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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 antiinflammatory 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.


INTRODUCTION
Linear IgA bullous dermatosis (LABD) is a rare skin bullous condition in young children and adults. The causes of LABD are unknown, it is considered to be an autoimmune disease. Certain medications can cause LABD. In these cases, the blisters appear after starting the medication and disappear after stopping it.
Other reported causative diseases include some systemic autoimmune and non-autoimmune diseases. [1][2][3][4][5][6] Patients have itchy tense blisters with a clear fluid, often arranged in clusters or rings so-called "cluster of jewels", "string of pearls" affecting the skin with occasional mucosal involvement. The diagnosis is usually confirmed with a skin biopsy. Special staining and direct immune fluorescence (DIF) show the deposition of the IgA in the skin along the basement membrane zone (BMZ). [1][2][3][4][5][6] The treatment of choice is dapsone with the main adverse effects of methemoglobinemia and hemolytic anemia. Other treatments include systemic and topical  corticosteroids, sulfapyridine, colchicine,  like  dicloxacillin,  oxacillin,  trimethoprim/  sulfamethoxazole,  flucloxacillin,  e  Immunosuppressants like cyclophosphamide cyclosporine, mycophenolate mofetil and immunoglobulin (IVIG) taken in patients respond to the above-mentioned drugs. [1][2][3][4][5][6][7][8] In the medical literature, there are only reports regarding the role of non-steroidal anti inflammatory drugs (NSAIDs) in the pathogenesis of LABD. 3 We report a new case of drug-induced LABD following the administration of aspirin.

CASE REPORT
A 13-month-old boy was referred to the clinic of Allergy and Immunology with a generalized blistering skin eruption. He was diagnosed as atypical mucocutaneous lymph node syndrome a history of high fever lasting for 10 days associated with non-purulent conjunctivitis, ESR=57, CRP=20 and dilated mild right coronary artery (RCA) and left coronary artery (LCA) without aneurysm in echocardiography. The patient was treated dose aspirin (80 mg/kg) and IVIG and discharged with daily use of low dose aspirin (5mg/kg) recommended for a two-week follow-up visit.
One week after the administration of patient started to develop generalized eruption as grouped tense blisters, localized initially in the perineum and testis and progressed to the trunk, face and extremities. Several vesicles were seen at the edge of the annular lesion, representing the classic "string of beads" sign ( Figure 1A   In the medical literature, there are only a few case steroidal antiin the pathogenesis of induced LABD old boy was referred to the clinic of generalized blistering skin eruption. He was diagnosed as atypical e according to history of high fever lasting for 10 days associated purulent conjunctivitis, ESR=57, CRP=20, and dilated mild right coronary artery (RCA) and left coronary artery (LCA) without aneurysm in echocardiography. The patient was treated with high and IVIG and discharged with (5mg/kg) and up visit. administration of aspirin, the patient started to develop generalized eruption as grouped tense blisters, localized initially in the perineum and testis and progressed to the trunk, face, vesicles were seen at the edge the classic "string of ar and plantar surfaces were not involved. There was no report of any mucosal involvement including eyes. Aspirin was discontinued as a possible culprit agent. Medical history and clinical examination ruled out the presence of common triggers of erythema multiform such as herpes virus infection. Tzank smear showed many neutrophils and some histiocytes without any pieces of evidence infection. Differential blood count was normal except thrombocytosis (possibly due to previous mucocutaneous lymph node syndrome period) without neutrophilia or eosinophilia. There was no change in liver function parameters. Serum levels of immunoglobulins including IgA were within normal limits. A skin biopsy was taken from a trunk lesion and in histopathological examination showed subepidermal bullae with predominantly eosinophils and some neutrophils entrapped in a fibrin network associated with perivascular lymphocytic infiltration and some interstitial eosinophils (Figure 2 C). DIF examination demonstrated linear deposits of IgA along the BMZ, without IgG and C3 deposits, consistent with a diagnosis of Linear IgA bullous dermatosis.
The child was treated with topical corticosteroid and dapsone (0.5 mg/kg/day) after measuring of glucose-6-phosphate dehydrogenase activity and slowly increased until 2 mg/kg/day. The characteristic lesions of LABD began to regress dramatically in The target lesions improved soon with some remaining post-inflammatory hyperpigmentations (PIH) ( Figure  1C). Dapsone, 2 mg/kg daily, is well tolerated by the patient and continued despite clearance of all lesions to prevent any possible relapse of the lesions ( Figure 1D).

