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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)
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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
Mechanism of Etanercept PC RF Autoantibodies B PC B Activates Inflammation Joint damage Activates T T T T FLS FLS T APC/DC T Etanercept Activates X TNFa MΦ MΦ
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
Tempo Trial MTX Klareskog et al. Lancet. 2004;363:675
COMET – combo vs monotherapy 86 71 67 49 48 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.