R.A for portland

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Diagnosis and Management of Rheumatoid Arthritis A Patient Centered Approach M FArooq Ali M.D , FACP, FACR

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Out comes are Better In RA treated Early with DMARDS/Biologics

ACR 1987 criteria for the classification of rheumatoid arthritis:

ACR 1987 criteria for the classification of rheumatoid arthritis Need at least four of seven criteria: 1. Morning stiffness lasting at least 1 hr 2. Soft- tissue swelling or fluid in at least 3 joint areas simultaneously 3. At least one area swollen in a wrist, MCP, or PIP joint 4. Symmetric arthritis 5. Rheumatoid nodules 6. Abnormal amounts of serum rheumatoid factor 7. Erosions or bony decalcification on radiographs of the hand and wrist

Rheumatoid arthritis: ulnar deviation and muscle artrophy, hands:

Rheumatoid arthritis: ulnar deviation and muscle artrophy, hands

Rheumatoid arthritis: subcutaneous nodule, olecranon:

Rheumatoid arthritis: subcutaneous nodule, olecranon

Clinical Course of RA:

Clinical Course of RA Type 1 = Self-limited—5% to 20% Type 2 = Minimally progressive—5% to 20% Type 3 = Progressive—60% to 90% Years Severity of Arthritis Pincus. Rheum Dis Clin North Am . 1995;21:619.

Rheumatoid Arthritis: Treatment Principles:

Rheumatoid Arthritis: Treatment Principles Confirm the diagnosis Determine where the patient stands in the spectrum of disease When damage begins early, start aggressive treatment early Use the safest treatment plan that matches the aggressiveness of the disease Monitor treatment for adverse effects Monitor disease activity, revise Rx as needed

Rheumatoid Arthritis: Typical Course:

Pincus, et al. Rheum Dis Clin North Am . 1993;19:123–151. Rheumatoid Arthritis: Typical Course Damage occurs early in most patients 50% show joint space narrowing or erosions in the first 2 years By 10 years, 50% of young working patients are disabled Death comes early Multiple causes Compared to general population Women lose 10 years, men lose 4 years

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Principles of RA Therapy Early institution of DMARD therapy Escalation of MTX to maximum tolerated dose Institution of additional DMARDs for persistent activity

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New(er) RA Treatment Paradigms Early MTX as first-line therapy Early addition (3-6 months) of biologic for persistent activity

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Currently Available TNF Inhibitors Etanercept Adalimumab Infliximab

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The State of TNF Inhibitor Therapy The majority of patients who receive TNF inhibitors get a significant benefit in both symptoms and signs Not everyone treated with a TNF inhibitor improves sufficiently, however

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Responses to TNF Inhibitors 60-80% initial response ~10% drop-off per year

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Classes of TNF Inhibitors Human MAb: adalimumab Murine/human MAb: infliximab Soluble receptor: etanercept

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DAS28: Disease Activity Score Score 2.6 3.2 5.1 Remission Low Severe Moderate Remission = DAS28 2.6 for at least 6 consecutive months Emery P et al. ACR 2004: abstract 355

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44 Swollen Joint Count 28 Swollen Joint Count DAS Joint Counts

Calculating DAS and DAS28 Scores:

Calculating DAS and DAS28 Scores DAS 1 0.54 x √ RAI + 0.065 x √ SJC + 0.33 x ln ESR + 0.0072 x GH DAS28 2 0.56 x √(t28) + 0.28 x √(sw28) + 0.70 x ln ESR + 0.014 x GH t28, number of painful joints out of 28; sw28: number of swollen joints out of 28; ESR, mm/first hour, Westergren method; GH, general health or PGA of disease activity on 100-mm VAS. 1 van der Heijde DM et al. J Rheumatol. 1993;20:579-581. 2 van Gestel AM et al. Arthritis Rheum. 1998;41:1845-1850.

