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 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 UCL

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

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

Deforming arthropathy What is severe disease ? 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 UCL

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

Asanuma Y. et al.

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

Which therapeutic goals in a newly diagnosed LN patient ? 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

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

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

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

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

Cyclophosphamide therapy IV pulse Oral CPM SLE DPM PSS PAN MPA ... !?! WEGENER

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 Austin 1985, Boumpas 1992, Gourley 1996, Illei 2001

The NIH regimen for LN IV CYC 0.75 - 1 g/m2 WBC nadir (d14): 1,500 - 4,000/ml monthly for 6 months quarterly for 1 year after CR IV MP 1 g/m2 monthly for 12 - 36 months

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

The NIH regimen - Concern #1 Toxicity NIH TRIALS (%tage patients) Side-effect 1st 2nd 3rd Infection 10 5 26 H. zoster 25 15 Ovarian failure 45 38 52

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

The changing picture of LN Study from Heidelberg 1989-1989 1990-1999 Baseline proteinuria (g/l) 46 17 Baseline renal impairment (%) 40 Chronicity on baseline biopsy (%) 33 10 Time delay to renal biopsy (m) 15.4 3.9 Fiehn C. et al. Ann Rheum Dis 2003; 62: 435-9

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

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 UCL

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

EURO-LUPUS regimen INDUCTION MAINTENANCE 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 taper GC by 2.5 mg q2w plateau at 5-7.5 mg UCL

Houssiau et al., Arthritis Rheum, 2002; 46: 2121-2131 ELNT - Treatment failure 50 60 70 80 90 100 LD HD Free of Failure (%) HD LD HR: 0.79 (CIs: 0.30-2.14) 12 24 36 48 60 Follow-up (months) UCL Houssiau et al., Arthritis Rheum, 2002; 46: 2121-2131

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

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

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

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

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

ELNT - Severe infections Adverse event All (n = 89) HD IV CPM (n = 45) LD (n = 44) Severe infections (n patients) 15 10 5 Episodes 24 17 7 Type Pneumonia Other bacterial inf. Cytomegalovirus Herpes zoster 6 4 3 1 2 UCL Houssiau et al., Arthritis Rheum, 2002; 46: 2121-2131

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

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

Induction versus maintenance therapy Can we do better ?

Renal remission rate Study (GC + ISD arm) Remission (%) Gourley et al., 1996 65 - 75 Chan et al., 2000 76 - 81 Houssiau et al., 2002 54 - 71 Contreras et al., 2004 83

Renal relapse rate Relapse rate: 37 % 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: 692-696 UCL

Chronic renal impairment rate Long-term studies ESRD (%) Illei et al., 2001 9 Houssiau et al., 2002 5 Contreras et al., 2004 8

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

Toxicity NIH TRIALS Side-effect 1st 2nd 3rd Infection 10 5 26 (%tage patients) Side-effect 1st 2nd 3rd Infection 10 5 26 H. zoster 25 15 Ovarian failure 45 38 52

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

LN impacts survival Euro-Lupus Project N- N+

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

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

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

Can MMF replace IV CYC for induction ? FDA-sponsored Study 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 ! Ginzler E. et al. ACR meeting 2003

FDA-sponsored Study MMF IV CYC P CR 20% 6% 0.014 PR 30% NS CR + PR 50% Ginzler E. et al. ACR meeting 2003 MMF IV CYC P CR 20% 6% 0.014 PR 30% NS CR + PR 50% 26% 0.007 Rp switch 8% 0.034 Sev. pyog. inf. 6 13 0.03 CR: normal serum creatinine, proteinuria < 0.5 g/d and inactive urinary sediment

What is the optimal maintenance regime ? Unsolved issues What is the optimal maintenance regime ? Quarterly IV CYC AZA MMF UCL

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

Miami Study Induction therapy Maintenance 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 Contreras et al. NEJM 2004; 350: 971

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

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

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

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

Mok and Lai , Am J Kidney Dis 2002; 40: 447 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

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

Refractory case ? BEWARE !

Subacute endocarditis #1 - SRD look alikes Subacute endocarditis Cholesterol emboli

#2 - Infection

#3 - Lack of compliance 329 SLE patients 25.5 % non-compliant with prescribed GC regime during the past week Reasons: feeling better, fearing SE, use of alternative therapies Lin et al., Zhonghua Yi Xue Za Zhi 1995;56:244-51

If you suspect a lack of compliance (females, adolescents) add IV glucocorticoids

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

Less clinical activity 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

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

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

Refractory disease ? Look alikes Infections Damage Compliance Soft treatment Unusual manifestation

Bone marrow transplantation Nonmyeloablative allogeneic Autologous Nonmyeloablative allogeneic

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

Autologous Haematopoietic Stem Cell Transplantation 1: Mobilization of CD34 HSC IV CYC : 2.0 gm/m2 and G-CSF (5 mg/kg/d) Leukapheresis 10-12 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: 701-707 Traynor et al., A&R 2002; 46: 2917-2923

EBMT/EULAR Autologous Haematopoietic Stem Cell Transplantation data base

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

AHSCT in SLE - Chigaco experience median follow-up: 36 months (12-66) Traynor et al., The Lancet 2000; 356: 701-707 Traynor et al., A&R 2002; 46: 2917-2923

Mortality in AHSCT N Death TRD Reference SLE 53 22.6 13.2 SS 57 22.8 % TRD Reference SLE 53 22.6 13.2 Lupus 2004; 13: 168 SS 57 22.8 8.7 ARD 2004; 63: 974 MS 85 8.2 5.9 J Neurol 2002; 249: 1088 RA 76 1.3 J Rheum 2004; 31: 482

Conclusions AHSCT- 2005 « 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 ?

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 Burt et al., AR 2004; 50: 2466 Pavletic, AR 2004; 50: 2387

High dose cyclophosphamide Immunoablation IV CPM: 50 mg/kg/d for 4 consecutive days Mesna (UromitexanR) G-CSF: 5 mg/kg/d starting day 10, until neutrophils ≥ 1,000/ml 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 Johns Hopkins Ann Intern Med 1998; 129: 1031

High dose cyclophosphamide 14 Refractory SLE patients 9 nephritis: 4 CR - 3 PR - 2 NR 2 cutaneous: 2 PR 3 CNS: 1 CR - 2 PR CR maintained up to 4 years No death Flare in 2 PR CR: no disease activity no treatment (except pred.: 5 mg/d) Petri et al. Arthritis Rheum 2003; 48: 166-173

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

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

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

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

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

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

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