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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%