Understanding emerging treatment paradigms in rheumatoid arthritis

Treatment strategies for rheumatoid arthritis (RA) will continue to evolve as new drugs are developed, as new data become available, and as our potential to achieve greater and more consistent outcomes becomes more routine. Many patients will find both symptom relief and modest control of their disease with disease-modifying antirheumatic drugs (DMARDs), yet this course of therapy is clearly not effective in all patients. In fact, despite strong evidence that intensive treatment in the early stages of RA can slow or stop disease progression and may prevent disability, many patients continue to be managed in a stepwise manner and are treated with an ongoing monotherapy regimen with DMARDs. There is now a large body of evidence demonstrating the success of treating RA patients with anti-TNF therapy, usually in combination with methotrexate. As a result of the increased use of anti-TNF therapy, treatment paradigms have changed – and our practice is beginning to reflect this change. In the present review, we summarize the salient points of several recently proposed and emerging treatment paradigms with an emphasis on how these strategies may impact future practice.


Introduction
To evaluate the success of any treatment paradigm, it is critical to defi ne the optimal treatment goals in rheu matoid arthritis (RA) and to determine how achievement can be measured.

Treatment goals
Untreated infl ammation leads to tissue damage; and the longer RA is left untreated, the greater the extent of the damage [1]. As most joint damage is largely irreversible, persistent damage will inevitably result in greater disability [1]. Th e treatment goals in RA therefore include [2,3]: prevention or control of joint damage; prevention of disease progression; prevention of loss of joint function; a decrease of symptoms (for example, pain and stiff ness), and achievement of remission or low disease activity; improvement in quality of life (QoL) and maintenance of lifestyle; achievement of drug-free remission; and rapid control of underlying infl ammation.
Diagnosis and treatment of RA early in the disease course provides symptom relief and also prevents longterm structural damage and functional decline [4], with a concomitant improvement in QoL and maintenance of everyday activities of daily living. Considering the accepted concept of early treatment in the disease course, a window of opportunity may exist whereby therapeutic intervention could have a disproportionate impact on outcome, resulting in remission induction and maintenance of response after cessation of treatment [5]. Th e ultimate goal of treatment is to achieve drug-free remission. Previously, despite the fact that drug-free remission is the ideal outcome of therapy, remission in patients with RA was considered rare and unpredictable at the outset of disease [6]. Five-year data from the Behandel-Strategieën (BeSt) study, however, indicate that 19% of patients who received initial combination treatment with methotrexate (MTX) and infl iximab achieved drug-free remission [7] -emphasizing that rapid control of underlying infl ammation is critical.

