Results
Search Results and Study Selection
Figure 1 summarises the review flowchart in accordance with PRISMA statement. The electronic search of EMBASE, the Cochrane Library and PubMed yielded a total of 283 studies. Four additional unpublished records were identified in the ClinicalTrials.gov, each with a different ClinicalTrial.gov identifier from the published reports (Additional file 2: Table S2). A total of 259 records were screened after the removal of the duplicates. After scanning the titles and abstracts, 216 records were removed as they were not clinical trials of tofacitinib. Full texts of 43 studies were retrieved for more detailed evaluation, of which 34 were then excluded since they were not related to the treatment of RA. Another study was excluded as it investigated pain, physical functioning and health status but not efficacy and safety measures of tofacitinib in the treatment of RA. As a result, eight eligible studies were included in this systematic review, contributing a total sample size of 3,791. A standardised summary table of the included studies is presented in Table 1.
Methodological Quality
All studies stated that they were double-blind, however half of the studies did not report the method of allocation sequence and concealment. Co-interventions and baseline characteristics were similar for the tofacitinib and placebo groups for all studies. All studies had potential risks of bias as some of the outcomes stated in the trial protocol were not reported. Another potential bias might be introduced by switching from placebo to active medication in some patients previously receiving placebo in four studies. This potential bias was addressed in two studies using the method of imputation of no response, with "advancement penalty".
Efficacy
The doses used and the treatment duration are shown in Figures 2 and 3. ACR20 response rates were found to be significantly higher in those patients receiving tofacitinib versus placebo at doses ≥3 mg bid. A non-significant dose-dependent response trend was observed from 1 to 5 mg bid (Additional file 3: Figure S1). ACR20 response rates were significantly greater in tofacitinib treatment versus placebo at 5 mg bid (RR 2.20; 95% CI 1.58, 3.07) and 10 mg bid (RR 2.38; 95% CI 1.81, 3.14) after 12 weeks of treatment. The higher ACR20 response rates in patients receiving tofacitinib sustained at week 24 for 5 mg bid (RR 1.94; 95% CI 1.55, 2.44) and 10 mg bid (RR 2.20; 95% CI 1.76, 2.75) (Figure 2). Moreover, tofacitinib was also significantly more efficacious than placebo as measured by ACR50 response rate (Figure 3). ACR50 response rates were significantly greater in tofacitinib treatment at 5 mg bid (RR 2.91; 95% CI 2.03, 4.16) and 10 mg bid (RR 3.32; 95% CI 2.33, 4.72) after 12 weeks.
(Enlarge Image)
Figure 2.
ACR20 response rates for different doses of tofacitinib at week 12 and week 24.
(Enlarge Image)
Figure 3.
ACR50 response rates for 5 mg bid and 10 mg bid of tofacitinib at week 12 and week 24.
For the efficacy measures which were only reported in respective single studies, significantly higher ACR20 and ACR50 response rates were observed in patients receiving doses ≥5 mg tofacitinib versus placebo at week 6, 12 and 24 (Additional file 4: Figure S2). A significantly higher response rate was also observed in ACR50 for 3 mg tofacitinib versus placebo at week 24.
Fleischmann et al. and van Vollenhoven et al. also compared the efficacy of tofacitinib with adalimumab at month 3 and 6 respectively (Table 2). At month 3, there was a statistically significant difference in ACR20 response rate in patients receiving ≥5 mg bid tofacitinib versus adalimumab. At the dose of 5 mg bid, the RR of ACR20 and ACR50 response rates were 1.65 (95% CI 1.08, 2.53) and 1.95 (95% CI 1.00, 3.80) in patients receiving tofacitinib versus adalimumab respectively. The corresponding figures at 10 mg bid were 1.97 (95% CI 1.32, 2.92) and 2.35 (95% CI 1.26, 4.38) respectively. At month 6, there were no significant differences in ACR20 response rates in patients receiving tofacitinib versus adalimumab.
Safety
The most commonly reported infections and immune-related AEs during the 12-week tofacitinib treatment period are shown in Table 3. There were no statistically significant differences in patients receiving tofacitinib versus placebo in the incidences of infections, neutropenia and withdrawal due to AEs. However, significantly fewer patients withdrew from tofacitinib than placebo (RR 0.60; 95% CI 0.45, 0.78). Similarly, the patient withdrawal rate due to lack of efficacy was significantly lower in the patients receiving tofacitinib versus placebo (RR 0.18; 95% CI 0.09, 0.35).
The mean neutrophil count significantly declined in patients receiving tofacitinib versus placebo. The mean serum creatinine was found to be significantly higher for tofacitinib 10 mg bid versus placebo. The mean percentage change of HDL/LDL was significant higher in patients receiving tofacitinib versus placebo. The RRs of the mean changes of ALT > 1 ULN and AST > 1 ULN were statistically significant (Additional file 5: Table S3).
Sensitivity Analysis
The RR of ACR20 response rate did not significantly change with the exclusion of data from Tanaka et al.. For the tofacitinib treatment at 3 mg bid, the RR slightly reduced from 2.20 (95% CI 1.20, 4.04) to 1.65 (95% CI 1.18, 2.30), however, the heterogeneity was significantly reduced to 0% (Additional file 6: Table S4). Similarly, the RR of ACR20 response rate for the tofacitinib treatment at 5 mg bid (2.20; 95% CI 1.58, 3.07) did not change significantly (1.94; 95% CI 1.55, 2.43) but led to a reduction in heterogeneity. Although the inclusion of Tanaka et al. led to substantial heterogeneity, it did not materially alter the conclusion. No data for ACR50 response rate was available for sensitivity analysis.