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UCL Les traitements immunosuppresseurs dans les rhumatismes systémiques BR Lauwerys Service de Rhumatologie Cliniques Universitaires Saint-Luc Université.

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Presentation on theme: "UCL Les traitements immunosuppresseurs dans les rhumatismes systémiques BR Lauwerys Service de Rhumatologie Cliniques Universitaires Saint-Luc Université."— Presentation transcript:

1 UCL Les traitements immunosuppresseurs dans les rhumatismes systémiques BR Lauwerys Service de Rhumatologie Cliniques Universitaires Saint-Luc Université catholique de Louvain D.E.S. en Médecine Interne Année académique

2 UCL Plan 1.Indications 2.Induction versus Entretien 3.Cas réfractaires

3 UCL Indications Tout rhumatisme systémique n’est pas grevé d’une diminution du pronostic vital. Pas d’indication de traitement immunosuppresseur dans LED avec arthrite / sérosite / rash / leucopénie SS limitée ou diffuse avec atteinte purement cutanée myopathies inflammatoires sans atteinte alvéolaire inflammatoire vasculite nécrosante avec FSS <1

4 PAN Five Factor Score Proteinuria ≥ 1g/d Renal impairment CNS involvement GI involvement Cardiac involvement IV CPM only if FFS > 1 L. Guillevin et al.

5 Prognostic value of FFS in necrotizing vasculitis Guillevin et al., 2001

6 ACTIVITY Fever Gangrene Polyneuropathy Rash Arthritis Glomerulonephritis Cytopenias Thrombosis Grand mal DAMAGE Disease-related ESRD Deforming arthropathy Cutaneous scarring Cognitive impairment Optic atrophy Valvular disease APL antibody-related Iatrogenic What is severe disease ? UCL

7 Clinical disease: MI, angina 6 % to 10 % Subclinical disease: 30 % to 40 % Risk factors: hypercholesterolaemia hypertension steroid use homocysteine The iceberg of atherosclerosis in SLE Bruce et al., Toronto

8 Asanuma Y. et al.

9 EFFICACY TOXICITY RELAPSES The ideal remission - INDUCING treatment is efficient and not toxic The ideal remission - MAINTAINING treatment prevents relapses Induction versus maintenance therapy The concept

10 To achieve prompt remission (i.e. proteinuria < 1g/d in the absence of impaired renal function) To maintain remission and prevent renal flares (very common and associated with a poor outcome) To avoid renal impairment With minimal toxicity UCL Which therapeutic goals in a newly diagnosed LN patient ?

11 GGAlways consider dividing the dose by two! Gradual tapering down to ‘physiological doses’ IV GC ‘pulses’ Remission-inducing treatment

12 UCL

13 Reduced bone mineral density in SLE Houssiau et al., Br J Rheumatol 1996; 35: UCL

14 Jardinet et al., Rheumatology 2000; 39: Reduced bone mineral density in SLE UCL

15 UCL

16 UCL

17 UCL CYCPlatinum standard Highly toxic (bladder, ovaries, bone marrow) Not always needed IV versus oral Low- versus high-dose IV Remission-inducing treatment

18 Cyclophosphamide therapy IV pulse Oral CPM SLEDPMPSSPANMPA...!?!WEGENER

19 Austin 1985, Boumpas 1992, Gourley 1996, Illei 2001 The NIH regimen The platinum standard for LN extended course (≥ 30 months) high (HD) IV CYC combined to GC superior to oral or IV GC alone

20 The NIH regimen for LN IV CYC g/m 2 WBC nadir (d14): 1, ,000/  l monthly for 6 months quarterly for 1 year after CR IV MP1 g/m 2 monthly for months

21 The 1st NIH trial Austin et al., 1985 p < 0.05

22 The NIH regimen - Concern #1 Toxicity NIH TRIALS (%tage patients) Side-effect1st2nd3rd Infection10526 H. zoster Ovarian failure

23 Louvain LN Cohort ( ) The NIH regimen - Concern #2 Appropriate for mild/early cases ? Serum albumin (g/dl) Serum creatinine (mg/dl) 56 % 16 % 2 % 26 %

