Linear IGA Dermatosis

Article Author:
Courtney Bernett
Article Editor:
Juan Rosario-Collazo
Updated:
9/12/2018 2:29:29 PM
PubMed Link:
Linear IGA Dermatosis

Introduction

Linear IgA bullous dermatosis (LABD), also known as linear IgA dermatosis or linear IgA disease, is a relatively rare subepidermal vesiculobullous disease that can occur in both adults and children. In children, the disease is known as "chronic bullous disease of childhood" and tends to have a distinct clinical appearance, but the underlying pathogenesis of the disease remains the same. In the adult form of the disease, a drug-induced etiology must be thoroughly considered.

Etiology

The main underlying etiology of LABD is circulating IgA anti-basement membrane zone antibodies directed against the 97 kDa portion of BPAG2 (bullous pemphigoid antigen 2) in the lamina lucida. 

As previously mentioned, drug-induced LABD is a frequent underlying cause in adults. The most frequently incriminated drug is vancomycin, which is responsible for nearly 50% of the cases of drug-induced LABD, but other antibiotics including penicillins, cephalosporins, and rarely, sulfonamides antibiotics may cause the erroneous formation of the IgA antibodies precipitating the clinical presentation of LABD. Other frequently implicated medications include ACEIs (specifically, captopril), NSAID class (diclofenac, naproxen, among others), and phenytoin. Numerous case reports of additional inciting medications are available in the literature, but a few of them include commonly used medications such as allopurinol, amiodarone, furosemide, atorvastatin, glyburide, angiotensin receptor blockers, verapamil, acetaminophen, and the influenza vaccination. Generally, drug-induced LABD typically starts within the first month of drug administration.

Epidemiology

LABD may occur across all age spectrums (in adults and children) with the average age of onset in adults occurring at 2 separate peaks, one in the teenage and early adult years and the other occurring in the sixth decade of life. In children, the age of onset is classically in the "pre-school years" (average age of 4.5 years old). The estimated incidence ranges from 0.2 to 2.3 per 1,000,000 million per year.

Pathophysiology

The underlying cause of LABD is circulating IgA anti-basement membrane zone antibodies directed against the 97 kDa portion of BPAG2 (bullous pemphigoid antigen 2, also known as BP180) in the lamina lucida. The 97 kDa subunit lies within the well-known NC16A domain of the BPAG2 molecule. Additionally, some patients may display autoantigens toward LAD-1 (a 120 kDa truncated domain of BPAG2). In bullous pemphigoid (BP), circulating IgG antibodies bind to the MCW-1 area of the NC16A domain which is closer to the amino-terminus, while the 97 kDa subunit lies at the carboxy terminus. The pathophysiology of the sub-lamina densa variant remains poorly understood, but it is suspected that collagen type VII is the underlying antigen.

Various theories regarding potential causative factors in the production of the offending IgA antibodies exist and include infectious etiologies, autoimmune disease, induction secondary to malignancy, or gastrointestinal disease. There have been reports of loose associations of LABD occurring in patients with Celiac disease, Crohn's disease, ulcerative colitis, systemic lupus erythematosus, rheumatoid arthritis, dermatomyositis, and multiple sclerosis. The relationship between LABD and underlying malignancy is also weak, but there have been reports of LABD occurring concurrently in patients with lymphoproliferative disorders, and thyroid, bladder, colon, renal, or esophageal cancers. Numerous other malignancies have also been reported in case reports. Varicella-zoster virus (VZV) infection, resulting in either chicken pox or a shingles outbreak, may be the erroneous inciting factor leading to the formation of the IgA anti-basement membrane zone antibodies, along with other infections such as respiratory infections. Reports of an association between LABD and psoriasis have also been published.

Genetic predisposition may also be partially responsible for the development of chronic bullous disease of childhood or LABD, and several human leukocyte antigen (HLA) types have been implicated as portending an increased risk of disease development. HLA-B8, HLA-DR3, HLA-DQ2, and HLA-cw7 are well known for the association with both the childhood and adult variants of LABD.

