Discontinuation of Methotrexate After Initiation of Tofacitinib in the Treatment of Rheumatoid Arthritis

Purpose and Aim of the Study

According to international recommendations, the standard for RA treatment are disease-modifying antirheumatic drugs (DMARDs). In the first line, conventional synthetic DMARDs (csDMARDs) such as MTX are recommended, and in case of insufficient effectiveness, the addition of biological or targeted DMARDs. Biological and targeted treatments can be gradually discontinued upon achieving sustained remission, similarly to MTX later on.

Tofacitinib is an oral Janus kinase (JAK) inhibitor used in the treatment of moderate to severe RA in patients with inadequate response or intolerance to MTX. It can be administered as monotherapy or in combination with MTX or another non-biological/non-targeted DMARD. Its efficacy at a dose of 5 or 10 mg twice daily, both in monotherapy and in combination, has been demonstrated in controlled studies for up to 114 months. Administering tofacitinib as monotherapy in previously untreated patients or in those with an inadequate response to csDMARDs or biological DMARDs led to alleviation of RA symptoms and signs.

The combination of tofacitinib with MTX has proven efficacy, but it is associated with problematic adherence. Within 2 years, 30% of patients discontinue MTX, half of whom cite poor tolerance, especially elevated liver enzymes and gastrointestinal issues, as the reason. Following the initiation of treatment with tocilizumab, 31% of patients reduce or discontinue MTX within 6 months, and 38% within one year. The recent randomized ORAL Shift study demonstrated that some RA patients who achieve low disease activity on tofacitinib + MTX can discontinue MTX without significant worsening of RA activity.

An American-Canadian team attempted to evaluate this approach in real-world practice. The authors used retrospective data from health insurance databases and compared treatment outcomes in RA patients who discontinued or interrupted MTX after starting tofacitinib versus those who continued MTX therapy combined with tofacitinib.

Methodology and Analyzed Data

This retrospective analysis included patients from the MarketScan^® databases who started treatment with tofacitinib combined with oral MTX between January 2013 and April 2017. Patients had to have records from 12 months before and 12 months after the first tofacitinib prescription, and each of the mentioned drugs had to be prescribed to them at least twice. They were then categorized into groups with persistent MTX treatment (≤ 90-day gap in MTX use), MTX discontinuation (> 90-day gap in MTX use and end of 12-month follow-up), and MTX interruption (> 90-day gap in MTX use).

The persistence and adherence to tofacitinib treatment and its effectiveness were evaluated. Persistence was defined as ≤ 90-day gap in tofacitinib use, and adherence as the proportion of days covered by treatment. Effectiveness was assessed based on six parameters including adherence ≥ 80%, absence of dose escalation of tofacitinib from 5 to 10 mg, absence of switching to another biological/targeted DMARD, absence of adding a non-biological DMARD, absence of increased doses of oral glucocorticoids, and ≤ 1 glucocorticoid injection. Additional monitored parameters included healthcare costs related to RA and overall healthcare expenses.

Findings

In total, 671 patients were included, 75.1% continued MTX treatment, 19.5% discontinued, and 5.4% interrupted. Persistence, adherence, and effectiveness of tofacitinib were comparable after 12 months between the group with persistent MTX treatment and the group that discontinued MTX. Persistence on tofacitinib was 68.7% in the persistent MTX treatment group and 72.5% in the MTX discontinuation group (odds ratio [OR] 0.87; 95% confidence interval [CI] 0.56–1.37; p = 0.56). Adherence to tofacitinib was 74% and 73% respectively in these groups.

All six effectiveness parameters were comparable between the continued MTX treatment group and the MTX discontinuation group (OR 0.90; 95% CI 0.59–1.37; p = 0.62), although the percentage of patients switching to another modern DMARD was higher in the continued MTX use group (11.4% vs. 4.6%; p = 0.003).

Healthcare costs related to RA (p < 0.0001) and total expenses on pharmacotherapy (p < 0.05) were significantly higher in the continued MTX treatment group compared to the MTX discontinuation group.

Discussion and Conclusion

The results of this real-world data analysis from the USA suggest that in RA patients starting treatment with tofacitinib combined with oral MTX, MTX can be discontinued without negatively impacting persistence, adherence, and treatment efficacy of tofacitinib compared to those continuing MTX therapy. Additionally, discontinuation of MTX is associated with reduced healthcare costs for RA. These findings indicate the potential for a personalized therapeutic approach tailored to the specific needs and treatment tolerance of RA patients.

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Source: Cohen S. B., Haraoui B., Curtis J. R. et al. Impact of methotrexate discontinuation, interruption, or persistence in US patients with rheumatoid arthritis initiating tofacitinib + oral methotrexate combination. Clin Ther 2022 Jun 3: S0149-2918(22)00153-9, doi: 10.1016/j.clinthera.2022.05.002 [Epub ahead of print].