PemphigusPemphigusTiffany Hsu #529Tiffany Hsu #529Joanne Kim #140Joanne Kim #140

Jonathan Miller #149Jonathan Miller #149Hamid Shafizadeh #174Hamid Shafizadeh #174

Pemphigus PathogenesisPemphigus PathogenesisIntraepithelial blister formation results from Intraepithelial blister formation results from breakdown breakdown

of intercellular adhesion, thus producing of intercellular adhesion, thus producing epithelial cell epithelial cell

separation known as acantholysisseparation known as acantholysisCaused by antibody-mediated autoimmune Caused by antibody-mediated autoimmune reaction to reaction to

desmogleins (Dsg), desmosomal transmembrane desmogleins (Dsg), desmosomal transmembrane

glycoproteins, leading to acantholysis glycoproteins, leading to acantholysis Classified into pemphigus vulgaris (PV), with Classified into pemphigus vulgaris (PV), with

suprabasal acantholysis, and pemphigus suprabasal acantholysis, and pemphigus foliaceus (PF), foliaceus (PF),

with acantholysis in the more superficial with acantholysis in the more superficial epidermisepidermisPemphigus vulgaris is characterized by IgG Pemphigus vulgaris is characterized by IgG

autoantibodies against desmoglein 3 (Dsg 3), autoantibodies against desmoglein 3 (Dsg 3), whereas whereas

the target of PF is Dsg1, although about 50% of the target of PF is Dsg1, although about 50% of PV PV

patients also have Dsg1 autoantibodies; patients also have Dsg1 autoantibodies; desmoplakin is desmoplakin is

another targetanother target

PathogenesisPathogenesis

Circulating autoantibodies are responsible Circulating autoantibodies are responsible for disruption of intercellular junctions and for disruption of intercellular junctions and loss of cell-to-cell adhesion.loss of cell-to-cell adhesion.

Extent of epithelial cell separation are Extent of epithelial cell separation are directly proportional to the titer of directly proportional to the titer of circulating pemphigus antibody.circulating pemphigus antibody.

It is believed pemphigus antibody, once It is believed pemphigus antibody, once bound to the target antigen (desmoglein 1, bound to the target antigen (desmoglein 1, desmoglein 3, desmoplakin), activates an desmoglein 3, desmoplakin), activates an epithelial intracellular proteolytic enzyme epithelial intracellular proteolytic enzyme that acts at the desmosome-tonofilament that acts at the desmosome-tonofilament complex.complex.

Clinical PresentationClinical Presentation

Three major types of pemphigus:Three major types of pemphigus: Pemphigus vulgarisPemphigus vulgaris Pemphigus folaceusPemphigus folaceus Paraneoplastic pemphigusParaneoplastic pemphigus

Pemphigus vulgaris is by far the most Pemphigus vulgaris is by far the most common of the three types.common of the three types.

Clinical PresentationClinical Presentation

Pemphigus presents with vesicles and/or bulla on Pemphigus presents with vesicles and/or bulla on skin and mucous membranes.skin and mucous membranes.

These vary in size from 1-3 cm in diameter.These vary in size from 1-3 cm in diameter. These rupture quickly and more often appear as These rupture quickly and more often appear as

ulcerations.ulcerations. The mucous membranes of the mouth are the The mucous membranes of the mouth are the

most common site for pemphigus lesionsmost common site for pemphigus lesions Other common sites:Other common sites:

Face and scalpFace and scalp Chest and armpitsChest and armpits groingroin

Pemphigus vulgarisPemphigus vulgaris

Pemphigus vulgarisPemphigus vulgaris

Clinical PresentationClinical Presentation

Most common age group initially Most common age group initially diagnosed with pemphigus is 40-60 diagnosed with pemphigus is 40-60 years old.years old.

Children are very rarely affected.Children are very rarely affected. People of Jewish or Mediterranean People of Jewish or Mediterranean

descent are most commonly descent are most commonly diagnosed.diagnosed.

Diagnostic tests for Diagnostic tests for PemphigusPemphigus

Positive Nikolsky signPositive Nikolsky sign Indirect fluorescent antibody (IFA) Indirect fluorescent antibody (IFA) -the qualitative and semi-quantitative detection of -the qualitative and semi-quantitative detection of

antibodies antibodies

associated with pemphigusassociated with pemphigus The direct immunofluorescence The direct immunofluorescence

test (DIF)test (DIF) -detects the antibody deposition in the tissues -detects the antibody deposition in the tissues -very reliable diagnostic test for pemphigus -very reliable diagnostic test for pemphigus -can remain positive for several years after regression of -can remain positive for several years after regression of

the the disease disease

Pemphigus Pemphigus ImmunofluorescenceImmunofluorescence

Histology of PemphigusHistology of PemphigusPemphigus typically displays acantholysis with some dyscanthosis Pemphigus typically displays acantholysis with some dyscanthosis near near the granular layer. The acantholytic, rounded cells are termed the granular layer. The acantholytic, rounded cells are termed Tzanck cells, Tzanck cells, which are pathognomonic to Pemphigus Vulgariswhich are pathognomonic to Pemphigus Vulgaris

Within the papillary dermis there is a sparse Within the papillary dermis there is a sparse perivascular lymphocytic infiltrate with scattered perivascular lymphocytic infiltrate with scattered eosinophils. eosinophils.

