UCL Les traitements immunosuppresseurs dans les rhumatismes systémiques BR Lauwerys Service de...

UCLUCL

Les traitements immunosuppresseurs Les traitements immunosuppresseurs dans les rhumatismes systémiquesdans les rhumatismes systémiques

BR LauwerysBR LauwerysService de RhumatologieService de Rhumatologie

Cliniques Universitaires Saint-LucCliniques Universitaires Saint-Luc

Université catholique de LouvainUniversité catholique de Louvain

D.E.S. en Médecine InterneD.E.S. en Médecine Interne

Année académique 2004-2005Année académique 2004-2005

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PlanPlan

1.1. IndicationsIndications

2.2. Induction Induction versusversus Entretien Entretien

3.3.Cas réfractairesCas réfractaires

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IndicationsIndicationsTout rhumatisme systémique n’est pas grevé d’une Tout rhumatisme systémique n’est pas grevé d’une

diminution du pronostic vital.diminution du pronostic vital.

Pas d’indication de traitement immunosuppresseur dans Pas d’indication de traitement immunosuppresseur dans

LED avec arthrite / sérosite / rash / leucopénieLED avec arthrite / sérosite / rash / leucopénie

SS limitée ou diffuse avec atteinte purement cutanéeSS limitée ou diffuse avec atteinte purement cutanée

myopathies inflammatoires sans atteinte alvéolaire myopathies inflammatoires sans atteinte alvéolaire inflammatoireinflammatoire

vasculite nécrosante avec FSS <1vasculite nécrosante avec FSS <1

PAN Five Factor ScorePAN Five Factor Score

Proteinuria ≥ 1g/dProteinuria ≥ 1g/dRenal impairmentRenal impairmentCNS involvementCNS involvementGI involvementGI involvement

Cardiac involvementCardiac involvement

IV CPMIV CPMonly ifonly if

FFS > 1FFS > 1

L. Guillevin L. Guillevin et alet al..

Prognostic value of FFS Prognostic value of FFS

in necrotizing vasculitisin necrotizing vasculitis

Guillevin et al., 2001Guillevin et al., 2001

ACTIVITY

FeverGangrene

PolyneuropathyRash

ArthritisGlomerulonephritis

CytopeniasThrombosisGrand mal

DAMAGE

Disease-relatedESRD

Deforming arthropathyCutaneous scarring

Cognitive impairmentOptic atrophy

Valvular diseaseAPL antibody-related

Iatrogenic

What is severe disease ?

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Clinical disease: MI, angina6 % to 10 %

Subclinical disease:30 % to 40 %

Risk factors:hypercholesterolaemiahypertensionsteroid usehomocysteine

The iceberg of atherosclerosis in SLE

Bruce et al., Toronto

Asanuma Y. Asanuma Y. et alet al..

EFFICACYEFFICACY

TOXICITYTOXICITY

RELAPSESRELAPSES

The ideal The ideal remission - INDUCING remission - INDUCING

treatment is treatment is efficient and not toxicefficient and not toxic

The ideal The ideal remission - MAINTAINING remission - MAINTAINING

treatment treatment prevents relapsesprevents relapses

Induction Induction versusversus maintenance therapy maintenance therapy

The conceptThe concept

To To achieve prompt remissionachieve prompt remission ((i.e.i.e. proteinuria < 1g/d in the absence of impaired proteinuria < 1g/d in the absence of impaired renal function)renal function)

To To maintain remission andmaintain remission and prevent renal prevent renal flaresflares (very common and associated with a (very common and associated with a poor outcome)poor outcome)

To To avoid renal impairmentavoid renal impairment

With With minimal toxicityminimal toxicityUCLUCL

Which therapeutic goals in a Which therapeutic goals in a newly diagnosed LN patient ?newly diagnosed LN patient ?

GGGG Always consider dividing Always consider dividing the dose by two!the dose by two!

