Evaluation and Management of Systemic Lupus Erythematosus, 2015

Transcription

1 Evaluation and Management of Systemic Lupus Erythematosus, 2015 Michelle Petri, MD, MPH Professor of Medicine, Johns Hopkins University School of Medicine Director, Hopkins Lupus Center Baltimore, MD February 20, 2016 CSRO JW Marriott San Francisco, CA

2 This CME activity is intended for practicing physicians, and other health care providers who may treat patients who have Systemic Lupus Erythematosus. There is no fee for participation in this CME activity. This program is made possible through an educational grant from UCB, Inc.

3 Accreditation This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint providership of University Health Services Professional Education Programs (UHS-PEP) of Virginia Commonwealth University Health System and Miller Professional Group. UHS-PEP is accredited by the ACCME to provide continuing medical education for physicians. UHS-PEP designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credits. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

4 CME Credit Statements To receive continuing education credit, please complete the evaluation and Verification of Participation form and submit following the meeting. Credit Statements will be mailed within four weeks of activity completion.

5 IT IS ALSO A REQUIREMENT UPON EACH SPEAKER TO NOTIFY HIS/HER AUDIENCE WHENEVER OFF-LABEL USE IS DISCUSSED.

6 Please Complete and Return In the CME section of your meeting folders you will find the Program evaluation form Verification of participation form These documents are used to evaluate the effectiveness of our programming, and to justify future educational programs of this quality. Please be sure to return these completed forms to the speaker at the end of the program. Please be aware you will receive (via ) a follow-up questionnaire similar to the educational effectiveness survey you will complete for this program. It will come from the address rheumreply@optonline.net Please be sure to return the completed follow up questionnaire.

7 Conflict of Interest Disclosures Presenters Michelle Petri, MD has reported participated in clinical trials for GSK, Medimmune, Pfizer and UCB; and is a Consultant for GSK, Pfizer, UCB and BMS. The Planners of this activity report the following disclosure information: John Boothby, Director, Continuing Medical Education, UHS- PEP has nothing to disclose. Alan Epstein, MD is a member of the Speaker s Bureau for Abbvie, Janssen, BMS, Celgene, Pfizer, Genentech and GSK. Max Hamburger, MD is a member of the Speaker s Bureau for UCB, BMS, Abbvie, Crescendo Bio and GSK; and is a Grant Recipient for UCB, BMS and Abbvie.

8 Objectives Upon completion of this program, attendees will be able to: Evaluate the importance of the disease burden in SLE, consequences of inadequate disease control, and consequences of inflammatory burden on patients, their families, their communities and the healthcare system; Describe and discuss the impact of disease activity on patient outcomes, and the challenges of implementing treat to target concepts as applicable in the management of this highly pleomorphic disease; Apply current concepts of management including approaches to measurement of organ inflammation and/or involvement and disease activity; Collaborate with patients in the implementation of treatment goals; and Apply the principles of evidence based medicine to optimize SLE patient care by 1) Effectively using currently available tools for assessing disease activity in patients with lupus; evaluating the EULAR monitoring guidelines and applying them into the care of their lupus patients; and 2) Applying the treatment strategies from the EULAR and ACR guidelines and SLICC in their clinical practices and thereby optimizing patient care and functioning.

9 Treat to Target(s) The Lupus 12 Step Program Michelle Petri MD MPH Johns Hopkins University School of Medicine

10 1. Classification Criteria Help in Everyday Practice (i.e. Diagnosis)

11 SLICC* Classification Criteria At least 1 clinical + at least 1 immunologic criterion (for a total of 4) OR lupus nephritis by biopsy (in the presence of ANA or anti-dna antibodies) SLICC has recommended that BOTH the revised ACR criteria AND the new SLICC classification criteria be used *Systemic Lupus International Collaborating Clinics Petri M et al. Arthritis Rheum. 2012;64:

12 SLICC Revision of ACR Classification Criteria Clinical Criteria 1. Acute/subacute cutaneous lupus 2. Chronic cutaneous lupus 3. Oral/Nasal ulcers 4. Non-scarring alopecia 5. Inflammatory synovitis with physician-observed swelling of two or more joints OR tender joints with morning stiffness 6. Serositis 7. Renal: Urine protein/creatinine (or 24-hr urine protein) representing at least 500 mg of protein/24 hr or red blood cell casts 8. Neurologic: seizures, psychosis, mononeuritis multiplex, myelitis, peripheral or cranial neuropathy, cerebritis (acute confusional state) 9. Hemolytic anemia 10. Leukopenia (<4000/mm 3 at least once) OR Lymphopenia (<1000/mm 3 at least once) 11. Thrombocytopenia (<100,000/mm 3 ) at least once DERMATOLGIC 4 OTHER SYSTEMS HEMATOLOGIC Petri M et al. Arthritis Rheum. 2012;64:

13 SLICC Revision of ACR Classification Criteria Immunologic Criteria 1. ANA above laboratory reference range 2. Anti-dsDNA above laboratory reference range (except ELISA: >2-fold laboratory reference range) 3. Anti-Sm 4. Antiphospholipid antibody lupus anticoagulant false-positive test for syphilis anticardiolipin at least twice normal or medium-high titer anti-b 2 glycoprotein 1 5. Low complement low C3 low C4 low CH50 6. Direct Coombs test in absence of hemolytic anemia Petri M et al. Arthritis Rheum. 2012;64:

14 2. Understand Lupus Activity Indices Used in Clinical Trials (Measure Activity That is Really Lupus)

15 Physician s Global Assessment (PGA) Used to assess the patient s overall condition A visual analogue scale (10cm) ranging from 0 3 points (no activity to severe life-threatening activity) 0.3-point increase (10%) = clinically-relevant worsening 1 Correlates with other disease activity indices Severe means the worst in the universe of lupus, not the worst for an individual patient 1. Furie, RA et al. Arthritis Rheum 61: Petri et al. J Rheumatol 1992;19:53-9.

