Comparison of the efficacy and safety of tofacitinib and peficitinib in patients with active rheumatoid arthritis: A Bayesian network meta-analysis of randomized controlled trials
Young Ho Lee | Gwan Gyu Song
Department of Rheumatology, Korea University College of Medicine, Seoul, Korea
Correspondence
Young Ho Lee, MD, PhD, Department of Rheumatology, Korea University Anam Hospital, Korea University College of Medicine, 73, Goryeodae-ro, Seongbuk-gu, Seoul 02841, Korea.
Email: [email protected]
Abstract
Objectives: The relative efficacy and safety of tofacitinib and peficitinib were as- sessed in patients with rheumatoid arthritis (RA) with an inadequate response to disease-modifying antirheumatic drugs (DMARDs).
Method: We performed a Bayesian network meta-analysis to combine direct and in- direct evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of tofacitinib and peficitinib in combination with DMARDs in patients with an inadequate response to DMARDs.
Results: Nine RCTs, including 3836 patients, met the inclusion criteria. Fifteen pair- wise comparisons were performed, including six direct comparisons of seven inter- ventions. Tofacitinib 10 mg+methotrexate (MTX) and peficitinib 150 mg+MTX were among the most effective treatments for patients with active RA with an inadequate DMARD response. The efficacy of tofacitinib 10 mg+MTX, peficitinib 150 mg+MTX or tofacitinib 5 mg+MTX tended to be higher than that of adalimumab+MTX. The ranking probability based on the surface under the cumulative ranking curve indi- cated that tofacitinib 10 mg+MTX had the greatest probability of being the best treatment to achieve the American College of Rheumatology 20 response rate, fol- lowed by peficitinib 150 mg+MTX, tofacitinib 5 mg+MTX, adalimumab+MTX, pefi- citinib 100 mg+MTX, and placebo+MTX. No significant differences were observed in the incidence of serious adverse events after treatment with tofacitinib+MTX, peficitinib+MTX, adalimumab+MTX, or placebo+MTX.
Conclusions: In patients with RA with an inadequate response to DMARDs, tofaci- tinib 10 mg+MTX and peficitinib 150 mg+MTX were the most efficacious interven- tions and were not associated with a significant risk of serious adverse events.
K E Y WO R D S
network meta-analysis, peficitinib, rheumatoid arthritis, tofacitinib
1 | INTRODUC TION
Rheumatoid arthritis (RA) is a systemic autoimmune disorder charac- terized by chronic inflammation of the synovial joints, which results
in disability and reduced quality of life.1 Disease-modifying antirheu- matic drugs (DMARDs) have been used in patients with RA to de- crease inflammation, delay bone loss, and increase functional ability. Methotrexate (MTX), an efficient antirheumatic DMARD2 is one of
© 2020 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd
Int J Rheum Dis. 2020;00:1–8.
wileyonlinelibrary.com/journal/apl | 1
the most commonly used DMARDs for RA.3 However, not all pa- tients respond to this drug; 30% of the patients stop treatment within 1 year, typically owing to lack of effectiveness or the occurrence of adverse effects.4 Patients with an inadequate response to MTX are often treated with biological DMARDs (bDMARDs). Introduction of bDMARDs definitely made possible remission from the disease and inhibition of joint damages.5 Since a substantial proportion of patients do not respond adequately to these therapies or experience unaccept- able side effects6 and those with inadequate responses to bDMARDs have shown poorer responses with subsequent bDMARD treatment, new therapies are needed.7 Intracellular pathways, including those mediated by Janus-activated kinases (JAKs: JAK1, JAK2, JAK3, and tyrosine kinase 2 [Tyk2]), are essential to immune cell activation, cy- tokine production, and cytokine signaling.8 Small-molecule JAK inhib- itors for the treatment of RA are therefore under development for clinical use.9 Tofacitinib selectively inhibits JAK-1, JAK-2, and JAK-3 with specificity for JAK-1 and JAK-3 over JAK-2, and effectively modu- lates adaptive and innate immunity.10,11 Tofacitinib is an approved JAK inhibitor that can be used for RA treatment. Peficitinib (ASP015K) is an effective selective JAK3 inhibitor that blocks signal transduction and consequently prevents immune reactions. For patients with moderate to severe active RA who did not respond adequately or who could not tolerate conventional synthetic DMARDs (csDMARDs), peficitinib has been investigated.12-14
For patients with active RA who have incomplete DMARD re-
sponse, multiple clinical trials have been conducted to determine the efficacy and safety of tofacitinib and peficitinib.12,13,15-21 All these drugs were very effective in placebo-controlled trials; however, owing to a lack of head-to-head tests, the relative efficacy and safety of to- facitinib and peficitinib are uncertain. In the absence of head-to-head trials with relevant comparators, it is important for the assessment of the effect of one procedure against another to incorporate evidence from randomized controlled trials (RCTs). Network meta-analysis is a possible method to assess the comparative efficiencies of several treatments by integrating evidence across a network of RCTs, even when head-to-head comparisons have not been performed,22,23 as op- posed to traditional meta-analysis.24-28 The purpose of this study was to use a network meta-analysis to examine the relative effectiveness and safety of tofacitinib and peficitinib in patients with active RA.
