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Les traitements immunosuppresseurs dans les rhumatismes syst

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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 2004-2005 UCL

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Plan Indications Induction versus Entretien Cas réfractaires UCL

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Indications Tout rhumatisme systémique n'est pas grevé d'une decrease du pronostic indispensable. 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 UCL

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PAN Five Factor Score Proteinuria ≥ 1g/d Renal disability CNS contribution GI inclusion Cardiac association IV CPM just if FFS > 1 L. Guillevin et al .

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

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What is extreme malady ? Movement Fever Gangrene Polyneuropathy Rash Arthritis Glomerulonephritis Cytopenias Thrombosis Grand mal DAMAGE Disease-related ESRD Deforming arthropathy Cutaneous scarring Cognitive disability Optic decay Valvular ailment APL immune response related Iatrogenic UCL

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Clinical sickness: MI, angina 6 % to 10 % Subclinical illness: 30 % to 40 % Risk elements: hypercholesterolaemia hypertension steroid utilize homocysteine The chunk of ice of atherosclerosis in SLE Bruce et al., Toronto

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Asanuma Y. et al .

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Induction versus upkeep treatment The idea EFFICACY The perfect reduction - INDUCING treatment is productive and not harmful TOXICITY The perfect abatement - MAINTAINING treatment avoids backslides RELAPSES

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Which helpful objectives in a recently analyzed LN understanding ? To accomplish incite abatement ( i.e. proteinuria < 1g/d without hindered renal capacity) To keep up reduction and forestall renal flares (exceptionally normal and related with a poor result) To maintain a strategic distance from renal debilitation With negligible danger UCL

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Remission-inciting treatment GG Always consider isolating the measurements by two! Steady decreasing down to 'physiological measurements' IV GC "beats"

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UCL

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Reduced bone mineral thickness in SLE UCL Houssiau et al ., Br J Rheumatol 1996; 35: 244-247

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Reduced bone mineral thickness in SLE UCL Jardinet et al ., Rheumatology 2000; 39: 389-392

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UCL

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UCL

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Remission-inciting treatment CYC Platinum standard Highly poisonous (bladder, ovaries, bone marrow) Not constantly required IV versus oral Low-versus high-dosage IV UCL

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Cyclophosphamide treatment IV beat Oral CPM SLE DPM PSS PAN MPA ... !?! WEGENER

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The NIH regimen The platinum standard for LN developed course (≥ 30 months) high (HD) IV CYC joined to GC better than oral or IV GC alone Austin 1985, Boumpas 1992, Gourley 1996, Illei 2001

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The NIH regimen for LN IV CYC 0.75 - 1 g/m 2 WBC nadir (d14): 1,500 - 4,000/m l monthly for 6 months quarterly for 1 year after CR IV MP 1 g/m 2 monthly for 12 - 36 months

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p < 0.05 Austin et al ., 1985 The first NIH trial

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The NIH regimen - Concern #1 Toxicity

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5 56 % 2 % 4 3 Serum egg whites (g/dl) 2 1 26 % 16 % 0 0.4 1.3 1.6 0.7 1 1.9 2.2 Serum creatinine (mg/dl) The NIH regimen - Concern #2 Appropriate for gentle/early cases ? Louvain LN Cohort (1985-2002)

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

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The NIH regimen - Concern #3 Does not counteract renal flares Illei et al ., Arthritis Rheum 2002; 46: 995-1002

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Induction of reduction Short-course (a couple of months) with a « incisive » immunosuppressant Maintenance of abatement Long-term utilize (5 years ?) of a « safe » immunosuppressant The returned to standard treatment of LN Sequential utilization of cytotoxic treatments UCL

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Euro-Lupus Nephritis Trial Induction of abatement CYC IV NIH regimen versus CYC IV scaled down heartbeats (6 x 500 mg; q2weeks) Maintenance of reduction AZA UCL

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EURO-LUPUS regimen INDUCTION 3 x 750 mg IV MP qd 6 x 500 mg IV CPM q2w 0.5 mg pred./kg/d 1 month MAINTENANCE AZA 2 mg/kg/d at 3m decrease GC by 2.5 mg q2w level at 5-7.5 mg UCL

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100 90 80 70 60 50 0 12 24 36 48 60 ELNT - Treatment disappointment 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; 46: 2121-2131

