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Pemphigus vulgaris is a rare chronic blistering skin disease and the most common form of
pemphigus Pemphigus ( or ) 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 "pustule". In pemphigus, autoantibody, autoantibodies form against de ...
. Pemphigus was derived from the Greek word ''pemphix'', meaning blister. It is classified as a
type II hypersensitivity Type II hypersensitivity, in the Hypersensitivity, Gell and Coombs classification of allergic reactions, is an antibody mediated process in which IgG and IgM antibodies are directed against antigens on cells (such as circulating red blood cells) or ...
reaction in which
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique mo ...

antibodies
are formed against
desmosome A desmosome (; #Etymology, "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin language, Latin for ''adhering spot''), is a cell (biology), cell structure specialized for cell-to-cell adhesion. A type of Cell juncti ...

desmosome
s, 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. Over time the condition inevitably progresses without treatment: lesions increase in size and distribution throughout the body, behaving physiologically like a severe burn. 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. Nevertheless, in 1998, pemphigus vulgaris was the fourth most common cause of death due to a skin disorder. The disease mainly affects middle-aged and older adults between 50–60 years old. There has historically been a higher incidence in women.


Signs and symptoms

Pemphigus vulgaris most commonly presents with oral
blister A blister is a small pocket of body fluid Body fluids, bodily fluids, or biofluids are liquid A liquid is a nearly incompressible In fluid mechanics Fluid mechanics is the branch of physics concerned with the mechanics Mecha ...

blister
s (buccal and palatine mucosa, especially), but also includes cutaneous blisters. Other
mucosal A mucous membrane or mucosa is a membrane A membrane is a selective barrier; it allows some things to pass through but stops others. Such things may be molecules, ions, or other small particles. Biological membranes include cell membranes (ou ...
surfaces, the
conjunctiva The conjunctiva is a tissue (biology), tissue that lines the inside of the eyelids and covers the sclera (the white of the human eye, eye). It is composed of non-keratinized, stratified squamous epithelium with goblet cells, stratified columnar ...
, nose,
esophagus The esophagus (American English American English (AmE, AE, AmEng, USEng, en-US), sometimes called United States English or U.S. English, is the set of varieties of the English language native to the United States. Currently, American E ...

esophagus
,
penis A penis (plural ''penises'' or ''penes'' () is the primary sexual organ that male animals use to inseminate females (or hermaphrodites) during Copulation (zoology), copulation. Such organs occur in many animals, both #Vertebrates, vertebrate ...

penis
,
vulva The vulva (plural: vulvas or vulvae; derived from Latin for wrapper or covering) consists of the external female sex organs. The vulva includes the mons pubis In human anatomy The human body is the structure of a human being. It is com ...

vulva
,
vagina In mammal Mammals (from Latin language, Latin , 'breast') are a group of vertebrate animals constituting the class (biology), class Mammalia (), and characterized by the presence of mammary glands which in Female#Mammalian female, femal ...

vagina
,
cervix The cervix or cervix uteri (Latin, 'neck of the uterus') is the lower part of the uterus The uterus (from Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. L ...

cervix
, and
anus The anus (from Latin Latin (, or , ) is a classical language A classical language is a language A language is a structured system of communication Communication (from Latin ''communicare'', meaning "to share" or "to be in ...

anus
, may also be affected. Flaccid blisters over the skin are frequently seen with sparing of the skin covering the palms and soles. Blisters commonly erode and leave ulcerated
lesion A lesion is any damage or abnormal change in the tissue of an organism, usually caused by disease or Trauma (medicine), trauma. ''Lesion'' is derived from the Latin ''laesio'' "injury". Lesions may occur in plants as well as animals. Types The ...
s and erosions. A positive Nikolsky sign (induction of blistering in normal skin or at the edge of a blister) is indicative of the disease. Severe pain with chewing can lead to weight loss and
malnutrition Malnutrition is 'a state of nutrition in which a deficiency or excess (or imbalance) of energy, protein and other nutrients causes measurable adverse effect on tissue and body form (body shape, size and composition) and function and clinical ou ...
.