Histopathology

Complete histopathological examination of tissue from a patient with suspected LABD should include an examination of both a standard hematoxylin and eosin (H and E) stained specimen along with direct immunofluorescence (DIF). On routine H and E staining, a subepidermal blistering process is observed with a predominately neutrophilic infiltrate. Early in the disease process, this neutrophilic infiltrate may be mainly localized to the dermal papillae and be confused for the "papillary dermal neutrophilic stuffing" seen in dermatitis herpetiformis. Later in the disease process, after the subepidermal split becomes apparent, large numbers of eosinophils may intermix with the neutrophilic infiltrate in the dermis. This creates a diagnostic dilemma because bullous pemphigoid can have similar findings.

One clue that may help sway the examiner more toward the diagnosis of LABD, over DH or BP, is the manner in which the neutrophils appear to almost "line up" at the basement membrane. Generally, a definitive diagnosis of LABD is not able to be confidently made based on H and E alone. Therefore, the DIF remains essential in procuring the diagnosis of a vesiculobullous disorder.

Immunopathology remains the gold standard for establishing a diagnosis of LABD or chronic bullous disease of childhood, with the classic findings being linear deposition of IgA at the basement membrane zone. Two histopathologic subtypes of the disease exist and are categorized by the location of the IgA deposition. The most common variant is the lamina lucida subtype followed by the sub-lamina densa variant.

History and Physical

LABD in adults can have varied presentation, making it difficult to distinguish from other autoimmune vesiculobullous diseases such as bullous pemphigoid (BP). Patients may present with scattered, tense bullae on a background of non-inflamed skin, while others may develop a more herpetiform appearance to their lesions with prominent erythema beneath the vesicles or bullae. The lesions typically have a widespread distribution and usually involve the trunk and extremities but can also involve the scalp, genital area or face. Some patients may have to expand annular vesiculobullous plaques or even a presentation mimicking toxic epidermal necrolysis (TEN). In chronic bullous disease of childhood, the classic clinical presentation includes annular erythematous lesions with a ring of vesicles, commonly referred to as a "crown of jewels" or "string of pearls." In children, the lesions most commonly occur on the abdomen, lower back, thighs, groin area, and around the eyes and mouth. The "crown of jewels" or "string of pearls" is less commonly observed in the adult form.

Like many other autoimmune vesiculobullous disorders such as pemphigus vulgaris (PV), BP, and cicatricial pemphigoid (CP), LABD can also have mucous membrane involvement in about 50% of patients, making the examination of mucous membrane surfaces such as the oral mucosa, conjunctivae, nares, and genital areas an important component of a complete examination in patients with suspected vesiculobullous disorders. Like CP, the mucosal involvement in LABD may result in significant scarring. The most commonly involved mucosal surfaces are the oral mucosa and conjunctiva. Interestingly, drug-induced LABD, particularly drug-induced LABD secondary to vancomycin, tends to be much more severe and may mimic toxic epidermal necrolysis (TEN) and may even have a positive Nikolsky sign.

There have been reports of atypical variants/presentations of LABD including an eczematous form, prurigo nodularis-like form, urticarial form, morbilliform presentation, and even a seborrheic dermatitis-like presentation of LABD.

Both the adult and childhood form of LABD can vary symptomatically from completely asymptomatic, to mild or severe pruritus or burning sensation.

Evaluation

By far, the most important aspect of the workup for LABD is obtaining biopsies for histopathological examination. The clinician should obtain two punch biopsies, one for routine hematoxylin and eosin (H and E) staining and the other for direct immunofluorescence (DIF). The biopsy for routine H and E should be obtained from an actual skin lesion, while the sample for DIF should be obtained from the perilesional skin. Additional workup may include indirect immunofluorescence (IIF) to test for the presence or absence of circulating IgA anti-basement membrane zone antibodies, which may be found in up to 70% of LABD patients but are not found in patients with DH. In the lamina lucida subtype of LABD, these antibodies will adhere to the roof of a salt-split skin test (epidermal side), while in the sub-lamina densa variant the antibodies will adhere to the floor (dermal side).

A thorough history and physical examination may significantly help guide the clinician towards a diagnosis of LABD, even before the pathology report returns. A complete review of medications, including all over-the-counter medications along with vitamins and mineral supplements, is crucial to help rule out drug-induced LABD.