PREMIER:

PREMIER A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment Breedveld FC, Weisman MH, Kavanaugh AF, et al. A&R:2006;54 (1); 26-37

PREMIER Study Design:

104-week double-blind, active controlled phase PREMIER Study Design PREMIER *7.5 mg weekly escalated to 20 mg/wk by Week 8 as needed/as tolerated Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37 MTX* weekly (n=257) HUMIRA 40 mg eow (n=274) HUMIRA 40 mg eow + MTX* (n=268) 104 0 Week 52 799 patients Randomization Primary end points †

Major Inclusion Criteria1,2:

Major Inclusion Criteria 1,2 Age >18 years RA diagnosis: defined by 1987-revised ACR criteria Disease duration <3 years  8 swollen joints of 66 joints assessed  10 tender joints of 68 joints assessed  1 joint erosion or RF positivity ESR 28 mm/h or CRP 1.5 mg/dL Negative pregnancy test (serum) for women of childbearing potential Contraception use if applicable PREMIER 1. Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37 2. Data on file, Abbott Laboratories

Baseline Demographic and Clinical Characteristics*:

Baseline Demographic and Clinical Characteristics * HUMIRA + MTX n=268 HUMIRA n=274 MTX n=257 Age (yrs), mean 52 ± 14.0 52 ± 13.5 52 ± 13.1 % females 72 77 74 % with prior DMARDs 33 33 32 % Corticosteroid use 36 37 35 Years since diagnosis, mean 0.7 ± 0.8 0.7 ± 0.8 0.8 ± 0.9 SJC (0-66), mean 21.1 ± 11.2 21.8 ± 10.5 22.1 ± 11.7 TJC (0-68), mean 30.7 ± 14.2 31.8 ± 13.6 32.3 ± 14.3 JE, score (mean) 11.0 ± 12.3 11.3 ± 11.3 13.6 ± 13.6 JSN, score (mean) 7.1 ± 9.6 7.5 ± 9.4 8.2 ± 10.7 PREMIER Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37 *Unless otherwise indicated, results are mean ± SD.

Baseline Demographic and Clinical Characteristics (cont’d)*:

Baseline Demographic and Clinical Characteristics (cont’d)* HUMIRA + MTX n=268 HUMIRA n=274 MTX n=257 DAS28, mean 6.3 ± 0.9 6.4 ± 0.9 6.3 ± 0.9 CRP (mg/dL) 3.9 ± 4.2 4.1 ± 3.9 4.0 ± 4.0 mTSS, mean 18.1 ± 20.1 18.8 ± 19.0 21.9 ± 22.2 Estimated annual TSS progression 25.6 26.7 27.4 % RF Positive 85 83 84 HAQ DI, mean 1.5 ± 0.6 1.6 ± 0.6 1.5 ± 0.6 PREMIER Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37 * Unless otherwise indicated, results are mean ± SD.

Patient Disposition at 2 Years:

Patient Disposition at 2 Years PREMIER Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37 HUMIRA + MTX n=268 HUMIRA n=274 MTX n=257 % % % Completed* 76 † 61 66 Withdrawn 24 39 34 Reason AE 12 10 7 Lack of efficacy 5 19 18 *A total of 539 patients (68%) completed the 2-year study † P <0.001 HUMIRA + MTX vs. HUMIRA or MTX alone

ACR Responses at Years 1 and 2 Prespecified Comparison HUMIRA + MTX vs MTX Alone:

ACR Responses at Years 1 and 2 Prespecified Comparison HUMIRA + MTX vs MTX Alone Patients who withdrew or had missing values were considered nonresponders ξ P <0.001 for HUMIRA + MTX vs HUMIRA alone and P =0.022 vs MTX alone * P <0.001 vs HUMIRA alone and P =0.002 vs MTX alone † P =0.043 vs HUMIRA alone; # P <0.001 vs HUMIRA alone and vs MTX alone PREMIER ACR20 ACR70 HUMIRA + MTX HUMIRA MTX 46 47 26 28 28 28 * * HUMIRA + MTX HUMIRA MTX ACR50 Week 52 Week 104 HUMIRA + MTX HUMIRA MTX 62 59 42 37 46 43 # # Percentage of Patients 0 20 40 60 80 73 69 54 49 63 56 † ξ * Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37

No Radiographic Progression Patients with Δ TSS ≤0.5 at Weeks 52 and 104 Prespecified Comparison HUMIRA + MTX vs MTX Alone:

No Radiographic Progression Patients with Δ TSS ≤ 0.5 at Weeks 52 and 104 Prespecified Comparison HUMIRA + MTX vs MTX Alone Week 52 Week 104 PREMIER * * † 64 51 37 61 45 34 0 20 40 60 80 Percentage of Patients † HUMIRA + MTX (n=268) HUMIRA (n=274) MTX (n=257) * P <0.01 for HUMIRA + MTX vs HUMIRA alone and MTX alone. † P <0.01 for HUMIRA alone vs MTX alone Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37 Approximately twice as many patients experienced no radiographic progression on HUMIRA + MTX vs MTX monotherapy at 2 years

Clinical Remission by DAS28 <2.6 Pre-specified Comparison HUMIRA + MTX vs MTX Alone:

