Understanding the costs, health consequences and barriers to using RNA-based selection of rituximab for people with rheumatoid arthritis (R4-RA-Econ)

Background Rheumatoid arthritis is a prevalent chronic autoimmune inflammatory disease affecting 0.8% of the population. Patients experience painful joint swelling, reduced mobility, fatigue, and permanent joint damage.

The B-cell depleting agent rituximab is a second-line biologic treatment after failure of a tumour necrosis factor inhibitor. However, rituximab is inadequately effective for patients with low B-cells in the synovial tissue.

This population has a high burden of disease and ineffective treatment prolongs disease activity, morbidity, and increases the risk of irreversible damage. A safe/well-tolerated synovial tissue biopsy and RNA molecular profiling reliably identifies B-cell poor patients.

The R4-RA RCT (PI: Pitzalis) demonstrated that prescribing a different treatment (tocilizumab) to B-cell poor patients significantly improves quality of life and disease activity.

Understanding how this biopsy-based molecular profiling test-and-treatment strategy (hereafter targeted-rituximab ) improves downstream cost and patient benefit is essential to support its implementation in the NHS.

Aim This research aims to estimate the indicative incremental costs, health consequences (benefits and harms), key drivers of cost-effectiveness, the value of a definitive trial for targeted-rituximab to treat rheumatoid arthritis, and explore key barriers to uptake and implementation in the NHS. Method The project is divided over four workstreams (objectives below).

Patient involvement is embedded in each workstream.

WS1: estimate the direct health care cost per patient of biopsy-based molecular profiling A robust microcosting study will estimate the direct cost to the NHS of the tissue biopsy and molecular profiling test. Resources consumed and unit costs will be identified from published sources and expert elicitation where required.

WS2: identify the key drivers of whether targeted-rituximab is cost-effective compared with current practice, and estimate the value of a definitive trial to support decision-making A probabilistic decision-analytic model-based economic evaluation and value of information analysis will estimate the cost-effectiveness of targeted-rituximab, based on current R4-RA trial evidence, and the value of further data collection (expected value of sample information).

WS3: explore potential barriers and opportunities to implement targeted-rituximab into the NHS A qualitative study will perform semi-structured one-to-one interviews with key stakeholders (n=30: patients/carers; clinicians; service commissioners) to identify barriers and facilitators to implementing targeted-rituximab by thematic framework analysis.

WS4: develop a proposal for a definitive pragmatic RCT with internal pilot study to assess the effectiveness and cost-effectiveness of targeted-rituximab compared with current practice for RA A proposal for the NIHR Health Technology Assessment programme will be written using outputs from the earlier work packages.

Timeline The research will be delivered over 12-months informed by the applicants extensive experience of delivering similar projects.

Impact and Dissemination The immediate impact of this research will strengthen the design of a definitive pragmatic RCT to assess the clinical and cost-effectiveness of targeted-rituximab.

Over the longer term, this research will provide a step-change benefit to people with severe rheumatoid arthritis who face substantial unmet need in current practice, and will deliver value for money to the NHS by optimising expenditure on high-cost treatments.

The dissemination strategy maximises impact by engaging patients and the public, clinical rheumatologists, and NHS policymakers.