Implementing Outcomes Goals in the Treatment of Rheumatoid Arthritis. Treating Rheumatoid Arthritis To Target

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1 Implementing Outcomes Goals in the Treatment of Rheumatoid Arthritis Treating Rheumatoid Arthritis To Target Max Hamburger, MD May 3, 2012 Sandestin Hilton Sandestin, FL

2 Disease Course of RA RA is a chronic and progressive disease Joint damage and physical disability lead to reduced quality of life and premature mortality in RA Damage occurs early, even in presence of what is measured as low disease activity Bridges SL Jr et al. Arthritis Care Res. 2010;62:624. Wolfe F et al. Arthritis Rheum. 1998;41:1571.

3 Achievable Therapeutic Goals for RA Improvement in signs and symptoms Improvement in patient-reported outcomes Inhibition of structural progression Preservation of normal functionality

4 Remission is the Principle Therapeutic Outcomes Target Relieving symptoms is important but The Primary and Ultimate goal is achieving disease remission without delay Smolen JS et al. Ann Rheum Dis. 2010;69:964.

5 Remission is Associated With Best Functional Outcome Koevoets et al. Arthritis Rheum 2009;60 :957

6 HAQ Even in Good ACR Responders Remission 1 Leads to Best Results 0.75 ACR Score is a Change Score Functional Status TNFi+MTX 38% 50% 12% 56% 41% 3% ACR50 Aletaha et al. Arthritis Rheum ACR70 REM LDA MDA by SDAI Disease Stat 19

7 Remission and Low Disease Activity are Achievable Disease State Targets Do the Clinical and Radiographic Benefits Make Early Aggressive Management Compelling?

8 Progression of vdh-sharp Score Disease Activity is Associated With Significant Progression of Joint Damage Disease Activity Categories by SDAI* Rem LDA MDA HDA MTX-54 wks Smolen JS et al. Ann Rheum Dis. 2009;68:823. *Similar results when using CDAI

9 Mean residual HAQ scores (SEM) in remission Irreversible Loss of Physical Functioning Is Due to Joint Damage 0.5 Elimination of disease activity as a cause of disability By assessing patients (n~300) in stringent SDAI remission Joint damage is usually irreversible and leads to irreversible disability Achieving remission is not the only task in RA therapy prevention of damage by achieving remission early is the Challenge <2.5 (n=69) (n=66) (n=67) >22.9 (n=68) Radiographic scores (quartiles) Aletaha et al. Arthritis Rheum 2006;54:

10 Disease Activity Score TICORA: Intensive Treatment Resulted in Better Disease Response 6 DAS Scores Intensive group (n=53) Routine group (n=50) Month P <0.0001, Intensive vs Routine after month 3. Grigor C, et al. Lancet. 2004;364:

11 Intensive Treatment Resulted in Better Radiologic Scores in Ticora Median parameter Intensive group (n=53) Routine group (n=50) P values Erosion score Joint space narrowing Total Sharp score Grigor C, et al. Lancet. 2004;364:

12 Original BeSt Trial Protocol/Groups Group 1 (n=125): 25 mg/week SSZ leflunomide : MTX up to Group 2 (n=122): from MTX add SSZ add hydroxychloroquine Group 3 (n=133): : MTX + SSZ + prednisone 60 mg tapered to 7.5 mg (Initial COBRA Combination) Group 4 (n=128): : MTX (7.5 mg/wk for 2 weeks, then 15 mg/wk) and infliximab (3 mg/kg at week 0, 2, and 6, then every 8 weeks), doses increased or reduced to zero depending on DAS De Vries-Bouwstra JK, et al. ACR 67 th Annual Meeting; Abstract: #LB18. De Vries-Bouwstra. EULAR 2004 abstract OP0103.

13 Outcome in 5th BeSt group 1 year Routine Care (n=201): Early RA patients from Dutch clinics meeting BeSt criteria DAS-driven Therapy (n=234): Groups 1 and 2 from BeSt trial those on conventional therapy and not biologics 1-year assessment Routine Care DAS-driven Therapy P-value HAQ ΔDAS <0.001 ESR 19 (6 to 37) 13 (3 to 28) Conclusion: Intensive therapy achieves better outcomes than routine care Goekoop-Ruiterman YPM, et al. ACR, Washington DC 2006, #843 13

14 Importance of Early Effective Intervention

15 Patients Achieving Remission (%) Prospective cohort study 190 Patients with early DMARD naïve RA Baseline DAS28 = 5.1 Treatment to remission (DAS28 <2.6) DREAM: Tight Control and Conclusion: remission in early RA is possible with tight, step-up DMARD monotherapy or DMARD and biologic combination therapy Kuper I, et al. Ann Rheum Dis. 2008;67(Suppl II):48. Remission in Early RA Treatment Protocol Based on Response Week 1 MTX 15 mg/week Week 8 MTX 25 mg/week Week 12 MTX 25 mg/week + SSZ 2 g/day Week 20 MTX 25 mg/week + SSZ 3 g/day Week 24 MTX 25 mg/week + TNFi (ADA) Remission Rates Week 24 Week Time (weeks)

16 DREAM: 2-Year Results 534 RA Patients with RA less than 1 year Treatment adjustments every 4-8 weeks to DAS28 less than 2.6. MTX-MTX+SSZ- MTX+TNFi At 2 years Remission 61.5%, LDA 16%, MDA 19.6% HDA 2.8% 69.9% (100 patients) had no radiologic progression More patients in remission without radiologic progression than group with active disease, (DAS28 >3.2) 72.7% vs 59.4% Vermeer, M, et al. Presented at: American College of Rheumatology (ACR) 2010 Annual Scientific Meeting; November 7-11, 2010; Atlanta, GA. Abstract 1771.

