Drug treatments for rheumatoid arthritis: looking backwards to move forwardsBMJ 2015; 350 doi: https://doi.org/10.1136/bmj.h1192 (Published 13 March 2015) Cite this as: BMJ 2015;350:h1192
- Pierre Miossec, professor of clinical immunology
- 1Department of Clinical Immunology and Rheumatology and Immunogenomics and Inflammation research Unit, University of Lyon, Edouard Herriot Hospital, 69437 Lyon, France
Over the past 40 years the clinical picture has improved for patients with rheumatoid arthritis thanks to key steps in drug development and care strategy. These steps include the introduction of methotrexate in 1980 and the first inhibitors of tumour necrosis factor (TNF) in 2000. This was followed by the development of new biotechnology products to target other cytokines, cell subsets, and cell interaction pathways. All these products are expensive drugs with obvious consequences for health systems with limited resources.
In parallel, trials have also continued to test old drugs used in new more modern ways, starting with the combination of methotrexate, sulfasalazine, and hydroxychloroquine. The real surprise came from a recent demonstration that this combination was as effective as the combination of methotrexate and the TNF inhibitor etanercept.1 2 The linked paper by Scott and colleagues (doi:10.1136/bmj.h1046) is another example of a trial of TNF inhibitors compared with intensive treatment comprising a combination of conventional disease modifying anti-rheumatic drugs.3 The primary objective of this non-inferiority trial was to examine whether the drug combination could achieve similar clinical benefits to a TNF inhibitor but at lower costs.
This open label pragmatic trial (called the TACIT trial) included patients with rheumatoid arthritis who were eligible for TNF inhibitors under current guidance from the National Institute for Health and Care Excellence. Of 432 patients screened, 101 started treatment with a TNF inhibitor and 104 started treatment with the drug combination. Various drugs were used during the trial, to reflect routine practice. The most common TNF inhibitor was adalimumab (58/101) and the most common drug combination was methotrexate and leflunomide (62/104).
The primary outcome was the change in disability scores (health assessment questionnaire, range 0.00 to 3.00) over 12 months. Scores decreased in both groups, but slightly more in the group treated initially with disease modifying drugs (−0.45 v −0.30). The difference was below the authors’ prespecified threshold for non-inferiority (0.22). Changes in quality of life, progression of erosions, rate of induction of remission (44/101 with TNF v 36/104 with combination drugs), and serious adverse events (18/101 v 10/104) were comparable in both treatment arms. In conclusion, drug combinations resulted in non-inferior outcomes compared with starting TNF inhibitors. There were also differences. At six months, TNF inhibitors were associated with lower disease activity relative to drug combinations, a difference not seen at 12 months, and indicating the rapid effect of TNF inhibition. Conversely, drug combinations were associated with lower health and social care costs, saving £3615 (€4930; $5585) per patient during in the first six months and £1930 per patient during months 6-12.
The good news is that a combination of traditional drugs was not inferior to a biological option as found in previous trials.1 2 It is too early to say, however, which combination of disease modifying drugs is likely to work best. This remains an important question for future studies, preferably in larger populations with adequate power for firm conclusions. Further questions remain about the long term effects of treatments on joint destruction and disability. When researchers compared methotrexate head to head against the TNF inhibitor etanercept, participants treated with etanercept had fewer joint changes on repeat radiographs.4 In the TACIT trial, 12 months of follow-up is far too short to assess long term safety or the balance of benefit and risk. Long term studies are needed, again in larger populations. In the end, we might never get the clear answers needed to make therapeutic choices.
When two treatment options for rheumatoid arthritis look equally good in a trial, the reality for patients is that they are often equally bad. Whatever new compounds are tested, usually 30% of the patients will not respond. Another limitation is that rheumatoid arthritis is a chronic disease.5 When active treatment stops, active disease often restarts. One option, at least in responders, is to continue treatment, but at a reduced dose.6
Timing is important in the treatment of rheumatoid arthritis, and we might be using drugs in the wrong sequence. Progress in cancer treatment finally came when drugs were combined, given intravenously at high dose during the early phase of treatment, then simplified later. If we were to take the same approach to rheumatoid arthritis then we would combine drugs at the start of treatment and not wait for traditional monotherapies to fail.7 Economic analysis will have to balance the extra cost of drugs against potential savings made by society as a consequence of reduced disability. We must also invest in research to help to improve understanding of disease heterogeneity. None of the studies described here has assessed the use of biomarkers and personalised medicine in this context.8
Considering rheumatoid arthritis care today, the best way to improve overall outcomes is to act earlier.9 This is common sense, but now we know why. Over the years, the daily pressure of chronic inflammation induces molecular changes in cells at the disease site, leading to reduced response to cell death signals.10 Over time, the disease pathways change, starting with an immunological disease with classic interactions between immune cells and their derived soluble products. Later, the disease is less immunologically driven while remaining immunologically induced.11 Today we don’t focus on the late targets responsible for chronicity.
The future of treatments for rheumatoid arthritis used to be seen as progressing through research evaluating new biomarkers and testing new expensive drugs. The TACIT trial challenges this orthodoxy and gives fresh hope to more patients around the world that they can achieve equal or better disease control with combinations of established, low cost, and easy to produce alternatives.
Cite this as: BMJ 2015;350:h1192
Competing interests: I have read and understood the BMJ policy on declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; not externally peer reviewed.
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