1. SLE: An Update for 2015 Neil Kramer, MD, FACR, FACP Medical Director Institute for Rheumatic & Autoimmune Diseases

2. Case Presentation History: GC is a 21-year-old previously healthy black male who initially presented to the hospital 8 months earlier with severe inflammatory polyarthritis, weight loss (20 lbs), fevers, and alopecia. The arthritis was incapacitating and he was hospitalized 3 times in 2 months for inability to walk. On those admissions GC was found to also have generalized lymphadenopathy, anemia, and a low WBC. A lymph node biopsy revealed a reactive node but GC was told he had lymphoma and was scheduled for a bone marrow biopsy. Exam: cachectic and ill-appearing, T 101, diffuse alopecia, multiple firm, large, nontender moveable lymph nodes in the cervical, axillary, and groin areas Labs: WBC 2400, Hg/Hct 10/31.2, platelets 155,000 albumin 3.1, multiple cultures negative, HIV negative ANA+, dsDNA+, SSA+, SSB+, RNP+

3. What is SLE? Systemic autoimmune disease with multi-organ inflammation Systemic autoimmune disease with multi-organ inflammation Characterized by production of pathogenic auto- antibodies, directed primarily against nucleic acids and their binding proteins, reflecting a global loss of self-tolerance Characterized by production of pathogenic auto- antibodies, directed primarily against nucleic acids and their binding proteins, reflecting a global loss of self-tolerance

4. Pathogenesis of SLE

5. Development of Autoantibodies before the Clinical Onset of Systemic Lupus Erythematosus 130 patients, 520 matched controls for whom stored serum available SLE patients: SLE patients: ANA, anti-Ro, La, APL precede dx by many years ANA, anti-Ro, La, APL precede dx by many years Anti-Sm, RNP appear months before dx Anti-Sm, RNP appear months before dx Anti-DNA intermediate Anti-DNA intermediate Controls Controls 9% 1:40 ANA 9% 1:40 ANA 2-3% anti-DNA, Ro, APL, RNP 2-3% anti-DNA, Ro, APL, RNP None anti-Sm or La None anti-Sm or La Arbuckle MR et al. NEJM 2003;349:1526

6. SLE: Natural History

7. Clinical features of 130 patients prior and subsequent to a diagnosis of SLE Heinlen LD, et al. Arthritis Rheum. 2007;56:2344-2351. Length of follow-up ranged from 9.4 years prior to diagnosis and 6 years post diagnosis. Retrospective analysis of US military hospital databases Total Positive Before Diagnosis* Total Positive Ever* Malar RashDiscoid RashPhotosensitivityOral UlcersArthritisPericarditisPleuritisProteinuriaRenal CastsSeizuresPsychosis Hemolytic Anemia LeukopeniaLymphopenia Thrombocytopenia Serositis Renal Disease CNS Disease Hematological Abnormality Number of SLE Patients 100 80 60 40 20 0 120

8. Barr et al. Arthritis Rheum 1999;42:2682

9. SLE: Easy to Diagnose

10. Shmerling R. N Engl J Med 2003;349:1499-1500S Antinuclear Antibody (ANA) Test Results in a Hypothetical Population

11. IMMUNOFLUORESCENT ANA PATTERNS

12. ANA: Sensitivity In Autoimmune And Nonrheumatic Diseases AUTOIMMUNE DISEASE AUTOIMMUNE DISEASE SLE SLE Drug-induced LE Drug-induced LE Discoid LE Discoid LE Scleroderma Scleroderma MCTD MCTD PM/DM PM/DM RA RA Sjogren’s Sjogren’s NON-RHEUMATIC DISEASE NON-RHEUMATIC DISEASE Hashimoto/Graves’ Hashimoto/Graves’ Autoimmune hepatitis Autoimmune hepatitis Primary autoimmune cholangitis Primary autoimmune cholangitis Primary Pulmonary Hypertension Primary Pulmonary Hypertension SENSITIVITY (%) 95-100 100 10-15 60-80 100 60 52 40-70 45-50 100 40

13. Y Multiplexing: Flow cytometric immunoassay based on multiplexed fluorescent microspheres (beads) Multiple antibodies can be detected in 1 reaction using multiple antigen beads. Patient’s SSA antibody=Y; Detection antibody = Y CenB SSA Sm SSB Scl70 RNP SSB RiboP Sm dsDNA Scl70 RNP SSA Y Y Y Y Control

14. SLE Pathogenesis

15. SLICC Revision of ACR Classification Criteria for SLE Renal biopsy compatible with lupus nephritis AND positive ANA or anti-dsDNA OR 4 of the following criteria, including at least one clinical and one immunologic Petri et al. Arthritis Rheumatol 2012;64:2677-2686

16. SLICC 2012 Revision of ACR Classification Criteria for SLE: CLINICAL CRITERIA 1. Acute cutaneous LE (malar, bullous, SCLE) 2. Chronic cutaneous LE 3. Oral/Nasal ulcers 4. Nonscarring alopecia 5. Inflammatory polyarthritis 6. Serositis 7. Renal: ≥500 mg proteinuria or RBC casts 8. Neurologic: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, cerebritis 9. Hemolytic anemia 10. Leukopenia (<4000 at least once) OR lymphopenia (<1000 at least once) 11. Thrombocytopenia (<100,000 at least once)

