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MEDICAL FRONTIERS - 12th Annual European Congress of Rheumatology (EULAR)

London, UK / May 25-28, 2011

London - Relative to disease-modifying antirheumatic drugs (DMARDs), the targeted biologic agents have demonstrated remarkable efficacy, often achieving full restoration of function in patients with refractory and disabling symptoms. It has been predicted that the level of clinical remission achieved with these agents will reduce the risk of long-term disability by slowing or even halting progression. New data reinforce that hypothesis, associating a combination of a tumour necrosis factor inhibitor (TNF-I) and a DMARD with radiologic non-progression. The results are preliminary but they are consistent with the highly effective anti-inflammatory effect that permits biologics to preserve remission over periods that now extend beyond 5 years with the initially introduced TNF-I drugs. Biologic registries now collecting data from participating centres suggest that biologics have a predictable safety profile and remain efficacious in the long term.

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

Increasing confidence about where biologics fit in the management of rheumatoid arthritis (RA) has been created by the very large datasets with the oldest tumour necrosis factor inhibitors (TNF-Is), which include the TNF-soluble receptor fusion protein etanercept and the TNF-a monoclonal antibody (MAb) infliximab. There are also expanding datasets with newer TNF-I agents, such as certolizumab and golimumab, as well as with the inhibitor of the interleukin-6 (IL-6) receptor tocilizumab. These agents not only produce clinical remissions in patients with an inadequate response to disease-modifying antirheumatic drugs (DMARDs), but they also promise to change the long-term outcome. New data with etanercept provide an example of the evidence behind this hypothesis.

Emphasis on Controlling Inflammation and Obtaining Durable Remission

According to Prof. Josef S. Smolen, Medical University of Vienna, Austria, “Per the recent EULAR recommendations, treatment should result in the lowest disease state achievable. Here, we report good symptom control and radiologic non-progression in 82% of patients with an inadequate response to methotrexate [MTX] alone after a biologic was added.” Presenting results at EULAR on 834 patients participating in the open-label PRESERVE study, Prof. Smolen reported that all patients had been insufficiently controlled on MTX at enrolment. With the addition of etanercept, indicators of disease activity, including the disease activity score (DAS)28, simplified disease activity index (SDAI) and health assessment questionnaire (HAQ) fell by 46% to 65% relative to baseline by 36 weeks.

Similar data have been reported with other biologics, such as infliximab in combination with MTX, but not all studies have included a radiographic follow-up. Due to the increasing emphasis on controlling the underlying disease process, particularly inflammation, there is growing interest in looking beyond symptoms to markers of complete or near-complete disease quiescence. While DMARDs remain the first-line therapy in initial disease, the 2010 EULAR recommendations referred to by Prof. Smolen now suggest that therapy should be adjusted at frequent intervals in order to achieve remission. The goal is to achieve more durable remissions with the least likelihood of progressive joint damage.

These adjustments can and should include a switch from one TNF-I to another, according to data from STURE (Stockholm TNF Follow-up Registry). In this registry, 670 of 850 patients who had previously failed a TNF-I were switched to another biologic. By the end of 6 months, there were statistically significant improvements in measures of disease activity such as DAS28, regardless of the agent to which the patient was switched. Of these switches, moving from a TNF-a MAb to etanercept provided better control at 6 months than switching from one TNF-a MAb to another on the basis of the rates of good response (29.4% vs. 20.9%; P=0.009) (Figure 1). However, the main point of this study was that “patients having failed anti-TNF therapy do benefit from switching to other TNF-Is,” according to senior author Dr. Katerina Chatzidionysiou, Unit for Clinical Therapy Research, Inflammatory Diseases, Karolinska Institute, Stockholm, Sweden.

Evaluation of Biologic Treatment Duration and Serious Infections

Data from biologic registries such as STURE provided the basis for numerous presentations at the 2011 EULAR meeting on the relative efficacy and safety of these drugs. Of 2 of the largest, one compared TNF-I agents for serious infections while another compared them for longevity on treatment. As registry data are collected in a non-randomized or blinded fashion, the comparisons identify potential differences that need verification in prospective and randomized studies, but the observed differences do encourage the hypothesis that TNF-I drugs may not be interchangeable.

