What’s New in Lupus?

Jeffrey Carlin, MDSection Head,

Division of RheumatologyVirginia Mason Medical Center

Clinical Associate ProfessorUniversity of Washington

Key Points

• Diagnosing Lupus– ANA testing

• Treatment Options• New Therapeutic Agents• Adjuvant Therapy

Lupus Demographics

USA Incidence(per 100,000per year)

Prevalence(per 100,000)

All 5.1 52.2

White 1.4 7.4

Black 4.5 19.5

Puerto Rican

2.2 18.0

Danchenko N et al Lupus 2006:308-318

Incidence and Prevalence of SLE:

Rochester, MN

Uramoto KM et al Arth Rheum 1999;46-50

SLE - Etiology• The etiology of SLE remains unknown• Yet, SLE is clearly multifactorial:

– Genetic factors– Immunologic factors– Hormonal factors– Environmental factors

EBV?

Genetic predisposition

InfectionAbnormal (control of) immune responses

Hormonal factors

Baseline immunological abnormalities

SLE

Interferon-α Stimulation

Ronneblom L, Alm GV Arth Res Ther 2003;68-75

Evironmental Triggers of SLE

• UV Light• Drugs (>100 Identified)• Smoking• Infections

– Pet Dogs– Lab workers– EBV

• Silica• Mercury

When Does Lupus Begin?

Arbuckle M, et al NEJM 2003

Stages in Development of Pathogenic Autoimmunity

ANA Techniques

Frequencies of Positive ANA’s in Normal individuals

Pooled ANA DataHep-2 Cell Lines

68.3

31.7

13.3

5 3.3

0

10

20

30

40

50

60

70

80

Negative 1:40 1:80 1:160 1:320Fluorescence/Dilution Level

Per

cen

tag

e

Tan E.M., et al Arthritis and Rheum 1997

Estimated Prevalence of ANA + in the US Population

Satoh M et al Arth & Rheum 2012;64:2319-2127

Positive ANA

High Probability of

CTD

IdentifySpecific

ANA Antigen

Search for OtherEvidence of Disease Or Organ Involvement

Consider AncillaryLab Tests

Low Probabilityof

CTD

Low TiterANA

High Titer ANA

FollowPt

ReassurePt Search for Other

Evidence of Disease Or Organ Involvement

IdentifySpecific Antigen

Remember!

A positive ANA does not mean the patient has a connective tissue disease, but a negative ANA will R/O CTD

Lab investigations• Screen- CBC, urinanalysis & serum creatinine• Anti ds DNA

• In about 60% with SLE• Levels often reflect disease activity• with Rx ( ANA remains +)• If normal – safe to Rx in chronic phase

• ENA’s• complement

• In ¾ untreated esp. with nephritis• APLA

In 1/3 to ½Associated with renal arterial, venous & glomerular thrombosis

Anti-Ds DNA AntibodyAnti- Histone Antibody

Antibodies directed against exposed parts of the Nucleosome

Anti-ds DNA Antibodies

• Large literature suggesting these are strong biomarkers

• Used widely in clinical practice– High Titer IgG anti-dsDNA predict nephritis

• But not in immediate future!

– High Affinity anti-dsDNA associated with flare– Glomerular IC enriched for anti-dsDNA

Extractable Nuclear Antigens(ENA’S)

• Autoantibodies against nuclear ribonucleoproteins/nuclear components– SSA, SSB, Sm, RNP, anti-Histone

• ELISA assays• Useful for helping to confirm diagnosis

– used as adjunct to ANA• Not useful for disease monitoring

– need not be repeated once identified

Anti-U1 SnRNP Antibodies

Anti-RNP Ab

Anti-Sm Ab

Antigen SLE Drug-Induced

Native DNA 40% No

Denatured DNA 70% 75-80%

Histones 70% >95%

SM Antigen 30% No

Nuclear RNP 30% No

Ribosomal RNP 10%

SSA/Ro 35% No

SSB/La 15% No

Prevalence of Autoantibodies in SLE

Antigen SLE Clinical Associations

Native DNA 40% Nephritis (and flare)

Denatured DNA 70% Non-Specific

Histones 70% Drug-Induced Lupus

SM Antigen 30% Severe SLE

Nuclear RNP 30% Arthritis

Ribosomal RNP 10%

SSA/Ro 35% SCLE, Sjogren’s NLS

SSB/La 15% SCLE, Sjogren’s NLS

Significance of Autoantibodies in SLE

Antibody Clustering in SLE

• Cluster 1 - anti-Sm/RNP Ab’s– Primarily skin involvement– Less proteinuria, anemia, thrombocytopenia

