POS0219 EFFECT OF LOW-DOSE METHOTREXATE ON ESTIMATED GLOMERULAR FILTRATION RATE AND KIDNEY ADVERSE EVENTS IN THE CARDIOVASCULAR INFLAMMATION REDUCTION TRIAL
Authors: J. Sparks, K. Vanni, M. Sparks, C. Xu, L. Santacroce, R. Glynn, P. Ridker, D. Solomon
Journal: Annals of the Rheumatic Diseases (2021)

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 &lt;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/1.73m 2 , 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 &lt;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 &lt;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 &lt;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 ) Events Rate per 100 person-years (95%CI ) Events Rate per 100 person-years (95%CI ) SCr collected at safety visits Any event* 159 3.42 (2.93, 3.98) 187 4.06 (3.53, 4.67) 0.83 (0.67, 1.02) Mild (SCr 1.5-1.9x baseline) 154 3.47 (2.97, 4.06) 177 4.06 (3.51, 4.69) 0.85 (0.68, 1.06) Moderate (SCr 2-2.9x baseline) 19 0.41 (0.26, 0.64) 24 0.52 (0.35, 0.78) 0.78 (0.43, 1.43) Severe (SCr ≥3x baseline) 2 0.04 (0.01, 0.17) 5 0.11 (0.05, 0.26) 0.40 (0.08, 2.04) Adjudicated clinical kidney adverse events Any event* 37 0.80 (0.58, 1.11) 42 0.92 (0.68, 1.24) 0.87 (0.56, 1.36) Mild 24 0.52 (0.35, 0.77) 25 0.55 (0.37, 0.81) 0.95 (0.55, 1.67) Moderate 11 0.24 (0.13, 0.43) 11 0.24 (0.13, 0.43) 1.00 (0.43, 2.29) Severe 4 0.09 (0.03, 0.23) 8 0.17 (0.09, 0.35) 0.50 (0.15, 1.64) New dialysis 1 0.02 (0.00, 0.15) 3 0.17 (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.