Interleukin-6 Inhibition in Patients With Rheumatoid Arthritis: Long-term Safety and Tolerability
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.
Adjunct Clinical Professor, Division of Immunology/Rheumatology
“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.”
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.
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