Cardiovascular Inflammation Reduction Trial Research Articles

Coronary Flow Reserve, Inflammation, and Myocardial Strain: The CIRT-CFR Trial

Inflammation is a key determinant of cardiovascular outcomes, but its role in heart failure is uncertain. In patients with cardiometabolic disease enrolled in the prospective, multicenter ancillary study of CIRT (Cardiovascular Inflammation Reduction Trial), CIRT-CFR (Coronary Flow Reserve to Assess Cardiovascular Inflammation), impaired coronary flow reserve was independently associated with increased inflammation and myocardial strain despite well-controlled lipid, glycemic, and hemodynamic profiles. Inflammation modified the relationship between CFR and myocardial strain, disrupting the association between cardiac blood flow and function. Future studies are needed to investigate whether an early inflammation-mediated reduction in CFR capturing microvascular ischemia may lead to heart failure in patients with cardiometabolic disease. (Cardiovascular Inflammation Reduction Trial [CIRT]; NCT01594333; Coronary Flow Reserve to Assess Cardiovascular Inflammation [CIRT-CFR]; NCT02786134).

Abstract 140: Plasma Interleukin-6 Levels And Cardiovascular Events In The Cirt Trial: Consistent Associations For Incident Coronary, Cerebrovascular, And Peripheral Artery Disease

Introduction: Inflammation is causally related to atherothrombosis. Interleukin-1β (IL-1β) and interleukin-18 (IL-18) require NLRP3 inflammasome for activation and have downstream effects on interleukin-6 (IL-6), a marker previously associated with high risk of coronary artery and cerebrovascular disease (CCVD). However, data pertaining to peripheral artery disease (PAD) are sparse and could offer druggable targets in this disease. Methods: We conducted a prospective cohort study of 4248 patients with type 2 diabetes or metabolic syndrome and prior coronary artery disease who participated in the NIH-funded Cardiovascular Inflammation Reduction Trial (CIRT). Participants were followed for up to 5 years for incident CCVD and symptomatic PAD events. Randomized treatment with low-dose methotrexate (vs. placebo) had no effect on event rates or plasma levels of inflammatory biomarkers. Baseline levels of IL-1β, IL-18, and IL-6 were tested for association with incident vascular events. Kaplan-Meier curves and Cox proportional hazards models (adjusted for traditional risk factors) were estimated. Results: In multivariable adjusted analyses, hazard ratios for the lowest (referent) to highest baseline quartiles of IL-6 were 1.0, 1.5, 1.8, and 2.0 (p-trend <0.001) and 1.0, 1.2, 2.5, and 2.0 (p-trend = 0.04) for incident CCVD (N=349) and PAD (N=87), respectively. Baseline IL-6 levels above vs. below the median (2.50 pg/ml) were associated with a 56% increased risk of CCVD (HR 1.56, 95% CI 1.26-1.93) and a 113% increased risk PAD (HR 2.13, 95% CI 1.36-3.32) (Figure 1). Baseline levels of IL-1β and IL-18 did not associate with incident CCVD or PAD. Conclusion: In this contemporary cohort of secondary prevention patients, elevated IL-6 was associated with both incident CCVD and PAD. These data support exploration of direct IL-6 inhibition for PAD prevention, a strategy currently being pursued to reduce risk of coronary artery and cerebrovascular disease.

Interleukin-6 Levels and Cardiovascular Events in the Cardiovascular Inflammation Reduction Trial: Consistent Associations for Incident Coronary, Cerebrovascular, and Peripheral Artery Disease

Interleukin-6 Levels and Cardiovascular Events in the Cardiovascular Inflammation Reduction Trial: Consistent Associations for Incident Coronary, Cerebrovascular, and Peripheral Artery Disease

Coronary Flow Reserve, Inflammation and Myocardial Strain in the Cardiovascular Inflammation Reduction Trial (CIRT-CFR)

Coronary Flow Reserve, Inflammation and Myocardial Strain in the Cardiovascular Inflammation Reduction Trial (CIRT-CFR)

POS0219 EFFECT OF LOW-DOSE METHOTREXATE ON ESTIMATED GLOMERULAR FILTRATION RATE AND KIDNEY ADVERSE EVENTS IN THE CARDIOVASCULAR INFLAMMATION REDUCTION TRIAL