17 Patient Response (%) Patient Response (%) TNFI in Early RA MTX therapy vs MTX plus TNFI therapy in 12-month clinical trials of IFX (ASPIRE), ADA (PREMIER), and ETN (COMET) in early, MTX-naive RA 100 MTX Monotherapy 100 TNFi + MTX ASPIRE PREMIER COMET 0 ASPIRE PREMIER COMET ACR20 ACR70 Conclusion: initial use of TNFI + MTX is more effective clinically than MTX monotherapy in early RA patients Smolen JS, et al. Lancet. 2007;370: St. Clair EW, et al. Arthritis Rheum. 2004;50(11): Breedveld FC, et al. Arthritis Rheum. 2006;54(1): Emery P, et al. Lancet. 2008;372(9636):

18 Increase of Sharp Score MTX Alone or in Combination with TNFi or Biologic Agents in Early RA: Radiographic Progression Estimated Annual Radiographic Progression MTX Biological Agent ASPIRE PREMIER TEMPO SAMURAI Changes in Sharp (or van der Heijde-modified Sharp) score during MTX monotherapy or treatment with MTX + IFX (ASPIRE), MTX + ADA (PREMIER), MTX + ETN (TEMPO), or DMARD monotherapy (80% MTX) vs TCZ monotherapy (SAMURAI) Differences between MTX monotherapy + treatment arms are significant (P<.001) for all trials Conclusion: the initial use of TNFi or biological agents with MTX therapy in early RA resulted in significant decreases in radiographic progression in early RA patients Smolen JS, et al. Lancet. 2007;370(9602):

19 Patient Response (%) Change in TSS AGREE: Abatacept Therapy in Early RA 2-Year, randomized, double-blind, controlled trial of 509 MTX-naïve patients with early RA Abatacept(ABA) + MTX Combination therapy vs MTX monotherapy Co-primary endpoints were proportion of patients reaching DAS28-defined remission (CRP) and joint damage progression (GmTSS; TS) at year 1 Significantly more radiographic progression in MTX group vs ABA + MTX group (mean change in TSS 1.06 vs 0.63, respectively; P =.04) Reaching DAS28-Defined Remission at Year 1 Radiographic Progression at Year P<.001 P = MTX ABA + MTX 0.0 MTX ABA + MTX Conclusion: Initial use of ABA + MTX was more efficacious clinically and radiographically than MTX monotherapy in early RA patients Westhovens R, et al. Ann Rheum Dis. 2009;68(12):

20 What s New? ACR/EULAR Collaborative Efforts International Treat to Target Task Force New RA Classification New Remission criteria

21 Overall Approach to RA Evaluation and Management Early diagnosis Newly established 2010 RA classification criteria Measuring RA disease activity Quantitatively establish and document a baseline Compare quantitative RA measurements at progressive time points Identify ultimate target of therapy-remission Existent definitions of remission Newly proposed ACR/EULAR definitions of remission in RA clinical trials Treatment strategy to continuously strive to push disease toward improvement Advance therapy in stepwise fashion while continuously measuring disease to achieve goal-or as close as is reasonably feasible

22 Rationale for Treating to Target in RA Widely accepted in other areas of medicine: Hypertension, Diabetes, Hyperlipidemia Disease activity predicts damage, disability Disease activity can be reliably assessed with core set variables, composite measures 2011: Biomarkers make an appearance New therapeutics offer likelihood of improved outcomes Remission /Low disease activity are achievable in many patients HTN = hypertension DM = diabetes mellitus 1. Smolen JS et al. Ann Rheum Dis. 2009;68: Aletaha D et al. Arthritis Rheum. 2008;58:2622.

23 New Proposed RA Disease Remission and Classification Criteria

24 2010 ACR/EULAR RA Classification Criteria 2010 RA Classification Criteria 1 joint with synovitis (excluding the DIP, first MTP and first CMC joints) Absence of alternative diagnosis that better explains synovitis Achievement of total score of 6 (of 10) from individual scores in 4 domains Joint involvement patterns Serologic abnormality Elevated acute-phase response Symptom duration Aletaha D, et al. Arthritis Rheum. 2010;62(9): Swollen/Tender Joints (0-5) 1 Large joint Large joints Small joints Small joints 3 >10 Joints ( 1 small joint) 5 Serology (0-3) Negative RF AND ACPA 0 Low-positive RF OR ACPA 2 High-positive RF OR ACPA 3 Symptom Duration (0-1) <6 Weeks 0 6 Weeks 1 Acute Phase Reactants (0-1) Normal CRP AND normal ESR 0 Abnormal CRP OR abnormal ESR 1 Patients with a score of 6 have definite RA

25 2010 RA Classification Considerations Use of criteria should be limited to target populations with no other explanation for their synovitis Criteria are not designed as a referral tool for PCPs Provide standardized approach to determine which patients with undifferentiated synovitis will be the subgroup with the highest probability of persistent or erosive RA Can be enrolled in clinical trials Other studies through the use of uniform criteria Those who most likely will derive benefit from and receive DMARD intervention MTX use within 1 year (in studied populations) was considered gold standard of RA

26 Standardizing the Definition of Remission Felson DT et al. Arthritis Rheum. 2011;63:573.

27 How To Define Remission? No pain Patient Global Assessment Physician Global Assessment HAQ = 0: normal off/on treatment TJC = 0, SJC = 0 ESR/CRP nl ACR70, 90 DAS44 <1.6, DAS28 <2.6, SDAI <3.3, CDAI <2.8, RAPID No radiographic/structural progression

28 ACR/EULAR Definitions of Remission in RA Clinical Trials 2 New definitions of remission: can be uniformly applied Boolean-based definition At any point, patient must satisfy all of the following: TJC 1 SJC 1 CRP 1 mg/dl Patient Global Assessment 1 (on a 0-10 scale) Must count feet/ankles (>28-joint count = more stringency) Index-based definition SDAI score of 3.3 SDAI = TJC+SJC+Patient Global+Physician Global+CRP BUT uses only 28-joint count Inclusion of Patient Global in SDAI mitigates against underestimation of disease activity and,therefore, misclassification of remission Felson DT, et al. Arthritis Rheum. 2011;63(3):

