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  • 1

    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

  • 2

    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

  • 3

    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

  • 4

    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

  • 5

    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

  • 6

    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

  • 7

    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