Background:Low-dose methotrexate (LD-MTX) is a common first-line treatment for systemic rheumatic diseases, and its use is contraindicated in advanced chronic kidney disease (CKD) because it is primarily excreted by the kidneys. Among patients with preserved kidney function, the safety of LD-MTX on estimated glomerular filtration rate (eGFR) and kidney adverse events (AEs) has not been established.Objectives:To investigate the effect of LD-MTX on eGFR and kidney AEs using data from a randomized clinical trial.Methods:We performed a secondary analysis for eGFR and kidney AEs using the randomized double-blind, placebo-controlled Cardiovascular Inflammation Reduction Trial. Adults with known cardiovascular disease and diabetes and/or metabolic syndrome were randomly allocated to oral LD-MTX (target dose 15-20 mg/week) or placebo. All participants took folic acid 1 mg six days/week. Exclusion criteria included systemic inflammatory disease and creatinine clearance <40 mL/min (by Cockcroft-Gault). eGFR was calculated using the CKD-EPI formula. Clinical kidney AEs were blindly adjudicated. The least-squares mean change of eGFR from baseline was calculated at each study visit; the difference in eGFR slopes between LD-MTX and placebo was compared using a modified intention-to-treat approach. We also compared rates of kidney AEs for LD-MTX versus placebo using Cox proportional hazards models.Results:A total of 2,391 subjects were randomized to LD-MTX and 2,395 to placebo. At baseline, mean age was 66 years, 19% were female, mean eGFR was 80.0 mL/min/1.73m2, and 18% had stage 3 CKD or worse. Median follow-up duration was 23 months, and median LD-MTX dose was 16 mg/week. Those randomized to LD-MTX had less decline in eGFR over the entire follow-up compared to placebo (slope difference 1.12, 95%CI 0.59-1.65, p<0.001, Figure 1). Those with CKD stage 3 or worse on LD-MTX saw less eGFR decline than those with CKD stage 2 or better (slope difference among CKD stage 3 or worse: 2.46, 95%CI 1.10-3.82, p<0.001; p for interaction 0.02). The LD-MTX group had higher eGFR than placebo over the first 24 months of study follow-up (p<0.05 at each visit). On safety laboratory monitoring, there were 159 acute kidney injury AEs in the LD-MTX group and 187 in the placebo group (HR 0.83, 95%CI 0.67-1.02, Table 1). There were 37 clinical kidney AEs in the LD-MTX group and 42 in the placebo group (0.87, 95%CI 0.56-1.36). One subject began dialysis in the LD-MTX group compared to 3 in the placebo group.Table 1.Rates and hazard ratios for kidney adverse events per random assignment of low-dose methotrexate or placebo in the Cardiovascular Inflammation Reduction Trial (n=4,786).Low-dose methotrexate (n=2,391)Placebo (n=2,395) (reference)HR (95%CI)EventsRate per 100 person-years (95%CI)EventsRate per 100 person-years (95%CI)SCr collected at safety visitsAny event*1593.42 (2.93, 3.98)1874.06 (3.53, 4.67)0.83 (0.67, 1.02)Mild (SCr 1.5-1.9x baseline)1543.47 (2.97, 4.06)1774.06 (3.51, 4.69)0.85 (0.68, 1.06)Moderate (SCr 2-2.9x baseline)190.41 (0.26, 0.64)240.52 (0.35, 0.78)0.78 (0.43, 1.43)Severe (SCr ≥3x baseline)20.04 (0.01, 0.17)50.11 (0.05, 0.26)0.40 (0.08, 2.04)Adjudicated clinical kidney adverse eventsAny event*370.80 (0.58, 1.11)420.92 (0.68, 1.24)0.87 (0.56, 1.36)Mild240.52 (0.35, 0.77)250.55 (0.37, 0.81)0.95 (0.55, 1.67)Moderate110.24 (0.13, 0.43)110.24 (0.13, 0.43)1.00 (0.43, 2.29)Severe40.09 (0.03, 0.23)80.17 (0.09, 0.35)0.50 (0.15, 1.64)New dialysis10.02 (0.00, 0.15)30.17 (0.09, 0.35)0.34 (0.04, 3.17)*Acute kidney injury presence and severity was defined by KDIGO (Kidney Disease: Improving Global Outcomes) classification.CI, confidence interval; HR, hazard ratio; SCr, serum creatinine.Conclusion:These results demonstrate the kidney safety of LD-MTX among patients without advanced CKD at baseline. We observed a possible beneficial effect of LD-MTX on preserving kidney function, suggesting that inflammation may be involved in the pathogenesis of CKD in this population.Disclosure of Interests:Jeffrey Sparks Consultant of: Dr. J Sparks has performed consultancy for Bristol-Myers Squibb, Gilead, Inova Diagnostics, Optum, and Pfizer unrelated to this work., Grant/research support from: Dr. J Sparks has received research support from Bristol-Myers Squibb., Kathleen Vanni: None declared, Matthew Sparks: None declared, Chang Xu: None declared, Leah Santacroce: None declared, Robert Glynn Grant/research support from: Dr. Glynn has received grant support unrelated to the present research from AstraZeneca, Kowa, Pfizer, and Novartis., Paul Ridker Consultant of: Dr. Ridker has served as a consultant to Corvidia, Inflazome, and CiviBioPharm., Grant/research support from: Dr. Ridker receives research support unrelated to the present study from Kowa, Novartis, and Amarin., Daniel Solomon Grant/research support from: Dr. Solomon receives research support unrelated to the present study from Abbvie, Amgen, Corrona, Genentech, Janssen, and Pfizer.

