Progress Toward the Cure of Rheumatoid Arthritis? The BeSt Study

ARTHRITIS & RHEUMATISM Vol. 52, No. 11, November 2005, pp 3326 3332 DOI 10.1002/art.21503 2005, American College of Rheumatology EDITORIAL Progress Toward the Cure of Rheumatoid Arthritis? The BeSt Study Michael H. Weisman It is remarkable how the treatment of rheumatoid arthritis (RA) has changed over the past decades. In 1975, when this author began his academic practice, rheumatologists often did not use the word treatment. We talked about managing the patient, not treating the disease, and we certainly were cautious, indeed tentative, in the management of early disease. The word cure was absent from our lexicon. We dared not to combine our drugs how could you tell which one was working or which one was responsible for the side effects? We even worried that some of our drugs such as high-dose corticosteroids were causing the common and sometimes life-threatening vasculitic complications of RA. Now, rheumatologists often speak of remission and we hardly ever see vasculitis and other severe systemic manifestations in RA patients. Therefore, it is important to put into perspective a provocative and very creative study of RA treatment by Goekoop-Ruiterman et al, reported in this issue of Arthritis & Rheumatism, with the acronym BeSt (a Dutch acronym for Behandel- Strategieën, or treatment strategies ) (1). This study compares treatment strategies that aggressively treat early-onset RA with combinations of drugs (even including high doses of steroids), a study that likely will change our management of RA even more! How and why did we get here? The BeSt study: what did it show? The BeSt study is a single-blind, multicenter randomized clinical trial comparing 4 treatment strategies: sequential substitution monotherapy (for treatment Michael H. Weisman, MD, FACP, FACR: Cedars-Sinai Medical Center, Los Angeles, California. Dr. Weisman has received consulting fees or honoraria (less than $10,000 per year) from Abbott, Amgen, Bristol-Myers Squibb, Centocor, Isis, Pfizer, Roche, and TAP. Address correspondence and reprint requests to Michael H. Weisman, MD, FACP, FACR, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, B-122, Los Angeles, CA 90048. E-mail: weisman@cshs.org. Submitted for publication June 22, 2005; accepted in revised form August 9, 2005. group 1), step-up add-on combination therapy (for treatment group 2), initial combination therapy with a short course of high-dose prednisone (for treatment group 3), and initial combination therapy with the tumor necrosis factor (TNF) antagonist infliximab (for treatment group 4). The study had a common goal for all 4 strategies, namely, to obtain a clinically significant low level of disease activity (a Disease Activity Score in 44 joints [DAS 44 ]of 2.4) (2) with intensive monitoring every 3 months, at which time the treating physician immediately adjusted therapy by a preset algorithm to a more intensive regimen if treatment failed to result in a DAS 44 of 2.4. Alternatively, if a patient achieved an adequate response (a DAS 44 of 2.4) for 6 consecutive months from any of the 4 regimens, the drugs were subsequently tapered in a preset manner to a maintenance dose of monotherapy. Prednisone and infliximab were always the first drugs to be tapered to zero. If a patient had a disease flare after a drug taper, that drug was reintroduced at the last effective dose. Prednisone could be reintroduced only once. Primary end points were the Dutch version of the Health Assessment Questionnaire (3) and radiographic damage assessed according to the modified Sharp/Van der Heijde score (SHS) (4). All patients were evaluated by research nurses blinded to treatment assignment; the research nurse calculated the DAS 44 every 3 months and made the decision of whether to adjust medications. Radiographs were scored paired, in random order, and independently by 2 assessors. The results of the study were very impressive. Five hundred eight patients with very early RA were evenly balanced after randomization; these patients had active (mean SD DAS 44 of 4.4 0.9), early (median duration of symptoms of 23 weeks), and severe (72% had erosions) disease at baseline. The 2 combination therapy groups achieved a sustained low DAS 44 and functional improvement more rapidly than did the groups receiving sequential monotherapy or step-up combination therapy. At 1 year of followup, patients treated with both initial combinations had less progres- 3326

