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Pemphigus Vulgaris
Introduction
Pemphigus vulgaris (PV) is an autoimmune disease that results in blisters on cutaneous and mucosal surfaces and is characterized primarily by acantholysis.[1] Pemphigus is derived from pemphix, the Greek word for blister. Pemphigus was first described in 1788 by Stephen Dickson, who observed a patient with a blister on her tongue.[2] Although PV is not contagious as initially thought, there have been possible triggers identified that might induce PV in patients with other autoimmune disorders.[1]
Etiology
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Etiology
The precise etiology of pemphigus vulgaris is unknown; however, multiple studies have linked pemphigus vulgaris with autoantibodies targeting cadherins, ultimately leading to acantholysis and dissociation of keratinocytes.[3][4]. Some patients at risk may have a genetic predisposition for pemphigus vulgaris.[5][6] Several studies have linked PV with human leukocyte antigen (HLA) class II alleles.[7] HLA-DRB1 0402 is associated with PV in Ashkenazi Jews; DRB1 1401/04 and DQB1 0503 HLA alleles are associated with PV in non-Jewish patients of European or Asian descent.[8][9][10] Environmental factors, such as diet, stress, viral infections, medications, ultraviolet radiation, ionizing radiation therapy, pesticides, and allergens, may all induce immune dysregulation leading to a flare of PV.[1][11][12]
Exposure to certain medications like penicillamine and captopril can trigger PV. Such a trigger can happen through the effects on binding to molecules involved in cell adhesion, influence on enzymes that mediate keratinocyte aggregation, and by stimulating neoantigen formation.[13] Furthermore, nonsteroidal antiinflammatory agents, penicillin, and cephalosporins have also been associated with drug-induced PV.[13][14] Finally, controversial case reports associating PV with certain foods like red wine, garlic, leek, and peppers exist, though such an association is not supported by robust evidence.[15]
Epidemiology
Though PV is prevalent worldwide, the occurrence of PV may be related to ethnicity and geographic location.[16][7] The reported incidence is between 0.1 and 0.5 per 100,000 people per year.[17] However, a higher rate is recorded in certain ethnicities.[18] Ashkenazi Jews have been found to have an increased incidence of PV, and the average onset of PV is usually seen between the ages of 40 and 60 years.[19] Also, people in India, Southeast Europe, and the Middle East are at greatest risk for PV.[20] The prevalence of PV is roughly the same in men and women. However, in Tunisia, PV is more common in women than men by a ratio of 4 to 1.[1][19]
PV has been shown to have a genetic component, although familial cases are uncommon.[21] Patients with PV have been found to have a higher frequency of nonsymptomatic first-degree relatives with circulating PV–immunoglobulin G (IgG) antibodies compared with healthy controls. Additionally, first-degree relatives were found to have a higher prevalence of autoimmune diseases. DQB1*0503 and DRB1*0402 are two of the most common PV-associated alleles, with the latter protective against rheumatoid arthritis. PV has been associated with myasthenia gravis and ulcerative colitis.[22][23]
Pathophysiology
PV is caused by autoantibodies that target cadherins, specifically desmogleins, though there may be some role for desmocollin; thus, this is a type 2 hypersensitivity reaction.[24][25] Acantholysis, or the loss of keratinocyte–keratinocyte adhesion, is interrupted by circulating IgG autoantibodies to intercellular adhesion molecules.[26][27] Acantholysis is seen as a result of the autoantibodies destroying the intracellular connections, leading to bullae that can easily rupture (known clinically as the Nikolsky sign).
