14/9/2014 Pemphigus Vulgaris

http://emedicine.medscape.com/article/1064187-overview 1/9
Pemphigus Vulgaris
Author: Bassam Zeina, MD, PhD; Chief Editor: Dirk M Elston, MD more...
Updated: Jun 12, 2014
Practice Essentials
Pemphigus vulgaris is an autoimmune, intraepithelial, blistering disease affecting the skin and mucous membranes.
It is mediated by circulating autoantibodies directed against keratinocyte cell surfaces. A potentially life-threatening
disease, it has a mortality rate of approximately 5-15%.
[1]
Signs and symptoms
Mucous membranes
Mucous membranes of the oral cavity are involved in almost all patients with pemphigus vulgaris
Patients may have ill-defined, irregularly shaped, gingival, buccal, or palatine erosions, which are painful and
slow to heal
Intact bullae are rare in the mouth
Erosions may be seen on any part of the oral cavity, and they may spread to involve the larynx, with
subsequent hoarseness
In juvenile pemphigus vulgaris, stomatitis is the presenting complaint in more than 50% of cases
Other mucosal surfaces may be involved, including the conjunctiva,
[2]
esophagus (causes odynophagia
and/or dysphagia),
[3]
labia, vagina, cervix, vulva,
[4]
penis, urethra, nasal mucosa, and anus
Skin
Primary lesion of pemphigus vulgaris is a flaccid blister filled with clear fluid that arises on healthy skin or on
an erythematous base
Blisters are fragile and may rupture, producing painful erosions (the most common skin presentation)
Nails
Acute or chronic paronychia, subungual hematomas, and nail dystrophies affecting one or several fingers or toes
have been reported with pemphigus vulgaris.
[5, 6]
Vegetating pemphigus vulgaris
Lesions in skin folds readily form vegetating granulations. In some patients, erosions tend to develop excessive
granulation tissue and crusting; these individuals display more vegetating lesions.
See Clinical Presentation for more detail.
Diagnosis
Laboratory studies include the following:
Histopathology: Demonstrates an intradermal blister; the earliest changes consist of intercellular edema with
loss of intercellular attachments in the basal layer
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Direct immunofluorescence (DIF): On normal-appearing perilesional skin
[7]
; demonstrates in vivo deposits of
antibodies and other immunoreactants, such as complement
Indirect immunofluorescence (IDIF): If DIF results are positive; circulating intercellular antibodies are detected
using IDIF in 80-90% of patients with pemphigus vulgaris
See Workup for more detail.
Management
The aim of pharmacologic therapy for pemphigus vulgaris is to reduce inflammatory response and autoantibody
production. Medications used in the diseases treatment include the following:
Corticosteroids: Discourage the inflammatory process by inhibiting specific cytokine production
Immunosuppressants: Should be considered early in the course of disease as steroid-sparing agents
See Treatment and Medication for more detail.
Image library
Early, small blister filled with clear fluid arises on healthy skin.
Background
Pemphigus is derived from the Greek word pemphix meaning bubble or blister. Pemphigus describes a group of
chronic bullous diseases, originally named by Wichman in 1791. The term pemphigus once included most bullous
eruptions of the skin, but diagnostic tests have improved, and bullous diseases have been reclassified.
The term pemphigus refers to a group of autoimmune blistering diseases of the skin and mucous membranes
characterized histologically by intraepidermal blister and immunopathologically by the finding of in vivo bound and
circulating immunoglobulin G (IgG) antibody directed against the cell surface of keratinocytes. The 3 primary subsets
of pemphigus include pemphigus vulgaris, pemphigus foliaceus, and paraneoplastic pemphigus.
[8]
Each type of
pemphigus has distinct clinical and immunopathologic features. Pemphigus vulgaris accounts for approximately 70%
of pemphigus cases.
Pathophysiology
Pemphigus vulgaris is an autoimmune, intraepithelial, blistering disease affecting the skin and mucous membranes
and is mediated by circulating autoantibodies directed against keratinocyte cell surfaces. In 1964, autoantibodies
against keratinocyte surfaces were described in patients with pemphigus. Clinical and experimental observations
indicate that the circulating autoantibodies are pathogenic. An immunogenetic predisposition is well established.
Blisters in pemphigus vulgaris are associated with the binding of IgG autoantibodies to keratinocyte cell surface
molecules. These intercellular or pemphigus vulgaris antibodies bind to keratinocyte desmosomes and to
desmosome-free areas of the keratinocyte cell membrane. The binding of autoantibodies results in a loss of cell-to-
cell adhesion, a process termed acantholysis. The antibody alone is capable of causing blistering without
complement or inflammatory cells.
