**4. Clinical features**

**Disease and Subtype(s)** *(alternate terms)*

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(FS))

IgA pemphigus Rare

Subcorneal pustular dermatosis *("Sneddon-Wilkinson*

*disease")*

Familial benign chronic pemphigus *("Hailey-Hailey disease")*

Intraepidermal neutrophilic IgA dermatosis

Paraneoplastic pemphigus Common &

Endemic pemphigus ( "Brazillian pemphigus" or "Fogo Sevagem"

Common (endemic form)

(all 3 forms of IgA pemphigus)

very severe

**Clinical Presentation Natural History/**

PF and FS are identical clinically, histologically, and serologically but differ significantly, *epidemiologically*, with marked geographic clustering in Brazil, being a diseases of people resident in/or near the rainforests. The autoimmune response in FS is thought to be triggered by a putative

environmental factor.

of the eye.

antigens.

Rare, characterised by pruritic, flaccid vesicles and/or pustules in annular pattern with central crusting, sometimes hypopyon\*

Pathogenesis: related to the neutrophilic infiltrate in the epidermis rather than solely to the binding of IgA to target epidermal

DIF: IgA (cf IgG seen in all other forms of pemphigus) deposits in lower epithelium or

Subcorneal (beneath the stratum corneum) blister containing neutrophils with epidermal acanthosis and spongiosis, results

Deeper, intra-epidermal blister containing neutrophils with epidermal acanthosis and spongiosis, results in more marked blistering

Polymorphous skin eruption, consisting of blisters, erosions, and targetoid lesions; severe mucous membrane involvement. DIF: IgG deposits on entire epidermal cell surfaces +/- granular-linear complement auto-antibodies to rat bladder epithelium in

It presents a chronic recurrent bullous and vesicular dermatitis of intertriginous areas that is characterized histologically by

entire epidermal cell surfaces

in superficial fragile blistering.

and consequent ulceration.

75% of cases.

Rare Not a true form of pemphigus, as it is not antibody mediated.

suprabasilar acantholysis.

**Prognosis/ Outcome**

Recalcitrant to treatment with corticosteroids

**Target Antigens**

Desmoglein 3 (& Desmoglein

1)

Fatal Desmoglein 3,

chronic, relapsing– remitting course

Desmoplakin 1, Desmoplakin 2, BP 230, evoplakin, periplakin, others

Desmocollin 1

#### **4.1. Pemphigus vulgaris**

Patients with PV usually present, in the initial stage, with highly painful erosions of the oral mucosa (Figures 1, 2) [23], but other mucous membranes such as the nasal, laryngo-esophageal, genital, anal and conjunctival mucosae can be involved. Some patients have mucosal dominant disease whereas in others cutaneous lesions develop and manifest as flaccid blisters followed by denuding and ulceration (Figure 3). A direct Nikolksy's sign can be elicited where tangential pressure on the on perilesional skin causes the epidermis to separate from the dermis. Skin lesions have a predilection for the trunk, groins, axillae, scalp, face, and pressure points. Secondary infection and dehydration are frequent cause of morbidity and mortality. Studies that differentiate PV according to clinical phenotype have shown a lower mortality in patients with predominantly mucosal PV (1–17%) compared with those with mucocutaneous PV (34– 42%)[24].

#### **4.2. Pemphigus foliaceus**

Non-endemic PF usually presents in middle age or older adults whereas endemic PF is more common in children and young adults. FS in Tunisian affect women 4 times as often as men [7]. In both non-endemic and endemic PF, patients usually report the eruption of blisters on the scalp, face and upper trunk but they are fragile and some patients present instead with multiple painful crusted erosions (Figure 4). There is no history of mucosal involvement.

**Figure 1.** Pemphigus vulgaris with palatal ulceration and bleeding

**Figure 2.** Pemphigus vulgaris with desquamative gingivitis

Pemphigus erythematosus is considered to be combination of PF and systemic lupus erythe‐ matosus typified by the presence of erosions in a malar distribution. Drug-associated cases may implicate angiotensin-converting enzyme inhibitors [25], penicillamine [26] or rifampicin [27]. There may be an intercurrent medical history of bullous pemphigoid [28], myasthenia gravis [29] or other autoimmune diseases [30]. PF has been associated with various malignan‐ cies such as non-Hodgkin's lymphoma [31], prostate cancer [32], and cutaneous squamous cell cancer [33].

**Figure 4.** Pemphigus foliaceus characterised by exfoliative erythroderma

**Figure 3.** Pemphigus vulgaris characterised by multiple ulcers over the lower back

the spectrum, PF can result in an exfoliative erythroderma.

