Linear immunoglobulin A (IgA) dermatosis (LAD) is an autoimmune subepidermal vesiculobullous disease that may be idiopathic or drug-induced. Children and adults are affected, with disease of the former historically referred to as chronic bullous dermatosis of childhood. The clinical presentation is heterogeneous and appears similar to other blistering diseases, such as bullous pemphigoid and dermatitis herpetiformis. Examples are shown below.
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Bullous lesions on the genital area in a child with linear IgA dermatosis.
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Bullous lesions of the palmar surface in an elderly man with vancomycin-induced linear immunoglobulin A (IgA) dermatosis.
Linear IgA dermatosis is an autoimmune disease histopathologically characterized by the linear deposition of IgA at the basement membrane zone (BMZ). Antibody deposition leads to complement activation and neutrophil chemotaxis, which eventuates in loss of adhesion at the dermal-epidermal junction and in blister formation. Disease in children is immunologically identical to that of adults. The mechanism of loss of self-tolerance to target antigens is unknown.
Within the dermal-epidermal junction, different antigenic target sites, including the lamina lucida, the sublamina densa, or both locations simultaneously, have been identified. The best-characterized antigen is a 97-kd protein extracted from human epidermis that binds IgA antibodies from sera of patients with linear IgA dermatosis. Sera that binds the 97-kd antigen localizes to the lamina lucida of salt-split skin. Originally thought to be a unique protein of the lamina lucida, further research reveals that the 97-kd protein may represent a portion of the extracellular domain of the 180-kd bullous pemphigoid antigen (BPAg2).[1]
The same patient sera have been shown to bind a 120-kd antigen in the BMZ. The 97- and 120-kd antigens may represent cleaved fragments of BPAg2, which exist as such in vivo or are produced by proteolytic digestion in vitro. These smaller molecules could also be alternative splicing products of the same BPAg2 gene. Because antibodies that bind the 97- and 120-kd antigens do not recognize the 180-kd BPAg2, the former may express unique epitopes distinct from those of the parent protein.
A case series reported patients with sera not reactive against the 97-kd antigen but rather against both bullous pemphigoid antigens. Of 11 patients, a 230-kd antigen (BPAg1) was recognized in 6 patients and BPAg2 was recognized in 5 patients. The authors suggest that an IgA-specific immune response may occur against bullous pemphigoid antigens in linear IgA dermatosis. These results are provocative given that the 97-kd linear IgA dermatosis antigen may represent a portion of the extracellular domain of BPAg2.
A 285-kd target antigen has been identified in the lamina lucida and the sublamina densa; this antigen is recognized by circulating antibodies in some patients with linear IgA dermatosis, but it has not been further characterized.
A 250-kd dermal antigen corresponding to collagen VII of anchoring fibrils has also been reported as a target antigen in some patients.
Some patients possess IgA and IgG antibodies toward laminin 332 in what Zone et al described as linear IgA/IgG bullous dermatosis.[2, 3] Additionally, subunits of laminin 332 have been the targeted antigen in vancomycin-induced linear IgA dermatosis.[4] Antilaminin 332 antibodies are typically seen in malignancy-associated mucous membrane pemphigoid (MMP).
The etiology underlying drug-induced linear IgA dermatosis remains elusive but is speculated to be caused by an immune response towards a drug-derived hapten-protein antigen. As with its spontaneous counterpart, the antigen is highly variable.
Linear IgA dermatosis illustrates the importance of identifying the target antigen. In cases in which type VII collagen is the molecule against which the antibody response is directed, patients are less likely to be responsive to treatment. Thus, viewing this condition as a subset of epidermolysis bullosa acquisita is better. Similarly, patients with antibodies directed against the bullous pemphigoid antigens may be classified as having bullous pemphigoid but with an IgA response rather than an IgG response; those with antibodies towards laminin 332 may potentially have mucosal involvement. Until more patients are reported whose antibody response is detailed to the molecular level and until this definition becomes clinically available, these heterogeneous patients will continue to be grouped into a single category, linear IgA dermatosis.
The list of agents implicated in linear IgA dermatosis continues to grow, especially with regard to medications. Many patients report prodromal events, such as illnesses or ingestion of drugs. In absent large series or a preponderance of case reports, only a subset of cases have identifiable causes. Gluten-sensitive enteropathy is not associated with linear IgA dermatosis. Various causes are discussed.
