RA Disease Management

Schematic Representation of the Course of RA Over 30 Years Inflammation Disability Radiographic Scores Kirwan J. J Rheumatol. 1999;26:720-5.

Current RA Treatment Strategy for 2009 DMARD (Step-up/triple therapy ) MTX SSZ Biologic 1 Anti-TNF Etanercept Infliximab Adalimumab Biologic 2 Rituximab Abatacept DAS28 driven

Goals of Therapy

ACR Goals of Therapy in RA Symptom relief Improvement in physical function Reduce physical disability Slowing/arresting progression of structural damage Guidelines for the Management of RA. Arthritis Rheum. 1996; 39:

Key Principles of RA Management  Detect and refer early  Treat immediately  Tailor treatment to the individual Control inflammation: The fundamental concept of RA treatment

Progress in management of RA in recent years DrugsObjectivesConcepts 1985MTX/SSZ Signs & symptoms 1995Combination Leflunomide  joint damage 2000 TNF blockers Stop joint damage Early treatment Prevent joint damage Tight control Early intensive ttt 2008Remission

Traditional Approach

Traditional Therapies Wilske and Haeley. J Rheumatol 1989 Exp methods MTX, axathioprine Penicillamine, gold, hydroxychloroquine Physcial medicine, rehabilitation Salicylates, NSAIDs Patient education, rest, application of heat or cold Surgery Glucocorticoid (systemic or intra-articular)

Treatment of RA With DMARDs Traditional DMARDs 1 MTX Hydroxychloroquine Sulfasalazine Leflunomide “Biologics DMARDs” 2-5 Etanercept Infliximab Adalimumab Anakinra Abatacept Rituximab Combination Treatment ACR Subcommittee on Rheumatoid Arthritis Guidelines. Arthritis Rheum. 2002;46: Combe B, et al. Ann Rheum Dis. 2007;66: Kineret ® (anakinra) Prescribing Information, Amgen Corporation. Thousand Oaks, Calif. 4. Orencia ® (abatacept) Prescribing Information, Bristol-Myers Squibb Company, Princeton, NJ. 5. Rituxan ® (rituximab) Prescribing Information, Genentech, Inc., South San Francisco, Calif.

Methotrexate Persistence Kaplan-Meier survival estimates of DMARD usage Proportion on DMARD CJ Edwards et al, Rheumatology, 2005, 44 (11):1394-8

The Famous Combination Studies  ARC low dose glucocorticoid study group trial  Methotrexate-Cyclosporin combination study  RAIN study of Methotrexate + SSP + HCQ: (triple therapy)  COBRA study: SSP + MTX + Prednisolone or SSP alone  Fin-RACo Trial: SSP+MTX+HCQ+Prednisolone vs single drug +/- Prednisolone

Best Use of MTX

Best Use of DMARDs: Early Median Sharp Score Lard LR et al. Am J Med. 2001;111: Delayed treatment (median treatment lag time, 123 days; n=109) Early treatment (median treatment lag time, 15 days; n=97) * *P<0.05 vs delayed-treatment group.

Even Earlier: PROMPT Study PROMPT study Prospective, double-blind, n=110 with UA MTX 15mg/wk vs placebo (if became ACR positive changed to MTX) Dose adjusted 3 monthly by DAS 12/12 study medication tapered to nil Followed for 30/12 van Dongen et al, Arthritis Rheum May;56(5):

PROMPT– Results after 18 months Remission Undifferentiated arthritis & other diagnosis ACR-criteria RA, treated with MTX Placebo MTX 15 mg/wk OR 0.38 P = 0.05 n=110

Best Use of DMARDs: Protocol Driven

TICORA Study of Intensive vs Routine Treatment: DAS Scores *P < * * * * * * Months Mean DAS score Routine Intensive Grigor C, et al. Lancet. 2004;364:

* P<0.02, ** P<0.002, Mann-Whitney Radiographic Progression: 0 and 18 Months Erosion scoreNarrowing scoreTotal Sharp score RoutineIntensive ** * Grigor C et al. Lancet 2004; 364: 263 Median change in erosion, joint space narrowing and total Sharp score

Key Anti-TNF Trials Late ARMADAAdalimumab ATTRACTInfliximab TEMPOEtanercept Early ASPIREInfliximab ERAEtanercept PREMIERAdalimumab

TEMPO Trial Klareskog et al. Lancet 2004; 363: ENBREL (n=223) MTX (n=228) Randomized (N=686) ITT Population (N=682) Failure on  1 DMARD No recent MTX ACR-N 24 Weeks  Total Sharp Score 52 Weeks EndpointsBaseline Enbrel ® (etanercept) + MTX (n=231) –Withdrawals: MTX, 30%; ENBREL, 24%; ENBREL + MTX, 16%

Primary Radiographic Endpoint: Change in TSS From Baseline - Year 3 * P < 0.05, Etanercept vs MTX † P < 0.05, combination vs MTX ‡ P < 0.05, combination vs Etanercept 5.95 (CI 2.96, 8.94) 1.61* (CI 0.41, 2.81) †‡ (CI –1.07, 0.78) van der Heijde D, et al. ACR 2005, Abstract L10.

No Radiographic Progression Long-term Safety & Efficacy TEMPO Trial - Year 3 Results van der Heijde D, et al. ACR 2005, Abstract L10.

When to use anti-TNF?  Straight away  After DMARD failure DAS28 >5.1 or less  Late

Predicting Prognosis

Predicting prognosis Severity markerPrognostic factor ErosionsSmoking, HLA DRB1, HAQ, XR damage, RF & anti-CCP, ESR & CRP DisabilityHAQ, female, many joints, nodules, RF, >64yrs MortalityHLA DRB1, HAQ, RF & anti- CCP 1. J Morel & B Combe, Best Pract Res Clin Rheumatol, 2005, 19: D Symmons & A Silman, Arthritis Res Therapy, 2006, 8: 214

Gene expression profiling of PBMCs from RA patients PBMCs from RA 330 differentially expressed genes TNF receptor (p75) RANTES NF  B RAGE Edwards CJ et al. Mol Med :40-58

Gene expression predicting anti- TNF responders ? Changes to gene expression profiles in infliximab responders vs non-responders 18 RA patients, infliximab 3mg/kg PBMCs 0, 2, 14, 22 wks Inflammatory genes decreased at 2 weeks and remained low in responders Early gene expression changes predicting clinical response to etanercept 19 RA patients, etanercept 50mg/wk PBMCs 0, 72 hrs Early down-regulation predicted response at 3 months –NFKBIA, CCL4, IL8, IL1B, TNFAIP3, PDE4B, PPP1R15A and ADM 1. Sekiguchi et al, Rheumatology, 2008, 47, ; 2. Koczan et al, Arth Res & Ther, 2008, 10, R50

For early aggressive treatment we need the following Early referal Reliable diagnosis Effective & safe therapies Prognostic predictors Disease activity measures Decrease disease activity & prevent joint damage

Key Messages Set clear disease activity targets TICORA TEAR CAMERA Earlier treatment PROMPT COMET Therapeutic memory BeST B cell targeting

Key Messages Predict prognosis Collateral damage outcomes

Definition of Remission Clinical Remission ACR/DAS criteria, or normal acute phase response, no clinical synovitis Imaging Remission No radiographic damage progression No significant synovitis on sensitive imaging True Remission A state of low disease activity with no progression of structural damage

Clinical Remission by DAS28 Based on VAS of 100mm Prevoo MLL et al. Arthritis Rheum 1995;38:44-8. van Gestel AM et al. J Rheumatol 1999;26: DAS28 Score Severe Moderate Low Remission Disease Activity DAS28 <2.6

