Dermatology Dr. Ahmed Abdulhussein Alhuchami
Autoimmune Bullous Diseases
The dermo-epidermal junction
The basement membrane lies at the interface between the epidermis and dermis.
Electron microscopy shows that the lamina densa (rich in type IV collagen) is separated from the basal cells by an electron-lucent area, the lamina lucida. The plasma membrane of basal cells has hemidesmosomes (containing bullous pemphigoid antigens, collagen XVII and α6 β4 integrin). The lamina lucida contains the adhesive macromolecules, laminin-1,. Fine anchoring filaments (of laminin-5) cross the lamina lucida and connect the lamina densa to the plasma membrane of the basal cells. Anchoring fibrils (of type VII collagen), extend from the papillary dermis to the deep part of the lamina densa.
Pemphigus GroupGroup of disorders with loss of intraepidermal adhesion because of autoantibodies directed against proteins of the desmosomal complex that hold keratinocytes together. Pemphigus can be divided into:
1. The deep form: pemphigus vulgaris, with its reactive state, pemphigus vegetans.
2. The superficial form: pemphigus foliaceus, with its lupus-like variant, pemphigus erythematosus
Pemphigus Vulgaris (PV)
Definition: Severe, potentially fatal disease with intraepidermal blister formation on skin and mucosa caused by autoantibodies against desmogleins.
Epidemiology: not uncommon in our country affecting young adults with equal male:female ratio.
Pathogenesis:Genetic predisposition: HLA associations exist.
Patients develop antibodies against desmoglein 3 (Dsg3) and later desmoglein 1 (Dsg1). The bound antibodies activate proteases that damage the desmosome, leading to acantholysis.
Serum antibody titer usually correlates with disease activity.
Occasionally drugs cause pemphigus: penicillamine, captopril.
Clinical features: Sites of predilection include oral mucosa, scalp, face, mechanically stressed areas, nail fold, intertriginous areas (can present as intertrigo). The blisters are not stable, as the epidermis falls apart; therefore, erosions and crusts common.
Usually has three stages:
1-Oral involvement: In 70% of patients, PV starts in the mouth with painful erosions. Other mucosal surfaces can also be involved.
2- Additional localized disease, often on scalp. (Always check the scalp in patients with unexplained oral erosions.)
3-Generalized disease, flaccid blisters that rupture to painful, poorly healing crusted erosions and ulcers; blisters hard to find. Pruritus is uncommon.
Diagnostic approach: Clinical evaluation; check sites of predilection.
Nikolsky sign: Gentle rubbing allows one to separate upper layer of epidermis from lower, producing
blister or erosion. Fairly specific for pemphigus.
Histology: Can be helpful, but often just erosions or nonspecific changes. When a fresh lesion is biopsied, acantholysis is seen (free-floating, rounded keratinocytes) with retention of basal layer keratinocytes (tombstone effect) and mild dermal perivascular infiltrates.
Direct immunofluorescence: Perilesional skin shows deposition of IgG, C3. Antibodies surround the individual keratinocytes.
Indirect immunofluorescence: 90% of sera show positive reaction; titer can be used to monitor disease course.
ELISA: Can be used.
Therapy: Because of the dangers of pemphigus vulgaris, and the difficulty in controlling it, patients should be treated in a specialized unit. Treatment needs regular follow-up and is usually prolonged. Systemic corticosteroids are necessary for long periods of time. Resistant and severe cases need very high doses of systemic steroids, such as prednisolone 80–320 mg/day, and the dose is dropped only when new blisters stop appearing.
Patients should be screened for osteoporosis and latent tuberculosis before starting long-term corticosteroid therapy. Osteoporosis prophylaxis may be warranted.
The main cause of morbidity and mortality today in patients with pemphigus vulgaris is corticosteroid side-effects. For this reason, corticosteroids are always combined with steroid-sparing agents. Immunosuppressive mycophenylate mofetil, are often used as steroid-sparing agents.
New and promising approaches include plasmapheresis and intravenous immunoglobulin as used in other autoimmune diseases. In superficial pemphigus, smaller doses are usually needed, and the use of topical corticosteroids may help too.
supportive and Topical measures: good nutrition, fluid replacement, daily bathing, k permanganate compresses, local anesthetic gels in the mouth before meals, antiseptics and anticandidal measures may also be useful. agents, such as azathioprine or cyclophosphamide and, recently, High-dose intravenous immunoglobulin (HIVIg) ;
(2 g/kg every 3–4 weeks) may help gain quick control whilst waiting for other drugs to work.
Rituximab ( Anti-CD20 monoclonal antibody) has been reported to help multidrug resistance, IV , once a week for 4 weeks.
Bullous Pemphigoid (BP)
Definition: hemidesmosomes in the basement membrane zone (BMZ).
Epidemiology: Favors elderly, with male:female ratio of 2:1.
Pathogenesis: Autoantibodies are directed against two hemidesmosomal proteins: called bollous pemphigoid antigens (BPAGs )1and 2.
The binding of autoantibodies leads to complement activation, attraction of eosinophils, release of proteases, and separation between the epidermis and dermis.
Less common causes include drugs (benzodiazepine, furosemide, penicillin, sulfasalazine), sunlight, and ionizing radiation. Clinical features:
Before blisters develop, pruritus, dermatitic, and urticarial lesions may be present. The blisters tend to develop in these areas.
Blisters are tense and stable. They often have a fluid level and some are hemorragic. In contrast to pemphigus, the Nikolsky sign is negative.
The course is chronic and benign. The lesions involve the trunk, extremities, and intertriginous areas, with the oral mucosa involved in about one third of the cases.
Diagnostic approach: Laboratory: elevated ESR, eosinophilia, increased IgE.
Histology: subepidermal blister with cellular infiltrate containing many eosinophils and neutrophils. Direct immunofluorescence: band of IgG and C3 along BMZ.
Indirect immunofluorescence: circulating antibodies are positive but not correlate with the disease activity.
ELISA: identifies antibodies against both BPAGs.
Therapy: Mainstay is systemic corticosteroids: In the acute phase, prednisolone at a dosage of 40–60 mg/day is usually needed to control the eruption. The dosage is reduced as soon as possible, and patients end up on a low maintenance regimen of systemic steroids, taken on alternate days until treatment is stopped. Immunosuppressive agents (azathioprine) may also be required as steroid-sparing agent. Some patients do well on high-potency topical corticosteroids; worth a try with localized disease or systemic problems (especially diabetes mellitus). Large open blisters and erosions may require topical antiseptics.