| What are blistering diseases in adults? | 1. Autoimmune bullous eruption: Pemphigus,
bullous pemphigoid
2. Pemphigoid gestationis
3. Dermatitis herpetiformis
4. Porphyria cutanea tarda |
| What is Pemphigus? | • Pemphigus is derived from the Greek word pemphix meaning bubble or blister. Pemphigus describes a group of chronic bullous diseases
• Incidence varies from 0.5-3.2 cases/100,000 population
• Autoimmune blistering disease of the skin and mucous
membranes characterized histologically by intraepidermal blister and immunopathologically by the finding of in vivo bound and circulating immunoglobulin G (IgG) antibody directed against the cell surface of keratinocytes. Pemphigus vulgaris (PV) accounts for approximately 70% of pemphigus cases |
| How is pathogenesis of Pemphigus? | • Blisters in pemphigus vulgaris are associated with the
binding of IgG autoantibodies to keratinocyte cell
surface molecules (desmoglein 1 and 3)
• These antibodies bind to keratinocyte desmosomes
and to desmosome-free areas of the keratinocyte cell
membrane
• The binding of autoantibodies results in a loss of cellto-cell adhesion, a process termed acantholysis
• The antibody alone is capable of causing blistering
without complement or inflammatory cells |
| How are Abs and complements causing pemphigus? | • Mucocutaneous form of PV: antidesmoglein 1 & 3
• Mucosal form only: antidesmoglein 3
• Active disease: circulating IgG1 & IgG4
• Antibody binding may activate complement with
the release of inflammatory mediators and
recruitment of activated T cells
• IL 2 is the main activator of T lymphocytes, and
increased soluble receptors have been detected
in patients with active pemphigus vulgaris |
| How are phenotypes of pemphigus? | • (MHC) class II molecules, in particular alleles
of human leukocyte antigen DR4 and HLA DRw6, are common in patients with pemphigus vulgaris
• Associated diseases: myasthenia gravis;
thymoma |
| How is clinical presentation of pemphigus? | • Pemphigus vulgaris involves mucosa in 50-70%
of patients with a mortality rate of approximately 5-15%
• The mean age of onset is approximately 50-60
years
• Prognosis is worse in patients with extensive
pemphigus vulgaris and in older patients
• All patients have mucosal
lesions at some point in the
course of their disease
• Mucosal lesions may be the only sign for an average of 5 months before skin lesions develop, or they may be the sole manifestation of the disease
• The diagnosis of pemphigus vulgaris should be considered in any patient with persistent oral erosive lesions |
| How are lesions of pemphigus appearance? | • Intact bullae are rare in the mouth
• More commonly, patients have ill-defined, irregularly shaped, gingival, buccal, or palatine erosions, which are painful and slow to heal
• The erosions extend peripherally with shedding of the epithelium
• Erosions may spread to involve the larynx, with subsequent hoarseness. The patient often is unable to eat or drink |
| What is Niklosky sign? | • Nikolsky sign: In patients with active
blistering, firm sliding pressure with a finger
separates normal-appearing epidermis,
producing an erosion
• This sign is not specific for pemphigus vulgaris
and is found in other active blistering diseases |
| What is differential of pemphigus? | • Bullous pemphigoid
• Dermatitis herpetiformis
• Erythema multiforme
• Linear IgA dermatosis |
| What are labs for pemphigus? | • Histopathology
• Direct immunofluorescence (DIF) on normalappearing perilesional skin
• Indirect immunofluorescence (IDIF) using the
patient's serum if DIF results are positive
Histology:
• Histopathology from the
edge of a blister:
• Basal cells are separated from one another and stand like a row of tombstones on the floor of the blister, but they remain attached to the basement membrane Eosinophilic spongiosis in some patients |
| What are lab results of Pemphigus? | • DIF: IgG deposited on the surface of the keratinocytes in and around lesions. IgG1 and IgG4 are the most common subclasses
• Complement components such as C3 and Ig M are present less frequently than IgG. DIF shows intercellular deposition throughout the epidermis
• IDIF: presence of circulating IgG that bind to epidermis (80-90% of patients with pemphigus vulgaris). The titer of circulating antibody correlates with disease course |
| How is pemphigus tx? | • Therapy must be tailored for each patient, taking into account preexisting and coexisting conditions
• Corticosteroids (1 mg/kg/d) have improved overall mortality, but now much of the mortality and morbidity in these patients relates to the adverse effects of therapy
• Immunosuppressive drugs (eg. Azathioprine) are
steroid sparing and should be considered early in the
course of the disease
• EGF may speed healing of localized lesions.
