Effectiveness of Tofacitinib in rheumatoid arthritis patients stratified by background Methotrexate dose group
The results of study confirm the greater clinical and radiographic efficacy of Tofacitinib plus Methotrexate (MTX) as compared to placebo plus Methotrexate in rheumatoid arthritis (RA) patients showing inadequate response to MTX.
Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as Methotrexate (MTX) are the first-line treatment option for patients suffering from rheumatoid arthritis (RA).
Conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as Methotrexate (MTX) are the first-line treatment option for patients suffering from rheumatoid arthritis (RA). The patients who show an inadequate response(IR) to csDMARDs are advised for treatment with other possibilities: biologic DMARDs (bDMARDs) like tumor necrosis factor inhibitors (TNFi) or targeted synthetic small-molecule DMARDs (tsDMARDs) given in combination with csDMARDs. Early interventions with csDMARDs, usually MTX has been favorable in attaining a promising clinical response in few patients, with resulting modification of the course of the disease. Also, there is some evidence which suggest that the concomitant use of MTX in combination with a bDMARD such as Tofacitinib can be beneficial in achieving treatment goals.
Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The effectiveness and safety of Tofacitinib 5 and 10 mg twice daily (BID), as monotherapy or in combination with csDMARDs has been evaluated in Phase 2 and Phase 3 clinical trials and long-term extension studies. Both MTX naïve patients and those with an IR to treatment with DMARDs, including csDMARDs (primarily MTX) and TNFi were included in the clinical development program of Tofacitinib.
ORAL Scan was a Phase 3 clinical trial that assessed Tofacitinib 5/10 mg BID vs. placebo, all with stable background MTX, in MTX-IR patients with RA. There was an improvement in the clinical manifestation of the disease, and the advancement of structural damage was also reduced with Tofacitinib plus MTX as compared to placebo plus MTX at month 6.
Rationale behind research
- There is lack of data regarding the effect of Methotrexate doses (minimum or maximum) in conjunction with bDMARD on the clinical outcomes
- The present study is the post hoc analysis of the data from the ORAL scan that focuses on evaluating the effectiveness of Tofacitinib in combination with Methotrexate doses (minimum or maximum) in patients who have rheumatoid arthritis.
To evaluate the beneficial effects of Tofacitinib when administered in combination with different dose ranges of Methotrexate
- Study outcomes
- Efficacy analysis by American College of Rheumatology (ACR 20/50/70), least squares mean (LSM) change from baseline in Clinical Disease Activity Index (CDAI) score, and the proportion of patients achieving low disease activity (CDAI score≤10) and remission (CDAI score≤2.8);
- Functional status assessed by LSM change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, including the proportion of patients achieving HAQ-DI <0.5.
- Radiographic progression analysis by LSM change from baseline in van der Heijde modified Total Sharp Score (mTSS)
Time Points: Baseline, and after 3 and 6 months
Baseline: There were no significant variations in the baseline demographics and disease characteristics across the MTX dose categories.
- Clinical efficacy: At months 3 and 6, ACR20/50/70 response rates were higher for both Tofacitinib doses vs. Placebo across all MTX doses.
- Disease activity and functional outcomes: At month 3, mean changes from baseline in CDAI and HAQ-DI were significantly higher for both Tofacitinib doses vs. placebo, irrespective of MTX category; improvements were maintained at month 6. Both Tofacitinib doses demonstrated improvements in DAS28–4(ESR), and less structural progression vs. placebo, across MTX doses at month 6.
Figure 1: Proportion of patients achieving CDAI ≤10 at month 6 by MTX dose category
Figure 2: Proportion of patients achieving CDAI ≤2.8 at month 6 by MTX dose category
Figure 3: Proportion of patients achieving HAQ-DI < 0.5 at month 6 by MTX dose category
- Radiographic progression: No clear relationship between radiographic progression and MTX dose was observed at month 6 with Tofacitinib 5 or 10 mg BID. Generally, less radiographic progression was observed with both Tofacitinib 5 and 10 mg BID plus MTX compared with placebo plus MTX. In the placebo-treated patients, less radiographic progression was observed in the moderate and high MTX dose groups compared with the low MTX dose group.
The present study confirms that the concomitant use of a bDMARD with MTX can be clinically beneficial in MTX-IR patients. But, it is still not clear if there is a minimum dose of MTX that, when given in combination with bDMARDs, affects clinical outcomes.
A previous trial of MTX- and bDMARD-naïve patients treated with Adalimumab 40 mg every other week in conjunction with MTX at different doses showed an inclination towards increased efficacy with increasing MTX doses. However, the effectiveness of Adalimumab plus 10/20 mg of MTX weekly seemed equivalent. The Dutch Rheumatoid Arthritis Monitoring (DREAM) registry also reported similar kind of results.
Overall, the outcomes of this study indicate that the effect of Tofacitinib is irrespective of background MTX dose and that concomitant high-dose MTX may not be required for Tofacitinib efficacy.