Efficacy and Safety of JAK Inhibitors for Rheumatoid Arthritis: A Meta-Analysis
Abstract
:1. Introduction
2. Methods
2.1. Literature Searches and Study Selection
2.2. Inclusion and Exclusion Criteria
2.3. Data Extraction and Outcome Measures
2.4. Statistical Analyses
3. Results
3.1. Study Characteristics
3.2. Risk of Bias Assessment
3.3. Efficacy
3.3.1. ACR20, ACR50, and ACR70
3.3.2. HAQ-ID
3.4. Safety
3.4.1. AEs and SAEs
3.4.2. Infections and Serious Infections
3.4.3. HZ
3.4.4. Upper Respiratory Tract Infections
3.4.5. Thromboembolic Events
3.4.6. MACE
3.4.7. Neoplasm
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
RA | Rheumatoid arthritis |
csDMARDs | Conventional disease-modifying-drugs |
MTX | Methotrexate |
DAS28-4[ESR] | 28-joint disease activity score using erythrocyte sedimentation rate |
JAK | Janus kinases |
STAT | Signal transduction and activator of transcription |
JAKinibs | JAK inhibitors |
ACR 20 | American College of Rheumatology 20% |
HAQ-DI | Health Assessment Questionnaire—Disability Index |
AE | Adverse events |
SAE | Serious adverse events |
HZ | Herpes zoster |
MD | Mean differences |
RR | Risk ratio |
CI | Confidence intervals |
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Author (Year) | Region | Trial Identifier | Follow-Up | No. of Patients | Dose |
---|---|---|---|---|---|
Tofacitinib | |||||
Kremer 2009 [19] | Worldwide | NCT00147498 | 6 weeks | 264 | 5, 15, 30 mg twice daily |
Tanaka 2011 [20] | Japan | NCT00603512 | 12 weeks | 140 | 1, 3, 5, 10, 15 mg twice daily |
Vollenhoven 2012 [21] | America and Europe | NCT00853385 | 24 weeks | 513 | 5, 10 mg twice daily |
Fleischmann 2012a [22] | Worldwide | NCT00550446 | 24 weeks | 274 | 1, 3, 5, 10, 15 mg twice daily |
Fleischmann 2012 b [23] | Worldwide | NCT00814307 | 24 weeks | 611 | 5, 10 mg twice daily |
Kremer 2012 [24] | America and Europe | NCT00413660 | 12 weeks | 507 | 1, 3, 5, 10, 15 mg twice daily, 20 mg/day |
Burmester 2013 [25] | America and Europe | NCT00960440 | 12 weeks | 399 | 5, 10 mg twice daily |
Kremer 2013 [26] | Worldwide | NCT00856544 | 24 weeks | 792 | 5, 10 mg twice daily |
Heijde 2013 [27] | Worldwide | NCT00847613 | 24 weeks | 797 | 5, 10 mg twice daily |
Boyle 2015 [28] | Worldwide | NCT00976599 | 4 weeks | 29 | 10 mg twice daily |
Tanaka 2015 [29] | Japan | NCT00687193 | 12 weeks | 317 | 1, 3, 5, 10, 15 mg twice daily, 20 mg/day |
Kremer 2015 [30] | Worldwide | NCT01484561 | 6 weeks | 148 | 10 mg twice daily |
Baricitinib | |||||
Keystone 2015 [31] | Worldwide | NCT01185353 | 12 weeks | 301 | 1, 2, 4, 8 mg once daily |
Tanaka 2016 [32] | Japan | NCT01469013 | 12 weeks | 145 | 1, 2, 4, 8 mg once daily |
Genovese 2016 [33] | Worldwide | NCT01721044 | 24 weeks | 527 | 2, 4 mg once daily |
Taylor 2017 [34] | Worldwide | NCT01710358 | 24 weeks | 1307 | 4 mg once daily |
