Pemphigus Vulgaris

Curtis Ingold; Nishad Sathe; Moien AB Khan

Pemphigus Vulgaris

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Continuing Education Activity

Pemphigus vulgaris is a rare autoimmune disease that causes blistering on cutaneous and mucosal surfaces. As the most prevalent type of pemphigus, its onset typically occurs between ages 40 and 60, affecting both genders equally. This activity explores the historical context and etiology of PV, tracing back to its initial description in 1788, shedding light on its pathogenesis involving acantholysis, which leads to blister formation. The course discussion reviews the role of the interprofessional team in managing patients with PV, highlighting collaborative strategies for comprehensive patient care.

Learners will gain insights into the evolving understanding of PV, dispelling earlier notions of contagion while exploring potential triggers associated with the onset in individuals with existing autoimmune disorders. This session aims to enhance clinicians' comprehension of the clinical presentation, diagnosis, and management approaches for PV. By fostering collaborative efforts among healthcare professionals, this activity seeks to improve outcomes for individuals affected by PV while exploring evolving perspectives on its triggers and management paradigms.

Objectives:

Identify the underlying autoimmune mechanisms and immunological factors involved in the etiology of PV, recognizing the pathophysiological basis of blister formation.
Implement evidence-based evaluation strategies for PV, integrating diagnostic tools and methods to ensure comprehensive assessment.
Determine the optimal management strategies for patients with PV, incorporating tailored treatments into patient care plans to improve outcomes.
Coordinate efforts among the interprofessional team to ensure a cohesive and integrated approach to patient care.

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

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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Pemphigus Vulgaris

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Details

References

[1]

Patel F, Wilken R, Patel FB, Sultani H, Bustos I, Duong C, Zone JJ, Raychaudhuri SP, Maverakis E. Pathophysiology of Autoimmune Bullous Diseases: Nature Versus Nurture. Indian journal of dermatology. 2017 May-Jun:62(3):262-267. doi: 10.4103/0019-5154.159620. Epub [PubMed PMID: 28584368]

[2]

Dickson S. Observations on Pemphigus. The London medical journal. 1788:9(Pt 3):309-324 [PubMed PMID: 29139718]

[3]

Jain VR, Mahajan RS, Rathi SS, Biyani VV, Ninama KR, Marfatia YS. Oral Mucosal Lesions - A Study of 369 Cases. Indian dermatology online journal. 2023 Mar-Apr:14(2):213-220. doi: 10.4103/idoj.idoj_203_22. Epub 2023 Mar 3 [PubMed PMID: 37089853]

Level 3 (low-level) evidence

[4]

Zhu Y, Su J, Zhang P, Deng M, Wu R, Liu Y, Su Y, Li S. The dysregulation of circulating innate lymphoid cells is related to autoantibodies in pemphigus vulgaris. International immunopharmacology. 2023 Apr:117():109921. doi: 10.1016/j.intimp.2023.109921. Epub 2023 Feb 24 [PubMed PMID: 36841156]

[5]

Drenovska K, Ivanova M, Vassileva S, Shahid MA, Naumova E. Association of specific HLA alleles and haplotypes with pemphigus vulgaris in the Bulgarian population. Frontiers in immunology. 2022:13():901386. doi: 10.3389/fimmu.2022.901386. Epub 2022 Aug 2 [PubMed PMID: 35983062]

[6]

Salviano-Silva A, Farias TDJ, Bumiller-Bini V, Castro MS, Lobo-Alves SC, Busch H, Pföhler C, Worm M, Goebeler M, van Beek N, Franke A, Wittig M, Zillikens D, de Almeida RC, Hundt JE, Boldt ABW, Ibrahim S, Augusto DG, Petzl-Erler ML, Schmidt E, Malheiros D. Genetic variability of immune-related lncRNAs: polymorphisms in LINC-PINT and LY86-AS1 are associated with pemphigus foliaceus susceptibility. Experimental dermatology. 2021 Jun:30(6):831-840. doi: 10.1111/exd.14275. Epub 2021 Jan 15 [PubMed PMID: 33394553]

[7]

Baker J, Seiffert-Sinha K, Sinha AA. Patient genetics shape the autoimmune response in the blistering skin disease pemphigus vulgaris. Frontiers in immunology. 2022:13():1064073. doi: 10.3389/fimmu.2022.1064073. Epub 2023 Jan 10 [PubMed PMID: 36703961]

