Survival Benefit of High Dose Versus Usual Dose of Baricitinib in Hospitalized Patients with COVID-19: A Systematic Review
Main Article Content
Abstract
Baricitinib is an oral selective Janus kinase 1 and 2 inhibitor with known anti-inflammatory and anti-viral properties. In patients hospitalized for coronavirus disease 2019 (COVID-19), baricitinib has shown to reduce the risk of death in line with dexamethasone and tocilizumab. However, the most effective and safe dose or optimal dose of baricitinib in severe COVID-19 was not addressed.
We conducted this systematic review to assess whether higher than usual dose could further improve survival as primary outcome. The need of ICU (Intensive care Unit) and Invasive or non-invasive positive pressure ventilation, time to wean from oxygen, length of stay at hospital and adverse events were analyzed as secondary outcome.
We included 10,032 patients in 5 studies (2 randomised control trials and 3 high quality clinical trials). Among them,5,071 patients received baricitinib at different dosage (4909 patients received 4 mg once daily and 162 patients got more than 4 mg daily) and 4961 received standard of care. Baseline characteristics including mean age, sex, co-morbidities, inflammatory marker (C-reactive protein/CRP) were similar across the intervention and standard care groups.
4 out of 5 trials showed significant survival benefit in baricitinib group usual to higher dose (4 to 8 mg daily). Use of higher dose in 3 controlled trials was associated with significant reduction in admission to ICU and requirement of invasive or non-invasive ventilation support, shortening of hospital stay and earlier stabilization of oxygen status which was not evident in two randomized control trials using usual dose (4 mg daily). There was no significant difference in any serious adverse events or opportunistic infections between higher dose versus usual dose group.
Therefore, baricitinib in higher dose could be a potent, highly effective and safe immunomodulatory drug in hospitalized patients with severe COVID-19.
Keywords:
baricitinib, high dose, COVID‐19, efficacy, JAK‐inhibitor, safety
Article Details
How to Cite
HUQ, Shihan Mahmud Redwanul et al.
Survival Benefit of High Dose Versus Usual Dose of Baricitinib in Hospitalized Patients with COVID-19: A Systematic Review.
Medical Research Archives, [S.l.], v. 10, n. 9, sep. 2022.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/3076>. Date accessed: 18 apr. 2024.
doi: https://doi.org/10.18103/mra.v10i9.3076.
Section
Review Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Tziolos, N., Karofylakis, E., Grigoropoulos, I., Kazakou, P., Koullias, E., Savva, A., Kranidioti, H., Pelekanou, A., Boulouta, A., Pirounaki, M., Tsiodras, S., Georgiopoulos, G., Boumpas, D. T., Kavatha, D., Thomas, K., Vassilopoulos, D., & Antoniadou, A. (2022). Real-Life Effectiveness and Safety of Baricitinib as Adjunctive to Standard-of-Care Treatment in Hospitalized Patients with Severe Coronavirus Disease 2019. Open Forum Infectious Diseases, 9(1). https://doi.org/10.1093/ofid/ofab588
2. CSSEGISandData (2020). COVID-19 Data Repository by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. [online] GitHub.
3. Selvaraj, V., Finn, A., Lal, A., Khan, M. S., Dapaah-Afriyie, K., & Carino, G. P. (2022). Baricitinib in hospitalised patients with COVID-19: A meta-analysis of randomised controlled trials. EClinicalMedicine, 49, 101489. https://doi.org/10.1016/j.eclinm.2022.101489
4. Dexamethasone in Hospitalized Patients with Covid-19. (2021). New England Journal of Medicine, 384(8), 693–704. https://doi.org/10.1056/NEJMoa2021436
5. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital 506 with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. (n.d.). Lancet 2021.
6. WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group, 509 Shankar-Hari M, Vale CL, et al. Association Between Administration of IL-6 Antagonists 510 and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA 2021; 511 326(6): 499-518. (n.d.)
