Blocking Antibody Burden Stratifies Immune Heterogeneity to Guide Precise Immunotherapy With Cyclosporine A in Recurrent Implantation Failure
Ling Guo, Shuteng Zhang, Jingjing Li, Yanxia Yu, Qingxia Meng, Tianqi DuBackground
To evaluate whether the burden of negative peripheral blood blocking antibody (BA) items can stratify recurrent implantation failure (RIF) patients for cyclosporine A (CsA) treatment response.
Methods
This retrospective cohort study included 427 women (517 frozen embryo transfer cycles) with RIF. BA panel measured blocking activity against CD3, CD4, CD8, and CD56. Cycles were grouped by BA burden (0–2 vs. 3‐4 negative items) and further classified by CsA use. Adjusted modified Poisson regression with generalized estimating equations and interaction terms was applied to estimate relative risks (RR) and effect modification.
Results
In the low‐burden subgroup (0–2, n = 335), CsA was associated with moderate improvements (implantation RR = 1.36, 95% CI 1.04–1.78; clinical pregnancy RR = 1.42, 95% CI 1.11–1.81; live birth RR = 1.43, 95% CI 1.05–1.96). In the high‐burden subgroup (3‐4, n = 182), effects were substantially larger (implantation RR = 2.95, 95% CI 1.64–5.31; clinical pregnancy RR = 2.73, 95% CI 1.56–4.76; live birth RR = 2.86, 95% CI 1.53–5.32). Interaction was significant for implantation (RR = 2.17, p = 0.019) and clinical pregnancy (RR = 1.92, p = 0.036), and borderline for live birth (RR = 1.99, p = 0.055). Absolute differences in the high‐burden group reached 29.3% for implantation, 32.8% for clinical pregnancy, and 26.5% for live birth.
Conclusions
BA negativity burden modifies CsA treatment effect, with substantially greater benefits in patients with three to four negative items. This pragmatic blood‐based biomarker may help identify RIF patients most likely to respond to CsA, supporting precision immunomodulation. Prospective validation is warranted.