Targeting Synovitis in Early Rheumatoid Arthritis
Targeting Synovitis in Early Rheumatoid Arthritis
Patients with rheumatoid arthritis are at risk of developing permanent joint damage and
 disability. This study hopes to identify the most effective way of using existing arthritis
 medication to minimise the chances of developing permanent disability. Patients will have
 their arthritis activity assessed using an ultrasound machine. If there is still evidence of
 active arthritis the participant's arthritis medication will be increased until the arthritis
 is in remission. The effectiveness of this approach will be compared to the traditional
 method of assessing arthritis using clinical examination.

 Furthermore, it is extremely important to identify those patients most at risk of aggressive
 disease. The investigators hope to produce a more accurate measurement of disease prognosis
 by examining the relationship between a series of blood tests and how well controlled
 rheumatoid arthritis appears after 18 months of therapy. Some patients will also be asked to
 donate samples of joint fluid and joint lining for additional analysis.
PURPOSE 1 - to determine whether it is possible to achieve better control of inflammatory
 joint disease activity in early rheumatoid arthritis by using musculoskeletal ultrasound,
 instead of clinical examination, to identify the presence, or absence, of synovitis

 NULL HYPOTHESIS 1 - using musculoskeletal ultrasound to confirm / refute the presence of
 ongoing synovitis will NOT allow better control of early rheumatoid arthritis nor prevent
 progression of destructive joint disease despite patients receiving more intensive disease
 modifying therapy regimens

 PURPOSE 2 - to determine whether baseline measures of certain biochemical and pathological
 factors, associated with the development of inflammatory synovitis, are predictive of
 response to therapy in early rheumatoid arthritis and short term outcome measures of
 inflammatory joint disease activity, functional ability and quality of life

 NULL HYPOTHESIS 2 - serial measures of biochemical and pathological factors, associated with
 the development of inflammatory synovitis, will NOT correlate with short term outcome
 measures of disease activity and therefore cannot be used to predict a patient's prognosis
 nor identify those at risk of progressive, destructive joint disease

 TRIAL DESIGN - randomised, prospective single blinded trial of treatment strategy with a
 nested study correlating baseline measures and 18 month outcomes

 Investigators will not be blinded to treatment group. Treatment decisions and escalation of
 therapy will be dictated by a standardised protocol. The sequence of therapy escalation will
 be identical for both groups. The groups will differ on the threshold needed to progress to
 the next treatment step

 Assessors of disease activity, radiological and pathological outcomes will be blinded to
 treatment group and their findings will form the basis of each groups final outcome measures

 TREATMENT PROTOCOL - the sequence of therapy escalation will be the same for each group. The
 groups differ by the 'trigger' required to progress to the next treatment step. Therapy will
 escalated in each group if the measured disease activity exceeds that groups threshold
 trigger. Changes in DMARD therapy doses and/or combinations take three months to reach
 maximum effect; therefore, at least a three month gap will be left between each treatment
 escalation

 PRIMARY OUTCOME MEASURE

 1. Magnetic Resonance Imaging of Dominant Wrist - baseline and 18 months. Images will be
 scored using the OMERACT RAMRIS(Rheumatoid Arthritis Magnetic Resonance Imaging Score)
 atlas. The change in each patient's synovitis and erosion scores will be pooled and
 compared for each intervention group

 2. 44 joint Disease Activity Score - Mean change of DAS44 with time will represent the rate
 of response to treatment. Mean area under curve DAS44 will represent overall level of
 disease activity throughout the study period

 SECONDARY OUTCOME MEASURES

 1. European League Against Rheumatism Response Rates - A EULAR Good response is defined as
 a greater than 1.2 change in DAS44 and a final DAS44 less than 2.4. Disease remission is
 defined as DAS44 less than 1.6

 2. Functional Measures - Health Assessment Questionnaire and EuroQoL-5D questionnaires at
 enrollment and then every 3 months.

 3. Plain Xrays - plain xrays of hands, wrists and feet at baseline and 18 months. Change in
 Sharp score between baseline and 18 month films will be reported

 4. Biomarker analysis - analyses will include specific genetic factors(genomic DNA), gene
 expression (RNA analysis), novel autoantibody assays, cytokine / emerging inflammatory
 protein profiling, lipid / lipoprotein based markers, metabolic assays and assessment of
 bone and cartilage turnover markers.

 Samples will be collected at baseline, 3 months and 12 months (if not commenced on
 etanercept), immediately before commencing etanercept, 3 months and 6 months after commencing
 etanercept and 3 months after cessation. Final disease outcome measures for each patient will
 be correlated with baseline biomarker values to determine if any predictive relationships
 exist.

 All values will be entered into a logistical regression analysis to try and create a
 statistical predictive model. Serial biomarker analyses will demonstrate how the different
 components of the pathogenetic process respond to the different stages of DMARD therapy.
Inclusion Criteria:

 1. Patients attending Early RA clinics with newly diagnosed RA or anti-CCP +ve
 Undifferentiated Arthritis (UA)

 2. Active disease (DAS28 > 3.2)

 3. DMARD naïve or DMARD monotherapy for less than 6 weeks

 4. Aged 18 or more

 Exclusion Criteria:

 1. Significant liver disease and/or abnormality of liver function tests

 2. AST / ALT > x2 normal, Alkaline Phosphatase > x2.5 normal

 3. Renal impairment - serum creatinine > 200 μmol/l, eGFR < 30

 4. Cytopenias - white cell count < 4.0, haemoglobin < 10, platelet < 150

 5. Pregnancy or planned pregnancy

 6. Contraindication to MRI

 7. Other co-morbid condition that in the opinion of the investigator would preclude the
 use of sequential or combination DMARD therapy