Oral pemphigus without skin lesions treated with pulse steroid therapy.

Pemphigus is an autoimmune disease affecting the skin and mucosae. Oral lesions are common and sometimes are the only manifestations of the disease. The clinical presentations of pemphigus might mimic other vesiculobullous lesions of the oral cavity. We report a case of a 60-year-old male patient who complained of erosive lesions in the oral cavity. The lesions were diagnosed as pemphigus based on histopathological examination and immunofluorescence findings. The patient did not respond to topical steroids and low doses of systemic steroids. Since the patient began developing dermatological manifestations, he was administered pulse steroid therapy. He is currently under observation and his clinical signs and symptoms show improvement, although he has developed hyperglycemia as a complication.

INTRODUCTION

Pemphigus is an autoimmune disease that is mediated by B-lymphocytes. Autoantibodies develop against the antigens present in the desmosome-tonofilament junction of the intercellular bridges of epithelium. Such autoantibodies fix complement and initiate inflammation, which results in a suprabasilar split in the epithelium of skin and mucous membrane.[1] Thus, vesicles and bullae are the primary manifestations of this condition. Although skin is the most commonly affected site, mucous membranes in different regions may also show the characteristic lesions of pemphigus. It is of particular importance that oral mucosal lesions may sometimes precede skin lesions in some patients and sometimes may also be the only manifestation of the condition.[1]

CASE REPORT

A 60-year-old male patient reported to the outpatient department of our institute, with the chief complaint of burning sensation in the mouth for the past 3 months. He had no abusive habits, and his past dental history and family history were noncontributory. The patient was not under any medications. He had initially visited a general practitioner, who had prescribed him multivitamin tablets. When the lesions did not subside, he consulted a general dentist, who had first treated him symptomatically, with topical anesthetic gel and mouthwash. Later, he was advised antifungal drugs by the same dentist. However, since there was no real improvement in his condition, he was referred to us, 3 months after his initial oral lesions. A thorough intraoral examination revealed numerous erosive lesions on the right and left buccal mucosae, gingiva, floor of the mouth, soft palate, and oropharynx [Figure 1]. Similar erosive lesions were also observed in the nasal mucosa. Few of these eroded areas showed tissue tags over them. However, no intact vesicles or bullae were noticed. A general examination to identify similar lesions elsewhere in the body turned out to be negative. Based on the history and clinical findings, a vesiculobullous lesion was suspected. Pemphigus, mucous membrane pemphigoid, bullous lichen planus, erythema multiforme, and chronic ulcerative stomatitis were considered under differential diagnosis.

Figure 1

Oral lesions during the patient's first clinical visit showing erosive lesions on the buccal mucosa, palate, gingiva, and alveolar mucosa

Under local anesthesia, an incisional biopsy was performed from the edge of the eroded area in the buccal mucosa, taking care to include apparently unaffected mucosa also. Two samples were taken, and one was fixed in 10% neutral buffered formalin for routine histopathology. The other sample was immersed and transported in Michel's medium for direct immunofluorescence study.

Histopathology revealed the presence of a parakeratotic stratified squamous epithelium that showed features of intraepithelial blister formation. Most areas showed suprabasilar clefting with only the basal layer of epithelium attached to the underlying connective tissue. Within these clefts, numerous round-to-ovoid epithelial cells with large hyperchromatic nuclei and minimal eosinophilic cytoplasm, suggestive of acantholytic (Tzanck) cells, were also evident [Figures 2 and 3]. The histopathological features were suggestive of pemphigus. Direct immunofluorescence revealed intercellular staining of the epithelium with IgG, in a typical fishnet pattern, which was diagnostic of pemphigus [Figure 4]. Therefore, on the basis of clinical, histopathological, and immunofluorescence findings, a final diagnosis of pemphigus was made.

