Abstract
Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We investigated concomitant methotrexate (MTX) dose on tofacitinib efficacy/safety in Japanese RA patients.
Methods: This post hoc analysis pooled data from a 3-month phase 2 study (NCT00603512) and a 24-month phase 3 study (NCT00847613). Patients (N= 254) received tofacitinib (low-dose (1 or 3 mg), 5 mg, 10 mg) twice daily (BID) or placebo, with low-dose (>0 to 8 mg/week) or high-dose (>8 mg/week) MTX. Efficacy (ACR20/50/70 and DAS28-4 (ESR)<2.6 response rates; changes from baseline (CFB) in DAS28-4 (ESR) and HAQ-DI) and safety (adverse events (AEs), discontinuations due to AEs, serious AEs, and deaths) were assessed through month 3.
Results: At month 3, ACR20/50/70 response rates, mean DAS28-4 (ESR) CFB and HAQ-DI CFB were similar across MTX doses and generally greater for all tofacitinib doses versus placebo. AE rates with low-dose/high-dose MTX were: placebo, 28.6%/52.9%; tofacitinib low-dose, 50.0%/66.7%; 5 mg BID, 56.5%/64.3%; 10 mg BID, 73.8%/67.7%.
Conclusion: Tofacitinib efficacy in Japanese RA patients may be unaffected by background MTX dose. AE rates with low-dose versus high-dose MTX were lower with placebo, tofacitinib low-dose or 5 mg BID, but not 10 mg BID, with no apparent differences across system organ class/laboratory parameters.
Introduction
Rheumatoid arthritis (RA) is a chronic and debilitating autoimmune disease characterized by inflammation of the articular synovium leading to deformity, progressive disability, and ultimately, joint destruction [Citation1]. As a result, RA has a major effect on health status and quality of life [Citation2]. In Japan, the prevalence of RA differs by region but is estimated to range from 0.6 to 1.0% [Citation3], and the unique genetic and environmental backgrounds of the Japanese population can influence the efficacy and safety of treatments for RA in Japanese patients, compared with Western patients [Citation4].
The current guidelines of the European League Against Rheumatism (EULAR) have identified RA remission or low disease activity as primary goals of treatment, through the use of a ‘treat-to-target’ approach [Citation5]. EULAR recommends the use of conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), such as methotrexate (MTX), in conjunction with glucocorticoids, with the aim of target attainment within 6 months [Citation5]. In addition, current guidelines from the American College of Rheumatology (ACR) and the Asia Pacific League of Associations for Rheumatology recommend initial treatment with csDMARDs, such as MTX [Citation6,Citation7]. Not all patients achieve treatment goals with MTX and for those patients with an inadequate response, biologic (b)DMARDs or targeted synthetic DMARDs, such as tofacitinib, are alternative options when poor prognostic factors are present [Citation5,Citation6,Citation8].
A recent study has reported that increasing the dose of MTX administered concomitantly with the bDMARD adalimumab is associated with an increase in the proportion of patients achieving clinical efficacy endpoints [Citation9]. A study in Japan has also shown that adalimumab plus MTX ≥10 mg/week consistently resulted in better improvement in disease activity score in 28 joints (DAS28) and resulted in more patients with DAS28-remission, compared with adalimumab plus MTX <10 mg weekly [Citation10]. In a further Japanese study, MELODY, which assessed the effects of adalimumab in combination with a range of MTX doses (>0 to <4, 4 to <6, 6 to <8, 8 to <10, and ≥10 mg/week), low disease activity/remission rates improved with increasing MTX dose up to 6 to <8 mg/week, plateauing at the higher doses [Citation11].
While increasing the MTX dose can improve outcomes, adverse events (AEs) with MTX have also been reported to be dose dependent [Citation9,Citation12]. In the MELODY study, there were no significant differences in the incidences of serious infections or serious adverse drug reactions between MTX dose groups; although, there was a significantly higher incidence of infections in patients who received the highest MTX dose [Citation11]. Furthermore, mean MTX dose has been shown to be an independent risk factor for the onset of lymphoproliferative disease in Japanese patients with RA [Citation12].
