Case report: A case of epidermolysis bullosa acquisita with IgG and IgM anti-basement membrane zone antibodies relapsed after COVID-19 mRNA vaccination.

We report a case of autoimmune bullous disease (AIBD) with IgG and IgM autoantibodies against epidermal basement membrane zone (BMZ), which showed recurrence of mucocutaneous lesions after coronavirus disease 2019 (COVID-19) mRNA vaccination. A 20-year-old Japanese woman with a 4-year history of epidermolysis bullosa acquisita (EBA) presented to our clinic. She noticed fever and rash on the same day and visited at our hospital 2 days later. Physical examination revealed blisters, erosions and erythema on the face, shoulder, back, upper arms, and lower lip. A skin biopsy from the forehead showed subepidermal blister. Direct immunofluorescence showed linear depositions of IgG, IgM, and C3c in the epidermal BMZ. By indirect immunofluorescence of 1M NaCl-split normal human skin, circulating IgG autoantibodies were bound to the dermal side of the split at 1:40 serum dilution, and circulating IgM antibodies were bound to the epidermal side of the spilt. After the increase of prednisolone dose to 15 mg/day, the mucocutaneous lesions resolved in a week. The present case is the first case of possible EBA with IgG and IgM anti-BMZ antibodies, in which the mucocutaneous lesions were recurred after COVID-19 mRNA vaccination. Clinicians should be aware that bullous pemphigoid-like AIBDs, including EBA and IgM pemphigoid, might be developed after COVID-19 mRNA vaccination.

Simultaneous development of generalized pustular psoriasis and pemphigoid with multiple autoantibodies in a complete responder of pembrolizumab for lung cancer.

Patients with psoriasis vulgaris have a higher incidence of pemphigoid than the general population. However, there are only a few concise reports on the coexistence of generalized pustular psoriasis (GPP) and pemphigoid. The authors describe a rare case of the simultaneous development of GPP and pemphigoid with multiple autoantibodies (i.e., BP180-C-terminal, 200-kDa protein, and laminin 332 proteins) in a complete responder of immune checkpoint inhibitor (ICI) treatment for lung cancer. Anti-interleukin 17 inhibitors for the GPP and oral corticosteroids at 10 mg/day for the pemphigoid effectively achieved remission in both diseases. It may not be uncommon to detect multiple autoantibodies in patients with pemphigoid; however, the detection of autoantibodies to more than three antigens in a single patient is relatively rare. In the current patient, the severe inflammation of GPP might have generated multiple autoantibodies. In addition, although pembrolizumab achieved a complete response and was discontinued 9 months before the onset of GPP and pemphigoid, the ICI might have affected the development of the two diseases. This case report adds useful information to the limited knowledge regarding the coexistence of GPP and pemphigoid, and aids in a better understanding of the pathological mechanisms and treatment options for such patients. Furthermore, the possibility that more patients may develop multiple autoimmune and autoinflammatory diseases in the era of ICIs should be recognized.

[Refractory esophageal stricture of esophageal mucous membrane pemphigoid after allogeneic hematopoietic stem cell transplantation].

Haploidentical allogeneic hematopoietic stem cell transplantation from her brother was performed on a 41-year-old lady with no prior history of pemphigoid to treat recurrent AML. On day 59 following transplantation, she experienced esophageal stenosis. During immunosuppressive therapy for graft vs. host disease, this condition was controlled with periodic esophageal dilatation (GVHD). Her esophageal stricture, which required periodic dilatation, grew worse after she stopped immunosuppressive therapy because of recurrent AML. The esophageal mucosa was easily hemorrhagic and desquamative. Histologic analysis revealed that the squamous cell layers had been divided. Indirect immunofluorescence was negative for IgG and positive for IgA on the epidermal layers, while direct immunofluorescence showed a linear deposition of IgG on the basement membrane zone. It was determined through immunoblotting utilizing recombinant protein of BP180 C-terminal domain that both IgG and IgA antibodies were present, supporting the diagnosis of mucous membrane pemphigoid with anti-BP180. After allogeneic transplantation, basal epidermal cell destruction by GVHD may result in autoimmune blistering disorders, which expose basement membrane proteins and antigen presentation. A similar mechanism could apply to our situation. For rare GVHD cases, a thorough histological diagnosis is required.

