Interview conducted by April Cashin-Garbutt, BA Hons (Cantab)
What are tumor necrosis factor inhibitors (TNFis) and how effective are they at treating rheumatoid arthritis (RA)?
Tumor necrosis factor inhibitors (TNFis) are used to treat inflammatory conditions, such as RA. These agents work by blocking TNF, an important mediator of inflammation in RA, in order to help reduce inflammation and stop disease progression.
Why do some patients fail to adequately respond to TNFis?
Some RA patients will experience an adequate initial response to a TNFi, followed by a secondary non-response, which may be due to the development of anti-drug antibodies.
In primary non-responders, there is never any response, which suggests that other mediators may be more important than TNF.
How many patients that do respond to TNFis lose responsiveness over time? What is the reason for this?
Up to 40% of patients either have inadequate response or lose responsiveness to TNFis over time. This may be due to the development of anti-drug antibodies in secondary non-responders.
Does switching TNFis always work?
No, switching TNFis does not always work; however, this method does work better in secondary non-responders where TNF is clearly a key mediator of the inflammation.
Why has data on the comparative effectiveness of different switching strategies so far been limited?
The high cost of these types of studies explains why data on the comparative effectiveness of different switching strategies so far has been limited.
Please can you outline your recent research into the comparative effectiveness of alternative TNFi inhibitors in RA patients with inadequate response to one previous TNFi?
Since there have been no head-to-head trials of different switching strategies, the SWITCH-RA study was designed to compare Rituxan with an alternative TNFi in patients with an inadequate response to a previous TNFi in real-life practice conditions.
It was a prospective, global, multicenter, open-label, observational study, which enrolled patients less than four weeks after they were switched from an initial TNFi to either Rituxan (n = 604) or an alternative TNFi (n = 507).
Of these, 405 patients receiving Rituxan and 323 patients receiving the TNFi were available for primary endpoint analysis. The primary endpoint for this trial was change in Disease Activity Score in 28 joints (DAS28) at six months. This is an established measure of disease activity in RA.
There is an additional U.K. national study funded by the National Institute for Health Research that is investigating the comparative effectiveness of alternative biologics after TNFi failure. In this patient population, one TNFi, golimumab, has previously shown efficacy.
What were your main findings and were your results limited in any way?
The SWITCH-RA study found that after discontinuation of a first TNFi, patients switching to Rituxan achieved greater clinical effectiveness on average over six months compared with patients switching to an alternative TNFi.
The mean change in disease activity score at six months for those given Rituxan was -1.5, compared with -1.1 for those on a second TNFi (P=0.007). The statistically significant difference was seen among patients who discontinued the initial TNFi because of inefficacy but not in those who discontinued because of intolerance. Adverse event rates were similar in all groups.
Improvements were significantly greater in seropositive patients; however, there were too few seronegative patients for adequate statistical power to assess this.
What further research needs to be done to improve our understanding of the effectiveness of switching TNFis?
As with any treatment strategies, additional research is helpful in expanding the body of evidence that supports treatment recommendations. The studies underway should help to answer many questions.
What do you think the future holds for RA treatments?
I believe we will continue to see more targeted RA therapies that will help a broader range of patients to manage their symptoms more effectively and with fewer side effects.
Where can readers find more information?
The SWITCH-RA study is published online in the Annals of the Rheumatic Diseases (http://ard.bmj.com/content/early/2014/01/17/annrheumdis-2013-203993.short?g=w_ard_ahead_tab#aff-2).
About Professor Paul Emery
Paul Emery is the Arthritis Research UK Professor of Rheumatology and Director of the Leeds Institute of Rheumatic and Musculoskeletal Medicine and the Director of the Leeds Musculoskeletal Biomedical Research Unit at Leeds Teaching Hospitals Trust, U.K.
Professor Emery was President of EULAR 2009-2011. He has served on the editorial boards of all the major rheumatology journals. He was inaugural President of ISEMIR (International extremity MRI society). He is an NIHR Senior Investigator. He is a recipient of the Roche Biennial Award for Clinical Rheumatology; the Rheumatology Hospital Doctor of the Year award 1999; and EULAR prize 2002 for outstanding contribution to rheumatology research. In 2012 he was awarded the Carol Nachman Prize.
Professor Emery’s research interests centre around the immunopathogenesis and immunotherapy of rheumatoid arthritis, SpA and connective tissue diseases. He has a special interest in the factors leading to persistent inflammation. He has published over 850 peer-reviewed articles in this area.