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Treatment of LN

Treatment of LN. An European perspective Frédéric A. HOUSSIAU Department of Rheumatology Cliniques universitaires Saint-Luc LOUVAIN Medical School XXXV Congreso de la SEN Malaga, October 9-12, 2005. High-dose IV CYC. Remission rate : 80% Relapse rate: 35% ESRD: 5-10%

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Treatment of LN

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  1. Treatment of LN An European perspective Frédéric A. HOUSSIAU Department of Rheumatology Cliniques universitaires Saint-Luc LOUVAIN Medical School XXXV Congreso de la SEN Malaga, October 9-12, 2005

  2. High-dose IV CYC Remission rate : 80% Relapse rate: 35% ESRD: 5-10% Side-effects: +++

  3. Why European initiatives ? European LN patients differ from American LN patients Ethnic background !

  4. Prognostic factors Afro-American race Poor socio-economic status Severe clinical onset High CI, AI Uncontrolled hypertension Renal relapse Non-compliance Poor initial response to therapy UCL

  5. Why European initiatives ? European LN patients differ from American LN patients Less severe disease at baseline?

  6. LN : Bedside classification 5 56 % 2 % 4 3 Serum albumin (g/dl) 2 1 26 % 16 % 0 0.4 1.3 1.6 0.7 1 1.9 2.2 Serumcreatinine(mg/dl) Louvain LN Cohort (1985-2002) UCL

  7. B o u m p a s 8 0 E L N T 6 0 Percentage of patients 4 0 2 0 0 C r e a t > 1 . 3 m g / d l P r o t e i n u r i a > 3 . 5 g / d ELNT - Patients UCL

  8. The changing picture of LN Study from Heidelberg Fiehn C. et al. Ann Rheum Dis 2003; 62: 435-9

  9. The cyclophosphamide saga Towards lower doses of IV CYC ? Euro-Lupus Group 1990-2000

  10. Euro-Lupus Nephritis Trial 90 SLE patients biopsy-proven proliferative GN (III, IV, Vc/d) ≥ 500 mg daily proteinuria not treated with ISD UCL

  11. Euro-Lupus Nephritis Trial 750 mg IV methylprednisolone pulse d1, d2 and d3 0.5 mg/kg/d oral prednisolone 1 month (1 mg/kg/d in severe cases) tapered down to 7.5 mg/d at 6 months UCL

  12. MINIMISATION LD IV CYC HD IV CYC NIH-like regime 6 monthly pulses 2 quarterly pulses start AZA w 44 6 pulses 500 mg q2 weeks start AZA w 12 Euro-Lupus Nephritis Trial UCL

  13. ELNT - Baseline data UCL Houssiau et al., Arthritis Rheum, 2002

  14. 100 90 80 70 60 50 0 0 12 24 36 48 60 ELNT - Treatment failure LD HD Free of Failure (%) HD LD HR: 0.79 (CIs: 0.30-2.14) Follow-up (months) UCL Houssiau et al., Arthritis Rheum, 2002

  15. HD HD 1.4 4.0 LD LD 3.5 1.3 3.0 1.2 2.5 Serum Creatinine (mg/dl) 1.1 24-hour Proteinuria (g) 2.0 1.0 1.5 0.9 1.0 0.5 0.8 0 0 12 12 0 3 6 0 3 6 Months Months ELNT - Kinetics p < 0.005 for « repeated measures » analyses (ANOVA) p > 0.05 for « between groups » comparisons UCL Houssiau et al., Arthritis Rheum, 2002

  16. 4 2 1 0 0 4 . 0 9 0 3 . 8 8 0 3 . 6 7 0 3 . 4 3 . 2 6 0 3 . 0 5 0 2 . 8 0 0 12 0 3 6 Months ELNT - Kinetics . Serum C 3 (mg/dl) Serum Albumin (g/dl) HD HD LD LD 12 0 3 6 Months p < 0.005 for « repeated measures » analyses (ANOVA) p > 0.05 for « between groups » comparisons UCL Houssiau et al., Arthritis Rheum, 2002

  17. HD HD LD LD 8 4 0 7 3 5 6 3 0 Prednisolone (mg/day) 2 5 5 ECLAM Score 4 2 0 3 1 5 2 1 0 1 5 0 3 6 12 0 3 6 12 0 0 M o n t h s M o n t h s ELNT - Kinetics p < 0.005 for « repeated measures » analyses (ANOVA) p > 0.05 for « between groups » comparisons UCL Houssiau et al., Arthritis Rheum, 2002

  18. Baseline Followup 20 p = 0.013 p = 0.001 15 Activity index (mean ± SEM) 10 5 0 HD group LD group Pathology UCL

  19. Pathology UCL

  20. ELNT - Severe infections UCL Houssiau et al., Arthritis Rheum, 2002; 46: 2121-2131

  21. ELNT - Long term follow-up 100 80 60 LD 40 20 HD 0 p = 0.34 HR: 0.35 (0.04-3.37) Free of ESRD (%) [46] [45] [44] [42] [37] [27] [22] [8] HD [44] [43] [42] [40] [35] [31] [19] [6] LD 0 1 2 3 4 5 6 7 8 Follow-up (years) UCL Houssiau et al., Arthritis Rheum, 2004; 50: 3934-3940

