Atherosclerotic plaque development results from the accumulation of apolipoprotein B-containing lipoproteins in the vessel intima, followed by monocyte infiltration (14). Monocyte-derived macrophages fail to eliminate the modified lipoproteins and transform into highly inflammatory foam cells, releasing Tumor Necrosis Factor-α (TNF-α) and interleukin-1β (IL-1β), exacerbating endothelial dysfunction and perpetuating the inflammatory response (30). Macrophage dysfunction also manifests as a failed attempt to clear apoptotic cells within plaque (a process called efferocytosis), which results in cell debris accumulation and early plaque development. Recently, it has been shown that failed efferocytosis relate to an enhance expression of the transcription factor GATA-2, which in turn results in the dysregulation of key regulatory proteins (31). Advanced atherosclerotic plaques are characterized by a lipid-rich core consisting of foam cells, cell debris, and extracellular cholesterol, as well as a fibrous cap composed of extracellular matrix and smooth muscle cells. In the later stages of the disease, plaque disruption may occur, potentially leading to an ACS (12, 14, 25). Autopsy studies and intravascular imaging through optical coherence tomography (OCT) have recognized three plaque phenotypes in atherosclerotic ACS: plaque rupture, plaque erosion, and eruptive calcific nodule, with the latter being significantly less common. The composition of the advanced plaque will determine whether it is prone to rupture or erosion (32, 33).

Ruptured plaques typically encompass a thin cap fibroatheroma (TCFA) overlying a large lipidic and necrotic core; when rupture occurs, the core components become exposed to the circulation, causing in situ thrombosis and impaired distal flow (16, 33). Inflammation has a key role in the pathophysiology of plaque rupture, with an abundance of macrophages and foam cells—along with, to a lesser extent, T cells- typically near the margins of the fissure (34, 35). Conversely, in eroded plaques, the fibrous cap remains intact, but erosion of the endothelial layer exposes the extracellular matrix (ECM) components to the circulation, initiating thrombosis (36). Unlike ruptured plaques, this phenotype typically involves fibrous plaques rich in ECM components -such as glycosaminoglycans and proteoglycans-, rather than lipids (37); and they have fewer inflammatory cells and more smooth vascular muscle cells (36). The pathophysiology of plaque erosion is complex and markedly distinct from that of ruptured plaques. This involves disturbances in local flow patterns and accumulation of subintimal low molecular weight hyaluronan, leading to the activation of toll-like receptor 2 (TLR 2) and the desquamation of endothelial cells (38–40). Subsequently, neutrophils react releasing neutrophil extracellular traps (NETs), as detailed below, with final platelet-rich thrombus generation (41, 42). Table 1 delineates the main characteristics distinguishing plaque rupture from plaque erosion.

As observed, macrophages play a pivotal role in the pathogenesis of TCFA and plaque rupture (43). In more advanced atherosclerotic lesions, macrophages accumulate within the plaque as cell debris and release matrix metalloproteinases, which degrade the fibrous cap, predisposing to plaque rupture (44, 45). The nucleotide-binding oligomerization domain-like receptor, pyrin domain-containing 3 (NLRP3) inflammasome is a multimeric protein complex responsible for generating IL-1β and interleukin 18 (IL-18) by monocyte/macrophages (18, 46). Elevated expression levels of NLRP3 inflammasome components have been detected in human atherosclerotic plaques (47), correlating with disease severity (48). Additionally, they have been found to be elevated in ACS patients compared to controls (49). Conversely, the administration of a specific NLRP3 inflammasome inhibitor—MCC950—results in less plaque development and a reduction in the inflammasome cytokine products in murine models (50, 51). Notably, peripheral monocytes in ACS patients appear to be “primed” for inflammasome activation (52), highlighting the importance of the IL-1β axis and proposing it as a potential target for therapeutic interventions, as demonstrated in the CANTOS trial (20).