Dougados 2017 [35] | Worldwide | NCT01721057 | 24 weeks | 684 | 2, 4 mg once daily |
Li 2020 [36] | China, Brazil, Argentina | NCT02265705 | 12 weeks | 290 | 4 mg once daily |
Upadacitinib | |||||
Kremer 2016 [37] | Worldwide | NCT01960855 | 12 weeks | 276 | 3, 6, 12, 18 mg twice daily |
Genovese 2016 [38] | Worldwide | NCT02066389 | 12 weeks | 299 | 3, 6, 12, 18 mg twice daily, 24 mg once daily |
Burmester 2018 [39] | Worldwide | NCT02675426 | 12 weeks | 661 | 15, 30 mg once daily |
Genovese 2018 [40] | Worldwide | NCT02706847 | 24 weeks | 499 | 15, 30 mg once daily |
Fleischmann 2019 [41] | Worldwide | NCT02629159 | 12 weeks | 1304 | 15 mg once daily |
Kameda 2020 [42] | Japan | NCT02720523 | 12 weeks | 148 | 15, 30 mg once daily |
Decernotinib | |||||
Fleischmann 2015 [43] | Worldwide | NCT01052194 | 12 weeks | 204 | 25, 50, 100, 150 mg twice daily |
Genovese 2016a [44] | Worldwide | NCT01754935 | 12 weeks | 43 | 100, 200, 300 mg once daily |
Genovese 2016b [45] | Worldwide | NCT2011-004419-22 | 24 weeks | 358 | 100, 150, 200 mg once daily, 100 mg twice daily |
Peficitinib | |||||
Takeuchi 2016 [46] | Japan | NCT01649999 | 12 weeks | 281 | 25, 50, 100, 150 mg once daily |
Genovese 2017 [47] | Worldwide | NCT01565655 | 12 weeks | 289 | 25, 50, 100, 150 mg once daily |
Kivitz 2017 [48] | Worldwide | NCT01554696 | 12 weeks | 378 | 25, 50, 100, 150 mg once daily |
Takeuchi 2019 [49] | Japan | NCT02305849 | 12 weeks | 519 | 100, 150 mg once daily |
Tanaka 2019 [50] | Japan, Korea, Taiwan | NCT02308163 | 12 weeks | 307 | 100, 150 mg once daily |
Filgotinib | |||||
Kavanaugh 2017 [51] | Worldwide | NCT01894516 | 24 weeks | 283 | 50, 100, 200 mg once daily |
Westhovens 2017 [52] | Worldwide | NCT01888874 | 24 weeks | 594 | 50, 100, 200 mg once daily and twice daily |
Vanhoutte 2017 1 [53] | Republic of Moldova | NCT01384422 | 4 weeks | 36 | 100 mg twice daily or 200 once daily |
Vanhoutte 2017 2 [53] | Worldwide | NCT01668641 | 4 weeks | 91 | 30, 75, 150, 300 mg once daily |
Genovese 2019 [54] | Worldwide | NCT02873936 | 24 weeks | 449 | 100, 200 mg once daily |
Outcomes | Studies (n) | RR | Lower 95% CI | Upper 95% CI | I2 | Outcomes | Studies (n) | RR | Lower 95% CI | Upper 95% CI | I2 |
---|---|---|---|---|---|---|---|---|---|---|---|
ACR-20 | Infections | ||||||||||
All RCTs | 36 | 2.03 | 1.85 | 2.23 | 65% | All RCTs | 21 | 1.29 | 1.19 | 1.39 | 0% |
Tofacitinib | 11 | 2.21 | 1.86 | 2.63 | 52% | Tofacitinib | 3 | 1.30 | 1.00 | 1.94 | 0% |
Baricitinib | 6 | 1.95 | 1.57 | 2.42 | 78% | Baricitinib | 5 | 1.22 | 1.09 | 1.37 | 0% |
Upadacitinib | 6 | 1.99 | 1.68 | 2.36 | 64% | Upadacitinib | 6 | 1.38 | 1.22 | 1.56 | 0% |
Decernotinib | 3 | 2.61 | 1.70 | 4.01 | 31% | Decernotinib | 2 | 1.43 | 0.80 | 2.58 | 37% |
Peficitinib | 5 | 2.01 | 1.32 | 3.05 | 84% | Peficitinib | 2 | 1.01 | 0.66 | 1.56 | 0% |
