PEMPHIGUS VULGARIS: CLINICAL FEATURES,HISTOLOGY & TREATMENT
Author: Sanketh DS, MDS
Pemphigus vulgaris is an autoimmune muco-cutaneous condition occurring as a result of inappropriate production of auto-antibodies against desmosomes holding the epithelial cells together, leading to an intra-epithelial blister formation. There is widespread ulceration of the skin, oral mucosal and other mucosal surfaces causing much pain and debilitation.
There are four types of pemphigus recognised, each differing in the level of intra-epithelial involvement: pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus and pemphigus erythematosus.
Pemphigus vulgaris is the most common type involving the oral mucosa and skin. Pemphigus vegetans, considered to be a variant of vulgaris can involve the oral mucosa and skin and presents with vegetating plaques with pustules and ulceration. Pemphigus foliaceus is endemic in Brazil and occurs predominantly on the skin. Pemphigus erythematosus is a more localised, less severe form of foliaceus manifesting as a malar rash on the face resembling lupus erythematosus.
There are several types of cellular junctions in the oral mucosal epitheium, one group of which is called Macula adherens or Desmosomes. Desmosomes or any cellular junctions for that matter are composed primarily of three proteins: transmembrane proteins, cytoplasmic adapter proteins and cytoskeletal filament. In the desmosomal junction desmoglein and desmocollin form the transmembrane proteins and their interaction creates a dense line in the middle of the intercellular space.
Pemphigus is a type II hypersensitivity reaction, where the desmoglein components of the desmosomes are primarily targeted by auto-antibodies severing inter-epithelial junctions resulting in a split. It has been speculated that the T helper cells happen to recognise the desmoglein epitopes leading to B cell activation and antibody formation. These anti-bodies may activate intracellular proteolytic enzymes that act on desmogleins. Antibodies IgG4 of the IgG immunoglobulin are the predominant antibodies causing the attack.
While desmoglein 3 is predominant in the oral mucosal epithelial junctions, desmoglein 1 is present in the dermis. Also desmoglein 3 is concentrated in the parabasal layers while desmoglein 1 is present in the superficial epithelial layers. If patients develop auto-antibodies to desmoglein 3 there is a split in the parabasal layers affecting the oral mucosa, and the epidermis is affected with a superficial split, when desmoglein 1 is targeted. Patients with pemphigus vulagris develop antibodies against demoglein 3, with the oral mucosa affected and progress to develop antibodies against desmoglein 1 with a subsequent involvement of the skin. However patients with pemphigus vulgaris may also have lesions restricted to the oral cavity.
This hypothesis however, is still clouded in controversy and there have been other non-desmoglein adhesion proteins also proposed to be involved in this condition.
Pemphigus vulgaris has an equal gender predilection occurring in the 4th – 6th decades with the average age at diagnosis being 50. This condition often commences with oral mucosal symptoms in approximately 60% of cases as much as 1 year prior to skin lesions.
Bullae may rapidly rupture leaving painful, raw irregularly shaped erosions and ulcers. Ulcers may range from a few millimetres to several centimetres occurring haphazardly in the oral mucosa. Bullae are seldom seen in the oral cavity probably because of their friable nature which ruptures early. Free margins of the gingiva are commonly affected due to chronic abrasion during tooth brushing. Lateral margins of the tongue where constant frictional activity occurs may commonly have symptomatic erosions and ulcers. Other sites involved are palate, labial mucosa, buccal mucosa and ventral tongue. Patients are often unable to eat or drink due to the discomfort caused by these erosions.
A characteristic feature of pemphigus vulgaris is Nikolsky’s sign where a gentle lateral pressure or traction on the clinically unaffected peri-lesional tissue could induce stripping of epithelium or bulla formation.
Pemphigus vulgaris also shows a “bulla spread sign” or the “Asboe Hansen sign” which refers to the extention of the blister to the adjacent unblistered skin/mucosa when pressure is applied on top of the bulla. This sign however can be elicited in other vesicullo-bullous lesions as well.
Pemphigus vegetans is a variant of vulgaris having muco-cutaneous manifestations. It occurs as two different clinical subtypes, with one occurring as erosions and ulcers (Neumann type) and the other occurring as pustules (Hallopeau). Both clinical subtypes of vegetans subsequently develop plaque like vegetations. A feature of this variant of pemphigus vulgaris is the “cerebriform tongue”, characterised by a pattern of sulci and gyri on the dorsum of the tongue.
Microscopy shows an intraepithelial split at the level of the parabasal layer (supra-basilar split). At times, all superficial layers are stripped away leaving only the basal layer intact resembling “ a row of tombstones” . The split or the separation occurring in the spinous layer is called acantholysis and the split cells lose their polygonal shape becoming round . These cells are called Tzanck cells and are often identified in exfoliative cytological preparations. A mild- moderate chronic inflammatory infiltrate may be seen in the adjacent connective tissue.
The microscopic diagnosis can be confirmed by a direct immunofluorescence procedure, which shows antibodies (IgG) and complement(C3) in the intercellular spaces forming a “chicken wire” appearance. There is no staining in the basement membrane zone. Indirect immunofluorescence is also 80-90% of the times positive showing a similar appearance.
Systemic corticosteroids (usually prednisone) are administered with other immunosuppressive drugs like azathioprine or mycophenolate mofetil. Topical corticosteroids are administered for oral lesions.
High doses of systemic corticosteroids are commenced and are reduced slowly after the lesions have healed. The patient is then maintained at a low dose to exercise control over the condition. Pemphigus vulgaris is characterised by its remissions and exacerbations despite control with corticosteroids.
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