Assessing adequate treatment response in patients with rheumatoid arthritis

Clinical Therapeutics/Volume 31, Number 6, 2009

Commentary

Assessing Adequate Treatment Response in Patients With Rheumatoid Arthritis Martin Jan Bergman, MD

Department ofRheumatology, Taylor Hospital) Ridley Park) Pennsylvania; and Department ofMedicine) Drexel University College ofMedicine) Philadelphia) Pennsylvania ABSTRACT Background: Rheumatoid arthritis (RA) presents a substantial socioeconomic burden that is potentially reduced by individualized, appropriate management strategies. Integral to such strategies is recognizing the need for treatment changes when patients inadequately respond or do not respond to treatment. However, there might be little or no agreement as to what constitutes treatment failure or an adequate response. Currently used American College of Rheumatology response criteria and the disease activity score may underestimate the magnitude of treatment failure when applied in clinical practice, and, having been designed to differentiate responses between large groups, they may be of limited value in monitoring individual patients. Objective: The aim of this commentary was to assess how treatment failure and clinical remission/ response have been defined in clinical studies. Methods: A PubMed search (1948-2009) was conducted to identify clinical studies or reviews containing the following search terms: rheumatoid arthritis and treatment [ailure, inadequate response, biologic therapy. DMARD. radiographic response. and remission. Select clinical reports in patients with RA were included if remission or treatment failure, radiographic or other, was a study end point. Results: Thirty-three studies were identified. The present assessment found no consensus as to what represents a practical definition of treatment failure or clinical remission in the clinical studies assessed. The definitions varied from the complete absence of any clinical disease to computer-generated numeric scales. The variability in clinical definitions of treatment failure or remission seems to have been mainly attributed to the time at which assessments were made, making it difficult to determine what treatment failure or remission means in individual patients with RA in clinical practice. June 2009

Conclusions: Based on the findings of the present commentary, standard definitions of treatment failure or clinical remission/response are needed. Aggressive treatment strategies with specific clinical goals may result in better long-term outcomes. Early evidence of treatment effect may serve to improve clinical outcomes, including remission, and help define and align treatment goals in patients with RA. (Clin Ther. 2009;31:1219-1231) © 2009 Excerpta Medica Inc. Key words: rheumatoid arthritis, outcome measures, treatment.

INTRODUCTION Rheumatoid arthritis (RA) is a chronic, progressive, and disabling musculoskeletal disease that affects ~0.6% of the adult US population 1,2 and results in an economic burden estimated at $16 billion (year-2000 US $).3 Direct medical costs of health resource utilization account for one third of this burden, while the remaining two thirds result from indirect costs mainly associated with lost productivity-' This burden was illustrated in a recent report in which a median of 66% of employed patients with RA lost a median of 39 work days over a 12-month period." Substantial individual patient burden is characterized by compromised physical function and lower quality of life (QOL) compared with general population normal values. 5 ,6 Consequently, therapies that reduce disease activity and slow disease progression or induce durable remission are of clinical benefit to patients and of economic benefit to the health care system and society Accepted for publtcation April 2, 2009 dotl 0_1 016!J-c1lnthera_2009_06_00S 0149-2918/$ - see front matter

© 2009 Excerpta Medica Inc All rights reserved.

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due to reduced health resource utilization and increased productivity. Economic benefits have been suggested by findings from studies in which clinically meaningful improvement was associated with lower overall health care costs compared with no improvement.If Savings were from both direct costs from less resource utilization and indirect costs related to reduced productivity. Appropriate patient management is integral in obtaining the clinical and economic benefits expected with currently available therapeutic options. Treatment for the purpose of reducing the risk for and severity of symptoms is an insufficient management strategy with respect to long-term outcomes in patients with RA. Regardless of the initial therapeutic regimen, it is important to recognize when a change in treatment is needed because of an inadequate clinical response or loss of efficacy. However, the differences between treatment failure and adequate improvement have not been clearly defined. While efficacy is a primary parameter in clinical trials, effectiveness in clinical practice is dependent on a variety of factors that are substantially different from those used in clinical trials. 9 ,10 Specific differentiating treatment parameters in clinical practice include the perceptions and expectations of the patient and provider, convenience of drug administration, and positive or negative effects of treatment on a patient's activities of daily living. 10,11 The concepts of efficacy and effectiveness as applied to RA, including the range of improvements such as remission and "low disease activity" that have been reported with newer treatment strategies, have changed dramatically now that RA management is no longer focused primarily on pain reduction and inflammation suppression.Uv-' Biologic disease-modifying antirheumatic drugs (DMARDs) target specific components or functions of several key pathways in the imrnunopathogenesis of RA, such as cytokines (infliximab, adalirnumab, anakinta}, T-cell activation (abatacept), and B cells (rituxirnab ).14-1 9 Since the use of biologic DMARDs has become more common compared with that of conventional DMARDs, it has become clear that there is a need for more standardized clinical assessment parameters and tools, including those used for the measurement of clinical, radiographic, and patient-centered outcomes.l'' Consequently, it has become increasingly important to establish which outcomes should be used for the determination of the ineffectiveness of a specific treatment. 1220