Update on the Inflammatory Hypothesis of Coronary Artery Disease.

The pathogenesis and progression of coronary artery disease (CAD) is now known to be largely driven by inflammation on top of the well-accepted role for the disequilibrium between cholesterol deposition and removal from the arterial wall. Recent clinical trials have supported the inflammatory hypothesis of CAD and will be discussed in this review. The clinical trial Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) found that treatment with canakinumab, an anti-interleukin-1β agent, resulted in a reduction in non-fatal myocardial infarction, non-fatal stroke, or death. This provided evidence for the inflammatory hypothesis of CAD. However, canakinumab is not cost-effective for widespread therapy and more cost-effective treatments are warranted. The Cardiovascular Inflammation Reduction Trial (CIRT), Colchicine Cardiovascular Outcomes Trial (COLCOT), and Low-Dose Colchicine 2 (LoDoCo2) are recent clinical trials that increased the understanding of the inflammatory hypothesis of CAD. Cost-effective therapies targeting inflammation are the future of preventative CAD treatment. Additional clinical trials with anti-inflammatory and anti-cytokine agents would help delineate the most beneficial target for CAD prevention.

Adverse effects related to methotrexate polyglutamate levels: adjudicated results from the cardiovascular inflammation reduction trial.

Methotrexate is widely used at low dosages (LD-MTX) for non-oncologic indications and is associated with a variety of adverse effects (AEs). We sought to determine whether concentrations of the active metabolite, MTX polyglutamates (MTX-PGs) 1-5, correlate with AEs. We examined data from the LD-MTX arm of the randomized double-blind Cardiovascular Inflammation Reduction Trial (CIRT). All AEs were blindly adjudicated and monitoring laboratories were tested centrally. The MTX-PGs 1-5 were assessed in one reference laboratory using liquid chromatography-tandem mass spectrometry. Based on prior literature, MTX-PGs 3-5 were chosen as the exposure of interest and quartiles of MTX-PGs 3-5 were assessed for their relationship with all AEs and each pre-specified category of AE using adjusted Cox proportional hazards regression. Of the 2391 subjects randomized to LD-MTX, MTX-PG levels were available for 1319 subjects (median dosage 16.1 mg/week) from the 8 month visit. We followed these subjects for a median of 2.2 years [interquartile range (IQR) 1.5-2.9]. Higher MTX-PG3-5 levels were related to an increased risk of anaemia [compared with quartile 1 (Q1); hazard ratio (HR) for Q4 1.27 (95% CI 0.98, 1.65), P for trend = 0.05] and a decreased risk of thrombocytopenia [HR for Q4 0.52 (95% CI 0.32, 0.84), P for trend = 0.05]. MTX-PG3-5 levels >134 nmol/l were associated with an increased risk of liver abnormalities [HR 1.36 (95% CI 1.08, 1.72)]. Higher MTX- PG3-5 levels were modestly associated with LD-MTX AEs, including anaemia and liver function abnormalities, but a reduced risk of thrombocytopenia and haemorrhage. NCT01594333.