29 Patients The Implications of Remission Varies According to the Method Used 621 RA patients 2 consecutive visits in remission Residual 28 SJC Patients with 1 Swollen Joint 128 Patients reaching remission 90 macr: 18.5% DAS28 <2.6: 19.6% SDAI 3.3: 16.7% CDAI 2.8: 18.0% Examined percentage of patients with 1 SJC 0 macr DAS28 <2.6 SDAI 3.3 CDAI 2.8 Mierau M, et al. Rheumatology (Oxford). 2007;46(6):

30 Recent Recommendations on Treating to Target in RA Target: remission or lowest disease activity possible Monitoring: every 1-3 months Adjustments: as needed to achieve target Smolen JS et al. Ann Rheum Dis. 2010;69:631.

31 Task Force Actions Objectives and background Objective: develop a set of recommendations aimed at improving the management of rheumatoid arthritis (RA) in clinical practice Treatment targets have been identified in other disease states, resulting in improved outcomes Similar targets have not been defined for RA First step: Steering committee conducts systematic literature search aimed at treating-to-target strategy trials in RA Smolen JS et al. Ann Rheum Dis. 2010;69(4):

32 Steering Committee Actions The Steering Committee of the International Task Force designed the search protocol to discover treating-to-target strategy trials in rheumatoid arthritis. The Steering Committee consisted of rheumatologists and a patient with RA, who were identified on the basis of their expertise in treating RA, participation in clinical trials, development of consensus statements, and regional distribution across Europe and North America. Schoels et al published the results in the Annals of the Rheumatic Diseases in The clinical trial data identified as a result of this search served as the basis for the treatment recommendations of the International Treat-To-Target Task Force. M Schoels, R Knevel, D Aletaha, et al. Ann Rheum Dis. 010;69(4):

33 Systematic Literature Search Protocol Literature Search designed to identify randomized, controlled clinical trials of any RA drug treatment in which a clear outcome treatment target was the primary endpoint Therapeutic consequences of failing to reach the target were predetermined Treatment targets could be defined by clinical, laboratory, patient-reported, functional, or radiographic variables Outcomes as defined in the respective trials were compared between treatment groups Schoels M et al. Ann Rheum Dis. 2010;69(4):

34 Literature Search Flow Chart

35 Literature Search Summary All studies investigating early disease showed significantly better clinical outcomes of the targeted approach 2 of 4 studies that compared radiographic outcomes showed significant benefit of targeted treatment Study designs and evaluated targets were heterogeneous One study focused on late disease and found no advantage of tight control on the primary functional outcome (HAQ)

36 Literature Search Conclusions Few studies have used a randomized approach to test the value of treatment to a specified target Studies discovered in the literature search do provide evidence of clinical benefits of treating to target in rheumatoid arthritis More data are needed Treating to target in patients with longstanding RA has not been sufficiently investigated Schoels M et al. Ann Rheum Dis. 2010;69(4):

37 Guidelines Development Steering Committee formulated provisional recommendations in line with EULAR standards Summit meeting of Task Force Expert Committee: >60 experts from various regions of the world, including 5 patient representatives Provisional recommendations discussed & amended in breakout and plenary sessions 3 rounds of anonymous voting via digital system resulted in 10 recommendations Category of the evidence, evidence or expert-opinion based, categorized as I to IV, with IV based entirely on expert opinion Strength of recommendation categorized as A (highest) to D (lowest) The level of agreement with each recommendation used a 10-point scale 1=do not agree 10=agree completely Smolen JS et al. Ann Rheum Dis. 2010;69(4):

38 Recommendation Ratings Evidence, Strength, Agreement, and Votes for Each Recommendation

39 Overarching Principles (A) The treatment of rheumatoid arthritis must be based on a shared decision between patient and rheumatologist. Not only must the patient be informed on the therapeutic options and the reasons for recommending a particular therapeutic approach by weighing benefit and risk, but the patient should participate in the decision as to which treatment should be applied (B) The primary goal of treating the patient with rheumatoid arthritis is to maximize long-term health-related quality of life through control of symptoms, prevention of structural damage, normalization of function and social participation. (C) Abrogation of inflammation is the most important way to achieve these goals. (D) Treatment to target by measuring disease activity and adjusting therapy accordingly optimizes outcomes in rheumatoid Arthritis.

40 Recommendation #1 The primary target for treatment of rheumatoid arthritis should be clinical remission. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

41 Recommendation #2 Clinical remission = absence of signs and symptoms of inflammatory disease activity. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

42 Recommendation #3 Remission should be the target. Based on available evidence, low disease activity may be an acceptable alternative, particularly in long-standing established disease. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

43 Recommendation #4 Until the desired treatment target is reached, therapy should be adjusted at least every 3 months. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

44 Recommendation #5 Measures of disease activity should be documented regularly - as frequently as monthly in patients with high/moderate disease activity and every 3-6 months in those with sustained low disease activity or remission. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

45 Recommendation #6 Use of validated composite measures of disease activity is necessary in routine clinical practice to guide treatment decisions. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

46 Recommendation #7 Structural changes and physical function should be considered when making clinical decisions, in addition to assessing disease activity. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

47 Recommendation #8 The desired treatment target should be maintained throughout the remaining course of the disease. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

48 Recommendation #9 The choice of the (composite) measure of disease activity and the target for treatment. may be influenced by consideration of comorbidities, patient factors, and treatmentrelated risks. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

49 Recommendation #10 Each patient must be appropriately informed about the treatment target.. and the strategy planned to reach this target with his or her rheumatologist. Smolen JS et al. Ann Rheum Dis. 2010;69:631.

