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JOURNAL CLUB 2008 - Rheumatology

Editorial Overview:

Cornelia F. Allaart, MD, PhD

Associate Professor, Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands

The newly published data from the BeSt (Behandel Strategieën) study, which validated the importance of closely monitoring rheumatoid arthritis (RA) disease activity to improve outcome, can be considered immediately relevant to clinical care. When therapy was adjusted to maintain tight control, 80% of patients sustained low levels of disease activity over a follow-up that now exceeds four years. A substantial minority, up to almost one in five of the patients who started treatment with methotrexate+infliximab, has now achieved a drug-free complete remission. The greatest protection from radiological progression was observed in those initiated on combination methotrexate with prednisone or with infliximab. BeSt is the first large study to confirm that drug discontinuation is a realistic option for patients optimally treated early after onset of RA.

The Need for Early and Intensive Therapy

The natural history of RA is one of progression with a high risk of irreversible damage to affected joints. Prior to BeSt results, the early use of disease-modifying antirheumatic drugs (DMARDs) had already been established as a strategy for improving long-term outcome. The BeSt trial results build on this previous paradigm. The findings showed that disease progression can be contained and sometimes driven into a sustained remission by regularly monitoring RA and adjusting therapy according to disease activity. Although the most effective strategy for preventing joint damage at the end of four years was an initial combination of the DMARD methotrexate with either prednisone or with the tumour necrosis factor alpha (TNF-a) inhibitor infliximab, the most important message from BeSt is that early, intensive disease activity-driven therapy can change the course of RA.

In BeSt, a randomized multicentre study conducted in The Netherlands, four treatment strategies were compared in 508 patients. Initial therapy for two of the arms was a single agent; the other two groups were initiated on a combination. Treatments in all four arms were adjusted, including stepping up to combination therapy in those initiated on monotherapy if needed to achieve a disease activity score (DAS) of =2.4.

The four-year results are the latest in a series of publications that corroborate the principle that combination therapy is more effective than monotherapy for early functional improvements and for inhibiting objective joint damage (Van Der Kooij et al. Ann Rheum Dis Online First: 28 July 2008). When results at four years are compared to those at two years (Goekoop-Ruiterman et al. Ann Intern Med 2007; 146:406-15), the proportion with disease control and disease remission were remarkably similar, confirming that the early benefits are sustained long-term. Again, initial combination therapy was the superior strategy at both two and four years.

DAS-guided Treatment

The DAS-guided treatment protocol was a key design element of the BeSt study. After randomization, patients were evaluated every three months by a clinician blinded to treatment assignment. If patients had a DAS of =2.4, they were stepped up to the next therapy in their assigned treatment pathway. After the first two years of the study, patients on maintenance dose monotherapy who achieved a DAS <1.6 for six consecutive months were tapered at each subsequent three-month evaluation up to and including discontinuation of treatment.

In the specific pathways, those assigned to group 1 received sequential monotherapy starting with methotrexate. Patients were switched to sulfasalazine, leflunomide, and finally to a methotrexate/infliximab combination as needed to achieve the treatment goal. Group 2 patients were also started on methotrexate monotherapy but switched at the next step to a combination of methotrexate and sulfasalazine, which was intensified as needed by first adding hydroxychloroquine and then adding prednisone before moving to methotrexate/infliximab. Group 3 started on the combination of methotrexate, sulfasalazine, and prednisone before hydroxychloroquine was added; if needed, they were switched to methotrexate, cyclosporine A, and prednisone before being offered methotrexate/infliximab. Group 4 was started on methotrexate/infliximab; therapy could be switched to sulfasalazine and leflunomide if needed.

At two years, 80% of the patients in BeSt, regardless of strategy, were at the treatment goal of =2.4. At four years, the proportion was 81%, underscoring the remarkable stability achieved when tight control is introduced early in the course of the disease. In addition, 43% of patients at four years (42% at two years) were in clinical remission as defined by DAS <1.6. By protocol, drug-free remission could not be achieved within the BeSt protocol at two years, but it was a possible outcome at four years, and 13% of the study population reached this measure of treatment success. The findings validate DAS-guided therapy regardless of initial treatment, but treatment strategy did make a difference for a number of important outcomes.

