This is a 12-month, prospective, observational cohort trial involving Primary Care Trusts (PCTs) wishing to take part in the study and the Early Arthritis Clinic (Anti-CCP sub-clinic) at Chapel Allerton Hospital. The approximate duration of subject participation will be 12 months and the approximate total duration of the study will be 10 years. Patients who have not developed inflammatory arthritis within the 12 month period will have the opportunity to continue follow up within the clinic on an annual basis with additional visits as clinically indicated until the development of IA.

There is accumulating evidence for the need to identify patients with rheumatoid arthritis (RA) early. Damage occurs early and early treatment is effective. Clearly there is a need to improve ways of identifying these patients.

It is recognised that patients with RA often have non-specific musculoskeletal complaints in the months or years prior to development of RA (unpublished observations). Family members of patients with RA are also at greater risk of developing RA.

Given we know that earlier identification of patients enables earlier treatment and this leads to better long-term outcomes, we need a method of identifying patients at the pre-clinical stage of disease.

C-reactive protein (CRP) is an acute phase reactant, produced by the liver, primarily in response to stimulation by interleukin-6 (IL-6). The lower limit of detection of routine CRP is 8mg/dL (or higher), yet the mean CRP in the general population is <2mg/dL11 (as measured by high sensitivity assays). Therefore, patients with early RA may have low-grade inflammation not detected by routine CRP. This has been demonstrated in patients with established disease12, but no studies have been done in early disease. Disease activity variables correlated with increases in highly-sensitive CRP (hs-CRP) and hs-CRP was better than ESR at predicting disease activity and severity12. Interestingly, on retrospective analysis of blood donor serum, increased levels of hs-CRP have been noted in RA patients during the pre-clinical phase, most commonly within the two years prior to symptom onset13. This suggests immunologic changes occur prior to the development of the symptomatic stage and provides an exciting tool for assisting in the diagnosis of very early inflammatory disease

Inclusion Criteria:

For the purpose of this study, "musculoskeletal complaint" is defined as any new joint / muscular symptoms, including (but not limited to)

• Rotator cuff tendonitis / subacromial bursitis
• Carpal tunnel syndrome
• Tendonitis e.g. epicondylitis "New" complaint is defined as a symptom in which the patient has not previously reported to their GP.

GP and Musculoskeletal referred patients:

Subject must fulfil all of the following conditions or characteristics in order to be considered for study enrolment or participation:

1. Is age > 18 years
2. Has a new musculoskeletal complaint or has a family member with RA
3. Is capable of understanding and signing an informed consent form

Rheumatology Clinic referred patients:

Subject must fulfil all of the following conditions or characteristics in order to be considered for study enrolment or participation:

1. Is age > 18 years
2. Has a new musculoskeletal complaint
3. Is capable of understanding and signing an informed consent form
4. Has tested CCP Ab positive

Exclusion Criteria:

GP and Musculoskeletal referred patients:

Subjects with any of the following conditions or characteristics will be excluded

1. Patients with clinical synovitis
2. Patient fulfils 1987 ACR Criteria or the 2010 ACR/EULAR criteria for RA
3. For the MRI imaging component, the following exclusions will apply; pacemaker, surgical clips within the head, certain inner ear implants, neuro-electrical stimulators or metal fragments within the eye or head or eGFR < 45 ml/min/1.73 m2. 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.

Rheumatology clinic referred patients:

Subjects with any of the following conditions or characteristics will be excluded

1. Patient has tested CCP Ab negative
2. Patient fulfils 1987ACR Criteria or the 2010 ACR/EULAR criteria for RA
3. For the MRI imaging component, the following exclusions will apply; pacemaker, surgical clips within the head, certain inner ear implants, neuro-electrical stimulators or metal fragments within the eye or head or eGFR < 45 ml/min/1.73 m2. 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.

Patients who are attending GP Practices in the Yorkshire and surrounding regions.