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Early Diagnosis and Management of Oral Pemphigus Vulgaris Lesions of Various Presentations
J Oral Med Pain 2023;48:174-180
Published online December 30, 2023;  https://doi.org/10.14476/jomp.2023.48.4.174
© 2023 Korean Academy of Orofacial Pain and Oral Medicine

Seo-Young Choi1 │Soo-Min Ok2 │Sung-Hee Jeong2 │Yong-Woo Ahn2 │ Hye-Min Ju2

1Department of Oral Medicine, Dental Research Institute, Pusan National University Dental Hospital, Yangsan, Korea
2Department of Oral Medicine, Dental Research Institute, Dental and Life Science Institute, School of Dentistry, Pusan National University, Yangsan, Korea
Correspondence to: Hye-Min Ju
Department of Oral Medicine, Dental Research Institute, Dental and Life Science Institute, School of Dentistry, Pusan National University, 49 Busandaehak-ro, Mulgeumeup, Yangsan 50612, Korea
E-mail: jc2wma@pusan.ac.kr
https://orcid.org/0000-0002-9252-6717
Received December 1, 2023; Revised December 11, 2023; Accepted December 11, 2023.
This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Pemphigus vulgaris (PV) is a chronic autoimmune bullous disease caused by autoantibodies to proteins in the oral mucosa and skin. It is a rare disease with an annual incidence of 2.059 per million in South Korea. In many patients with PV, oral mucosal lesions precede other lesions elsewhere, and oral lesions can be the only manifestation. Early diagnosis is important because the disease has a high mortality rate if untreated appropriately in the early stages, and rapid treatment initiation is associated with rapid disease control. Oral PV lesions are clinically variable. In this study, we describe oral PV lesions in a 60-year-old woman, a 75-year-old man, and a 60-year-old man presenting with various clinical presentations. Oral PV lesions can affect any part of the oral mucosa, including the buccal mucosa, gingiva, tongue, palate, and free mucosa, and can vary in appearance from desquamative gingivitis, painful ulcers, and erosions to aphthous-like stomatitis. Clinicians should be aware of the difficulty of early diagnosis in PV, particularly when oral lesions are the only manifestation, and should consider many factors, including the patient’s age, to make an accurate diagnosis and manage oral lesions to improve the patient’s quality of life and avoid delayed diagnosis.
Keywords : Autoimmune disease; Pemphigus; Pemphigus vulgaris
INTRODUCTION

Pemphigus vulgaris (PV) is a chronic autoimmune bullous disease that forms easily breakable blisters, erosion, and ulcers on the skin and mucous membranes. PV results from autoantibodies against desmosomal intercellular adhesion molecules, specifically desmoglein 3 and/or desmoglein 1 [1]. In South Korea, the annual incidence of PV is approximately 2.059 per 1 million individuals, making it a rare disease but the most common among autoimmune bullous diseases [2,3]. PV is a lethal disease with a 75% mortality rate if untreated early; therefore, early diagnosis is critical [4]. The diagnosis is based on the identification of clinical manifestations and confirmed through biopsy. Direct immunofluorescence is employed for the conclusive diagnosis of PV. In PV and other bullous autoimmune diseases, such as mucous membrane pemphigoid (MMP), which share a similar clinical presentation to PV, oral lesions appear early in the disease before other lesions appear elsewhere, and oral lesions can be the only manifestation during disease progression [5]. Oral lesions most commonly occur in the buccal mucosa, as well as in the gingiva, tongue, and palate [6,7]. Oral PV lesions are generally persistent; however, early in the disease stage, they may appear to spontaneously resolve and recur [7]. Therefore, differentiating PV from other similar oral lesions based on the clinical appearance is extremely difficult. Clinical presentation, histopathology, immunofluorescence, and serologic tests should be considered when making a definitive diagnosis [5]. Once diagnosed with PV, patients are treated with systemic steroids and immunosuppressants for several years [8,9]. In this study, we present three patients with various forms of oral PV and discuss early diagnosis and adjunctive oral management.

Written informed consent was obtained from all patients at the initial visit. This study was approved by the Institutional Review Board of Busan National University Dental Hospital (IRB No. 2023-11-009).