[8]

Firooz A, Mazhar A, Ahmed AR. Prevalence of autoimmune diseases in the family members of patients with pemphigus vulgaris. Journal of the American Academy of Dermatology. 1994 Sep:31(3 Pt 1):434-7 [PubMed PMID: 8077468]

[9]

Szafer F, Brautbar C, Tzfoni E, Frankel G, Sherman L, Cohen I, Hacham-Zadeh S, Aberer W, Tappeiner G, Holubar K. Detection of disease-specific restriction fragment length polymorphisms in pemphigus vulgaris linked to the DQw1 and DQw3 alleles of the HLA-D region. Proceedings of the National Academy of Sciences of the United States of America. 1987 Sep:84(18):6542-5 [PubMed PMID: 2888115]

[10]

Lombardi ML, Mercuro O, Ruocco V, Lo Schiavo A, Lombari V, Guerrera V, Pirozzi G, Manzo C. Common human leukocyte antigen alleles in pemphigus vulgaris and pemphigus foliaceus Italian patients. The Journal of investigative dermatology. 1999 Jul:113(1):107-10 [PubMed PMID: 10417627]

[11]

Tavakolpour S. Pemphigus trigger factors: special focus on pemphigus vulgaris and pemphigus foliaceus. Archives of dermatological research. 2018 Mar:310(2):95-106. doi: 10.1007/s00403-017-1790-8. Epub 2017 Nov 6 [PubMed PMID: 29110080]

[12]

Crocker C. Radiation-induced pemphigus in a patient with an invasive ductal carcinoma of the breast: a case report. Oxford medical case reports. 2020 Jan:2020(1):omaa001. doi: 10.1093/omcr/omaa001. Epub 2020 Jan 31 [PubMed PMID: 32038873]

Level 3 (low-level) evidence

[13]

Brenner S, Goldberg I. Drug-induced pemphigus. Clinics in dermatology. 2011 Jul-Aug:29(4):455-7. doi: 10.1016/j.clindermatol.2011.01.016. Epub [PubMed PMID: 21679874]

[14]

Feng S, Zhou W, Zhang J, Jin P. Analysis of 6 cases of drug-induced pemphigus. European journal of dermatology : EJD. 2011 Sep-Oct:21(5):696-9. doi: 10.1684/ejd.2011.1428. Epub [PubMed PMID: 21697060]

Level 3 (low-level) evidence

[15]

Ruocco V, Ruocco E, Lo Schiavo A, Brunetti G, Guerrera LP, Wolf R. Pemphigus: etiology, pathogenesis, and inducing or triggering factors: facts and controversies. Clinics in dermatology. 2013 Jul-Aug:31(4):374-381. doi: 10.1016/j.clindermatol.2013.01.004. Epub [PubMed PMID: 23806154]

[16]

Celere BS, Vernal S, Brochado MJF, Segura-Muñoz SI, Roselino AM. Geographical foci and epidemiological changes of pemphigus vulgaris in four decades in Southeastern Brazil. International journal of dermatology. 2017 Dec:56(12):1494-1496. doi: 10.1111/ijd.13714. Epub 2017 Jul 24 [PubMed PMID: 28737218]

Level 2 (mid-level) evidence

[17]

Langan SM, Smeeth L, Hubbard R, Fleming KM, Smith CJ, West J. Bullous pemphigoid and pemphigus vulgaris--incidence and mortality in the UK: population based cohort study. BMJ (Clinical research ed.). 2008 Jul 9:337(7662):a180. doi: 10.1136/bmj.a180. Epub 2008 Jul 9 [PubMed PMID: 18614511]

[18]

Kneisel A, Hertl M. Autoimmune bullous skin diseases. Part 1: Clinical manifestations. Journal der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology : JDDG. 2011 Oct:9(10):844-56; quiz 857. doi: 10.1111/j.1610-0387.2011.07793.x. Epub [PubMed PMID: 21955378]

[19]

Porro AM, Seque CA, Ferreira MCC, Enokihara MMSES. Pemphigus vulgaris. Anais brasileiros de dermatologia. 2019 Jul 29:94(3):264-278. doi: 10.1590/abd1806-4841.20199011. Epub 2019 Jul 29 [PubMed PMID: 31365654]

[20]

Kridin K. Pemphigus group: overview, epidemiology, mortality, and comorbidities. Immunologic research. 2018 Apr:66(2):255-270. doi: 10.1007/s12026-018-8986-7. Epub [PubMed PMID: 29479654]

