Joint Ventures: The B-Cell Story, Part 1 — From Rituximab to the Next Frontier

In this episode of Joint Ventures, hosts Jack Arnold, MBBS, PhD, an academic clinical lecturer in rheumatology at the University of Leeds, and Rihards Buss, MD, a consultant rheumatologist at Freeman Hospital, Newcastle, are joined by guest Lucy Carter, MBBS, PhD, a consultant rheumatologist at Newcastle upon Tyne NHS Foundation Trust and honorary clinical senior lecturer at Newcastle University, to examine nearly 2 decades of B cell–targeted therapy in rheumatic disease — a story that has proven considerably more complicated than its early promise suggested.

Carter opens by framing why B cells have long represented such an intuitive therapeutic target: auto-antibodies are characteristic of many rheumatic diseases, B cells are potent effector cells, and auto-reactivity in the B cell compartment is a consistent feature across conditions ranging from the polyclonal pathology of lupus to the more focally expanded disease of Sjögren. Rituximab arrived in this space largely by extraction from the oncology field rather than by rational design for autoimmune disease — a distinction that, Carter argues, matters when trying to explain its complicated clinical trial record.

That record is considerable. In lupus, the phase II/III EXPLORER trial in extrarenal disease and the LUNAR trial in proliferative lupus nephritis both failed to meet their primary endpoints. In Sjögren, the TEARS and TRACTISS trials — the 2 largest randomized controlled trials of rituximab in primary Sjögren — similarly came up short, despite secondary signals including improvements in salivary flow rate in patients with residual glandular function in TRACTISS, and transient fatigue benefit in TEARS. The group is measured about attributing these failures purely to the drug: Carter points to evolving trial design, endpoint insensitivity, the challenge of disentangling chronic glandular damage from active inflammation, and the penetration limits of peripheral B cell depletion into tertiary lymphoid structures as contributing factors.

A key mechanistic insight from Carter's own work at UCLH with Professor Michael Ehrenstein concerns what happens after B cell depletion. When rituximab depletes B cells, BAFF (B cell activating factor) surges in response — a homeostatic drive to repopulate the B cell compartment that, because BAFF tilts B cells toward auto-reactivity, may actually worsen disease rebound in some patients. Depth of depletion, she argues, matters enormously: rituximab leaves residual B cell pathology through incomplete depletion, immunogenicity as a chimeric antibody, and genetic variability in drug response.

This sets the stage for the REGENCY and ALLEGORY data from obinutuzumab — a glycoengineered, type II anti-CD20 monoclonal antibody with a fully humanized structure. REGENCY, in active lupus nephritis, demonstrated a complete renal response at week 76 in 42.7% of obinutuzumab-treated patients versus 30.9% in placebo, published in the New England Journal of Medicine in 2025. The group discusses intriguing REGENCY re-biopsy data suggesting histological remission and B cell depletion within the kidney even in patients classified as proteinuria non-responders — pointing to hyper-filtration and damage-driven proteinuria as confounders of the renal endpoint. ALLEGORY, in non-renal systemic lupus erythematosus (SLE), published in the New England Journal of Medicine in March 2026, showed obinutuzumab superior to placebo on the primary endpoint of SRI-4 response at 52 weeks (76.7% vs 53.5%), with all key secondary endpoints met — including a steroid reduction to below 7.5 mg/day in 80% of the obinutuzumab arm versus 54% of placebo. Arnold singles out this steroid-sparing signal as clinically critical, given established links between cumulative glucocorticoid exposure and long-term damage accrual.

The episode closes on CAR-T therapy as a proof-of-concept disruptor that has reframed thinking across the entire field, with early data demonstrating that deep depletion can enable physiological B cell reconstitution and durable remission — raising the question of where obinutuzumab and the emerging pipeline sit relative to that benchmark, and who the right candidates for each approach are. Those questions are set to be addressed in Part 2.

“Now we have to ask the question of how much it's clearly superior. How much more superior is [CAR-T] to obinuztuzumab and the other emerging B cell therapies, and where does it fit in a single patient journey, and who are the right candidates for it… it's just a big unresolved area,” Carter said.

Arnold’s disclosures include Alumis, Roche, and Novartis. Buss and Carter have no relevant disclosures to report.

References

1. Merrill JT, Neuwelt CM, Wallace DJ, et al. Efficacy and safety of rituximab in moderately-to-severely active systemic lupus erythematosus: the randomized, double-blind, phase II/III systemic lupus erythematosus evaluation of rituximab trial. Arthritis Rheum. 2010;62(1):222-233. doi:10.1002/art.27233

2. Rovin BH, Furie R, Latinis K, et al; LUNAR Investigator Group. Efficacy and safety of rituximab in patients with active proliferative lupus nephritis: the Lupus Nephritis Assessment with Rituximab study. Arthritis Rheum. 2012;64(4):1215-1226. doi:10.1002/art.34359

3. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, et al. Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann Intern Med. 2014;160(4):233-242. doi:10.7326/M13-1085

4. Bowman SJ, Everett CC, O'Dwyer JL, et al. Randomized controlled trial of rituximab and cost-effectiveness analysis in treating fatigue and oral dryness in primary Sjögren's syndrome. Arthritis Rheumatol. 2017;69(7):1440-1450. doi:10.1002/art.40093

5. Furie RA, Rovin BH, Pendergraft WF III, et al; REGENCY Trial Committees and Investigators. Efficacy and safety of obinutuzumab in active lupus nephritis. N Engl J Med. 2025;392(15):1471-1483. doi:10.1056/NEJMoa2410965

6. Furie RA, Dall'Era M, Vital EM, et al; ALLEGORY Trial Investigators. Efficacy and safety of obinutuzumab in active systemic lupus erythematosus. N Engl J Med. Published online March 6, 2026. doi:10.1056/NEJMoa2516150