Gradual tapering down to Gradual tapering down to ‘physiological doses’‘physiological doses’

IV GC ‘pulses’IV GC ‘pulses’

Remission-inducing treatmentRemission-inducing treatment

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Reduced bone mineral density in SLE

Houssiau et al., Br J Rheumatol 1996; 35: 244-247 UCLUCL

Jardinet et al., Rheumatology 2000; 39: 389-392

Reduced bone mineral density in SLE

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CYCCYC Platinum standardPlatinum standardHighly toxic Highly toxic (bladder, ovaries, bone marrow)(bladder, ovaries, bone marrow)

Not always neededNot always needed

IV IV versusversus oral oral

Low- Low- versusversus high-dose IV high-dose IV

Remission-inducing treatmentRemission-inducing treatment

Cyclophosphamide therapyCyclophosphamide therapy

IV pulseIV pulse Oral CPMOral CPM

SLESLEDPMDPMPSSPSSPANPANMPAMPA

......

!?!!?!

WEGENERWEGENER

Austin 1985, Boumpas 1992, Gourley 1996, Illei 2001Austin 1985, Boumpas 1992, Gourley 1996, Illei 2001

The NIH regimenThe NIH regimenThe platinum standard for LNThe platinum standard for LN

extended course (≥ 30 months)extended course (≥ 30 months)

high (HD) IV CYChigh (HD) IV CYC

combined to GCcombined to GC

superior to oral or IV GC alonesuperior to oral or IV GC alone

The NIH regimen for LNThe NIH regimen for LN

IV CYCIV CYC 0.75 - 1 g/m0.75 - 1 g/m22

WBC nadir (d14): 1,500 - 4,000/WBC nadir (d14): 1,500 - 4,000/ll

monthly for 6 monthsmonthly for 6 months

quarterly for 1 year after CRquarterly for 1 year after CR

IV MPIV MP 1 g/m1 g/m22

monthly for 12 - 36 monthsmonthly for 12 - 36 months

The 1st NIH trial The 1st NIH trial

Austin et al., 1985

p < 0.05

The NIH regimen - Concern #1The NIH regimen - Concern #1

ToxicityToxicity

NIH TRIALSNIH TRIALS(%tage patients)(%tage patients)

Side-effectSide-effect 1st1st 2nd2nd 3rd3rd

InfectionInfection 1010 55 2626

H. zosterH. zoster 2525 55 1515

Ovarian failureOvarian failure 4545 3838 5252

Louvain LN Cohort(1985-2002)

The NIH regimen - Concern #2The NIH regimen - Concern #2Appropriate for mild/early cases ?Appropriate for mild/early cases ?

0

1

2

3

4

5

0.4 0.7 1 1.3 1.6 1.9 2.2

Se

rum

alb

um

in

Se

rum

alb

um

in (

g/dl

)(g

/dl)

SerumSerum creatininecreatinine (mg/dl)(mg/dl)

56 %56 %

16 %16 %

2 %2 %

26 %26 %

The changing picture of LNThe changing picture of LN

1989-19891989-1989 1990-19991990-1999

Baseline proteinuria (g/l)Baseline proteinuria (g/l) 4646 1717

Baseline renal impairment (%)Baseline renal impairment (%) 4040 1717

Chronicity on baseline biopsy (%)Chronicity on baseline biopsy (%) 3333 1010

Time delay to renal biopsy (m)Time delay to renal biopsy (m) 15.415.4 3.93.9

Study from HeidelbergStudy from Heidelberg

Fiehn C. Fiehn C. et al.et al. Ann Rheum Dis 2003; 62: 435-9 Ann Rheum Dis 2003; 62: 435-9

The NIH regimen - Concern #3The NIH regimen - Concern #3Does not prevent renal flaresDoes not prevent renal flares

Illei Illei et alet al., Arthritis Rheum 2002; 46: 995-1002., Arthritis Rheum 2002; 46: 995-1002

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The revisited standard treatment of LNThe revisited standard treatment of LNSequential use of cytotoxic therapiesSequential use of cytotoxic therapies

Induction of remissionInduction of remission

Short-course (a few months)Short-course (a few months)with a « incisive » immunosuppressantwith a « incisive » immunosuppressant

Maintenance of remissionMaintenance of remission

Long-term use (5 years ?)Long-term use (5 years ?)of a « safe » immunosuppressantof a « safe » immunosuppressant

