Download Bullous Pemphigoid Updated

Bullous Pemphigoid:
Is prednisone the only option?
Wynnie Lau
Pharmacy Resident 2010-2011
Medicine Rotation
Updated 14 Nov2010
Outline
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Case
Background
Clinical Question
Discussion of evidence
Case conclusion/recommendations
Case of MK
ID
78 yo, 75kg, Caucasian male, NKA living at a care centre
CC
Large bullae on left arm, thorax, inner thigh and scrotum
onset 2wks ago
Case of MK
HPI
3 August
First noticed large brownish bulla in left armpit that was
painful and itchy
6 August
MD at care centre prescribes hydrocortisone cr applied BID
10 August MD at care centre dx pt with Herpes Zoster and starts
Acyclovir 800mg 5x/day X 7days
13 August MD at care centre prescribes diphenhydramine allergy crm
applied BID prn
14 August MD at care centre prescribes fucidan 2% cream applied daily
16 August
pt admitted to RCH and dx with bullous impetigo and
started cephalexin 500mg QID + Probenecid 300mg TID
17 August Pt transferred to VGH CTU blue to be consulted by Derm
Case of MK
PMHx/
HTN
MedsPTA Dyslipidemia
Meds at
hospital
Felodipine 7.5mg daily
Atorvastatin 40mg daily
Osteoarthritis
APAP 325 – 650mg prn
T#3 q4-6h prn
CVA 2009 resulting in R
sided Hemiparesis
ASA 81mg daily
Ramipril 5mg BID
Hypothyroid
Levothyroxine 75mcg daily
Depression
Sertraline 50mg daily
Same as @ home but Ramipril held
Case of MK
Vitals BP 112/72
PE
HR88 RR20
O2Sats 96%RA
Temp36.7
CNS
O x3
HEENT
Unremarkable
CV
S1, S2, no murmur, reg HR, no CP, unremarkable JVP
Resp
Bilateral air entry, no SOB
GI/GU
Rash and blisters on abdomen, bullae inner thigh
and scrotum
Extremities large flacid bullae on left arm and thorax; oozing
blood from left arm; rash and blisters on leg and hip
Labs
WBC 11.4
Na 139
Neut 6.6 Eosino 2.4
K 4.6
SCr 105
HgB 107
INR 1.1
Glucose 6.2
Diagnosis
17Aug
23Aug
VGH diagnosis: Bullous Pemphigoid (BP)
Pathology finds linear IgG + C3 deposit along
basement membrane zone from L upper thigh
Bullous Pemphigoid
Definition
Autoimmune blistering disease
Diagnosis
Biopsy required for direct immunofluorescence
linear deposits of C3 along basement membrane
zone found in 100% of pt; IgG found in 65-95%
Ref 1, 2, 4
Bullous Pemphigoid
Epidemiology
Frequently in >65 years old
in US 10 per 1 million population
Morbidity and
mortality
Mortality rate ≤ 40% at 1year
Pruritus of lesions, pain of ruptured bullae
Epidermis loss  infections/fluid imbalance
Mortality 2o to infection
Ref 1, 2, 4
Bullous Pemphigoid
Clinical Presentation Urticarial plaques; vescicles and/or bullae
Distribution generalized ie. Inner thighs, groin,
axillae, flexural
Ref 1
Bullous Pemphigoid
Causes
Precise reason unknown
Drug induced BP (Penicillins & furosemide)
Goal of
therapy
Heal existing
Reduce new formations
Induce remission
Ref 3-5
Bullous Pemphigoid
Drug induced BP
– Reports of 30 medications
– Frequently: diuretics and neuroleptics
– List include ACEi especially captopril, enalapril
– Hypothesis
• Drugs change antigenicity to induce synthesis of
antibodies against basal membrane zone
Ref 5-6
Bullous Pemphigoid
Treatment
Topical corticosteroids
oral corticosteroid (Prednisone 1mg/kg/day)
Azathioprine (2-3mg/kg/d)
Cyclophosphamide (1-2mg/kg/day)
Methotrexate (10-25mg/week)
Cyclosporin (6mg/kg/day)
Ref 3
MK’s DRPs
MK is at risk of adverse events including increased blood
pressure and blood glucose secondary to use of systemic
corticosteroids and would benefit from a reassessment of
his bullous pemphigoid treatment
MK’s DRPs
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MK is at risk for infections secondary to open blisters as a result of his bullous
