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In 1998 Edwards and Cambridge from University College London became increasingly convinced that B-lymphocytes were critically involved in the development of rheumatoid arthritis. 1 For some people at the time, this seemed a pathological heresy! However, taking advantage of the approval by the FDA of rituximab [anti-CD20] for the treatment of non-Hodgkin’s lymphoma, from 1999 onwards they started treating patients with rheumatoid arthritis with this B-cell depleting agent. Its effectiveness was obvious and in 2006 NICE approved it for use in rheumatoid arthritis.Working with other colleagues in the Lupus Clinic, I started treating patients with SLE in 2000 with the same combination of rituximab, cyclophosphamide and steroids which had been used to treat the patients with rheumatoid arthritis. By 2009, we had reported on our first 50 patients noting considerable success for diverse lupus manifestations2 and many other centres reported equally good results. However, disappointingly, major trials in the treatment of lupus nephritis and non-renal lupus did not meet the primary endpoints though a detailed post-hoc analysis did show encouraging trends in those trials.The use of rituximab at the time of diagnosis in patients with lupus nephritis was demonstrated by Lightstone and her colleagues,3 but a trial designated to confirm the result failed to recruit sufficient patients. However, data published by the British Society of Rheumatology’s biologic register also confirmed its effectiveness in a multi-centre major UK study.4 B-cell depletion has also been shown to be successful in ANCA-positive vasculitis and in mesangial nephropathy.As rituximab contains approximately 20% mouse protein, a significant number of lupus patients [approximately 15%] are unable to continue its use long-term due to allergic responses or significant reductions in total IgG.However, recent success using obinutuzumab, a fully-humanized anti-CD20 in both Phase 2 and Phase 3 trials5 has once more highlighted the potential for this ‘easy-to-use’ approach to lupus treatment. It is notable that Georg Schett [personal communication] has described CAR T-cell therapy as an ‘expensive form of depletion’! B-cell depletion is now surely here to stay in the treatment of lupus.References Edwards JC, Cambridge G. Rheumatoid arthritis: the predictable effect of small immune complexes in which antibody is also antigen. Br J Rheumatol. 1998;37(2):126–30. doi: 10.1093/rheumatology/37.2.126Lu TY, Ng KP, Cambridge G, et al. A retrospective seven-year analysis of the use of b cell depletion therapy in systemic lupus erythematosus at university college london hospital: the first fifty patients. Arthritis Rheum. 2009;61(4):482–7. doi: 10.1002/art.24341Condon MB, Ashby D, Pepper RJ, et al. Prospective observational single-centre cohort study to evaluate the effectiveness of treating lupus nephritis with rituximab and mycophenolate mofetil but no oral steroids. Ann Rheum Dis. 2013;72(8):1280–6. doi: 10.1136/annrheumdis-2012-202844McCarthy EM, Sutton E, Nesbit S, et al. Short-term efficacy and safety of rituximab therapy in refractory systemic lupus erythematosus: results from the british isles lupus assessment group biologics register. Rheumatology (Oxford) 2018;57(3):470–79. doi: 10.1093/rheumatology/kex395Furie RA, Rovin BH, Garg JP, et al. Efficacy and safety of obinutuzumab in active lupus nephritis. N Engl J Med. 2025;392(15):1471–83. doi: 10.1056/NEJMoa2410965Learning Objectives At the end of this presentation participants will be able to:Discuss the origins of B-cell depletion therapy in autoimmune rheumatic diseasesExplain that early use of rituximab/β-cell depletion may substantially reduce the steroid requirement for many SLE patientsExplain the potential advantage of a fully humanised B-cell depleting agent