UCL

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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

Plan Indications Induction versus Entretien Cas réfractaires UCL

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

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 .

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

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

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

Asanuma Y. et al .

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

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

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

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

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

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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

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

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

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

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

The NIH regimen - Concern #1 Toxicity

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)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Induction versus upkeep treatment Can we improve ?

Renal abatement rate

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

Chronic renal debilitation rate

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

Toxicity

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

LN impacts survival Euro-Lupus Project N - N +

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Refractory case ? Be careful !

#1 - SRD carbon copies Subacute endocarditis Cholesterol emboli

#2 - Infection

#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

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

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

The reaction to CYC may be identified with cytochrome P4