Frontiers in Immunology · Oct 31, 2026
Inflammatory Target Engagement and Cardiovascular Protection: A Systematic Review and Meta-Regression of Randomized Immunomodulatory Trials
By Musa Bin Bashir, Fabrice Yves Ndjana Lessomo, Bibek Shrestha et al.
Background: Randomized trials of anti-inflammatory therapy for atherosclerotic cardiovascular disease have given inconsistent results. We examined whether the degree of inflammatory target engagement, measured as the on-treatment reduction in high-sensitivity C-reactive protein (hsCRP) relative to control, explains this variation. Methods: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov and the WHO International Clinical Trials Registry Platform were searched from inception to 21 October 2026 for randomized trials of immunomodulatory agents reporting cardiovascular outcomes and/or on-treatment hsCRP or interleukin-6 (IL-6). Hazard ratios (HRs) were pooled with random-effects models (restricted maximum likelihood with Hartung–Knapp–Sidik–Jonkman intervals), the association between relative hsCRP reduction and treatment effect was examined by exploratory meta-regression, and risk of bias and certainty of evidence were assessed with RoB 2 and GRADE. Results: Thirty-three trials (88,416 participants) were included; 11 (68,901 participants) contributed to the primary analysis of 3-point major adverse cardiovascular events (MACE). Across 20 trials with a quantifiable reduction, hsCRP was lowered by 52–88% with IL-6 blockade, 45–71% with interleukin-1 (IL-1) blockade, 10–39% with colchicine, 10–27% with p38 mitogen-activated protein kinase (MAPK) inhibition and 12–16% with phospholipase A2 inhibition, and not at all with methotrexate. Immunomodulatory therapy did not significantly reduce MACE (HR 0.94, 95% CI 0.86–1.03; I² = 45%; prediction interval 0.78–1.14; low certainty). Point estimates were lowest for canakinumab (0.85, 0.74–0.98) and colchicine (0.86, 0.70–1.05), but differences between pathways were not statistically significant (P = 0.15), and a post hoc grouping of IL-1, colchicine and methotrexate trials (HR 0.88, 0.78–0.99) had low credibility. In six trials, each additional 10% reduction in hsCRP was associated with an HR of 0.96 (0.81–1.15; P = 0.60); estimates were similar after adjustment for clinical setting and when restricted to measurements taken at least 90 days after the index event. Conclusions: Anti-inflammatory therapy as a class did not robustly reduce MACE. In this exploratory, observational and imprecise analysis, we found no evidence that the magnitude of hsCRP suppression explains differences in cardiovascular benefit across mechanisms; the data neither support nor refute a proportional relationship. Pathway-specific protection and the value of hsCRP as a surrogate endpoint remain hypotheses for individual-participant and within-trial analyses.