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MANAGEMENT OF BULLOUS PEMPHIGOID. What are the current problems ?

Pascal JOLY MD, PhD Rouen University Hospital France Coordinator of the French Study Group on autoimmune bullous skin diseases « Groupe Bulle ». MANAGEMENT OF BULLOUS PEMPHIGOID. What are the current problems ?. What should we take into account for optimal management of BP ?.

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MANAGEMENT OF BULLOUS PEMPHIGOID. What are the current problems ?

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  1. Pascal JOLY MD, PhD Rouen University Hospital France Coordinator of the French Study Group on autoimmune bullous skin diseases « Groupe Bulle » MANAGEMENT OF BULLOUS PEMPHIGOID.What are the current problems ?

  2. What should we take into account for optimal management of BP ? • main characteristics of patients (+++) • main characteristics of BP (localized, mild, extensive) • what is demonstrated from the literature ? • how data from the literature can help me to manage my patients ?

  3. Main characteristics of BP patients • elderly: mean age : 81 to 83 years-old incidence : 300 cases/M/year over 80 years • poor general condition : Karnowsky index : 60% 1/3 patients bed ridden • frequency of cardiovascular and Neurological disorders (dementia) with high functional impairment Neurological disorder in patients with bullous pemphigoidCordel N et al, Dermatology, 2007 French study on 341 BP patients : 40% neurological disorder(s) 20% severe dementia • 20% Parkinson’s disease, stroke

  4. Risk factors of Bullous Pemphigoid • prospective multicentre case- control study > 300 patients performed in France • major risk factors : -1 debilitating neurological disorders : • dementia (OR : 3.5) • Parkinson’s disease (OR : 2.0) • stroke (OR : 2.0) -2 major functionnal impairment, bed ridden patients (OR : 2.2) -3 chronic drug intake : diuretics : spironolactone (OR : 1.9), psycholeptics (OR : 2.1)

  5. Prognostic factors of BP Prediction of survival of patients with BP JOLY P et al – Arch Dermatol 2005;141:691-98 • deleterious prognostic factors - older age * - cardiac insufficiency - dementia - past history of stroke - poor general condition * NOT – extent of BP (+++), -number of daily new bullae * Multivariate analysis

  6. Prognostic factors of BP • POOR prognosis in European Countries one year mortality: -30 to 40% in France (probably overestimated (hospital-based series) -25-30% in Germany (hospital-based series) • -20% in the UK (probably underestimated: based exclusively on GP, excluding patients hospitalized in dermatotogy dept and in nursing homes • mortality rate 2 to 4 times higher than in the general population

  7. What should we take into account for optimal management of BP ? • main characteristics of patients (+++) • main characteristics of BP (localized, mild, extensive) • what is demonstrated from the literature ? • how data from the literature can help me to manage • my patients ?

  8. Oral corticosteroids • considered main stay of treatment for 20 years • Prednisone more effective than prednisolone (Lebrun-Vigne et al – Arch Dermatol 1999) - rate of disease control : 70 – 80 % 3 doses proposed : - high doses : 0.75 mg/kg/d to 1.25 mg/kg/d (no difference : Morel P et al – 1984) - medium doses : 0.5 mg/kg/d - low doses : 0.25 – 0.3 mg/kg/d

  9. It is clear from the literature, what we should not do… • use HIGH doses oral CS (especially in elderly patients) -Roujeau JC et al. Arch Dermatol 1998 - Rzani B et al. Arch Dematol 2OO2 - Joly P et al. N Engl J Med 2002 Mortality rate : 35% to 40% main causes of death : infections, stroke, acute cardiac failure,… • use LOW doses of oral CS for EXTENSIVE BP - Roujeau JC et al. Lancet 1984 0 of 15 BP patients controlled by: 0.3mg/kg/d oral prednisone

  10. It is clear from the literature, what we should not do… • Routine use of immunosuppressive drugs - Guillaume JC et al. Arch Dermatol 1993 NO BENEFIT (disease control, doses of CS), MORE SEVERE COMPLICATIONS • IV Ig - poorly convincing data: open series of «recalcitrant BP» (Do recalcitrant BP still exist ??) - decrease of CS doses (CS doses are always decreased) - very expensive - some adverse events: aseptic meningitis

  11. A comparison of oral methyl prednisolone plus azathioprine or mycophenolate mofetil for the treatment of Bullous pemphigoidBeissert S et al, Arch Dermatol, 2007 • 73 BP patients in Germany • Oral methylprednisolone+ azathioprine or MMF • Primary end-point: - cumulative dose of CS • - rate of remission • Complete remission: 38/38 (100%) CS+Aza • 35/35 (100%) CS+MMF • Median dose of CS: 4967g (Aza) vs 5754g (MMF) (NS) • Severe treatment side efect: 24% vs 17% (NS) • Conclusion: « MMF and aza demonstrate similar efficacy » +/- • « MMF: lower toxicity profile than Aza » Yes, but… • Infections more frequent in MMF group

  12. What is clearly demonstrated from the literature ? A comparison of oral and topical corticosteroids Joly P et al. N Engl J Med 2002;346:321-7 • To date, the only treatment regimen which has demonstrated a superiority as compared to oral CS is: High potency topical CS - better efficacy in controlling both localized andextensive BP - reduced morbidity and mortality as compared to 1mg/kg/d oral CS - diabetes melitus, bone fractures, infections (pneumoniae), psychiatric syndroms, myopathy..

