Predict Who Will Respond to B-Cell Depletion Before You Enroll Them

B-cell-directed therapies such as anti-CD20 antibodies and CD19 CAR-T cells deliver meaningful benefit in autoimmune disease, yet a substantial minority of patients fail to meet standard clinical response criteria. In real-world and refractory lupus cohorts, overall response rates to rituximab typically range around 40–70% — roughly 30–60% non-responders, depending on population and endpoint (Rheumatology, 2018; Reumatología Clínica, 2016). Both pivotal randomized rituximab trials in lupus — EXPLORER in extrarenal SLE and LUNAR in proliferative lupus nephritis — failed to achieve their prespecified primary endpoints, despite robust B-cell depletion and serologic changes (Nature Reviews Rheumatology, 2012).

Even next-generation CD19 CAR-T therapies, which can induce profound drug-free remissions, show incomplete response: in Kyverna's Phase 2 KYSA-8 trial in stiff-person syndrome, 81% of 26 treated patients achieved at least a 20% improvement in a timed 25-foot walk test at week 16 — implying that about 19% did not reach this clinically meaningful threshold (Kyverna Therapeutics, 2025; FirstWord Pharma, 2025). Emerging case series also describe relapse after initially successful CAR-T in autoimmune indications, underscoring that durable disease control is not universal (Nature Medicine, 2026).

Despite this, patient selection for B-cell-targeted therapies still depends on broad serological markers (ANA, anti-dsDNA) and global activity indices such as SLEDAI and BILAG in SLE or DAS28 in rheumatoid arthritis — tools that confirm diagnosis and quantify overall activity but do not determine whether disease is presently driven by pathogenic B-cell clones (Emerging B-Cell Therapies in SLE, 2021).

Mechanistic studies show that anti-CD20 agents spare long-lived plasma cells lacking CD20, and that persistent disease may be sustained by autoreactive T cells, established fibrosis, or innate immune pathways such as type I interferon signaling. Enrolling patients whose disease is not primarily B-cell-driven dilutes observed effect sizes and increases required sample sizes, contributing to costly late-stage trial failures — with Phase 3 autoimmune programs often demanding investments in the tens to low hundreds of millions of dollars (Novel and Future Therapeutic Options in Systemic Autoimmune Diseases, 2024).

The development landscape is crowded: contemporary reviews describe well over one hundred therapeutic candidates in clinical development for lupus and related systemic autoimmune diseases worldwide, intensifying pressure to match mechanism to the right patients at the right time.