Bullous Pemphigus: A Comprehensive Review of a Complex Autoimmune Disease of the Skin and Mucous Membranes

ABSTRACT


INTRODUCTION
Pemphigus bullosus, also known as pemphigus vulgaris, is a rare, chronic and potentially serious autoimmune disease of the skin and mucous membranes. It falls within the group of intraepidermal blistering diseases, characterized by the formation of flaccid and fragile intraepidermal blisters, due to the loss of cohesion of epidermal cells, specifically at the cell junctions known as desmosomes.1 RELEVANCE 4Bullous pemphigus is of great clinical and scientific relevance due to its autoimmune nature, its potential severity and its impact on the quality of life of affected patients. This dermatological disease represents a diagnostic and therapeutic challenge for healthcare professionals and is the focus of numerous medical and pharmacological investigations.2 Clinically, pemphigus bullosus is a highly disabling entity, characterized by the formation of fragile and painful intraepidermal blisters that can ulcerate, triggering a clinical picture marked by pain, pruritus and general discomfort. These blisters can affect the skin and mucous membranes, including the oral cavity, which can interfere with food intake and verbal communication, leading to a considerable reduction in patients' quality of life.2 In addition, the possibility of secondary infections in the affected areas, along with the risk of sepsis and systemic complications, adds a potentially life-threatening component to this disease. The morbidity associated with bullous Corresponding Author: Paola Daniela Guerrero Ramírez pemphigus is significant and can adversely affect the psychological and emotional well-being of patients, which in turn can impact their social and work life.2,3 From a scientific point of view, bullous pemphigus presents a complex and enigmatic etiopathogenesis, involving a misdirected immune response that results in the production of autoantibodies against key desmosomal proteins, such as desmoglein 1 and 3. This particularity makes it a valuable model for the study of the underlying mechanisms of autoimmunity and loss of immune tolerance.4,5 Advances in the understanding of the immunopathological mechanisms of bullous pemphigus have led to the development of more specific and effective therapeutic approaches. Immunosuppressive treatments, such as corticosteroids and immunomodulators, have significantly improved the management of the disease and have allowed more adequate control of the clinical manifestations.6 In addition, research into targeted therapies, such as rituximab and other biologic agents, has shown promising results in the treatment of bullous pemphigus, underscoring its importance as a field of study for the development of more selective and less toxic therapies.6 The relevance of bullous pemphigus also extends to the field of public health, as the proper identification and management of this disease requires close collaboration between dermatologists, immunologists, pathologists and other specialists, which encourages multidisciplinarity in medical care and the establishment of clinical practice guidelines.6 Bullous pemphigus represents a highly relevant clinical entity due to its impact on patients' quality of life, its complex immunologic etiopathogenesis, and its role as a model for research in autoimmunity and targeted therapies. Its proper management and understanding are fundamental to improve clinical outcomes and provide a more efficient and personalized therapeutic approach to individuals affected by this disease.6,7 EPIDEMIOLOGY Epidemiologic analysis of bullous pemphigus provides a detailed overview of the prevalence, incidence, demographic distribution, and potential risk factors associated with this rare and serious autoimmune disease of the skin and mucous membranes. Although the epidemiology of bullous pemphigus varies according to geographic regions and populations studied, a general overview can be provided.7,8 The prevalence of bullous pemphigus is considered low, ranging from 0.1 to 2.8 cases per 100,000 persons in the general population. However, this rate can vary significantly among different geographic areas and ethnic groups, with a higher frequency reported in certain high-incidence regions, such as southeastern Europe, North Africa, and parts of Asia and Latin America.8 This dermatologic disorder predominantly affects adults, with an average age of onset between the fourth and sixth decade of life, although it can also occur in younger people, including childhood and adolescence, although less frequently. There is a discrete predilection for the female sex, with the ratio of females to males varying between 1.2:1 and 3:1 in different populations studied.8 Bullous pemphigus is a multifactorial disease, involving genetic, environmental and immunologic factors. A higher incidence has been observed in certain ethnic groups and genetically predisposed families, suggesting a possible hereditary basis for the disease. However, the underlying genetic mechanisms and specific markers related to its development are still under investigation.8 As for environmental risk factors, several hypotheses have been put forward, such as the influence of certain viral and bacterial infections, as well as exposure to specific drugs, such as penicillamine and captopril, which may trigger or contribute to the development of the disease in genetically susceptible individuals.9 In terms of morbidity and mortality, bullous pemphigus can present a considerable burden to patients and the healthcare system. The most common complications include secondary blister infections and ulcerations, which can lead to sepsis and increase the associated morbidity and mortality. In addition, the psychological and emotional impact on those affected can be significant, as the disease can be debilitating and negatively affect quality of life.9 CLINIC Bullous pemphigus exhibits a complex and characteristic clinical manifestation, reflecting its autoimmune nature and its potentially severe impact on the skin and mucosa. Its clinical presentation is characterized by the appearance of intraepidermal cutaneous and mucosal blisters, which arise due to the loss of intercellular adhesion in epidermal cells, specifically at desmosomal junctions.9 These blisters are typically flaccid, fragile and serous in content and may vary in size from small vesicles to large extended blisters. Their rupture may result in erosions and painful superficial ulcerations. These lesions may occur in isolation or in groups, and tend to be located in areas of increased skin friction, such as the trunk, face, extremities, oral and genital cavity.9 The clinical picture of bullous pemphigus can evolve in the form of outbreaks, with exacerbations and remissions, which adds complexity to the monitoring and management of the disease. These recurrences can be triggered by precipitating factors, such as infections, trauma, emotional stress, hormonal changes or exposure to certain medications.9 Involvement of the oral mucosa, known as mucosal bullous pemphigus, is a distinctive and relevant feature and is seen in most affected patients. These lesions may initially manifest in the mouth as painful ulcers, white or erythematous plaques, and progress to the formation of intraepithelial blisters. Dysphagia, odynophagia and slurred speech can have a major impact on the patient's quality of life.10 It is common to find a symmetrical distribution of skin and mucosal lesions in bullous pemphigus, although they may also exhibit an asymmetrical or acral distribution, which adds a challenging diagnostic component for healthcare professionals.10 The diagnosis of pemphigus bullosus is based on a combination of clinical, histological and immunofluorescent findings. Skin biopsy reveals the presence of suprabasal intraepidermal blisters with acantholysis, while direct immunofluorescent staining shows immunoglobulin and complement deposition at intercellular junctions. Detection of circulating autoantibodies against desmosomal proteins by serological techniques can be a valuable diagnostic aid.10 The progression of bullous pemphigus can vary from localized and benign forms to generalized and more severe forms, which may require hospitalization and intensive management. In this context, early diagnosis and appropriate treatment are crucial to reduce the morbidity and mortality associated with this pathology.11 In summary, bullous pemphigus manifests clinically as an autoimmune blistering disease of the skin and mucosa, with the formation of fragile and painful blisters. Mucosal involvement, particularly oral, is frequent and adds to the complexity of the clinical picture. Timely recognition and an appropriate therapeutic approach are essential to improve the quality of life of patients and to avoid possible systemic complications.11

