ORIGEN Y PRINCIPIOS DEL MODELO DE LAS IM

• Epidermolysis bullosa (EB) comprises a group of genetically determined skin disorders characterized by blistering of the skin (Fig.

12.1) and mucosae at birth or soon afterwards, following mild mechanical trauma (due to increased fragility of skin). Thus an alternative term for these disorders could be the

‘mechanobullous’ disorders.

• There are three main types of EB:

– EB simplex (intraepidermal split due to disruption of basal keratinocytes)

– Junctional EB (split through the basement membrane zone)

– Dystrophic EB (split in the subepidermal level).

• EB simplex is the commonest and mildest form of EB of autosomal dominant inheritance. It is characterized by onset of blistering over trauma prone sites at birth or infancy. Lesions heal without scarring.

Mucosae, nails and hair are essentially uninvolved.

• Junctional EB are autosomal recessive disorders and are broadly classified into two main types, the lethal and non-lethal forms.

They present at birth or soon after with severe fragility of the skin leading to extensive blistering and denudation. Oropharyngeal mucosae may be severely involved. Teeth may be malformed and prematurely lost and nails may be shed. This is the most fatal type of EB.

• Dystrophic EB is characterized by skin fragility, scarring with milia (Fig. 12.2), nail changes (Fig. 12.3) and have either autosomal recessive or dominant inheritance. The more severe autosomal recessive form is characterized by:

Fig. 12.1: Epidermolysis bullosa—baby showing multiple erosions

Fig. 12.2: Epidermolysis bullosa dystrophica–knee showing hemorrhagic bullae with scarring, milia and pigmentation

– Onset at birth or early infancy

– Blistering of skin mainly over trauma prone sites

– Oral blisters and scarring leading to ankyloglossia and microstomia

– Esophageal lesions causing painful dysphagia and later esophageal strictures.

– Perianal blistering, erosions and scarring causing stenosis and fecal retention.

– Ocular complications—symblepharon, corneal erosions and opacity

– Repeated blistering and progressive scarring—contractures and deformities (e.g. ‘Mitten hands’).

• Diagnostic techniques include skin biopsy, electron microscopy to ascertain the level of split and structures involved, antigen mapping and immunohistochemistry. No autoantibodies are demonstrated in the sera.

Prenatal DNA testing can be advised to couples at risk of having affected children.

• No specific treatment is available for EB and thus the mainstay of treatment is based on avoidance of provoking factors. Management of the neonate includes maintaining adequate nutrition and hydration and prevention of sepsis. Other aspects include care of the oral cavity, teeth, eyes and management of contra-ctures and deformities.

• Gene therapy appears as a realistic goal in the future.

PEMPHIGUS

• Pemphigus is derived from the Greek

‘pemphix’ meaning blister or bubble and is characterized by intraepidermal blistering at various levels in the epidermis.

• The key pathogenic process in this group of disorders is disruption of the intercellular cementing substance due to an autoantibody attack on the cellular adhesion proteins (desmogleins) leading to acantholysis.

• The pemphigus group of disorders includes two major types (and their variants) and several other minor types. The major types are:

– Pemphigus vulgaris (variant – Pemphigus vegetans): level of split-suprabasal.

– Pemphigus foliaceus (variant – Pem-phigus erythematosus): level of split – subcorneal.

• The other minor types of pemphigus include paraneoplastic pemphigus, drug induced pemphigus, IgA pemphigus and neonatal pemphigus.

Pemphigus Vulgaris

• Most common form of pemphigus, accounting for up to 80% of pemphigus cases. Occurs at any age, most commonly between fourth- sixth decades. In India, it occurs at younger age.

• It is due to IgG antibodies directed against epidermal cell adhesion molecules (desmoglein 3)- disruption of intercellular cementing substance—loss of adhesion between epidermal cells (acantholysis) intraepidermal blistering.

Clinical Features

• Almost all patients have mucosal lesions, 50–70% present with painful oral erosions.

Lesions may be limited to oral cavity for months to one year (Fig. 12.4).

Fig. 12.3: Epidermoloysis bullosa dystrophica–

albopapuloid lesions over the dorsa of feet and some of the toenails completely lost

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• Skin – flaccid bullae on normal or erythe-matous skin, with a predilection for scalp, face (Fig. 12.5), trunk (Figs 12.6 and 12.7), axillae and groins and pressure sites.

Bullae rupture producing painful erosions that show no tendency to heal spontaneously.

• Pruritus is absent or negligible.

• Nikolsky’s sign and Bulla spread sign (Asboe-Hansen sign) are positive. (Other disorders with positive Nikolsky’s sign are

staphylococcal scalded skin syndrome, toxic epidermal necrolysis, etc.).

• Other mucosae involved are conjunctiva, pharynx, larynx, oesophagus, urethra, vulva and cervix.

Fig. 12.4: Pemphigus vulgaris—painful erosions involving tongue and lips

Fig. 12.5: Pemphigus vulgaris—extending erosions without tendency to heal over the face

Fig. 12.6: Pemphigus vulgaris—involving chest Fig. 12.7: Pemphigus vulgaris—involving back

• Prognosis is poor without treatment but with systemic steroids mortality has been reduced to 5–15 %.

• Pemphigus may be associated with other autoimmune diseases such as thymoma, myasthenia gravis and malignancies like lymphomas and bronchogenic carcinoma.

Diagnosis

• Tzanck smear from the floor of the blister shows acantholytic cells. Acantholytic cell is a large, rounded epidermal cell with a large nucleus, perinuclear halo and peripheral condensation of cytoplasm (Fig. 12.8).

• Histopathological examination of a blister shows a supra-basal cleft in the epidermis.

