Efficacy of Methotrexate and/or Etanercept for treatment of RA

Rheumatoid Arthritis:

Rheumatoid Arthritis

• RA has an incredibly high disease burden and cost to society

• Drastic affect on quality of life• Increased disability (80% disabled after 20

years of disease)• Patients with RA have shorter life

expectancies • It is important to initiate therapy early so

as to halt/slow disease progression

Pathogenesis

• Exact mechanism unknown

• Most likely related to acute and chronic inflammation in the synovium in addition to a proliferate and destructive process of joint tissues

Treatment Options

• Methotrexate has been one of the mainstays of RA treatment– Action: Inhibits dihydrofolate reductase

• Over the past few years newer biologic disease modifying anti-rheumatic drugs have been developed

• These drugs target select aspects of the immune response so as to decrease inflammation

Etanercept

• Recombinant fusion protein of the TNF (tumor necrosis factor) receptor that is solubilized by linking to the Fc portion of human IgG1

• Inhibits TNF: cytokine produced primarily by macrophages

• Administered by subcutaneous injection twice weekly

• Extremely expensive

TNF

RF Autoantibodies

Activates

ActivatesActivates

Inflammation Joint damage

B B

T

T T

T

FLS

PC

PC

FLS

MΦ MΦ

T T

APC/DC

Mechanism of Etanercept

EtanerceptX

Clinical Question

• Is Etanercept superior to MTX when used as a monotherapy for early RA?

• Is combination therapy consisting of both MTX and Etanercept superior to either MTX or Etanercept alone?

ACR Response Criteria

≥ 20% / 50% / 70% Improvement in:

• Number of swollen joints (SJC)

• Number of tender joints (TJC)

• Improvement of at least three of the following:

• Patient Global Assessment

• Physician Global Assessment

• Patient Pain Scale

• Health Assessment Questionnaire (HAQ)

• ESR or CRP

Felson DT et al. Arthritis Rheum. 1993; 41: 1564-1570

ERA (Early rheumatoid arthritis trial)

Tempo Trial

MTX

Klareskog et al. Lancet. 2004;363:675

COMET – combo vs monotherapyACR Score

0

20

40

60

80

100

AR20 ACR50 ACR70

Pro

po

rtio

n o

f p

ati

en

ts (

%)

Methotrexate

Etanercept +Methotrexate

86

71

48

67

49

28

Emery et al. Lancet 2008; 372: 375–82

Negatives / Side effects

• Entanercept – Injection site infections– Good safety profile for the most part – rare events

resulting from immunosuppression (TB, opportunistic infections, URIs), slightly increased risk of lymphoma and CHF, drug induced lupus

• MTX – Pneumonitis,hepatic toxicity, anemia,

thrombocytopenia, leukopenia, slightly increased risk of lymphoma, alopecia, mouth ulcers, N/V

- Frequent laboratory testing needed. (3-6 times a year) Requires folic acid supplementation.

Conclusions• Patients on Etanercept vs MTX monotherapy experience

a small but statistically significant improvement in ACR 20,50,70 at 1 year. Etanercept reduced disease activity, arrested structural damage, and decreased disability more effectively then MTX.

• Etanercept has been shown to be a safe therapy which actually has a slightly lower serious infection rate then MTX.

• Combination therapy is substantially more effective in achieving all ACR levels then either therapy alone and should be used without hesitation in severe cases of RA.

• Combination therapy results in no increase in serious infection rates over MTX alone.