• Cluster 2 - anti-dsDNA/SSA/SSB Ab’s– Highest incidence of renal disease– Secondary Sjogren’s

• Cluster 3 -anti-dsDNA/LAC/ACL Ab’s– Arterial/Venous thrombosus, livedo reticularis– Highest incidence of CVA’s

Hopkins Lupus Cohort Study -1,357 patients Average follow-up 9.6 years

To CH, Petri M Arthritis and Rheum 2005

ACR SLE Classification Criteria(SOAP BRAIN MD)

1. Serositis: (a) pleuritis, or (b) pericarditis

2. Oral ulcers3. Arthritis4. Photosensitivity

10. Malar rash11. Discoid rash

5. Blood/Hematologic disorder: (a) hemolytic anemia or(b) leukopenia of < 4.0 x 109 (c) lymphopenia of < 1.5 x 109 (d) thrombocytopenia < 100 X

109

6. Renal disorder: (a) proteinuria > 0.5 gm/24 h or 3+ dipstick or(b) cellular casts

7. Antinuclear antibody (positive ANA) 8. Immunologic disorders:

(a) raised anti-native DNA antibody binding or(b) anti-Sm antibody or (c) positive anti-phospholipid antibody work-up

9. Neurological disorder: (a) seizures or (b) psychosis

". ..A person shall be said to have SLE if four or more of the 11 criteria are present, serially or simultaneously, during any interval of observation."

SLICC Criteria for Lupus• Acute Cutaneous

– Malar rash, subacute cutaneous lupus rash, bullous lupus

• Chronic Cutaneous– Discoid Lupus, Lupus

panniculitis• Oral/Nasal Ulcers• Non-scarring Alopecia• Synovitis• Serositis

• Renal– Urine protein/creat ratio >

500mg/24 hrs or active renal sediment

• Neuro– Sz, pyschosis, myelitis,

mononeuritis, peripheral neuropathy

• Heme– Hemolytic anemia, neutropenia,

lymphopenia thrombocytopenia• Immunological

– ANA, DNA, Sm, Low Complements, Coombs +, Antiphospholipid Ab’s

Petri M et al, Arth & Rheum 2012; 64: 2677–2686

Performance of SLICC Criteria

1997 ACR Criteria 2012 SLICC Criteria

Sensitivity 2907349 (83%) 340/349(97%)

Specificity 326/341 (96%) 288/341(84%)

Misclassified cases 74 62

Petri M et al, Arth & Rheum 2012; 64: 2677–2686

Clinical Features on Presentation in SLE

• Arthritis or Arthralgia 55%• Skin Involvement 20%• Nephritis 5%• Fever 5%• Other 15%

Organ Involvement in the Course of SLE

– Joints 90%– Skin

• Rashes 70%– Discoid Lesions 30%– Alopecia 40%

– Pleurisy/Pericarditis 60%– Kidney 50%– Raynaud’s 20%– Mucous Membranes 15%– CNS (Seizures/Psychosis/CVA) 15%

50% Patients Have Organ Damage In the Course of Disease

24.2%15.0%12.6%11.7%10.4%10.1% 7.4% 7.4% 5.5% 6.1% 2.5% 1.2%

MusculoskeletalNeuropsychiatricOcularRenalPulmonaryCardiovascularGastrointestinalSkinPeripheral VascularDiabetes MellitusMalignancyPremature Gonadal Failure

Malar Rash- Note Sparing of Nasolabial Folds

Acute Cutaneous

Discoid Lupus

Chronic Cutaneous: DiscoidNote Scarring, Hyperpigmentation

Follicular Plugging

Which patient has SLE?

Subacute Cutaneous Lupus

Annular eruptionPapular squamous eruption

Livedo Reticularis

Non-specific Skin Manifestations

Raynaud’s with tissue breakdown

Vasculitis

Jaccoud’s Arthopathy: Nonerosive, Reducible Deformities

Nodules Possible

Joint Disease in SLE

DX Antibodies Clinical Features

APS ACL, antiB2GP1, LA

Thrombosis inflammation

ITP anti-IIb/IIIa, PF4 Bleeding <20KThrombosis

Hemolytic Anemia

Coomb’s + Hemolysis

TTP VWB multimer proteaseantibodies

Catastrophic APSHELLP SyndromeTTP of SLE

Bleeding anti-FVIII (IX, X!, XII, XIII)

Hematomas, HematuriaGI/mucosal bleeds

Severe Hematologic Syndromes of SLE

Anti-Cardiolipin Antibody Syndrome• Recurrent arterial or venous events• Obstetrical

– Recurrent miscarriages/fetal growth retardation• Thrombocytopenia• Incidence of + Antibodies in SLE

– LAC -30%– ACL- 23-27%– Anti- B2 Glycoprotein 1 - 20%

• 2 + tests 12 weeks apart to confirm diagnosis!

