Cochrane Review
Bullous Pemphigoid
Gudula Kirtschig, MD
Dermatologist
Bullous Pemphigoid
Blistering of the skin in the elderly
Incidence: at least 6 new cases per
1.000.000 per year in Western Europe
Mortality without treatment: 24% at 1y
Mortality with treatment: 20 40% at 1y
Bullous Pemphigoid
Oral Corticosteroid Treatment
Oral corticosteroids will suppress the blistering,
but probably not alter the duration of disease
Problem:
high doses and long-term medium doses are
associated with potentially severe morbidity
and possibly increased mortality
Bullous Pemphigoid Treatment
with oral Corticosteroids
Steroid associated adverse effects
Weight gain
Hypertension
Diabetes mellitus
Infections
Osteoporosis
Bullous Pemphigoid Treatment
Addition of various drugs to reduce adverse effects of
oral steroids
Immunosuppressants / cytotoxic drugs
Azathioprine
Cyclosporin
Methotrexate
Mycophenolate mofetil
Plasma exchange
Anti-inflammatory drugs
Dapsone
Tetracyclines / erythromycin / nicotinamide
Are they steroid sparing ?
A Cochrane systematic review was
performed to assess the effects of
treatment in Bullous Pemphigoid
Systematic literature search in 2003: 7 RCTs (634 patients)
Review up-date in 2005: no new RCT
Publication of 8th RCT in 2007 (73 patients)
Review up-date planned for 2008
Comparisons
lower vs higher doses of corticosteroids
different types of corticosteroids
corticosteroids vs corticosteroids + azathioprine
corticosteroids vs cortico. + plasma exchange
azathioprine + cortico. vs MMF + cortico.
corticosteroids vs tetracycline + nicotinamide
corticosteroids vs very potent topical steroids
Morel 1984, not blinded
prednsiolone 0.75 vs prednsiolone 1.25 mg/kg
24/26 vs 22/24 patients
Follow-up: 51 days
Outcome: disease control (new blisters)
Result: no sign. difference in effectiveness
Deaths: 2/24 and 3/22
no higher dose than 0.75mg/kg/day
Dreno 1993, double blind
prednisolone 1.16 vs methylprednisolone 1.17mg/kg
(1.46mg/kg pred)
29 vs 28 patients
Follow-up: 10 days
Outcome: disease control (blisters, itch)
Results: large reduction in blisters,
no difference between groups
Deaths: none (only 10 days follow up)
Burton 1978, not blinded
azathioprine + prednisone vs prednisone
(2.5mg/kg aza + 30-80mg pred)
12 vs 13 patients
Follow-up: 3 years
Outcome: - ? disease control
- cumulative pred dose
Results:
- disease control 9/12 vs 9/13
- 45% reduction of pred in aza group
Deaths: 3/12 vs 4/13 (together 28% at 3 years)
Guillaume 1993, not blinded
azathioprine + prednisolone vs prednsiolone
(100 150mg/d + 1mg/kg, 0.5mg/kg at 3m, 0.2mg/kg at 6m)
36/36 vs 31/32 patients
Follow-up: 6 months
Outcome: disease control (no new blisters for 4 wks)
Result: 14/36 vs 13/31: no difference in effectiveness
Deaths: 6/36 vs 5/31 at 6 months
(more severe complications in azathioprine group)
Beissert 2007, not blinded
azathioprine 2mg/kg + methylprednisolone 0.5mg/kg vs
mycophenolate mofetil 2g/d + methylpred (0.6mg/kg pred)
38 vs 35 patients
Follow-up: 720 days (circa 2 years)
Outcome: (1) disease control
Results:
Deaths:
(2)
cumulative steroid dose
(1)
remission in all after 24d 19 vs 42d 55
(2)
cum steroid dose 4967mg12191 vs 5754mg9693
2/37 (1 lost for follow-up) vs 0/35
severe AE 9/38 vs 6/35
No statistically significant difference between groups
Roujeau 1984, not blinded
plasmapheresis + prednsiolone 0.3 mg/kg vs
prednsiolone 0.3 mg/kg
22/24 vs 15/17 patients
Follow-up: 6 months
Outcome: disease control (no new blisters) at 1 month
Results: 0.3mg/kg
13/22 vs 0/15
1mg/kg
21/22 vs 8/15
Control with less than of total pred dose in PE group: significant
Deaths: none; similar AE profile
Guillaume 1993, not blinded
plasma exchange + prednisolone vs prednsiolone 1mg/kg
31/32 vs 31/32 patients
Follow-up: 6 months
Outcome: disease control (no new blisters for 4 wks)
Result: 9/31 vs 13/31
Deaths: 3/31 vs 5/31
severe AE including deaths 6/31 vs 10/31
no advantage of additional plasma exchange
Guillaume 1993, not blinded
azathioprine (100-150mg) + prednsiolone vs
plasma exchange + prednisolone (1mg/kg)
36 vs 31/32 patients
Follow-up: 6 months
Outcome: disease control (no new blisters for 4 wks)
Result: 14/36 vs 9/31 at 6 months
Deaths: 6/36 vs 3/31 at 6 months
Total AE 15/36 vs 6/31 including deaths: almost stat. significant
Joly 2002, not blinded
moderate disease: 10 new blisters / day
40mg/d clobetasol propionate cream vs
prednisone 0.5mg/kg/d
77 vs 76 patients
Follow-up: 1 year
Outcome:
(1) survival
Results:
(1) 70% vs 70%
severe AE 32% vs 38%
(2) disease control at 3 wks
(2) 100% vs 94%
Joly 2002, not blinded
extensive disease: > 10 new blisters / day
40mg/d clobetasol propionate cream vs
prednisone 1.0mg/kg/d
93 vs 95 patients
Follow-up: 1 year
Outcome:
(1) survival
(2) disease control at 3 wks
Results:
(1) 76% vs 58%: significant
severe AE 29% vs 54%
(2) 99% vs 91%: significant
Fivenson 1994, not blinded
Prednisone vs nicotinamide + tetracycline
(40-80mg vs 1.5g + 2g)
6 vs 14 patients
Follow-up: 10 months
Outcome: disease control at 8 wks (blisters, itch)
Results at 8 wks: 1 complete, 5 partial (6/6) vs
5 com, 5 par (10/14), 1 non, 1 progression, 2 lost
Deaths: 1 vs 0 (more severe AE in pred group)
Conclusions
Very potent topical steroids are effective and
seem safe
(their use in extensive BP may be limited by
side effects, costs, and practical factors)
Starting doses of prednisolone greater than
0.75mg/kg/day do not seem to give additional
benefit
Conclusions
The effectiveness of the addition of plasma
exchange or azathioprine to syst. steroids has
not been established
No difference in efficacy comparing
azathioprine and mycophenolate mofetil (in
combination with steroids)
Combination treatment with tetracycline and
nicotinamide may be useful although this needs
further validation
Co-workers
N. Khumalo, South Africa
G. Kirtschig, Netherlands
S. Hollis, UK
P. Middleton, Australia
D. Murrell, Australia
F. Wojnarowska, UK
What to do next?
Starting doses of prednisolone
greater than 0.75 mg/kg/day do not
seem to give additional benefit
Combination treatment with
tetracycline and nicotinamide may
be useful although this needs further
validation
A 9th RCT!
