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Pemphigus

Pemphigus is a group of rare, chronic autoimmune blistering disorders that cause flaccid blisters and painful erosions on the skin and mucous membranes, primarily due to autoantibodies targeting desmoglein proteins in , leading to loss of known as . These conditions affect approximately 0.5 to 3.2 cases per 100,000 people annually worldwide, with higher incidence in populations of Ashkenazi Jewish, Mediterranean, , or Eastern descent, and typically onset between ages 50 and 60. Although not contagious, pemphigus can be life-threatening if untreated due to secondary infections or complications, but early intervention with immunosuppressive therapies has significantly improved outcomes. The main types of pemphigus include , the most common form accounting for about 70% of cases, which often begins with oral erosions before spreading to the skin and other mucous membranes; , a milder variant limited to the skin (typically the scalp, face, chest, and back) without mucosal involvement; and rarer subtypes such as paraneoplastic pemphigus, associated with underlying malignancies, and pemphigus vegetans, characterized by thickened, vegetating lesions. Drug-induced pemphigus, triggered by medications like or inhibitors, represents another variant that may resolve upon drug discontinuation. The underlying cause is an aberrant where IgG autoantibodies bind to desmoglein 3 (DSG3) in mucosal forms or both DSG3 and desmoglein 1 (DSG1) in mucocutaneous forms, disrupting intercellular junctions without significant inflammation or complement activation. , such as HLA-DR4 or HLA-DRw6 alleles, increases susceptibility, while environmental triggers like , UV exposure, or certain drugs may initiate the disease in genetically prone individuals. Symptoms typically include fragile blisters that rupture easily to form erosions, often accompanied by , burning, or itching, with oral involvement in up to 80% of cases leading to difficulties in eating or speaking. Diagnosis involves a combination of clinical examination, showing and IgG deposits via direct , and serological tests for anti-desmoglein antibodies to confirm the autoimmune . Treatment primarily relies on systemic corticosteroids like to suppress the , often combined with steroid-sparing immunosuppressants such as , mycophenolate mofetil, or rituximab, a targeting B cells, which has shown efficacy in achieving remission. Supportive care includes wound management, infection prevention, and nutritional support, with long-term monitoring to minimize side effects like or from prolonged therapy. With modern treatments, the exceeds 80%, though overall mortality remains 2 to 3 times higher than the general , mainly from or treatment-related complications rather than the disease itself.

Overview

Definition

Pemphigus refers to a group of rare, potentially life-threatening autoimmune blistering diseases of and mucous membranes, characterized by the formation of intraepidermal blisters resulting from autoantibodies targeting desmogleins, which are key components of desmosomal in . The term "pemphigus" derives from the Greek word pemphix, meaning blister or bubble, reflecting the disease's hallmark vesicular lesions. Pemphigus is classified into several major subtypes, including (PV), the most common form affecting both skin and mucosa; (PF), which is limited to the skin; paraneoplastic pemphigus (PNP), associated with underlying malignancies; and IgA pemphigus, characterized by IgA autoantibodies. Other variants include fogo selvagem, an endemic form of PF prevalent in certain regions of . Worldwide, the incidence of pemphigus ranges from 0.5 to 16 new cases per million person-years annually, with variations by subtype, geographic region, and population.

Epidemiology

Pemphigus is a rare autoimmune blistering disorder with varying global incidence and prevalence depending on subtype and population. The global incidence of (PV), the most common form, is estimated at 2.83 per 1,000,000 person-years, with reported rates ranging from 0.098 to 5 per 100,000 population across studies. A 2023 meta-analysis estimated the pooled global incidence of PV at 2.83 per million person-years. PV shows marked ethnic disparities, with higher incidence among (up to 4- to 10-fold increased risk compared to other Caucasians) and those of Mediterranean origin, while rates are notably lower in African populations. Pemphigus foliaceus (PF) is rarer overall, but endemic forms exhibit higher localized prevalence. Geographic variations are pronounced, particularly for , which occurs endemically as fogo selvagem in rural areas of southern and midwestern (e.g., states of , , Paraná, , and ), as well as in parts of , , , and . This form is linked to environmental exposures, including bites from the Simulium nigrimanum, which may trigger autoantibody production against desmoglein-1. In non-endemic regions, predominates, with higher incidences reported in areas like (up to 5 per 100,000). Demographically, pemphigus typically peaks in the 50- to 60-year age group, though endemic can affect younger individuals, including children, in high-risk areas. exhibits a slight female predominance (female-to-male ratio approximately 1.4:1), while shows more equal gender distribution or minimal female bias in some cohorts. Genetic factors play a key role in susceptibility, with PV strongly associated with (specifically DRB10402) and HLA-DQ alleles like DQB10503, conferring increased risk in susceptible populations. Environmental triggers, including certain drugs (e.g., compounds, inhibitors) and exposure, can precipitate or exacerbate disease onset. Mortality has dramatically declined since the introduction of corticosteroids in the , when pre-treatment fatality rates exceeded 75-90% due to complications like and fluid loss; current rates range from 5% to 15%, primarily from treatment-related side effects or comorbidities.

