhibits autoantibodies from depositing at the BMZ. Furthermore, the drop in tissue pH causes tissue-bound autoantibodies to detach from the BMZ. Complement fragments are activated not only on IgG but also on the cell surface of cells close to IgG during complement activation. IgG may detach from the BMZ under low pH condition induced by inflammation, but some complement fragments remain at the BMZ. These phenomena may help to explain why C3 is more sensitive than IgG when DIF is used to diagnose BP.

The Syk Inhibitor Entospletinib Abolishes Dermal-Epidermal Separation in a Fully Human Ex Vivo Model of Bullous Pemphigoid.

Bullous pemphigoid (BP) is an autoantibody-mediated blistering skin disease characterized by local inflammation and dermal-epidermal separation, with no approved targeted therapy. The Syk tyrosine kinase is critical for various functions of the immune response. Second-generation Syk inhibitors such as entospletinib are currently being tested for hematological malignancies. Our aim was to test the effect of entospletinib in a fully human model system of BP. Incubating BP serum-treated human frozen skin sections with normal human granulocytes and fresh plasma triggered dermal-epidermal separation that was dependent on complement, NADPH oxidase, and protease activity. Entospletinib dramatically reduced dermal-epidermal separation with a half-maximal inhibitory concentration of ≈16 nM. Entospletinib also reduced ROS production, granule release, and spreading of human granulocytes plated on immobilized immune complexes consisting either of a generic antigen-antibody pair or of recombinant collagen type XVII (BPAg2) and BP serum components (supposedly autoantibodies). However, entospletinib did not affect the chemotactic migration of human granulocytes or their responses to nonphysiological stimulation by phorbol esters. Entospletinib had no effect on the survival of granulocytes either. Taken together, entospletinib abrogates dermal-epidermal separation, likely through inhibition of granulocyte responsiveness to deposited immune complexes. Entospletinib or other Syk inhibitors may provide therapeutic benefits in BP.

A case of anti-laminin γ1 (p200) pemphigoid developed after dipeptidyl peptidase-4 inhibitor administration.

A 73-year-old man with diabetes mellitus was referred to our department for ultraviolet treatment for erythematous skin lesions with itching. On dipeptidyl peptidase-4 inhibitor (DPP-4i) sitagliptin (Januvia®) for diabetes mellitus, the erythematous skin lesions appeared and spread to the whole body. At the initial visit, erythema multiforme-like skin lesions with crusts were observed on the trunk and extremities, and the patient was suspected to have drug eruption. Histopathology demonstrated eosinophilic infiltration in the superficial dermis and inflammatory cell infiltration in the epidermis. Sitagliptin was discontinued, and erythematous lesions improved with oral prednisolone. Thereafter the patient was treated with phototherapy and  betamethasone sodium phosphate infusion for residual prurigo. However, blistering skin lesions appeared 5 months later. Histopathological findings were subepidermal blisters with eosinophilic abscess, and bullous pemphigoid was suspected. CLEIAs for autoantibodies to desmoglein 1 (Dsg1), Dsg3 and BP180 were negative. Direct immunofluorescence showed linear depositions of immunoglobulin G (IgG) and C3 at the epidermal basement membrane zone, and indirect immunofluorescence detected IgG anti-epidermal basement membrane zone antibodies, reacting with the dermal side of 1M NaCl-split normal human skin. IgG antibodies reacted with 200 kDa laminin γ1 (p200) by immunoblotting using dermal extracts. These results indicated that this patient was diagnosed with anti-laminin γ1 (p200) pemphigoid developed after DPP-4i administration. Although reports of DPP-4i-related bullous pemphigoid have accumulated, cases of anti-laminin γ1 (p200) pemphigoid developed after DPP-4i administration are rarely reported.

Comparison of gut microbiota dysbiosis between pemphigus vulgaris and bullous pemphigoid.