Tofacitinib is an oral Janus kinase inhibitor for the treatment of RA. The efficacy and safety of tofacitinib 5 and 10 mg twice daily (BID) administered as monotherapy or in combination with csDMARDs, mainly MTX, in patients with moderately to severely active RA, has been demonstrated in global phase 2 [13–15] and phase 3 trials of up to 24 months’ duration [Citation16–21], and in long-term extension studies with up to 114 months’ observation [Citation22–24]. In Japan, the efficacy and safety of tofacitinib in patients with RA as monotherapy [Citation25] and in combination with MTX [Citation26] has been demonstrated in two randomized, 12-week, phase 2 studies (A3921040 [NCT00687193] and A3921039 [NCT00603512]), and in an LTE study (A3921041 [NCT00661661]) [Citation24]. In addition, 118 Japanese patients were included in the global phase 3, 24-month randomized controlled trial ORAL Scan (A3921044 [NCT00847613]) [Citation20]. Tofacitinib 5 mg BID administered as monotherapy or in combination with csDMARDs is approved in Japan for the treatment of patients with RA who have an inadequate response to at least one csDMARD or bDMARD [Citation27]. The higher dose of 10 mg BID has not been approved for use in Japan for patients with RA.
In this analysis, we describe the efficacy and safety of tofacitinib administered for 12 weeks with low-dose (>0 to ≤8 mg/week) or high-dose (>8 mg/week) MTX in Japanese patients with RA who were enrolled in a Japanese phase 2 or a global phase 3 study.
Materials and methods
Study design and patients
In this post hoc analysis, data were pooled from Japanese patients with RA who had been treated with tofacitinib in a Japanese phase 2 (A3921039 [NCT00603512]) [Citation26] or a global phase 3 (ORAL Scan, A3921044 [NCT00847613]) [Citation20] randomized controlled trial.
Full details of the study designs have been reported previously [Citation20,Citation26]. In summary, A3921039 was a 12-week, randomized, double-blind, placebo-controlled, parallel-group phase 2 study of patients with moderately to severely active RA. Patients eligible for enrollment had an inadequate response to MTX received continuously for ≥4 months at a stable dose of ≥6 mg/week for ≥6 weeks prior to baseline. Patients were randomized 1:1:1:1:1 to receive tofacitinib 1 mg, 3 mg, 5 mg, 10 mg, or placebo BID. All patients remained on their stable dose of background MTX throughout the study (mean MTX dose, 8.1–9.0 mg/week) [Citation26].
ORAL Scan was a 24-month, randomized, double-blind, placebo-controlled, parallel-group phase 3 study [Citation20]. Eligible patients had moderately to severely active RA and an inadequate response to ≥6 weeks’ stably dosed MTX. In the global study, the target MTX dose was 15–25 mg weekly; before and during the study, weekly doses of MTX >25 mg were not permitted for any patient and stable weekly doses of MTX <15 mg were permitted only in the presence of intolerance to, or toxicity from, higher doses or where higher doses would not be in accordance with local regulatory approval (as in Japan). Patients were randomized 4:4:1:1 to receive tofacitinib 5 mg BID, tofacitinib 10 mg BID, placebo advanced to tofacitinib 5 mg BID, or placebo advanced to tofacitinib 10 mg BID. Patients randomized to placebo were advanced to tofacitinib at 3 months if they did not meet minimal responder criteria (≥20% improvement in swollen and tender joint counts) or at 6 months for all other patients. Therefore, all data collected up to month 3 on patients randomized to placebo reflect exposure only to placebo. Tofacitinib dose adjustment was not permitted during the study.
Data were pooled across studies by treatment group, i.e. for patients receiving low-dose tofacitinib (1 mg or 3 mg BID), tofacitinib 5 mg BID, tofacitinib 10 mg BID, or placebo. For each tofacitinib dose level, data were also stratified based on MTX dose, i.e. low-dose (>0 to ≤8 mg/week) or high-dose (>8 mg/week) background MTX.
