On 23 April 2018, the Food and Drug Administration-based Advisory Committee approved the use of baricitinib 2 mg for the treatment of rheumatoid arthritis and suggested the possibility of serious adverse events associated with baricitinib 4 mg. Hence, we aimed to systematically compare the risk of adverse drug events observed with baricitinib 2 mg versus 4 mg for the treatment of patients with rheumatoid arthritis.
Electronic databases including the Cochrane library, MEDLINE, EMBASE and http://www.ClinicalTrials.gov were searched for relevant English publications until April 2018. Adverse drug events at 12 weeks and 24 weeks were considered as the clinical endpoints. RevMan 5.3 software was used to analyze the data whereby risk ratios (RR) and 95% confidence intervals (CI) were calculated.
Four trials consisting of a total of 959 participants were included in this analysis. At 12 weeks, no significant difference was observed between 2 mg and 4 mg baricitinib for serious adverse events (RR 1.33; 95% CI 0.63–2.78; p = 0.46), any adverse events after the start of therapy (RR 1.09; 95% CI 0.98–1.21; p = 0.13), discontinuation of drugs due to adverse events (RR 1.19; 95% CI 0.61–2.34; p = 0.60), malignancies (RR 3.03; 95% CI 0.12–73.90; p = 0.50), and major adverse cardiac events (RR 2.95; 95% CI 0.12–71.91; p = 0.51). Infections including herpes zoster infections and serious infections were also similarly manifested. At 24 weeks, serious adverse events (RR 1.84; 95% CI 1.02–3.30; p = 0.04) were significantly higher with baricitinib 4 mg compared with the 2-mg dosage. However, total adverse events after the start of therapy, discontinuation of drug due to adverse events, malignancies, major adverse cardiac events, infections including herpes zoster, and serious infections were not significantly different between the two doses.
No significant differences in adverse drug events were observed between baricitinib 2 mg and 4 mg at 12 weeks’ follow-up. However, this analysis showed the risk of serious adverse events to be significantly higher with baricitinib 4 mg compared with baricitinib 2 mg at 24 weeks’ follow-up. This hypothesis should be confirmed in larger trials with longer follow-up time periods.
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Engdahl C, Bondt A, Harre U, Raufer J, Pfeifle R, Camponeschi A, Wuhrer M, Seeling M, Mårtensson IL, Nimmerjahn F, Krönke G, Scherer HU, Forsblad-d’Elia H, Schett G. Estrogen induces St6gal1 expression and increases IgG sialylation in mice and patients with rheumatoid arthritis: a potential explanation for the increased risk of rheumatoid arthritis in postmenopausal women. Arthritis Res Ther. 2018;20(1):84.
Guo Q, Wang Y, Xu D, Nossent J, Pavlos NJ, Xu J. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res. 2018;27(6):15.
Turan S, Walker S. Janus kinase inhibitors for the treatment of rheumatoid arthritis. Hosp Pharm. 2017;52(10):667–8.
Nakayamada S, Kubo S, Iwata S, Tanaka Y. Recent progress in JAK inhibitors for the treatment of rheumatoid arthritis. BioDrugs. 2016;30(5):407–19.
Al-Salama ZT, Scott LJ. Baricitinib: a review in rheumatoid arthritis. Drugs. 2018;78(7):761–72.
Markham A. Baricitinib: first global approval. Drugs. 2017;77(6):697–704.
Zamora NV, Tayar J, Lopez-Olivo MA, Christensen R, Suarez-Almazor M. Baricitinib for rheumatoid arthritis: a systematic review and meta-analysis. Arthritis Rheumatol. 2016;68 (suppl 10). https://acrabstracts.org/abstract/baricitinib-for-rheumatoid-arthritis-a-systematic-review-and-meta-analysis/. Accessed 22 Aug 2018.
FDA briefing document—Arthritis Advisory Committee meeting, 23 April 2018.
Higgins JP, et al. Assessing risk of bias in included studies. Cochrane handbook for systematic reviews of interventions. New York: Wiley; 2008. p. 187–241.
Liberati A, Altman DG, Tetzlaff J, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ. 2009;339:b2700.
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. Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study. Ann Rheum Dis. 2017;76(1):88–95.
Genovese MC, Kremer J, Zamani O, Ludivico C, Krogulec M, Xie L, Beattie SD, Koch AE, Cardillo TE, Rooney TP, Macias WL, de Bono S, Schlichting DE, Smolen JS. Baricitinib in patients with refractory rheumatoid arthritis. N Engl J Med. 2016;374(13):1243–52.
Keystone EC, Genovese MC, Schlichting DE, de la Torre I, Beattie SD, Rooney TP, Taylor PC. Safety and efficacy of baricitinib through 128 weeks in an open-label, longterm extension study in patients with rheumatoid arthritis. J Rheumatol. 2018;45(1):14–21.
Tanaka Y, Emoto K, Cai Z, Aoki T, Schlichting D, Rooney T, Macias W. 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. 2016;43(3):504–11.
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. Safety and efficacy of baricitinib at 24 weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate. Ann Rheum Dis. 2015;74(2):333–40.
Ethical approval was not applicable for this systematic review and meta-analysis.
Conflict of interest
Feng Huang and Zu-chun Luo declare that they have no competing interests.
No external funding was used in the preparation of this manuscript. This research was supported by the National Natural Science Foundation of China (nos. 81560046, 81760057) and Guangxi Natural Science Foundation (no. 2016GXNSFAA380002).
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Huang, F., Luo, Zc. Risk of Adverse Drug Events Observed with Baricitinib 2 mg Versus Baricitinib 4 mg Once Daily for the Treatment of Rheumatoid Arthritis: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. BioDrugs 32, 415–423 (2018). https://doi.org/10.1007/s40259-018-0304-3