Pathophysiology

Pemphigus is an
autoimmune disease An autoimmune disease is a condition arising from an abnormal immune response An immune response is a reaction which occurs within an organism for the purpose of defending against foreign invaders. These invaders include a wide variety of differe ...

autoimmune disease
caused by
antibodies An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and Viral disease, viruses. The antibody recognizes a unique mo ...

antibodies
directed against both
desmoglein 1 Desmoglein-1 is a protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme cat ...
and
desmoglein 3 Desmoglein-3 is a protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme cat ...
present in
desmosomes A desmosome (; "binding body"), also known as a macula adherens (plural: maculae adherentes) (Latin Latin (, or , ) is a classical language belonging to the Italic languages, Italic branch of the Indo-European languages. Latin was originally s ...
. Loss of desmosomes results in loss of cohesion between
keratinocyte Keratinocytes are the primary type of Cell (biology), cell found in the epidermis (skin), epidermis, the outermost layer of the skin. In humans, they constitute 90% of epidermal skin cells. Basal cells in the stratum basale, basal layer (''st ...
s in the
epidermis The epidermis is the outermost of the three layers that comprise the skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate Vertebrates () comprise all species of animal Animals (also calle ...
, and a disruption of the barrier function served by intact skin. The process is classified as a
type II hypersensitivity Type II hypersensitivity, in the Hypersensitivity, Gell and Coombs classification of allergic reactions, is an antibody mediated process in which IgG and IgM antibodies are directed against antigens on cells (such as circulating red blood cells) or ...
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 The basement membrane is a thin, pliable sheet-like type of extracellular matrix In biology Biology is the natural science that studies life and living organisms, including their anatomy, physical structure, Biochemistry, chemical processe ...
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 Nikolsky's sign is a clinical Dermatology, dermatological Medical sign, sign, named after Pyotr Nikolsky (1858–1940), a Russians, Russian physician who trained and worked in the Russian Empire. The sign is present when slight rubbing of the skin r ...
. This is a contrasting feature from
bullous pemphigoid Bullous pemphigoid is an autoimmune Autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other body normal constituents. Any disease that results from such an aberrant immune response is termed ...
, which is thought to be due to anti-hemidesmosome antibodies, and where the detachment occurs between the
epidermis The epidermis is the outermost of the three layers that comprise the skin Skin is the layer of usually soft, flexible outer tissue covering the body of a vertebrate Vertebrates () comprise all species of animal Animals (also calle ...
and
dermis The dermis or corium is a layer of skin between the epidermis (skin), epidermis (with which it makes up the cutis (anatomy), cutis) and subcutaneous tissues, that primarily consists of dense irregular connective tissue and cushions the body from s ...
(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 Pemphigus ( or ) 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 "pustule". In pemphigus, autoantibody, autoantibodies form against de ...
(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 Nikolsky's sign is a clinical Dermatology, dermatological Medical sign, sign, named after Pyotr Nikolsky (1858–1940), a Russians, Russian physician who trained and worked in the Russian Empire. The sign is present when slight rubbing of the skin r ...
, 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 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 The desmogleins are a family of desmosomal cadherinImage:Adherens Junctions structural proteins.svg, 350px, Principal interactions of structural proteins at cadherin-based adherens junction. Actin filaments are linked to α-actinin and to membrane ...
. Pemphigus vulgaris is easily confused with
impetigo Impetigo is a bacterial infection Pathogenic bacteria are bacteria Bacteria (; common noun bacteria, singular bacterium) are a type of Cell (biology), biological cell. They constitute a large domain (biology), domain of prokaryotic mi ...

impetigo
and
candidiasis Candidiasis is a fungal infection Mycosis is an infectious disease An infection is the invasion of an organism's body Tissue (biology), tissues by Pathogen, disease-causing agents, their multiplication, and the reaction of host (biology), ...

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 An antibiotic is a type of antimicrobial An antimicrobial is an agent that kills microorganism A microorganism, or microbe,, ''mikros'', "small") and ''organism In biology, an organism () is any organic, life, living system t ...
treatment.