All studies were conducted in accordance with the Declaration of Helsinki and International Conference on Harmonisation Guidelines for Good Clinical Practice. The protocols were approved by the Institutional Review Board at each study center. All patients provided written informed consent.
Efficacy assessments
Efficacy endpoints included proportion of patients achieving 20%, 50% or 70% improvement in ACR criteria (ACR20/50/70 response rates), proportion of patients achieving a DAS in 28 joints, erythrocyte sedimentation rate (DAS28-4 [ESR])<2.6 (remission) [Citation6], change from baseline in DAS28-4 (ESR) score, and change from baseline in the Health Assessment Questionnaire-Disability Index (HAQ-DI) score. Efficacy data are reported up to month 3.
Safety assessments
All available safety data through month 3 are presented. Safety endpoints include AEs, discontinuations due to AEs, serious AEs (defined as any AE which was life-threatening, required either in-patient hospitalization or prolongation of existing hospitalization, or resulted in persistent or significant disability, incapacity or congenital birth defects, or death), and all-cause mortality.
Statistical analyses
In this post hoc analysis, the primary analysis population was the full analysis set, which included all randomized Japanese patients who received at least one dose of study medication and had at least one post-baseline measurement. For binary variables, missing values were imputed using the non-responder imputation method (NRI; nonresponsive patients who advanced at month 3, or those who discontinued from treatment for any reason prior to month 3 were set to nonresponsive; at month 3, there were 26 patients with imputed ACR20/50/70 values, and 25 patients with imputed DAS28-4 [ESR]<2.6 values); for continuous variables, no imputation was applied. The safety analysis set was defined as those patients who received at least one dose of study medication. All efficacy and safety endpoints are reported by descriptive statistics (i.e. no formal hypothesis tests were conducted).
Results
Patients
A total of 254 Japanese patients from the two studies (A3921039 and ORAL Scan [A3921044]) were randomized to receive low-dose tofacitinib (n = 55), tofacitinib 5 mg (n = 74), tofacitinib 10 mg BID (n = 73), or placebo (n = 52). Of these, 157 patients received tofacitinib or placebo with low-dose MTX (low-dose tofacitinib, n = 34; tofacitinib 5 mg BID, n = 46; tofacitinib 10 mg BID, n = 42; placebo, n = 35) and 97 patients received tofacitinib or placebo with high-dose MTX (low-dose tofacitinib, n = 21; tofacitinib 5 mg BID, n = 28; tofacitinib 10 mg BID, n = 31; placebo, n = 17; ). The mean weekly MTX dose for patients receiving low-dose MTX and high-dose MTX at baseline was 7.2–7.5 mg/week and 11.2–11.5 mg/week, respectively. Only two Japanese patients received a weekly dose of MTX >16 mg (tofacitinib 10 mg BID, n = 1; placebo, n = 1). Within each tofacitinib dose group, demographics and baseline disease characteristics were generally similar among patients receiving low-dose and high-dose MTX (), with the exception of numerical differences in the proportion of female patients (low-dose tofacitinib and tofacitinib 10 mg BID groups), and glucocorticoid use (placebo group), prior bDMARD use (all groups), and weight (low-dose tofacitinib group).
Table 1. Summary of patient demographics and baseline characteristics.
Efficacy
At month 3, the proportions of patients achieving ACR20 response rates were numerically greater with all doses of tofacitinib, compared with placebo. Similar ACR20 response rates were achieved by patients receiving tofacitinib with low-dose, compared with high-dose MTX. Likewise, more patients receiving tofacitinib than receiving placebo achieved ACR50 and ACR70 responses, and ACR50/70 response rates were similar for patients receiving tofacitinib with low-dose MTX, compared with high-dose MTX. Numerically greater proportions of patients achieved ACR20/50 responses following placebo with high-dose MTX than those receiving placebo with low-dose MTX. In contrast, ACR70 response rates were similar in patients receiving placebo with low-dose MTX and in those receiving placebo with high-dose MTX ().