Filgotinib | 5 | 1.80 | 1.43 | 2.27 | 46% | Filgotinib | 2 | 1.50 | 0.53 | 4.20 | 37% |
ACR-50 | ACR-70 | ||||||||||
All RCTs | 35 | 3.12 | 2.48 | 3.93 | 84% | All RCTs | 33 | 3.87 | 3.02 | 4.97 | 56% |
Tofacitinib | 11 | 3.43 | 2.30 | 5.12 | 78% | Tofacitinib | 11 | 4.15 | 2.21 | 7.80 | 74% |
Baricitinib | 6 | 2.73 | 2.03 | 3.66 | 64% | Baricitinib | 6 | 3.81 | 2.97 | 4.89 | 0% |
Upadacitinib | 6 | 2.25 | 1.12 | 4.52 | 96% | Upadacitinib | 6 | 4.53 | 3.53 | 5.83 | 0% |
Decernotinib | 3 | 4.72 | 2.48 | 8.96 | 0% | Decernotinib | 3 | 4.06 | 1.50 | 10.98 | 0% |
Peficitinib | 5 | 2.84 | 1.42 | 5.70 | 82% | Peficitinib | 5 | 3.64 | 1.32 | 10.05 | 73% |
Filgotinib | 4 | 5.56 | 2.79 | 11.06 | 11% | Filgotinib | 2 | 3.41 | 0.94 | 12.40 | 45% |
HAQ-DI | Serious infections | ||||||||||
All RCTs | 20 | −0.31 | −0.34 | −0.28 | 0% | All RCTs | 29 | 1.30 | 0.92 | 1.86 | 0% |
Tofacitinib | 7 | −0.34 | −0.39 | −0.28 | 0% | Tofacitinib | 8 | 1.35 | 0.72 | 2.55 | 0% |
Baricitinib | 2 | −0.24 | −0.33 | −0.15 | 0% | Baricitinib | 6 | 0.91 | 0.48 | 1.71 | 0% |
Upadacitinib | 5 | −0.31 | −0.36 | −0.26 | 0% | Upadacitinib | 6 | 1.92 | 0.83 | 4.47 | 4% |
Decernotinib | 2 | −0.24 | −0.48 | −0.01 | 72% | Decernotinib | 2 | 2.58 | 0.49 | 13.63 | 0% |
Peficitinib | 1 | −0.22 | −0.42 | −0.02 | - | Peficitinib | 4 | 2.63 | 0.59 | 11.73 | 0% |
Filgotinib | 3 | −0.33 | −0.44 | −0.22 | 44% | Filgotinib | 3 | 0.67 | 0.18 | 2.44 | 0% |
Adverse events | Herpes zoster | ||||||||||
All RCTs | 34 | 1.10 | 1.05 | 1.14 | 25% | All RCTs | 25 | 1.59 | 1.09 | 2.32 | 0% |
Tofacitinib | 11 | 1.06 | 0.98 | 1.15 | 29% | Tofacitinib | 4 | 1.28 | 0.72 | 2.29 | 0% |
Baricitinib | 5 | 1.10 | 1.01 | 1.21 | 48% | Baricitinib | 6 | 3.15 | 1.19 | 8.33 | 0% |
Upadacitinib | 6 | 1.19 | 1.11 | 1.28 | 7% | Upadacitinib | 6 | 1.25 | 0.56 | 2.81 | 0% |
Decernotinib | 3 | 1.32 | 0.97 | 1.78 | 40% | Decernotinib | 1 | 1.79 | 0.09 | 34.04 | - |
Peficitinib | 5 | 1.04 | 0.94 | 1.16 | 0% | Peficitinib | 5 | 2.13 | 0.51 | 8.92 | 37% |
Filgotinib | 5 | 0.96 | 0.84 | 1.10 | 0% | Filgotinib | 3 | 0.97 | 0.21 | 4.51 | 0% |
Serious adverse events | Upper respiratory infection | ||||||||||
All RCTs | 34 | 0.94 | 0.77 | 1.15 | 0% | All RCTs | 15 | 1.26 | 0.97 | 1.63 | 0% |
Tofacitinib | 11 | 0.74 | 0.47 | 1.18 | 20% | Tofacitinib | 8 | 1.20 | 0.69 | 2.10 | 33% |
Baricitinib | 6 | 0.92 | 0.65 | 1.31 | 0% | Baricitinib | 2 | 1.22 | 0.78 | 1.89 | 0% |
Upadacitinib | 6 | 1.72 | 0.92 | 3.25 | 18% | Upadacitinib | 1 | 1.34 | 0.63 | 2.83 | - |
Decernotinib | 3 | 1.47 | 0.58 | 3.71 | 0% | Decernotinib | 1 | 1.24 | 0.28 | 5.52 | - |
Peficitinib | 5 | 0.95 | 0.46 | 1.96 | 0% | Peficitinib | 2 | 1.60 | 0.69 | 3.67 | 0% |
Filgotinib | 3 | 0.70 | 0.24 | 2.07 | 46% | Filgotinib | 1 | 0.89 | 0.30 | 2.60 | - |
Thromboembolic events | MACE | ||||||||||
All RCTs | 13 | 1.04 | 0.38 | 2.84 | 0% | All RCTs | 16 | 1.02 | 0.45 | 2.34 | 0% |
