BERLIN—Clinical advances are catching up with rheumatoid arthritis (RA)—and remission is becoming the new normal—but early diagnosis is still critical to successful treatment, one expert said here in an overview of recent therapeutic progress at the European League Against Rheumatism (EULAR) 2012 Annual European Congress of Rheumatology, held June 6–9.
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In an overall uplifting assessment of clinical advancements in rheumatology, Paul Emery, MD, director of MSK Biomedical Unit at the Leeds Teaching Hospitals Trust in the United Kingdom, said that a sharpened focus on predisease states has been a major reason for the inroads.
“The good news is this: The classical features of rheumatoid arthritis are disappearing,” Dr. Emery said. “We’ve understood, in the last few years, that the phenotype of RA isn’t a fixed endpoint, but it’s a continuum of phenotypes that ends up with that of rheumatoid. And because of that, we’ve intervened to make a difference in that endpoint.”
In a second part of the clinical update, Josef Smolen, MD, chair of the department of rheumatology at the Medical University of Vienna in Austria, reviewed the latest work on biologic therapies, which generally shows promise but, in many cases, doesn’t show superior performance to conventional approaches. He also stressed the importance of treat-to-target approaches.
The Goal: Remission
Dr. Emery said the EULAR recommendations on remission, issued in 2010, have helped rheumatologists appreciate the importance, and the feasibility, of remission as a goal.1 The EULAR recommendations suggest that remission or low disease activity (LDA) should be the aim, with monitoring every one to three months until the target is obtained—with targets depending on whether doctors are dealing with early or established RA. The importance of monitoring has been established in recent trials.2
The 2011 ACR/EULAR RA remission criteria have helped standardize the definition of remission, he said, but no set of remission criteria predicts flare.3 In one study, flare was found to be associated with worse baseline function and quality of life. It also found that, in patients with positive Power Doppler imaging, the risk of flare was four times greater.4 “There is independent helpful information provided by imaging in patients with remission,” Dr. Emery said.
He also touched on new insights into cardiovascular (CV) risk associated with RA. Some findings have been contradictory. One study found that RA patients who discontinue statins have a heightened risk of acute myocardial infarction, while another concluded that statin use brings an increased risk of RA.5,6
“Therapies that switch off inflammation have this interesting differential effect—by switching off inflammation they’re advantageous, by switching off the drive to the liver they change the lipid profile. And at the moment, the jury strongly suggests that it’s more important to switch off the inflammation,” Dr. Emery said.
Data are just beginning to show that the RA therapies are beneficial in terms of CV risk, he said. “It’s quite clear the mortality is improving on these therapies and it’s almost certainly due to the improved cardiovascular profile,” he said.
For established RA, it may not be wise to withdraw the biologic.Overall, withdrawal in patients will lead to flares in the vast majority of the patients. This is different in early disease.
—Josef Smolen, MD
Early Diagnosis of RA
With early diagnosis being so important, the rise of early arthritis clinics has been a big step forward, Dr. Emery said. “Early arthritis clinics, I’m pleased to say, are now worldwide”—including in South America and the Middle East, he said. The 2010 ACR/EULAR Classification Criteria for RA mean that the more clear-cut classification of newly presenting patients will help lead to earlier diagnoses. “You’re going to be diagnosed with RA very, very much earlier,” he said.
“The new criteria have been incredibly important for major advances,” Dr. Emery continued. “They can allow new licenses as well, because [earlier identification of RA] will, I think, allow different drugs to get licensed for new diseases.” He noted that, while synovitis plays a big role in the criteria, it can be difficult to diagnose.
Dr. Emery emphasized the value of imaging in early arthritis patients. A 2010 study found that, in seronegative patients, the probability of developing inflammatory arthritis was just 6%, but with certain clinical and radiographic features considered together, the probability was boosted to 30%—even 94% when certain ultrasound features were present.7
In a final note, Dr. Emery stressed the importance of using predictive tools in small samples of patients to better direct larger trials. He also highlighted the problem with studies against placebo.
In his review of biologic therapies, Dr. Smolen began by saying that the EULAR management guidelines do not suggest biologics as a first-line treatment in the early stage of RA.
“It is fair to state that nothing [other] than [a] combination of methotrexate plus glucocorticoids is better at this stage of the disease,” he said “Biologics come into place when this therapy fails.” But, he said, progress has been made with many therapies targeting the IL-17 cytokine, as well as IL-6 and IL-20.
His larger question, though, was whether biologics perform better than synthetic disease-modifying agents.
In the IDEA study, patients were randomized to receive methotrexate plus the anti–tumor necrosis factor (TNF) drug infliximab (Remicade) or methotrexate plus IV methylprednisolone. After 26 weeks in both arms, if DAS 28 scores were 2.4 or lower, the therapy was continued at current doses; if higher, it was escalated.8 The study found that the two arms performed similarly.
“Treat to target is effective in early disease—rapid and sustained remission can be achieved by both ways, but obviously this [the nonbiologic approach] is the more affordable way,” said Dr. Smolen. But he also noted that 15% of patients, whose disease activity remained high after 26 weeks, were switched from nonbiologic therapy to biologic, and benefited.