CASE REPORT

1. Case 1

A 60-year-old female patient was referred to the Department of Oral Medicine from the Department of Periodontics at Pusan National University Dental Hospital, with a complaint of peeling gums. She had no systemic disease other than hypertension, severe calculus deposition, and generalized desquamative gingivitis (Fig. 1). The appearance of the gingival lesions in the maxillary anterior region was similar to that of MMP; however, the margins of the bilateral mandibular gingival lesions were messy and predominantly involved papillary tips, suggesting PV. The patient was taking oral steroids for psoriasis and was prescribed a topical steroid and antibiotic gargle. A corticosteroid and antibiotic gargle (0.06% prednisolone and 1% ampicillin hydrate solution) was applied for 5-10 min once, three times daily, to treat the lesion. Histopathology and immunofluorescence were recommended at the initial consultation; however, the patient refused because of pain in the mouth and fear of the test. Eight days later, the patient visited our department earlier than scheduled complaining of worsening of the syndrome. New lesions appeared in the right buccal mucosa, and intact vesicles were also observed (Fig. 2). At the second visit, intralesional injection (dexamethasone disodium phosphate injection 5 mg/mL; Yuhan Medical) and oral corticosteroids (10 mg prednisolone) were administered for 2 weeks because the patient had stopped taking the corticosteroids prescribed by a private dermatologist. At the third visit 2 weeks later, re-epithelialization of the right buccal mucosa lesion had begun; however, the margins of the lesion were irregular; therefore, systemic corticosteroids (dexamethasone disodium phosphate 5 mg/mL) were injected intramuscularly to treat the residual lesion. Following periodontal management with the use of corticosteroids, the patient reached the early end point at visit 4, 2 weeks later. Oral corticosteroid tapering was initiated, and oral lesions were managed with corticosteroid gargle (0.06% prednisolone solution). The oral lesions were fairly well controlled; however, 6 months later, the patient experienced a sudden relapse (Fig. 2). New lesions appeared in both the buccal mucosa and tongue, and the established lesions on the right buccal mucosa expanded laterally. On the same day, an incisional biopsy of the oral lesion was performed, and histopathological findings revealed lichenoid lymphocyte infiltration and chronic inflammation. The sudden appearance of new lesions and relapse shortly after the withdrawal of oral corticosteroids prescribed by a private dermatology clinic led to a strong diagnostic suspicion of PV and referral to dermatology. She was subsequently diagnosed with PV by the dermatology department, and her oral lesions are being managed therein.


2. Case 2

A 75-year-old man with complete dentures who had been treated in our department for oral candidiasis presented with ulceration in his mouth. The ulcer healed within the usual healing duration of 2-4 weeks and presented as a solitary aphthous lesion. The lesion healed over time; however, because of the trauma-prone condition of using a complete denture, the patient was followed up to confirm healing and monitor the development of new ulcers. During the follow-up, new ulcers continued to emerge at intervals of 2 months and 1 month. During continuous follow-up with the intermittent use of corticosteroid ointment and gargle because of frequent recurrences, the appearance of the lesion changed 5 months after the initial ulceration (Fig. 3). Corticosteroid gargle (0.06% prednisolone solution) and topical antifungal agent (PMS-Nystatin suspension; Pharmascience Inc.) were prescribed to manage the oral lesions and prevent candidiasis resulting from long-term use of corticosteroids. After 2 weeks, the patient exhibited cutaneous lesions on the face and scalp. The patient was diagnosed with shingles at a private dermatology clinic; however, skin lesions were present, and oral lesions showed a peeling appearance, chronic erosion, and ulcers. He was recommended to undergo examination at a university hospital for a definitive diagnosis (Fig. 4). Corticosteroids (10 mg prednisolone, Solondo tablet; Yuhan Medical) were administered orally. Corticosteroids (dexamethasone disodium phosphate 5 mg/mL) were injected intramuscularly. A corticosteroid gargle (0.06% prednisolone solution) was used as the adjuvant treatment. The patient had been managed at the dermatology department of Pusan National University Hospital and had not visited since his symptoms had improved; however, he returned after 6 months because of the emergence of a tongue lesion. Histopathological examination of the oral cavity and skin foci was performed at the dermatology department of the university hospital during his absence, and he was diagnosed with PV. Topical corticosteroid agents are used to control oral lesions.