7. Richardson, P., Griffin, I., Tucker, C., Smith, D., Oechsle, O., Phelan, A., Rawling, M., Savory, E., & Stebbing, J. (2020). Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet, 395(10223), e30–e31. https://doi.org/10.1016/S0140-6736(20)30304-4
8. Stebbing, J., Krishnan, V., Bono, S., Ottaviani, S., Casalini, G., Richardson, P. J., Monteil, V., Lauschke, V. M., Mirazimi, A., Youhanna, S., Tan, Y., Baldanti, F., Sarasini, A., Terres, J. A. R., Nickoloff, B. J., Higgs, R. E., Rocha, G., Byers, N. L., Schlichting, D. E., … Corbellino, M. (2020). Mechanism of baricitinib supports artificial intelligence‐predicted testing inCOVID ‐19 patients. EMBO Molecular Medicine, 12(8). https://doi.org/10.15252/emmm.202012697
9. Rubin, R. (2022). Baricitinib Is First Approved COVID-19 Immunomodulatory Treatment. JAMA, 327(23), 2281. https://doi.org/10.1001/jama.2022.9846
10. Kalil, A. C., & Stebbing, J. (2021). Baricitinib: the first immunomodulatory treatment to reduce COVID-19 mortality in a placebo-controlled trial. The Lancet Respiratory Medicine, 9(12), 1349–1351. https://doi.org/10.1016/S2213-2600(21)00358-1
11. Marconi, V. C., Ramanan, A. v, de Bono, S., Kartman, C. E., Krishnan, V., Liao, R., Piruzeli, M. L. B., Goldman, J. D., Alatorre-Alexander, J., de Cassia Pellegrini, R., Estrada, V., Som, M., Cardoso, A., Chakladar, S., Crowe, B., Reis, P., Zhang, X., Adams, D. H., Ely, E. W., … Zirpe, K. (2021). Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. The Lancet Respiratory Medicine, 9(12), 1407–1418. https://doi.org/10.1016/S2213-2600(21)00331-3
12. Group RC, Horby PW, Emberson JR, et al. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. medRxiv2022: 2022.03.02.22271623. (n.d.).
13. Assadiasl, S., Fatahi, Y., Mosharmovahed, B., Mohebbi, B., & Nicknam, M. H. (2021). Baricitinib: From Rheumatoid Arthritis to COVID‐19. The Journal of Clinical Pharmacology, 61(10), 1274–1285. https://doi.org/10.1002/jcph.1874
14. Papp, K. A., Menter, M. A., Raman, M., Disch, D., Schlichting, D. E., Gaich, C., Macias, W., Zhang, X., & Janes, J. M. (2016). A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK ) 1/JAK2 inhibitor, in patients with moderate‐to‐severe psoriasis. British Journal of Dermatology, 174(6), 1266–1276. https://doi.org/10.1111/bjd.14403
15. Simpson, E. L., Lacour, J. ‐P., Spelman, L., Galimberti, R., Eichenfield, L. F., Bissonnette, R., King, B. A., Thyssen, J. P., Silverberg, J. I., Bieber, T., Kabashima, K., Tsunemi, Y., Costanzo, A., Guttman‐Yassky, E., Beck, L. A., Janes, J. M., DeLozier, A. M., Gamalo, M., Brinker, D. R., … Reich, K. (2020). Baricitinib in patients with moderate‐to‐severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phaseIII trials. British Journal of Dermatology, 183(2), 242–255. https://doi.org/10.1111/bjd.18898
16. Dougados, M., van der Heijde, D., Chen, Y.-C., 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. Annals of the Rheumatic Diseases, 76(1), 88–95. https://doi.org/10.1136/annrheumdis-2016-210094
17. Bronte, V., Ugel, S., Tinazzi, E., Vella, A., de Sanctis, F., Canè, S., Batani, V., Trovato, R., Fiore, A., Petrova, V., Hofer, F., Barouni, R. M., Musiu, C., Caligola, S., Pinton, L., Torroni, L., Polati, E., Donadello, K., Friso, S., … Olivieri, O. (2020). Baricitinib restrains the immune dysregulation in patients with severe COVID-19. Journal of Clinical Investigation, 130(12), 6409–6416. https://doi.org/10.1172/JCI141772
18. Hasan, Md. J., Rabbani, R., Anam, A. M., Huq, S. M. R., Polash, M. M. I., Nessa, S. S. T., & Bachar, S. C. (2021). Impact of high dose of baricitinib in severe COVID-19 pneumonia: a prospective cohort study in Bangladesh. BMC Infectious Diseases, 21(1), 427. https://doi.org/10.1186/s12879-021-06119-2
19. Hasan, M. J., Rabbani, R., Anam, A. M., & Huq, S. M. R. (2020). Additional baricitinib loading dose improves clinical outcome in COVID-19. Open Medicine, 16(1), 041–046. https://doi.org/10.1515/med-2021-0010
20. NIH (2021). Clinical Spectrum. [online] COVID-19 Treatment Guidelines. Available at: https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/. (n.d.).