Efficacy of Early Combination Therapy

Overall, initial combination therapy was superior to initial monotherapy for many clinical measures, and an initial methotrexate/infliximab combination therapy was superior to an initial combination of methotrexate, sulfasalazine, and prednisone.

Specifically, in a last-observation-carried-forward (LOCF) analysis, the proportion of patients over the four years of study who did not reach, or lost, disease control (DAS >2.4) on the initial treatment step was 17% in group 4 (initiated on methotrexate/infliximab), 23% in group 3, which was the other group initiated on combination therapy, and no less than 49% and 48% for groups 1 and 2, respectively, who started with methotrexate monotherapy. This means that more patients in groups 1 and 2 had to change or increase their medication, whereas in groups 3 and 4, the majority of patients could decrease or stop. Efficacy is the primary explanation. There were no significant differences in the rate of dropouts for adverse events. Especially for infliximab, the high discontinuation rate (48%) after four years because of continued good response is remarkable. As “rescue” therapy later in the course of the disease, the drug
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Table 1.

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In a subsequent analysis (van der Kooj et al. Ann Rheum Dis 2007;66:1356-62), treatment with conventional DMARDs after failure with methotrexate was unlikely to provide a DAS <2.4, even though 71% of patients switched to methotrexate/infliximab were successfully treated, a result that encourages early use of a biologic in methotrexate failures.

Radiographic Outcomes Support Early Combination Therapy

The differences in radiographic outcomes may be even more impressive. Progressive joint damage over the four years was observed in only 31% of patients on methotrexate/infliximab and 38% of the other combination arm vs. 51% and 54% for the group 1 and 2 initial monotherapy arms, respectively (P<0.05 for group 4 vs. groups 1 or 2). When mean Sharp-van der Heijde (SVDH) scores were compared, the median total change in score and the median change in erosion score was half as great in group 4 vs. group 1 or 2.Group 3 patients initiating therapy on the combination of methotrexate, sulfasalazine and prednisone had non-statistically significant higher scores for radiographic outcomes than those in the methotrexate/infliximab group, but these patients also achieved significantly greater protection against progression when compared to the initial monotherapy groups.

The differences in radiological progression at four years may be even more significant than the relative advantage for the combination regimens observed in the one-year BeSt results (Goekoop-Ruiterman et al. Arthritis Rheum 2005;52:3381-90). By the trial design, patients not well controlled on initial therapy were eventually switched to combination therapy, including the potential to receive infliximab with methotrexate, so the expectation would be for differences between groups to diminish over time. The fact that the differences persisted provides strong evidence that there is a window of opportunity in which initial combination therapy can secure the best outcome. In other words, once radiological damage is initiated, progression becomes more difficult to control.

Achieving Drug-free Remission

The evidence of drug-free remission is another remarkable and important finding in the BeSt study. Of those initiated on methotrexate/infliximab, 18% of patients at four years were in remission off of therapy. The rates were 8% in the other combination group, 14% in group 1 and 12% in group 2. At some point in the study, 27% of patients in group 4, 16% in group 3, 17% in group 2 and 21% in group 1 achieved drug-free remission. In the majority of patients who achieve drug-free remission, the effect is sustained. The average duration is now two years. Although early switching to a biologic reduces the amount of time that disease is uncontrolled, even patients who failed multiple courses of DMARDs still have a substantial potential to achieve biologic-free remission on infliximab. In BeSt, patients who failed multiple courses of DMARDs and received delayed treatment with infliximab, two-year data indicated that 15% still achieved a biologic-free remission.

Again, the trial design of switching patients on initial monotherapy to combination regimens if inadequately controlled would be expected to minimize differences in this outcome. In clinical practice, the opportunity for drug-free remission may be even greater than that documented in BeSt, which tapered agents one by one only after patients had been in remission for at least six months. By adding more predictive factors of sustained remission, such as level of rheumatoid factor, markers of inflammation, or lack of erosion at baseline, it may be possible to taper and discontinue therapy more quickly in selected patients. Also a drawback of the BeSt study design is that we included only patients who fullfilled ACR classification criteria and who had high disease activity. Starting treatment in an earlier phase could lead to higher remission rates still.