The primary objectives of the present study were to determine how treatment [ailure and clinical remission/response were defined in clinical studies and how a standard definition of clinical remission, one that is meaningful for individual patients in clinical practice, could be defined. The secondary purposes of this commentary were to assess the current concepts of treatment failure and to outline the need for a standard definition of treatment [ailure, as well as the need for regular assessments of outcomes to identify the most effective approach to the treatment of individual patients. MATERIALS AND METHODS A PubMed search (years: 1948-2009; key terms: rheumatoid arthritis and treatment [ailure, inadequate response. biologic therapy. DMARD. radiographic response, and remission) was performed to identify randomized, controlled trials (RCTs); meta-analyses; prospective cohort analyses; and longitudinal studies. Select studies of patients with RA were included in the commentary if treatment failure or remission, radiographic or other, was defined as a study end point. No other specific inclusion or exclusion criteria were used. The definitions of treatment [ailure and clinical remission as end points across selected studies were compared to determine the differences between studies and how those differences might relate to current practice standards. RESULTS A total of 33 indexed studies were identified and select studies discussed. The studies were surveyed for the definitions of treatment [ailure and clinical remission that were used for the classification of outcomes in patients with RA. Defining and Assessing Treatment Failure Treatment failure has been temporally characterized as primary or secondary, depending on how long after treatment initiation it occurs. Primary treatment [ailure has been defined as a failure to achieve an adequate response or the occurrence of intolerable adverse events within a limited period after treatment initiation.U Secondary treatment [ailure has been defined as an initial response to treatment, followed by a loss of response despite dose adjustments (if dose adj ustments were possible); the necessity of a treatment switch or the addition of a concurrent medicaVolume 31 Number 6

M.J. Bergman

tion to the treatment regimen; or the onset of adverse events.I! Because clinical trials of RA treatments have assessed only primary treatment failure, whereas both primary and secondary treatment failure are observed in clinical practice, there may be a substantial dichotomy between definitions of treatment [ailure in clinical trials versus clinical practice. This dichotomy is further complicated by differences in patient populations between the 2 settings, as well as by which end points are being measured and how. As mentioned in a review of clinical trials of RA treatment by Wolfe et al,22 efficacy in clinical trials is often assessed using differences in outcomes between the study drug and an active control or placebo. While a difference in outcomes might be statistically significant and relevant for drug development, it might not be clinically relevant. Efficacy of an RA treatment in clinical trials might also be determined using a predefined change in disease activity, which is typically assessed using either the American College of Rheumatology (ACR) response criteria-s' or the disease activity score (DAS).24 An ACR20 response represents a 20% improvement in specified parameters and might be used as the primary efficacy end point. Therefore, not achieving an ACR20 response could be considered as treatment failure, and achievement of the ACR20 response could be considered as treatment success. In pivotal RCTs of tumor necrosis factor (TNF) antagonists administered at recommended therapeutic doses, primary treatment [ailure, defined as not having achieved the ACR20 response, was reported in up to 29% of 59 patients with RA who received etanercept 25 mg twice weekly,25 50% of 86 patients who received inflixirnab 3 mg/kg every 8 weeks.i'' and 33% of 69 patients who received adalimumab 20 mg every other week. 27 The ACR50 response (ie, the proportion of patients with a 50% improvement in specified ACR criteria) might be used to assess efficacy in clinical trials because it represents a stronger clinical response than the ACR20. 28 However, if the ACR50 is used as the primary efficacy determinant, the proportion of patients considered treatment failures would likely be higher than if the ACR20 were used (Figure 125-27 ). Furthermore, because the ACR20 or ACR50 values represent changes compared with a previous time point, they are of limited utility in clinical practice and clinical decision making. June 2009