pemphigoid and would benefit from a reassessment of his bullous pemphigoid treatment
MK is experiencing continued pruritus secondary to his bullous pemphigoid and would
benefit from a reassessment of his bullous pemphigoid treatment
MK is experiencing a 14 day history of worsening rash and blisters secondary to his bullous
pemphigoid and would benefit from a reassessment of his bullous pemphigoid treatment
MK is experiencing continued erythema, blisters and pruritus secondary to improper
treatment with cephalexin for his bullous pemphigoid, an autoimmune disorder and would
benefit from a reassessment of his bullous pemphigoid treatment
MK is experiencing continued erythema, blisters and pruritus secondary to improper
treatment with fusidan cream for his bullous pemphigoid, an autoimmune disorder and
would benefit from a reassessment of his bullous pemphigoid treatment
MK is experiencing continued erythema, blisters and pruritus secondary to improper
treatment with acyclovir for his bullous pemphigoid, an autoimmune disorder and would
benefit from a reassessment of his bullous pemphigoid treatment
MK is at risk of mortality secondary to increased blood pressures due to his held ramipril and
requires close monitoring of his blood pressure treatment
MK is at risk for deep vein thrombosis clot secondary to being bed bound and immobile and
would benefit from a reassessment of his DVT prophylaxis
MK is at risk for a cardiovascular event currently taking a statin and would benefit from an
assessment of his lipid levels
Clinical Question
P
Elderly patient >65 year old newly diagnosed and active bullous
pemphigoid as confirmed by IF studies
I
Systemic corticosteroid
C
Other oral and/or topical treatments
O
Time to resolution of symptoms
Adverse effects
survival rates
Search strategy
• Terms: Bullous Pemphigoid, Pemphigoid,
Prednisone, methotrexate, azathioprine,
cyclophosphamide, cyclosporine
• Limits: Humans
• Databases: PubMED, Medline, EMBASE, Google
– 2 Systematic Review
– RCTs – 10 (5 French)
– Prospective open label – 5
– Retrospective analysis – 4
Review of Evidence
Interventions for bullous pemphigoid (Review)
Kirtschig G, Middleton P, Bennett C, Murrell DF, Wojnarowska F, Khumalo NP
Cochrane Database Systematic Review 2010; 10.
Kirtschig et al. 2010
Studies included 10 RCT, n=1049
Patients
Pt of any age treated for BP (confirmed by IF)
Interventions
Any intervention to treat BP
1o outcome
2o outcome
Regression or healing of skin lesions
QoL, duration of remission, complications, AE
Last search performed 10th August 2010
Heterogeneous data made difficult to pool results
Kirtschig et al.
• Summary
– Starting doses Prednisone >0.75mg/kg/d no added benefit
– Prednisone 0.5mg/kg/d may be adequate for disease control
– Very potent topical steroids effective however use in extensive
disease is limited by practicality and side effects
– Additional azathioprine or MMF efficacy unknown
– Tetracycline + nicotinamide may be useful – further research
Kirtschig et al.
Intervention
Comparator
# of
study
# of pts Study
author
Prednisone 1.25mg/kg
Prednisone 0.75mg/kg
1
50
Morel
Methylprednisolone
Prednisone
1
57
Dreno
Prednisone + azathioprine
Prednisone
2
100
25
Guillaume
Burton
Nicotinamide + tetracycline
Prednisone
1
20
Fivenson
Clobetasol propionate cream Prednisone po
1
341
Joly 2002
Mild clobetasol cream
standard clobetaosol cream
1
312
Joly 2009
Azathioprine +
methylprednisolone
MMF + methylprednisolone
1
73
Beissert
Controlled trial of azathioprine and plasma
exchange in addition to prednisolone in the
treatment of Bullous Pemphigoid
Guillaume JC, Vaillant L, Bernard P, Pieard C, Prost C, Labeille B, Guillot B et al.
