Bullous Pemphigoid: Is prednisone the only option?

Wynnie LauPharmacy Resident 2010-2011

Medicine Rotation8 September 2010

Outline

• Case• Background• Clinical Question• Discussion of evidence• Case conclusion/recommendations

Case of MKID 78 yo Caucasian male, NKA living at a care centre

CC Large bullae on left arm, thorax, inner thigh and scrotum – onset 2wks

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 cream 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 MKPMHx/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

Major Depressive Disorder 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 L arm, and thorax oozing blood from upper and lower 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 Albumin

Diagnosis

• 17 Aug @ VGH dx Bullous Pemphigoid– Started clobetasol 0.05% ung applied BID to AAand Prednisone 90mg (1mg/kg)

• 23 August pathology confirmed dx with linear IgG + C3 deposit along basement membrane zone from L upper thigh

Bullous PemphigoidDefinition Autoimmune blistering disease

Diagnosis Bx required for direct immunofluorescence to find linear deposits of C3 along basement membrane zone found in 100% of pt; igG found in 65-95%

Epidemiology Frequently in >65 years oldin US 10 per 1 million population

Clinical Presentation Urticarial plaques; vescicles and/or bullaeDistribution generalized ie. Inner thighs, groin, axillae, flexural

Morbidity/mortality Pruritus of urticarial lesions Pain in areas of ruptured bullaelose protective epidermis infections/ fluid imbalanceMortality often 2o to infection Ref 1-2

Bullous Pemphigoid

Ref 1

Bullous Pemphigoid

Causes Precise reason unknownDrug induced BP (Penicillins & furosemide with rare cases of captopril)

Goal of therapy

Heal existing lesions Reduce blister formation, urticarial lesions & pruritusPrevent appearance of new lesions

Ref 3-5

Bullous Pemphigoid

Drug induced BP– Approximately 30 medications suspected in past– Frequently involve diuretics and neuroleptic drugs– Among the list include ACE inhibitors especially

captopril, enalapril – Hypothesized that drugs may 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 death secondary to long term 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

Clinical Question

P Elderly patient >65 year old diagnosed with Bullous Pemphigoid

I Systemic corticosteroid

C Other oral treatments

O Time to resolution of symptomsAdverse effectssurvival rates

Search strategy• Terms: Bullous Pemphigoid, Pemphigoid,

Prednisone, methotrexate, azathioprine, cyclophosphamide, cyclosporine

• Limits: Humans• Databases searched: PubMED, Medline, EMBASE

– 1 Systematic Review– RCTs – 7 (5 French)– Open label prospective – 5 (1 German)– Retrospective analysis – 4 – Case report – 2

SummaryReference #of

ptType of Study Age (range)

yrsConcomitant

Kjellman P et al 98 Retrospective 83 (N/A) Mtx, Mtx+Pred, Pred, Topical corticosteroid

Downham and chapel

9 Retrospective 68 (27-87) Pred

Bohm and Bauer 3 Prospective 74 (N/A) Pred

Heilborn et al 11 Prospective 81 (73-91) None

Bara et al 16 Prospective 84 (N/A) None

Paul et al 8 Retrospective 73 (63-87) Pred

Dereure et al 18 Prospective 77 (61-93) None

McCluskey et al 17 Retrospective 73 (63-81) Dap/Aza/Cyclo/Pred/cyclophosphamide/none

Review of Evidence

A retrospective analysis of patients with bullous pemphigoid treated with methotrexate

Petra Kjellman, Hanna Eriksson, Peter Berg

Arch Dermatol 2008; 144(5):612-616

Ref 8

Kjellman et al Design Retrospective study, Single Centre

Patients All pt dx with BP between Jan 1999 – Dec 2003 (inclusive)

Intervention 1. MTX - 5mg/wk + folic acid 5mg on the other 6 days + topical betamethasone dipropionate BID until disease controlled; if insufficient - ↑ by 2.5mg/wktapered when disease was controlled

Comparison 1. MTX + Prednisone – started similar to intervention with 10-20mg/d Prednisone added until disease controlled

2. Prednisone – 40-80mg/d3. Topical Betamethasone gel – mild BP who responded w/in a wk

Outcomes MTX MTX + Pred Pred Topical P value

Remission Rate @ 24mo (%) 43 35 0 83 <0.001

Median tx time (months) 11 20 4 <0.001

Kjellman et al

• 145 pt dx – 7 lost to follow up and excluded• 138 pt incl – 98 began MTX w median 5mg/wk dose• 61 continued with MTX mono-therapy

– Weekly median 5mg (2.5-17.5mg)– Median cumulative dose 280mg (15-3280mg)

• 37 given MTX + prednisone– Median weekly 6mg (2.5-15mg)– Median cumulative dose 440mg (30-2250mg)

Kjellman et al

• 40 pt did not receive MTX– 15 – treated with HD prednisone alone

• 4 patients had anemia/renal insufficiency• 1 already taking cytotoxic drugs• 5 due to MD preference• 5 d/c MTX due to AE (2GIT, 1 anemia in 3 weeks, 1 ↑ liver

enzymes, 1 alveolitis)

