Challenges & OpportunitiesChallenges & Opportunitiesin the Treatment of RAin the Treatment of RA

Lawrence A Jacobs, MDLawrence A Jacobs, MDJune 19, 2009June 19, 2009

Rheumatology AssociatesRheumatology AssociatesTulsa, OklahomaTulsa, Oklahoma

Why Early Diagnosis & Treatment?Why Early Diagnosis & Treatment?

Clinical Spectrum of RAClinical Spectrum of RAClinical Spectrum of RAClinical Spectrum of RA

Images courtesy of J. Cush, 2002.Images courtesy of J. Cush, 2002.

Joint Erosions Occur Early in RAJoint Erosions Occur Early in RA

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1010

2020

3030

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Up to 93% of patients with 2 years of RA may have radiographic abnormalities

Rate of progression is significantly more rapid in the first year than in the second and third years

Radiographic changes in the feet are important indicators of disease progression in RA

Up to 93% of patients with 2 years of RA may have radiographic abnormalities

Rate of progression is significantly more rapid in the first year than in the second and third years

Radiographic changes in the feet are important indicators of disease progression in RA

MTP

Total

Hand

MTP

Total

Hand

van der Heijde DM et al. J Rheumatol. 1995;22:1792–1796;Fuchs HA et al. J Rheumatol. 1989;16:585–591; McQueen FM, et al. Ann Rheum Dis. 1998;57:350–356.

van der Heijde DM et al. J Rheumatol. 1995;22:1792–1796;Fuchs HA et al. J Rheumatol. 1989;16:585–591; McQueen FM, et al. Ann Rheum Dis. 1998;57:350–356.

YearYear

% o

f J

oin

ts A

ffec

ted

%

of

Jo

ints

Aff

ecte

d

Four of Seven Criteria RequiredFour of Seven Criteria Required

Morning Stiffness lasting 1 Hour or moreMorning Stiffness lasting 1 Hour or more Sort tissue swelling (Synovitis) of 3 or Sort tissue swelling (Synovitis) of 3 or

more joints X 6 weeksmore joints X 6 weeks Swelling of PIP, MCP or Wrist Joints X 6 Swelling of PIP, MCP or Wrist Joints X 6

weeksweeks Symmetrical arthritis X 6 WeeksSymmetrical arthritis X 6 Weeks Subcutaneous Nodules (Vasculitis)Subcutaneous Nodules (Vasculitis) Positive Rheumatoid Factor or CCPPositive Rheumatoid Factor or CCP Radiographic Erosions or periarticular Radiographic Erosions or periarticular

osteopeniaosteopenia

Biologic DMARDs Biologic DMARDs

Efficacy: Signs and Symptoms of DiseaseEfficacy: Signs and Symptoms of Disease

Etanercept + MTX: ACR Response Rates at 24 Weeks

Etanercept + MTX: ACR Response Rates at 24 Weeks

*P 0.001; †P 0.05Weinblatt ME, et al. N Engl J Med. 1999;340:253–259.*P 0.001; †P 0.05Weinblatt ME, et al. N Engl J Med. 1999;340:253–259.

00

1010

2020

3030

4040

5050

6060

7070

8080

ACR-20ACR-20 ACR-50ACR-50 ACR-70ACR-70

% o

f P

atie

nts

% o

f P

atie

nts

*71*

71

2727

*39*

39

33

†15†

15

00

Etanercept 25 mg + MTX

Placebo + MTX

Etanercept 25 mg + MTX

Placebo + MTX

Adalimumab + MTX (ARMADA):ACR Response Rates at 24 and 52 Weeks

Adalimumab + MTX (ARMADA):ACR Response Rates at 24 and 52 Weeks

*P ≤ 0.001ARMADA = Anti-TNF Research Program of the Monoclonal Antibody D2E7 [adalimumab] in Rheumatoid Arthritis StudyWeinblatt ME, et al. Arthritis Rheum. 2003;48:35–45; Data on file; Abbott Laboratories.

*P ≤ 0.001ARMADA = Anti-TNF Research Program of the Monoclonal Antibody D2E7 [adalimumab] in Rheumatoid Arthritis StudyWeinblatt ME, et al. Arthritis Rheum. 2003;48:35–45; Data on file; Abbott Laboratories.

Placebo + MTX

Adalimumab 40 mg EOW + MTX

Placebo + MTX

Adalimumab 40 mg EOW + MTX

1515 88

55

*66*

66

*54*

54

*27*

27

00

1010

2020

3030

4040

5050

6060

7070

ACR-20

ACR-20

ACR-50ACR-50 ACR-70

ACR-70

% o

f P

atie

nts

% o

f P

atie

nts

7070

4949

2525

24 Weeks (Double Blind)

24 Weeks (Double Blind)

52 Weeks (Open Label Extension)

52 Weeks (Open Label Extension)

ACR-20

ACR-20

ACR-50ACR-50 ACR-70

ACR-70

Adalimumab + MTX: Sustained Efficacy Over 5 YearsAdalimumab + MTX: Sustained Efficacy Over 5 Years

Breedveld FC, et al. Arthritis Rheum. 2003;48(Suppl):S118 [Abstract 198].Breedveld FC, et al. Arthritis Rheum. 2003;48(Suppl):S118 [Abstract 198].