  13. What is not clearly demonstrated, but could be interesting in the treatment of BP • medium doses of oral corticosteroids • combined treatment with topical CS and Methotrexate • antibiotics

  14. Are medium doses oral CS effective for the treatment of extensive BP ? • 0.75mg/d prednisolone:as effective as 1.25mg/d (Morel P et al.Ann Dermatol 1984) No major difference for treatment side effects • 0.3mg/d : not effective in controlling extensive BP(Roujeau JC et al. Lancet 1984) • 0.5mg/d : only one study in the literature My experience : - localized BP : topical CS easier, more effective - mild BP : often effective – well tolerated - extensive BP : 0.5mg/kg/d: only occasionally effective

  15. Medium doses of oral corticosteroidsPrednisone 0.5 mg/kg/d • poorly evaluated in the literature • one study in the literature (Joly P et al – N Engl J Med – 2002) - moderate BP :  10 new blisters daily  rate of complete remission by day 21 : 72/76 (95 %)  rate of relapse : 39/76 (40 %) • efficacy in extensive BP not evaluated Personal experience : 0.5 mg/kg/d : only occasionaly effective

  16. Methotrexate and topical CS Dereure O et al. Arch Dermatol 2002:138;1255-6 Bara C et al. Arch Dermatol 2003:139;1506-7 • 2 Single centre open studies in France • initial treatment with topical CS until control of BP lesions (15 days) • low doses MTX 10 - 15 mg/week • contra indications : - renal insufficiency - creatinine clearance (< 40 ml/min) - liver disfunction - anemia, neutropenia • seems effective, well tolerated,easy to use • to be confirmed by a controlled study

  17. Methotrexate and topical CS Kjelman P et al. Arch Dermatol 2008:144;612-16 • retrospective study 98 patients treated with : - MTX alone (n=61) 50 % mild disease - MTX + prednisone (n=37) 32 % mild disease • median dose MTX : 5 mg/w (2.5 – 10 mg) • doses of prednisone : 10 – 20 mg/d (initially or secondary added) • severe MTX side effect (stop treatment) : n=5 • rate of remission at 24 months : 43 % (MTX alone), 35 % (MTX + P) • median time to achieve CR remission : - 6 months mild BP - 17 months severe BP • « among to our groving clinical experience of MTX today, we usually increase the dose of MTX to 12.5 g/d»

  18. Tetracyclines and nicotinamide (Fivenson D et al. Arch Dermatol 1994) • single centre randomized study • suggested that tetracyclines and nicotinamide could be as effective as oral CS in the treatment of BP • very small number of patients: 6 vs 14 !!! • method of randomization not clear... • high rate of drop out patients • QUESTION: is the absence of difference due to efficacy of tetracyclines, or to a lack of statistical power of the study ? • data not confirmed by another study since 10 years

  19. What should we take into account for optimal management of BP ? • main characteristics of patients (+++) • main characteristics of BP (localized, mild, extensive) • what is demonstrated from the literature ? • how data from the literature can help me to manage • my patients ?

  20. How can I manage BP patients in view of the main data from literature 2) is hospitalization required for the treatment of BP patients ? • hospitalization is NOT responsible for a higher mortality rate in BP patients 1 year survival rate of BP out patients : 72 % (95 % CI 58 %-86 %) in patients : 67 % (95 % CI 62 %-73 %) COLBERT R et al. J Invest Dermato 2005;122:1091-95 JOLY P. et al. J Invest Dermatol 2005;124:664-5

  21. How can I manage BP patients in view of the main data from literature Hospitalization • not useful : - localized BP - « young » patients with mild BP • proposed for : - old patients in poor general condition (mild/extensive BP) - patients with associated disorders (cardiac insufficiency, diabete melitus…) - extensive BP

  22. Which treatment can we propose for our patients ? • localized BP : topical CS clobetasol propionate 10 g/day • mild BP (< 10 daily new blisters) - medium doses of oral CS ? (prednisone : 0,5 mg/kg/d) - medium doses of topical CS (clobetasol propionate 20-30 g/d) - initial topical cs + Methotrexate ?

  23. Treatment of mild forms of BP • patients with a good prognosis (« young » patients, good general condition) • both treatments can be proposed - prednisone 0,5 mg/kg/day - initial topical CS + Methotrexate - topical CS 2) patients with risk factors (old age, poor general condition) - topical cs (+++) - initial topical cs + MTX ?

  24. Patients with extensive BP Effective treatments - high doses of oral CS (prednisone 0,75-1 mg/kg/d) - high doses of topical CS (clobetasol propionate 30-40/d) - topical CS and MTX ? Patients with a good prognosis (young, good general condition) - both treatments Patients with risk factors (old age, poor general condition) - topical CS (+++) - topical CS + MTX ? - medium doses oral CS

  25. Conclusion • keep in mind : - the objective of treatment - the three deleterious predictors of BP: • high doses of oral CS • old age • poor general condition • be very cautious to treat elderly patients • avoid agressive treatments,especially if they have not been robustly evaluated

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