Neutrophils play significant roles throughout all stages of atherosclerosis development (53). They promote foam cell formation and metalloproteinase-induced plaque instability (54, 55). They release extracellular matrix proteinases (i.e., elastase and proteinase-3) which contribute to plaque destabilization (56–59) and facilitate monocyte recruitment and activation (60, 61). Of particular relevance is their role in the pathogenesis of plaque erosion through NETosis. NETs are web-like structures composed of DNA, histones, neutrophil elastase, and myeloperoxidase, released upon neutrophil activation (62). This leads to neutrophil-platelet aggregation and cytokine release from macrophages, lymphocytes, and endothelial cells, creating a potent pro-inflammatory and pro-thrombotic environment (63–66). Furthermore, NETs have also been found in ruptured plaques (67) and can further stimulate macrophages for cytokine production, fostering the inflammatory milieu during an ACS (68, 69). On the other hand, inflammasome activation promotes neutrophil recruitment and NETs formation in atherosclerotic plaques (70). The key role of this NETs-monocyte cross-talk is further exemplified by a recent experiment by Schumski et al. (71). Here, the injection of lipopolysaccharide into hypercholesterolemic mice resulted in a myeloid-dependent increased of atherosclerotic plaque size and the deposition of NETs in the arterial lumen. Conversely, the inhibition of NETs release prevents lesion expansion secondary to lipopolysaccharide administration.

In addition to their role in thrombus formation, platelets have emerged as important regulators of inflammation and immune responses implicated in the onset and progression of atherosclerosis (72). They act as a key link between leukocytes and endothelial cells by binding to dysfunctional endothelium, thereby facilitating the recruitment of leukocytes to the subendothelial compartment and initiating the inflammatory cascade during atherogenesis (73). Moreover, platelets are increasingly recognized for their involvement in lipid metabolism, influencing monocyte differentiation into macrophages and modulating macrophage lipid accumulation, thus promoting foam cell formation and plaque destabilization (74). Additionally, platelets exhibit migratory capabilities, being attracted by cytokines and chemokines to migrate through endothelial barriers and actively translocate into atherosclerotic lesions, where they interact with monocytes and assist in their migration (75–77). Accordingly, studies in atherosclerotic-prone Ldlr^+/− mice have shown that induced platelet apoptosis via Bcl-x_L inhibition results in reduced atherosclerotic plaque formation (78).

The role of inflammation in the onset and progression of atherosclerosis is supported by the recognition of increased cardiovascular (CV) risk associated with the presence of clonal hematopoiesis of indeterminate potential (CHIP) (79). These age-acquired somatic mutations occurring in hematopoietic stem cells within the bone marrow may confer upon them a competitive advantage, thereby facilitating the accumulation of their progeny—including mutated macrophages and neutrophils—in the peripheral blood. The majority of CHIP cases can be attributed to mutations in only a handful of genes, with all but one of them implicated in DNA or histone methylation defects, potentially influencing the modulation of inflammatory gene expression (79). For instance, monocytes/macrophages carrying CHIP-related mutations in Tet2, DNMT3A, or JAK2VF promote inflammasome activation, thus exhibiting increased expression of IL-1 and IL-6, alongside other inflammatory mediators (79–81). On the other hand, neutrophils carrying the JAK2VF mutation exhibit heightened NETosis (82). In addition to supporting the role of inflammation in atherosclerosis, the CHIP hypothesis may serve as a plausible bridge connecting age and atherosclerosis, which may occur, at least partly, through inflammation (83).

Following an initial ACS patients remain at increased CV risk, experiencing recurrent events in up to 20% of cases within 3 years, despite adherence to current guideline-directed medical therapy (6, 7). Notably, only one-third of these events are related to culprit lesions at the index event, while the other two-thirds are related to non-culprit lesions (84), underscoring the importance of plaque progression. Persistent coronary inflammation, extending beyond the culprit lesion, likely contributes to this progression. Ischemic events associated with non-culprit lesions typically involve TCFA or lipid-rich plaques, features strongly correlated with heightened inflammation (7, 80). Consequently, there exists substantial evidence supporting the relationship between persistent inflammation and the risk of recurrent cardiovascular events (85). Furthermore, hs-CRP seems to be a stronger predictor than residual cholesterol risk of new cardiovascular events and death (86).

Following acute coronary obstruction, infarct size and the acute remodeling that follows thereafter (also called infarct expansion), are directly related to ischemic time and ensuing cell death; and reperfusion injury, the latter also known as ischemic-reperfusion injury

Late in the course of MI, changes in LV size, shape, and thickness involving both the infarcted and non-infarcted myocardial segments are observed (26, 27). Adverse remodeling resulting in LV dilatation strongly correlates to adverse cardiovascular outcomes, such as heart failure (HF) and mortality (28, 110).