Summary

The four-year results of BeSt have provided a framework for an improved approach to both immediate and long-term control of RA. The most recent results confirm that outcomes are better on initial combination regimens than monotherapy. Findings also demonstrate that patients should be monitored closely for disease activity and uptitrated to more effective regimens as needed to keep disease activity low. Although infliximab, one of the two agents in the most effective initial combination, is not currently reimbursed as an upfront therapy in many countries, BeSt results demonstrate that persistent disease activity warrants more aggressive therapy as a strategy early after RA onset. This approach increases the likelihood of preventing radiological progression and introduces the potential for a drug-free remission.

questions and answers

Panel

Boulos Haraoui, MD, FRCPC

Université de Montréal, Montreal, Quebec

Algis V. Jovaisas, MD, FRCPC

University of Ottawa, Ottawa, Ontario

Majed Khraishi, MB, BCh, FRCPC

Memorial University of Newfoundland, St. John’s, Newfoundland

Cathy E. Flanagan, MD, MDCM, FRCPC

Royal Columbia Hospital, New Westminster, British Columbia

Cornelia F. Allaart, MD, PhD

Leiden University Medical Center, Leiden, The Netherlands

How is remission defined for RA and is it achievable given current treatment options?

Dr. Jovaisas: Whereas once we would have been happy with a purely clinical definition of remission, I think we now have good data to suggest that we should go beyond control of symptoms to at least work toward radiological and laboratory remission as well. Subclinical activity of disease does pose a risk of a worse long-term outcome, and the BeSt trial did provide evidence that remissions are at least sometimes achievable.

Dr. Haraoui: Given the multiplicity of outcomes in evaluating RA (signs and symptoms, function, quality of life, radiographic damage, etc.), the definition of remission should encompass several items. Some are interrelated, such as the relationship between radiographic damage and function, but some are also dependent on other factors. There is, however, a consensus that what we like to call true remission is the combination of clinical remission plus radiographic remission. Therefore we need to define clinical remission based on validated outcomes such as the DAS or more simple tools such as the SDAI and CDAI. As for radiographic remission, it is defined by the absence of progression of radiographic damage. True remission is achievable in RA, more so in early RA compared to established RA, when a strategy of targeted outcome is pursued with frequent clinical evaluations and medication adjustments.

Dr. Flanagan: Remission can be defined using either the DAS 28 or DAS 44 criteria as was done in the BeSt trial. With the present treatment options, including the TNF biologics, we can achieve remission in a significant number of patients but not in all. Some rheumatologists feel that using DAS 28 is not sensitive enough, because a patient with this DAS score could still have up to six swollen joints. Recently some trials and some rheumatologists have been using the CDAI or SDAI which requires patients to have no active joints to be declared in remission.

Dr. Allaart: It is important to differentiate remission from control. With the introduction of better therapies, there appears to be an opportunity to not only control disease to improve immediate quality of life but also to achieve remission likely to have a profound effect on long-term outcome. In the BeSt study, sensitive measures of disease activity allowed RA to be treated independent of symptoms, and this is likely to have played a role in the impressive long-term outcomes observed in this study. Remission is not something that we can promise in all patients, even those treated aggressively early on, but it is now an outcome to which we can aspire.

Dr. Khraishi: Remission in RA is either defined by a DAS score (usually DAS 28 ESR) of <2.6, or less commonly by the ACR remission criteria. Although both criteria sets are mainly used in research settings, they are becoming more commonly used in clinical settings. In clinical settings, many rheumatologists consider a swollen joint count of zero as an indicator of remission. One of the unsettled issues is whether inhibition of radiological bone damage should be considered part of complete remission. In any case, a clinical remission defined by the DAS 28 definition or by the absence of swollen joints is definitely achievable with current therapy options and treatment algorithms.

