Leflunomide Versus Sulfasalazine/Methotrexate in Rheumatoid Arthritis:an Ultrasound/Magnetic Resonance Imaging Study

1. Male and female patients aged between 21 and 65 years.
2. Patients with no childbearing potential (For example postmenopausal or sterilised) or have decided not to have offspring(s).
3. All female patients must consent not to get pregnant/breastfeed, male patients must consent not to father a child and all must consent to practice effective birth control.
4. Fulfills either the 1987 ACR criteria and/or the 2010 ACR / EULAR RA Classification Criteria.
5. Seropositivity: Rheumatoid factor (RF) and/or anti -cyclic citrullinated protein antibodies (anti-CCP) must be positive.
6. MCPJ(s) and/or Wrist(s) joint(s) involvement.
7. Rheumatoid arthritis patients (less than 5 years duration) who remain at least moderately active based on DAS28 score of > 3.2, following 3 months of therapy with an optimal dose of methotrexate(e.g. at least 15 mg/week).
8. If patient is on oral corticosteroids, this should not exceeding 10mg prednisolone daily (or oral steroid equivalent) for at least 4 weeks and should be at an unchanged dose for at least 2 weeks before entering study.
9. If patient is on NSAIDs, this should be at an unchanged dose for at least 2 weeks before entering study.
10. Glomerular filtration rate > 60 mls/min/1.73m2.

Exclusion Criteria

1. Patient known to have the following medical condition(s) will be excluded:

   1. Other autoimmune disease /inflammatory joint disease/connective tissue disease ( e.g. lupus, seronegative spondylarthropathy (e.g. ankylosing spondylitis/psoriatic arthropathy ), reactive arthritis, overlap syndrome, primary sjogren syndrome and mixed connective tissue disease.)
   2. Inflammatory arthritis with onset before 18 years old.
   3. Current or previous history of cancer or lymphoproliferative disease.
   4. HIV positive status, Hepatitis B/C positive status.
   5. Persistent and/or severe infection in the previous 12 weeks.
   6. Major traumatic injury, terminal illness, or other medical condition(s)that could place the patient at risk to participate in the study.
   7. Clinically relevant cardiovascular (e.g unstable ischemic heart disease), neurological (e.g recent stroke), gastroenterology (e.g active peptic ulcer disease), renal (e.g chronic renal failure), hepatic (e.g alcoholic liver disease, fatty liver) and any other major systemic disease that could i) place the patient at risk to participate in the study; or ii) make protocol implementation difficult; or iii) make study results interpretation difficult.
   8. Presence of any known condition(s)/circumstance(s) which would negatively impact compliance or study completion.

2. Impaired laboratory parameters:

   1. Hemoglobin less than 10.5 g/dl, white blood count less than 4 x 10 (9)/L , platelet count less than 150 x 10(9)/L.
   2. Deranged Liver function test: e.g. elevated AST/ALT.
3. Wants to consume alcohol while taking the study medications.
4. Body weight that is less than 45 kg.
5. Pregnancy/Breastfeeding/Male patient wishing to father children.

6. Patients with the following medication history will be excluded:

   1. History of Glucose 6 Phosphate Dehydrogenase (G6PD) deficiency.
   2. Known allergy to: i) study medications; or ii) contrast; or iii) drugs whose chemical structures are similar (e.g. sulphonamides, salicylates, etc).
   3. On anticoagulation for any reasons.
   4. Previous treatment (within the last 4 weeks) with: i) oral corticosteroid greater than prednisolone equivalent of 10mg/day; or ii) parenteral/intra-articular corticosteroid injection.
   5. Previous treatment (within the last 12 weeks) with: i) other DMARDs such as sulfasalazine,hydroxychloroquine,chloroquine,gold salts, etc; or ii) investigational drug(s); or iii) other immunosuppressive agents such as cyclophosphamide,cyclosporin,azathioprine and any biologic agents, e.g. anti-TNF.
   6. Previous treatment(any duration) with i) Leflunomide; or ii) Sulfasalazine used together with methotrexate
7. Contraindication to MRI (e.g. pacemakers, metallic implants/stents, claustrophobia).