Rapid Treatment Response in Rheumatoid Arthritis: A Valuable Indicator of Reduced Risk of Joint Damage

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

PRIORITY PRESS - 75th Annual Meeting of the American College of Rheumatology

Chicago, Illinois / November 5-9, 2011

Chief Medical Editor: Dr. Léna Coïc, Montréal, Quebec

There is substantial evidence that earlier response to rheumatoid arthritis (RA) treatment correlates with better long-term outcomes regardless of the end point employed to measure control. TNF inhibitors and other types of biologics typically offer faster and more complete response than disease-modifying antirheumatic drugs (DMARDs); however, the relationship between early response and better long-term outcome appears to be independent of therapy.

“It is not only the target you reach but the time it takes to reach that target,” stated Dr. Edward Keystone, Director, Rebecca MacDonald Centre for Arthritis and Autoimmune Diseases, Mount Sinai Hospital, Toronto, Ontario. One of the leaders in exploring the impact of speed of disease control on outcome, he reported that trials with DMARDs, such as the CAMERA study with methotrexate (MTX) (Ann Rheum Dis 2011;70:1099-103), as well as new data with biologics support the same premise. This has immediate significance for clinical decisions, including switch strategies, designed to provide patients with protection from suboptimal disease control.


The RAPID1 Trial: Support for Early Control


The newest and perhaps most important support for the critical role of early control was evidence presented by Dr. Keystone that linked response at 12 weeks with risk of joint structural damage at 52 weeks. The data were drawn from the RAPID1 trial, which randomized moderate-to-severe RA patients to receive MTX with either the TNF inhibitor certolizumab pegol or placebo. The control at 12 weeks was assessed with RAPID3 (Routine Assessment of Patient Index Data 3) and EULAR Disease Activity Score (DAS28 [ESR]) response criteria. It was correlated with modified Total Sharp Score (mTSS) at 52 weeks.

When good or moderate control was compared to poor control with either set of criteria, the differences in mTSS scores were substantial. Of patients in the MTX/certolizumab arm who achieved good or moderate RAPID3 response at 12 weeks, 79% were non-progressors at week 52; for poor responders, 70% remained non-progressors at 52 weeks; of patient in the MTX/placebo arm with poor response, 51% were non-progressors. Very similar percentages were produced by using the EULAR DAS28 (ESR) criteria.

In RAPID1, 77.6% and 66.8% of those in the certolizumab arm achieved a EULAR DAS28 (ESR) and RAPID3 response, respectively, at 12 weeks vs. 29.1% and 23.5% receiving MTX alone. According to Dr. Keystone, these were very good rates of early response relative to previously published studies evaluating other biologics, including other TNF inhibitors. However, he stressed that the mTSS data are consistent with a much larger set of data that have correlated ACR20 response rates at 12 weeks with likelihood of disease control at 52 weeks.

“How early can you say that non-response predicts a bad outcome? We now can show that a response by 12 weeks with many different types of criteria predicts who will have an adequate response at 52 weeks,” Dr. Keystone told ACR delegates. He indicated that the consistency of this finding suggests that it could be used to guide treatment.


Remission at the Molecular Level


The importance of early response is just one of the concepts changing RA treatment goals. While recent guidelines have promoted treating to target and tight control, these principles are being driven by the opportunity to achieve disease control at a molecular level. Prior to biologics, treatment was largely based on control of acute symptoms. Recurrent flares were a signal to intensify treatment, but biologics have created the opportunity for a more profound level of disease control that includes avoiding disease flares, now understood to represent a manifestation of persistent inflammatory activity.

“If you have a flare, you are not in remission,” stated Prof. Iain McInnes, Head, Division of Immunology, Infection, and Inflammation, University of Glasgow, UK. Based on the experience with biologics, he reported that clinical researchers are starting to explore the concept of remission at the molecular level. Although he cautioned that it might be for long-term, he maintained that “this is really the goal we want to achieve.” According to Prof. McInnes, reaching this level of control is likely to depend on bioinformatics, which permits several interactive and redundant disease pathways to be measured at once, but biologics “have made a fantastic difference” not just in controlling RA but moving toward disease control at the level of fundamental disease processes.

In this regard, Dr. Vivian Bykerk, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, agreed that the introduction of biologics has created more rigorous definitions of disease control and that even occasional flares are an ominous sign of suboptimal treatment. Like Prof. McInnes, she contended that “patients who flare frequently are probably not in remission,” based on the likelihood that the flares are driven by ongoing inflammatory activity. She noted that patients who flare are more likely to have radiological progression than those without flares, even when disease activity scores are otherwise similar.


Disease Suppression Beyond Symptom Control


The concept that there is a level of fundamental control of RA that extends beyond suppression of symptoms is being increasingly embraced by experts looking to clinical trials to compare agents on this basis. In particular, trials with biologics are increasingly looking to rigorous definitions of long-term benefit.

For example, the phase III SCAN study, with the Janus kinase inhibitor tofacitinib, included structural damage at 24 months as an outcome separate from disease control. In this study, 797 patients with active RA and an inadequate response to MTX were randomized to 1 of 2 doses of this agent or placebo. According to Prof. Désirée van der Heijde, Department of Rheumatology, University of Leiden, The Netherlands, the interim 1-year mTSS score results showed that both tofacitinib doses were superior (P<0.05) to placebo. “Not only did a higher proportion of placebo patients have progression, a higher proportion had severe progression,” she reported.

While overall long-term response is important, the role of early response as a predictor of likelihood of fundamental disease suppression, including protection from structural damage, is being pursued. In new 16-week extension data from the REALISTIC study, it was noted that those switched in the double-blind phase from placebo/DMARD to certolizumab/DMARD in the extension phase rapidly achieved a level of response near that of those originally initiated on the biologic plus a DMARD. This rapid response was also achieved in a group of patients who had failed previous TNF inhibitors.?“These results are encouraging because they show that the rapid improvement in disease activity as a result of the clinical response to certolizumab is sustained in patients who failed on previous therapy,” reported Prof. Maxime Dougados, Cochin Hospital, René Descartes University, Paris, France.

At the end of 12 weeks in the double-blind REALISTIC study, patients initially randomized to certolizumab or placebo with a DMARD were invited to participate in an open-label extension phase. While the TNF inhibitor was superior to DMARD alone for all clinical end points at 12 weeks, there was no significant difference in outcome scores 16 weeks later once placebo patients went on active therapy. In the context of evidence that rapid response is an important predictor of long-term benefit, these data contribute to the evidence that biologics have the potential to change the natural history of RA.




The concepts of rapid control and treat-to-target are assuming a new dimension on the basis that these appear to have profound effects on disease activity when achieved with biologics. There are now substantial data that the speed of response has prognostic implications and may be useful for selecting an initial agent or in guiding switch strategies when early response is poor. By seeking early, complete responses and treating to a target that includes suppression of flares, the goal is to halt the fundamental molecular processes that drive RA. Biologics are credited with making this approach viable.

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