Bullous Pemphigoid: Is prednisone the only option?

1. Bullous Pemphigoid: Is prednisone the only option? Wynnie LauPharmacy Resident 2010-2011Medicine Rotation 8 September 2010

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. Diagnosis • 17 Aug @ VGH dx Bullous Pemphigoid • Started clobetasol 0.05% ung applied BID to AA and Prednisone 90mg (1mg/kg) • 23 August pathology confirmed dx with linear IgG + C3 deposit along basement membrane zone from L upper thigh

7. Bullous Pemphigoid Ref 1-2

8. Bullous Pemphigoid Ref 1

9. Bullous Pemphigoid Ref 3-5

10. 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

11. Bullous Pemphigoid Ref 3

12. 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

13. Clinical Question

14. 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

15. Summary

16. Review of Evidence

17. 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

18. Kjellman et al

19. 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)

20. 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

21. Kjellman et al

22. Kjellman et al

23. Kjellman et al - Results

24. 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

25. 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

26. 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

27. Dereure et al

28. Dereure et al - Results

29. 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

30. 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

31. 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

32. Summary

33. Back to MK…

34. Monitoring Plan

35. Monitoring Plan

36. 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. • 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

37. 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

38. Heilborn et al

39. Heilborn et al

40. Heilborn et al

41. Heilborn et al - results

42. 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