The DAS might represent a more appropriate clinical trial end point than the ACR criteria because it takes into consideration not only the change in disease activity but also the current disease activity (Table 1).24 Nonetheless, some patients with a moderate response on the DAS might still have a DAS score of 3.2 to 5.1, indicating the presence of at least moderate disease activity. The requirement of a laboratory test (erythrocyte sedimentation rate or C-reactive protein concentration), which may be unavailable at the time of an office visit in as many as 50% of instances.I" and the need for a dedicated calculator make this measurement unsuitable for some clinicians.I'' However, in a validation study in 285 patients with RA of high, moderate, or low severity or near remission, Pincus et a13 1 reported that the RAPID3 (Routine Assessment of Patient Index Data 3 )32-34 assessment correlated significantly with the 28-joint count DAS (DAS-28)a modified, shorter version of the DAS-and Clinical Disease Activity Index (CDAI) criteria (P < 0.001) and might be a useful tool in busy practices. A clinically meaningful association between clinical manifestation of disease and radiographic evidence of disease might not exist, or the parameters might not consistently correlate well. In a subgroup analysis of an RCT, Smolen et a13 5,36 reported that, in 340 patients with moderate to severe RA, after 1 year of treatment with infliximab + methotrexate (MTX) or placebo + MTX, there was significant slowing of radiographic progression (mean changes in modified Sharp/van der Heijde score, 0.83 vs 7.91; P < 0.001 for all comparisons of infliximab + MTX vs MTX) in patients who did not achieve an ACR20 response. Conversely, a prospective cohort study that followed up 187 patients with RA in clinical remission for up to 2 years reported clinically relevant radiographic progression as measured using Sharp scores (change in Sharp/van der Heijde score ::::5) in 7% of patients with persistent remissionY These findings suggest that clinical disease activity alone might not be adequate for the determination of meaningful treatment response. Because clinical trials might employ rigorous inclusion and exclusion criteria, patients in trials are not necessarily representative of those seen by clinicians in the practice setting. Several observational studies have reported that 5 % to 42 % of patients in clinical practice would meet all entry criteria for the major RCTs of anti-TNF agents. 9,38,39 Although a longitudinal analysis in patients with RA, by Kingsley et al,40 re1221

Clinical Therapeutics

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Figure 1. Pro po rt io ns of pa t ients w it h prim ary trea tm en t failu re in clinica l tri a ls of tumor necrosis fa ctor inhib itors based on use of American College of Rheumatology (ACR) response crite ria for inadequate response. 25-27 ACR20 = 20% im prove ment in sp ecified ACR parameters; ACR50 = 50 % im pro vement in s pec if ied ACR param et ers.

ported that 68% of 754 patients in clinical practice fulfilled clinical trial inclusion criteria at some point, 32 % of patients did not. Clinicians should also take into account ethical and practical considerations when deciding whether a patient must meet clinical trial criteria to qualify for receiving a specific therapy. Studies that have assessed general patient eligibility for theoretic inclusion in any given clinical trial have found that the majority of patients seen in clinical prac-

tice would have been excluded from a clinical trial based on the presence of lower disease activity than required. 9,38- 40 In an observational cohort study in 1458 patients with RA in clinical practice settings from the Rheumatoid Arthritis Observation of Biologic Therapy (RABBIT [in German]) registry, Zink et a139 reported that patients in clinical practice had a greater burden of comorbid disease and a higher rate of previous use of DMARDs compared with patients in clinical trials (populations included were from

Tabl e I. Europ ean Leag ue Aga inst Rheumati sm respon se crite ria based on th e 28-joi nt co unt d isease activit y score (DAS-28) .24 Im prove me nt in DAS-28 Present DAS-28 <3 .2* 3.2-5 .1 >5.1

<0.6

0.6-1 .2

>1.2

No resp on se No resp o nse No resp on se

Mod er ate resp o nse Mod erate resp onse No resp on se

Goo d resp onse Mod erate resp on se Mod erate resp on se

*A sco re <2. 6 is co nsidered d isea se remissio n.

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ATTRACT [Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy],"! ARMADA [Anti-TNF Research Study Program of the Monoclonal Antibody D2E7 in Rheumatoid Arthritis],27 and TEMPO [Trial of Etanercept and Methotrexate with Radiographic Patient Outcomesl.v as well as trials reported by Moreland et a143 and van de Putte et a1 44). As a result, and because patients enrolled in clinical trials generally have higher disease activity than patients in clinical practice, it might be difficult to extrapolate a definition of effectiveness as it would apply to an individual patient based on efficacy outcomes in clinical trials. For example, when using the ATTRACT trial as a comparison for inclusion status, 52.2% of the 101 patients from the RABBIT registry who met the inclusion criteria for ATTRACT had an ACR20 response, whereas 44.3% of the 271 patients from the RABBIT registry who did not meet the inclusion criteria for ATTRACT had an ACR20 response. Further evidence of the difficulty in describing an agent's effectiveness and sustainability between clinical trials and clinical practice comes from Duclos et al,45 who reported in a single-center, retrospective analysis that of the 770 patients assessed, 39.4% were receiving the same TNF inhibitor in clinical practice after 3 years, a retention rate that is lower than those observed across clinical trials. The patient perspective should also be considered when determining adequacy of response. Patientcentered outcomes, such as function, fatigue, and QOL, have been suggested as tools that can help to better discriminate active treatment from placebo in clinical trials because the placebo effect is less pronounced when such variables are taken into account.v' Guidance for the use of patient-centered outcomes as end points in clinical trials has been published.i" and these outcome measures have become increasingly important for assessing the effectiveness of RA treatments in clinical practice.f" In principle, treatment response may be inadequate from the patient's perspective, even if an adequate decrease in clinical disease activity is documented. To further distinguish statistical significance from clinical relevance with regard to patient-centered outcomes in RA, the concept of minimal clinically important difference (MCID)-the smallest difference in an outcome that is perceived by the patient to be of clinical benefit 49-gained recognition. MCID is unrelated to statistical significance, and while often used as an outcome measure in clinical trials, especially in June 2009

