B-Cells

Ten patients with severe, treatment-refractory systemic sclerosis were given teclistamab, a BCMA × CD3 bispecific T cell engager approved for myeloma, off label. B cells and plasma cells almost disappeared from bone marrow and skin, anti-topoisomerase titres fell by a median of 70.6%, and skin, lung and cardiac measures improved within 12 weeks. The price was universal severe hypogammaglobulinaemia, frequent infections and two deaths in patients with advanced heart disease, in a small, retrospective, uncontrolled series.

Two phase 3 trials (779 patients) tested ianalumab, a B-cell-depleting antibody that also blocks BAFF-R, in active Sjögren’s disease. Monthly 300 mg reduced ESSDAI more than placebo at week 48, by 1.3 points in NEPTUNUS-1 (P = 0.0496) and 1.0 point in NEPTUNUS-2 (P = 0.04), and every-3-months dosing did not. The hierarchy then broke: ESSDAI response and symptom scores did not differ, so the secondary results cannot support causal claims, and the placebo groups improved a great deal.

CD19 CAR-T cells can produce drug-free remission in lupus, but they delete B cells rather than restore tolerance. This review makes the case for engineered regulatory T cells carrying a T cell receptor for a disease-relevant antigen (TCR-Tregs), which suppress locally and spread suppression to bystander cells. The human data are still polyclonal Tregs, CAR-Tregs and tolerogenic dendritic cells; TCR-Tregs are preclinical, and the main barrier is manufacturing cost, which the authors propose to address with banked, gene-edited iPSC-derived products.

In the 194-patient phase 3 INDIGO trial, weekly subcutaneous obexelimab, a bifunctional antibody that dampens B cells through CD19 and FcγRIIb without depleting them, cut the risk of IgG4-related disease flare by more than half (HR 0.44) and reduced rescue glucocorticoid exposure by about two-thirds over 52 weeks. The comparator was a steroid taper alone, and fewer than 4 in 10 patients on obexelimab reached complete remission.

Fifteen patients with multidrug-resistant RA received blinatumomab at roughly a tenth of the haematology dose. All 15 achieved at least ACR20 and synovial B cells were depleted, but 14 of 15 flared within a median five months. The more provocative observation is what happened next: seven patients responded for over three months to b/tsDMARDs that had already failed them — raising the possibility that partial depletion resensitises rather than resets.

ALLEGORY is a phase 3 RCT of the type II anti-CD20 antibody obinutuzumab added to standard therapy in active non-renal SLE. It met its primary endpoint (SRI-4 76.7% vs 53.5% at week 52) and all five key secondary endpoints, achieving both steroid-sparing and a ~40% reduction in flare hazard — reinforcing that depth of B-cell depletion matters and that type II succeeds where rituximab failed.

A 2026 narrative review of T-cell engagers (TCEs) in autoimmune rheumatic disease — off-the-shelf bispecific antibodies that redirect a patient’s own T cells against autoreactive B/plasma cells, pitched as a repeatable, dose-adjustable alternative to CAR-T. Early efficacy across SLE, SSc, RA, myositis and Sjögren’s is real but preliminary, and the review’s headline problem is under-dosing relative to oncology, which likely drives frequent relapse.

A 2026 narrative review arguing that B cells are the single through-line of Sjögren disease — connecting autoantibodies, glandular pathology, the highest lymphoma risk of any autoimmune disease, and the emerging drug pipeline. Endotyping by B-cell activity may identify who develops lymphoma and who responds to B-cell-targeted therapy, as newer BAFF/APRIL, CD40L, BTK and FcRn agents succeed where rituximab failed.