Bullous Pemphigoid Is prednisone the only option Wynnie
Bullous Pemphigoid: Is prednisone the only option? Wynnie Lau Pharmacy Resident 2010 -2011 Medicine Rotation 8 September 2010
Outline • • • Case Background Clinical Question Discussion of evidence Case conclusion/recommendations
Case of MK ID 78 yo Caucasian male, NKA living at a care centre CC Large bullae on left arm, thorax, inner thigh and scrotum – onset 2 wks 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 800 mg 5 x/day X 7 days 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 500 mg QID + Probenecid 300 mg TID 17 August Pt transferred to VGH CTU blue to be consulted by Derm
Case of MK PMHx/ HTN Meds. PTA Dyslipidemia Meds at hospital Felodipine 7. 5 mg daily Atorvastatin 40 mg daily Osteoarthritis APAP 325 – 650 mg prn T#3 q 4 -6 h prn CVA 2009 resulting in R sided Hemiparesis ASA 81 mg daily Ramipril 5 mg BID Hypothyroid Levothyroxine 75 mcg daily Major Depressive Disorder Sertraline 50 mg daily Same as @ home but Ramipril held
Case of MK Vitals BP 112/72 PE HR 88 RR 20 O 2 Sats 96%RA Temp 36. 7 CNS O x 3 HEENT Unremarkable CV S 1, S 2, 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 Na 139 NEUT 6. 6 Eosino 2. 4 K 4. 6 SCr 105 Hg. B 107 INR 1. 1 Glucose 6. 2 Albumin
Diagnosis • 17 Aug @ VGH dx Bullous Pemphigoid – Started clobetasol 0. 05% ung applied BID to AA and Prednisone 90 mg (1 mg/kg) • 23 August pathology confirmed dx with linear Ig. G + C 3 deposit along basement membrane zone from L upper thigh
Bullous Pemphigoid Definition Autoimmune blistering disease Diagnosis Bx required for direct immunofluorescence to find linear deposits of C 3 along basement membrane zone found in 100% of pt; ig. G found in 65 -95% Epidemiology Frequently in >65 years old in US 10 per 1 million population Clinical Presentation Urticarial plaques; vescicles and/or bullae Distribution generalized ie. Inner thighs, groin, axillae, flexural Morbidity/mortality Pruritus of urticarial lesions Pain in areas of ruptured bullae lose protective epidermis infections/ fluid imbalance Mortality often 2 o to infection Ref 1 -2
Bullous Pemphigoid Ref 1
Bullous Pemphigoid Causes Goal of therapy Precise reason unknown Drug induced BP (Penicillins & furosemide with rare cases of captopril) Heal existing lesions Reduce blister formation, urticarial lesions & pruritus Prevent 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 corticosteroids oral corticosteroid (Prednisone 1 mg/kg/day) Azathioprine (2 -3 mg/kg/d) Cyclophosphamide (1 -2 mg/kg/day) Methotrexate (10 -25 mg/week) Cyclosporin (6 mg/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 symptoms Adverse effects survival rates
Search strategy • Terms: Bullous Pemphigoid, Prednisone, methotrexate, azathioprine, cyclophosphamide, cyclosporine • Limits: Humans • Databases searched: Pub. MED, Medline, EMBASE – 1 Systematic Review – RCTs – 7 (5 French) – Open label prospective – 5 (1 German) – Retrospective analysis – 4 – Case report – 2
Summary Reference #of pt Type of Study Age (range) yrs Kjellman P et al 98 Retrospective 83 (N/A) Mtx, Mtx+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 None Mc. Cluskey et al 17 Retrospective 73 (63 -81) 77 (61 -93) Concomitant Dap/Aza/Cyclo/Pred/cy clophosphamide/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 - 5 mg/wk + folic acid 5 mg on the other 6 days + topical betamethasone dipropionate BID until disease controlled; if insufficient - ↑ by 2. 5 mg/wk tapered when disease was controlled Comparison 1. MTX + Prednisone – started similar to intervention with 10 -20 mg/d Prednisone added until disease controlled 2. Prednisone – 40 -80 mg/d 3. Topical Betamethasone gel – mild BP who responded w/in a wk Outcomes MTX + Pred Remission Rate @ 24 mo (%) 43 35 Median tx time (months) 11 20 Pred 0 Topical P value 83 <0. 001 4 <0. 001