Did the BeSt study produce a change in perception about the window of opportunity for early aggressive therapy of RA to affect long-term outcome?

Dr. Haraoui: The BeSt trial elegantly demonstrated the concept of treating early, treating to target, and using frequent medication adjustments to reach the goal. The added value of BeSt is that it compared different therapeutic strategies in pursuing the same goals and showed that the most effective strategy is the early use of a combination of methotrexate plus infliximab in rapidly achieving that goal and suppressing more effectively the progression of radiographic damage. However, it did not explore other treatment strategies such as the combination of two or three DMARDs at optimal doses from the outset.

Dr. Flanagan: The BeSt study did change perception about treating aggressive RA early to prevent future damage. It is very exciting to think that we may be able to achieve a disease and drug-free remission by treating patients early and aggressively with infliximab and thereby halt the progression.

Dr. Allaart: The extension of the BeSt study has shown that permanent infliximab discontinuation is possible and that even drug-free remission is a realistic option. The fact that the difference in radiological progression, already present after one year of treatment, is still statistically significant is also remarkable, given the high percentage of patients in the initial monotherapy arms that have switched to combination therapy with prednisone or infliximab. This is strong evidence that a window of opportunity does exist, where initial combination therapy can secure the best outcome, and initial monotherapy risks radiological damage becoming a runaway train.

Dr. Khraishi: Overall, the BeSt study added much to the way we understand and practice effective therapy of RA. However, other studies of biological therapies are confirming that early effective therapy of RA with or without biologics can induce remissions and cause more pronounced inhibition of radiological damage. The BeSt results have been with the targeted therapies. We are also aware now that radiological joint damage can occur very early in many RA patients.

Dr. Jovaisas: In progressive joint disease, it is logical to assume that effective early intervention will provide better long-term outcomes by slowing damage, but the BeSt study provided an objective confirmation. It may not be necessary to start every RA patient on an anti-TNF agent to achieve an acceptable long-term outcome, but BeSt did demonstrate that it is important to pay attention to early disease control to try to prevent joint damage. The BeSt study suggested that aggressive control of inflammation does, as we would anticipate, prevent joint damage.

In the BeSt study, therapy was adjusted on the basis of DAS, which was intensively monitored. Should treatment decisions be based increasingly on objective measures of disease activity rather than on symptoms alone?

Dr. Jovaisas: This may have been the most important lesson from the BeSt study. By treatment group comparisons, the best outcomes were in those who received anti-TNF therapy, but the close monitoring and therapy adjustments performed in all treatment groups clearly contributed to the high rates of disease control over the course of follow-up in each of the study groups. This type of monitoring in order to adjust treatments is a reasonable approach in daily practice that has the potential to improve patient outcomes.

Dr. Haraoui: Given the nature of RA, which is characterized by both biological and clinical inflammation which does not always correlate with the functional impairments, a composite assessment tool inclusive of all the disease aspects needs to be used. One cannot effectively rely on one single measure. The most validated and accepted instrument is the DAS which was used in the BeSt trial. Nevertheless, it is not a user-friendly instrument in daily clinical practice and simpler scores have been developed and validated such as the SDAI and CDAI and their use should be encouraged.

Dr. Khraishi: It is plausible to set objective outcome measures and treat accordingly. However, other considerations, such as toxicity and the preferences of the patient, must be taken into consideration. In addition, the significance of just a few swollen non-tender joints is still debatable.

Dr. Allaart: In the BeSt study in all patients, a full 66/68 joint count is done every three months. Currently there is not an integrated method to use the information on all joints, so we used the DAS 44 instead, and it worked very well. Both patients and rheumatologists can see if improvement occurs, but since neither are very good at estimating (or accepting) whether or not disease activity is sufficiently low, it is important to calculate the disease activity and adjust the therapy to get below a certain limit.

Dr. Flanagan: Treatment should definitely be adjusted based on objective measures. Studies such as TICORA (Tight Control for Rheumatoid Arthritis), FinRACo (Finnish RA Combination Therapy) and others have clearly shown that monitoring patients often, such as once per month, and using objective measures such as the DAS to make treatment decisions to allow tight control, have made a very significant impact on the clinical and radiological progression of arthritis compared with usual practice.

