The aspiration of precision glucocorticoid pharmacotherapy in immune-mediated diseases: where do we stand in integrating pharmacogenomics and biomarkers for individualized treatment?

Vollständiger Abstract

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Glucocorticoids remain among the most widely prescribed immunosuppressive and anti-inflammatory agents worldwide, yet their clinical use is complicated by substantial inter-individual variability in both therapeutic response and adverse effects. Despite decades of clinical experience, glucocorticoid prescribing remains largely empirical, with limited integration of precision medicine approaches that could optimize therapeutic outcomes while minimizing toxicity. This review synthesizes current evidence on emerging precision approaches to glucocorticoid therapy across three key domains: pharmacogenomic determinants (including variants in NR3C1, FKBP5, CYP3A4/5, and ABCB1) that modulate immune cell responsiveness to glucocorticoids; pharmacokinetic variability and model-informed precision dosing strategies; and disease-specific biomarker-guided approaches across major immune-mediated conditions including respiratory diseases, rheumatologic conditions, inflammatory bowel disease, polymyalgia rheumatica, and critical illness. Genetic variants in glucocorticoid receptor signaling and drug metabolism pathways have suggested some associations with treatment response and adverse effects, although none are yet acknowledged as clinically actionable by consensus resources. Disease-specific immunological biomarkers including eosinophil counts, inflammatory cytokines, and pharmacodynamic endpoints suggest the promise of individualized dose optimization. Risk stratification for glucocorticoid-induced osteoporosis—mediated through OPG/RANKL signaling and monocyte-osteoclast crosstalk—incorporating both clinical factors and pharmacogenetic markers may facilitate targeted prevention strategies. The integration of pharmacogenomic testing, immune biomarker monitoring, and pharmacokinetic modeling represents an aspirational paradigm shift from empirical dosing to individualized immunomodulatory therapy. It should be acknowledged that, as of the time of writing, this precision framework remains largely investigational: routine clinical practice continues to rely predominantly on indication-specific regimens and empirical tapering protocols. This review is explicitly forward-looking, aiming to outline a research agenda for precision glucocorticoid therapy in immune-mediated diseases.