Remission in RA Importance of Structural Damage Determinants of Structural Damage Interrelationship synovitis and damage Remission Clinical and Imaging Impact of DMARDs Effect of TNF antagonists

Effect of anti-inflammatory therapy on BMD Corticosteroids are associated with bone loss RCT prednisolone 7.5 mg vs placebo in patients with early RA (< 2years disease duration) with a radiographic endpoint 1 Examinations of the radiographs (95 patients) with DXR to study 2-year changes in hand bone density 2 1. Kirwan et al N Engl J Med 1995;333: Haugeberg et al. Arch Intern Med 2005;165:

Does anti-inflammatory treatment reduce atherosclerosis / CVD? Non-naproxen NSAIDs increase risk of thrombotic CV events Anti-TNF drugs may reduce atherosclerosis DMARDs and anti-TNF drugs seem to reduce CVD / CV mortality

McCarey DW et al. Lancet 2004;363: The effect of statin therapy in RA Atorvastatin (n=58) Placebo (n=58) P Primary outcome measure Disease activity score Disease activity score Secondary outcome measures Erythrocyte sedimentation rate (mm/h) Erythrocyte sedimentation rate (mm/h) C-reactive protein (log mg/L) C-reactive protein (log mg/L) < LDL-cholesterol (mmol/L) LDL-cholesterol (mmol/L) < HDL-cholesterol (mmol/L) HDL-cholesterol (mmol/L) Intercellualar adhesion molecule1 (ng/mL) Intercellualar adhesion molecule1 (ng/mL) Interleukin 6 (pg/mL) Interleukin 6 (pg/mL)

Choi HY et al. Lancet 2002;359: ICD-9 code Deaths Hazard ratio (95% CI) All-cause mortality All ( ) CV mortality ( ) Non-CV mortality ( ) Effect of methotrexate on mortality in RA

Tools Optimized MTX Combination therapy Anti-TNF therapy Processes Early treatment –Avoid treatment delay –Take advantage of “window of opportunity” Patient monitoring –DAS New Therapeutic Possibilities for RA – Remission is a Realistic Goal

Cumulative Probability Plot of Radiographic Progression Unchanged Lower Score Moderate Progression

Why Is Structural Damage Important? Cummulative measure, reflects disease control Surrogate marker for long-term outcome (physical function, employment) In cohorts ~ stable disease activity –Very slow increase in HAQ score –Constant progression in structural damage

Relationship Between X-ray Progression and Physical Function - TEMPO Trial X-ray progression and HAQ scores were determined at baseline, Year 1 and Year 2 After adjustment for co- variates, Sharp-score was a statistically significant determinant of HAQ-score (p<0.0001) Progression of radiographic damage over a relatively short period of time leads to deterioration of physical function van der Heijde D, et al. Abstract 1456, ACR Negative Zero Mild Severe Progression

Cumulative Probability Plot of Radiographic Outcome Unchanged Lower Score Moderate Progressors Rapid Progression Rapid Progressors

ACR Response TEMPO Trial - Year 3 Results ACR Response * P<0.05, etanercept vs. MTX † P<0.05 combination vs. MTX ‡ P<0.05 combination vs. etanercept * † ‡ 71 † ‡ 49 † ‡ ACR20ACR50ACR70 Percent of Patients MTX (n=228) Etanercept (n=223) Etanercept + MTX (n=231) van der Heijde D, et al. ACR 2005, Abstract L10.

Radiological Damage in RA Patients on Sustained Remission Gr é gory C, et al. Abstract 346, ACR ? is their radiological progression over 5-years in recent RA patients with persistent remission (Between Y3 and Y5) 191 RA patients <1 year on SSZ, MTX or Both Available patients: (22.4%) Remission with DAS44 <1.6 at 3 and 5 years 6 (20%) patients had radiographic progression or new erosions between Y3 and Y5

Cumulative Probability (%) Change In Total XR Score All Asymptomatic X-ray Progression in Symptomatic and Asymptomatic Joints Brown A et al. Arthritis Rheum 2008; in press.