Some patients with RA have rapidly progressive disease. Is it important to attempt to identify these patients for more intensive therapy?

Dr. Haraoui: Several attempts have been made to screen and categorize patients. The only proven risk factors for more severe disease are the presence of rheumatoid factor (RH), the presence of high-titre anti-CCP antibodies, and the evidence of erosive disease or of high inflammatory markers (ESR, CRP) at the time of presentation. The combination of these different factors in the same patient increases that risk. We have also learned from the ASPIRE trial that patients treated with methotrexate monotherapy who still maintain a degree of high disease activity and/or high CRP/ESR after 14 weeks have more radiographic damage progression at week 52.

Dr. Khraishi: This is one of the most important issues that we face nowadays, specifically with our ability to induce remission with new medications or approaches. Most rheumatologists believe that identifying these patients allow us to be more aggressive in our therapy very early and set objective outcome measures for them. One consideration for implementing biologic therapy earlier is that from various studies, TNF antagonists appear to have greater efficacy in preventing structural damage of the joint as compared to traditional DMARDs.

Dr. Flanagan: It is very important to identify the patients who have early aggressive disease. We know that most of the radiological damage occurs in the first two years of the disease, so if we treat early, we have a better chance of preventing damage. We also know that not all patients will need aggressive treatment. For example, some patients do well on methotrexate alone and do not require biologics. Therefore, we need to identify patients with a poor prognosis and then treat them early and aggressively to prevent future damage and alter the course of their disease.

Dr. Allaart: Some patients clearly have more aggressive RA than others. However, currently it is not possible to identify differences in risk at the beginning of treatment. I would rather treat all patients aggressively from the start, with the option of early discontinuation of some or all of the drugs, than miss the window of opportunity and risk permanent damage and less disease control by starting with monotherapy and change to more effective drug combinations only later.

Dr. Jovaisas: Recent data, including those from BeSt, suggest that treatment adjustments should be made according to disease activity to single out those with the most aggressive disease. In patients who are not adequately controlled with initial therapy, treatments should be stepped up. By using this approach, one will identify those patients who require more intensive therapy.

What criteria should be used to identify patients who require more intensive therapy?

Dr. Flanagan: We know many of the factors that herald a poor prognosis. These include a positive RF, a positive CCP (especially both a positive RF and positive CCP), a high CRP, the presence of the shared epitope in genetic testing, and the presence of erosions in early disease. The use of ultrasound and/or MRI of the hands to evaluate for the presence of synovitis is being used more and more. Studies with ultrasound in Europe are helping to determine if patients with normal X-rays who still have synovitis undetectable on clinical exam require more aggressive treatment. We still need better measures to identify the patients most in need of early aggressive therapy with a lot of attention now being paid to potential biomarkers.

Dr. Haraoui: The proven risk factors, which include the presence of RH, high titres of anti-CCP antibodies, strong expression of inflammatory markers, such as CRP, and evidence of erosive disease are all useful.

Dr. Allaart: Maybe I would turn the risk assessment around and try to identify who is likely to have relatively mild disease (for example, non-smoking male patients, with negative antibodies, no early damage, low disease activity and few swollen joints). Still, we know that some of these patients will show damage progression and would have been better off with the same aggressive treatment.

Dr. Khraishi: I feel that positive anti-CCP, positive RH, early age of onset, strong family history of RA (suggesting a strong genetic component), aggressive disease from the outset as manifested by a high degree of joint involvement, high levels of inflammatory mediators such as CRP or early erosions, and extra-articular manifestations are indicators of poor prognosis. Smokers also seem to have more aggressive disease.

Dr. Jovaisas: Based on the BeSt study, it would be appropriate to develop a specific set of criteria with which to identify patients likely to be at risk for accelerated progression. We have identified many risk factors, but a scoring system might be useful for more rapidly assessing risk to single out patients who might be candidates for early use of aggressive therapies.