relation to function, MCID may not necessarily represent an adequate response."? Ideally, improvement in patient-reported outcomes should result in values that restore or approach normal population values. The restoration of normal values was reported, with regard to QOL improvements, when abatacept was used in 258 patients with RA and an inadequate response to prior anti-TNF treatrnent-" and in 652 patients who had an inadequate response to MTX.51 In both of these multicenter, double-blind RCTs, mean healthrelated QOL (as measured using scales of physical and social functioning, pain, general and mental health, and vitality) significantly improved with the use of abatacept 10 mg/kg at days 1, 15, and 29 and every 28 days thereafter (P < 0.001).50,51 In those patients, improvement was correlated with change in disease activity as assessed using standard response criteria.51 That the current definitions of treatment response are inadequate is troublesome in the clinical setting, where a practical and practicable approach must prevail, and suggests that new concepts are needed to define and measure response. New approaches should take into account important indicators of disease activity, including clinical (eg, tender, swollen joints; erythrocyte sedimentation rate; C-reactive protein), radiographic, and patient-centered outcomes, to determine and document the range of treatment effects achievable with the biologic DMARDs in clinical practice. Defining and Assessing Treatment Response/ Clinical Remission

Regardless of the definition of treatment response! clinical remission. early aggressive treatment with conventional or biologic DMARDs has consistently been reported to be associated with better patient outcomes compared with TNF inhibitors. 52-58 The greatest opportunity in which the initiation of aggressive treatment can dramatically improve outcomes appears to be in early-stage RA.5 9-61 As a result, an aggressive approach has been incorporated into the ACR guidelines for early-stage RA management.v-f' Although some payers might associate aggressive treatment with expense in terms of higher drug-acquisition costs, a higher cost may be offset by improved outcomes, increased productivity, and overall lower resource utilization costs. 8,64,65 The goal of therapy for RA is disease remission, but only with the introduction of the biologic DMARDs 1223

Clinical Therapeutics

has this goal become realized in a meaningful way. Despite this important treatment advance, clinical remission has not been consistently defined in clinical trials and observational studies. As found by Makinen et a1 66 in a single-center observational cohort study in 127 patients with early-stage RA, the proportion of patients achieving remission is likely dependent on the definition of remission (by ACR criteria, clinical criteria, or radiographic criteria) (Figure 2). Similarly, Khanna et a1 67 reported in an observational study in 200 patients with early-stage RA that at any particular time point during treatment, the rates of remission and minimal disease activity were dependent on how each state was defined. For example, the lowest response rates at 6 months for minimal disease activity and remission definitions were with DAS-28 0:;2.85 (20%) and the ACR criteria (0.7%), respectively. Current definitions of remission. using ACR or DAS criteria (Table II), have not been developed for use in terms of defining a treatment goal. Furthermore, neither the ACR nor the DAS criteria consider structural damage or physical function; they simply provide a limited assessment from the patient's per-

P < 0.00 1

75 60

spective. The ACR criteria include fatigue, which is omitted in the modified ACR criteria. The DAS incorporates a patient's global assessment measurement that relates more to clinical end points than to the impact of the disease on function and activities of daily living.20.68.69 The US Food and Drug Administration (FDA) has recommended using more stringent criteria to define remission. such as the ACR remission criteria plus the absence of radiographic progression over a continuous 6-month period during which the patient is not receiving any antirheumatic treatment. 70 While the FDA recommendation likely defines a true biological state of disease remission, the requirement for true remission to occur in the absence of DMARD treatment may be unrealistic in clinical practice because RA is a chronic disease. Two additional definitions suggested by the FDA may be more practical for clinicians: (1) documentation of a complete clinical response identical to that of remission, but with ongoing treatment; and (2) a major clinical response, defined as the maintenance of an ACR70 response for ::::6 months.I'' Although these definitions allow for impartial and reproducible evidence of a treat-

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Fig ure 2. Proportion of patients with rheumatoid arthritis meeting different remissio n crite ria at 5 years after d iagnosis. In th e modified American Co llege of Rheumatology (ACR) criteria, t he fati gu e compon ent was excluded, clinical remission was defin ed a s no tender or swo llen joints and normal eryt hrocyte sedimentatio n rate, and radiographic remission wa s defi ned by t he a bsenc e of wo rsening of erosions and no new ero sio ns from baseline to 5 years. 6 6 P va lue for t he co m pa riso n between t he sets of re mission crite ria.

