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Arthur Weinstein, MD, FACP, FRCP, MACR Professor of Medicine, Georgetown University

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.

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Arthur Weinstein, MD, FACP, FRCP, MACR Professor of Medicine, Georgetown University

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  1. Systemic Lupus ErythematosusTranslating Pathophysiology into New Therapies Traduciendo fisiopatologia en nuevos tratamentosAsociacion Costarricense Medicina InternaAugust 7, 2015 Arthur Weinstein, MD, FACP, FRCP, MACR Professor of Medicine, Georgetown University

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

  3. SLE Disclosures Research Investigator: 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 • 1850-1900 - skin disease (Cazenave, Kaposi, von Hebra) • 1900 - 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

  5. SLE History Autoimmunity • 1946 - LE cells in marrow (Hargraves) • 1954-57 - LE cell due to antibody to nuclei (ANA) (Miescher, Friou) • 1957 - anti-DNA in SLE (Kunkel) • 1970’s - low complement levels (Vaughan) • 1980’s – antiphospholipid antibodies (Hughes) • 2000’s – genome wide association studies (GWAS)

  6. SLE - Systemic Autoimmune DiseaseKey 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)

  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

  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:e000056 doi:10.1136/lupus-2014-000056 Putterman C et al

  11. “Prognostic” Autoantibodies(SLICC inception cohorts) Anti-C1q antibodies Lupus Nephritis Anti-ribosomal P antibodies CNS lupus Anti-phospholipid antibodies Stroke (LAC, anticardiolipin) • Yin et al. Lupus. 2012 Sep;21(10):1088-97. Diagnostic value of serum anti-C1q antibodies in patients with lupus nephritis: a meta-analysis. • Hanly et al. Ann Rheum Dis. 2011 Oct;70(10):1726-32. Autoantibodies as biomarkers for the prediction of neuropsychiatric events in systemic lupus erythematosus.

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

  13. Rate of SLE Mortality Remains HighRelative to the General Population Rateof 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 General Population • ≥60 • 16-24 • 25-39 • 40-59 • SLE Patient Age (years) Bernatsky S, et al. Arthritis Rheum. 2006;54:2550-2557.

  14. 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 Percent of Patients With SDI ≥1 1 Year(N=232) 5 Years(N=232) 25 Years(N=6) 20 Years(N=75) 15 Years(N=143) 10 Years(N=232) Mean Damage Score 0.11 0.42 0.77 1.01 1.26 2.17 Corticosteroids use an important contributor to long term damage accrual- up to 50% in 15 years Chambers SA, et al. Rheumatology (Oxford). 2009;48:673-675.

  15. Pittsburgh lupus cohortCoronary 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) 35-44 age group 50X increased In Framingham youngest 34, in SLE group any age Manzi S et al. Am J Epidemiol 1997

  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

  18. Genetic Associations in SLE (GWAS studies) Crow M. N Engl J Med 2008;358:956-961

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

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

  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 dermo-epidermal junction, synovial membrane) - complement activation (low C3 and C4 levels, complement split products on cells) • can get antibody-mediated cytotoxicity - RBC, leukocyte, platelet

  22. Drugs Approved and Drugs Used to Treat SLE BENLYSTA

  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

  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

  25. ?Cyclophosphamide for Remission MaintenanceSequential Therapies for Proliferative Lupus Nephritis N Engl J Med 2004;350:971-80

  26. Targeted Therapeutic Approaches in Systemic Lupus Erythematosus belimumab anti-IL-6 tocilizumab Th17 rituximab abatacept TTregs anti-interferon sifalimumab epratuzumab Modified from Rahman A, Isenberg D. N Engl J Med 2008;358:929-939

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

  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 t1/2 = 76 hours Multidose t1/2 = 206 hours Total 2 Gm by IV infusion 500mg weekly x 4 or 1Gm x2 14 days apart RTX Berinstein NL, et al. Ann Oncol 1998;9:995-1001; Maloney DG, et al. J Clin Oncol 1997;15:3266–74; Maloney DG, et al. Blood. 1997;90:2188–95.

  29. Does Rituximab work in SLE?Systematic review 188 patients Clinical response/ treated patients % of response Cardiopulmonary 12/12 100 Haematological 50/53 94 Renal 94/103 91 Articular 92/101 91 CNS 26/29 89 Mucosal/cutaneous 79/88 89 Alveolar haemorrhage 2/2 100 Haemolyticanaemia 24/25 96 Thrombocytopenia 15/16 93 Cutaneousvasculitis 17/19 89 Ramos-Casals M: Lupus 2009

  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 2010

  31. B- Lymphocyte Stimulator (BLyS) Is Elevated in Patients With Autoimmune Disease; correlates with disease activity 50 40 30 BLyS Protein (ng/mL) 20 10 0 Normal (n = 38) SLE Sera (n = 40) P <0.0001 SLE Plasma (n = 110) P <0.0001 RA (n = 44) P <0.001 RAsf (n = 57)P <0.0001 Zhang J et al. J Immunology. 2001;166:6-10; Petri M et al. Arthritis Rheum 2008

  32. Fully human monoclonal antibody targets soluble BlyS Inhibition of BLyS can result in autoreactive B-cell apoptosis LymphoStat-B (Belimumab) Autoimmune Disease Autoreactive B-cell survival Inhibition of Survival by Belimumab Autoreactive B-cell apoptosis

  33. SRI Response Rate in Autoantibody-Positive Belimumab-Treated Patients Over 7 years Ginzler et al J Rheumatol 2014 Double Blind, n=321 Seropositive Patients All Belimumab-Treated Patientsa Placebo Belimumab 1, 4, 10 mg/kg 46%* 29% Responder Rate, % Responder Rate, % n = 252 205 187 171 158 142 Study Week Years of Belimumab Treatment *

  34. Decrease Flare Rate Over 7 Years

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

  36. Incidence Rates of AEs, Infections, Malignancies, and Mortality aRate = (100X no. of patients starting given AE in given interval)/(total patient-years in given interval); bpatients originally randomized to placebo are included from 1st 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

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