Introduction
The term pemphigus encompasses a group of chronic potentially life-threatening autoimmune mucocutaneous diseases characterized by blistering of cutaneous surfaces, mucosal surfaces or both [
1]. Several subtypes of pemphigus have been identified, including pemphigus vulgaris, pemphigus vegetans, pemphigus foliaceus, pemphigus erythematosus, paraneoplastic pemphigus and IgA pemphigus [
2]. Pemphigus vulgaris (PV) is the most common variant that affects the oral cavity. In PV, serum autoantibodies (IgG) are directed against desmosomal components (desmoglein 1 and/or desmoglein 3) that adhere keratinocytes to each other [
3]. Subsequently, keratinocyte separation, acantholysis, and intraepithelial splitting occur, which manifest clinically as cutaneous and/or mucosal blisters [
1]. Approximately 70.0% of cases exhibit oral signs that precede skin or other mucosal lesions [
4]. Exclusive oral involvement may be seen in almost 50.0% of PV cases [
5]. Oral lesions of PV start as multiple vesicles and/or bullae, which are rarely observed due to the fragile nature of the bullae and the mechanical stress caused during the daily activities of eating and speaking [
6]. Rupture of vesicles or bullae leads to painful widespread erosions and ulcerations that primarily affect the buccal mucosa, tongue, palate and lips, which eventually heal without scarring [
6]. Desquamative gingivitis can be seen in severe cases of PV [
7‐
9]. For PV diagnosis, clinicians must correlate disease history with the clinical and histopathological findings. Direct immunofluorescence (DIF) is used for the definitive diagnosis of PV, which demonstrates characteristic intercellular deposits of IgG and C3 in the epithelium layer [
1]. Indirect immunofluorescence (IIF) may be useful for monitoring disease activity [
10].
Oral PV may mimic several diseases that cause mucosal erosions and/or ulcerations. Erythema multiforme (EM) is one of those mimickers. EM is an acute, mucocutaneous, immune-mediated self-limiting condition that often resolves within a few weeks without mention of sequalae. EM commonly affects young adults between the second and fifth decades with no specific gender predication [
11,
12]. The pathogenesis of EM has been suggested to be a type IV hypersensitivity reaction mediated by cytotoxic T cells [
13]. Numerous factors may trigger such a reaction, including infection with Human adenovirus (HAdV), HSV-1 and HSV-2 [
14‐
16]. Mycoplasma pneumoniae was found to be associated with EM, especially in children [
17,
18]. Drug-induced EM is reported in approximately 10.0% of cases and is most commonly associated with the use of nonsteroid anti-inflammatory drugs, sulfonamides, antiepileptics, and antibiotics [
19]. The spectrum and classification of EM have been discussed based on the clinical course [
20].
Oral mucosal involvement in EM may precede other lesions or may arise in isolation [
13]. The typical oral presentation of EM includes diffuse shallow ulcerations and/or erosions commonly in the anterior part of the oral cavity and primarily affects the nonkeratinized mucosa. Lip involvement typically presents as swelling, cracking and hemorrhagic crusting [
12]. The diagnosis of EM is based entirely on the clinical presentation and patient’s history, with no specific test to confirm the diagnosis. However, a biopsy may be indicated in atypical cases of EM to exclude other differential diagnoses, such as pemphigus, pemphigoid and others [
21]. Microscopic examination of EM lesions is characterized by inflammatory infiltration of the basement membrane with the presence of T cells and macrophages. Intra- and subepithelial bullae formation may result from necrosis in the basal and supra-basal layers, and DIF examination may illustrate nonspecific deposition of C3 and fibrin along the basement membrane [
13]. EM oral mucosal lesions can be treated with topical high-potency steroids for cases with minimal mucosal involvement. However, patients with more severe lesions may require systemic steroid therapy [
21].
Oral PV may be misdiagnosed as EM in a subgroup of patients presenting with lip hemorrhage and crusting. Therefore, this case series emphasizes that oral PV may be misdiagnosed as EM. This series highlights the importance of a comprehensive history, clinical examination and incisional biopsies for this subgroup of patients.