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Tab le II. Rheumatoid arthritis rem ission cr iteria as defined by the American Co lleg e of Rheuma t o logy (ACR) and the disease activity score (DAS) criteria.20,68 ACR criteria Comp lete clinica l re missio n requ ires meeti ng a minim um of 5 of the fo llowing lastin g at lea st 2 co nsec utive months: Mor ning stiffness <15 minu tes No fat igue No histo ry of jo int pa in No joint tenderness o r pa in on motion No soft-tiss ue swe lling in joints or ten do n s heaths West erg re n ESR <30 mrn/h after 1 hour in women or <20 mrn/h after 1 hour in me n DAS criteria 1) Remission defi ned as a DAS <1.6 using a com posite ind ex of t he fo llowing measure me nt s: Rit ch ie articular index of te nder joints 44 Swo llen joint co unt West ergre n ESR* Pa t ie nt 's globa l assessment 2) Remission defined as a DAS-28 <2.6 usi ng a composite index of t he fo llowing measurements: Abbreviated 28 -joint co unt for te nde r and swo llen joints, o mitti ng t he feet West ergre n ESR* Pa t ie nt 's glo ba l assessment Adap ted wit h perm ission .i'' ESR = eryt hro cyte sedimen tat ion ra t e; DAS-28 = 28 -joint co unt DAS. "Cvrea ctive protein may be used instead of ESR in some versions of t he DAS and th e DAS-28 .

ment effect, the patient's perspective is only minimally incorporated. The findings from the present commentary on available criteria, in addition to the FDA's perspective on quantifying treatment effect, suggest that standardization of the definitions of treatment [ailure and clinical remission is urgently needed. However, regardless of the state of these definitions, individualized disease management should include realistic treatment goals to determine when other therapeutic options should be considered. A universal definition for both treatment [ailure and clinical remission might yield more aggressive therapy targeted toward one set of end points, result in overall improvements in disease outcomes, and indicate which therapies are actually inducing remission in a particular patient. In general, and based on the findings from a literature review by Bakker et al,71 more aggressive therapy has been successful in patients with RA despite the lack of a universally accepted definition of treatment [ailure, June 2009

and the authors suggested that this approach may be appropriate for use in clinical practice. While nonresponse to 1 TNF antagonist does not preclude success with another TNF antagonist, success may not always be obtained.i" and treatment [ailure, defined as an inability to induce or maintain remission, with 2 TNF antagonists may be predictive of nonresponse to a third agent. 73 The mechanisms of action of the nonbiologic DMARDs are fundamentally different from those of the TNF antagonists, which may explain the differences in outcomes found in clinical trials of these agents. 14,15,17-19 Also, clinical response and treatment [ailure were defined differently (ie, per the ACR response criteria) in RCTs of the biologic DMARDs abatacept and etanercept. In 5 double-blind RCTs of abatacept, 4 required 12 tender and 10 swollen joints at randomization, but the fifth did not specify a tender or swollen joint count for eligibility (response: ACR criteria on 66 swollen or 68 tender joint count scales).74-78 1225

Clinical Therapeutics

In 4 double-blind RCTs of etanercept, eligible patients had ::::12 tender and ::::10 swollen joints at screening (68 swollen or 71 tender joint count scales using ACR).25,42,79,80 Studies of adalirnumab, infliximab, and rituxirnab have also used the ACR criteria to measure clinical response and treatment failure. In 5 double-blind RCTs of adalirnumab, ::::9 tender and ::::6 swollen joints were the minimum requirement for eligibility (response: ACR criteria on 66 swollen or 68 tender joint count scales). 27,44,57,81,82 Two pivotal multicenter, doubleblind RCTs that assessed inflixirnab enrolled patients with a median swollen joint count of 19 or 20 (depending on the study) and a median tender joint count of 31 (response: ACR criteria on 66 swollen or 68 tender joint count scales).26,83 In 2 trials of rituximab, patients were required to have ::::8 tender and ::::8 swollen joints, with disease activity assessed using ACR response criteria on 66 swollen or 68 tender joint count scales, European League Against Rheumatism (EULAR) response criteria, and DAS score on a 28-joint scale. 84,85 The DMARD abatacept blocks a specific T-cell function (full activation) that is a central component of RA pathogenesis.!" and the DMARD rituxirnab depletes B cells, which play an important role in RA by binding to a protein on the cell surface. 18 Abatacept has been approved as a first-line agent for reducing signs and symptoms of RA, inducing major clinical response'? (defined as the maintenance of an ACR 70 for at least 6 months 70), inhibiting the progression of structural damage, and improving physical function in adult patients with moderately to severely active RA.17 Rituximab is indicated for the treatment of moderate to severe RA in patients with a history of nonresponse to :::: 1 TNF inhibitor. 18 In both the randomized, double-blind, placebocontrolled phase (n = 258) and the long-term extension phase (n = 217) in patients with active RA in ATTAIN (Abatacept Trial in Treatment of Anti-TNF Inadequate Responders), the use of abatacept was associated with clinically meaningful improvements in fatigue, pain, and sleep.86,87 Across pivotal trials of abatacept, patients reported that QOL was improved based on scores from the 36-item Short Form Health Survey; the Health Assessment Questionnaire; and a visual analog scale that measured pain, sleep, and fatigue. 88 In 2 RCTs84,85 in 627 patients who did not respond to previous anti-TNF treatment,84,85 rituxi1226

