Elsevier

Clinics in Dermatology

Volume 30, Issue 1, January–February 2012, Pages 38-50
Clinics in Dermatology

Linear immunoglobulin A bullous dermatosis

https://doi.org/10.1016/j.clindermatol.2011.03.008Get rights and content

Abstract

Linear immunoglobulin A (IgA) bullous dermatosis, also known as linear IgA disease, is an autoimmune mucocutaneous disorder characterized by subepithelial bullae, with IgA autoantibodies directed against several different antigens in the basement membrane zone. Its immunopathologic characteristic resides in the presence of a continuous linear IgA deposit along the basement membrane zone, which is clearly visible on direct immunofluorescence. This disorder shows different clinical features and distribution when adult-onset of linear IgA disease is compared with childhood-onset. Diagnosis is achieved via clinical, histopathologic, and immunopathologic examinations. Two common therapies are dapsone and sulfapyridine, which reduce the inflammatory response and achieve disease remission in a variable period of time.

Introduction

Linear immunoglobulin A (IgA) bullous dermatosis, also known as linear IgA disease (LAD), is an autoimmune mucocutaneous disorder characterized by subepithelial bullae caused by IgA autoantibodies directed against several antigens of different molecular weight located in the basement membrane zone (BMZ) of the skin and all mucosal tissues with stratified squamous epithelia. The first description of LAD appeared in 1901 to 1905,1, 2 when 15 children were reported who developed nonpruritic blisters mainly involving the oral cavity, ears, nose, eyes, ankles, wrists, and the genitalia and were classified as having dermatitis herpetiformis (DH), despite some relevant clinical differences with DH.

Many years after later, a review of the literature of the previous 50 years found 22 cases of alleged DH in children.3 Of these 22 patients, 18 showed clinical features pointing more to bullous pemphigoid (BP) than to DH, and this was thus defined as a separate new entity called “bullous pemphigoid of childhood.” Ten years later, six new cases of alleged childhood DH were reported,4 but due to negative immunologic results, the authors argued that the terms “childhood BP” and “childhood DH,” were not appropriate, because they were not able to fit all of the rigorous criteria for DH, as previously established.5 As a result, the authors decided to classify this disorder as a new, separate entity, using the generic term “benign chronic bullous dermatosis of childhood” (CBCD).4

During the following years, despite the well-known notion that BP and DH were separate entities, some patients were reported with borderline, overlapping clinical and immunohistopathologic features.6, 7 This “enigma” was actually solved in 1979, when repeated observations led to the decision that CBDC was not a generic term to indicate any kind of subepidermal bullous disease of childhood but only those showing the presence of continuous linear deposits of IgA and complement 3 (C3) deposition along the BMZ.8 CBDC, also called IgA linear dermatosis of childhood, was thus classified as a new and separate entity from both DH and BP.8

If, on the one hand, about 30 years ago LAD and CBDC were recognized as separate entities; on the other hand, more than 20 years have passed since the discovery that these disorders both share the same single and unique antigen.9, 10 Currently, this disorder is widely recognized as a single entity with two variants: adult-onset LAD and childhood-onset LAD, with slightly different clinical features and different peaks of onset. Despite this information, the childhood variant is still known as CBDC.11

Section snippets

Epidemiology

LAD is not a very common disease in the adult or in the child. It may affect people of all races and, at least theoretically, of all ages, but actually two peaks have been predominantly observed: childhood-onset and adult-onset. The first usually appears after age 6 months, even though several newborns with LAD have been described,12, 13 and before the age of 5 or 6, rarely persisting after puberty. Conversely, the adult-onset form appears after puberty or later in life, generally after age 60.

Genetic background

During the last 30 years, few investigations have been performed on a possible genetic association, so it appears quite difficult to draw any definite conclusion. No fairly strong genetic background to LAD has yet been reported. Similarly, to the best of our knowledge, no ethnic group predilection or susceptibility has ever been reported, as well as familiar cases.

Most of the previous investigations of LAD in children and in adults have just revealed an association with human leukocyte antigen

Pathophysiology

As in many other autoimmune diseases, the etiology or the underlying pathophysiologic mechanism that triggers the autoimmune response in LAD still remains largely unknown. Many investigations during the last 30 years have identified different antigens involved in the pathophysiology of LAD.