In the analysis of infections undertaken with data from the DREAM (Dutch Rheumatoid Arthritis Monitoring) registry, the agents compared were adalimumab, infliximab and etanercept. On the basis of rates/100 patient-years of follow-up, the rates were 3.31 for adalimumab, 4.13 for infliximab and 2.14 for etanercept, according to lead author Dr. Sanne van Dartel, Radboud University, Nijmegen, The Netherlands. Although the rates between the TNF-a MAbs did not differ statistically, the lower infection rate on etanercept translated into a hazard ratio reduction of approximately 40% vs. either adalimumab or infliximab after adjusting for a variety of factors, includi
RD use (Figure 2).

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The comparison of the anti-TNF therapies for long-term survival on therapy was based on data drawn from the GISEA (Gruppo Italiano per lo Studio dell’Early Arthritis) registry. The registry followed 324 patients who started adalimumab, 218 patients who started infliximab and 311 patients who started etanercept in the years 2003-2004. At baseline, there were no differences in these groups for a large array of variables, such as age, disease duration, DAS28 or pain, according to senior author Dr. Florenzo Iannone, Rheumatology Unit, Department of Internal Medicine and Public Health, University of Bari, Italy. At 4 years, the survival rates were 36.4% on adalimumab, 37.6% on infliximab and 51.4% on etanercept. Again, although the difference between the TNF-a MAbs was not statistically significant, the longer survival on etanercept was significantly different from both (P<0.0001). Use of concomitant DMARDs, particularly MTX, predicted longer survival for any of the TNF-I agents.

It is perhaps relevant that etanercept, which blocks TNF through competitive binding, was significantly different from adalimumab and infliximab, MAbs that block the TNF receptor. The data from these observational studies suggest that the mechanism of TNF inhibition may be important for significant outcomes, although prospective studies are needed.

The speculation that some differences may relate to the low relative immunogenicity of etanercept has also never been definitively tested. As a result, there is no consensus about first-line use of one biologic over another in the treatment of RA. Rather, the available data indicate that all of the currently approved agents are effective and provide an acceptable benefit:risk ratio in appropriately selected RA patients.

When to Introduce a Biologic: Evidence from Ankylosing Spondylitis and Psoriatic Arthritis Studies

One of the consistent controversies regarding the use of biologics for any of the arthritides is how soon to introduce these agents when DMARDs are not providing control. This is a complex question influenced by a variety of issues, including cost. The decisions may be best made on a patient-specific basis, but the progressive types of arthritis, such as ankylosing spondylitis (AS), may provide a particularly good framework to pose this question because of the high risk of disability. Several institutions are evaluating early introduction of biologics on the premise that this approach may reduce the risk of disability relative to late intervention when joint damage is irreversible.

“When we compared our cohort of relatively young individuals started on biologics relatively early after their diagnosis, response rates were higher than those previously reported in clinical studies or the British Society of Rheumatology (BSR) Biologics Database,” reported Dr. Jon Rees, Defence Medical Rehabilitation Centre, Headley Court, Surrey, UK. Providing data on just 35 AS patients evaluated at his institution and then comparing outcomes to other databases in which biologics were typically started later in the disease course, Dr. Rees reported, “Our data support the premise that early initiation of anti-TNF therapy should be encouraged.”

In this experience, the average age of the AS patients when initiated on either adalimumab or etanercept, the 2 biologics employed at Dr. Rees’s centre, was 35, which is about 5 to 7 years younger than the 3 frequently cited trials with biologics in AS or in the BSR Biologics Database. In addition, the average disease duration was 7 years, which was 1 to 6 years shorter than that of the other datasets, which evaluate adalimumab, etanercept and infliximab. Although the pre-treatment Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) scores were slightly higher in the 35 patients treated at Dr. Rees’s centre relative to the trial groups, the number of patients achieving BASDAI 50 was substantially higher (77% vs. 51% to 57%). The one patient with a significant side effect, which was an injection-site reaction, was switched successfully to an alternative biologic.

