BASICS
DESCRIPTION
- Linear immunoglobulin A (IgA) dermatosis is a chronic autoimmune blistering skin disease that affects both adult and pediatric populations (1).
- Both adult and pediatric forms are characterized by subepidermal blisters, neutrophilic infiltrates, and linear deposition of IgA antibodies along the basement membrane zone.
- Although the adult and pediatric forms of linear IgA disease share immunopathologic and immunogenetic characteristics, there are notable differences in their clinical presentations and disease courses.
EPIDEMIOLOGY
- Adult linear IgA disease is either idiopathic or drug-induced, with most patients are >60 years.
- Childhood linear IgA disease (also known as chronic bullous disease of childhood) appears in children between the ages of 6 months and 10 years, and has an average age of onset between 3 and 5 years (2,3).
- Most childhood cases are idiopathic, benign, and self-limited in nature with spontaneous remission within 2 to 5 years.
- No gender predominance has been confirmed in either the adult or childhood form.
Incidence
- Linear IgA dermatosis is an uncommon disease; most studies cite an incidence of <1 person per 250,000 per year.
- Although rare, chronic bullous disease of childhood is the most common autoimmune blistering disorder in children.
ETIOLOGY AND PATHOPHYSIOLOGY
- The underlying mechanism is not known. Like other autoimmune blistering disorders, it is characterized by autoantibody formation against structural proteins in the epidermis or basement membrane zone.
- Although a number of structural antigens have been implicated in linear IgA dermatosis, most cases involve the 180-kDa bullous pemphigoid antigen 2 (BPAg2), otherwise known as collagen XVII. Specifically, antibodies against the 97-kDa and 120-kDa degradation products of BPAg2 are seen.
- BPAg2 is a transmembrane protein of the lamina lucida layer of the basement membrane zone (BMZ). IgA antibody deposition in the lamina lucida with complement activation and inflammatory cell chemotaxis (primarily neutrophils) results in histologic division of the epidermis and dermis and subsequent subepidermal blister formation.
Genetics
Studies have demonstrated significantly increased frequencies of human leukocyte antigen (HLA) haplotypes Cw7, B8, DR3, and DQW2. Although frequencies are stronger in children with the disease, the HLA associations are similar in adults and children, supporting the hypothesis that adult linear IgA disease and chronic bullous disease of childhood are variant forms of the same autoimmune blistering disease.
RISK FACTORS
Many medications have been cited as agents known to induce adult linear IgA disease (4):
- Vancomycin is the most commonly associated medication.
- Angiotensin-converting enzyme (ACE) inhibitors, especially captopril; angiotensin receptor blockers
- Lithium
- Antibiotics, including penicillin, sulfamethoxazole/trimethoprim, and cephalosporins
- Furosemide
- Atorvastatin
- Amiodarone
- Diclofenac
- Carbamazepine; phenytoin
- Interleukin 2; interferon- ³
- Sulfasalazine
- Ustekinumab
COMMONLY ASSOCIATED CONDITIONS
- Associations with malignancy has been reported:
- Lymphoma, both Hodgkin and non-Hodgkin
- Leukemia, such as chronic lymphocytic leukemia
- Nonhematopoietic malignancies are less common but include cancers of the breast, bladder, and esophagus.
- Associations with inflammatory bowel disease, especially with ulcerative colitis
- Case reports suggest possible additional associations with autoimmune diseases, such as rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, multiple sclerosis, IgA nephropathy, and Sj Άgren syndrome.
DIAGNOSIS
HISTORY
- Idiopathic forms of linear IgA dermatosis usually have a prodrome of pruritus or burning that occurs weeks prior to onset of blisters (bullae). Hives or urticaria may precede bullae. Additionally, patients may report oral, conjunctival, or other mucosal lesions which may be associated with pain.
- Drug-induced adult linear IgA disease manifests shortly after initiation of offending medication (24 hours to 13 days after the initiation of vancomycin).
PHYSICAL EXAM
- The classic cutaneous lesion is a tense vesicle or small bullae, often with surrounding erythema which can arise from either an urticarial plaque or papular base or from normal skin. Urticarial lesions without vesicles may also be seen.
- The distinctive pattern of vesicular and bullous lesions in an annular or "string-of-pearls " arrangement may be present in adult disease, but it is more common in the childhood form.
- Eroded bullae may appear as superficial erosions or crusted lesions.
- Distribution of lesions differs among the various types of linear IgA dermatosis. Idiopathic adult linear IgA disease may resemble other blistering disorders, such as bullous pemphigoid, with vesicles and bullae showing a predilection for trunk, axillae, thighs, and flexural forearms.
- ~50% of patients will demonstrate intact vesicles or erosions involving mucosa or desquamative gingivitis and erosive cheilitis. Hoarseness may also be indicative of pharyngeal involvement.
- Ocular involvement is possible and may result in fibrous adhesions of the conjunctiva (symblepharon), turning out of the eyelids (ectropion), and growth of eyelashes toward the conjunctiva (trichiasis).