Seventeen case reports have implicated vancomycin in linear IgA dermatosis. Of all reported causative drugs, it is the best-documented agent in the literature.[5] Vancomycin-loaded bone cement has even been described to protract linear IgA dermatosis.[6, 7] Other potential triggers and include the following: amiodarone, ampicillin sodium, captopril, cefamandole nafate, cyclosporine, depot sulfonamide, diclofenac,[8] glibenclamide, interferon gamma and interleukin 2, iodine contrast agent, lithium carbonate, penicillin sodium, phenytoin sodium, somatostatin, sulfamethoxazole/trimethoprim, sulfisoxazole, topical sodium hypochlorite (1), moxifloxacin, amoxicillin-clavulanate, and vigabatrin. Infliximab was described as a cause of linear IgA dermatosis and may represent a paradoxical autoimmune reaction similar to that seen in antitumor necrosis factor agent‒induced psoriasis.[9] Immunotherapy treatment regimens have been documented to cause several subtypes of immunobullous disease, including linear IgA dermatosis.[10]
The development of linear IgA bullous dermatosis has been reported following influenza vaccination in a 54-year-old woman.[11]
Preceding illnesses, such as typhoid, brucella, tuberculosis, antibiotic-treated tetanus, varicella, herpes zoster, Paecilomyces lung infection, gynecologic infections, and upper respiratory infections, have all been reported in association with linear IgA dermatosis. The significance of these associations is uncertain. Their potential role in stimulation of the IgA mucosal system has yet to be elucidated.
Linear IgA dermatosis associated with malignancy has been reported in as many as 5% of cases. Lymphoproliferative malignancies, specifically Hodgkin disease, non-Hodgkin lymphoma (eg, following stem cell transplantation),[12] chronic lymphocytic leukemia, and angioimmunoblastic T-cell lymphoma have been described.[13, 14] Linear IgA dermatosis has also been reported with solid tumors, such as bladder carcinoma. Other associated malignancies include polycythemia rubra vera, plasmacytoma, multiple myeloma, ocular melanoma, squamous cell carcinoma of the esophagus, breast carcinoma, uterine carcinoma, eccrine carcinoma, metastatic squamous cell carcinoma, colon carcinoma, thyroid carcinoma, retroperitoneal carcinoma, metastatic hypernephroma, pancreatic carcinoma, and hydatidiform mole. The validity of the association between linear IgA dermatosis and malignancy remains to be proven.
Because linear IgA dermatosis is itself an autoimmune disease, an association with other such disorders is interesting despite proven causality. Cases have been described in association with systemic lupus erythematosus, dermatomyositis, rheumatoid arthritis, polymyalgia rheumatica, hypothyroidism, chronic hepatitis, Crohn disease, ulcerative colitis, multiple sclerosis, acquired hemophilia, and IgA nephropathy. Again, these associations may be coincidental.
Linear IgA dermatosis in children has been reported in association with human leukocyte antigen B8 (HLA-B8), but the significance of this finding is unknown.
Pancreatic lipase deficiency has been reported once in association with linear IgA dermatosis.
The prevalence of linear IgA dermatosis in Utah has been estimated as 0.6 per 100,000 adults. The prevalence in children has not been reported.
International
The incidence of adult linear IgA dermatosis in southern England has been estimated to be 1 case in 250,000 population per year. The incidence in France has been reported as 0.13 in 250,000 population.[15] A 32-year retrospective study from Tunisia noted that linear IgA dermatosis is the most common autoimmune bullous disease in children in Tunisia; it reportedly occurs commonly in preschool-aged boys.[16]
Sex
Some case series have reported a slight female preponderance; the female-to-male ratio is 1.6:1.
Age
Linear IgA dermatosis has a bimodal age of onset. Disease in children commences at ages ranging from 6 months to 10 years, with a mean of 3.3-4.5 years based on two case series. Disease of adults ranges from 14-83 years, with a mean of 52 years. Disease is most common in the nonreproductive years. Drug-induced disease is more likely to occur in the older population because this group is often being treated for multiple medical conditions.
The mean duration of idiopathic linear IgA dermatosis of childhood is 3.9 years, ranging from 2.1-7.9 years. Remission has been reported to occur in 64% of children, in most cases within 2 years. Disease of adults is more protracted, with a mean duration of 5.6 years, lasting anywhere from 1-15 years. The remission rate in adults is less than that in children (48%). The disease tends to wax and wane in severity. Drug-induced cases typically resolve quickly once the causative agent is identified and withdrawn. However, a recent study comparing spontaneous versus drug-induced linear IgA dermatosis found the latter to be more severe, with larger erosions, sometimes mimicking toxic epidermal necrolysis.[17] Cutaneous lesions usually heal without scarring.
