Current issue
Archive
Online first
About the Journal
Editorial Office
Editorial Board
Publisher
Editorial Policies
Ethical standards and procedures
Abstracting and indexing
Reviewers
Honorary Reviewers
Subscription
Contact
Most read articles
Instructions for authors
Article processing charge (APC)
Books and Events
Books
Events
REVIEW PAPER
Safety and efficacy of tocilizumab for rheumatoid arthritis: a systematic review and metaanalysis of clinical trial studies
1
Department of Biostatistics and Epidemiology, School of Public Health, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
2
Department of Rheumatology, Golestan Hospital, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
3
Research Center of Thalassemia and Hemoglobinopathies, Health Research Institute, Ahvaz Jundishapur University of Medical
Sciences, Ahvaz, Iran
Submission date: 2021-01-03
Final revision date: 2021-03-24
Acceptance date: 2021-05-25
Online publication date: 2021-07-11
Publication date: 2021-07-16
Reumatologia 2021;59(3):169-179
KEYWORDS
TOPICS
ABSTRACT
The present systematic review and meta-analysis was conducted to assess the effect of tocilizumab (TCZ) in patients with rheumatoid arthritis (RA). We systematically searched all potential articles in the main databases, including PubMed, Scopus, EMBASE, Web of Sciences (ISI), and Cochrane Center. The search was subsequently updated in December 2020. The initial review and extraction of information were performed independently by two authors to collect the first author and publication year; sample size; mean age of the intervention and control groups; the dose of TCZ, and the follow-up duration. Outcomes of interest include the ACR20, ACR50, ACR70, total complication rate, and the occurrence of remission. Any disagreements between the reviewers were resolved by discussion and re-check of the article and consultation with a third reviewer. After reviewing and culling, 15 clinical trials comparing the clinical efficacy of TCZ and its comparators in the treatment of patients with RA entered the qualitative and quantitative synthesis. Tocilizumab 8 mg was statistically better than 4 mg or placebo for ACR responses. Significant clinical adverse events in patients with RA treated with TCZ, such as abnormal liver function tests (LFTs) and infections, were more frequent than in comparator groups. This systematic review and meta-analysis suggest that the combination therapy of TCZ with other drugs such as methotrexate and disease-modifying antirheumatic drugs has been studied for various clinical effects concerning safety and clinically significant adverse events. Although the data are promising, long-term performance and safety data need to be fully identified, as well as the risks and benefits of TCZ, especially appropriate timing, dosage, and regimen.
REFERENCES (55)
1.
Guo Q, Wang Y, Xu D, Nossent J, et al. Rheumatoid arthritis: pathological mechanisms and modern pharmacologic therapies. Bone Res 2018; 6: 15, DOI: 10.1038/s41413-018-0016-9.
2.
Deane KD, Demoruelle MK, Kelmenson LB, et al. Genetic and environmental risk factors for rheumatoid arthritis. Best Pract Res Clin Rheumatol 2017; 31: 3–18, DOI: 10.1016/j.berh.2017.08.003.
3.
Mori H, Sawada T, Nishiyama S, et al. Influence of seasonal changes on disease activity and distribution of affected joints in rheumatoid arthritis. BMC Musculoskelet Disord 2019; 20: 30, DOI: 10.1186/s12891-019-2418-2.
4.
Croitoru AE, Dogaru G, Man TC, et al. Perceived influence of weather conditions on rheumatic pain in Romania. Advances in Meteorology 2019; 2019: 9187105, DOI: 10.1155/2019/9187105.
5.
Heidari B. Rheumatoid Arthritis: early diagnosis and treatment outcomes. Caspian J Intern Med 2011; 2: 161–170.
6.
Molokhia M, McKeigue P. Risk for rheumatic disease in relation to ethnicity and admixture. Arthritis Res 2000; 2: 115–125, DOI: 10.1186/ar76.
7.
van Vollenhoven RF. Sex differences in rheumatoid arthritis: more than meets the eye. BMC Med 2009; 7: 12, DOI: 10.1186/1741-7015-7-12.
8.
Davis JM, 3rd, Matteson EL, American College of Rheumatology. My treatment approach to rheumatoid arthritis. Mayo Clin Proc 2012; 87: 659–673, DOI: 10.1016/j.mayocp.2012.03.011.
