Arthritis Prevention In the Pre-clinical Phase of RA with Abatacept.

Rheumatoid arthritis is a common chronic inflammatory immune-mediated disease
of joints. If not adequately treated the condition leads to destruction of
synovial joints and significant disability. RA is costly to individuals and
their families; one third of patients with arthritis stop work within 2 years
of onset because of their disease.

The introduction of therapeutic strategies that focus on early, intensive
treatment with synthetic and biological disease modifying anti-rheumatic drugs
(DMARDs) has transformed the treatment of RA. Clinical trials have
demonstrated that this approach leads to higher proportions of patients
achieving periods of sustained clinical remission. This is associated with
improved function and slowing or even prevention of joint damage over time.
Indeed, intensive *treat-to-target* strategies in patients with very early RA
can subsequently lead to extended periods of drug free remission in a subset of
patients. If the pre-clinical phase of disease could be defined with accuracy,
targeting therapy to those at highest risk of developing the more severe form
of disease would have the potential to prevent or at the very least delay the
onset of RA. Were such an approach to be successful, symptoms and signs of
arthritis, disability and the potential risks of unemployment could be
prevented, and the development of potentially life-threatening co-morbidities
associated with chronic inflammatory diseases, such as cardiovascular disease
and infection, substantially reduced.

The combination of the serum ACPA and joint pain (termed arthralgia), in the
absence of clinically detectable synovitis, is considered to most accurately
define subjects at high risk of progressing to RA. Data from longitudinal
observational cohorts indicate that ~ 40% of such subjects progress to
clinically apparent arthritis within 18 months. The combination of IgM
rheumatoid factor (RF) and high serum ACPA levels define those at highest risk;
recent unpublished data indicate that the risk of developing disease in
subjects with high titre ACPA in the absence of RF may be comparable to
ACPA+RF+ subjects. It follows from this that ACPA+RF+ or ACPA+RF-arthralgia
individuals would provide a valid target population for therapeutic
intervention aimed at prevention of the syndrome we recognise as RA.

The aim of this clinical trial is to evaluate the feasibility, efficacy and
acceptability of abatacept therapy in subjects at high risk of developing RA.

A randomised, placebo controlled clinical trial of abatacept in ACPA+
rheumatoid factor (RF)+ or ACPA+ subjects with arthralgia.
206 subjects will be recruited to the study. (181 in the UK and 25 in the
Netherlands). If recruitment is going well it is poosible to recruit more
patients. Recruitment is possible till 31-1-2018.

Study subjects will be randomised 1:1 to receive weekly injections of abatacept
(125mg) or placebo, administered by subcutaneous injection

Risk for the patient
* Blood sampling: pain during blood collection, bruising or bleeding after
blood collection, minor dizziness and in rare cases infection can occur as a
result of blood sampling.
* Medication use: possible side effects of the study medication (see page 27
and 28 of the protocol)

Burden for the patient
* 10 outpatient visits (1 screening, 1 baseline en 8 follow-up visits)
* 52 weeks weekly injection
* 3 x X-rays of hands and feet
* 5x ultrasonography of selected joints (wrists, hands and feet)*
* 1x chest X-ray
* 10x blood and urine collection
* Completion of patient diary
* Completion of 9 questionnaires (6 questionnaires 5x, 1 questionnaire 9x, 1
questionnaire 2x and 1 questionnaire 1x)