Measures of disease activity
Th e acute-phase response, a nonspecifi c reaction to infl ammation, is characterized by an increase in the synthesis of certain plasma proteins by the liver, including C-reactive protein (CRP), haptoglobin, and α 1 -antitrypsin [8]. Measuring alterations in acute-phase proteins is an indirect way of determining the presence and severity of infl ammation [9]. Th e erythrocyte sedimentation rate (ESR) and the CRP level are the most commonly used measures of infl ammation in RA [8].
Increased CRP levels are associated with decreased functional ability [10] and with increased disease activity Abstract Treatment strategies for rheumatoid arthritis (RA) will continue to evolve as new drugs are developed, as new data become available, and as our potential to achieve greater and more consistent outcomes becomes more routine. Many patients will fi nd both symptom relief and modest control of their disease with disease-modifying antirheumatic drugs (DMARDs), yet this course of therapy is clearly not eff ective in all patients. In fact, despite strong evidence that intensive treatment in the early stages of RA can slow or stop disease progression and may prevent disability, many patients continue to be managed in a stepwise manner and are treated with an ongoing monotherapy regimen with DMARDs. There is now a large body of evidence demonstrating the success of treating RA patients with anti-TNF therapy, usually in combination with methotrexate. As a result of the increased use of anti-TNF therapy, treatment paradigms have changed -and our practice is beginning to refl ect this change. In the present review, we summarize the salient points of several recently proposed and emerging treatment paradigms with an emphasis on how these strategies may impact future practice. and radiological progression in RA [11,12]. CRP is considered a more specifi c marker of infl ammation than the ESR and also serves as a predictor of functional status and joint damage [13]. Additionally, CRP correlates with response to therapy as CRP levels lower or normalize in RA patients following eff ective treatment [11]. Although CRP is the accepted marker of infl ammation, the ESR can provide useful additional information, particularly regard ing disease severity; routine analyses of both CRP and the ESR may therefore be benefi cial [13].
In terms of remission, defi nitions that can be used include the American Rheumatism Association preliminary remission criteria and the defi ned cut-off points for the disease activity score (DAS), the disease activity score in 28 joints (DAS28), the clinical disease activity index, and the simplifi ed disease activity index [14]. Use of the DAS to evaluate disease activity in RA (as in several of the trials described here) has been extensively validated, and current clinical practice is guided by DAS monitoring [15,16]. Th is DAS tool was developed decades ago when medications and treatment goals were diff erent. Some suggest that DAS28 remission criteria are not stringent enough, and that cut-off points for low/moderate/high disease activity and remission may in the future need to be lower because of more aggressive RA therapy [16].
Furthermore, a Spanish group recently added to the body of evidence supporting use of ultrasound for quantifying infl ammation in RA [17]. Ultrasound with power Doppler can be considered an extension of the clinical examination because it provides direct visualiza tion and assessment of synovitis, which may be con sidered a surrogate for disease activity. Th ese researchers examined 42 joints in each of 97 patients in remission, and compared the ultrasound fi ndings with results from the DAS28 and the simplifi ed disease activity index in the same patients. Interestingly, 92 of 97 (95%) patients supposedly in remission displayed synovial hypertrophy. Th ey found that the simplifi ed disease activity index was superior to the DAS28 in determining absence of infl am matory activity, and therefore in determining remission [17].
Th e American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR) are currently preparing a new defi nition of remission plus updated recommendations, and both organizations encourage researchers to pursue consensus on a uniform defi nition that may include imaging modalities [14].
Persistent infl ammation in RA leads to cartilage and bone destruction [18]. Infl ammation and subsequent radiological progression drive disability in RA [19]. Although the degree of disability varies among patients, it is clear that a proportion of patients have disease that progresses particularly rapidly. In this patient subset, rapid control of infl ammation is even more important to prevent accumulation of permanent damage. Th e key to long-term disease control is therefore achieving prompt and substantial control of infl ammation.

Disease progression is patient specifi c
It has long been recognized that progression of RA is heterogeneous, which means there is high variability in progression and disease activity among patients. Recognition of patients with rapidly progressing disease is critical to identify candidates where intensive therapy may have the most impact in terms of preventing disease progression and maintaining function. Biological markers exist that may be useful in predicting patients at risk for active, progressive disease. Markers such as CRP and the ESR are extensively used to measure the level or degree of infl ammation in patients with RA [20].
Th e Persistent Infl ammatory Symmetrical Arthritis (PISA) scoring system has been used in clinical trials to establish patients with poor prognosis who are likely to have rapidly progressing RA [21]. One point each is awarded for rheumatoid factor positivity, for possession of the shared epitope (HLA-DR1/DR4/DR10), for a CRP level >20 mg/l, for female gender, and for a Health Assess ment Questionnaire raw score >4; and two points are awarded for a Health Assessment Questionnaire raw score >11. A PISA score ≥3 indicates a poor prognosis [21]. Although this test is used in clinical trials to identify patients with poor prognoses, it is not clear why the PISA system is not practical for routine clinical practice apart from the shared epitope with all the other measures that are routinely used [22].
In routine clinical practice, several factors have been shown to help predict which patients are at risk for radiological progression [23,24]. Th ese biological markers/ clinical indicators include an elevated ESR and CRP level, evidence of erosion, number of swollen joints, high DAS score, and functional ability using the Health Assessment Questionnaire. Autoantibodies, such as rheumatoid factor and anti-cyclic citrullinated peptide antibodies, also are important predictors of outcome in RA. Although these factors are not defi nitive, if a patient exhibits these clinical signs then the physician can be confi dent that, without treatment, the patient is more likely to progress rapidly with disability (Table 1).
Patients with rapidly progressing disease require immediate and intensive control of infl ammation to halt disease. Identifi cation of these patients is therefore impor tant as it off ers a greater opportunity to change the course of disease.

