Experimental Medicine Studies of the Brain in Patients With Rheumatoid Arthritis REALISE

The study will involve participants aged over 18 years with RA and are scheduled to start outpatient anti-TNF treatment (with Adalimumab) as part of standard clinical care, who meet the inclusion criteria and none of the specified exclusion criteria. All will give full informed consent. This is a single-blind, randomised placebo-controlled waiting list study and after screening and consent, eligible participants will be randomised (1:1) to receive either adalimumab or placebo.

The study comprises standard care screening for anti-TNF therapy (incorporated into the study to allow us to fast track screening), a total of 7 research visits and one remote visit via telephone. At Visit 1 (Day 0) and Visit 4 ((14 ± 2 days from Visit 3), participants will undergo 7T MRI and MRS Neuroimaging protocols that incorporate resting-state and task-based fMRI and glutamate MRS measures. At Visit 1A (1 - 7 days from Visit 1) and Visit 4A (1 - 7 days from Visit 4), participants will undergo an optional SPECT scanning protocol. This visit will involve a 160ml blood draw, from which monocytes will be isolated and radiolabelled before being reinjected prior to SPECT scanning.

Inclusion criteria

• Adults ≥ 18 years < 75 years.
• Physician diagnosed moderate to severe RA.
• No previous biologic disease modifying antirheumatic drug therapy
• Usual care physician has confirmed the patient is eligible for anti-TNF treatment for active RA in line with the license for adalimumab (originator or biosimilar) and local practice subject to satisfactory completion of standard pre-biologic safety screening. Standard pre-biologic safety screening includes but not limited to exclusion of latent TB infection according to local protocol, chest X-ray, negative HIV screen, negative Hepatitis screen antibody, negative Hepatitis B surface antigen [Hep B sAg] and negative Hepatitis B anti-core antibody [Hep B cAb]

Note: Participant consent to treatment with adalimumab will have been obtained by the usual care team as per standard practice at site and will be prior to any approach for this study.

• Participant agrees to either immediate or delayed commencement of adalimumab.
• Self-reported sickness behaviour (fatigue, depression, anxiety) with one component > 4 on NRS
• Right-handed (to reduce neuroimaging heterogeneity).
• Women of Child-Bearing Potential (WoCBP) must be willing to use of effective contraception for study duration. Further information is provided in appendix 1
• Willing to participate and give informed consent for this research study.

Exclusion criteria

• Inability to provide written informed consent.
• Severe physical impairment (e.g. blindness, deafness, paraplegia).
• Pregnant, planning pregnancy or breast feeding.
• Serious infection including sepsis, tuberculosis and opportunistic infections such as invasive fungal infections.
• Severe liver or renal disease.
• Clinically diagnosed major confounding neurological disease including Multiple Sclerosis, Stroke, Traumatic Brain Injury, Parkinson's Disease, Alzheimer's Disease or similar neurodegenerative disease.
• Previous biologic disease modifying antirheumatic drug therapy with adalimumab, etanercept, qolimumab, infliximab, certolizumab, abatacept, tocilizumab, sarilumab, rituximab, tofacitinib or upadacitinib.
• Recent (within 4 weeks prior to Visit 1 baseline) use of intra-muscular or intra-articular steroid injections.
• Contraindications to MRI (e.g. metal implants, claustrophobia).
• Contraindications to Adalimumab.
• Concurrent or previous use of any other medicinal product (excluding vaccinations) that may, in the Principal Investigator's opinion, influence underlying disease activity through effects on immune and/or inflammatory responses.

If consenting to SPECT component, the following exclusions apply:

• Haemoglobin less than 100g/L
• Contraindications to SPECT protocol (e.g. hypersensitivity to Technetium or Stannous Chloride, recent Nuclear Medicine Procedure)
• Unwilling not to donate body fluids such as blood, sperm etc. for at least 24 hours after SPECT imaging at visits 1A and 4A.
• Unwilling to avoid close contact with children or people who are pregnant for 24 hours following SPECT imaging