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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 MHSStacy P. Ardoin, MD, MHS Assistant Professor Clinical Medicine

Adult and Pediatric RheumatologyNationwide Children’s Hospital

Ohio State University

ObjectivesObjectivesObjectivesObjectives• Present a case of a patient with SLE

• Review long-term complications of SLE

with focus on atherosclerosiswith focus on atherosclerosis

• Discuss recent clinical trials in non-

renal SLE

• Discuss good news about an old SLE

drug (hydroxychloroquine)

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 miscarriagesg

• Medications• multivitamin, oral contraceptive

• Soc HX: • single, works full time, smokes ½ pack

cigarettes daily• FHX:

• Hypertension, DM-2, no autoimmune disease

Case: NicoleCase: NicoleCase: NicoleCase: Nicole• Exam:

• HR 105, BP 147/90 • malar rash • polyarticular arthritis

L b• Labs: • WBC 2,200 (absolute lymphocytes 800)• H/H 10.5/32 • ESR 45 mm/hr• Urinalysis with 100 mg/dl protein, 15 RBCs• +ANA, +double stranded DNA, +anticardiolipin IgG• Low C3 and C4

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ACR 1997 Classification CriteriaACR 1997 Classification Criteria

• Malar rash

• Discoid rash

• Photosensitivity

• Oral/nasal ulcers

• Cytopenia

• Encephalopathy– seizure or psychosis

• ANA

S l• Non-erosive

arthritis

• Pleuritis/pericarditis

• Nephritis

• Serology– anti-double stranded

DNA

– anti-Smith

– anti-phospholipid antibody

ACR 1997 Classification CriteriaACR 1997 Classification Criteria

• Malar rash

• Discoid rash

• Photosensitivity

• Oral/nasal ulcers

• Cytopenia

• Encephalopathy– seizure or psychosis

• ANA

S l• Non-erosive

arthritis

• Pleuritis/pericarditis

• Nephritis

• Serology– anti-double stranded

DNA

– anti-Smith

– anti-phospholipid antibody

4 OF 11 CRITERIA GIVES 96% SENSITIVITY/SPECIFICITY

Pathophysiology of SLEPathophysiology of SLEExposure(s)

Immune dysregulation

Susceptible host

TissueTissue damagedamage



Susceptible hostGenes Gender/Sex Hormones


3



UV lightDrugsInfectious agents

Susceptible hostGenes Gender/Sex Hormones




UV lightDrugsInfectious agents

Complement activationImmune complex deposits

Susceptible host

Immune complex depositsB and T cell hyper-reactivityLoss of self toleranceAutoantibodiesCytokines

Genes Gender/Sex Hormones


Lymphocyte proliferation

MHC class II expression (HLA DR)

Immune cell maturation

Macrophage, B and T

lymphocyte

Autoantibody formation and autoreactivity

Immune Dysregulation in SLEImmune Dysregulation in SLE

maturation (e.g., CD40,

B7)

Inflammatory cytokines

Adhesion molecules

Endothelial NO synthase

lymphocyte activation

Vessel inflammation

Vasculitis and organ damage

Survival in SLESurvival in SLESurvival in SLESurvival in SLE5 year 10 year

Adult 95% 90%

Pediatric1975 83% 76%

Predictors of poor outcomeChildhood onsetLow SESHealth care accessEducationRace/ethnicity

1975

2003

83%

99%

76%

86%

Male genderDisease activityCNSRenal

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The Bimodal Mortality Pattern of SLEThe Bimodal Mortality Pattern of SLE

Death

CV Disease

Death

Time

SLEInfection

Urowitz M Am J Med 1976; 60: 221

Causes of Death in SLECauses of Death in SLE• Early: Within first 5 years of diagnosis

Active SLE Infection

Abu-Shakra M, et al. J Rheum 1995; 1265-70

• Late: > 5 years since diagnosis InfectionAtherosclerosisMalignancy

MalignancyMalignancyMalignancyMalignancy• Increased incidence in SLE

– Cervical HPV infection and cancer

– Hodgkins lymphoma

– Lung cancer

– Breast cancer

• Hydroxychloroquine protective?

• Malignancy screening and prevention key

Nath Arthritis Rheum 2007, Bin Lung Cancer 2007, Bernatsky Rheumatology 2007, Bernatsky J Rheum 2003, Ruiz-Irastoyoa Ann Rheum 2007.