A “super-compensation hypothesis” recently submitted by Sinha et al. proposes that additional factors may also play a role in PV.[28] Multiple mechanisms for antibody-induced acantholysis have been suggested, including the induction of signal transduction and the inhibition of adhesive molecule function through steric hindrance, which can trigger cell separation.[29] The pathogenesis of PV has been described in more detail by Hammers et al.[30]
In patients with PV, autoantibodies against desmoglein 1 (Dsg 1) and desmoglein 3 (Dsg 3) is the purported cause.[31] Desmogleins are transmembrane glycoproteins that are an integral part of desmosomes which, in part, are required for cell–cell adhesion via interaction with intermediate filaments. The most common targets of desmoglein for IgG antibodies are the extracellular cadherin domains, which can result in the loss of desmosome-adhesive properties. These signaling pathways trigger endocytosis, depletion, and direct inhibition of Dsg 3 interactions.[32] It is generally believed that the amino portion of the cadherin proteins is most implicated in the pathogenesis of acantholysis leading to PV.[33]
Many animal models have shown that enzymatic inactivation of Dsg 1 and gene deletion of Dsg 3 results in pathology similar to PV.[34][35] This phenomenon was observed to be dose-dependent and suggests that reducing the circulating levels of IgG against Dsg 1 and Dsg 3 can improve patient outcomes.[36] In patients with primarily cutaneous disease, Dsg 1 likely plays a role more superficially, whereas Dsg 3 is more likely to be found in deeper cutaneous structures and mucous membranes.[37][38] The implication is that Dsg 3 can compensate for the absence of Dsg 1 in mucosal structures (thus demonstrating PV in cutaneous lesions only). In contrast, Dsg 1 without Dsg 3 is insufficient to manage mucous membranes or cutaneous lesions alone, implying that Dsg 1 is in lower proportion in mucous membranes.
The binding of antibodies to desmogleins has been confirmed by epitope mapping and is presumed to disrupt desmoglein binding by affecting steric hindrance.[39] Another theory for the pathophysiology of PV is the desmoglein nonassembly depletion hypothesis. This theory suggests that autoantibodies not only bind desmoglein but that they also bind each other, leading to crosslinking and the inability of desmosomes to maintain cell–cell adhesion.[40][41]
Histopathology
Histopathologic evaluation of PV should be performed with both a hematoxylin and eosin (H&E) biopsy on lesional skin that is stored in formalin and a second biopsy for direct immunofluorescence on nonlesional skin that is not stored in formalin but rather in an appropriate medium such as Michel medium.[42][43]
The classic histopathologic finding is suprabasilar acantholysis, leaving a tombstone appearance in the remaining basal keratinocytes; there may be eosinophils present as well.[44][45][46] The pemphigus vegetans variant may have similar findings with additional papillomatosis and hyperkeratosis, often present in skin folds, such as the inguinal or axillary folds.[47][48]
History and Physical
PV is a blistering disease that initially presents on the oral mucosa in 80% of cases.[3][49] These intraoral blisters often rupture, leaving painful erosions, which may affect patients' oral intake, leading to potential malnutrition.[50][51] Cutaneous lesions traditionally appear in patients with PV after the first oral blisters have presented.[52] Vesicles, erosions, or bullae may appear on erythematous or normal-appearing skin. A Nikolsky sign is described as a blister formation with minor pressure or trauma and is seen in PV.[53]
Due to the painful nature of oral lesions, PV can impair nutritional status. Mucosal PV can be found in the conjunctiva, nasal mucosa, larynx, pharynx, esophagus, penis, vagina, and anus.[54] When presenting in the cervix, PV can elicit a diagnostic challenge by conflating the Pap smear results, which may reveal inauthentic dysplastic changes.[54][55][56] Cutaneous lesions are commonly found on the face, trunk, groin, scalp, and armpits. PV usually spares the palms and soles.[57] Blisters can heal without scarring but may result in changes in the pigment. Alopecia may be observed when PV affects the scalp.[58] Rarely, PV will involve nails when the disease is severe.[19][59] Another rare manifestation of PV is pemphigus herpetiformis, where PV can present with urticarial plaques and cutaneous vesicles arranged in a herpetiform or annular arrangement.
Evaluation
The diagnosis of PV is based on clinical, histopathologic, and laboratory studies. An H&E biopsy should be performed on lesional skin, which can be analyzed to show the characteristic histopathologic findings. Direct immunofluorescence is an important tool for the diagnosis of PV, which shows a net-like or chicken wire–like pattern of IgG in the epidermis.[60][61] Enzyme-linked immunosorbent assay (ELISA) testing, which is commercially available, will show serum IgG against Dsg 1, Dsg 3, or both in most samples.[19][59]
Tzanck smear and histology examination will show acantholysis.[19] Serological studies like indirect immunofluorescence (IIF), which should be performed on monkey esophagus as a substrate, and ELISA can detect circulating autoantibodies that bind epithelial cell surface antigens.[62][63]
In patients with positive direct immunofluorescence (DIF) results, ELISA testing will show serum IgG against Dsg 1, Dsg 3, or both.[59] Additional workup should include vitals, pregnancy testing in select populations, a complete blood count (CBC), a metabolic panel, antinuclear antibody (ANA), and a urinalysis. A bone density scan may be needed early in the disease to ensure proper prevention of osteoporosis in at-risk patients who may be on a longer course of systemic glucocorticoids. Also, quality of life and disease activity should be documented to ensure a baseline for further monitoring. Two validated severity scoring systems include the Pemphigus Disease Area Index (PDAI) and the Autoimmune Bullous Skin Disorder Intensity Score (ABSIS), which can be completed in 2 to 5 minutes.[64]
Treatment / Management
First-line Treatment
Systemic corticosteroids
Systemic corticosteroids have significantly impacted the treatment of PV and remain the backbone of its management.[65] The first-line treatment of mild PV is systemic corticosteroids, which take several weeks to achieve a response.[64] Tapering down of the dose can be initiated when symptoms are improved, but if the reappearance of more than 3 lesions occurs, dosing should be increased again to induce remission.[66]
Anti-CD20 monoclonal antibodies
Anti-CD20 monoclonal antibodies, such as rituximab and ofatumumab, are the preferred modality to use in conjunction with corticosteroids for first-line treatment in moderate-to-severe pemphigus.[59] Rituximab is an anti-CD20 monoclonal antibody that stops B lymphocytes from maturing into autoantibody-producing plasma cells. It is administered intravenously, and response is usually seen within 3 months. Common side effects include infusion-related reactions such as nausea, vomiting, headache, and fever.[66] A rare serious side effect of rituximab is progressive multifocal leukoencephalopathy (PML), which has also been seen in other monoclonal antibodies.[67]
Second-line Treatment
Steroid-sparing immunosuppressives
Second-line treatment in combination with corticosteroids may include steroid-sparing immunosuppressives, such as azathioprine or mycophenolate mofetil (MMF).[66] Azathioprine is a purine analog that inhibits purine synthesis; it can be administered orally or by intravenous infusion. For patients on azathioprine, testing of the thiopurine methyltransferase (TPMT) enzyme should be performed to ensure that the metabolism of azathioprine is appropriate since the failure of this process may lead to bone marrow suppression, causing pancytopenia, thrombocytopenia, and leukopenia.[68][69][68] MMF functions as an immunosuppressant by inhibiting purine synthesis; it can be administered orally or by intravenous infusion. MMF is usually effective within 2 months of initiating treatment. Common side effects include nausea, vomiting, diarrhea, and abdominal discomfort. Intravenous administration can cause superficial thrombophlebitis and thrombosis.[66]
Third-line Treatment
Third-line treatments for PV include intravenous immunoglobulin (IVIG), cyclophosphamide, dapsone, immunoadsorption, and methotrexate.[66][70] Some studies have suggested treatment with other agents, such as apremilast or cyclophosphamide; pain-controlling medications may also be necessary depending on the patient's involvement.[71][72][73][72]
Emerging Therapies
Most of the emerging therapies that could be effective for PV are monoclonal antibodies, with the cost being a major restriction to large trials. Obinutuzumab, ofatumumab, and veltuzumab are anti-CD20 monoclonal antibodies that may be an alternative to rituximab. Other therapies that may offer hope in PV include medications that target B-cell–derived B-cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), CD19, Bruton kinase (BTK), and interleukin (IL-4).[32] Future PV research should focus on better understanding the specific pathogenic molecules and cytokines, after which better therapies can be produced.[74]
