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PRIORITY PRESS - 12th Annual European Congress of Rheumatology (EULAR)

London, UK / May 25-28, 2011

Disease modifying antirheumatic drugs (DMARDs) are an appropriate first-line rheumatoid arthritis (RA) therapy. They are effective in a substantial proportion of patients with mild-to-moderate disease, but more effective agents should be started or introduced quickly in cases of inadequate response. The revised EULAR guidelines have provided a rationale for tight and early control even in countries with health care systems that attempt strict regulation of the order of RA therapies. This guideline-recommended approach is based on the risk of irreversible joint damage and treatment-resistant disease due to delay of effective treatment.

Clinical Response at 3 Months Highly Predictive of 1-year Response

The 2010 EULAR guidelines state that the treatment target should be preferably reached within 3 months but attained at a maximum of 6 months. Although several studies testing the concept of tight control have required a treatment switch at 3 months in the absence of a full remission, this may not be realistic in many areas of the world that require multiple DMARD failures before permitting biologics, according to Dr. Peter Taylor, Kennedy Institute of Rheumatology, Imperial College, London, UK. “In my practice, I take a middle position. If a patient has achieved a good partial response at 3 months, then I wait until 6 months before changing the therapy. However, If there is very little or no improvement by 3 months, then I modify therapy at that time,” he told EULAR delegates.

Dr. Taylor noted that data derived from such studies as RAPID 1 (Rheumatoid Arthritis Prevention of Structural Damage) which evaluated 783 patients receiving 1 of 2 doses of certolizumab with methotrexate (MTX), have demonstrated that a clinical response at 3 months was highly predictive of response at 1 year.

The response at 3 months appears relevant to biologics as well as DMARDs. As an example, Dr. Taylor cited the data from the DREAM (Dutch Rheumatoid Arthritis Monitoring) Registry, which is tracking response to all biologics in The Netherlands. In that registry, a lower response in disease activity score (DAS) 28 at 3 months predicted higher failure rates at 6 months. Specifically, for those with a lower DAS28 improvement but still =0.6, the rate of unsuccessful treatment at 6 months was 17%. Dr. Taylor suggested a poor partial response at 3 months “may provide the best trade-off” to conserve expensive resources “by preventing prolonged administration of treatment to those who will not ultimately respond.”

Modifying Therapy: REALISTIC Data

By modifying therapy, the approach at 3 months can include the intensification of DMARD therapy by increasing the dose or employing a combination, or it can mean switching to or introducing a biologic. In new data from the phase IIIb REALISTIC (RA Evaluation in Subjects receiving TNF Inhibitor Certolizumab Pegol) trial presented at EULAR, 1063 patients with active RA and an inadequate response were randomized in a 4:1 ratio to certolizumab pegol 400 mg at weeks 0, 2 and 4 followed by 200 mg every 2 weeks or to a placebo injection every 2 weeks. All patients were permitted to remain on DMARD therapy.

The primary end point of ACR20 was reached by 51.1% of those receiving the biologic vs. 25.9% of those in the control group (P<0.001). The difference in the secondary end point of ACR50 (26.6% vs. 9.9%; P<0.001) was of similar magnitude favouring the addition of the biologic. When stratified by previous exposure to a tumour necrosis alpha (TNF-a) inhibitor, the addition of certolizumab remained substantial in those with prior exposure (47.2% vs. 27.5%; P<0.01) and those with no prior exposure (53.5% vs. 25.0%; P<0.001). The response rates relative to control patients were also similar regardless of the number of TNF-a inhibitor prior exposures and type or number of concomitant DMARDs. The adverse event and serious adverse event rates were comparable across the study arms.

Perhaps most importantly, early control of RA by any means, including rapid introduction of a TNF-a inhibitor and a DMARD, appears to lead to better long-term outcome. In new data from the phase III PREMIER (Patients With Early Rheumatoid Arthritis) study which randomized RA patients to the TNF-a adalimumab, MTX or in combination, patients initially randomized to the combination and followed for 8 years in an open-label extension had greater comprehensive remission (28.7%) than those initially randomized to either adalimumab alone (11.8%) or MTX alone (16.9%).

“There were fewer patients in the combination group who were radiographic progressors at year 8 [56.3% vs. 73.0% and 72.9% for ADA and MTX monotherapy, respectively]. Similarly, initial randomization to combination therapy was associated with a greater proportion of patients achieving high levels of disease control [DAS28 <2.6: 71.3%, 49.5%, 58.4%, respectively],” reported Dr. Ferdinand Breedveld, Division of Rheumatology, Leiden University Medical Center, The Netherlands.

When to Consider a Biologic

While the revised 2010 EULAR guidelines encourage regular therapy modifications to rapidly achieve a remission, one of the unanswered questions is when or whether biologics can be considered in patients with low to moderate disease activity. In new data from CERTAIN (Certolizumab Pegol in the Treatment of RA: Remission Induction and Maintenance in Patients with Low Disease Activity), 194 patients were randomized to the biologic or placebo. Again, patients could continue DMARD therapy. The average duration of RA in this population was about 4.5 years.

“More than twice as many certolizumab patients had a remission [defined as CDAI =2.8] at both weeks 20 and 24 relative to placebo,” Prof. Josef S. Smolen, Medical University of Vienna, Austria, told EULAR delegates. Equally important, fewer actively-treated patients developed moderate or high disease activity at week 24 (37% vs. 70.4%; P<0.01). Treatment was well tolerated. Serious side effects were not significantly different on the biologic vs. placebo (5.2% vs. 7.1%).

“In RA patients with longstanding low to moderate disease activity, the addition of certolizumab to non-biologic DMARDs increased rates of remission and inhibited progression,” stated Dr. Smolen, indicating that this might be a reasonable approach in patients with persistent symptoms.

Reaching Specific Goals: The Treat-to-Target Approach

While tight disease control is being recommended more actively in RA, the concept of treat-to-target is also being promoted to capture the concept of regular treatment adjustments to reach specific goals defined collaboratively between the physician and the patient. “Treat to target is the concept of identifying an agreed-upon therapeutic goal and adjusting therapy on a regular basis with a metric that is meaningful to both the patient and the clinician,” explained Dr. Maya Buch, Senior Lecturer in Rheumatology, University of Leeds, UK, during the EULAR scientific sessions.

Dr. Buch cited several studies, such as TICORA (Effect of a Treatment Strategy of Tight Control for Rheumatoid Arthritis), that have found that this kind of intensive management improves outcomes. In TICORA, 111 RA patients were randomly allocated to either intensive management or routine care (Grigor et al. Lancet 2004; 364:263-9).

In that study, the likelihood of having a good response or being in remission was 5.8 times greater (P<0.0001) in the intensive group, and a cost analysis found that the intensive therapy was actually more cost-effective. “Treating to target depends on frequent monitoring, but it is associated with better outcomes, and patients typically prefer this approach,” she remarked. She was able to cite a survey newly released at EULAR in which 87% of RA patients agreed that establishing personal treatment targets would have a positive impact on their disease management.

Summary

The priority of patients consulting a physician about RA is an improvement in symptoms, but the standard of care is control of disease, which is a more encompassing concept. By frequently adjusting therapy at regular intervals while employing strict measures of control of symptoms and inflammation, there is an opportunity to slow or halt the progression of disease that will eventually include irreversible joint damage. There is now strong support for the concepts of tight control and treating to target in the effort to put to work the ever-expanding array of treatment options that can suppress disease activity at levels that were not previously possible.