Adult-onset linear IgA bullous dermatosis: a retrospective single-center cohort study of 81 patients and literature review.

BACKGROUND: Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disorder that may be drug-induced or paraneoplastic. We aim to characterize features of LABD and determine differentiating factors among idiopathic, drug-induced, or malignancy-associated diseases. METHODS: We conducted a single-center retrospective chart review of adult patients with linear IgA bullous dermatosis at a large tertiary referral center and a literature review of adult linear IgA bullous dermatosis. RESULTS: Eighty-one patients were included in the study. Ten patients (12.3%) had comorbid malignancy and nine (11.1%) had inflammatory bowel disease. Median disease duration was significantly shorter in both drug-induced (1.2 vs. 48.8 months; P < 0.001) and malignancy-associated (1.7 vs. 48.8 months; P < 0.001) LABD compared with idiopathic LABD. Recurrent episodes occurred significantly more often in idiopathic LABD compared to those with drug-induced (76.1 vs. 11.5%; P < 0.001) or malignancy-associated disease (76.1 vs. 33.3%; P = 0.019). Time to diagnosis was significantly shorter in the drug-induced (0.2 vs. 5.4 months; P < 0.001) and malignancy-associated groups (0.7 vs. 5.4 months; P = 0.049) compared with idiopathic; similarly, time to improvement was significantly shorter in both drug-induced (0.4 vs. 3.0 months; P < 0.001) and malignancy-associated disease (1.1 vs. 3.0 months; P = 0.016). Clinical morphology was indistinguishable between groups. Limitations included retrospective data collection, data from tertiary referral centers, and limited racial and ethnic diversity. CONCLUSION: Screening for underlying malignancy, as well as for a predisposing medication or possibly inflammatory bowel disease, may be advisable in patients with LABD, particularly when it is newly diagnosed.

Molecular Tumor Board Case Series: Targeted Treatments For Cancer And Their Toxicities: Amivantamab-Induced Linear IgA Bullous Dermatosis.

In the era of targeted treatments based on next generation sequencing (NGS) analysis, clinicians must be diligent in aligning patients with treatments giving them the best chance of survival while weighing the risk of toxicity caused by agents targeting specific gene mutations. In this case, we describe a patient with Epidermal Growth Factor Receptor (EGFR) exon 20 insertion mutation positive recurrent lung adenocarcinoma who received amivantamab and experienced severe dermatologic toxicity.

Linear IgA bullous dermatosis in an acute myeloid leukemia patient: a rare case report.

Linear IgA bullous dermatosis (LABD) is a rare autoimmune bullous disease characterized by linear IgA deposition along the skin basal membrane. In children, LABD classically presents with a "cluster of jewels" appearance, whereas in adults the classic presentation is itchy papules with tense vesicles and bullae on an erythematous base. We report the case of a 41-year-old woman with LABD that we suspect was induced by acute myeloid leukemia presenting with multiple vesicles and bullae that coalesced, forming the typical clinical manifestation of LABD and confirmed with histopathological and direct immunofluorescence. The patient was treated with a combination of oral and topical corticosteroids with excellent results.

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 in the setting of angioimmunoblastic T-cell lymphoma.

We report an 80-year-old male developing linear IgA bullous dermatosis (LAD) in the setting of angioimmunoblastic T-cell lymphoma (AITL). This phenomenon is rare, as only three cases have been described in the literature. The pathophysiologic process can be attributed to dysregulation in somatic hypermutation and the expression of chemokine receptor 5 in AITL, contributing to increased IgA. Immunoglobulin production resulting from clonal plasma cell expansion may be because of the B-cell promotional effect by neoplastic follicular helper T-cells. Beyond providing a pathophysiologic platform for AITL-associated LAD, we also briefly summarized prior cases. This report demonstrates the importance of considering LAD in the differential diagnosis for patients with a bullous eruption in the setting of AITL.

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.

Ulcerative colitis complicated with linear immunoglobulin A bullous dermatosis.

Linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare disorder involving subepidermal blistering characterised by IgA deposition along the basement membrane. The clinical features of LABD are variable but can include bullae, vesicles and erythematous lesions. Histopathology reveals formation of subepidermal bullae and linearly deposition of IgA in the basement membrane of the epidermis. LABD has been reported as a rare complication of ulcerative colitis (UC). We report the case of a young woman with UC complicated by LABD. The latter manifested as vesicles with erythema on almost the entire body. A biopsy of the skin lesions revealed linear IgA deposits in the basement membrane according to a direct immunofluorescence assay. Prednisolone administration resulted in clinical remission of UC but poor improvement of skin lesions. Oral administration of diaminodiphenyl sulfone led to improvement of blisters. Thereafter, abdominal and skin symptoms did not recur and she was discharged from hospital.

