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.