1 Update on Systemic Lupus Update on Systemic Lupus Erythematosus Erythematosus (SLE) (SLE) Update on Systemic Lupus Update on Systemic Lupus Erythematosus Erythematosus (SLE) (SLE) Stacy P. Ardoin, MD, MHS Assistant Professor Clinical Medicine Adult and Pediatric Rheumatology Adult and Pediatric Rheumatology Nationwide Children’s Hospital Ohio State University Objectives Objectives Objectives Objectives • Present a case of a patient with SLE • Review long-term complications of SLE with focus on atherosclerosis • Discuss recent clinical trials in non- renal SLE renal SLE • Discuss good news about an old SLE drug (hydroxychloroquine)
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Update on Systemic Lupus Update on Systemic Lupus ErythematosusErythematosus (SLE)(SLE)
Update on Systemic Lupus Update on Systemic Lupus ErythematosusErythematosus (SLE)(SLE)
Stacy P. Ardoin, MD, MHS Assistant Professor Clinical Medicine
Adult and Pediatric RheumatologyAdult and Pediatric RheumatologyNationwide Children’s Hospital
Ohio State University
ObjectivesObjectivesObjectivesObjectives• Present a case of a patient with SLEp
• Review long-term complications of SLE
with focus on atherosclerosis
• Discuss recent clinical trials in non-
renal SLErenal SLE
• Discuss good news about an old SLE
drug (hydroxychloroquine)
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Case: NicoleCase: NicoleCase: NicoleCase: Nicole• 31 yr old
• 8 week history of fatigue, facial rash, hair loss, joint pain
• Past Medical History• 2 first trimester miscarriages
• Medications• multivitamin, oral contraceptive
• Soc HX:• Soc HX: • single, works full time, smokes ½ pack
Incidence of MI per 1000 person years in women with Incidence of MI per 1000 person years in women with SLE (Pittsburgh) and from the Framingham Offspring SLE (Pittsburgh) and from the Framingham Offspring Study: 1980Study: 1980--19931993
Age SLE Framingham Rate(yrs) (N=498) (N=2208) Ratio 95%CI
• Low Dose CYC: 500 mg every 2 weeks for 6 doses/Cumulative Dose 3g
Houssiau, et al., Arth Rheum, 2002
• High Dose CYC: 0.5‐1g/m2 monthly for 6 months, followed by 2 quarterly pulses/Cumulative Dose >8g
• Done mainly in Caucasians with mild‐moderate disease• The current Immune Tolerance Network CTLA4 Trial is using Euro‐
Lupus in African American, Asian, Hispanic, and Caucasian
Prevention of Kidney Failure in the LongPrevention of Kidney Failure in the Long--TermTerm
Austin, et al, NEJM, 1986 Gourley, et al, Ann Int Med, 1996
• These seminal studies, despite criticism of low numbers at follow‐up showed that the addition of CYC to steroids improved the long‐term outcome of kidneys in LN
• The benefit of CYC was not seen for about 3‐5 years• All new therapies/regimens should provide similar evidence to be generally
accepted as equivalent to CYC for long‐term kidney survival
months• Occurrence of steroid‐resistant flare• Doubling of SCr
Houssiau, et al., Arth Rheum, 2002; Ann Rheum Dis, 2010
Mean Follow‐Up 119 111
Mean Age 40 42
Deaths 2 5
Doubling SCr 5 6
ESRD 4 2
10 Year Follow‐Up
MAJOR NEW FINDINGS IN THE MAJOR NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LNTHERAPY OF PROLIFERATIVE LN
• LOW‐DOSE CYCLOPHOSPHAMIDE IS EFFECTIVE INDUCTION THERAPY IN SOME POPULATIONSINDUCTION THERAPY IN SOME POPULATIONS
• MMF AND IV CYCLOPSHOSPHAMIDE ARE EQUALLY EFFECTIVE AS INDUCTION THERAPY
• RITUXIMAB DOES NOT IMPROVE INDUCTIONRITUXIMAB DOES NOT IMPROVE INDUCTION THERAPY
• MMF MAY BE THE IMMUNOSUPPRESSIVE OF CHOICE FOR MAINTENANCE THERAPY
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MMF MMF vsvs CyclophosphamideCyclophosphamide
Black, H
ispan
icc, Mixed
•370 Class III/IV LN patients‐ALMS Trial
•Randomized to IV CYC pulses for 6 months or MMF 3 gm/d target dose for 6 months
Appel, et al., JASN, 2009 Isenberg, et al., Rheumatology, 2010
MMF Concerns and CaveatsMMF Concerns and Caveats•Despite ALMS results, and fact that ALMS was NOT designed as a non‐inferiority trial, it has increasingly become standard of care