Subcorneal pustular dermatosis-type IgA pemphigus associated with multiple myeloma: A case report and literature review.

Immunoglobulin A (IgA) pemphigus, also known as intercellular IgA dermatosis, is a rare autoimmune bullous disease presenting with IgA anti-keratinocyte cell surface autoantibodies. Concomitant lymphoproliferative disorders have been reported in IgA pemphigus, including IgA monoclonal gammopathy of undetermined significance and IgA type multiple myeloma (MM). A 35-year-old Japanese woman with a 3-year history of pruritic papulovesicles on her lower legs and trunk was referred to our department. Histopathological examination revealed acantholytic blisters, and results of both direct and indirect immunofluorescence were negative. Direct and indirect immunofluorescence were still negative 3 years and 7 months later. Approximately 7 years after her first visit, the patient was re-referred to us because of disease exacerbation. Histopathological findings revealed subcorneal blistering with acantholysis, in which neutrophil-dominant inflammatory cells were present. Indirect immunofluorescence was positive for IgA on the epidermal cell surface and both desmoglein (Dsg) 1/3 and (Dsc) desmocollin 1-3 enzyme-linked immunosorbent assays (ELISAs) for IgA were positive. The histological findings and positive Dsc1 IgA ELISA led to the diagnosis of subcorneal pustular dermatosis (SPD)-type IgA pemphigus. Further examination revealed hyper-IgA globulinemia, increased serum IgA-κ protein, and increased plasma cells in the bone marrow, enabling the diagnosis of IgA type MM. Daratumumab, lenalidomide, and dexamethasone (DLd) therapy was effective for both the MM and the skin lesions, resulting in negative results on Dsg1/3 and Dsc1-3 IgA ELISAs. The association between IgA pemphigus and IgA type multiple myeloma remains unclear, and only seven cases including the present case have been reported. Literature review revealed associations between SPD-type and IgA κ chain in IgA pemphigus and MM, and that in most cases the onset or diagnosis of MM was simultaneous or occurred after the diagnosis of IgA pemphigus. Therefore, clinicians should be aware of the development of multiple myeloma during the clinical course of patients with SPD-type IgA pemphigus.

Anti-laminin 332 antibodies in graft-versus-host disease-associated bullous pemphigoid after allogeneic peripheral blood stem cell transplantation.

We report a 48-year-old woman with bullous pemphigoid (BP) with antibodies against the B3 subunit of laminin 332 after the development of graft-versus-host disease (GVHD). She was diagnosed with recurrent acute lymphoblastic leukemia at 40 years of age and underwent two rounds of allogeneic peripheral blood stem cell transplantations (PBST). Two and a half years after the second PBST, multiple tense blisters appeared on her face, hands, and lower legs. The diagnosis of BP was based on hematoxylin eosin and immunofluorescence staining and immunoblotting analyses. A combination regimen of topical corticosteroids (clobetasol propionate) and tetracycline/niacinamide was administered. Complete clinical resolution was achieved after four weeks of therapy without the use of immunosuppressive drugs. To maintain the graft-versus-tumor effect, topical corticosteroids and immunomodulatory drugs are preferred for BP after hematopoietic stem cell transplantation considering the risk of recurrence of hematologic malignancies. To date, there have been no reports of successful treatment of GVHD-associated BP without immunosuppressive drugs. Chronic GVHD is characterized by the production of autoantibodies. Furthermore, this autoimmune subepidermal blistering disease, BP, may be a manifestation of chronic GVHD. However, the precise mechanism of autoantibody production in chronic GVHD is not yet fully elucidated.

A Case of Anti-BP180-type Mucous Membrane Pemphigoid with IgG and IgA Autoantibodies Showing Distinct Reactivities.