3. Case 3

A 60-year-old man visited the Department of Oral Medicine at the Pusan National University Dental Hospital with a complaint of stomatitis that prevented him from eating. He had been treated with ibuprofen, cefaclor, and prednisolone orally for 1 month in a private ENT clinic for the same symptoms, with no improvement. On initial examination, bilateral erosive and ulcerative lesions of the buccal mucosa were observed, and the left buccal lesion was judged to be healing with a slightly elevated appearance (Fig. 5). Bilateral buccal mucosal lesions were peripherally extended from the occlusal line, with no lesions in the gingival, palatal, or tongue areas. After prescribing topical corticosteroids, an incisional biopsy was performed the next day, and the histopathological findings were suprabasal acantholysis suggestive of PV. At his next visit, he was referred to dermatology and otolaryngology for a cutaneous lesion behind the right ear and frequent nasal bleeding, respectively. Oral corticosteroids (Solondo tablet 5 mg; Yuhan Medical) (20 mg prednisolone tapering by 5 mg) and corticosteroid gargle (0.06% prednisolone solution) were prescribed. After 8 days, the lesions showed little improvement; therefore, corticosteroids (10 mg prednisolone, Solondo tablet) were administered for 2 more weeks. In addition, to manage oral lesions, clobetasol propionate ointment (Dermovate ointment 10 g; GlaxoSmithKleinKorea) was applied three times a day for 2 weeks. At his next visit 2 weeks later, the patient stated that he had visited the dermatology department at Yangsan Pusan National University Hospital and was informed that the cutaneous foci had resolved, making diagnosis difficult. To reduce the severity of oral lesions, 5 mg of corticosteroid intralesional injection (Tamceton injection 40 mg/mL, Hanall Biopharma) was administered to both buccal mucosa. Oral corticosteroids were administered continuously, and oral lesions were managed with corticosteroid gargle, clobetasol propionate ointment, and intralesional injection of corticosteroids. The patient subsequently requested to be evaluated at another hospital and was referred, and after a series of tests, he was diagnosed with PV.

DISCUSSION

Pemphigus has three major subtypes: PV, pemphigus foliaceus (PF), and paraneoplastic pemphigus. PV and pemphigus foliaceus account for 90%-95% of pemphigus diagnoses. PV and PF can be identified by the presence or absence of an intraoral lesion. PF has prominent cutaneous lesions and few intraoral lesions [4]. PV is more prevalent in Asian countries, including South Korea, and is the most common autoimmune disease in South Korea [2]. The incidence is higher among people aged 40-60 years, with a slight predominance among women [2,4]. Oral PV lesions appear early during the disease and have various presentations. It may appear as a large painful ulcerated area or as a recurrent aphthous-like oral lesion with intermittent lesions. It can also appear as desquamative gingivitis when restricted to the gingiva [1]. This diversity of oral PV lesions can lead to a diagnostic delay until a cutaneous lesion and/or other mucosal lesions have developed [10]. In particular, patients with oral lesions of desquamative gingivitis experience longer diagnostic delays than patients with ulcers and erosion [1]. In addition to diagnostic delay, approximately half of patients with desquamative gingivitis have a history of unnecessary periodontal treatment [1]. Moreover, 100% of the misdiagnoses of desquamative gingivitis were made by dentists, reflecting the difficulty of obtaining an accurate early diagnosis when patients with early gingival PV lesions present to the dentist [1]. Delayed diagnosis results in patients receiving unnecessary treatment (e.g., antibiotics, antifungals, vitamins, and colchicine) before appropriate PV treatment; as a result, rapid disease control through early treatment is not achieved. Approximately 95% of patients with oral lesions that present as aphthous ulcers have been misdiagnosed with recurrent aphthous stomatitis (RAS) [11]. In addition, patients with typical forms of oral PV, rather than transient oral lesions, are often misdiagnosed with RAS [11]. This reflects the fact that many clinicians do not consider PV when making an early diagnosis. Femiano et al. [7] reported five patients with PV who presented with ulcers with an erythematous halo centrally covered by a solitary yellow–grayish pseudomembrane, similar to an aphthous ulcer. All these patients showed lesions with the characteristics of RAS, where a lesion develops, heals, and then a new lesion develops. These self-healing abortive lesions differ from typical oral PV lesions in that they do not extend laterally and are not positive for the Nikolsky sign [11]. To avoid misdiagnosing isolated PV lesions as aphthae, age- and race-adjusted serological testing to detect circulating autoantibodies is recommended in patients with recurrent aphthous-like lesions [11].

In the first case, oral lesions appeared as desquamative gingivitis and could be mistaken for simple periodontitis. In the upper and lower anterior teeth, the difference between periodontitis and oral MMP lesions was not obvious. However, careful examination of the bilateral mandibular molars reveals that the lesions have unclear margins and predominate on the papillary tips, making PV more likely than MMP [12]. The patient was judged to have achieved the early endpoint after 4 weeks of oral corticosteroids; however, continued follow-up to monitor the worsening of the lesions would have proved useful in the diagnosis of PV. The second patient had an edentulous alveolus, which made it difficult to determine the extent of the lesion involving the papillary tip. He had recently been wearing a complete denture, which is at risk of trauma. In addition, the solitary lesion healed completely without spontaneous scarring, and unlike the case reported by Femiano et al. [7], it was an oval-shaped lesion on the nonkeratinized mucosa, which is commonly affected by RAS, making early diagnosis very difficult. However, given the patient’s age, which is not a risk factor for RAS, and the very frequent recurrence, follow-up was crucial to catch up with the changes in the appearance of the lesion during the follow-up. The patient was diagnosed with shingles when the cutaneous lesions developed, and a case in India of a patient developing PV after infection with varicella-zoster virus was reported [13]. During viral infection, epitopes are modified by the primary immune process and released with the host’s self-proteins, and B and T lymphocytes initiate a secondary immune response against previously sequestered self-proteins, resulting in epitope spreading, which can lead to autoimmune disease. This epitope spreading is also associated with the transition of mucous-dominant PV to mucocutaneous PV [13]. Conversely, histopathological and immunofluorescence examinations of cutaneous lesions in a patient with mucous-dominant PV revealed that varicella-zoster virus caused cutaneous lesions similar to pemphigus cutaneous lesions [14]. Thus, whether the second patient’s cutaneous lesions were secondary to varicella-zoster virus or true new PV cutaneous lesions is unclear; however, in either case, they are diagnostically valuable. The third patient had no gingival, mucosal, or palatal lesions other than the buccal mucosa; however, bilateral buccal lesions were relatively typical of oral PV lesions, and he complained of frequent bleeding from the nasal mucosa, suggesting PV.