The targeted antigens are located in the BMZ of stratified squamous epithelium and amnion and are absent from transitional epithelium, and some organs of the gastrointestinal, pulmonary, and genitourinary

Clinical features

Cutaneous manifestations of LAD patients (Figure 1) very often mimic those exhibited by BP patients. These lesions appear as clear or hemorrhagic vesicles (or both) or bullae that have risen out of normal skin, sometimes with an erythematous or urticarial base.11, 23, 81 Bullae or vesicles are generally tense, vary in size, and frequently tend to form annular or polycyclic plaques due to the coalescence of lesions.3

Besides the age of onset, another difference between the adult-onset and

Precipitating factors

One of the most intriguing characteristics of LAD is that its onset is often associated with several precipitating factors: most LAD cases have been correlated with drugs and systemic diseases and, less frequently, with traumatic events such as burns99 and ultraviolet light exposure.100 Pregnancy, however, ameliorated clinical conditions mostly in the third trimester, probably due to a major glycosylation of IgA fostered by estrogens and prolactin that would cause an alteration of the ability

Diagnosis

The diagnosis of LAD is mainly based on three different parameters:

  • •

    clinical,

  • •

    histopathologic,

  • •

    immunologic.

The clinical features have already been discussed.

The histolopathogic features are represented by the presence of a subepithelial blister with a predominant neutrophilic infiltrate in the upper epidermis that forms papillary microabscesses, even though eosinophils and mononuclear cells sometimes may accompany the inflammatory infiltrate.11, 81, 124

Because it is very often hard to distinguish

Treatment

Although LAD is not considered to be a potentially fatal disease, the management might be complex and require a multidisciplinary approach. Specifically, consultation with an ophthalmologist, otolaryngologist, or gastroenterologist may prove helpful in delineating eye scarring (symblephara) or upper respiratory and digestive tract strictures. An estimation by these specialists of ongoing extracutaneous disease activity is also helpful to the dermatologist when titrating therapy. Before systemic

Conclusions

Considering the data present in the literature, we may conclude that LAD is a unique disease, characterized by the deposition of linear IgA along the BMZ clearly visible on DIF. A copresence of IgA and IgG may be also occasionally seen, however, highlighting the notion that LAD is a heterogeneous disorder. This heterogeneity is also manifested by the number of target antigens (epithelial, dermal, or both sites), the BMZ space involved (multiple distribution of immune deposits in the lamina

Acknowledgments

Funding for this work was provided by the Office of Research and Development, Palo Alto Veteran's Affairs Medical Center, Palo Alto, California, USA; and the Oral Medicine Unit, Department of Odontostomatological and Maxillofacial Sciences, Federico II University of Naples, Naples, Italy.

References (152)

  • ZillikensD. et al.

    Autoantibodies in a subgroup of patients with linear IgA disease react with the NC16A domain of BP1801

    J Invest Dermatol

    (1999)
  • LinM.S. et al.

    Autoimmune responses in patients with linear IgA bullous dermatosis: both autoantibodies and T lymphocytes recognize the NC16A domain of the BP180 molecule

    Clin Immunol

    (2002)
  • ZoneJ.J. et al.

    IgA autoimmune disorders: development of a passive transfer mouse model

    J Investig Dermatol Symp Proc

    (2004)
  • HofmannS.C. et al.

    Plasmin plays a role in the in vitro generation of the linear IgA dermatosis antigen LADB97

    J Invest Dermatol

    (2009)
  • JensenP.J. et al.

    Epidermal plasminogen activator is abnormal in cutaneous lesions

    J Invest Dermatol

    (1988)
  • BairdJ. et al.

    mRNA for tissue-type plasminogen activator is present in lesional epidermis from patients with psoriasis, pemphigus, or bullous pemphigoid, but is not detected in normal epidermis

    J Invest Dermatol

    (1990)
  • LiuZ. et al.

    The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo

    Cell

    (2000)
  • WeinbergM.A. et al.

    Mucocutaneous features of autoimmune blistering diseases

    Oral Surg Oral Med Oral Pathol Oral Radiol Endod

    (1997)
  • ChanL.S. et al.

    Oral manifestations of linear IgA disease

    J Am Acad Dermatol

    (1990)
  • AultbrinkerE.A. et al.

    Linear IgA disease. The ocular manifestations

    Ophthalmology

    (1988)
  • LetkoE. et al.

    Linear IgA bullous disease limited to the eye: a diagnostic dilemma: response to intravenous immunoglobulin therapy

    Ophthalmology

    (2000)
  • BowenJ.T.