Classic treatment strategies
Th e traditional treatment paradigms in RA are based on one of two approaches: sequential monotherapy or stepup combination therapy ( Figure 1) [25].
In sequential monotherapy, treatment is initiated with traditional disease-modifying antirheumatic drug (DMARD) monotherapy, such as MTX. If there is insuffi cient or no response, patients are switched to mono therapy with another traditional DMARD, such as sulfasalazine [2]. Th is therapeutic approach may be repeated several times until combination therapy with a DMARD plus a biologic agent, or with a corticosteroid, is introduced as a last resort [2].
In the step-up approach, therapies with the least toxicity are utilized early, and more intensive therapies are added because of lack of response or toxicity. Patients may benefi t from consultation with physical or occupational therapists, social workers, and/or patient educators. Nonsteroidal anti-infl ammatory drugs or local low-dose systemic steroids may be considered for control of symptoms. Th e ACR recommends starting treatment with a DMARD within 3 months of diagnosis, whereas the EULAR recommends that DMARD treatment begins as soon as possible [2,26]. DMARDs may be changed or added in patients with inadequate response to treatment (that is, ongoing active disease after 3 months of maximal therapy). Patients who continue to have a suboptimal response may be advanced to receive additional trials of DMARDs, whether used alone or in combination, or may receive treatment with biologic agents [2].
In practice, the frequency of patient visits with a rheumatologist is often determined by disease type. Patients with rapidly progressing disease are prioritized for early review and are seen more often. A pan-European survey of rheumatologists (n = 457) established how the rheumatologists identify and treat particular patient types in everyday practice [27]. Forty percent of respondents reported that they see patients with rapidly progress ing disease monthly, whereas only 3% see patients with stable disease on a monthly basis. Th is perceived need for assessment of this group allows rheumatologists to better achieve treatment goals through identifi cation

Sequential Monotherapy
Step-up Combination Therapy

No response
No response of these patients and use of intensive treatment paradigms such as early use of biologics [27].
Traditional treatments can be suboptimal for patients with RA, because these therapies do not fully address the underlying infl ammation driving the disease progression. In particular, response to DMARD monotherapy is frequently suboptimal, and patients with severe RA treated with MTX often exhibit only partial improvement [28]. A signifi cant proportion of patients, however, can attain a state of very low disease activity or remission with DMARDs [29]. Regardless of studies showing DMARD combination therapy to be more eff ective than monotherapy, single-drug treatment remains the initial treatment approach for most patients [3]. DMARDs have a relatively slow onset of action (1 to 6 months) and may have a less favorable side-eff ect profi le than some other therapies [3,30]. In fact, toxicity is the most common reason for discontinuing treatment with MTX [30]. In addition, conventional DMARDs, even when used intensively, might be less eff ective in reducing radiographic progression than TNF inhibitors [31]. To meet the RA treatment goals of preventing and controlling joint damage, preventing disease progression and loss of joint function, and improving patients' QoL, the underlying infl ammation of RA must be rapidly suppressed and controlled [2,3].

Biologic agents: addressing unmet needs
DMARDs alone, including the current gold standard MTX, do not control disease severity, prevent bone and cartilage damage, or maintain QoL in a considerable proportion of RA patients [32,33]. Th e ideal, most eff ective treatment should provide rapid and sustained suppression of infl ammation, resulting in the maintenance of function and prevention of joint damage [5]. In patients with well-established RA, biologic agents have been shown to eff ectively improve clinical, functional and radiographic outcomes and to retard radiographic progres sion [5,34]. Both the ACR and the EULAR, however, currently limit recommendations for addition of a biologic to patients with high disease activity and poor prognosis in whom the DMARD treatment goal was not achieved, and to DMARD-naïve patients with poor prognostic markers [29,34]. As is true for any drug, biologic agents do not achieve optimal response in all patients, and response may diminish over time in some patients.