9.
Crofford LJ. Use of NSAIDs in treating patients with arthritis. Arthritis Res Ther 2013; 15 Suppl 3(Suppl 3): S2, DOI: 10.1186/ar4174.
10.
Zarghi A, Arfaei S. Selective COX-2 inhibitors: a review of their structure-activity relationships. Iran J Pharm Res 2011; 10: 655–683.
11.
van Laar M, Pergolizzi JV Jr, Mellinghoff HU, et al. Pain treatment in arthritis-related pain: beyond NSAIDs. Open Rheumatol J 2012; 6: 320–330, DOI: 10.2174/1874312901206010320.
12.
Kay J, Upchurch KS. ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford) 2012; 51 (Suppl 6): vi5–vi9, DOI: 10.1093/rheumatology/kes279.
13.
Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62: 2569–2581, DOI: 10.1002/art.27584.
14.
Smolen JS, Aletaha D, Barton A, et al. Rheumatoid arthritis. Nat Rev Dis Primers 2018; 4: 18001, DOI: 10.1038/nrdp.2018.1.
15.
Sheppard M, Laskou F, Stapleton PP, et al. Tocilizumab (actemra). Hum Vaccin Immunothe 2017; 13: 1972–1988, DOI: 10.1080/21645515.2017.1316909.
16.
Tanaka T, Narazaki M, Kishimoto T. IL-6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 2014; 6: a016295–a016295, DOI: 10.1101/cshperspect.a016295.
17.
Teitsma XM, Marijnissen AKA, Bijlsma JW, et al. Tocilizumab as monotherapy or combination therapy for treating active rheumatoid arthritis: a meta-analysis of efficacy and safety reported in randomized controlled trials. Arthritis Res Ther 2016; 18: 211, DOI: 10.1186/s13075-016-1108-9.
18.
Biggioggero M, Crotti C, Becciolini A, Favalli EG. Tocilizumab in the treatment of rheumatoid arthritis: an evidence-based review and patient selection. Drug Des Devel Ther 2019; 13: 57–70, DOI: 10.2147/DDDT.S150580.
19.
Rubbert-Roth A, Furst DE, Nebesky JM, et al. A Review of recent advances using tocilizumab in the treatment of rheumatic diseases. Rheumatol Ther 2018; 5: 21–42, DOI: 10.1007/s40744-018-0102-x.
20.
Moher D, Shamseer L, Clarke M, et al. Preferred reporting items for systematic review and meta-analysis protocols (PRISMA–P) 2015 statement. Syst Rev 2015; 4: 1, DOI: 10.1186/2046-4053-4-1.
21.
Higgins JPT, Thomas J, Chandler J, et al. Cochrane handbook for systematic reviews of interventions. John Wiley & Sons, Chichester 2019.
22.
Higgins JP, Altman DG, Gøtzsche PC,et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928, DOI: 10.1136/bmj.d5928.
23.
Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560, DOI: 10.1136/bmj.327.7414.557.
24.
DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188, DOI: 10.1016/0197-2456(86)90046-2.
25.
Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959; 22: 719–748.
26.
Gabay C, Emery P, van Vollenhoven R, et al. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet 2013, 381: 1541–1550, DOI: 10.1016/S0140-6736(13)60250-0.
27.
Bijlsma JWJ, Welsing PMJ, Woodworth TG, et al. Early rheumatoid arthritis treated with tocilizumab, methotrexate, or their combination (U-Act-Early): a multicentre, randomised, double-blind, double-dummy, strategy trial. Lancet 2016; 388: 343–355, DOI: 10.1016/S0140-6736(16)30363-4.
28.
Burmester GR, Rigby WF, van Vollenhoven RF, et al. Tocilizumab in early progressive rheumatoid arthritis: FUNCTION, a randomised controlled trial. Ann Rheum Dis 2016, 75: 1081–1091, DOI: 10.1136/annrheumdis-2015-207628.
29.