Discussion
In the current case series, we reported six patients with oral PV who presented first with a clinical picture that mimicked EM. The anterior part of the oral cavity was affected by lip swelling, hemorrhage and crusting. The intraoral findings were primarily widespread erosions and ulcerations. Three patients had skin lesions during the course of the disease. The patients’ histories of persistent lesions for several months in addition to the fact that the patients denied the occurrence of prodromal symptoms or a new drug intake calls into question the tentative EM diagnosis. Thus, PV was considered another differential diagnosis. Few studies have reported similar findings of lip lesions among PV patients [
22‐
25].
This case series included three young adults and three older adults and included five females and one male all of middle eastern decent. The most common age of PV presentation has been reported to be between the 4th and 6th decades [
26]. A female predominance was reported in a study conducted in Kuwait [
27], whereas an equal gender distribution was noticed among PV patients from Finland [
28]. On the other hand, a few other studies have reported male predominance [
29,
30]. The female predominance suggests a hormonal relationship [
31]. In the Arab world, PV is the most common subtype in Egypt, Sudan, Morocco, Syria, Kuwait, Saudi Arabia and Yemen [
32]. PV is well known to be prevalent among specific ethnic groups, such as individuals of Ashkenazi Jewish and Mediterranean ancestries [
33]. Interestingly, Kridin and coworkers have shown that the Arab population was affected by PV at a younger age compared to the Jewish population, which could be explained by the genetic susceptibility associated with HLA types [
33].
In the current series, incisional biopsies from the perilesional mucosa were taken from all six patients demonstrating acantholysis (Tzank cells), intraepithelial clefting and a tombstone pattern, which was suggestive of PV. DIF was performed for Cases 1, 2 and 3, demonstrating intercellular deposition of IgG (Cases 1 and 2) and both IgG and C3 (Case 3).
The aim of treating patients with PV is to achieve rapid control of the disease, followed by consolidation and maintenance phases [
1]. According to the British Association of Dermatologists, the management of PV has two phases. The induction phase controls disease activity, and the maintenance phase prevents relapse with minimal drug concentration [
33]. Systemic corticosteroid dose calculation is based on disease severity. For mild PV cases, a steroid dose of 0.5–1 mg/kg/day is commonly used, whereas treatment of severe PV cases may be initiated at 1–2 mg/kg/day [
34]. Once PV lesions are controlled, the systemic steroid dose may be tapered [
34]. Systemic steroids are frequently combined with other immunosuppressants, such as azathioprine, mycophenolate mofetil, cyclophosphamide, methotrexate, immunomodulators such as high-dose intravenous immunoglobulin (IVIG), or antibody-eliminating procedures such as immunoadsorption [
33]. Oral lesions can also be managed with topical steroids in the form of an oral gel or mouthwash [
35]. Intralesional steroid therapy may be indicated for refractory oral lesions [
35]. All patients in this case series were managed with systemic steroids, i.e., prednisolone 0.5-1 mg/kg/day, together with steroid-sparing agents and topical steroid mouthwashes.
This case series was limited by the fact that DIF was not performed in all the patients. Such investigation requires specific facilities that are not readily available in all health care services. Furthermore, in the case of test availability in the private sector, the cost may not be affordable for most of the patients who were originally seen in governmental or educational hospitals. Although DIF was not performed in three cases, the routine histopathological examination of all specimens in this series was consistent with classic PV histology, as described earlier in the literature.
In conclusion, this case series emphasizes that oral PV may be misdiagnosed as EM in a subgroup of patients who present with persistent lip hemorrhage and crusting. Misdiagnosing PV as EM affects the treatment plan and outcome of the patients. EM is a self-limiting condition that requires supportive care in most cases and perhaps a short course of treatment. In contrast, PV requires long-term treatment to control disease activity and minimize relapse. Therefore, a comprehensive history, clinical examination and incisional biopsies should be considered in such patients.
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