Lesions of the mucous membranes heal with scarring and pose considerable morbidity. Desquamative gingivitis may secondarily damage teeth. Ocular linear IgA dermatosis may be indistinguishable from cicatricial pemphigoid and lead to blindness.[18] Involvement of the pharynx, the larynx, the nose, the rectum, and the esophagus has been reported.
A retrospective study of 12 women with linear IgA dermatosis showed improvement during pregnancy, usually by 10 weeks' gestation. Improvement was most marked in the third trimester. The most common agent used for treatment of linear IgA dermatosis is dapsone, which is classified as pregnancy class C (uncertain safety; animal studies show an adverse effect, no human studies) by the US Food and Drug Administration. In this series, the authors observed no serious adverse effects from dapsone during 11 pregnancies. Postpartum relapses of linear IgA dermatosis were common, occurring in 1 case within 2 hours. The range of time to relapse for the remaining 11 patients was 1-6 months, with 3 patients achieving complete remission at 2 years. Fetal outcome was unaffected by the disease.[19]
Some patients note a prolonged period of prodromal itching or transient pruritus or burning before lesions appear. Patients with ocular manifestations may complain of pain, grittiness, or discharge.
Bullae may be chronic, or lesions may appear acutely, as seen in drug-induced disease. Rash latency in vancomycin-induced cases of linear IgA dermatosis ranges from 1-13 days after the first dose. Review of medication exposures and delineation of the drug timeline are crucial in identifying potential inciting agents.
The classic primary lesions of linear IgA dermatosis are clear and/or hemorrhagic round or oval vesicles or bullae on normal, erythematous, or urticarial skin. Cutaneous manifestations may also include erythematous plaques, blanching macules and papules, fixed drug eruption–like dusky patches with central violaceous changes,[20] or targetoid erythema multiforme–like lesions. The diagnosis is not dependent on the presence of vesicles and/or bullae and a morbilliform variant has been described.[21]
Bullae may be discrete or arranged in a herpetiform pattern, often described as the cluster of jewels sign. Alternatively, vesicles and bullae may be seen at the edge of annular or polycyclic lesions, the appearance of which has been described as the string of beads sign (see the images below). Rarely, linear IgA dermatosis may exhibit an isomorphic phenomenon.[22]
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Annular lesions demonstrating the string of beads sign.
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Bullous lesions of the palmar surface in an elderly man with vancomycin-induced linear immunoglobulin A (IgA) dermatosis.
The distribution of linear IgA dermatosis differs between adults and children. Lesions in children are typically localized to the lower abdomen and anogenital areas, with frequent involvement of the perineum (see the image below). Other sites of involvement include the feet, hands, and face, particularly the perioral area. In adults, the trunk and the limbs are most commonly affected. In adults, involvement of the perineum and the perioral area is less common than in children. Lesions in both children and adults may be distributed symmetrically or asymmetrically. Dermatitis herpetiformis–like involvement of the extensor surfaces of the knees and the elbows is seen infrequently. Crusts, excoriations, erosions, or ulcers may be present.
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Bullous lesions on the genital area in a child with linear IgA dermatosis.
Oral manifestations are common in children and adults with linear IgA dermatosis. Oral lesions include vesicles, ulcerations, erythematous patches, erosions, desquamative gingivitis, or erosive cheilitis, and they may precede skin lesions.[23]
Both children and adults frequently complain of ocular symptoms, such as grittiness, burning, or discharge. Ophthalmologic findings even in the absence of ocular complaints may include subconjunctival fibrosis, shrinkage of the fornices, symblepharon formation, and cicatricial entropion with trichiasis (see the image below).[24]
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Persons with linear immunoglobulin A (IgA) dermatosis may present with prominent ocular signs and symptoms.
Direct immunofluorescence study of both perilesional skin and healthy skin typically shows linear deposition of IgA at the BMZ. Linear deposition of C3 may also be seen. Direct immunofluorescence study of salt-split skin reveals IgA deposition on either the dermal side (blister floor) or the epidermal side (blister roof). Some patients demonstrate both linear IgA deposition and immunoglobulin G (IgG) deposition at the BMZ. Immunoglobulin M (IgM) deposition has rarely been reported.
