clinical topic updates

Interleukin-6 Inhibition in Patients With Rheumatoid Arthritis: Long-term Safety and Tolerability

by Vibeke Strand, MD, MACR, FACP


The interleukin-6 (IL-6) inhibitors have a well-established record in the treatment of rheumatoid arthritis (RA). Available data suggest that there may be some differences between available agents, although this needs further study. The positive impact of these agents on patient-reported outcomes (PROs) is of interest and may add to the body of knowledge regarding tolerability.

Expert Commentary

Vibeke Strand, MD, MACR, FACP

Adjunct Clinical Professor, Division of Immunology/Rheumatology
Stanford University School of Medicine
Biopharmaceutical Consultant
Palo Alto, CA

“Over the last several years, we have accumulated a lot more knowledge about the long-term safety of the soluble IL-6 receptor antagonists. There is some indication that there may be differences between agents, which is something that we did not really expect.

Vibeke Strand, MD, MACR, FACP

Over the last several years, we have accumulated a lot more knowledge about the long-term safety of the soluble IL-6 receptor antagonists. There is some indication that there may be differences between agents, which is something that we did not really expect.

One thing that we have learned from the recently reported ENTRACTE study is that the cardiovascular safety of tocilizumab and etanercept are similar, with researchers reporting similar rates of major adverse cardiovascular events with both treatments. There are fewer data with sarilumab, but incidence rates of major adverse cardiovascular events per 100 patient-years of 0.5 for patients receiving sarilumab in combination with conventional synthetic disease-modifying antirheumatic drugs and 0.2 for patients receiving sarilumab monotherapy have been reported. There are some data showing that tocilizumab is associated with an increased risk of gastrointestinal perforation due to diverticulitis compared with rituximab and abatacept. Whether this will also be seen with sarilumab is unknown, but so far there has been no signal of an increased risk. The IL-6 inhibitors also carry the risk for serious infection.

PROs are increasingly recognized as important outcomes. Fatigue is a major component of an inflammatory immune-mediated disease and is a very difficult component to treat. Fatigue and persistent pain are among the things we worry about most. Quality-of-life assessments such as the 36-Item Short Form Health Survey (SF-36) can give an overall picture of the disease burden, looking at mental, physical, emotional, and functional impacts. Data from a phase 3 study comparing sarilumab monotherapy with adalimumab monotherapy found that sarilumab was associated with significantly improved PROs compared with adalimumab. In addition, PROs in patients who were crossed from adalimumab to sarilumab improved to catch up to those seen in patients who had been assigned sarilumab from the outset. This indicates that the beneficial effect was clearly due to sarilumab and may in part be related to the profound effect that IL-6 inhibitors have on C-reactive protein. PRO improvements have also been reported with tocilizumab, whether delivered intravenously or subcutaneously.

These data indicate the importance of assessing PROs in clinical practice. The Routine Assessment of Patient Index Data 3 (RAPID3), which is a pooled index of patient global assessment of status, pain, and function, is an easy test to perform. In our telemedicine practice, we have been asking patients to answer the questions in front of us on the screen so that we can get some nonverbal cues as they are filling it out. The Rheumatoid Arthritis Impact of Disease (RAID) questionnaire is also a good assessment that is not very long and covers some of the domains that are impacted by RA. If patients are filling out the SF-36, there are programs that convert the scores into a graphic display so that they can easily track how they are progressing.


Choy E, Freemantle N, Proudfoot C, et al. Evaluation of the efficacy and safety of sarilumab combination therapy in patients with rheumatoid arthritis with inadequate response to conventional disease-modifying antirheumatic drugs or tumour necrosis factor α  inhibitors: systematic literature review and network meta-analyses. RMD Open. 2019;5(1):e000798. doi:10.1136/rmdopen-2018-000798

Choy EH, De Benedetti F, Takeuchi T, Hashizume M, John MR, Kishimoto T. Translating IL-6 biology into effective treatments. Nat Rev Rheumatol. 2020;16(6):335-345. doi:10.1038/s41584-020-0419-z

Emery P, Rondon J, Parrino J, et al. Safety and tolerability of subcutaneous sarilumab and intravenous tocilizumab in patients with rheumatoid arthritis. Rheumatology (Oxford). 2019;58(5):849-858. doi:10.1093/rheumatology/key361

Fleischmann R, Genovese MC, Lin Y, et al. Long-term safety of sarilumab in rheumatoid arthritis: an integrated analysis with up to 7 years’ follow-up. Rheumatology (Oxford). 2020;59(2):292-302. doi:10.1093/rheumatology/kez265

Gabay C, Emery P, van Vollenhoven R, et al; ADACTA Study Investigators. Tocilizumab monotherapy versus adalimumab monotherapy for treatment of rheumatoid arthritis (ADACTA): a randomised, double-blind, controlled phase 4 trial. Lancet. 2013;381(9877):1541-1550. doi:10.1016/S0140-6736(13)60250-0

Giles JT, Sattar N, Gabriel S, et al. Cardiovascular safety of tocilizumab versus etanercept in rheumatoid arthritis: a randomized controlled trial. Arthritis Rheumatol. 2020;72(1):31-40. doi:10.1002/art.41095

Kivitz A, Wallace T, Olech E, et al. Long-term safety and efficacy of subcutaneously administered tocilizumab for adult rheumatoid arthritis: a multicenter phase 3b long-term extension study. Rheumatol Ther. 2016;3(2):291-304. doi:10.1007/s40744-016-0043-1

Pawar A, Desai RJ, Solomon DH, et al. Risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study. Ann Rheum Dis. 2019;78(4):456-464. doi:10.1136/annrheumdis-2018-214367

Rempenault C, Lukas C, Combe B, et al. Risk of diverticulitis and gastro-intestinal perforation in rheumatoid arthritis treated with tocilizumab compared to rituximab and abatacept: a prospective propensity-matched cohort study. Ann Rheum Dis. 2020;79(1 suppl):17. doi:10.1136/annrheumdis-2020-eular.3471

Strand V, Gossec L, Proudfoot CWJ, et al. Patient-reported outcomes from a randomized phase III trial of sarilumab monotherapy versus adalimumab monotherapy in patients with rheumatoid arthritis. Arthritis Res Ther. 2018;20(1):129. doi:10.1186/s13075-018-1614-z

Strand V, Michalska M, Birchwood C, et al. Impact of tocilizumab monotherapy on patient-reported outcomes in patients with rheumatoid arthritis from two randomised controlled trials. RMD Open. 2017;3(2):e000496. doi:10.1136/rmdopen-2017-000496

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