Linear IgA Bullous Dermatosis:

Not so “straight” forward.

Jamie Hale DO PGY4

Dermatology Resident

Largo Medical Center/NSUCOM

Objectives

Case discussion

Review pathogenesis of Linear IgA Bullous Dermatosis

(LABD)

Discuss Epidermolysis Bullosa Aquisita (EBA) variant

Review treatment options

Case Background

CC: 10 year old male with “blisters” of entire body x 2

years

HPI: Patient had extensive bullae and erosions involving

entire body for past two years. He admitted to

associated pruritus and pain. Caretaker stated these

lesions waxed and waned but never resolved.

PMHx: Asthma

FMHx: Denied any family history of blistering disorder.

Case Background cont.

Medications: Albuterol prn

Allergies: NKDA

ROS: Positive for pain and pruritus of skin lesions. Denied

any fever/chills or developmental delay.

Physical Exam

Multiple bullae, vesicles, and erosions grouped in an

annular pattern involving the trunk, extremities, face, and

genitals

Many lesions exhibited honey-colored crusts and

excoriations

Histopathology

Neutrophils, along with fewer numbers of eosinophils,

aligned along the dermoepidermal junction and

aggregated within the papillary dermal tips. There was

basal vacuolization with subepidermal blister formation.

Immunofluorescence

On direct immunofluorescence there was a thick linear

IgA deposition along the epidermal basement

membrane zone.

The thick linear fibrillar staining of IgA localized mostly at

the dermal floor of the subepidermal blister. There was

no IgG, C3, C5b-9, or fibrinogen deposition.

The findings were diagnostic of linear IgA bullous

dermatosis favoring the epidermolysis bullosa

acquisita/type VII collagen variant.

Treatment Course

Our patient was started on Dapsone 50mg daily with a

low dose of oral steroids. He initially cleared but after two

months he began to develop new bullae and vesicles.

At his follow up, mycophenolate mofetil 500mg bid and

topical triamcinolone 0.1% ointment bid were started.

During this time he was treated for multiple secondary

bacterial infections, including MRSA, and was treated

with clindamycin and trimethoprim/sulfamethoxazole.

Treatment Course cont.

After 8 months there was no improvement in his

condition.

After being presented at a grand rounds, it was decided

to treat him based on a study by Kwatra and Jorizzo and

he was started on a combination of methotrexate 7.5 mg

weekly and prednisone 30 mg daily.

On follow up two months later, he had marked

improvement but much of his body surface was still

involved. His prednisone dose was lowered to 20 mg daily and methotrexate was increased to 10mg.

Treatment Course cont.

One month later, the patient was 80% clear.

Despite this at his next follow up appointment 3 months

later he was flaring with at least 50% worsening of skin

lesions.

He was referred to Drs. Schachner (pediatric dermatology) and Nousari (immunobullous) in Miami and

after much evaluation the joint group of physicians have

decided to try treatment more consistent with EBA.

LABD Overview

Linear IgA Bullous Dermatosis (LABD) is a rare, autoimmune, subepidermal vesiculobullous disease that is characterized immunopathologically by the linear deposition of IgA at the basement membrane zone (BMZ).

There are two variations of LABD, adult-onset and childhood-onset (also called Chronic Bullous Dermatosis of Childhood).

LABD can be idiopathic or drug-induced.

Antibodies bind to the epidermal side of the BMZ characterizing classic LABD as well as antibodies binding to the dermal side of the BMZ characterizing IgA mediated-Epidermolysis Bullosa Acquisita (IgA-EBA).

LABD Overview cont.

Rare disease, 0.1 to 2.3 cases per million individuals per

year

Bimodal age of onset: 6 months to 6 years and > 60 years

old

No clear gender predilection

LABD Causes

Idiopathic

Drug related: Most commonly vancomycin but also

reported with phenytoin, amiodarone, captopril, and

NSAIDs

Possible infectious etiology: upper respiratory tract infections, typhoid, brucella, tetanus, varicella-zoster, and

gynecologic infections

Increased frequency of HLA Cw7, B8, DR3, and DQ2

LABD Pathogenesis

It is not fully understood but many studies demonstrate both humoral and cellular mechanisms.

It is an inflammatory process that starts with activation of the complement cascade and recruitment of neutrophils.

Neutrophils release proteolytic enzymes resulting in separation of the dermo-epidermal junction.

The IgA antibodies are thought to contribute directly to the destruction of the basement membrane zone, recruit neutrophilic infiltrate, and activate complement.

LABD Pathogenesis cont.

Most patients have autoantibodies against the BP-180 antigen but many other antigens have been documented.

Type VII collagen has classically been described as the antigen targeted in epidermolysis bullosa acquisita by IgG antibodies.

When Type VII collagen is targeted by IgA antibodies it is classified as IgA-EBA. Some authors believe this to be a subset of LABD while others believe it to be a subset of EBA.