Serum should be obtained for indirect immunofluorescence studies. Approximately 50% of patients with linear IgA dermatosis have detectable circulating antibody that binds to the BMZ. Sensitivity is greater for immunofluorescence studies performed on salt-split healthy human skin. Circulating antibody titers are typically low (1:10 to 1:20). When present, linear deposition of antibody is observed at the BMZ or at the blister roof or floor in salt-split skin. Children with linear IgA dermatosis may demonstrate circulating anti-BMZ antibodies more frequently than adults.
Immunohistochemical staining of laminin 332 and collagen IV along the floor of bullae can aid in the diagnosis, although the finding is nonspecific and can be seen in other bullous dermatoses where the schism lies above the lamina densa.[25]
In patients with atypical presentations, additional testing, including bacterial culture and Gram stain of blister fluid to rule out bullous impetigo and Tzanck smear to rule out herpes virus infection, may be helpful.
Early urticarial papules or plaques reveal neutrophils aligned along the BMZ accompanied by vacuolar change. Neutrophilic microabscesses may be seen in dermal papillae (see the image below).
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Neutrophilic microabscesses in linear immunoglobulin A (IgA) dermatosis.
Fully developed lesions reveal subepidermal blistering with a predominantly polymorphonuclear infiltrate, although mononuclear cells and eosinophils may be present. Obtaining a frozen section of a blister roof may be helpful in some patients to rule out full-thickness epidermal necrosis as seen in toxic epidermal necrolysis.
In cases of suspected drug-induced disease, a lymphocyte-stimulation test has been reported successful in identifying ampicillin/sulbactam as the causative agent.[26] However, access issues with this test may limit its utility in clinical practice.
Bullae do not need special care, as long they remain intact. Ruptured lesions and erosions should be covered with sterile dressings. Infected lesions may be treated with topical mupirocin and sterile dressing changes twice daily.
Consult a dermatologist. Additionally, consult an ophthalmologist. Patients with linear IgA dermatosis can have changes, such as fine scarring, in the absence of ocular complaints. Therefore, most, if not all, patients once diagnosed should be seen by an ophthalmologist.
Patients should be closely monitored after initiating therapy with dapsone or sulfapyridine. The medication tables (see Medication) provide appropriate laboratory follow-up intervals. If patients do not respond to dapsone or sulfapyridine, the diagnosis should be reconsidered.
Large, randomized, placebo-controlled, double-blind studies have not been performed for the treatment of linear IgA dermatosis in children or adults. Most cases have been reported to respond to dapsone or sulfapyridine.[27, 28] Some clinicians favor the use of sulfapyridine because of the lower incidence of adverse effects[29] ; however, sulfapyridine is not available in the United States. The closely related sulfasalazine has been reported as a therapeutic option.[30] Some patients' conditions may not respond to sulfapyridine but do respond to treatment with dapsone. A response may be seen in 48-72 hours. A patient with concomitant linear IgA dermatosis and chronic idiopathic urticaria exhibited resolution of both diseases with omalizumab; a trial off the drug led to reactivation of disease.[31] Other reportedly useful medications include prednisone, sulfamethoxypyridazine, colchicine, dicloxacillin, mycophenolate mofetil, and intravenous immunoglobulin.
Tetracycline and niacinamide combination therapy has been reported as a possible therapeutic option.[32] This regimen, or niacinamide with any tetracycline-class antibiotic, has been well documented in the treatment of bullous pemphigoid.
Rituximab has shown efficacy in the treatment of bullous dermatoses and has been reported in the treatment of linear IgA dermatosis.[33, 34, 35, 36]
Drug-induced disease may be treated merely by withdrawal of the offending agent. In cases of linear IgA dermatosis induced by vancomycin, new lesions stop forming within approximately 2 weeks of withdrawal.[37] Particularly severe cases of drug-induced linear IgA dermatosis respond to a short course of oral corticosteroids.
Clinical Context:
Dapsone is bactericidal and bacteriostatic against mycobacteria; the mechanism of action is similar to that of sulfonamides where competitive antagonists of PABA prevent formation of folic acid, inhibiting bacterial growth.
Clinical Context:
Prednisone is an immunosuppressant used for the treatment of autoimmune disorders; it may decrease inflammation by reversing increased capillary permeability and suppressing PMN activity. Prednisone stabilizes lysosomal membranes and suppresses lymphocyte and antibody production.
These agents have anti-inflammatory properties and cause profound and varied metabolic effects. In addition, these agents modify the body's immune response to diverse stimuli.