Treatment GoalsTreatment Goals

Reduce inflammatory response Reduce inflammatory response

-decrease blister formation-decrease blister formation -promote healing of blisters and erosions-promote healing of blisters and erosions

Reduce autoantibody productionReduce autoantibody production Use minimal dose of medication Use minimal dose of medication

needed to control the diseaseneeded to control the disease

Conventional TherapyConventional Therapy

Systemic corticosteroidsSystemic corticosteroids -1 mg/kg prednisone initially used with gradual tapering-1 mg/kg prednisone initially used with gradual tapering -severe adverse side effects: HTN, osteoporosis, -severe adverse side effects: HTN, osteoporosis, atherosclerosis, peptic ulcer disease, aseptic necrosis, atherosclerosis, peptic ulcer disease, aseptic necrosis,

diabetes, diabetes, susceptibility to infections, septicemia, otherssusceptibility to infections, septicemia, others

Immunosuppressive and anti-inflammatory Immunosuppressive and anti-inflammatory agents agents

-Used in combo with corticosteroids to provide a -Used in combo with corticosteroids to provide a potential corticosteroid-sparing effect (minimize steroid potential corticosteroid-sparing effect (minimize steroid

use)use) -adverse side effects-adverse side effects

Other TherapiesOther Therapies

DapsoneDapsone MethotrexateMethotrexate Mycophenolate mofetilMycophenolate mofetil Dexamethasone-Cyclophosphamide Dexamethasone-Cyclophosphamide

Pulse TherapyPulse Therapy PlasmapheresisPlasmapheresis Rituximab + Intravenous Immune Rituximab + Intravenous Immune

GlobulinGlobulin

Other TherapiesOther Therapies Dapsone (anti-inflammatory)Dapsone (anti-inflammatory) -clinical response usually seen after 1st week of treatment-clinical response usually seen after 1st week of treatment -most common adverse effect: hemolytic anemia-most common adverse effect: hemolytic anemia Methotrexate (immunosuppressant) Methotrexate (immunosuppressant) -risk of megaloblastic anemia, bone marrow suppression, liver and -risk of megaloblastic anemia, bone marrow suppression, liver and renal toxicityrenal toxicity Mycophenolate Mofetil (chemotherapeutic)Mycophenolate Mofetil (chemotherapeutic) -inhibits lymphocyte proliferation-inhibits lymphocyte proliferation -more studies with long-term follow up are needed to determine -more studies with long-term follow up are needed to determine efficacy and proper dosingefficacy and proper dosing Dexamethasone-Cyclophosphamide Pulse Therapy (Anti-inflammatory Dexamethasone-Cyclophosphamide Pulse Therapy (Anti-inflammatory

+ chemotherapeutic agent)+ chemotherapeutic agent) -studies have shown remission of PV, but patients suffered multiple -studies have shown remission of PV, but patients suffered multiple infections due to receiving high doses of immunosuppressantsinfections due to receiving high doses of immunosuppressants Plasmapheresis Plasmapheresis -reduces the autoantibody in the plasma through a filtration -reduces the autoantibody in the plasma through a filtration mechanismmechanism -for severe refractory PV-for severe refractory PV -few studies done; no established protocol-few studies done; no established protocol

Other TherapiesOther Therapies Rituximab (monoclonal antibody) + Intravenous Immune Rituximab (monoclonal antibody) + Intravenous Immune

Globulin (IVIg)Globulin (IVIg) -study published October 2006: study on 11 patients who had -study published October 2006: study on 11 patients who had

inadequate inadequate responses to conventional therapy responses to conventional therapy -Initially 2 cycles of rituximab given once weekly for 3 weeks and -Initially 2 cycles of rituximab given once weekly for 3 weeks and

IVIg IVIg given in the 4th week; followed by monthly infusion of rituximab given in the 4th week; followed by monthly infusion of rituximab

and IVIg and IVIg for 4 consecutive monthsfor 4 consecutive months -Of 11 patients, 9 had complete and rapid resolution of lesions and -Of 11 patients, 9 had complete and rapid resolution of lesions and a clinical remission lasting an average of 31 months. All a clinical remission lasting an average of 31 months. All immunosuppressive therapy, including prednisone, could be immunosuppressive therapy, including prednisone, could be discontinued before ending rituximab treatment in all patients. discontinued before ending rituximab treatment in all patients. Side effects that have been associated with rituximab were not Side effects that have been associated with rituximab were not observed, nor were infections.observed, nor were infections. -recommended for refractory PV-recommended for refractory PV -larger, controlled study needed-larger, controlled study needed

1. Pemphigus is characterized by IgG autoantibodies against which 1. Pemphigus is characterized by IgG autoantibodies against which proteins:proteins:

A. DesmogleinsA. Desmogleins

B. EpiligrinB. Epiligrin

C. CollagenC. Collagen

D. Bullous pemphigoid antigen-2D. Bullous pemphigoid antigen-2

Answer: AAnswer: A

2. What is the most common type of pemphigus?2. What is the most common type of pemphigus?

A. Pemphigus foliaceusA. Pemphigus foliaceus

B. Pemphigus vulgarisB. Pemphigus vulgaris

C. Paraneoplastic pemphigusC. Paraneoplastic pemphigus

D. None of the aboveD. None of the above

Answer: BAnswer: B