Eosinophil-rich linear IgA bullous dermatosis induced by mRNA COVID-19 booster vaccine.

We present a case of eosinophil-rich linear IgA bullous disease (LABD) following the administration of a messenger RNA COVID-19 booster vaccine. A 66-year-old man presented to the emergency department with a 3-week history of a pruritic blistering rash characterized by fluid-filled bullae and multiple annular and polycyclic plaques. He was initially diagnosed with bullous pemphigoid based on a biopsy showing a subepidermal blister with numerous eosinophils. However, direct immunofluorescence studies showed linear IgA and IgM deposition along the basement membrane zone with no immunoreactivity for C3 or IgG. Additionally, indirect immunofluorescence was positive for IgA basement membrane zone antibody. The patient was subsequently diagnosed with LABD and initiated on dapsone therapy with resolution of his lesions at 3-month follow-up. This case illustrates the growing number of autoimmune blistering adverse cutaneous reactions from vaccination. Dermatopathologists should be aware that features of autoimmune blistering diseases can overlap and may not be distinguishable based on these histopathological findings alone. Confirmation with direct immunofluorescence and/or serological studies may be necessary for accurate diagnosis.

Linear IgA bullous dermatosis associated with immunotherapy.

Linear IgA bullous dermatosis (LABD) is a rare mucocutaneus blistering autoimmune disease caused by IgA autoantibodies. Its clinical manifestation can be indistinguishable from bullous pemphigoid (BP), a similar autoimmune bullous disease caused by IgG and IgE autoantibodies. Although BP has been reported as an adverse cutaneous effect of immunotherapy, LABD has rarely been associated with immunotherapy in the literature. We present the case of a 67-year-old woman with metastatic ovarian cancer receiving anti-PD1 and anti-CTLA4 with new onset pruritic tense bullae to the trunk, hands, elbows (in annular distribution) that occurred after immunotherapy. Skin biopsy showed subepidermal blister with abundant neutrophils on H&E histology, and linear IgA staining at the basement membrane on direct immunofluorescence consistent with the diagnosis of LABD. The condition did not improve on initial prednisone taper, but blisters rapidly resolved a few days after initiation of dapsone therapy. We favor that our patient's LABD is secondary to her immunotherapy. Our case highlights the importance of both H&E histology and direct immunofluorescence in diagnosis of blistering disorders in patients on immunotherapy to help in choosing the most effective treatment option in an attempt to avoid discontinuation of immunotherapy.

Assessment of Clinical and Laboratory Use of the Cutaneous Direct Immunofluorescence Assay.

IMPORTANCE: Dermatologists submit direct immunofluorescence (DIF) biopsies on a daily basis, using an assay detecting immunoreactant deposition with a panel that has traditionally comprised immunoglobulin (Ig) G, IgA, IgM, C3, and fibrin, with or without albumin antibodies. OBJECTIVES: To evaluate and compare the frequency of immunoreactants in DIF biopsies submitted over an 8-year period and assess use by dermatologists based on clinical impression. DESIGN, SETTING, AND PARTICIPANTS: A quality improvement study was conducted in a community outreach reference laboratory associated with a large academic medical center. Results of 2050 consecutive DIF skin biopsies submitted to the laboratory between April 1, 2012, and June 12, 2020, were analyzed by final pathologic diagnosis and antibody subtype positivity, in comparison with clinical impression. Biopsies in which the submitting physician had not performed the biopsy were excluded. MAIN OUTCOMES AND MEASURES: Histopathologic findings and the results of DIF biopsies using the standard 6-antibody panel were evaluated in correlation with the submitted clinical diagnosis to assess immunoreactivity of the assay. RESULTS: Of 2050 DIF biopsies submitted, 367 (17.9%) were positive; IgG, IgA, and C3 alone identified all primary immunobullous disease cases (pemphigoid, pemphigus, linear IgA, and dermatitis herpetiformis), and IgA, C3, and fibrin antibodies alone identified all vasculitis cases. A panel of IgG, IgA, IgM, and fibrin identified all cases of lupus erythematosus. DIF results were positive in less than half of cases of hematoxylin and eosin biopsy-confirmed lupus erythematosus (23 of 47 [49%]). A total of 247 biopsies were submitted for clinical diagnoses not optimally supported on DIF: lichen planus, porphyria, and connective tissue disease. CONCLUSIONS AND RELEVANCE: The findings of this study suggest that there is a knowledge gap among dermatologists relating to the opportunity for high-value, cost-conscious use of DIF. The practice of reflexive antibody testing using a 6-antibody panel for all DIF biopsies is likely unnecessary. DIF protocols tailored to the clinical diagnosis may enhance cost-effectiveness without loss of test sensitivity or specificity.