50 T2T Treatment Algorithm Smolen JS et al. Ann Rheum Dis. 2010;69:631.

51 Bridging to Clinical Practice Strict definitions for remission needed Should be closely linked with clinical practice Onset and sustainability of remission are important Easy to use and reliable measurement and assessment tools required Important variables = SJC, TJC, APR Patient-based component is important RAPID-3, SDAI, CDAI TJC = tender joint count APR = acute phase reactant SDAI = simplified disease activity index CDAI = clinical disease activity index Van Tuyl LHD et al. Arthritis Rheum. 2009;61:704. Smolen JS et al. Ann Rheum Dis. 2010;69:964.

52 What Do We Do Currently? How many of the attendees today measure disease activity routinely? By gestalt? By a composite measure? Using biomarkers? How many of the attendees today make an adjustment or change in treatment based on estimation of disease activity? How many of the attendees today have a defined set of variables that represents their concept of remission?

53 What Do We Do Currently? Is disease state a concept you consider? Is it a concept you consider as a goal? Can you estimate the proportion of your patients who are in the following disease states: Remission Low Moderate High disease activity?

54 Effective Treatment Prevents Bad Outcome

55 Reduced CV Risk Associated with Effective Treatment of RA All Cardiovascular diseases MTX Adjusted HR 0.84 (0.80 to 0.87) Anti TNF Adjusted HR 0.71 (0.56 to 0.89) Myocardial infarction MTX Adjusted HR 0.82 (0.74 to 0.91) Anti TNF Adjusted HR 0.42 (0.21 to 0.81) Heart failure No anti-tnf: 3.8% Anti-TNF: 3.1% (p<0.05) Cardiovascular death MTX vs non-mtx: HR = 0.3

56 Impact of Anti-TNFs on Mortality in Patients with RA Swedish Registry Effective therapy reduces cardiovascular risk and mortality Hazard ratio: 95% CI Anti-TNF exposed Anti-TNF exposed adjusted for HAQ Anti-TNF exp. adj. for HAQ and co-morbidity Swedish RA patients <80 years Mortality and cardiovascular mortality in 1534 pts, 949 on TNF blockers Adjusted for age, sex, disease severity markers and baseline comorbidities Jacobsson L, et al. ARD 2007

57 Remission Improves Cardiovascular Risk Factors Swedish RA patients <80 years Mortality and cardiovascular mortality in 1534 pts, 949 on TNF blockers Adjusted for age, sex, disease severity markers and baseline comorbidities Provan et al. Ann Rheum Dis. 2011; 70:812-7.

58 Clinical Measurement

59 What We Can Measure Gestalt: is not standardized nor quantified: unable to compare visit to visit Formal joint counts Patient global assessment* Physician global assessment HAQ/MDHAQ* Laboratory values: ESR/CRP, RA, ACP/CCP Categorical outcomes measures ACR 20, 50, 70* Continuous measurement tools DAS* SDAI* CDAI* GAS* MDHAQ + SF36* RAPID* Imaging results Biomarkers *Is or contains patient-reported outcome measures.

60 What We DO Measure Scored HAQ Patient Global VAS Pain VAS 28 Joint Count DAS ESR CRP CCP Surveymonkey Courtesy Jack Cush, MD.

61 Gestalt: Merriam Webster Definition Gestalt: a structure, configuration, or pattern of physical, biological, or psychological phenomena so integrated as to constitute a functional unit with properties not derivable by summation of its parts Gestalt is not a metric it cannot be used to measure anything in a way that can be communicated objectively to another scientist Physician Global Gestalt on a Visual Analog Scale 61

62 - T h e y The Joint is the Rheumatologist s Organ and the Target of RA Joint counts are important predictors Joints MUST NOT be excluded from assessment

63 Increase in vdh-sharp Score at Week 54 Correlation of Disease Activity with Damage: Swollen Joint Count SJ 3 SJ 4--9 SJ >10 Average Swollen Joint Count During Trial Smolen et al, Arthritis Rheum 2006; 54:

64 28 Joint Swollen/Tender Count IP 2 PIP MCP Wrist 2 Elbow 2 Shoulder 2 Knee

65 The Value of Composite Indices Patients vary in the predominance of symptoms Different symptoms are associated with different outcomes Joint swelling is associated with radiographic damage Joint tenderness is associated with functional impairment Acute phase reactants and patient reported outcomes also provide important information Composite scores encompass most aspects of the disease and are related to all outcomes

66 Composite Measures Used as Outcomes in RA Clinical Trials ACR 20/50/70 Response A change measure 20/50/70% Improvement in SJCs and TJCs with concomitant improvement ( 20/50/70%) in at least 3 of the following 5 measures: Patient s Global Assessment (VAS 0-10) Physician s Global Assessment (VAS 0-10) Patient s Assessment of Pain (VAS 0-10) Acute-phase Reactant (ESR or CRP) Functional Disability (HAQ) DAS28 measures disease activity and provides for disease state TJC (0-28) SJC (0-28) ESR or CRP Levels General health assessment (VAS 0-100) Felson DT, et al. Arthritis Rheum. 1998;41(9): van Gestel AM, et al. Arthritis Rheum. 1998;41(10):

67 Indices to Assess Disease Activity in RA Disease State or Change Score? ACR DAS28 SDAI CDAI RAPID /PAS # Tender joints # Swollen joints MD global ESR or CRP - Patient function Patient pain Patient global

68 Clinical Measurements Tools Scoring Remission LDA Moderate Disease Activity High Disease Activity SDAI >26 CDAI >22 GAS >20 DAS >3.7 RAPID < 3.0 <6 6 and 12 >12 Aletaha D, et al. Clin Exp Rheumatol. 2005;23(Suppl 39):S100-S108. Cush JJ. Presented at: 2005 ACR Annual Scientific Meeting; November 12-17, 2005; San Diego, CA. Abstract 1854.