Figure 1. (a) ACR20, (b) ACR50, and (c) ACR70 response rates at month 3. Low MTX, >0 to ≤8 mg/week; high MTX, >8 mg/week; error bars represent 95% confidence intervals. ACR20/50/70: American College of Rheumatology, 20%/50%/70% improvement; BID: twice daily; MTX: methotrexate; n: number of patients responding; N: number of patients assessed.
For patients who received low-dose MTX, the proportions achieving DAS28-4 (ESR)<2.6 at month 3 were numerically greater with all doses of tofacitinib, compared with placebo. In the smaller high-dose MTX group, the proportions of patients achieving DAS28-4 (ESR)<2.6 were generally similar for placebo and all tofacitinib doses ().
Figure 2. Proportion of patients achieving DAS28-4 (ESR)<2.6 at month 3. Low MTX, >0 to ≤8 mg/week; high MTX, >8 mg/week; error bars represent 95% confidence intervals. BID: twice daily; DAS28-4 (ESR): disease activity score in 28 joints, erythrocyte sedimentation rate; MTX: methotrexate; n: number of patients responding; N: number of patients assessed.
Improvements from baseline in DAS28-4 (ESR) at month 3 were numerically greater for all tofacitinib doses versus placebo, regardless of MTX dose (). Improvements tended to be greater when tofacitinib 5 and 10 mg BID were given with low-dose versus high-dose MTX. For patients receiving low-dose tofacitinib, improvements from baseline in DAS28-4 (ESR) were similar regardless of the MTX dose.
Figure 3. Change from baseline in DAS28-4 (ESR) at month 3. Low MTX, >0 to ≤8 mg/week; high MTX, >8 mg/week; error bars represent standard error. BID: twice daily; DAS28-4 (ESR): disease activity score in 28 joints, erythrocyte sedimentation rate; MTX: methotrexate; N: number of patients assessed.
At month 3, greater changes from baseline (CFB) in HAQ-DI were observed in patients receiving tofacitinib 5 or 10 mg BID with low-dose MTX compared with those receiving tofacitinib 5 or 10 mg BID in combination with high-dose MTX. Conversely, greater CFB in HAQ-DI occurred with high-dose MTX compared with low-dose MTX in patients receiving low-dose tofacitinib. All tofacitinib-treated patients achieved numerically greater CFB in HAQ-DI than patients receiving placebo ().
Figure 4. Change from baseline in HAQ-DI at month 3. Low MTX, >0 to ≤8 mg/week; high MTX, >8 mg/week; error bars represent standard error. BID: twice daily; HAQ-DI: Health Assessment Questionnaire-Disability Index; MTX: methotrexate; N: number of patients assessed.
Safety
Up to month 3, AEs were experienced by 50.0%, 56.5%, 73.8%, and 28.6% of patients receiving low-dose MTX with low-dose tofacitinib, tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively. In contrast, with high-dose MTX, AEs were experienced by 66.7%, 64.3%, 67.7%, and 52.9% of patients receiving low-dose tofacitinib, tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively. The proportions of patients receiving low-dose MTX who discontinued due to AEs were 2.9%, 8.7%, and 11.9% following low-dose tofacitinib, tofacitinib 5 mg BID, and tofacitinib 10 mg BID; no discontinuations were reported for patients receiving placebo with low-dose MTX. Discontinuations due to AEs were experienced by 4.8%, 7.1%, 12.9%, and 11.8% of patients receiving high-dose MTX with low-dose tofacitinib, tofacitinib 5 mg BID, tofacitinib 10 mg BID, and placebo, respectively ().
Table 2. Summary of AEs up to month 3.