- Patients with drug-induced adult linear IgA disease may show variable distribution of lesions, although mucosal involvement is far less common in this variant.
- Chronic bullous disease of childhood preferentially involves the lower trunk, groin, buttocks, genitalia, and thighs. Children may also present with facial lesions, especially periorally, and the majority of children have oral mucosal involvement. Of note, children may present with isolated genital lesions, which may be misdiagnosed as sexual abuse.
DIFFERENTIAL DIAGNOSIS
- Bullous pemphigoid, dermatitis herpetiformis, and nodular prurigo with excoriations
- If a drug is suspected to be the causative agent, life-threatening drug reactions such as Stevens-Johnson syndrome and toxic epidermal necrolysis must be ruled out.
- Often, the clinical features of adult linear IgA dermatosis and epidermolysis bullosa acquisita overlap, and both share autoantibodies targeting collagen VII. Family history should help distinguish the two diagnoses.
- Papular urticaria may present similarly; however, unlike chronic bullous disease of childhood, it rarely affects the face or genital regions and is usually of shorter duration.
- Chronic bullous disease of childhood can resemble genetic epidermolysis bullosa; however, these can be distinguished with family and clinical history about to onset of disease.
DIAGNOSTIC TESTS & INTERPRETATION
- Immunofluorescence (IF) study of clinically uninvolved skin is critical for diagnosis of linear IgA disease; diagnosis can be supported but not confirmed by histology alone.
- Direct IF (DIF) revealing linear IgA deposition along BMZ is diagnostic.
- Indirect IF of IgA BMZ autoantibodies are found in the majority of patients with chronic bullous disease of childhood but in <25% of adult patients.
Test Interpretation
- DIF of perilesional normal skin showing linear IgA deposition along the basement membrane zone is diagnostic. Some cases may show IgG deposition as well.
- Standard hematoxylin and eosin staining of lesional skin in linear IgA disease reveals subepidermal blisters with a neutrophil predominant infiltrate. The pattern is indistinguishable from that of dermatitis herpetiformis and bullous lupus erythematosus. Occasional eosinophils may be present, and rarely, the quantity of eosinophils may be equivalent to neutrophils, causing confusion with bullous pemphigoid. Papillary dermal microabscesses may also be present.
TREATMENT
Given the paucity of linear IgA dermatosis, no large, randomized controlled trials have evaluated treatment.
GENERAL MEASURES
Usually, drug-induced adult linear IgA disease is self-limited and resolves within 2 to 6 weeks following discontinuation of the offending agent.
MEDICATION
Common medical treatment of linear IgA dermatosis falls into two categories:
- Medications with clinically observed antineutrophil properties
- Immunosuppressives/anti-inflammatory medications
First Line
- Dapsone has been observed to be effective in treating inflammatory skin diseases characterized by neutrophilic infiltrates (1,4) and thus, is generally accepted as the primary treatment of linear IgA disease.
- Dapsone is a sulfone derivative whose mechanism of action relies on inhibition of the folic acid pathway.
- Most patients ' disease can be controlled with a dosage of 100 to 200 mg daily (1 mg/kg/day in children).
- Important potential side effects include methemoglobinemia, agranulocytosis, and neuropathy. Some clinicians may regularly monitor methemoglobin levels and CBCs, including reticulocytes.
- Dapsone can also cause hemolytic anemia in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency; thus, G6PD levels, CBC with differential, and liver function test should be obtained prior to starting the drug (3).
Second Line
Systemic steroids, given their extensive side effect profile, are generally reserved for severe or recalcitrant cases in which case they may be used alone or in combination with another medication such as dapsone.
ISSUES FOR REFERRAL
Linear IgA dermatosis often involves both ocular and oral mucosa, in which case referral to ophthalmology or otolaryngology may be prudent. Even in the absence of eye complaints or gross eye findings described earlier, patients may have other ocular changes identifiable by an ophthalmologist.
ADDITIONAL THERAPIES
- Other sulfones, such as sulfapyridine, have been found effective but are not readily available in the United States.
- Colchicine may be effective in dermatoses characterized by a heavy infiltrate of neutrophils such as linear IgA dermatosis.
- Case studies note responses to intravenous immunoglobulin (IVIG), erythromycin, and mycophenolate mofetil.
- General wound care guidelines for skin lesions include sterile dressings with petrolatum for eroded bullae and topical antibiotics such as mupirocin for secondarily infected wounds.
- Wound infections typically present with spreading redness, worsening pain, poor healing, malodorous discharge, and occasional systemic symptoms such as fever. If a wound infection is suspected, a wound culture should be obtained prior to starting antibiotics.
INPATIENT CONSIDERATIONS
Severe cases with extensive body surface involvement or those cases requiring IV medications (e.g., IVIGs) may warrant inpatient management.
ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Regular follow-up should be scheduled to assess for improvement, drug response, and necessary tailoring of therapy.
PATIENT EDUCATION
- Patients should be educated about the risk of methemoglobinemia during treatment with dapsone and should seek medical care in the case of shortness of breath or blue lips or tongue.
