Salient
features
Linear Immunoglobulin A
Dermatosis
·
Rare
blistering disease with onset typically after fourth decade of life.
·
Linear
band of immunoglobulin (Ig) A at the dermal–epidermal basement membrane.
·
Clinical
presentations may mimic dermatitis herpetiformis, bullous pemphigoid, and
cicatricial pemphigoid.
·
May
occur in association with many drugs, including vancomycin.
·
May
occur in association with inflammatory bowel diseases, but is only rarely
associated with gluten-sensitive enteropathy.
·
Rarely
seen in association with malignancy, specifically lymphoid malignancy.
·
Histology
shows sub epidermal collection of neutrophils at the basement membrane, often
collecting in papillary tips with sub epidermal blisters.
·
Patients
have relatively low titers of circulating IgA autoantibodies, most frequently
against portions of BPAG2 (type XVII collagen), or rarely against BPAG1, LAD
285, type VII collagen, and others.
·
Most
patients respond dramatically to treatment with dapsone; some require
adjunctive systemic corticosteroids.
·
Prognosis
is variable with both spontaneous remissions and longstanding disease.
Chronic Bullous Disease of
Childhood
·
Rare
blistering disorder of childhood presenting predominantly in children younger
than 5 years of age.
·
Linear
IgA at the dermal–epidermal basement membrane.
·
Clinical
presentation of tense bullae, often in perineum and perioral regions, giving a
“cluster-of-jewels” appearance. New lesions sometimes appear around the
periphery of previous lesions with a collarette of blisters.
·
Histology
shows sub epidermal collection of neutrophils at the basement membrane, similar
to linear IgA bullous dermatosis.
·
Most
patients respond dramatically to treatment with dapsone.
·
Spontaneous
remissions, often within 2 years, are frequent.
Introduction
LABD is an immune-mediated, sub epidermal vesiculobullous
eruption that occurs in both adults and children. It has been defined on the
basis of a unique immunopathology consisting of f homogeneous linear deposition
of IgA along the cutaneous BMZ. Linear IgA disease (LAD) is the most frequent
autoimmune blistering disease in infants and children. In adults, the clinical
findings of LABD may resemble those of DH or bullous pemphigoid (BP), but in
children, the cutaneous features may be clinically unique. Some overlap is seen
with BP (in patients with dual IgG and IgA deposition along the DEJ), with MMP
(in patients with predominant mucosal involvement) and EBA (in patients with
IgA autoantibodies against type VII collagen).
Tense bullae, vesicles and annular erythema are the
clinical hallmarks. Frequently, blisters are arranged annularly, a formation
referred to as ‘crown of jewels’, and mucous membrane lesions are present. Skin
lesions have the same morphology in children and adults; however, they arise
more abruptly in children and sites of predilection are different, which
developed predominantly in flexural areas, particularly the lower trunk, thigh
and groin in preschool children.
The
childhood form is most frequently termed “chronic bullous disease of childhood”
(CBDC). It is invariably characterized by the linear deposition of IgA along
the BMZ as well as circulating antibodies against the same BMZ antigens
described in the adult form.
Based upon
the site of IgA deposition as determined by immunoelectron microscopy, there
are at least two distinct types of LABD: a lamina lucida type (majority) and a
sublamina densa type. In adults, LABD is frequently drug-induced.
Epidemiology
The true
incidence of LABD is unknown. In adults, the average age of onset of LABD is
after 60 years of age. There appears to be a slight female preponderance.
Childhood LABD occurs younger than 5 years of age.
Pathogenesis
Cleavage ectodomains of BPAG2.COOH, carboxy terminus; NH2,
amino terminus; TM, transmembrane region
Both BP and
the lamina lucida type of LABD have lamina lucida deposition of immunoglobulin
and are associated with BMZ vesiculation. However, the antigenic specificity
differs. In BP, the pathogenic IgG antibodies bind the MCW-1 region of the NC16
domain of BP antigen 2 (BPAG2; BP180), whereas the epitopes that have
stimulated an IgA response in LABD are more toward the carboxy terminus of the
same molecule. In adult and childhood LABD patients, this IgA antibody was
found, on immunoblot, to react against a 97 k Da antigen in an epidermal
extract. Subsequently, the 97 k Da antigen was found to represent a cleaved
ectodomain of BPAG2, referred to as LABD97. Why BP antibodies should react
predominantly with antigens near the transmembrane portion of BPAG2 and LABD
antibodies react with cleaved epitopes near or within the collagenous domain
are unclear.