69 Continuous Measures: Disease Activity Indices SDAI* TJC (0-28) SJC (0-28) Patient Global Assessment (0-10) Physician Global Assessment (0-10) CRP (mg/dl) CDAI* TJC (0-28) SJC (0-28) Patient Global Assessment (0-10) Physician Global Assessment (0-10) Eliminates ESR/CRP *Both are highly correlated with DAS28, ACR20/50/70, and HAQ. Aletaha D, et al. Clin Exp Rheumatol. 2005;23(Suppl 39):S100-S108.

70 RAPID (Routine Assessment of Patient Index Data) Measures Index: RAPID 3 RAPID 4 PT JC RAPID 4 MD JC Physical Function Pain Patient Global Estimate Patient Joint Count (RADAI) MD/Assessor Joint Count MD/Assessor Global Estimate

71 Pincus T, et al. Bull NYU Hosp Jt Dis. 2009;67(2): RAPID3

72 Limitations of Composite Measurement Tools Accuracy of clinical joint assessments-inter-rater variability TJCs in context of FM, nodal OA Swollen joints fibrous thickening vs synovitis Patient global and assessment questions Inadequate to address RA inflammatory activity currently Frequently reflects comorbid symptoms (HA, back pain, FMS) Includes nonreversible functional impairment Adds to scoring of measures that are used to make clinical treatment decisions HAQ/MDHAQ allows for irreversible disability (floor effect) Acute-phase reactants Even if current measurements available not always reflective of underlying disease activity

73 HAQ Score Patients (%) Functional Limitation in RA: Irreversible/Reversible? Evaluation of HAQ Score Pooled analysis of individual patient data from 6 clinical trials (N = 2763) Evaluated patients in remission (n = 295), defined as: SJC 3 TJC 3 CRP 2.3 mg/dl Evaluator global assessment of disease activity 25 mm Substantial functional impairment remained despite remission in long-standing RA Reversible HAQ, which illustrated responsiveness to treatment decreased over time Irreversible HAQ, showing damage over time, increased significantly Aletaha D, et al. Arthritis Rheum. 2006;54(9): Reversible HAQ Irreversible HAQ 67 HAQ in Remission <2 Years 2-5 Years 5-10 Years >10 Years 0.73 <2 Years 2-5 Years 5-10 Years 10 Years

74 Biomarkers

75 The Potential of Multi-biomarker Tests in RA Such assays may capture the complex, heterogeneous biology of RA Multiple biological pathways active in RA Different pathways active at different levels in different patients Unlikely that a single biomarker can cover all relevant biology Combination of biomarker levels into single score allows simple interpretation Potential tests include measurement of disease activity, risk of structural damage, prediction of therapy response, and others 75

76 Multi-biomarker Approaches May Better Capture the Biological Complexity of RA Complex diseases involving multiple biological pathways are less likely to be captured by single biomarkers Multi-biomarker approaches can integrate information from diverse pathways into a single quantitative score for simple interpretation Choy and Panayi. N Engl J Med. 2001;344:

77 IL-6, TNF-RI VCAM-1 EGF, VEGF systemic inflammatory response MMP-1, MMP-3 YKL-40 leptin, resistin SAA, CRP res lep peripheral CRP SAA SAA res lep lep res peripheral blood and organs Vectra DA: Multiple Pathways Represented VCAM1 VCAM1 endothelial cells B, plasma cells T cells VCAM1 IL-6 TNFRI IL-6 IL-6 TNFRI res TNFRI EGF VEGF MMP1 leukocyte recruitment & angiogenesis EGF adaptive immunity VCAM1 res YKL40 IL-6 SAA MMP1 VEGF VCAM1 IL-6 res TNFRI monocytes, macrophages, dendritic cells IL-6 TNFRI VEGF EGF YKL40 VCAM1 IL-6 IL-6 fibroblastlike synoviocytes synovial tissue TNFRI IL-6 IL-6 res IL-6 IL-6 TNFRI IL-6 VEGF EGF IL-6 IL-6 hyperplasia TNFRI EGF VEGF TNFRI EGF innate immunity MMP1 YKL40 MMP3 res EGF YKL40 YKL40 osteoclasts VCAM1 VEGF IL-6 lep res osteoblasts chondrocytes MMP1 MMP3 cartilage degradation neutrophils bone bone erosion cartilage YKL40 synovial fluid Crescendo Bioscience 77

78 Informing RA Treatment Decisions (1) Patient-generated + (3)Joint Exam) + (4) Lab + (5) Joint Score and (2) AM Stiffness) Data & Imaging Biomarkers (6) Physician Global Estimate of Disease Activity ( Quantified on a VAS) + (7) Risk/Benefit Assessment Including Safety Monitoring + (8) Patient Preference Treatment Decision Adapted from Tim Harrington, The Uses of Disease Activity Scoring and the Physician Global Assessment of Disease Activity for Managing Rheumatoid Arthritis in Rheumatology Practice J Rheum 2009;36:925-9

79 To Further Optimize Therapy We Need To Address The Following Who should or should not be treated aggressively? Who is likely or not to respond to a particular therapy? How long should one persist with a therapy before discontinuing It? What should be the algorithm of biologic use?