Clinical Features

Signs and Symptoms

Pemphigus is characterized by the development of painful erosions and flaccid blisters on and mucous membranes, often beginning with oral lesions in 50–70% of cases of (PV), where these initial manifestations can precede skin involvement by weeks or months. These blisters arise due to intraepidermal , a process driven by autoantibodies targeting desmogleins, leading to loss of adhesion and fragile bullae that rupture easily to form shallow, crusted erosions. The Nikolsky sign, where gentle pressure or friction causes epidermal shearing and blister extension, is a hallmark feature observable in active lesions. Skin lesions typically present as scattered vesicles or bullae on an erythematous base, progressing to widespread erosions that heal without scarring but may leave post-inflammatory hyper- or , particularly in individuals with darker tones. Mucosal involvement is prominent in , affecting the gingival, buccal, and esophageal regions with severe, painful erosions that impair eating, speaking, and swallowing, whereas in (), it is milder and limited to superficial sites such as the and face, without true disease. Secondary bacterial or fungal infections are common due to denuded areas, exacerbating discomfort. Systemic signs include significant from erosions, potential fluid and loss from extensive skin involvement, and risks of or , especially with oral lesions; fever and are rare but may occur in severe cases with secondary infections. The disease often progresses from localized lesions to generalized involvement, with untreated cases potentially leading to denudation covering more than 30% of the and life-threatening complications like .

Variants by Presentation

Pemphigus vulgaris (PV) represents the most prevalent subtype, manifesting with fragile, flaccid intraepidermal blisters that arise on normal or erythematous skin and rapidly rupture to form extensive, painful erosions. Mucosal surfaces are involved in over 90% of cases, beginning with the oral cavity and potentially extending to the eyes, , , genitalia, and , resulting in symptoms such as , hoarseness, and discomfort during intercourse. The disease exhibits a chronic, indolent progression with deep leading to slower blister evolution compared to superficial variants, typically sparing the palms and soles. In contrast, (PF) is characterized by superficial confined to the upper , producing transient vesicles that erode into scaly, crusted plaques resembling cornflakes, primarily in seborrheic regions such as the , face, and upper . Unlike PV, mucosal involvement is absent, and symptoms are generally milder, limited to pruritus or burning sensations, with individual lesions healing more rapidly but the overall condition persisting chronically and potentially disseminating. Paraneoplastic pemphigus (PNP), often linked to underlying neoplasms like or , displays a heterogeneous polymorphous eruption including vesicles, bullae, erosions, and lichenoid or erythema multiforme-like plaques across the skin. Severe, refractory with painful oral erosions is a hallmark, frequently accompanied by involvement of other mucosae and extracutaneous sites such as the lungs (causing ) and . The presentation is aggressive with rapid progression and multi-organ implications, distinguishing it from other variants by its association with malignancy and poor prognosis. IgA pemphigus, a neutrophil-driven variant, typically presents with pruritic annular or circinate erythematous plaques studded with flaccid vesicles or pustules on the trunk, axillae, and areas. Mucosal lesions are uncommon, though rare reports note oral or perianal involvement; the is milder than classical pemphigus, with vesicles in about 81% of cases and pustules in 75%, often resolving with minimal scarring. Subtypes include the subcorneal pustular (most common) and intraepidermal neutrophilic types, both sharing a relapsing but generally benign trajectory. Fogo selvagem, an endemic variant of observed in rural and other South American areas, features superficial flaccid blisters that rupture to form erosive, crusted lesions in seborrheic distributions, frequently with a distinctive butterfly-shaped across the malar face. As with , no mucosal erosions occur, and the onset is gradual over weeks to months, beginning localized before possible generalization to the trunk and extremities. High familial aggregation is notable, affecting up to 20% of relatives in endemic foci, linked to environmental triggers like insect exposure. Pemphigus vegetans, a rare localized form of , is characterized by thickened, vegetating plaques in flexural and areas, often accompanied by nail dystrophy and mucosal involvement. It typically affects middle-aged adults and presents with pustules or erosions that evolve into vegetative lesions, following a more benign course than classic but still requiring immunosuppressive therapy. Rare forms of pemphigus include drug-induced cases, which phenotypically resemble or (with predominance in a 4:1 ratio) and emerge shortly after exposure to culprit agents such as thiol drugs like or , featuring corresponding blistering and erosive patterns that may resolve upon drug cessation. Gestational pemphigus, an uncommon pregnancy-associated manifestation, mirrors with onset of flaccid bullae and mucosal erosions during the second or third trimester, potentially flaring postpartum and transmitting autoantibodies transplacentally to cause transient neonatal lesions.