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CYC IV NIH regimenCYC IV NIH regimenversusversus

CYC IV mini-pulses CYC IV mini-pulses (6 x 500 mg; q2weeks) (6 x 500 mg; q2weeks)

AZAAZA

Euro-Lupus Nephritis TrialEuro-Lupus Nephritis Trial

Induction of remissionInduction of remission

Maintenance of remissionMaintenance of remission

3 x 750 mg IV MP qd3 x 750 mg IV MP qd

6 x 500 mg IV CPM q2w6 x 500 mg IV CPM q2w

0.5 mg pred./kg/d 1 month0.5 mg pred./kg/d 1 month

INDUCTIONINDUCTION

AZA 2 mg/kg/d at 3mAZA 2 mg/kg/d at 3m

taper GC by 2.5 mg q2wtaper GC by 2.5 mg q2w

plateau at 5-7.5 mgplateau at 5-7.5 mg

MAINTENANCEMAINTENANCE

EURO-LUPUS regimen

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ELNT - Treatment failureFr

ee o

f Fa

ilure

(%

) LD

0 12 24 36 48 60

Follow-up (months)

50

60

70

80

90

100

0HR: 0.79 (CIs: 0.30-2.14)

LDHD

HD

Houssiau Houssiau et alet al., Arthritis Rheum, 2002; 46: 2121-2131., Arthritis Rheum, 2002; 46: 2121-2131UCLUCL

ELNT - RemissionELNT - Remission

Remission: < 10 RBC/hpf, 24-h proteinuria < 1g, no DSC

0

0.2

0.4

0.6

0.8

1

0 12 24 36 48 60

Follow-up (months)

LDPro

bab

ility

of r

em

issi

on

LD

HD

HR: 1.26 (CIs 0.72-2.21)

HD

UCLUCL Houssiau Houssiau et alet al., Arthritis Rheum, 2002; 46: 2121-2131., Arthritis Rheum, 2002; 46: 2121-2131

ELNT - Early response to therapyELNT - Early response to therapy

00

11

22

33

44

55

BaselineBaseline Month 3Month 3 Month 6Month 6

24h

pro

tein

uri

a (g

)24

h p

rote

inu

ria

(g)

Good renal outcomeGood renal outcome Poor renal outcomePoor renal outcome UCLUCL

pp = 0.018 = 0.018

pp = 0.011 = 0.011

Adjustment for baseline Adjustment for baseline creatinine by ANCOVAcreatinine by ANCOVA

ANOVAANOVApp = 0.0003 = 0.0003

Houssiau Houssiau et alet al., Arthritis Rheum, 2004; 50: 3934-3940., Arthritis Rheum, 2004; 50: 3934-3940

Multivariate analysis of predictors of Multivariate analysis of predictors of good long-term renal outcomegood long-term renal outcome

Variable P OR 95% CI

____________________________________________________________________Age (< 30 years) 0.99 1.0 0.2-5.1Gender (female) 0.98 0 NABaseline diastolic pressure (< 90 mm Hg) 0.77 1.3 0.3-5.9Baseline serum creatinine (< 1.4 mg/dl) 0.06 7.7 0.9-65.6Baseline serum albumin (≥ 3 g/dl) 0.31 0.4 0.1-2.2Baseline 24h proteinuria (< 3 g) 0.81 0.8 0.1-4.6WHO class (III or Vc) 0.32 0.3 0-3.4Activity index (< 10) 0.53 2.0 0.2-18.4Chronicity index (<1) 0.11 4.0 0.7-21.9Treatment allocation (HD IV CYC) 0.33 0.4 0.1-2.3ACEI use (yes) 0.34 2.3 0.4-12.5Serum creatinine at 6 months (drop) 0.01 14.9 2.0-111.824h proteinuria at 6 months (< 1 g) 0.03 6.3 1.2-34.4

____________________________________________________________________


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0

5

10

15

20

Act

ivity

inde

x (m

ean

± S

EM

)

LD group

FollowupBaseline

HD group

p = 0.013

p = 0.001

ELNT - PathologyELNT - Pathology


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ELNT - PathologyELNT - Pathology


ELNT - Severe infectionsELNT - Severe infections

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Adverse eventAdverse event AllAll

(n = 89)(n = 89)

HDHD

IV CPMIV CPM(n = 45)(n = 45)

LDLD

IV CPMIV CPM(n = 44)(n = 44)

Severe infections Severe infections (n patients)(n patients) 1515 1010 55

EpisodesEpisodes 2424 1717 77

TypeType

PneumoniaPneumonia

Other bacterial inf.Other bacterial inf.

