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What’s New in Lupus?

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.

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What’s New in Lupus?

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  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 Incidence and Prevalence of SLE: Rochester, MN Uramoto KM et al Arth Rheum 1999;46-50 Danchenko N et al Lupus 2006:308-318

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

  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;64:2319-2127

  12. Positive ANA High Probability of CTD Low Probability of CTD Low Titer ANA 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 AntibodyAnti- 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

  20. Significance of Autoantibodies in SLE

  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) 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 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."

  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 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 5% • Fever 5% • Other 15%

  26. 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%

  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% 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

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

  35. 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- 23-27% • Anti- B2 Glycoprotein 1 - 20% • 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

  38. 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

  39. 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

  40. 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

  41. 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)

  42. 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

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

  44. 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

  45. 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

  46. Hydroxychlorquine Reduces Organ Damage Fessler B, et al Arth & Rheum 2005;1473-1480

  47. 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

  48. 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

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

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