Pathophysiology

Autoimmune Mechanisms

Pemphigus is an organ-specific autoimmune disease characterized by the production of autoantibodies against desmosomal proteins in keratinocytes, which disrupts intercellular adhesion and leads to intraepidermal blistering through acantholysis, the separation of keratinocytes. In the most common variants, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), immunoglobulin G (IgG) autoantibodies, predominantly of the IgG4 subclass, target desmoglein 3 (DSG3) and desmoglein 1 (DSG1), respectively, as key desmosomal cadherins responsible for maintaining epidermal integrity.90360-b) In IgA pemphigus, a rarer variant, IgA autoantibodies similarly attack desmosomal components, resulting in distinct pustular lesions with less pronounced acantholysis. The pathogenic effects of these autoantibodies extend beyond simple binding, involving both direct steric hindrance that blocks trans-interactions between desmogleins and desmocollins in s, and indirect disruption of intracellular signaling cascades. Steric interference impairs assembly and stability, while signaling alterations—such as activation of p38 (MAPK) and (PKC)—induce cytoskeletal reorganization, desmoglein , and loss of . These processes culminate in apoptosis, mediated by caspase-8 activation and Fas ligand expression, alongside inflammatory responses characterized by release (e.g., IL-17A from Th17 cells) and infiltration that amplify tissue damage. Autoantibody production is orchestrated by adaptive immune responses, with + T cells playing a central role in driving B-cell activation and class switching. Th2 cells, in particular, secrete interleukin-4 (IL-4) and interleukin-13 (IL-13), which promote IgG4 production and B-cell differentiation into autoantibody-secreting plasma cells. The initiation of this autoimmune cascade often stems from , including HLA class II alleles like HLA-DRB1*04:02 that enhance of desmogleins to T cells, combined with a breakdown in self-tolerance. Environmental factors, such as drugs (e.g., ) that directly induce or infections (e.g., via molecular mimicry), further trigger or exacerbate loss of tolerance in susceptible individuals.

Molecular Targets

In (PV), autoantibodies primarily target desmoglein 3 (Dsg3), a desmosomal expressed in mucosal epithelia, leading to intraepithelial blistering confined to mucous membranes in initial stages. In contrast, (PF) is characterized by autoantibodies against desmoglein 1 (Dsg1), which is predominantly expressed in the superficial layers of the , resulting in subcorneal . Severe cases of PV often involve combined autoantibodies against both Dsg1 and Dsg3, particularly when the disease progresses to mucocutaneous involvement, where anti-Dsg1 antibodies emerge alongside persistent anti-Dsg3 reactivity. Paraneoplastic pemphigus (PNP), a variant associated with underlying malignancies, features a broader autoantibody profile beyond desmogleins, targeting plakin family proteins that anchor intermediate filaments to desmosomes and hemidesmosomes. Key non-desmoglein antigens in PNP include envoplakin and periplakin, which are consistently recognized by patient sera and contribute to the severe, widespread acantholysis observed. Epitope mapping studies have identified distinct pathogenic and non-pathogenic sites on the ectodomains of Dsg1 and Dsg3, with pathogenic autoantibodies predominantly binding to conformational epitopes in the N-terminal extracellular cadherin domain (EC1). These EC1 epitopes facilitate steric hindrance or signaling disruption of desmosomal adhesion, whereas non-pathogenic antibodies often target linear epitopes in other ectodomains (EC2–EC5) that do not induce loss of cell adhesion. In active pemphigus, autoantibodies are predominantly of the IgG4 isotype, with high titers correlating to disease severity and reflecting Th2-biased immune responses; IgG1 subclasses may also contribute but are less dominant. These IgG4 antibodies exhibit high affinity for Dsg antigens, enhancing their pathogenic potential through sustained binding and reduced clearance. Animal models have confirmed the pathogenicity of anti-Dsg antibodies via passive transfer experiments, where injection of patient-derived IgG or monoclonal anti-Dsg3 antibodies into neonatal or adult mice reproduces intraepidermal blistering and acantholysis, mimicking human disease histology.