CytomegalovirusCytomegalovirus

Herpes zosterHerpes zoster

77

66

44

77

44

55

33

55

33

11

11

22


A short- course of A short- course of low-dose IV CYC low-dose IV CYC

might be enough in might be enough in the induction phasethe induction phase

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Lesson from the ELNT

IV CYC therapyIV CYC therapyVaccinations are safe and efficient Vaccinations are safe and efficient

in patients with systemic in patients with systemic rheumatic disorders.rheumatic disorders.

Vaccination with pneumococcal Vaccination with pneumococcal antigens is required before antigens is required before

starting CYC therapystarting CYC therapy

Life attenuated vaccines should Life attenuated vaccines should be avoided in be avoided in

immunocompromised patientsimmunocompromised patientsUCLUCL

Induction Induction versusversus maintenance maintenance therapytherapy

Can we do better ?Can we do better ?

Renal remission rateRenal remission rate

StudyStudy (GC + ISD arm) (GC + ISD arm) RemissionRemission(%)(%)

Gourley Gourley et alet al., 1996., 1996 65 - 7565 - 75

Chan Chan et alet al., 2000., 2000 76 - 8176 - 81

Houssiau Houssiau et alet al., 2002., 2002 54 - 7154 - 71

Contreras Contreras et alet al., 2004., 2004 8383

Renal relapse rateRenal relapse rate46 LN patients diagnosed and followed-up at UCL46 LN patients diagnosed and followed-up at UCL

(64 ± 49 months)(64 ± 49 months)

Relapse rate: Relapse rate: 37 %37 %40 ± 24 (mean ± SD) months after diagnosis of LN40 ± 24 (mean ± SD) months after diagnosis of LN

80 % on AZA by the time of flaring80 % on AZA by the time of flaring

El Hachmi El Hachmi et alet al. , Lupus 2003, 12: 692-696. , Lupus 2003, 12: 692-696 UCLUCL

Chronic renal impairment rateChronic renal impairment rate

Long-term studiesLong-term studies ESRDESRD(%)(%)

Illei Illei et alet al., 2001., 2001 99

Houssiau Houssiau et alet al., 2002., 2002 55

Contreras Contreras et alet al., 2004., 2004 88

Prognostic factorsPrognostic factorsAfro-American raceAfro-American race

Poor socio-economic statusPoor socio-economic status

Non-complianceNon-compliance

Severe clinical onsetSevere clinical onset

High CI, AIHigh CI, AI

Uncontrolled hypertensionUncontrolled hypertension

Renal relapseRenal relapse

Poor initial response to therapyPoor initial response to therapy

ToxicityToxicity

NIH TRIALSNIH TRIALS(%tage patients)(%tage patients)

Side-effectSide-effect 1st1st 2nd2nd 3rd3rd

InfectionInfection 1010 55 2626

H. zosterH. zoster 2525 55 1515

Ovarian failureOvarian failure 4545 3838 5252

LN: key figuresLN: key figures

Remission rateRemission rate :: 80%80%

Relapse rate:Relapse rate: 35%35%

ESRD:ESRD: 5-10%5-10%

Side-effects:Side-effects: ++++++

LN impacts survivalLN impacts survival

N+

Euro-Lupus ProjectEuro-Lupus Project

N-

Is IV CYC the best Is IV CYC the best choice during the choice during the induction phase ?induction phase ?