16 SELENA-SLEDAI Petri M at al. N Engl J Med Dec 15;353(24):2550-8;

17 SELENA-SLEDAI Flare index Petri M at al. N Engl J Med Dec 15;353(24):2550-8;

18 BILAG Organ Systems are individually scored: Constitutional, Mucocutaneous, Neuropsychiatric, Musculoskeletal, Cardiorespiratory, Gastrointestinal, Ophthalmic, Renal, Haematological Each organ is scored for severity over the past month: based on the net impact of individual symptoms A=severe B=moderate C=mild D=inactive organ E=never active organ Symptom Last Month Progress This Month Score Organ System Severe Arthritis Same or Worse A Musculoskeletal Severe Arthritis Significantly Improving B Musculoskeletal No Rash New Severe Rash A Mucocutaneous Severe Rash Significantly Improving B Mucocutaneous Moderate Rash Significantly Improving C Mucocutaneous

19

20 SLE Responder Index (SRI) Used in Belimumab Phase III Trials SELENA-SLEDAI 4-point reduction in SELENA-SLEDAI score 1 Assesses 24 weighted variables to indicate overall disease severity BILAG No new BILAG A or 2 new BILAG B organ domain scores 2 Measures flare activity and severity across 8 organ domains PGA No worsening in PGA (<0.3-point increase) 3 An overall assessment of changes in patient condition and disease severity SRI SRI Responders Had to Meet All 3 Criteria 1. Petri M at al. N Engl J Med Dec 15;353(24):2550-8; 2. Hay EM, et al. Q J Med. 1993;86(7): ; 3.Navarra SV, et al. Lancet 2011;377:

21 BILAG-based Composite Lupus Assessment: BICLA Used in Epratuzumab Phase II and III Trials Landmark assessment All organs with moderate or severe activity at baseline (BILAG A) have improved: BILAG A (severe) improves to B (moderate) C (mild) or D (no activity) BILAG B (moderate) improves to C (mild) or D (no activity) and There is no worsening by BILAG, SLEDAI or Physician s Global Assessment (PGA may not increase by more than 10% of the scale)

22 SLE Responder Index: Responders vs Nonresponders Parameter SRI Resp (n=761) SRI Nonresp (n=923) > 7 point reduction 40.3% 1.3% # organ domains improved (BILAG/SS) 1.45/ /0.39 % Change in PGA -58.3% -34.9% Severe flare rate (SLE Flare Index) at wk % 29.1% Reduction in prednisone to <7.5 mg/d 25.5% 16.4% Increase in prednisone to >7.5 mg/d 4% 22% Changes in DNA/C3/C4-34%/14%/40% -26%/9%/29% SF-36: PCS/MCS (MCID=2.5) 4.9/ /1.7 Fatigue (FACIT/SF-36 Vitality; MCID=4/5) 5.2/10.4 3/6.5 Furie R et al. ACR 2011; Strand V et al. ACR 2011 Furie et al. Lupus Sci Med Jun 26;1:e doi: /lupus-2014

23 3. Avoid Maintenance Prednisone > 6 mg

24 Prednisone Is Directly or Indirectly Responsible for 80% of Organ Damage over 15 Years CVS=cardiovascular system; GI=gastrointestinal; MSK=musculoskeletal NP=neuropsychiatric Gladman DD, et al. J Rheum. 2003;30(9):

25 A Prednisone Dose of 6 mg or More Increases Organ Damage by 50% Prednisone Average Dose Hazard Ratio >0-6 mg/day 1.16 >6-12 mg/day 1.50 >12-18 mg/day 1.64 >18 mg/day 2.51 Adjusted for confounding by indication due to SLE disease activity Thamer M et al. J Rheumatol. 2009;36:

26 Prednisone Itself Increases the Risk of Cardiovascular Events Prednisone use Observed Number of CVEs Rate of Events/1000 Person- Years Never taken Currently taking Age-Adjusted Rate Ratios (95% CI) P Value 1.0 (reference group) 1-9 mg/d (0.8, 2.0) mg/d (1.5, 3.8) mg/d (3.1,8.4) < Magder LS, Petri M. Am J Epidemol. 2012;176:

27 4. Non-immunosuppressive Immunomodulators Can Control Mild-Moderate SLE, Helping to Avoid Steroids

28 Immunomodulators Hydroxychloroquine 1 Vitamin D 2 Prasterone (synthetic dihydroepiandrosterone, or DHEA) 3 1. Petri M. Lupus. 1996;5(Suppl 1):S16-S Petri M et al. Arthritis Rheum. 2013;65: Petri M et al. Arthritis Rheum. 2002;46:

29 Hydroxychloroquine as Background Therapy Reduction in Flares Canadian Hydroxychloroquine Study Group. N Engl J Med. 1991;324: Reduction in organ damage Fessler BJ et al. Arthritis Rheum. 2005;52: Reduction in lipids Reduction in thrombosis Improvement in survival Triples mycophenolate mofetil response Petri M. Lupus. 1996;5(Suppl. 1):S16-S22. Wallace DJ et al. Am J Med. 1990;89: Pierangeli SS, Harris EN. Lupus. 1996;5: Petri M. Scand J Rheumatol. 1996;25: Alarcon GS et al. Arthritis Rheum. 2005;52:S726. Ruiz-Irastorza G et al. Lupus. 2005;14:220. Kasitanon N et al. Lupus. 2006;15: Prevents seizure Hanly JG et al. Ann Rheum Dis. 2012;71;

