Title: Treatment Intensities and Targets In Rheumatoid Arthritis Therapy: Integrating Patients' And Clinicians' Views – The TITRATE Programme
Funder: Department of Health and Social Care

Abstract: 7.1 AIMS AND OBJECTIVES We aim to improve outcomes for rheumatoid arthritis (RA) patients with intermediate disease activities. They form the majority of patients in specialist clinics. We believe the treatment paradigm needs changing for all patients. Short-term high intensity treatments should induce remission. Treatment should then be tapered to low maintenance levels. This approach should convert intermediate disease activity into remission resulting in less disability and better quality of life. Our research will span 3 work streams: a. Best for Patients - equipping patients to receive intensive management. b. Trial Evidence For Efficacy - trials and extension studies to show if intensive management and treatment tapering are effective. c. Real Life Evidence For Efficacy And Cost Effectiveness - supportive evidence from observational studies and systematic reviews. 7.2 BACKGROUND RA affects 580,000 English adults with 26,000 new diagnoses each year. Its follow-up involves 600,000 outpatient visits annually. Its annual direct NHS costs are £560M; work-related disability costs £1,800M. RA involves joint and systemic inflammation. Uncontrolled active RA causes disability and reduces quality of life. Disease modifying drugs (DMARDs), steroids and biologics like tumour necrosis factor inhibitors decrease disease activity and improve disability. National Institute for Health & Clinical Excellence (NICE) 2009 guidance outlined best practice for RA. It recommended intensive management for active, early RA. This gives remission in 30% of patients leaving most (50-60%) with ongoing intermediate disease activity. They often develop substantial disability. Our programme addresses this major evidence gap –optimal care for intermediate disease activity. 7.3 RESEARCH PLANS The programme has 3 work streams, each with an aim and specific themes. Work Stream A: Best For Patients a. Aim Developing patient-led implementation strategies to help patients with intermediate disease activity receive intensive management. b. Themes (i) Equipping patients to receive and potentially benefit from intensive management (ii) Understanding patients’ views on intensive management and tapering (iii) A partnership of patients and clinicians to implement intensive management in routine NHS care Work Stream B. Trial Evidence For Efficacy a. Aim To show if intensive management is effective, and whether treatment tapering is possible in responders. b. Themes: (i) 12-month pragmatic open label multicentre randomised controlled trial with individual randomisation comparing intensive management with standard care in 358 RA patients with intermediate disease activity (ii) Assessing reasons for incomplete responses (iii) Pilot non-inferiority randomised controlled trial of treatment tapering in responders Work Stream C: Real World Evidence For Efficacy And Affordability a. Aim To provide supportive evidence that intensive management will achieve sustained remissions, improve clinical outcomes and is cost effective. b. Themes: (i) Observational studies and completed trials: over 6000 RA patients followed for up to 10 years in 2 completed observational studies, 2 completed trials and 2 ongoing observational studies will provide data about how controlling intermediate disease activity affects disability (ii) The literature will be systematically reviewed to examine how changes in disease activity affect disability (iii) Health economic studies will use data from all stages of the programme to examine the impact of intensive management on costs and health outcomes as Quality Adjusted Life Years (QALYs) 7.4 RESEARCH TEAM Our multidisciplinary team spans rheumatology, nursing, general practice, epidemiology, psychology, statistics, health economics, qualitative research, NHS management and includes two patients. The team have a strong publication record (over 400 relevant papers) and a good track record in obtaining and delivering peer-reviewed grants (>£15M current/recent funding). They have delivered key guidelines and standards of care for RA. 7.5 PROGRAMME MANAGEMENT An independently chaired management group will oversee the research; it will involve clinicians, other researchers and patients. 7.6 RESEARCH ENVIRONMENT The research will be hosted within an Academic Health Science Centre and involve a registered Clinical Trials Unit. 7.7 OUTPUTS, OUTCOMES AND IMPACT Research findings will be presented at meetings, published in peer-reviewed journals and used to change NHS practice. 7.8 PATIENT AND PUBLIC INVOLVEMENT Patients have lead roles in much of the research and have contributed to the design of the whole programme. 7.9 ETHICAL IMPLICATIONS Research ethics committees will approve the research with informed consent obtained for all studies. Although drug treatment incurs some risks, these should not be higher than standard care. 7.10 JUSTIFICATION FOR RESOURCES Funding is needed for the applicants, 4 research staff.

Lay abstract: Rheumatoid arthritis (RA) is a major health problem in England. One adult in a hundred has RA. It affects more women. RA costs the NHS over half a billion pounds each year and the British economy nearly two billion pounds annually. The main problem in RA is inflamed joints. Poorly controlled joint inflammation results in disability and also reduces patients' quality of life. Several conventional drugs reduce RA joint inflammation. They are called disease modifying drugs, or DMARDs. Steroids also help. New biologics like tumour necrosis factor inhibitors work very well but are too expensive to give to every patient. Patients with many inflamed joints have active disease. They need intensive management. This means giving several DMARDs at the same time usually with steroids. Biologics are used if the RA remains active. This approach is recommended by the National Institute for Health and Clinical Excellence. One third of patients with active disease achieve remission with intensive management. When patients have sustained remission they do not become disabled. Unfortunately two thirds of patients do not achieve remission. They have ongoing disease activity. This type of grumbling arthritis - neither very active nor in remission - is called intermediate disease activity. With current treatment they are likely to become disabled over time. Our programme will focus on this key problem. It will show if patients who have intermediate disease activity benefit from receiving intensive management. If this works far more of them will have sustained remissions and they will be less disabled. The programme has three parts. Firstly, we will help patients understand and choose intensive treatments. We will also find out their views on this approach. Secondly, we will run trials to see if increasing treatment works and if it can be tapered when patients are in sustained remission. Thirdly we will use everyday practice follow up studies to make certain remission reduces disability and that achieving it is affordable. The end result should be to enable most patients with RA to achieve sustained remissions. This would reduce long term disability and enhance their quality of life. Intensive management may initially cost more but we hope to show sustained low disability levels reduce NHS costs and give substantial long-term savings. Our final step will be to work with patients to ensure the NHS makes use of the results to improve care for RA patients.

Research activity codes: 8.1 ORGANISATION AND DELIVERY OF SERVICES;7.3 MANAGEMENT AND DECISION MAKING
Health categories: INFLAMMATORY AND IMMUNE SYSTEM