2 | MATERIAL S AND METHODS
2.1 | Identification of eligible studies and data extraction
We conducted an exhaustive search for studies that examined the efficacy and safety of tofacitinib and peficitinib in patients with ac- tive RA who showed an inadequate response to DMARDs including MTX. A literature search of the MEDLINE and EMBASE database, the Cochrane Controlled Trials Register, and conference proceedings from the American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) was used to identify available articles
published up to November 2019. The following key words and subject terms were used in the search: “tofacitinib”, “peficitinib”, and “rheuma- toid arthritis”. All references in the studies were reviewed to identify additional works not included in the electronic databases. RCTs were included if they met the following criteria: (a) the study compared tofac- itinib or peficitinib with DMARDs to placebo+DMARDs for the treat- ment of active RA which responded inadequately to DMARDs; (b) the study provided endpoints for the clinical efficacy and safety of tofaci- tinib or peficitinib at 3 or 6 months; and (c) the study included patients diagnosed with RA based on the American College of Rheumatology (ACR) criteria for RA29 or the 2010 ACR/EULAR classification criteria.30 The exclusion criteria were: (a) the study included duplicate data; and (b) the study did not contain adequate data for inclusion. The efficacy out- come was the number of patients who fulfilled the ACR 20% improve- ment criteria (achieved an ACR20 response), and the safety outcome was the number of patients who experienced serious adverse events (SAEs). The following information was extracted from each study: first author, year of publication, country in which the study was conducted, dosages of tofacitinib and peficitinib, follow-up period for the outcome evaluation, and efficacy and safety outcomes. The data were extracted from original studies by two independent reviewers. Any discrepancy between the reviewers was resolved by consensus. We quantified the methodological quality of studies using a Jadad score31 ranging from 0 to 5. Quality was classified as high (a score of 3-5) or low (a score of 0-2). We conducted this network meta-analysis in accordance with the guidelines provided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.32
2.2 | Evaluation of statistical associations for network meta-analysis
In RCTs that compared multiple doses of tofacitinib and peficitinib in different arms, the results from the different arms were simul- taneously analyzed. The efficacy and safety of tofacitinib and pefi- citinib in different arms were ordered according to the probability of being ranked as the best performing regimen. We performed a Bayesian random-effects network meta-analysis using NetMetaXL33 and WinBUGS statistical analysis program version 1.4.3 (MRC Biostatistics Unit, Institute of Public Health, Cambridge, UK). The Bayesian approach offers greater flexibility in the use of more com- plex models and different outcome types, enabling the simultaneous comparison of all treatment options. Bayesian method combines a prior probability distribution, which reflects a prior belief of the pos- sible values of the pooled effect, with a likelihood distribution of the pooled effect based on the observed data to obtain a posterior probability distribution.34 In order not to influence the observed re- sults by the prior distribution, a non-informative or vague prior dis- tribution often is used for the pooled effect.35 In this case, posterior results are not influenced by the prior distribution but are affected by the observed data as in a frequentist meta-analysis.35,36 Although frequentists use the sampling distribution as the basis of statisti- cal inference, the posterior distribution obtained with the Bayesian
approach permits calculating the probability that each treatment can produce better outcomes than those produced by competing interventions.34,37 We chose a random-effects model for the net- work meta-analysis, as it incorporates between-study variations and utilizes a conservative method. The random network model was se- lected prior to the statistical analysis. We used the Markov chain Monte Carlo method to obtain pooled effect sizes.38 All chains were run with 10 000 burn-in iterations followed by 10 000 monitoring iterations. The information on relative effects was converted to a probability that a treatment was the best, second best, and so on, or to the ranking of each treatment, which was called the surface under the cumulative ranking curve (SUCRA)39 and was expressed as a percentage. The SUCRA value was 1 when a treatment was certain to be the best and 0 when a treatment was certain to be the worst. SUCRA values enabled the overall ranking of treatments
for a particular outcome, simplifying the information on the effect of each treatment into a single number and consequently facilitat- ing decision-making. A league table can arrange the presentation of summary estimates by ranking the treatments in the order of the most pronounced impact on the outcome under consideration, based on the SUCRA value.39 We reported the pairwise odds ratio (OR) and 95% credible interval (CrI) (or Bayesian confidence interval) and adjusted for multiple-arm trials. Pooled results were considered statistically significant if the 95% CrI did not contain the value 1.