30 Hydroxychloroquine for Lupus Nephritis Continuing hydroxychloroquine improves complete response rates with mycophenolate mofetil Kasitanon N et al. Lupus 2006;15:

31 Criteria of Low and Higher Risk for Developing Retinopathy Dosage Low Risk < 6.5 mg/kg hydroxychloroquine < 3 mg/kg chloroquine Higher Risk Duration of use < 5 years > 5 years >6.5 mg/kg hydroxychloroquine > 3 mg/kg chloroquine Habitus Lean or average fat High fat level (unless dosage is appropriately low) Renal/liver disease None Present Concomitant retinal disease None Present Age < 60 years > 60 years Marmor MF et al. Ophthalmol 2002;109:

32 Only SLE Patients with Visual Symptoms Need High Tech hsuhr-oct (Optical Coherence Tomography) or mferg (multifocal electroretinogram) Rodriguez-Padilla JA, et al. Arch Ophthalmol 2007;125:

33 Common Causes of Abnormalities Optical Coherence Tomography Serous retinopathy Multifocal Electroretinogram Cataracts

34 Top: Normal Spectralis spectral domain optical coherence tomography (SD OCT) image with intact photoreceptor inner segment/outer segment junction (IS/OS). Bottom: Spectralis SD OCT from the left eye of patient 10 showing the flying saucer sign of hydroxychloroquine retinopathy, an ovoid appearance of the central fovea created by preservation of central foveal outer retinal structures (seen between the black arrows) surrounded by perifoveal loss of the photoreceptor IS/OS junction, and perifoveal outer retinal thinning. Abbreviations: ILM, internal limiting membrane; IPL, inner plexiform layer; OPL, outer plexiform layer; ELM, external limiting membrane; RPE, retinal pigment epithelium. From: Chen E1, Brown DM, Benz MS, Fish RH, Wong TP, Kim RY, Major JC. Spectral domain optical coherence tomography as an effective screening test for hydroxychloroquine retinopathy (the flying saucer sign). Clin Ophthalmol Oct 21;4: doi: /OPTH.S14257.

35 High-Speed Ultra High-Resolution Optical Coherence Tomography Findings in Hydroxychloroquine Retinopathy¹ Question: are early toxic effects from hydroxychloroquine (HCQ) detectable by hsuhr-oct before clinical signs or symptoms Fifteen patients referred for evaluation of HCQ maculopathy were studied. Six age-matched patients with normal visual function were studied with hsuhr-oct hsuhr-oct abnormality severity of maculopathy seemed to correlate with severity of mferg and visual field testing Unable to find an asymptomatic patient with evidence of definite damage on hsuhr-oct ¹Julio A. Rodriguez-Padilla, et al, Arch Ophthalmol. 2007;125:775-78J0

36 Increasing 25-Hydroxy Vitamin D Modestly Helps Disease Activity and Urine Protein/CR Model allowing slope to differ before and after 40 ng/ml Disease Measure Slope over range of 0-40 ng/ml (95% CI) P-value Slope over range of 40 ng/ml (95% CI) P-value Physician s Global Assessment 0.04 ( 0.08, 0.01) ( 0.02, 0.04) 0.50 SELENA-SLEDAI 0.22 ( 0.41, 0.02) ( 0.01, 0.24) Log Urinary Protein/Creatinine 0.03 ( 0.05, 0.02) ( 0.01, 0.00) 0.24 SELENA-SLEDAI = Safety of Estrogens in Lupus Erythematosus National Assessment version of the Systemic Lupus Erythematosus Disease Activity Index. Petri M et al. Arthritis Rheum. 2013;65:

37 20-Unit Increase in 25-Hydroxy Vitamin D 13% decrease in odds of having a PGA score of 1 or more 21% decrease in odds of having a SLEDAI score of 5 or more 15% decrease in odds of having a urine pr/cr > 0.5 Petri, et al. Arthritis Rheum 2013;65:

38 Vitamin D May Have Cardiovascular and Hematologic Benefits Targher G et al. Semin Thromb Hemostasis. 2012;38:

39 Vitamin D Reduced Thrombosis in Some Clinical Studies Cancer RCT: calcitriol+docetaxel vs. docetaxel (P=0.01) 1 General population lowest tertile of vitamin D: 37% (CI 15-64%) increased rate of VTE 2 Higher rates of VTE in African-Americans 3 VTE are seasonal: highest risk in winter; sunbathing reduces rise of VTE by 30% 4 Honolulu Heart Program: Low vitamin D predicted 34-year incident stroke in Japanese-American men. HR 1.22 (CI ), P= Asian Indian cohort: mean vitamin D lower in CAD P= Beer TM et al. Br J Haematol. 2006;135: Brøndum-Jacobsen P et al. J Thromb Haemost. 2013;11: Grant WB. Am J Hematol. 2010;85: Lindqvist PG et al. J Thromb Haemost. 2009;7: Kojima G et al. Stroke. 2012;43: Shanker J et al. Coron Artery Dis. 2011;22:

40 DHEA (Prasterone) 200 mg Daily NOT FDA-approved In women with disease activity, reduction in prednisone to 7.5 mg/day achieved in 51% vs. 29% on placebo (P=0.03). 1 In women with disease activity, improvement or stabilization achieved in 58.5% vs. 44.5% on placebo (P=0.017) 2 1. Petri M et al. Arthritis Rheum. 2002;46: Petri M et al. Arthritis Rheum. 2004;50:

41 Prasterone Reduces SLE Flares

42 DHEA and Bone Density Prasterone provides mild protection against bone loss At month 18 with 200 mg vs. 100 mg: Dose-dependent increase in spine BMD (P=0.02) Sanchez-Guerrero J et al. J Rheumatol. 2008;35:

43 5. Treatment of Lupus Nephritis is NOT Just Immunosuppression!