Level 3 (low-level) evidence

[21]

Vodo D, Sarig O, Sprecher E. The Genetics of Pemphigus Vulgaris. Frontiers in medicine. 2018:5():226. doi: 10.3389/fmed.2018.00226. Epub 2018 Aug 14 [PubMed PMID: 30155467]

[22]

Guptill JT, Sleasman JW, Steeland S, Sips M, Gelinas D, de Haard H, Azar A, Winthrop KL. Effect of FcRn antagonism on protective antibodies and to vaccines in IgG-mediated autoimmune diseases pemphigus and generalised myasthenia gravis. Autoimmunity. 2022 Dec:55(8):620-631. doi: 10.1080/08916934.2022.2104261. Epub 2022 Aug 29 [PubMed PMID: 36036539]

[23]

Seo JW, Park J, Lee J, Kim MY, Choi HJ, Jeong HJ, Lee JW, Jung SY, Kim WK. A case of pemphigus vulgaris associated with ulcerative colitis. Intestinal research. 2018 Jan:16(1):147-150. doi: 10.5217/ir.2018.16.1.147. Epub 2018 Jan 18 [PubMed PMID: 29422810]

Level 3 (low-level) evidence

[24]

Alshami ML, Aswad F, Abdullah B. Desmogleins 1, 3, and E-cadherin immunohistochemical expression within mucocutaneous pemphigus vulgaris. The Pan African medical journal. 2022:42():186. doi: 10.11604/pamj.2022.42.186.35429. Epub 2022 Jul 7 [PubMed PMID: 36212929]

[25]

Ishii N. Significance of anti-desmocollin autoantibodies in pemphigus. The Journal of dermatology. 2023 Feb:50(2):132-139. doi: 10.1111/1346-8138.16660. Epub 2022 Dec 28 [PubMed PMID: 36578135]

[26]

Mihai S, Sitaru C. Immunopathology and molecular diagnosis of autoimmune bullous diseases. Journal of cellular and molecular medicine. 2007 May-Jun:11(3):462-81 [PubMed PMID: 17521373]

[27]

Hertl M, Eming R, Veldman C. T cell control in autoimmune bullous skin disorders. The Journal of clinical investigation. 2006 May:116(5):1159-66 [PubMed PMID: 16670756]

[28]

Sinha AA, Sajda T. The Evolving Story of Autoantibodies in Pemphigus Vulgaris: Development of the "Super Compensation Hypothesis". Frontiers in medicine. 2018:5():218. doi: 10.3389/fmed.2018.00218. Epub 2018 Aug 14 [PubMed PMID: 30155465]

[29]

Sitaru C, Zillikens D. Mechanisms of blister induction by autoantibodies. Experimental dermatology. 2005 Dec:14(12):861-75 [PubMed PMID: 16274453]

[30]

Hammers CM, Stanley JR. Mechanisms of Disease: Pemphigus and Bullous Pemphigoid. Annual review of pathology. 2016 May 23:11():175-97. doi: 10.1146/annurev-pathol-012615-044313. Epub 2016 Feb 22 [PubMed PMID: 26907530]

[31]

Amagai M, Tsunoda K, Zillikens D, Nagai T, Nishikawa T. The clinical phenotype of pemphigus is defined by the anti-desmoglein autoantibody profile. Journal of the American Academy of Dermatology. 1999 Feb:40(2 Pt 1):167-70 [PubMed PMID: 10025740]

[32]

Didona D, Maglie R, Eming R, Hertl M. Pemphigus: Current and Future Therapeutic Strategies. Frontiers in immunology. 2019:10():1418. doi: 10.3389/fimmu.2019.01418. Epub 2019 Jun 25 [PubMed PMID: 31293582]

[33]

Amagai M, Karpati S, Prussick R, Klaus-Kovtun V, Stanley JR. Autoantibodies against the amino-terminal cadherin-like binding domain of pemphigus vulgaris antigen are pathogenic. The Journal of clinical investigation. 1992 Sep:90(3):919-26 [PubMed PMID: 1522242]

[34]

Hartmann V, Hariton WV, Rahimi S, Hammers CM, Ludwig RJ, Müller EJ, Hundt JE. The human skin organ culture model as an optimal complementary tool for murine pemphigus models. Laboratory animals. 2023 Aug:57(4):381-395. doi: 10.1177/00236772221145647. Epub 2023 Jan 16 [PubMed PMID: 36647613]

Level 3 (low-level) evidence

[35]

Boch K, Dräger S, Zillikens D, Hudemann C, Hammers CM, Patzelt S, Schmidt E, Langan EA, Eming R, Ludwig RJ, Bieber K. Immunization with desmoglein 3 induces non-pathogenic autoantibodies in mice. PloS one. 2021:16(11):e0259586. doi: 10.1371/journal.pone.0259586. Epub 2021 Nov 3 [PubMed PMID: 34731225]

[36]

Egu DT, Schmitt T, Waschke J. Mechanisms Causing Acantholysis in Pemphigus-Lessons from Human Skin. Frontiers in immunology. 2022:13():884067. doi: 10.3389/fimmu.2022.884067. Epub 2022 May 20 [PubMed PMID: 35720332]

[37]

Kawamura T, Muramatsu K, Orita A, Mai Y, Sugai T, Haga N, Fujimura Y, Miyauchi T, Izumi K, Koga H, Ishii N, Ujiie H. Two cases of Hallopeau-type pemphigus vegetans with anti-desmoglein 1 and anti-desmocollin 3 antibodies without mucosal involvement. Journal of the European Academy of Dermatology and Venereology : JEADV. 2023 Apr:37(4):e508-e510. doi: 10.1111/jdv.18704. Epub 2022 Nov 7 [PubMed PMID: 36305887]

Level 3 (low-level) evidence

[38]

Jindal A, Rao C, Pai SB, Rao R. Utility of oral mucosa as a substrate for the serodiagnosis of pemphigus: A descriptive analysis. Indian journal of dermatology, venereology and leprology. 2022 Mar-Apr:88(2):156-161. doi: 10.25259/IJDVL_469_20. Epub [PubMed PMID: 34491669]

[39]

Ishii K, Yoshida K, Stanley JR, Yamagami J, Amagai M, Ishiko A. Pemphigus Vulgaris and Foliaceus IgG Autoantibodies Directly Block Heterophilic Transinteraction between Desmoglein and Desmocollin. The Journal of investigative dermatology. 2020 Oct:140(10):1919-1926.e7. doi: 10.1016/j.jid.2020.02.010. Epub 2020 Mar 3 [PubMed PMID: 32142800]

[40]

Schmitt T, Waschke J. Autoantibody-Specific Signalling in Pemphigus. Frontiers in medicine. 2021:8():701809. doi: 10.3389/fmed.2021.701809. Epub 2021 Aug 9 [PubMed PMID: 34434944]

[41]

Oktarina DA, van der Wier G, Diercks GF, Jonkman MF, Pas HH. IgG-induced clustering of desmogleins 1 and 3 in skin of patients with pemphigus fits with the desmoglein nonassembly depletion hypothesis. The British journal of dermatology. 2011 Sep:165(3):552-62. doi: 10.1111/j.1365-2133.2011.10463.x. Epub [PubMed PMID: 21692763]

[42]

Sielski L, Baker J, DePasquale MC, Attwood K, Seiffert-Sinha K, Sinha AA. Desmoglein compensation hypothesis fidelity assessment in Pemphigus. Frontiers in immunology. 2022:13():969278. doi: 10.3389/fimmu.2022.969278. Epub 2022 Sep 23 [PubMed PMID: 36211362]

[43]

Garg R, Bhojani K. Non infective bullous lesions: a diagnostic challenge in a minimally equipped centre- based solely on microscopic findings. African health sciences. 2020 Jun:20(2):885-890. doi: 10.4314/ahs.v20i2.42. Epub [PubMed PMID: 33163055]

[44]

Papara C, Danescu S, Rogojan L, Leucuta DC, Candrea E, Zillikens D, Baican A. Lymphocyte-predominant lesional inflammatory infiltrates of the skin are associated with mucosal-dominant phenotype in pemphigus. Journal of cutaneous pathology. 2023 Aug:50(8):754-762. doi: 10.1111/cup.14395. Epub 2023 Feb 14 [PubMed PMID: 36680509]

[45]

Gottesman SP, Abedi SM, Rosen JR, Gottlieb GJ. Hailey-Hailey-Like Pattern of Acantholysis on the Scalp Should Raise the Possibility of Incipient Pemphigus Vulgaris. The American Journal of dermatopathology. 2019 Apr:41(4):286-288. doi: 10.1097/DAD.0000000000001298. Epub [PubMed PMID: 30640761]

