The main aim of the study is to determine whether TNFi instituted as first-line therapy in early RA confers better outcomes (clinical, structural and immunological) compared to delayed TNFi start; implying particular dominance of TNF in early disease, a changing role of TNF with disease duration and hence, confirmation of a biological window of opportunity.

Inclusion Criteria:

• Male and female patients aged between 18 and 80 years.
• Diagnosis of rheumatoid arthritis (new 2010 ACR/EULAR RA classification criteria).
• Symptom onset within the preceding 12 months.
• Patients with active RA at baseline: clinical evidence of synovitis (or imaging evidence of synovitis in cases of uncertainty/subclinical disease) in hand and/or wrist joints evaluable by ultrasound and MRI, and DAS28-ESR>3.2.
• Seropositivity for anti-citrullinated peptide antibody (ACPA) and/or rheumatoid factor. If ACPA and rheumatoid factor are both negative, presence of power Doppler in at least 1 joint on ultrasound imaging.
• DMARD-naive (with the exception of previous exposure to hydroxychloroquine for an indication other than RA).
• All male and female subjects biologically capable of having children must agree to use a reliable method of contraception for the duration of the study and 24 weeks after the end of the study period. Acceptable methods of contraception are surgical sterilisation, oral, implantable or injectable hormonal methods, intrauterine devices or barrier contraceptives.

Exclusion Criteria:

• Previous treatment with DMARDs for the management of RA.

• Intramuscular or intra-articular (of non-target joint) corticosteroid within 28 days of the screening visit; intra-articular steroid of the chosen target joint within 12 weeks of screening.

• Oral steroid of greater than 10mg prednisolone daily, or change in oral steroid dose within 28 days of study drug initiation at the baseline visit.

• Use (including use as required) of more than one NSAID, change in NSAID or change in dose of NSAID within 28 days of the baseline visit.

• Contraindications to MRI (e.g. pacemaker) or unable or unwilling to attend for all imaging assessments. In patients with previous penetrating trauma to the eye, or patients at high risk of previous metal foreign body injury to the eye (e.g. welding), skull x-ray will be performed; these patients may be included in the absence of residual metal fragments on x-ray.

• Pregnancy or breastfeeding.

• Other contraindications to TNFi as determined by local prescribing guidelines and physician discretion, including:

  • Active infection, open leg ulcers, previously infected prosthetic joint (unless completely removed), septic arthritis in last year, HIV, Hepatitis B or Hepatitis C carriers, previous malignancy within 10 years (except basal cell carcinoma), severe heart failure (New York Heart Association grade 3 or more), any history of demyelinating disease, uncontrolled diabetes, pulmonary fibrosis, bronchiectasis, previous PUVA therapy (of >1000 Joules), history of TB or evidence of latent TB on chest x-ray/TB testing (in the latter event, a patient may be included if treated with isoniazid and pyridoxine one month before starting the study and for a further 6 months whilst on study treatments).

• History of other significant medical conditions, including:

  • Severe pulmonary disease, defined as requiring previous hospital admission or supplemental oxygen.
  • Active or severe cardiovascular disease: uncontrolled hypertension, myocardial infarction within 12 months of screening, unstable angina within 6 months of screening.
  • Other immunodeficiency disorders.
  • Connective tissue diseases, e.g. primary Sjogren's syndrome, systemic sclerosis, systemic lupus erythematosus, polymyositis.
  • Psoriasis.
  • Renal impairment (creatinine ≥ 175µmol/L).
  • Blood disorders: neutropenia (neutrophils < 2.0 x 109/L), thrombocytopenia (platelets < 125 x 109/L), or anaemia (haemoglobin < 8 g/dL).
  • Abnormal liver function (alanine transaminase, ALT > 3 x upper limit of normal).

• Planned surgery within the study period which is expected to require omission of any study medication of 28 days or more.