17. SLICC Revision of ACR Classification Criteria for SLE: IMMUNOLOGIC CRITERIA 1. ANA above laboratory reference range 2. Anti-DNA above laboratory reference range (except ELISA: 2 x above range) 3. Anti-Sm antibody 4. Antiphospholipid antibody Lupus anticoagulant False positive test for syphilis Anticardiolipin (at least 2x normal or medium-high titer Anti-β-2 glycoprotein 1 5. Low complement: C3, C4 or CH 50 6. Direct Coombs in absence of hemolytic anemia

18. What Is Not SLE? Sjogren’s syndrome Fibromyalgia with positive ANA HIV related “pseudo-SLE” Lymphoproliferative disorders High titer ANA associated with: Chronic liver disease Chronic liver disease Interstitial lung disease Interstitial lung disease Autoimmune thyroid disease Autoimmune thyroid disease

19. Genetics and Lupus Lupus is more common in families with lupus or other immune system diseases Some groups, such as African Americans, Hispanics, and Asians get lupus more commonly and with more severe symptoms ≈50% concordance in MZ twins 15-25% concordance in DZ twins 10% first degree relatives affected Over 30 SLE associated genes:  Apoptosis  Complement receptors  Fc-γ receptors 2A and 3A  HLA class II genes  Epigenetics: DNA methylation Kaiser and Criswell, Curr Opin Rheum 2010

20. Environmental Triggers Of SLE Ultraviolet light Drugs Smoking Infections Major physical/psychological stresses Food additives (ie. hydrazines, L-canavanine) ? Silica ?Mercury

21. Drug-Induced Systemic Lupus Erythematosus (DILE) Epidemiology DILESLE Epidemiology DILESLE Age of onset 50 to 70 years20 to 30 years Age of onset 50 to 70 years20 to 30 years Race White > BlackBlack > White Race White > BlackBlack > White Female/male ratio 1:19:1 Female/male ratio 1:19:1 Laboratory Diagnosis Laboratory Diagnosis ANA 98%98% ANA 98%98% Anti-dsDNA <0.1%**85% Anti-dsDNA <0.1%**85% Anti-histone90%50% Anti-histone90%50% Complement levelsNormal + Decreased Complement levelsNormal + Decreased **anti-TNF DILE closer to 60-70% + anti-TNF DILE closer to 15%

22. Drug-Induced Systemic Lupus Erythematosus (DILE) Nephritis and CNS abnormalities rare Resolution of symptoms after stopping drug (1 to 4 weeks) Classically associated with hydralazine, isoniazid, procainamide, thiazides (cutaneous), statins TNF antagonists—exceptions to rules

23. Importance Of Estrogen In SLE Marked increased incidence post-menarche Pre-menstrual flares Increased disease activity post-partum period Increased incidence of SLE with postmenopausal ERT 1 BUT No exacerbation by birth control pills 2 No apparent flare of SLE with postmenopausal ERT 3 AVOID in presence of antiphospholipid ab 1 Sanchez-Guerrero et al. Ann Int Med 1995;122:430 2 Petri M, et al. NEJM 2005 3 Sanchez-Guerrero et al. Arthritis Rheum 2007;56:3070

24. Randomized Single-blind Trial of Contraceptive Methods in Women with SLE Combined OC (N=54) Progestin- only pill (N=54) IUD(N=54) p Value p Value Flare0.67 3 month 3 month0.590.650.60 12 month 12 month0.910.930.88 Severe Flare 0.62 3 month 3 month0.020.070.04 12 month 12 month0.050.100.04 Sanchez-Guerrero J, et al. NEJM 2005

25. The SELENA Trials: OC 1 and HRT 2 Use of OC was not associated with an increase in severe, mild- to-moderate or total flares in ACA – women with inactive or stable/active SLE Use of OC was not associated with an increase in severe, mild- to-moderate or total flares in ACA – women with inactive or stable/active SLE Use of HRT was not associated with an increase in severe flares, but was with mild-to- moderate flares. Use of HRT was not associated with an increase in severe flares, but was with mild-to- moderate flares. 1 Petri M. N Engl J Med 2005;353:2550 2 Buyon J. Ann Intern Med 2005;142:953

26. OC-Safety of Estrogens in LE National Assessment (SELENA) Trial Use of OC was not associated with an increase in severe, mild- to-moderate or total flares Use of OC was not associated with an increase in severe, mild- to-moderate or total flares Use of OC was not associated with an increase in renal flares Use of OC was not associated with an increase in renal flares ACA + excluded ACA + excluded Petri M, et al. NEJM 2005