Linear IgA dermatosis in association with angioimmunoblastic T-cell lymphoma infiltrating the skin: A case report with literature review.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive form of peripheral T-cell lymphoma, characterized by systemic symptoms, diffuse lymphadenopathy, hepatosplenomegaly and immunodysregulation. Half of AITL is associated with cutaneous symptoms, but only few cases with bullous eruption have been described. Association with a linear IgA dermatosis is extremely rare. Linear IgA dermatosis can be idiopathic, or linked with drug intake or neoplastic disorders. Some cases of linear IgA dermatosis presenting as toxic epidermal necrolysis (TEN) have been described, most of them being drug induced. We here present the case of a 72-year-old man recently diagnosed with AITL who developed a bullous eruption, presenting as TEN. Histopathology showed deep cutaneous involvement of the lymphoma with a sub-epidermal blistering and direct immunofluorescence revealed a heavy IgA linear deposit on the dermal-epidermal junction. A diagnosis of linear IgA dermatosis associated with cutaneous involvement of an angioimmunoblastic T-cell lymphoma was made. Chemotherapy and corticosteroids allowed cutaneous improvement but the patient died of his lymphoma shortly after.

Adult linear IgA bullous dermatosis: report of three cases

Abstract: Linear immunoglobulin A bullous dermatosis is a rare autoimmune disease that usually has an excellent prognosis in childhood; however, its control is more difficult in adults. It presents heterogeneous clinical manifestations and is frequently confused with other bullous diseases such as bullous pemphigoid and Duhring's dermatitis herpetiformis. Dermatologists' awareness of this disease contributes to early diagnosis and appropriate treatment. We thus report three cases of linear immunoglobulin A dermatosis in adults.

Previously misdiagnosed linear IgA dermatosis resolved with dapsone.

This is the case of a 25-year-old African American woman with a 3-week history of itching with burning, blistering lesions on her torso and extremities. Medical history was unremarkable. Medical treatments included three visits to urgent care, where she was treated with antivirals, oral and topical steroids, antibiotics and antifungals unsuccessfully. We performed a skin biopsy, and immunoflorescent studies revealed a linear deposition of IgA antigen at the basement membrane. The clinical diagnosis of linear IgA dermatosis (LAD) was established, with no eliciting cause, other than potential occupational exposure to Chlamydophila psittaci via her employment in a pet store. This is the first case to our knowledge to report such an association. However, confirmation of the exposure would only establish correlation, not causality. Resolution of symptoms and blisters was achieved with dapsone treatment. Accordingly, we highlight the crucial importance of reviewing exposures, along with the potential aetiology of LAD.

Diagnostic patterns and delays in autoimmune blistering diseases of the mouth: A cross-sectional study.