A B C Linear IgA Bullous Dermatosis (LABD); "String of pearls" sign C) Disappearing lesions after treatment D) complete improved lesions after treatment with dapsone
Iran J Allergy Asthma Immunol, / 551 surfaces were not involved. There was no report of any mucosal involvement including eyes. Aspirin was discontinued as a possible culprit agent.
Medical history and clinical examination ruled out the presence of common triggers of erythema multiform such as herpes virus infection. Tzank smear showed many neutrophils and some histiocytes of herpes virus erential blood count was normal except thrombocytosis (possibly due to previous ucocutaneous lymph node syndrome in the sub-acute period) without neutrophilia or eosinophilia. There was no change in liver function parameters. Serum of immunoglobulins including IgA were within normal limits. A skin biopsy was taken from a trunk lesion and in histopathological examination showed subepidermal bullae with predominantly eosinophils and some neutrophils entrapped in a fibrin network iated with perivascular lymphocytic infiltration and some interstitial eosinophils (Figure 2 A, B and demonstrated linear deposits of IgA along the BMZ, without IgG and C3 deposits, consistent with a diagnosis of Linear IgA bullous The child was treated with topical corticosteroid mg/kg/day) after measuring of phosphate dehydrogenase activity and slowly mg/kg/day. The characteristic lesions of LABD began to regress dramatically in one week. The target lesions improved soon with some remaining inflammatory hyperpigmentations (PIH) (Figure mg/kg daily, is well tolerated by the patient and continued despite clearance of all lesions to f the lesions ( Figure 1D). Figure 2 In a one-month cardiology follow-up visit, aspirin was readministered to prevent any cardiac complications of mucocutaneous lymph node syndrome. Skin lesions reappeared in less than 72 hours that included new bullous lesions in the trunk and acral regions. Therefore, aspirin immediately discontinued again and dapsone continued.

DISCUSSION
Linear IgA Bullous Dermatosis (LABD) is a rare autoimmune bullous dermatosis, but the most common autoimmune bullous dermatosis in children. [2][3][4][5]8 The immune system produces IgA antibodies which are incorrectly and linear deposited in the top layer of the skin and can cause damage to the structure of the skin, as a result, a blister appears. 1,2,8 LABD may be triggered by some causes as prodromal diseases including upper airway or urinary tract infections, brucellosis, salmonella enteritis, immunization (varicella or influenza vaccine), systemic autoimmune diseases (systemic lupus erythematosus, psoriasis, rheumatoid arthritis, dermatomyositis, Crohn's disease, ulcerative colitis), malignancies (Hodgkin's disease, B cell lymphoma, Bladder cancer, esophageal cancer) and others. [1][2][3][4] Drugs such as antibiotics, analgesics, antihypertensives, antiepileptics, or immunosuppressants have been identified as potential causative agents to develop LABD. [1][2][3] Antibiotics and NSAIDs are most frequent in children. 4 Because LABD is clinically indistinguishable from other autoimmune bullous dermatoses, other differentials should be considered. 1,2,4 (Table  1).Diagnosis of LABD requires a high index of suspicion and early confirmation with dermopathologic studies and specific staining technics like DIF. [1][2][3]8 Histologically, subepidermal blisters are observed in association with neutrophilic and eosinophilic infiltration, which is also observed in bullous pemphigoid and dermatitis herpetiform. 1,2,4,5 Although, the clinical presentation with "string of pearls" appearance is highly characteristic for LABD, but a definitive diagnosis is based on DIF, which is pathognomonic for LABD, revealing linear deposits of IgA on the BMZ. 1,2,8 Mucosal involvement was seen in 45.5% children and 14.8% adult patients with LABD, but there is no mucosal involvement in our patient. 4,9 Early diagnosis is important for proper management because discontinuing the culprit drug is most crucial. 6 It may be challenging to identify the causative agent of LABD because many patients are treated with multiple drugs. 1,2,4 The use of the Naranjo algorithm to estimate the probability of adverse drug reaction can help in establishing the correct diagnosis. 3,6,10 In our presenting case, there were many findings highly suggestive of aspirin-induced LABD such as the appearance of characteristic lesions one week after administration of aspirin, rapidly clearance of the lesions after the withdrawal of the drug, lack of mucosal involvement, reappearing new lesions after readministration of aspirin and IgA deposition and not IgG and C3 in BMZ in DIF study. To establish the diagnosis of aspirin-induced LABD, we applied the Naranjo algorithm, based on the answer to 10 questions, to reach a correct "causality assessment" between the suspected drug (aspirin) and the adverse event. Naranjo probability scale implies an adverse drug reaction score of <2: doubtful; 2 -4: possible; 5 -8: probable; >9: definite. 10 We achieved a score of 6 in this case which determined the probable causative role of aspirin.
Up to date, there are only a few case reports of NSAID-induced LABD including only one case of the aspirin-induced disease. NSAIDs such as piroxicam, diclofenac, and naproxen are some culprits that have been previously reported. [11][12][13][14] In 2017, Gatto et al, reported the first case of aspirin-induced LABD with a possible association, following aspirin use in the management of cold in a two-year-old boy. 14 In other forms of autoimmune bullous dermatoses, Durda et al reported a case of bullous pemphigoid related to aspirin in a 76-year-old man in Turkey in the 2010. 15 The pathogenesis of LABD remains unclear. However, more studies are needed for a better understanding of the pathogenesis, trigger factors, and optimal treatment of LABD.