27. Menopausal hormonal therapy in women with systemic lupus erythematosus Double-blind, randomized trial comparing estrogen-progestin vs placebo for 2 years No difference in: No difference in: Global/maximal disease activity Global/maximal disease activity Incidence of flares Incidence of flares Medication use Medication use But: But: Thromboses in 3 HRT vs 1 placebo Thromboses in 3 HRT vs 1 placebo Sanchez-Guerrero et al. Arthritis Rheum 207;56:3070

28. Cutaneous Lupus Lupus Specific Lupus Specific Acute Acute Malar erythema Generalized erythema Bullous LE Bullous LE Subacute Cutaneous LE Subacute Cutaneous LE Annular Papulosquamous Chronic Chronic Localized discoid Generalized discoid Lupus profundus Lupus non-specific Panniculitis Urticaria Vasculitis Livedo reticularis Oral lesions Non-scarring alopecia Associated conditions Psoriasis Lichen planus Porpyria (PCT)

29. Cutaneous LE: skin biopsy

30. Cutaneous Lupus

31. Cutaneous LE: the hand

32. Subacute cutaneous LE

33. Cutaneous LE: other forms Bullous LE DLE of scalp Neonatal LE Lupus profundus

34. Systemic lupus erythematosus: bullous lesions, palate

35. Cutaneous LE: Non-medical Management Rule out drug-induced LE (growing list) Rule out drug-induced LE (growing list) Smoking cessation Smoking cessation Environmental Photoprotection Environmental Photoprotection Car windows only block UVB Car windows only block UVB Fluorescent tube lights emit UVB Fluorescent tube lights emit UVB Photocopiers emit UVA Photocopiers emit UVA Sunscreens: UVA and UVB, water-resistant, high SPF Sunscreens: UVA and UVB, water-resistant, high SPF Protective clothing Protective clothing

36. Systemic lupus erythematosus: hand, Jaccoud's arthropathy

37. SLE- Musculoskeletal Manifestations Lupus related Inflammmatory polyarthritis Polymyositis Osteonecrosis Calcinosis cutis/myositis ossificans Associated Fibromyalgia Steroid induced osteoporosis Gout

38. Osteonecrosis In SLE Frequency: Distribution: Risk factors: 18% hip>knee>shoulder> tarsal/carpal Prednisone>20mg/day Vasculitis Raynaud’s Antiphospholipid antibodies

39. Avascular necrosis: crescent sign, hip (roentgenogram)

40. Avascular necrosis: proximal femurs (MRI)

41. SLE: Pleuropulmonary Manifestations Pleurisy Acute pneumonitis Chronic consolidation Pulmonary hemorrhage Interstitial lung disease Pulmonary hypertension Infections

42. SLE: CARDIAC Pericarditis Myocarditis LV diastolic dysfunction Liebman-Sacks endocarditis Pulmonary hypertension Coronary arteritis Coronary Atherosclerosis

43. Hahn, B. H. N Engl J Med 2003;349:2379-2380 Accelerated Atherosclerosis In SLE

44. Percent Prevalence of Subclinical Disease Subclinical Cardiovascular Disease Is Prevalent in Women With SLE 1. El-Magadmi M, et al. Circulation. 2004;110:399-404. 2. Ahmad Y, et al. Rheumatology. 2007;46:983‐988. N=62 N=200N=38N=100 Endothelial Dysfunction 1 Carotid Plaque 2 P=0.04 Percent Prevalence of Subclinical Disease Study 1: Mean age was 48 years, disease duration was 11 years, 88% were white. Endothelial dysfunction was measured by Doppler ultrasound of the brachial artery to determine change in blood flow. Endothelial dysfunction was defined as flow-mediated dilation ≤4.5%. Study 2: Mean age was 48 years, median disease duration was 12 years, and all were white. Carotid plaque was detected using B-mode ultrasound. STUDY 1 STUDY 2 0 20 40 60 80 100 26.3 54.8 Control SLE P<0.01 0 20 40 60 80 100 3 21 Control SLE

46. Hematologic Manifestations Of SLE Anemia Of chronic disease Of chronic disease Coombs + autoimmune hemolysis Coombs + autoimmune hemolysis Leukopenia Granulocytopenia Granulocytopenia Lymphopenia Lymphopenia Thrombocytopenia Antiphospholipid antibody syndrome

47. SLE: Gastrointestinal & Hepatic  Uncommon SLE manifestations  Peritonitis (analogous to pleuritis, pericarditis)  Pancreatitis  Severe abdominal pain often indicates mesenteric vasculitis, resembling medium vessel vasculitis (PAN)  Diverticulitis may be masked by steroids  Hepatic abnormalities more often due to therapy than to SLE itself  “Lupoid hepatitis”—obsolete name for autoimmune hepatitis