Lupus NephritisClass I: normal glomeruli (~8% of biopsies) Class II: pure mesangial alterations (~40% of biopsies) Class III: focal glomerulonephritis (~15% of biopsies) Class IIIA: focal segmental glomerulonephritis (~12%

of biopsies) Class IIIB: focal proliferative glomerulonephritis Class IV: diffuse glomerulonephritis (~25% of biopsies) Class V: diffuse membranous glomerulonephritis (~8% of

biopsies) Class VI: advanced sclerosing glomerulonephritis

Prognosis in Lupus Nephritis

• Predictors of poor prognosis:– Black race– Male– Anemia– creatinine– Nephrotic range proteinuria– Glomerular & tubulointerstitial scarring – Severe tubulointerstitial nephritis– Chroniciy index > 3

ACR NOMENCLATURE AND CASE DEFINITIONS FOR NEUROPSYCHIATRIC LUPUS SYNDROMES

Central nervous systemAseptic meningitisCerebrovascular diseaseDemyelinating syndromeHeadache (including migraine and benign intracranial hypertension)Movement disorder (chorea)MyelopathySeizure disordersAcute confusional stateAnxiety disorderCognitive dysfunctionMood disorderPsychosis

ARTHRITIS & RHEUMATISM 1999, pp 599-608

Prevalence of 12 NP Clinical Syndromes in CNS lupus (N=300)

• Headache 24%• CVA 18%• Mood disorder 17%• Cognitive dysfunction 11%• Psychosis 8%• Seizure disorder 8%• Anxiety Disorder 7%• Aseptic meningitis 4%• Acute confusional state 4%• Transverse myelopathy 1%• Movement disorder 1%• Demyelinating syndrome 1%

Sanna G, et al Journal of Rheumatology 2003:30;985-992

Diagnostic Studies in CNS Lupus• CT• MRI• SPECT• PET• MRA• CT angiogram• Conventional angiograms• CSF analyses

– Cells– Protein– Oligoclonal bands– IgG/albumin index– Cytokines

• EEG• Neuropsychological testing• Anti-neuronal antibodies (e.g. ribosomal-P, neurofilimant,

NR2 NMDA glutamate receptor)

Current Goals of Rx with SLE

• Control daily symptoms that decrease quality of life

• Manage acute periods of potentially life-threatening or organ threatening involvement

• Minimize risk of life-threatening disease flare-ups during periods of disease stabilization

Treatment• Hydroxychloroquine• Corticosteroids• ASA• NSAIDS• Azathioprine• MTX/Leflunomide• Mycophenolate Mofetil• Cyclophosphamide• Anticoagulants• Biologics

RX For SLEREQUIRESA DISCLAIMER

EULAR Treatment Guidelines:General Management

• Antimalarials and/or Glucocorticosteroids– Use in pts w/o major organ manifestations

• NSAID’s– Use judiciously for limited period of time in pts at low risk

of complications with this drug class• Immunosuppressive Rx

– Use in non-responsive pts or in pts where dose of corticosteroids cannot be decreased to acceptable doses for chronic use

Anti-malarials• All patients should be on Rx if tolerated

– 2 studies show decrease frequency of major/minor flares– Mild anti-platelet effect– Beneficial cholesterol effects

• Useful for skin/joint/pleurisy/pericarditis• Hydroxychloroquine safer than Chloroquine

– Eye evaluation every 6 month-year• Atabrine does not cause eye toxicity but can cause

yellow skin

Hydroxychlorquine Reduces Organ Damage

Fessler B, et al Arth & Rheum 2005;1473-1480

Hydroxychloroquine in Lupus Pregnancy

• No HCQ exposure during pregnancy (N=163)• Continuous use of HCQ during pregnancy (N=56) • Cessation of HCQ treatment either in the 3 months prior to or

during the first trimester of pregnancy (N=38) • Results

– No difference in congenital abnormalities, stillborns miscarriages

– Higher incidence of Lupus Activity and Flare in Non-users

Clowse, M et al A & R 2006:54; 3640-3647

Immunosuppressives

• Methotrexate-(+ Hydroxychloroquine)– 7.5-25mg/week– Best for arthritis

• Azathioprine- (+ Hydroxychloroquine)– Check TMPT assay pre-rx– Useful for joint/skin/nephritis– 3-6 months for effect