AtherosclerosisAtherosclerosis• Increased incidence and

earlier presentation in SLE

• Bland vasculopathy (not vasculitis)

• Independent of Framingham risk factors, glucocorticoid use

• “Lupus factor” elusive– Inflammation, dyslipidemia,

autoantibodies

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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

15-24 6.33 0.00 25 34 3 66 0 0025-34 3.66 0.00 35-44 8.39 0.16 52.43 [21.6, 98.5]45-54 4.82 1.95 2.47 [0.8, 6.0]55-64 8.38 1.99 4.21 [1.7, 7.9]

Manzi, et al. Am J Epidemiol, 1997

15202530354045

%

Role of Traditional Risk FactorsRole of Traditional Risk FactorsRole of Traditional Risk FactorsRole of Traditional Risk Factors

• High frequency of CV risk factors in SLE.

• After adjusting for CHD i k i th

05

1015

1 2 3 4 5 6 7 8

# risk factors

risk using the Framingham risk factor estimate, patients with SLE still had a 7- to 10-fold increased risk of CHD and stroke.

Esdaile JM, Arthritis Rheum 2001

89.7% have > 3 CV risk factors

19001900 19101910 19201920 19301930 19401940 19501950 19601960 19701970 19801980 19901990 20002000 20102010 20112011

AspirinLeflunomide*

Hydroxychloroquine

Cyclophosphamide*

Timeline for SLE Drug DevelopmentTimeline for SLE Drug Development

Methotrexate*

19001900 19101910 19201920 19301930 19401940 19501950 19601960 19701970 19801980 19901990 20002000 20102010 20112011

Glucocorticoids

Rituximab*

Azathioprine*

* Not an FDA approved indication

Mycophenolate mofetil*

Belimumab

Treatment of SLETreatment of SLETreatment of SLETreatment of SLE• Tailored to organ involvement

• Few controlled trials

Mild diseaseMild disease

HydroxychloroquineHydroxychloroquineNSAIDsNSAIDsLow dose corticosteroidsLow dose corticosteroidsM th t tM th t t

Severe disease

MethotrexateMethotrexateLeflunomideLeflunomideAzathioprineAzathioprineBelimumabBelimumabHigh dose corticosteroidsHigh dose corticosteroidsMycophenolateMycophenolate mofetilmofetilCyclophosphamideCyclophosphamide

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EXPLORER TRIALRituximab to Treat Non-Renal SLE

Study Design

EXPLORER TRIALRituximab to Treat Non-Renal SLE

Study Design

Active non-renal SLE (n=257)

Placebo (days 1 15 158 162)Rituximab (days 1 15 168 182)

Background immunosuppression

52 wk follow up

Mean age 40.4yNonwhite 42%

Primary EndpointPrimary Endpoint: major or partial clinical : major or partial clinical response (BILAG)response (BILAG)

Placebo (days 1, 15, 158, 162)Prednisone taper

(n= 189)

Rituximab (days 1, 15, 168, 182)Prednisone taper

(n=88)

Secondary Endpoints: Time to disease flare

Quality of lifeMerrill JT, et al. Arthritis Rheum. 2010; 62:222-33

EXPLORER Trial: Proportion of patients with major, partial or no clinical response at 52 weeks

EXPLORER Trial: Proportion of patients with major, partial or no clinical response at 52 weeks

50

60

70

80

P = 0.9750

tie

nts

(%

)

0

10

20

30

40

No Clinical Response

Partial Clinical Response

Major Clinical Response

Major + Partial

Placebo

Rituximab

Pro

po

rtio

n o

f P

a

Merrill JT, et al. Arthritis Rheum. 2010; 62:222-33.

Belimumab to Treat Active Non-Renal SLE: Study Design

Belimumab to Treat Active Non-Renal SLE: Study Design

Active non-renal SLE (n-867)

PlaceboBelimumab 1 mg/kg

Background immunosuppression

52 wk follow upMean age 35 yNonwhite 75%

Belimumab 10 mg/kg

Primary Endpoint: Improvement in SLE Primary Endpoint: Improvement in SLE Responder Index (SRI)Responder Index (SRI)

Placebo(n=288)

Belimumab 1 mg/kg(n=289)

Secondary Endpoints: Physician Global Assessment

Belimumab 10 mg/kg(n=290)

Navarra S et al. Lancet 2011; 377: 721-731

h Im

pro

ved

er I

nd

ex (

SR

I)

Efficacy of Efficacy of BelimumabBelimumab to Treat Active Nonto Treat Active Non--Renal SLE Renal SLE at 52 Weeks at 52 Weeks

Odds ratio for response to belimumab 10 mg/kg vs placebo1.83 (1.30 to 2.59), p = 0.0006

Pro

po

rtio

n w

ith

SL

E R

esp

on

de

Navarra S et al. Lancet 2011; 377: 721-731

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Lupus Atherosclerosis Prevention (LAPS) Study Design

Lupus Atherosclerosis Prevention (LAPS) Study Design

Adult SLE(n = 200)