Dear Editor, Mucous membrane pemphigoid (MMP) is an autoimmune blistering disease characterized by erosive mucosal lesions mainly on the oral and ocular mucosae (1). We report a case of oral and ocular anti-BP180-type MMP with variable IgG and IgA reactivities and underlying dementia. An 84-year-old Japanese man presented with a 4-year history of erosions in the oral cavity and on the conjunctivae, with progressive vision impairment. The medical history included benign prostatic hyperplasia, cataract, sinusitis, and dementia. Physical examination revealed erosions and white atrophic scars along the gingival mucosa and on the hard palate (Figure 1, a, b). Conjunctival inflammation and corneal scarring were also observed only on the left eye (Figure 1, c, d). No lesions were observed on the skin or on any other mucosae. A skin biopsy from the patient's oral mucosa showed lymphocytic infiltration in the superficial dermis without apparent subepithelial blister. Direct immunofluorescence showed linear depositions of IgG, IgA, and C3 at the epithelial basement membrane zone (Figure 1, e-g). Circulating IgG and IgA autoantibodies were not detected by indirect immunofluorescence of normal human skin, while circulating IgA, but not IgG, autoantibodies were bound to the epidermal side of 1M NaCl-split normal human skin at 1:10 serum dilution (Figure 1, h, i). Commercially available IgG enzyme-linked immunosorbent assays (ELISAs) of BP180 NC16a domain, BP230, and type VII collagen (MBL, Nagoya, Japan) showed negative results. IgG and IgA immunoblotting analyses of six different antigen sources, including BP180 C-terminal domain recombinant protein, were all negative. However, ELISA of full-length BP180 was slightly positive for IgG antibodies (index = 5.79; cut-off <4.64). Immunoblotting analysis of full-length BP180 was negative for both IgG and IgA antibodies (Figure 1, j, k). Immunoblotting analysis of hemidesmosome-rich fraction was negative for both IgG and IgA antibodies to integrin ß4 (Figure 1, l). Based mainly on the clinical and immunological findings, we established a diagnosis of MMP with IgG and IgA autoantibodies, likely reactive with BP180. Because the patient refused systemic treatments, we prescribed a mouth rinse sodium gualenate hydrate and eyedrops of fluorometholone and purified sodium hyaluronate, which did not improve the oral and ocular mucosal symptoms during the 8 month follow-up period (Figure 1, m, n). Both IgG and IgA autoantibodies in anti-BP180-type MMP tend to react with the C-terminal domain of BP180 (2), and IgG autoantibodies in 39.7% of MMP patients reactive with the epidermal side of split skin were reported to be positive with BP180 C-terminal domain (3). The full-length BP180 ELISA shows excellent sensitivity for diagnosing BP180-type MMP (4). The different IgG and IgA reactivities among various methods used in the present study may be attributed either to different methodologies (i.e., immunoblotting or ELISA) or to the different substrates, since BP180-type MMP targets various regions of BP180, including the NC16a domain, the C-terminal domain, and the intracytoplasmic region (5). Precise diagnosis for MMP by various immunological methods is critical, because urgent and extensive treatments are necessary for the ocular and laryngeal lesions, which may result in loss of eyesight and airway obstruction, respectively. Acknowledgments: We express our gratitude to Ms. Mako Mine and Dr. Daisuke Hayashi, Department of Dermatology, Osaka City University Graduate School of Medicine in Osaka, Japan for the HD-rich fraction immunoblotting analysis, and Dr. Yoshiaki Hirako, Division of Biological Science, Graduate School of Science, Nagoya University, Nagoya, Aichi, Japan for the preparation of the HD-rich fraction sample. This work was supported by JSPS KAKENHI Grant Number JP20k08684 and the Hirosaki University Research Support System.