48. LIVEDO RETICULARIS

49. The Antiphospholipid Antibody Syndrome CLINICAL CRITERIA CLINICAL CRITERIA Thrombosis Thrombosis One or more confirmed episodes: arterial, venous or small- vessel thrombosis; exclusion of other causes; male <55 yr; female < 65 yr One or more confirmed episodes: arterial, venous or small- vessel thrombosis; exclusion of other causes; male <55 yr; female < 65 yr Complications of pregnancy Complications of pregnancy ≥ 1 unexplained fetal deaths >10 wks ≥ 1 unexplained fetal deaths >10 wks ≥ 1 pre-eclampsia/placental insufficiency < 34 wks ≥ 1 pre-eclampsia/placental insufficiency < 34 wks 3 unexplained consecutive spontaneous abortions < 10 wks 3 unexplained consecutive spontaneous abortions < 10 wks aPL associated aPL associated Cardiac valve disease Cardiac valve disease Livedo reticularis Livedo reticularis Thrombocytopenia Thrombocytopenia Nephropathy Nephropathy Miyakis et al. J Thromb Haemost 2006;4:295

50. The Antiphospholipid Antibody Syndrome (cont.) LABORATORY CRITERIA LABORATORY CRITERIA Demonstration on 2 or more occasions at least12 weeks apart of: Demonstration on 2 or more occasions at least12 weeks apart of: IgG or IgM anticardiolipin antibodies (at moderate to high titer) IgG or IgM anticardiolipin antibodies (at moderate to high titer) anti-beta 2 glycoprotein I antibodies (at moderate to high titer) anti-beta 2 glycoprotein I antibodies (at moderate to high titer) Lupus Anticoagulant Lupus Anticoagulant DEFINITE DIAGNOSIS: at least one clinical and one laboratory criteria DEFINITE DIAGNOSIS: at least one clinical and one laboratory criteria

51. aPL Antibody Syndrome: Current Treatment Recommendations VascularThrombosus prevention Asymptomatic aPL +No treatment Venous thrombosisWarfarin INR 2.0-3.0 Arterial thrombosisWarfarin INR 3.0 Recurrent thrombosisWarfarin INR 3.0-4.0 + ASA CAPSAnticoagulation + steroids + IVIG + plasmapheresis Erkan Rheum Dis Clin Norh Am 2006;32:129 Lim JAMA 2006;295:1050

52. Warfarin for aPL antibody syndrome No data to indicate efficacy for: Microangiopathic nephropathy Microangiopathic nephropathy Valvular heart disease Valvular heart disease Livedo reticularis Livedo reticularis Leg ulcers Leg ulcers UBOs on MRI UBOs on MRI Congnitive dysfunction Congnitive dysfunction

53. Neuropsychiatric Lupus (NPSLE)  19 case definitions of NP manifestations  Most commonly — Cognitive dysfunction — Headache — Mood disorder  Anxiety  Psychosis*  Depression — Seizures* — Vascular disease – *Part of the classification criteria for SLE Anatomic distribution

54. Patient EM EM, an 18-year-old black female presents to the ER with acute onset of confusion and hallucinations Her parents report that she has been complaining of “fatigue” for the last 6 months and has lost 5 lbs. An ANA ordered by her primary physician last week was 1:1280 Abnormal physical findings include a low-grade fever of 100 o F, and several small oral ulcers Labs: strongly positive anti-dsDNA antibody, borderline anti-Sm and normal levels of C3 and C4

55. Epidemiology of NPSLE Cumulative incidence is ~30%–40% In early disease ~20% of patients already have atrophy on brain MRI ~10% have focal lesions Only 1/3 of NP manifestations are directly attributable to SLE

56. Neuropsychiatric Lupus Neurologic Seizures Seizures Stroke syndrome Stroke syndrome Movement disorder Movement disorder Headache Headache Transverse myelitis Transverse myelitis Cranial neuropathy Cranial neuropathy Peripheral neuropathy Peripheral neuropathy Psychiatric Organic brain syndrome Psychosis Psychoneurosis Cognitive dysfunction

58. Attribution of NP Events is Critical 2/3 of CNS events are due to other causes: Infections Medication toxicity Hypertension Toxins (cocaine) Stroke linked to atherosclerotic disease Hemorrhage Reactive depression, anxiety “NPSLE Mimics” — Posterior reversible leukoencephalopathy syndrome — Thrombotic thrombocytopenic purpura

59. CNS Lupus What is it? Clinical differential diagnosis Active SLE Thromboembolic (+/- APL antibodies) Atherosclerotic Infectious Drug toxicity (steroids, NSAID, cyclosporine, azathioprine) Toxic/metabolic Pathophysiology Vasculopathy vs. vasculitis Anti-neuronal antibody mediated

61. Proposed Model for Antibody-Mediated Neurotoxicity Antibody in circulation Antibody penetrates brain tissue Transient or permanent functional impairment Nature of impairment may depend on antibody titer or location of antibody penetration Insult to the BBB (often not disease related) Entry of cytokines and chemokines Anti-NMDA receptor Anti-ribosomal P Other? Stress Smoking Infection Flare

66. NPSLE – Identifying the Cause Will Determine Treatment NPSLE manifestations may occur during periods of disease quiescence in other organs Correct ascertainment and attribution is critical — for example, an ischemic stroke due to long- standing diabetes and hypertension should not be treated with immunosuppression and/or anticoagulation!