21. Chen, C. Y., Chen, W. C., Hsu, C. K., Chao, C. M., & Lai, C. C. (2021). Clinical efficacy and safety of Janus kinase inhibitors for COVID-19: A systematic review and meta-analysis of randomized controlled trials. International immunopharmacology, 99, 108027. https://doi.org/10.1016/j.intimp.2021.108027
22. Lin, Z., Niu, J., Xu, Y., Qin, L., Ding, J., & Zhou, L. (2021). Clinical Efficacy and Adverse Events of Baricitinib Treatment for Coronavirus Disease-2019 (COVID-19): A Systematic Review and Meta-Analysis. SSRN Electronic Journal. https://doi.org/10.2139/ssrn.3929406
23. Limen, R. Y., Sedono, R., Sugiarto, A., & Hariyanto, T. I. (2022). Janus kinase (JAK)-inhibitors and coronavirus disease 2019 (Covid-19) outcomes: a systematic review and meta-analysis. Expert Review of Anti-Infective Therapy, 20(3), 425–434. https://doi.org/10.1080/14787210.2021.1982695
24. Chen, C., Wang, J., Li, H., Yuan, L., Gale, R. P., & Liang, Y. (2021). JAK-inhibitors for coronavirus disease-2019 (COVID-19): a meta-analysis. Leukemia, 35(9), 2616–2620. https://doi.org/10.1038/s41375-021-01266-6
25. Bhimraj, A., Morgan, R. L., Shumaker, A. H., Baden, L., Chi-Chung Cheng, V., Edwards, K. M., Gandhi, R. T., Gallagher, J. C., Muller, W. J., O’Horo, J. C., Shoham, S., Wollins, D. S., & Falck-Ytter, Y. (2022). Lessons Learned from Coronavirus Disease 2019 (COVID-19) Therapies: Critical Perspectives from the Infectious Diseases Society of America (IDSA) COVID-19 Treatment Guideline Panel. Clinical Infectious Diseases, 74(9), 1691–1695. https://doi.org/10.1093/cid/ciab882
26. COVID-19 Treatment Guidelines. (2021). Hospitalized Adults: Therapeutic Management. [online] Available at: https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/hospitalized-adults--therapeutic-management/. (n.d.).
27. www.who.int. (n.d.). Therapeutics and COVID-19: living guideline. [online] Available at: https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2022.4 [Accessed 23 Jul. 2022]. (n.d.).
28. Frediansyah A, Tiwari R, Sharun K, Dhama K, Harapan H. Antivirals for COVID-19: A critical review. Clin Epidemiol Glob Health.2021;9:90–98. (n.d.).
29. Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.Cell. 2020;181(5):1016–1035. e19. (n.d.).
30. Strand V, Ahadieh S, DeMasi R, et al. THU0211 Meta-analysis of serious infections with baricitinib, tofacitinib and biologic dmards in rheumatoid arthritis. Ann Rheum Dis 2017; 76:284
2. CSSEGISandData (2020). COVID-19 Data Repository by the Center for Systems Science and Engineering (CSSE) at Johns Hopkins University. [online] GitHub.
3. Selvaraj, V., Finn, A., Lal, A., Khan, M. S., Dapaah-Afriyie, K., & Carino, G. P. (2022). Baricitinib in hospitalised patients with COVID-19: A meta-analysis of randomised controlled trials. EClinicalMedicine, 49, 101489. https://doi.org/10.1016/j.eclinm.2022.101489
4. Dexamethasone in Hospitalized Patients with Covid-19. (2021). New England Journal of Medicine, 384(8), 693–704. https://doi.org/10.1056/NEJMoa2021436
5. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital 506 with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. (n.d.). Lancet 2021.