- Linear IgA dermatosis is not a contraindication to pregnancy. In fact, as with many other autoimmune diseases, most patients actually show improvement during pregnancy, especially in the 3rd trimester.
- Patients should be made aware that fetal outcome is unaffected by the disease, although expectant mothers may be advised to stop dapsone treatment (pregnancy Category C). Postpartum relapse is common.
PROGNOSIS
- Most patients respond quickly to dapsone, precluding the need for more aggressive treatment.
- Chronic bullous disease of childhood usually remits spontaneously by puberty with no long-term sequelae.
COMPLICATIONS
Blindness occurs in a minority of patients; again, highlighting the value of ophthalmologic evaluation following diagnosis.
REFERENCES
11 Patr cio P, Ferreira C, Gomes MM, et al. Autoimmune bullous dermatoses: a review. Ann N Y Acad Sci. 2009;1173:203 " 210.22 Kharfi M, Khaled A, Karaa A, et al. Linear IgA bullous dermatosis: the more frequent bullous dermatosis of children. Dermatol Online J. 2010;16(1):2.33 Chen S, Mattei P, Fischer M, et al. Linear IgA bullous dermatosis. Eplasty. 2013;13:ic49.44 Ahronowitz I, Fox L. Severe drug-induced dermatoses. Semin Cutan Med Surg. 2014;33(1):49 " 58.
ADDITIONAL READING
- Collier PM, Kelly SE, Wojnarowska F. Linear IgA disease and pregnancy. J Am Acad Dermatol. 1994;30(3):407 " 411.
- Collier PM, Wojnarowska F, Welsh K, et al. Adult linear IgA disease and chronic bullous disease of childhood: the association with human lymphocyte antigens Cw7, B8, DR3 and tumour necrosis factor influences disease expression. Br J Dermatol. 1999;141(5):867 " 875.
- Hern ‘ndez N, Borrego L, Soler E, et al. Sulfasalazine-induced linear immunoglobulin A bullous dermatosis with DRESS. Acta Dermosifiliogr. 2013;104(4):343 " 346.
- Jheng-Wei L, Yi-Chin S, Wen-Hung C. Vancomycin-induced linear IgA bullous dermatosis mimicking toxic epidermal necrolysis. Indian J Dermatol Venereol Leprol. 2011;77(4):537.
- Kim JS, Choi M, Nam CH, et al. Concurrent drug-induced linear immunoglobulin A dermatosis and immunoglobulin A nephropathy. Ann Dermatol. 2015;27(3):315 " 318.
- Kobe Y, Setoguchi D, Kitamura N. Dapsone-induced agranulocytosis leading to perianal abscess and death: a case report. J Med Case Rep. 2011;5:107.
- McDonald HC, York NR, Pandya AG. Drug-induced linear IgA bullous dermatosis demonstrating the isomorphic phenomenon. J Am Acad Dermatol. 2010;62(5):897 " 898.
- Mintz EM, Morel KD. Clinical features, diagnosis, and pathogenesis of chronic bullous disease of childhood. Dermatol Clin. 2011;29(3):459 " 462.
- Schumann H, Baetge J, Tasanen K, et al. The shed ectodomain of collagen XVII/BP180 is targeted by autoantibodies in different blistering skin diseases. Am J Pathol. 2000;156(2):685 " 695.
- Takegami Y, Makino T, Matsui K, et al. Coexistence of antilaminin-332-type mucous membrane pemphigoid, lamina lucida-type linear IgA bullous dermatosis and Sj Άgren syndrome. Clin Exp Dermatol. 2013;38(2):194 " 196.
- Venning VA. Linear IgA disease: clinical presentation, diagnosis, and pathogenesis. Dermatol Clin. 2011;29(3):453 " 458.
- Yamada S, Makino T, Jinnin M, et al. Association of linear IgA bullous disease with ulcerative colitis: a case of successful treatment with infliximab. Dermatology. 2013;227(4):295 " 298.
- Zone JJ. Clinical spectrum, pathogenesis and treatment of linear IgA bullous dermatosis. J Dermatol. 2001;28(11):651 " 653.
CODES
ICD10
L13.8 Other specified bullous disorders
ICD9
694.8 Other specified bullous dermatoses
SNOMED
- Linear IgA dermatosis (disorder)
- Adult linear immunoglobulin A disease (disorder)
- Chronic bullous dermatosis of childhood (disorder)
- Drug-induced linear IgA disease (disorder)
CLINICAL PEARLS
- Linear IgA dermatosis is an autoimmune blistering disorder with a bimodal age distribution involving children <5 years and adults >60 years.
- Idiopathic or medication-induced etiologies are most common.
- Ocular and oral mucosal involvement can be a major cause of morbidity, including blindness.
- Diagnosis is made with direct immunofluorescence, demonstrating linear IgA deposition at the basement membrane zone.
- Linear IgA dermatosis responds well to first-line treatment with dapsone.