Control underlying infl ammation to prevent disability and stop disease progression
Th e fi rst ACR guidelines for the management of RA were developed in 1996 and were subsequently updated in 2002 and 2008 [2,34,35]. Once the initial steps in the management of RA -establishing the diagnosis, perform ing a baseline evaluation, and estimating the prognosis [2] -are complete, one must move on to consider the optimal treatment strategy for the patient.
Th e new treatment paradigm recognizes the potential window of opportunity for therapeutic intervention in early disease. Early therapeutic intervention in RA reduces long-term disability and joint damage [6]; the use of the most eff ective therapy is therefore appropriate in early treatment [5]. Some studies have evaluated the eff ectiveness of TNF inhibitors (etanercept, adalimumab, infl iximab) in early RA [4,5,36,37].
In the double-blind Combination of Methotrexate and Etanercept in Active Early Rheumatoid Arthritis study, patients with early RA (disease duration, 3 to 24 months) were randomized to receive either MTX plus etanercept (50 mg/kg) combination therapy or MTX monotherapy [36]. At 52 weeks, 50% (95% confi dence interval (CI), 44 to 56%) of patients in the combination treatment group achieved clinical remission (DAS28 <2.6) with few swollen or tender joints, compared with 28% (95% CI, 23 to 33%) of patients on MTX monotherapy. Furthermore, 80% (95% CI, 75 to 85%) of patients in the combination treatment group and 59% (95% CI, 53 to 65%) of patients in the MTX group achieved radiographic nonprogression (modifi ed total Sharp score change ≤0.5). Th ese results suggest that in addition to achieving an immediate improvement in disability, longer-term disability may be preventable by inhibiting radiographic progression. Th e study also suggests that remission is an achievable goal in patients with early severe RA within the fi rst year of treatment with etanercept plus MTX [36].
Th e PREMIER study was a randomized, double-blind clinical trial comparing the effi cacy of adalimumab (40 mg/kg) plus MTX combination therapy versus MTX monotherapy or adalimumab monotherapy in patients with early RA (disease duration <3 years) [37]. Combination therapy was superior to both adalimumab and MTX mono therapy in all outcomes in the study. At 1 year, 43% of patients receiving combination therapy achieved clinical remission (DAS28 <2.6), compared with 23% and 21% of patients receiving adalimumab monotherapy and MTX monotherapy, respectively (P <0.001 for both compari sons). Following the second year of treatment, nearly one-half (49%) of patients receiving combi nation therapy achieved clinical remission, compared with only 25% of patients receiving adalimumab monotherapy and 25% of patients receiving MTX monotherapy (P <0.001 for both comparisons). Patients receiving combination therapy demonstrated a mean increase in total Sharp score of 1.3 Sharp units, compared with 3.0 units in those receiving adalimumab monotherapy (P = 0.002) and 5.7 units in those receiving MTX monotherapy (P <0.001) at 1 year. After 2 years of treatment, patients receiving combination therapy continued to have signifi cantly less radiographic progression (mean change, 1.9 Sharp units) compared with those receiving either adalimumab monotherapy (5.5 units) or MTX monotherapy (10.4 units) (P <0.001 for both compari sons). Th e study demonstrates the superi ority of combination therapy with adalimumab and MTX over adalimumab monotherapy or MTX mono therapy with respect to achieving clinical remission and stopping disease progression in patients with early, aggressive RA [37].
In a double-blind study, 20 previously untreated patients with early RA (<12 months of symptoms) of poor prognosis (PISA scoring system) received either MTX plus infl iximab (3 mg/kg) combination therapy or MTX monotherapy for 12 months [5]. Treatment was discontinued after 12 months and patients were followed for an additional 12 months. Infl iximab plus MTX treatment was found to reduce magnetic resonance imaging (MRI) evidence of synovitis and joint damage compared with MTX alone. MRI synovitis scores dropped from 5.5 at baseline to 3.4 at week 14 in the infl iximab group, compared with a reduction from 6.2 to 5.9 in the MTXalone group (P <0.05). Th e diff erence was maintained after 12 months of treatment (3.8 vs. 6.6, respectively; P <0.05). In the infl iximab group, rapid improvements in physical function were sustained throughout the 12-month treatment period. Disease activity remained below remission levels in 70% of patients 12 months after the withdrawal of therapy. Similar benefi ts were seen in QoL. Th ese results suggest that the rapid control of infl ammation demonstrated by infl iximab confers longterm functional, QoL, and MRI benefi ts [5].
Th is study by Quinn and colleagues also shows that CRP levels rapidly return to normal levels in patients receiving infl iximab combination therapy. Indeed, a single infl iximab infusion normalizes mean CRP levels ( Figure 2). Th e reduction in CRP is signifi cantly greater in the infl iximab group compared with the MTX-alone group (P <0.05) and corresponds with suppression of infl ammatory joint disease (MRI synovitis) and resultant prevention of structural damage (MRI erosions) [5].
In the Tight Control of RA study, intensive management with conventional DMARDs, an intra-articular steroid, and frequent clinical assessments was compared with routine outpatient care [31]. Th e primary outcome measures were a mean decrease in the DAS and in the proportion of patients with a good response. Th e mean decrease in the DAS was greater in the intensive group than in the routine group (-3.5 vs. -1.9; 95% CI, 1.1 to 1.2; P <0.0001). Additionally, patients treated intensively were more likely to have a good response (45/55 (82%) vs. 24/55 (44%); 95% CI, 2.4 to 13.9; P <0.0001) or to be in remission defi ned by DAS <1.6 (36/55 (65%) vs. 9/55 (16%); 95% CI, 3.9 to 23.9; P <0.001). Th e Tight Control of RA study showed that a strategy of intensive outpatient management substantially improves disease activity, radiographic disease progression, physical function, and QoL at no additional cost [31]. [5]. AUC, area under the curve; CRP, C-reactive protein; MTX, methotrexate. Reproduced with permission from [5].

