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7th Annual European Congress of Rheumatology (EULAR)

Amsterdam, The Netherlands / June 21-24, 2006

There is a growing consensus that remission in rheumatoid arthritis (RA) now includes both symptom control and prevention of structural damage. Achieving both goals is particularly challenging in patients with rapidly progressing disease. While patients with mild or slowly progressive RA appear to be adequately managed with NSAIDs and/or disease-modifying antirheumatic drugs (DMARDs), rheumatologists participating in a survey singled out patients with rapidly progressing RA as a group that requires a distinct management strategy. Particularly for this subgroup, many clinicians currently reserve therapies targeted at tumour necrosis factor alpha (TNFa), a pro-inflammatory cytokine that drives a cascade of events promoting joint destruction, but there were substantial differences when these agents are considered.

According to Dr. Ian B. McInnes, Centre for Rheumatic Diseases, University of Glasgow, UK, “Historically, we have waited until the patient is doing poorly before adjusting therapy, but there is now a movement to try to recognize active inflammation early on and introduce effective therapy before the joint destruction occurs. If we wait to introduce the most effective therapies for control of inflammation until after there is already structural damage, then we miss the opportunity to protect against this disability.”

Currently, strategies differ, according to the six-country survey presented by Dr. McInnes. When asked what action they would take in a patient who has been on methotrexate therapy for at least a year and is now exhibiting significant progression of their disease, rheumatologists in Spain, Italy and the UK reported that they were likely to switch the patient to another DMARD. In Canada and Germany, physicians were more likely to adjust the dose of methotrexate. Rheumatologists in France and Italy were the most likely to start a TNFa blocking agent. Dr. McInnes explained that the results of this survey just completed in May 2006 included 458 rheumatologists and revealed that 97% consider rapid progressors as a distinct group in the RA population. The majority—88% of the total survey respondents—reported that they manage this group differently from other RA patients.

Progression of RA is unpredictable. Some individuals have symptomatic disease for years with no significant structural damage to the joint, others demonstrate rapidly progressive RA at the onset of disease, while still others experience periodic episodes of intense joint inflammation followed by periods of relative quiescence. Eventually, the majority of RA patients experience significant joint destruction as a result of rapid or sustained episodes of progressive disease, with published estimates ranging from 60% to 90%. Adequate therapy was once defined as acceptable control of symptoms, but the high risk of cumulative joint destruction has changed treatment goals to include protection against both symptoms and structural damage to the joint.

The problem in adjusting therapies, including introducing TNFa inhibitors to control rapidly progressing RA patients, is defining this subgroup. According to the survey, there are several methods now employed at different centres to identify the rapidly progressing patient, varying from use of such clinical markers as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) to counting tender or swollen joints or evaluating X-ray progression data. The survey revealed that less than one third of rheumatologists routinely employ magnetic resonance imaging (MRI) to identify these patients, although again, there was considerable variability among countries.

“The context in RA is inflammation. Joint inflammation leads to radiographic progression and the degree of radiographic damage directly correlates with the level of physical function. Furthermore, persistent joint swelling during therapy is associated with greater radiographic progression of joint damage, demonstrating the need to control inflammation,” explained Dr. McInnes.

New Findings with Combination Therapy

While TNFa inhibitors have been recognized as being among the most effective agents for controlling inflammation and have been widely used in patients with advanced RA, there is debate about when they should be introduced to help reduce risk of long-term disability. According to Dr. Paul Emery, Clinical Director of Rheumatology, Leeds Teaching Hospitals Trust, Professor of Rheumatology and Head, Academic Unit of Musculoskeletal Disease, Leeds University, UK, these agents are being offered relatively quickly in the US when patients continue to demonstrate significant inflammation despite treatment on sequential or combination DMARDs. He suggested that recent work at his own institution supports early treatment. In a double-blind trial published last year (Quinn et al. Arthritis Rheum 2005;52(1):27-35), there was objective evidence of protection from joint destruction at the end of 12 months. “In this study, patients with early and poor-prognosis RA, who were randomized to receive infliximab along with methotrexate, had less radiological progression than those receiving methotrexate alone, and this corresponded with a variety of signs that inflammation was being suppressed, including a normalization of CRP,” noted Dr. Emery. He cited previous evidence that high CRP and ESR levels have been associated with greater radiographic progression in patients on an active therapy such as methotrexate, and emphasized that the results are consistent with the conclusion that rapidly progressing RA may be considered for initial treatment with combination infliximab/methotrexate.

The 20 patients in this study had symptoms for fewer than 12 months at enrolment. They were randomized to methotrexate/infliximab or methotrexate alone. At 54 weeks, 80% of those in the combination group vs. 40% of those randomized to methotrexate and placebo achieved a 50% improvement in the American College of Rheumatology criteria (ACR50) (Figure 1). An ACR70 improvement was achieved in 70% and 30%, respectively (P<0.05 for all comparisons). More importantly from the perspective of long-term outcome, MRI scores were significantly better with no new erosions observed on combination treatment vs. methotrexate alone. CRP levels were normalized in the combination group within 2 weeks of initiating therapy.

Figure 1. ACR Response at 54 Weeks

TNFa is an appropriate target of the inflammatory cascade because it appears to play a central role in upregulating other inflammatory mediators. Once the cascade has been initiated, it triggers release of adhesion molecules that bring inflammatory cells into the joint and produce release of matrix metalloproteinases, such as collagenase and gelatinase, which are involved in enzymatic digestion of cartilage. Evidence that inhibition of TNFa plays a central role in an anti-inflammatory effect and protection from tissue damage was derived from a substudy of non-responder patients (Smolen et al. Arthritis Rheum 2005;52(4):1020-30). In this study, patients who failed to achieve an ACR20 at week 54 still demonstrated inhibition of structural damage that was statistically significant compared with patients who received methotrexate plus placebo (P<0.05 to P<0.001).