Immunosuppressive II

• Leflunomide- (+ Hydroxychloroquine)– 3rd line for joint/skin/nephritis– Very tetragenic

• Mycophenylate– Use for nephritis– 3rd line for skin/joint

Mycophenolate Mofetil

• Hydrolyzed to active form: Mycophenolic acid• Inhibits Inosine Monophosphate Dehydrogenase: Blocks purine

synthesis• Affects activated/dividing lymphocytes• Originally developed to prevent allograft rejection• Dosed: 500 Mg PO BID – 1.5g PO BID

Remission rates: MMF vs IVC

0

10

20

30

40

50

60

Complete Remission Partial Remission Complete + PartialRemission

MMF IVC

16/71

4/69

21/7117/69

37/71

21/69

Intent-to-Treat analysis

p = NSp = 0.005

p = 0.009

Res

po

nd

ing

(%

)

Ginzler, E. et al., N Engl J Med 2005;353:2219-28

Induction Rx of Lupus Nephritis

Oral MMF IV CTX P value Randomized/Rx’d 71/71 69/66 Study Endpoint 66 64 Completed 24 wks Rx 56 42 0.017 Complete Remission 16 4 0.005 Treatment Failure 34 48 0.01 Death 0 3 UGI Toxicity 23 25 Hematologic Toxicity 21 31 Infection/Serious 40/1 56/6

Ginzler E et al NEJM; 353:2219-28

Belimumab Mechanism of Action

Slow onset

Lancet 2011

Belimumab

Reduction in Steroid Dose

Time to Flare

Belimumab Improved or Stabilized SLE Disease Activity and Reduced Flare Rate during 3 Years

of Therapy

Furie Eular 2008; Merrill ACR 2011 6 year data

0%

20%

40%

60%

80%

52 wkPBO

52 wk 76 wk 128 wk 160 wk

Per

cent

Fla

re

SS flares

Severe SS flare

Belimumab (Benlysta)

• 1st new drug for SLE in 50 yrs• Pts most appropriate for rx have musculoskeletal,

cutaneous, immunological disease despite standard of care– Not studied in CNS or renal disease– Unknown effect in African Americans

• Side effects– Hypersensitiviy reactions– Low risk of serious infections– Depression

SLE Rx AlgorithmSLE Severity

Mild• Skin

Manifestations• Arthritis

Moderate• Mild/Moderate Nephritis• Thrombophlebitis• Major Serositis

Induction RxIV MMF x3 days followed by:

AZA (2mg/kg/d) or MMF 2-3 gms/d+

Prednisone .5 mg/kg x 4-6 wk, then taper

RxHCQ or MTX

+ Prednisone

Severe• Severe Nephritis

(Class 4 or 5 with renal impairment)

• Severe refractory thrombocytopenia/hemolytic anemia

• Pulmonary hemorrhage• CNS disease• Vasculitis

Induction RxIV MMF

Or CTX( 750 mg/m2)

+IV CYC 1 gm x3 d

Maintenance RxCTX 750mg/m2/mo x 6mo

or MMF 2-3 gm/day

+Prednisone Taper

MaintenanceAZA or MMF

+Steroid Taper

+(?)Belimumab

EULAR SLE Treatment Guidelines:Adjuvant Therapy

• Photoprotection– May be helpful in skin manifestations

• Estrogens– BCP’s/ERT’s can be used, but accompanying risks should

be assessed• Lifestyle modifications

– Smoking cessation, wgt loss, exercise likely to be helpful• Other Agents

– Statins, Bisphophonates, Ca/Vit D, low dose ASA, anti-hypertensives (including ACE inhibitors) should be considered depending upon situation

Lupus Mortality

• Early Mortality– Infections– Lupus-related

• Late Mortality– Cardiovasular Disease– Malignancies

Proposed Care Pathway for Management of SLE Patients

Registration of pts with SLE

Screening for risk factors

Assessment of clinical manifestations

Management for individual risk factors as per guidelines

Known CHD

No known CHD BMI <25kg/m2

BMI > 25kg/m2 Wgt Reduction

?Steroid Adjustment

Individual risk factor mgmt

BP

Cholesterol

Diabetes

Wajed J et al Rheumatology 2003

Thank You!