“As a health centre for a military population, our patients tend to be younger than those seen at a typical clinic, but these data indicate that better response is achieved with biologics when patients are treated younger and earlier in their disease,” Dr. Rees told EULAR delegates. He indicated that the potential for early treatment to improve long-term outcome would be followed.

However, there are emerging data indicating that greater improvement in joint mobility in AS patients does improve physical function, which is a quantifiable benefit for introducing biologics at a relatively early stage. New data were derived from the ASCEND study, which was a double-blind trial in AS patients that associated etanercept with a greater symptom improvement at 16 weeks than sulfasalazine (P<0.0001) (Braun et al. Arthritis Rheum 2011;63(6):1543-51). As reported here at EULAR, results ind
tion between improvement in spinal mobility and physical function.

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“For each improvement in Bath AS Metrology Index [BASMI], the estimated improvement in Bath AS Functional Index [BASFI] was 4.01 (P<0.0001),” reported Dr. Joachim Sieper, Head of Rheumatology, Charité Hospital, Berlin, Germany. While the advantage of the biologic was observed as early as week 2 of treatment (Figure 3), there was incremental improvement through the course of the 16-week trial, but the biologic treatment resulted in “greater improvement in function than sulfasalazine, even after controlling for the relative advantage in the improvement in mobility.”

The principle of early treatment in those with the most severe inflammatory disorders appears to carry over to individuals with psoriatic arthritis (PsA) when compared to psoriasis alone. Several of the biologics approved for use in joint diseases are also approved for psoriasis, including several TNF-I agents. The 273-patient PRISTINE (Psoriasis Study to Assess Efficacy and Safety in Subjects Taking Etanercept 50 mg Once Weekly and Twice Weekly with Adjunct Therapy) trial included 84 psoriasis patients with a secondary diagnosis of PsA with greater measures of disease burden, including fatigue, sleep, work productivity and quality of life. Not surprisingly, the relief of these measures of disease bu
ductivity, with the biologic etanercept was even more profound in this group than in those with psoriasis alone.

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“After 24 weeks on therapy, both groups improved significantly, but the relative improvements were greater in the arthritis group,” reported Dr. Nopadon Noppakun, Division of Dermatology, Department of Medicine, Chulalongkorn University, Bangkok, Thailand (Figure 4). Although not all of the relative improvements in the disease burden measures reached statistical significance, several such as fatigue (P=0.014) and 5-dimensional quality-of-life score (P=0.021) did, and all of the measures improved 50% to 100% in the arthritis group from baseline. The study is part of a large body of data that draws attention to the greater potential advantages of early use of biologics in those individuals with the most severe disease.

Treatment vs. Disability Costs

“The early use of biologics is something that always initiates discussion of costs, but we need to consider this issue carefully, particularly in populations when uncontrolled disease produces disability,” stated Dr. Tom W.J. Huizinga, Head, Department of Rheumatology, Leiden University Medical Center, The Netherlands. He cited data from the COMET (Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis) study which found that 24% of patients treated with MTX alone had stopped working. While this is an important cost that should be part of calculations, Dr. Huizinga expressed greater concern about the trajectory of disability in patients with RA or other inflammatory joint diseases.

“If you plot damage over time, the slope of the curve in patients treated with biologics is lower. This provides the evidence that treating patients early is going to end in less cumulative disability,” Dr. Huizinga explained to delegates. He indicated that this is the orientation that is being adopted by many experts in the field. Although some individuals, particularly those with mild disease, can achieve acceptable and persistent control on DMARDs, delaying therapy in those who are destined for irreversible progression may no longer make sense based on the established safety and efficacy of available biologics.

Summary

Biologics have changed the trajectory of progressive, inflammatory joint diseases by controlling the underlying pathophysiological process. Evidence that these agents can prevent progression on a radiological basis has contributed to interest in earlier use with the intent of preventing or reducing disability. The data demonstrating that biologics are not interchangeable establish opportunities to switch therapies to improve response or to avoid adverse events. While treatment costs are an issue, early use of biologics in patients with the most severe disease and the greatest likelihood of progression has the potential to be highly effective in improving patient health outcomes and controlling resource costs.