IgA class antibodies from patients
with the sublamina densa type of LABD have been reported to bind to type VII
collagen in anchoring fibrils.
There have been reports in the
literature of the association of LABD with various disorders such as
gastrointestinal diseases such as gluten-sensitive enteropathy; autoimmune
diseases such as systemic lupus erythematosus,
dermatomyositis, as well as thyrotoxicosis, autoimmune hemolytic anemia
and rheumatoid arthritis; malignancies such as B-cell lymphoma, chronic
lymphocytic leukemia, and carcinoma of the bladder, thyroid, colon and
esophagus; and infections such as varicella zoster virus and upper respiratory
infections. The significance of these associations has yet to be determined,
but they may play a role in the initial stimulation of the IgA mucosal immune
system.
There are multiple reports of
drug-induced LABD, with vancomycin being one of the more common inducers. In
the case of these medications, they may stimulate the immune system to produce
an IgA class antibody in a predisposed individual. Drug-induced LABD usually
remits within 2–6 weeks of cessation of the drug. However, some cases have
persisted for months.
|
DRUG-INDUCED LINEAR IgA BULLOUS DERMATOSIS |
|
Common |
|
1.
Vancomycin |
|
Less common |
|
1.
Penicillins 2.
Cephalosporins 3.
Captopril
> other ACE inhibitors 4.
NSAIDs:
diclofenac, naproxen, oxaprozin, piroxicam |
|
Uncommon |
|
1.
Phenytoin 2.
Sulfonamide
antibiotics: sulfamethoxazole, sulfisoxazole |
|
Rare |
|
1.
Amiodarone 2.
Angiotensin
receptor blockers: candesartan, eprosartan 3.
Atorvastatin 4.
Carbamazepine 5.
Cyclosporine 6.
Furosemide 7.
Gemcitabine 8.
Glyburide 9.
Granulocyte
colony-stimulating factor 10.
Influenza
vaccination 11.
Interferon-α
and interferon-γ 12.
Interleukin-2 13.
Lithium
carbonate 14.
PUVA 15.
Rifampin 16.
Somatostatin 17.
Verapamil 18.
Vigabatrin |
Clinical Features
In both children and adults, the individual lesions are similar
including tense bullae and vesicles, urticated plaques, erosions and erythema. However, the vesiculobullous lesions often appear in a
herpetiform arrangement on erythematous and/or normal-appearing skin. Some
patients present with expanding annular plaques, while others have lesions that
are scattered and asymmetric. Bullae and vesicles frequently arise in an
annular pattern with blistering along the edge of lesions forming the so‐called
‘string‐of‐pearls’,
‘crown of jewels’ or ‘cluster of jewels’ sign. Of note, this sign in not
pathognomonic for LAD and may also be seen in BP.
Pruritus is variable from absent to severe. In children,
lesions arise more abruptly compared to adults and tend to involve the perioral
area and perineum in addition to the other predilection sites, trunk and limbs.
Latter localizations are mainly involved in adult patients.
Mucosal involvement is common (in about 70% of patients)
with mostly oral erosions and ulcers; nasal crusting and genital lesions may
also occur. When mucous membrane lesions are predominant there is a diagnostic
overlap with MMP. In patients with ocular scarring, the diagnosis of MMP is
appropriate. As in BP, lesions tend to heal without scarring unless extensive super
infection occurs. Milia formation is uncommon.
