A. Definition

1. Pemphigus is a group of related anti-desmosomal autoantibody producing diseases
   1. Pemphigus vulgaris (PV) - autoantibodies to desmoglein 3 ± desmoglein 1
   2. Pemphigus foliaceus - antidesmoglein 1 autoantibodies
   3. Paraneoplastic pemphigus
2. Pemphigus is a serious autoimmune skin disease with intraepithelial blisters
   1. PV Mucosal dominant - autoantibodies to desmoglein 3 only
   2. PV Mucocutaneous - flaccid blisters and erosions on skin and oral mucosa; autoantibodies to both desmogleins 3 and 1
   3. Almost invariably fatal if left untreated
3. Mainly affects persons in 4th-6th decades
4. Relatively rare, with 0.75-5 cases per million persons annually (PV 7:1 versus foliaceous)

B. Symptoms of PV

1. About 65% have oral lesions which may be only manifestation
2. Blisters usually not intact
   1. Easily extended with fingers (positive Nikolsky Sign)
   2. Contrast bullous pemphigoid, where blisters remain intact with pressure (not extend)
3. Flaccid blisters, fragile skin, erosions
4. Progressive respiratory failure with bronchiolitis obliterans can occur [4]
5. Triggers [1]
   1. Dental work
   2. Sun exposure
   3. Radiographs
   4. Stress
   5. Trauma
6. Potentially fatal disease

C. Pathology [4]

1. PV with intraepithelial blister with IgG, C3 or both along keratinocyte surface
   1. Blisters develop just above the the basal-cell layer
   2. Thus, blisters are "low" in the epidermis
   3. Epidermal acantholysis is characteristic pathological finding
2. Antibodies in PV
   1. Against so-called PV Antigens
   2. Primarily anti-desomoglein 3 (desmosomal transmembrane protein) Abs
   3. Anti-desmosomal and hemidesmosomal plakin autoantibodies
3. Anti-Desmoglein Abs
   1. Major response against Desmoglein 3, a 130kD glycoprotein
   2. Desmoglein 3 belongs to the cadherin (calcium dependent adherin protein) family
   3. Antibodies to desmoglein 1 appear in mucocutaneous forms of PV
   4. Antibodies bound to desmogleins interfere with normal desmosome function
   5. This leads to intraepithelial adhesion breakdown, causing blisters
   6. Breakdown of desmogleins occur in staphylococcal scalded skin syndrome
4. Genetic Linkages in PV
   1. Highest prevalence in Mediterranean or jewish ancestry
   2. Increased risk in HLA-DRB1*0402 Ashkenazi Jews
   3. Increased risk in HLA-DRB1*401/04 and DQB1*0503 non-Jewish Europeans and Asians
   4. Rarely affects more than one family member
5. Antidesmoglein autoantibodies affect skin and can also affect respiratory epithelium [5]
6. Consider underlying neoplastic disease in all patients with PV

D. Differential Diagnosis [1,2,3]

1. Biopsy with immunofluorescence is required for most diagnoses
2. Serum autoantibodies tests are now available for some diagnoses including PV
3. Differential Diagnosis
   1. Hepetic lesions
   2. Paraneoplastic Pemphigus
   3. Pemphigus Foliaceus
   4. Pemphigus Neoplastica
   5. Erythema multiforme major
   6. Staphylococcal scalded skin syndrome [2]
4. Pemphigus Foliaceus [2,5]
   1. Affects adults with lesions occuring only on the skin
   2. Mucous membranes not affected
   3. Erosions, crusts, fragile skin with very superficial blisters (just below stratum corneum)
   4. May occur after administration of penicillamine and some other agents
   5. Autoantibodies to desmoglein 1 but not desmoglein 3 found
   6. Endemic ("fogo selvagem") and sporadic forms of pemphigus foliaceus described
   7. Autoantibodies to desmoglein I are found in "normal" persons in regions of endemic disease
   8. Both non-endemic and endemic forms associated with HLA DRB1*0102 and 0404
   9. Treatment is less aggressive than for PV
5. Paraneoplastic Pemphigus [3]
   1. Autoimmune vesicular eruption associated with certain neoplasms
   2. Associations: non-Hodgkin's lymphoma (52%)
   3. May resemble cutaneous lupus, erythema multiforme, with tense blisters
   4. Antibodies are variable, against desmoplakins, desmogliens 1, 3; BPA, others
   5. Thus, both intraepithelial and subepithelial blisters are present
   6. Treatment of underlying disease often improves cutaneous symptoms
   7. Glucocorticoids and/or mycophenolate may be beneficial

