O14 Rituximab objective outcome measures trial in SLE (ROOTS): outcomes of randomised and rescue rituximab therapy in a double-blind randomised placebo-controlled trial

Objective (i) Assess a novel musculoskeletal SLE trial design with objective eligibility and endpoints and a low-glucocorticoid standard of care; (ii) further validate Lupus Arthritis and Musculoskeletal Disease Activity Score (LAMDA) and MSK ultrasound; (ii) preliminary evidence for efficacy of Rituximab. Methods Enrolment required clinical synovitis and/or ultrasound tenosynovitis/joint power Doppler with ≤10mg prednisolone. Patients were randomized to 1000mg Rixathon or placebo, on days 1 and 15, each preceded by 100mg methylprednisolone. BILAG-2004, SLEDAI-2K, LAMDA, tender and swollen joint counts, physician global, patient MSK pain and global VAS, PROs, BICLA, SRI-4 were evaluated monthly. US of both hands and wrists was performed at 0 and 16 weeks. The primary endpoint was feasibility. The key efficacy timepoint was 16-weeks. After 16-weeks placebo patients with active disease were eligible for rescue rituximab with repeat follow-up assessments. US and LAMDA were validated against BILAG-MSK improvement using baseline-adjusted regression. Results Of 27 patients randomised, 12 received placebo, of whom 9 received rescue. BILAG-MSK domain at baseline was scored A in 7/27 (26%), B in 16/27 (59%) and C in 2/27 (7.4%). At 16 weeks, BILAG-MSK response was significantly associated with improvement in LAMDA (OR 0.48, 95% CI 0.18, 0.84); US joints grey-scale (OR 0.56, 95% CI 0.28, 0.85) and US tendons PD (OR 0.33, 95% CI 0.04, 1.01). Unexpectedly, some outcome measures showed greater improvement in patients who received methylprednisolone and placebo than with methylprednisolone and rituximab. These measures then converged by 16 weeks (figure 1). However, pooling all rituximab cycles administered (as initial therapy or as rescue) showed significant improvement in LAMDA (coefficient(95% CI) -2.68 (--4.02, -0.09)), number of joints with US-PD>0 (-0.59(-1.16, -0.02)), and number of joints with GS>1 (-2.68(-4.74, -0.62) at 16 weeks (figure 2). Conclusions SLE arthritis trials offer a homogenous trial population, low GCs, and validated objective outcome measures. Initial worsening before benefit with rituximab may be explained by increased antigenic load and removal of B cell regulatory functions before beneficial effects on plasma cells and B cell antigen presentation are manifest. Detecting such nuances may reflect the greater sensitivity of this trial design. Acknowledgements This study was funded by NIHR and Sandoz.