Figure 2. Infl iximab rapidly normalizes C-reactive protein levels in rheumatoid arthritis
Th e concept of using tight control of RA to drive disease-management decisions is also illustrated by the BeSt study [4]. Pisetsky off ers some very real conclusions in his 'provocative and very creative' [38] landmark randomized clinical trial on treatment strategies for RA [39]. Treatment adjustments were made every 3 months in an eff ort to obtain low disease activity (DAS in 44 joints (DAS44) ≤2.4) and may be described as DASdriven therapy [7]. Previous data have indicated that treatment with a DMARD such as MTX combined with a TNF inhibitor is more eff ective than DMARD monotherapy [4]. Th e anti-TNF therapy (infl iximab) used in the BeSt study also has a rapid onset of action (as early as 2 weeks) [2], a favorable safety profi le, and sustained eff ects in many RA patients [4].
Th e development of TNF inhibitors presents clinicians with eff ective treatment options. Th e increase in therapeutic choices, however, leaves open the question of what is the optimal therapeutic strategy in patients presenting with RA. In an attempt to answer this question, the BeSt study compared the clinical and radiographic outcomes of four diff erent treatment strategies: sequential monotherapy; step-up combination therapy; initial combination therapy with tapered high-dose prednisone; and initial combination therapy with infl iximab (Figure 3). Th e common goal in all strategies was to rapidly and eff ectively reduce disease activity by tight monitoring and immediate adjustment of therapy in the case of an insuffi cient response [4]. Th e BeSt study is the fi rst in which decisions about changing the dosage or discontinuing infl iximab treatment were dictated by DAS calculations before every infusion [40]. It is possible that some conclusions drawn from this study may be extrapolated to all TNF inhibitors.
Th e specifi c objective for each treatment group in the BeSt study was to reach and sustain a DAS44 ≤2.4, indicating low disease activity. After 1 year, this goal was attained by 53% of patients on sequential monotherapy (P = 0.004 vs. prednisone; P = 0.001 vs. infl iximab), by 64% on step-up combination therapy, by 71% on initial combination therapy with tapered high-dose prednisone, and by 74% on initial combination therapy with infl iximab ( Figure 4) [4].
Patients treated with initial combination therapy, with either prednisone or infl iximab, had greater and more rapid functional improvement than patients treated with sequential monotherapy or step-up combination therapy. Additionally, clinical improvement measured by ACR response criteria was achieved earlier and by a greater number of patients treated with initial combination therapy than in the other two groups [4].
Th e patients in each group did not necessarily remain in their initial treatment protocol since treatment was adjusted every 3 months in patients who did not reach and sustain DAS44 ≤2.4. In the sequential monotherapy group, approximately 50% of patients required treatment adjustment and 67% of patients had no progression or radiographic joint damage, suggesting that the initial time of 3 months on MTX monotherapy is too long to prevent erosion. Conversely, 93% of patients receiving infl iximab initially have no progression of joint damage [4].
Four years after starting combination treatment with infl iximab and MTX, 51% (61/120) of the patients with very early RA had discontinued infl iximab and still had DAS44 ≤2.4. Of these 61 patients that were off infl iximab treatment at year 4, 17% (20/120) remained in clinical remission (DAS44 <1.6 for ≥6 months) after stopping all antirheumatic drugs without showing progression of joint damage ( Figure 5). Additionally, those 17% of patients receiving initial infl iximab combination therapy had discontinued all antirheumatic drugs and achieved clinical remission. Radiographic progression was highest in patients who had failed MTX and infl iximab treatment, and was minimal in those 20 patients who discontinued all antirheumatic therapy ( Figure 6) [41].
At 5 years, up to 51% of patients achieved remission (DAS <1.6) after sequential monotherapy treatment. Of those remissions, 39% of patients remained on initial sequential monotherapy and 81% remained on the initial allocation to combination treatment with infl iximab (P <0.001 vs. sequential monotherapy). Overall, 48% of all patients achieved remission and up to 19% achieved drugfree remission. Initial treatment of patients with early, active RA with infl iximab and MTX off ers the opportunity to discontinue infl iximab in the majority of patients once a low DAS is achieved and maintained without fl are of the disease. Additionally, a low dosage of MTX may maintain a low level of disease activity in most responders [40].  [4]. HAQ, Health Assessment Questionnaire. Reproduced with permission from [4].