67. Management of NPSLE Immunosuppression for inflammatory manifestations Cyclophosphamide is superior to high-dose steroids for severe cognitive disturbance and psychosis Anticoagulation for patients with APL antibody manifestations Traditional drugs for headache, seizures, stroke, and mood disorders Stress management and psychotherapy Many SLE patients use alternative medicines

74. Patient EM Resolution of symptoms and decrease in anti-DNA antibodies over 6–8 weeks is followed by steroid taper over the next 6 months. She is maintained on Plaquenil and followed every 3 months but is lost to follow-up after 2 years 3 years later, at age 23 she presents with fevers and joint pains after returning from a trip to Jamaica. In the last 3 days she has noticed mild swelling of both ankles Anti-DNA antibodies have increased by 200% since her last visit. Anti-Sm is now strongly positive; both C3 and C4 are decreased below normal Urinalysis reveals 300 mg/dL proteinuria and 5 WBC/hpf; her serum creatinine is normal

75. SLE: Renal (Lupus Nephritis) Develops in up to 50% of patients Develops in up to 50% of patients 10% SLE patients go to dialysis or transplant 10% SLE patients go to dialysis or transplant Hallmark clinical finding is proteinuria; hematuria; renal insufficiency; hypertension Hallmark clinical finding is proteinuria; hematuria; renal insufficiency; hypertension Nephritis remains the most frequent cause of disease-related death.

76. The Poor Man’s Renal Biopsy

77. Systemic lupus erythematosus: glomerulonephritis, focal

78. ISN/RPS* Classification of Lupus Nephritis I minimal mesangial lupus nephritis II mesangial lupus nephritis III focal proliferative lupus nephritis IV diffuse proliferative lupus nephritis V membranous lupus nephritis VI advanced sclerotic lupus nephritis Classes III and IV further subdivided on basis of activity, chronicity and scarring *ISN=International Society of Nephrology RPS=Renal Pathology Society

79. Illei, G. G. et. al. Ann Intern Med 2001;135:248-257 Kaplan-Meier analysis of failure of therapy with cyclophosphamide plus methylprednisolone(circles),cyclophosphamide only(squares),or methylprednisolone only(triangles)

80. IV cyclophosphamide for lupus nephritis: a gentler approach? High-dose: 1 gm/m 2 x 6 months, then q 3 months x 2 more doses Low-dose: 500 mg q 2 weeks x 6 doses Both followed by azathioprine All p=NS Houssiau FA et al. Arthritis Rheum 2002;46:2121

81. Mycophenolate mofetil as induction therapy for DPLN  MMF (2 g x 6 mo., then 1 g x 6 mo) + prednisone  CY ( 2.5 mg/kg/d x 6 mo), then AZA (1.5 mg/kg/d x 6 mo) + prednisone Chan TM et al. N Engl J Med. 2000;343:1156

82. MMF vs CYC for Proliferative GN Appel et al. J M Soc Nephrol 2009; 20: 1103-1112

83. Maintenance After IV Cyclophosphamide Induction For Lupus Nephritis Contreras, G. et al. N Engl J Med 2004;350:971-980

84. ALMS Trial: Kaplan–Meier Curves for Time to Treatment Failure and Time to Renal Flare Dooley MA et al. N Engl J Med 2011;365:1886- 1895

85. Azathioprine versus mycophenolate mofetil for long-term immunosuppression in lupus nephritis: results from the MAINTAIN Nephritis Trial Fewer renal flares were observed in patients receiving MMF but the difference did not reach statistical significance Houssiau et al. Ann Rheum Dis 2010

86. MMF vs CYC for Pure Membranous Lupus Nephritis Radhakrishnan et al. Kidney Int. 2010; 77:152-160

87. Trial profile and patient disposition. Houssiau F A et al. Ann Rheum Dis doi:10.1136/ard.2010.131995 ©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

88. Serial measurements of 24-h proteinuria, serum albumin, serum creatinine, serum C3, haemoglobin, ECLAM, SLEDAI and tapering of GCs over time. Houssiau F A et al. Ann Rheum Dis doi:10.1136/ard.2010.131995 ©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

89. Kaplan–Meier probability analysis of renal flare. Houssiau F A et al. Ann Rheum Dis doi:10.1136/ard.2010.131995 ©2010 by BMJ Publishing Group Ltd and European League Against Rheumatism

90. ACR 2012 Guidelines for Treatment of Type III and IV Lupus Nephritis

91. ACR 2012 Guidelines for Type V Lupus Nephritis

92. Rituxilup for Lupus Nephritis (Rituximab + MMF with minimal glucocorticoids ) 50 consecutive patients, no control group 1 g Rituximab + 500 mg iv methylpredisolone days 1and 15 1 g Rituximab + 500 mg iv methylpredisolone days 1and 15 Start MMF ≤ 3 g day 16 Start MMF ≤ 3 g day 16 No prednisone!!! No prednisone!!! CR: PCR< 50mg protein/mmole creatinine + serum creatinine ≤15% above baseline PR: PCR 50% reduction from baseline + serum creatinine ≤15% above baseline Condon MB. Ann Rheum Dis 2013;72:1280-6