OBJECTIVES: To describe the natural history and factors influencing diagnostic delays among patients with autoimmune blistering diseases of the mouth. MATERIALS AND METHODS: In this cross-sectional study, 27 newly diagnosed patients were interviewed, and professional and patient delays were calculated. Disease extent and severity scores were determined using Saraswat scoring system. RESULTS: Twenty-seven patients were interviewed and examined. Patient delay was significantly longer in patients who had desquamative gingivitis as initial presentation, in those who tried to use home remedies and over the counter medications, and in patients with less severe disease. Most patients (n = 21 [77.7%]) made more than one consultation, and the mean time needed to reach a definitive diagnosis (i.e. professional delay) was 83.2 ± 21.4 days (range from 21 to 130 days). Professional delay was significantly correlated with the number of previous consultations (r = .78) and was significantly longer in patients who had desquamative gingivitis as initial presentation. CONCLUSION: Diagnosis of oral blistering diseases is often delayed. Diagnostic delay is more common in patients presenting with desquamative gingivitis and those with less severe disease. Improving patients and healthcare professionals' awareness about oral blistering diseases might help reduce diagnostic delay.

Vancomycin Mediates IgA Autoreactivity in Drug-Induced Linear IgA Bullous Dermatosis.

Vancomycin (VCM) is known to induce linear IgA bullous dermatosis (LAD). However, in contrast to conventional LAD, in which circulating IgA autoantibodies against basement membrane proteins are commonly detected, patient sera from VCM-induced LAD yields negative results in indirect immunofluorescence microscopy, and the targeted autoantigen remains undetermined. By using sera from a typical patient with VCM-induced LAD, we identified that co-incubation of sera with VCM resulted in linear IgA deposition at the basement membrane zone by indirect immunofluorescence. Patient sera reacted with the dermal side of 1 mol/L NaCl-split skin and with the recombinant noncollagenous (i.e., NC1) domain of type VII collagen by both immunoblot and ELISA in the presence of VCM. The investigation of an additional 13 patients with VCM-induced LAD showed that 10 out of the 14 sera (71.4%) reacted with the NC1 domain of type VII collagen by ELISA when spiked with VCM, whereas only 4 (28.6%) tested positive without it. The enhancement of reactivity to NC1 by VCM, as determined by optical density via ELISA, was observed in 10 out of the 14 sera (71.4%). These findings indicate that type VII collagen is a target autoantigen in VCM-induced LAD and that VCM mediates IgA autoreactivity against type VII collagen, providing an insight into mechanisms involved in drug-induced autoimmune disease.

Case of shift from linear immunoglobulin A bullous dermatosis to pemphigus herpetiformis for a short period of time.

Pemphigus herpetiformis (PH) is a rare variant of pemphigus characterized by erythemas and vesicles, tending to present with annular-shaped lesions. Immunologically, immunoglobulin (Ig)G deposition at the keratinocyte cell surfaces is observed. Linear IgA bullous dermatosis (LABD) is a rare subepidermal blistering disease with linear IgA deposits at the epidermal basement membrane zone (BMZ). The annular-shaped skin lesions in PH mimic clinical manifestation of other autoimmune bullous diseases, including LABD, although PH and LABD have different immunological and histopathological features. Herein, we report the first case of a shift from LABD to PH. A 70-year-old Japanese man presented annular erythemas surrounded by vesicles on the trunk and extremities. Histopathological examination revealed subepidermal bullae and eosinophilic spongiosis. Direct immunofluorescence demonstrated linear IgA deposits at the epidermal BMZ. Immunoblot analyses of normal human epidermal and dermal extracts, supernatant of HaCaT cells, recombinant proteins of BP180 NC16a and C-terminal domains, and purified laminin-332 showed no reactivity for either IgG or IgA. IgG chemiluminescent enzyme immunoassays for desmogleins 1 and 3, and BP180 were all negative. These findings led to the diagnosis of sole LABD. Although oral prednisolone temporarily improved the skin lesions, annular erythema without vesicles remained. A new skin biopsy revealed subcorneal pustules with eosinophils, but no subepidermal bullae. Direct immunofluorescence revealed IgG and C3 deposition at the keratinocyte cell surfaces. IgG enzyme-linked immunosorbent assay for mammalian desmocollins 1-3 revealed desmocollin 1 reactivity. Based on these findings, we made a diagnosis of sole PH.

