AB0276 HOW FAST CAN METHOTREXATE BE ESCALATED IN RHEUMATOID ARTHRITIS? A MULTICENTRE, PARALLEL-GROUP RANDOMIZED CONTROLLED TRIAL (MEIRA)
Authors: S. Jain, V. Dhir, A. Aggarwal, S. Maurya, R. Gupta, B. Leishangthem, A. Khullar, V. Dhawan, G. Naidu, S. K. Sharma, A. Sharma, S. Jain
Journal: Annals of the Rheumatic Diseases (2021)

Background: Literature regarding the optimal dose escalation strategy of methotrexate (MTX) in RA is scant and ambiguous (1). Concerns regarding the safety of rapid escalation may lead to delayed attainment of the optimal dose and treatment target. Objectives: To compare the efficacy, safety and tolerability of fast versus usual dose escalation of oral MTX in RA. Methods: This multicenter, open-label (assessor blinded) RCT included patients with active RA (SJC≥2 and TJC≥4) aged 18-55 years, not on DMARDs (except HCQ and/or low-dose prednisolone) and with disease duration &lt;5 years. Patients were randomized 1:1 into two groups with the same starting dose of oral MTX (15 mg/week), but escalated either by 5 mg every 2 weeks (fast escalation group) or 5 mg every 4 weeks (usual escalation group), till a maximum of 25 mg/wk. Primary outcome was proportion of EULAR good responders at 16 weeks. Secondary outcomes were change in DAS28-3 and EULAR responders (good or moderate) at 8 and 16 weeks, change in Indian HAQ at 16 weeks, and symptomatic (questionnaire based) and laboratory adverse effects over 16 weeks. RBC MTX polyglutamate-3 levels were measured using HPLC in both groups. There was an open-label extension phase till 24 weeks (use of other DMARDs was permitted beyond 16 weeks if target was not met), and DAS28-3 at 24 weeks was compared. Trial Reg : CTRI/2018/12/016549 Results: 178 patients (mean age 39.8 (8.6) years, 84% females) with mean disease duration of 1.9 (1.4) years were randomized (89 in each group). Mean DAS28ESR-3 and DAS28CRP-3 at enrollment were 6.3 (0.9) and 5.4 (1.1). At 16 weeks, there was no significant difference in good EULAR response by DAS28ESR-3 (5.6, 7.9%, p=0.9) or DAS28CRP-3 (28.1, 22.5%, p=0.8) between the two groups (Figure 1). The change in DAS28-ESR-3 at 8, 16 and 24 weeks (or by DASCRP-3, not shown) and improvement in HAQ at 16 weeks were also not significantly different (Table 1). Notably, there was no significant difference in symptomatic GI or CNS adverse effects, incidence of cytopenia, transaminitis or rates of drug discontinuation. RBC MTX polyglutamate-3 levels at 8 and 16 weeks were also similar (Table 1). Table 1. Key secondary efficacy and safety outcomes Parameter Usual Fast p-value Efficacy Delta DAS28-ESR-3 (Mean±SD) -8 wk -ITT (n=178) -0.9 ± 1.0 -0.8 ± 0.9 0.5 -PP (n=139) -1.2 ± 1.0 -1.1 ± 1.0 0.5 -16 wk -ITT -1.3 ± 1.1 -1.3 ± 1.0 0.9 -PP -1.6 ± 1.1 -1.6 ± 0.9 1 -24 wk -ITT -1.6 ± 1.3 -1.5 ± 1.1 0.3 -PP -2.1 ± 1.2 -1.8 ± 1.1 0.14 Delta Indian HAQ (16 wk) -0.7 ± 0.6 -0.8 ± 0.6 0.2 Adverse effects Serious AE 0 0 - Death 0 0 - Symptomatic AE ever* n (% ) Vomiting 7 (8) 7 (8) 1 Nausea 22 (26) 26 (30) 0.5 Stomach ache 16 (19) 17 (20) 0.9 Loss of appetite/bad taste 21 (25) 27 (31) 0.3 Lethargy 20 (24) 21 (25) 1 Dizziness 19 (23) 16 (19) 0.5 Irritability/anxiety 14 (16) 14 (16) 1 Laboratory AE ever* [n/N times done (%)] Transaminitis episodes (&gt;40IU/L) 52/224 (23) 52/219 (24) 0.9 -Significant (&gt;80 IU/L) 5/224 (2) 8/219 (4) 0.4 Thrombocytopenia episodes (&lt;150000/uL) 10/224 (5) 13/218 (6) 0.5 -Significant (&lt;100000/uL) 2/224 (1) 2/218 (1) 1 Leucopenia episodes (&lt;4000/uL) 2/224 (1) 3/220 (1.5) 0.8 -Significant (&lt;3500/uL) 1/224 (0.5) 2/220 (1) 0.8 Methotrexate levels MTX-polyglutamate-3 (nmol/L) -8 wk 25.8 ± 10.5 26.9 ± 13.6 0.6 -16 wk 40.7 ± 20.9 40.1 ± 23.4 0.9 *Ever=any time during the study ITT= intention-to-treat, PP=per-protocol, AE=adverse effect Figure 1. EULAR response and change in DAS28ESR-3 over time Conclusion: A faster escalation of MTX (5 mg every 2 weeks) reaching 25 mg/week by 4 weeks did not have a significantly higher rate of adverse effects (symptomatic or laboratory) compared to an escalation by 5 mg every 4 weeks. Although not more efficacious, it may shorten the time to recognize MTX failure, and optimize treat-to-target. References: [1]Visser K, Katchamart W, Loza E, et al. Multinational evidence-based recommendations for the use of methotrexate in rheumatic disorders with a focus on RA: integrating systematic literature research and expert opinion of a broad international panel of rheumatologists in the 3E Initiative. Ann Rheum Dis. 2009;68(7):1086–93 Disclosure of Interests: None declared