Efficacy and Safety of Tofacitinib Not Impacted by Dose-Switching


While patients with rheumatoid arthritis may benefit from either increasing or decreasing their dosage of tofacitinib, post-hoc analysis indicates that safety and efficacy of the medication is not impacted by these changes.

Increasing tofacitinib dosage from 5 to 10 mg twice daily (BID) or reducing dosage from 10 to 5 mg BID did not affect the efficacy or safety of the medicine in patients with rheumatoid arthritis (RA), according to a study published in Springer.1

“Many DMARDs offer prescribers flexibility with different dosing regimens, permitting a tailored approach by means of scaling up treatment to meet therapeutic targets or to treat flares in RA, or dosing down in response to adverse events (AEs) or remission,” investigators stated. “In clinical practice, Dose-up strategies with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) can result in improved outcomes for patients with RA, suggesting a rationale for this approach. The judicious dosing down of therapies in the context of sustained (≥ 6 months) remission or low disease activity (LDA) can [also] be part of the therapeutic strategy, according to the most recent European Alliance of Associations for Rheumatology (EULAR) guidelines for the management of RA.”

In this post-hoc analysis of the open-label, long-term extension study, ORAL Sequel (NCT00413699), investigators determined whether patients treated with tofacitinib would be affected by dosage changes. Patients received either 5 mg BID (Stay-on 5), 10 mg BID (Stay-on 10), their dosage was increased from 5 to 10 mg BID (Dose-up), or the medication was reduced from 10 to 5 mg (Dose-down). Changes from baseline regarding the Disease Activity Score in 28 joints (DAS28), DAS28 minimum clinically important difference (MCID), LDA, Health Assessment Questionnaire-Disability Index (HAQ-DI), Clinical Disease Activity Index (CDAI), Simplified Disease Activity Index (SDAI), and remission (DAS28 scores < 2.6, CDAI scores ≤ 2.8, SDAI scores ≤ 3.3) were recorded. Safety, which included adverse events (AEs), discontinuation of the medication, AEs of special interest, and serious AEs, was assessed by exposure-adjusted event rates (EAERs).

Eligible patients had a clinical diagnosis of RA according to the American College of Rheumatology (ACR) 1987 Revised criteria and showed inadequate response to csDMARDs, biologic DMARDs (bDMARDs), and were methotrexate-naïve (MTX-naïve).

Dosage adjustments could be made at any time and patients were able to either receive tofacitinib as monotherapy or in combination with background RA medication, excluding bDMARDs.

Of the 4481 patients observed, 23.4% (n = 1049) switched their dosage at least 1 time, 4.9% (n = 218) were switched 2 times, and 2.0% (n = 90) switched more than twice. A total of 1037 patients began treatment on 5 mg BID, of which 27.0% (n = 280) had their dosage increased to 10 mg BID. For patients initially receiving 10 mg BID (n = 2916), 16.3% (n = 476) had a reduction in medication to 5 mg BID.

DAS28 was shown to improve at higher rates (p < 0.05) in the Dose-up cohort compared with the Stay-on 5 group at the 3-, 9-, and 12-month follow-ups. These results were mirrored in both MCID and remission rates. HAQ-DI scores were higher in the Dose-up group compared with the Stay-on 5 group beginning at month 6. SDAI and CDAI scores were significantly improved in the Dose-up group when compared with the Stay-on 5 group from month 9 onwards. Conversely, baseline changes were comparable in the Dose-down and Stay-on 10 groups at these checkpoints. The rates of LDA and safety were similar across all treatment groups.

AEs and serious AEs were comparable across the 4 groups between months 3 to 6 and 6 to 12. However, at baseline and 3 months, the Dose-down group had a higher percentage of AEs when compared with the Stay-on 10 group (39.1% vs 33.4%). Those who switched doses were more likely to discontinue treatment with tofacitinib. Generally, rates of AEs were low. Serious infections (SIs), herpes zoster (HZ), deep vein thrombosis (DVT), and pulmonary embolism (PE) were similar between the Dose-up group and Stay-on 5 group as well as the Dose-down group and Stay-on 10 group.

The post-hoc nature and open-label design limits the analysis as the ORAL Sequel study was not originally designed to determine safety and efficacy between the 4 groups analyzed. Additionally, patients included in this study were previously shown to have tolerability for tofacitinib. This potentially indicates that switching doses may have been based on disease activity rather than safety or efficacy reasons, which may introduce bias.

“In this analysis, dosing up from tofacitinib 5 to 10 mg BID was associated with improved efficacy up to 12 months compared with staying on 5 mg BID,” investigators concluded. “Importantly, patients dosing down from 10 to 5 mg BID generally did not significantly differ in terms of their disease activity, versus those remaining on 10 mg BID.”

Currently, the recommended dosage of tofacitinib is 5 mg BID.


Mueller RB, Schulze-Koops H, Furst DE, et al. Effect of dose adjustments on the efficacy and safety of tofacitinib in patients with rheumatoid arthritis: a post hoc analysis of an open-label, long-term extension study (ORAL Sequel) [published online ahead of print, 2022 Jan 1]. Clin Rheumatol. 2022;10.1007/s10067-021-05908-z. doi:10.1007/s10067-021-05908-z

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