Clinical Remission by DAS28 <2.6 Pre-specified Comparison HUMIRA + MTX vs MTX Alone PREMIER 43 23 21 49 25 25 0 10 20 30 40 50 60 HUMIRA + MTX HUMIRA MTX Week 52 Week 104 Percentage of Patients * * * P <0.001 for HUMIRA + MTX vs MTX alone and HUMIRA alone (n=268) (n=274) (n=257) Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37

Change in TSS Prespecified Comparison HUMIRA + MTX vs MTX Alone :

Change in TSS Prespecified Comparison HUMIRA + MTX vs MTX Alone PREMIER * P <0.001 for HUMIRA + MTX vs MTX alone 1.9 10.4 1.3 0.8 5.7 3.5 0 2 4 6 8 10 12 0 26 52 78 104 HUMIRA + MTX (n=268) MTX (n=257) * * * Mean Change From Baseline Weeks Adapted from Breedveld FC, et al. Arthritis Rheum. 2006;54(1):26-37 5x greater inhibition of radiographic progression with HUMIRA + MTX vs MTX monotherapy at 2 years

Major Clinical Response at Year 2 Prespecified Comparison HUMIRA + MTX vs MTX Alone:

Major Clinical Response at Year 2 Prespecified Comparison HUMIRA + MTX vs MTX Alone PREMIER Percentage of Patients 49 25 27 0 10 20 30 40 50 60 HUMIRA + MTX (n=268) HUMIRA (n=274) MTX (n=257)  Major clinical response (FDA definition): Subjects achieving and maintaining ACR70 response for 6 continuous months over 2 years. * P <0.001 for HUMIRA + MTX vs MTX alone and HUMIRA alone Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37

PREMIER Summary:

PREMIER Summary Nearly one of 2 patients (49%) with moderate to severe early RA achieved clinical remission measure (DAS28<2.6) with HUMIRA plus MTX at 2 years vs 25% treated with MTX alone Nearly twice as many patients on HUMIRA plus MTX had no radiographic progression (ΔTSS≤ 0.5) at 2 years, vs MTX alone (61% vs 34%, respectively) Five times greater inhibition of radiographic progression at 2 years with HUMIRA + MTX vs MTX alone Greater inhibition of radiographic progression with HUMIRA + MTX vs MTX alone at every level of clinical response (nonresponders; ACR20; ACR50; ACR70) at 6 months and 2 years In MTX-naïve subjects with recent onset moderate to severe RA in the PREMIER trial, overall rates of AEs were comparable in each treatment arm Safety profile in PREMIER consistent with other HUMIRA RA clinical trials Please see Important Safety Information at the end of the presentation. Serious and sometimes fatal side effects have been reported with HUMIRA, including TB and other serious infections PREMIER Adapted from Breedveld FC, et al. Arthritis Rheum . 2006;54(1):26-37 Emery P, et al. Presented at: Annual Meeting of the European League Against Rheumatism; June 21-24, 2006; Amsterdam, The Netherlands. Abstract OP0113. Data on file, Abbott Laboratories

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Rituximab - FDA-approved for lymphoma in 1997 Abatacept Status of Newer Biologics - FDA-approved February, 2006 for - patients with moderately severe RA - inadequate response to > 1 DMARDs - use in combination with MTX UPDATE UPDATE - FDA-approved December, 2005 for - patients with moderately severe RA - inadequate response to > 1 DMARDs - use as monotherapy or with DMARDs other than TNF antagonists or anakinra

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Abatacept modulates the immune response by binding to CD80/CD86 on an antigen-presenting cell (APC), such as a dendritic cell, thus preventing costimulatory binding of CD28 on naive T cells and attenuating T-cell activation. Abatacept: Mechanism of Action

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ATTAIN A batacept T rial in the T reatment of A nti-TNF IN adequate (RA) Responders 391 patients (randomized 2:1 to abatacept:placebo) Abatacept fixed doses (~10 mg/kg) 500-750-1000 mg All patients on ≥ 1 additional DMARD (78% MTX)

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ATTAIN Trial: 6-month Data Genovese MC, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor  inhibition. N Engl J Med . 2005; 353:1114-1123. ACR 20, ACR 50, ACR 70 Responses

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ATTAIN Trial: 6-month Data DAS28 Remissions and "Low Disease Activity" Genovese MC, et al. Abatacept for rheumatoid arthritis refractory to tumor necrosis factor  inhibition. N Engl J Med . 2005; 353:1114-1123.