First-Line Rituximab in Systemic Lupus Erythematosus Trial (FIRST)

Research Question In people with early moderate to severe systemic lupus erythematosus (SLE), is it more clinically and cost-effective to use rituximab (RTX) first-line or after failure of conventional immunosuppressant therapies? Background SLE is a life-long autoimmune disease that causes inflammation and damage to a range of organs. It is more severe in children and people of non-European ancestries. Current practice is to treat SLE with a series of conventional immunosuppressants combined with glucocorticoids (GC), but evidence for the sequence in which they should be used is weak. Under current guidelines, if this approach fails, and people have moderate/severe SLE, a more effective therapy, RTX, can be added to these agents later as usual care. This approach may not be optimal since SLE is most severe within the first 12 months of diagnosis, with the highest mortality, GC exposure and healthcare resource use. Aims/Objectives To determine the clinical and cost-effectiveness of RTX given first-line or after failure of conventional immunosuppressants in people with moderate to severe SLE. Methods We will conduct a multicentre, double-blind, randomised, placebo-controlled, superiority trial with an internal pilot. We will recruit 128 people aged 5 years or older, with a new SLE diagnosis, moderate to severe disease activity, and within 4 weeks from starting their first immunosuppressant, from 20 NHS hospitals with SLE clinics, representative of population age, sex and ancestries. The participants will be randomised 1:1, stratified by ancestry and disease activity, to receive standard of care (SOC) using conventional immunosuppressant and GC combined with either placebo (control) or add-on first-line RTX at 0 and 6 months (intervention). Participants will be followed monthly for 12 months. The primary outcome will be the cumulative time where SLE disease activity is adequately controlled on an acceptable GC dose, as defined by the Lupus Low Disease Activity State (LLDAS) over 12 months. Key secondary outcomes include other assessment of disease activity, patient-reported outcomes, medications use (GCs, additional immunosuppressants), organ damage, adverse events, healthcare resource use and costs. The primary and secondary outcomes will be analysed using the intention-to-treat principle via a mixed-effects linear regression model including treatment group, ancestry and disease activity as fixed effects, and site as a random effect. Cost-effectiveness will be evaluated using a within-trial cost-utility analysis from NHS, as well as personal and societal perspectives over 12 months. This research is being co-designed at all stages with our PPIE advisory group (PAG), including members from underserved groups. Timelines An embedded 12-month pilot phase will enable assessment of the recruitment strategy and feasibility. The full study will take 54 months. Impact and Dissemination Our findings will provide the best evidence for treatment of people with moderate to severe SLE in its most severe phase to improve long-term outcomes. We will shape our dissemination strategies with our PAG, engaging with rheumatology communities, patient groups and other stakeholders, to ensure wide implementation of the research outputs. We will co-present at professional society meetings and organise press releases through universities and NHS. Our findings will be published in high-impact journals and used to inform national and international guidelines.