44 ACR Guidelines for Kidney Biopsy Indications for Kidney Biopsy* Increasing serum creatinine without compelling alternative causes (eg, sepsis, hypovolemia, or medication) Confirmed proteinuria of 1.0 gm/24 hours (either 24-hour urine specimens or spot protein-creatinine ratios) Combinations of the following, assuming the findings are confirmed in at least 2 tests done within a short period of time and in the absence of alternative causes: Proteinuria 0.5 gm per 24 hours plus hematuria, defined as 5 RBCs per HPF Proteinuria 0.5 gm per 24 hours plus cellular casts *All recommendations are level of evidence C. Hahn BH, et al. Arthritis Care Res. 2012;64:

45 EULAR Guidelines for Kidney Biopsy Indications for Kidney Biopsy Any sign of renal involvement; in particular, urinary findings including reproducible proteinuria 0.5 g/24 hours especially with glomerular haematuria and/or cellular casts Clinical, serological or laboratory tests correlate modestly with renal biopsy findings. Proteinuria of 0.5 g/24 hours. Level of Evidence Statement Strength 2 C 2 B Bertsias GK, et al. Ann Rheum Dis. 2012;71:

46 Adjunctive Therapy for Proteinuria ACE-inhibitor Angiotensin receptor blocker Duran-Barragan S, et al. Rheumatology : Spironolactone 25 mg or eplerenone 50 mg Epstein. Am J Med 2006;119:

47 ACR Guidelines: Adjunctive Therapies All SLE patients with nephritis should be treated with a background of hydroxychloroquine unless there is a contraindication (level C evidence) For patients with proteinuria 0.5 gm/24 hours (or equivalent by protein/creatinine ratios on spot urine samples), a blockade of the renin angiotensin system, which drives intraglomerular pressure, is recommended (level A evidence for nondiabetic chronic renal disease) Target blood pressure of 130/80 mm Hg (level A evidence for nondiabetic chronic renal disease) Statin therapy should be introduced in patients with low-density lipoprotein cholesterol 100 mg/dl (level C evidence) Women of child-bearing potential with active or prior lupus nephritis receive should counseling regarding pregnancy risks conferred by the disease and its treatments (level C evidence) Hahn BH, et al. Arthritis Care Res. 2012;64:

48 EULAR Guidelines: Adjunctive Therapies Angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for proteinuria or hypertension (level of evidence: 2; strength of statement: B) Cholesterol lowering with statins for persistent dyslipidaemia (strength of statement: C) Hydroxychloroquine (level of evidence: 3; strength of statement: C) Acetyl-salicylic acid in patients with anti-phospholipid antibodies (strength of statement: C) Calcium and vitamin D supplementation (strength of statement: C) Bertsias GK, et al. Ann Rheum Dis. 2012;71:

49 Initial Therapy: Class IV ACR Mycophenolate mofetil (2-3 gm total daily orally) or IV cyclophosphamide along with glucocorticoids is recommended (level A evidence) EULAR Evidence suggestions that mycophenolate mofetil may be more likely to induce improvement in patients who are African American or Hispanic Mycophenolic acid (mycophenolate mofetil target dose: 3 g.day for 6 months or mycophenolic acid sodium at equivalent dose) (level of evidence: 1; statement strength: A) or low-dose intravenous cyclophosphamide (total dose 3 g over 3 months) in combination with glucocorticoids (level of evidence: 1; statement strength: B) are recommended as initial treatment as they have the best efficacy/toxicity ratio Hahn BH, et al. Arthritis Care Res. 2012;64: Bertsias GK, et al. Ann Rheum Dis. 2012;71:

50 Responders (%) Non-Caucasians Do Better with Mycophenolate Mycophenolate Mofetil IV Cyclophosphamide P = 0.24 P = 0.83 P =.03 Post Hoc Analysis P = Asian Caucasion Combined Other* African American *Includes African Americans. Isenberg D, et al. Rheumatology (Oxford). 2010;49:

51 Initial Therapy: Class IV How Much Steroid? ACR Pulse IV glucocorticoids ( mg methylprednisolone daily for 3 doses) in combination with immunosuppressive therapy is recommended, followed by daily oral glucocorticoids (0.5-1 mg/kg/ day), followed by a taper to the minimal amount necessary to control disease (level C evidence) EULAR To increase efficacy and reduce cumulative glucocorticoid doses, treatment regimens should be combined initially with 3 consecutive pulses of IV methylprednisolone mg, followed by oral prednisone 0.5 mg/kg/day for 4 weeks, reducing to 10 mg/day by 4-6 months Hahn BH, et al. Arthritis Care Res. 2012;64: Bertsias GK, et al. Ann Rheum Dis. 2012;71:

52 There May Still Be a Role for Rituximab: Can We Avoid Steroids? Condon MB, et al. Ann Rheum Dis. 2013;72:1280-6; Fischer-Betz et al. J Rheumatol. 2012;39:

53 Multitarget Therapy for Induction Treatment of Lupus Nephritis Multi-Target (Tacrolimus + MMF) IV Cytoxan Complete Remission 45.9% 25.6% Overall Response 83.5% 63.0% Liu Z, et al. Ann Intern Med 2015;162:18-26.