Pemphigus vulgaris antigen
Intercellular adhesion in the epidermis involves several keratinocyte cell surface molecules. Pemphigus antibody
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binds to keratinocyte cell surface the molecules desmoglein 1 and desmoglein 3. The binding of antibody to
desmoglein may have a direct effect on desmosomal adherens or may trigger a cellular process that results in
acantholysis. Antibodies specific for nondesmosomal antigens also have been described in the sera of patients with
pemphigus vulgaris; however, the role of these antigens in the pathogenesis of pemphigus vulgaris is not known.
Antibodies
Patients with the mucocutaneous form of pemphigus vulgaris have pathogenic antidesmoglein 1 and antidesmoglein
3 autoantibodies. Patients with the mucosal form of pemphigus vulgaris have only antidesmoglein 3 autoantibodies.
Patients with active disease have circulating and tissue-bound autoantibodies of both the immunoglobulin G1 (IgG1)
and immunoglobulin G4 (IgG4) subclasses.
[9, 10]
More than 80% of the patients with active disease produce autoantibodies to the desmosomal protein desmoglein.
Disease activity correlates with antibody titers in most patients.
[11]
In patients with pemphigus vulgaris, the presence
of antidesmoglein 1 autoantibodies, as determined by enzyme-linked immunosorbent assay (ELISA), is more closely
correlated with the course of the disease compared with antidesmoglein 3 autoantibodies. Lack of in vivo antibody
binding (reversion to a negative result on direct immunofluorescence) is the best indicator of remission and can help
predict a lack of flaring when therapy is tapered.
Complement
Pemphigus antibody fixes components of complement to the surface of epidermal cells. Antibody binding may
activate complement with the release of inflammatory mediators and recruitment of activated T cells. T cells are
clearly required for the production of the autoantibodies, but their role in the pathogenesis of pemphigus vulgaris
remains poorly understood. Interleukin 2 is the main activator of T lymphocytes, and increased soluble receptors
have been detected in patients with active pemphigus vulgaris.
Frequency
United States
Pemphigus vulgaris is uncommon, and the exact incidence and prevalence depends on the population studied.
International
Pemphigus vulgaris has been reported to occur worldwide. Pemphigus vulgaris incidence varies from 0.5-3.2 cases
per 100,000 population. Pemphigus vulgaris incidence is increased in patients of Ashkenazi Jewish descent and
those of Mediterranean origin. Few familial cases have been reported.
Mortality/Morbidity
Pemphigus vulgaris is a potentially life-threatening autoimmune mucocutaneous disease with a mortality rate of
approximately 5-15%.
[1]
Mortality in patients with pemphigus vulgaris is 3 times higher than the general population.
Complications secondary to the use of high-dose corticosteroids contribute to the mortality rate. Morbidity and
mortality are related to the extent of disease, the maximum dose of systemic steroids required to induce remission,
and the presence of other diseases. Prognosis is worse in patients with extensive pemphigus vulgaris and in older
patients.
Pemphigus vulgaris involves mucosa in 50-70% of patients. This may limit oral intake secondary to dysphagia.
Blistering and erosions secondary to the rupture of blisters may be painful and may limit the patient's daily activities.
Additionally, Patients with pemphigus vulgaris typically heal without scarring unless the disease is complicated by
severe secondary infection.
Reversion of direct immunofluorescence (DIF) to negative can be useful to predict sustained remission after
withdrawal of medication. Plucked hairs are an alternative to skin biopsy to provide a specimen for
immunofluorescence, as the pilar sheath epithelium of the anagen hair typically demonstrates immunofluorescence
comparable to skin. DIF on plucked hairs may be more acceptable to the patient than serial skin biopsies.
[12, 13]
Race
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Pemphigus vulgaris affects persons of all races. The prevalence of pemphigus vulgaris is high in regions where the
Jewish population is predominant.
[14]
For example, in Jerusalem, the prevalence of pemphigus vulgaris is estimated
at 1.6 cases per 100,000 population; in Connecticut, the prevalence has been reported as 0.42 cases per 100,000
population.
[15]
The incidence in the United Kingdom is 0.68 case per 100 000 persons per year. The incidence of
pemphigus vulgaris in Tunisia is estimated at 2.5 cases per million population per year (3.9 in women, 1.2 in men),
while in France, the incidence is 1.3 cases per million population per year (no significant difference between men
and women).
