Comparison of the efficacy and safety of tocilizumab, sarilumab, and olokizumab in patients with active rheumatoid arthritis: a network meta-analysis of randomized controlled trials.

Vergleich der Wirksamkeit und Sicherheit von Tocilizumab, Sarilumab und Olokizumab bei Patienten mit aktiver rheumatoider Arthritis: Netzwerk-Metaanalyse von randomisierten kontrollierten Studien.

Publisher: Springer Country of Publication: Germany NLM ID: 0414162 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1435-1250 (Electronic) Linking ISSN: 03401855 NLM ISO Abbreviation: Z Rheumatol Subsets: MEDLINE

Publication: 2006- : Heidelberg : Springer
Original Publication: Darmstadt, Steinkopff.

Antirheumatic Agents*/adverse effects ; Arthritis, Rheumatoid*/diagnosis ; Arthritis, Rheumatoid*/drug therapy ; Antibodies, Monoclonal, Humanized*; Humans ; Adalimumab/adverse effects ; Network Meta-Analysis ; Treatment Outcome ; Bayes Theorem ; Randomized Controlled Trials as Topic ; Methotrexate/adverse effects ; Drug Therapy, Combination

Objective: This study compared the relative efficacy and safety of olokizumab, tocilizumab, and sarilumab in rheumatoid arthritis (RA) patients who were intolerant or responding inadequately to methotrexate (MTX).
Methods: We performed a Bayesian network meta-analysis to combine direct and indirect evidence from randomized controlled trials (RCTs) to examine the efficacy and safety of olokizumab, tocilizumab, and sarilumab in RA patients who were intolerant or responding inadequately to MTX.
Results: Six RCTs comprising 4439 patients met the inclusion criteria. Tocilizumab, sarilumab, olokizumab, and adalimumab treatments achieved a significant American College of Rheumatology 20% (ACR20) response rate compared with placebo. However, tocilizumab was associated with the most favorable surface area using the cumulative ranking curve (SUCRA) for the ACR20 response rate. The ranking probability based on the SUCRA indicated that tocilizumab treatment had the highest probability of providing the best ACR20 response rate, followed by sarilumab, olokizumab every 2 weeks (Q2W), olokizumab Q4W, adalimumab 40 mg, and placebo. The ACR50 and 70 response rates showed a distribution pattern similar to that of the ACR20 response rate. However, olokizumab Q4W had a higher ranking probability than olokizumab Q2W. The SUCRA rating showed that the placebo was the best intervention with the least adverse events (AEs) and withdrawal due to AEs, followed by interleukin‑6 inhibitors.
Conclusion: Tocilizumab, sarilumab, and olokizumab are more effective than adalimumab and have similar efficacy and safety in RA patients with inadequate responses to MTX.
(© 2023. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Aletaha D, Landewe R, Karonitsch T et al (2008) Reporting disease activity in clinical trials of patients with rheumatoid arthritis: EULAR/ACR collaborative recommendations. Arthritis Care Res 59(10):1371–1377. (PMID: 10.1002/art.24123)
Aletaha D, Smolen JS (2002) The rheumatoid arthritis patient in the clinic: comparing more than 1,300 consecutive DMARD courses. Rheumatology 41(12):1367–1374. (PMID: 10.1093/rheumatology/41.12.136712468815)
Brown S, Hutton B, Clifford T et al (2014) A Microsoft-Excel-based tool for running and critically appraising network meta-analyses—an overview and application of NetMetaXL. Syst Rev 3(1):110. (PMID: 10.1186/2046-4053-3-110252674164195340)
Burmester GR, Lin Y, Patel R et al (2016) Efficacy and safety of sarilumab monotherapy versus adalimumab monotherapy for the treatment of patients with active rheumatoid arthritis (MONARCH): a randomised, double-blind, parallel-group phase III trial. Ann Rheum Dis. https://doi.org/10.1136/annrheumdis-2016-210310. (PMID: 10.1136/annrheumdis-2016-21031028007755)
Caldwell DM, Ades A, Higgins J (2005) Simultaneous comparison of multiple treatments: combining direct and indirect evidence. BMJ 331(7521):897. (PMID: 10.1136/bmj.331.7521.897162238261255806)
De Bruyn S, Gachalyi B, Rojkovich B et al (2012) Anti-IL‑6 receptor Nanobody (ALX-0061) seamless “first-in-human” phase I/II POC study in patients with active RA on stable MTX treatment. In: Arthritis And Rheumatism. Wiley-Blackwell, Hoboken.
Dias S, Welton NJ, Sutton AJ et al (2013) Evidence synthesis for decision making 4 inconsistency in networks of evidence based on randomized controlled trials. Med Decis Making 33(5):641–656. (PMID: 10.1177/0272989X12455847238045083704208)
Felson DT, Anderson JJ, Meenan RF (1990) The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Results of two metaanalyses. Arthritis Rheum 33(10):1449–1461. (PMID: 10.1002/art.17803310011977391)
Fleischmann R, van Adelsberg J, Lin Y et al (2016) Sarilumab and non-biologic disease-modifying antirheumatic drugs in patients with active RA and inadequate response or intolerance to TNF inhibitors. Arthritis Rheumatol. https://doi.org/10.1002/art.39944. (PMID: 10.1002/art.39944271110896099512)
Genovese M, Fleischmann R, Fiore S et al (2013) SAT0117 sarilumab, a subcutaneously-administered, fully-human monoclonal antibody inhibitor of the IL‑6 receptor: relationship between eular responses and change from baseline of selected clinical parameters. Ann Rheum Dis 72(Suppl 3):A620–A620. (PMID: 10.1136/annrheumdis-2013-eular.1843)