Diagnosis

Clinical Evaluation

The clinical evaluation of pemphigus begins with a detailed patient history to identify the onset and progression of symptoms, which typically start with painful oral erosions before extending to cutaneous involvement in pemphigus vulgaris (PV). Progression is assessed through functional impacts such as pruritus, pain, dysphagia, and effects on quality of life, often leading to nutritional challenges in severe mucosal cases. A thorough drug exposure history is essential, as agents like D-penicillamine and angiotensin-converting enzyme inhibitors can induce pemphigus foliaceus or vulgaris. Family history is reviewed to rule out genetic predispositions, though pemphigus is primarily sporadic, and a malignancy screen is recommended for suspected paraneoplastic pemphigus (PNP), including imaging and tumor markers given its association with underlying neoplasms. Physical examination focuses on lesion distribution, which in PV commonly affects the , face, , , and areas while sparing palms and soles, with flaccid bullae or erosions on erythematous or normal . The Nikolsky sign, elicited by applying gentle pressure to perilesional to induce blistering, indicates epidermal fragility and is positive in active disease. The Tzanck sign, observed via bedside smear of blister fluid revealing acantholytic cells (rounded with large nuclei), supports intraepidermal but requires cytologic preparation. Mucosal involvement is carefully assessed, occurring in up to 80% of PV cases initially in the oral cavity and potentially extending to ocular, genital, or esophageal sites, with painful erosions that may cause significant morbidity. Characteristic symptoms, such as fragile blisters rupturing to form erosions, guide the suspicion of pemphigus during this evaluation. Differential diagnosis includes subepidermal bullous disorders like , which features tense bullae and pruritus in elderly patients without mucosal predominance. Hailey-Hailey disease presents with flaccid vesicles in areas due to genetic but lacks autoantibodies. and Stevens-Johnson syndrome are distinguished by targetoid lesions and acute onset often triggered by infections or drugs, with more widespread mucosal necrosis. Biopsy is indicated when clinical features suggest pemphigus to confirm , particularly in cases with presentation or to differentiate from mimics; a punch from the edge of an early intact vesicle is preferred for , showing suprabasal in . The Pemphigus Disease Area Index (PDAI) is a validated scoring system for assessing disease severity, integrating , , and mucosal involvement by evaluating number, size, and activity across anatomical sites, with total scores ranging from 0 to 250 for activity. Cutoff values of 0-8 for mild, 9-24 for moderate, and ≥25 for severe disease have been established through international validation studies.

Laboratory Tests

Laboratory confirmation of pemphigus relies on histopathological examination, studies, and serological assays to detect autoantibodies targeting desmosomal proteins such as desmogleins. is a cornerstone of diagnosis, typically performed on perilesional tissue and stained with hematoxylin and eosin. In (PV), the hallmark finding is suprabasal , where separate above the basal layer, resulting in intraepidermal clefts or blisters with a characteristic "row of tombstones" appearance of basal cells adhering to the basement membrane. In contrast, (PF) shows superficial confined to the granular layer of the , leading to subcorneal clefting without deeper involvement. Direct immunofluorescence (DIF) on biopsy specimens reveals intercellular deposition of IgG and complement component throughout the , producing a distinctive "fishnet" or pattern that confirms the autoimmune nature of the disease. This pattern is highly specific for pemphigus and distinguishes it from subepidermal blistering disorders. Indirect (IIF) detects circulating autoantibodies in patient serum using substrates like monkey , where IgG binds to the intercellular spaces of , with titers correlating to disease activity. Monkey is preferred over other substrates for its superior sensitivity in identifying pemphigus-specific antibodies. () quantifies anti-desmoglein 1 (Dsg1) and anti-desmoglein 3 (Dsg3) IgG antibodies, aiding in subtype differentiation and disease monitoring; for instance, PV is associated with anti-Dsg3 positivity, while PF shows anti-Dsg1 elevation, and titers above 20 RU/mL are generally indicative of active disease. is more sensitive than IIF for detecting low-level antibodies and tracks response to therapy through serial measurements. For paraneoplastic pemphigus (PNP), additional immunoblotting identifies antibodies against plakin family proteins such as envoplakin and periplakin, which are characteristic of this variant and help differentiate it from other pemphigus subtypes. Salt-split skin immunofluorescence may be employed in the to distinguish pemphigus (epidermal-side staining) from subepidermal bullous diseases like (dermal-side staining).