Chronic LV dilatation initiates early after MI and progresses for months or years thereafter, resulting in dilatation of the viable segments of the LV, as a compensatory mechanism for maintaining stroke volume despite the loss of significant myocardial mass (26, 27). The acute drop in stroke volume fosters the activation of a neurohumoral response, resulting in both hemodynamic and molecular changes. However, the neurohumoral response does not account for the discrepancy observed between the size of the initial MI and the magnitude of chronic LV remodeling. The inflammatory process involved in infarct healing and acute remodeling may also affect chronic LV remodeling (111, 112). In fact, the balance between a pro-inflammatory response with matrix degradation vs. a reparative response with collagen deposition may explain different degrees of late LV dilation (113, 114). Elevated levels of CRP measured at hospital admission, during the first days, or at discharge consistently predict adverse ventricular remodeling and HF (115, 116). On the other hand, persistent post-MI inflammation represents an additional potential pathogenetic mechanism of adverse ventricular remodeling. Proinflammatory cytokines such as TNF-a, IL-1β and IL-18 can exert direct actions on cardiomyocytes, leading to a cardio-depressant effect, cytotoxicity, and induction of apoptosis (114).

The NLRP3 inflammasome is a cytosolic, multimeric protein complex composed of three distinct components: NLR family pyrin domain-containing 3 (NLRP3), the adaptor protein apoptosis-associated speck-like protein containing a caspase-recruitment domain (ASC), and caspase-1 (122, 123). Triggered by various activators such as monosodium urate (MSU), cholesterol crystals, and ATP, a two-step process is initiated, leading to the activation of the potent inflammatory cytokines IL-1β and IL-18 (124–126). The NLRP3 inflammasome plays a central role in up-regulating the inflammatory milieu in ACS patients, making it an attractive target for modulating ACS-associated athero-inflammation.

Both basic and clinical studies have demonstrated the inhibitory effect of colchicine on the NLRP3 inflammasome. The initial study by Martinon and colleagues conducted on THP1 cells exposed to MSU crystals, revealed the suppressive effect of colchicine upon the NLRP3 inflammasome (127). Additionally, in bone marrow-derived macrophages and peripheral blood monocytes from FMF patients, colchicine administration markedly suppressed IL-1β expression (128). Furthermore, in peripheral blood monocytes from ACS patients, colchicine inhibited caspase-1 activity and IL-1β production (52).

While the exact pathway of colchicine's inhibition of the NLRP3 inflammasome remains elusive, recent studies have provided important insights. Using J774 macrophages treated with inflammasome inducers, Misawa et al. demonstrated that colchicine administration hindered the intracellular transport of ASC, preventing the co-localization of NLRP3, ASC, and caspase-1, thereby impeding inflammasome effector activity (129). Another study by Otani and colleagues observed the inhibitory effect of colchicine on caspase-1 protein expression in a mice model of NSAID small intestinal injury, without affecting mRNA levels of NLRP3 or IL-1 (130). Pore formation is a key step in ATP-induced inflammasome activation. Colchicine was shown to strongly inhibit P2X7 membrane pore formation in ATP-stimulated mouse peritoneal macrophages, resulting in decreased reactive oxygen species and IL-1β release (131). These findings, though diverse, collectively suggest that colchicine modulates various aspects of the NLRP3 inflammasome, particularly affecting its effector functions.

Regardless of the precise mechanism, the inhibition of monocyte/macrophage cytokine production by colchicine in ACS patients holds the potential to modulate processes following acute coronary occlusion and myocardial necrosis, as will be discussed later.

Previous research has extensively described the impact of colchicine on neutrophil function (132–134). Of importance, as a result of the lack of the P glycoprotein efflux pump, the drug accumulates in abundance within neutrophils, affecting their activity (135). In brief, colchicine impairs neutrophil chemotaxis and endothelial adhesion, seemingly through effects on E- and L-selectin. Additionally, colchicine appears to influence neutrophil deformability and motility, further hindering recruitment and extravasation.

Levels of NETosis positively correlate with myocardial infarct size, and NETs release inversely associates with myocardial perfusion after coronary angioplasty in ACS patients (136). Colchicine administration 6–24 h before coronary angioplasty in ACS patients resulted in a seven-fold lower production of NETs, measured in the coronary sinus during the procedure (137). Interestingly, this effect appeared to be driven by cytoskeleton α-tubulin stabilization, impairing NETs transport and release. Supporting these findings, colchicine has also been shown to limit NETosis in gallstones (138) and in neutrophils isolated from individuals with Behcet's disease (139).