Bullous pemphigoid and milia: prevalence and clinical laboratory findings in a Brazilian sample

Abstract Background: Bullous pemphigoid (BP) associated with milia lesions has been increasingly reported, but its prevalence has not been reported in a Brazilian BP population yet. Objectives: To describe the occurrence and clinical-laboratorial findings of BP-milia association in a southeastern Brazilian sample. Methods: A descriptive study based on the medical charts of 102 BP patients was accomplished. Clinical and laboratory data of BP-milia patients were compiled. Total serum IgE measurements, immunoblot assays based on basement membrane zone antigens, and HLA-DQ alleles typing were performed. Results: Milia was evident in 8 (7.8%) BP patients, five males, aged between 46 and 88 years. Increased total IgE levels were determined in 7 (87.5%) of the eight patients. In five of eight patients, immunoblotting showed IgG reactivity against the BP180-NC16a domain but not against collagen VII or laminin-332; it also revealed reactivity against the BP180 C-terminal domain or LAD-1, or both in four of them. The HLA-DQB1*03:01 and HLA-DQA1*05:05 alleles were identified in three of five BP-milia patients. Moreover, three of five cases presented the HLA-DQB1*06 allelic group. Study limitations: HLA determination was performed in five patients. Conclusions: Milia formation in BP patients seems to be less uncommon than previously admitted. Laboratory data revealed increased IgE; autoantibodies against the BP180 C-terminal domain or LAD-1, or both; and the HLA-DQB1*06 allelic group, described for the BP-milia association. Careful determination of antibodies against basement membrane zone molecules and HLA characterization in different populations may provide further insights into this association. © 2022 Sociedade Brasileira de Dermatologia. Published by Elsevier España, S.L.U. This is an open access article under the CC BY license (https://creativecommons.org/licenses/by/4.0/).

Bullous pemphigoid and milia: prevalence and clinical laboratory findings in a Brazilian sample.

BACKGROUND: Bullous pemphigoid (BP) associated with milia lesions has been increasingly reported, but its prevalence has not been reported in a Brazilian BP population yet. OBJECTIVES: To describe the occurrence and clinical-laboratorial findings of BP-milia association in a southeastern Brazilian sample. METHODS: A descriptive study based on the medical charts of 102 BP patients was accomplished. Clinical and laboratory data of BP-milia patients were compiled. Total serum IgE measurements, immunoblot assays based on basement membrane zone antigens, and HLA-DQ alleles typing were performed. RESULTS: Milia was evident in 8 (7.8%) BP patients, five males, aged between 46 and 88 years. Increased total IgE levels were determined in 7 (87.5%) of the eight patients. In five of eight patients, immunoblotting showed IgG reactivity against the BP180-NC16a domain but not against collagen VII or laminin-332; it also revealed reactivity against the BP180 C-terminal domain or LAD-1, or both in four of them. The HLA-DQB1*03:01 and HLA-DQA1*05:05 alleles were identified in three of five BP-milia patients. Moreover, three of five cases presented the HLA-DQB1*06 allelic group. STUDY LIMITATIONS: HLA determination was performed in five patients. CONCLUSIONS: Milia formation in BP patients seems to be less uncommon than previously admitted. Laboratory data revealed increased IgE; autoantibodies against the BP180 C-terminal domain or LAD-1, or both; and the HLA-DQB1*06 allelic group, described for the BP-milia association. Careful determination of antibodies against basement membrane zone molecules and HLA characterization in different populations may provide further insights into this association.

Dermoscopic furrow ink test of the palmar lesion in loricrin keratoderma.

