Pemphigus vulgaris

• Wichmann, 1793
• Hebra, 1860

Rare, severe blistering autoimmune disease in which autoantibodies are directed against structural proteins of the skin and mucosa. Unlike pemphigoid, intraepithelial cleavage occurs.

• All pemphigus diseases together
  • Incidence: 1-2/1,000,000 / year
  • Of these, 80% are pemphigus vulgaris patients, after which pemphigus foliaceus is the most common
• Incidence
  • Switzerland: 0.6-0.76 / million inhabitants / year
  • Germany: 1.5/million population/year
  • Greece: 8.0/ million inhabitants / year
  • Individual religion-related population groups: 16.1- 32 / million inhabitants / year
  • M = F
• Age peak: 40th-60th yrs

• Autoantibodies against desmoglein 1 and/or 3 destroy desmoglein, which functions as an adhesion molecule for keratinocytes

• Associations:
  • Autoimmune diseases
    • Myasthenia gravis
    • Thymoma
    • Lupus erythematosus
  • Neoplasms
    • Lymphomas
    • Carcinomas
  • Medicines, esp
    • D-penicillamine
    • Rifampicin
    • ACE inhibitors
    • Diclofenac
    • Propanolol
    • Indometacin
    • Pyrazolone derivatives
    • Cephalosporins
  • Physical stimuli
    • Burns
    • UV irradiation
    • X-ray irradiation
  • HLA class II alleles DQB1, DRB1

• Localisation
  • Mucous membranes (oral cavity and genital), umbilicus, intertrigines. Potentially, the entire remaining integument may be affected

• Both on the mucous membranes (involvement in 50%), but also cutaneously, blisters are often not visible initially. Rather, erosions, aphthae or "eczematous" skin changes appear. In the course, blistering, erosions and crust formation occur. Secondary infections can lead to scarring and healing
• If there is laryngeal involvement, hoarseness may occur; if there is oesophageal involvement, there may be difficulty swallowing.
• Nikolski's phenomenon I: Lateral spatula pressure causes bullae to be triggered: positive
• Nikolski's phenomenon II: Bullae can be displaced by lateral spatula pressure: positive

• Anamnesis according to S2k- AWMF guideline:
  • Time of the first appearance of the lesions
  • Pain (where, when)
  • Stomatitis, dysphagia, hoarseness?
  • Conjunctivitis?
  • Epistaxis?
  • Dysuria?
  • Weight loss?
  • Medication history?
  • Ethnic background
• Clinical
• Biopsy
  • Dermatopathology (small intact blister by biopsy)
  • Direct immunofluorescence (4 mm punch biopsy from perilesional skin or mucosa (<1cm adjacent to a blister)
• Indirect immunofluorescence (IF)
  • Monkey oesophagus
  • Desmoglein 3-ELISA (no western blot recommended)
  • Desmoglein 1-ELISA (no Western blot recommended)

There are > 50 non-desmoglein target antigens which can/should be determined if appropriate.

Recommendations according to S2-guideline

Mucous membranes (oral cavity and genital), umbilicus, intertrigines. Potentially the entire remaining integument can be affected.

• Suprabasal acantholysis. Inflammatory infiltrates and oedema are visible in the corium

• Direct immunofluorescence
  • IgG deposits (and often C1, C3, C4, rarely IgM or IgA) in the intercellular space of the epidermis

• Potentially lethal
• Rarely complete healing

General measures:

• Avoid trauma
• In case of dysphagia/hoarseness: ENT consultation
• On diagnosis, penicillamine and rifampicin should be discontinued
• In case of resistance to therapy, discontinuation of ACE inhibitors, pyrazolone derivatives and cephalosporins is indicated
• A diagnosis of the cause of pemphigus vulgaris is not recommended according to the S2 guidelines
• Prophylactically swab lesions every 2 days to be prepared for bacterial superinfection

Topical therapy:

• Mometasone fuorate cream / solution / ointment
• Clobetasol cream 1-2 dgl (for 1-3 days)
• Betamethasone & Triamcinolone / Chlorhexidine Cream
• Betamethasone & Fusidic Acid Cream
• Skin defects when systemic immunosuppression active: sulfadiazine or sodium hyaluronate, Polyvidon iodine wound ointment / solution / ointment gauze
• In the area of intertrigines insertion of linen flaps
• In cutaneous involvement over joint regions, physiotherapy should be performed to prevent contractures

In case of oral mucosal involvement:

• Passaged food
• Avoiding spicy, acidic foods
• Triamcinolone acetonide paste or adhesive gel
• Lidocaine mouth gel
• Camilla extract oral pharyngeal spray

Systemic infestation:

• Glucocorticoids
  • Prednisolone p.o. 1mg/kg daily
  • Until no new blisters appear, then slow! Reduction - no new blisters should occur here
    • Maintenance dose: 10-20 mg 1x tgl.
• Chimeric anti-CD20 monoclonal antibody
• Rituximab i.v. 275 mg/m² KOF (day 0, 7, 14, 21)
  • Premedication:
    • Analgesics
    • 1000 mg paracetamol p.o.
    • Glucocorticoids
      • Prednisolone p.o. 100 mg 1x tgl.
  • First infusion:
    • Initial infusion rate: 50 mg/h
    • After 1 hour, an increase of 50 mg/h every 30 minutes up to 400 mg/h can be considered
  • Additional infusions:
    • Initial infusion rate: 100 mg/h
    • After 1 hour, increase by 100 mg/h up to 400 mg/h
    • Rituximab must not be administered undiluted and not as a short infusion!
    • If respiratory symptoms or hypotension occur, 24-hour monitoring is indicated

• Azathioprine p.o. 1x tgl
  • Initial: 1-3 mg/kg bw
  • Progression: reduction by approx. 0.5 mg/kg bw to the lowest still effective dosage
  • CAVE: With concomitant administration of allopurinol, a reduction of the azathioprine dose to a ¼ dose is indicated
• Mycophenolate mofetil p.o. 1-1.5 g 2x tgl.
• In case of resistance to therapy:
  • Dexamethasone-cyclophosphamide- shock therapy
• Alternatives:
  • Ciclosporin p.o. 5 mg/kg bw daily
    • Take independently of meals
  • IVIG i.v. 250-400 mg/kg bw daily for 3-5 days every 3-4 weeks for 3-6 cycles
    • Initial dose: 0.4-0.8 g/kg bw
    • In the course: 0.2 g/kg bw every 3 to 4 weeks
    • Determination of the IgG serum level always immediately before the next infusion!
    • An IgG valley level of at least 5 to 6 g/l should be achieved before re-infusion.
• H1 blockers e.g. anithistamines
  • Levocetirizine p.o. 5 mg 1x tgl.
  • Desloratadine p.o. 5 mg 1x tgl.
  • Fexofenadine p.o. 180 mg 1x tgl.

Skin specialist checks

• Initially every 2 weeks, then every 1-3 months until complete remission
• After complete remission under therapy every 3-6 months
• According to S2- guidelines, before discontinuing immunosuppressive medication, consideration may be given to performing a repeat direct immunofluorescence

1. Aberer W, Wolff-Schreiner EC, Stingl G, Wolff K. Azathioprine in the treatment of pemphigus vulgaris. Journal of the American Academy of Dermatology 1987;16:527-33.
2. Amagai M, Hashimoto T, Shimizu N, Nishikawa T. Absorption of pathogenic autoantibodies by the extracellular domain of pemphigus vulgaris antigen (Dsg3) produced by baculovirus. Journal of Clinical Investigation 1994;94:59-67.
3. Turner MS, Sutton D, Sauder DN. The use of plasmapheresis and immunosuppression in the treatment of pemphigus vulgaris. Journal of the American Academy of Dermatology 2000;43:1058-64.
4. Kim SC, Chung YL, Kim J, Cho NJ, Amagai M. Pemphigus vulgaris with autoantibodies to desmoplakin. Br J Dermatol 2001;145:838-40.
5. Ljubojevic S, Lipozencic J, Brenner S, Budimcic D. Pemphigus vulgaris: a review of treatment over a 19-year period. Journal of the European Academy of Dermatology and Venereology 2002;16:599-603.
6. Schlesinger N, Katz M, Ingber A. Nail involvement in pemphigus vulgaris. Br J Dermatol 2002;146:836-9.
7. Cooper HL, Healy E, Theaker JM, Friedmann PS. Treatment of resistant pemphigus vulgaris with an anti-CD20 monoclonal antibody (Rituximab). Clin Exp Dermatol 2003;28:366-8.
8. Mimouni D, Nousari CH, Cummins DL, Kouba DJ, David M, Anhalt GJ. Differences and similarities among expert opinions on the diagnosis and treatment of pemphigus vulgaris. Journal of the American Academy of Dermatology 2003;49:1059-62.
9. Payne AS, Ishii K, Kacir S, et al. Genetic and functional characterization of human pemphigus vulgaris monoclonal autoantibodies isolated by phage display. Journal of Clinical Investigation 2005;115:888-99.
10. Shimanovich I, Herzog S, Schmidt E, et al. Improved protocol for treatment of pemphigus vulgaris with protein A immunoadsorption. Clin Exp Dermatol 2006;31:768-74.
11. Eming R, Nagel A, Wolff-Franke S, Podstawa E, Debus D, Hertl M. Rituximab Exerts a Dual Effect in Pemphigus Vulgaris. Journal of Investigative Dermatology 2008;128:2850-8.
12. Chams-Davatchi C, Mortazavizadeh A, Daneshpazhooh M, et al. Randomized double blind trial of prednisolone and azathioprine, vs. prednisolone and placebo, in the treatment of pemphigus vulgaris. Journal of the European Academy of Dermatology and Venereology 2012:no-no.
13. Nast, A. (2016). S2k-Leitlinie: Diagnostik und Therapie des Pemphigus vulgaris / foliaceus und des bullösen Pemphigoids. Awmf.org. Retrieved 31 May 2016, from http://www.awmf.org/leitlinien/detail/ll/013-071.html
14. Lebwohl, Mark. Treatment of Skin Disease: Comprehensive Therapeutic Strategies. Elsevier, 2014. Print.