80 Classic Predictors Of Prognosis

81 Baseline Predictors Of Poor Prognosis Less Likely To Achieve Remission Rapid Radiographic Progressors Female Gender Smoker - Early Age of Onset High DAS High CRP/ESR High HAQ Poor Response to Rx (6 mo.) Positive RF/anti-CCP BSL Katchamart W et al, Systemic /Review 2008 Smolen et al, Arth rheum 2006, 54:702

82 Smoking As A Predictor Of Response In Early RA Saevarsdottir S et al, Arth & Rheum 2011, Vol 63, pp 26-36

83 High Inflammation Is a Predictor of Significant Structural Damage Baseline ESR/CRP MTX + Placebo MTX + Infliximab P High CRP and ESR 4.71 SD (n=152) 0.63 SD 6.76 (n=401) High CRP or ESR 3.03 SD 8.68 (n=77) 0.26 SD 4.27 (n=207) Normal CRP and ESR 1.81 SD 7.27 (n=49) 0.21 SD 3.18 (n=101) NS Changes in modified Sharp Score Very High Risk of Progression High Risk of Progression Moderate Risk of Progression Low Risk of Progression Smolen J, et al. Arthritis Rheum. 2006;54:

84 Timing Of Response Is Predictive Of Long Term Outcome Is Response To Treatment at 12 Weeks a Better Predictor of Outcomes Than Baseline Measures Of Activity?

85 ACR Core Set Measures & 12 Weeks Is A Better Determinant Of Radiographic Outcome Initial 12 Weeks CRP 0.292* 0.477*** ESR *** MHAQ Patients pain estimation *** Patients global estimation *** Swollen joint count 0.279* 0.434** Tender joint count Physicians global *** DAS28-(CRP) 0.384** 0.592*** Correlation coefficients between measure and Modified Sharp Score Change *p<0.05 **p<.01 ***p<. 001 Ichikawa Y et al, J of Rheum 2010; 37:4; doi: /jrheum

86 Importance of Disease State How Predictive Of The Long Term Outcome Is The Disease State Achieved At 12 Weeks?

87 Rapid Control of Signs & Symptoms is Predictive of a Good Long-Term Response Early RA (N=1342) Established RA (N=712) REM + LDA at 1 year REM + LDA at 1 year For a majority of patients, the disease state achieved within the first 12 weeks is highly predictive of the degree of clinical outcome at 1 year Rem= Remission LDA= Low Disease Activity Aletaha, Smolen, Keystone et al. Arth & Rheum. 2007;56:

88 Is There A Cost Of Delay In Responding At 24 vs 12 Weeks On Long Term Outcome?

89 Timing of Good Responses: Effects On Long Term Clinical Outcome in RA Keystone et al, ACR 2010 Poster # 1102

90 Timing of Good Responses: Effect On Long Term Radiographic Progression in RA Keystone et al, ACR 2010 Poster # 1102

91 Predictors Of Sustained Remission

92 Rapid Remission With TNF-blockers Is The Most Important Factor Associated With Sustained Remission Results: Established RA patients (n=602) Sustained remission : DAS28<2.6 over at least 6 months. Results at year 3: DREAM REGISTRY The most important factor associated with sustained remission was time to first remission; the sooner patients achieved their first remission, the higher the chance on sustainability of remission (p<0.001). Schipper et al. EULAR 2010 SAT0046

93 Conclusions The timing of achieving a biologic response predicts long term outcome. The more rapid the response, the better the long term outcome. Treatment response at 12 weeks is a better outcome predictor than baseline disease

94 Summary Newly established 2010 RA classification criteria Facilitates earlier disease recognition for clinical study and research Implications for clinical practice-earlier diagnosis and definition of those at risk for more severe disease Consistent RA disease measurement: Now the standard of care? Yes! Enables quantitative baseline measure Enables quantitative comparative disease measures over time Facilitates dialogue between rheumatologists

95 Summary Newly proposed definition of remission ultimate target of therapy Specific definitions of remission in RA clinical trials Applications in clinical practice Consistently use treatment strategy to continuously push disease toward improvement Advance therapy while continuously measuring disease to achieve goals or as close as is reasonably feasible

96 Appendix

97 Mean (95% CI) radiographic progression Mean (95% CI) radiographic progression Progression of Damage is Related to Joint Swelling (>1SJC) Even in DAS28 Remission p= p= no SW SW no SW SW Remission Non remission 0.5 SDAI ( 3.3) CDAI ( 2.8) DAS28 (<2.6 and no SW) DAS28 (remission: <2.6) Definition of Remission Pooled data from ASPIRE, ERA, Leflunomide, PREMIER and TEMPO studies, patients relaiving methotrexate monotherapy; SW=joint swelling;aletaha D and Smolen JS. Arthritis Rheum (in press)

98 TICORA (Tight Control in RA) Study Design Glascow, UK Single-blind RCT in RA patients with DAS > 2.4 (N=111) Intensive care protocol (55) SSZ,+MTX & HCQ, titrate MTX, titrate SSZ, +Pred, Change to CSA/MTX Joint Injections liberally Patients assessed monthly After 3 mo, oral treatment escalated at monthly assessment if DAS =>2.4 Physicians were obligated to change therapy based on DAS results Grigor C, et al. Lancet. 2004;364:

99 TICORA Grigor C,et al. Lancet 2004; 364:

100 TICORA (Tight Control in RA) Study Design Routine care protocol (55) DMARD monotherapy in patients with active synovitis Addition of 2nd DMARD at physician discretion Patients assessed at 3-mo intervals with no formal composite measure of disease activity Grigor C, et al. Lancet. 2004;364:

101 TICORA (Tight Control in RA) Study Design Primary outcome Mean drop in DAS Proportion of patients with in score from baseline by > 1.2) (DAS < 2.4 and drop Secondary outcome Proportion of patients in (DAS < 1.6) Modified TSS at 18 mo Grigor C, et al. Lancet. 2004;364:

102 BeSt Trial Study Design Netherlands Study design: multicenter, randomized, single-blind, intent-to-treat (ITT) analysis of 4 groups Objective: evaluate clinical and radiologic outcomes after 1 year N=508 patients with early RA (<2 years by ACR criteria) DMARD naïve Baseline demographics similar in all 4 groups De Vries-Bouwstra JK, et al. ACR 67 th Annual Meeting; Abstract: #LB18. De Vries-Bouwstra. EULAR 2004 abstract OP0103.