54 Lupus Nephritis Maintenance Therapy : MMF is Superior to Azathioprine Time to treatment failure N=227 Time to renal flare Dooley MA, et al. N Engl J Med. 2011;365: Not FDA-indicated for SLE

55 Lupus Nephritis: Other Options Belimumab Not studied specifically in SLE patients with active nephritis 1,2 Leflunomide For mild-to-moderate SLE disease 3 Induction therapy for renal flare 4,5 Tacrolimus Consider in MMF-resistant or partial response patients, alone or in combination 6-9,12 Approved for treatment of LN in Japan For severe nephritis (Class IV/V) 6,10 Rituximab LUNAR trial was negative 11 Leflunomide, tacrolimus, and rituximab are not FDA-indicated for SLE 1. Navarra S, et al. Lancet. 2011;377(9767):721-31; 2. Dooley MA, et al. ACR/AHCP annual meeting. November 4-9, 2011;Chicago, IL; 3. Tam LS, et al. Lupus. 2004;13:601-4; 4. Wang HY, et al. Lupus. 2008;17(638-44); 5. Tam LD, et al. Ann Rheum Dis. 2006;65:417-8; 6. Yap DY et al. Nephrology. 2012; /j x; 7. Li X, et al. Nephrol Dial Transplant. 2011; doi: /ndt/gfr484; 8. Cortes-Hernandez J, et al; Nephrol Dial Transplant. 2010;25(12): Lanata CM, et al. Lupus. 2010:19(8): Szeto CC, et al. Rheumatology. 2008;47(11): ; 11. Rovin BH, et al. Arth Rheum. 2012; doi: /art Chen W, et al. Lupus. 2012:21(7):

56 6. Biologics in SLE

57 There are Many Potential Targets for SLE Biologics Sifalimumab X Anti-IL-6 E-mab CTX TACI-Ig BAFF-R-Ig Anti-BLyS M. Ramanujam and A. Davidson. Arthritis Research and Therapy. X X X : X CTLA4Ig X Anti-CD40L X X Anti-CD40L Adapted from Ramanujam M, Davidson A. Arthritis Res Therapy. 2004;6:

58 A Post-hoc Analysis Identifies SLE Patients Likely to Respond to Belimumab Characteristics associated with greater treatment effect (p<0.1) SELENA SLEDAI score: 10 (vs 9) Complement: low C3/C4 (vs normal) Steroid use: greater (vs no/less) Characteristics not associated with treatment effect (p>0.1) Study Region Race van Vollenhoven, et al. Ann Rheum Dis, [April Epub ahead of print, doi: /annrheumdis ].

59 The Subgroup with BOTH High Anti-dsDNA and Low Complement is About 20% More Likely to Respond to Belimumab van Vollenhoven RF, et al. Presented at EULAR 2011; May 25-28, 2011; London, UK

60 A Post-hoc Analysis Shows the Organ Systems that Respond to Belimumab Improvement = decrease in SS score within an organ domain Manzi S, et al. Ann Rheum Dis, [May Epub ahead of print, doi: /annrheumdis ].

61 Belimumab Reduced Severe Flares Cervera R, et al. Presented at EULAR 2011: Annual European Congress of Rheumatology; May 25 28, 2011; London, UK

62 Seven Year Followup on Belimumab Open label 296 patients SLE Responder Index Year 2 57% Year 7 65% Anti-dsDNA Prednisone 40-60% 50-55% Ginzler EM, et al. J Rheumatol. 2014;41:300-7

63 Epratuzumab (Anti-CD22) Mechanism of Action 1. Antigen binds to the BCR and induces B cell activation 1,2 2. CD22 negatively regulates the BCR on B cells 3 3. Emab binds CD22 and acts as a regulator of BCR-driven activation of B cells 3 BCR CD22 CD79α/β Localisation 4 CD22 phosphorylation 5,6 Cascade of downstream signalling leading to calcium influx 1 Gene transcription 1 Effector molecule recruitment 3 Reduced calcium flux 4 Reduced BCR signalling 4 Internalisation 5 and removal of BCR proteins from the B cell surface 7 B cell activation 2 B cell modulation 8 1 Tedder T F & Engel P. Immunol Today. 1994;15: Mok M Y. Int J Rheum Dis. 2010;13(1): Dörner T et al. Int Rev Immunol. 2012;31: Sieger N et al. Arth Rheum. 2013;65: Carnahan J et al. Clin Cancer Res. 2003;9:3982S-90S. 6 Qu Z et al. Blood. 2008;111: Rossi E A et al. Blood. 2013;122: Jacobi A M et al. Ann Rheum Dis 2008;67:

64 This document is for internal use only % of untreated Epratuzumab Mechanism of Action Glossary Epratuzumab induces the loss of BCR-related proteins from the B cell surface in vitro Epratuzumab Labetuzumab (isotype control) CD22 internalised into B cells Experiments with primary human B cells CD19 trogocytosis on to monocytes Experiments with Daudi B cell line and primary human monocytes Epratuzumab is not currently approved for the treatment of SLE Adapted from Rossi, E. et al. Blood. 2013; 122(17):

65 7. SLE Pregnancy is High Risk 4,500/year U.S. SLE pregnancies 20-fold increase mortality OR 1.7 C-section OR 2.4 Preterm labor OR 3.0 Pre-eclampsia Ginzler EM, et al. Am J Obstet Gynecol. 2008;199:127.e1-6

66 Adverse Pregnancy Outcome APO No APO LAC 39% 3% (p < ) Lockshin MD et al. Arthritis Rheum. 64:2311-8, 2012.

67 Comparison of Heparin/Aspirin vs Aspirin for Pregnancy-APS Author Year Size Comparison Arm 1 Kutteh Heparin initiated at 10,000 units daily in 2 divided doses Aspirin 81 mg/day Rai UF Heparin 5000 units twice daily Aspirin 75 mg Farquharson LMW Heparin 5000 units Aspirin 75 mg Comparison Arm 2 Aspirin 81 mg Aspirin 75 mg Aspirin 75 mg Study Outcome Heparin/aspirin Heparin/aspirin No difference

68 8. Progress on Coronary Artery Disease

69 Coronary Artery Disease in SLE Substantial increased risk that cannot be completely explained by traditional Framingham risk factors 1 Hospitalization for acute myocardial infarction (AMI) 2.3 times higher in SLE 2 Risk of cardiovascular events is 2.66 times higher in SLE vs Framingham cohort 3 1. Esdaile JM, et al. Arthritis Rheum 2001;44: ; 2. Ward MM. Arthritis Rheum. 1999;42(2):338-46; 3. Magder LS, Petri M. Am J Epidemiol. In press.