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Unsolved issuesUnsolved issues

Lymphocytes, unlike most eukariotic cells, lack Lymphocytes, unlike most eukariotic cells, lack

the salvage pathway that also generates GTPthe salvage pathway that also generates GTP

MMF: a new star twinkling in the skyMMF: a new star twinkling in the sky

Inhibitory properties of MPAInhibitory properties of MPA

lymphocyte proliferationlymphocyte proliferation

vascular smooth muscle proliferationvascular smooth muscle proliferation

mesangial cell proliferation mesangial cell proliferation

inhibits glycosylationinhibits glycosylation

iNOS renal cortical expressioniNOS renal cortical expression

Short-term (Short-term (24 weeks24 weeks) remission-) remission-induction study comparing MMF induction study comparing MMF

and NIH IV CYC in and NIH IV CYC in 140140 LN patients LN patients

MMF: maximum tolerated dose, MMF: maximum tolerated dose, adad 3 g/d3 g/d; 63% reached 3 g !; 63% reached 3 g !

FDA-sponsored Study

Ginzler E. et al. ACR meeting 2003Ginzler E. et al. ACR meeting 2003

Can MMF replace IV Can MMF replace IV CYC for induction ?CYC for induction ?

FDA-sponsored Study

MMFMMF IV CYCIV CYC PP

CRCR 20%20% 6%6% 0.0140.014

PRPR 30%30% 20%20% NSNS

CR + PRCR + PR 50%50% 26%26% 0.0070.007

Rp switchRp switch 8%8% 20%20% 0.0340.034

Sev. pyog. inf.Sev. pyog. inf. 66 1313 0.030.03

CR: normal serum creatinine, proteinuria < 0.5 g/d and inactive urinary sedimentCR: normal serum creatinine, proteinuria < 0.5 g/d and inactive urinary sediment

Ginzler E. Ginzler E. et alet al. ACR meeting 2003. ACR meeting 2003

What is the optimal What is the optimal maintenance regime maintenance regime

??

Quarterly IV CYCQuarterly IV CYCAZAAZAMMFMMF UCLUCL

Unsolved issuesUnsolved issues

ELNT - Renal flaresELNT - Renal flares

Houssiau Houssiau et alet al., Arthritis Rheum, 2002., Arthritis Rheum, 2002

0 12 24 36 48 60

LD

HD

100

80

60

40

20

0

Follow-up (months)

Fre

e o

f re

nal

flare

(%

)

LDHD

HR: 0.90 (CIs: 0.40-2.04)

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Miami StudyMiami Study

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

Induction therapyInduction therapy

IV CYC pulses: 4 to 7 qm (541 ± 40 mg/m2)IV CYC pulses: 4 to 7 qm (541 ± 40 mg/m2)Prednisone:Prednisone: 0.6 ± 0.3 mg/kg/d (0 -3 mo)0.6 ± 0.3 mg/kg/d (0 -3 mo)

0.3 ± 0.2 mg/kg/d (4 to 6 mo)0.3 ± 0.2 mg/kg/d (4 to 6 mo)

Maintenance therapyMaintenance therapy

IV CYC: 0.5 to 1 g/m2 q3m (25 mo)IV CYC: 0.5 to 1 g/m2 q3m (25 mo)AZA: 1 to 3 mg/kg/d (29 mo)AZA: 1 to 3 mg/kg/d (29 mo)MMF: 500 to 3000 mg/d (30 mo)MMF: 500 to 3000 mg/d (30 mo)

Prednisone:Prednisone: 0.21 ± 0.15 IV CYC0.21 ± 0.15 IV CYC0.12 ± 0.13 MMF0.12 ± 0.13 MMF0.15 ± 0.14 AZA0.15 ± 0.14 AZA

Contreras et al. NEJM 2004; 350: 971

p = 0.02


**

**

**

**

**

****


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

European based multicenter trial comparing European based multicenter trial comparing AZA and MMF as remission-maintaining AZA and MMF as remission-maintaining

therapy of proliferative LN after remission-therapy of proliferative LN after remission-inducing treatment with IV CYCinducing treatment with IV CYC