Adverse Effects of Low-Dose Methotrexate in a Randomized Double-Blind Placebo-Controlled Trial: Adjudicated Hematologic and Skin Cancer Outcomes in the Cardiovascular Inflammation Reduction Trial.

ObjectiveLow‐dose methotrexate (LD‐MTX), a cornerstone in the treatment of rheumatoid arthritis, is associated with a moderately increased risk of anemia, leukopenia, and skin cancers, but the risks of myelosuppression and malignancy during LD‐MTX use remain incompletely described. We examined the risks of cytopenias and skin cancers among patients taking LD‐MTX versus placebo in a large randomized controlled trial (RCT).MethodsWe prespecified secondary analyses of a double‐blind, placebo‐controlled RCT that included adults with known cardiovascular disease and diabetes or metabolic syndrome in the United States and Canada. Subjects were randomly allocated to LD‐MTX (20 mg/week maximum) or placebo. All subjects received folic acid (1 mg daily for 6days/week). We assessed the frequency of blindly adjudicated hematologic and malignant adverse events (AEs).ResultsA total of 2391 subjects were randomized to LD‐MTX (mean dosage 14.9 mg/week), and 2395 were randomized to placebo. During follow‐up, in the LD‐MTX arm, simultaneous two‐line cytopenias (n = 92 [3.9%]) or pancytopenia (n = 13 [0.54%]) were infrequent. Pancytopenia developed as soon as 4 months and as late as 3.5 years after beginning LD‐MTX, though the latter subject had been recently diagnosed with multiple myeloma. Overall skin cancer risk was increased in users of LD‐MTX compared with users of placebo, which driven largely by a statistically significant increased risk of squamous cell skin cancer (hazard ratio [HR] 3.31; 95% confidence interval [CI] 1.63‐6.71). Melanoma was increased in LD‐MTX, but this was not statistically significant (HR 2.33; 95% CI 0.60‐9.01).ConclusionsAmong subjects using LD‐MTX, simultaneous two‐line cytopenias and pancytopenia were uncommon. We found more cases of skin cancer, particularly squamous cell carcinomas, in the LD‐MTX arm than the placebo arm.

Pulmonary Adverse Events in Patients Receiving Low‐Dose Methotrexate in the Randomized, Double‐Blind, Placebo‐Controlled Cardiovascular Inflammation Reduction Trial

ObjectiveWe previously reported that low‐dose methotrexate (MTX) was associated with an increased risk of pulmonary adverse events (AEs) in a large randomized, placebo‐controlled trial. Herein, we report details on the predictors and severity of pulmonary AEs.MethodsWe conducted a prespecified analysis of pulmonary AEs in the Cardiovascular Inflammation Reduction Trial. Adults with known cardiovascular disease and diabetes/metabolic syndrome were randomly allocated to receive low‐dose MTX (target dose 15–20 mg/week) or placebo after a 6–8‐week open‐label run‐in phase in which all patients received low‐dose MTX. Individuals with systemic inflammatory diseases were excluded. Pulmonary AEs were adjudicated in a blinded manner. We described severe pulmonary AEs and examined associations of baseline characteristics with pulmonary AEs in patients receiving low‐dose MTX.ResultsA total of 2,391 subjects were randomized to receive low‐dose MTX and 2,395 to receive placebo. There were 13 severe pulmonary AEs (0.5%) and 7 cases of possible pneumonitis (0.3%) in the low‐dose MTX group, compared to 8 (0.3%) and 1 (<0.1%), respectively, in the placebo group. Among those randomized to receive low‐dose MTX, risk factors for any pulmonary AE included female sex (hazard ratio [HR] 1.69 versus male sex [95% confidence interval (95% CI) 1.16–2.45]), white race (HR 2.35 versus other race [95% CI 1.03–5.36]), and insulin use (HR 1.60 versus non‐use [95% CI 1.11–2.30]). The only risk factor for severe pulmonary AEs was older age at baseline (HR 1.09 per year increase [95% CI 1.02–1.16]).ConclusionIn this large placebo‐controlled trial, pulmonary AEs, including possible pneumonitis, were uncommon but were more likely to occur in those randomized to receive low‐dose MTX. White race, older age, male sex, and insulin use were associated with an increased risk of pulmonary AEs in those receiving low‐dose MTX.

