In the past decade, the treat-to-target concept has gained broad acceptance. Both the ACR and European League Against Rheumatism (EULAR) management recommendations include adding biologic therapies to the treatment regimen for rheumatoid arthritis (RA) patients who do not sufficiently respond to methotrexate monotherapy. “What EULAR says is that if [methotrexate use fails], you should essentially try to add the biologics within six months,” says Josef Smolen, MD, professor at the Medical University of Vienna, Austria.
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In a study published November 2018 in the Annals of the Rheumatic Diseases, Dr. Smolen and co-authors wanted to determine what baseline disease characteristics and factors of early disease activity best predict a patient’s response to methotrexate treatment and radiographic progression at six months.1
The researchers reasoned that clues could be discerned by using data collected during two large RA studies and conducting a post-hoc analysis. Dr. Smolen, who is editor in chief of the Annals of the Rheumatic Diseases, explains the reasoning behind the retrospective analysis: Given what is now clear—that disease activity can be slowed with the addition of biologics—“We cannot address this question [comparing methotrexate alone with combined therapy] in a long-term prospective trial anymore. It would be unethical,” he says.
The researchers used pooled data from two clinical trials with different protocols when patients did not achieve methotrexate response. In the PREMIER study, performed in the early 2000s, patients were followed for two years and assessed for clinical, functional and radiologic outcomes at one year. Patients continued their initial methotrexate therapy for up to two years. These patient data were then compared with patient data from the OPTIMA study, which was performed 10 years later. In the latter trial, the treatment protocol called for adding adalimumab to therapy after six months if patients showed an insufficient response to methotrexate.2,3
The 6-Month Treatment Decision
The authors found baseline disease activity, as shown in composite measures, was the strongest predictor of insufficient response to initial therapy at six months. Further, clinical disease activity at four, eight and 12 weeks—assessed by Disease Activity Score 28 (DAS28), the System Disease Activity Index (SDAI) and the Clinical Disease Activity Index (CDAI)—was another predictor of response to methotrexate therapy at six months.
“When looking at the outcomes after the six-month point, patients in OPTIMA who immediately received the biologic agent when not achieving the target of low disease activity fared much better than those who continued their insufficiently efficacious methotrexate in PREMIER,” Dr. Smolen says. “Thus, the other time point is six months. If you have not achieved the outcome you targeted and agreed on with your patient by six months—the remission for early disease or low disease activity—then you should also change your therapy. So for the methotrexate situation, if you haven’t improved on methotrexate, ideally with glucocorticoids, as we recommend, by at least 50% in your CDAI score within three months, forget the methotrexate [monotherapy] and add a biologic.”
Interestingly, because men and women respond differently to methotrexate therapy, the data also suggest women with early RA may benefit from frequent, early disease activity monitoring. This monitoring would allow clinicians and patients the opportunity to adjust treatment as early as the first three months of therapy, the authors note.
“These data confirm the recommendations to really make a major decision [about treatment] at six months. It confirms treat to target. It confirms EULAR, and in some respects, the ACR management recommendations,” says Dr. Smolen. “In the treat-to-target recommendations, we provide two time points: If you have not improved by three months by at least 50%, then you have a very low chance of reaching the good outcome by six months. So if you have less than 50% improvement on the clinical disease activity index, the CDAI, then you should swap already, or add [the biologic].”
Implementation Barriers Remain
David S. Pisetsky, MD, PhD, professor of medicine and immunology at Duke University School of Medicine, Durham, N.C., and an associate editor of the Annals of the Rheumatic Diseases, concurs the study underlines the recommendations of adding biologics if the disease indicators are present. However, he says, such recommendations raise a number of challenges.
“Part of the challenge is more prompt identification of patients who present with signs and symptoms of inflammatory arthritis,” he explains. “In treat to target, one of the priorities is early recognition by providers that a patient has an inflammatory arthritis.” Primary care providers may not be experienced enough to recognize the signs. And with the shortage of rheumatologists, access to the proper assessments can be delayed in certain places in the U.S. and other countries.
“The importance of these data is they show that there are features that bespeak the need for more and early therapy,” Dr. Pisetsky says. This may entail more frequent and intensive visits early in the course of disease, and require more precise measures of disease activity.
“Primary care providers are being given many responsibilities,” he says. “Where does recognition of RA fit in? Some kind of triage system may be necessary to ensure patients with inflammatory arthritis are seen soon after presentation.”
Possible solutions may lay in using allied providers trained in assessments or telemedicine consults with rheumatologists who can direct the primary provider on which laboratory tests to order. But another issue that’s raised by treat-to-target recommendations is access to more expensive medications, at least in the U.S., says Dr. Pisetsky.
“Rheumatologists often discuss how much time they spend getting approval of medications,” he says. “We rheumatologists want early access for patients, we want them to recognize symptoms, we want an effective screening strategy to get those people who have a likelihood of inflammatory arthritis to us, and then we have to have the time to evaluate them and educate them. [A diagnosis of RA] is a big change in someone’s life.”
Disclosure of and education about this potentially long-lasting, serious condition cannot always be achieved in a 15-minute office visit, Dr. Pisetsky says. “I think we have to figure out ways to do a lot of work efficiently.”
Gretchen Henkel is a health and medical journalist based in California.
- Smolen JS, van Vollenhoven RF, Florentinus S, et al. Predictors of disease activity and structural progression after treatment with adalimumab plus methotrexate or continued methotrexate monotherapy in patients with early rheumatoid arthritis and suboptimal response to methotrexate. Ann Rheum Dis. 2018 Nov;77(11):1566–1572.
- Breedveld FC, Weisman MH, Kavanaugh AF, et al. The PREMIER study: A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum. 2006 Jan;54(1):26–37.
- Kavanaugh A, Fleischmann RM, Emery P, et al. Clinical, functional and radiographic consequences of achieving stable low disease activity and remission with adalimumab plus methotrexate or methotrexate alone in early rheumatoid arthritis: 26-week results from the randomised, controlled OPTIMA study. Ann Rheum Dis. 2013 Jan;72(1):64–71.