DIAGNOSIS
The diagnosis of bullous pemphigus involves a clinical and integrated approach, based on the correlation of clinical, histopathological, immunofluorescent and serological findings. Given the complexity and similarity of this entity to other blistering diseases, careful evaluation by medical professionals with expertise in dermatology and autoimmune diseases is essential.12 The diagnostic approach begins with a detailed clinical history and physical examination, which seeks to identify the presence of cutaneous and/or mucosal blisters, as well as the distribution, characteristics, recurrence, duration of lesions and triggering factors. Involvement of the oral cavity and other mucous membranes is highly suggestive of bullous pemphigus and may be a hallmark sign.13 Diagnostic confirmation is achieved by performing a skin biopsy of a recent and representative lesion, which is subjected to detailed histopathological analysis. In the histological study, the presence of suprabasal intraepidermal blisters is observed, accompanied by acantholysis and the formation of round bodies. These findings are highly characteristic of bullous pemphigus, although they can also be seen in other blistering diseases.13 The next crucial step in diagnosis is direct immunofluorescent staining (DIF) of the skin biopsy, which identifies immunoglobulin and complement deposition at the level of intercellular junctions in areas of acantholysis. This feature reveals the presence of autoantibodies directed against specific desmosomal proteins, such as desmoglein 1 and 3, confirming the autoimmune nature of bullous pemphigus.14 In addition, detection of circulating autoantibodies by serologic techniques, such as immunoblot or immunoprecipitation, can be useful to strengthen the diagnosis and assess disease activity and severity. However, negative serology does not completely exclude the diagnosis of bullous pemphigus, especially in early stages of the disease or in localized forms.14 It is important to note that the differential diagnosis of bullous pemphigus encompasses a wide variety of conditions, including pemphigus foliaceus, bullous pemphigoid, dermatitis herpetiformis, erythema multiforme, and other autoimmune and non-autoimmune blistering diseases. Therefore, exclusion of these entities by careful clinical and histologic evaluation is essential to reach an accurate diagnosis.14 In summary, the diagnosis of bullous pemphigus requires a comprehensive approach combining clinical evaluation, histopathologic study and direct immunofluorescent staining. Confirmation of the presence of specific autoantibodies and exclusion of other blistering diseases are essential to establish a definitive diagnosis and provide an appropriate and timely therapeutic approach.15