Mortality Rates are Declining

Bernatsky S et al, Arth & Rheum; 2006: 2550-2557

Additional Lupus Related Measures

• Aspirin- Known vascular disease SLE + One risk factor Anticardiolipin Ab/LAC

• ACE inhibitors- Prevalent CVD including CHF LVH DM Preferred second drug for hypertension

Wajed J et al Rheumatology 2003

Oral Contraceptives in SLE

• SELENA Trial (Safety of Estrogen in Lupus Erythematosus)– Double-blind non-inferiority, multicenter– OC’s did not increase expected flare rate in mild-

moderate disease1

• Single blind uncontrolled, single center BCP vs IUD (Mexico City)2

– Similar flare rates • Neither study addressed severe active disease

1. Petri, M et al NEJM 2005;353:2550-2558

2. Sanchez-Guerrero J, NEJM, 2005;353:2539-2549

Is Atherosclerosis Increased in SLE?

498 women with SLE at University of Pittsburgh 2208 women in Framingham Offspring Study

Lupus pts 35-44 years: MI 50 x more likely

Risk Factors: Older age at SLE Dx Longer lupus disease duration Longer corticosteroid use Hypercholesterolemia Post menopause

Manzi et al Am J Epidemiol 1997

Is Atherosclerosis Increased in SLE?

Adjusted rates in Canadian SLE pt for baseline traditional risk factors (age, sex, BP, cholesterol, smoking glucose, LVH) using Framingham logistic regression equations

263 SLE patients: 21 MI, 19 CVA, 37 any CVD

Event RR 95%CI

MI 8.3 (4.9-12.4)

CVA 6.7 (3.6-10.9)

Any 5.7 (3.9-7.7)

Esdaile et al Arthritis and Rheum 2001

Histopathologic Classification of Lupus Nephritis

Class I. Minimal mesangial nephritisClass II. Mesangial proliferative nephritisClass III. Focal lupus nephritis (<50% of glomeruli are involved)

A. Active lesions: focal proliferative GN A/C. Active and chronic lesions: focal proliferativ and

sclerosing GN C. Chronic inactive lesions with glomerular scarring: focal

sclerosing GN. Class IV. Diffuse lupus nephritis (>50% of glomeruli are involved)

diffuse segmental (IV-s) type, when only a part of the involved glomeruli are affected

diffuse global GN (IV-G), when the entire glomeruli are affected

IV-S (A), IV-G (A), IV-S (A/C), IV-G (C),IV-S (C),

Class V. Membranous lupus nephritisMay associate with findings characterised in class III/IV.

Class VI. Sclerosing glomerulonephritis90% of glomeruli are sclerotic

Rituximab

• Rituximab is a novel genetically engineered

anti-CD20 therapeutic monoclonal antibody that selectively depletes CD20+ B cells

Shaw et al, 2003: Silverman & Weisman, 2003 – Roche core set

Blys/BAFF

Lupus Rx Algorithm

Crow M, NEJM 2008;359:956-961

SLE Genes: Ethnic DifferencesGENE CAUC AFR references

TNF alpha X Hum Immunol 65:622

16q12-13 X E J Hum Gen 12:668

12q24 X Am J Hum Gen 74:73

FcgRIIIa X Rheum (Ox) 42:446

FcgRIIa X J Clin Invest 95:1348

11p13 (discoid) X J Inv Derm Sym 9:64

NO synth prom X J Rheum 30:60

FasL 1q23 X J Immun 170:132

Arce-Salinas C, Rodrigues-Carcia F, EULAR 2008 THU0234

SLEDAI= SLE Disease Activity Index

Wallace in Arthritis and Allied Conditions, 13th Ed V2, p1319 Koopman, ed

%

YEARS

IMPROVED SURVIVAL IN SLE: 1955-1990

Ideal Risk Factors

• BP- <130/60• LDL-<2.6 mmol/l• Diabetes- FBS < 100

Random BS <110• Smoking- stop!• Obesity- BMI<25kg/m2

Wajed J et al Rheumatology 2003

Rahman A, Isenberg D, NEJM; 2008: 929-039

Lupus nephritis

Class I Minimal mesangial Normal light microscopy; abnormal electron microscopy

Class II Mesangial proliferative

Hypercellular on light microscopy

Class III Focal proliferative <50% glomeruli involved

Class IV Diffuse proliferative >50% glomeruli involved; segmental/global

Class V Membranous Predominantly nephrotic disease

Class VI Advanced sclerosing

Chronic lesions and sclerosis

Lupus Genetics

• + ANA in general population- 5-15%• Prevalence in 1st degree relative- 10% • Concordance in monozygotic twins- 25%• Concordance in dizygotic twins- 2%