rnab (2 infusions of 1000 mg each) was associated with improved ACR and EULAR responses, including improvement in QOL. The Combination Therapy in Patients With Early Rheumatoid Arthritis (COBRA) tria15 2 was the first randomized study of an aggressive "step-down" approach with a combination of drugs (sulfasalazine 2 g/d + prednisolone tapered from 60 mg/d to 7.5 mg/d over 6 weeks) in patients with early-stage RA (n = 76). The use of sulfasalazine + prednisolone was associated with improved ACR response and radiographic damage score compared with sulfasalazine alone, used in a more conventional "step-up" approach. While that study used step-down therapy, the FINRACo (Finnish Rheumatoid Arthritis Combination Therapy) trials? compared the effects of aggressive therapy (flexible dosing combination of conventional DMARDs + prednisolone) with those of DMARD monotherapy on achieving DAS remission by ACR criteria. In the FIN-RACo study, a significantly greater proportion of patients in the aggressive-therapy group achieved remission (defined using the DAS-28 criteria), compared with the monotherapy group at 2 years (37% vs 18%; P = 0.003). In addition, at 5-year followup, radiographic disease progression and work disability rates were lower in the aggressive-therapy group than in patients who received monotherapy.54,90,91 The Tight Control of Rheumatoid Arthritis (TICORA) tria192 was a single-blind RCT in 110 patients with active RA treated with standard or aggressive care. This was the first study to use a targeted approach and regular (every 3 months) assessments and whose design required the addition of different medications (eg, hydroxychloroquinolone, sulfasalazine, prednisolone) if the target measure was not attained. Using this strategy, patients who received aggressive therapy compared with routine care had significantly greater responses, measured by both EULAR-defined remission (65% vs 16%; P < 0.001) and response (defined as a DAS score <2.4 and a decrease from baseline score >1.2) (82% vs 44%; P < 0.001). The 2-year Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA) tria158 compared the effects of an aggressive strategy (oncemonthly clinic visits with adjustment of therapy based on predefined response criteria, using a computerized decision program) with those of conventional care (visits every 3 months and treated as in routine clinical practice). In that trial, of patients who were treated Volume 31 Number 6

M.J. Bergman

more aggressively, 50% achieved at least 1 period of remission (3 months) compared with 37% in the conventional-care group (P = 0.03). The Behandel Stratagieen (BeSt) tria156 was a multicenter, randomized, open-label study in 508 patients with active RA (defined as disease of <2 years' duration, with ::::6 tender and swollen joints on a 68 joint count) and either an erythrocyte sedimentation rate ::::28 or a Patient Global Assessment visual analog scale score ::::20 mm on a 0 to 100-mm scale. It is the only study to have compared initial aggressive management using initial DMARD therapy + inflixirnab (3 mg/kg at weeks 0, 2, and 6 and every 8 weeks thereafter) with 3 other strategies (sequential DMARD monotherapy, step-up DMARD combination therapy, and initial DMARD combination therapy with tapered high-dose prednisone). Any changes in a patient's treatment were based on assessment every 3 months to evaluate whether low disease activity (DAS 0:;2.4 in 44 joints) was achieved. 58 Although the 2 more aggressive treatments, inflixirnab + MTX and MTX + sulfasalazine + prednisone, were associated with earlier functional improvement, as measured using the DAS, Health Assessment Questionnaire.>! and radiographic scores, at 1 to 2 years there was a convergence among all 4 groups in several outcomes, including functional ability, remission, and QOL. The convergence of treatment effects between groups was likely due to required changes in therapy when treatment goals were not met in the groups initiated on less aggressive therapy. 93 DISCUSSION The results obtained from the literature search might not have provided a complete view of all end-point definitions, which might have introduced bias into this assessment. However, the findings from the present commentary suggest that a combination of regular assessments and aggressive treatment targeted toward a predefined goal can improve RA outcomes. Under such conditions, treatment failure may be defined as a lack of achievement of a clinical target, thereby informing clinicians and patients as to what may be the best treatment approach for patients who are most at risk for progressive disease (ie, earlier and more aggressive treatment). CONCLUSIONS The present commentary of selected clinical reports found that the definitions of response, remission. June 2009

