Transcript Lupus 2013
What’s New in Lupus?
Jeffrey Carlin, MD Section Head, Division of Rheumatology Virginia Mason Medical Center Clinical Associate Professor University of Washington
Key Points
• • • • Diagnosing Lupus – ANA testing Treatment Options New Therapeutic Agents Adjuvant Therapy
Lupus Demographics
Incidence and Prevalence of SLE: Rochester, MN
USA All White Black Incidence (per 100,000 per year) 5.1
1.4
4.5
Prevalence (per 100,000) 52.2
7.4
19.5
Puerto Rican 2.2
18.0
Uramoto KM et al Arth Rheum 1999;46-50 Danchenko N et al Lupus 2006:308-318
SLE - Etiology
• The etiology of SLE remains unknown • Yet, SLE is clearly multifactorial: – Genetic factors EBV?
– Immunologic factors – Hormonal factors – Environmental factors Genetic predisposition Infection Baseline immunological abnormalities Abnormal (control of) immune responses Hormonal factors 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 Data Hep-2 Cell Lines
80 70 20 10 0 60 50 40 30 68.3
Negative 31.7
13.3
5 1:40 1:80
Fluorescence/Dilution Level
1:160 3.3
1:320 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 Identify Specific ANA Antigen of CTD Consider Ancillary Lab Tests Search for Other Evidence of Disease Or Organ Involvement Reassure Pt Low Titer ANA Low Probability of CTD High Titer ANA Identify Specific Antigen Follow Pt Search for Other Evidence of Disease Or Organ Involvement
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 ½ Associated with renal arterial, venous & glomerular thrombosis
Anti-Ds DNA Antibody Anti- 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-Sm Ab Anti-RNP Ab
Prevalence of Autoantibodies in SLE Antigen Native DNA Denatured DNA Histones SM Antigen Nuclear RNP Ribosomal RNP SSA/Ro SSB/La SLE 40% 70% 70% 30% 30% 10% 35% 15% Drug Induced No 75-80% >95% No No No No
Significance of Autoantibodies in SLE Antigen Native DNA SLE Clinical Associations 40% Nephritis (and flare) Denatured DNA 70% Non-Specific Histones 70% Drug-Induced Lupus SM Antigen Nuclear RNP 30% Severe SLE 30% Arthritis Ribosomal RNP 10% SSA/Ro 35% SSB/La 15% SCLE, Sjogren’s NLS SCLE, Sjogren’s NLS
Antibody Clustering in SLE
Hopkins Lupus Cohort Study -1,357 patients Average follow-up 9.6 years • • •
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 To CH, Petri M Arthritis and Rheum 2005
ACR SLE Classification Criteria
(SOAP BRAIN MD) 1.
S
10. 11. erositis:
M D
(a) pleuritis, or (b) pericarditis 2.
O
ral ulcers 3.
A
rthritis 4.
P
hotosensitivity alar rash iscoid rash
". ..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."
5.
B
lood/Hematologic disorder: (a) hemolytic anemia or (b) leukopenia of < 4.0 x 10 9 (c) lymphopenia of < 1.5 x 10 9 (d) thrombocytopenia < 100 X 10 9 6.
R
enal disorder: (a) proteinuria > 0.5 gm/24 h or 3+ dipstick or (b) cellular casts 7.
A
ntinuclear antibody (positive ANA) 8.
I
mmunologic disorders: (a) raised anti-native DNA antibody binding or (b) anti-Sm antibody or (c) positive anti-phospholipid antibody work-up 9.
