Bullous Pemphigoid: Is prednisone the only option?

1. Bullous Pemphigoid: Is prednisone the only option? Wynnie LauPharmacy Resident 2010-2011Medicine Rotation Updated 14 Nov2010

2. Outline • Case • Background • Clinical Question • Discussion of evidence • Case conclusion/recommendations

3. Case of MK

4. Case of MK

5. Case of MK

6. Case of MK

7. Diagnosis

8. Bullous Pemphigoid Ref 1, 2, 4

9. Bullous Pemphigoid Ref 1, 2, 4

10. Bullous Pemphigoid Ref 1

11. Bullous Pemphigoid Ref 3-5

12. 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

13. Bullous Pemphigoid Ref 3

14. 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

15. MK’s DRPs • 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

16. Clinical Question

17. 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

18. Review of Evidence

19. Interventions for bullous pemphigoid (Review) Kirtschig G, Middleton P, Bennett C, Murrell DF, Wojnarowska F, Khumalo NP Cochrane Database Systematic Review 2010; 10.

20. Kirtschig et al. 2010 Last search performed 10th August 2010 Heterogeneous data made difficult to pool results

21. 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

22. Kirtschig et al.

23. 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

24. Guillaume et al 1993

25. Guillaume et al 1993

26. Guillaume et al 1993

27. Guillaume et al. 1993

28. 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

29. 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

30. A comparison of oral and topical corticosteroids in patients with Bullous Pemphigoid Bullous diseases French Study Group NEJM 2002; 346(5): 321 - 7

31. Joly et al. 2002

32. Joly et al. 2002

33. Joly et al. 2002 Kaplan-Meier estimates of overall survival of pt: p values determined by log rank test

34. Joly et al. 2002

35. Joly et al. 2002

36. 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

37. Joly et al. 2002 • Limitations • Limited AE reported • Inconvenient and costly topical regimen • Compliance not mentioned • Unclear whether new-onset or relapse

38. Back to MK…

39. Back to MK…

40. Monitoring Plan

41. Monitoring Plan

42. References • 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.