EDITORIAL 3327 sion of radiographic damage than did the groups receiving sequential monotherapy or step-up combination therapy. Did the group receiving initial combination therapy with infliximab display more success in limiting radiographic progression than the group receiving initial combination therapy with prednisone? Table 2 and Figure 4 in the article by Goekoop-Ruiterman et al indicate a numeric (but not statistically significant) advantage of the infliximab group at 1 year. However, a subanalysis of only patients without erosive disease at baseline revealed that the combination with infliximab was more successful than the combination with prednisone in terms of preventing the development of new erosions at 1 year (P 0.028). Toxic effects were not different among the groups. The goal of the BeSt investigators was to find the optimum strategy to prevent damage and preserve function through real-world regimens frequently employed by rheumatologists. The authors note the marked improvement in all groups at the end of 1 year (one-third of the entire cohort achieved remission of their disease, defined as a DAS 44 of 1.6); they attribute this to the tight control achieved by close monitoring and immediate dose adjustments. The authors provide 3 important observations derived from their efforts: 1) tight control allowed 40% of patients in groups 1 and 2 treated with methotrexate (MTX) alone to achieve a sustained suppression of disease activity; 2) the differences in radiographic progression scores at 1 year, although statistically significant, were small from a clinical perspective; and 3) patients in groups 3 and 4 had more rapid relief of symptoms and improvement in function. The authors describe both an argument and a counterargument arising from their observations: aggressive treatment with combinations of expensive drugs would overtreat a large proportion of patients, yet early suppression of disease activity may have an important influence on subsequent long-term disability and damage. What are the challenges coming from the BeSt study? Rheumatologists have to confront several challenges from the BeSt study almost on a daily basis in our practice. Do we treat patients aggressively, which ones, and with what agents? Do we overtreat some patients to get the greatest benefit for all? What is the role of steroids? How do we interpret radiographic data showing change in the SHS and their potential clinical significance? Have the BeSt researchers moved the field forward, and in what way? In order to address these issues, the following 4 questions will be asked of the literature in general and the BeSt doctors in particular. 1. Do combinations of drugs in established disease provide more clinical and radiographic benefit than single drugs alone? 2. Is there a window of opportunity to treat early RA? Is aggressive treatment more beneficial than a conservative or gradualist approach in the long run, with the possibility of affecting the important outcome of mortality? 3. Should corticosteroids be part of an early aggressive approach? Do corticosteroids do more good than harm, and is there a safe steroid regimen? 4. Do targeted biologic agents yield radiographic improvement out of proportion to control of inflammation? Is it because of their unique mechanism of action? Do combinations of drugs in established disease achieve a greater clinical and radiographic benefit compared with single agents alone? This part of the story begins with a 1987 report by Scott and colleagues (5) revealing that more than half of 100 RA patients at a London teaching hospital were either dead or severely disabled after 20 years of modern treatment. This study confirmed the dismal state of RA treatment in the 1980s. Cognizant of the emerging and successful use of MTX in the US over the same time period, Wilske and Healey suggested, 2 years later, in 1989 (6), that we must change our approach. Their reported method (without any data to back it up at the time) suggested that rheumatologists should act like oncologists (i.e., treat all patients with full-dose combinations of drugs at the outset, then sequentially withdraw the most toxic ones, leaving patients to receive maintenance therapy with the most benign compound). In their report, Wilske and Healey recognized that multiple drugs have different mechanisms of action, and they proposed that a combination of agents employed at a critical stage of inflammation could have a longlasting effect on bone and joint integrity. It took a full 7 years before O Dell and colleagues (7) provided the data to support the method of Wilske and Healey. O Dell and colleagues were able to demonstrate convincingly that combinations of conventional disease-modifying antirheumatic drugs (DMARDs) were more effective than and just as safe as single agents in the treatment of established disease. Currently, and with the use of the anti-tnf biologic agents, this