Differential diagnosis
In both age groups, dermatitis herpetiformis (antibodies
against epidermal and or tissue transglutaminase with granular deposits of IgA
in the dermal papillae by direct IF microscopy), BP (autoantibodies against the
DEJ preferentially of the IgG isotype and reactivity against BP180 and/or
BP230), MMP (predominant mucosal involvement) and EBA (reactivity against type
VII collagen) need to be distinguished. Key clinical and immunopathological
features of these diseases are summarized below:
Pemphigoid diseases. Autoantibody specificities and
diagnostically relevant clinical signs. Main target antigens are indicated in
bold italics:
|
Disease |
Autoantibody |
Clinical
signs of diagnostic relevance |
|
Bullous
pemphigoid (BP) |
BP180
NC16A, BP230 |
Tense
blisters, erosions, intense pruritus, old age (>75 years); no predominant
mucosal involvement |
|
Mucous
membrane pemphigoid (MMP) |
BP180, laminin 332, BP230, α6β4 integrin, laminin
311 |
Predominant
mucosal involvement |
|
Linear IgA
disease |
LAD‐1, BP230 (IgA reactivity) |
Tense
blisters, erosions; no predominant mucosal involvement |
|
Pemphigoid gestationis |
BP180
NC16A, BP230 |
Erythema,
papules, rarely vesicles, intense pruritus; pregnancy or postpartum period |
|
Anti‐p200/laminin γ1 pemphigoid |
p200 antigen
laminin γ1 |
Tense
blisters, erosions; <75 years of age; no predominant mucosal involvement |
|
Epidermolysis
bullosa acquisita |
Type
VII collagen |
Mechanobullous
(like epidermolysis bullosa) and inflammatory variant (like BP or MMP) |
|
Bullous
systemic lupus erythematosus (SLE) |
Type I: type VII collagen b Type II:
BP180, BP230, laminin 332 |
SLE present;
tense blisters, erosions; no predominant mucosal involvement; excellent
response to dapsone |
|
Lichen planus
pemphigoides |
BP180
NC16A, BP230 |
Tense
blisters independent of lichen planus lesions |
|
Cicatricial pemphigoid |
BP180, BP230,
laminin 332 |
Blisters and
erosions that heal with scarring and/or milia formation. No predominant
mucosal involvement |
Disease course and
prognosis
Patients with LAD almost always respond well to
treatment. Relapses may occur over the next 2–4 years but are usually less
severe than the initial disease episode. During pregnancy, the disease appears
to improve with relapses within a few months postpartum. Most children go into
complete remission within 2 years of disease onset and only very rarely the
disease persists after puberty. Drug‐induced LAD usually
heals within 4–8 weeks after discontinuation of the drug. Some cases, however,
have persisted for months.
Pathology
LABD
is a sub epidermal vesicular dermatosis in which neutrophils predominate. In
early urticarial papules or plaques, neutrophils are aligned along the BMZ,
accompanied by vacuolar change and sometimes by neutrophilic micro abscesses in
dermal papillae. These papillary dermal collections, if numerous enough, can
resemble the picture seen in DH. In fully developed lesions, there are
subepidermal bullae in which neutrophils are present in the in the blister cavity
and the underlying upper dermis, either alone or with
eosinophils. Eosinophils can become more numerous over time, particularly in
adults, thus mimicking the histopathologic picture of bullous pemphigoid.
Although in most cases distinguishing between DH and LABD is impossible by light
microscopy, a linear distribution of neutrophils along the BMZ and neutrophils
at the very tips of dermal papillae favor LABD. However, the latter cannot be
considered a specific finding.
LABD can be
subdivided on the basis of immunoelectron microscopy findings: most patients
have IgA deposits within the lamina lucida. Less commonly, there is deposition
of IgA in the sublamina densa, associated with anchoring fibrils. In a few
cases, deposits of IgA have been observed in both sites. In one report, the
deposition of IgA was initially in the lamina lucida, but later had a combined
pattern.
