Abstract
Janus kinases (JAKs) play an important role in intracellular signaling for multiple cytokines in the pathogenesis of RA. Baricitinib is an oral, selective JAK 1 and 2 inhibitor which has been shown to be effective in the treatment of RA in several clinical trials. This meta-analysis aims to aggregate currently available data to assess the overall efficacy and safety of baricitinib in RA. We searched PubMed, EMBASE, and Cochrane CENTRAL from inception through 09/24/17 with restriction to English language. We excluded meeting abstracts without full text publication. We used RevMan 5.3 to perform meta-analysis between groups on baricitinib (2 and 4 mg daily) and placebo using random effect model calculating odds ratio (OR) as well as 95% confidence interval (CI). Compared to placebo, 2 mg of baricitinib was more effective in achieving ACR20 [54 vs. 36.6%; OR 2.09; 95% CI 1.60–2.71; p < 0.00001; I2 0%], ACR50 [31.6 vs. 10.3%; OR 2.3; 95% CI 1.68–3.15; p < 0.00001; I2 0%], and ACR70 responses [18.7 vs. 5.1%; OR 4.05; 95% CI 2.54–6.44; p < 0.00001; I2 0%]. Similarly, 4 mg of baricitinib daily was more effective than placebo. Baricitinib 2 mg once daily did not increase any adverse events [65.3 vs. 62.4%; OR 1.03; 95% CI 0.80–1.34; p = 0.8; I2 0%], serious adverse events [3.5 vs. 5%; OR 0.68; 95% CI 0.37–1.27; p = 0.22; I2 0%], and herpes zoster [1.2 vs. 0.4%; OR 2.34; 95% CI 0.27–20.47; p = 0.44; I2 37%] as compared to placebo. Similarly, 4 mg of baricitinib did not increase the risk of serious adverse events but increased herpes zoster infection [OR 3.88; 95% CI 1.36–11.06; p = 0.01; I2 0%] when compared to placebo. Baricitinib is effective in treatment of RA, and did not appear to have significant safety concerns during the first 6 months of treatment.
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References
Tanaka Y (2015) Recent progress and perspective in JAK inhibitors for rheumatoid arthritis: from bench to bedside. J Biochem 158(3):173–179. https://doi.org/10.1093/jb/mvv069
Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH, National Arthritis Data W (2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I Arthritis Rheum 58(1):15–25. https://doi.org/10.1002/art.23177
Mahajan TD, Mikuls TR (2018) Recent advances in the treatment of rheumatoid arthritis. Curr Opin Rheumatol:1. https://doi.org/10.1097/BOR.0000000000000496
Wailoo A, Hock ES, Stevenson M, Martyn-St James M, Rawdin A, Simpson E, Wong R, Dracup N, Scott DL, Young A (2017) The clinical effectiveness and cost-effectiveness of treat-to-target strategies in rheumatoid arthritis: a systematic review and cost-effectiveness analysis. Health Technol Assess 21(71):1–258. https://doi.org/10.3310/hta21710
Kunwar S, Dahal K, Sharma S (2016) Anti-IL-17 therapy in treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Rheumatol Int 36(8):1065–1075. https://doi.org/10.1007/s00296-016-3480-9
Naz SM, Symmons DP (2007) Mortality in established rheumatoid arthritis. Best Pract Res Clin Rheumatol 21(5):871–883. https://doi.org/10.1016/j.berh.2007.05.003
Dadoun S, Zeboulon-Ktorza N, Combescure C, Elhai M, Rozenberg S, Gossec L, Fautrel B (2013) Mortality in rheumatoid arthritis over the last fifty years: systematic review and meta-analysis. Joint Bone Spine 80(1):29–33. https://doi.org/10.1016/j.jbspin.2012.02.005
Bukhari MA, Wiles NJ, Lunt M, Harrison BJ, Scott DG, Symmons DP, Silman AJ (2003) Influence of disease-modifying therapy on radiographic outcome in inflammatory polyarthritis at five years: results from a large observational inception study. Arthritis Rheum 48(1):46–53. https://doi.org/10.1002/art.10727
Smolen JS, Breedveld FC, Burmester GR, Bykerk V, Dougados M, Emery P, Kvien TK, Navarro-Compán MV, Oliver S, Schoels M, Scholte-Voshaar M, Stamm T, Stoffer M, Takeuchi T, Aletaha D, Andreu JL, Aringer M, Bergman M, Betteridge N, Bijlsma H, Burkhardt H, Cardiel M, Combe B, Durez P, Fonseca JE, Gibofsky A, Gomez-Reino JJ, Graninger W, Hannonen P, Haraoui B, Kouloumas M, Landewe R, Martin-Mola E, Nash P, Ostergaard M, Östör A, Richards P, Sokka-Isler T, Thorne C, Tzioufas AG, van Vollenhoven R, de Wit M, van der Heijde D (2016) Treating rheumatoid arthritis to target: 2014 update of the recommendations of an international task force. Ann Rheum Dis 75(1):3–15. https://doi.org/10.1136/annrheumdis-2015-207524
Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC et al (2010) Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 69(4):631–637. https://doi.org/10.1136/ard.2009.123919
Singh JA, Saag KG, Bridges SL et al (2016) 2015 American College of Rheumatology Guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol 68(1):1–26. https://doi.org/10.1002/art.39480
Fatimah N, Salim B, Nasim A, Hussain K, Gul H, Niazi S (2016) Frequency of methotrexate intolerance in rheumatoid arthritis patients using methotrexate intolerance severity score (MISS questionnaire). Clin Rheumatol 35(5):1341–1345. https://doi.org/10.1007/s10067-016-3243-8
Storage SS, Agrawal H, Furst DE (2010) Description of the efficacy and safety of three new biologics in the treatment of rheumatoid arthritis. Korean J Intern Med 25(1):1–17. https://doi.org/10.3904/kjim.2010.25.1.1
Rivellese F, Lobasso A, Barbieri L, Liccardo B, De Paulis A, Rossi FW (2018) Novel therapeutic approaches in rheumatoid arthritis: role of Janus kinases inhibitors. Curr Med Chem doi:https://doi.org/10.2174/0929867325666180209145243, 25
Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, **e L, Beattie SD, Koch AE, Cardillo TE, Rooney TP, Macias WL, de Bono S, Schlichting DE, Smolen JS (2016) Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med 374(13):1243–1252. https://doi.org/10.1056/NEJMoa1507247
Schwartz DM, Kanno Y, Villarino A, Ward M, Gadina M, O'Shea JJ (2017) JAK inhibition as a therapeutic strategy for immune and inflammatory diseases. Nat Rev Drug Discov 16(12):843–862. https://doi.org/10.1038/nrd.2017.201
Kuriya B, Cohen MD, Keystone E (2017) Baricitinib in rheumatoid arthritis: evidence-to-date and clinical potential. Ther Adv Musculoskelet Dis 9(2):37–44. https://doi.org/10.1177/1759720X16687481
Richez C, Truchetet ME, Kostine M, Schaeverbeke T, Bannwarth B (2017) Efficacy of baricitinib in the treatment of rheumatoid arthritis. Expert Opin Pharmacother 18(13):1399–1407. https://doi.org/10.1080/14656566.2017.1359256
Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, Covington MB, Thomas B, Collier P, Favata MF, Wen X, Shi J, McGee R, Haley PJ, Shepard S, Rodgers JD, Yeleswaram S, Hollis G, Newton RC, Metcalf B, Friedman SM, Vaddi K (2010) Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. J Immunol 184(9):5298–5307. https://doi.org/10.4049/jimmunol.0902819
Markham A (2017) Baricitinib: first global approval. Drugs 77(6):697–704. https://doi.org/10.1007/s40265-017-0723-3
(2017) FDA issues concerns about optimal baricitinib doses for the treatment of moderate-to-severe rheumatoid arthritis and delays drug approval. Rheumatology 1 56(8):e22. https://doi.org/10.1093/rheumatology/kex245
Lilly and Incyte Provide Update on Baricitinib (25 July 2017). Eli Lilly and Company, Indianapolis
Verden A, Dimbil M, Kyle R, Overstreet B, Hoffman KB (2017) Analysis of spontaneous postmarket case reports submitted to the FDA regarding thromboembolic adverse events and JAK inhibitors. Drug Saf 41:357–361. https://doi.org/10.1007/s40264-017-0622-2
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. Ann Intern Med 151(4):W65–W94
Moher D, Liberati A, Tetzlaff J, Altman DG, Group P (2010) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg 8(5):336–341. https://doi.org/10.1016/j.ijsu.2010.02.007
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. https://doi.org/10.1002/sim.1186
Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003) Measuring inconsistency in meta-analyses. BMJ 327(7414):557–560. https://doi.org/10.1136/bmj.327.7414.557
Tang JL, Liu JL (2000) Misleading funnel plot for detection of bias in meta-analysis. J Clin Epidemiol 53(5):477–484
Ioannidis JP, Trikalinos TA (2007) The appropriateness of asymmetry tests for publication bias in meta-analyses: a large survey. CMAJ 176(8):1091–1096. https://doi.org/10.1503/cmaj.060410
