It is almost 20 years since B-cell depletion using rituximab [anti CD20] was introduced for the treatment of systemic lupus erythematosus (SLE).1 Despite the failure of two major clinical trials2 both the ACR and EULAR guidelines recommend rituximab for the treatment of lupus nephritis and NHS England permits its use more widely. Well over 50,000 SLE patients worldwide have been treated with rituximab and it seems to be very effective for many haematological, musculoskeletal, dermatological and renal aspects of lupus.3 Increased risk of infection and hypogammaglobinaemia remain concerns.4 Newer fully-humanized anti-CD20 monoclonal antibodies (e.g. ofatumumab) offer a way forward for those who become allergic to rituximab, which is 20% murine. Research indicates that there are at least two types of anti-CD20 antibodies. In contrast, anti-plasma cell therapies have been much less widely utilized. Some studies using bortezomib (anti-proteasome) have been reported5 and studies with experimental anti CD19 monoclonals are under way. Although significant reductions in autoantibodies (and immunoglobulins) and a rise in serum complement have been noted, precursor B-cells and T-cells largely remain unaffected resulting in a rapid re-population of short-lived plasma cells. This result suggests that this approach will need to be combined with other B-cell therapies. Learning objectives Describe the role anti–CD20 antibodies in the treatment of SLE Explain the benefits of rituximab and ofatumumab for patients with SLE Discuss utilization of proteasome inhibitors, such as bortezomib, for the treatment of SLE References Leandro MJ, Edwards JC, Cambridge G, et al. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis & Rheumatism 2002;46(10):2673–77. Ramos L, Isenberg D. Rituximab: the Lupus Journey. Current Treatment Options in Rheumatology 2015;1(1):30–41. Murphy G, Isenberg DA. New therapies for systemic lupus erythematosus — past imperfect, future tense. Nature Reviews Rheumatology 2019;15(7):403–12. Hennessey A, Lukawska J, Cambridge G, et al. AB0443 Infusion reactions to rituximab in systemic lupus erythematosus: a retrospective analysis. Annals of the Rheumatic Diseases 2017;76(Suppl 2):1205–05. Alexander T, Cheng Q, Klotsche J, et al. Proteasome inhibition with bortezomib induces a therapeutically relevant depletion of plasma cells in SLE but does not target their precursors. European Journal of Immunology 2018;48(9):1573–79.