103 BeSt Trial Protocol/Groups Change in treatment protocol dictated by 3 monthly determinations of DAS with goal of DAS 2.4 If DAS > 2.4, next step in protocol If DAS 2.4, maintain or taper, according to protocol De Vries-Bouwstra JK, et al. ACR 67 th Annual Meeting; Abstract: #LB18. De Vries-Bouwstra. EULAR 2004 abstract OP0103.

104 % of Patients BeST:Patients in Remission* Mono Step-up Combo Anti-TNF All patients discontinued infliximab at month Month *Remission indicates DAS < 2.4. De Vries-Bouwstra JK, et al. Ann Rheum Dis; 2004;63(1):

105 SWEFOT Early RA; symptoms <1 year; No other DMARD; DAS28 >3.2; N = 487 MTX monotherapy 20 mg/week 3-4 months MTX + SSZ + HCQ ( CsA) (n = 130) MTX + IFX ( ETN) (n = 128) 3 Months 12 Months 24 Months Screening and inclusion Randomization of patients with DAS28 >3.2 (30% of patients responded to initial MTX, 16% in remission at 12 months, 75% of MTX patients maintain LDA) van Vollenhoven RF, et al. Arthritis Rheum. 2009;60 (Suppl 10): Primary endpoint: patients with EULAR good response (%) Re-randomization of patients with LDA or remission Conclusion: in Early RA with insufficient response to MTX, the addition of anti-tnf results in less radiologic progression over 24 months than the addition of conventional DMARDs

106 Percentage SWEFOT: Primary Endpoint at 12 Months EULAR Good Responder; Nonresponder; ITT Population (%) Triple Therapy 32/123, 7 Missing MTX + IFX 50/120, 8 Missing P<.02 RR Arm A MTX + SSZ + HCQ ( CsA) Arm B MTX + IFX ( ETN) van Vollenhoven RF, et al. Arthritis Rheum. 2009;60 (Suppl 10):1010.

107 SWEFOT: Results at 24 Months: EULAR Good Response Clinical Results at 24 Months Triple (Arm A) MTX + IFX (Arm B) EULAR Good Response EULAR Good/Moderate Response Remission Differences Not Statistically Significant (P =.016) van Vollenhoven RF, et al. Arthritis Rheum. 2009;60 (Suppl 10):1010.

108 Total vdh-s SWEFOT: X-Ray Progression to 24 Months Total Scores ITT Population (all radiographs used irrespective of treatment no extrapolations) ITT Triple ITT MTX-IFX 6 4 P <.0001 vs baseline for both arms at 12 and 24 months 2 0 Baseline 12 Months 24 Months Conclusion: in patients with early RA who do not achieve LDA with MTX monotherapy, adding a TNFi results in less radiographic progression than addition of nonbiologic DMARDs van Vollenhoven RF, et al. Arthritis Rheum. 2009;60 (Suppl 10):1010.

109 COMET and PREMIER Establish That Remission Is an Attainable Goal in the Treatment of RA Emery P, et al. Lancet. 2008;372: Breedveld FC, et al. Arthritis Rheum. 2006;54:26-109

110 Initial Treatment With Regimens Containing Biologic DMARDs Results in Less Radiographic Progression Group 1 Group 2 Group 3 Group 4 Sequential Mono Tx n=125 Step-Up Combo Tx n=122 Initial COBRA Combo Tx n=133 Initial MTX + Infliximab n=128 P value* HAQ (mean change) SHS** progression (median) <0.001 No SHS progression (%) Discontinuation <1 year (n) Serious AEs (n) Pt would choose therapy 36% 30% 41% 81% *P value = MTX + infliximab versus sequential monotherapy or step-up combination therapy. **SHS indicates Sharp/van der Heijde radiographic score. 110 De Vries-Bouwstra JK, et al. ACR 67 th Annual Meeting, 2003; Abstract: #LB18. De Vries-Bouwstra. EULAR 2004 abstract OP0103; De Vries- Bouwstra. EULAR 2004 abstract OP0001.

111 Mean Change in TSS PREMIER Subanalysis: Mean Change in TSS for MTX Alone vs ADA + MTX N <ACR20 ACR20 to <50 ACR50 to <70 2 Years * * ACR70 to < ACR100 ADA + MTX (n = 240) MTX Alone (n = 213) *P <.01; P<.05 vs MTX alone. <ACR20 = nonresponder. Emery P, et al. Presented at: European League against Rheumatism (EULAR) 2007 Annual Meeting; June 13-16, 2007; Barcelona, Spain. Abstract THU Conclusions ADA plus MTX led to less radiographic progression than MTX monotherapy at essentially all levels of clinical response: joint erosion and JSN Clinically detectable disease must be eliminated for MTX monotherapy to control joint damage as effectively as ADA + MTX 2.15

112 Patients (%) Patients (%) Mean Change in Genant Score IMAGE: RTX in Early RA Key inclusion: RA <4 years; MTX-naïve; SJC 8; TJC 8; CRP 1.0 mg/dl; if RF-negative, >1 erosion Re-treatment >week 24 if DAS28 >2.6 ACR20 ACR50 ACR70 ACR90 MTX (n = 232) RTX 500 mg (n = 239) RTX 1000 mg (n = 244) Radiographic Scores at Week * * 0.45 TSS Erosion Score Joint Space Narrowing ACR Responses at Week MTX (n = 249) 9 RTX 2 x 500 mg (n = 249) RTX 2 x 1000 mg (n = 250) *P<.05; P<.01; P<.001 ; P<.05; P<.0001; P.001. Tak PP, et al. Ann Rheum Dis. 2011;70(1): Adjusted P values comparing RTX + MTX groups with MTX alone Proportion of Patients with No Radiographic Change (change mtts 0) Conclusion: Initial use of RTX + MTX was more efficacious clinically and radiographically than MTX monotherapy in early RA patients TSS * 67 Erosion Score