[46]

See SHC, Peternel S, Adams D, North JP. Distinguishing histopathologic features of acantholytic dermatoses and the pattern of acantholytic hypergranulosis. Journal of cutaneous pathology. 2019 Jan:46(1):6-15. doi: 10.1111/cup.13356. Epub 2018 Nov 5 [PubMed PMID: 30203619]

[47]

Ng JKM, Cheung CM, Choi PCL, Ip EC, Li JJX, Chan AWS. A rare presentation of pemphigus vegetans as an isolated vegetative lesion-Review of histopathological clues and treatment effects in multiple biopsy specimens. Journal of cutaneous pathology. 2023 Mar:50(3):201-208. doi: 10.1111/cup.14375. Epub 2023 Jan 4 [PubMed PMID: 36502456]

[48]

Jabri H, Hali F, Elkaroini D, Mahdaoui S, Alatawna H, Chiheb S. Pemphigus vegetans-Neumann variant of the vulva. International journal of dermatology. 2023 Jun:62(6):841-842. doi: 10.1111/ijd.16702. Epub 2023 Apr 26 [PubMed PMID: 37098705]

[49]

Davarmanesh M, Zahed M, Sookhakian A, Jehbez S. Oral Pemphigus Vulgaris Treatment with Corticosteroids and Azathioprine: A Long-Term Study in Shiraz, Iran. Evidence-based complementary and alternative medicine : eCAM. 2022:2022():7583691. doi: 10.1155/2022/7583691. Epub 2022 Sep 17 [PubMed PMID: 36164397]

[50]

Korbl JD, Brusch A, Lucas M, von Nida J, Wood BA, Leecy TN, Harvey NT. A case of severe cutaneous and mucosal erosions. Clinical and experimental dermatology. 2020 Aug:45(6):780-782. doi: 10.1111/ced.14233. Epub 2020 May 14 [PubMed PMID: 32410330]

Level 3 (low-level) evidence

[51]

Yang M, Wu H, Zhao M, Long H, Lu Q. Vitamin D status in patients with autoimmune bullous dermatoses: a meta-analysis. The Journal of dermatological treatment. 2022 May:33(3):1356-1367. doi: 10.1080/09546634.2020.1810606. Epub 2020 Aug 26 [PubMed PMID: 32799714]

Level 1 (high-level) evidence

[52]

Lamichhane R, Chaudhary S. Delayed Diagnosis of Pemphigus Vulgaris Initially Presenting as an Oral Ulcer: A Case Report. JNMA; journal of the Nepal Medical Association. 2022 Jul 1:60(251):641-643. doi: 10.31729/jnma.7594. Epub 2022 Jul 1 [PubMed PMID: 36705190]

Level 3 (low-level) evidence

[53]

Silva SC, Nasser R, Payne AS, Stoopler ET. Pemphigus Vulgaris. The Journal of emergency medicine. 2019 Jan:56(1):102-104. doi: 10.1016/j.jemermed.2018.10.028. Epub 2018 Nov 30 [PubMed PMID: 30503724]

[54]

Kavala M, Topaloğlu Demir F, Zindanci I, Can B, Turkoğlu Z, Zemheri E, Cam OH, Teksen A. Genital involvement in pemphigus vulgaris (PV): correlation with clinical and cervicovaginal Pap smear findings. Journal of the American Academy of Dermatology. 2015 Oct:73(4):655-9. doi: 10.1016/j.jaad.2015.06.057. Epub 2015 Jul 17 [PubMed PMID: 26194705]

[55]

Munhoz de Paula Alves Coelho K, Stall J, Henrique Condeixa de França P, Cristina de Carvalho Tavares L, Stefanello Bublitz G, Loos B, Carvalho Costa L, Fronza Júnior H. Pemphigus vulgaris of the cervix: diagnostic difficulties associated with the Pap test. Diagnostic cytopathology. 2015 Aug:43(8):635-7. doi: 10.1002/dc.23269. Epub 2015 Feb 26 [PubMed PMID: 25728997]

[56]

Akhyani M, Chams-Davatchi C, Naraghi Z, Daneshpazhooh M, Toosi S, Asgari M, Malekhami F. Cervicovaginal involvement in pemphigus vulgaris: a clinical study of 77 cases. The British journal of dermatology. 2008 Mar:158(3):478-82 [PubMed PMID: 18070212]

Level 3 (low-level) evidence

[57]

Hertl M, Veldman C. Pemphigus--paradigm of autoantibody-mediated autoimmunity. Skin pharmacology and applied skin physiology. 2001 Nov-Dec:14(6):408-18 [PubMed PMID: 11598441]

[58]

Xie D, Bilgic A, Abu Alrub N, Dicle Ö, Murrell DF. Clinical manifestations of alopecia in autoimmune blistering diseases: A cross-sectional study. JAAD international. 2023 Mar:10():6-13. doi: 10.1016/j.jdin.2022.08.025. Epub 2022 Oct 11 [PubMed PMID: 36387063]

Level 2 (mid-level) evidence

[59]

Schmidt E, Kasperkiewicz M, Joly P. Pemphigus. Lancet (London, England). 2019 Sep 7:394(10201):882-894. doi: 10.1016/S0140-6736(19)31778-7. Epub [PubMed PMID: 31498102]

[60]

Helm M, Helm LA, Clebak KT, Foulke G. Autoimmune Skin Conditions: Autoimmune Blistering Disease. FP essentials. 2023 Mar:526():13-17 [PubMed PMID: 36913658]

[61]

Asokan S, Rai R, Boppe A, Umamaheswari G. Evaluation of the Role of Oral Mucosal Direct Immunofluorescence and Salivary Desmoglein 1 and 3 Enzyme-Linked Immunosorbent Assay in Patients With Oral Mucosal Pemphigus. Indian dermatology online journal. 2022 Sep-Oct:13(5):617-619. doi: 10.4103/idoj.idoj_44_22. Epub 2022 Sep 5 [PubMed PMID: 36304655]

[62]

Pohla-Gubo G, Hintner H. Direct and indirect immunofluorescence for the diagnosis of bullous autoimmune diseases. Dermatologic clinics. 2011 Jul:29(3):365-72, vii. doi: 10.1016/j.det.2011.03.001. Epub [PubMed PMID: 21605801]

[63]

Hocke J, Krauth J, Krause C, Gerlach S, Warnemünde N, Affeldt K, van Beek N, Schmidt E, Voigt J. Computer-aided classification of indirect immunofluorescence patterns on esophagus and split skin for the detection of autoimmune dermatoses. Frontiers in immunology. 2023:14():1111172. doi: 10.3389/fimmu.2023.1111172. Epub 2023 Feb 28 [PubMed PMID: 36926325]

[64]

Harman KE, Brown D, Exton LS, Groves RW, Hampton PJ, Mohd Mustapa MF, Setterfield JF, Yesudian PD. British Association of Dermatologists' guidelines for the management of pemphigus vulgaris 2017. The British journal of dermatology. 2017 Nov:177(5):1170-1201. doi: 10.1111/bjd.15930. Epub [PubMed PMID: 29192996]

[65]

Hertl M, Jedlickova H, Karpati S, Marinovic B, Uzun S, Yayli S, Mimouni D, Borradori L, Feliciani C, Ioannides D, Joly P, Kowalewski C, Zambruno G, Zillikens D, Jonkman MF. Pemphigus. S2 Guideline for diagnosis and treatment--guided by the European Dermatology Forum (EDF) in cooperation with the European Academy of Dermatology and Venereology (EADV). Journal of the European Academy of Dermatology and Venereology : JEADV. 2015 Mar:29(3):405-14. doi: 10.1111/jdv.12772. Epub 2014 Oct 22 [PubMed PMID: 25338479]

[66]

Kridin K. Emerging treatment options for the management of pemphigus vulgaris. Therapeutics and clinical risk management. 2018:14():757-778. doi: 10.2147/TCRM.S142471. Epub 2018 Apr 27 [PubMed PMID: 29740210]

[67]

Benjamin O, Goyal A, Lappin SL. Disease-Modifying Antirheumatic Drugs (DMARD). StatPearls. 2024 Jan:(): [PubMed PMID: 29939640]

[68]

Mohammadi O, Kassim TA. Azathioprine. StatPearls. 2024 Jan:(): [PubMed PMID: 31194347]

[69]

Davis A, Dickson AL, Daniel LL, Nepal P, Zanussi J, Miller-Fleming TW, Straub PS, Wei WQ, Liu G, Cox NJ, Hung AM, Feng Q, Stein CM, Chung CP. Association Between Genetically Predicted Expression of TPMT and Azathioprine Adverse Events. Research square. 2023 Jan 13:():. pii: rs.3.rs-2444787. doi: 10.21203/rs.3.rs-2444787/v1. Epub 2023 Jan 13 [PubMed PMID: 36711487]

[70]

Murrell DF, Peña S, Joly P, Marinovic B, Hashimoto T, Diaz LA, Sinha AA, Payne AS, Daneshpazhooh M, Eming R, Jonkman MF, Mimouni D, Borradori L, Kim SC, Yamagami J, Lehman JS, Saleh MA, Culton DA, Czernik A, Zone JJ, Fivenson D, Ujiie H, Wozniak K, Akman-Karakaş A, Bernard P, Korman NJ, Caux F, Drenovska K, Prost-Squarcioni C, Vassileva S, Feldman RJ, Cardones AR, Bauer J, Ioannides D, Jedlickova H, Palisson F, Patsatsi A, Uzun S, Yayli S, Zillikens D, Amagai M, Hertl M, Schmidt E, Aoki V, Grando SA, Shimizu H, Baum S, Cianchini G, Feliciani C, Iranzo P, Mascaró JM Jr, Kowalewski C, Hall R, Groves R, Harman KE, Marinkovich MP, Maverakis E, Werth VP. Diagnosis and management of pemphigus: Recommendations of an international panel of experts. Journal of the American Academy of Dermatology. 2020 Mar:82(3):575-585.e1. doi: 10.1016/j.jaad.2018.02.021. Epub 2018 Feb 10 [PubMed PMID: 29438767]

[71]

Garcia N, Patel OU, Graham L. Novel pain management therapies for patients with pemphigus. International journal of dermatology. 2023 Apr:62(4):575-578. doi: 10.1111/ijd.16331. Epub 2022 Jul 4 [PubMed PMID: 35781697]

[72]

Sigmund AM, Winkler M, Engelmayer S, Kugelmann D, Egu DT, Steinert LS, Fuchs M, Hiermaier M, Radeva MY, Bayerbach FC, Butz E, Kotschi S, Hudemann C, Hertl M, Yeruva S, Schmidt E, Yazdi AS, Ghoreschi K, Vielmuth F, Waschke J. Apremilast prevents blistering in human epidermis and stabilizes keratinocyte adhesion in pemphigus. Nature communications. 2023 Jan 9:14(1):116. doi: 10.1038/s41467-022-35741-0. Epub 2023 Jan 9 [PubMed PMID: 36624106]

[73]

Patil S, Mustaq S, Hosmani J, Khan ZA, Yadalam PK, Ahmed ZH, Bhandi S, Awan KH. Advancement in therapeutic strategies for immune-mediated oral diseases. Disease-a-month : DM. 2023 Jan:69(1):101352. doi: 10.1016/j.disamonth.2022.101352. Epub 2022 Mar 24 [PubMed PMID: 35339251]

[74]

Bilgic A, Murrell DF. What is novel in the clinical management of pemphigus. Expert review of clinical pharmacology. 2019 Oct:12(10):973-980. doi: 10.1080/17512433.2019.1670059. Epub 2019 Sep 29 [PubMed PMID: 31550941]

[75]

Aslanova M, Yarrarapu SNS, Zito PM. IgA Pemphigus. StatPearls. 2024 Jan:(): [PubMed PMID: 30085605]

[76]

Lepe K, Yarrarapu SNS, Zito PM. Pemphigus Foliaceus. StatPearls. 2024 Jan:(): [PubMed PMID: 29763004]

[77]

Kappius RH, Ufkes NA, Thiers BH. Paraneoplastic Pemphigus. StatPearls. 2024 Jan:(): [PubMed PMID: 31536300]

[78]

Kridin K, Zelber-Sagi S, Bergman R. Pemphigus Vulgaris and Pemphigus Foliaceus: Differences in Epidemiology and Mortality. Acta dermato-venereologica. 2017 Oct 2:97(9):1095-1099. doi: 10.2340/00015555-2706. Epub [PubMed PMID: 28536732]

[79]

Weinstein RS. Glucocorticoid-induced osteoporosis and osteonecrosis. Endocrinology and metabolism clinics of North America. 2012 Sep:41(3):595-611. doi: 10.1016/j.ecl.2012.04.004. Epub 2012 May 23 [PubMed PMID: 22877431]