Management

Pharmacological Treatments

The pharmacological management of pemphigus primarily aims to suppress autoimmune activity by targeting desmoglein autoantibodies through immunosuppressive and immunomodulatory agents, achieving disease control while minimizing long-term toxicities. First-line therapies typically combine systemic corticosteroids with rituximab for moderate-to-severe cases, as recommended by international consensus guidelines. Adjuvant immunosuppressants serve as steroid-sparing options to reduce cumulative glucocorticoid exposure. In refractory or life-threatening presentations, adjunctive procedures like intravenous immunoglobulin (IVIG) and plasmapheresis are employed to rapidly deplete circulating antibodies. Systemic corticosteroids, such as , remain the cornerstone of initial therapy due to their potent effects that halt formation. The standard induction regimen starts at 1 mg/kg/day orally, with tapering initiated once new lesions cease for 2-4 weeks, aiming for the lowest to prevent . Prolonged use, however, carries significant risks including , , , and increased infection susceptibility, necessitating bone density monitoring and prophylaxis with bisphosphonates or calcium/ supplementation in at-risk patients. Steroid-sparing immunosuppressants are introduced early to facilitate dose reduction and improve remission rates. , a analog that inhibits proliferation, is commonly used at 2-3 mg/kg/day orally, adjusted based on (TPMT) enzyme activity to avoid myelosuppression; therapeutic effects typically emerge within 4-8 weeks. , which blocks synthesis in B and T cells, serves as an alternative at 1-2 g/day divided doses, particularly in patients intolerant to , with comparable efficacy in achieving complete remission when combined with . Rituximab, an anti-CD20 that depletes B cells and reduces production, is now a first-line agent for moderate-to-severe (PV) and foliaceus (PF) per 2020 European S2k and international guidelines. The preferred induction regimen involves two 1 g intravenous infusions two weeks apart, often alongside corticosteroids, yielding remission rates exceeding 80% and steroid-free periods in many cases; maintenance dosing of 500 mg at 6-12 months may be required for sustained control. An alternative protocol of 375 mg/m² weekly for four doses is also effective, with lower infection risks compared to higher cumulative doses. For severe or refractory disease unresponsive to standard therapy, IVIG at 2 g/kg per cycle (administered as 0.4 g/kg/day over 5 days) modulates immune responses by neutralizing autoantibodies and is often combined with rituximab for synergistic effects. Plasmapheresis, involving 3-5 exchanges of 1-1.5 plasma volumes over 1-2 weeks, rapidly removes pathogenic IgG antibodies in crisis situations, typically paired with immunosuppressive agents to prevent rebound. Treatment regimens may vary by pemphigus subtype to optimize efficacy. In pemphigus foliaceus, dapsone—a with and immunomodulatory properties—is used as an or first-line option at 1-1.5 mg/kg/day orally (up to 150 mg/day), particularly for superficial erosions, with screening required to mitigate hemolytic risks. For paraneoplastic pemphigus (PNP), addressing underlying with or targeted therapies is essential alongside , as autoimmune control alone is insufficient.

Supportive Care

Supportive care in pemphigus plays a crucial role in alleviating symptoms, promoting , and preventing secondary complications such as , particularly given the fragile nature of and mucosal lesions. These measures complement disease-modifying therapies by focusing on daily strategies tailored to the extent of erosions and needs. Wound care emphasizes gentle handling of affected to minimize and facilitate re-epithelialization. Non-adherent dressings, such as silicone-based or jelly-impregnated options, are recommended to cover erosions and blisters, reducing during dressing changes and preventing adherence to bedding or clothing. baths or soaks with agents like can help cleanse lesions and lower bacterial load without disrupting fragile tissue. In cases of extensive involvement, consultation with wound care specialists ensures aseptic techniques, such as wearing gloves during changes, to avoid introducing pathogens. Pain management and nutritional support are essential, especially for patients with oral or widespread mucosal that impairs eating and daily function. Over-the-counter analgesics or, in severe cases, opioids may be used judiciously for discomfort from erosions, while local gels applied to mucosal surfaces provide targeted relief. To address malnutrition risks from painful swallowing or reduced intake, nutritional consultation with a is advised, incorporating soft or liquid diets, protein-rich smoothies, and pH-balanced foods to ease consumption and support healing. Maintaining a food journal helps identify triggers and ensure adequate and intake. Infection prevention strategies prioritize and barrier methods to mitigate the high risk of secondary bacterial or fungal superinfections, which can exacerbate morbidity. Regular moisturization with emollients prevents cracking, while avoiding scratching through measures like wearing gloves at night reduces micro-tears that serve as entry points for pathogens. Topical antibiotics may be applied to colonized erosions as a prophylactic measure, and patients should receive updated vaccinations, including pneumococcal and , to bolster immunity without active disease flares. Good overall , such as frequent laundering of and using talcum powder to prevent sticking, further aids in maintaining a clean . For patients with prominent oral involvement, dental and practices are vital to prevent complications like caries or . Soft-bristled or toddler-sized toothbrushes paired with non-irritating, non-mint toothpaste minimize trauma to erosions, and antimicrobial mouth rinses (e.g., diluted or ) promote cleanliness without stinging. A soft avoids foods, and more frequent dental visits—every three months—are recommended for professional cleanings and monitoring. These steps help sustain oral health and reduce pain during meals. A multidisciplinary approach optimizes outcomes by integrating expertise from dermatologists, who oversee lesion management; rheumatologists or immunologists for systemic oversight; ear, nose, and throat specialists for severe mucosal disease; dietitians for nutritional needs; and psychologists for emotional support, as and can lead to . This collaborative care model, involving nurses and wound specialists as needed, ensures holistic management and improves .

