SYSTEMIC LUPUS ERYTHEMATOSUS

1. SYSTEMIC LUPUS ERYTHEMATOSUS Violeta Rus, MD, PhD Associate Professor of Medicine Rheumatology and Clinical Immunology

2. Systemic Lupus Erythematosus Epidemiology Pathogenesis Clinical Features Treatment

3. SLE: prototypical systemic autoimmune disease

4. EPIDEMIOLOGY • One of the most common autoimmunediseases (1:2500). 2. Female:male ratio is 9:1 3. Mean age at diagnosis is 30; peak age is between 15 and 45 • African-Americanand Hispanic womenhave a 3-5 fold greater incidence compared to whites (frequency 1:245) • Incidence of SLE has tripled in the past four decades

5. EPIDEMIOLOGY

6. PATHOGENESIS Etiology unknown: • Genetic predisposition • Environmental factors • Abnormalities of the immune system

7. GENETIC FACTORS • Genetic predisposition: • Familial clustering • Concordance rate in monozygotic twins (24%) higher than in dizygotic twins (1-3%) • Genome studies • Complex pattern: many genes (50) may be contributing to SLE.

8. GENETIC FACTORS Chromosome location Candidate Odds GenesRatio • 1q23 FcγRII ~4 • 1q25-31 ? • 1q41-q44 PARP • 2q35-37 PDCD1 ~2.6 • 4p16 ? • 6p11-p21 MHC class II:DR3 ~3 MHC class III: TNFα C2, C4 ~4.5 • 12q24 ? • 16q12-q13 OAZ

9. ENVIRONMENTAL FACTORS • DRUGS • hydralazine, procainamide, D-penicillamine • reversible with stopping of medication • associated with anti-histone autoantibody. • Viral illness: Epstein-Barr virus • UV light

10. PATHOGENESIS

11. Phases in the Development of Lupus Arbuckle, M. R. et al. N Engl J Med 2003;349:1526-1533

12. Malar Rash Discoid rash Photosensitivity Oral ulcers Arthritis Serositis Renal disorder Neurologic disorder Hematologic disorder Classification criteriaof SLE(1997 ACR revised criteria) • 10. Immunologic disorder • - anti-dsDNA OR • - anti- Sm OR • - antiphospholipid antibody: • positive IgG or IgM ACL Abs • lupus anticoagulant OR • false positive VDRL • 11. Abnormal titer of ANA at any • point in time in absence of drugs For diagnosis: any 4 of 11 criteria

13. 1. MALAR (butterfly) RASH CLINICAL FEATURES Facial eruption in a patient with systemic lupus erythematosus.

14. 2. DISCOID LUPUS • coin and round-shaped scalyplaques • hyperpigmentation at the periphery • central atrophy and depigmentation

15. 4.Oral ulcers

16. ALOPECIA Lupus hair: short, friable hair in frontal area Diffuse hair loss is most common in lupus, although patchy baldness can appear. Hair regrows slowly when the disease becomes inactive.

17. 5. SLE -Arthritis transitory arthritis; reversible hand deformities

18. Major Organ Involvement in SLE

19. Kidney involvement- glomerulonephritis Brain involvement-stroke Heart involvement- pericarditis

20. Neonatal lupus- anti-Ro (SSA) • Typical skin rash with predilection for the periorbital area • transient • Echocardiogram of congenital heart block • Permanent: requires pace-maker

21. Diagnostic tools for SLE Laboratory tests: Tests for autoantibodies: • Antinuclear antibody test (ANA) –major serological feature of lupus • Other autoantibody tests (anti-dsDNA, anti-Sm, anti-RNP, anti-Ro [SSA], anti-La [SSB]) • Anticardiolipin antibody Tests for disease activity: • Complement levels (C3,C4), anti-dsDNA Routine labs to monitor “silent involvement”: • Complete blood count • Erythrocyte sedimentation rate (ESR) • Urinalysis • Blood chemistries Kidney biopsy Skin biopsy

22. ANA Homogenous pattern Specificity: histone Disease association SLE, Drug-Induced Lupus Peripheral (ring) pattern Specificity: dsDNA Disease association: SLE Speckled pattern Specificity: Sm, Ro, La Disease association SLE, neonatal lupus Sjogren sdr

23. ANA– DISEASE SUBSETS ASSOCIATIONS Antibody to % Disease association

24. ANA

25. ANA Frequency in normal population: • 3.3% at titer of 1:320 and 31.7% at titer of 1:40 • Increases with age:10-37% of elderly >70 y/o • Higher in healthy first-degree relatives of patients with autoimmune diseases