2.3 | Inconsistency assessment
Inconsistency refers to the extent of disagreement between di- rect and indirect evidence.40 Assessments of inconsistency are
TA B L E 1 Characteristics of individual studies included in the meta-analysis and systematic review
797 MTX-IR Tofacitinib Placebo+MTX (160), tofacitinib 5 mg+MTX (321),
tofacitinib 10 mg+MTX (316)
717 MTX-IR Tofacitinib Placebo+MTX (108), tofacitinib 5 mg+MTX (204),
tofacitinib 10 mg+MTX (201), adalimumab 40 mg+MTX
(204)
Kremer, 201218 214 MTX-IR Tofacitinib Placebo+MTX (69), tofacitinib 5 mg+MTX (71),
tofacitinib 10 mg+MTX (74)
Tanaka, 201119 84 MTX-IR Tofacitinib Placebo+MTX (28), tofacitinib 5 mg+MTX (28),
tofacitinib 10 mg+MTX (28)
Tanaka, 201920 307 DMARD-IR Peficitinib Placebo+MTX (102), peficitinib 100 mg+MTX (101),
peficitinib 150 mg+MTX (104)
Takeuchi, 201921 518 MTX-IR Peficitinib Placebo+MTX (174), peficitinib 100 mg+MTX (170),
peficitinib 150 mg+MTX (174)
Genovese 201712 173 DMARD-IR Peficitinib Placebo+MTX (51), peficitinib 100 mg+MTX (58),
peficitinib 150 mg+MTX (64)
Kivitz 201613 234 MTX-IR Peficitinib Placebo+MTX (72), peficitinib 100 mg+MTX (84),
peficitinib 150 mg+MTX (78)
Placebo+MTX vs. tofacitinib 5 mg+MTX 5 1466
Tofacitinib 5 mg+MTX vs. tofacitinib 10 mg+MTX 5 1879
Tofacitinib 5 mg+MTX vs. adalimumab+MTX 1 408
Placebo+MTX vs. peficitinib 100 mg+MTX 4 811
Peficitinib 100 mg+MTX vs. peficitinib 150 mg+MTX 4 835
Abbreviations: adalimumab 40 mg, once every alternate week; DMARDs, disease-modifying antirheumatic drugs; Doses: peficitinib, once daily; Doses: tofacitinib, twice daily; IR, incomplete response; MTX, methotrexate or conventional synthetic DMARDs, including MTX; MTX, once a week.
important when conducting a network meta-analysis, because an inconsistency plot yields information that can help identify the loops in which the inconsistency is present.41 We plotted the posterior mean deviance of the individual data points in the
FI G U R E 1 Evidence network diagram of network meta-analysis comparisons. The width of each edge is proportional to the number of randomized controlled trials comparing each pair of treatments, and the size of each treatment node is proportional to the number of randomized participants (sample size). (A) Placebo+MTX,
(B) tofacitinib 5 mg+MTX, (C) tofacitinib 10 mg+MTX, (D) adalimumab+MTX, (E) peficitinib 100 mg+MTX, (F) peficitinib 150 mg+MTX. MTX, methotrexate
inconsistency model against the posterior mean deviance in the consistency model to assess the network inconsistency between the direct and indirect estimates in each loop.42 A sensitivity test was performed by comparing the random and fixed-effects models.
3 | RESULTS
3.1 | Studies included in the meta-analysis
In total, 682 studies were identified through the electronic or manual searches; of these, 12 were selected for a full-text review based on the title and abstract details. Three studies were ex- cluded because they were duplicate or irrelevant. Thus, 9 RCTs, which included 3836 patients (1887 efficacy-related events and 1428 safety-related events) met the inclusion criteria.12,13,15-21 The search results contained 15 pairwise comparisons, including 6 direct comparisons and 7 interventions (Table 1, Figure 1). The Jadad scores of the studies were between 3 and 5, which were in- dicative of high-quality studies. The relevant features of the stud- ies included in the meta-analysis are provided in Table 1.