3328 WEISMAN hypothesis has been shown to be true in multiple studies revealing that a biologic agent can provide additional and clinically significant benefit to that already achieved with MTX alone in established disease (8 10). Does the BeSt study add anything to answer this question? Yes, but only indirectly, since the BeSt researchers addressed this question in early, but not in established, disease. The combination of standard DMARD agents at the outset (although with corticosteroids) did show more rapid clinical improvement and a more favorable radiographic result either compared with tight control with sequential monotherapy or compared with tight control with step-up combination therapy. A direct comparison of the latter 2 strategies disclosed no difference between them either in clinical or in radiographic outcome. The BeSt data confirm prior experience (11) that the combination of sulfasalazine (SSZ) and MTX has little or no additive therapeutic effect; combining them was no better than switching in the BeSt trial. Therefore, it appears that the optimal use of a combination should be at the outset, and not later. The BeSt researchers make the point that starting with a single DMARD is a missed opportunity. Is there a window of opportunity to treat RA? Is aggressive treatment more beneficial in the long run with the possibility of affecting the important outcome of mortality? A study of patients with early arthritis performed in Manchester, UK, using the technique of propensity scoring as a method of adjusting for disease severity in observational cohorts (12), revealed that institution of standard DMARD regimens within the first 6 months of disease reduced the amount of radiographic damage at 5 years compared with institution of these same drugs later. Lard et al compared the effects of delayed and early treatment strategies in successive cohorts of patients with early RA; a smaller area under the curve (AUC) of disease activity as well as a reduced Sharp radiographic score were seen in the early treatment strategy group (13). In the TICORA (tight control for rheumatoid arthritis) study, when patients with earlyonset disease were randomly assigned to tight control employing an aggressive and intensive outpatient disease management program (even including liberal use of systemic corticosteroids) and compared with patients receiving usual rheumatologic care, the employment of aggressive management had greater effects on disease activity as well as on subsequent joint damage (14). All of these data appear to solidly support the conclusion reached by the BeSt investigators that early aggressive treatment has significant long-term benefits. Changes in the early mortality typically attributed to RA give further testimony to the benefit of early institution of aggressive management. A very large community-based observational cohort assembled by Mitchell and coworkers in the 1970s and 1980s (15) revealed that the survival rate of RA patients was reduced substantially (50%) compared with populationmatched controls. In addition to the traditional influence on mortality from demographic variables of age and male sex, multivariate analysis identified baseline variables reflecting disease activity and severity (functional class, rheumatoid factor [RF] titer, number of involved joints) that independently influenced survival. The separation of mortality from that in the comparator population occurred almost immediately in this cohort. The experience of the Mayo Clinic was similar, as reported by Gabriel and colleagues (16). Mortality in RA patients occurred early in the disease course and did not improve in successive cohorts assembled from 1955 to 1985 in spite of improved survival of the age- and sex-matched Rochester, MN residents during this exact time frame. Dr. Gabriel already knew the negative answer to the question when she titled her article Mortality in rheumatoid arthritis: have we made an impact in 4 decades? However, mortality data from an inception cohort beginning in 1985 reflecting early, aggressive, and sustained DMARD treatment tell a different story. As shown in Figure 1, Kroot and colleagues (17) were able to show that in 622 patients followed up over 10 years, mortality did not differ from that in age- and sexmatched controls from the general population of The Netherlands. The usual baseline disease severity and activity characteristics such as RF status, functional capacity, and disease activity were not statistically significant predictors of death, suggesting that treatment may have had an important influence on this result. Even recently published mortality data (Figure 2) from Gabriel and colleagues at the Mayo Clinic (18) reveal that the separation of mortality in RA patients from that in the comparator population really does not take place until well after 5 years of disease, and male sex was no longer a risk factor for death in the Mayo Clinic population. Whether these improving mortality data can be attributed to a reduction in cigarette smoking or other changes in ambient care remains unclear; however, an aggressive disease management approach in patients diagnosed earlier as having RA cannot be discounted. The BeSt study may be right on target here.