•Although MMF is perceived as safer than CYC, ALMS showed a similar incidence of adverse events for MMF and CYC, including serious infections and death; while not statistically significant, there were almost twice as many withdrawals for side‐effects from the MMF arm
Adverse Events
MMF IVC
Chan, et al., JASN, 2005
•Long‐term outcomes are key for a true comparison with CYC
Deaths 9 (4.9%) 5 (2.8%)
W/drawals 24 (13%) 13 (7.2%)
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LongLong--Term Outcome After MMF TreatmentTerm Outcome After MMF Treatment
80
100u
re (%
)MMF AZA
20
40
60
80
Pat
ien
ts w
ith
Tx
fail
u
16%21%
36%
11%
28%32%
Data from the ALMS Maintenance Trial‐Ninth International Congress on SLE, Vancouver, 2010
0
Overall Induction MMF Induction IVC
P
LongLong--Term Outcome: MMF Term Outcome: MMF vsvs Oral CTXOral CTX
ProteinuriaNo Flare
Comparing induction with MMF to CYC, after median of 64 months there were no differences in renal function; however MMF group trended to have more relapses, prolonged proteinuria >1gm/d, and more subjects with SCr > 2 mg/dl, all risk factors for CKD.
Chan, et. al. JASN 2005
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Choosing Initial TherapyChoosing Initial Therapy
•Consider a full-dose CYC protocol for patients with severe, proliferative LN; severity is defined as rapidly progressive loss of kidney function, usually accompanied by widespread crescents and glomerular capillary necrosis
•WHY: IV CYC protocols have been used in prospective trials in patients with severe LN whereas MMF and Euro-lupus have mainly been used to treat mild-moderate LN
•Consider Euro-lupus, low-dose CYC protocol for Caucasian patients with mild-moderate LN
•WHY: Euro-lupus has not been tested in a BlackWHY: Euro lupus has not been tested in a Black population, a group that traditionally has more severe LN than Caucasians
•Consider MMF in those patients who have received CYC in the past and are near or above a life-time cumulative dose of 36 grams
Biomarkers of Renal Response Biomarkers of Renal Response A PostA Post--Hoc Analysis of ALMSHoc Analysis of ALMS
ODDS OF A RENAL RESPONSE AT 24 WEEKS BASED ON PARAMETER IMPROVEMENT AT 8 WEEKS‐MULTIVARIATE
MODEL
PARAMETER ODDS RATIO 95% CI
↓ proteinuria by ≥25% 2.9 1.6‐5.1
Normalization of C3/C4* 2.7 1.4‐5.0
Dall’Era et al., Arth Care Res, 2011
*only applicable if patients had baseline low C3 and C4
Do we need to think about changing therapy sooner during induction?
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Therapeutic Drug Monitoring for MMFTherapeutic Drug Monitoring for MMFImproving OutcomesImproving Outcomes
Lertdumrongluk et al., Kidney Int, 2010
• Responders have a higher mycophenolic acid area under the curve (12 hour) than non‐responders
• Response rate increases with increasing mycophenolic acid area under the curve
• This is not practical for most patients with LN undergoing MMF therapy
Therapeutic Drug Monitoring for MMFTherapeutic Drug Monitoring for MMFImproving OutcomesImproving Outcomes
• Need to have a practical way to determine therapeutic MMF dosing
• The trough and one hour peak MPA were significantly correlated with the MPA‐AUC and also response
• For trough MPA r=0.90• For 1 hour Peak MPA r=0.92• One may be able to use trough and
peak to optimize MMF dosing• Our recommendation:
Lertdumrongluk et al., Kidney Int, 2010
Dose MMF so that: Trough level is 3 mg/l 1 hour peak level is > 22 mg/l
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MAJOR NEW FINDINGS IN THE MAJOR NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LNTHERAPY OF PROLIFERATIVE LN
• LOW‐DOSE CYCLOPHOSPHAMIDE IS EFFECTIVE INDUCTION THERAPY IN SOME POPULATIONSINDUCTION THERAPY IN SOME POPULATIONS
• MMF AND IV CYCLOPSHOSPHAMIDE ARE EQUALLY EFFECTIVE AS INDUCTION THERAPY
• RITUXIMAB DOES NOT IMPROVE INDUCTIONRITUXIMAB DOES NOT IMPROVE INDUCTION THERAPY
• MMF MAY BE THE IMMUNOSUPPRESSIVE OF CHOICE FOR MAINTENANCE THERAPY
What About Rituximab?