113 Trials Comparing Targeted vs Routine Care TICORA: Tight control vs routine care Primary and secondary outcome measures (EULAR good response and DAS remission) were significantly more frequent in the intensive management group (n=55) than in the routine care group (n=55). CAMERA: Open-label intensive computer-assisted monitoring vs routine monitoring Outcome measure set at remission for 3 months: duration of remission in all periods together was significantly longer in the intensive group (n=151) 11.6 months compared to 9.1 months in the routine group (n=148). Grigor C et al. Lancet. 2004;364(9430): Verstappen SM et al. Ann Rheum Dis. 2007;66(11);

114 Trials Comparing Targeted vs Routine Care Fransen et al: Systematic monitoring (DAS28) vs routine monitoring At Week 24 more patients in the DAS28 group (n=205) reached low disease activity (LDA). In the routine care group (n=179), the LDA was relatively unchanged. Symmons et al: Aggressive vs symptomatic therapy in established RA Significant deterioration in primary outcome measure, physical function (HAQ), was found in both study arms. Intensive group (n=233) failed to show significant differences compared with routine care (n=233) regarding HAQ changes. Fransen J et al. Ann Rheum Dis. 2005;64(9): Symmons D et al. Health Technol Assess. 2005;9(34):iii-78.

115 Trials Comparing Two Targeted Strategies Edmonds et al: SJC-steered vs CRP-steered vs routine care In intensive group I, the swollen joint count <3 target was met in 29% of patient visits (n=85). In intensive group II, the normal C-reactive protein target was met in 41% of patient visits (n=82). Across all arms the average area under the curve CRP met target in 28% of patients, but the AUC swollen joint count was less than 3 in only 12%. Van Tuyl et al: Intensified COBRA treatment 2 monitoring measures One group in this study aimed at DAS28 <3.2 (n=11), the other at suppressing cartilage degradation (n=10). After 40 weeks of treatment, 19 of 21 patients (90%) had achieved remission. ACR improvement rates were higher than previously noted in literature. Edmonds J et al. Ann Rheum Dis. 2007;66(suppl II):325. van Tuyl LH et al. Ann Rheum Dis. 2008;67(11):

116 Nonrandomized Cohort Study Comparing Two Targeted Strategies Stenger et al: Prospective follow-up study comparing 2 targeted strategies 2 years of follow-up comparison of 2 high-risk subgroups Radiographic progression in the aggressively treated experimental-hr group to be significantly lower than that in control-hr group. Cumulative CRP values also significantly lower in experimental-hr group, compared to routine care control-hr.

117 The Concept of Induction and Remission in Early RA Maintenance of biologic-free disease control in early RA patients after induction of low disease activity with ADA plus MTX 207 (44%) of 466 ERA, MTX-naive ADA + MTX patients achieved DAS<3.2 at week 26 and were randomized to placebo + MTX (n=102) or ADA + MTX (n = 105) through week 78 (LOCF). ADA + MTX/placebo+MTX vs ADA+MTX/ADA+MTX ACR20/50/70 = 94/80/65 vs 95/89/77% (P =.72,.11,.05) DAS <3.2/2.6 = 81/86 vs 91/86% (0.04/0.001) TSS change <0.5/mean = 89%/0.3 vs 81%/0.1 (0.06/0.69) Conclusion: ERA patients who achieve LDA maintained good clinical, radiographic, and functional control, including patients who had ADA withdrawn At 2 years (n = 210), 64.3% of patients achieved remission, 75.7% a good EULAR response Median time to remission 22 (12-37) weeks; more than 60% sustained remission for longer than 6 months Majority of patients achieved remission on conventional DMARDs Emery P, et al. Ann Rheum Dis. 2011;70(Suppl 3):262.

118 The Concept of Induction and Remission in Early RA Discontinuation of IFX and potential predictors of persistent LDA in patients with ERA and DAS-steered therapy In the BeST study, 120 ERA patients were treated with initial MTX + IFX and 109 patients used MTX + IFX after failing (DAS>2.4) on 3 previous treatment steps. If DAS remained <2.4 then IFX was tapered and then stopped IFX was discontinued in 77/120 from the initial and 27/109 from the delayed treatment groups (52% of total), median symptom duration at time of cessation was 23 months. In the year after cessation, the median SvH score did not increase regardless of flare IFX Was restarted in 48% after a median period of 17 months, 84% again achieved DAS<2.4 Conclusion: Cessation of IFX was successful in 52%, with higher success rates in patients initially treated with IFX At 2 years (n = 210), 64.3% of patients achieved remission, 75.7% a good EULAR response Median time to remission 22 (12-37) weeks; more than 60% sustained remission for longer than 6 months Majority of patients achieved remission on conventional DMARDs Van den Broek, et al. Ann Rheum Dis. 2011;70(Suppl 3):413.

119 ACR/EULAR Definitions of Remission in RA Clinical Trials Evidence-based consensus method: OMERACT and ACR/EULAR accordance Pass OMERACT filter of truth/discrimination/feasibility Trial data were analyzed For patient-reported outcomes Ability of candidate measures to predict later good radiographic and functional outcomes DAS28 CRP Remission did not predict good radiographic outcomes as well as the other candidate definitions did Proposed remission criteria: have NOT been validated in observational datasets Next charge of the working group

120 Increase in vdh-sharp Score at Week 54 Correlation of Baseline Activity With Damage: CRP PL+MTX CRP <0.6 CRP 0.6- <3 CRP 3.0 Baseline CRP Smolen et al, Arthritis Rheum 2006; 54: