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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 Childrens 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 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

ANAS 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

ANAS 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

Pathophysiology of SLEPathophysiology of SLEExposure(s)

Immune dysregulation

Susceptible hostGenes Gender/Sex Hormones TissueTissue damagedamage

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Pathophysiology of SLEPathophysiology of SLEExposure(s)

Immune dysregulation

UV lightDrugsInfectious agents

Susceptible hostGenes Gender/Sex Hormones TissueTissue damagedamage

Pathophysiology of SLEPathophysiology of SLEExposure(s)

Immune dysregulation

UV lightDrugsInfectious agents

Complement activationImmune complex deposits

Susceptible host

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

Genes Gender/Sex Hormones TissueTissue damagedamage

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

19752003

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

GlucocorticoidsRituximab*

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 DesignActive 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

80P = 0.9750

tient

s (%

)

0

10

20

30

40

NoClinicalResponse

PartialClinicalResponse

MajorClinicalResponse

Major+Partial

Placebo

Rituximab

Prop

ortio

n of

Pa

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

prov

eder

Inde

x (S

RI)

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

Prop

ortio

n w

ithSL

E R

espo

nde

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 therapy2 year follow up

Mean age: 44 yrsMean SLEDAI: 2Nonwhite: 39%

Pr