Burmester GR, Rubbert-Roth A, Cantagrel A, et al. A randomised, double-blind, parallel-group study of the safety and efficacy of subcutaneous tocilizumab versus intravenous tocilizumab in combination with traditional disease-modifying antirheumatic drugs in patients with moderate to severe rheumatoid arthritis (SUMMACTA study). Ann Rheum Dis 2014, 73: 69–74, DOI: 10.1136/annrheumdis-2013-203523.
30.
Choy EH, Bernasconi C, Aassi M, et al. Treatment of rheumatoid arthritis with anti-tumor necrosis factor or tocilizumab therapy as first biologic agent in a global comparative observational study. Arthritis Care Res (Hoboken) 2017; 69: 1484–1494, DOI: 10.1002/acr.23303.
31.
Dougados M, Kissel K, Conaghan PG, et al. Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study. Ann Rheum Dis 2014; 73: 803–809, DOI: 10.1136/annrheumdis-2013-204761.
32.
Emery P, Keystone E, Tony HP, et al. IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologicals: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 2008; 67: 1516–1523, DOI: 10.1136/ard.2008.092932.
33.
Genovese MC, McKay JD, Nasonov EL, et al. Interleukin-6 receptor inhibition with tocilizumab reduces disease activity in rheumatoid arthritis with inadequate response to disease- modifying antirheumatic drugs: the tocilizumab in combination with traditional disease-modifying antirheumatic drug therapy study. Arthritis Rheum 2008; 58: 2968–2980, DOI: 10.1136/ard.2008.092932.
34.
Jones G, Sebba A, Gu J, et al. Comparison of tocilizumab monotherapy versus methotrexate monotherapy in patients with moderate to severe rheumatoid arthritis: the AMBITION study. Ann Rheum Dis 2010; 69: 88–96, DOI: 10.1136/ard. 2008.105197.
35.
Kivitz A, Olech E, Borofsky M, et al. Subcutaneous tocilizumab versus placebo in combination with disease-modifying antirheumatic drugs in patients with rheumatoid arthritis. Arthritis Care Res (Hoboken) 2014; 66:1 653–1661, DOI: 10.1002/acr.22384.
36.
Kremer JM, Blanco R, Brzosko M, et al. Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with inadequate responses to methotrexate: results from the double-blind treatment phase of a randomized placebo-controlled trial of tocilizumab safety and prevention of structural joint damage at one year. Arthritis Rheum 2011; 63: 609–621, DOI: 10.1002/art.30158.
37.
Nishimoto N, Yoshizaki K, Miyasaka N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2004; 50: 1761–1769, DOI: 10.1002/art.20303.
38.
Smolen JS, Beaulieu A, Rubbert-Roth A, et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo- controlled, randomised trial. Lancet 2008; 371: 987–997, DOI: 10.1016/S0140-6736(08)60453-5.
39.
Yazici Y, Curtis JR, Ince A, et al. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis 2012; 71: 198–205, DOI: 10.1136/ard.2010.148700.
40.
Fleischmann RM, Halland AM, Brzosko M, et al. Tocilizumab inhibits structural joint damage and improves physical function in patients with rheumatoid arthritis and inadequate responses to methotrexate: LITHE study 2-year results. J Rheumatol 2013; 40: 113–126, DOI: 10.3899/jrheum.120447.
41.
González-Vacarezza N, Alemán A, González G, Pérez A. Rituximab and tocilizumab for the treatment of rheumatoid arthritis. Int J Technol Assess Health Care 2014; 30: 282–288, DOI: 10.1017/S0266462314000221.
42.
Navarro G, Taroumian S, Barroso N, et al. Tocilizumab in rheumatoid arthritis: a meta-analysis of efficacy and selected clinical conundrums. Semin Arthritis Rheum 2014; 43: 458–469, DOI: 10.1016/j.semarthrit.2013.08.001.
43.
Kaneko Y, Kato M, Tanaka Y, I et al. Tocilizumab discontinuation after attaining remission in patients with rheumatoid arthritis who were treated with tocilizumab alone or in combination with methotrexate: results from a prospective randomised controlled study (the second year of the SURPRISE study). Ann Rheum Dis 2018; 77: 1268–1275, DOI: 10.1136/annrheumdis-2018-213416.
44.
Scott LJ. Tocilizumab: A review in rheumatoid arthritis. Drugs 2017; 77: 1865–1879, DOI: 10.1007/s40265-017-0829-7.