MAINTAINMAINTAIN NEPHRITIS TRIAL NEPHRITIS TRIAL

Euro-Lupus Nephritis Trial GroupEuro-Lupus Nephritis Trial Group

CoordinatorCoordinatorFrédéric A. HoussiauFrédéric A. Houssiau

Université de Louvain - BelgiumUniversité de Louvain - Belgium

INDUCTION OF REMISSIONINDUCTION OF REMISSION

GlucocorticoidsGlucocorticoids

IV CYC mini-pulses : 6 x 500 mg q2 weeksIV CYC mini-pulses : 6 x 500 mg q2 weeks

MAINTENANCE OF REMISSIONMAINTENANCE OF REMISSION

AZAAZA MMFMMF

MAINTAINMAINTAIN NEPHRITIS TRIAL NEPHRITIS TRIAL

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MMF - Toxicity in LNMMF - Toxicity in LNVery good toxicity profileVery good toxicity profileBetter in LN than in tranplant patientsBetter in LN than in tranplant patients

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

MMF MMF vsvs AZA - The cost issue AZA - The cost issue

MMFMMF4,000 €/year 4,000 €/year (B)(B)

AZAAZA400 €/year 400 €/year (B)(B)

BEWARE !BEWARE !

Refractory case ?Refractory case ?

#1 - SRD look alikes

Cholesterol emboliCholesterol emboliSubacute endocarditisSubacute endocarditis

#2 - InfectionInfection

#3 - Lack of compliance#3 - Lack of compliance

Lin Lin et alet al., Zhonghua Yi Xue Za Zhi 1995;56:244-51., Zhonghua Yi Xue Za Zhi 1995;56:244-51

329 SLE patients329 SLE patients

25.5 % non-compliant with 25.5 % non-compliant with prescribed GC regime during the prescribed GC regime during the past weekpast week

Reasons: feeling better, fearing Reasons: feeling better, fearing SE, use of alternative therapiesSE, use of alternative therapies

#3 - Lack of compliance#3 - Lack of compliance

If you suspect a lack of If you suspect a lack of compliance (females, compliance (females,

adolescents)adolescents)

add IV glucocorticoidsadd IV glucocorticoids

#4 - Too soft treatment#4 - Too soft treatment

AZA: 2 to 2.5 mg/kgAZA: 2 to 2.5 mg/kg

6TG titers ?6TG titers ?

MMF: 2 to 3 gMMF: 2 to 3 g

Pharmacogenomics ?Pharmacogenomics ?

The response to CYC might be related to The response to CYC might be related to cytochrome P450 genetic polymorphismcytochrome P450 genetic polymorphism

CYP2B6*5 alleleCYP2B6*5 allele

CYP2C19*2 alleleCYP2C19*2 allele

Less active enzymeLess active enzyme

Less CYC Less CYC metabolitesmetabolites

Less clinical Less clinical activityactivity

The response to CYC might be related to The response to CYC might be related to cytochrome P450 genetic polymorphismcytochrome P450 genetic polymorphism

Takada K Takada K et alet al., A&R 2004; 50: 2202., A&R 2004; 50: 2202

#5 - Unexpected finding#5 - Unexpected finding

Beware of unusual Beware of unusual manifestations of manifestations of

an already unusual an already unusual diseasedisease

Refractory disease ?Refractory disease ?Look alikesLook alikesInfectionsInfectionsDamageDamageComplianceComplianceSoft treatmentSoft treatmentUnusual manifestationUnusual manifestation

Bone marrow transplantationBone marrow transplantation

Allogeneic Allogeneic

AutologousAutologous

Nonmyeloablative allogeneicNonmyeloablative allogeneic

Allogeneic bone marrow transplantation (ABMT)

11: : MyeloablationMyeloablation to delete host immune system to delete host immune system

Conditioning regimeConditioning regime

Chemotherapy/Irradation Chemotherapy/Irradation

22: : TransplantationTransplantation

Allogeneic HLA-matched BMAllogeneic HLA-matched BM

Haematological malignanciesHaematological malignancies

Serendipitous cure of coincidental AIDSerendipitous cure of coincidental AID

15% mortality (? EVDN)15% mortality (? EVDN)

Graft-Versus-HostGraft-Versus-Host Disease Disease

If the autoimmune diathesis resides at the If the autoimmune diathesis resides at the level of the HSC, cure is achievablelevel of the HSC, cure is achievable