Figure 2

Histopathological examination showed the basal layer of epithelial cells (red arrowheads) separated from the rest of the epithelium by a cleft-like space (black asterisks) (H and E, ×200)

Figure 3

Freely floating Tzanck cells (red arrowheads) along with red blood cells, visible in the cleft-like spaces (H and E, ×400)

Figure 4

Direct immunofluorescence with IgG shows a typical fishnet type of positive fluorescence, along the intercellular junctions (white arrowheads) of the epithelium

The patient was initially prescribed tablet prednisolone 10 mg twice daily for 15 days. However, no marked response was noticed. In the meantime, the patient also started complaining of pruritus in the skin of the trunk region and he was referred to a dermatologist for review. The patient was admitted as an inpatient and was advised pulse steroid therapy. As part of the first phase of this treatment, he received 100 mg of dexamethasone in 500 ml of 5% dextrose on 3 consecutive days. Cyclophosphamide (500 mg) was also administered intravenously on day 2. In addition, the patient also received 50 mg of oral cyclophosphamide daily. The patient has been scheduled to receive this treatment once every month, until all lesions disappear. Between the monthly visits, the patient was advised to take tablet prednisolone (30 mg in the morning and 10 mg in the night), along with topical betamethasone for the skin lesions and triamcinolone gel for oral lesions. The patient has already undergone two courses of the first phase of the pulse steroid therapy and is scheduled to receive the third course shortly. His signs and symptoms have shown marked improvement, and the number of lesions has reduced considerably [Figure 5]. However, as a side effect of the pulse steroid therapy, the patient has developed hyperglycemia, for which he is under antidiabetic medications currently.

Figure 5

Oral lesions showed marked improvement following two courses of Phase I of the pulse steroid therapy

DISCUSSION

Pemphigus includes a group of autoimmune diseases in which autoantibodies are produced against the epithelial intercellular junctions, resulting in blister formation. Most estimates regarding the epidemiology of pemphigus are based on European and American studies. However, Kanwar and De, in their review of cases of pemphigus reported from India noted that the incidence of pemphigus was higher in Indian population (4.4 cases per million population) than European data.[2]

Genetic factors seem to play an important role in the etiology of pemphigus. Several human leukocyte antigen alleles have been identified as risk factors, although their role is yet unclear.[3] Along with these genetic factors, certain environmental triggers also seem to be essential for the disease to occur. Certain drugs might interfere and alter the keratinocyte membrane biochemistry and the immune balance, ultimately resulting in acantholysis. Other environmental agents such as viruses and diet have also been under investigation, with no conclusive results till date.[4]

The classic clinical presentation of pemphigus is the development of vesicles and bullae in the skin and mucosa. These fluid-filled blisters are the result of loss of intercellular junctions within the epithelium. Autoantibodies in pemphigus have been identified to target desmoglein (Dsg) 1 and Dsg 3 in the desmosomal complex. Dsg 1 is mostly seen within the epithelium of skin, while Dsg 3 is commonly seen in mucosal epithelium.[5] Recent studies also implicate the role of keratinocyte acetylcholine receptors as potential targets for autoantibodies in pemphigus.[45] The loss of intercellular junctions (acantholysis) results in the formation of suprabasal clefts along with fluid accumulation within the epithelium. Isolated keratinocytes seen within these clefts lose their typical polygonal shape to become round and undergo apoptosis. These apoptotic-isolated keratinocytes have a characteristic histopathological appearance and are termed Tzanck cells.[1]

Patients with pemphigus are usually between 40 and 60 years of age.[6] Clinically, they present with multiple flaccid vesicles and bullae on different parts of the body. Skin lesions are common, and it is easy to identify intact blisters on the skin. However, in as much as 60% of the cases, oral lesions precede skin lesions.[1] Some reports claim this percentage to be even higher, with 70%–90% of cases showing oral presentation of lesions much before skin lesions.[7] Many patients may also develop oral lesions exclusively.[1] Due to frictional trauma during speech, mastication, etc., most oral blisters tend to rupture within a very short period. Patients, therefore, complain of profound pain and burning sensation throughout the oral cavity. An intraoral examination will reveal the presence of raw denuded areas anywhere within the oral cavity. Similar ulcerations may also be noticed in other mucous membranes. Different types of pemphigus have been identified based on the clinical presentation of the lesions, and the most common form that has oral manifestations is pemphigus vulgaris. Gingiva is less commonly affected by lesions of pemphigus, and in rare instances, it may be the only site affected.[8910] Lesions of gingiva appear as extensive erythema and erosions.[8] Such lesions have been termed desquamative gingivitis, although use the term is not generally recommended since it is descriptive and nonspecific in nature. A wide range of diseases can cause manifestations that have been collectively called desquamative gingivitis.[11]

Dagistan et al., López-Jornet and Bermejo-Fenoll, Javali and Zainab, Ohta et al., Kumar et al., and several others have shown in the past that oral lesions precede skin lesions frequently.[7891012] However, early identification of the disease seems to be difficult, as oral lesions might be mistaken for less severe and more common lesions of the oral cavity, such as aphthous ulcers, traumatic ulcers, and oral candidiasis. Ohta et al. observed that 1 year had elapsed from the onset of oral lesions to the definitive diagnosis of pemphigus, in their case.[10] The same holds true in our case, wherein the patient had initially been treated symptomatically for oral ulcers and then given antifungal treatment when the lesions did not subside. Three months following his initial oral complaints, he was finally referred to us.