TREATMENT
The treatment of bullous pemphigus is a complex and multifaceted therapeutic challenge that requires an individualized and multidisciplinary approach to achieve disease control and improve the quality of life of affected patients. Since it is an autoimmune disease, the therapeutic approach focuses on suppressing the dysfunctional immune response and reducing the formation of new blisters.15 The mainstay of treatment is the use of immunosuppressive agents, such as systemic corticosteroids, which are the firstline therapy in most cases. These drugs, such as prednisone or prednisolone, are administered in high doses at the beginning of treatment, with a subsequent gradual reduction to reach the minimum effective dose. This strategy seeks to control inflammation and autoantibody production, preventing the formation of new blistering lesions.15 Corresponding Author: Paola Daniela Guerrero Ramírez However, prolonged and high-dose use of corticosteroids can be associated with significant side effects, such as suppression of the immune system, osteoporosis, weight gain, hypertension, diabetes, and cataracts, among others. Therefore, corticosteroid treatment should be carefully monitored, and patients may require additional therapy to minimize adverse effects.16 In refractory cases or with intolerance to corticosteroids, immunomodulators such as azathioprine, mycophenolate mofetil or cyclophosphamide are used, which act by selectively suppressing the immune response and reducing the production of autoantibodies. These agents are useful as adjuvant therapy or in combination with corticosteroids, making it possible to reduce the doses of the latter and, therefore, their side effects.16 In addition, biologic therapy, represented by rituximab, a monoclonal antibody directed against B cells, has been shown to be highly effective in the treatment of bullous pemphigus resistant to other therapies. Rituximab works by eliminating autoantibody-producing B cells, which can induce sustained remission and significantly improve the clinical picture.16 Local therapy plays an important role in the management of bullous pemphigus, particularly for mucosal lesions. Topical application of high-potency corticosteroids or immunomodulators, such as tacrolimus or pimecrolimus, can reduce inflammation and accelerate healing of oral ulcers.16 Special attention should also be paid to skin and mucosal care, with emphasis on the prevention of secondary infections and proper management of skin lesions to avoid exacerbation of the disease.16 In situations of acute outbreaks or therapeutic resistance, intravenous immunoglobulin therapy or plasmapheresis may be considered to eliminate circulating autoantibodies and reduce the immune load.16 It is important to mention that the treatment of bullous pemphigus is a continuous process, requiring close medical follow-up and regular monitoring of the response to treatment and side effects. Therapy can be modified according to the clinical evolution of the patient, adapting to individual needs and aiming to achieve sustained remission and a better quality of life.16 Treatment of bullous pemphigus involves a combination of immunosuppressive agents and adjuvant therapies, which are selected according to the severity of the disease and the individual patient's response. The main objective is to control disease activity, reduce blistering and minimize the adverse effects of the treatments used. A comprehensive approach and multidisciplinary care are essential to improve the clinical outcomes and quality of life of patients affected by this complex autoimmune disease.16

CONCLUSIONS
In conclusion, bullous pemphigus represents a cutaneous and mucosal disease of autoimmune nature, characterized by the formation of fragile and painful intraepidermal blisters due to the loss of cell adhesion at desmosomal junctions. Its complex and varied clinical presentation, with cutaneous and mucosal blistering lesions, including the oral cavity, can generate a considerable decrease in the quality of life of patients and increase the associated morbidity and mortality.
The diagnosis of bullous pemphigus requires careful clinical, histopathological and immunofluorescent evaluation to confirm the presence of acantholysis and the deposition of specific autoantibodies at intercellular junctions. Exclusion of other blistering and autoimmune diseases is essential to establish an accurate diagnosis and provide an appropriate and timely therapeutic approach.
Treatment of bullous pemphigus is based on the administration of systemic immunosuppressants, such as corticosteroids and immunomodulatory agents, with the aim of suppressing the autoimmune response and reducing the formation of new blisters. Biological therapy with rituximab has proven to be an effective therapeutic option in resistant cases.
Comprehensive management of this disease also involves addressing local care and the prevention of secondary infections, along with close medical follow-up to evaluate the response to treatment and monitor possible side effects.
Bullous pemphigus continues to be the subject of intense scientific research, with the aim of improving the understanding of its immunopathological mechanisms and developing more specific and less toxic therapies. Multidisciplinary medical care and collaboration between different specialties, such as dermatology, immunology and pathology, are essential to achieve early diagnosis and optimal management of this complex clinical entity.
In short, bullous pemphigus is a dermatologic pathology of high clinical and scientific relevance that represents a diagnostic and therapeutic challenge. Current knowledge of its etiopathogenesis and treatment, together with comprehensive and personalized medical care, will contribute to improving the quality of life of affected patients and to advancing the approach to this autoimmune disease of the skin and mucous membranes.