Palmoplantar keratodermas (PPK) comprise a heterogeneous group of keratinization disorders that gradually progress during childhood, resulting in difficulties to establish a diagnosis and to identify a candidate gene for sequencing. Dermoscopic examination with staining of palmoplantar skin using a whiteboard marker, so-called "furrow ink test", could be a useful tool for differentiation between furrow and ridge in understanding the morphological characteristics of PPK. One of the striking features in autosomal dominant loricrin keratoderma (LK) is diffuse PPK with honeycomb pattern. In this study, we performed dermoscopic furrow ink test in a Japanese family of LK with the most frequent mutation c.684dup, p.Ser229Valfs*107 in the loricrin gene. The severe lesion revealed that irregular circular hyperkeratoses were aggregated and normal structures of furrows and ridges were disrupted. To accurately describe the nature of this dermoscopic patterned skin surface, we suggest that the condition could be termed as "irregular cobblestone appearance" rather than "honeycomb pattern". Regular cobblestone appearance to maintain parallel furrow structure was observed in early or mild hyperkeratotic lesions. Eccrine sweat glands that open on the surface of ridges nearly disappeared, resulting in hypohidrosis.

The Second Study of Clinical and Immunological Findings in Anti-laminin 332-Type Mucous Membrane Pemphigoid Examined at Kurume University-Diagnosis Criteria Suggested by Summary of 133 Cases.

Background: Recently, we published an article retrospectively summarizing the results in 55 anti-laminin 332 (LM332)-type mucous membrane pemphigoid (MMP) cases examined at Kurume University, which were diagnosed by strict inclusion criteria, including positive reactivity in direct immunofluorescence and absence of antibodies to non-LM332 autoantigens. However, indirect immunofluorescence using 1M-NaCl-split normal human skin (ssIIF) is also valuable for diagnosis of anti-LM332-type MMP. Methods: In this second study, we selected 133 anti-LM332-type MMP cases, which were diagnosed by our different inclusion criteria: (i) immunoglobulin G (IgG) deposition to basement membrane zone (BMZ) by direct immunofluorescence or IgG reactivity with dermal side of split skin by ssIIF, (ii) positivity for at least one of the three subunits of LM332 by immunoblotting of purified human LM332, and (iii) the presence of mucosal lesions. Clinical, histopathological, and immunological findings were summarized and analyzed statistically. Although these cases included the 55 previous cases, the more detailed study for larger scale of patients was conducted for further characterization. Results: Clinically, among the 133 patients, 89% and 43% patients had oral and ocular mucosal lesions, respectively, 71% had cutaneous lesions, and 17% had associated malignancies. Histopathologically, 93% patients showed subepidermal blisters. The sensitivities of ssIIF and direct immunofluorescence are similar but are significantly higher than indirect immunofluorescence using non-split human skin (both p < 0.001). In immunoblotting of purified LM332, patient IgG antibodies most frequently reacted with LMγ2 subunit (58%), followed by LMα3 (49%) and LMß3 (36%). Thirty-four percent patients recognized additional non-LM332 autoantigens. Statistical analysis revealed that autoantibodies against non-LM332 autoantigens might stimulate the production of anti-LMγ2 antibodies. Conclusions: This retrospective study further characterized in more detail the clinical and immunological features of 133 cases of anti-LM332-type MMP, in which the new diagnostic criteria without positive direct immunofluorescence reactivity were useful for the diagnosis. Higher frequency with anti-LMγ2 antibodies suggested more significant pathogenic role of this subunit. Additional autoantibodies to non-LM332 autoantigens detected in one-third of the patients may contribute to complexity in anti-LM332-type MMP, including the induction of anti-LMγ2 antibodies.

A gene-centric approach to biomarker discovery identifies transglutaminase 1 as an epidermal autoantigen.

Autoantigen discovery is a critical challenge for the understanding and diagnosis of autoimmune diseases. While autoantibody markers in current clinical use have been identified through studies focused on individual disorders, we postulated that a reverse approach starting with a putative autoantigen to explore multiple disorders might hold promise. We here targeted the epidermal protein transglutaminase 1 (TGM1) as a member of a protein family prone to autoimmune attack. By screening sera from patients with various acquired skin disorders, we identified seropositive subjects with the blistering mucocutaneous disease paraneoplastic pemphigus. Validation in further subjects confirmed TGM1 autoantibodies as a 55% sensitive and 100% specific marker for paraneoplastic pemphigus. This gene-centric approach leverages the wealth of data available for human genes and may prove generally applicable for biomarker discovery in autoimmune diseases.