Trimethoprim-sulfamethoxazole-induced linear IgA bullous disease presenting as toxic epidermal necrolysis.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is an autoimmune blistering skin disorder characterized by linear IgA deposits along the dermoepidermal junction. Usually idiopathic, LABD can be drug-induced. OBJECTIVE: To report the atypical characteristics of a case of trimethoprim-sulfamethoxazole-induced LABD presenting as toxic epidermal necrolysis (TEN). METHODS: A 63-year-old woman treated with trimethoprim-sulfamethoxazole for Pneumocystis jirovecii infection developed a generalized maculopapular rash with herpetiform lesions, rosette-like lesions, and tense bullae with Nikolsky sign. RESULTS: Anti-basement membrane zone antibodies were negative, but immunoblot revealed a 160 kDa band corresponding to subepidermal class IgA desmoglein 1. Skin biopsy specimens revealed a subepidermal bulla and direct immunofluorescence showed linear IgA deposition along the basement membrane zone. A diagnosis of toxic epidermal necrolysis was excluded and replaced by trimethoprim-sulfamethoxazole-induced LABD. CONCLUSION: We report a case of trimethoprim-sulfamethoxazole-induced LABD with a 160 kDa IgA desmoglein 1 found by immunoblotting analysis, probably by epitope spreading.

Sublamina densa-type linear IgA bullous dermatosis with IgA autoantibodies specific for type VII collagen: a case report and clinicopathological review of 32 cases.

Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disorder characterized by linear deposits of IgA at the basement membrane zone(BMZ) and/or by circulating IgA anti-BMZ antibodies. Comparing with other immuno-bullous diseases, LABD represents a heterogeneous disease entitywith diversity of pathogenic IgA autoantibodies to different hemidesmosomal antigens and an association with malignancies and occasional drug use. We herein present an 82-year-old Japanese man with LABD, whose indirect immunofluorescence using 1M NaCl-split skin showed positive staining for IgA at the dermal side alone. Fluorescence overlay antigen mapping using laser scanning confocal microscopy (FOAM-LSCM) was employed to examine the in vivo bound patient's IgA, which was specific for type VII collagen (COL7), a prominent antigen of the sublamina densa. One year later, he developed malignant lymphoma, suggesting the diagnosis of paraneoplastic LABD. We reviewed 32 cases of sublamina-densa type LABD with anti-COL7 IgA antibodies thus far reported in the literature to compare the clinicopathological characteristics of this rare disease variant and emphasize that COL7 is the main autoantigen in sublamina densa disease.

Flame figures in linear IgA bullous dermatosis: a novel histopathologic finding.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is an autoimmune subepidermal blistering disease usually with a neutrophil rich inflammatory infiltrate, and characterized by linear IgA deposition at the basement membrane zone (BMZ), and neutrophil predominant dermal inflammation. We report a case of LABD with numerous eosinophils and flame figure formation, a unique histopathologic finding not previously reported. A 69-year-old woman presented with a rapidly progressive, intensely pruritic rash over forearms, breasts, axillae, hips, and thighs. Thelesions were comprised of annular vesicles and bullae with hemorrhagic crusts and erosions. The clinical differential diagnosis included bullous pemphigoid(BP), LABD, and epidermolysis bullosa aquisita (EBA). RESULTS: A biopsy from a bullous plaque on the wrist revealed a subepidermal blister with neutrophils and numerous eosinophils with flame figure formation.Direct immunofluorescent (DIF) microscopy revealed linear deposition of IgA at the BMZ. CONCLUSIONS: Although unusual, the combined findings supported a diagnosis of LABD. Increased eosinophils may be associated with drug-induced LABD and may explain the numerous eosinophils in our case. It is important to be aware of this finding as the pathology may easily be misdiagnosed as BP, or possibly bullousWells syndrome. This case emphasizes that combined clinical, pathologic, and DIF findings are essential in the diagnosis of bullous dermatoses.