70 How Can We Detect Cardiovascular Disease Early in SLE? Coronary calcium CT 1 Carotid duplex 2 In the FUTURE, techniques such as coronary CTA can detect early noncalcified coronary plaques 3 1. Kiani AN et al. J Rheumatol. 2008;35: Maksimowicz-McKinnon K et al. J Rheumatol. 2006;33: Kiani AN et al. J Rheumatol. 2010;37:

71 Prevention of CAD in SLE

72 Atorvastatin Did Not Change 1. Coronary calcium 2. Carotid intima media thickness 3. Carotid plaque Petri M et al. Ann Rheum Dis 2010;70: Schanberg LE et al. Arthritis Rheum. 2012;64:

73 Can We Reduce Cardiovascular Risk? Assess traditional cardiovascular risk factors and treat to target Hypertension Obesity Hyperlipidemia (hydroxychloroquine) Smoking Sedentary Lifestyle Diabetes (hydroxychloroquine) Mycophenolate: slowed progression in mice 3 and transplant patients 4 Prednisone > 10 mg increases CV event risk 5 Statin did NOT reduce progression in mice 3 nor in two clinical trials: Adult 1 Pediatric 2 1. Petri MA, et al. Ann Rheum Dis. 2011;70(5):760-5; 2. Schanberg LE, et al. Arthtiris Rheum. 2012;64(1):285-96; 3. van Leuven SI, et al. Ann Rheum Dis ;71(3):408-14; 4. Gibson WT, Hayden MR. Ann N Y Acad Sci Sep;1110:209-21; 5. Magder L, et al. Am J Epidemiol. 2012; in press.

74 9. Prevention of Thrombosis in SLE: Are We There Yet?

75 Lupus Anticoagulant Is More Highly Associated With Thrombosis Risk Petri M, et al. Ann Intern Med. 1987;106(4): Derksen RH, et al. Ann Rheum Dis. 1988;47(5): Ginsberg JS, et al. Blood. 1995;86(10): Horbach DA, et al. Thromb Haemost. 1996;76(6): Simioni P, et al. Thromb Haemost. 1996;76(2): Wahl DG, et al. Lupus. 1997;6(5):

76 Cumulative S(t) If Lupus Anticoagulant is Present, There is a 50% Chance of Thrombosis Time Since SLE Diagnosis (years) Somers E, Magder LS, Petri M. J Rheumatol. 2002;29:

77 Aspirin Insufficient for APS Prophylaxis Aspirin has NOT been proven effective to reduce thrombosis from antiphospholipid antibodies Ginsburg KS, et al. Ann Intern Med. 1992;117: ; Erkan et al. Arthritis Rheum 2007;56:

78 Hydroxychloroquine Prevents Thrombosis in SLE Study Study Design Outcome Wallace et al, 1987 retrospective P < 0.05 Petri et al, 1994 prospective cohort OR 0.3 Ruiz-Irastorza et al, 2006 prospective cohort HR 0.28 Tektonidou et al, 2009 case-control HR 0.99 Jung et al, 2010 nested case-control OR 0.31 Petri M. Curr Rheumatol Reports 2010:13:77-80

79 10. Don t Make Fibromyalgia WORSE (It s Bad Enough as it is!)

80 Treating Pain: Tai Chi 12 weeks 79% of tai chi group vs 39% of control had clinically meaningful improvement* (P=0.0001) 24 weeks 82% of tai chi vs 53% control had clinically meaningful improvement (P=0.009) FIQ=fibromyalgia impact questionnaire; * clinically meaningful change in FIQ = 8.1 points Wang C, et al. N Engl J Med.2010;363(8):

81 Fatigue Among most common complaints in lupus patients (50-80% of patients) 1 Chronic fatigue does not correlate with disease activity 2 Highly correlated with fibromyalgia, pain, depression, sleep abnormalities, poor quality of life 2-5 Associated with reduced physical fitness 6 1. Tench CM et al. Rheumatology. 2000;39(11): ; 2. Wang B, et al. J Rheumatol. 1998;25(5):892-5; 3. Gladman D, et al. J Rheum. 1997;24:2145-9; 4. Bruce IN, et al. Arthritis Rheum. 1998; 41(suppl.9):S333; 5. Carr FN, et al. ACR/AHCP annual meeting. November 4-9, 2011;Chicago, IL.

82 Exercise for SLE-related Fatigue Clinical global impression change score No (%) in exercise group (n=33) No (%) in relaxation group (n=28) No (%) in control group (n=32) Very much better 3 (9) 4 (14) 1 (3) Much better 13 (40) 4 (14) 4 (13) A little better 5(15) 4(14) 3(9) No change 6(18) 10(36) 14(41) A little worse 4(12) 4(15) 10(31) Much worse 2(6) 2(7) 1(3) Very much worse Tench CM, et al. Rheumatology. 2003;42:

83 11. Don t Forget New Information on Common Drugs

84 Cardiovascular Risk of NSAIDS Salvo F, et al. Cardiovascular events associated with the long-term use of NSAIDs: a review of randomized controlled trials and observational studies. Expert Opin Drug Saf. 2014;13: Chinthapalli K. High dose NSAIDs may double the risk of heart attacks and heart failure, says new study. BMJ. 2013;346:f3533. Trelle S, et al. Cardiovascular safety of non-steroidal anti-inflammatory drugs: network meta-analysis. BMJ. 2011;342:c7086.