A Case of Possible Concurrence of Dermatitis Herpetiformis and Linear Immunoglobulin A / Immunoglobulin G Bullous Dermatosis.

Dear Editor, Linear immunoglobulin (Ig) A bullous dermatosis (LABD), one subtype of subepidermal autoimmune bullous skin diseases (AIBDs), is characterized by linear deposit of only IgA along the basement membrane zone (BMZ) on direct immunofluorescence (DIF) (1,2). Patients showing linear deposits of both IgA and IgG are diagnosed with linear IgA/IgG bullous dermatosis (LAGBD) (3,4). Dermatitis herpetiformis (DH) is another type of subepidermal AIBD characterized by clinically pruritic erythematous skin lesions with vesicles on the elbows, knees, and buttocks with granular IgA deposits of IgA by DIF (5). In this study, we report a Japanese case of a patient who showed possible concurrence of DH and LAGBD based on clinical, histological, and immunological findings. A 72-year-old Japanese man who had a past history of dyslipidemia and resected lung cancer but was not taking any medicines, presented with a one-year history of blistering skin lesions. Physical examination revealed erythemas and peripherally arranged vesicles and erosions on the bilateral elbows, knees, and the buttock (Figure 1, a-c). Mucous membranes were not involved. The results of all laboratory tests were within normal ranges, except for increased serum IgA level 351 mg/dL (normal ranges; 46-260 mg/dL). Skin biopsy histopathologically showed subepidermal blisters infiltrated with neutrophils and eosinophils (Figure 1, d). DIF showed deposits of IgG, IgA, and complement component 3 along the BMZ mainly in granular but partially in a linear pattern (Figure 1, e-g). Circulating IgG (Figure 1, h) and IgA (Figure 1, i) autoantibodies were not detected by indirect immunofluorescence (IIF) of normal skin, however, circulating IgA (Figure 1, j) but not IgG (Figure 1, k) antibodies were bound to both the epidermal and dermal sides by IIF of 1M NaCl-split normal skin. Commercially available enzyme-linked immunosorbent assays (ELISAs) for BP180 NC16a domain, BP230, and type Vll collagen (MBL, Nagoya, Japan), showed negative results for both IgG and IgA antibodies. IgG in-house ELISA for full length BP180 was also negative. IgG and IgA immunoblotting analyses of different antigen sources, including normal human epidermal and dermal extracts, recombinant proteins of NC16a, and C-terminal domains of BP180 region, BP230, purified laminin 332, and concentrated culture supernatant of HaCaT cells for LAD-1, were all negative. IgA ELISAs of tissue- and epidermal-transglutaminases were negative (1.92 AU/mL and 20.98 AU/mL, respectively; normal range <22.0 AU/mL). The patient was successfully treated with only topical corticosteroids with occasional mild local relapses. Japanese DH is different from European DH in some respects, i.e., DH is very rare in Japan due to genetic/HLA difference, absence of celiac disease, and frequent fibrillar IgA deposition in DIF. Therefore, we believe that this case is interesting as a rare Japanese DH case with complicated conditions. The clinical and immunochemical characteristics in the present case were compatible for both DH and LAGBD. Clinical features of vesicles on erythemas on the knees and buttock suggested DH, while histopathological features were compatible with LAGBD but also with DH, DIF results suggested both LAGBD and DH, and the results of IIF of 1M NaCl-split skin suggested LAGBD. All biochemical studies for autoantigens were negative, which suggested DH. However, autoantigens are not clearly detected in many LAGBD cases, either. IgA anti-epidermal transglutaminase antibody, a DH marker, was negative, but the titer was relatively high but within normal range. Therefore, we considered that this case might have developed DH and LAGBD concurrently. However, there may be two other possibilities: [1] this case was DH and non-pathogenic circulating autoantibodies were secondary production, and [2] LAGBD cases may sometimes show granular-linear BMZ deposition of IgG and IgA. Future studies on similar cases are needed to clarify our speculations.