24 The changing picture of LN Baseline proteinuria (g/l) 4617 Baseline renal impairment (%) 4017 Chronicity on baseline biopsy (%) 3310 Time delay to renal biopsy (m) Study from Heidelberg Fiehn C. et al. Ann Rheum Dis 2003; 62: 435-9

25 The NIH regimen - Concern #3 Does not prevent renal flares Illei et al., Arthritis Rheum 2002; 46:

26 UCL The revisited standard treatment of LN Sequential use of cytotoxic therapies Induction of remission Short-course (a few months) with a « incisive » immunosuppressant Maintenance of remission Long-term use (5 years ?) of a « safe » immunosuppressant

27 UCL CYC IV NIH regimen versus CYC IV mini-pulses (6 x 500 mg; q2weeks) AZA Euro-Lupus Nephritis Trial Induction of remission Maintenance of remission

28 3 x 750 mg IV MP qd 6 x 500 mg IV CPM q2w 0.5 mg pred./kg/d 1 month INDUCTION AZA 2 mg/kg/d at 3m taper GC by 2.5 mg q2w plateau at mg MAINTENANCE EURO-LUPUS regimen UCL

29 ELNT - Treatment failure Free of Failure (%) LD Follow-up (months) HR: 0.79 (CIs: ) LD HD Houssiau et al., Arthritis Rheum, 2002; 46: UCL

30 ELNT - Remission Remission: < 10 RBC/hpf, 24-h proteinuria < 1g, no DSC Follow-up (months) LD Probability of remission LD HD HR: 1.26 (CIs ) HD UCL Houssiau et al., Arthritis Rheum, 2002; 46:

31 ELNT - Early response to therapy Baseline Month 3 Month 6 24h proteinuria (g) Good renal outcome Poor renal outcome UCL p = p = Adjustment for baseline creatinine by ANCOVA ANOVA p = Houssiau et al., Arthritis Rheum, 2004; 50:

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

33 UCL Activity index (mean ± SEM) LD group Followup Baseline HD group p = p = ELNT - Pathology Houssiau et al., Arthritis Rheum, 2004; 50:

34 UCL ELNT - Pathology Houssiau et al., Arthritis Rheum, 2004; 50:

35 ELNT - Severe infections UCL Adverse event All (n = 89) HD IV CPM (n = 45) LD IV CPM (n = 44) Severe infections (n patients) Episodes24177 TypePneumonia Other bacterial inf. Cytomegalovirus Herpes zoster Houssiau et al., Arthritis Rheum, 2002; 46:

36 A short- course of low-dose IV CYC might be enough in the induction phase UCL Lesson from the ELNT

37 IV CYC therapy Vaccinations are safe and efficient in patients with systemic rheumatic disorders. Vaccination with pneumococcal antigens is required before starting CYC therapy Life attenuated vaccines should be avoided in immunocompromised patients UCL

38 Induction versus maintenance therapy Can we do better ?

39 Renal remission rate Study (GC + ISD arm) Remission(%) Gourley et al., Chan et al., Houssiau et al., Contreras et al.,

40 Renal relapse rate 46 LN patients diagnosed and followed-up at UCL (64 ± 49 months) Relapse rate: 37 % 40 ± 24 (mean ± SD) months after diagnosis of LN 80 % on AZA by the time of flaring El Hachmi et al., Lupus 2003, 12: UCL

41 Chronic renal impairment rate Long-term studies ESRD(%) Illei et al., Houssiau et al., Contreras et al.,

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

43 Toxicity NIH TRIALS (%tage patients) Side-effect1st2nd3rd Infection10526 H. zoster Ovarian failure

44 LN: key figures Remission rate:80% Relapse rate:35% ESRD:5-10% Side-effects:+++

45 LN impacts survival N+ N+ Euro-Lupus Project N- N-

46 Is IV CYC the best choice during the induction phase ? UCL Unsolved issues

47 Lymphocytes, unlike most eukariotic cells, lack the salvage pathway that also generates GTP MMF: a new star twinkling in the sky

48 Inhibitory properties of MPA lymphocyte proliferation vascular smooth muscle proliferation mesangial cell proliferation inhibits glycosylation iNOS renal cortical expression

49 Short-term (24 weeks) remission- induction study comparing MMF and NIH IV CYC in 140 LN patients MMF: maximum tolerated dose, ad 3 g/d; 63% reached 3 g ! FDA-sponsored Study Ginzler E. et al. ACR meeting 2003 Can MMF replace IV CYC for induction ?