Many studies attribute the heterogeneous nature of this disease to the multiple antigens targeted.

LABD Clinical Manifestations

LABD consists of a combination of annular bullae, vesicles, and/or papules found in groups.

Subepidermal bullae are tense and often form a “cluster of jewels” or rosette pattern.

Children often have lesions on face, lower abdomen, perineal, and anogenital regions with generalization to the trunk extremities, hands, and feet.

Pruritus is common.

Mucosal involvement has been noted in up to 80% of adult patients but varies in children.

IgA-EBA Clinical Manifestations

Lesions vary and resemble those of classic LABD.

Lesions have been described as erythematous urticarial

plaques, vesicles, bullae, and erythema-multiforme-like.

Scarring and milia may occur.

Diagnosis

Difficult due to similarity of many immunobullous diseases

Requires hematoxylin-eosin stained biopsies with direct and indirect immunofluorescence studies

Histology: subepidermal blister with a primarily neutrophilic infiltrate in the superficial dermis

DIF: linear deposition of IgA along the basement membrane

IIF: circulating IgA antibodies to antigens on the BMZ but only positive in 30-50%

Diagnostic Dilemma

Most antibodies in LABD bind to the 97kDa and 120kDa antigens, fragments of the BP180 hemidesmosome in the lamina lucida

This causes mapping to the epidermal side of the salt-split skin

Another pattern found was antibodies binding to both sides of the lamina densa creating a “mirror image”

Cases like ours have documented IgA antibodies binding to collagen type VII in the lamina densa and sublamina densa causing mapping to the dermal side of the salt-split skin

Treatment

There are no large, randomized, controlled trials on the

treatment of LABD in adults or children to date.

Successful treatment has been based on previous case

studies and observations.

Treatment: Dapsone

Historically, Dapsone is the treatment of choice due to its

anti-inflammatory and immunomodulatory effects.

It is thought to inhibit lysosomal activity, myeloperoxidase

mediated iodination, and adherence of neutrophils to

the basement membrane zone.

Dose of 50-200mg/day for adults and 0.5-2mg/kg/day for

children have been documented.

The response is usually fast and causes long-lasting remission.

Treatment: Dapsone cont.

Side effects: Most patients experience a benign hemolysis that partially corrects itself with a compensatory reticulocytosis.

Potentially fatal side effects: hepatotoxicity, dapsone hypersensitivity syndrome, agranulocytosis, and aplastic anemia.

Other side effects: methemoglobinemia, peripheral motor neuropathy, paresthesias, and weakness

Monitoring: screen for G6PD deficiency, baseline CBC with differential and liver function tests, weekly CBC x 1 month then monthly for 6 months

Treatment cont.

Other treatments include:

Sulfonamides: sulfapyridine, sulfasalazine

Oral antibiotics: tetracycline

Immunomodulants: corticosteroids, tacrolimus, mycophenolate mofetil, azathioprine, methotrexate, cyclosporine, cyclophosphamide, immunoadsorption, rituximab, and IVIg

Adjunctive treatments: colchicine and thalidomide

IgA-EBA demonstrates mixed results with dapsone

Others: colchicine, sulfapyridine, cyclophosphamide, methotrexate, and plasmapheresis have all been used

Our Patient

Failed Dapsone with corticosteroids

Failed mycophenolate mofetil with corticosteroids

Failed methotrexate with corticosteroids

Due to patient compliance and economic burden, IVIg could not be tried

After consultation with Drs. Schachner and Nousari in

Miami we feel the next best course of action is rituximab

infusion.

Treatment: Rituximab

Chimeric monoclonal antibody targeted against CD 20, a receptor located on B-cells

CD20 contributes to B-cell activation and differentiation

Originally used to treat B-cell tumors and autoimmune diseases

Lozinski et al successfully treated a patient with classic LABD with rituximab

There are no current case reports of IgA-EBA treated with rituximab but many exist demonstrating clearance of classic forms of EBA.

Most common side effects: mild to moderate infusion-related reactions but there is risk of sepsis with cases of Pneumocystis carinii and Pseudomonas reported

Treatment: Rituximab cont.

Three studies: Weekly infusions x 4 weeks

Another: weekly infusions at lowered dose x 5 weeks due

to poor health of the patient

All had concomitant use of adjunctive treatments such

as corticosteroids or immunomodulatory agents.

Our patient will begin Rituximab and continue

mycophenolate mofetil.

Conclusion

Not all immunobullous diseases are “straight” forward

diagnoses.

Immunofluorescence with serration mapping is important

to distinguish between diseases such as classic LABD and

IgA-EBA.

Not all diseases with a self-remitting prognosis self-remit.

Treatment resistance can always happen.

Every immunobullous patient is unique and their treatment should be tailored to them specifically.

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