Prognosis and Complications

Outcomes

The long-term prognosis for pemphigus patients has improved significantly with modern immunosuppressive therapies, particularly rituximab, which has become a cornerstone for achieving sustained remission. Approximately 40–50% of patients treated with rituximab attain complete remission off therapy, with rates up to 48% reported in cohort studies after 1–3 years. Overall mortality rates range from 5–10%, primarily due to treatment-related complications such as infections, though rates are markedly higher in elderly patients or those with paraneoplastic pemphigus (PNP), where untreated underlying malignancies can lead to up to 90% mortality. Relapse occurs in 40–60% of cases, often linked to the re-emergence of anti-desmoglein (Dsg) autoantibodies, with of anti-Dsg titers serving as a key serological tool to predict and detect recurrences early. While pemphigus typically results in minimal scarring due to its intraepidermal blistering mechanism, the chronic nature of the disease imposes a substantial psychological burden, including elevated rates of anxiety, , and reduced , affecting up to 50% of patients. Several factors influence recovery outcomes, with early enabling prompt and higher remission rates, particularly when rituximab is initiated soon after onset. Low initial anti-Dsg antibody titers at correlate with better , as they indicate milder activity and faster response to therapy. Additionally, (PF) generally carries a more favorable outlook than (PV), with lower mortality and less severe mucosal involvement contributing to improved long-term survival.

Associated Risks

Pemphigus, especially (), predisposes patients to severe complications arising from extensive erosions that disrupt the skin and mucosal barriers, facilitating secondary bacterial infections and potentially leading to . This barrier dysfunction significantly contributes to morbidity, with infections accounting for approximately 40–60% of deaths, as the leading cause in many cohorts. In historical cohorts, has been a leading cause of mortality, underscoring the need for vigilant wound care to mitigate this risk. Esophageal involvement in PV affects 47–68% of patients, manifesting as erosions; scarring and strictures are rare in PV, unlike in other bullous diseases. These may necessitate endoscopic for management. Systemic therapy, a cornerstone of pemphigus management, carries substantial risks including steroid-induced diabetes mellitus, , and posterior subcapsular cataracts from prolonged high-dose exposure. These metabolic and skeletal complications can exacerbate overall health decline in affected patients. Immunosuppressive agents further heighten vulnerability to opportunistic infections, such as , particularly in regimens combining multiple drugs. Rituximab, an anti-CD20 biologic, is associated with infusion-related reactions in 5–16% of patients as serious events, though mild reactions are more common, including fever, chills, and rare severe requiring and monitoring. Paraneoplastic pemphigus (PNP) is intrinsically linked to underlying malignancies, with nearly all cases associated with such as or . Long-term in pemphigus patients may elevate the risk of development, as evidenced by population-based studies showing significant associations. To address these risks, patients on chronic corticosteroids undergo regular assessments via to detect and manage early, alongside infection screening such as chest imaging or prophylaxis for opportunistic pathogens in high-risk scenarios.