Welsing et al. Arthritis Rheum 2004;50: * RF Positive Patients Const. Low DASFluct. Low DASFluct. High DASConst. High DAS Baseline TSS = Time (Yrs) Sharp Score Baseline TSS = Time (Yrs) Sharp Score Control of Structural Damage is Greatest with Continuous Control of Disease Activity*

Landewé R et al. Abstract 867, ACR TEMPO trial - Disconnect between Disease Activity Radiographic Progression Change in Sharp Score by Treatment Group Stratified For Subcategories of ta-CRP* * Time-averaged CRP

Disconnect Between Disease Activity and Radiographic Progression Change in Sharp Score by Treatment Group Stratified for Subcategories of ta-DAS* * Time-averaged DAS Landewé R et al. Abstract 867, ACR 2005.

Remission on DMARDs DMARDs frequently produce clinical remission DMARDs rarely produce imaging remission Hence DMARDs rarely produce true remission Explains progression of damage in patients in clinical remission on DMARDs? What happens with TNF antagonists?

BeSt Trial - Disposition of patients in the anti-TNF arm: 120 enrolled 8 stopped for side effects 22 did not achieve response 13 continued 77 stopped because they achieved a DAS44 <2.4 –46 were on 3mg/kg –22 on 6 mg/kg –6 on 7.5 mg/kg –3 on 10 mg/kg Van der Bijl AE, et al. ACR 2005, Abstract 876.

Induction of remission in patients with ERA treated with anti-TNF – BeSt Trial Outcome at 3 Years 67 MTX mono 23 combination 30 next steps 18 no DMARD 46 MTX mono 21 combination 31 next steps 4 lost to FU Van der Kooij. Abstract 1306, ACR 2006.

QUEST – RA study March ,363 pts from 48 sites in 15 countries Clinical assessment by rheumatologist and self reported questionnaire by patients Co-morbidites recorded MI, angina, coronary disease, coronary bypass surgery, stroke Risk factors recorded Hypertension, hyperlipidemia, DM, smoking, physical activity, BMI Naranjo A, et al. Arthritis Res Ther 2008; 10: R30

Quest RA Study – effects of therapy on risk of CV morbidity AgentH.R.95% CI Methotrexate to 0.89 Leflunomide to 0.79 Sulfasalasine to 0.98 Glucocorticoids to 0.98 Biologic agents to 0.81 (P<0.05) Naranjo A, et al. Arthritis Res Ther 2008; 10: R30

Does good clinical control translate into NO radiographic progression?

Predictors of radiographic progression in early RA patients treated with MTX

CRP Change And Radiographic Progression - PREMIER Trial CRP Levels: % with No Radiographic Progression van der Heijde DF, et al. Ann Rheum Dis 2005;64(Suppl III):436-7 (SAT0085)

CRP Levels: % with No Radiographic Progression van der Heijde DF, et al. Ann Rheum Dis 2005;64(Suppl III):436-7 (SAT0085) CRP Change And Radiographic Progression - PREMIER Trial

TICORA Study of Intensive vs Routine Treatment: DAS Scores *P < * * * * * * Months Mean DAS score Routine Intensive Grigor C, et al. Lancet. 2004;364:

Clinical Results at 18 Months P< Mean Fall in DAS P< %40%ACR % 65% 82% Intensive Care (n=50) P=0.021 P= P=0.09 P< P-value 4.0SF12 Physical Summary Score -0.47Change in HAQ -14Change in CRP (mg/dL) 18%ACR70 16%EULAR Remission 44% EULAR Good Response (DAS ≤2.4 and fall of 1.2 from baseline) Routine Care (n=53) Aim for a Target –TICORA Trial Grigor C, et al. Lancet. 2004;364:

* P<0.02, ** P<0.002, Mann-Whitney Radiographic Progression: 0 and 18 Months Erosion scoreNarrowing scoreTotal Sharp score RoutineIntensive ** * Median change in erosion, joint space narrowing and total Sharp score Grigor C, et al. Lancet. 2004;364:263

Early RA: Early DMARD therapy MTX dose mg/week (within 1-2 months) + glucocorticoid Cobra? Long-standing RA: If previosuly inadequate dose: Optimize DMARD (MTX) dose + glucocorticoid DAS28 improvement >1.2 or HAQ improvement >0.5 within 3-4 months Smolen, Sokka, Pincus, Breedveld, Clin Exp Rheumatol 2003 Switch to another DMARD + glucocorticoid Add a biologic agent (eg, TNF- antagonist) or NO Add another DMARD + glucocorticoid Add a biologic agent (eg,TNF- antagonist) or NO SDAI <3.3 or DAS28 < 2.4 or HAQ <0.5 within 4 months by adjusting dosages X-rays YES Continue DMARD therapy, lower corticosteroids YES Algorithm for Achieving Therapeutic Success in RA

Predictors of radiographic progression of patients treated with MTX in the ASPIRE trial Predictors of radiographic progression of patients treated with MTX in the ASPIRE trial Baseline CRP Baseline ESR Week 14 DAS Mean CRP over 52 weeks Mean ESR over 52 weeks Smolen J et al. Arthritis Rheum 2006;54:702

Treatment Goals for RA Today TREAT EARLY Any delay impacts on outcomes TREAT OPTIMALLY Combination of traditional DMARDS TARGET CLINICAL REMISSION Targeted outcomes / Tight control EARLY USE OF BIOLOGICS

DAS28 after 14wks of MTX Tx Predicts Rapid Radiographic Progression If a ERA subject continues to have a DAS28 score > 4 after 14 weeks of MTX 20mg the subject can expect to experience rapid radiographic progression. Smolen J et al. Arthritis Rheum 2006;54:702

What Factors Will Predict Persitemt and Erosive RA? Visser et al, Arth Rheum, Feb 2002

Patients were startified according to: CRP levels: 15 DAS44: –<1.6 (remission) / (Low disease activity) – (moderate diseaseactivity) – >3.7 (high disease activity) Results: In the MTX group only the High CRP and High DAS progress In the MTX + ETN no progresson regardless of CRP level and disease activity Landewé R et al. ACR 2005, Abstract 867. TEMPO trial - Disconnect between Disease Activity / Inflammation and Radiographic Progression (2 year data)

Total no. of joints with US synovitis Brown, Arthritis Rheum 2006; 54: 3761 Patients (n) Patients NOT satisfying ACR Remission Criteria (n) Patients satisfying ACR Remission Criteria (n) Clinical Remission on DMARDs in 100 RA patients: # of Patients with US Synovitis (ACR Remission vs non ACR Remission)

Combe B, et al: Arthritis Rheum. 2001;44: Conclusion: early destruction, high ESR, IgM RF positivity and DR type predict destruction during 3 years of disease Stepwise Logistic Regression Analysis of Predictive Factors of Radiographic Progression

Treatment Strategies in Early RA Sequential MONO-Therapy STEP-UP Therapy Initial COMBO Therapy Initial BIOLOGIC Therapy MTX + SSZ + PRED MTX + Biologic 1. SSZMTX + SSZ MTX + CSA + PRED SSZ 2. LEFMTX + SSZ + HCQ MTX + Biologic LEF 3. MTX + Biologic MTX + SSZ + HCQ + PRED MTX + CSA + PRED 4. MTX + Biologic 5. BeSt

Radiographic Progression P = 0.003* Goekoop-Ruiterman YPM, et al. Abstract L4 ACR * Overall P-value, SDD = smallest detectable difference Early DMARD Intervention - BeST Trial Year 2 Outcomes