26. ANA • Sensitivity: 98% (2% false negative results) (ability of a test to detect pts who have the disease) • Specificity:86% (significant # of false positives) (ability of a test to detect pts who do not have the disease) • Positive Predictive Value 11% (performs poorly as a screening test) (probability that a positive test correctly identifies an individual who actually has the disease)

27. Accumulation of Systemic Lupus Erythematosus Autoantibodies

28. Disease progression • Variable (from clinically ‘silent’ to rapidly progressive) and unpredictable • Flares and remissions • Survival has improved over the past decades: from <50% to >90% five-year survival 20 year survival is 70% • Mortality: 3-5 times greater than general population • Causes of death: • Active disease: nephritis, vasculitis, organ failure • Infections (treatment-related immunosuppressive therapy) • Cardiovascular: accelerated atherosclerosis (women aged 35–44 with SLE have 50-fold increased risk of MI) • Risk of death increased by: race, low socio-economic status, cardiovascular risk factors (smoking, diabetes, elevated cholesterol/lipids)

29. Clinical Forms Of Severe Lupus

30. PROGNOSIS • Variable • Factors affecting prognosis: • Demographic and social • Genetic and immunological • Histopathological • Treatment strategy

31. TREATMENT OF SLE • Three drugs have FDA approval for SLE: • ASA (1940) • Cortisone (1950) • Antimalarials (1956) • From 1960s : Azathioprine, Methotrexate, cyclophosphamide, Cellcept • 2011: first FDA approval for new drug for lupus

32. TREATMENT Mild Disease

33. UV light Protection Both UVA and UVB induce lesions: • Sun-protecting clothing • Sunblock SPF >30 (applies to UVB only) • UVA protection: Zn oxide; Ti dioxide; Avobenzone • UV light-blocking films on home and auto windows • Camouflage cosmetics (Dermablend, Covermark) • Avoid photosensitizing drugs (ex: HCTZ)

34. Antimalarials • Hydroxychloroquine (Plaquenil) • HQ: Start at 400mg/d; maintenance 200mg/d • Smoking decreases efficacy of antimalarials • Adverse effects: Retinopathy • Risk minimal at < 6mg/kg HQ • Baseline (within first mo) and biannual eye exam

35. TREATMENTSevere Disease Corticosteroids High dose (i.e. prednisone 1 mg/kg/day  or 1g IV methylprednisolone)  Immunosuppressives Azathioprine (Imuran)      Cyclophophamide (Cytoxan)  Methotrexate   Mycophenylate mofetil (Cellcept) 

36. TREATMENT- Severe Disease Cyclophosphamide: IV equally effective but less toxic than PO (by mouth) • Adverse effects: - bone marrow suppression - infections (herpes zoster) - hemorrhagic cystitis - persistent amenorrhea: risk depends on patient’s age and cumulative dose • Short course: 0% <25 y/o; 25% />31 • Longer course: 17%<25 y/o 100%/>31 Mycophenolate mofetil (Cellcept): diarrhea, myelotoxicity

37. Benlysta (Belimumab) • First FDA-approved drug for SLE in 50 years • Targets a growth factor for B cells called BLYSS (BAFF) • Monthly IV infusion • Two large trials: 865 patients and 819 patients - reduction in disease activity: 14% vs 9% with placebo - reduction in flare rate - reduction in prednisone dose However… • Magnitude of the benefit: modest • Not indicated for severe cases; efficacy in AA unknown • Costly

38. Treatment of SLE: Into the 21st Century BLyS inhibitors Proteasome inhibitors pDC Anti-B cell antibodies sBLyS mBLyS BR3 IFN IFN blockade TLR inhibitors cytokines DC B TLR9 TLR inhibitors B7.1/2 B7.1/2 TLR2 TLR4 TLR6 TLR7 TLR8 IFN blockade CTLA4-Ig Abatacept CD28 CD40 IL-2, 4 IL-10 TNF IFN IL-12p40 IFN T CXCL13 CXCR4 IP-10 S1P CD40L pDC TNF blockade MØ TNF IL-1 IL-6 Cytokine inhibitors IFN- IL-12 IL-23 TNF Lymphocyte signaling inhibitors Chemokine - Lymphocyte trafficking modulators IL-6 blockade PC

39. Future therapies in SLE Drug Target Epratuzumab CD20 LY 2127399 BLyS B cell therapies Atacicept BLyS, April A -623 BLyS Orencia CD80, CD86Costimulation Lupuzor T Lymphocytes Laquinimod T Lymphocytes T cell therapies MEDI- 545 Interferon- alpha Rontalizumab Interferon- alpha IFNalpha- Kinoid Interferon- alpha Anti-Cytokine therapy