Treat-to-Target Works for RA. But What Is It?

In rheumatoid arthritis (RA), the mantra is treat-to-target (T2T), early and [[{"type":"media","view_mode":"media_crop","fid":"24793","attributes":{"alt":"rheumatoid arthritis","class":"media-image media-image-right","height":"157","id":"media_crop_5550198888821","media_crop_h":"0","media_crop_image_style":"-1","media_crop_instance":"2192","media_crop_rotate":"0","media_crop_scale_h":"0","media_crop_scale_w":"0","media_crop_w":"0","media_crop_x":"0","media_crop_y":"0","style":"float: right;","title":" ","typeof":"foaf:Image","width":"200"}}]]aggressively.¹ The trouble is that there's little agreement on where that "target" is, the best way to know when it has been reached, or the best methods of aiming for it.

Guidelines from both the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) say the treatment goal in RA should be remission or low disease activity (LDA), which they define by different composite measures.

Overall, the evidence for T2T is “good but not stellar,” and there are few practical guidelines for its use in every day clinical practice, observed University of Toronto rheumatologist Edward Keystone MD at the ACR pediatric rheumatology meeting in Orlando last month.

“In practice I look at a patient and see how they’re doing at three months," added Dr. Keystone, who is director of the Rebecca MacDonald Centre for Arthritis and Autoimmune Disease at Mount Sinai Hospital in Toronto. "If there’s some progress I continue. If not, I change the medication.”

So in the rheumatologist’s office as in the best-practices literature, that “target” may always be in motion.

Shifting Goal Posts

The concept of T2T originated with other chronic diseases, such as hypertension and diabetes, and the numerical goals for “normal,” “low”, and “high” glucose and blood pressure are assessed regularly. The strategy has been adopted for RA and is now being looked at for other rheumatic diseases such as systemic lupus erythematosus (SLE).²

However, as a report in the April Arthritis & Rheumatology points out, even in hypertension or diabetes, the reality of achieving “tight control” can be difficult and is not always clear-cut. While T2T has many potential benefits, “there’s relatively weak evidence of long term benefits in RA, as opposed to other chronic diseases.”¹

The authors ask: Is T2T “a proven paradigm or a hypothesis requiring more complete testing?”

The answer seems to be the latter.

For one thing, they point out, treatment targets vary across clinical trials in RA, as do rates of attaining those targets, ranging from 31% to 82%.¹

Comparing RA with other chronic diseases, the report notes that in diseases such as diabetes or hypertension, in which "flares" aren't recognized symptomatically, the T2T strategy recommends intensifying treatments when numeric targets aren't reached. In RA, of course, flares are symptomatic, perhaps confusing rather than clarifying the target.

Setting remission as a target “largely obscures the fact that there’s no universally-accepted definition of remission,” observes another 2014 analysis of T2T.³

“This has provoked a lively debate over “whether treatment should be targeted at achieving low disease activity, clinical remission, or imaging remission,” write the authors of the analysis in the Annals of the Rheumatic Diseases.⁴

Taking a Hard Look at T2T

Recent studies do show successful outcomes for T2T.

A recent analysis in Arthritis Research & Therapy concludes that targeting remission (as defined in terms of the simplified disease activity index or SDIA) not only produces better outcomes for patients, but is more cost-effective, than aiming for LDA.⁴

One of the longest-running studies shows that T2T can produce remission (defined according to DAS28, the Disease Activity Score in 28 joints) that is sustained as long as three years.⁵

Data from the Dutch Rheumatoid Arthritis Monitoring remission induction cohort found that using a T2T approach in very early RA produces high remission rates, improves physical function and health related quality of life, and also limits radiographic damage.⁵

At the same time, the Annals authors point out that T2T may not be the best strategy for treating some RA patients at very low risk, “for whom the pursuit of more costly, very stringent treatment targets results in no net gain or even net harm (for instance, from rare but serious adverse events, like infections).”⁴

Therefore, they say further research in T2T is needed, not only to define remission more clearly, but also to:

•   test the incremental benefit of pursuing remission rather than LDA, or imaging remission rather than LDA/clinical remission,
•   capture the impact of therapeutic strategies on generic health-related quality of life and comorbidities as well as disease-specific outcomes,
•   and explore whether any advantages that may accrue are restricted to subpopulations of patients at high risk, although more accurate predictors of prognosis and harm are needed.

Future clinical trials must also “capture disutility (adverse effects, harms and additional costs), as well as utility," they add, "using a range of patient-centered outcomes.”⁴

References:

1.   Solomon DH, Bitton A, Katz JN, et al. Treat to Target in Rheumatoid Arthritis. Fact, Fiction, or Hypothesis? Arthritis & Rheumatology (2014) 66: 775–782. doi:10.1002/art.38323.

2.   van Vollenhoven RF, Mosca M, Bertsias G, et al., Treat-to-target in systemic lupus erythematosus: recommendations from an international task force. Ann Rheum Dis. (2014) Apr 16. doi: 10.1136/annrheumdis-2013-205139.

3.   Porter D, Dale J, Sattar N. How low to aim in rheumatoid arthritis? Learning from other disciplines. Ann Rheum Dis 2014;73:480–482. doi:10.1136/annrheumdis-2013-204339.

4.   Radner H, Smolen JS, Aletaha D. Remission in rheumatoid arthritis: benefit over low disease activity in patient-reported outcomes and costs.Arthritis Research & Therapy (2014) 16:R56  doi:10.1186/ar4491. Published: 21 February 2014.

5.   Vermeer M, Kuper HH, Bernelot HJ, et al., Sustained Beneficial Effects of a Protocolized Treat-to-Target Strategy in Very Early Rheumatoid Arthritis: Three-Year Results of the Dutch Rheumatoid Arthritis Monitoring Remission Induction Cohort.Arthritis Care & Research  (2013) 65:1219–1226. doi:10.1002/acr.21984.