Introduction
Autoimmune subepidermal blistering diseases are caused by immunological loss of tolerance
to components of hemidesmosomes, triggering humoral and cellular responses.
1
C3 and IgG deposition along the basement membrane zone is characteristic of bullous
pemphigoid (BP).
1
,
2
Alternately, IgA deposition at the basement membrane zone is consistent with linear
IgA bullous dermatosis (LABD).
1
,
3
An immunological overlap spanning the clinical and immunologic spectrum between BP
and LABD has been reported and referred to as linear IgA/IgG bullous dermatosis (LAGBD).
3
,
4
LAGBD has a unique clinical presentation, immunologic properties, and distinct therapeutic
options
1
,
5, 6, 7 including rituximab.
Case report
A 43-year-old African American man presented with a 7-month history of a worsening
erythematous and pruritic rash, which had progressed to blisters and ocular pain 4 weeks
prior the presentation. Topical triamcinolone and 2 weeks of 60 mg prednisone had
failed to improve the rash. The patient denied any medication changes, history of
malignancy, autoimmune disease, or inflammatory bowel disease. Past medical history
was significant for end-stage renal disease secondary to hypertension (on hemodialysis)
and obstructive sleep apnea. Medications included clonazepam, promethazine, metoprolol,
and gabapentin. Physical examination showed numerous erosions with collarettes of
scale and tense bullae in “string of pearls” annular configurations on the bilateral
arms, thighs, and trunk (Fig 1, A and B). Mucosal involvement included sloughing of
the left eye conjunctiva and tongue.
Fig 1
Erosions, collarettes of scale, and tense bullae with examples of annular “string
of pearl” configurations. A, Left back and arm. B, Right thigh. C, Resolution of bullae
16 days after initiation of rituximab, mycophenolate mofetil, and prednisone; erosions
and collarettes of scale persisted.
Histopathology from skin biopsies with hematoxylin-eosin stain and direct immunofluorescence
microscopy was consistent with BP, demonstrating a subepidermal split, an eosinophil-rich
inflammatory infiltrate (Fig 2), strong linear C3 deposition, equivocal IgG, and absent
IgA along the basement membrane zone. However, indirect immunofluorescence with salt
split skin revealed both linear IgG and IgA at the roof of the induced blister (epidermal
staining pattern). Enzyme-linked immunosorbent assay was positive for circulating
anti-BP180 antibodies in the patient's serum, with IgG and IgA titers of 1:160 and
1:20, respectively. Anti-BP230 antibodies were absent.
Fig 2
Biopsy specimens obtained from the right posterior shoulder. A, subepidermal blister.
No necrosis of keratinocytes noted. B, Mixed inflammatory infiltrate including lymphocytes,
histiocytes, and abundant eosinophils extending down to the level of the superficial
vascular plexus. (Hematoxylin-eosin stain.)
After an additional 2 weeks of prednisone without improvement, the patient was started
on rituximab 375 mg/m2 weekly for 4 weeks and mycophenolate mofetil 500 mg twice daily.
Prednisone was increased to 80 mg (0.5 mg/kg body weight). Dapsone was avoided due
to anemia; methotrexate was avoided due to end-stage renal disease and morbid obesity.
Gabapentin was discontinued due to the possibility of drug-induced BP.
1
,
8
Ophthalmology recommended prednisolone acetate ophthalmic suspension, and tobramycin,
and dexamethasone ointments. Age-appropriate cancer and autoimmune disease screenings
were recommended. Bullae completely cleared after 4 rituximab infusions (Fig 1, C),
and prednisone was tapered over a month. The disease relapsed 9 months after initial
treatment, but cleared with 2 additional rituximab infusions.
Discussion
Autoimmune subepidermal blistering diseases are rare. The BP incidence is 6-13 per
million people and typically affects adults over 60 years of age. The LABD incidence
is 0.3-2.3 per million and may present both in children and adults.
1
A review of 45 LAGBD cases in Japan showed that 49% of the patients were younger than
60 years of age.
9
In BP, the most common antigens are BP230 (a 230-kDa intracellular protein) and BP180
(a 180-kDa transmembrane glycoprotein).
1
Antibodies against BP180 are believed to induce the initial blisters, while anti-BP230
antibodies enhance the inflammatory reaction.
1
,
2
In LABD, the target antigens are the 97-kDa or 120-kDa fractions of BP180 carboxy-terminus.
In LAGBD, IgG and IgA antibodies target BP180 most commonly,
4
,
10, 11, 12, 13, 14 and, less often, laminin-332
11
,
15
,
16
and BP230.
11
,
14
,
17
Drug-induced BP and LABD have been reported
1
; there is, however, no specific association of LAGBD with drugs.
7
,
10, 11, 12, 13, 14, 15, 16, 17, 18 LAGBD has been reported in patients with ulcerative
colitis,
13
B-cell lymphoma,
17
and colorectal carcinoma.
11
Clinical manifestations of BP and LABD are variable and can overlap. LAGBD presentations
include erythema,
10
,
14
pustules,
14
tense bullous lesions
7
,
10, 11, 12
,
16
,
17
and small vesicles in annular patterns.
10
,
13
,
16
Ocular and oral mucosa
7
,
11
involvement, as well as a case of LAGBD-related interstitial pneumonia,
19
have been reported. The relationship between LAGBD clinical manifestations and the
type of predominant antibody highlights that BP, LAGBD, and LABD are on a spectrum.
20
Histopathologic evaluation shows subepidermal bullae.
1
Eosinophilic spongiosis and/or dermal infiltrate of eosinophils are seen in BP. LABD
shows predominantly neutrophilic infiltrates.
1
LAGBD has mixed eosinophilic and neutrophilic infiltrates.