Archives of Dermatology 1993; 129:49-53
Guillaume et al 1993
Design
Prospective RCT unblinded Oct 1984–Sept 1989, 4 centers
Patient N=100, avg 75yo, active pemphigoid, hospitalized, skin
biopsy and IF studies to confirm BP
Exclusion: localized disease, corticosteroid or
immunosuppressive drugs in month, contraindications to
study medications
Guillaume et al 1993
Comparison
Group 1: (n=32) Prednisone 1mg/kg x 4wks
↓ q2wks until 0.5mg/kg @ 3mo
↓ 0.2mg/kg @ 6mo
Intervention Group 2: (n=36) Azathioprine 150mg/d (>60kg) or
100mg/d (<60kg) + Prednisone
Group 3: (n=32) 4 large volume Plasma exchange
in first 2 wks + Prednisone
Guillaume et al 1993
Outcomes Follow up – 6months
1) Disease control at 4wks (≤ 1 new blister) &
6months (no new blisters), resolution of erythema
and no more than minimal pruritus
Guillaume et al. 1993
Prednisone
Pred+Aza
Controlled
N= 31
N = 36
At 1week
39%
44%
At 2 week
68%
72%
At 3 week
71%
80.5%
At 4 week
71%
80.5%
At 6 months
42%
39%
Relapse
7
10
Death
5
6
Major S/E (including
death)
10
15
Pred +
Plasma
exchange
P value
NSS
Not
considered
Guillaume et al. 1993
Prednisone
Pred + AZA
Pred + plasma
Total deaths
5
6
3
Severe (incl .death)
10
15
6
4 – cytopenia
3 – hepatitis
1 – MI during
procedure
Complications 2o to intervention
Causes of death
• 4 – Pulmonary embolism
• 2 – Sepsis
• 1 – cerebral stroke
• 1 – acute renal failure
• 1 – respiratory distress
• 1 – wasting syndrome
• 3 – unknown reasons
Overall death rate 14/98
14.3% at 6months
Guillaume et al. 1993
• Summary
– “Benefit, if any, of adding azathioprine/plasma
exchange to Prednisone 1mg/kg is negligible”
– 14/36 Pred vs 13/31 Pred+AZA RR0.93
• Limitations
– Trial stopped at interim
– Only composite outcome reported
A comparison of oral and topical corticosteroids
in patients with Bullous Pemphigoid
Bullous diseases French Study Group
NEJM 2002; 346(5): 321 - 7
Joly et al. 2002
Design
P RCT non-blinded 20 centers in France Jan 1996-Dec 1998
Patient N=341, BP confirmed by IF
stratified to moderate (<10 new blisters/d) and
extensive (>10 new blisters/d) group
Exclusion: predominant mucosal involvement, treatment
with oral/topical corticosteroids, dapsone or
immunosuppressive drugs in previous 6mo
Joly et al. 2002
Intervention
Moderate n= 153
Extensive n=188
40 g 0.05% clobetasol BID
Comparison
Prednisone 0.5mg/kg po
Outcomes
Prednisone 1mg/kg
Follow up average 360days
1) Survival
2) Disease control at 3wks (# of new blisters)
3) Complications
Joly et al. 2002
Kaplan-Meier estimates of overall survival of pt: p values determined by log rank test
Joly et al. 2002
Moderate
Topical
(n=77)
Oral
(n=76)
Pneumonia
8
Other severe infection
(arthritis, cellulitis, peritonitis
or septicemia)
3
Diabetes requiring insulin
2
7
MI/ cardiac failure
7
6
Psychosis/delirium
0
Stroke
Extensive
Topical
(n=93)
Oral
(n=96)
P value
11
6
11
NSS
5
2
11
P value
P = 0.02
4
13
P =0.04
4
11
NSS
4
0
6
P = 0.03
4
4
7
5
DVT/PE
4
6
5
4
Bone fracture
3
3
2
4
Total
35
29
NSS
27
41
P=0.006
Cumulative hospital stay (day)
