eMedicine Specialties > Dermatology > Bullous Diseases

Linear IgA Dermatosis

Author: Peter A Klein, MD, Staff Physician, Department of Dermatology, University Hospital, State University of New York at Stony Brook
Coauthor(s): Jeffrey P Callen, MD, Professor of Medicine, Chief, Division of Dermatology, University of Louisville School of Medicine
Contributor Information and Disclosures

Updated: Jan 29, 2009

Introduction

Background

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.

Pathophysiology

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 recent 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.

Linear IgA dermatosis illustrates the importance of identifying the target antigen. In cases where 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. 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.

Frequency

United States

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.² Estimates have not been reported for linear IgA dermatosis in children.

Mortality/Morbidity

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. 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.³ 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.⁴

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 2 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.

Clinical

History

• 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.

Physical

• 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, 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 (Billet et al).
  • 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 Media File 1).
  • 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 Media File 2). Other sites of involvement include the feet, the hands, and the 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 frequent 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.
• 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.⁵
• 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 Media File 3).⁶

Causes

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.

• Seventeen case reports have implicated vancomycin in linear IgA dermatosis. Of all reported causative drugs, it is the best-documented agent in the literature.⁷ Other potential triggers and include the following: amiodarone, ampicillin sodium, captopril, cefamandole nafate, cyclosporine, depot sulfonamide, diclofenac, 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.
• 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, and chronic lymphocytic leukemia have been described.⁸ 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.

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