Higgins JP, Altman DG, Gotzsche PC, Juni P, Moher D, Oxman AD, Savovic J, Schulz KF, Weeks L, Sterne JA, Cochrane Bias Methods G, Cochrane Statistical Methods G (2011) The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 343:d5928. https://doi.org/10.1136/bmj.d5928
Guyatt GH, Oxman AD, Vist GE, Kunz R, Falck-Ytter Y, Alonso-Coello P, Schunemann HJ, Group GW (2008) GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 336(7650):924–926. https://doi.org/10.1136/bmj.39489.470347.AD
Guyatt GH, Oxman AD, Kunz R, Vist GE, Falck-Ytter Y, Schunemann HJ, Group GW (2008) What is “quality of evidence” and why is it important to clinicians? BMJ 336(7651):995–998. https://doi.org/10.1136/bmj.39490.551019.BE
Fleischmann R, Schiff M, van der Heijde D, Ramos-Remus C, Spindler A, Stanislav M, Zerbini CAF, Gurbuz S, Dickson C, de Bono S, Schlichting D, Beattie S, Kuo WL, Rooney T, Macias W, Takeuchi T (2017) Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol 69(3):506–517
Taylor PC, Keystone EC, Van Der Heijde D, Weinblatt ME, Del Carmen Morales L, Gonzaga JR, Yakushin S, Ishii T, Emoto K, Beattie S, Arora V, Gaich C, Rooney T, Schlichting D, Macias WL, De Bono S, Tanaka Y (2017) Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 376(7):652–662
Tanaka Y, Emoto K, Cai Z, Aoki T, Schlichting D, Rooney T, Macias W (2016) Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis receiving background methotrexate therapy: a 12-week, double-blind, randomized placebo-controlled study. J Rheumatol 43(3):504–511
Dougados M, van der Heijde D, Chen YC, Greenwald M, Drescher E, Liu J, Beattie S, Witt S, de la Torre I, Gaich C, Rooney T, Schlichting D, de Bono S, Emery P (2017) Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis 76(1):88–95. https://doi.org/10.1136/annrheumdis-2016-210094
Keystone EC, Taylor PC, Drescher E, Schlichting DE, Beattie SD, Berclaz PY, Lee CH, Fidelus-Gort RK, Luchi ME, Rooney TP, Macias WL, Genovese MC (2015) Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis 74(2):333–340. https://doi.org/10.1136/annrheumdis-2014-206478
Emery P, Blanco R, Maldonado Cocco J, Chen YC, Gaich CL, Delozier AM, De Bono S, Liu J, Rooney T, Chang CHC, Dougados M (2017) Patient-reported outcomes from a phase III study of baricitinib in patients with conventional synthetic DMARD-refractory rheumatoid arthritis. RMD Open 3(1):e000410. https://doi.org/10.1136/rmdopen-2016-000410
Smolen JS, Kremer JM, Gaich CL, DeLozier AM, Schlichting DE, **e L, Stoykov I, Rooney T, Bird P, Sanchez Burson JM, Genovese MC, Combe B (2017) Patient-reported outcomes from a randomised phase III study of baricitinib in patients with rheumatoid arthritis and an inadequate response to biological agents (RA-BEACON). Ann Rheum Dis 76(4):694–700. https://doi.org/10.1136/annrheumdis-2016-209821
Tanaka Y, Ishii T, Cai Z, Schlichting D, Rooney T, Macias W (2018) Efficacy and safety of baricitinib in Japanese patients with active rheumatoid arthritis: a 52-week, randomized, single-blind, extension study. Mod Rheumatol 28(1):20–29. https://doi.org/10.1080/14397595.2017.1307899
Keystone EC, Genovese MC, Schlichting DE, de la Torre I, Beattie SD, Rooney TP, Taylor PC (2018) Safety and efficacy of baricitinib through 128 weeks in an open-label, longterm extension study in patients with rheumatoid arthritis. J Rheumatol 45(1):14–21. https://doi.org/10.3899/jrheum.161161
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SK had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of data analysis. SK, CC, and FC were involved in study design. SK and FC were involved in acquisition of data. SK was involved in statistical analysis and interpreted the data. SK, CC, and FC were involved in manuscript preparation.
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Kunwar, S., Collins, C.E. & Constantinescu, F. Baricitinib, a Janus kinase inhibitor, in the treatment of rheumatoid arthritis: a systematic literature review and meta-analysis of randomized controlled trials. Clin Rheumatol 37, 2611–2620 (2018). https://doi.org/10.1007/s10067-018-4199-7
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DOI: https://doi.org/10.1007/s10067-018-4199-7