93. Tacrolimus ≤ MMF for Lupus Nephritis Open-label, randomized 6 month induction: Pred. 0.6 mg/kg x 6 wks then tapered + TAC 0.06-0.1 mg/kg/day OR MMF 2-3 gm/day Responders (79%) maintenance azathioprine Mok CC et al. Ann Rheum Dis 2014 Dec30

94. Lupus ESRD Stop immunosuppression Stop immunosuppression Survival in renal transplants is good Survival in renal transplants is good 1 year: 88% (91% in non-SLE) 1 year: 88% (91% in non-SLE) 5 years: 81% (83% in non-SLE) 5 years: 81% (83% in non-SLE) 10 years: 71% (74% in non-SLE) 10 years: 71% (74% in non-SLE) Recurrence of lupus nephritis is low Recurrence of lupus nephritis is low Rejection: 25% (most lose graft) Rejection: 25% (most lose graft) SLE recurrence: 3% SLE recurrence: 3% Norby GE, et al. ArthritisRheum 2011; 63:733-7 Norby GE, et al. ArthritisRheum 2011; 63:733-7 Contreras G, et al. J M Soc Nephrol 2010;21:1200-7 Contreras G, et al. J M Soc Nephrol 2010;21:1200-7

95. Life Threatening Lupus Myocarditis Pancreatitis Digital gangrene Pulmonary. Hemorrhage CNS vasculitis Coronary arteritis Mesenteric vasculitis Pulmonary embolism Hemolytic anemia Pericardial tamponade TTP Pulmonary hypertension Budd-Chiari syndrome Marrow aplasias

96. Primary Causes Of Death Among 222 SLE Patients* Active SLE (31%) Renal (18%) Renal (18%) CNS (7%) CNS (7%) Other (5%) Other (5%) Infection (33%) SLE active (19%) SLE active (19%) SLE inactive (5%) SLE inactive (5%) CVA (3%) Pulm embolism (4%) MI (4%) GI bleed (2%) Unknown (13%) Unrelated (9%) *Rosner et al. Arthritis Rheum 1982. 25:612 Deaths among 1103 patients followed over 13 years at 9 University centers

97. Mortality in SLE  International cohort of 9547 patients  Overall SMR was 2.4 (CI 2.3-2.5)  Dramatic decrease in SMR for infectious and renal deaths between decades 1970-79 and 1990-2001  But, no change in SMR for cardiovascular deaths  Patients < age 40 (SMR 10.7) and patients with disease duration < 1 year (SMR 5.4) at greatest risk Bernatsky et al. A&R 2006;54:2550 Absolute number and standardized mortality ratio (SMR) estimates by cause of death 7.9

99. To Flare Or Not To Flare: That is the Question Serologically active clinically quiescent: 8-22% of patients Serologically active clinically quiescent: 8-22% of patients Toronto (anti-DNA,C3, C4): 40% flare rate witin one year 1 Toronto (anti-DNA,C3, C4): 40% flare rate witin one year 1 New York (anti-DNA,C3,C3a): 40% flare rate within 90 days 2 New York (anti-DNA,C3,C3a): 40% flare rate within 90 days 2 London (anti-DNA, anti-nucleosome: 65% flare within one year 3 London (anti-DNA, anti-nucleosome: 65% flare within one year 3 Pre-emptive prednisone may reduce flares Pre-emptive prednisone may reduce flares 30 mg above baseline dose reduced flare (2/22 vs 20/24) 4 30 mg above baseline dose reduced flare (2/22 vs 20/24) 4 30 mg taper over 4 weeks reduced severe flares by 35% 2 30 mg taper over 4 weeks reduced severe flares by 35% 2 Clinically active serologically quiescent 5: : 12% of 514 patients followed Clinically active serologically quiescent 5: : 12% of 514 patients followed Major organ inolvement in 2/3 of patients (CNS, renal, vasculitis) Major organ inolvement in 2/3 of patients (CNS, renal, vasculitis) BOTTOM LINE: Individualize, weigh risk/benefit, always rule out alternative causes Bootsma Lancet 1995 5 1 LeBlanc JRheum 1994;21:2239 2 Tseng A&R 2006;54:3623 3 Ng A&R 2006;55:900 4 Bootsma Lancet 1995 5 Gladman JRheum 2003;30:1960

100. SLE Pathogenesis

101. Lupus Therapies Mild disease (constitutional, rash, arthritis, serositis) Mild disease (constitutional, rash, arthritis, serositis) NSAIDS NSAIDS Antimalarials Antimalarials Limited corticosteroids Limited corticosteroids Moderate disease (serositis, mild nephritis, myositis, pneumonitis, cytopenias, mild disease unresponsive) Moderate disease (serositis, mild nephritis, myositis, pneumonitis, cytopenias, mild disease unresponsive) Corticosteroids Corticosteroids Azathioprine Azathioprine Methotrexate Methotrexate Belimumab Belimumab Severe disease (nephritis, vasculitis, pulmonary hemorrhage, CNS, TTP) Pulse steroids Cyclophosphamide IVIG Plasmapheresis Mycophenolate mofetil Rituximab Protocols FDA approved drugs for SLE: FDA approved drugs for SLE: aspirin, corticosteroids, hydroxychloroquine, belimumab

