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.