Pemphigus is defined as a group of life-threatening blistering disorder of skin and mucous membrane characterized by acantholysis (loss of keratinocyte to keratinocyte adhesion). The process of acantholysis is induced by circulatory autoantibodies to intercellular adhesion molecules [9]. There are five major categories of pemphigus: PV, pemphigus foliaceus, PNP, drug-induced pemphigus and IgA pemphigus. Each form of this disease has antibodies directed against different target cell surface antigen, resulting in a lesion forming in different layers of the epithelium [10]. The oral mucosa is the initial site of involvement in 70%-90% of the cases before involvement of the skin and other mucosal sites [1]. Nasal, conjunctival, pharyngeal, laryngeal, esophageal and genital mucosa are the other mucosal sites that may be affected.

The etiology of PV is uncertain as is with other auto-immune diseases [17,18]. In some cases, it is found to have a strong genetic basis, as it has been reported in certain racial groups, for example, the Ashkenazi Jews and those of Mediterranean descent. Strong association between certain HLA class II alleles has also been demonstrated. Other initiating factors include certain foods, infection, neoplasms, and drugs. The drugs commonly implicated are those in the thiol group, in particular captopril, penicillamine, and others such as rifampicin⁶. PV is believed to occur as a result of autoantibodies directed against the components of epithelial desmosomes. The desmosomes consist of two membrane-bound adhesion molecules, Dsg [11] and desmocollin, which are linked to the cytoskeleton through intracellular plakoglobin, plakophilin and des mop akin [12]. Dsg consists of two subtypes, Dsg-1 and Dsg-3, which are expressed variably in the skin and oral mucosa. Dsg-3 is expressed in the basal layers of the epidermis while the superficial epidermal cells predominantly express Dsg-1. In the oral mucosa, Dsg-3 expression predominates over Dsg-1. Thus, the oral epithelial integrity is exclusively dependent on Dsg-3, which is targeted by the autoantibodies in cases of PV affecting the oral cavity [6].

The binding of Pemphigus Vulgaris antibody activates protease, whereas more recent evidence supports the theory that the Pemphigus vulgaris antibodies directly block the adhesion function of the desmoglein [13,14,15]. The separation of cells called acantholysis takes place in the lower layers of stratum spinosum, which results in the formation of supralaminar bulla. The bulla increasingly involves a larger area of epithelium, resulting in loss of large area of skin and mucosa.

The classical lesion of pemphigus is a thin walled bulla that are very fragile and rupture easily, giving rise to painful and hemorrhagic erosions arising on otherwise normal skin or mucosa. A characteristic sign of the disease may be obtained by the application of pressure to intact bullae. In a patient with Pemphigus Vulgaris, bullae enlarge by extension to an apparently normal surface. Another characteristic sign of the disease is the pressure to apparently normal area resulting in the formation of a new lesion. This phenomenon, called Nikolysky sign, results from the upper layer of the skin pulling away from the basal layer. Nikolysky sign is also found to be positive in toxic epidermal necrolysis, scalded skin syndrome (both of which are acute conditions) and mucous membrane pemphigoid [16].

Most patients with oral lesions could be initially misdiagnosed, usually as aphthous stomatitis, gingivostomatitis, erythema multiforme, erosive lichen planus, or oral candidiasis, and may be improperly treated for months or years. Other differential diagnoses include dermatitis herpetiformis and cicatricial pemphigoid¹. If proper history is taken, the clinician should be able to distinguish the lesions of pemphigus from those caused by acute viral infections like herpes and erythema multiforme. Immunosuppressed patients present with recurrent herpetic simplex infections in the form of atypical ulcers, which may last several weeks or months if undiagnosed and untreated. Moreover, the presence of Tzank cells may complicate the diagnosis. Since in the present case, the patient did not give history of immunocompromise like chemotherapy, organ transplant or acquired immune deficiency syndrome, recurrent herpes simplex infection could be safely ruled out.

