Linear IgA Dermatosis

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Background

Linear immunoglobulin A (IgA) dermatosis (LAD; also referred to as linear IgA bullous disease [LABD]) is an autoimmune subepidermal vesiculobullous disease that may be idiopathic or drug-induced. Children and adults are affected, with LAD in 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. (See the images below.)



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Bullous lesions on genital area in child with linear immunoglobulin A (IgA) dermatosis.



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Bullous lesions of palmar surface in elderly man with vancomycin-induced linear immunoglobulin A (IgA) dermatosis.

Pathophysiology

LAD is an autoimmune disease histopathologically characterized by the linear deposition of IgA at the basement membrane zone (BMZ).[1] 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 in 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, and 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 LAD. Sera that bind the 97-kd antigen localize to the lamina lucida of salt-split skin. This 97-kd protein, originally thought to be a unique protein of the lamina lucida, may represent a portion of the extracellular domain of the 180-kd bullous pemphigoid antigen (BPAg2).[2]

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 on 11 patients with sera that were not reactive against the 97-kd antigen but were reactive against the two bullous pemphigoid antigens.[3] A 230-kd antigen (BPAg1) was recognized in six patients and BPAg2 in five. The authors suggested that an IgA-specific immune response may occur against bullous pemphigoid antigens in LAD. These results are provocative, given that the 97-kd LAD 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 LAD but 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.[4, 5] Additionally, subunits of laminin 332 have been the targeted antigen in vancomycin-induced LAD.[6] Antilaminin 332 antibodies are typically seen in malignancy-associated mucous membrane pemphigoid (MMP).

The process underlying drug-induced LAD remains elusive but is speculated to involve an immune response towards a drug-derived hapten-protein antigen. As with its spontaneous counterpart, the antigen is highly variable.

LAD 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, it is better to view this condition as a subset of epidermolysis bullosa acquisita. 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 immunoglobulin G (IgG) response; those with antibodies towards laminin 332 may 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 the single category of LAD.

Etiology

The list of agents implicated in LAD continues to grow, especially with regard to medications. Many patients report prodromal events, such as illnesses or ingestion of drugs. Only a subset of cases have identifiable causes. Gluten-sensitive enteropathy is not associated with LAD. Various causes are discussed.

Numerous case reports have implicated vancomycin in LAD. Of all reported causative drugs, vancomycin is the best-documented agent in the literature.[7] Vancomycin-loaded bone cement has even been described as causing protracted LAD.[8, 9] Other potential triggers include the following:

Infliximab has been described as a cause of LAD and may represent a paradoxical autoimmune reaction similar to that seen in anti–tumor necrosis factor (TNF) agent‒induced psoriasis.[11] Immunotherapeutic regimens have been documented to cause several subtypes of immunobullous disease, including LAD.[12, 13]

The development of LABD has been reported following influenza vaccination in a 54-year-old woman.[14]

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 LAD. The significance of these associations is uncertain. Their potential role in stimulation of the IgA mucosal system has yet to be elucidated.

Association with malignancy has been reported in as many as 5% of LAD cases. Lymphoproliferative malignancies—specifically, Hodgkin disease, non-Hodgkin lymphoma (eg, following stem cell transplantation),[15] chronic lymphocytic leukemia, and angioimmunoblastic T-cell lymphoma—have been described.[16, 17] LAD has also been reported with solid tumors, such as bladder carcinoma. Other associated malignancies include the following:

The validity of the association between LAD and malignancy remains to be proven.

Because LAD 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 (SLE), dermatomyositis, rheumatoid arthritis (RA), polymyalgia rheumatica, hypothyroidism, chronic hepatitis, Crohn disease, ulcerative colitis, multiple sclerosis (MS), acquired hemophilia, and IgA nephropathy. Again, these associations may be coincidental.

LAD in children has been reported in association with human leukocyte antigen (HLA)-B8, but the significance of this finding remains to be defined.

Pancreatic lipase deficiency has been reported in association with LAD.

LAD has been cited as a rare potential complication of vaccinations (eg, for COVID-19[18] or human papillomavirus [HPV] infection[19] ), but the risk appears to be quite low.

Epidemiology

US and international statistics

The prevalence of LAD in Utah has been estimated as 0.6 per 100,000 adults. The prevalence in children has not been reported.

The incidence of adult LAD 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.[20]  The incidence in Korea has been reported as 1.3 in 100,00 population per year.[21] A 32-year retrospective study from Tunisia noted that LAD was the most common autoimmune bullous disease in children in Tunisia; it reportedly occurred commonly in preschool-aged boys.[22]

Age- and sex-related demographics

LAD has a bimodal age of onset. In children, age at onset of disease ranges from 6 months to 10 years (mean, 3.3-4.5 y, according to two case series). In adults, age at onset ranges from 14 to 83 years (mean, 52 y). In a Korean study using a nationwide database, the mean age at diagnosis was 55.9 years.[21] 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.

Some case series have reported a slight female preponderance, with a female-to-male ratio of approximately 1.6:1.