3.2 | Network meta-analysis of the efficacy of tofacitinib and peficitinib in RCTs
Tofacitinib 10 mg+MTX is listed in the top-left of the diagonal of the league table (OR, 4.20; 95% CrI, 2.23-8.80), because it was associated
TA B L E 2 League tables showing the results of the network meta-analysis comparing the effects of all drugs including odds ratios and 95% credible intervals. (A) Efficacy: odds ratio > 1 indicates that the top-left treatment is better. (B) Tolerability: odds ratio < 1 indicates that the top-left treatment is better
(A) Tofacitinib 10 mg+MTX
1.03 (0.40-3.07) Peficitinib
150 mg+MTX
1.14 (0.56-2.14) 1.10 (0.36-2.76) Tofacitinib 5 mg+MTX
1.43 (0.43-4.96) 1.39 (0.31-5.74) 1.25 (0.39-4.55) Adalimumab+MTX
1.59 (0.63-4.83) 1.55 (0.74-3.28) 1.40 (0.57-4.40) 1.12 (0.27-4.96) Peficitinib
100 mg+MTX
4.20 (2.23-8.80) 4.07 (1.89-8.62) 3.68 (2.00-8.22) 2.93 (0.88-10.47) 2.63 (1.22-5.44) Placebo+MTX
(B) Peficitinib 150 mg+MTX
0.87 (0.17-4.02) Adalimumab+MTX
0.72 (0.27-2.01) 0.85 (0.24-2.81) Placebo+MTX
0.52 (0.20-1.52) 0.61 (0.13-2.67) 0.72 (0.26-1.83) Peficitinib
100 mg+MTX
0.38 (0.11-1.25) 0.46 (0.13-1.33) 0.53 (0.25-1.03) 0.72 (0.23-3.06) Tofacitinib 10 mg+MTX
0.36 (0.11-1.21) 0.43 (0.13-1.27) 0.51 (0.24-1.00) 0.68 (0.22-2.52) 0.95 (0.56-1.67) Tofacitinib 5 mg+MTX
Abbreviation: MTX, methotrexate.
TA B L E 3 Rank probability of the efficacy of tofacitinib and peficitinib based on the number of patients who achieved an American College of Rheumatology 20% response (A) and the safety based on the number of serious adverse events (B)
(A) Efficacy
with the most favorable SUCRA for the ACR20 response rate, whereas placebo+MTX is listed in the bottom right of the diagonal of the league table because it was associated with the least favorable results (Table 2). All doses of JAK inhibitors achieved a significant ACR20 response compared with placebo+MTX (Table 2). The effi- cacy of tofacitinib 10 mg+MTX, peficitinib 150 mg+MTX, and tofaci- tinib 5 mg+MTX tended to be greater than that of adalimumab+MTX (Table 2, Figure 2). The ranking probability based on SUCRA indicated that tofacitinib 10 mg+MTX had the highest probability of being the best treatment in terms of the ACR20 response rate, followed by peficitinib 150 mg+MTX, tofacitinib 5 mg+MTX, adalimumab+MTX, peficitinib 100 mg+MTX, and placebo+MTX (Table 3).
3.3 | Network meta-analysis of the safety of
Abbreviations: MTX, methotrexate; SUCRA, surface under the cumulative ranking curve.
and tofacitinib 5 mg+MTX groups (Table 2, Figure 2). However, the number of SAEs did not differ significantly between the tofacitinib and peficitinib groups (Table 2, Figure 2). The ranking probability
FI G U R E 2 Bayesian network meta-analysis results of randomized controlled studies on the relative efficacy (A) and safety (B) of tofacitinib and peficitinib. MTX, methotrexate; OR, odds ratio; CrI., credible interval
based on SUCRA values indicated that peficitinib 150 mg+MTX, adalimumab+MTX, and placebo+MTX had higher probabilities of being the safest treatment, followed by peficitinib 100 mg+MTX, tofacitinib 10 mg+MTX, and tofacitinib 5 mg+MTX (Table 3).
3.4 | Inconsistency and sensitivity analyses
Inconsistency plots were used to assess the network inconsistencies between the direct and indirect estimates. Some inconsistencies be- tween direct and indirect estimates were found in the network meta- analysis of efficacy. Two points in the plot of the efficacy (placebo from the Kivitz et al study and tofacitinib 10 mg from the Tanaka et al study) appeared to have a higher than expected posterior mean deviance. However, a sensitivity analysis that removed the outlier studies did not meaningfully change the network meta-analysis results, indicating a low possibility of inconsistencies that might significantly affect the network meta-analysis results. In addition, the results of the random- and fixed-effects models yielded the same interpretation, indicating that the results of this network meta-analysis were robust (Figure 2).