102. Expert Opinion Treatment 2015 Arthritis Care & Research March 2015

103. Expert Opinion Treatment 2015

104. Hydroxychloroquine (Kalia. Dermatologic Therapy 2007;20:160-74) Beneficial effects in SLE Beneficial effects in SLE Skin, joint and constitutional symptoms Skin, joint and constitutional symptoms Decreases the incidence of disease flares 1 Decreases the incidence of disease flares 1 Decreases incidence of thrombotic events 2 Decreases incidence of thrombotic events 2 Decreases end-organ damage 3 Decreases end-organ damage 3 Decreases incidence of malignancy 4 Decreases incidence of malignancy 4 Increases survival 5 Increases survival 5 Safe in pregnancy 6 Safe in pregnancy 6 Ancillary effects Ancillary effects Reduces cholesterol, TG, LDL levels by up to 15-20% 7 Reduces cholesterol, TG, LDL levels by up to 15-20% 7 Improved glucose tolerance, reduced incidence to type 2 diabetes 8 Improved glucose tolerance, reduced incidence to type 2 diabetes 8 1 Canadian HCQ Group Lupus 1993;7:80 2 Petri. Lupus 1996;5:S16 3 Fessler A&R 2005;52:1473 4 Ruiz- Irastorza, Ann Rheum Dis 2007;66:815 5 Alarcon, Ann Rheum Dis. 2007 6 Clowse A&R 2006;54:3640 7 Wallace, Am J Med 1990;89:322 8 Wasko, JAMA 2007;298:187

105. Targeted Therapeutic Approaches in SLE APCTB Y CTLA4-Ig  CD22 B-cell toleragen  BlySS TACI-IG  CD20  IL-10 Peptide Antibody IL-10 Apoptotic material 1 2 Costimulatory Factors, eg, BlyS Innate Adaptive

106. New Therapeutic Strategies—Targeted Immunotherapy Immune targeted therapy — B-cell directed — Cytokine inhibitors — Costimulation blockade — Peptide inhibitors — Kinase inhibitors — T regulatory cells Stem cell transplant Yildirim-Toruner C, Diamond B. J Allergy Clin Immunol. 2011;127:303-312.

107. Case Presentation History: KA was a 23-year-old black woman who was hospitalized with a 2-week history of extreme fatigue, fever, and pain and swelling of her hands, wrists, elbows, knees, and ankles. She had been previously healthy and was 3 months postpartum. Exam: T 103, thin, ill-appearing in severe pain, malar rash, polyarthritis (all joints) Labs: WBC 3.2, hb/hct 7.2/21, platelets 32,000, BUN/Cr 32/1.3 UA: protein 100, RBC 10–20, WBC 0–5/HPF peripheral smear: schistocytes ANA+, dsDNA+, Ro+, La+, Sm+

108. Case Presentation T 100.2, BP 130/90, ulceration on the palate, erythematous malar rash, diffuse lymphadenopathy and synovitis of the MCP/PIP joints Exam: T 100.2, BP 130/90, ulceration on the palate, erythematous malar rash, diffuse lymphadenopathy and synovitis of the MCP/PIP joints WBC 2.5, total protein 9.0, albumin 3.0, Hg/Hct 11/32, BUN/Cr 11/.06 UA: 100 mg/dL protein, RBC 20–40, WBC 0–1/HPF ANA+, anti-dsDNA+, anti-Sm+ Labs: WBC 2.5, total protein 9.0, albumin 3.0, Hg/Hct 11/32, BUN/Cr 11/.06 UA: 100 mg/dL protein, RBC 20–40, WBC 0–1/HPF ANA+, anti-dsDNA+, anti-Sm+ History: A 13-year-old Hispanic female with no past medical history presented to the ER with an 8-week history of joint pain and swelling in the hands, knees, and ankles, and fever, myalgias, pleuritic chest pain, weight loss, and a facial rash that worsened with sun exposure. She had been seen initially at a local clinic and treated for “cellulitis” with oral Keflex. 2 days prior to this presentation she was seen in another ER, found to have a temperature of 103, proteinuria, and anemia, was told it was a “viral syndrome” and discharged home.

