In presenting the new recommendations in the management of rheumatoid arthritis, speakers at this year’s EULAR addressed the role of combined triple therapy with conventional DMARDs among other topics. Their benefit compared with extended therapy with biologic supplementation is unclear, according to Robert B.M. Landewé, MD, Amsterdam. Nevertheless, the new guidelines advocate this form of therapy somewhat more explicitly than in 2010.
The first issue was how the 2010 EULAR recommendations have performed. “In particular, our recommendations on combined DMARD therapy met with criticism because we preferred monotherapy with conventional DMARDs (csDMARDs) to combined csDMARD therapy and, because we found studies that exclusively examined combined csDMARD therapies unconvincing,” noted Robert B.M. Landewé, MD, Amsterdam. “To do that, you have to know how to measure the performance of such recommendations in the first place. Evidence-based medicine should take into account research findings on the one hand, and clinical data such as experience, preferences, local habits, and last but not least individual patient values such as fears and perceptions in order to arrive at an optimal decision for a recommendation. So the reevaluation that’s going on now continues to be about whether there’s a use for combined csDMARD therapy in the treatment of RA patients.”
Swefot
The Swefot trial (2012) investigated the question: “What to do if an adequate dose of MTX does not result in a DAS 28≤3.2 after three months: triple combination (addition of sulfasalazine and hydroxychloroquine) or addition of infliximab?” The authors conclude, “Complementary biologic treatment is a valid option for patients who fail initial MTX treatment. However, the improved clinical outcomes at 12 months and the better radiographic results at 24 months should be weighed against the underwhelming clinical difference at 24 months and the significantly higher cost [1]. There are several concerns about this study: “Overall, it is rather unsuitable for considering whether the triple combination can be recommended before supplementation with a biologic,” Dr. Landewé said.
TEAR and tREACH
The TEAR trial (2012) examined the question of whether patients with new-onset RA are best treated with boosted DMARD or direct combination therapy. The 2×2 factorial design was used to assign participants to one of four treatment groups: direct treatment with MTX plus etanercept, direct oral triple therapy (MTX plus sulfasalazine plus hydroxychloroquine), or boosted MTX monotherapy to one of the combination therapies (MTX plus etanercept or MTX plus sulfasalazine plus hydroxychloroquine) at week 24 if DAS28-ESR ≥3.2 [2]. “The authors conclude that triple therapy and etanercept supplementation are comparable in terms of clinical outcomes,” Dr. Landewé said. “There are concerns about this study as well, however; after all, the study was designed to contrast direct versus stepwise therapy, not primarily to compare triple therapy with biologic supplementation. So again, this study is of little use in determining whether triple therapy is useful in treating RA.” The same is true of the 2013 tREACH study [3].
“Ultimately, even science and randomized control trials (RCTs) are always open to interpretation because they are exercised by humans, not machines. Therefore, they cannot be seen as the only references for a recommendation; a supplement of expert and patient opinions is needed in any case,” Dr. Landewé concluded his presentation.
RA Recommendations 2013: What’s New?
“The 2010 recommendations were not about saying that the combination of csDMARD therapies was wrong, but that it was not necessary,” said Prof. Josef Smolen, MD, Vienna. Based on new findings, however, these combination therapies can now be advocated somewhat more explicitly. According to Prof. Smolen, it is necessary to put the 2013 EULAR recommendations in perspective. Compared to 2010 recommendations:
the 2013 EULAR recommendations continue to emphasize the efficacy of csDMARDS, including combination therapy (first-line).
they consider all biological agents to be equally effective and safe for initial biological therapy (secondline).
they reiterate the preference for the use of biologics in combination with MTX, rather than monotherapy.
they do not in any way recommend the use of biologics as a first-DMARD strategy.
they deal with biosimilars and tofacitinib.
Compared to the ACR 2012 update:
- the 2013 EULAR recommendations are of a more general nature. They do not list individual scenarios.
- they deal with glucocorticoids, but not with minocycline.
- they do not recommend the use of biologics as a first-treatment strategy. This is because the efficacy of a treat-to-target strategy with the addition of biologics after inadequate response to MTX has high rates of evidence.
- they do not recommend monotherapy with TNF inhibitors or other biologics.
“Overall, the EULAR 2013 Update has been developed for a broad target audience. Addressed are, of course, rheumatologists, patients, physicians, scientists, but also other representatives of the healthcare system such as hospital managers, health insurers and politicians. We invoke three overarching principles: First, we want to examine treatment targets, and second, we want to identify treatment approaches and assess their risk, always addressing conventional, biologic, “targeted synthetic,” and biosimilar DMARDs,” Prof. Smolen concluded. “Our recommendations are based on three systematic literature reviews: The first looked at conventional DMARDs, the second at biologics, and the third at safety issues.”
Source: “Update of EULAR Rheumatoid Arthritis Management Recommendations,” EULAR, June 12-15, 2013, Madrid.
Literature:
- Van Vollenhoven RF, et al: Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, non-blinded, parallel-group Swefot trial. Lancet. 2012 May 5; 379(9827): 1712-1720.
- Moreland LW, et al: A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: the treatment of Early Aggressive Rheumatoid Arthritis Trial. Arthritis Rheum. 2012 Sep; 64(9): 2824-35.
- Porter DR, et al: Step-up therapy remains an appropriate option. Ann Rheum Dis 2013; 72: 72-78.