Th e BeSt study illustrates that early and intensive suppression of RA activity with a TNF inhibitor may provide earlier clinical improvement and less progression of joint damage. Furthermore, the use of initial combination therapy does not result in increased toxicity. Additionally, combination therapy can be withdrawn successfully and less treatment adjustments are needed than with initial monotherapies. Th is cooperative study in an organized healthcare setting demonstrated that there appears to be an opportunity for patients initially diagnosed with RA to achieve a lasting benefi t in the course of their disease. Furthermore, true clinical remission without any continuing or ongoing mainte nance therapy may even be possible [42].
In terms of selection of therapy, the most recent ACR guidelines recommend use of TNF inhibitors in DMARD-näive patients with early RA and high disease activity. Combination treatment of a TNF inhibitor plus MTX is recommended if high disease activity is present for 3 to 6 months or for <3 months with features of a poor prog nosis (plus reimbursement-related qualifi cations) [34]. Current EULAR guidelines recommend use of TNF inhibi tors when the initial DMARD-alone strategy has failed and poor prognostic factors (that is, autoantibodies, high disease activity, early erosions) are present [29].
Data from the BeSt study indicate that initial treatment with infl iximab plus MTX results in signifi cantly better functional ability over 5 years than other treatment strategies [7]. In addition, infl iximab provides rapid disease control with corresponding suppression of infl am matory disease resulting in functional, QoL, and MRI damage benefi ts [5]. Th e early use of TNF inhibitors may have a specifi c eff ect on the processes that sustain underlying infl ammation [5].
As part of any treatment decision process, one must consider both the benefi ts as well as possible safety risks. Additionally, patient-specifi c parameters need to be considered when selecting a treatment strategy. One such treatment strategy can include early intensive treatment with biologic therapy. Th ere are safety considerations with the use of biologics such as TNF inhibitors, which include risk of infections, lymphoma, and infusion-site or injection-site reactions. Patients should be monitored regularly for potential safety issues while being treated with a TNF inhibitor.
In the BeSt study, no signifi cant diff erences were found in the number of adverse events and withdrawals between the groups during the fi rst 12 months [4]. In particular, no cases of tuberculosis or opportunistic infec tions were reported [4]. In clinical studies with infl ixi mab, adverse reactions are observed in approximately 60% of infl iximab-treated patients and 40% of placebo-treated patients. Infusion-related reactions are the most common adverse reactions reported, and dyspnea, urticaria, and headache are the most common causes of discontinuation [43].
Clinical practice is beginning to change as a result of a paradigm shift that incorporates the increased use of TNF inhibitor treatment strategies. Optimal treatment of patients with RA requires comprehensive coordinated care and the expertise of a number of healthcare providers. Proper identifi cation of patients with active, progressive disease is important; early intervention therefore off ers a tremendous opportunity to change the course of disease and avoid the serious consequences of disease progression [2,26]. At each follow-up visit, the disease must be assessed as being active or inactive. Tracking disease progression can be diffi cult, and patients at risk for active, progressive disease may go undetected. Occasionally, joint examination alone may not adequately refl ect disease activity and structural damage; periodic measurements of other factors that may be predictive of radiological progression can therefore be assessed in routine clinical practice. Such factors include the ESR or CRP level and functional status as well as radiographic examinations of involved joints. Intensive   Figure 6. Less radiographic progression with infl iximab combination therapy [41]. SHS, Sharp-van der Hiejde score. treatment before the onset of joint damage and disability has the ability to improve patient outcomes and may prevent irreversible joint damage [2,26]. Equally important is identifi cation of patients who will respond optimally to biologic agents and/or to early intensive therapy. Evidence suffi cient to support predictors of response, however, is lacking [29,44,45].