109. Case Presentation History: MG is a 35-year-old woman from Ecuador who was brought to the hospital by her brother for increasingly bizarre behavior. She had originally come to this country 2 years previously in order to work and send money home to her husband and children. During her 1st year here, MG became very withdrawn and depressed to the point where she lost her job. Her brother thought she missed her family and sent her back to Ecuador. At home she continued to worsen with increasing depression, confusion, paranoia and hallucinations, despite multiple medical evaluations. MG was sent back to the United States for medical attention. Exam: T 101, faint malar erythema, incoherent and extremely combative; attempted to kick or bite anyone who came near her Labs: WBC 2.9, hb/hct 10/29, normal chemistries and UA, extensive cultures negative, HIV negative positive ANA, anti-dsDNA, Ro (SSA), La (SSB), Sm, RNP

110. Case Presentation History: GC is a 21-year-old previously healthy black male who initially presented to the hospital 8 months earlier with severe inflammatory polyarthritis, weight loss (20 lbs), fevers, and alopecia. The arthritis was incapacitating and he was hospitalized 3 times in 2 months for inability to walk. On those admissions GC was found to also have generalized lymphadenopathy, anemia, and a low WBC. A lymph node biopsy revealed a reactive node but GC was told he had lymphoma and was scheduled for a bone marrow biopsy. Exam: cachectic and ill-appearing, T 101, diffuse alopecia, multiple firm, large, nontender moveable lymph nodes in the cervical, axillary, and groin areas Labs: WBC 2400, Hg/Hct 10/31.2, platelets 155,000 albumin 3.1, multiple cultures negative, HIV negative ANA+, dsDNA+, SSA+, SSB+, RNP+

111. Patient EM EM responds to high-dose MMF and prednisone. She is maintained on low dose MMF and 5 mg prednisone daily for 2 years and is then switched to azathioprine as she wants to get pregnant She has 2 uneventful pregnancies at age 27 and 29 but gains 50 lbs over this time, which she is unable to lose 2 subsequent arthritic flares are treated with moderate-dose prednisone She is maintained on plaquenil and prednisone 7.5 mg/day She requires an ACE inhibitor for mild hypertension and at age 36 develops type 2 diabetes. Her HbA1C is always above normal At age 43 she presents to the ER with central chest pain on exertion and is found to have an inferior myocardial infarction

112. Rituximab for Moderately to Severely Active Extra-renal SLE* Merrill et al. Arthritis Rheum 2010;62:222

113. Rituximab: Improvement in Immunologic Parameters

114. Rituximab : No difference All Subjects

115. Rituximab: Response Depends on Race Merrill et al. Arthritis Rheum 2010;62:222

116. Innate immune responses in SLE Activ. B Activ. T B cell T cell Mature DC Activ. mono/macrophage Immat. pDC INCREASED IFN  Bacteria Viruses SLE DNA/IC CpG DNA ssRNA dsRNA TLR9 TLR7 TLR3 ICAM-1 CD86 MHC-I IL12p70 IFNg IL-10 BlyS TNFa IL-1 IL-12 Immune complexes in SLE bind TLR7

117. B-Cell Growth Factors and Receptors 117

118. BLyS Levels in SLE 118

119. Phase 3 Belimumab International SLE Study (BLISS-76) 119 RANDOMIZERANDOMIZE  819 adult subjects with SLE diagnosis (ACR criteria)  SELENA-SLEDAI ≥6; positive ANA (≥1:80) and/or anti- dsDNA (≥ 30 IU/mL); results from 2 independent time points  Stable standard of care therapy for at least 30 days Belimumab 1 mg/kg + Standard of Care Placebo + Standard of Care Belimumab 10 mg/kg + Standard of Care

120. BLISS-76 Primary Efficacy Endpoint (Patient Response Rate) ≥4-point improvement in SELENA SLEDAI score ≥4-point improvement in SELENA SLEDAI scoreAND No new BILAG 1A/2B flares No new BILAG 1A/2B flaresAND No worsening in PGA (<0.3-point increase) No worsening in PGA (<0.3-point increase) 120 SLE Responder Index at Week 52

121. BLISS-76 Primary Efficacy Endpoint at Week 52 121 Belimumab

122. Inhibiting APRIL and/or BLyS BLyS APRIL Proteoglycans TACI BCMA BAFF-R B-cell Lymphostat-B (Anti-BLyS) Ab BAFF-R-IG (Soluble receptor that binds BLyS only) TACI-Ig (Soluble receptor that binds BLyS and APRIL)

123. Atacicept inhibits the function of BLys and APRIL Atacicept is a fusion protein formed between the extracellular domain of the naturally occurring human TACI receptor and the Fc domain of human IgG1 Atacicept is a fusion protein formed between the extracellular domain of the naturally occurring human TACI receptor and the Fc domain of human IgG1 Atacicept B-cell rDNA technology Fc domain of human IgG Extracellular domain of TACI receptor

124. Past, Present and Future Treatment of SLE 1950’s-early 2000’s: Shotgun Immunosuppression Corticosteroids Anti-malarials “Pulse corticosteroids” Azathioprine Cyclophosphamide Mycophenolate mofetil Methotrexate Leflunomide Calcineurin inhibitors The New Millenium: Targeted Immunosuppression B cells: Depletion: rituximab Inhibition: belimumab Modulation: epratuzumab Co-stimulatory pathways Abatacept CD40 ligand Cytokines Interferon-α IL-6, 12, 17………..∞ Signal transduction pathways Syk kinases Jak kinases Toll-like receptor pathways Proteasome inhibition bortezomib