Idiopathic linear IgA bullous dermatosis: prognostic factors based on a case series of 72 adults.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is a clinically and immunologically heterogeneous, subepidermal, autoimmune bullous disease (AIBD), for which the long-term evolution is poorly described. OBJECTIVES: To investigate the clinical and immunological characteristics, follow-up and prognostic factors of adult idiopathic LABD. METHODS: This retrospective study, conducted in our AIBD referral centre, included adults, diagnosed between 1995 and 2012, with idiopathic LABD, defined as pure or predominant IgA deposits by direct immunofluorescence. Clinical, histological and immunological findings were collected from charts. Standard histology was systematically reviewed, and indirect immunofluorescence (IIF) on salt-split skin (SSS) and immunoblots (IBs) on amniotic membrane extracts using anti-IgA secondary antibodies were performed, when biopsies and sera obtained at diagnosis were available. Prognostic factors for complete remission (CR) were identified using univariate and multivariate analyses. RESULTS: Of the 72 patients included (median age 54 years), 60% had mucous membrane (MM) involvement. IgA IIF on SSS was positive for 21 of 35 patients tested; 15 had epidermal and dermal labellings. Immunoelectron microscopy performed on the biopsies of 31 patients labelled lamina lucida (LL) (26%), lamina densa (23%), anchoring-fibril zone (AFz) (19%) and LL+AFz (23%). Of the 34 IgA IBs, 22 were positive, mostly for LAD-1/LABD97 (44%) and full-length BP180 (33%). The median follow-up was 39 months. Overall, 24 patients (36%) achieved sustained CR, 19 (29%) relapsed and 35% had chronic disease. CR was significantly associated with age > 70 years or no MM involvement. No prognostic immunological factor was identified. CONCLUSIONS: Patients with LABD who are < 70 years old and have MM involvement are at risk for chronic evolution.

Vancomycin-associated linear IgA disease mimicking toxic epidermal necrolysis

Abstract Linear IgA dermatosis is a rare subepidermal autoimmune blistering disease characterized by linear deposition of IgA along the basement membrane zone. In the last three decades, many different drugs have been associated with the drug-induced form of the disease, especially vancomycin. We report a case of vancomycin-induced linear IgA disease mimicking toxic epidermal necrolysis. The aim of this work is to emphasize the need to include this differential diagnosis in cases of epidermal detachment and to review the literature on the subject and this specific clinical presentation.

Linear IgA and IgG bullous dermatosis

Abstract Childhood linear immunoglobulin A dermatosis is a rare autoimmune vesiculobullous disease. It results in linear deposition of autoantibodies (immunoglobulin A) against antigens in the basal membrane zone, leading to subepidermal cleavage. Additional depositions of immunoglobulin G and complement-3 might occur. It is still debated whether concomitant findings of immunoglobulins A and G should be considered a subtype of this dermatosis or a new entity. Further studies are needed to recognize this clinical variant.

Vancomycin-induced linear IgA bullous dermatosis: associations.

UNLABELLED: Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disease. LABD is considered mostly idiopathic, butsome cases have been reported to be drug-induced, mainly associated with vancomycin (VCM).We present two cases of LABD possibly associated with VCM used for cardiac surgery prophylaxis; in the presented cases, the eruptions occurred only after VCM withdrawal, therefore leaving a question about the relationship between VCM and LABD in these cases.We reviewed previous reports of VCM-induced LABD and analyzed the following parameters: gender, age, recent medical history, concurrent medication, latency period, progression after withdrawal, time to resolution, treatment, and rechallenge. RESULTS: The causal relationship between VCM and LABD was often unclear; patients frequently had concurrent medication and symptoms frequently began and/or progressed after VCM withdrawal. Among the 46 reviewed patients in addition to our two cases (n=48), 20 (42%) had recent history of cardiac procedure, cardiac infection, congestive heart failure, or aortic aneurism. CONCLUSION: Further investigation is needed to ascertain the association between LABD, VCM, and heart disease.