Background/Purpose: To evaluate possible interaction effect by concomitant methotrexate (MTX) use on the risk of drug discontinuation for adalimumab (ADA) compared with etanercept (ETN) in anti-tumor necrosis factor (anti-TNF)-naïve patients with rheumatoid arthritis (RA).

Methods: This retrospective nationwide population-based cohort study identified 4592 anti-TNF-naïve RA patients (age at diagnosis ≥ 16 years) in whom ETN (n = 2,609) or ADA (n = 1,983) was initiated using administrative data. The outcome was the time to anti-TNF drug discontinuation. We defined drug discontinuation as non-persistence of prescription for more than 84 days. After adjusting for baseline characteristics and concomitant use of disease modifying anti-rheumatic drugs (DMARDs), the risk of drug discontinuation for ADA compared with that of ETN was quantified by calculating relative risk (RR) with 95% confidence intervals (CI) using Cox proportional hazard regression analysis for the follow-up time before and after one year. Subgroup analysis was conducted based on the average weekly dose of concomitant methotrexate use (i.e. not use, ≤10 mg, >10mg).

Results: During the first year of follow-up, 562 of 1,982 ADA users and 682 of 2,609 ETN users withdrew anti-TNF drugs after 1,507 and 2,094 person-years of follow-up respectively, and the incidence rates of drug withdrawal were 0.37 and 0.33 case per person-year. The crude and adjusted RRs of drug discontinuation for ADA compared with ETN were 1.16 (95% CI, 1.04–1.30) and 1.10 (95% CI, 0.98–1.23). The adjusted RR with 95% CIs for those with 0, ≤10mg/week and >10 mg/week concomitant MTX use were 0.83 (0.64–1.06), 0.91 (0.75–1.11) and 1.53 (1.28–1.82) respectively (p for interaction <0.001). If the follow-up time exceeded one year, 376 of 969 ADA users and 616 of 866 ETN users discontinued anti-TNF drugs after 1,012 and 1,846 person-years of follow-up respectively, and the incidence rates of drug discontinuation were 0.37 and 0.33 case per person-year. The crude and adjusted RRs of drug discontinuation for ADA compared with ETN were 1.07 (95% CI, 0.94–1.22) and 0.98 (95% CI, 0.86–1.12). The adjusted RRs with 95% CIs for those with 0, ≤10mg/week and >10 mg/week concomitant MTX use were 0.85 (0.68–1.06), 0.93 (0.77–1.15) and 1.42 (1.06–1.90) respectively (p for interaction 0.026).

Conclusion: Among anti-TNF naïve RA patients, compared with ETN users, ADA users had a significantly higher risk of drug discontinuation if the concomitant MTX dose was more than 10 mg/week.

Table 1. The adjusted relative risks with 95% confidence intervals of drug discontinuation for ADA compared with ETN
Follow-up time	No MTX use	≤10 mg/week	>10 mg/week	P value for interaction
Within 1 year	0.83 (0.64–1.06)	0.91 (0.75–1.11)	1.53 (1.28–1.82)	<0.001
After 1 year	0.85 (0.68–1.06)	0.93 (0.77–1.15)	1.42 (1.06–1.90)	0.026
Note: Cox proportional hazard regression analyses per conducted after adjusting for the variables with p values less than 0.2 in univariate comparisons between adalimumab and etanercept, including sex, age at anti-TNF initiation, RA duration, Charlson comorbidity index (≤1, >2) within one year before anti-TNF use, the use of MTX (not use, ≤10 mg/week, >10 mg/week), leflunomide, salazopyrin, non-steroid anti-inflammatory drugs within one year before and after anti-TNF use, and average daily prednisolone equivalent (≤5 mg, >5 mg) within one year before anti-TNF use.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/concomitant-methotrexate-use-and-the-risk-of-drug-discontinuation-for-adalimumab-compared-with-etanercept-in-anti-tnf-naive-rheumatoid-arthritis-patients-a-nationwide-population-based-cohort-study/