Neutrophils and NETs actively contribute to plaque destabilization, complications, and myocardial remodeling post-MI. Therefore, their inhibition by colchicine could positively impact ACS patients.

Platelet activity is crucial for intracoronary thrombus formation following plaque destabilization and complications (i.e., rupture or erosion) (140). NETs, on the other hand, can promote thrombosis by enhancing all platelet functions (adhesion, activation, and aggregation) and increasing the accumulation of prothrombotic factors such as von Willebrand factor and fibrinogen (141).

In vitro, colchicine has been shown to reduce platelet aggregation by interfering with cytoskeleton rearrangement through cofilin and LIM domain kinase 1 inhibition (142). In healthy subjects, a single oral dose of 1.8 mg has been shown to reduce leukocyte-platelet aggregation (both monocyte and neutrophil) and levels of surface markers of platelet activity, including p-selectin and PAC-1 (activated GP IIb/IIIa) (143). Moreover, in another experiment, platelets from patients receiving dual antiplatelet therapy incubated with colchicine resulted in a reduction in Thrombin Receptor Activating Peptide (TRAP)-induced platelet aggregation (144). Furthermore, in subjects with clopidogrel resistance, the addition of colchicine also inhibited ADP-induced platelet aggregation (144).

Given the role of NETs in coronary thrombosis (145), it is plausible that the inhibition of NETs formation by colchicine, as previously described, can result in reduced thrombus production and thus a more favorable phenotype after acute plaque destabilization.

Evidence from both animal models and clinical studies supports a positive effect of colchicine upon atherosclerotic plaque formation. In a rabbit model of atherosclerosis induced by a high cholesterol diet and balloon endothelial denudation, colchicine treatment reduced the relative increase in aortic wall volume, measured as normalized wall index, and inflammation, measured as 18F-FDG uptake in PET/CT imaging, which could potentially lead to plaque stabilization (146). Furthermore, in a prospective non-randomized observational study including 80 patients with recent ACS, colchicine administration was associated with a reduction in low attenuation plaque volume (LAPV)—a CT scan surrogate of plaque instability and predictor of future coronary events. A positive correlation between LAPV and reduced hs-CRP levels was also reported (147).

Two randomized control trials (RCT) have examined the impact of colchicine on hard clinical outcomes in the aftermath of an ACS. The COLCOT trial randomized 4,745 patients to receive colchicine (0.5 mg daily) or placebo within 30 days post-MI. Colchicine led to a significant reduction of the primary outcome (a composite of death from cardiovascular causes, resuscitated cardiac arrest, myocardial infarction, stroke, or urgent hospitalization for angina leading to coronary revascularization) by 23% (HR 0.77; 95% CI 0.61–0.96; p = 0.02). This was mainly driven by a significant reduction in the incidence of stroke (HR 0.26; 95% CI 0.10–0.70) and urgent hospitalization for angina leading to coronary revascularization (HR 0.50; 95% CI 0.31–0.81) (148). Interestingly, in a post-hoc analysis of COLCOT, time-to-treatment initiation (i.e., length of time between the index MI and the initiation of colchicine) was inversely correlated with colchicine clinical benefit. Indeed, when administered in-hospital within the first 3 days after the event, colchicine was associated with a 48% reduction in the risk of ischemic events, which contrasted with a lack of benefit when started later (4–7 days, and 7–30 days) (149). A second study, the COPS trial, was an Australian-based study that randomly assigned 795 patients diagnosed with MI or unstable angina to receive colchicine (0.5 mg BID for 1 month, then 0.5 mg daily for 11 months) vs. placebo (150). Although the original trial failed to demonstrate a benefit on the 1-year primary outcome, an extended 24-month follow-up did show a significant 40% reduction in the composite of all-cause mortality, ACS, ischemia-driven- unplanned-urgent revascularization, and non-cardioembolic ischemic stroke (151). Of note, just as in COLCOT, the main outcome was driven by a significant reduction in urgent revascularization (HR, 0.19; 95% CI 0.05–0.66; p = 0.009) (151). It is noteworthy that the magnitude of the benefit obtained with colchicine in patients with previous ACS is comparable to that achieved by each of the mainstay therapies for the secondary prevention of coronary artery disease—such as antiplatelet agents and statins—and has been achieved against a background of modern optimal treatment with these therapies (152, 153). Table 2 summarizes the available data on colchicine in atherosclerotic plaque stabilization and prevention of acute coronary events.