Kjellman et al • 145 pt dx – 7 lost to follow up and excluded • 138 pt incl – 98 began MTX w median 5 mg/wk dose • 61 continued with MTX mono-therapy – Weekly median 5 mg (2. 5 -17. 5 mg) – Median cumulative dose 280 mg (15 -3280 mg) • 37 given MTX + prednisone – Median weekly 6 mg (2. 5 -15 mg) – Median cumulative dose 440 mg (30 -2250 mg)
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 (2 GIT, 1 anemia in 3 weeks, 1 ↑ liver enzymes, 1 alveolitis) – 25 used betamethasone gel only due to mild disease
Kjellman et al %men Mean age (years) Moderate (10 -50 blisters) Blood eosinophils before tx Days in hospital Kjellman et al MK 42. 8% Male 81 78 38. 4% Moderate 1300/mc. L (median, in 50. 9% of pt) 2400/mc. L 10 (median, 0 -81 d) 9
Kjellman et al
Kjellman et al - Results
Kjellman et al conclusions • Low dose MTX + topical betamethasone safe and effective (maximum, MTX 12. 5 mg/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-J Arch 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 -3 weeks + with po/IM MTX 7. 5 mg/wk (<60 kg) or 10 mg/wk (≥ 60 kg) 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 -10 months 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 8 months and 13 able to stop after • Adverse events – 5 patients weary after 3 months w/o significant liver test disruptions – Asymptomatic Hg. B decrease in 6 pts • 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 Hg. B decrease observed in 6/18 • 8 -10 mo 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
Summary Prednisone Methotrexate Dosing 0. 75 mg/kg – 1 mg/kg ≤ 12. 5 mg/wk (starting at 5 mg/wk and titrating up by 2. 5 mg/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 <15 m. L/min Evidence Clinical response within 1 -2 weeks from RCTs Lack of RCT Summary Effective and safe but limited by At low doses can be considered the high dosages required in for moderate to moderately extensive BP severe disease
Back to MK… 18 Aug Started 1 mg/kg Prednisone x 5 d + clobetasol 0. 05% ung BID to affected area 20 Aug no delirium/agitation on dose 22 Aug no new lesions/no pain BG 5 -7 mmol/L 26 Aug discharged home on prednisone 60 mg clobetasol for pruritis lesions or if new lesions applied BID prn Ramipril was not restarted as BP was ~133/71 27 April Decrease to 50 mg 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
References 1. 2. 3. 4. 5. 6. 7. 8. 9. Goldstein, BG and Goldstein A. Bullous Pemphigoid and other pemphigoid disorders. Upto. Date. Last lit review May 2010. 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 2 nd. 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. Kjellman P, Eriksson H, Berg P. A retrospective analysis of patients with bullous pemphigoid treated with methotrexate. Arch Dermatol 2008; 144(5): 612 -616 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 al Design Prospective, noncomparative, open label, single centre Patients 11 pt dx with generalized BP 1996 -1997, consecutively chosen, >70 yo, unresponsive to topical betamethasone BID X 1 wk Intervention MTX 5 mg/wk + betamethasone dipropionate topical daily X 1 -2 wks then prn; MTX increased 2. 5 mg/wk if >2 new blisters/wk (max MTX 15 mg/wk) Comparison None Outcomes @ 24 mo: 7/11 patients in remission and 2 requiring ongoing tx
Heilborn et al
Heilborn et al MK 36. 4% Male 81 78 Severity Unknown Moderate 10 -50 Blisters Blood eosinophils before tx 1600/mc. L 2600/mc. L 129. 6 111 %men Mean age (years) Hg. B before MTX
Heilborn et al - results
Heilborn et al • Side effects – 2 pt died w/o indication MTX was cause – Decrease Hg. B 20 -35% in 5 patients obs in 1 st wk which normalized over time w/o change in MTX – 1 nausea & lack of appetite given folic acid 6 d/wk – 1 given abx because of erysipelas during beginning of mtx w/o drop in WBC to suggest MTX cause
- Slides: 42