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1 0 . 8 0 . 6 0 . 4 0 . 2 0 2 4 1 2 3 6 4 8 6 0 F o l o w - u p ( m o n t h s ) ELNT - Remission LD HR: 1.26 (CIs 0.72-2.21) HD Probability of abatement HD LD Remission: < 10 RBC/hpf, 24-h proteinuria < 1g, no DSC UCL Houssiau et al ., Arthritis Rheum, 2002; 46: 2121-2131

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ELNT - Early reaction to treatment Adjustment for pattern creatinine by ANCOVA p = 0.018 5 ANOVA p = 0.0003 p = 0.011 4 3 2 1 0 Good renal result Houssiau et al ., Arthritis Rheum, 2004; 50: 3934-3940 24h proteinuria (g) Month 6 Month 3 Baseline UCL Poor renal result

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Multivariate examination of indicators of good long haul renal result Houssiau et al ., Arthritis Rheum, 2004; 50: 3934-3940

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Baseline Followup 20 p = 0.013 p = 0.001 15 Activity list (mean ± SEM) 10 5 0 HD aggregate LD bunch ELNT - Pathology UCL Houssiau et al ., Arthritis Rheum, 2004; 50: 3934-3940

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ELNT - Pathology UCL Houssiau et al ., Arthritis Rheum, 2004; 50: 3934-3940

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

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Lesson from the ELNT A short-course of low-measurements IV CYC may be sufficient in the acceptance stage UCL

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IV CYC treatment Vaccinations are sheltered and proficient in patients with systemic rheumatic issue. Immunization with pneumococcal antigens is required before beginning CYC treatment Life lessened antibodies ought to be maintained a strategic distance from in immunocompromised patients UCL

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Induction versus upkeep treatment Can we improve ?

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Renal abatement rate

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Renal backslide rate 46 LN patients analyzed and followed-up at UCL (64 ± 49 months) Relapse rate: 37 % 40 ± 24 (mean ± SD) months after finding of LN 80 % on AZA when of flaring UCL El Hachmi et al . , Lupus 2003, 12: 692-696

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Chronic renal debilitation rate

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Prognostic elements Afro-American race Poor financial status Non-consistence Severe clinical onset High CI, AI Uncontrolled hypertension Renal backslide Poor beginning reaction to treatment

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Toxicity

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

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LN impacts survival Euro-Lupus Project N - N +

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Unsolved issues Is IV CYC the best decision amid the enlistment stage ? UCL

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MMF: another star twinkling in the sky Lymphocytes, dissimilar to most eukariotic cells, do not have the rescue pathway that likewise creates GTP

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Inhibitory properties of MPA lymphocyte expansion vascular smooth muscle multiplication mesangial cell multiplication restrains glycosylation iNOS renal cortical expression

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Can MMF swap IV CYC for acceptance ? FDA-supported Study Short-term ( 24 weeks ) abatement acceptance think about looking at MMF and NIH IV CYC in 140 LN patients MMF: greatest endured dosage, promotion 3 g/d ; 63% achieved 3 g ! Ginzler E. et al. ACR meeting 2003

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FDA-supported Study Ginzler E. et al . ACR meeting 2003 CR: typical serum creatinine, proteinuria < 0.5 g/d and latent urinary residue

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Unsolved issues What is the ideal upkeep administration ? Quarterly IV CYC AZA MMF UCL

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

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Miami Study Induction treatment IV CYC beats: 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 treatment 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 Contreras et al. NEJM 2004; 350: 971

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

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Miami Study * Contreras et al. NEJM 2004; 350: 971

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MAINTAIN NEPHRITIS TRIAL European based multicenter trial looking at AZA and MMF as reduction keeping up treatment of proliferative LN after abatement instigating treatment with IV CYC Euro-Lupus Nephritis Trial Group Coordinator Frédéric A. Houssiau Université de Louvain - Belgium

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MAINTAIN NEPHRITIS TRIAL INDUCTION OF REMISSION Glucocorticoids IV CYC small scale beats : 6 x 500 mg q2 weeks MAINTENANCE OF REMISSION AZA MMF UCL

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

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

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Refractory case ? Be careful !

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#1 - SRD carbon copies Subacute endocarditis Cholesterol emboli

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#2 - Infection

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#3 - Lack of consistence 329 SLE patients 25.5 % rebellious with recommended GC administration amid the previous week Reasons: resting easy, dreading SE, utilization of option treatments Lin et al ., Zhonghua Yi Xue Za Zhi 1995;56:244-51

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#3 - Lack of consistence If you speculate an absence of consistence (females, young people) include IV glucocorticoids

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

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The reaction to CYC may be identified with cytochrome P4

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