In the five-year results of BeSt, 51% of patients randomized to initially receive methotrexate and infliximab were able to achieve DAS 44 remission and maintain that remission despite having withdrawn infliximab therapy. In addition, 18% of patients initiated on methotrexate and infliximab were able to stop infliximab and all DMARD therapy entirely. Based on this longer-term data (five-year analysis), will infliximab be used increasingly as an induction therapy to achieve prolonged disease quiescence?

Dr. Haraoui: So far, infliximab is the only agent shown in clinical trials to be able to induce remission which could be sustained, at least in some patients, after withdrawal. The pursuit of such a strategy is very appealing and should be encouraged with benefits for both the patient and third-party payers.

Dr. Khraishi: The answer should be yes, although many rheumatologists feel that this is a class effect and we may see similar benefits with TNF inhibitors other than infliximab.

Dr. Allaart: I would readily start with initial combination therapy including infliximab or maybe another anti-TNF (there are no data, but there is likely to be some sort of a class effect), if reimbursement rules were changed. The BeSt health-economics evaluation shows that this may even be cost-effective in the long term. For now, probably initial combination therapy including prednisone is the best alternative, provided prednisone is not continued. And of course if the disease flares after discontinuation of prednisone, combination treatment with anti-TNF is the next step.

Dr. Jovaisas: There are important issues of benefit-to-risk and benefit-to-cost that need to be resolved before all RA patients can be considered candidates for biologic therapies. However, the evidence from BeSt that at least some patients can achieve a prolonged drug-free remission is very exciting. We do not yet know if any of these remissions will be indefinite, essentially providing cure for what was once an essentially incurable disease, but such outcomes will affect calculations for clinical and cost benefits from the perspective of patients and third-party payers.

Dr. Flanagan: The five-year results of the BeSt trial are impressive. It would have been even better to have results from a randomized and controlled trial, but BeSt was a large study of early RA patients with poor prognostic factors. The fact that a significant number of patients treated initially with infliximab and methotrexate are disease- and drug-free at five years is likely to lead to more use of this regimen early in the disease course. One important obstacle is the lack of coverage by formularies and governments. It is clearly a good option in selected patients if it were available. If more data can be collected to demonstrate cost or outcome benefits, such as increased drug-free survival or an ability to return to work, it is likely that more third-party payers will reimburse this strategy.

Are the BeSt data relevant to current clinical practice?

Dr. Flanagan: The BeSt study is relevant to clinical practice as it shows that we should be trying to determine which patients have a poor prognosis and have aggressive disease as soon as possible, at the time of diagnosis, and we should treat these patients early and aggressively using objective measures to tightly control their disease activity, get the patients in remission and keep them there. We should try to get these patients on biologic treatment as soon as possible; if it is feasible, treatment with infliximab and methotrexate would be a good option for the patient with early, very aggressive RA in order to try to achieve and maintain remission and try to get the patient disease and drug-free.

Dr. Jovaisas: The protocol employed in BeSt in regard to starting with combinations and uptitrating therapies in response to disease activity is possible to reproduce in routine clinical practice, and I think clinicians will be highly influenced by the results. This was a paradigm-shifting study in proving the hypothesis that early and aggressive disease control provides better outcomes than less rigorous management.

Dr. Haraoui: Definitely. It has taught us several lessons: one is that we can achieve a better outcome when patients are treated early; another is that we should target treatment to achieve prolonged remission; a third is that earlier use of an anti-TNF agent is preferable to less aggressive therapy; lastly, it has taught us that remission is an achievable goal and can be sustained drug-free in at least some patients.

Dr. Khraishi: I believe so. Specifically, aggressive treatment with or without a biologic and intense monitoring of response from the onset of therapy are two examples of how those data are affecting our approach to RA therapy now.

Dr. Allaart: Yes, I do believe the BeSt results can and should be applied to routine patient management today. BeSt has shown that, regardless of treatment strategy, low disease activity can be achieved in more than 80% of the patients if you adapt your treatment aiming at such a goal, and more than 40% even achieve remission. Goal-orientated, disease activity-driven treatment should be the basis of RA treatment.