N
eurological disorder: (a) seizures or (b) psychosis
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
Sensitivity Specificity Misclassified cases
1997 ACR Criteria
2907349 (83%) 326/341 (96%) 74
2012 SLICC Criteria
340/349(97%) 288/341(84%) 62 Petri M et al, Arth & Rheum 2012; 64: 2677 –2686
Clinical Features on Presentation in SLE
• • • • • Arthritis or Arthralgia Skin Involvement Nephritis Fever Other 55% 20% 5% 5% 15%
Organ Involvement in the Course of SLE
– – – – – – –
Joints Skin
•
Rashes
– –
Discoid Lesions Alopecia Pleurisy/Pericarditis Kidney Raynaud’s Mucous Membranes CNS (Seizures/Psychosis/CVA) 90% 70% 30% 40% 60% 50% 20% 15% 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% Musculoskeletal Neuropsychiatric Ocular Renal Pulmonary Cardiovascular Gastrointestinal Skin Peripheral Vascular Diabetes Mellitus Malignancy Premature Gonadal Failure
Acute Cutaneous
Malar Rash- Note Sparing of Nasolabial Folds
Discoid Lupus
Chronic Cutaneous: Discoid Note Scarring, Hyperpigmentation Follicular Plugging
Which patient has SLE?
Subacute Cutaneous Lupus
Papular squamous eruption Annular eruption
Livedo Reticularis
Non-specific Skin Manifestations
Vasculitis Raynaud’s with tissue breakdown
Joint Disease in SLE
Jaccoud’s Arthopathy: Nonerosive, Reducible Deformities Nodules Possible
Severe Hematologic Syndromes of SLE DX Antibodies Clinical Features APS ITP ACL, antiB2GP1, LA anti-IIb/IIIa, PF4 Thrombosis inflammation Bleeding <20K Thrombosis Hemolytic Anemia TTP Bleeding Coomb’s + VWB multimer protease antibodies anti-FVIII (IX, X!, XII, XIII) Hemolysis Catastrophic APS HELLP Syndrome TTP of SLE Hematomas, Hematuria GI/mucosal bleeds
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 Nephritis
Class 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 system Aseptic meningitis Cerebrovascular disease Demyelinating syndrome Headache (including migraine and benign intracranial hypertension) Movement disorder (chorea) Myelopathy Seizure disorders Acute confusional state Anxiety disorder Cognitive dysfunction Mood disorder Psychosis ARTHRITIS & RHEUMATISM 1999, pp 599-608
Prevalence of 12 NP Clinical Syndromes in CNS lupus (N=300) • • • • • • • • • • • • Headache CVA Mood disorder Cognitive dysfunction Psychosis Seizure disorder Anxiety Disorder Aseptic meningitis Acute confusional state Transverse myelopathy Movement disorder Demyelinating syndrome 11% 1% 24% 18% 17% 8% 8% 7% 4% 4% 1% 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 SLE REQUIRES A 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) – 3 rd line for joint/skin/nephritis – Very tetragenic Mycophenylate – Use for nephritis – 3 rd 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
60 50 40 30 20 10 0 Intent-to-Treat analysis p = 0.005
16/71 4/69 Complete Remission p = NS 21/7 1 17/69 Partial Remission p = 0.009
37/71 21/69 Complete + Partial Remission MMF IVC Ginzler, E. et al., N Engl J Med 2005;353:2219-28
Induction Rx of Lupus Nephritis
Randomized/Rx’d Study Endpoint Completed 24 wks Rx Complete Remission Treatment Failure Death UGI Toxicity Hematologic Toxicity Infection/Serious Oral MMF 71/71 66 56 16 34 0 23 21 40/1 IV CTX 69/66 64 42 4 48 3 25 31 56/6 P value 0.017 0.005 0.01 Ginzler E et al NEJM; 353:2219-28
Belimumab Mechanism of Action
Lancet 2011 Slow onset
Belimumab
Reduction in Steroid Dose Time to Flare