Prognosis

The mean duration of idiopathic LAD of childhood is 3.9 years (range, 2.1-7.9 y). Remission has been reported to occur in 64% of children, in most cases within 2 years. LAD is more protracted in adults, with a mean duration of 5.6 years (range, 1-15 y). The remission rate in adults is lower than that in children (48%). LAD tends to wax and wane in severity. Drug-induced cases typically resolve quickly once the causative agent is identified and withdrawn. However, a study comparing spontaneous LAD with drug-induced LAD found the latter to be more severe, with larger erosions, sometimes mimicking toxic epidermal necrolysis (TEN).[23] 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 LAD may be indistinguishable from cicatricial pemphigoid and may lead to blindness.[24] Involvement of the pharynx, the larynx, the nose, the rectum, and the esophagus has been reported.

A retrospective study of 12 women with LAD showed improvement during pregnancy, usually by 10 weeks' gestation; improvement was most marked in the third trimester.[25] The most common agent used for treatment of LAD is dapsone, which is classified as pregnancy class C by the US Food and Drug Administration (FDA). In this series, the authors observed no serious adverse effects from dapsone during 11 pregnancies. Postpartum relapses of LAD were common. In one patient, relapse occurred within 2 hours; in the remaining 11, time to relapse ranged from 1 to 6 months, with three patients achieving complete remission at 2 years. Fetal outcome was unaffected by the disease.

History

Some patients with linear immunoglobulin A (IgA) dermatosis (LAD; also referred to as linear IgA bullous disease [LABD]) 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 LAD ranges from 1 to 13 days after the first dose. Review of medication exposures and delineation of the drug timeline are crucial in identifying potential inciting agents.

Physical Examination

The classic primary lesions of LAD are clear and/or hemorrhagic round or oval vesicles or bullae on normal, erythematous, or urticarial skin. (See the image below.) Cutaneous manifestations may also include erythematous plaques, blanching macules and papules, fixed drug eruption–like dusky patches with central violaceous changes,[26] 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.[27]



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Bullous lesions of palmar surface in elderly man with vancomycin-induced linear immunoglobulin A (IgA) dermatosis.

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 image below). Rarely, LAD may exhibit an isomorphic phenomenon.[28]



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Annular lesions demonstrating "string of beads" sign in linear immunoglobulin A (IgA) dermatosis.

The distribution of LAD differs between adults and children. In children, lesions are typically localized to the lower abdomen and anogenital areas (see the image below), with frequent involvement of the perineum. 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; involvement of the perineum and the perioral area is less common than in children. In both children and adults, lesions  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 genital area in child with linear immunoglobulin A (IgA) dermatosis.

Oral manifestations are common in children and adults with LAD. Oral lesions include vesicles, ulcerations, erythematous patches, erosions, desquamative gingivitis, or erosive cheilitis, and they may precede skin lesions.[29]

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.[30]  (See the image below.)



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Persons with linear immunoglobulin A (IgA) dermatosis may present with prominent ocular signs and symptoms.

Laboratory Studies

In linear immunoglobulin A (IgA) dermatosis (LAD; also referred to as linear IgA bullous disease [LABD]), direct immunofluorescence study of both perilesional skin and healthy skin typically shows linear deposition of IgA at the basement membrane zone (BMZ).[31] 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 LAD 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 LAD may demonstrate circulating anti-BMZ antibodies more frequently than adults do.

Immunohistochemical staining of laminin 332 and collagen IV along the floor of bullae can aid in the diagnosis, though the finding is nonspecific and can be seen in other bullous dermatoses where the schism lies above the lamina densa.[32]

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 herpesvirus infection, may be helpful.

Other Tests

In cases of suspected drug-induced LAD, a lymphocyte-stimulation test has been reported successful in identifying ampicillin/sulbactam as the causative agent.[33] However, access issues with this test may limit its utility in clinical practice.

Histologic Findings

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, though 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 (TEN).

The histopathologic features of LAD overlap with those of bullous lupus erythematosus.[34]  The two conditions are differentiated by means of immunofluorescence studies and serology.

Medical Care

In the treatment of linear IgA dermatosis (LAD; also referred to as linear IgA bullous disease [LABD]), bullae do not need special care, provided that 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.

Large randomized placebo-controlled double-blind studies have not been performed for the treatment of LAD in children or adults. Most cases have been reported to respond to dapsone or sulfapyridine.[35, 36]  The European Academy of Dermatology and Venereology (EADV) has stated that dapsone is the treatment of choice for LAD.[31] Some clinicians have favored the use of sulfapyridine because of the lower incidence of adverse effects[37] ; however, sulfapyridine is not available in the United States. The closely related sulfasalazine has been reported as a therapeutic option.[38, 39]

Some patients' conditions may not respond to sulfapyridine but do respond to treatment with dapsone. A response may be seen in 48-72 hours.

Topical corticosteroids (eg, betamethasone and clobetasol) have been used to treat LAD, particularly in pediatric patients.[1]

Other reportedly useful medications have included prednisone, sulfamethoxypyridazine, colchicine, dicloxacillin, mycophenolate mofetil, and intravenous immunoglobulin (IVIG).

