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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
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Plan

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

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Indications
Tout rhumatisme systémique nest pas grevé dune
diminution du pronostic vital. Pas dindication
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 lt1
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PAN Five Factor Score Proteinuria 1g/d Renal
impairment CNS involvement GI involvement Cardiac
involvement
IV CPM only if FFS gt 1
L. Guillevin et al.
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Prognostic value of FFS in necrotizing vasculitis
Guillevin et al., 2001
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What is severe disease ?
ACTIVITY Fever Gangrene Polyneuropathy Rash Arthr
itis Glomerulonephritis Cytopenias Thrombosis Gran
d mal
DAMAGE Disease-related ESRD Deforming
arthropathy Cutaneous scarring Cognitive
impairment Optic atrophy Valvular disease APL
antibody-related Iatrogenic
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The iceberg of atherosclerosis in SLE
Bruce et al., Toronto
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Asanuma Y. et al.
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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
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Which therapeutic goals in a newly diagnosed LN
patient ?
To achieve prompt remission (i.e. proteinuria lt
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
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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
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Houssiau et al., Br J Rheumatol 1996 35 244-247
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Reduced bone mineral density in SLE
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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
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Cyclophosphamide therapy
IV pulse
Oral CPM
SLE DPM PSS PAN MPA ...
!?! WEGENER
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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
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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
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The 1st NIH trial
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The NIH regimen - Concern 1
Toxicity
NIH TRIALS (tage patients) NIH TRIALS (tage patients) NIH TRIALS (tage patients) NIH TRIALS (tage patients)
Side-effect Side-effect 1st 2nd 3rd
Infection Infection 10 5 26
H. zoster H. zoster 25 5 15
Ovarian failure Ovarian failure 45 38 52
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The NIH regimen - Concern 2
Appropriate for mild/early cases ?
Louvain LN Cohort (1985-2002)
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The changing picture of LN
Study from Heidelberg
1989-1989 1990-1999
Baseline proteinuria (g/l) 46 17
Baseline renal impairment () 40 17
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
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The NIH regimen - Concern 3
Does not prevent renal flares
Illei et al., Arthritis Rheum 2002 46 995-1002
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The revisited standard treatment of LN Sequential
use of cytotoxic therapies
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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
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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 taper GC by 2.5 mg
q2w plateau at 5-7.5 mg
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ELNT - Treatment failure
LD
HD
Free of Failure ()
HD
LD
HR 0.79 (CIs 0.30-2.14)

Follow-up (months)
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Houssiau et al., Arthritis Rheum, 2002 46
2121-2131
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ELNT - Remission
LD
HR 1.26 (CIs 0.72-2.21)
HD
Probability of remission
HD
LD
Remission lt 10 RBC/hpf, 24-h proteinuria lt 1g,
no DSC
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Houssiau et al., Arthritis Rheum, 2002 46
2121-2131
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ELNT - Early response to therapy
Houssiau et al., Arthritis Rheum, 2004 50
3934-3940
24h proteinuria (g)
Month 3
Month 6
Baseline
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Poor renal outcome
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Multivariate analysis of predictors of good
long-term renal outcome
Houssiau et al., Arthritis Rheum, 2004 50
3934-3940
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ELNT - Pathology
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Houssiau et al., Arthritis Rheum, 2004 50
3934-3940
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ELNT - Pathology
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Houssiau et al., Arthritis Rheum, 2004 50
3934-3940
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ELNT - Severe infections
Adverse event All (n 89) HD IV CPM (n 45) LD IV CPM (n 44)
Severe infections (n patients) 15 10 5
Episodes 24 17 7
Type Pneumonia Other bacterial inf. Cytomegalovirus Herpes zoster 7 6 4 7 4 5 3 5 3 1 1 2
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Houssiau et al., Arthritis Rheum, 2002 46
2121-2131
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Lesson from the ELNT
A short- course of low-dose IV CYC might be
enough in the induction phase
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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
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Induction versus maintenance therapy
Can we do better ?
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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
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Renal relapse rate
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El Hachmi et al. , Lupus 2003, 12 692-696
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Chronic renal impairment rate
Long-term studies ESRD ()
Illei et al., 2001 9
Houssiau et al., 2002 5
Contreras et al., 2004 8
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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
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Toxicity
NIH TRIALS (tage patients) NIH TRIALS (tage patients) NIH TRIALS (tage patients) NIH TRIALS (tage patients)
Side-effect Side-effect 1st 2nd 3rd
Infection Infection 10 5 26
H. zoster H. zoster 25 5 15
Ovarian failure Ovarian failure 45 38 52
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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 choice during the induction
phase ?
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MMF a new star twinkling in the sky
Lymphocytes, unlike most eukariotic cells, lack
the salvage pathway that also generates GTP
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Inhibitory properties of MPA
lymphocyte proliferation vascular smooth muscle
proliferation mesangial cell proliferation
inhibits glycosylation iNOS renal cortical
expression
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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
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FDA-sponsored Study
Ginzler E. et al. ACR meeting 2003
MMF IV CYC P
CR 20 6 0.014
PR 30 20 NS
CR PR 50 26 0.007
Rp switch 8 20 0.034
Sev. pyog. inf. 6 13 0.03
CR normal serum creatinine, proteinuria lt 0.5
g/d and inactive urinary sediment
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Unsolved issues
What is the optimal maintenance regime
? Quarterly IV CYC AZA MMF
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ELNT - Renal flares
LD
Free of renal flare ()
HD
HR 0.90 (CIs 0.40-2.04)
Follow-up (months)
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Houssiau et al., Arthritis Rheum, 2002
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Miami Study
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
Contreras et al. NEJM 2004 350 971
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Miami Study
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Miami Study