PV requires an average total treatment duration of 5-10 years, and the time to achieve complete remission after the initiation of oral corticosteroids varies from 1.5 months to 3 years [9]. The challenge in PV treatment is to minimize side effects during these prolonged periods of corticosteroid or immunosuppressant therapy. If oral lesions persist despite systemic treatment, they should be managed with topical corticosteroids rather than increasing oral medications [15]. Topical corticosteroids should be used as an adjunct to oral medications and are not recommended as a first-line treatment for patients with PV [4]. Additional immunosuppressive agents, such as azathioprine (1-3 mg/kg/day) or mycophenolate mofetil (2 g/day), are frequently prescribed at the onset of treatment or for stubborn cases to attain superior or faster management of the disorder. Recently, rituximab, a chimeric monoclonal antibody that targets the CD20 antigen of B lymphocytes, has shown great potential as a therapeutic alternative for PV [16]. The management of oral lesions is essential to improve the patient’s quality of life, including food intake. In all three cases, oral lesions were managed with topical corticosteroid gargles, ointment, and corticosteroid intralesional injections to prevent exacerbations and reduce pain. In the last patient, the oral lesions did not respond to oral corticosteroid therapy, and the use of high-potency corticosteroid intralesional injections and high-potency corticosteroid ointments resulted in the partial re-epithelialization of the lesions.

Clinicians should be aware that early diagnosis is difficult in cases of PV in which oral lesions are the only symptom. Even if early lesions are present, such as simple ulcerative lesions or gingivitis, patients with unclear desquamative margins, symptoms suggestive of mucosal morbidity other than that of the oral cavity, such as nosebleeds, frequent recurrences, and abnormal healing periods, should be followed up, taking into account factors such as the patient’s age and systemic condition, and the oral lesions should be managed. Accurate early diagnosis is necessary to ensure that patients do not suffer from delayed diagnosis and accompanying unnecessary treatment and that appropriate initial therapy can be started as soon as needed.

CONFLICTS OF INTEREST

Soo-Min Ok serves on the editorial board of the Journal of Oral Medicine and Pain. But she has no role in the decision to publish this article. Except for that, no potential conflict of interest relevant to this article was reported.

DATA AVAILABILITY STATEMENT

Data sharing is not applicable to this article because no new data were created or analyzed in this study.

FUNDING

This study was supported by a Clinical Research Grant, Pusan National University Dental Hospital 2022.

AUTHOR CONTRIBUTIONS

Conceptualization: SYC, HMJ. Data curation: SMO, SHJ, YWA. Formal analysis: SMO, SHJ, YWA, HMJ. Funding acquisition: HMJ. Methodology: SMO, SHJ. Project administration: HMJ. Visualization: SYC. Writing - original draft: SYC. Writing - review & editing: HMJ.

Figures
Fig. 1. Case 1: Generalized gingival lesions and severe calculus deposition at the first visit.
Fig. 2. Case 1: Change of the oral lesion on the right buccal mucosa. (A) Exfoliating margins of the lesions and intact blisters. (B) Re-epithelialization of the established lesions. (C) Relapse of lesions.
Fig. 3. Case 2: Recurrent oral lesions. (A) Aphthous-like lesion on the floor of the mouth. (B) Aphthous-like lesion on the lower vestibule (2 months later from A). (C) Aphthous-like lesion on the ventral surface of the tongue (1 month later from B). (D) Oral lesion appearance turns into a bullous disease.
Fig. 4. Case 2: Cutaneous and oral lesions. (A) Cutaneous lesions on the face and scalp. (B) Extended oral lesions.
Fig. 5. Case 3: Oral lesions on both buccal mucosa. (A) Lesion on the right buccal mucosa showing erosion and bleeding. (B) Lesion on the left buccal mucosa showing partial healing.
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