Nasopharyngitis was the most common AE across all treatment groups. Abdominal discomfort and constipation were experienced by patients receiving high-dose MTX. With tofacitinib 5 mg BID, 14.3% and 7.1% of patients experienced abdominal discomfort and constipation, respectively; 5.9% of patients receiving placebo experienced constipation. AEs of elevated blood cholesterol occurred most frequently in patients who received tofacitinib 10 mg BID with high dose MTX; however, elevations in blood cholesterol levels did not appear to be related to MTX or tofacitinib dose ().
Up to month 3, serious AEs were experienced by seven patients receiving tofacitinib with low-dose MTX (low-dose tofacitinib, n = 2; tofacitinib 5 mg BID, n = 2; tofacitinib 10 mg BID, n = 3) and one patient receiving tofacitinib (5 mg BID) with high-dose MTX. Serious infections were experienced by one patient receiving tofacitinib (10 mg BID) with low-dose MTX and one patient receiving tofacitinib (5 mg BID) with high-dose MTX. Two patients receiving tofacitinib 10 mg BID with low-dose MTX, one patient receiving tofacitinib 5 mg BID with high-dose MTX and one patient receiving tofacitinib 10 mg BID with high-dose MTX experienced herpes zoster. In addition, there was one reported treatment-related death during the 3-month period (patient receiving tofacitinib 5 mg BID with high-dose MTX).
In general, patients receiving placebo or tofacitinib with low-dose MTX were less likely to exhibit confirmed increases in ALT levels than patients receiving concurrent high-dose MTX (22/157 [14.0%] and 18/97 [18.6%] of total patients receiving low-dose MTX and high-dose MTX, respectively). However, of two patients with a confirmed ALT ≥3x the upper limit of normal, both received tofacitinib with low-dose MTX (tofacitinib 5 mg BID, n = 1 [2.2%]; tofacitinib 10 mg BID, n = 1 [2.4%]). The proportion of patients with increased levels of AST was similar in patients receiving low-dose MTX compared with those receiving concurrent high-dose MTX (n = 13 [8.3%] and n = 8 [8.2%] of total patients receiving low-dose MTX and high-dose MTX, respectively). No patients exhibited confirmed AST ≥2x or ≥3x upper limit of normal ().
Table 3. Summary of laboratory abnormalities up to month 3.
Mild, moderate, and severe lymphopenia were defined as total lymphocyte count of ≥1.5 to 2 × 1000/mm3, ≥1.0 to <1.5 × 1000/mm3, and ≥0.5 to <1.0 × 1000/mm3, respectively [Citation28]. At month 3, most lymphopenia cases were rated as mild or moderate regardless of treatment. Severe lymphopenia was generally less frequent in patients receiving low-dose MTX compared with high-dose MTX. One patient (n = 1 [3.8%]) receiving tofacitinib 10 mg BID with high-dose MTX had potentially life-threatening lymphopenia (defined as total lymphocyte count of <0.5 × 1000/mm3 [28]; ).
At month 3, the frequency of neutropenia was low across treatment groups. One patient (n = 1 [4.0%]) receiving tofacitinib 5 mg BID with high-dose MTX and two patients (n = 2 [5.1%]) receiving tofacitinib 10 mg BID with low-dose MTX exhibited moderate to severe neutropenia [Citation28] ().
Up to month 3, three patients exhibited severe reduction in hemoglobin levels (defined as >2.0 to <3.0 g/dL decrease from baseline); two following low-dose MTX (placebo, n = 1 [2.9%]; tofacitinib 10 mg BID, n = 1 [2.4%]) and one following high-dose MTX (tofacitinib 10 mg BID, n = 1 [3.4%]; ).
Discussion
The effect of background MTX dose on clinical outcomes in Japanese patients with RA has not been fully explored. In this post hoc analysis of pooled data from one phase 2 and one phase 3 study, we assessed the efficacy and safety of tofacitinib administered with low-dose (0 to ≤8 mg/week) or high-dose (>8 mg/week) MTX over 3 months in Japanese patients with RA.
