Optimal care for early RA patients: the challenge of translating scientific data into clinical practice

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1 RHEUMATOLOGY Review Rheumatology 2011;50: doi: /rheumatology/ker131 Advance Access publication 30 March 2011 Optimal care for early RA patients: the challenge of translating scientific data into clinical practice Patrick Verschueren 1 and René Westhovens 1 REVIEW Abstract Although the evidence is clear and most rheumatologists agree that RA should be treated early and intensively, it obviously remains a challenge to put this paradigm into practice. Patient- as well as physician-related factors determine the delay before the disease is recognized and treated appropriately. There is still a need for education in this context. Optimal treatment allocation depends on the determination of prognostic factors, but should also take into account the patient s perspective to be effective. Patients perceptions about the disease and its medical management need to be adjusted as soon as possible. Initiation of intensive or complex treatment regimens is most feasible in a clinical setting, where rheumatologists work together with other health-care professionals, such as nurse specialists. Until now there does not seem to have been a difference in terms of efficacy between intensive RA treatment strategies based on a combination of classical DMARDs with glucocorticoids or with TNF-blocking agents, but given the costs biologicals cannot be considered first-line therapy. More scientific work is needed to identify individuals that could benefit from biologicals early in the disease. Given the long-term benefits of rapid disease control, health authorities should consider investing in a better implementation of intensive treatment regimens based on combinations of classical DMARDs and glucocorticoids. Key words: Early RA, Treatment strategy, Combinatietherapie Bij Reumatoïde Artritis, Biologicals, Health policy. Introduction Current recommendations for RA treatment ask for early intensive therapy with clear targets in terms of disease control during follow-up, but they are less explicit on what should be the content of these intensive treatment regimens [1 4]. There is plenty of evidence that early intensive treatment strategies with conventional DMARDs, especially in combination with oral glucocorticoids or biologicals, are superior to monotherapy with MTX [5 12]. The early combination of conventional DMARDs with a TNF blocker does not seem to improve the clinical and radiological outcome compared with combination with glucocorticoids [13]. Obviously, a potential persistent need for biologicals after early initiation is no attractive perspective for the health-care budget. In contrast, early intensive combination therapy with traditional DMARDs and bridging steroids is feasible in daily practice, 1 Department of Rheumatology, University Hospital Leuven, Leuven, Belgium. Submitted 17 December 2010; revised version accepted 1 March Correspondence to: Patrick Verschueren, Department of Rheumatology, University Hospital Leuven, Herestraat 49, B-3000 Leuven, Belgium. patrick.verschueren@uz.kuleuven.ac.be with excellent clinical and cost effectiveness [14, 15]. Nevertheless, this kind of strategy is rarely used [16 19]. In the current review, we focus on the theoretical framework of successful early RA treatment, describe the present situation in the field and put forward strategies to promote the application of the basic treatment principles in daily practice. Last but not least, the research agenda needed to optimize treatment of early RA is discussed. Early disease recognition and timely referral to the rheumatologist A key element in successful patient care in RA is early recognition of the disease. Public awareness of the clinical presentation and potential consequences of a RA is still poor and many patients wait too long before presenting their symptoms to medical professionals (Westhovens et al., Belgian 2005 data, unpublished). There is evidence that this process is influenced by gender differences, coping styles, sociocultural background and even ethnicity [20 23]. Raising public awareness about the disease by carefully designed information campaigns in the lay press and new media could be an essential first step in improving the effectiveness of RA care.! The Author Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please journals.permissions@oup.com