4 | DISCUSSION
Recent studies of RA treatment have focused on small molecules that can inhibit intracellular kinases (such as those in the JAK path- ways). Trends in the treatment of the new small molecules have begun to include specific targeting of the JAK pathways. As patients with RA may receive tofacitinib or peficitinib if they are refractory or intolerant to or contraindicated by DMARDs, it is important to determine the optimal treatment methods. In addition to efficacy, the safety of tofacitinib and peficitinib is a key factor in the selection of therapeutic treatment in patients with RA.
We performed a network meta-analysis to compare the efficacy and safety of tofacitinib and peficitinib in patients with active RA and an inadequate response to DMARDs. With regard to effectiveness, our network meta-analysis showed that tofacitinib 10 mg+MTX and peficitinib 150 mg+MTX were the most effective treatments for active RA, followed by tofacitinib 5 mg+MTX, adalimumab+MTX, peficitinib 100 mg+MTX, and placebo+MTX. Although no explana- tion was determined for these findings, discrepancies in the efficacy between JAK inhibitors and adalimumab were suggested. The safety of peficitinib 150 mg+MTX, adalimumab+MTX, placebo+MTX, and peficitinib 100 mg+MTX treatments was higher than that for tofaci- tinib 10 mg+MTX and tofacitinib 5 mg+MTX. Nonetheless, the num- ber of SAEs was not significantly different among the six treatments, suggesting comparable safety among the different tofacitinib and peficitinib regimens. Tofacitinib has been approved for use by the Food and Drug Administration (FDA), USA, as a JAK inhibitor; pefici- tinib is used in Japan and is undergoing evaluation for FDA approval. Treatment with tofacitinib and peficitinib shows a statistically signif- icant improvement in the ACR20 response criteria compared with placebo, with no statistically significant variations in the incidence
of SAEs between the JAK inhibitors and placebo. However, rank probability of the safety based on the number of SAEs showed a better SUCRA in perficitinib 150 mg+MTX than other treatments. Nevertheless, our network meta-analysis offers different informa- tion from previous reviews, as it has produced a standardized order for the relative efficacy and safety of JAK inhibitors in patients with active RA.
The results of the network meta-analysis that combined evi- dence from both direct and indirect comparisons to evaluate rela- tive efficacy and safety of peficitinib were consistent with previous meta-analyses, and indicated that treatment with tofacitinib and peficitinib resulted in a statistically substantial improvement on the basis of the ACR20 response criteria.43,44 However, our network me- ta-analysis is different from previous meta-analyses, as we were able to generate a ranking order of the relative effectiveness and safety of tofacitinib and peficitinib treatments in patients with active RA.
Our findings should be viewed with caution because of the lim- itations to this analysis. First, only 3 or 6 months were used for fol- low-up. Therefore, for assessing the long-term effects, the follow-up period was too short and longer comparative studies are required. Second, the nature and patient characteristics of the trials included were heterogeneous; hence, disparities among the studies could have influenced the analytical results. Second, the efficacy and safety ef- fects of tofacitinib and peficitinib in patients with RA were not dis- cussed in depth in this study. Instead, the study was focused on the effectiveness based only on the number of patients achieving ACR20 and on the safety based on the number of SAEs, without evaluation of all other outcomes.45 Nevertheless, this meta-analysis has several strengths. First, the RCTs included in this network meta-analysis were all of high quality and considerably consistent. Second, the number of patients in each study ranged from 84 to 797, and this analysis in- cluded a total of 3836 patients. Network meta-analysis integrates all available data to allow for the simultaneous comparisons of different treatment options that lack direct head-to-head comparisons. In con- trast with the individual studies, more accurate data were obtained by increasing the statistical power and resolution through a pooling of the independent analyses and ranking of the efficacy and safety of JAK inhibitors at the doses tested in patients with active RA. This was the first network meta-analysis of the relative efficacy and safety of tofacitinib and peficitinib in individuals with RA.
In summary, we performed a meta-examination of a Bayesian
network of 9 RCTs and found that the most successful treatments for patients with RA with inadequate response to DMARD ther- apy were tofacitinib 10 mg+MTX and peficitinib 150 mg+MTX and that neither of these treatments were associated with a consider- able risk of an SAE. The relative efficacy and safety of tofacitinib and peficitinib in many patients with active RA who have an in- adequate response to DMARDs should be assessed in long-term studies.
ACKNOWLEDG EMENTS
No specific grants were received from any public, commercial or non-profit sector funding agencies.
CONFLIC T OF INTEREST
The researchers have no conflicts of interest in financial or non- financial terms.
ORCID
Young Ho Lee https://orcid.org/0000-0003-4213-1909
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