Systemic Lupus Erythematosus

Transcription

1 Systemic Lupus Erythematosus Translating Pathophysiology into New Therapies Traduciendo fisiopatologia en nuevos tratamentos Asociacion Costarricense Medicina Interna August 7, 2015 Arthur Weinstein, MD, FACP, FRCP, MACR Professor of Medicine, Georgetown University 1

2 Dr. Srur, Dr. Acuña, Dr. Monge Gracias por haberme invitado a hablar en este congreso

3 Research Investigator: SLE Disclosures Rituximab (anti-cd20) for Lupus Nephritis (Genentech) Epratuzumab (anti-cd22) for Lupus (Immunomedics and UCB) Lymphostat B / Belimumab [Benlysta] (anti-blys) for SLE phases 1, 2 and 3 and extensions (HGS/GSK) -CURRENT Cell-bound complement activation products for SLE diagnosis (Exagen Diagnostics)- CURRENT Consultant /Speakers Bureau: HGS and GSK Benlysta for SLE - past Consultant /Board of Directors: Exagen Diagnostics (stock holder) - CURRENT

4 SLE History Clinical/Path Features skin disease (Cazenave, Kaposi, von Hebra) systemic disease - erythema exuditavum multiforme (Osler and others) 1940 s collagen disease modern era - SLE subsets classes of renal disease, subacute cutaneous LE, neonatal lupus, antiphospholipid syndrome, borrowed treatments present markers of diagnosis and disease activity, large controlled clinical trials 4

5 SLE History Autoimmunity LE cells in marrow (Hargraves) LE cell due to antibody to nuclei (ANA) (Miescher, Friou) anti-dna in SLE (Kunkel) 1970 s - low complement levels (Vaughan) 1980 s antiphospholipid antibodies (Hughes) 2000 s genome wide association studies (GWAS) 5

6 SLE - Systemic Autoimmune Disease Key Features Multisystem organ involvement joints, skin, kidney, brain, serositis Microvascular inflammation immediate and long term consequences Autoantibodies ANA, anti-dna, antibodies to red cells, white cells, platelets, other autoantibodies (anti-phospholipid) 6

7 Frequency of SLE manifestations

8 Lupus Spectrum Disorders Skin Subacute cutaneous lupus, bullous lupus CNS Myelopathy, neuromyelitis Lupoid sclerosis Renal crescentic/progressive GN (ANCA), thrombotic microangiopathy (APL) Hematological TTP MAS/hemophagocytic syndrome APLS features strokes, gangrene, valvular heart disease (Libman-Sachs), CAPS

9 Diagnosis of SLE ANA universally present anti-dna, anti-smith autoantibodies specific, lack sensitivity skin, kidney tissue pathology- characteristic low complement (C3 and C4) relatively specific and reflects pathophysiology (active disease) but lack sensitivity complement activation products in plasma (short-lived) or cell-bound (CB-CAPS) - more sensitive than hypocomplementemia 9

10 CB-CAPS as a diagnostic tool At activation C3/C4 break down into fragments such as C4d and C3d these bind to circulating cells (CBCAPS): measured by flow cytometry- eg erythrocyte (EC4d) and B-cell (BC4d) Lupus Sci Med 2014;1:e doi: /lupus Putterman C et al 10

11 Prognostic Autoantibodies (SLICC inception cohorts) Anti-C1q antibodies Lupus Nephritis Anti-ribosomal P antibodies CNS lupus Anti-phospholipid antibodies Stroke (LAC, anticardiolipin) 1. Yin et al. Lupus Sep;21(10): Diagnostic value of serum anti-c1q antibodies in patients with lupus nephritis: a meta-analysis. 2. Hanly et al. Ann Rheum Dis Oct;70(10): Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus. 11

12 SLE Survival 2000 s max in middle aged >45yrs 44% of all rheumatic disease deaths 12

13 Rate of SLE Mortality Remains High Relative to the General Population General Population Rate of Death Compared to the Age-Matched General Population 19.2 X Greater Rate 8.0 X Greater Rate 3.7 X Greater Rate 1.4 X Greater Rate SLE Patient Age (years) Bernatsky S, et al. Arthritis Rheum. 2006;54:

14 Percent of Patients With SDI 1 One-Third of SLE Patients Accrue Permanent Organ Damage Within 5 Years of Diagnosis and 50% within 10 years Percentage of Patients With Permanent Organ Damage Mean Damage Score 1 Year (N=232) 5 Years (N=232) 10 Years (N=232) 15 Years (N=143) 20 Years (N=75) 25 Years (N=6) Corticosteroids use an important contributor to long term damage accrual- up to 50% in 15 years Chambers SA, et al. Rheumatology (Oxford). 2009;48:

15 Pittsburgh lupus cohort Coronary Artery Disease in SLE 498 women with SLE - 33 developed CAD (f/u 13 years, ages 15-74) 2208 women in the Framingham study 36 developed CAD 6.6% (SLE) vs. 1.6 % (population) age group 50X increased In Framingham youngest 34, in SLE group any age Manzi S et al. Am J Epidemiol

16 SLE PATHOGENESIS?UNIFYING HYPOTHESIS

17 HEREDITY & GENES 10% chance of SLE in family of patient with lupus 2% concordance dizygotic twins, 25% monozygotic PROTEINS 17

18 Genetic Associations in SLE (GWAS studies) Crow M. N Engl J Med 2008;358:

19 GENES CAN BE TURNED ON & OFF Upregulation of interferon I genes in SLE interferon signature of active SLE 19

20 Immunological Response Lymphocytes in SLE Immune Dysregulation Self or exogenous antigens + Th CELL Cytokines Interleukins (IL-6, BLys, ) ++ Macrophage/ APC Tregs, Th17cells - ++ B CELL Auto Antibodies ++ Ts CELL 20

21 Tissue Damage in SLE is Antibody Mediated the target antigens are double-stranded (ds)- DNA, nucleohistones circulating (or in situ) immune complexes form, lodge in vascular and nonvascular basement membranes (kidney glomeruli, skin dermoepidermal junction, synovial membrane) - complement activation (low C3 and C4 levels, complement split products on cells) can get antibody-mediated cytotoxicity - RBC, leukocyte, platelet 21

22 Drugs Approved and Drugs Used to Treat SLE BENLYSTA 22

23 SLE Common Treatments Prednisone oral low (<0.5mg/kg/day) to moderate to high dose (>1mg/kg/day) [IV pulse acute, severe] hydroxychloroquine (Plaquenil) rash, fatigue, joint, muscle pains, thrombovascular- can be used in pregnancy prevents flares methotrexate, leflunomide (Arava) arthritis azathioprine (Imuran) maintenance mycophenolate (CellCept) - skin, renal induction/maintenance cyclophosphamide (Cytoxan) I.V. remission induction - renal, brain inflammation, vasculitis 23

24 Tweaking Treatments HCQ the lupus vitamin - prevents flares, prevents/slows organ damage, decreases thrombosis, may improve survival Use corticosteroids in high doses for acute flares, limit long term use use other immunosuppressive agents Mycophenolate mofetil (CellCept) for lupus nephritis induction and maintenance Tacrolimus for lupus/lupus nephritis Euro-Lupus nephritis regimen for IV cyclophosphamide 500mg q 2 weeks x 6 24

25 ?Cyclophosphamide for Remission Maintenance Sequential Therapies for Proliferative Lupus Nephritis N Engl J Med 2004;350:

26 Targeted Therapeutic Approaches in Systemic Lupus Erythematosus Th17 anti-il-6 tocilizumab belimumab rituximab TTregs abatacept anti-interferon sifalimumab epratuzumab Modified from Rahman A, Isenberg D. N Engl J Med 2008;358:

27 Targeted Treatments B-cell Rituximab B cell lysis Belimumab B cell apoptosis 27

28 Rituximab Anti-CD20 Monoclonal Antibody Rituximab Induces B-cell death via several mechanisms Chimeric murine/human monoclonal antibody Long serum half-life: At a dose of 375 mg/m2 Single dose t 1/2 = 76 hours Multidose t 1/2 = 206 hours RTX Total 2 Gm by IV infusion 500mg weekly x 4 or 1Gm x2 14 days apart Berinstein NL, et al. Ann Oncol 1998;9: ; Maloney DG, et al. J Clin Oncol 1997;15: ; Maloney DG, et al. Blood. 1997;90:

29 Does Rituximab work in SLE? Systematic review 188 patients Clinical response/ treated patients % of response Cardiopulmonary 12/ Haematological 50/53 94 Renal 94/ Articular 92/ CNS 26/29 89 Mucosal/cutaneous 79/88 89 Alveolar haemorrhage 2/2 100 Haemolytic anaemia 24/25 96 Thrombocytopenia 15/16 93 Cutaneous vasculitis 17/19 89 Ramos-Casals M: Lupus

30 Does Rituximab work in SLE? Serology (Explorer trial) 257 pts active SLE Background therapy MTX, MMF, AZA Steroid taper Rituximab infusions- baseline and 6 months No differences in clinical end points Merrill JT et al : Arthritis Rheum

31 B- Lymphocyte Stimulator (BLyS) Is Elevated in Patients With Autoimmune Disease; correlates with disease activity Normal (n = 38) SLE Sera (n = 40) P < SLE Plasma (n = 110) P < RA (n = 44) P <0.001 Zhang J et al. J Immunology. 2001;166:6-10; Petri M et al. Arthritis Rheum 2008 RAsf (n = 57) P <

32 LymphoStat-B (Belimumab) Autoimmune Disease Fully human monoclonal antibody targets soluble BlyS Autoreactive B-cell survival Inhibition of Survival by Belimumab Inhibition of BLyS can result in autoreactive B-cell apoptosis Autoreactive B-cell apoptosis Belimumab: A Potential New Approach to SLE Treatment 32

33 Responder Rate, % Responder Rate, % SRI Response Rate in Autoantibody-Positive Belimumab- Treated Patients Over 7 years Ginzler et al J Rheumatol 2014 Double Blind, n=321 Seropositive Patients 46%* All Belimumab-Treated Patients a 29% Placebo Belimumab 1, 4, 10 mg/kg n = Study Week Years of Belimumab Treatment * Belimumab: A Potential New Approach to SLE Treatment 33

34 Decrease Flare Rate Over 7 Years 34

35 Change in Autoantibody Levels Over 7 years Placebo Belimumab Extension-Continuation (all belimumab-treated patients) a Years of Treatment b b b b a Patients switched from placebo to belimumab are included from 1 st belimumab exposure; b median percent change of zero. 35

36 Incidence Rates of AEs, Infections, Malignancies, and Mortality a Rate = (100X no. of patients starting given AE in given interval)/(total patient-years in given interval); b patients originally randomized to placebo are included from 1 st belimumab exposure. Malignancies excludes non-melanoma skin cancer and includes unspecified lung malignancies; 7 deaths Ginzler EM et al: Disease control and safety of belimumab plus standard therapy over 7 years in patients with systemic lupus erythematosus. J Rheumatol 2014

37 CASE: SLE with rash, joints, fatigue 24 year recently married woman has a 2 year history of mild to moderate SLE skin rashes, joint pains, fatigue controlled with plaquenil 400mg and 7.5 mg prednisone daily. She now has a 3 month history of increasing fatigue, episodic low grade fevers, more joint pains hands, wrists and knees and hair coming out with combing. She works as an accountant and has been able to continue working. On examination she has a malar blush, thinning of hair at the temples, joint swelling and tenderness bilateral wrists and MCP joints 2 & 3. Labs show mild anemia, WBC 2500 with lymphopenia. Urine protein 500mg, no blood. Serum creatinine 1.0 mg/dl. ANA 1:320 homogeneous. Anti DNA 200 units (normal<20). Other antibodies neg. C3-60, C4-5.

38 CASE: SLE with rash, joints, fatigue Does she have mild, moderate or severe SLE flare? How would you treat this flare pulse steroid, moderate dose oral steroid, high dose oral steroids, other? What would you use for long term control? methotrexate, prednisone 10mg/day, CellCept, tacrolimus,? rituximab, belimumab What is her SLEDAI score? 17 (>12- mod to severe) Recurrent active SLE and low grade active SLE is common and undertreated

39 Quantitate Disease Activity Test for Prognostic Markers Treat to Target studies ---Low disease Activity Comparative Effectiveness Studies Early vs Late use of Immunosuppressives GRACIAS