50 FDA-sponsored Study MMF IV CYC P CR20%6%0.014 PR30%20%NS CR + PR 50%26%0.007 Rp switch 8%20%0.034 Sev. pyog. inf CR: normal serum creatinine, proteinuria < 0.5 g/d and inactive urinary sediment Ginzler E. et al. ACR meeting 2003

51 What is the optimal maintenance regime ? Quarterly IV CYC AZAMMF UCL Unsolved issues

52 ELNT - Renal flares Houssiau et al., Arthritis Rheum, LD HD Follow-up (months) Free of renal flare (%) LD HD HR: 0.90 (CIs: ) UCL

53 Miami Study Contreras et al. NEJM 2004; 350: 971 Induction therapy IV CYC pulses: 4 to 7 qm (541 ± 40 mg/m2) Prednisone:0.6 ± 0.3 mg/kg/d (0 -3 mo) 0.3 ± 0.2 mg/kg/d (4 to 6 mo) Maintenance therapy IV CYC: 0.5 to 1 g/m2 q3m (25 mo) AZA: 1 to 3 mg/kg/d (29 mo) MMF: 500 to 3000 mg/d (30 mo) Prednisone:0.21 ± 0.15 IV CYC 0.12 ± 0.13 MMF 0.15 ± 0.14 AZA

54 Contreras et al. NEJM 2004; 350: 971 p = 0.02 Miami Study

55 * * * * * * * Contreras et al. NEJM 2004; 350: 971

56 European based multicenter trial comparing AZA and MMF as remission-maintaining therapy of proliferative LN after remission- inducing treatment with IV CYC MAINTAIN NEPHRITIS TRIAL Euro-Lupus Nephritis Trial Group Coordinator Frédéric A. Houssiau Université de Louvain - Belgium

57 INDUCTION OF REMISSION Glucocorticoids IV CYC mini-pulses : 6 x 500 mg q2 weeks MAINTENANCE OF REMISSION AZAMMF MAINTAIN NEPHRITIS TRIAL UCL

58 MMF - Toxicity in LN Very good toxicity profile Better in LN than in tranplant patients Mok and Lai, Am J Kidney Dis 2002; 40: 447

59 MMF vs AZA - The cost issue MMF 4,000 €/year (B) AZA 400 €/year (B)

60 BEWARE ! Refractory case ?

61 #1 - SRD look alikes Cholesterol emboli Subacute endocarditis

62 Infection #2 - Infection

63 #3 - Lack of compliance Lin et al., Zhonghua Yi Xue Za Zhi 1995;56: SLE patients 25.5 % non-compliant with prescribed GC regime during the past week Reasons: feeling better, fearing SE, use of alternative therapies

64 #3 - Lack of compliance If you suspect a lack of compliance (females, adolescents) add IV glucocorticoids add IV glucocorticoids

65 #4 - Too soft treatment AZA: 2 to 2.5 mg/kg 6TG titers ? MMF: 2 to 3 g Pharmacogenomics ?

66 The response to CYC might be related to cytochrome P450 genetic polymorphism CYP2B6*5 allele CYP2C19*2 allele Less active enzyme Less CYC metabolites Less clinical activity

67 The response to CYC might be related to cytochrome P450 genetic polymorphism Takada K et al., A&R 2004; 50: 2202

68 #5 - Unexpected finding Beware of unusual manifestations of an already unusual disease

69

70

71

72 Refractory disease ? Look alikes InfectionsDamageCompliance Soft treatment Unusual manifestation

73 Bone marrow transplantation AllogeneicAutologous Nonmyeloablative allogeneic

74 Allogeneic bone marrow transplantation (ABMT) 1: Myeloablation to delete host immune system Conditioning regime Chemotherapy/Irradation 2: Transplantation Allogeneic HLA-matched BM Haematological malignancies Serendipitous cure of coincidental AID 15% mortality (? EVDN) Graft-Versus-Host Disease If the autoimmune diathesis resides at the level of the HSC, cure is achievable