In both non-endemic and endemic PF, superficial flaccid vesicles and bullae may be evident and a positive Nikolsky sign is commonly elicited. However, the fragility of these lesions result in the formation of scaled erosions reflecting detachment of the stratum corneum from the stratum granulosum described as a 'corn flakes' appearance (Figure 5). At the severe end of

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**Figure 3.** Pemphigus vulgaris characterised by multiple ulcers over the lower back

**Figure 4.** Pemphigus foliaceus characterised by exfoliative erythroderma

Pemphigus erythematosus is considered to be combination of PF and systemic lupus erythe‐ matosus typified by the presence of erosions in a malar distribution. Drug-associated cases may implicate angiotensin-converting enzyme inhibitors [25], penicillamine [26] or rifampicin [27]. There may be an intercurrent medical history of bullous pemphigoid [28], myasthenia gravis [29] or other autoimmune diseases [30]. PF has been associated with various malignan‐ cies such as non-Hodgkin's lymphoma [31], prostate cancer [32], and cutaneous squamous cell

**Figure 1.** Pemphigus vulgaris with palatal ulceration and bleeding

110 Skin Biopsy - Diagnosis and Treatment

**Figure 2.** Pemphigus vulgaris with desquamative gingivitis

cancer [33].

In both non-endemic and endemic PF, superficial flaccid vesicles and bullae may be evident and a positive Nikolsky sign is commonly elicited. However, the fragility of these lesions result in the formation of scaled erosions reflecting detachment of the stratum corneum from the stratum granulosum described as a 'corn flakes' appearance (Figure 5). At the severe end of the spectrum, PF can result in an exfoliative erythroderma.

**Figure 5.** Pemphigus foliaceus with large scaly and crusted erosions over the trunk giving a 'corn flakes' appearance

PF causes significant morbidity as the lesions are painful and patients are prone to secondary infection, dehydration and metabolic disturbances with fatalities reported for those cases involving exfoliative erythroderma.

> to the basement membrane (tombstone pattern), which forms the floor of the blister. The roof of the blister comprises relatively intact superficial epidermal layers with the stratum corneum showing a basketweave pattern. Hematoxylin and eosin staining demonstrates suprabasalar acantholysis and infiltration with predominantly neutrophils and eosinophils. A sparse perivascular lymphocytic and eosinophilic inflammatory infiltrate is found in the upper dermis [35] (Figure 6). In contrast, intraepidermal splitting is found subcorneally in PF with the initial formation of vacuoles within the intercellular spaces of the granular and/or upper spinous layers of the epidermis. [34] The vacuoles become larger and eventually lead to subcorneal blister formation within the upper epidermis (Figure 7). Hematoxylin and eosin staining show variable amounts of acantholytic keratinocytes, neutrophils, and fibrin within the blisters (Figure 8). Chronic PF lesions may show evidence of papillomatosis, acanthosis, hyperkeratosis, parakeratosis, and follicular plugging. The papillary dermis contains an inflammatory infiltrate composed of small numbers of neutrophils, eosinophils, and lympho‐

> **Figure 6.** Medium power view of a skin biopsy from a patient with pemphigus vulgaris showing acantholysis of the suprabasal keratinocytes leaving a single layer of basal keratinocytes attached to the basement membrane (tomb‐ stone pattern), which forms the floor of an intraepidermal blister. The roof of the blister comprises relatively intact superficial epidermal layers with the stratum corneum. A sparse perivascular lymphocytic and eosinophilic inflamma‐

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Biopsy for direct immunofluorescence should be taken from perilesional mucosa and/orskin [36]. Biopsy of lesional tissue is not useful as immunoreactants are rapidly degraded by inflammatory activity [37]. To prevent the destruction of immunoreactants, specimens must be snap frozen and stored at temperatures below -70°C or placed in special transport media (such as Michel's medium) [36]. In direct immunofluorescence, specimens are incubated with fluorescein isothiocyanate-labelled antibodies against immunoglobulins, complement or fibrinogen, and examined with a fluorescent microscope [36]. In PV, direct immunofluores‐

cytes.

**5.2. Direct immunofluorescence**

tory infiltrate is found within the upper dermis.

#### **4.3. Differential diagnosis**

Clinically, the differential diagnosis for mucosal lesions of PV (before the development of cutaneous disease) includes herpes simplex virus, lichen planus, mucous membrane (cicatri‐ cial) pemphigoid: erythema multiforme, and paraneoplastic pemphigus. The differential diagnosis for cutaneous involvement include other autoimmune blistering skin conditions, such as pemphigus foliaceus, pemphigus vegetans, IgA pemphigus, paraneoplastic pemphi‐ gus, bullous pemphigoid, linear IgA disease, erythema multiforme, Grover's disease, and Hailey-Hailey disease.

The differential diagnosis of endemic and nonendemic PF includes bullous impetigo, IgA pemphigus, pemphigus herpetiformis, drug eruptions, subcorneal pustular dermatosis, and systemic lupus erythematosus. If lesions are localized to the face or scalp with abundant scaling and yellow crusting, seborrheic dermatitis needs to be considered. The differential diagnosis of exfoliative erythroderma as the manifestation of PF includes papulosquamous diseases such as psoriasis, pityriasis rubra pilaris, and Drug Reaction with Eosinophilia and Systemic Symptoms.