Immunity, inflammation and the vasculature in the COVID-19 era

Immunity, inflammation and the vasculature in the COVID-19 era

Comparison of interleukin-6, C-reactive protein, and low-density lipoprotein cholesterol as biomarkers of residual risk in contemporary practice: secondary analyses from the Cardiovascular Inflammation Reduction Trial.

In epidemiologic cohorts initiated >30 years ago, inflammatory biomarkers, such as interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hsCRP) were shown to independently predict future cardiovascular events with a magnitude of effect comparable to that of low-density lipoprotein cholesterol (LDLC). Whether aggressive contemporary therapy for atherosclerosis has altered these relationships is unknown yet has major implications for future drug development. Interleukin-6, hsCRP, and LDLC were measured at baseline in up to 4168 North American patients enrolled in the contemporary Cardiovascular Inflammation Reduction Trial with prior myocardial infarction or multivessel coronary disease who additionally had diabetes or metabolic syndrome and were followed for a period of up to 5 years for incident major recurrent cardiovascular events and all-cause mortality. Three-quarters of the cohort were previously revascularized and the great majority was taking statins, angiotensin blocking agents, beta-blockers, and antithrombotic agents. Participants were randomly allocated to low-dose methotrexate 15 mg weekly or to placebo. Randomized use of methotrexate had no effect on event rates nor plasma levels of IL-6, hsCRP, or LDL over time. Yet, baseline levels of IL-6, hsCRP, and LDLC were all predictors of major recurrent cardiovascular events; adjusted hazard ratios [HR; 95% confidence interval (CI)] for the lowest to highest baseline quartiles of IL-6 were 1.0 (referent), 1.66 (1.18-2.35), 1.92 (1.36-2.70), and 2.11 (1.49-2.99; P < 0.0001), while adjusted HRs for increasing quartiles of hsCRP were 1.0 (referent), 1.28 (0.92-1.79), 1.73 (1.25-2.38), and 1.79 (1.28-2.50; P < 0.0001) and adjusted HRs for increasing quartiles of LDLC were 1.0 (referent), 1.12 (0.78-1.62), 1.25 (0.87-1.79), and 2.38 (1.72-3.30; P < 0.0001). Effect estimates were not statistically different in these analyses for comparisons between IL-6, hsCRP, or LDLC, although IL-6 was the strongest predictor of all-cause mortality. The highest absolute risks were observed among those with elevated levels of both cholesterol and inflammation [HR 6.4 (95% CI 2.9-14.1) for those in the top quartiles of baseline IL-6 and LDLC, HR 4.9 (95% CI 2.6-9.4) for those in the top quartiles of baseline hsCRP and LDLC, both P < 0.0001]. Despite aggressive contemporary secondary prevention efforts, the relationships between inflammation, cholesterol, and cardiovascular risk are largely unchanged from those described two decades ago. These data are consistent with the hypothesis that future treatments for atherosclerosis may require a combination of inflammation inhibition and additional cholesterol reduction. ClinicalTrials.gov NCT01594333.

From CANTOS to CIRT to COLCOT to Clinic: Will All Atherosclerosis Patients Soon Be Treated With Combination Lipid-Lowering and Inflammation-Inhibiting Agents?

From CANTOS to CIRT to COLCOT to Clinic: Will All Atherosclerosis Patients Soon Be Treated With Combination Lipid-Lowering and Inflammation-Inhibiting Agents?

New evidence on the role of inflammation in CVD risk.

Based on compelling data from animal and human studies, over the past few decades, the viewpoint of atherosclerosis as an exclusively lipid-driven disease, has been gradually replaced by the concept of a chronic low-grade inflammatory process of the arterial wall. This review presents a brief description on the role of inflammation in atherosclerosis, and examines selected anti-inflammatory interventions that have been tested in clinical trials designed to prevent adverse cardiovascular disease (CVD) events and excess CVD risk. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study trial has provided convincing evidence that neutralization of the interleukin (IL)-1β inflammatory pathway by the selective antibody canakinumab reduces major CVD events and significantly lowers IL-1β, IL-6 and high-sensitivity C-reactive protein, without affecting low-density lipoprotein cholesterol levels. In contrast, in the latest Cardiovascular Inflammation Reduction Trial, low-dose methotrexate compared with placebo did not reduce CVD events, probably because there was no reduction in IL-1β, or in downstream inflammatory biomarker levels either. Notwithstanding the utilization of effective medical treatments including statins and proprotein convertase subtilisin/kexin type 9 inhibitors or precise revascularizations, the recurrence of CVD events remains unacceptably high. Canakinumab is, at present, the only anti-inflammatory agent that has been proven to reduce cardiovascular events in patients with elevated markers of inflammation without modifying cholesterol levels. Nevertheless, clinical application related to this new evidence and associated knowledge has not yet been implemented in daily practice.