Tofacitinib | 2 | 0.19 | 0.01 | 2.91 | 35% | Tofacitinib | 3 | 2.43 | 0.31 | 19.07 | 0% |
Baricitinib | 2 | 2.38 | 0.27 | 20.84 | 0% | Baricitinib | 5 | 0.59 | 0.10 | 3.40 | 21% |
Upadacitinib | 5 | 1.65 | 0.33 | 8.35 | 0% | Upadacitinib | 5 | 1.17 | 0.32 | 4.22 | 0% |
Decernotinib | 1 | 0.77 | 0.03 | 18.52 | - | Decernotinib | 2 | 0.76 | 0.08 | 7.22 | 0% |
Peficitinib * | 2 | - | - | - | - | Peficitinib * | 1 | - | - | - | - |
Filgotinib | 1 | 1.49 | 0.06 | 36.24 | - | Filgotinib | 0 | - | - | - | - |
Neoplasms | |||||||||||
All RCTs | 19 | 1.70 | 0.74 | 3.89 | 0% | ||||||
Tofacitinib | 1 | 9.50 | 0.56 | 162.20 | - | ||||||
Baricitinib | 5 | 1.03 | 0.26 | 4.10 | 0% | ||||||
Upadacitinib | 6 | 1.50 | 0.40 | 5.54 | 0% | ||||||
Decernotinib | 5 | 2.92 | 0.35 | 24.20 | 0% | ||||||
Peficitinib | - | - | - | - | - | ||||||
Filgotinib * | 2 | - | - | - | - |
Variables | No. of Studies | No. of Patients | Effect | NNT/NNH | Quality of the Evidence (GRADE) | Quality Domains and Assessments | Importance | ||
---|---|---|---|---|---|---|---|---|---|
JAKinibs Group | Placebo Group | Relative (95% CI) | Absolute (95% CI) | ||||||
ACR20 | 36 | 6191/10,361 (59.8%) | 1251/4255 (29.4%) | RR 2.03 (1.85 to 2.23) | 303 more per 1000 (from 250 more to 362 more) | 4 | ⨁⨁⨁◯ MODERATE | Risk of bias: not serious Inconsistency: not serious Indirectness: not serious Imprecision: not serious Other: publication bias strongly suspected a | Critical |
ACR50 | 35 | 3800/10,061 (37.8%) | 551/4107 (13.4%) | RR 3.10 (2.63 to 3.66) | 282 more per 1000 (from 219 more to 357 more) | 5 | ⨁⨁⨁◯ MODERATE | Risk of bias: not serious Inconsistency: not serious Indirectness: not serious Imprecision: not serious Other: publication bias strongly suspected a | Important |
ACR70 | 33 | 1946/9963 (19.5%) | 212/4078 (5.2%) | RR 3.87 (3.02 to 4.97) | 149 more per 1000 (from 105 more to 206 more) | 7 | ⨁⨁⨁◯ MODERATE | Risk of bias: not serious Inconsistency: not serious Indirectness: not serious Imprecision: not serious Other: publication bias strongly suspected a | Important |
Adverse events | 34 | 5735/10,181 (56.3%) | 2162/4079 (53.0%) | RR 1.10 (1.05 to 1.14) | 53 more per 1000 (from 27 more to 74 more) | 30 | ⨁⨁⨁⨁ HIGH | Risk of bias: not serious Inconsistency: not serious Indirecteness: not serious Imprecision: not serious Other: none | Critical |
Serious adverse events | 34 | 321/9898 (3.2%) | 136/4181 (3.3%) | RR 0.94 (0.77 to 1.15) | 2 fewer per 1000 (from 7 fewer to 5 more) | 1000 | ⨁⨁⨁◯ MODERATE | Risk of bias: not serious Inconsistency: seriousIndirectness: not serious Imprecision: not serious Other: publication bias strongly suspected a | Important |
Infection | 21 | 1696/6292 (27.0%) | 695/2948 (23.6%) | RR 1.29 (1.19 to 1.39) | 68 more per 1000 (from 45 more to 92 more) | 30 | ⨁⨁⨁⨁ HIGH | Risk of bias: not serious Inconsistency: not serious Indirectness: not serious Imprecision: not serious Other: none | Important |
Serious infection | 29 | 155/9043 (1.7%) | 37/3879 (1.0%) | RR 1.30 (0.92 to 1.86) | 3 more per 1000 (from 1 fewer to 8 more) | 143 | ⨁⨁⨁⨁ HIGH | Risk of bias: not serious Inconsistency: serious Indirectness: not serious Imprecision: not serious Other: none | Important |
Herpes zoster | 25 | 160/7700 (2.1%) | 28/3533 (0.8%) | RR 1.59 (1.09 to 2.32) | 5 more per 1000 (from 1 more to 10 more) | 77 | ⨁⨁⨁⨁ HIGH | Risk of bias: not serious Inconsistency: serious b Indirectness: not serious Imprecision: serious Other: none | Important |
Upper respiratory infection | 15 | 315/5491 (5.7%) | 74/1733 (4.3%) | RR 1.26 (0.97 to 1.63) | 11 more per 1000 (from 1 more to 27 more) | 72 | ⨁⨁⨁◯ MODERATE | Risk of bias: not serious Inconsistency: not serious Indirectness: not serious Imprecision: not serious Other: publication bias strongly suspected a | Not important |
Thromboembolic events | 13 | 12/4455 (0.3%) | 3/2241 (0.1%) | RR 1.04 (0.38 to 2.84) | 0 fewer per 1000 (from 1 fewer to 2 more) | 500 | ⨁⨁◯◯ LOW | Risk of bias: not serious Inconsistency: not serious Indirectness: not serious Imprecision: serious b: Other: publication bias strongly suspected a | Important |
MACE | 16 | 20/5704 (0.4%) | 5/2735 (0.2%) | RR 1.02 (0.45 to 2.34) | 0 fewer per 1000 (from 1 fewer to 2 more) | 500 | ⨁⨁◯◯ LOW | Risk of bias: serious Inconsistency: not serious Indirectness: not serious Imprecision: serious b: Other: publication bias strongly suspected a | Not IMPORTANT |
Neoplasms | 19 | 27/5885 (0.5%) | 4/3051 (0.1%) | RR 1.70 (0.74 to 3.89) | 1 fewer per 1000 (from 0 fewer to 4 more) | 250 | ⨁⨁◯◯ LOW | Risk of bias: serious Inconsistency: not serious Indirectness: not serious Imprecision: serious b: Other: publication bias strongly suspected a | Not IMPORTANT |
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Wang, F.; Tang, X.; Zhu, M.; Mao, H.; Wan, H.; Luo, F. Efficacy and Safety of JAK Inhibitors for Rheumatoid Arthritis: A Meta-Analysis. J. Clin. Med. 2022, 11, 4459. https://doi.org/10.3390/jcm11154459
Wang F, Tang X, Zhu M, Mao H, Wan H, Luo F. Efficacy and Safety of JAK Inhibitors for Rheumatoid Arthritis: A Meta-Analysis. Journal of Clinical Medicine. 2022; 11(15):4459. https://doi.org/10.3390/jcm11154459
Chicago/Turabian StyleWang, Faping, Xiaoju Tang, Min Zhu, Hui Mao, Huajing Wan, and Fengming Luo. 2022. "Efficacy and Safety of JAK Inhibitors for Rheumatoid Arthritis: A Meta-Analysis" Journal of Clinical Medicine 11, no. 15: 4459. https://doi.org/10.3390/jcm11154459
APA StyleWang, F., Tang, X., Zhu, M., Mao, H., Wan, H., & Luo, F. (2022). Efficacy and Safety of JAK Inhibitors for Rheumatoid Arthritis: A Meta-Analysis. Journal of Clinical Medicine, 11(15), 4459. https://doi.org/10.3390/jcm11154459