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Bullous Pemphigoid: Is prednisone the only option?
Wynnie LauPharmacy Resident 2010-2011
Medicine RotationUpdated 14 Nov2010
Outline
• 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/MedsPTA
HTN Felodipine 7.5mg daily
Dyslipidemia Atorvastatin 40mg daily
Osteoarthritis APAP 325 – 650mg prnT#3 q4-6h prn
CVA 2009 resulting in R sided Hemiparesis
ASA 81mg dailyRamipril 5mg BID
Hypothyroid Levothyroxine 75mcg daily
Depression Sertraline 50mg daily
Meds at hospital Same as @ home but Ramipril held
Case of MKVitals BP 112/72 HR88 RR20 O2Sats 96%RA Temp36.7
PE 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 Neut 6.6 Eosino 2.4 HgB 107 INR 1.1 Na 139 K 4.6 SCr 105 Glucose 6.2
Diagnosis17Aug VGH diagnosis: Bullous Pemphigoid (BP)
23Aug 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 immunofluorescencelinear 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 oldin US 10 per 1 million population
Morbidity andmortality
Mortality rate ≤ 40% at 1yearPruritus of lesions, pain of ruptured bullaeEpidermis loss infections/fluid imbalanceMortality 2o to infection
Ref 1, 2, 4
Bullous Pemphigoid
Ref 1
Clinical Presentation Urticarial plaques; vescicles and/or bullaeDistribution generalized ie. Inner thighs, groin, axillae, flexural
Bullous Pemphigoid
Causes Precise reason unknownDrug induced BP (Penicillins & furosemide)
Goal of therapy
Heal existingReduce new formationsInduce 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 corticosteroidsoral 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 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
MK’s DRPs
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 symptomsAdverse effectssurvival 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
Last search performed 10th August 2010Heterogeneous data made difficult to pool results
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 Regression or healing of skin lesions2o outcome QoL, duration of remission, complications, AE
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 10025
GuillaumeBurton
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
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
Guillaume et al. 1993
Prednisone Pred+Aza Pred + Plasma exchange
Controlled N= 31 N = 36 P value
At 1week 39% 44%
NSSNot considered
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
Prednisone Pred + AZA Pred + plasma
Total deaths 5 6 3
Severe (incl .death) 10 15 6
Complications 2o to intervention 4 – cytopenia3 – hepatitis
1 – MI during procedure
Guillaume et al. 1993
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
• 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
Guillaume et al. 1993
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 IFstratified 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
Intervention Moderate n= 153 Extensive n=188
40 g 0.05% clobetasol BID
ComparisonPrednisone 0.5mg/kg po Prednisone 1mg/kg
Outcomes Follow up average 360days
1) Survival2) Disease control at 3wks (# of new blisters)3) Complications
Joly et al. 2002
Joly et al. 2002
Kaplan-Meier estimates of overall survival of pt: p values determined by log rank test
Joly et al. 2002Moderate Extensive
Topical (n=77)
Oral (n=76) P value Topical
(n=93)Oral
(n=96) P value
Pneumonia 8 11
NSS
6 11 NSS
Other severe infection (arthritis, cellulitis, peritonitis or septicemia)
3 5 2 11P = 0.02
Diabetes requiring insulin 2 7 4 13 P =0.04
MI/ cardiac failure 7 6 4 11 NSS
Psychosis/delirium 0 4 0 6 P = 0.03
Stroke 4 4 7 5
NSSDVT/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
Joly et al. 2002Moderate Extensive
Topical
Oral P value Topical Oral P value
Pt with disease regression at 3 wks
100% 94%
NSS
99% 91% P=0.01
Survival rate @ 1yr 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
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– 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
Daily while at hospital
MD, pharmacist
Pneumonia Daily while at hospital
MD, pharmacist
Blood pressure control Daily MD, pharmacist
Blood Glucose control Daily then weekly
MD
References1. Goldstein, BG and Goldstein A. Bullous Pemphigoid and other pemphigoid disorders. UptoDate. Last lit
review May2010. 2. Lipsker Dan and Borradori Luca. Bullous Pemphigoid: what are you? Urgent need of definitions and
diagnostic criteria. Dermatology. 2010. 3. Mutasim, DF. Autoimmune Bullous Dermatoses in the elderly: an update on pathophysiology, diagnosis
and management. Drugs Aging. 2010:27(1):1-19. 4. Zhu Yi, Fitzpatrick JE< Kornfeld BW. Lichen planus pemphigoides associated with ramipril. Int J
Dermatol. 2006 Dec; 45(12):1453-5. 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. 6. Walsh SR, Hogg D, mydlarski PR. Bullous pemphigoid: from bench to bedside. Drugs. 2005; 65(7):905-
26.7. Rzany Berthold et al. Risk factors for lethal outcome in patients with bullous pemphigoid. Arch
Dermatol. 2002; 138: 903-908.8. Kirtschg et al. Interventions for bullous pemphigoid (review). Cochrane Database of Systematic Reviews
2010; 10. 9. Joly et al. A comparison of oral and topical corticosteroids in patients with bullous pemphigoid. NEJM
2002; 346(5):321-7.