    Six cases of bullous dermatitis following vaccination, and resembling dermatitis herpetiformis

    J Cutan Dis

    (1901)
  • BowenJ.T.

    Dermatitis herpetiformis in children

    J Cutan Dis

    (1905)
  • KimR. et al.

    Dermatitis herpetiformis in children. Relationship to bullous pemphigoid

    Arch Dermatol

    (1961)
  • JordonR.E. et al.

    Childhood bullous dermatitis herpetiformis. Negative immunofluorescent tests

    Arch Dermatol

    (1970)
  • HoneymanJ.F. et al.

    The enigma of bullous pemphigoid and dermatitis herpetiformis

    Arch Dermatol

    (1972)
  • JablonskaS. et al.

    Dermatitis herpetiformis and bullous pemphigoid. Intermediate and mixed forms

    Arch Dermatol

    (1976)
  • ChorzelskiT.P. et al.

    IgA linear dermatosis of childhood (chronic bullous disease of childhood)

    Br J Dermatol

    (1979)
  • PothupitiyaG.M. et al.

    Distribution of the antigen in adult linear IgA disease and chronic bullous dermatosis of childhood suggests that it is a single and unique antigen

    Br J Dermatol

    (1988)
  • LeeS.Y. et al.

    Linear IgA bullous dermatosis in a neonate

    Arch Dis Child Fetal Neonatal Ed

    (2004)
  • NandaA. et al.

    Linear IgA bullous disease of childhood: an experience from Kuwait

    Pediatr Dermatol

    (2006)
  • NandaA. et al.

    Spectrum of autoimmune bullous diseases in Kuwait

    Int J Dermatol

    (2004)
  • KenaniN. et al.

    Childhood linear IgA bullous dermatosis in Tunisia

    Pediatr Dermatol

    (2009)
  • AboobakerJ. et al.

    Chronic bullous dermatosis of childhood—clinical and immunological features seen in African patients

    Clin Exp Dermatol

    (1991)
  • MulyowaG.K. et al.

    Autoimmune subepidermal blistering diseases in Uganda: correlation of autoantibody class with age of patients

    Int J Dermatol

    (2006)
  • KanwarA.J. et al.

    Chronic bullous dermatosis of childhood in north India

    Pediatr Dermatol

    (2004)
  • RatnamK.V. et al.

    Chronic bullous dermatosis of childhood in Singapore

    Int J Dermatol

    (1986)
  • JinP. et al.

    Chronic bullous dermatoses in China

    Int J Dermatol

    (1993)
  • HoriguchiY. et al.

    Linear IgA dermatosis: report of an infantile case and analysis of 213 cases in Japan

    J Dermatol

    (2008)
  • KleinPA et al.

    Linear IgA dermatosis

  • ZillikensD. et al.

    Incidence of autoimmune subepidermal blistering dermatoses in a region of central Germany

    Arch Dermatol

    (1995)
  • BertramF. et al.

    Prospective analysis of the incidence of autoimmune bullous disorders in Lower Franconia, Germany

    J Dtsch Dermatol Ges

    (2009)
  • BernardP. et al.

    Incidence and distribution of subepidermal autoimmune bullous skin diseases in three French regions Bullous Diseases French Study Group

    Arch Dermatol

    (1995)
  • WongS.N. et al.

    Spectrum of subepidermal immunobullous disorders seen at the National Skin Centre, Singapore: a 2-year review

    Br J Dermatol

    (2002)
  • BurgeS. et al.

    Chronic bullous dermatosis of childhood persisting into adulthood

    Pediatr Dermatol

    (1988)
  • TalhariC. et al.

    Ocular linear IgA disease resulting in blindness

    Arch Dermatol

    (2006)
  • SatoK. et al.

    Initial presentation and fatal complications of linear IgA bullous dermatosis in the larynx and pharynx

    J Laryngol Otol

    (2005)
  • MarsdenR.A. et al.

    A study of benign chronic bullous dermatosis of childhood and comparison with dermatitis herpetiformis and bullous pemphigoid occurring in childhood

    Clin Exp Dermatol

    (1980)
  • EdwardsS. et al.

    Chronic bullous disease of childhood in three patients of Polynesian extraction

    Clin Exp Dermatol

    (1990)
  • HashimotoK. et al.

    HLA antigens in dermatitis herpetiformis among Japanese

    J Dermatol

    (1980)

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