Belimumab Improved or Stabilized SLE Disease Activity and Reduced Flare Rate during 3 Years of Therapy 80% 60% 40% 20% 0% 52 wk PBO 52 wk 76 wk 128 wk 160 wk SS flares Severe SS flare Furie Eular 2008; Merrill ACR 2011 6 year data
Belimumab (Benlysta)
• • • 1 st 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
Mild
•
Skin Manifestations
•
Arthritis Rx HCQ or MTX + Prednisone
SLE Rx Algorithm
SLE Severity
Moderate
•
Mild/Moderate Nephritis
•
Thrombophlebitis
•
Major Serositis Induction Rx IV 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 Severe
•
Severe Nephritis (Class 4 or 5 with renal impairment)
•
Severe refractory thrombocytopenia/hemolytic anemia
•
Pulmonary hemorrhage
•
CNS disease
•
Vasculitis Induction Rx IV MMF Or CTX( 750 mg/m2) + IV CYC 1 gm x3 d Maintenance AZA or MMF + Steroid Taper +(?) Belimumab Maintenance Rx CTX 750mg/m2/mo x 6mo or MMF 2-3 gm/day + Prednisone Taper
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 Known CHD Management for individual risk factors as per guidelines No known CHD BMI > 25kg/m 2 BMI <25kg/m 2 Wgt Reduction ?Steroid Adjustment Wajed J et al Rheumatology 2003 Individual risk factor mgmt BP Cholesterol Diabetes
Thank You!
Mortality Rates are Declining
Bernatsky S et al, Arth & Rheum; 2006: 2550-2557
Additional Lupus Related Measures
• Aspirin • ACE inhibitors Known vascular disease SLE + One risk factor Anticardiolipin Ab/LAC 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 disease 1 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
MI CVA Any
RR
8.3
6.7
5.7
95%CI
(4.9-12.4) (3.6-10.9) (3.9-7.7) Esdaile et al Arthritis and Rheum 2001
Histopathologic Classification of Lupus Nephritis Class I.
Class II.
Class III.
Minimal mesangial nephritis Mesangial proliferative nephritis Focal lupus nephritis (<50% of glomeruli are involved) A.
A/C.
Active lesions: focal proliferative GN 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-S (A/C), IV-G (C), IV-S (C), IV-G (A), Class V.
Membranous lupus nephritis
May associate with findings characterised in class III/IV.
Class VI. Sclerosing glomerulonephritis
90% 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
GENE SLE Genes: Ethnic Differences CAUC AFR references TNF alpha 16q12-13 12q24 FcgRIIIa FcgRIIa 11p13 (discoid) NO synth prom FasL 1q23 X X X X X X X X
Hum Immunol 65:622 E J Hum Gen 12:668 Am J Hum Gen 74:73 Rheum (Ox) 42:446 J Clin Invest 95:1348 J Inv Derm Sym 9:64 J Rheum 30:60 J Immun 170:132
SLEDAI= SLE Disease Activity Index Arce-Salinas C, Rodrigues-Carcia F, EULAR 2008 THU0234
IMPROVED SURVIVAL IN SLE: 1955-1990
% YEARS Wallace in Arthritis and Allied Conditions, 13 th Ed V2, p1319 Koopman, ed
Ideal Risk Factors
• • • • • BP- <130/60 LDL-<2.6 mmol/l Diabetes- FBS < 100 Random BS <110 Smoking- stop!
Obesity- BMI<25kg/m 2 Wajed J et al Rheumatology 2003
Rahman A, Isenberg D, NEJM; 2008: 929-039
Class I Class II Class III Class IV Class V Class VI
Lupus nephritis
Minimal mesangial Normal light microscopy; abnormal electron microscopy Mesangial proliferative Focal proliferative Hypercellular on light microscopy <50% glomeruli involved Diffuse proliferative Membranous Advanced sclerosing >50% glomeruli involved; segmental/global Predominantly nephrotic disease Chronic lesions and sclerosis
Lupus Genetics
• • • • + ANA in general population Prevalence in 1 st degree relative 5-15% 10% Concordance in monozygotic twins- 25% Concordance in dizygotic twins 2%