Standard therapy

2 year follow upMean age: 44 yrsMean SLEDAI: 2Nonwhite: 39%

Primary Endpoint: CT coronary calcium Primary Endpoint: CT coronary calcium scorescore

PlaceboAtorvastatin 40 mg/day

Secondary Endpoints: CIMT

Disease activity (SLEDAI)

Inflammatory Mediators (hs-CRP))

MeasureMean

baselineMean 2 years

Mean change

P Value

Difference in change, statin

minus placebo (95% CI)

P Value

Loge (coronary artery calcium score + 1)

LAPS Study: LAPS Study: Change in Coronary Calcium Score and CIMTChange in Coronary Calcium Score and CIMT

Atorvastatin1.16 1.24 0.08 0.52

−0.08 (−0.39 to 0.23) 0.62

Placebo 1.19 1.35 0.15 0.16

Carotid intima media thickness (mm)

Atorvastatin 0.59 0.66 0.07 <0.0001−0.02 (−0.05 to 0.01) 0.24

Placebo 0.57 0.66 0.09 <0.0001

Petri et al Ann Rheum Dis 2011

Atherosclerosis Prevention in Pediatric Lupus Erythematosus

Study Design

Atherosclerosis Prevention in Pediatric Lupus Erythematosus

Study Design

Pediatric SLE (>10 and <21)(n = 221)

Standard therapy

APPLE

3 year follow up

Mean age 15.7 yNonwhite 65%SLEDAI 4.7LDL 86HSCRP 3.6

Primary Endpoint: IMT progressionPrimary Endpoint: IMT progression

hydroxychloroquine, ASA, folate, AHA TLC diet + placebo

hydroxychloroquine, ASA, folate, AHA TLC diet + atorvastatin

Secondary Endpoints: Disease Severity (SLEDAI, SLICC)

Quality of Life (PedsQL)Inflammatory Mediators (hs-CRP))

APPLE Results: CIMT EndpointsAPPLE Results: CIMT EndpointsAPPLE Results: CIMT EndpointsAPPLE Results: CIMT Endpoints

Mean-Max Common

Mean-Mean

Mean-Max

Mean-Mean Common

Atorvastatin slower Placebo slower

APPLE

Mean-Mean Near Wall

Mean-Max Near Wall

Mean-Mean Far Wall

Mean-Max Far Wall

Mean-Mean Bifurcation

Mean-Max Bifurcation

Mean-Mean Internal

Mean-Max Internal

Difference of CIMT Progression (mm/year) with 95% CI-0.0125 -0.0100 -0.0075 -0.0050 -0.0025 0.0000 0.0025 0.0050

Schanberg et al, Arthritis Rheum 2010

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HydroxychloroquineHydroxychloroquine• Antimalarial; limited toxicity

• Beneficial in SLE

– Prevents flares

– Improves lipid profiles

– Improves pregnancy outcomesp p g y

– Reduces clotting risk

– Associated with decreases in mortality, renal morbidity, malignancy

• Mechanism

– Mediates Toll-like receptor 7, 9 signaling?Tsakonas Lupus 1998, Alarcon Ann Rheum Dis 2007, Costedoat-Chalumeau Arthritis Rheum2006, Lafyatis Arthritis Rheum 2006, Clowse Arthritis Rheum 2006, Rahman J Rheum 1999, Kasitanon Lupus 2006.

Back to our CaseBack to our Case: Nicole: NicoleBack to our CaseBack to our Case: Nicole: Nicole

• Additional evaluation:• 24 hour urine protein with 2 grams protein • LDL 144, HDL 38

• Plan:Plan: • Prednisone• Hydroxychloroquine• Address CV risk: dyslipidemia, BP, tobacco

use• Referral to nephrology to evaluate for lupus

nephritis

New Developments in the New Developments in the Treatment of Lupus NephritisTreatment of Lupus Nephritis

New Developments in the New Developments in the Treatment of Lupus NephritisTreatment of Lupus Nephritis

B d H R i MD FACP FASNBrad H. Rovin, MD, FACP, FASNProfessor of Medicine and Pathology

Vice Chairman of Research for Internal MedicineDirector, Division of Nephrology

The Ohio State University College of Medicine

• LOW‐DOSE CYCLOPHOSPHAMIDE IS EFFECTIVE INDUCTION THERAPY IN SOME POPULATIONS

• MMF AND IV CYCLOPSHOSPHAMIDE ARE EQUALLY EFFECTIVE AS INDUCTION THERAPY

MAJORMAJOR NEW FINDINGS IN THE NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LNTHERAPY OF PROLIFERATIVE LN

EFFECTIVE AS INDUCTION THERAPY

• RITUXIMAB DOES NOT IMPROVE INDUCTION THERAPY

• MMF MAY BE THE IMMUNOSUPPRESSIVE OF CHOICE FOR MAINTENANCE THERAPY

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LowLow--Dose (EuroDose (Euro--Lupus) CyclophosphamideLupus) Cyclophosphamide

