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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.
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
Post-Hoc Analysis
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, 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].”