Autologous Haematopoietic Stem Cell Transplantation

11: : Mobilization of CD34 HSCMobilization of CD34 HSC

IV CYCIV CYC : 2.0 gm/m : 2.0 gm/m22 and and G-CSFG-CSF (5 (5 g/kg/d)g/kg/d)

Leukapheresis 10-12 days laterLeukapheresis 10-12 days later

Purification of CD34 HSC ± T-cell depletion (purging)Purification of CD34 HSC ± T-cell depletion (purging)

CryopreservationCryopreservation

22: : MyeloablationMyeloablation

IV CYCIV CYC (200 mg/kg in 4 divided daily doses (200 mg/kg in 4 divided daily doses of 50 mg/kg) combined with of 50 mg/kg) combined with ATGATG (90 mg/kg (90 mg/kg in 3 divided daily dose of 30 mg/kg) in 3 divided daily dose of 30 mg/kg)


Infusion of thawed CD34 HSCInfusion of thawed CD34 HSCTraynor Traynor et alet al., The Lancet 2000; 356: 701-707., The Lancet 2000; 356: 701-707

Traynor Traynor et alet al., A&R 2002; 46: 2917-2923., A&R 2002; 46: 2917-2923

QuickTime™ et undécompresseur TIFF (LZW)sont requis pour visionner cette image.

EBMT/EULAR Autologous

Haematopoietic Stem Cell Transplantation

data base

57 patients (50 diffuse)57 patients (50 diffuse)

Median disease duration: 36 (2-159) monthsMedian disease duration: 36 (2-159) months

Lung disease: 57 %Lung disease: 57 %

Median followup: 20 (<1-81) monthsMedian followup: 20 (<1-81) months

Farge Farge et alet al., Ann Rheum Dis 2004; 63: 974., Ann Rheum Dis 2004; 63: 974

Autologous Haematopoietic Stem Cell Transplantation in systemic sclerosis

53 patients (65% renal involvement)53 patients (65% renal involvement)

Median disease duration: 60 (2-236) monthsMedian disease duration: 60 (2-236) months

Prior cyclophosphamide: 86 %Prior cyclophosphamide: 86 %

Median followup: 23 (<1-78) monthsMedian followup: 23 (<1-78) months

66% remission (SLEDAI < 3)66% remission (SLEDAI < 3)

32% relapses in patients with 32% relapses in patients with prior remissionprior remission

Jayne Jayne et alet al., Lupus 2004; 13: 168., Lupus 2004; 13: 168

Autologous Haematopoietic Stem Cell Transplantation in SLE

AHSCT in SLE - Chigaco experience

15 SLE15 SLE

median follow-up: median follow-up: 36 months (12-66)36 months (12-66)

Traynor et al., The Lancet 2000; 356: 701-707

Traynor et al., A&R 2002; 46: 2917-2923

Mortality in AHSCTMortality in AHSCT

NN DeathDeath%%

TRDTRD%%

ReferenceReference

SLESLE 5353 22.622.6 13.213.2 Lupus 2004; 13: 168Lupus 2004; 13: 168

SSSS 5757 22.822.8 8.78.7 ARD 2004; 63: 974ARD 2004; 63: 974

MSMS 8585 8.28.2 5.95.9 J Neurol 2002; 249: 1088J Neurol 2002; 249: 1088

RARA 7676 1.31.3 1.31.3 J Rheum 2004; 31: 482J Rheum 2004; 31: 482

Conclusions AHSCT- 2005Conclusions AHSCT- 2005

« Effective » in most patients« Effective » in most patientsNo controled trials so farNo controled trials so farRelapses are commonRelapses are commonHSCT offers no cure of AIDHSCT offers no cure of AIDHigh treatment-related mortalityHigh treatment-related mortalityPatient’s selection ?Patient’s selection ?Optimal conditioning regime ?Optimal conditioning regime ?

