Demise of the triple
Triple therapy, the combination of methotrexate (MTX), sulfasalazine (SSZ), and hydroxychloroquine (HCQ), appears to be effective in selective patients with rheumatoid arthritis (RA). Three large, well-designed clinical trials have compared triple therapy to the combination of MTX and a biological TNF inhibitor (TNF-i) with favorable, or at least non-inferior, conclusions with regards to efficacy and safety, and triple therapy was dramatically less costly.
Triple therapy in clinical trials
The first study, the Swefot trial (2009), showed that in patients with early RA who were incomplete responders to MTX the addition of SSZ and HCQ led to clinical improvements that were not clinically different at 12 months from the addition of the TNF-i infliximab . At 24 months there was still no convincing clinical difference between the two treatment groups, however the triple therapy group demonstrated a small measurable increase in radiographic progression compared with the TNF-i group . The second study, the TEAR trial (2012), showed that in patients with early RA there were no differences in disease activity scores during weeks 48–102 between patients given the TNF-i etanercept plus MTX and those receiving triple therapy, although again there was less radiographic progression in the TNF-i group by the end of the second year . In the third study, the RACAT trial (2013), triple therapy was found to be non-inferior to the TNF-i etanercept plus MTX, with similar changes from baseline by week 48 in disease activity scores and no significant differences in radiographic progression, pain, or quality of life indices .
Clinical uptake of triple therapy
Despite this evidence, the choice to use triple therapy does not appear commensurate with the opportunities to use it. In a 2016 review of US insurance claims data from 24,576 patients with RA during 2009–2014, 2,739 patients (11.1%) were intensified to biologic disease-modifying anti-rheumatic drugs (DMARDS) compared to 181 patients (0.7%) whose treatment was intensified to triple therapy . This study included the time period during which the important randomized controlled trials that reported similar efficacy for triple therapy and biologic DMARDs were published. Although it is possible that the seminal trials were published too late to influence the clinical uptake of triple therapy, the authors noted that the use of triple therapy did not increase over time. Since the publication of this trial, there seems to be little to no evidence that the use of triple therapy is increasing and perhaps even that it is decreasing further.
Why is triple therapy underutilized?
Triple therapy is efficacious, is much less expensive, is available in pill form, and is at least as safe as the combination of MTX and biologic DMARDs, but is underutilized. The reasons for this are unclear, but several issues are worth mentioning. Triple therapy requires that the patient comply with all three drugs, with the maximum dose including 10 MTX, six SSZ, and two HCQ tablets daily. Compliance may be a significant issue with this number of tablets and the corresponding schedule. Compliance with a biologic DMARD often requires a single weekly, biweekly or monthly injection or infusion, which may be perceived as far simpler. Reported adverse events with triple therapy are still significant and not dramatically fewer than with MTX plus biologic DMARD combinations. Triple therapy may take a long time to be effective; in the trials highlighted above some patients required nearly 12 months of therapy before a response was observed. Biologic therapies often are efficacious within three to four months, and that difference may be important for patients and rheumatologists.
For rheumatologists, there may be still other concerns. The clinical trials that investigated triple therapy have been subject to interpretative questions, like all published trials, and perhaps they have lost some of their influence. The radiographic differences between triple therapy and biologics may be important to some practitioners. The potential to achieve “higher endpoints” (e.g. ACR70, DAS28-ESR<2.6) with biologic therapy may be also important to some. In the USA there may already be insurance-mandated step-up regulations for prescribing therapy for many RA patients. Perhaps there is worry that professional support for triple therapy and its very significant cost savings compared to biologics will lead to an insistence by insurance carriers and governing organizations on the use of triple therapy before biologics, leading to diminution of choice and control of care. The current guidelines from the American College of Rheumatology (ACR) do not include any order of preference for treatment choice after initial DMARD failure, perhaps a somewhat curious decision given the available data, the myriad difficulties of completing large clinical trials comparing triple therapy to biologics, and the cost differences . The European League Against Rheumatism (EULAR) 2017 RA treatment guidelines comment on the use of combinations of conventional DMARDs, but do not define a specific role for triple therapy, and even suggest avoiding its use in RA patients with risk factors for a poor prognosis . The consensus amongst international thought leaders regarding the appropriate place of triple therapy in the treatment of RA seems to be dissolving, if it ever truly existed.
The perception question seems very significant. The use of biologic agents in RA has received massive support from the pharmaceutical industry, while triple therapy has virtually no support beyond the academic centers where the seminal studies were performed. The potential dramatic efficacy of biologics in RA has corresponded with the emergence of the lofty goals of remission, the holy grail of all chronic diseases, and this linkage may be tantalizing for patients and rheumatologists. Biologics are new, targeted, perceived as powerful, and promoted, while triple therapy is not. Biologics are state of the art and the hope for the future, immunologically engineered, and multiplying. Each emerging biologic has its own intensive campaign of support which is virtually impossible for the RA patient and rheumatologist to ignore. Given these potent forces, triple therapy may be perceived as a barrier between patients and the biologic treatment strategy preferred by their rheumatologists or even by the internet-informed patients themselves. The situation has now devolved to the point where questions about whether or not triple therapy will be a viable treatment strategy in the near future are being asked.
In baseball the triple, once considered one of the most exciting plays in sports, is disappearing. The ballparks have changed, the players have changed, the baseball itself has changed, and the powerful clamor for home runs now rules the game. One of the most exciting plays in the sport has been relegated to the statistical memories of computers and purists. RA and its treatment are certainly not a game. RA treatment strategies, however, while science and evidence based, still involve decisions which are complex and influenced by a large number of factors, and they are rapidly changing and hopefully truly evolving. Triple therapy may have already been relegated to the statistical memory of rheumatologic purists.
- Van Vollenhoven RF, Emestam S, Geborek ES et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomized trial. Lancet 2009; 374:459-66.
Van Vollenhoven RF, Geborek P, Foslind K et al. Conventional combination treatment versus biological treatment in methotrexate refractory early rheumatoid arthritis: 2-year follow-up of the randomized, non-blinded, parallel group Swefot trial. Lancet 2012; 379:1712-20.
Moreland LW, O’Dell JR, Paulus HE 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; 64:2824-35.
O’Dell JR, Mikulis TR, Taylor TH et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Eng J Med 2013; 369:307-18.
Sparks JA, Krumme AA, Shrank WH et al. Brief Report: Intensification to triple therapy after treatment with nonbiologic disease-modifying antirheumatic drugs for rheumatoid arthritis in the United States from 2009 to 2014. Arthritis Rheum 2016; 68:1588-95.
Singh JA, Saag KG, Bridges SL Jr et al. 2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheum 2016; 68:1-25.
Smolen JS, Landewe R, Bijlsma J et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann Rheum Dis 2017; 76:960-77.