In this analysis, efficacy at month 3 tended to be either numerically greater or similar when patients received tofacitinib 5 mg BID (the approved dose in Japan) with low-dose versus high-dose MTX. A similar trend was observed for tofacitinib 10 mg BID, but was not observed with low-dose tofacitinib (1 or 3 mg BID). Previously, a phase 3 study of tofacitinib in combination with MTX also found greater efficacy versus placebo, regardless of MTX dose [Citation29], and comparable results across MTX doses have also been reported from a registry of patients with RA treated with bDMARDs, including adalimumab, etanercept, and infliximab [Citation30]. A recent sub-analysis of pooled phase 3 data with certolizumab pegol also revealed no difference in clinical effect with different background MTX doses [Citation31]. In contrast, a trial of patients treated with adalimumab 40 mg every other week in combination with MTX (2.5, 5, 10, or 20 mg per week) noted a statistically significant trend for increased efficacy with increasing MTX dose, although the efficacy of adalimumab with MTX 10 mg/week appeared to be equivalent to that with MTX 20 mg/week [Citation9]. Furthermore, in a more recent study in Japan, greater proportions of patients achieved DAS endpoints with adalimumab administered with ≥10 mg MTX compared with adalimumab plus <10 mg MTX [Citation10]. In addition, another study in Japanese patients reported that etanercept was more effective when administered with increasing doses of MTX [Citation32].
The efficacy of bDMARDs can be reduced by anti-bDMARD immune responses [Citation33,Citation34]. Anti-bDMARD responses have previously been shown to be reduced by the immunosuppressive activity of MTX [Citation35]. Therefore, it is possible that, in some patients, MTX may suppress the immune responses that abrogate bDMARD efficacy when used in combination [Citation36], thus improving the effectiveness of adalimumab and other bDMARDs, and this may explain the superior responses observed in some of the studies discussed above [Citation9,Citation10,Citation32].
With regard to efficacy compared with placebo, ACR20/50/70 response rates, the proportion of patients achieving DAS28-4 (ESR)<2.6, and CFB in DAS28-4 (ESR) and HAQ-DI, were generally numerically greater for patients receiving tofacitinib (low-dose, 5 mg BID, and 10 mg BID) at month 3 than those on placebo, regardless of MTX dose. The exceptions to this were the proportions of patients achieving DAS28-4 (ESR)<2.6 with low-dose tofacitinib and tofacitinib 10 mg BID administered with high-dose MTX; in these instances, rates were numerically higher with placebo. These results are consistent with results from a post hoc analysis of data from a global study that reported higher ACR20/50/70 response rates and mean CFB in HAQ-DI and clinical disease activity index with tofacitinib 5 and 10 mg BID versus placebo at month 3, irrespective of MTX dose [Citation29].
Previously, MTX treatment was shown to reduce plasma concentrations of interleukin (IL)-6, and clinically relevant radiographic progression of RA was correlated with higher IL-6 plasma levels after treatment [Citation37]. Therefore, it is possible that the higher DAS28-4 (ESR)<2.6 rates in patients receiving placebo with high-dose MTX compared with low-dose MTX may be due to MTX-dose-dependent IL-6 suppression. Furthermore, in the high-dose MTX group, similar rates of DAS28-4 (ESR)<2.6 were observed in patients receiving tofacitinib and those receiving placebo. Tofacitinib has also been shown to inhibit IL-6 [38]. Therefore, if IL-6 activity is being abrogated by MTX, concomitant tofacitinib treatment would not necessarily lead to increased IL-6-inhibition and, therefore, may not confer additional benefit to patient outcomes.
