1. 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
UCL

2. Plan
Indications
Induction versus Entretien
Cas réfractaires
UCL

3. 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

4. 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.

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

6. 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

7. 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

8. Asanuma Y. et al.

9. 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

10. 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

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

12. UCL

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

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

15. UCL

16. UCL

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

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

19. 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

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

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

22. 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

23. 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
( )

24. The changing picture of LN
Study from Heidelberg
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

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

26. 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

27. 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

28. 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 mg
UCL

29. 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: ) 12 24 36 48 60
Follow-up (months)
UCL
Houssiau et al., Arthritis Rheum, 2002; 46:

30. Houssiau et al., Arthritis Rheum, 2002; 46: 2121-2131
ELNT - Remission . 2 4 6 8 1
HR: 1.26 (CIs ) 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:

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

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

33. 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:

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

35. 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:

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

37. 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

38. Induction versus maintenance therapy
Can we do better ?

39. Renal remission rate Study (GC + ISD arm) Remission (%)
Gourley et al., 1996
Chan et al., 2000
Houssiau et al., 2002
Contreras et al., 2004 83

40. 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:
UCL

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

42. 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

43. 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

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

45. LN impacts survival
Euro-Lupus Project N- N+

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

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

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

49. 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

50. 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

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

52. 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: ) 12 24 36 48 60
Follow-up (months)
UCL
Houssiau et al., Arthritis Rheum, 2002

53. 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

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

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

56. 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

57. 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

58. 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

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

60. Refractory case ?
BEWARE !

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

62. #2 - Infection

63. #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

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

65. #4 - Too soft treatment
AZA: 2 to 2.5 mg/kg
6TG titers ?
MMF: 2 to 3 g
Pharmacogenomics ?

66. 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

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

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

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

73. Bone marrow transplantation Nonmyeloablative allogeneic
Autologous
Nonmyeloablative allogeneic

74. 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

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

76. EBMT/EULAR Autologous Haematopoietic Stem Cell Transplantation data base

77. 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

78. 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)

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

80. 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

81. 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 ?

82. 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

83. 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

84. 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:

85. 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

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

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

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

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

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

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