In the SWEFOT trial, patients were started on methotrexate and, if they still had moderate to high disease activity after three months, were switched to either conventional triple therapy (sulfasalazine, hydroxychloroquine, and methotrexate) or infliximab.9 There were advantages in the infliximab arm after a year, but after two years, “these differences were not apparent,” Dr. Smolen said. “Neither clinical nor radiologic.”
The results aren’t easily interpreted, he said. One take-home message might be that traditional therapy can yield similar results to infliximab if it is sustained long enough. On the other hand, Dr. Smolen said, 24 of 130 patients had to withdraw from the conventional arm because of lack of efficacy, while just 5 of 128 dropped out from the biologic arm due to lack of efficacy.
Dr. Smolen called the TEAR study “one of the most complex clinical trials he’s seen in recent years—or ever.” The study started with two pairs of arms. The first pair included a conventional triple-therapy arm and a methotrexate-plus-etanercept arm. The second pair included subjects who all started on methotrexate then, if their disease activity was moderate to high, were switched to either standard triple therapy or etanercept.
Those in the etanercept arms collectively were more likely to have profound effects, with a higher percentage of ACR70 response rates and better radiographic outcomes, but the overall performance was similar in both the biologic and nonbiologic arms. Dr. Smolen also had doubts about the power of this study, because the dropout rate was much higher than anticipated.
Dr. Smolen said a major question among rheumatologists is how biologics compare.
In the AMPLE trial, immunomodulator abatacept plus methotrexate was compared with TNF-inhibitor adalimumab plus methotrexate in patients with active disease, and there was overall a very close similarity in this analysis.10
But Dr. Smolen suggested that more work needs to be done in this area, noting that comparative effectiveness research is something rheumatologists crave. He said that since it’s been found that a third of patients taking TNF-inhibitors don’t take them in conjunction with methotrexate or another biologic, as is generally suggested, more needs to be known about how they work as monotherapies.
In the ADACTA study, subcutaneous tocilizumab was compared to subcutaneous adalimumab, with the results significantly favoring tocilizumab.11
The emergence of biologics has raised still another question: When can they be withdrawn, if at all. Dr. Smolen said that the research has shown that it depends on the stage of the disease. “For established RA, it may not be wise to withdraw the biologic,” he said. “Overall, withdrawal in patients will lead to flares in the vast majority of the patients. This is different in early disease.”
Thomas Collins is a freelance medical writer based in Florida.
- Smolen JS, Landewé R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis. 2010;69:964-975.
- Katchamart W, Bombardier C. Systematic monitoring of disease activity using an outcome measure improves outcomes in rheumatoid arthritis. J Rheumatol. 2010;37:1411-1415.
- Felson DT, Smolen JS, Wells G, et al. American College of Rheumatology/European League Against Rheumatism provisional definition of remission in rheumatoid arthritis for clinical trials. Arthritis Rheum. 2011;63:573-586.
- Saleem B, Brown AK, Quinn M, et al. Can flare be predicted in DMARD treated RA patients in remission, and is it important? A cohort study. Ann Rheum Dis. 2012 Jan 31. [Epub ahead of print]
- De Vera MA, Choi H, Abrahamowicz M, Kopec J, Goycochea-Robles MV, Lacaille D. Statin discontinuation and risk of acute myocardial infarction in patients with rheumatoid arthritis: A population-based cohort study. Ann Rheum Dis. 2011;70:1020-1024.
- de Jong HJ, Klungel OH, van Dijk L, et al. Use of statins is associated with an increased risk of rheumatoid arthritis. Ann Rheum Dis. 2012;71:648-654.
- Freeston JE, Wakefield RJ, Conaghan PG, Hensor EM, Stewart SP, Emery P. A diagnostic algorithm for persistence of very early inflammatory arthritis: The utility of power Doppler ultrasound when added to conventional assessment tools. Ann Rheum Dis. 2010;69:417-419.
- Nam JL, Villeneuve E, Hensor EMA, et al. Inhibition of structural damage with two intensive treatment strategies using infliximab or high dose intravenous steroid followed by treat to target in DMARD naïve rheumatoid arthritis (the IDEA study)—a preliminary report. Ann Rheum Dis. 2012;71(Suppl3):106.
- van Vollenhoven RF, Geborek P, Forslind K, 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;379:1712-1720.
- Schiff M, Fleischmann R, Weinblatt M, et al. Abatacept SC versus adalimumab on background methotrexate in RA: One year results from the ample study. Ann Rheum Dis. 2012;71(Suppl3):60.
- Gabay C, Emery P, van Vollenhoven R, et al, Tocilizumab (TCZ) monotherapy is superior to adalimumab (ADA) monotherapy in reducing disease activity in patients with rheumatoid arthritis (RA): 24-week data from the phase 4 ADACTA trial. Ann Rheum Dis. 2012;71(Suppl3):152.