minimal disease actunty, inadequate response, and treatment failure were not consistent across studies. This variability and the differences between patients enrolled in trials compared with those in clinical practice settings suggest a need for standardization of these definitions. However, regardless of the status of these definitions, RA management should take into account 2 principles. The first, in the opinion of the author, is an aggressive, evidenced-based approach to therapy with the intent of achieving specific targets or goals, such as a low DAS, CDAI, or RAPID3 score. These goals should be flexible and customized to the patient, as no single measure has been found to be completely predictive of outcome for all patients. The second principle is the incorporation of regularly scheduled assessments to determine whether therapeutic goals are achieved. In clinical trials and clinical practice, relative changes in clinical disease activity, as conventionally assessed using the ACR or DAS criteria, may not be appropriate as the sole target or assessment criterion. Treatment goals and definitions of response should include radiographic and patientreported outcomes, which might provide a more accurate assessment of long-term progression and patient benefits. The availability of biologic DMARDs with different mechanisms of action would provide options for achieving the desired treatment goals in patients with RA. ACKNOWLEDGMENTS Editorial support was funded by Bristol-Myers Squibb (BMS). The author thanks Grant Tower, PhD, and Sean Gregory, PhD, Health Science Communications, New York, New York, for providing editorial support toward the preparation and submission of the manuscript. Dr. Bergman has received consultant's fees from BMS, Union Chimique Belge, Abbott, Roche/Genentech, Amgen, and Wyeth/Pfizer; has received research grants from Abbott and BMS; and has been a member of the speakers' bureau at Abbott, Takeda, and BMS. REFERENCES 1. National Institute of Arthnns and Musculoskeletal and Skin Diseases. Handout on health: Rheumatoid arthntis. http://www. n lams. n I h.gov/ Health_I nfo.' Rheu rnauc, Disease/default.asp. Accessed September 9,2008. 2. Helmick CG, Felson DT, Lawrence RC, et al. Estimates of the prevalence of arthntis and other rheumatic conditions

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Dunlop DD, Manheim LM, Yehn EH, et al. The costs of arthnns. Arthritis Rheum. 2003;49:101-113.

4.

Burton W, MOrrison A, Maclean R, Ruderman E. Systematic review of studies of productivity loss due to rheumatoid arthritis. Occup Med (Lond). 2006;56:18-27. 5. Kosinski M, KUjawski SC, Martin R, et al. Health-related quality of hfe In early rheumatoid arthritis: Impact of disease and treatment response. AmJ Manag Care. 2002;8:231-240. 6. UhligT, LogeJH, Knstiansen IS, Kvren TK. Quantification ofreduced healthrelated quality of life In patients with rheumatoid arthnns compared to the general population.j Rheumatol. 2007; 34:1241-1247. 7. Kavanaugh A, Han C, Bala M. Functional status and radiographic JOint damage are associated with health economic outcomes In patients with rheumatoid arthnus.j Rheuma-

8.

12. Emery P. Treatment of rheumatoid arthritis. 8M}. 2006;332:152-155. 13. Weaver AL. The Impact of new biologicals In the treatment of rheumatoid arthntis. Rheumatology (Oxford). 2004;43(Suppl 3 ):11117-11123. 14. Enbrel (etanercept) [package insert]. Thousand Oaks, Calif: lrnrnunex Corporation; 2006. 15. Hurrura (adahmumab ) [package insert]. North Chicago, III: Abbott Laboratones; 2008. 16. Kmeret (anakmra) [package Insert]. Thousand Oaks, Calif: Amgen; 2006. 17. Orencia (abatacept) [package insert]. Pnnceton, NJ: Bnstol-Myers Squibb; 2008. 18. Rrtuxan (rituxrrnab ) [package Insert]. South San Francisco, Calif: Blogen Idec Inc. and Genentech USA, Inc; 2008. 19. Rerrucade (mfhxrmab ) [package insert]. Malvern, Pa: Centocor, Inc; 2007. 20. Sesin CA, Bingham CO III. Remission In rheumatoid arthntis: Wish-

tol. 2004;31 :849-855.

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sence and gross Income: Expenence from the FIN-RACo trial. Ann Rheum DIs. 2006;65:899-904. 9. Sokka T, PinCUS T. Most patients receiving routine care for rheumatoid arthntis In 2001 did not meet inclu-

sion cntena for most recent clinical tnals or American College of Rheumatology cntena for remission. J Rheumatol. 2003;30:1138-1146. O. Fischer D, Stewart AL, Bloch DA, et al. Captunng the patient's view of change as a clinical outcome measure.JAMA. 1999;282: 1157-1162. 1. Marshall NJ, Wilson G, Lapworth K, Kay LJ. Patients' perceptions of treatment with anu-Tl-lf therapy for rheumatoid arthritis: A qualitative study. Rheumatology(Oxford). 2004;43: 1034-1038.

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Furst D, Genovese M, Kremer J, et al. Defining treatment failure and success In rheumatoid arthntis and practical applications of new biologics. http.y/www.rnedscape.com/ vlewprogram/6721. Accessed September 9, 2008. 22. Wolfe F, Michaud K, Dewitt EM. Why results of clinical trials and observational studies of antrturnour necrosis factor (antl-TNF) therapy differ: Methodological and interpretive Issues. Ann Rheum DIs. 2004; 63(Suppl 2):1113-1117. 23. Felson DT, Anderson JJ, Boers M, et al. American College of Rheumatology. Preliminary definition of Improvement In rheumatoid arthnns. Arthritis Rheum. 1995;38:727-735. 24. Dept of Rheumatology, University Medical Centre, NIJmegen, the Netherlands. Disease Activity Score In rheumatoid arthntrs. http:// www.das-score.nljwww.das-score. nlj. Accessed September 5, 2008.