The basal keratinocytes remain attached to the basement membrane but are separated from each other and stand like a ‘row of tombstones’.

• Immunofluorescence studies are the gold standard in diagnosis of the autoimmune blistering disorders. In pemphigus vulgaris, direct immunofluorescence done on the lesional skin shows deposition of intercellular IgG throughout the epidermis in a ‘fish-net’

pattern (Fig. 12.9). Indirect immuno-fluorescence done to determine levels of pathogenic antibodies in the sera of the

patients shows circulating intercellular IgG antibodies in 80–90% of the cases. Levels of these antibodies correlate with disease activity.

Pemphigus Vegetans

It is a clinical variant of pemphigus vulgaris characterized by vegetating lesions primarily in the flexures (Figs 12.10 and 12.11). Initial lesions are bullae or pustules, which rupture and progress to form vegetating plaques.

Pemphigus Foliaceous

• This disorder, characterized by blistering at a higher level in the epidermis is less common than pemphigus vulgaris and accounts for only 15–20 % of pemphigus cases.

• It is caused by IgG antibodies directed against intercellular adhesion molecules (desmoglein 1) found predominantly in the upper epidermis—disruption of intercellular cementing substance of upper epidermal cells-subcorneal blister formation.

• Clinically, pemphigus foliaceous is less severe than pemphigus vulgaris and is characterized by crusted, moist, scaly lesions in a seborrheic distribution (Fig. 12.12) involving scalp, face, chest and upper back. Blistering may not be obvious due to the superficial level of the split (very transient nature of blisters).

Fig. 12.8: Tzanck smear showing large rounded epidermal cells with large nuclei, perinuclear halo and peripheral condensed cytoplasm (Acantholytic cell)

Fig. 12.9: Direct immunofluorescence showing fish net pattern

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• Oral lesions are uncommon.

• Nikolsky’s sign is invariably positive (Fig. 12.13).

Diagnosis

• Tzanck smear from fresh erosion shows acantholytic cells.

• Histology shows a subcorneal cleft with acantholysis.

• Immunofluorescence findings are usually indistinguishable from pemphigus vulgaris.

Prognosis of this disorder is better than pemphigus vulgaris. This benign disorder responds well to treatment.

Fig. 12.10: Pemphigus vegetans—vegetating moist lesions occurring in the axilla

Fig. 12.11: Pemphigus vegetans—vegetating moist lesions in the retroauricular area

Fig. 12.12: Pemphigus foliaceous—moist scaly lesions in seborrheic areas of the face

Fig. 12.13: Nikolsky’s sign – tangential pressure with finger tip producing moist erosion due to peeling of skin

Pemphigus Erythematosus

It is a variant of pemphigus foliaceous charac-terized by immunological features of both pemphigus and lupus erythematosus (LE), that is, intercellular IgG and C3 in the epidermis (as in pemphigus) and in the basement membrane zone (as in LE) and antinuclear antibodies (as in LE). Clinically, erythematous, scaly rash over the nose and cheeks simulate LE while lesions on the trunk are similar to those in pemphigus foliaceous.

Other Variants of Pemphigus

• Endemic pemphigus foliaceous (Fogo Selvagem) is a variant of pemphigus foliaceous, endemic to certain parts of South America and is postulated to be precipitated by bites of the black fly (Simuliidae). The burnt appearance and burning sensation gave the disease its name, fogo selvagem, meaning

“wild fire”.

• Drug induced pemphigus (penicillamine, captopril, pyritinol, penicillin, rifampicin)—

clinically commonly present as pemphigus foliaceous.

• Paraneoplastic pemphigus—a polymor-phous blistering eruption with muco-cutaneous ulcerations having an underlying neoplasm.

• Pemphigus herpetiformis—superficial vesicles and inflammatory papules occur in herpetiform distribution.

• IgA pemphigus—has bound and circulating IgA autoantibodies against intraepidermal cell surface antigens and clinically may resemble subcorneal pustular dermatosis.

• Juvenile pemphigus— pemphigus occurring before 20 years of age

• Neonatal pemphigus— due to transplacental transfer of maternal anti-intercellular cement substance antibodies to the fetus. Blisters resolve in 2 weeks.

Differential Diagnosis

When skin is involved, other autoimmune vesiculobullous disorders need to be differen-tiated from pemphigus. On rare occasions, bullous impetigo, dyskeratotic acantholytic disorders (Darier’s disease, Hailey Hailey disease, Grover’s disease) can cause a problem.

When only the oral mucosa is involved, the following should be considered-aphthous ulcerations, oral erosive lichen planus, herpetic gingivostomatitis, erosive candidiasis, and erythema multiforme.

When both skin and oral mucosa are involved, it closely resembles erythema multiforme, Stevens Johnson syndrome, toxic epidermal necrolysis, bullous systemic lupus erythematosus, and generalized bullous fixed drug eruption.

Treatment of Pemphigus

• The mainstay of therapy in the pemphigus group of disorders is with systemic steroids, which can be given as conventional therapy (oral prednisolone in the dose of 1 mg per kg body weight) or as pulse therapy. An upcoming mode of therapy is the dexa-methasone cyclophosphamide pulse regimen consisting of 100 mg of IV dexamethasone in 5% dextrose infusion on 3 consecutive days of each month combined with IV cyclopho-sphamide 500 mg bolus dose on day 1 of the pulse and oral cyclophosphamide 50 mg daily on other days. This therapy reduces the conventional side effects of steroids.

• The other modalities of therapy include adjuvant therapy with dapsone, azathioprine, cyclosporine, methotrexate, gold salts, mycophenolate mofetil, intravenous immunoglobulin therapy and plasmapheresis and are essentially to reduce the side effects of steroids or to control the severe form of pemphigus.

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