Pemphigus vulgaris

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Pemphigus vulgaris
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Micrograph of pemphigus vulgaris with the characteristic "tombstoning". H&E stain.
Specialty Dermatology   OOjs UI icon edit-ltr-progressive.svg

Pemphigus vulgaris is a rare chronic blistering skin disease and the most common form of pemphigus. Pemphigus was derived from the Greek word pemphix, meaning blister. [1] It is classified as a type II hypersensitivity reaction in which antibodies are formed against desmosomes, components of the skin that function to keep certain layers of skin bound to each other. As desmosomes are attacked, the layers of skin separate and the clinical picture resembles a blister. These blisters are due to acantholysis, or breaking apart of intercellular connections through an autoantibody-mediated response. [2] Over time the condition inevitably progresses without treatment: lesions increase in size and distribution throughout the body, behaving physiologically like a severe burn.

Contents

Before the advent of modern treatments, mortality for the disease was close to 90%. Today, the mortality rate with treatment is between 5-15% due to the introduction of corticosteroids as primary treatment. [3] Nevertheless, in 1998, pemphigus vulgaris was the fourth most common cause of death due to a skin disorder. It is thus still deemed "potentially fatal".

The disease mainly affects middle-aged and older adults between 50 and 60 years old. There has historically been a higher incidence in women. [4]

Signs and symptoms

Pemphigus vulgaris Pemphgoid vulgaris.jpg
Pemphigus vulgaris

Pemphigus vulgaris most commonly presents with oral blisters (buccal and palatine mucosa, especially), but also includes cutaneous blisters. Other mucosal surfaces, the conjunctiva, nose, esophagus, penis, vulva, vagina, cervix, and anus, may also be affected. Flaccid blisters over the skin are frequently seen with sparing of the skin covering the palms and soles. [5]

Blisters commonly erode and leave ulcerated lesions and erosions. A positive Nikolsky sign (induction of blistering in normal skin or at the edge of a blister) is indicative of the disease. [5]

Severe pain with chewing can lead to weight loss and malnutrition. [5]

Pathophysiology

Pemphigus is an autoimmune disease caused by antibodies directed against both desmoglein 1 and desmoglein 3 present in desmosomes. Loss of desmosomes results in loss of cohesion between keratinocytes in the epidermis, and a disruption of the barrier function served by intact skin. The process is classified as a type II hypersensitivity reaction (in which antibodies bind to antigens on the body's own tissues). On histology, the basal keratinocytes are usually still attached to the basement membrane leading to a characteristic appearance called "tombstoning". Transudative fluid accumulates in between the keratinocytes and the basal layer (suprabasal split), forming a blister and resulting in what is known as a positive Nikolsky's sign. This is a contrasting feature from bullous pemphigoid, which is thought to be due to anti-hemidesmosome antibodies, and where the detachment occurs between the epidermis and dermis (subepidermal bullae). Clinically, pemphigus vulgaris is characterized by extensive flaccid blisters and mucocutaneous erosions. The severity of the disease, as well as the mucosal lesions, is believed to be directly proportional to the levels of desmoglein 3. Milder forms of pemphigus (like foliacious and erythematoses) are more anti-desmoglein 1 heavy.

The disease arises most often in middle-aged or older people, usually starting with a blister that ruptures easily. It can also start with blisters in the mouth. The lesions can become quite extensive.

Diagnosis

Because it is a rare disease, diagnosis is often complicated and takes a long time. Early in the disease patients may have erosions in the mouth or blisters on the skin. These blisters can be itchy or painful. Theoretically, the blisters should demonstrate a positive Nikolsky's sign, in which the skin sloughs off from slight rubbing, but this is not always reliable. The gold standard for diagnosis is a punch biopsy from the area around the lesion that is examined by direct immunofluorescent staining, in which cells are acantholytic, that is, lacking the normal intercellular connections that hold them together. These can also be seen on a Tzanck smear. These cells are basically rounded, nucleated keratinocytes formed due to antibody mediated damage to cell adhesion protein desmoglein.

Pemphigus vulgaris is easily confused with impetigo and candidiasis. IgG4 is considered pathogenic. The diagnosis can be confirmed by testing for the infections that cause these other conditions, and by a lack of response to antibiotic treatment. [6]

Treatment

Corticosteroids and other immunosuppressive medications have historically been employed to reduce pemphigus symptoms, yet steroids are associated with serious and long-lasting side effects and their use should be limited as much as possible. Intravenous immunoglobulin, mycophenolate mofetil, methotrexate, azathioprine, and cyclophosphamide have also been used with varying degrees of success.

An established alternative to steroids are monoclonal antibodies such as rituximab, which are increasingly being used as first-line treatment. In summer 2018, the FDA granted full approval to rituximab for this application, following successful fast track evaluation. [7] In numerous case series, many patients achieve remission after one cycle of rituximab. Treatment is more successful if initiated early on in the course of disease, perhaps even at diagnosis. Rituximab treatment combined with monthly IV immunoglobulin infusions has resulted in long-term remission with no recurrence of disease in 10 years after treatment was halted. [8] This was a small trial study of 11 patients with 10 patients followed to completion.

Due to the successful use of rituximab, an anti-CD20 monoclonal treatment, in managing this disease, other anti-CD20 drugs such as ocrelizumab, [9] veltuzumab, [10] and ofatumumab [11] have been explored as potential treatments.

Key companies in Pemphigus Vulgaris therapeutics include Principia Biopharma, Topas Therapeutics and Argenx BVBA.[ citation needed ] Rituximab demonstrated superior efficacy compared to mycophenolate mofetil in a Phase III clinical trial, results of which were published in 2021. [12]

Epidemiology

Pemphigus vulgaris is a relatively rare disease that only affects about 1 to 5 people in 1 million in the United Kingdom, with an incidence of 1-10 cases per 1 million people across the world. There is an estimated prevalence of 14,000+ cases in the United States [13] and 42,400+ in the seven major markets (US, UK, Japan, Germany, France, Italy, Spain) which is five times as prevalent as Pemphigus foliaceous.[ citation needed ]

Cases of P. vulgaris usually don't develop until after the age of 50 or so. The disease is not contagious which means it cannot be spread from person to person. [14] In 2012, Israeli researchers indicated they had identified a genetic cause for the disease, which they indicated as 40 times more likely to afflict Jews compared to other demographic groups. [15]

The data pool is small for rare diseases. Some sources claim females being more affected by the disease, for others men and women are equally affected. The patient advocacy organisation NORD sees people of many different cultures and racial backgrounds simllarly affected, but with a prevalence for Ashkenazi Jews, people of Mediterranean, North Indian and Persian descent. [16] There has been no found difference in the rate of disease when looking at socioeconomic factors as well. [13] If left untreated, 8 of 10 people with the disease die within a year with a cause of death being infection or loss of fluids, which is very common for raw, open sores that are characteristic of P. vulgaris. With treatment, only about 1 in 10 people with the disease die, either from the condition, or side effects of the medicine. [14]

An effect of the disease being so rare is that there is not enough evidence to prove that the treatments currently being used are actually as effective as they could be. Doctors are trying to find effective steroid-sparing agents to use in the treatment, to decrease the side effects of long term steroid treatment. The small amount of case numbers make it hard to test statistical significance between the affected and the control groups when testing if these types of systematic treatments are effective. [17]

Research

Research into using genetically modified T-cells to treat pemphigus vulgaris in mice was reported in 2016. [18] [19] Rituximab indiscriminately attacks all B cells, which reduces the body's ability to control infections. In the experimental treatment, human T cells are genetically engineered to recognize only those B cells that produce antibodies to desmoglein. In PV, autoreactive B cells produce antibodies against Dsg3, disrupting its adhesive function and causing skin blistering. By expressing Dsg3 on their surfaces, the CAAR-T cells lure those B cells in and kill them. The Dsg 3 CAAR-T cells eliminated Dsg3-specific B cells in lab dishes and in mice, the researchers reported at the time.

See also

Related Research Articles

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<span class="mw-page-title-main">Desmosome</span> Cell junction involved in cell-to-cell adhesion

A desmosome, also known as a macula adherens, is a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adhesions randomly arranged on the lateral sides of plasma membranes. Desmosomes are one of the stronger cell-to-cell adhesion types and are found in tissue that experience intense mechanical stress, such as cardiac muscle tissue, bladder tissue, gastrointestinal mucosa, and epithelia.

<span class="mw-page-title-main">Pemphigus</span> Blistering autoimmune diseases

Pemphigus is a rare group of blistering autoimmune diseases that affect the skin and mucous membranes. The name is derived from the Greek root pemphix, meaning "blister".

<span class="mw-page-title-main">Rituximab</span> Biopharmaceutical drug

Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia, rheumatoid arthritis, granulomatosis with polyangiitis, idiopathic thrombocytopenic purpura, pemphigus vulgaris, myasthenia gravis and Epstein–Barr virus-positive mucocutaneous ulcers. It is given by slow intravenous infusion. Biosimilars of Rituxan include Blitzima, Riabni, Ritemvia, Rituenza, Rixathon, Ruxience, and Truxima.

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<span class="mw-page-title-main">Bullous pemphigoid</span> Autoimmune disease of skin and connective tissue characterized by large blisters

Bullous pemphigoid is an autoimmune pruritic skin disease that typically occurs in people aged over 60, that may involve the formation of blisters (bullae) in the space between the epidermal and dermal skin layers. It is classified as a type II hypersensitivity reaction, which involves formation of anti-hemidesmosome antibodies, causing a loss of keratinocytes to basement membrane adhesion.

Nikolsky's sign is a clinical dermatological sign, named after Pyotr Nikolsky (1858–1940), a Russian physician who trained and worked in the Russian Empire. The sign is present when slight rubbing of the skin results in exfoliation of the outermost layer. A typical test would be to place the eraser of a pencil on the roof of a lesion and spin the pencil in a rolling motion between the thumb and forefinger. If the lesion is opened, then the Nikolsky's sign is present/positive.

<span class="mw-page-title-main">Hailey–Hailey disease</span> Medical condition

Hailey–Hailey disease (HHD), or familial benign chronic pemphigus or familial benign pemphigus, was originally described by the Hailey brothers in 1939. It is a genetic disorder that causes blisters to form on the skin.

The desmogleins are a family of desmosomal cadherins consisting of proteins DSG1, DSG2, DSG3, and DSG4. They play a role in the formation of desmosomes that join cells to one another.

<span class="mw-page-title-main">Desmoglein-1</span> Protein found in humans

Desmoglein-1 is a protein that in humans is encoded by the DSG1 gene. Desmoglein-1 is expressed everywhere in the skin epidermis, but mainly it is expressed in the superficial upper layers of the skin epidermis.

<span class="mw-page-title-main">Desmoglein-3</span> Protein found in humans

Desmoglein-3 is a protein that in humans is encoded by the DSG3 gene. In the skin epidermis Desmoglein-3 is expressed in the basal lower layers of the epidermis, and dominates in terms of expression on mucosal surfaces compared to Desmoglein-1.

<span class="mw-page-title-main">Pemphigoid</span> Autoimmune blistering diseases

Pemphigoid is a group of rare autoimmune blistering diseases of the skin, and mucous membranes. As its name indicates, pemphigoid is similar in general appearance to pemphigus, but, unlike pemphigus, pemphigoid does not feature acantholysis, a loss of connections between skin cells.

<span class="mw-page-title-main">Dermatitis herpetiformis</span> Chronic autoimmune disorder leading to blistering skin

Dermatitis herpetiformis (DH) is a chronic autoimmune blistering skin condition, characterised by intensely itchy blisters filled with a watery fluid. DH is a cutaneous manifestation of coeliac disease, although the exact causal mechanism is not known. DH is neither related to nor caused by herpes virus; the name means that it is a skin inflammation having an appearance similar to herpes.

Pemphigus foliaceus is an autoimmune blistering disease of the skin. Pemphigus foliaceus causes a characteristic inflammatory attack at the subcorneal layer of epidermis, which results in skin lesions that are scaly or crusted erosions with an erythematous (red) base. Mucosal involvement is absent even with widespread disease.

Pemphigus erythematosus is simply a localized form of pemphigus foliaceus with features of lupus erythematosus.

Paraneoplastic pemphigus (PNP) is an autoimmune disorder stemming from an underlying tumor. It is hypothesized that antigens associated with the tumor trigger an immune response resulting in blistering of the skin and mucous membranes.

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<span class="mw-page-title-main">Bullous impetigo</span> Medical condition

Bullous impetigo is a bacterial skin infection caused by Staphylococcus aureus that results in the formation of large blisters called bullae, usually in areas with skin folds like the armpit, groin, between the fingers or toes, beneath the breast, and between the buttocks. It accounts for 30% of cases of impetigo, the other 70% being non-bullous impetigo.

Mucous membrane pemphigoid is a rare chronic autoimmune subepithelial blistering disease characterized by erosive lesions of the mucous membranes and skin. It is one of the pemphigoid diseases that can result in scarring.

Primary cutaneous diffuse large B-cell lymphoma, leg type (PCDLBCL-LT) is a cutaneous lymphoma skin disease that occurs mostly in elderly females. In this disease, B cells become malignant, accumulate in the dermis and subcutaneous tissue below the dermis to form red and violaceous skin nodules and tumors. These lesions typically occur on the lower extremities but in uncommon cases may develop on the skin at virtually any other site. In ~10% of cases, the disease presents with one or more skin lesions none of which are on the lower extremities; the disease in these cases is sometimes regarded as a variant of PCDLBL, LT termed primary cutaneous diffuse large B-cell lymphoma, other (PCDLBC-O). PCDLBCL, LT is a subtype of the diffuse large B-cell lymphomas (DLBCL) and has been thought of as a cutaneous counterpart to them. Like most variants and subtypes of the DLBCL, PCDLBCL, LT is an aggressive malignancy. It has a 5-year overall survival rate of 40–55%, although the PCDLBCL-O variant has a better prognosis than cases in which the legs are involved.

References

  1. ↑ Cholera M, Chainani-Wu N (June 2016). "Management of Pemphigus Vulgaris". Advances in Therapy. 33 (6): 910–958. doi:10.1007/s12325-016-0343-4. PMC   4920839 . PMID   27287854.
  2. ↑ Beigi PK (2018). "History of Pemphigus Vulgaris". A Clinician's Guide to Pemphigus Vulgaris. Springer, Cham. p. 13. doi:10.1007/978-3-319-67759-0_3. ISBN   978-3-319-67758-3. S2CID   91065046.
  3. ↑ King DF, Holubar K (October 1983). "History of pemphigus". Clinics in Dermatology. 1 (2): 6–12. doi:10.1016/0738-081X(83)90019-6. PMID   6400552.
  4. ↑ Gupta VK, Kelbel TE, Nguyen D, Melonakos KC, Murrell DF, Xie Y, et al. (July 2011). "A globally available internet-based patient survey of pemphigus vulgaris: epidemiology and disease characteristics". Dermatologic Clinics. 29 (3): 393–404, vii–iii. doi:10.1016/j.det.2011.03.016. PMID   21605804.
  5. 1 2 3 "Pathogenesis, clinical manifestations, and diagnosis of pemphigus". www.uptodate.com. Retrieved 2017-04-03.
  6. ↑ Kaplan DL (2009). "Dermclinic". Consultant. 49 (3). Archived from the original on 2012-02-13. Retrieved 2009-04-02.
  7. ↑ "FDA Approves Genentech's Rituxan (Rituximab) for Pemphigus Vulgaris". Genentech. Retrieved 24 December 2019.
  8. ↑ Ahmed AR, Kaveri S, Spigelman Z (December 2015). "Long-Term Remissions in Recalcitrant Pemphigus Vulgaris". The New England Journal of Medicine. 373 (27): 2693–2694. doi: 10.1056/NEJMc1508234 . PMID   26716930.
  9. ↑ de-la-Rosa-Fernández E, Loizate-Sarrionandia I, González-Rodríguez J, Herrero-Moyano M, Fernández-de-Misa-Cabrera R, Suárez-Hernández J (April 2023). "Ocrelizumab, an alternative to rituximab in refractory pemphigus vulgaris management". Journal of the European Academy of Dermatology and Venereology. 37 (9): e1104–e1106. doi:10.1111/jdv.19133. PMID   37102356. S2CID   258355167.
  10. ↑ Ellebrecht CT, Choi EJ, Allman DM, Tsai DE, Wegener WA, Goldenberg DM, Payne AS (December 2014). "Subcutaneous veltuzumab, a humanized anti-CD20 antibody, in the treatment of refractory pemphigus vulgaris". JAMA Dermatology. 150 (12): 1331–1335. doi:10.1001/jamadermatol.2014.1939. PMC   5897695 . PMID   25133328.
  11. ↑ Klufas DM, Amerson E, Twu O, Clark L, Shinkai K (August 2020). "Refractory pemphigus vulgaris successfully treated with ofatumumab". JAAD Case Reports. 6 (8): 734–736. doi:10.1016/j.jdcr.2020.05.034. PMC   7369462 . PMID   32715065.
  12. ↑ Werth VP, Joly P, Mimouni D, Maverakis E, Caux F, Lehane P, et al. (June 2021). "Rituximab versus Mycophenolate Mofetil in Patients with Pemphigus Vulgaris". The New England Journal of Medicine. 384 (24): 2295–2305. doi: 10.1056/NEJMoa2028564 . PMID   34097368. S2CID   235359759.
  13. 1 2 "Pemphigus". www.pemphigus.org. Retrieved 2019-12-03.
  14. 1 2 "Pemphigus Vulgaris | Causes, Symptoms and Treatment". patient.info. 2 May 2018. Retrieved 2019-11-18.
  15. ↑ Shamah D (April 20, 2012). "Researchers Discover Gene Responsible for Devastating Skin Disease". The Times of Israel. Retrieved 30 December 2022.
  16. ↑ "Pemphigus and Pemphigoid". NORD (National Organization for Rare Disorders). Retrieved 2019-11-18.
  17. ↑ Daniel BS, Murrell DF (2014-05-06). "Management of pemphigus". F1000Prime Reports. 6: 32. doi: 10.12703/P6-32 . PMC   4017903 . PMID   24860654.
  18. ↑ Gallagher J (2016-07-01). "'Civil war' in immune system can fight disease". BBC News, Health. Retrieved 2016-07-01.
  19. ↑ Ellebrecht CT, Bhoj VG, Nace A, Choi EJ, Mao X, Cho MJ, et al. (July 2016). "Reengineering chimeric antigen receptor T cells for targeted therapy of autoimmune disease". Science. 353 (6295): 179–184. Bibcode:2016Sci...353..179E. doi:10.1126/science.aaf6756. PMC   5343513 . PMID   27365313.
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