Treatment / Management

Multiple different treatment options have arisen for LABD since its original discovery in the 1970s, but the most commonly used medication to treat the disorder is oral dapsone. Fortunately, the disease is exceptionally responsive to dapsone and improvement can be seen within 2 to 3 days of drug initiation. Relatively low doses of dapsone are required for successful disease management, with an average of 100 mg daily for adults, while children generally require 1 to 2 mg/kg per day. Patients on dapsone should be monitored closely for development of hemolytic anemia, agranulocytosis, dapsone hypersensitivity syndrome, leukopenia, cholestatic jaundice, peripheral neuropathy, and nephrotic syndrome. Occasionally, patients may also require adjunctive administration of oral corticosteroids to gain initial control of the disease. Sulfapyridine remains as another treatment option.

Interestingly, multiple antibiotic therapies, such as the tetracycline class, dicloxacillin, and trimethoprim-sulfamethoxazole, have also proven to be beneficial in controlling the disease but no specific underlying infectious etiology has ever been discovered. In patients with drug-induced LABD secondary to vancomycin, patients may benefit from discontinuing the vancomycin, but then adding a new antibiotic such as doxycycline with the added benefit of relatively similar microbial coverage, and it may also serve as a potential treatment for the patient's LABD. Nicotinamide 1.5 g per day may be beneficial as an adjunctive treatment.

Differential Diagnosis

The differential diagnosis for LABD should include other vesiculobullous diseases such as dermatitis herpetiformis, bullous pemphigoid, epidermolysis bullosa acquisita, bullous impetigo, or pemphigus vulgaris. There have also been numerous reports of LABD mimicking erythema multiforme and TEN. Dermatitis herpetiformis has very similar findings on immunohistochemical staining, with the main difference being the granular deposition of IgA, instead of linear deposition as in LABD. Bullous pemphigoid is characterized by linear deposits of IgG along the epidermal basement membrane zone. Unfortunately, at times there can be a mixed linear deposition of both IgG and IgA at the basement membrane which creates a diagnostic conundrum. Different options exist as far as classifying this specific deposition pattern as either bullous pemphigoid or LABD.

Prognosis

The prognosis for both LABD and the pediatric variant, "chronic bullous disease of childhood" are both generally promising. Spontaneous remission may occur in 30% to 60% of adult patients, usually only occurring after years of active disease. In children, the disease tends to spontaneously remit within 2 to 4 years after onset, which is exceptionally reassuring for parents. Since systemic therapies may be masking a patient's spontaneous remission, the general recommendation is to periodically attempt to withdraw these medications to evaluate for the unknown remission of the disease.

Drug-induced LABD also has a good prognosis with most cases remitting within 2 to 6 weeks after the inciting medication is discontinued.

Consultations

Consultations for a patient suspected of a vesiculobullous disease should be directed toward a dermatologist. In a patient with a known diagnosis of linear IgA bullous disease with the suspected associated gastrointestinal disease, autoimmune disease, or malignancy, the patient should be referred to the respective specialists.

Pearls and Other Issues

  • Always consider drug-induced LABD in adults with a new diagnosis of LABD.
  • Chronic bullous disease of childhood has a reassuring prognosis as most of the cases spontaneously resolve within a few years of onset.
  • Vancomycin is the most common cause of drug-induced LABD.
  • Loose associations exist between LABD and malignancy, gastrointestinal disease, and autoimmune disease.
  • Classic histopathological findings on H and E include subepidermal split, rich neutrophilic infiltrate +/- eosinophils.
  • Classic DIF finding is linear IgA deposited along the basement membrane zone.
  • Classic IIF finding is circulating IgA antibodies deposited on the epidermal side of salt-split skin (lamina lucida subtype) or circulating IgA antibodies deposited on the dermal side of salt-split skin (sub-lamina densa subtype).
  • Vancomycin-induced LABD is associated with a severe presentation of the disease that may mimic TEN. 
  • At least 2 initial biopsies should be obtained, one of an actual lesion for H and E and another from a perilesional area for DIF.
  • The most commonly used treatment is dapsone.