EDITORIAL 3329 Figure 1. Kaplan-Meier survival curve of 622 patients with recentonset rheumatoid arthritis compared with that of age- and sex-matched controls from the general population of The Netherlands. Error bars indicate 95% confidence intervals of the study group. Adapted, with permission, from ref. 17. Should corticosteroids be part of an early aggressive approach? Do corticosteroids do more good than harm, and is there a safe steroid regimen? The successful employment of high-dose prednisone with a rapid taper in 1 of the 4 treatment arms of the BeSt study brings the steroid issue sharply into focus. It is possible that an initial pulse of corticosteroids at a critical time (the early window) may do more good than harm. Nevertheless, most rheumatologists, appropriately, have difficulty accepting prolonged corticosteroid use as an ongoing management strategy. Although many rheumatologists would be reluctant to believe it, corticosteroids have been shown to have a disease-modifying effect when the right dose and comparator populations are selected. Two largely forgotten studies from the UK in a population of patients with early RA (disease duration 3 24 months) were reported 45 years ago; the group that received only nonsteroidal antiinflammatory drugs displayed worsening of disease in terms of radiographic progression compared with the group that received prednisolone, with a statistically significant difference extending for 4 years of followup (19 21). Decades later in the UK, Kirwan further established the disease-modifying potential of corticosteroids by demonstrating a substantial decrease in erosion score as well as in newly eroded joints from the administration of 7.5 mg/day prednisolone compared with placebo in a cohort of patients with early RA (22). Similar data have come from The Netherlands in studies by Van Everdingen et al (23) in a cohort of patients newly diagnosed as having RA. Lowdose oral glucocorticoids as monotherapy resulted in an initial clinical effect that was not sustained, yet there was significantly less radiographic progression in the steroidtreated group. Do these low-dose steroid therapies cause unacceptable bone loss? On the one hand, a later followup of the Dutch cohort revealed osteoporotic fractures to have supervened more frequently in the steroid-treated group (24). On the other hand, a recently reported followup analysis of Kirwan s UK cohort revealed that diseaserelated hand bone loss (measured by digital x-ray radiogrammetry) actually decelerated as a result of prednisolone treatment (compared with placebo) at both 1- and 2-year time points (25). The controversy continues. Further support for the use of a high-dose and rapid-taper steroid regimen comes from the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial, a 2-arm, step-down bridge study that compared a combination of SSZ, MTX, and high-dose prednisolone with SSZ alone in a cohort of patients with early RA (26). Although the clinical difference between the 2 treatment arms was no longer present once the corticosteroids were tapered and discontinued, the radiographic benefit has persisted for 4 5 years of followup (27). What can we conclude about steroids from these studies, and do the BeSt data provide us with an additional perspective? The BeSt data support the concept that in early, active RA, the use of a high-dose regimen with a rapid taper will result in a longer term residual radiographic benefit once the steroids are gone. How high is high and how long can it be given? If it is true that extended followup of these short-course high- Figure 2. Observed survival rate among 609 Rochester, MN residents first diagnosed as having rheumatoid arthritis (RA) between January 1, 1955 and December 31, 1994, compared with expected survival rate (P 0.001). Adapted from ref. 18.

3330 WEISMAN dose and rapid-taper steroid-treated patients does not reveal problematic bone loss or fractures, a BeSt/ COBRA regimen of 60 mg/day with rapid taper to 7.5 mg/day over 7 weeks may do more good than harm. However, the use of these agents on a longer term maintenance basis continues to be problematic and probably will remain controversial for some time to come. Do targeted biologic agents yield radiographic improvement out of proportion to control of inflammation? Is it because of their unique mechanism of action? Data to answer the above questions are emerging; however, the interpretation is controversial. In the most recent studies examining anti-tnf biologic treatment in early RA in which a comparison is made between the combination (biologic agent and MTX) and MTX alone, the trials with all 3 anti-tnf agents (etanercept, infliximab, and adalimumab) reveal a similar phenomenon (28 30). Figure 3 illustrates changes in the percentage of patients achieving 50% improvement according to the American College of Rheumatology response criteria (an ACR50 response) (31) contrasted with numeric changes in the SHS for all 3 agents. The combination typically results in 50% greater clinical improvement than that gained with MTX alone. In contrast to the ACR50 response, the radiographic outcome with all 3 agents appears to be greatly superior a minimum 4-fold greater improvement is noted with these combinations compared with MTX alone. What remains controversial is the true clinical significance of the magnitude of the changes in the SHS. However, reducing the progression to near zero must not be ignored. Whether these findings are