Genovese MC, Fleischmann R, Kivitz AJ et al (2015) Sarilumab plus methotrexate in patients with active rheumatoid arthritis and inadequate response to methotrexate: results of a phase III study. Arthritis Rheum 67(6):1424–1437. (PMID: 10.1002/art.39093)
Genovese MC, McKay JD, Nasonov EL et al (2008) 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 Rheumatol 58(10):2968–2980. (PMID: 10.1002/art.23940)
Higgins J, Jackson D, Barrett J et al (2012) Consistency and inconsistency in network meta-analysis: concepts and models for multi-arm studies. Res Synth Methods 3(2):98–110. (PMID: 10.1002/jrsm.1044260620844433772)
Hochberg MC, Chang RW, Dwosh I et al (1992) The American College of Rheumatology 1991 revised criteria for the classification of global functional status in rheumatoid arthritis. Arthritis Rheum 35(5):498–502. (PMID: 10.1002/art.17803505021575785)
Huizinga TW, Fleischmann RM, Jasson M et al (2014) Sarilumab, a fully human monoclonal antibody against IL-6Rα in patients with rheumatoid arthritis and an inadequate response to methotrexate: efficacy and safety results from the randomised SARIL-RA-MOBILITY part A trial. Ann Rheum Dis 73(9):1626–1634. (PMID: 10.1136/annrheumdis-2013-20440524297381)
Kim H, Sung Y‑K (2021) Epidemiology of rheumatoid arthritis in Korea. J Rheum Dis 28(2):60–67. (PMID: 10.4078/jrd.2021.28.2.603747601310324889)
Kremer JM (2004) Toward a better understanding of methotrexate. Arthritis Rheum 50(5):1370–1382. (PMID: 10.1002/art.2027815146406)
Lee Y‑K, Bae S‑C (2021) Mortality in Korean patients with rheumatoid arthritis. J Rheum Dis 28(3):113–118. (PMID: 10.4078/jrd.2021.28.3.1133747599910324902)
Lee YH, Bae SC, Choi SJ et al (2012) Associations between interleukin-10 polymorphisms and susceptibility to rheumatoid arthritis: a meta-analysis. Mol Biol Rep 39(1):81–87. (PMID: 10.1007/s11033-011-0712-721553228)
Lee YH, Bae SC, Song GG (2011) The efficacy and safety of rituximab for the treatment of active rheumatoid arthritis: a systematic review and meta-analysis of randomized controlled trials. Rheumatol Int 31(11):1493–1499. (PMID: 10.1007/s00296-010-1526-y20473756)
Lee YH (2018) An overview of meta-analysis for clinicians. Korean J Intern Med 33(2):277–283. (PMID: 10.3904/kjim.2016.19529277096)
Mease P, Strand V, Shalamberidze L et al (2012) A phase II, double-blind, randomised, placebo-controlled study of BMS945429 (ALD518) in patients with rheumatoid arthritis with an inadequate response to methotrexate. Ann Rheum Dis 71(7):1183–1189. (PMID: 10.1136/annrheumdis-2011-20070422328739)
Moher D, Liberati A, Tetzlaff J et al (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269. (PMID: 10.7326/0003-4819-151-4-200908180-0013519622511)
Nasonov E, Fatenejad S, Feist E et al (2022) Olokizumab, a monoclonal antibody against interleukin 6, in combination with methotrexate in patients with rheumatoid arthritis inadequately controlled by methotrexate: efficacy and safety results of a randomised controlled phase III study. Ann Rheum Dis 81(4):469–479. (PMID: 10.1136/annrheumdis-2021-21987634344706)
Nishimoto N, Miyasaka N, Yamamoto K et al (2009) Study of active controlled tocilizumab monotherapy for rheumatoid arthritis patients with an inadequate response to methotrexate (SATORI): significant reduction in disease activity and serum vascular endothelial growth factor by IL‑6 receptor inhibition therapy. Mod Rheumatol 19(1):12–19. (PMID: 10.3109/s10165-008-0125-118979150)
Nurnberg W, Haas N, Schadendorf D et al (1995) Interleukin‑6 expression in the skin of patients with lupus erythematosus. Exp Dermatol 4(1):52–57. (PMID: 10.1111/j.1600-0625.1995.tb00222.x7757333)
Salanti G, Ades A, Ioannidis JP (2011) Graphical methods and numerical summaries for presenting results from multiple-treatment meta-analysis: an overview and tutorial. J Clin Epidemiol 64(2):163–171. (PMID: 10.1016/j.jclinepi.2010.03.01620688472)
Shaw S, Bourne T, Meier C et al (2014) Discovery and characterization of olokizumab: a humanized antibody targeting interleukin‑6 and neutralizing gp130-signaling. In: MAbs. Taylor & Francis, pp 773–781.
Smolen JS, Beaulieu A, Rubbert-Roth A et al (2008) Effect of interleukin‑6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371(9617):987–997. (PMID: 10.1016/S0140-6736(08)60453-518358926)
Smolen JS, Feist E, Fatenejad S et al (2022) Olokizumab versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med 387(8):715–726. (PMID: 10.1056/NEJMoa220130236001712)
Song GG, Bae SC, Lee YH (2014) Association of the MTHFR C677T and A1298C polymorphisms with methotrexate toxicity in rheumatoid arthritis: a meta-analysis. Clin Rheumatol 33(12):1715–1724. (PMID: 10.1007/s10067-014-2645-824794492)
Srirangan S, Choy EH (2010) The role of interleukin 6 in the pathophysiology of rheumatoid arthritis. Ther Adv Musculoskelet Dis 2(5):247–256. (PMID: 10.1177/1759720X10378372228704513383508)
Tanaka T, Narazaki M, Kishimoto T (2014) IL‑6 in inflammation, immunity, and disease. Cold Spring Harb Perspect Biol 6(10):a16295. (PMID: 10.1101/cshperspect.a016295251900794176007)
Valkenhoef G, Lu G, Brock B et al (2012) Automating network meta-analysis. Res Synth Methods 3(4):285–299. (PMID: 10.1002/jrsm.105426053422)
Yazici Y, Curtis JR, Ince A et al (2012) 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 71(2):198–205. (PMID: 10.1136/ard.2010.14870021949007)