  22. ELNT - Long term follow-up Mean (± SD) follow-up: 70 ± 17 months Houssiau et al., A&R, 2004; 50: 3934

  23. ELNT - Baseline pronostic factors UCL Houssiau et al., A&R, 2004; 50: 3934

  24. An understudied prognostic factors Does the initial response to immunosuppressive therapy predict long-term renal outcome in LN ? UCL

  25. Lack of prompt response is a poor prognostic factor Adjustment for baseline creatinine by ANCOVA p = 0.018 5 ANOVA p = 0.0003 p = 0.011 4 3 2 1 0 Good renal outcome Houssiau et al., A&R, 2004; 50: 3934 24h proteinuria (g) Month 6 Month 3 Baseline UCL Poor renal outcome

  26. Multivariate analysis of predictors of good long-term renal outcome Houssiau et al., Arthritis Rheum, 2004; 50: 3934-3940 UCL

  27. Lesson from the ELNT A short- course of low-dose IV CYC might be enough in the induction phase 6 x 500 mg q2w Euro-Lupus regimen UCL

  28. EURO-LUPUS regimen ADVANTAGES 30 minutes drip CYC infusion no need for hyperhydration no hospital stay low cost no need to monitor nadir WBC less side-effects UCL

  29. ELNT - Caveats Not blinded Not strict NIH regimen Not an equivalence study Less severe LN patients Few Blacks UCL

  30. The cyclophosphamide saga Gorman C et al., Rheumatology 2005; 44: 398-401

  31. Low-dose is superior to high-dose IV CYC for LN Pro: 45 % Con: 50 % No idea: 5 % Gorman C et al., Rheumatology 2005; 44: 398-401

  32. HD LD 100 80 LD 60 Free of renal flare (%) HD 40 AZA LD AZA 20 HD HR: 0.90 (CIs: 0.40-2.04) 0 0 12 24 36 48 60 Follow-up (months) ELNT - Renal flares UCL Houssiau et al., Arthritis Rheum, 2002

  33. Mycophenolate mofetil A new star twinckling in the sky

  34. Can MMF replace oral CYC for induction ? Group 1 MMF: 2g/d for 6 months 1g/d for 6 months Group 2 CPM: 2.5 mg/kg/d for 6 months AZA: 1.5 mg/kg/d for 6 months Chan et al. , NEJM 2000; 343: 1156

  35. Chan et al. , NEJM 2000; 343: 1156

  36. Can MMF replace oral CYC for induction ? After one year, all patients were on AZA More early relapses in MMF group Additional patients were given higher MMF doses for longer periods Long-term analysis on 32 MMF and 30 CYC patients Chan et al., JASN 2005; 16: 1076

  37. Chan’s study - Caveat Changes in treatment regimen over time (more MMF; longer period)

  38. LN : Mycophenolate mofetil MMF less toxic than CYC No evidence so far than MMF is less efficacious than CYC Pregnancy issue Superior to AZA for maintenance ?

  39. MAINTAIN NEPHRITIS TRIAL INDUCTION OF REMISSION Glucocorticoids IV CYC mini-pulses : 6 x 500 mg q2 weeks MAINTENANCE OF REMISSION AZA MMF houssiau@ruma.ucl.ac.be UCL

  40. MAINTAIN NEPHRITIS TRIAL MMF is superior to AZA as remission-maintaining therapy for lupus glomerulonephritis Hypothesis Study design Multi-center, randomized, unblinded, controlled trial 1ry endpoint Time to renal flare houssiau@ruma.ucl.ac.be

  41. Is MMF superior to AZA ?ASPREVA nephritis trial INDUCTION 6 months MAINTENANCE Up to 3 years MMF MMF Response? AZA Yes Re-randomise IVC Randomise No - exit study

  42. Induction: A reasonable choice GC 3 x IV MP 1000 mg 0.5 mg/kg/d pred. taper by 2.5 mg q2w + CYC6 x 500 q2w 6 x 750-1000 qm oral for 12w MMF 2-3 g/d or

  43. Advantages of IV CYC Optimal adherence to therapy Low cost

  44. LN - Treatment costs « Good value for money… »

  45. Maintenance: A reasonable choice Quarterly IV high-dose CYC (NIH regimen) Low-dose GC (5-7.5 mg/d pred.) + or AZA2.5 mg/kg/d MMF2 g/d UCL

  46. Optimal care for lupus patients BLOOD PRESSURE CONTROL (DBP ≤ 80 mm Hg) MINIMIZE PROTEINURIA (ACEI + DIURETICS) TREATMENT OF DYSLIPIDAEMIA STATINS! PREVENTION OF GC-INDUCED BONE LOSS IMMUNISATIONS STOP SMOKING UCL

  47. Asanuma Y. et al.

  48. Frequently Unanswered Questions Consensus on definitions Induction/maintenance: myth ? IS treatment: for how long ? Cost/effectiveness analysis Membranous vs proliferative GN Refractory cases

  49. You should not kill the patient to save their kidneys Steward Cameron

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