a result of a more rapid benefit achieved with the combination (achieved by an increased AUC) or whether they result from the unique presence of the targeted biologic agent is still a matter of conjecture; the data remain open to interpretation. Along similar lines, the ATTRACT (Anti Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy) investigators (32) have reanalyzed their data comparing infliximab treatment with placebo in RA patients with longstanding disease and an incomplete response to MTX. These investigators have generated the hypothesis that for patients who obtained either little or minimal clinical disease control with either placebo or biologic treatment, those who were treated with infliximab obtained a radiographic benefit. Figure 3. Percentage of patients achieving 50% improvement according to the American College of Rheumatology response criteria (an ACR50 response) (A) and numeric changes in the modified Sharp/Van der Heijde score (SHS) (B) from 3 similarly designed clinical trials in early rheumatoid arthritis (see refs. 27 29). Each trial (TEMPO [Trial of Etanercept and Methotrexate with Radiographic Patient Outcomes], ASPIRE [Active-Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset], and PREMIER) compared methotrexate (MTX) monotherapy with the combination (combo) of MTX and an anti tumor necrosis factor agent, and the results at the 1-year time point for each study are displayed. Values in B are the mean. Note the relatively large magnitude of radiographic improvement (B) compared with the more modest clinical improvement shown by the percentages of patients achieving an ACR50 response (A). In other words, for patients with comparable minor clinical improvement as measured by DAS or ACR20 responses, the biologic treatment had a greater effect on inhibition of structural damage. The editorial accompanying the article by Smolen et al in that issue of Arthritis & Rheumatism provides a biologic rationale for these observations by noting that there is an uncoupling of inflammation and radiographic erosion in animal models and in a variety of experimental conditions (33). The authors of the editorial nevertheless suggest that there may be aspects of the ATTRACT trial study design and executed subanalyses that might affect the validity of the conclusions drawn by Smolen et al. Does the BeSt study address this question? The radiographic data in the BeSt trial are consistent with the interpretation that biologics are superior to conventional agents in controlling radiographic progression.

EDITORIAL 3331 Although both combination treatment arms yielded clinically equivalent results, a separate analysis examining the patients in the combination treatment arms who did not have erosions at baseline revealed that, compared with the nonbiologic combination, the biologic treatment was more effective in suppressing the development of new erosions at 1 year. Although the question is far from answered definitively, the BeSt data add to the emerging interpretation that early institution of aggressive combination therapy containing targeted biologic agents might possess unique advantages for prevention of radiographic damage. Conclusions Generalizations from clinical trials to clinical practice are always difficult. Take-home messages have to be understood within the context of what the trial was specifically intending to accomplish. Further, we have yet to establish the clinical significance of a change in radiographic SHS with regard to functional disability and quality of life. The whole issue of cost is not addressed since, unless there are changes in health care funding around the world, these treatments are not going to be universally available. Given limited resources and efforts to maximize benefits, how are patients going to be selected for access to these interventions? Nevertheless, we can draw some very real conclusions from our BeSt colleagues; theirs is an outstanding study that will continue to reverberate in the rheumatology community for years to come. The authors should be congratulated for demonstrating the enormous power to be gained from a cooperative study in an organized health care setting. For patients at the time of their initial diagnosis of RA, there appears to be an opportunity to achieve a lasting benefit in their disease course. It may even be possible to create a true clinical remission absent any continuing or ongoing maintenance therapy. BeSt and other strategies tell us that tight control should be accomplished in any case, since most patients appear to do very well under intensive management regardless of the strategy. In early-onset disease, it would be particularly important to further define risk factors for poor outcome so that this group can be selected for aggressive intensive combination treatment containing biologics; if biologics are not available, a high dose and a short course of steroids as part of the combination might suffice. Strategies should continue to be developed to address the question of disease modification. The concept of a DMARD that prevailed in 1975 is now obsolete as we explore, on a molecular level, the relationship between inflammation and destruction. The words remission and cure have crept into our allowable language. We have accomplished a great deal in the past 3 decades. Is prevention possible in the next 3 decades? We re working on it. That would be truly the best solution. 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