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 Inflammation Joint damage B B T T T T FLS PC FLS MΦMΦMΦMΦ T T APC/DC Mechanism of Etanercept Etanercept X

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:

ERA (Early rheumatoid arthritis trial)

Tempo Trial MTX Klareskog et al. Lancet. 2004;363:675

COMET – combo vs monotherapy 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.