Clinical Context:
Sulfasalazine elicits anti-inflammatory effects. It has a high affinity for distribution to connective tissues. Sulfasalazine is metabolized to 5-aminosalicylic acid and sulfapyridine.
Clinical Context:
Dicloxacillin is used in the treatment of infections caused by penicillinase-producing staphylococci. It may be used to initiate therapy when staphylococcal infection is suspected.
Clinical Context:
Although an antibiotic, tetracycline has proven effective in linear IgA dermatosis, either alone or in conjunction with niacinamide (2 g/d). Efficacy may be due to anti-inflammatory properties.
Clinical Context:
Immune globulins neutralize circulating antibodies and down-regulate proinflammatory cytokines, including INF-gamma; They block Fc receptors on macrophages, suppress inducer T and B cells, augment suppressor T cells, and block the complement cascade.
These agents are used to improve the clinical and immunologic aspects of the disease. They may decrease autoantibody production and increase solubilization and removal of immune complexes.
Clinical Context:
Rituximab is a genetically engineered chimeric murine/human monoclonal antibody against human CD20, a molecule present in normal and malignant B lymphocytes. Rituximab is described in case reports as an effective treatment for linear IgA dermatosis.
Clinical Context:
Omalizumab is a recombinant, DNA-derived, humanized IgG monoclonal antibody that binds selectively to human IgE on the surface of mast cells and basophils. It reduces mediator release, which promotes an allergic response.
Monoclonal antibody effects vary depending on their receptor target. Omalizumab binds to IgE on the surface of mast cells and basophils. It reduces the release of these mediators that promote an allergic response.
What is linear IgA dermatosis?What is the pathophysiology of linear IgA dermatosis?What causes linear IgA dermatosis?What is the prevalence of linear IgA dermatosis in the US?What is the global prevalence of linear IgA dermatosis?What are the sexual predilections of linear IgA dermatosis?Which age groups have the highest prevalence of linear IgA dermatosis?What is the prognosis of linear IgA dermatosis?Which clinical history findings are characteristic of linear IgA dermatosis?Which physical findings are characteristic of linear IgA dermatosis?What are the differential diagnoses for Linear IgA Dermatosis?What is the role of lab testing in the workup of linear IgA dermatosis?Which histologic findings are characteristic of linear IgA dermatosis?What is the role of a lymphocyte-stimulation test in the diagnosis of linear IgA dermatosis?How is linear IgA dermatosis treated?Which specialist consultations are beneficial to patients with linear IgA dermatosis?What is included in the long-term monitoring of patients with linear IgA dermatosis?What is the role of medications in the treatment of linear IgA dermatosis?Which medications in the drug class Antineoplastics, Anti-CD20 Monoclonal Antibodies are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Immunoglobulins are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Antibiotics are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Anti-inflammatory agents are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Corticosteroids are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Leprostatic agents are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Monoclonal Antibodies, Anti-asthmatics are used in the treatment of Linear IgA Dermatosis?
Mark Tye Haeberle, MD, Assistant Clinical Faculty, Division of Dermatology, University of Louisville School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: UpToDate.
Coauthor(s)
Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine
Disclosure: Received honoraria from UpToDate for author/editor; Received royalty from Elsevier for book author/editor; Received dividends from trust accounts, but I do not control these accounts, and have directed our managers to divest pharmaceutical stocks as is fiscally prudent from Stock holdings in various trust accounts include some pharmaceutical companies and device makers for i inherited these trust accounts; for: Allergen; Celgene; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble; Amgen.
Specialty Editors
Richard P Vinson, MD, Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Disclosure: Nothing to disclose.
Jeffrey J Miller, MD, Associate Professor of Dermatology, Pennsylvania State University College of Medicine; Staff Dermatologist, Pennsylvania State Milton S Hershey Medical Center
Disclosure: Nothing to disclose.
Chief Editor
William D James, MD, Paul R Gross Professor of Dermatology, Vice-Chairman, Residency Program Director, Department of Dermatology, University of Pennsylvania School of Medicine
Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier; WebMD.
Additional Contributors
Russell Hall, MD, J Lamar Callaway Professor And Chair, Department of Dermatology, Duke University Medical Center, Duke University School of Medicine
Disclosure: Received consulting fee from Novan for consulting; Received consulting fee from Stieffel, a GSK company for consulting; Received salary from Society for Investigative Dermatology for board membership.
Acknowledgements
Peter A Klein, MD Associate Professor, Department of Dermatology, University Hospital, State University of New York at Stony Brook
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