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What’s New in Lupus? Jeffrey Carlin, MD Section Head,

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Presentation on theme: "What’s New in Lupus? Jeffrey Carlin, MD Section Head,"— 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 Treatment Options New Therapeutic Agents
ANA testing Treatment Options New Therapeutic Agents Adjuvant Therapy

3 Lupus Demographics USA Incidence Prevalence All 5.1 52.2 White 1.4 7.4
(per 100,000 per 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 Incidence and Prevalence of SLE: Rochester, MN Uramoto KM et al Arth Rheum 1999;46-50 Danchenko N et al Lupus 2006:

4 Abnormal (control of) immune responses
SLE - Etiology The etiology of SLE remains unknown Yet, SLE is clearly multifactorial: Genetic factors Immunologic factors Hormonal factors Environmental factors EBV? Genetic predisposition Baseline immunological abnormalities Infection Hormonal factors Abnormal (control of) immune responses 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 Low Probability of CTD Low Titer
High Titer ANA Identify Specific ANA Antigen Consider Ancillary Lab Tests Identify Specific Antigen Follow Pt Search for Other Evidence of Disease Or Organ Involvement Reassure Pt Search for Other Evidence of Disease Or Organ Involvement

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-Sm Ab Anti-RNP Ab

19 Prevalence of Autoantibodies in SLE
Antigen SLE Drug-Induced Native DNA 40% No Denatured DNA 70% 75-80% Histones >95% SM Antigen 30% Nuclear RNP Ribosomal RNP 10% SSA/Ro 35% SSB/La 15%

20 Significance of Autoantibodies in SLE
Antigen SLE Clinical Associations Native DNA 40% Nephritis (and flare) Denatured DNA 70% Non-Specific Histones Drug-Induced Lupus SM Antigen 30% Severe SLE Nuclear RNP Arthritis Ribosomal RNP 10% SSA/Ro 35% SCLE, Sjogren’s NLS SSB/La 15%

21 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

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

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 Criteria 2012 SLICC Criteria Sensitivity (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

25 Clinical Features on Presentation in SLE
Arthritis or Arthralgia 55% Skin Involvement 20% Nephritis % Fever % Other %

26 Organ Involvement in the Course of SLE
Joints % Skin Rashes % Discoid Lesions 30% Alopecia % Pleurisy/Pericarditis 60% Kidney % Raynaud’s % Mucous Membranes 15% 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 Acute Cutaneous Malar Rash- Note Sparing of Nasolabial Folds

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

30 Which patient has SLE?

31 Subacute Cutaneous Lupus
Papular squamous eruption Annular eruption

32 Livedo Reticularis

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

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

35 Severe Hematologic Syndromes of SLE
DX Antibodies Clinical Features APS ACL, antiB2GP1, LA Thrombosis inflammation ITP anti-IIb/IIIa, PF4 Bleeding <20K Thrombosis Hemolytic Anemia Coomb’s + Hemolysis TTP VWB multimer protease antibodies Catastrophic APS HELLP Syndrome TTP of SLE Bleeding anti-FVIII (IX, X!, XII, XIII) Hematomas, Hematuria GI/mucosal bleeds

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

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)
Headache 24% CVA % Mood disorder 17% Cognitive dysfunction 11% Psychosis 8% Seizure disorder 8% Anxiety Disorder 7% Aseptic meningitis % Acute confusional state 4% Transverse myelopathy 1% Movement disorder % 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 RX For SLE REQUIRES A DISCLAIMER 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)
7.5-25mg/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) Mycophenylate
3rd line for joint/skin/nephritis Very tetragenic Mycophenylate Use for nephritis 3rd 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
Intent-to-Treat analysis p = 0.009 37/71 p = NS Responding (%) p = 0.005 21/71 21/69 17/69 16/71 4/69 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 Reduction in Steroid Dose
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) 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

59 SLE Rx Algorithm SLE Severity Mild Severe Moderate Induction Rx
Skin Manifestations Arthritis Severe Severe Nephritis (Class 4 or 5 with renal impairment) Severe refractory thrombocytopenia/hemolytic anemia Pulmonary hemorrhage CNS disease Vasculitis Moderate Mild/Moderate Nephritis Thrombophlebitis Major Serositis Rx HCQ or MTX + Prednisone 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 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

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 Late Mortality Infections
Lupus-related Late Mortality Cardiovasular Disease Malignancies

63 Proposed Care Pathway for Management of SLE Patients
Known CHD Registration of pts with SLE Screening for risk factors Assessment of clinical manifestations Management for individual risk factors as per guidelines Individual risk factor mgmt BP Cholesterol Diabetes No known CHD BMI <25kg/m2 Wgt Reduction ?Steroid Adjustment BMI > 25kg/m2 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 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: 2. 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
CAUC AFR references TNF alpha X Hum Immunol 65:622 16q12-13 E J Hum Gen 12:668 12q24 Am J Hum Gen 74:73 FcgRIIIa Rheum (Ox) 42:446 FcgRIIa J Clin Invest 95:1348 11p13 (discoid) J Inv Derm Sym 9:64 NO synth prom J Rheum 30:60 FasL 1q23 J Immun 170:132

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

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

78 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


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

81 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

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

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