History and Research

Historical Development

The term "pemphigus," derived from the Greek word pemphix meaning "" or "," was first used by around 460–370 BCE to describe blistering skin conditions often associated with fever, marking one of the earliest recorded mentions of such dermatological manifestations in ancient . These ancient descriptions encompassed a broad range of bullous eruptions without precise differentiation, laying the groundwork for later classifications of autoimmune blistering diseases. In the , pemphigus began to be more systematically described and named, with the condition now known as first recognized as a distinct entity around 1791 by Johann Friedrich Wichmann, who applied the term to chronic bullous disorders of the skin and mucosa. By the mid-1800s, clinicians like Pierre Louis Cazenave further characterized its progressive nature, involving flaccid blisters and erosions, though differentiation from related conditions like remained unclear until the . This period saw initial attempts to distinguish pemphigus from other vesicular diseases based on clinical observations, but histological confirmation awaited later advances. A pivotal milestone occurred in 1953 when Walter F. Lever published seminal histological studies that clearly differentiated , characterized by intraepidermal , from subepidermal bullous disorders like , refining the diagnostic framework. In 1964–1965, Ernst H. Beutner and colleagues identified circulating intercellular autoantibodies in pemphigus patients using techniques, providing the first direct evidence of an autoimmune and shifting understanding from infectious or toxic causes to immune-mediated . Treatment advancements in the mid-20th century dramatically improved outcomes; the introduction of penicillin in the 1940s helped combat secondary bacterial infections that previously exacerbated the disease, while systemic corticosteroids, adopted in the early 1950s, reduced mortality rates from approximately 75% to around 30% by suppressing the autoimmune response and halting blister progression. Classification evolved further in the 1990s when Grant J. Anhalt and team defined in 1990 as a distinct variant associated with underlying neoplasms, characterized by severe mucosal involvement and autoantibodies targeting multiple antigens, including those beyond desmogleins.

Current Advances

Recent advances in the treatment of pemphigus have prominently featured the expansion of biologic therapies, with rituximab emerging as a cornerstone based on updated guidelines from 2017 to 2020. The European Academy of Dermatology and Venereology's 2020 S2K guidelines recommend rituximab, either alone or in combination with oral , as first-line therapy for moderate-to-severe and foliaceus, highlighting its superior efficacy over mycophenolate mofetil in achieving sustained remission and reducing dependence. Emerging anti-BAFF agents, such as , represent promising extensions of B-cell targeted approaches, with case reports demonstrating rapid clinical remission in refractory when used adjunctively after rituximab. Similarly, ianalumab (VAY736), an anti-BAFF receptor , was under investigation in early-phase trials for as of 2020, with potential to inhibit B-cell survival and production. Genetic research has advanced through genome-wide association studies (GWAS), uncovering key HLA and non-HLA susceptibility loci that inform disease predisposition and subtype specificity. A 2018 GWAS in the Chinese population identified distinct HLA class II haplotypes, such as for and for , alongside non-HLA variants contributing to risk. Notably, the ST18 gene, encoding a pro-apoptotic regulator, has been implicated in fogo selvagem (endemic ), with functional variants near ST18 associated with altered immune regulation and disease susceptibility in affected populations. These findings underscore the role of genetic-environmental interactions, particularly in endemic forms, and pave the way for personalized . Innovative vaccine strategies aim to restore by targeting desmoglein (Dsg) autoantigens, remaining largely in . Dsg3-based tolerogenic vaccines, such as peptide-coupled nanoparticles or tolerogenic carriers, have demonstrated antigen-specific tolerance induction in HLA-transgenic mouse models of , reducing pathogenic production and blistering without systemic . These approaches leverage regulatory T-cell activation to counteract autoreactive B- and T-cell responses, offering a potential curative avenue beyond symptom management. Diagnostic advancements focus on enhancing monitoring capabilities, with enzyme-linked immunosorbent assay () kits enabling rapid assessment of anti-desmoglein titers to guide therapy adjustments. Commercial ELISAs for anti-Dsg1 and anti-Dsg3 IgG correlate closely with disease activity, allowing point-of-care-like serial testing to predict flares and remission in pemphigus patients. This facilitates timely interventions, improving outcomes over traditional methods. Ongoing clinical trials explore targeted agents for refractory pemphigus, including (BTK) inhibitors like . The phase III trial of rilzabrutinib, completed in 2021, did not meet its primary endpoints for sustained remission in moderate-to-severe cases, though phase II data demonstrated efficacy and tolerability, with a 2024 randomized trial confirming its safety profile. has shown efficacy in case series for paraneoplastic pemphigus associated with B-cell malignancies, inhibiting autoantibody-driven inflammation and supporting its investigation in refractory non-paraneoplastic variants. These efforts highlight a shift toward precision , with future directions emphasizing combination regimens and long-term safety data. In 2025, a affirmed the efficacy of low-dose rituximab in pemphigus, achieving remission with fewer adverse effects compared to standard dosing. Additionally, chimeric antigen receptor T-cell (CAR-T) therapies targeting , such as rese-cel, are in early clinical trials for refractory cases, with data anticipated throughout 2025. Standardized outcome measures are under development to facilitate evaluation of these novel therapies in research.