Linear IGA bullous dermatosis potentially triggered by vaccination.

Linear IgA bullous dermatosis (LABD) is a mucocutaneous autoimmune blistering disease affecting both adults and children. It is caused by IgA antibodies targeting multiple antigens along the basement membrane zone, leading to disruption of dermoepidermal junction and development of bullous lesions which often presents in characteristic arrangement. Although most LABD cases have been reported to be idiopathic, different triggers have been described, including several drugs and infection. However, the occurrence of vaccine-induced cases of LABD is not widely known and accepted due to the few reports available. We present two cases of LABD occurred following different triggers, rising the suspicion for a possible pathogenetic role of vaccines.

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.

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.

Dermatosis IgA lineal asociada a sífilis secundaria / Linear IgA bullous dermatosis associated secondary syphilis

La dermatosis IgA lineal del adulto es una enfermedad que pertenece al grupo de las dermatosis ampollares adquiridas. De etiología desconocida e infrecuente, se presenta en adultos mayores y se asocia a múltiples fármacos, neoplasias y enfermedades autoinmunes e infecciosas. Se presenta el caso de un paciente con una dermatosis IgA lineal asociada a una sífilis secundaria.

Linear bullous IgA dermatosis of adult is a disease that belongs to the group of acquired bullous dermatoses. It is of unknown aetiology and infrequent in adults and is associated with drugs, neoplasms, autoimmune and infectious diseases. We present a case of a male patient in whom a linear IgA dermatosis and secondary syphilis coexist.

Bullous lesions in a young adolescent postrenal transplant.

Kidney transplant recipients frequently suffer from skin infections and malignancies. New dermatosis can appear after transplantation. Although children are maintained on varying degrees of chronic immunosuppression, there is still a possibility of autoimmune blistering skin conditions, which can pose a diagnostic challenge in terms of clinical presentation. Histopathology of skin lesions is very important which helps in correct diagnosis and prompt treatment. We report an extremely rare case of linear IgA dermatosis in a child who was postrenal transplant and treated successfully with dapsone and steroids.

Autoantibody Profile of a Cohort of 54 Italian Patients with Linear IgA Bullous Dermatosis: LAD-1 Denoted as a Major Auto-antigen of the Lamina Lucida Subtype.

Linear IgA bullous dermatosis (LABD) is characterized by presence of multiple IgA autoantibodies, and a comparatively lesser number of IgG antibodies, directed against different hemidesmosomal antigens. The main autoantigens are LAD-1, LABD-97, BP180 and BP230, type VII collagen and laminin 332. We retrospectively studied the serology of 54 Italian patients with LABD using enzyme-linked immunosorbent assay (ELISA), immunoblotting assay, and indirect immunofluorescence on monkey oesophagus and salt-split skin. Among these, indirect immunofluorescence of salt-split skin elicits the greatest sensitivity. Sixty-three percent of the sera were observed to be positive, with a lamina lucida pattern observed in 48%, a sub-lamina densa pattern in 2% and a mixed pattern in 13% of the cases. IgA reactivity to LAD-1 on immunoblotting was found in 52% of sera, to BP180-NC16A by ELISA in 32% and to BP230 in 26%. Only 17% of patients possessed circulating IgG autoantibodies. LAD-1 was determined to be a major autoantigen of the lamina lucida subtype. Combined serological assays demonstrated a high sensitivity (82%), suggesting that this approach could support diagnosis when a biopsy is not feasible or direct immunofluorescence results are negative.

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.

A Case of Linear IgA Bullous Dermatosis Induced by Aspirin Therapy.

Linear IgA bullous dermatosis (LABD) is a rare autoimmune blistering disease that may be triggered by some diseases and medications. For the latter one, non-steroidal anti-inflammatory drugs (NSAIDs) have been identified as one of the potential causative agents to develop LABD. Here, a rare case of drug-induced LABD is introduced. A 13-month-old Iranian boy presented with a history of generalized blisters, displaying the classic "string of pearls" sign who was eventually diagnosed as a case of LABD. In his admission, he was diagnosed whit Mucocutaneous lymph node syndrome and treated with aspirin.  Some features like appearing the characteristic lesions one week following the administration of aspirin, rapid clearance of lesions after the withdrawal of the drug, and reappearance of new lesions after readministration of aspirin were highly suggestive of aspirin-induced LABD. To establish the diagnosis, we used the "Naranjo probability score" which determined the probable causative role of aspirin. The diagnosis was confirmed by showing the positive IgA deposition in the basement membrane zone in a direct immunofluorescence study of the skin biopsy. The child was treated with dapsone with dramatical response to the drug.