Novel Antiatherosclerotic Therapies.

Many measures can control lipid risk factors for atherosclerosis. Yet, even with excellent control of dyslipidemia, other sources of risk remain. Hence, we must look beyond lipids to address residual risk. Lifestyle measures should form the foundation of cardiovascular risk control. Many pharmacological interventions targeting oxidation have proven disappointing. A large program tested inhibition of a LpPLA2 (lipoprotein-associated phospholipase A2), culminating in 2 large-scale clinical trials that did not meet their primary end points. A variety of antioxidants have not shown benefit in clinical trials. Numerous laboratory and clinical studies have inculpated inflammatory pathways in the pathogenesis of atherosclerotic events. The p38 MAPK (mitogen-activated protein kinase) inhibitor losmapimod and an inhibitor of a leukocyte adhesion molecule, P-selectin, did not alter adverse events in trials. Low-dose methotrexate, despite the promising observational studies, did not lower biomarkers of inflammation or alter cardiovascular outcomes in the CIRT (cardiovascular inflammation reduction trial). Four large-scale investigations underway will determine colchicine's ability to reduce recurrent events in secondary prevention. The CANTOS (Canakinumab Anti-inflammatory Thrombosis Outcomes Study) showed that an antibody that neutralizes IL (interleukin)-1β can reduce recurrent cardiovascular events in secondary prevention. The success of CANTOS points to the pathway that leads from the NLRP3 (NOD-like receptor family, pyrin domain-containing protein 3) inflammasome through IL-1β to IL-6 as an attractive target for further study and clinical development beyond lipid therapies to address the unacceptable burden of risk that remains despite our best current care in secondary prevention.

Anticytokine Agents: Targeting Interleukin Signaling Pathways for the Treatment of Atherothrombosis

The recognition that atherosclerosis is a complex chronic inflammatory disorder mediated through both adaptive and innate immunity has led to the hypothesis that anticytokine therapies targeting specific IL (interleukin) signaling pathways could serve as powerful adjuncts to lipid lowering in the prevention and treatment of cardiovascular disease. Cytokines involved in human atherosclerosis can be broadly classified as proinflammatory and proatherogenic (such as IL-1, IL-6, and TNF [tumor necrosis factor]) or as anti-inflammatory and antiatherogenic (such as IL-10 and IL-1rA). The recent CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcomes Study) has shown that specific targeting of IL-1β can significantly reduce cardiovascular event rates without lipid or blood pressure lowering. In CANTOS, the magnitude of benefit of this cytokine-targeted approach to atherosclerosis treatment was associated to the magnitude of reduction of the central signaling cytokine IL-6 and the downstream clinical biomarker high-sensitivity CRP (C-reactive protein). By contrast, in the recent CIRT (Cardiovascular Inflammation Reduction Trial), low-dose methotrexate neither reduced IL-1β, IL-6, or high-sensitivity CRP nor lowered cardiovascular event rates. Taken together, these 2 contemporary trials provide proof of principle that focused cytokine inhibition, not broad-spectrum anti-inflammatory therapy, is likely to be crucial for atheroprotection. This review provides an overview of cytokines in atherosclerosis, the potential benefits and risks associated with targeted anticytokine therapies, and a look to the future of clinical practices addressing residual inflammatory risk.

Investigating methotrexate toxicity within a randomized double-blinded, placebo-controlled trial: Rationale and design of the Cardiovascular Inflammation Reduction Trial-Adverse Events (CIRT-AE) Study.