Keywords: Network meta-analysis; Olokizumab; Rheumatoid arthritis; Sarilumab; Tocilizumab
Local Abstract: [Publisher, German] ZIEL: In der vorliegenden Studie wurde die relative Wirksamkeit und Sicherheit von Olokizumab, Tocilizumab und Sarilumab bei Patienten mit rheumatoider Arthritis (RA) verglichen, bei denen eine Unverträglichkeit und unzureichende Therapieantwort auf Methotrexat (MTX) bestand. [Publisher, German] Es wurde eine Bayes-Netzwerk-Metaanalyse durchgeführt, um direkte und indirekte Evidenz aus randomisierten kontrollierten Studien (RCT) für die Untersuchung der Wirksamkeit und Sicherheit von Olokizumab, Tocilizumab und Sarilumab bei RA-Patienten zu kombinieren, bei denen eine Unverträglichkeit und unzureichende Therapieantwort auf Methotrexat (MTX) bestand. [Publisher, German] Die Einschlusskriterien wurden von 6 RCT mit 4439 Patienten erfüllt. Unter Therapie mit Tocilizumab, Sarilumab, Olokizumab und Adalimumab wurde eine signifikante ACR20-Responserate (American College of Rheumatology 20 %) im Vergleich mit Placebo erzielt. Jedoch ging Tocilizumab mit der günstigsten SUCRA („surface area using the cumulative ranking curve“) für die ACR20-Responserate einher. Die Rankingwahrscheinlichkeit auf Grundlage der SUCRA zeigte, dass die Therapie mit Tocilizumab die höchste Wahrscheinlichkeit für die beste ACR20-Responserate aufwies, es folgten Sarilumab, Olokizumab alle 2 Wochen (Q2W), Olokizumab Q4W, Adalimumab 40 mg und Placebo. Die ACR50- und ACR70-Responseraten wiesen ein Verteilungsmuster auf, das dem der ACR20-Responserate ähnlich war. Allerdings bestand für Olokizumab Q4W eine höhere Rankingwahrscheinlichkeit als für Olokizumab Q2W. Das SUCRA-Rating ergab, dass Placebo die beste Intervention mit den wenigsten unerwünschten Ereignissen (AE) und Therapieabbruch aufgrund von AE war, es folgten Interleukin(IL)-6-Inhibitoren. [Publisher, German] Tocilizumab, Sarilumab und Olokizumab sind wirksamer als Adalimumab und weisen eine ähnliche Wirksamkeit und Sicherheit bei RA-Patienten mit unzureichender Therapieantwort auf MTX auf.

I031V2H011 (tocilizumab)
PAI71R1D2W (olokizumab)
NU90V55F8I (sarilumab)
FYS6T7F842 (Adalimumab)
0 (Antirheumatic Agents)
YL5FZ2Y5U1 (Methotrexate)
0 (Antibodies, Monoclonal, Humanized)

Date Created: 20230106 Date Completed: 20240221 Latest Revision: 20240221

20240221

10.1007/s00393-022-01315-0

36607422