MonthsMonths

ACR-20

ACR-50

ACR-70

ACR-20

ACR-50

ACR-70

% o

f P

atie

nts

% o

f P

atie

nts

(n = 53) (n = 53) (n = 36)(n = 36)

68686262

7575

6363

7777

30303636

5050 50504646

88 1111

28282424 2222

00

1010

2020

3030

4040

5050

6060

7070

8080

1212 2424 3636 4848 6060

Biologic DMARDs

Efficacy: Patients With Early RA

Biologic DMARDs

Efficacy: Patients With Early RA

Etanercept in Early RA: HAQ-DI Scores at 24 Months

Etanercept in Early RA: HAQ-DI Scores at 24 Months

≥ 0.5 Improvement≥ 0.5 Improvement ≥ 1.0 Improvement≥ 1.0 Improvement%

of

Pat

ien

ts%

of

Pat

ien

ts

00

1010

2020

3030

4040

5050

6060

3737

*55*

55

25252929

Etanercept25 mg

Etanercept25 mg

MTX20 mgMTX

20 mgEtanerce

pt25 mg

Etanercept

25 mg

MTX20 mgMTX

20 mg

7070

*P 0.001Genovese MC, et al. Arthritis Rheum. 2002;46:1443–1450.*P 0.001Genovese MC, et al. Arthritis Rheum. 2002;46:1443–1450.

Safety Considerations With Biologic DMARDsSafety Considerations With Biologic DMARDs

Serious infections

Opportunistic infections (TB)

Malignancies

Demyelination

Hematologic abnormalities

Administration reactions

Congestive heart failure

Autoantibodies and lupus

Serious infections

Opportunistic infections (TB)

Malignancies

Demyelination

Hematologic abnormalities

Administration reactions

Congestive heart failure

Autoantibodies and lupus

TEMPO: Infections and Serious Infections Etanercept + Methotrexate (at 52 Weeks)

TEMPO: Infections and Serious Infections Etanercept + Methotrexate (at 52 Weeks)

Number of Number of patientspatients

MTXMTX(n = 228)(n = 228)

Etanercept Etanercept (n = 223)(n = 223)

MTX + MTX + Etanercept Etanercept (n = 231)(n = 231) PP value* value*

Any Any infectioninfection††

148148(64.9%)(64.9%)

134134(60.1%)(60.1%)

158158(68.4%)(68.4%)

0.190.19

Serious Serious infectionsinfections

1010(4.4%)(4.4%)

1010(4.5%)(4.5%)

1010(4.3%)(4.3%)

1.001.00

*Fisher exact test; †No incidence of tuberculosis was noted in any treatment group. Klareskog L. Data presented at EULAR. Lisbon, Portugal, June 2003.*Fisher exact test; †No incidence of tuberculosis was noted in any treatment group. Klareskog L. Data presented at EULAR. Lisbon, Portugal, June 2003.

Infliximab: Postmarketing Infliximab: Postmarketing Reports of TuberculosisReports of Tuberculosis

Infliximab: Postmarketing Infliximab: Postmarketing Reports of TuberculosisReports of Tuberculosis

277 cases of active TB

All cases were within 6 months of treatment United States: 86 cases

55 cases in patients with RA 18 cases in patients with Crohn’s disease 13 cases in patients with unspecified disease 0.2 cases/1000 pt-years

European Union: 191 cases 1.4 cases/1000 pt-years

277 cases of active TB

All cases were within 6 months of treatment United States: 86 cases

55 cases in patients with RA 18 cases in patients with Crohn’s disease 13 cases in patients with unspecified disease 0.2 cases/1000 pt-years

European Union: 191 cases 1.4 cases/1000 pt-years

FDA Arthritis Advisory Committee meeting. March 4, 2003.FDA Arthritis Advisory Committee meeting. March 4, 2003.

August 2002August 2002August 2002August 2002

Etanercept: Malignancies and LymphomasEtanercept: Malignancies and Lymphomas

RA Clinical Trials

Patients 1272

Patient-years of follow-up 3806

Expected malignancies* 35

Observed malignancies 35

Malignancy SIR 1.0

Observed lymphomas 9

Lymphoma SIR 3.5

RA Clinical Trials

Patients 1272

Patient-years of follow-up 3806

Expected malignancies* 35

Observed malignancies 35

Malignancy SIR 1.0

Observed lymphomas 9

Lymphoma SIR 3.5*NCI (SEER), 2001, adjusted for age, gender distribution; SIR = standardized incidence ratioMoreland LW. Arthritis Rheum. 2002;46(suppl):S533. Abstract 427. Briefing document, FDA Arthritis Advisory Committee meeting. March 4, 2003.

*NCI (SEER), 2001, adjusted for age, gender distribution; SIR = standardized incidence ratioMoreland LW. Arthritis Rheum. 2002;46(suppl):S533. Abstract 427. Briefing document, FDA Arthritis Advisory Committee meeting. March 4, 2003.

Patients Patients With Disease With RACrohn’s

Patients 12981106

Patient-years of follow-up 24581646

Expected non-lymphoma malignancies* 17 10

Malignancy SIR 0.92.1

Observed lymphomas 4 2

Lymphoma SIR 6.48.7

Patients Patients With Disease With RACrohn’s

Patients 12981106

Patient-years of follow-up 24581646

Expected non-lymphoma malignancies* 17 10

Malignancy SIR 0.92.1

Observed lymphomas 4 2

Lymphoma SIR 6.48.7

Infliximab: Malignancies and LymphomasInfliximab: Malignancies and Lymphomas

*NCI (SEER), 2000, adjusted for age, sex distribution; SIR = standardized incidence ratioBriefing document, FDA Arthritis Advisory Committee meeting. March 4,2003.*NCI (SEER), 2000, adjusted for age, sex distribution; SIR = standardized incidence ratioBriefing document, FDA Arthritis Advisory Committee meeting. March 4,2003.