Treatment

Corticosteroid Corticosteroids are a class of steroid hormone A steroid hormone is a steroid A steroid is a biologically active organic compound In , organic compounds are generally any s that contain - . Due to carbon's ability to (form chains w ...
s 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 Immunoglobulin therapy, also known as normal human immunoglobulin (NHIG), is the use of a mixture of antibodies (immunoglobulins) to treat a number of health conditions. These conditions include primary immunodeficiency, immune thrombocytope ...
,
mycophenolate mofetil Mycophenolic acid (MPA) is an immunosuppressant medication used to prevent rejection following organ transplant Organ transplantation is a medical procedure in which an organ (anatomy), organ is removed from one body and placed in the body o ...

mycophenolate mofetil
,
methotrexate Methotrexate (MTX), formerly known as amethopterin, is a chemotherapy agent and immunosuppressive drug, immune-system suppressant. It is used to treat cancer, autoimmune diseases, and ectopic pregnancy and for medical abortions. Types of cancers ...

methotrexate
,
azathioprine Azathioprine (AZA), sold under the brand name Imuran, among others, is an immunosuppressive medication. It is used in rheumatoid arthritis Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typical ...

azathioprine
, and
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment Cancer Cancer is a group of ...

cyclophosphamide
have also been used with varying degrees of success. An established alternative to steroids are monoclonal antibodies such as
rituximab Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody A monoclonal antibody (mAb or moAb) is an antibody An antibody (Ab), also known as an immunoglobulin (Ig), is a large, Y-shaped protein used by the immun ...

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. 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. This was a small trial study of 11 patients with 10 patients followed to completion. Rituximab demonstrated superior efficacy compared to mycophenolate mofetil in a Phase III clinical trial, results of which were published in 2021.


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 30,000-40,000 cases in the United States. 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. There is currently no way of knowing who will be affected with P. vulgaris in their life as it is usually not a genetic disorder and is usually triggered later in life by environmental factors. Men and women are both equally affected and the disease has been found to affect people of many different cultures and racial backgrounds, especially Ashkenazi Jews, people of Mediterranean, North Indian and Persian descent. There has been no found difference in the rate of disease when looking at socioeconomic factors as well. 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. 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.


Research

Research into using genetically modified
T-cells A T cell is a type of lymphocyte A lymphocyte is a type of white blood cell in the immune system The immune system is a network of biological processes that protects an organism In biology, an organism (from Ancient Greek, Greek: ...
to treat pemphigus vulgaris in mice was reported in 2016. Rituximab indiscriminately attacks all
B cell #REDIRECT B cell 3D rendering of a B cell B cells, also known as B lymphocytes, are a type of white blood cell White blood cells (WBCs), also called leukocytes or leucocytes, are the cells of the immune system The immune system is a ne ...
s, 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. Penn's Aimee Payne, M.D., Ph.D., and Michael Milone, M.D., Ph.D., a co-inventor of Novartis’ CAR-T cancer therapy Kymriah, pioneered the CAAR-T idea and have founded biotech Cabaletta Bio, hoping to bring their therapies through clinical studies to the market. The MuSK-CAAR-T is the second candidate in its pipeline; the company has already received FDA clearance to test its lead project, DSG3-CAAR-T, in patients with mucosal pemphigus vulgaris (PV), and a phase 1 trial is expected to start in 2020.


See also

*
List of conditions caused by problems with junctional proteins A ''list'' is any set of items. List or lists may also refer to: People * List (surname)List or Liste is a European surname. Notable people with the surname include: List * Friedrich List (1789–1846), German economist * Garrett List (1943 ...
*
List of cutaneous conditions Many conditions affect the human integumentary system The integumentary system is the set of organs forming the outermost layer of an animal's body. It comprises the skin and its appendages, acting as a physical barrier between the external e ...
*
List of immunofluorescence findings for autoimmune bullous conditions Several cutaneous conditions can be diagnosed with the aid of immunofluorescence of human skin prepared for direct immunofluorescence using an anti-IgA antibody. The skin is from a patient with Henoch–Schönlein purpura: IgA deposits are foun ...


References


External links


Pemphigus vulgaris - DermNet New Zealand
{{Vesiculobullous disease Chronic blistering cutaneous conditions Rare diseases