Efficacy of Methotrexate and/or Etanercept for treatment of RARheumatoid Arthritis:

Rheumatoid ArthritisRA has an incredibly high disease burden and cost to societyDrastic affect on quality of lifeIncreased 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

PathogenesisExact 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 OptionsMethotrexate has been one of the mainstays of RA treatmentAction: Inhibits dihydrofolate reductaseOver the past few years newer biologic disease modifying anti-rheumatic drugs have been developedThese drugs target select aspects of the immune response so as to decrease inflammation

EtanerceptRecombinant 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

TNFaRF AutoantibodiesActivatesActivatesActivatesInflammation Joint damageBBTTTTFLSPCPCFLSMMTTAPC/DCMechanism of Etanercept EtanerceptX

Clinical QuestionIs 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 CRPFelson DT et al. Arthritis Rheum. 1993; 41: 1564-1570

ERA (Early rheumatoid arthritis trial)

Tempo TrialMTXKlareskog et al. Lancet. 2004;363:675

COMET combo vs monotherapy867148674928Emery et al. Lancet 2008; 372: 37582

Negatives / Side effects

Entanercept Injection site infectionsGood 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/VFrequent laboratory testing needed. (3-6 times a year) Requires folic acid supplementation.

ConclusionsPatients 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.

Top Left Early RABottom Left Late RARight characteristic hand findings.Radiograph showing erosions of the distal ulna.Image depicting Etanercept Inhibiting TNFAPC: antigen presenting cellDC: dendritic cellT: T cellB: B cellPC: plasma cellFLS: Fibroblast-like synoviocyteM: macrophageThe ACR (American College of Rheumatology) Response Criteria.A method for measuring response to RA therapy.Above graph: 1 year data. Etanercept 25 mg vs. MTX 20 mgACR 20% MTX 65% ETAN 72%

Bathon JM et al. N Engl J Med. 2000;343:1586-1593.Study: A comparison of etanercept and MTX in patients with early RA. Design: 12 month trial of 632 patients. Randomly assigned to either etanercept (10 or 25 mg) or MTX (20 mg). The patients were blinded by receiving either etanercept injections and placebo pills or placebo injections and MTX pills.Patients: all had RA diagnosis for no more then 3 years and were required to have active disease and had never been treated with MTX.Outcome pertinent to my clinical question: ACR scores on etanercept vs. MTX. The above graph is for etanercept at 25 mg. The MTX dose was titrated up over the initial weeks of the study to 20 mg per week. All patients received folate supplementation.Results: The 25 mg etanercept group had superior clinical responses as well as a more rapid rate of improvement. They also had a higher likelihood of achieving ACR 20,50,70 responses. The etanercept 10 mg group did not outperform MTX.Approximately the same number of patients withdrew from each arm of the study. The final numbers of patients were MTX (20 mg) 169, Etan (10 mg) 166, Etan (25 mg) 177 Serious adverse outcomes: Slightly better in the Etanercept group.

Overall: This study demonstrates that there is a small but significant superiority in etanercept monotherapy vs. MTX montherapy.

1 year dataKlareskog et al. Lancet. 2004;363:675.

Study: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized controlled trial. Klareskog et al. Lancet. 2004;363:675.Design: 686 patients were randomly allocated to treatment with etanercept 25 mg (subcutaneously twice a week), oral methotrexate (up to 20 mg every week), or the combination. Patients: To be eligible patients had to have had a poor response to at least 1 DMARD other then MTX and a disease duration between 6-20 months. They also had to have active rheumatoid arthritis.Outcome pertinent to my clinical question: Measured by the ACR criteria.Results: Single agent therapy. For ACR50 and ACR70, monotherapy with Etan vs. MTX was superior by a statistically significant margin. The combination therapy was substantially superior to either monotherapy for all ACR measures.The final number of patients in each arm of the study was MTX 159, Etan 170, Combo 193.Serious adverse outcomes: similar in all groups. Overall: The findings of this trial show that for etanercept is slightly more effective then MTX as a monotherapy and that combination therapy is substantially more effective then either therapy alone. It should be taken into account that patients in this trial had to have had an unsatisfactory response to one DMARD other then MTX before they were eligible. Thus these results do not have the same external validity as the other two studies to people who have not yet undergone DMARD therapy for RA. Despite this, the study still demonstrates the high eficacy of combination therapy.1 year dataEmery et al. Lancet 2008; 372: 37582

Study: Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheummtoid arthritis (COMET)Design: 12 month trial of 542 patients treated with either MTX alone (titrated up to 20 mg per week) or MTX with etanercept (50 mg per week).Patients: Disease duration 3-24 months, active disease, the patients had to never have received MTX or etanercept or any other TNF alpha antagonist, nor received any DMARDS or steroids for four weeks before starting the study.Outcome pertinent to my clinical question: Measured by the ACR criteria.Results: The combo was substantially superior to MTX alone. Remission achieved in 50% vs 28% at one year.The final number of patients in each arm of the study was MTX 159, Etan 170, Combo 193.Serious adverse outcomes: similar in both groups.

Overall: This trial showed the superior efficacy of combination therapy to MTX alone.