Differential diagnosis of Pemphigus Vulgaris can be done from other similar conditions by biopsy and direct immunofluorescence. Biopsies are best done on intact vesicles and bullae less than 24 hours old. The biopsy specimen should be taken from the advancing edge of the lesion, where the area of characteristic supralaminar acantholysis can be observed by the pathologist. Supra basilar split seen in Pemphigus Vulgaris helps distinguish this condition from sub-epithelial blistering diseases such as mucous membrane pemphigoid, bullous lichen planus and chronic ulcerative stomatitis. Indirect immunofluorescence is helpful in further distinguishing pemphigus from pemphigoid and other chronic oral lesions and is useful in following the progress of patient for pemphigus. The diagnosis is confirmed by the characteristic deposition of IgG and other C3 antibodies that bind to cell surface of perilesional skin or mucosa^19,20. Indirect immunofluorescence is less sensitive than direct immunofluorescence, but may be helpful if biopsy is difficult. ELISA has been developed that can detect desmoglein 1 and 3 in serum sample of patients with Pemphigus Vulgar [20]. The presence of anemia and submandibular gland lymphadenopathy along with painful stomatitis and acantholysis on histopathological investigations in the present case led to the differential diagnosis of paraneoplastic pemphigus. Absence of underlying lymphoproliferative disorder, the reduced severity of the lesions and absence of inflammation at the dermal-epidermal junction and keratinocyte necrosis in addition to characteristic acantholysis helped rule out this condition. Also, direct immunofluorescence of para neoplastic pemphigus shows deposition of IgG and complement along the basement membrane as well as on the keratinocyte surface in an intercellular location [21].

An important aspect of patient management is early diagnosis when lower doses of medication can be used for shorter periods of time to control the disease. Dental professionals must be sufficiently familiar with clinical manifestation of pemphigus vulgaris to ensure early diagnosis and treatment, since this in turn determines the prognosis and course of the disease. Institution of early treatment could prevent serious involvement of other mucosa and cutaneous sites and fatal complications. Without proper treatment, this condition can be fatal because of loss of the epidermal barrier function, leading to loss of body fluids and secondary bacterial infection [22]. Pemphigus Vulgaris is generally managed with local and systemic corticosteroid therapy. Treatment is administered in 2 phases: a loading phase, to control the disease, and a maintenance phase, which is further divided into consolidation and treatment tapering. Local treatment consists of a paste, an ointment or a mouthwash administered alone or in conjunction with systemic treatment. Intralesional injections of corticosteroids have been used for the management of persistent lesions [23]. In cases of extensive oral lesions or involvement of other mucosa and skin, systemic corticosteroid therapy is initiated immediately. The initial of prednisone 0.5–2 mg/kg is recommended [24]. Depending on the response, the dose is gradually decreased to the minimum therapeutic dose, taken once a day in the morning to minimize side effects. When steroids are used for longer periods of time, adjuvants such as Azathioprine or Cyclophosphamide are added to the regimen to reduce the complications of long-term corticosteroid therapy. Before the advent of corticosteroid therapy, pemphigus was fatal, with a mortality rate of up to 75% in the first year. It is still a serious disorder, but the 5% to 10% mortality rate is now primarily due to the side effects of therapy [25].

Emerging therapies include intravenous immunoglobulins, plasmapheresis, immunoadsorption (IA), Extracorporeal Photochemotherapy (ECP), monoclonal antibodies such as rituximab, Tumor Necrosis Factor-Alpha (TNF-α) antagonists, viz., infliximab and etanercept, cholinergic agonists, and other experimental therapies such as desmoglein 3 peptides and KC706⁴. Some studies have suggested Co-enzyme Q10 as adjuvant therapy for periodontal involvement in PV [26].

If undiagnosed, PV may lead to grave consequences. The article focuses on timely diagnosis and appropriate management of a pemphigus patient. Therefore, we need to induce and maintain remission with the lowest possible doses of medication, so as to minimize the risk of serious and potentially fatal adverse effects.