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

Abstract

Background 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. Design CIRT will randomize up to 7,000 participants with cardiovascular disease and no systemic rheumatic disease to either LDM (target dose 15–20 mg/week) or placebo for an average follow-up period of 3–5 years; subjects in both treatment arms receive folic acid 1 mg daily for six days each week. The primary endpoints of CIRT include recurrent 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. Summary 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.

Rheumatoid Arthritis Disease Activity Predicting Incident Clinically Apparent Rheumatoid Arthritis–Associated Interstitial Lung Disease: A Prospective Cohort Study

“…Conversely, we found no association of methotrexate use with risk of RA‐ILD, and a previous secondary analysis of placebo‐controlled studies showed no association of methotrexate use with pulmonary outcomes . An analysis of a double‐blind randomized placebo‐controlled trial of methotrexate is ongoing . Further studies are needed to establish whether disease activity affects the onset and course of RA‐ILD and to understand the role that particular DMARDs may play in its pathogenesis.…”

Protective effect of antirheumatic drugs on dementia in rheumatoid arthritis patients

“…There is also an association between the levels of cytokines important in the pathogenesis of RA, such as tumor necrosis factor-α or interleukin-10, and progression of dementia [8] , [31] , [32] . The widespread reporting of reductions in cardiovascular events associated with MTX use, many initially seen in patients with RA, has subsequently led to large-scale randomized controlled trials in the general population to assess whether MTX can improve outcomes after myocardial infarction [33] .…”

The Contribution of Autoantibodies to Inflammatory Cardiovascular Pathology

“…The CANTOS trial provides confirmation of the “inflammation hypothesis” in CVD through robust clinical analysis, a critical milestone on the path toward a more comprehensive understanding of the role of inflammation in CV pathology. Although the additional clinical trials are currently underway that target other inflammatory mediators in CVD ( 5 , 6 ), many unresolved questions remain regarding the specific cellular and molecular immune mechanisms that promote chronic CV inflammation. Therefore, a significant challenge facing the field of CVD research is to define these critical immune mediators, particularly those that can be targeted therapeutically.…”