– 25 used betamethasone gel only due to mild disease

Kjellman et al

Kjellman et al MK

%men 42.8% Male

Mean age (years) 81 78

Moderate (10-50 blisters) 38.4% Moderate

Blood eosinophils before tx 1300/mcL (median, in 50.9% of pt) 2400/mcL

Days in hospital 10 (median, 0-81d) 9

Kjellman et al

Kjellman et al - Results

Kjellman et al conclusions • Low dose MTX + topical betamethasone safe and

effective (maximum, MTX 12.5mg/wk)• Topical tx alone sufficient for mild • MTX did not reduce expected life span• AE includes

– 2 GIT irritation – after first dose– 1 Transient alveolitis – after 3 wks– 1 anemia– 1 increased liver enzyme levels

Kjellman et al

• Limitations– Retrospective study– Relation between severity of disease and time to

remission could not be proved significant due to low #s

– Higher hospital admission days in MTX+Pred reflects low # of pt with mild disease in group

– Unable to identiy spectrum of responders, partial responders and nonresponders or duration of therapy in each of groups nor % distribution

Treatment of Bullous Pemphigoid by Low-Dose Methotrexate Associated with short term potent topical steroids: an open prospective study of 18 cases

Dereure, O; Bessis D; Guillot B; Guilhous J-JArch Dermatol 2002; 138

Ref 9

Dereure et al

Design Prospective, noncomparative, open, single centre

Patients 18 pt dx with generalized BP

Intervention Initial whole body topical with clobetasol for 2-3weeks + with po/IM MTX 7.5mg/wk (<60kg) or 10mg/wk (≥60kg)

Comparison None

Outcomes Followed for at least 6 months All achieved clinical response with initial clobetasol and 17 continued on MTX monotherapy with d/c after 6-10months in 13 pt 4 pt continued with MTX monotherapy (3-4 months in process)

Dereure et al - Results

Dereure et al conclusions

• 17 pt – maintained on MTX monotherapy for 8months and 13 able to stop after

• Adverse events– 5 patients weary after 3 months w/o significant

liver test disruptions– Asymptomatic HgB decrease in 6pts

• 10/16 showed disappearance of immune deposits done 2 mo after remission

Dereure et al- conclusions

• Clobetasol topical + MTX with MTX continued• Good tolerance overall at 8 months with

asymptomatic HgB decrease observed in 6/18• 8-10mo MTX to obtain persistent remission

Dereure et al

• Limitations– Small study– Unknown degree of disease severity– Non-comparative – Unknown disease severity of patients involved– Total duration needed to achieve long last

response unknown

SummaryPrednisone Methotrexate

Dosing 0.75mg/kg – 1mg/kg ≤12.5mg/wk (starting at 5mg/wk and titrating up by 2.5mg/wk prn)

Adverse Events Diabetes mellitus, HTN, osteoporosis, cataracts, glaucoma, infections

N/V, stomatitis, reversible alopecia with low doses

Drug Interactions NSAID, warfarin, antidiabetic, antacids

NSAID, ASA, sulfonamides, tetracycline, PHN

Monitoring New lesions Cannot use in <15mL/min

Evidence Clinical response within 1-2 weeks from RCTs

Lack of RCT

Summary Effective and safe but limited by the high dosages required in extensive BP

At low doses can be considered for moderate to moderately severe disease

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

26 Aug discharged home on prednisone 60mg clobetasol for pruritis lesions or if new lesions applied BID prnRamipril was not restarted as BP was ~133/71

27 April Decrease to 50mg Prednisone

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?

Nausea/vomiting Daily MD, pharmacist, nurse

Hemoglobin drop by 20% Weekly MD, pharmacist

Stomatitis Weekly MD, pharmacist

Renal function Weekly MD, pharmacist

Hepatotoxicity Weekly for first 4 weeks then monthly

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. Kjellman P, Eriksson H, Berg P. A retrospective analysis of patients with bullous pemphigoid treated with

methotrexate. Arch Dermatol 2008; 144(5):612-616 9. Dereure O et al. Treatment of Bullous Pemphigoid by Low-Dose Methotrexate Associated with short

term potent topical steroids: an open prospective study of 18 cases. Arch Dermatol 2002; 138

Low dose oral pulse methotrexate as monotherapy in elderly patients with bullous pemphigoid

Johan Heilborn, Mona Stahle – Backdahl, Freidun Albertioni, Ismini Vassilaki, Curt Peterson, Eija Stephansson

J am acad Dermatol 1999; 40:741-9

Heilborn et alDesign Prospective, noncomparative, open label, single centre

Patients 11 pt dx with generalized BP 1996-1997, consecutively chosen, >70yo, unresponsive to topical betamethasone BID X1wk

Intervention MTX 5mg/wk + betamethasone dipropionate topical daily X1-2wks then prn; MTX increased 2.5mg/wk if >2 new blisters/wk (max MTX 15mg/wk)

Comparison None

Outcomes @ 24mo: 7/11 patients in remission and 2 requiring ongoing tx

Heilborn et al

Heilborn et al

Heilborn et al MK

%men 36.4% Male

Mean age (years) 81 78

Severity Unknown Moderate10-50 Blisters

Blood eosinophils before tx 1600/mcL 2600/mcL

HgB before MTX 129.6 111

Heilborn et al - results

Heilborn et al

• Side effects – 2 pt died w/o indication MTX was cause– Decrease HgB 20-35% in 5 patients obs in 1st wk

which normalized over time w/o change in MTX– 1 nausea & lack of appetite given folic acid 6d/wk– 1 given abx because of erysipelas during beginning

of mtx w/o drop in WBC to suggest MTX cause