Veterinary Aspects

Affected Species

Pemphigus, particularly the foliaceus variant, is most commonly reported in among domestic animals, where it manifests as an autoimmune blistering disease resembling (), with characteristic lesions including pustules, erosions, and crusts primarily affecting the face, paw pads, ears, and trunk. Breeds such as the and show a predisposition, with overrepresentation in case series indicating a possible genetic component. In , the disease typically presents with symmetrical scaling and crusting, often progressing from localized to generalized involvement if untreated. In , pemphigus is rarer than in and usually presents as with crusting and erosions on the face, pinnae, and footpads, while mucosal surfaces are generally spared, distinguishing it from deeper variants like . Cases in are often idiopathic but can be drug-induced, with certain drugs such as methimazole or amoxicillin implicated in triggering autoimmune responses leading to and similar cutaneous signs. The condition in felines tends to be less severe than in canines, with facial and pedal involvement predominating and systemic signs like fever or occasionally noted. Horses are affected by equine pemphigus foliaceus, a naturally occurring form characterized by generalized scaling, crusting, and alopecia, most prominently on the face, neck, legs, and trunk, often leading to a seborrheic appearance. This variant in equids can exhibit seasonal flares, potentially exacerbated by environmental factors such as ultraviolet exposure or insect activity, with lesions worsening in spring or summer in some reports. Diagnosis relies on histopathology showing subcorneal pustules and acantholytic keratinocytes, confirming autoantibody targeting of desmogleins. Experimental models of pemphigus have been developed in mice using transgenic approaches, such as those expressing anti-desmoglein 3 (anti-Dsg3) antibodies to recapitulate mucosal and cutaneous blistering akin to human . These models, including humanized Dsg3 transgenic mice crossed with Dsg3 knockouts, demonstrate pathogenicity of anti-Dsg3 IgG in inducing oral and erosions, aiding research into disease mechanisms and therapies. Pemphigus in animals is an autoimmune condition with no evidence of zoonotic transmission to , as it does not involve infectious agents and cannot be passed through contact or other means.

Comparative Features

Pemphigus in animals, particularly and , shares core pathological features with forms, characterized by resulting from autoantibodies targeting desmogleins in desmosomes, leading to intraepidermal blistering and erosions. In canine (), the predominant variant, anti-desmoglein 1 (Dsg1) antibodies predominate, mirroring superficial , while canine () involves anti-Dsg3, akin to suprabasal ; however, mucosal involvement is rarer in animals, with lesions primarily affecting haired skin rather than extensive oral or genital mucosa as seen in . Diagnostic approaches in veterinary medicine closely parallel those in humans, relying on skin biopsy for histopathological confirmation of acantholysis and direct immunofluorescence (DIF) or indirect immunofluorescence (IIF) to detect intercellular IgG deposition; however, enzyme-linked immunosorbent assays (ELISAs) for anti-desmoglein antibodies, while developed and validated in research settings for canine Dsg3 and Dsg1, lack widespread commercial validation and routine use in clinical veterinary practice compared to their established role in human diagnostics. Therapeutic strategies emphasize glucocorticoids as the cornerstone, such as prednisolone at 2-4 mg/kg daily, achieving disease control in approximately 90% of cases and 50-70% of cases, often combined with adjunctive immunosuppressants like cyclosporine (5-10 mg/kg daily) in and for steroid-sparing effects; newer agents such as mycophenolate mofetil or have shown promise in refractory cases as of 2025. In contrast, pemphigus increasingly incorporates targeted biologics like rituximab, which depletes B cells and induces longer remissions, a modality not yet standard in veterinary care due to cost and availability. in animals is generally fair to good, with exhibiting higher rates of remission (up to 90%) but increased relapse tendency compared to (50-70% remission), though overall outcomes remain guarded due to chronicity and potential adverse effects from long-term . Etiologically, animal pemphigus is predominantly idiopathic or linked to environmental triggers such as drugs, infections, or vaccinations, with minimal evidence of strong genetic predispositions like the HLA class II associations prominent in human and foliaceus. Canine PF serves as a valuable spontaneous animal model for human pemphigus research, facilitating testing of therapies like Bruton's tyrosine kinase inhibitors, which have demonstrated efficacy in reducing lesional severity in dogs and informed translational studies for human PF treatments.