25. Wemblatt ME, Kremer JM, Bankhurst AD, et al. A trial of etanercept, a recombinant tumor neCroSIS factor receptor:Fc fusion protein, In patients with rheumatoid arthntis receiving methotrexate. N EnglJ Med. 1999;340:253-259. 26. Marru R, St Clair EW, Breedveld F, etal, forthe ATTRACT Study Group. lnflixrmab (chrrnenc anti-tumour necrosis factor alpha monoclonal antibody) versus placebo In rheumatoid arthntis patients receiving concomitant methotrexate: A randorrused phase III trial. Lancet. 1999; 354:1932-1939. 27. Wemblatt ME, Keystone EC, Furst DE, et al. Adahrnurnab, a fully human anti-tumor necrosis factor alpha monoclonal antibody, for the treatment of rheumatoid arthnns In patients taking concomitant methotrexate: The ARMADA trial [published correction appears In Arthritis Rheum. 2003;48:855]. Arthritis Rheum. 2003; 48:35-45. 28. Chung CP, Thompson JL, Koch GG, et al. Are American College of Rheumatology 50% response cntena supenor to 20% cntena In distinguishIng active aggressive treatment In rheumatoid arthntis clinical trials reported since 1997? A meta-analysis of drscnrrunant capacities. Ann Rheum DIs. 2006;65:1602-1607. 29. Shaver T, Shahoun S, Anderson J, et al. The outcome of aggressive biologic therapy In clinical practice: Measurement by DAS remission and minimal disease actlvlty(MDA). Presented at: American College of Rheumatology 71 st Annual MeetIng, Boston, Mass, November 10-11, 2007. Abstract 323. 30. Shaver TS, Anderson JD, Weldensaul DN, et al. The problem of rheumatoid arthntis disease activity and remission In clinical practice. J Rheumatol. 2008;35:1015-1022. 31. PinCUS T, Sweanngen CJ, Bergman M, Yazrci Y. RAPID3 (Routine Assessment of Patient Index Data 3), a rheumatoid arthntis Index with-

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Boers M, for the COBRA Study Group. Demonstration of response In rheumatoid arthritis patients who are nonresponders according to the American College of Rheumatology 20% criteria: The paradox of beneficial treatment effects In nonresponders In the ATTRACT trial. Anti-Tumor Necrosis Factor Trial In Rheumatoid Arthntis with Con-

comitant Therapy. Arthritis Rheum. 2001 ;44:2703-2704. 36. Smolen JS, Han C, Bala M, et ai, for the ATTRACTStudy Group. EVidence of radiographic benefit oftreatment with mfhxrrnab plus methotrexate In rheumatoid arthritis patients who had no clinical Improvement: A detailed subanalysis of data from the anti-tumor necrosis factor trial In rheumatoid arthritis with concomitant therapy study. Arthritis Rheum. 2005;52:1020-1030. 37. Molenaar ET, Voskuyl AE, Dinant HJ, et al. Progression of radiologic damage In patients with rheumatord arthritis In clinical remission. Arthritis Rheum. 2004;50:36-42. 38. Sokka T, PinCUS T. Eligibility of patients In routine care for major

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coliconomus. 2004;22(Suppl 1):27-38. 49. Guyatt GH, Osoba D, Wu AW, et ai, for the Clinical Significance Consensus Meeting Group. Methods to explain the clinical significance of health status measures. Mayo Om Proc. 2002;77:371-383. 50. Westhovens R, Cole JC, LI T, et al. Improved health-related quality of life for rheumatoid arthntis patients treated with abatacept who have inadequate response to antl-TNF therapy In a double-blind, placebocontrolled, mulncentre randomized clinical trial. Rheumatology (Oxford). 2006;45: 1238-1246. 51. Russell AS, Wallenstein GV, LI T, et al. Abatacept Improves both the physical and mental health of patients with rheumatoid arthntrs who have Inadequate response to methotrexate treatment. Ann Rheum DIs. 2007;66:189-194. 52. Boers M, Verhoeven AC, Markusse HM, et al. Randorrused comparison of combined step-down prednisolone, methotrexate and sulphasalazme with sulphasalazme alone In early rheurnatord arthritis [published correction appears In Lancet. 1998;35:220]. Lancet. 1997;350:309-318. 53. Genovese MC, Bathon JM, Martin RW, et al. Etanercept versus rnetho-

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Address correspondence to: Martin Jan Bergman, MD, 8 Morton Avenue, Suite 304, Ridley Park, PA 19078. E-mail: [email protected] 1231