[16]
In Finland, where few people of Jewish or Mediterranean origin live, the prevalence is low, at 0.76
case per million population.
[17]
Sex
The male-to-female ratio is approximately equal. In adolescence, girls are more likely to be affected than boys.
Age
The mean age of onset is approximately 50-60 years; however, the range is broad, and disease onset in older
individuals and in children has been described. Patients are younger at presentation in India than in Western
countries.
[18]
Contributor Information and Disclosures
Author
Bassam Zeina, MD, PhD Consulting Staff, Department of Dermatology, Milton Keynes Hospital, UK
Bassam Zeina, MD, PhD is a member of the following medical societies: British Association of Dermatologists,
British Medical Association, and Royal Society of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Nicole Sakka, MBBS Foundation Year 2, Royal Liverpool and Broadgreen University Hospital, Liverpool, UK
Disclosure: Nothing to disclose.
Sohail Mansoor, MBBS, MSc Dermatologist and Lead Physician in Dermatologic Surgery, Department of
Dermatology, Barnet Hospital, UK
Sohail Mansoor, MBBS, MSc is a member of the following medical societies: American Academy of Anti-Aging
Medicine, American Academy of Dermatology, American Society for Dermatologic Surgery, Royal College of
Physicians and Surgeons of Glasgow, and Royal College of Physicians of the United Kingdom
Disclosure: Nothing to disclose.
Specialty Editor Board
Abby S Van Voorhees, MD Assistant Professor, Director of Psoriasis Services and Phototherapy Units,
Department of Dermatology, University of Pennsylvania School of Medicine, Hospital of the University of
Pennsylvania
Abby S Van Voorhees, MD is a member of the following medical societies: American Academy of Dermatology,
American Medical Association, National Psoriasis Foundation, Phi Beta Kappa, Sigma Xi, and Women's
Dermatologic Society
Disclosure: Amgen Honoraria Consulting; Abbott Honoraria Consulting; Merck Salary Management position;
Abbott Honoraria Speaking and teaching; Amgen Honoraria Review panel membership; Centocor Honoraria
Consulting; Leo Consulting; Merck None Other
Richard P Vinson, MD Assistant Clinical Professor, Department of Dermatology, Texas Tech University Health
Sciences Center, Paul L Foster School of Medicine; Consulting Staff, Mountain View Dermatology, PA
Richard P Vinson, MD is a member of the following medical societies: American Academy of Dermatology,
Association of Military Dermatologists, Texas Dermatological Society, and Texas Medical Association
14/9/2014 Pemphigus Vulgaris
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Disclosure: Nothing to disclose.
Jeffrey P Callen, MD Professor of Medicine (Dermatology), Chief, Division of Dermatology, University of
Louisville School of Medicine
Jeffrey P Callen, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of
Dermatology, American College of Physicians, and American College of Rheumatology
Disclosure: Auxillium Honoraria Consulting; Stiefel, a GSK company Honoraria Consulting; UpToDate Honoraria
author/editor; JAMA Dermatology Honoraria Associate editor and intermittent author; Elsevier Royalty Book
author/editor; Stock holdings in various trust accounts include some pharmaceutical companies and device
makers I do not control these accounts, but have directed our managers to divest pharmaceutical stocks as is
fiscally prudent I inherited these trust accounts
Joel M Gelfand, MD, MSCE Medical Director, Clinical Studies Unit, Assistant Professor, Department of
Dermatology, Associate Scholar, Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania
Joel M Gelfand, MD, MSCE is a member of the following medical societies: Society for Investigative Dermatology
Disclosure: AMGEN Consulting fee Consulting; AMGEN Grant/research funds Investigator; Genentech
Grant/research funds investigator; Centocor Consulting fee Consulting; Abbott Grant/research funds investigator;
Abbott Consulting fee Consulting; Novartis investigator; Pfizer Grant/research funds investigator; Celgene
Consulting fee DMC Chair; NIAMS and NHLBI Grant/research funds investigator
Chief Editor
Dirk M Elston, MD Director, Ackerman Academy of Dermatopathology, New York
Dirk M Elston, MD is a member of the following medical societies: American Academy of Dermatology
Disclosure: Nothing to disclose.
Additional Contributors
The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous author,
Mohsin Ali, MBBS, FRCP, MRCP, to the development and writing of this article.
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