E. Therapy

1. Typically treat with high dose glucocorticoids plus immunosuppressive agent(s)
   1. Good disease control
   2. Requirement for prolonged immunosuppression
   3. Most common cause of death in pemphigus vulgaris associated with immunosuppression
   4. Use of immunomodulatory drugs is increasing
2. Glucocorticoids
   1. Topical, oral, intravenous, or intralesional glucocorticoids are used
   2. Severe disease may be treated with 1gm/day methylprednisolone x 5 days (then po)
   3. Typical starting oral dose is 80mg po qd (40mg po bid) with gradual taper
   4. After new lesions stop appearing, may cut dose by 50% [3]
   5. Continue at 50% maximal dose until all lesions have cleared
   6. Then slowly taper prednisone over months
   7. 8-12 weeks of glucocorticoids are usually minimally required
   8. Taper to alternating day therapy (5-10mg prednisone po qod) if tolerated
   9. Oral ulcers / erosions are best treated with oral topical agents
   10. Oral intralesional injection of triamcinolone (20µg/L) often effective [1]
   11. All patients on glucocorticoids should be evaluated for tuberculosis and osteoporosis
   12. Topical glucocorticoids and antibiotics can improve local healing, prevent infection
   13. B-cell selective therapy appears safer and very effective (see below)
3. Mycophenolate Mofetil (CellCept®) [6]
   1. Immunosuppressive agents are usually used as glucocorticoid-sparing drugs
   2. Mycophenolate probably superior to methotrexate or azathioprine
   3. Should be given initially with glucocorticoids at onset of severe disease
   4. Combination of mycophenolate and glucocorticoids has cleared refractory PV [6]
   5. Must be maintained for 18-24 months during prednisone taper
   6. Dose 1.0-1.5gm bid po
4. B Cell Specific Therapy [7]
   1. Intravenous immunoglobulin (IVIg) is increasingly used over plasmapheresis
   2. Rituxumab (Rituxan®), an anti-CD20 B cell Ab, depletes circulating B cells
   3. 86% of 21 patients with glucocorticoid refractory pemphigus given a single 375mg IV dose rituximab had complete remission at 3 months; 9 of them relapsed with ~18 months [8]
   4. 10% of severe pemphigus patients given single dose rituximab had serious side effects [8]
   5. Combination of rituximab with IVIg lead to rapid resolution in 9 of 11 patients
   6. Rituximab given as 375mg/m2 body surface once weekly x 3 weeks
   7. IVIg was given 2gm/kg body weight in 4th week
   8. Repeat for second 4-week cycle
   9. In months 3, 4, 5, and 5, single infusion each of rituximab and IVIg at start of month
   10. All immunosuppressive agents were stopped in patients receiving rituximab prior to ending rituximab treatment
5. Other Immunosuppressive Agents
   1. In general, 8-12 weeks of therapy should be tried before increasing dose or changing drug
   2. Single agents are usually used with prednisone, and may be selected from choices below
   3. Azathioprine (Imuran®) can be used at 4mg/kg/day orally initial dose
   4. Methotrexate 7.5-15mg po q week (3 divided doses) may be tried prior to azathioprine
   5. Daspone is a reasonble alternative
   6. Cyclophosphamide (Cytoxan®) - most effective but least safe; reserved for last line
   7. Cyclophosphamide: initiate at 50mg/day po then increase to 100mg/day if tolerated

References

1. Bystryn JC and Rudolph JL. 2005. Lancet. 366(9474):61
2. Stanley JR and Amagai M. 2006. NEJM. 355(17):1800
3. Ahmed AR, Avram MM, Duncan LM. 2003. NEJM. 349(4):382 (Case Record)
4. Nousari HC, Deterding R, Wojtczack H, et al. 1999. NEJM. 340(18):1406
5. Warren SJP, Lin MS, Giudice GJ, et al. 2000. NEJM. 343(1):23
6. Grundmann-Kollmann M, Korting HC, Behrens S, et al. 1999. J Am Acad Dermatol. 40:957
7. Ahmed AR, Spigelman Z, Cavacini LA, Posner MR. 2006. NEJM. 355(17):1772
8. Joly P, Mouquet H, Roujeau JC, te al. 2007. NEJM. 357(6):545