• Rituximab as 1st or second-line therapy
• The anti-TNF drugs, sulfasalazine and pentoxifylline
have been reported as effective adjunctive treatments
• Dapsone has been suggested as a steroid-sparing
agent in the maintenance phase of PV
• Intravenous Ig therapy |
| What is Bullous pemphigoid? | • Bullous pemphigoid is a chronic, inflammatory,
subepidermal, blistering disease
• Periods of spontaneous remissions and
exacerbations. The disease can be fatal, particularly
in patients who are debilitated |
| How is clinical presentation of bullous pemphigoid? | • Bullous pemphigoid may present with several distinct clinical presentations, as follows:
• Generalized bullous form: The most common presentation; tense bullae arise on any part of the skin surface, with a predilection for the flexural areas of the skin
• Vesicular , vegetative, generalized erythroderma, urticarial , nodular form |
| How is dx of bullous pemphigoid? | • Histopathology: From the edge of a blister: subepidermal blister; the inflammatory infiltrate is typically polymorphous, with an eosinophil predominance; mast cells and basophils may be prominent early in the disease course
• DIF: on normal-appearing, perilesional skin
• IDIF: on the patient’s serum, if the DIF result is positive
• DIF: IgG and C3 deposition in a linear band at the dermal-epidermal junction, with IgG in salt-split skin found on the blister roof (epidermal side of split skin)
• IDIF: circulating IgG in the patient's serum that target the skin basement membrane component |
| How is tx of bullous pemphigoid? | • The goal of therapy in bullous pemphigoid is:
• Decrease blister formation
• Promote healing of blisters and erosions
• Determine the minimal dose of medication necessary to control the disease process
• The most commonly used medications for bullous pemphigoid are anti-inflammatory agents (eg, corticosteroids, tetracyclines, dapsone) and immunosuppressants (eg, azathioprine, methotrexate, mycophenolate mofetil, cyclophosphamide) |
| What is dermatitis herpetiformis (DH)? | • Autoimmune blistering disorder associated with a gluten sensitive antibodies (GSE)
• Characterized by grouped excoriations: erythematous, urticarial plaques; and papules with vesicles
• The classic location for lesions is on the extensor surfaces of the elbows, knees, buttocks, and back
• It is exquisitely pruritic, and the vesicles are often excoriated to erosions by the time of physical examination |
| How is dx of DH? | • Diagnosis requires DIF of a skin biopsy specimen showing deposition of IgA in a granular pattern in the upper papillary dermis
• Although most patients are asymptomatic, greater than 90% have an associated gluten- sensitive enteropathy upon
endoscopic examination
• Among patients with celiac disease, 15-25% develop dermatitis herpetiformis
• The mainstays of treatment are dapsone and a gluten-free diet |
| What is Pemphigoid Gestationis? | • Pemphigoid gestationis (PG) is a rare autoimmune
bullous dermatosis of pregnancy
• Most patients develop antibodies against 2
hemidesmosomal proteins, BP180 (BPAG2, collagen
XVII) and less frequently BP230
• Strong association with HLA-DR3 (61-80%) and HLADR4 (52%) (combination) |
| How is clinical presentation of pemphigoid gestationis? | • The initial clinical manifestations are erythematous urticarial patches and plaques, which are typically periumbilical
• These lesions progress to tense vesicles and blisters
• Some patients may present with urticarial plaques and may never develop blisters
• These hivelike plaques differ from true urticaria because of their relatively fixed nature
• The rash spreads peripherally, often sparing the face, palms, and soles. Mucosal lesions occur in less than 20% of cases |