45.
Nishimoto N, Amano K, Hirabayashi Y, et al. Drug free REmission/low disease activity after cessation of tocilizumab (actemra) Monotherapy (DREAM) study. Modern Rheumatol 2014, 24: 17–25, DOI: 10.3109/14397595.2013.854079.
46.
Cappelli LC, Palmer JL, Kremer J, Bingham CO 3rd. Tocilizumab treatment leads to improvement in disease activity regardless of CCP status in rheumatoid arthritis. Semin Arthritis Rheum 2017; 47: 165–169, DOI: 10.1016/j.semarthrit.2017.03.024.
47.
Haraoui B, Jamal S, Ahluwalia V, et al. Real-world tocilizumab use in patients with rheumatoid arthritis in Canada: 12-month results from an observational, noninterventional study. Rheumatol Ther 2018; 5: 551–565, DOI: 10.1007/s40744-018-0130-6.
48.
Jones G, Wallace T, McIntosh MJ, et al. Five-year efficacy and safety of tocilizumab monotherapy in patients with rheumatoid arthritis who were methotrexate- and biologic-naive or free of methotrexate for 6 months: the AMBITION study. J Rheumatol 2017; 44: 142–146, DOI: 10.3899/jrheum.160287.
49.
Bykerk VP, Östör AJK, Alvaro-Gracia J, et al. Long-term safety and effectiveness of tocilizumab in patients with rheumatoid arthritis and inadequate responses to csDMARDs and/or TNF inhibitors: an open-label study close to clinical practice. Clinical Rheumatology 2019; 38: 2411–2421, DOI: 10.1007/s10067-019-04535-z.
50.
Huizinga TWJ, Conaghan PG, Martin-Mola E, et al. Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study. Ann Rheum Dis 2015; 74: 35–43, DOI: 10.1136/annrheumdis-2014-205752.
51.
Romão VC, Santos MJ, Polido-Pereira J, et al. Comparative effectiveness of tocilizumab and tnf inhibitors in rheumatoid arthritis patients: data from the rheumatic diseases Portuguese register, Reuma.pt. Biomed Res Int 2015, 2015: 279890, DOI: 10.1155/2015/279890.
52.
Yazici Y, Curtis JR, Ince A, et al. Efficacy of tocilizumab in patients with moderate to severe active rheumatoid arthritis and a previous inadequate response to disease-modifying antirheumatic drugs: the ROSE study. Ann Rheum Dis 2012; 71: 198–205, DOI: 10.1136/ard.2010.148700.
53.
Navarro-Millán I, Singh JA, Curtis JR. Systematic review of tocilizumab for rheumatoid arthritis: a new biologic agent targeting the interleukin-6 receptor. Clin Ther 2012; 34: 788–802.e783, DOI: 10.1016/j.clinthera.2012.02.014.
54.
Maini RN, Taylor PC, Szechinski J, et al. Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 2006; 54: 2817–2829, DOI: 10.1002/art.22033.
55.
Pappas DA, John A, Curtis JR, et al. Dosing of Intravenous tocilizumab in a real-world setting of rheumatoid arthritis: analyses from the Corrona registry. Rheumatol Ther 2016; 3: 103–115, DOI: 10.1007/s40744-016-0028-0.
Copyright: © Narodowy Instytut Geriatrii, Reumatologii i Rehabilitacji w Warszawie. This is an Open Access journal, all articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International (CC BY-NC-SA 4.0) License (https://creativecommons.org/licenses/by-nc-sa/4.0/), allowing third parties to copy and redistribute the material in any medium or format and to remix, transform, and build upon the material, provided the original work is properly cited and states its license.
Share
RELATED ARTICLE
| eISSN: | 2084-9834 |
| ISSN: | 0034-6233 |
We process personal data collected when visiting the website. The function of obtaining information about users and their behavior is carried out by voluntarily entered information in forms and saving cookies in end devices. Data, including cookies, are used to provide services, improve the user experience and to analyze the traffic in accordance with the Privacy policy. Data are also collected and processed by Google Analytics tool (more).
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
You can change cookies settings in your browser. Restricted use of cookies in the browser configuration may affect some functionalities of the website.