Contreras et al. NEJM 2004 350 971
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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
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MAINTAIN NEPHRITIS TRIAL
INDUCTION OF REMISSION
Glucocorticoids IV CYC mini-pulses 6 x 500 mg
q2 weeks
MAINTENANCE OF REMISSION
AZA
MMF
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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
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MMF vs AZA - The cost issue
MMF 4,000 /year (B)
AZA 400 /year (B)
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Refractory case ?
BEWARE !
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1 - SRD look alikes
Subacute endocarditis
Cholesterol emboli
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2 - Infection
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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 199556244-51
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3 - Lack of compliance
If you suspect a lack of compliance (females,
adolescents) add IV glucocorticoids
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4 - Too soft treatment
AZA 2 to 2.5 mg/kg 6TG titers ? MMF 2 to 3
g Pharmacogenomics ?
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The response to CYC might be related to
cytochrome P450 genetic polymorphism
CYP2B65 allele CYP2C192 allele Less active
enzyme Less CYC metabolites Less clinical activity
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The response to CYC might be related to
cytochrome P450 genetic polymorphism
Takada K et al., AR 2004 50 2202
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5 - Unexpected finding
Beware of unusual manifestations of an already
unusual disease
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Refractory disease ?
Look alikes Infections Damage Compliance Soft
treatment Unusual manifestation
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Bone marrow transplantation
Allogeneic Autologous Nonmyeloablative allogeneic
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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
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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., AR 2002 46 2917-2923
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EBMT/EULAR Autologous Haematopoietic Stem Cell
Transplantation data base
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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 (lt1-81) months
Farge et al., Ann Rheum Dis 2004 63 974
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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
(lt1-78) months
Jayne et al., Lupus 2004 13 168
32 relapses in patients with prior remission
66 remission (SLEDAI lt 3)
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AHSCT in SLE - Chigaco experience
15 SLE median follow-up 36 months (12-66)
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Mortality in AHSCT
N Death 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 1.3 J Rheum 2004 31 482
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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 Patients selection ? Optimal
conditioning regime ?
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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
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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
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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
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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
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Plasma exchanges
Removal of whole plasma 2 to 4 L/session 3
sessions/week Albumin substitution Hypogammaglobul
inaemia Increased risk of infections
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Plasma exchanges
Lewis et al. NEJM 1992 326 1373
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Plasma exchanges
Few controlled trials HBV-related PAN Vasculitis
with severe renal impairment and pulmonary
haemorrage Critically ill patients
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Biologics
Rituximab, Anti-CD22 mAb CTLA4-Ig TNF-alpha
blocking agents (CD40L blocking Ab) .
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Take home messages
Induction and maintenance
GC CYC - AZA
MMF ?
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Take home messages
Remain an internist!
Beware of toxicity
Optimal care prevention of infections and
cardiovascular mortality