85 New Data on PPIs

86 Proton Pump Inhibitors Increase Osteoporotic Fractures Yu EW, et al. Proton pump inhibitors and risk of fractures: a meta-analysis of 11 international studies. Am J Med. 2011;124: Maggio M, et al. Use of proton pump inhibitors is associated with lower trabecular bone density in older individuals. Bone. 2013;57: Ding J, et al. The relationship between proton pump inhibitor adherence and fracture risk in the elderly. Calcif Tissue Int. 2014;94: Moberg LM, et al. Use of proton pump inhibitors (PPI) and history of earlier fracture are independent risk factors for fracture in postmenopausal women. The WHILA study. Maturitas. 2014;78:310-5

87 Proton-Pump Inhibitors Increase Risk of Cardiovascular Events Ghebremariam YT, et al. Unexpected effect of proton pump inhibitors: elevation of the cardiovascular risk factor asymmetric dimethylarginine. Circulation. 2013;128: Zou JJ, et al. Increased risk for developing major adverse cardiovascular events in stented Chinese patients treated with dual antiplatelet therapy after concomitant use of the proton pump inhibitor. PLoS One. 2014;9(1):e Shih CJ, et al. Proton pump inhibitor use represents an independent risk factor for myocardial infarction. Int J Cardiol. 2014;177: Leonard CE, Comparative Risk of Ischemic Stroke Among Users of Clopidogrel Together With Individual Proton Pump Inhibitors. Stroke Feb 5. pii: STROKEAHA [Epub ahead of print]

88 12. Don t Confuse Permanent Organ Damage with Active SLE or Co- Morbidity

89 Percent of Patients With SDI 1 One-Third of SLE Patients Accrue Permanent Organ Damage Within 5 Years of Diagnosis 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) Retrospective analysis of records for patients with 10 years of consistent follow-up presenting at the University College London Hospital SLE clinic. Year 0 represents time of diagnosis. Mean age at diagnosis was 31.2 years, 95% of patients were female, 72% were white, 14% were black, 10% were Asian (Indian), and 4% were "other." Chambers SA, et al. Rheumatology (Oxford). 2009;48:

90 Mean Total SLEDAI-2K Percent of Patients With SDI >0 Patients Still Accrue Organ Damage Even With Low Disease Activity Disease Activity Over 5 Years of Follow-up (N=298) Percentage of Patients With Organ Damage Over 5 Years of Follow-up (N=298) Years in Registry Years in Registry Prospective analysis of patients in the SLICC cohort recruited within 15 months of diagnosis and followed annually for 5 years. Mean age at enrolment: 35.3 years; 87% female; 55% white, 12% black, 14% Asian, 16% Hispanic, 2% other. At enrollment, mean disease duration=5.5 months; mean SLEDAI-2K score=5.9. Urowitz MB, et al. Arthritis Care Res. 2012;64:

91 NP Events at Enrollment (n=1404) (637 Events in 413 Patients) Neuropathy, Cranial 1.4% Myelopathy 1.1% Mononeuropathy 2.2% Polyneuropathy 3.3% Pyschosis 2.0% Acute Confusional State 3.6% Cerebrovascular Disease 4.9% Aseptic Meningitis 0.8% Movement Disorder 0.9% Myasthenia Gravis 0.2% Autonomic Disorder 0.2% Demyelinating Syndrome 0.3% Headache 44.9% Cognitive Dysfunction 5.3% Anxiety Disorder 5.8% Seizures and Seizure Disorders 7.7% Mood Disorders 15.4% Hanly JG, Urowitz MB, et al. Arthritis Rheum 56:265-73, 2007.

92 Headache Differential SLE headache Migraine headache: worsened by SSRIs Katsiari CG, et al. Headache Tjensvoll AB, etal. Cephalalgia 2010;31: Cerebral venous sinus thrombosis (if LAC+) Drug headache: NSAIDs, IVIG Infection Tumor Heal Your Headache. D Buchholz and SG Reich. Workman Publishing Co., 1st ed., 2002

93 Headache in SLE Headache is NOT increased in SLE compared to controls Mitsikostas DD, et al. Brain 127: , Whitelaw DA, Spangenberg JJ. Lupus 18: , 2009.

94 Mood Disorders Depression very common: 20% Utset TO et al. J Rheumatol 21: , Depression correlates with cognitive impairment Petri M, et al. J Rheumatol 37: , Depression may be related to SLE Utset TO et al. J Rheumatol 21: , Neuropsychiatric lupus OR 3.43 p= Secondary Sjogren s OR 2.97 p=0.0006

95 Cognitive Impairment is Frequent at Baseline in an Inception Cohort Scale Mean±SD (range) SELENA SLEDAI 3.9±4.6 (0-28) SLICC Damage Index 0.7±1.1 (0-4) Krupp Fatigue Inventory 4.7±1.7 (1-7) Calgary Depression Scale 5.0±4.6 (0-18) Automated Neuronetics Assessments Matrix (ANAM): 1 SD below controls: 60% 2 SD or more below controls: 19% Petri M, et al. J Rheumatol 37: , 2010

96 Cognitive Impairment at Diagnosis of SLE Improves or is Stable Over Time Cognitive impairment is common at baseline It improves over time Depression is the MOST important associate