Diagnosis
Diagnosis is based on
the combination of the clinical picture and direct IF microscopy. LABD can be difficult to diagnose clinically, especially in
adults, and is often confused with DH and BP. By definition, LABD is separated
from DH and BP on the basis of findings by DIF. Linear IgA deposition along the
BMZ in perilesional skin is characteristic of LABD, in contrast to either DH,
which shows granular deposition of IgA in dermal papillary tips or in a
continuous pattern along the basement membrane, or BP, which shows linear
deposition of IgG along the epidermal BMZ. The classification of cases
demonstrating both IgG and IgA along the BMZ is problematic. Some authorities
include only those patients with IgA as the sole BMZ immunoglobulin under the
term LABD and categorize all others as BP. Others categorize patients with both
IgG and IgA along the BMZ based on the predominant immunoglobulin by DIF.
Perhaps the most important point is that patients with IgA along the BMZ, alone
or in combination with IgG, are more likely to respond to dapsone therapy.
Distinguishing the sublamina densa form of LABD from epidermolysis bullosa acquisita
is also made on the basis of the class of immunoreactant and classification can
be problematic.
Circulating
anti-BMZ antibodies of the IgA class can be demonstrated in 60–70% of LABD
sera. In contrast, patients with DH have not been shown to have circulating
antibodies that bind to skin, and 60–70% of patients with BP demonstrate
circulating IgG class antibodies. Circulating IgA class anti-BMZ antibodies
from the lamina lucida type of LABD have been shown to adhere to the epidermal
side (roof) of salt-split skin, while patients with sublamina densa binding of
IgA on direct immunoelectron microscopy have serum antibodies which bind to the
dermal side of salt-split skin. Patients with both IgA and IgG at the BMZ
demonstrate binding to the epidermal side of salt-split skin. Whether or not
such antibody titers correlate with disease activity has not yet been
established.
For the morbilliform or TEN-like
presentation of LABD due to drugs, in particular vancomycin, routine microscopy
plus DIF aids in the diagnosis.
Treatment
The majority of patients with LABD respond to
either oral dapsone or sulfapyridine therapy. In localized or
limited disease very potent topical corticosteroids may suffice. Otherwise,
dapsone is regarded as first line treatment which may be used in combination
with the topical corticosteroids. Glucose‐6‐phosphate
dehydrogenase deficiency should be excluded before dapsone is prescribed. The
most frequent adverse events are anemia (a reduction of hemoglobin of 1–2 g/dL
can be expected), methaemoglobulinaemia and increased liver enzymes.
Agranunlocytosis is rare but can be fatal and at least monthly blood counts are
required and in case of fever, agranulocytosis needs to be excluded.
Sulfapyridine and, often better tolerated, sulfamethoxypyridazine are an
alternative for dapsone. Most patients with LABD have a clinical response
within 48–72 hours. Some patients may require concomitant low‐dose
prednisolone (0.25–0.5 mg/kg/day) to suppress blister formation. However, the majority of patients can be controlled
by dapsone alone. It has been observed that cases in which both IgG and IgA
deposits are present in the BMZ are those that are likely to require additional
therapy with systemic corticosteroids. The average
dose of dapsone required to control LABD in adults is 100 mg daily, but doses
as high as 300 mg daily may be needed. If doses >200 mg per day are
necessary, close monitoring should be undertaken. Children usually respond to a
dose of 1–2 mg/kg daily.
Successful treatment of both adult and childhood LABD
with antibiotics, including dicloxacillin, erythromycin, tetracycline (in those
>9 years of age), and trimethoprim–sulfamethoxazole, has been reported. No
specific microorganism was incriminated in these cases and therapeutic trials
were empirical. Mycophenolate mofetil, azathioprine and IVIg can be used as
steroid-sparing agents in patients who do not respond to a combination of
prednisone and dapsone or in patients with severe disease.
First line
Dapsone + very potent topical corticosteroids ±
prednisolone 0.25–0.5 mg/kg/day
Second line
Other sulfa drugs (sulfapyridine, sulfamethoxypyridazine)
Anti‐inflammatory antibiotics
(e.g. oxytetracycline, doxycycline) ± nicotinamide
Third line
Mycophenolates (2 g/day; 1.440 mg/day)
IVIG 2 g/kg/month
Immunoadsorption