Tetracycline and niacinamide combination therapy has been reported as a possible therapeutic option.[40]  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 LAD.[41, 42, 43, 44]

Several patients have been successfully treated with dupilumab.[45, 46, 47]

In one case report, a patient with concomitant LAD and chronic idiopathic urticaria exhibited resolution of both diseases with omalizumab; a trial off the drug led to reactivation of disease.[48]  

Drug-induced disease may be treated merely by withdrawal of the offending agent. In cases of vancomycin-induced LAD, new lesions stop forming within approximately 2 weeks of withdrawal.[49]  Particularly severe cases of drug-induced LAD may respond to a short course of oral corticosteroids.

Consultations

Consultation with a dermatologist and an ophthalmologist is appropriate. Patients with LAD can have changes, such as fine scarring, in the absence of ocular complaints. Once diagnosed, therefore, most if not all patients should be seen by an ophthalmologist.

Long-Term Monitoring

Patients should be closely monitored after therapy with dapsone or sulfapyridine is initiated. Appropriate laboratory follow-up intervals depend on the medication(s) used. If patients do not respond to dapsone or sulfapyridine, the diagnosis should be reconsidered.

Dapsone

Clinical Context: 

Sulfasalazine (Azulfidine, Azulfidine EN)

Clinical Context: 

Betamethasone topical (Alphatrex, BetaVal, Dermabet)

Clinical Context: 

Clobetasol (Clobex, Clobex Spray, Cormax)

Clinical Context: 

Prednisone (Deltasone, Prednisone Intensol, Rayos)

Clinical Context: 

Methylprednisolone (A-Methapred, DepoMedrol, Medrol)

Clinical Context: 

Dicloxacillin

Clinical Context: 

Tetracycline (Achromycin V, Actisite, Sumycin)

Clinical Context: 

Rituximab (Riabni, Rituxan, Rituximab-abbs)

Clinical Context: 

Dupilumab (Dupixent)

Clinical Context: 

Omalizumab (Xolair)

Clinical Context: 

Colchicine (Colcrys, Gloperba, Lodoco)

Clinical Context: 

Immune globulin IV (IGIV)

Clinical Context: 

Mycophenolate (CellCept, MMF, Myfortic)

Clinical Context: 

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?What is the role of a lymphocyte-stimulation test in the diagnosis of linear IgA dermatosis?Which histologic findings are characteristic 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 Tetracyclines are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Penicillins, Penicillinase-Resistant 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 Corticosteroids, Topical are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class 5-Aminosalicylic Acid Derivatives are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Antileprosy Agents are used in the treatment of Linear IgA Dermatosis?Which medications in the drug class Interleukin Inhibitors are used 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?

Author

Jeffrey P Callen, MD, Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of Louisville School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Biogen US (Adjudicator for study entry cutaneous lupus erythematosus); Priovant (Adjudicator for entry into a dermatomyositis study); IQVIA (Serono - adjudicator for a study of cutaneous LE) <br/>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 these trust accounts for: Stocks held in various trust accounts: Allergen; Amgen; Pfizer; 3M; Johnson and Johnson; Merck; Abbott Laboratories; AbbVie; Procter and Gamble;; Celgene; Gilead; CVS; Walgreens; Bristol-Myers Squibb.

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.

Chief Editor

William D James, MD, Emeritus Professor, Department of Dermatology, University of Pennsylvania School of Medicine

Disclosure: Received income in an amount equal to or greater than $250 from: Elsevier<br/>Served as a speaker for various universities, dermatology societies, and dermatology departments.

Additional Contributors

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.

Acknowledgements

Peter A Klein, MD Associate Professor, Department of Dermatology, University Hospital, State University of New York at Stony Brook

Disclosure: Nothing to disclose.

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Bullous lesions on genital area in child with linear immunoglobulin A (IgA) dermatosis.

Bullous lesions of palmar surface in elderly man with vancomycin-induced linear immunoglobulin A (IgA) dermatosis.

Bullous lesions of palmar surface in elderly man with vancomycin-induced linear immunoglobulin A (IgA) dermatosis.

Annular lesions demonstrating "string of beads" sign in linear immunoglobulin A (IgA) dermatosis.

Bullous lesions on genital area in child with linear immunoglobulin A (IgA) dermatosis.

Persons with linear immunoglobulin A (IgA) dermatosis may present with prominent ocular signs and symptoms.

Neutrophilic microabscesses in linear immunoglobulin A (IgA) dermatosis.

Annular lesions demonstrating "string of beads" sign in linear immunoglobulin A (IgA) dermatosis.

Bullous lesions on genital area in child with linear immunoglobulin A (IgA) dermatosis.

Persons with linear immunoglobulin A (IgA) dermatosis may present with prominent ocular signs and symptoms.

Neutrophilic microabscesses in linear immunoglobulin A (IgA) dermatosis.

Bullous lesions of palmar surface in elderly man with vancomycin-induced linear immunoglobulin A (IgA) dermatosis.