Inflammation-modulating agents in chronic limb-threatening ischemia: a narrative review of therapeutic potential and future directions

Abstract

Chronic limb-threatening ischemia (CLTI) represents the most severe form of peripheral artery disease (PAD), driven by both advanced atherosclerosis and chronic inflammation. Despite advancements in revascularization and medical therapy, outcomes remain poor. Inflammation has emerged as a key therapeutic target, and several anti-inflammatory agents are under investigation for potential benefit in CLTI. A comprehensive literature review was conducted using PubMed, Scopus, Embase, Google Scholar, and Web of Science to identify studies published between 1990 and 2025. Keywords included "chronic limb-threatening ischemia," "peripheral artery disease," "colchicine," "canakinumab," "methotrexate," "NLRP3 inflammasome," and "anti-inflammatory therapy." Eligible studies included original research, clinical trials, systematic reviews, and relevant guidelines focused on inflammation-targeted interventions in atherosclerosis and limb ischemia. Colchicine has shown significant reductions in major adverse cardiovascular events in large trials and retrospective PAD studies, though no randomized controlled trials (RCTs) have specifically addressed CLTI. Canakinumab reduced inflammatory biomarkers and improved walking performance in PAD but had no effect on plaque progression. Methotrexate did not demonstrate cardiovascular benefit in the Cardiovascular Inflammation Reduction Trial. Preclinical agents targeting the NLRP3 inflammasome (e.g., MCC950) have shown anti-inflammatory effects but lack human data. Nutraceuticals, including omega-3 fatty acids and polyphenols, may offer adjunctive benefits, though evidence remains limited. Inflammation-modulating therapies hold promise as adjuncts in CLTI management, potentially improving outcomes by targeting the underlying immune mechanisms of disease progression. However, current evidence is insufficient for clinical adoption in CLTI. Large-scale, well-designed RCTs focusing on limb-specific outcomes are necessary to clarify the role of these therapies in high-risk vascular populations.