The study will recruit patients referred to the Rheumatology Out-patient departments. Patients will be recruited to the study or control groups (healthy or disease controls who will be age and sex-matched) as needed. The study will first open to recruitment at Manchester University Hospitals NHS Foundation Trust and then open at other NHS Trusts. Patients will be asked to participate in longitudinal (clinical/imaging/biosample) data and/or sample collection that will improve our understanding of underlying disease mechanisms and identify improved diagnostic, prognostic and predictive biomarkers to understand progression of disease and drug response or resistance.

Main Study

Consent to this ethics' main programme will permit collection of routinely collected data and use for research activities. Patients may be recruited at any point along their disease continuum (e.g. time of initial diagnosis, before/after a new treatment intervention, at time of disease flare or stable state).

Patients with established disease who are recruited to the study during their follow up appointments will have pre-existing results and clinical documentation. These retrospective data may also be collected where possible using information documented in case-notes and/or hospital information systems.

Some study-specific information will also be collected.

In addition to the main study, participants will be offered the opportunity to consent to participate in one or more sub-studies which include the additional research procedures (entitled 'basic biological' and 'synovial biopsy'). It will be possible for patients to participate in more than one sub-study.

The sub-studies aim to explore the mechanisms that may underlie change over the disease continuum, not just at disease initiation. In particular, the researchers would wish to obtain samples and imaging that coincide with a change in disease profile as well as with loss of disease control. Acquiring pre- and post-treatment blood/tissue samples and images would allow the investigation of changes in disease pathogenesis, the role of specific therapies, and identification of treatment response indicators. The researchers would therefore ask the permission of some individuals to obtain samples or images at additional time-points to coincide with events along their disease continuum.

Basic Biological sub-study

This sub-study will facilitate identification of prognostic markers of disease, mechanism and predictive markers of drug response. As part of an in-house investigation of biomarkers and mechanisms, DNA, serum, plasma, synovial joint fluid, and urine may be collected and stored. Patients will have the opportunity to consent separately to the genetic (DNA) component.

A maximum of 75mls of blood may be taken to enable the range of experimental studies. The samples will be taken at relevant clinical time points related to diagnosis, disease profile, disease activity state and/or treatment related time points; thus samples may be taken at one time point or repeated depending on the individual study objective and status of the patient.

Synovial biopsy sub-study

Patients will be asked to consent to a synovial biopsy of an affected joint to provide synovial tissue for research purposes. Synovial joint fluid may also be collected as part of the biopsy procedure. This will be performed by a trained clinician within our department by ultrasound-guidance. Depending on the research question being addressed, biopsy may be taken at time of diagnosis; or before and after starting a new drug treatment; or at time of a change in disease activity/flare (that may/may not lead to change in therapy). If repeat biopsy is taken, this is typically 3 or 6 months after starting a new therapy; or may be a later time point if evaluating for change in disease characteristics and tissue biology over time.

Inclusion Criteria

1. Subject ≥ 18 years of age

2. Is capable of understanding and signing an informed consent form

3. Falls into one of the following:

   1. Pre-RA - Any musculoskeletal symptom (inflammatory and/or non-inflammatory) AND either RF and/orACPA positive.
   2. UA - Inflammatory joint symptoms (including joint pain, significant early morning stiffness and joint swelling) not fulfilling any classification criteria
   3. ERA - recent clinical diagnosis of RA EstRA - known diagnosis of RA supported by evidence of established inflammatory arthritis including but not limited to synovitis, erosion, tenosynovitis.

Exclusion Criteria

1. Age less than 18 years
2. Lack of capacity to give informed consent

People with early rheumatoid arthritis