Houssiau, et al., Arth Rheum, 2002

• Low Dose CYC: 500 mg every 2 weeks for 6 doses/Cumulative Dose 3g

• 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

LowLow--DoseDose CyclophosphamideCyclophosphamide--LongLong--Term ResultsTerm Results

Failure:• Absence of primary response at 6 months

• Occurrence of steroid‐resistant flare• Doubling of SCr

Houssiau, et al., Arth Rheum, 2002; Ann Rheum Dis, 2010

High Dose Low Dose

Randomized 46 44

Lost to Follow‐Up 3 3

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





10

Blac

MMF MMF vsvs CyclophosphamideCyclophosphamide

ck, Hisp

anic, M

ixed

•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

Chan, et al., JASN, 2005

•Long‐term outcomes are key for a true comparison with CYC

Adverse Events

MMF IVC

Deaths 9 (4.9%) 5 (2.8%)

W/drawals 24 (13%) 13 (7.2%)

LongLong--Term Outcome After MMF TreatmentTerm Outcome After MMF Treatment

60

80

100

ith

Tx

fail

ure

(%)

MMF AZA

Data from the ALMS Maintenance Trial‐Ninth International Congress on SLE, Vancouver, 2010

0

20

40

Overall Induction MMF Induction IVC

Pat

ien

ts w

i

16%21%

36%

11%

28%32%

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 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

Dall’Era et al., Arth Care Res, 2011

↓ proteinuria by ≥25% 2.9 1.6‐5.1

Normalization of C3/C4* 2.7 1.4‐5.0

*only applicable if patients had baseline low C3 and C4

Do we need to think about changing therapy sooner during induction?

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

Lertdumrongluk et al., Kidney Int, 2010

For 1 hour Peak MPA r 0.92• One may be able to use trough and

peak to optimize MMF dosing• Our recommendation:

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





What About Rituximab?

Screening

Rituximab + MMF (n=72)

Prednisone taper

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!

Follow‐up PeriodPlacebo + MMF (n=72)

Weeks 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

Primary Endpoint: Renal Response at Week 52Primary Endpoint: Renal Response at Week 52

30.6

54.1

26 430.6

43.0

30

40

50

60

of Patients

Placebo Rituximab

P=0.55*P=0.55*

15.3

26.4

0

10

20

30

Complete Renal Response (CRR)

Partial RenalResponse (PRR)

No Response (NR)

Proportion

* 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

45.0 47.8 50.0

70.0

55.0 52.650%

60%

70%

80%

oportion

Placebo Rituximab

9/20 14/20 11/23 16/29 13/26 10/19

45.0

0%

10%20%

30%

40%

Black (n=40) Hispanic (n=52) Caucasian (n=45)

Response Pro

13

MAJOR NEW FINDINGS IN THE THERAPY OF PROLIFERATIVE LN





ALMS Maintenance TrialTime to Treatment

Failure, n=227

MAINTAIN Nephritis TrialMAINTAIN Nephritis TrialTime to FlareTime to Flare

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

ApoptosisDeficient clearance1

Nucleosomes

Y Y

Y

Y Y

Auto-reactivePlasma Cell

YY

Y

Y

Y

Y

YAnti-dsDNA

2

Nucleosome-IC depositionin glomerular capillaries

Complement activationFcR activationTLR activation

Production of pro-inflammatory cytokinese.g. C3a/C5a, MCP-1, IL-17, IL-18

3

Anti-TLR

Anti-CD20(Rituximab, Ocrelizumab)

Endothelial CellGBM

PodocyteAnti-IL-6(Tocilizumab)

CTLA4 Ig

Y

Y

Auto-reactiveB Cell

Y

Y

Y

Y

YY YYY

Y Y

Y

Cell infiltration and activationMonocytes, Lymphocytes, pDCs

Increased production of cytokinesIFN‐a

Accelerated autoimmune responselocal, Th1-skewed

Increased IC accumulation andcomplement and FcR activation

Renal tissue damage

Anti-C5(Eculizumab)

Anti-IFN-α

Anti-CD22(Epratuzumab)

BLyS

APRIL

Anti-BLyS(Belimumab)

TACI-Ig(Atacicept)

4

MΦMΦ

ROSProteases

ROSProteases

MAC

IL-6

Auto-reactive

T Cell

CTLA4-Ig(Abatacept)

Lupuzor