Rituximab + MMF (n=72)Treatment Period
As suggested by the outcomes with CYC or MMF as initial therapy for proliferative LN, there is plenty of room for improvement in CR and PR rates!
Screening
Follow‐up PeriodPlacebo + MMF (n=72)
Prednisone taper
W kWeeks 1 and 2
(Days 1 and 15)
Week 16 Weeks
24 and 26
(Days 168 and 182)
Week 52
Week
78
= Study drug infusion.
= Corticosteroids: 2 doses of 1000 mg IV methlyprednisolone given on day 1 and day 2, 3, or 4. This was followed by oral prednisone initiated at 0.75 mg/kg/day and then tapered to10 mg/day by day 112
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Primary Endpoint: Renal Response at Week 52Primary Endpoint: Renal Response at Week 52
54.160ts
Placebo Rituximab
30.6
15.3
26.4 30.6
43.0
10
20
30
40
50
oportion of Patient
P=0.55*P=0.55*
0
10
Complete Renal Response (CRR)
Partial RenalResponse (PRR)
No Response (NR)
Pro
* Wilcoxon Rank‐sum test Mean MMF dose: Placebo: 2.4±0.62 g;Rituximab: 2.7±0.41 g
22/72 19/72 11/72 22/72 39/72 31/72
PrePre--Specified Analysis: Proportion of Specified Analysis: Proportion of SubjectsSubjectsAchieving Response by RaceAchieving Response by Race
70 080% Placebo Rituximab
45.0 47.8 50.0
70.0
55.0 52.6
20%
30%
40%
50%60%
70%
ponse Proportion
9/20 14/20 11/23 16/29 13/26 10/190%
10%20%
Black (n=40) Hispanic (n=52) Caucasian (n=45)
Res
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MAJOR NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LN
• LOW‐DOSE CYCLOPHOSPHAMIDE IS EFFECTIVE INDUCTION THERAPY IN SOME POPULATIONSINDUCTION THERAPY IN SOME POPULATIONS
• MMF AND IV CYCLOPSHOSPHAMIDE ARE EQUALLY EFFECTIVE AS INDUCTION THERAPY
• RITUXIMAB DOES NOT IMPROVE INDUCTIONRITUXIMAB DOES NOT IMPROVE INDUCTION THERAPY
• MMF MAY BE THE IMMUNOSUPPRESSIVE OF CHOICE FOR MAINTENANCE THERAPY
ALMS Maintenance TrialTime to Treatment
Failure, n=227
MAINTAIN Nephritis TrialMAINTAIN Nephritis TrialTime to FlareTime to Flare
Appel, ASN Denver 2010H i l A Rh Di 2010
Appel, ASN Denver 2010Houssiau et al., Ann Rheum Dis, 2010
• Open versus blinded (ALMS)• Different ethnic background• ALMS larger study• Composite endpoint in ALMS (ESRD, Flare, Double SCr, Rescue Meds)• Only patients with a response (including to MMF...) were entered in ALMS• In MAINTAIN patients were randomized for maintenance at baseline and given
maintenance after Euro‐Lupus no matter the response
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ApoptosisDeficient clearance1
Nucleosomes
Y Y
Y
Y Y YY
Y
Y
Y
YAnti-dsDNA
2
Nucleosome-IC depositionin glomerular capillaries
Complement activationFcR activationTLR activation
3
Y
Auto-reactiveB Cell
Auto-reactivePlasma Cell Y Y
Y Y
Production of pro-inflammatory cytokinese.g. C3a/C5a, MCP-1, IL-17, IL-18
Cell infiltration and activationMonocytes, Lymphocytes, pDCs
Increased production of cytokinesIFN‐a
Anti-C5(Eculizumab)
Anti-TLR
Anti-IFN-α
Anti-CD20(Rituximab, Ocrelizumab)
Anti-CD22(Epratuzumab)
Endothelial CellGBM
Podocyte
MΦMΦ
ROSProteases
ROSProteases
IL-6
Anti-IL-6(Tocilizumab)
CTLA4-Ig(Abatacept)
Y
Y
YY
Y
Y
YYYYY
Y YY
Accelerated autoimmune responselocal, Th1-skewed
Increased IC accumulation andcomplement and FcR activation