Early colchicine administration may modulate the initial inflammatory response triggered by myocardial necrosis and the subsequent neutrophil recruitment during ischemia-reperfusion (IR) injury, impacting infarct size and acute myocardial remodeling (Figure 2).

Two animal studies explored the effect of colchicine after myocardial necrosis using mice models with permanent ligation of the left anterior descending coronary artery. In the study by Fujisue et al, colchicine administered orally after the onset of MI attenuated the inflammatory response by reducing the infiltration of inflammatory cells—both granulocytes at 24 h and macrophages at 3 and 7 days -, the activation of the NLRP3 inflammasome, and the levels of pro-inflammatory cytokines in the infarcted myocardium (154). This resulted in a reduced acute LV remodeling, showing less expansion of the LV scar size at histology and lower LV diastolic and systolic diameters, as well as higher ejection fraction at 1 week, which translated into reduced short-term mortality due to cardiac rupture (154). Likewise, in another study by Li et al., colchicine showed reduced acute cardiac remodeling as assessed by echocardiography at 7 and 28 days, and increased mice survival; interestingly, in this study the anti-inflammatory effect was mediated by a reduction in NETosis (155).

Two studies have explored the effect of colchicine in I-R injury using mice models with transient ligation of the left coronary artery. Firstly, Akodad et al. tested intraperitoneal administration of low-dose colchicine before reperfusion and showed decreased myocardial injury as assessed by troponin levels and infarct size in autopsy at 24 h. This effect was accompanied by a decrease in plasma levels of key cytokines implicated in the post-ischemic inflammatory response, such as IL-6 and Monocyte Chemoattractant Protein-1 (MCP-1) (156). Secondly, Mori et al. showed that intraperitoneal administration of colchicine starting one day after artery ligation demonstrated reduced macrophage infiltration in infarcted areas on days 3 and 7 (157). The two studies cited above showed a decrease in plasma levels of MCP-1. Interestingly, the chemokine receptor CCR2 that responds to MCP-1 predominates in the proinflammatory Ly-6C ^(high) monocyte subset (M1), underpinning the possible role of colchicine in modulating the balance of the main monocyte subsets implicated in post-MI inflammatory response, in favor of a more reparative Ly-6C ^(low) (M2) phenotype. Furthermore, in the study by Fujisue et al., colchicine tended to attenuate M1 cytokines (TNF-α, IL-1β, and IL-6) and to increase M2 cytokines [interleukin-10 (IL-10) and TGF-β], suggesting that this drug could affect the M1/M2 balance (143). The colchicine effect upon MCP-1 expression has also been confirmed in human samples from patients with ACS, impairing human-derived mononuclear cell migration capacity (158).

There is also clinical evidence of the effect of colchicine in reducing infarct size in humans. As mentioned above, colchicine administration 6–24 h before coronary angioplasty in ACS patients resulted in a seven-fold lower production of NETs, measured in the coronary sinus during the procedure (137), which may translate into reduced infarct size. However, results from phase 2 RCTs have been conflicting. In the pivotal study conducted by Deftereos et al., peri-PCI colchicine administration to STEMI patients significantly reduced CK-MB area-under-the-curve concentrations and, in a subset of patients, infarct size assessed by cardiac magnetic resonance (MRI) 1 week after MI (159). Conversely, in the CONVERT-MI, a very similar study in patients with STEMI, colchicine showed no effect on infarct size, as assessed through both biomarkers and MRI (160).