6. WHO Rapid Evidence Appraisal for COVID-19 Therapies Working Group, 509 Shankar-Hari M, Vale CL, et al. Association Between Administration of IL-6 Antagonists 510 and Mortality Among Patients Hospitalized for COVID-19: A Meta-analysis. JAMA 2021; 511 326(6): 499-518. (n.d.)
7. Richardson, P., Griffin, I., Tucker, C., Smith, D., Oechsle, O., Phelan, A., Rawling, M., Savory, E., & Stebbing, J. (2020). Baricitinib as potential treatment for 2019-nCoV acute respiratory disease. The Lancet, 395(10223), e30–e31. https://doi.org/10.1016/S0140-6736(20)30304-4
8. Stebbing, J., Krishnan, V., Bono, S., Ottaviani, S., Casalini, G., Richardson, P. J., Monteil, V., Lauschke, V. M., Mirazimi, A., Youhanna, S., Tan, Y., Baldanti, F., Sarasini, A., Terres, J. A. R., Nickoloff, B. J., Higgs, R. E., Rocha, G., Byers, N. L., Schlichting, D. E., … Corbellino, M. (2020). Mechanism of baricitinib supports artificial intelligence‐predicted testing in
9. Rubin, R. (2022). Baricitinib Is First Approved COVID-19 Immunomodulatory Treatment. JAMA, 327(23), 2281. https://doi.org/10.1001/jama.2022.9846
10. Kalil, A. C., & Stebbing, J. (2021). Baricitinib: the first immunomodulatory treatment to reduce COVID-19 mortality in a placebo-controlled trial. The Lancet Respiratory Medicine, 9(12), 1349–1351. https://doi.org/10.1016/S2213-2600(21)00358-1
11. Marconi, V. C., Ramanan, A. v, de Bono, S., Kartman, C. E., Krishnan, V., Liao, R., Piruzeli, M. L. B., Goldman, J. D., Alatorre-Alexander, J., de Cassia Pellegrini, R., Estrada, V., Som, M., Cardoso, A., Chakladar, S., Crowe, B., Reis, P., Zhang, X., Adams, D. H., Ely, E. W., … Zirpe, K. (2021). Efficacy and safety of baricitinib for the treatment of hospitalised adults with COVID-19 (COV-BARRIER): a randomised, double-blind, parallel-group, placebo-controlled phase 3 trial. The Lancet Respiratory Medicine, 9(12), 1407–1418. https://doi.org/10.1016/S2213-2600(21)00331-3
12. Group RC, Horby PW, Emberson JR, et al. Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis. medRxiv2022: 2022.03.02.22271623. (n.d.).
13. Assadiasl, S., Fatahi, Y., Mosharmovahed, B., Mohebbi, B., & Nicknam, M. H. (2021). Baricitinib: From Rheumatoid Arthritis to COVID‐19. The Journal of Clinical Pharmacology, 61(10), 1274–1285. https://doi.org/10.1002/jcph.1874
14. Papp, K. A., Menter, M. A., Raman, M., Disch, D., Schlichting, D. E., Gaich, C., Macias, W., Zhang, X., & Janes, J. M. (2016). A randomized phase 2b trial of baricitinib, an oral Janus kinase (
15. Simpson, E. L., Lacour, J. ‐P., Spelman, L., Galimberti, R., Eichenfield, L. F., Bissonnette, R., King, B. A., Thyssen, J. P., Silverberg, J. I., Bieber, T., Kabashima, K., Tsunemi, Y., Costanzo, A., Guttman‐Yassky, E., Beck, L. A., Janes, J. M., DeLozier, A. M., Gamalo, M., Brinker, D. R., … Reich, K. (2020). Baricitinib in patients with moderate‐to‐severe atopic dermatitis and inadequate response to topical corticosteroids: results from two randomized monotherapy phase
16. Dougados, M., van der Heijde, D., Chen, Y.-C., 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. Annals of the Rheumatic Diseases, 76(1), 88–95. https://doi.org/10.1136/annrheumdis-2016-210094
17. Bronte, V., Ugel, S., Tinazzi, E., Vella, A., de Sanctis, F., Canè, S., Batani, V., Trovato, R., Fiore, A., Petrova, V., Hofer, F., Barouni, R. M., Musiu, C., Caligola, S., Pinton, L., Torroni, L., Polati, E., Donadello, K., Friso, S., … Olivieri, O. (2020). Baricitinib restrains the immune dysregulation in patients with severe COVID-19. Journal of Clinical Investigation, 130(12), 6409–6416. https://doi.org/10.1172/JCI141772
18. Hasan, Md. J., Rabbani, R., Anam, A. M., Huq, S. M. R., Polash, M. M. I., Nessa, S. S. T., & Bachar, S. C. (2021). Impact of high dose of baricitinib in severe COVID-19 pneumonia: a prospective cohort study in Bangladesh. BMC Infectious Diseases, 21(1), 427. https://doi.org/10.1186/s12879-021-06119-2
19. Hasan, M. J., Rabbani, R., Anam, A. M., & Huq, S. M. R. (2020). Additional baricitinib loading dose improves clinical outcome in COVID-19. Open Medicine, 16(1), 041–046. https://doi.org/10.1515/med-2021-0010
20. NIH (2021). Clinical Spectrum. [online] COVID-19 Treatment Guidelines. Available at: https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/. (n.d.).