Nonmyeloablative allogeneic HSCTNonmyeloablative allogeneic HSCT

11: : MildMild Conditioning regimeConditioning regime

Lower mortalityLower mortality

No complete immediate host immune system deletionNo complete immediate host immune system deletion


Allogeneic HLA-matched CD34 HSCAllogeneic HLA-matched CD34 HSC

Mixed chimerismMixed chimerismGradual conversion to full donor engraftmentGradual conversion to full donor engraftmentAdvantage of allogeneic BMT (the only one that Advantage of allogeneic BMT (the only one that potentially cures AID) with lower toxicitypotentially cures AID) with lower toxicity

Pavletic, AR 2004; 50: 2387Pavletic, AR 2004; 50: 2387

Burt Burt et alet al., AR 2004; 50: 2466., AR 2004; 50: 2466

High dose cyclophosphamideImmunoablation

Johns Hopkins Ann Intern Med 1998; 129: 1031

IV CPM: 50 mg/kg/d for 4 consecutive daysIV CPM: 50 mg/kg/d for 4 consecutive days

Mesna Mesna (Uromitexan(UromitexanRR))

G-CSF: 5 G-CSF: 5 g/kg/d starting day 10, g/kg/d starting day 10, until neutrophils ≥ 1,000/until neutrophils ≥ 1,000/ll

Not myeloablativeNot myeloablativeNo need for stem cell rescueNo need for stem cell rescue

(Stem cells strongly express aldehyde dehydrogenase which (Stem cells strongly express aldehyde dehydrogenase which inactivates aldophosphamide)inactivates aldophosphamide)

Dapsone: 3 x 100 mg/week for 6 monthsDapsone: 3 x 100 mg/week for 6 months

Petri et al.

Arthritis Rheum 2003; 48: 166-173

14 Refractory SLE patients

High dose cyclophosphamide

9 nephritis: 9 nephritis: 4 CR - 3 PR - 2 NR4 CR - 3 PR - 2 NR

2 cutaneous:2 cutaneous: 2 PR2 PR

3 CNS:3 CNS: 1 CR - 2 PR1 CR - 2 PR

CR: CR: no disease activityno disease activityno treatment (except pred.: 5 mg/d)no treatment (except pred.: 5 mg/d)

CR maintained up to 4 yearsCR maintained up to 4 years

No deathNo death

Flare in 2 PRFlare in 2 PR

Conclusions High-dose IV CYCConclusions High-dose IV CYC

« Easier » than AHSCT« Easier » than AHSCTSeems effective in lupus nephritisSeems effective in lupus nephritisNo death so far (luck ?)No death so far (luck ?)Limited experienceLimited experienceG-CSF incriminated in SLE flaresG-CSF incriminated in SLE flaresDelayed haematopoietic recoveryDelayed haematopoietic recovery

Plasma exchangesPlasma exchangesRemoval of whole plasmaRemoval of whole plasma

2 to 4 L/session2 to 4 L/session

3 sessions/week3 sessions/week

Albumin substitutionAlbumin substitution

HypogammaglobulinaemiaHypogammaglobulinaemia

Increased risk of infectionsIncreased risk of infections

Plasma exchangesPlasma exchanges

Lewis et al. NEJM 1992; 326: 1373

Plasma exchangesPlasma exchangesFew controlled trialsFew controlled trials

HBV-related PANHBV-related PAN

Vasculitis with severe renal Vasculitis with severe renal impairment and pulmonary impairment and pulmonary

haemorragehaemorrage

Critically ill patientsCritically ill patients

BiologicsBiologics

Rituximab, Anti-CD22 mAbRituximab, Anti-CD22 mAb

CTLA4-IgCTLA4-Ig

TNF-alpha blocking agentsTNF-alpha blocking agents

(CD40L blocking Ab)(CD40L blocking Ab)

……. .

Take home messagesTake home messages

Induction and maintenanceInduction and maintenance

MMF ?MMF ?

GC + CYC - AZAGC + CYC - AZA

Take home messagesTake home messages

Remain an “internist”!Remain an “internist”!

Optimal care = prevention of Optimal care = prevention of infections and cardiovascular infections and cardiovascular mortalitymortality

Beware of toxicityBeware of toxicity

UCL Les traitements immunosuppresseurs dans les rhumatismes systémiques BR Lauwerys Service de...

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