“TNFa is clearly one of the main pro-inflammatory cytokines responsible for inflammation and joint destruction in RA. In the clinical studies with TNFa inhibitors, we have seen a correlation between reductions in joint inflammation and a reduction in radiographic progression of joint damage, which, in turn, results in improved physical functioning. Anti-TNFa therapy may therefore present an opportunity to change the disease course in RA,” indicated Dr. Emery. “I think we should be asking ourselves whether we should be using these drugs to keep patients well rather than saving them for end-stage disease.”

Protection Against Radiographic Progression

The three TNFa inhibitors approved for use in Canada for RA are infliximab, etanercept and adalimumab. Each has been associated with protection against radiographic progression in controlled trials. In fact, an extension of TEMPO (Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes) has contributed to evidence that early use of TNFa inhibitors is likely to improve outcome when compared to delayed use. In the initial study, 628 patients were randomized to etanercept monotherapy, methotrexate monotherapy or the combination. Although this trial was not conducted in rapid progressors, which may be a more difficult population to control, the arm that received both etanercept and methotrexate did better than the arm that received methotrexate alone. In the open-label extension trial with 227 patients, both monotherapy groups were placed on combination therapy, but outcomes were not as good with first-line combination therapy.

BeST Trial: An Update

In evaluating TNFa inhibitors, perhaps the primary area of interest is at the level of joint destruction. While symptom management is important, the major role for these therapies is to block disease progression to thwart future disability. Such issues as relative TNFa inhibition and control of the inflammatory cascade may translate into different relative protection against structural damage in the joint. Another area of interest may be the relative ability of these agents to induce sustained remission even after therapy has been discontinued. In new three-year data from the BeST trial, which evaluated four treatment strategies in early RA (<2 years of symptoms), 55% of patients on the infliximab/methotrexate arm have discontinued infliximab. Although a small proportion did so because of insufficient disease control, most had achieved adequate reduction in inflammation to continue on a DMARD or another oral therapy to maintain control of their RA. However, a sizeable minority had stopped therapy altogether (Figure 2).

Figure 2. BeST Study:
rom status at 2 years

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“Remarkably, 27% of the patients who could permanently discontinue infliximab stopped all anti-rheumatic drugs and remained in clinical remission,” Dr. A. Egon Van der Bijl, Department of Rheumatology, Leiden University Medical Centre, The Netherlands, told the audience. Although he did not reject the possibility that some of these patients may actually be now free of RA, he added, “We are now following these patients to monitor the duration of remission.”

Early initiation of TNFa inhibitors in patients at greatest risk of structural damage to the joint is attractive, but cost has been an issue in determining which patients to treat. Several experts, including Dr. Emery, believe that better metrics are needed to isolate patients who are rapid progressors and to distinguish them from patients who are having a more limited disease flare, as radiographs are probably not sufficient for monitoring the disease course. Although there is no current consensus on which combination of clinical and laboratory markers are to be used to better classify patients, he suggested that they are likely to be developed.

“Traditional radiographs only reveal gross anatomical changes, and it usually takes considerable time before relevant changes are observable. Consequently, to avoid delays in predicting and identifying rapidly progressing patients, the use of more sensitive, rapid and reliable assessments of disease progression is necessary,” Dr. Emery commented. “Many potential predictors of structural damage have been identified, most of which are based on clinical signs of disease activity and/or inflammation and radiographic damage.”

Summary

Patients with rapid progression of RA defined by persistent and intense joint inflammation leading to structural damage are candidates for more aggressive therapy, including TNFa inhibitors. While the most potent anti-inflammatory therapies have typically been reserved for patients with advanced disease, earlier use has the potential to prevent joint damage and permanent disability. Although the vast majority of rheumatologists consider rapid progressors a distinct clinical subgroup which they manage differently, there is no general consensus about how these are best identified. With the BeSt study, which is expected to run for five years, it is hoped that a consensus will be derived for early management of disease and how initial treatment choices will affect long-term radiographic scores and the future severity of the disease.

Question and Answers

This question-and-answer session is based on an interview with Dr. Paul Emery, Clinical Director of Rheumatology, Leeds Teaching Hospitals Trust, Professor of Rheumatology and Head, Academic Unit of Musculoskeletal Disease, Leeds University, UK, during the scientific sessions.

Q: If evidence shows that joint destruction can be reduced with TNFa inhibitors, what prevents a more widespread use?

A: Cost. We are envious of clinicians in the US who seem to be able to get authorization to use these earlier, but here in Europe, we are in a very cost-sensitive environment. If you can treat patients early to prevent disability, it may be more cost-effective than treating late after the joint is damaged, particularly if the biologic can be discontinued.

Q: How long should a patient considered a candidate for TNFa inhibitors be kept on therapy?

A: That is an unresolved issue. In the US, they tend to taper therapy after a period in which the inflammation has been controlled, but I think if we had good reliable markers, we may be able to just withdraw therapy without tapering, with the hope that at least some patients will remain in remission.

Q: Are patients generally treated with a DMARD and a TNFa inhibitor?

A: Our best data is with methotrexate and a TNFa inhibitor. In many cases, we will want to maintain patients on methotrexate after withdrawing the TNFa inhibitor.

Q: Have the TNFa inhibitors changed the goals of therapy?

A: We are looking at remission in a different way. What patients want is immediate control of their symptoms, but we should also be worrying about the long-term integrity of the joint. I think with more potent control of inflammation, we have an opportunity to improve outcomes.