21. Chen, C. Y., Chen, W. C., Hsu, C. K., Chao, C. M., & Lai, C. C. (2021). Clinical efficacy and safety of Janus kinase inhibitors for COVID-19: A systematic review and meta-analysis of randomized controlled trials. International immunopharmacology, 99, 108027. https://doi.org/10.1016/j.intimp.2021.108027
22. Lin, Z., Niu, J., Xu, Y., Qin, L., Ding, J., & Zhou, L. (2021). Clinical Efficacy and Adverse Events of Baricitinib Treatment for Coronavirus Disease-2019 (COVID-19): A Systematic Review and Meta-Analysis. SSRN Electronic Journal. https://doi.org/10.2139/ssrn.3929406
23. Limen, R. Y., Sedono, R., Sugiarto, A., & Hariyanto, T. I. (2022). Janus kinase (JAK)-inhibitors and coronavirus disease 2019 (Covid-19) outcomes: a systematic review and meta-analysis. Expert Review of Anti-Infective Therapy, 20(3), 425–434. https://doi.org/10.1080/14787210.2021.1982695
24. Chen, C., Wang, J., Li, H., Yuan, L., Gale, R. P., & Liang, Y. (2021). JAK-inhibitors for coronavirus disease-2019 (COVID-19): a meta-analysis. Leukemia, 35(9), 2616–2620. https://doi.org/10.1038/s41375-021-01266-6
25. Bhimraj, A., Morgan, R. L., Shumaker, A. H., Baden, L., Chi-Chung Cheng, V., Edwards, K. M., Gandhi, R. T., Gallagher, J. C., Muller, W. J., O’Horo, J. C., Shoham, S., Wollins, D. S., & Falck-Ytter, Y. (2022). Lessons Learned from Coronavirus Disease 2019 (COVID-19) Therapies: Critical Perspectives from the Infectious Diseases Society of America (IDSA) COVID-19 Treatment Guideline Panel. Clinical Infectious Diseases, 74(9), 1691–1695. https://doi.org/10.1093/cid/ciab882
26. COVID-19 Treatment Guidelines. (2021). Hospitalized Adults: Therapeutic Management. [online] Available at: https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/hospitalized-adults--therapeutic-management/. (n.d.).
27. www.who.int. (n.d.). Therapeutics and COVID-19: living guideline. [online] Available at: https://www.who.int/publications/i/item/WHO-2019-nCoV-therapeutics-2022.4 [Accessed 23 Jul. 2022]. (n.d.).
28. Frediansyah A, Tiwari R, Sharun K, Dhama K, Harapan H. Antivirals for COVID-19: A critical review. Clin Epidemiol Glob Health.2021;9:90–98. (n.d.).
29. Ziegler CGK, Allon SJ, Nyquist SK, et al. SARS-CoV-2 Receptor ACE2 Is an Interferon-Stimulated Gene in Human Airway Epithelial Cells and Is Detected in Specific Cell Subsets across Tissues.Cell. 2020;181(5):1016–1035. e19. (n.d.).
30. Strand V, Ahadieh S, DeMasi R, et al. THU0211 Meta-analysis of serious infections with baricitinib, tofacitinib and biologic dmards in rheumatoid arthritis. Ann Rheum Dis 2017; 76:284