Safety profiles for low-dose tofacitinib, tofacitinib 5 mg, and tofacitinib 10 mg BID with background MTX in Japanese patients up to month 3 were generally consistent with findings in the global population from phase 3 clinical trials [Citation16,Citation18–21]. Nasopharyngitis was one of the most common AEs observed in this pooled analysis of phase 2 and phase 3 data, as well as in the respective individual studies [Citation20,Citation26]. No apparent differences across system organ class or laboratory parameters were observed; however, overall AE rates were numerically lower in patients receiving placebo, low-dose tofacitinib or tofacitinib 5 mg BID with low-dose MTX (28.6%, 50.0% and 56.5%, respectively), compared with those receiving high-dose MTX (52.9%, 66.7% and 64.3%, respectively). This is consistent with previous studies reporting that MTX toxicity is dose dependent [Citation9,Citation12]. In contrast, overall AE rates were numerically higher in patients receiving tofacitinib 10 mg BID with low-dose MTX, compared with high-dose MTX (73.8% and 67.7%, respectively).
In contrast, a recent sub-analysis of patients in the CONCERTO and MUSICA trials treated with adalimumab and MTX (CONCERTO: 2.5, 5, 10, or 20 mg/week; MUSICA: 7.5, or 20 mg/week) which included patients with a similar background to the present study (moderately to severely active RA and an inadequate response to MTX; MUSICA trial), and also patients with early RA who were bDMARD- and MTX-naïve (CONCERTO trial), found that AE rates remained steady among patients receiving different doses of MTX [Citation39]. The patient background in this sub-analysis was similar to that in our study; therefore, additional research is required to further investigate possible differences in the impact on safety outcomes between different background MTX doses in combination with tofacitinib, compared with different background MTX doses and concomitant bDMARDs.
This analysis has a number of limitations. This was a post hoc analysis involving only a small number of patients in some treatment groups; no hypotheses were tested and no statistical analyses were performed. Furthermore, assignment to MTX dose was non-random and the treatment groups were not equal in size. Taken together, these factors could confound the comparisons between the low-dose and high-dose MTX treatment groups. Other limitations include pooling of data from studies with different study designs and methodologies; for example, the primary efficacy endpoint was assessed at month 3 in A3921039 [26], whereas primary efficacy outcomes focused on time points ≥6 months in ORAL Scan [Citation20].
Conclusion
In conclusion, in this post hoc analysis of Japanese patients from a phase 2 study and a phase 3 study, efficacy appeared generally similar with low-dose or high-dose MTX in combination with tofacitinib (either 5 or 10 mg BID) in patients with moderately to severely active RA. The safety profile of tofacitinib was consistent with global findings and, up to month 3, overall AE frequency was generally lower with low-dose MTX than with high-dose MTX when patients received placebo or tofacitinib low-dose or 5 mg BID, but not 10 mg BID. Additional studies will be required to confirm these findings and to elucidate further the risk:benefit profile of concomitant tofacitinib and MTX treatment in patients with RA.
Conflict of interest
T. Takeuchi has received grants, consultancy fees, and/or speaking fees from AbbVie, Asahi Kasei, Astellas, AstraZeneca, AYUMI, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Eli Lilly Japan, Janssen, Mitsubishi Tanabe, Nippon Kayaku, Novartis, Pfizer Japan Inc, Taiho, Taisho Toyama, Takeda, and Teijin. H. Yamanaka has received consultancy fees or speaking fees from AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Mitsubishi Tanabe, Pfizer, Takeda, and UCB. K. Yamaoka has received consultancy fees, speaking fees, and/or honoraria from Actelion, Astellas, Chugai, Eisai, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Nippon Shinyaku, Pfizer Inc, and Takeda. Y. Tanaka has received consultancy fees, speaking fees, and/or honoraria from AbbVie, Asahi Kasei, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eli Lilly, GlaxoSmithKline, Janssen, Mitsubishi Tanabe, Pfizer Inc, Sanofi, Takeda, Teijin, and YL Biologics, and has received research grants from AbbVie, Astellas, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Eisai, Mitsubishi Tanabe, MSD, and Takeda. S. Toyoizumi and Y. Fukuma are employees of Pfizer Japan Inc. S. Arai, T. Hirose, and N. Sugiyama are employees and shareholders of Pfizer Japan Inc. R. DeMasi and S.H. Zwillich are employees and shareholders of Pfizer Inc.
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Funding
References
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