Two RCTs have evaluated the impact of colchicine in percutaneous coronary intervention (PCI) related MI. The Colchicine–PCI randomized controlled trial evaluated the effect of colchicine administration just before (1–2 h) PCI, in a mixed group of patients with stable angina and ACS. Pre-procedural colchicine did not protect against PCI-related myocardial injury (including PCI-related MI and MACE at 30 days) (161). Importantly, although they found that colchicine did decrease IL-6 and hs-CRP levels 24 h post PCI, it did not attenuate the increase of these biomarkers at 8 h, which may point to a lack of an anti-inflammatory effect of colchicine at the time of PCI, due to the short time of administration before the procedure. Thus, this might imply that the pharmacodynamic properties of colchicine require a longer time for the onset of its anti-inflammatory effect. Bearing this in mind, Cole and colleagues designed a similar RCT, administering colchicine to a mixed group of stable angina and ACS patients, but with a longer lead-in administration time before PCI (6–24 h) (162). They showed that colchicine administration significantly reduced major and minor peri-procedural MI and injury, especially in NSTEMI patients. Colchicine also significantly reduced pre-PCI inflammatory cytokine levels (IL-6, IL-1β, TNF-α, IFN-γ), and white blood cell counts, with no differences in post-PCI values (163). Table 3 summarizes the available studies on colchicine and acute myocardial injury.

Evidence for the role of colchicine in chronic LV remodeling is scarce, although the same preclinical animal models of MI or ischemia-reperfusion (I-R) injury can provide some insights into a potential role in late remodeling. In the aforementioned study by Fujisue et al., the reduction in post-MI acute remodeling was sustained throughout the study follow-up, with lower LV diastolic and systolic diameters, as well as higher ejection fraction at 4 weeks (154). In the model of I-R by Akodad et al., in addition to the acute cardioprotective effect, colchicine increased cardiac output in cardiac ultrasounds performed 8 weeks after transient artery ligation and lowered the histological assessment of fibrosis at 10 weeks after I-R injury (156). In the model of I-R by Mori et al, in addition to reduced macrophage infiltration, colchicine demonstrated reduced LV volumes and higher ejection fraction, as assessed by 99mTc-MIBI gated SPECT, with differences starting as early as 2 weeks after MI, but becoming statistically relevant at 8 weeks (157). Table 4 summarizes the available studies on colchicine and chronic LV remodeling. Translation of these results to clinical data is largely awaited.

Experimental evidence links IL-1 to atherosclerotic plaque formation, impaired vasodilation, and increased atherothrombosis (164). Interleukin-1 has two isoforms, IL-1α and IL-1β. While IL-1α ignites inflammation during MI, IL-1β expression during the subacute phase contributes to apoptosis and cardiac remodeling. As previously mentioned, in the CANTOS trial, patients with a history of MI and high levels of hs-CRP were randomized to receive either canakinumab or placebo, resulting in a 15% reduction in CV events, independent of aggressive cholesterol control (20).

Anakinra is an interleukin-1 receptor antagonist (IL-1Ra), resulting in the inhibition of both IL-1α and IL-1β. Patients with STEMI receiving anakinra showed lower levels of hs-CRP (165). Furthermore, a pooled analysis of the VCUART trials found anakinra to reduce the incidence of new-onset HF or hospitalization for HF at 1 year following STEMI (166). Although initial results seem promising, future trials testing the role of anakinra in ACS, and including a larger number of patients, are expected.

IL-6 is an effector cytokine downstream of IL-1β, playing a significant role in atherosclerosis. Cardiomyocytes produce IL-6 under ischemia, which leads to inflammation and cytotoxicity. Tocilizumab, a monoclonal antibody blocking IL-6 signaling, has shown success in treating conditions like rheumatoid arthritis (167). In a phase II trial involving non-STEMI patients, tocilizumab was shown to significantly reduce CRP levels (168). Recently, the ASSAIL-MI trial investigated the effect of a single dose of tocilizumab on STEMI patients within 6 h of symptoms, revealing a significant improvement in MRI-derived myocardial salvage index and less microvascular obstruction. In this trial, however, the reduction in final infarct size at 6 months was not statistically different, and the beneficial effect of tocilizumab seemed to be limited to patients presenting with more than 3 h after symptom onset (22). The ongoing ARTEMIS trial is testing the effect of Ziltivekimab, a novel IL-6 inhibitor, in patients admitted with myocardial infarction. The results are eagerly anticipated (clinicaltrials.gov/NCT06118281).

Methotrexate is an immunosuppressant drug with adenosine-mediated anti-inflammatory effects (169). It is commonly used as a treatment for systemic inflammatory diseases, including rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis. The CIRT trial administered low-dose methotrexate to patients with metabolic syndrome or type 2 diabetes with recent ACS. Methotrexate did not reduce levels of IL-1β, IL-6, or hs-CRP and was not associated with a reduction in cardiovascular events (21).