[80]

Lane NE. Glucocorticoid-Induced Osteoporosis: New Insights into the Pathophysiology and Treatments. Current osteoporosis reports. 2019 Feb:17(1):1-7. doi: 10.1007/s11914-019-00498-x. Epub [PubMed PMID: 30685820]

[81]

Puckett Y, Gabbar A, Bokhari AA. Prednisone. StatPearls. 2024 Jan:(): [PubMed PMID: 30521230]

[82]

Namazi N, Ariaeenejad S, Azad ME, Pishgahi M. Risk of Atrial Fibrillation in Pemphigus Vulgaris. Indian dermatology online journal. 2018 Jul-Aug:9(4):275-277. doi: 10.4103/idoj.IDOJ_205_17. Epub [PubMed PMID: 30050823]

[83]

Paracha MM, Sagheer F, Khan AQ. A clinic-epidemiological study of 148 patients of pemphigus at Lady Reading Hospital, Peshawar: a case series. JPMA. The Journal of the Pakistan Medical Association. 2023 Mar:73(3):659-662. doi: 10.47391/JPMA.6039. Epub [PubMed PMID: 36932776]

Level 2 (mid-level) evidence

[84]

Maruyama S, Yamazaki M, Abé T, Kato Y, Kano H, Sumita Y, Tomihara K, Tanuma JI. Liquid-based cytology for differentiating two cases of pemphigus vulgaris from oral squamous cell carcinoma. Diagnostic cytopathology. 2023 May:51(5):E170-E175. doi: 10.1002/dc.25117. Epub 2023 Feb 10 [PubMed PMID: 36762831]

Level 3 (low-level) evidence

[85]

Miyachi H, Konishi T, Hashimoto Y, Matsui H, Fushimi K, Inozume T, Yasunaga H. Clinical course and outcomes of pemphigus vulgaris and foliaceus: A retrospective study using a nationwide database in Japan. The Journal of dermatology. 2023 Feb:50(2):212-221. doi: 10.1111/1346-8138.16641. Epub 2022 Nov 24 [PubMed PMID: 36424909]

Level 2 (mid-level) evidence

[86]

Pankakoski A, Kluger N, Sintonen H, Panelius J. Clinical manifestations and comorbidities of pemphigus: a retrospective case-control study in southern Finland. European journal of dermatology : EJD. 2022 Jul 1:32(4):480-486. doi: 10.1684/ejd.2022.4266. Epub [PubMed PMID: 36301748]

Level 2 (mid-level) evidence

[87]

Karakioulaki M, Murrell DF, Kyriakou A, Patsatsi A. Investigation of comorbid autoimmune diseases in women with autoimmune bullous diseases: An interplay of autoimmunity and practical implications. International journal of women's dermatology. 2022 Oct:8(3):e053. doi: 10.1097/JW9.0000000000000053. Epub 2022 Oct 7 [PubMed PMID: 36225612]

[88]

Kadota H, Miyashita K, Fukushima S, Oryoji C, Hanada M, Yoshida S, Fujita H, Tachibana Y. Successful Management of a Severe Sacral Pressure Injury Penetrating to the Retroperitoneum. Wounds : a compendium of clinical research and practice. 2021 Mar:33(3):E24-E27 [PubMed PMID: 33914698]

[89]

Solanki VK, Nair PMK. Lifestyle medicine approach in managing pemphigus vulgaris: A case report. Explore (New York, N.Y.). 2023 Jul-Aug:19(4):617-620. doi: 10.1016/j.explore.2023.01.003. Epub 2023 Jan 7 [PubMed PMID: 36646613]

Level 3 (low-level) evidence

[90]

Czerninski R, Zadik Y, Kartin-Gabbay T, Zini A, Touger-Decker R. Dietary alterations in patients with oral vesiculoulcerative diseases. Oral surgery, oral medicine, oral pathology and oral radiology. 2014 Mar:117(3):319-23. doi: 10.1016/j.oooo.2013.08.006. Epub 2013 Oct 18 [PubMed PMID: 24144994]

[91]

Hübner S, Sarhan M, Schauer F. Use of Complementary and Alternative Medicine in Patients with Autoimmune Bullous Dermatoses: A Cohort Study Analysis of a Rare Disease Group. Complementary medicine research. 2023:30(3):221-229. doi: 10.1159/000529142. Epub 2023 Jan 16 [PubMed PMID: 36646063]