75 Autologous Haematopoietic Stem Cell Transplantation 1: Mobilization of CD34 HSC IV CYC : 2.0 gm/m 2 and G-CSF (5  g/kg/d) Leukapheresis days later Purification of CD34 HSC ± T-cell depletion (purging) Cryopreservation 2: Myeloablation IV CYC (200 mg/kg in 4 divided daily doses of 50 mg/kg) combined with ATG (90 mg/kg in 3 divided daily dose of 30 mg/kg) 3: Transplantation Infusion of thawed CD34 HSC Traynor et al., The Lancet 2000; 356: Traynor et al., A&R 2002; 46:

76 EBMT/EULAR Autologous Haematopoietic Stem Cell Transplantation data base

77 57 patients (50 diffuse) Median disease duration: 36 (2-159) months Lung disease: 57 % Median followup: 20 (<1-81) months Farge et al., Ann Rheum Dis 2004; 63: 974 Autologous Haematopoietic Stem Cell Transplantation in systemic sclerosis

78 53 patients (65% renal involvement) Median disease duration: 60 (2-236) months Prior cyclophosphamide: 86 % Median followup: 23 (<1-78) months 66% remission (SLEDAI < 3) 32% relapses in patients with prior remission Jayne et al., Lupus 2004; 13: 168 Autologous Haematopoietic Stem Cell Transplantation in SLE

79 AHSCT in SLE - Chigaco experience 15 SLE median follow-up: 36 months (12-66) Traynor et al., The Lancet 2000; 356: Traynor et al., A&R 2002; 46:

80 Mortality in AHSCT NDeath%TRD%Reference SLE Lupus 2004; 13: 168 SS ARD 2004; 63: 974 MS J Neurol 2002; 249: 1088 RA J Rheum 2004; 31: 482

81 Conclusions AHSCT « Effective » in most patients No controled trials so far Relapses are common HSCT offers no cure of AID High treatment-related mortality Patient’s selection ? Optimal conditioning regime ?

82 Nonmyeloablative allogeneic HSCT 1: Mild Conditioning regime Lower mortality No complete immediate host immune system deletion 2: Transplantation Allogeneic HLA-matched CD34 HSC Mixed chimerism Gradual conversion to full donor engraftment Advantage of allogeneic BMT (the only one that potentially cures AID) with lower toxicity Pavletic, AR 2004; 50: 2387 Burt et al., AR 2004; 50: 2466

83 High dose cyclophosphamide Immunoablation Johns Hopkins Ann Intern Med 1998; 129: 1031 IV CPM: 50 mg/kg/d for 4 consecutive days Mesna (Uromitexan R ) G-CSF: 5  g/kg/d starting day 10, until neutrophils ≥ 1,000/  l Not myeloablative No need for stem cell rescue (Stem cells strongly express aldehyde dehydrogenase which inactivates aldophosphamide) Dapsone: 3 x 100 mg/week for 6 months

84 Petri et al. Arthritis Rheum 2003; 48: Refractory SLE patients High dose cyclophosphamide 9 nephritis: 4 CR - 3 PR - 2 NR 2 cutaneous:2 PR 3 CNS:1 CR - 2 PR CR: no disease activity no treatment (except pred.: 5 mg/d) CR maintained up to 4 years No death Flare in 2 PR

85 Conclusions High-dose IV CYC « Easier » than AHSCT Seems effective in lupus nephritis No death so far (luck ?) Limited experience G-CSF incriminated in SLE flares Delayed haematopoietic recovery

86 Plasma exchanges Removal of whole plasma 2 to 4 L/session 3 sessions/week Albumin substitution Hypogammaglobulinaemia Increased risk of infections

87 Plasma exchanges Lewis et al. NEJM 1992; 326: 1373

88 Plasma exchanges Few controlled trials HBV-related PAN Vasculitis with severe renal impairment and pulmonary haemorrage Critically ill patients

89 Biologics Rituximab, Anti-CD22 mAb CTLA4-Ig TNF-alpha blocking agents (CD40L blocking Ab) ….

90 Take home messages Induction and maintenance MMF ? GC + CYC - AZA

91 Take home messages Remain an “internist”! Optimal care = prevention of infections and cardiovascular mortality Beware of toxicity


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