The role of low dose methotrexate (LDM) in potential serious toxicities remains unclear despite its common use. Prior observational studies investigating LDM toxicity compared LDM to other active drugs. Prior placebo-controlled clinical trials of LDM in inflammatory conditions were not large enough to investigate toxicity. The Cardiovascular Inflammation Reduction Trial (CIRT) is an ongoing NIH-funded, randomized, double-blind, placebo-controlled trial of LDM in the secondary prevention of cardiovascular disease. We describe here the rationale and design of the CIRT-Adverse Events (CIRT-AE) ancillary study which aims to investigate adverse events within CIRT. CIRT will randomize up to 7000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose: 15-20mg/week) or placebo for an average follow-up period of 3-5 years; subjects in both treatment arms receive folic acid 1mg daily for 6 days each week. The primary endpoints of CIRT include recurrent cardio vascular events, incident diabetes, and all-cause mortality, and the ancillary CIRT-AE study has been designed to adjudicate other clinically important adverse events including hepatic, gastrointestinal, respiratory, hematologic, infectious, mucocutaneous, oncologic, renal, neurologic, and musculoskeletal outcomes. Methotrexate polyglutamate levels and genome-wide single nucleotide polymorphisms will be examined for association with adverse events. CIRT-AE will comprehensively evaluate potential LDM toxicities among subjects with cardiovascular disease within the context of a large, ongoing, double-blind, placebo-controlled trial. This information may lead to a personalized approach to monitoring LDM in clinical practice.

ANTI-INFLAMMATORY THERAPY FOR ATHEROSCLEROSIS: CONTRIBUTION TO AND LESSONS OF RHEUMATOLOGY

According to modern views, chronic low-grade inflammation, the development of which is associated with the uncontrolled activation of both innate and acquired immunity, plays a fundamental role at all stages of the atherosclerotic process. The contribution of inflammation to the development of an atherosclerotic vascular lesion drew attention to the similarity of the mechanisms in the immunopathogenesis of atherosclerosis and the classic immunoinflammatory disease (IID) – rheumatoid arthritis (RA). Interleukin 1β (IL-1β), which plays an important role in the development of many acute and chronic IIDs, is of particular interest with regard to its implication in the pathogenesis of an atherosclerotic vascular lesion and as a promising therapeutic target. The atherosclerosis development mechanisms related to IL-1β determine the ability of cholesterol crystals and other proatherogenic factors to induce IL-1β synthesis due to NLRP3 inflammasome activation. There is strong evidence that inflammation plays a role in the development of atherosclerosis as a whole and that anti-inflammatory therapy has good prospects particularly in the randomized placebo-controlled trial (RPCT) CANTOS (Canakinumab ANti-inflammatory Thrombosis Outcomes Study) investigating the efficiency of treatment with canakinumab (Novartis International AG), an anti-IL-1β monoclonal antibodies, in patients with severe atherosclerotic vascular lesions as a new approach to secondary prevention of cardiovascular events. Methotrexate (MTX) has now been convincingly shown to be an effective drug (a gold standard) in not only controlling the inflammatory activity of RA, but also in significantly reducing the risks of cardiovascular catastrophes. This has served as a basis for planning the RPCT CIRT (The Cardiovascular Inflammation Reduction Trial) to evaluate the antiatherogenic effect of MTX in the general population of patients with coronary heart disease. The CANTOS results and the experience gained in rheumatology to determine the cardiovascular effects of innovative anti-inflammatory drugs are of great importance in improving the secondary prevention of atherosclerosis-related cardiovascular events.

Initial experience of carbon ion radiotherapy for unresectable locally advanced pancreatic cancer

