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What’s New in Lupus? Jeffrey Carlin, MD Section Head, Division of Rheumatology Virginia Mason Medical Center Clinical Associate Professor University of.

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Presentation on theme: "What’s New in Lupus? Jeffrey Carlin, MD Section Head, Division of Rheumatology Virginia Mason Medical Center Clinical Associate Professor University of."— Presentation transcript:

1 What’s New in Lupus? Jeffrey Carlin, MD Section Head, Division of Rheumatology Virginia Mason Medical Center Clinical Associate Professor University of Washington

2 Key Points Diagnosing Lupus – ANA testing Treatment Options New Therapeutic Agents Adjuvant Therapy

3 Lupus Demographics USAIncidence (per 100,000 per year) Prevalence (per 100,000) All White Black Puerto Rican Danchenko N et al Lupus 2006: Incidence and Prevalence of SLE: Rochester, MN Uramoto KM et al Arth Rheum 1999;46-50

4 SLE - Etiology The etiology of SLE remains unknown Yet, SLE is clearly multifactorial: –Genetic factors –Immunologic factors –Hormonal factors –Environmental factors EBV? Genetic predisposition Genetic predisposition Infection Abnormal (control of) immune responses Hormonal factors Baseline immunological abnormalities SLE

5 Interferon-α Stimulation Ronneblom L, Alm GV Arth Res Ther 2003;68-75

6 Evironmental Triggers of SLE UV Light Drugs (>100 Identified) Smoking Infections – Pet Dogs – Lab workers – EBV Silica Mercury

7 When Does Lupus Begin? Arbuckle M, et al NEJM 2003

8 Stages in Development of Pathogenic Autoimmunity

9 ANA Techniques

10 Frequencies of Positive ANA’s in Normal individuals Tan E.M., et al Arthritis and Rheum 1997

11 Estimated Prevalence of ANA + in the US Population Satoh M et al Arth & Rheum 2012;64:

12 Positive ANA High Probability of CTD Identify Specific ANA Antigen Search for Other Evidence of Disease Or Organ Involvement Consider Ancillary Lab Tests Low Probability of CTD Low Titer ANA High Titer ANA Follow Pt Reassure Pt Search for Other Evidence of Disease Or Organ Involvement Identify Specific Antigen

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

14 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

15 Anti-Ds DNA Antibody Anti- Histone Antibody Antibodies directed against exposed parts of the Nucleosome

16 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

17 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

18 Anti-U1 SnRNP Antibodies Anti-RNP Ab Anti-Sm Ab

19 AntigenSLE Drug- Induced Native DNA40%No Denatured DNA70%75-80% Histones70%>95% SM Antigen30%No Nuclear RNP30%No Ribosomal RNP10% SSA/Ro35%No SSB/La15%No Prevalence of Autoantibodies in SLE

20 AntigenSLEClinical Associations Native DNA40%Nephritis (and flare) Denatured DNA70%Non-Specific Histones70%Drug-Induced Lupus SM Antigen30%Severe SLE Nuclear RNP30%Arthritis Ribosomal RNP10% SSA/Ro35%SCLE, Sjogren’s NLS SSB/La15%SCLE, Sjogren’s NLS Significance of Autoantibodies in SLE

21 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

22 ACR SLE Classification Criteria (SOAP BRAIN MD) 1. Serositis: (a) pleuritis, or (b) pericarditis 2. Oral ulcers 3. Arthritis 4. Photosensitivity 10. Malar rash 11. Discoid rash 5. Blood/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 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."

23 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

24 Performance of SLICC Criteria 1997 ACR Criteria2012 SLICC Criteria Sensitivity (83%)340/349(97%) Specificity326/341 (96%)288/341(84%) Misclassified cases7462 Petri M et al, Arth & Rheum 2012; 64: 2677–2686

25 Clinical Features on Presentation in SLE Arthritis or Arthralgia55% Skin Involvement20% Nephritis 5% Fever 5% Other15%

26 Organ Involvement in the Course of SLE – Joints90% – Skin Rashes70% – Discoid Lesions30% – Alopecia40% – Pleurisy/Pericarditis60% – Kidney50% – Raynaud’s20% – Mucous Membranes15% – CNS (Seizures/Psychosis/CVA)15%

27 50% Patients Have Organ Damage In the Course of Disease 24.2% 15.0% 12.6% 11.7% 10.4% 10.1% 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

28 Malar Rash- Note Sparing of Nasolabial Folds Acute Cutaneous

29 Discoid Lupus Chronic Cutaneous: Discoid Note Scarring, Hyperpigmentation Follicular Plugging

30 Which patient has SLE?

31 Subacute Cutaneous Lupus Annular eruption Papular squamous eruption

32 Livedo Reticularis

33 Non-specific Skin Manifestations Raynaud’s with tissue breakdown Vasculitis

34 Jaccoud’s Arthopathy: Nonerosive, Reducible Deformities Nodules Possible Joint Disease in SLE

35 DXAntibodiesClinical Features APSACL, antiB2GP1, LA Thrombosis inflammation ITPanti-IIb/IIIa, PF4Bleeding <20K Thrombosis Hemolytic Anemia Coomb’s +Hemolysis TTPVWB multimer protease antibodies Catastrophic APS HELLP Syndrome TTP of SLE Bleedinganti-FVIII (IX, X!, XII, XIII) Hematomas, Hematuria GI/mucosal bleeds Severe Hematologic Syndromes of SLE

36 Anti-Cardiolipin Antibody Syndrome Recurrent arterial or venous events Obstetrical – Recurrent miscarriages/fetal growth retardation Thrombocytopenia Incidence of + Antibodies in SLE – LAC -30% – ACL % – Anti- B2 Glycoprotein % 2 + tests 12 weeks apart to confirm diagnosis!

37 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


39 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

40 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

41 Prevalence of 12 NP Clinical Syndromes in CNS lupus (N=300) Headache24% CVA18% Mood disorder17% 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;

42 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)

43 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

44 Treatment Hydroxychloroquine Corticosteroids ASA NSAIDS Azathioprine MTX/Leflunomide Mycophenolate Mofetil Cyclophosphamide Anticoagulants Biologics RX For SLE REQUIRES A DISCLAIMER

45 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

46 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

47 Hydroxychlorquine Reduces Organ Damage Fessler B, et al Arth & Rheum 2005;

48 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;

49 Immunosuppressives Methotrexate-(+ Hydroxychloroquine) – mg/week – Best for arthritis Azathioprine- (+ Hydroxychloroquine) – Check TMPT assay pre-rx – Useful for joint/skin/nephritis – 3-6 months for effect

50 Immunosuppressive II Leflunomide- (+ Hydroxychloroquine) – 3 rd line for joint/skin/nephritis – Very tetragenic Mycophenylate – Use for nephritis – 3 rd line for skin/joint

51 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

52 Remission rates: MMF vs IVC 16/71 4/69 21/7 1 17/69 37/71 21/69 Intent-to-Treat analysis p = NS p = p = Responding (%) Ginzler, E. et al., N Engl J Med 2005;353:

53 Induction Rx of Lupus Nephritis Ginzler E et al NEJM; 353:

54 Belimumab Mechanism of Action

55 Slow onset Lancet 2011

56 Belimumab Reduction in Steroid Dose Time to Flare

57 Belimumab Improved or Stabilized SLE Disease Activity and Reduced Flare Rate during 3 Years of Therapy Furie Eular 2008; Merrill ACR year data

58 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

59 SLE Rx Algorithm SLE Severity Mild Skin Manifestations Arthritis 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 Rx HCQ or MTX + Prednisone 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 Rx CTX 750mg/m2/mo x 6mo or MMF 2-3 gm/day + Prednisone Taper Maintenance AZA or MMF + Steroid Taper +(?) Belimumab

60 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


62 Lupus Mortality Early Mortality – Infections – Lupus-related Late Mortality – Cardiovasular Disease – Malignancies

63 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/m 2 BMI > 25kg/m 2 Wgt Reduction ?Steroid Adjustment Individual risk factor mgmt BP Cholesterol Diabetes Wajed J et al Rheumatology 2003

64 Thank You!

65 Mortality Rates are Declining Bernatsky S et al, Arth & Rheum; 2006:

66 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

67 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: Sanchez-Guerrero J, NEJM, 2005;353:

68 Is Atherosclerosis Increased in SLE? 498 women with SLE at University of Pittsburgh 2208 women in Framingham Offspring Study Lupus pts 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

69 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 Esdaile et al Arthritis and Rheum 2001

70 Histopathologic Classification of Lupus Nephritis Class I.Minimal mesangial nephritis Class II.Mesangial proliferative nephritis Class 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 nephritis May associate with findings characterised in class III/IV. Class VI. Sclerosing glomerulonephritis  90% of glomeruli are sclerotic

71 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

72 Blys/BAFF

73 Lupus Rx Algorithm

74 Crow M, NEJM 2008;359:

75 SLE Genes: Ethnic Differences GENECAUCAFRreferences 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: p13 (discoid) X J Inv Derm Sym 9:64 NO synth prom X J Rheum 30:60 FasL 1q23 X J Immun 170:132

76 Arce-Salinas C, Rodrigues-Carcia F, EULAR 2008 THU0234 SLEDAI= SLE Disease Activity Index

77 Wallace in Arthritis and Allied Conditions, 13 th Ed V2, p1319 Koopman, ed % YEARS IMPROVED SURVIVAL IN SLE:

78 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


80 Rahman A, Isenberg D, NEJM; 2008:

81 Lupus nephritis Class IMinimal mesangialNormal light microscopy; abnormal electron microscopy Class IIMesangial proliferative Hypercellular on light microscopy Class IIIFocal proliferative<50% glomeruli involved Class IVDiffuse proliferative>50% glomeruli involved; segmental/global Class VMembranousPredominantly nephrotic disease Class VIAdvanced sclerosing Chronic lesions and sclerosis

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

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