Differential Diagnosis
Differential diagnoses for PV include:
IgA Pemphigus
IgA pemphigus is similar to PV in that it has painful blisters, but IgA pemphigus does not present with oral mucosal blisters. DIF and IIF can both help to differentiate PV from IgA pemphigus.[75]
Pemphigus Foliaceus
Pemphigus foliaceus is similar to PV in the fact that it is an autoimmune blistering disease; however, similarly to IgA pemphigus, pemphigus foliaceus does not affect the oral mucosa since it is mostly due to Dsg 1 autoantibodies. Pemphigus foliaceus is less common than PV.[76]
Paraneoplastic Pemphigus
Paraneoplastic pemphigus also presents with mucocutaneous vesicles and bullae similar to PV. Paraneoplastic pemphigus can be differentiated from PV using IIF and immunoblot.[77]
Prognosis
Follow-up and response to treatment of PV should be monitored closely. PV is an active disease and often requires dose adjustments and changes in medications according to the response to treatment. Septicemia is the leading cause of death in PV.[19] A retrospective cohort study by Kridin et al. in Israel found that survival rates were lower in patients with PV compared with the general population. Patients who were diagnosed with PV at an older age had a lower survival rate. The median overall survival from the point of diagnosis was 10.1 years (0.2 to 29.8 years). There was not a statistically significant survival difference between men and women.[78]
Complications
Systemic corticosteroids, which are the backbone of PV treatment, are well known for causing osteoporosis and other complications. Corticosteroids have been reported to cause fractures in 30% to 50% and cause osteonecrosis in 9% to 40% of patients receiving long-term therapy.[79] The Fracture Risk Assessment (FRAX) is a tool used to further stratify the risk of osteoporotic fracture.[80] Other common side effects from corticosteroids include hyperglycemia, insomnia, increased appetite, hypertension, edema, adrenal suppression, cataracts, and delayed wound healing.[81]
A case-control study by Namazi et al. looked at the incidence of P-wave dispersion (PWD) in patients with PV. The authors reasoned that atrial fibrillation can be predicted by the presence of PWD and hypothesized that atrial fibrillation might be higher in PV patients. Patients were excluded if they had obesity, hyperlipidemia, hypertension, diabetes mellitus, and cardiopulmonary disease. The authors stated the limitations of their study included a small sample size of 90 patients and the use of corticosteroids was higher in the patients with PV. Regardless of those limitations, the incidence of PWD confirmed by electrocardiogram (ECG) was higher in the PV group than in the control group.[82]
Other complications could include other autoimmune diseases and malignancy.[83][84][85][86][87] Secondary infections may be common and should be prevented with a thorough care regimen, both with antifungal oral hygiene and careful avoidance of triggers that cause blistering.[88] Infections should be monitored carefully, as septicemia is the most common cause of death in patients with PV.[19]
Patients with significant oral involvement may need dietary adjustments to prevent complications.[89]
Deterrence and Patient Education
Patient education should include close follow-up visits with their provider and specialists. Medication compliance is integral to the management of PV and can be reinforced by the pharmacist's support. Patients should be provided information on support groups and resources on behavioral modulation, like dietary changes, to prevent the worsening of their disease.[90][91]
Enhancing Healthcare Team Outcomes
PV is a life-threatening autoimmune disease for which treatment is indicated. The goal of treatment in PV is to induce complete remission with minimal treatment-related adverse effects. Cutaneous and mucosal involvement in PV can cause significant pain and functional impairment. Local measures may help to improve patient symptoms. Due to the serious adverse effects, prolonged treatment with high doses of a systemic glucocorticoid is not recommended. A secondary infection like herpes simplex infection should be considered when lesions fail to respond to treatment. An interprofessional approach, including social workers, wound care staff, dieticians, nurses, physician assistants, nurse practitioners, pharmacists, dentists, primary care physicians, hospitalists, and dermatologists, can optimize outcomes.
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References
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