OBJECTIVE: Pemphigus vulgaris (PV) and bullous pemphigoid (BP) are two prevalent bullous diseases. Previous studies found that the antibodies of BP could be expressed in the intestinal epithelium and BP was tightly related to inflammatory bowel disease. Therefore, gut microbiota might also play an important role in bullous disease. However, the specific relationship between gut microbiota and bullous diseases remains unknown. Our study aimed to investigate the potential role of gut microbiota in the development and progression of different bullous diseases. METHODS: We conducted a prospective and observational cohort study at Peking Union Medical College Hospital. Untreated BP and PV patients were recruited, along with healthy controls (HC) who were spouses or caregivers of these patients. Fecal samples were collected, followed by 16S rRNA gene sequencing. Bioinformatics analyses were performed to assess the composition and function of gut microbiota. RESULTS: A total of 38 HC, 32 BP, and 19 PV patients were enrolled in this study. Compared to HC, BP, and PV exhibited a distinct gut microbiota composition, especially BP. The gut microbiota changes were mainly observed in the phylum Bacteroidetes, Firmicutes, and Proteobacteria. The ratio of Faecalibacterium to Escherichia-Shigella (F/E ratio) had a considerable predictive value (AUC: 0.705) for recognizing BP from PV. The levels of Faecalibacterium and Enterobacter were correlated to the anti-BP 180 and anti-desmoglein 3. Microbial functional prediction revealed elevated activity in pathways related to gut microbiota translocation significantly increased in BP patients, indicating a potential pathogenetic role in BP. CONCLUSIONS: Our study suggests that the composition of gut microbiota is specific in different bullous diseases and the role of gut microbiota differs. Gut microbiota could help distinguish BP and PV, and might play a role in the pathogenesis of different bullous diseases.

Survey: Preferred practice patterns in the diagnosis of mucous membrane pemphigoid amongst cornea specialists.

PURPOSE: To evaluate preferred diagnostic tools and treatment decision-making factors in cases suspicious of mucous membrane pemphigoid (MMP) amongst ophthalmologists and cornea specialists. METHODS: Web-based survey, consisting of 14 multiple choice questions, posted to the Cornea Society Listserv Keranet, the Canadian Ophthalmological Society Cornea Listserv, and the Bowman Club Listserv. RESULTS: One hundred and thirty-eight ophthalmologists participated in the survey. Eighty-six percent (86%) of respondents were cornea trained and practiced in either North America or Europe (83%). Most respondents (72%) routinely perform conjunctival biopsies for all suspicious cases of MMP. For those who do not, fear that biopsy will exacerbate inflammation was the most common reason to defer investigation (47%). Seventy-one percent (71%) performed biopsies from perilesional sites. Ninety-seven percent (97%) ask for direct (DIF) studies and 60% for histopathology in formalin. Most do not recommend biopsy at other non-ocular sites (75%), nor do they perform indirect immunofluorescence for serum autoantibodies (68%). Immune-modulatory therapy is started following positive biopsy results for most (66%), albeit most (62%) would not let a negative DIF influence the choice of starting treatment should there be clinical suspicion of MMP. Differences in practice patterns as they relate to level of experience and geographical location are contrasted to the most up-to-date available guidelines. CONCLUSION: Responses to the survey suggest that there is heterogeneity in certain practice patterns for MMP. Biopsy remains an area of controversy in dictating treatment plans. Identified areas of need should be targeted in future research.

Tissue Remodeling in Ocular Mucous Membrane Pemphigoid.

Purpose: Ocular mucous membrane pemphigoid (OcMMP) is a rare eye disease characterized by relapsing-remitting or persisting long-lasting inflammatory events associated with progressive scarring. Despite long-term immunomodulating therapy, abnormal fibrosis keeps worsening in patients with OcMMP. This study investigates the fibrotic process in patients with OcMMP, as well as the critical role of the epithelium in modulating the local fibrosis. Methods: In this prospective, observational pilot study, patients affected by long-lasting OcMMP were compared with age- and gender-matched healthy controls. Clinical grading was assessed, and conjunctival biopsy and impression cytology were performed. Conjunctival samples were used for quantifying the expression of transcripts regulating the inflammatory and fibrogenic processes. Results: Ocular surface clinical and functional markers worsened in patients with OcMMP with fibrotic disease progression. In more advanced disease stages, both impression cytologies and conjunctival biopsies revealed increased tissue remodeling and profibrotic markers (α-SMA and TGF-ß), and decreased levels of inflammatory markers (I-CAM1, IL-10, and IL-17). Increased epithelial expression of profibrotic markers and histological changes were detected. Conclusions: Chronic OcMMP is characterized by a progressive, aberrant self-sustaining fibrotic process that worsens clinical signs and symptoms. Conjunctival epithelial cells may transdifferentiate into myofibroblast-like phenotypes when chronically exposed to high levels of inflammation, as in the case of OcMMP. Tissue remodeling markers in OcMMP could be used as early diagnostic, prognostic, and therapeutic biomarkers, harvested in a non-invasive and painless procedure such as impression cytologies.