11
17
P=0.02
17
25
P=0.002
NSS
NSS
Joly et al. 2002
Moderate
Topical
Oral
Pt with disease
regression at 3 wks
100%
Survival rate @ 1yr
Extensive
P value
Topical
Oral
P value
94%
99%
91%
P=0.01
70%
70%
76%
58%
P=0.01
Disease Control 21d
100%
95%
99%
91%
P=0.01
Complications
38%
32%
29%
54%
P=0.006
Disease relapse
35% @
149d
± 118d
39% @
178d
± 109d
37% @
187d
± 118d
46% @
210d
± 133d
NSS
Joly et al. 2002
• Conclusions
– Prednisone 1mg/kg/d had 1yr mortality rate 41%
– In topical treatment – no diff in overall survival
– Pt with extensive BP
• Topical treatment had 43% RRR in 1 year mortality
Joly et al. 2002
• Limitations
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–
–
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Limited AE reported
Inconvenient and costly topical regimen
Compliance not mentioned
Unclear whether new-onset or relapse
Back to MK…
18 Aug
Started 1mg/kg Prednisone x 5d +
clobetasol 0.05% ung BID to affected area
20 Aug
no delirium/agitation on dose
22 Aug
no new lesions/no pain BG 5-7mmol/L
Back to MK…
26 Aug Discharge home
Prednisone 55 mg (0.75mg/kg) +
clobetasol crm for pruritic or new lesions BID prn
Ramipril held to be reassessed (BP~133/71)
27 Aug Decrease to Prednisone 50mg
8 Sept
Follow up with dermatology
Monitoring Plan
Efficacy end points
How often?
Who?
New lesions, bullae,
redness
Daily
Pt, MD, pharmacist,
nurse
Itchiness
Daily
Pt, MD, pharmacist,
nurse
Normalized
eosinophilia
2 weeks
MD, pharmacist, nurse
Disease remission
2 weeks
MD, pharmacist, nurse
Monitoring Plan
Toxicity End points
How often?
Who?
Psychosis/ delirium
Daily while at
hospital
MD, pharmacist,
nurse
Infection, WBC > 15 with
fever
Pneumonia
Daily while at
hospital
Daily while at
hospital
MD, pharmacist
Blood pressure control
Daily
MD, pharmacist
Blood Glucose control
Daily then
weekly
MD
MD, pharmacist
References
1.
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8.
9.
Goldstein, BG and Goldstein A. Bullous Pemphigoid and other pemphigoid disorders. UptoDate. Last lit
review May2010.
Lipsker Dan and Borradori Luca. Bullous Pemphigoid: what are you? Urgent need of definitions and
diagnostic criteria. Dermatology. 2010.
Mutasim, DF. Autoimmune Bullous Dermatoses in the elderly: an update on pathophysiology, diagnosis
and management. Drugs Aging. 2010:27(1):1-19.
Zhu Yi, Fitzpatrick JE< Kornfeld BW. Lichen planus pemphigoides associated with ramipril. Int J Dermatol.
2006 Dec; 45(12):1453-5.
Lee JJ, Downham TF 2nd. Furosemide-induced bullous pemphigoid: case report and review of literature. J
Drugs Dermatol. 2006 June; 5(6):562-4.
Walsh SR, Hogg D, mydlarski PR. Bullous pemphigoid: from bench to bedside. Drugs. 2005; 65(7):905-26.
Rzany Berthold et al. Risk factors for lethal outcome in patients with bullous pemphigoid. Arch
Dermatol. 2002; 138: 903-908.
Kirtschg et al. Interventions for bullous pemphigoid (review). Cochrane Database of Systematic Reviews
2010; 10.
Joly et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. NEJM
2002; 346(5):321-7.