Conclusions
Th e underlying infl ammation that is critical for disease progression in chronic infl ammatory diseases such as RA is not fully treated with traditional therapies. As conventional nonbiologic monotherapy is the fi rst treatment off ered to the majority of patients, it is clear that most patients are suboptimally or undertreated for RA. Important treatment goals in RA patients include achieving remission, prevention and control of joint damage, avoidance of further disease progression and loss of joint function, and improvement in QoL. In order to meet these challenges, the underlying infl ammation of RA must be rapidly suppressed and controlled [2,3].
Accumulating data show that intensive treatment strategies with biologic agents, especially the TNF inhibitors (that is, infl iximab), is more eff ective than sequential monotherapy or step-up combination therapy and should be adopted early in the course of RA [4]. TNF inhibitors show substantial effi cacy in combination with MTX, providing rapid and substantial benefi t and improvement in patient outcomes.
In addition to the importance of understanding the effi cacy and safety profi le of a particular drug in RA, recognizing the optimal treatment paradigm in which that drug fi ts is equally essential. Times are changing, and both our understanding of disease processes and the availa bility of new therapies also drive us to change our practice. In everyday practice, we now have ways to identify those patients who are at risk for more rapid disease progres sion and the ability to choose to treat these patients more intensively with biologic therapy. In doing this, the evidence suggests we will best prevent the long-term disability eff ects of RA for our patients.

Competing interests
FCB has received speaker fees from Pfi zer, Abbott, Centocor, Wyeth and Schering-Plough. BC has been a speaker and/or consultant for Abbott, BMS, MSD, Roche, Schering-Plough, UCB and Wyeth.