97 Additional Slides

98 ETIOLOGY Multifactorial Predisposing genetic factors---2/3risk Environmental factors---1/3 risk Development of autoantibodies linked to pathologic manifestations Preclinical phase with autoantibodies present years before clinical disease

99 Autoantibodies Precede the Diagnosis Of SLE By Years Arbuckle MR, et al. N Engl J Med. 2003;349(16):

100 Clinical SLE Preceded by Complicated Autoimmune Changes ANA, Anti-Ro, Anti-La, Antiphospholipid antibodies appear first Anti-dsDNA antibodies appear next Anti-Sm and Anti-RNP antibodies appear just before disease onset The number of autoantibody types continues to increase until the time of diagnosis

101 Immunopathogenesis

102

103 Induction of Surface Blebs during Apoptosis Rahman A, Isenberg DA. N Engl J Med 2008;358:

104 Mechanism Summary-I In SLE patients there is defective clearance of apoptotic cells Leads to exposure of intracellular immunogenic components Taken up by DC and presented to autoreactive B cells In the right genetic environment, these B cells may become activated to produce autoantibodies

105 Mechanism Summary-II Once autoantibodies (particularly anti-ds DNA) are present, they can complex with DNA exposed on dying cells Results in high levels of IFN-a production IFN-a encourages a feed-forward mechanism of continued plasma cell activation to produce increased amounts of autoantibodies and encourage further disease progression and tissue destruction

106 The interferon signature and its regulation in SLE More than half of patients with SLE show a dysregulation in the expression of genes in the IFN pathway The type I IFNs are potent cytokines (IFNα and IFNβ) and also mediate the Th1 response, sustain activated T cells, sustain B cell survival, and lower the B cell activation threshold These responses propagate proinflammatory cytokines, contributing to chronic inflammation and tissue damage IFN also acts as a bridging mechanism between the innate and adaptive immune systems One of the mechanisms of action of Plaquenil is to inhibit interferon alpha production by pdc s (also inhibits TLR signaling)

107

108

109 Complement Split Products Bound to RBCs May Help in Diagnosis of SLE SLE Other Diseases Normal Healthy EC4d Net MFI (CI 95%) 17.6 ( ) 6.3 ( ) 5.3 ( ) BC4d Net MFI (CI 95%) ( ) 34.9 ( ) 23.5 ( ) PC4d Net MFI (CI 95%) 16.2 ( ) 3.6 ( ) 2.0 ( ) ECR1 Net MFI (CI 95%) 13.3 ( ) 16.1 ( ) 20.7 ( ) ANA=antinuclear antibodies; BC4d=complement C4d levels on B cells; ds=double-stranded; EC4d=complement C4d levels on erythrocytes; ECR1=complement receptor 1 levels on erythrocytes; MFI=mean fluorescence intensity; MVC=mutated citrullinated vimentin antibodies; PC4d=complement C4d levels on platelets;sle=systemic lupus erythematous Kalunian KC. Abstract 597. Presented at: American College of Rheumatology, 2011.

110 Detection of New Clinical Activity in SLE Variable Detected Frequency of New Isolated Variables of Interest in 515 Patients, 3 Visits, 18 months Follow Up Number of visits with new variable (N=173) Cast Hematuria 10 9 Proteinuria Pyuria Low complement DNA antibodies Thrombocytopenia 8 7 Leukopenia 7 7 Serum creatinine 9 8 Hemoglobin 6 6 Number of patients with 1 visit with new variable (N=127) Key point: Patients should be followed with clinical and laboratory measures every 3 months Gladman DD, et al. Abstract Presented at American College of Rheumatology Annual Meeting

111 Hormone Replacemant Therapy The largest study of 351 postmenopausal women with SLE suggested only a small increase in the risk of flares Buyon et al, Ann Int Med 2005;142:953

112 Oral Contraceptive Therapy Double blind, randomized, noninferiority trial. 183 women with inactive(76%) or stable active(24%). Severe flares occurred in 7.7%receiving OC s and 7.6%receiving placebo. Rates of mild-moderate flares were 1.40 flares per person-year in patients on OC s and 1.44 flares per patient-year for subjects receiving placebo. Conclusion: oral contraceptives do not increase the risk of flare in women with SLE whose disease is stable. Petri et al. NEJM 353;24:2550, 2005.

113 Rate of SLE Mortality Remains High Relative to the General Population Age X Age X Age X Age > X Bernatsky S, et al. Arthritis Rheum. 2006;54:

114 Work Loss Is a Common Consequence of SLE At baseline, 26% were aged years and 60% were years Individuals who reached age 65 without work loss were censored Overall, 33% (160/484) of patients stopped working during the 4-year follow-up period Work loss associated with incident SLE manifestations by Year 4: Musculoskeletal: 34% (58/170) Neuropsychiatric: 38% (68/179) Thrombotic: 58% (34/59) Yelin E, et al. Arthritis Care Res (Hoboken). 2012;64:

115 ORGAN DAMAGE

116 Despite Improvements in Survival Rates, SLE Remains a Chronic Disease With Higher Than Expected Mortality Rate Survival rates significantly improved in patients diagnosed vs patients diagnosed However, survival is significantly worse than in the general population Uramoto KM, et al. Arthritis Rheum. 1999;42:46-50.

117 CONCLUSIONS 1) SLE is a complex disease with predisposing genetic and environmental factors. 2) SLE is difficult to diagnose. 6) Follow renal disease with urine protein/creatinine ratio. 7) Risk of coronary heart disease greatly increased in patients with SLE. 3) SLE is not a pain disease. 8) Hydroxychloroquine 4) Limit the use of Prednisone. 5) Selecting treatment can be difficult, but data are emerging that can help. 9) We have a lot of work to do: pt dx ed at age 20 has 1/6 chance of dying by age 35