Revision de Dynamed: Pemphigus vulgaris

En esta edición les ofrecemos una revision tomada de Dynamed sobre Penfigo asimismo una revision tomada de Pubmed con 390 resumenes de artículos sobre Penfigo Vulgar en los últimos dos años.

Revision de Dynamed

Pemphigus vulgaris

Diagnosis

• history and physical, IgG (and C3) on cell membranes by direct immunofluorescence – perilesional skin biopsy, indirect immunofluorescence of serum for circulating Ab

Rule out:

• drug-induced (penicillamine, captopril, rifampin)
• toxic epidermal necrolysis
• Stevens-Johnson syndrome
• paraneoplastic pemphigus; removal of localized hyaline vascular-type Castleman's tumor in 6 patients with paraneoplastic pemphigus led to resolution of cutaneous lesions in 6-11 weeks and mucosal lesions in 5-10 months (Lancet 2004 Feb 14;363(9408):525  
• Testing to consider:

• skin biopsy for histology and direct immunofluorescence, serum for indirect immunofluorescence

Blood tests:

• 80-90% + IgG (indirect immunofluorescence)
• desmoglein 3-ELISA had 90% sensitivity and 91% specificity in series of 97 patients with skin diseases (Arch Dermatol 1999 Feb;135(2):143 in JAMA 1999 Jun 2;281(21):1970v), summary can be found in Am Fam Physician 1999 Jul;60(1):273, editorial can be found in Arch Dermatol 1999 Feb;135(2):195, commentary can be found in Arch Dermatol 1999 Nov;135(11):1418

Pathology tests:

• intraepidermal acantholysis, severe intraepidermal bullae, sparing of basal layer ("row of tombstone appearance")

Other diagnostic testing:

• detached keratinocytes in Tzanck prep (acanthocytes)

Prognosis:

• 60-90% mortality before steroids, now 5-15%
• paraneoplastic pemphigus tends to be rapid and fatal despite immunosuppressive therapy (Mayo Clin Proc 1994 Sep;69(9):851)

Treatment overview:

• local skin care, treat like burn patients to prevent infections

Medications:

• sublesional steroids were sufficient (sparing need for systemic steroids or immunosuppressive agents) in 8 of 18 patients > 65 years old followed 3-15 years (J Am Geriatr Soc 1998 Jan;46(1):92)
• steroid-sparing immunosuppressives are mainstay of treatment

• options include azathioprine, cyclophosphamide, dapsone, mycophenolate mofetil
• azathioprine and mycophenolate mofetil may have similar efficacy and corticosteroid-sparing effects  

• based on unblinded randomized trial with non-significant trend
• 33 patients with pemphigus vulgaris and 7 patients with pemphigus foliaceus were treated with oral methylprednisolone 2 mg/kg/day and randomized to azathioprine (Imurek) 2 mg/kg once daily vs. mycophenolate mofetil (CellCept) 1,000 mg twice daily
• after blister formation ceased, crusts and erosions disappeared and reepithelialization of previous lesions started, then methylprednisolone was tapered
• after methylprednisolone was discontinued, then azathioprine or mycophenolate mofetil was tapered and ultimately discontinued
• therapy increased or restarted if new blister formation
• comparing azathioprine vs. mycophenolate mofetil

• 100% vs. 100% had inhibition of disease progression within 30 days
• 72% vs. 95% had complete healing of lesions (NNT 5 favoring mycophenolate mofetil but not statistically significant)
• mean time to complete remission 74 vs. 91 days (not significant)
• mean time from complete remission to recurrence of lesions 258 vs. 123 days (not significant)
• median cumulative steroid dose 8,916 vs. 9,334 mg (not significant)
• 33% vs. 19% grade 3 (severe) or 4 (life-threatening) adverse effects (not significant)

• Reference – Arch Dermatol 2006 Nov;142(11):1447

• steroid pulse therapy may not be effective

• oral dexamethasone 300 mg for 3 days per month no more effective than placebo in patients on conventional treatment

• 20 patients with pemphigus vulgaris treated with prednisolone 80 mg/day tapered over 19 weeks and azathioprine 3 mg/kg/day were randomized to oral dexamethasone 300 mg vs. placebo for 3-day pulses every month
• 8 of 11 dexamethasone vs. 9 of 9 placebo patients had remission
• no differences in mean time to remission (173 vs. 176 days) or mean duration of remission within first year (151 vs. 141 days)
• weight gain > 5% occurred in 8 of 11 dexamethasone vs. 1 of 9 placebo patients
• Reference – PEMPULS trial (Arch Dermatol 2006 May;142(5):570)

• high-dose pulse therapy with glucocorticoids might produce long-lasting benefits , based on retrospective study of 9 patients with pemphigus vulgaris treated with very high dose IV methylprednisolone sodium succinate (Solu-Medrol) and 6 patients not treated with pulse therapy (Arch Dermatol 1996 Dec;132(12):1435 in Am Fam Physician 1997 Apr;55(5):1924), commentary can be found in Arch Dermatol 1996 Dec;132(12):1499

• intravenous immunoglobulin (IVIG) not recommended due to very limited and conflicting evidence 

• IVIG 400 mg/kg/day for 5 days plus cyclophosphamide 100-150 mg/day led to > 80% reduction in skin lesions within 2 weeks in 5 of 6 patients with pemphigus vulgaris unresponsive to conventional therapy with high-dose steroids (J Am Acad Dermatol 2002 Sep;47(3):358 in JAMA 2002 Nov 27;288(20):2520)
• IVIG reported to be ineffective in small series (; retrospective series of 7 patients with pemphigus vulgaris treated with IVIG, 1 had partial response and 6 had no response (Mayo Clin Proc 2005 Jan;80(1):41  IVIG costs about $40-$55 per gram, plus cost of administration (The Medical Letter 2006 Dec 4/18;48(1249/1250):101)
• use of IV immunoglobulin (IVIG) not recommended (University HealthSystem Consortium guidelines on IVIG preparations which were withdrawn from National Guideline Clearinghouse on 2004 Dec 20 as no longer current)
• expert consensus statement on use of IVIG in treatment of autoimmune mucocutaneous blistering diseases can be found in Arch Dermatol 2003 Aug;139(8):1051 (JAMA 2003 Nov 5;290(17):2240)

• rituximab (anti-CD20 monoclonal antibody) associated with clinical response in 3 patients with refractory pemphigus vulgaris ((Arch Dermatol 2004 Jan;140(1):91 in JAMA 2004 Apr 28;291(16):1944)
• combination of rituximab and IVIG reported to be effective) in 9 of 11 patients (N Engl J Med 2006 Oct 26;355(17):1772), commentary can be found in N Engl J Med 2007 Feb 1;356(5):521

Prevention and Screening

• not applicable

Reviews:

• review of pemphigus can be found in Lancet 2005 Jul 2;366(9479):61  review of pemphigus can be found in JAMA 1999 Aug 11;282(6):572
• review of autoimmune bullous dermatoses can be found in Am Fam Physician 2002 May 1;65(9):1861
• review of autoimmune bullous (blistering) diseases can be found in Am Fam Physician 1997 Jun;55(8):2709
• review can be found in Lancet 1999 Aug 21;354(9179):667  
• case presentation can be found in J Fam Pract 2004 Dec;53(12):981  correction can be found in J Fam Pract 2005 Jan;54(1):36, commentary can be found in J Fam Pract 2005 Apr;54(4):355