| What are labs of pemphigoid gestationis? | • Histologic findings of a subepidermal blistering process and DIF: linear band of C3 deposition with or without Ig G (present in 20-25% of patients) along the basement membrane
• The DIF test is the key assay to differentiate pemphigoid gestationis (positive DIF findings) from pruritic urticarial papules and plaques of pregnancy (negative DIF findings)
• IDIF: for the detection of autoantibodies to BP180 antigen in patients with pemphigoid gestationis and that enzymelinked immunosorbent assay is useful to monitor autoantibody serum levels
• HLA-DR3/DR4 is present in 45% of patients with pemphigoid gestationis, as compared with 3% of the general population |
| How is tx of pemphigoid gestationis? | • Corticosteroids
• Even with optimum control, some blisters may continue to develop, and patients may have persistent pruritus
• The risks and benefits of therapy must always be evaluated for the mother and the fetus |
| What is Porphyria Cutanea Tarda (PCT)? | • PCT is an acquired and familial disorder in which
activity of the heme synthetic enzyme
uroporphyrinogen decarboxylase (UROD) is deficient
• Approximately 80% of all cases of PCT are acquired.
20% are familial, although the ratio may vary among
different geographic regions and ethnic groups
• Familial PCT most often arises from autosomal dominant inheritance of a single mutation of the UROD gene. Human UROD has been mapped to band 1p34. A rare recessive familial type of porphyria cutanea tarda in which both UROD alleles are mutated is termed hepatoerythropoietic porphyria
• Familial PCT without detectable UROD mutations
has been reported |
| What are triggers of PCT? | • Clinical expression of both sporadic and familial PCT most often requires exposure to environmental or infectious
agents or the presence of coexisting conditions that adversely affect hepatocytes and result in hepatic siderosis.
• Ethanol intake, estrogen therapies, hemochromatosis genes, and hepatitis and HIV infections are among these contributory factors
• Excess iron enhances formation of toxic oxygen species, increasing oxidative stress and apparently facilitating porphyrinogenesis by catalyzing the formation of oxidation products that inhibit UROD
• Reduction of hepatic UROD activity to approximately 25% of normal is required for clinical disease expression |
| How is clinical presentation of PCT? | • Fragility of sun-exposed skin after mechanical trauma, leading to erosions and bullae, typically on hands and forearms and occasionally on face or feet Healing of crusted erosions and blisters leaves milia, hyperpigmented patches, and hypopigmented atrophic scars
• Hypertrichosis over temporal and malar facial areas
• Pigmentary changes include melasmalike hyperpigmentation of the face
• A urine sample is often, but not always, grossly discolored with a tea- or wine-colored tint |
| What are labs of PCT? | • Urinary porphyrin levels are abnormally high in PCT
patients, with several hundred to several thousand
micrograms excreted in a 24-hour period
• The excess porphyrin pigment is often grossly
evident in visible light and yields a pink fluorescence
under Wood lamp (black light) radiation
• Skin biopsy findings by light microscopy DIF may be
consistent with a diagnosis of PCT but are not
unequivocally diagnostic
• DIF can help differentiate PCT from immunobullous
diseases with dermoepidermal junction cleavage
(epidermolysis bullosa acquisita, lupus erythematosus) in which the perivascular Ig deposition found in PCT is not observed |
| How is tx of PCT? | • Phlebotomy reduces iron stores, which improves
heme synthesis disturbed by ferro-mediated
inhibition of uroporphyrinogen decarboxylase
(UROD)
• Oral chloroquine phosphate (125-250 mg PO twice
weekly) or hydroxychloroquine sulfate (100-200 mg
PO 2-3 times/wk), doses much lower than those
used for antimalarial or photoprotective indications |
