1. Pemphigus Tiffany Hsu #529 Joanne Kim #140 Jonathan Miller #149 Hamid Shafizadeh #174

2. Pemphigus Pathogenesis  Intraepithelial blister formation results from breakdown of intercellular adhesion, thus producing epithelial cell of intercellular adhesion, thus producing epithelial cell separation known as acantholysis separation known as acantholysis  Caused by antibody-mediated autoimmune reaction to desmogleins (Dsg), desmosomal transmembrane desmogleins (Dsg), desmosomal transmembrane glycoproteins, leading to acantholysis glycoproteins, leading to acantholysis  Classified into pemphigus vulgaris (PV), with suprabasal acantholysis, and pemphigus foliaceus (PF), suprabasal acantholysis, and pemphigus foliaceus (PF), with acantholysis in the more superficial epidermis with acantholysis in the more superficial epidermis  Pemphigus vulgaris is characterized by IgG autoantibodies against desmoglein 3 (Dsg 3), whereas autoantibodies against desmoglein 3 (Dsg 3), whereas the target of PF is Dsg1, although about 50% of PV the target of PF is Dsg1, although about 50% of PV patients also have Dsg1 autoantibodies; desmoplakin is patients also have Dsg1 autoantibodies; desmoplakin is another target another target

3. Pathogenesis  Circulating autoantibodies are responsible for disruption of intercellular junctions and loss of cell-to-cell adhesion.  Extent of epithelial cell separation are directly proportional to the titer of circulating pemphigus antibody.  It is believed pemphigus antibody, once bound to the target antigen (desmoglein 1, desmoglein 3, desmoplakin), activates an epithelial intracellular proteolytic enzyme that acts at the desmosome-tonofilament complex.

4. Clinical Presentation  Three major types of pemphigus: Pemphigus vulgaris Pemphigus vulgaris Pemphigus folaceus Pemphigus folaceus Paraneoplastic pemphigus Paraneoplastic pemphigus Pemphigus vulgaris is by far the most common of the three types.

5. Clinical Presentation  Pemphigus presents with vesicles and/or bulla on skin and mucous membranes.  These vary in size from 1-3 cm in diameter.  These rupture quickly and more often appear as ulcerations.  The mucous membranes of the mouth are the most common site for pemphigus lesions  Other common sites: Face and scalp Face and scalp Chest and armpits Chest and armpits groin groin

6. Pemphigus vulgaris

8. Clinical Presentation  Most common age group initially diagnosed with pemphigus is 40-60 years old.  Children are very rarely affected.  People of Jewish or Mediterranean descent are most commonly diagnosed.

9. Diagnostic tests for Pemphigus  Positive Nikolsky sign  Indirect fluorescent antibody (IFA) -the qualitative and semi-quantitative detection of antibodies -the qualitative and semi-quantitative detection of antibodies associated with pemphigus associated with pemphigus  The direct immunofluorescence 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 the -can remain positive for several years after regression of the disease disease

10. Pemphigus Immunofluorescence

11. Histology of Pemphigus  Pemphigus typically displays acantholysis with some dyscanthosis near the granular layer. The acantholytic, rounded cells are termed Tzanck cells, the granular layer. The acantholytic, rounded cells are termed Tzanck cells, which are pathognomonic to Pemphigus Vulgaris which are pathognomonic to Pemphigus Vulgaris  Within the papillary dermis there is a sparse perivascular lymphocytic infiltrate with scattered perivascular lymphocytic infiltrate with scattered eosinophils. eosinophils.

12. Treatment Goals  Reduce inflammatory response -decrease blister formation -decrease blister formation -promote healing of blisters and erosions -promote healing of blisters and erosions  Reduce autoantibody production  Use minimal dose of medication needed to control the disease

13. Conventional Therapy  Systemic 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, diabetes, atherosclerosis, peptic ulcer disease, aseptic necrosis, diabetes, susceptibility to infections, septicemia, others susceptibility to infections, septicemia, others  Immunosuppressive and anti-inflammatory agents -Used in combo with corticosteroids to provide a -Used in combo with corticosteroids to provide a potential corticosteroid-sparing effect (minimize steroid use) potential corticosteroid-sparing effect (minimize steroid use) -adverse side effects -adverse side effects

14. Other Therapies  Dapsone  Methotrexate  Mycophenolate mofetil  Dexamethasone-Cyclophosphamide Pulse Therapy  Plasmapheresis  Rituximab + Intravenous Immune Globulin

15. Other Therapies  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) -risk of megaloblastic anemia, bone marrow suppression, liver and -risk of megaloblastic anemia, bone marrow suppression, liver and renal toxicity renal toxicity  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 dosing efficacy and proper dosing  Dexamethasone-Cyclophosphamide Pulse Therapy (Anti- inflammatory + 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 immunosuppressants infections due to receiving high doses of immunosuppressants  Plasmapheresis -reduces the autoantibody in the plasma through a filtration -reduces the autoantibody in the plasma through a filtration mechanism mechanism -for severe refractory PV -for severe refractory PV -few studies done; no established protocol -few studies done; no established protocol

16. Other Therapies  Rituximab (monoclonal antibody) + Intravenous Immune Globulin (IVIg) -study published October 2006: study on 11 patients who had inadequate -study published October 2006: study on 11 patients who had inadequate responses to conventional therapy responses to conventional therapy -Initially 2 cycles of rituximab given once weekly for 3 weeks and IVIg -Initially 2 cycles of rituximab given once weekly for 3 weeks and IVIg given in the 4th week; followed by monthly infusion of rituximab and IVIg given in the 4th week; followed by monthly infusion of rituximab and IVIg for 4 consecutive months for 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

17. 1. Pemphigus is characterized by IgG autoantibodies against which proteins: A. Desmogleins B. Epiligrin B. Epiligrin C. Collagen C. Collagen D. Bullous pemphigoid antigen-2 D. Bullous pemphigoid antigen-2 Answer: A 2. What is the most common type of pemphigus? A. Pemphigus foliaceus B. Pemphigus vulgaris B. Pemphigus vulgaris C. Paraneoplastic pemphigus C. Paraneoplastic pemphigus D. None of the above D. None of the above Answer: B