A diagnosis of pemphigus can usually be established with histopathological examination of an incisional biopsy. However, direct immunofluorescence is more specific and is considered as the gold standard for diagnosis. A direct immunofluorescence test aims to identify the localization of IgG autoantibodies and C3 complement within the tissue of the patient. In pemphigus, the fluorescence is characteristically seen in the intercellular regions of the epithelium, which gives it a fishnet or chicken mesh appearance.[12] Care must be taken to examine the perilesional tissue under direct immunofluorescence, since tissue obtained from actual lesion might result in false-negative result due to internalization of the immune reactants on the cell surface.[3] Indirect immunofluorescence can also be performed in patient's serum, and it gives an estimate of the amount of circulating autoantibodies.

Several other diseases may also have lesions similar to pemphigus and have to be considered in the differential diagnosis. Pemphigoid is an autoimmune disease in which antibodies are directed against hemidesmosome components of the basement membrane region. The blisters of pemphigoid are more taut and resistant to friction, although intraoral blisters rupture frequently. Histopathology and direct immunofluorescence can help differentiate pemphigus from pemphigoid. Paraneoplastic pemphigus usually has similar clinical presentations; however, it is commonly seen in association with neoplasms such as non-Hodgkin's lymphoma or leukemia.

Treatment is usually aimed at controlling the disease and preventing relapses. Systemic corticosteroids remain the gold standard treatment for pemphigus. The European Academy of Dermatology and Venereology recommends initial treatment with low doses of prednisolone (0.5 mg–1.5 mg/kg/day). If there is no adequate response, then this may be increased to up to 2.0 mg–2.5 mg/kg/day. Dagistan et al., Javali and Zainab, and Kumar et al. noticed almost complete resolution of the lesions in their respective patients, within a few weeks of systemic corticosteroid therapy.[7912] However, in some patients, especially those who are resistant to low-dose steroid therapy, pulse steroid therapy becomes essential.

The introduction of pulse steroid therapy for the management of pemphigus has offered a new treatment modality aimed at curing the disease rather than symptom alleviation. The dexamethasone-cyclophosphamide pulse (DCP) steroid therapy introduced by Abraham et al. has been widely used.[13] The recommended DCP steroid therapy schedule consists of four phases:[1314]

Phase 1: DCP therapy is given until signs and symptoms are present. DCP therapy includes monthly doses of 100 mg of dexamethasone dissolved in 500 mL of 5% dextrose by slow intravenous infusion over 2 h on 3 consecutive days, along with 500 mg of cyclophosphamide in the infusion on day 2. In between, the patients receive 50 mg of oral cyclophosphamide daily

Phase 2: Monthly DCP therapy and daily oral cyclophosphamide are continued for 9 months, even though the patients are in remission

Phase 3: Only oral cyclophosphamide 50 mg is given to patients for an additional 9 months

Phase 4: All treatments are withdrawn and patients are followed up for relapse, if any.

Doubts and questions regarding the rationale of use of high-dose intravenous steroids and steroid-sparing immunosuppressants remain. Numerous side effects and complications, including seizures, arrhythmias, hypertension, and diabetes, due to DCP steroid therapy have been reported. However, many studies have also noted that the benefits of pulse steroid therapy were much higher than the side effects noticed.[14]

Although mortality due to pemphigus has reduced since the regular use of corticosteroids, the disease is still associated with considerable morbidity and mortality. There is substantial burden on the quality of life, and death due to various complications is common.

CONCLUSION

It is well known that oral lesions of pemphigus may be the first sign and in some cases the only sign of the disease. It is, therefore, essential for the practicing dentist to be able to identify and diagnose such lesions as early as possible, for the benefit of the patient. Easy access to a direct immunofluorescence laboratory ensures that the diagnosis is confirmed easily. The benefits of pulse steroid therapy sometimes outweigh the side effects, as was evident in our patient.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

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Conflicts of interest

There are no conflicts of interest.