Rheumatoid arthritis (RA) is a debilitating chronic immune mediated inflammatory disease which affects 1% of the European population. RA is associated with significant joint damage, disability and an enhanced mortality. Current treatment strategies target patients once synovitis has been present for several months and it is clear that the patient has developed persistent disease. After the first 3 months of symptoms, we and others have shown that the persistence of chronic inflammation in the rheumatoid synovium is driven by hyperplastic stromal tissue which inhibits leukocyte apoptosis leading to the accumulation of inflammatory cells in the joint. Therapies at this stage of disease, with conventional disease modifying anti-rheumatic drugs (DMARDs) as well as drugs targeting TNF-alpha reduce disease activity but are unable to cure RA. We have now identified that the very early phase of synovitis in patients destined to develop RA (within the first 12 weeks of symptoms) represents a pathologically distinct phase of disease. This suggests that late disease is not just more of early disease and gives, for the first time, a clear rationale for very early intervention. Building on these recent observations, we propose to test the hypothesis that the disease processes in the very early stages of RA are fundamentally different to those in established chronic disease. This will be done by assessing whether treatment during this phase with the well-established gold standard modality of anti-TNF-alpha therapy and methotrexate can permanently switch off inflammation, preventing the development of RA and thereby effecting a cure of the disease.

Inclusion Criteria:

• Age over 18 years
• Synovial swelling of at least 1 joint confirmed by clinical assessment
• Duration of symptoms attributable to inflammatory joint disease (pain, swelling or early morning stiffness of >1 hour) of < 12 weeks.
• Seropositivity for RF and anti-CCP Ab
• Women of childbearing potential or men capable of fathering children must be using adequate birth control measures (eg, abstinence, oral contraceptives, intrauterine device, barrier method with spermicide, surgical sterilization) during the study.
• Female subjects of childbearing potential must test negative for pregnancy

Exclusion Criteria:

• Previous history of inflammatory arthritis.
• Previous use of DMARDs or anti-TNF-agents.
• Any current inflammatory condition with signs or symptoms that might confound the diagnosis (e.g. connective tissue disorders).
• Clinical evidence of latent or active granulomatous infection, including TB, histoplasmosis, or coccidioidomycosis, prior to study entry.
• Administration, or expected administration, of any live virus or bacterial vaccination within 3 months before the first administration of study agent, or during the trial.
• A history of an infected joint prosthesis, or administration of antibiotics for a suspected infection of a joint prosthesis, if that prosthesis has not been removed or replaced.
• Known infection with HIV, hepatitis B, or hepatitis C.
• A serious infection that in the opinion of the investigator precludes receipt of a TNF blocking agent.
• Serious and uncontrolled co-existing disease that in the opinion of the investigator preclude the use of TNF-blocking medication, methotrexate or depomedrone (including pulmonary disease on chest radiograph, congestive cardiac failure (NYHA grade 3 or 4), history of demyelinating disease such as multiple sclerosis or optic neuritis).
• Bleeding disorder of the use of anti-coagulants
• Any known malignancy or a history of malignancy within the previous 5 years (with the exception of a basal cell carcinoma that has been treated with no evidence of recurrence).
• Any other contraindication to etanercept, methotrexate or parenteral depomedrone.
• Patients will also be excluded with the following laboratory results: haemoglobin <8.5 gm/dl, total white cell count <3.5 x 109/litre, serum transaminase value more than twice the upper limit of normal, and serum creatinine >150 micromoles/litre.