Inflammation plays a fundamental role in atherothrombosis. Yet, whether direct inhibition of inflammation will reduce the occurrence of adverse cardiovascular outcomes is not known.The Cardiovascular Inflammation Reduction Trial (CIRT) (ClinicalTrials.gov NCT01594333) will randomly allocate 7,000 patients with prior myocardial infarction (MI) and either type 2 diabetes or the metabolic syndrome to low-dose methotrexate (target dose 15-20 mg/wk) or placebo over an average follow-up period of 3 to 5 years. Low-dose methotrexate is a commonly used anti-inflammatory regimen for the treatment of rheumatoid arthritis and lacks significant effects on lipid levels, blood pressure, or platelet function. Both observational and mechanistic studies suggest that low-dose methotrexate has clinically relevant antiatherothrombotic effects. The CIRT primary end point is a composite of nonfatal MI, nonfatal stroke, and cardiovascular death. Secondary end points are all-cause mortality, coronary revascularization plus the primary end point, hospitalization for congestive heart failure plus the primary end point, all-cause mortality plus coronary revascularization plus congestive heart failure plus the primary end point, incident type 2 diabetes, and net clinical benefit or harm. CIRT will use standardized central methodology designed to ensure consistent performance of all dose adjustments and safety interventions at each clinical site in a manner that protects the blinding to treatment but maintains safety for enrolled participants.CIRT aims to test the inflammatory hypothesis of atherothrombosis in patients with prior MI and either type 2 diabetes or metabolic syndrome, conditions associated with persistent inflammation. If low-dose methotrexate reduces cardiovascular events, CIRT would provide a novel therapeutic approach for the secondary prevention of heart attack, stroke, and cardiovascular death.

Methotrexate Inhibits Proliferation but not Proteoglycan Synthesis or Glycosaminoglycan Hyperelongation in Human Vascular Smooth Muscle Cells

Objectives: Atherosclerosis is a disease process involving the early deposition of lipids in the vessel wall trapped by modified proteoglycans and subsequently a chronic inflammatory process leading to the clinical events. MTX has been chosen to study the potential efficacy of an anti inflammatory agent in preventing atherosclerosis and secondary cardiovascular disease in the cardiovascular inflammation reduction trial (CIRT). Methods: We have investigated cell proliferation and growth factor stimulated synthesis in vascular smooth muscle (VSMC) to assess some of the direct effects of MTX. Experiments were conducted in cultured human VSMC. Proliferation was assessed by the gold standard technique of cell counting and synthesis by 35S radiosulafate incorporation and size analysis by SDS PAGE. Key findings: MTX had a concentration-dependent inhibitory effect on serum stimulated VSMC proliferation with a maximum and total inhibitory effect at 10 μM. Thrombin, platelet-derived growth factor and transforming growth factor beta stimulated synthesis and increased the size of the biglycan molecules but MTX (10 μM) had no effect on any of these responses. Conclusions: The outcome of a trial with MTX will reflect the potential of targeting inflammation for the prevention of atherosclerosis and it remains an interesting proposition to evaluate the effects of a proteoglycan inhibitor on atherosclerosis.

Role of vascular inflammation in coronary artery disease: potential of anti-inflammatory drugs in the prevention of atherothrombosis. Inflammation and anti-inflammatory drugs in coronary artery disease.

Coronary artery disease (CAD) and acute myocardial infarction (AMI) are inflammatory pathologies, involving interleukins (ILs), such as IL-1β, IL-6 and tumor necrosis factor (TNF)-α, and acute phase proteins production, such as for C reactive protein (CRP). The process begins with retention of low-density lipoprotein (LDL) and its oxidation inside the intima, with the formation of the "foam cells." Toll-like receptors and inflamassomes participate in atherosclerosis formation, as well as in the activation of the complement system. In addition to innate immunity, adaptive immunity is also associated with atherosclerosis through antigen-presenting cells, T and B lymphocytes. AMI also increases the expression of some ILs and promotes macrophage and lymphocyte accumulation. Reperfusion increases the expression of anti-inflammatory ILs (such as IL-10) and generates oxygen free radicals. Although CAD and AMI are inflammatory disorders, the only drugs with anti-inflammatory effect so far widely used in ischemic heart disease are aspirin and statins. Some immunomodulatory or immunosuppressive promising therapies, such as cyclosporine and colchicine, may have benefits in CAD. Methotrexate also has potential cardioprotective anti-inflammatory effects, through increased adenosine levels. The TETHYS trial (The Effects of mETHotrexate Therapy on ST Segment Elevation MYocardial InfarctionS trial) will evaluate low-dose methotrexate in ST elevation AMI. The CIRT (Cardiovascular Inflammation Reduction Trial), in turn, will evaluate low-dose methotrexate in patients with a high prevalence of subclinical vascular inflammation. The CANTOS (The Canakinumab Antiinflammatory Thrombosis Outcomes Study) will evaluate canakinumab in patients with CAD and persistently elevated CRP. The blockage of other potential targets, such as the IL-6 receptor, CC2 chemokine receptor and CD20, could bring benefits in CAD.