10
,
11
,
13
,
15
Direct immunofluorescence typically reveals the presence of linear deposits of IgG,
IgA, and C3. LAGBD has been reported to have IgA and IgG binding mostly to the epidermal
surface (as seen in this case),
10
,
12, 13, 14
,
17
,
21
and rarely combined epidermal-dermal
11
,
15
or dermal
16
sides.
Treatment starts with a review of medications to identify and discontinue drugs potentially
inducing the disease.
1
,
8
Age-appropriate screening for malignancy may be appropriate.
11
Systemic and topical corticosteroids are first-line treatment
1
,
2
; however, significant side effects are common. Dapsone treatment is an effective
option in LAGBD, limiting systemic immunosuppression.
2
,
7
,
13
,
16
,
17
Dapsone inhibits neutrophil adhesion and release of tissue-damaging oxidants and proteases.
6
Side effects include hemolytic anemia, methemoglobinemia, neutropenia, neuropathy,
and hepatitis. It is contraindicated for patients with anemia (as in our case), liver
disease, or low glucose-6-phosphate dehydrogenase enzyme levels.
6
Steroid-sparing adjunctive therapies include azathioprine, mycophenolate mofetil,
intravenous immunoglobulin,
1
and targeted therapies such as rituximab, an anti-CD20 monoclonal antibody. Rituximab
is Food and Drug Administration-approved for the treatment of pemphigus vulgaris.
Case reports describe rituximab use for both BP and LABD with higher efficacy observed
in IgG-dominant disease.
19
In BP, rituximab has a reported complete response rate of 85%, a recurrence rate of
29%, and an adverse effects rate of 24%.
22
Side effects include infections, anemia, syndrome of inappropriate antidiuretic hormone
secretion, drug fever, acute pruritus, peripheral arterial occlusive disease, and
tachycardia.
22
Rituximab is an important treatment option for patients with multiple medical co-morbidities
and severe disease as presented in this case report.
The case presented here highlights the importance of distinguishing between BP, LABD,
and LAGBD (Table I). The young age of the patient, mucosal involvement, and bullae
in an annular configuration were not typical for classic BP. Only by further evaluation
with indirect immunofluorescence and enzyme-linked immunosorbent assay were IgA antibodies
identified. The LAGBD diagnosis allows treatment with dapsone (not readily used for
BP) or rituximab in severe cases. Due to distinct clinical features, immunologic findings,
and treatment modalities, it is important for LAGBD to be recognized as a subtype
of subepidermal blistering disease.
Table I
Comparison of clinical, histological, and immunological findings in BP, LAGBD, and
LABD
Bullous pemphigoid (BP)
Linear IgA/IgG bullous dermatosis (LAGBD)
Linear IgA bullous dermatosis (LABD)
Epidemiology
•
6-13 cases per million
•
Onset over 60 years of age
•
Mean presentation age, 80 years
•
6.7% of the patients 0-15 years of age
•
42.3% 15-60 years of age
•
51% >60 years
9
•
0.3-2.3 cases per million
•
Childhood disease with mean age of 4.5 years; adult disease onset >60 years
Associated conditions/triggers
•
Medications
•
Autoimmune diseases
•
Neurological diseases
•
Trauma, burns, UV radiation
•
Gastrointestinal diseases
13
•
Malignancy
11
,
17
•
Medications
•
Autoimmune diseases
•
Gastrointestinal diseases
•
Malignancy
•
Infections
Pathogenesis (autoantibodies)
•
BP180
•
BP230
•
BP180
4
,
10, 11, 12, 13, 14
•
BP230
11
,
14
,
17
•
Laminin-332
11
,
15
,
16
•
97-kDa and 120-kDa fraction of BP180
•
BP180
•
BP230
•
Anti-Type VII collagen
Clinical presentation
•
Pruritus
•
Tense blisters and vesicles
•
Erosions and crusting
•
Urticarial and infiltrated papules and plaques
•
Oral involvement in 10%-30%
•
Eye, nose, pharynx, esophagus, and anogenital involvement is rare
•
Pruritus
•
Tense blisters and vesicles
•
Annular vesicular pattern
10
,
13
,
16
•
Erosions and crusting
•
Erythema
•
Ocular and oral mucosa involvement
7
,
11
•
Pruritus
•
Tense blisters and vesicles
•
Annular or hepetiform vesicular pattern
•
Erosions and crusting
•
Oral, ocular, nasal, pharyngeal, and esophageal involvement in up to 80% of patients
Subepidermal blisters
Pathology findings
Eosinophilic and mononuclear cell infiltrate
Mixed eosinophilic and neutrophilic infiltrate
10
,
11
,
13
,
15
Neutrophilic infiltrate
Direct immunofluorescence
IgG and/or C3
IgG + IgA and/or C3
IgA and/or C3
Indirect immunofluorescence
•
IgG
•
Mainly epidermal pattern
•
Combined epidermal/dermal pattern
•
IgG and IgA
•
Mainly epidermal pattern
10
,
12, 13, 14
,
17
,
21
•
Combined epidermal/dermal pattern
16
•
Rarely dermal pattern
16
•
IgA
•
Mainly epidermal pattern
•
Combined epidermal/dermal pattern
•
Rarely dermal pattern
9
BP, Bullous pemphigoid; LAGBD, linear IgA/IgG bullous dermatosis; LABD, linear IgA
bullous dermatosis.
Conflicts of interest
Henry K. Wong discloses contracted research for Solegenix, Abbot Laboratories, and
Galderma. Dmitry Nedosekin, Kelsey Derrick Wilson, Katelynn Campbell, and Sara Shalin
have no conflicts of interest to disclose.