2 Optimal care for early RA There is also a need to educate medical professionals in order to facilitate the diagnostic process in the early disease phase. In several countries carefully trained patient-partners are put at the frontline of medical education, offering students and postgraduate professionals the unique opportunity of sharing patient experiences and hands on training in musculoskeletal examination. Existing recommendations concerning referral of potential RA patients [3, 24] could be improved with treatment advice for the pre-diagnostic phase, avoiding preliminary use of medication disturbing the diagnostic process. Also the appropriate set of diagnostic tests to be used by primary care physicians in early arthritis could be better defined. Perhaps, in well-defined clinical situations with a reasonable level of suspicion of RA, the determination of ACPAs in combination with RF by general practitioners could improve the effectiveness of referral to the rheumatologist [25 27]. Easy access to rheumatology clinics for patients with early arthritis is a conditio sine qua non for effective RA disease management. Getting an appointment quickly, however, is often a challenge, given the shortage of rheumatologists in many countries. Facilitating access to a rheumatology consultation unfortunately always generates a risk of inappropriate patient referral, bypassing patients that are really in need of urgent advice [28]. Therefore, rheumatologists should be able to rely on a network of primary care physicians understanding and accepting the philosophy of early referral channels. Diagnostic and prognostic work-up Despite the fact that in many cases the diagnosis of RA can be made purely on clinical grounds, imaging modalities such as US and MRI can be very helpful if the clinical picture is less clear [29, 30]. Unfortunately, these techniques are not universally available and their implementation still depends largely on local expertise. In practice, the diagnostic process is often inspired by the existing classification criteria for RA, which unfortunately were not developed for that purpose [31]. The new American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria for RA have been developed to improve the poor sensitivity of the former ACR criteria in early disease [32]. Interestingly, the basic idea was not so much to predict fulfilment of the 1987 criteria in an earlier phase, but rather the need to start DMARD therapy in patients with a high probability of persistent and destructive disease. Not surprisingly the potent ACPA test was therefore incorporated in the new criteria [33]. The lack of standardization of this test is still a problem, and therefore the criteria would probably benefit from a more specific definition of ACPA results [34]. The new criteria will certainly improve early disease recognition, but there is also an inherent loss of specificity. In the hands of experienced rheumatologists this should not necessarily be problematic, since the criteria imply exclusion of other diseases better explaining the clinical picture. But in certain circumstances this lack of specificity could lead to a wrong diagnosis, bad treatment choices and inappropriate inclusion in clinical trials. Apart from the RA classification criteria, many other potential predictors of the disease course have been put forward. They range from demographic and clinical characteristics over serum, SF and synovial tissue-derived predictive factors to imaging techniques, including X-ray, US and MRI [35]. In general prediction models, combining different prognostic factors performs better than single predictors [36 39]. Recently, in analogy with cardiovascular prevention, a visual matrix model was developed predicting rapid radiographic progression under different treatment conditions, based on the results of a large randomized controlled trial [40]. Unfortunately, the positivepredictive performance of this model in daily practice turned out to be low, probably as a consequence of the fact that, contrary to the trial situation, good clinical practice demands prompt treatment adaptation in cases of insufficient response [41]. Expert opinion proved to be effective for the initial treatment choice, provided a tight control strategy was followed afterwards. Although step-down regimens in general perform better, overtreatment could perhaps be avoided in certain individuals using a prediction model. Newer matrix models based on patient populations treated in protocols more closely mimicking the real-life situation and incorporating stronger predictors, such as ACPA, would probably have a better predictive performance [42]. However, long-term response to therapy in terms of remission rate, radiographic damage, functionality and work participation can still better be predicted by the treatment effect during the first few months than by baseline parameters [43 45]. Importantly, the disease course can also be influenced by psychosocial patient characteristics. Illness perception, self-efficacy and the degree of social support a patient experiences are known to be important determinants of the physical outcome [46 48]. When deciding on the treatment strategy, rheumatologists should therefore not only take into account their patients somatic prognostic profile, but also the psychosocial circumstances in which they are confronted with a disease such as RA. It can take some time before such important but delicate information is exchanged, but this process can be facilitated by interaction with a nurse specialist and by the use of questionnaires [49]. In any case, education about the disease, its causes and consequences and the pharmacological as well as nonpharmacological management, is an essential prerequisite for a successful interaction of health professionals with RA patients and their environment [50]. A well-informed patient can be more easily convinced of the need to take unpleasant drugs such as DMARDs. Moreover, in the case of problems, well-educated patients will inform you immediately instead of running unnecessary risks by continuing the medication or, on the contrary, discontinuing essential medication without reason [51]. Therefore, it is not surprising that appropriate education can have long-term beneficial effects on disease outcome [52]

3 Patrick Verschueren and René Westhovens The present treatment paradigm for early RA The new RA treatment paradigm has two important components. First, aim at remission induction as soon as possible using intensive initial treatment strategies, and secondly, once that objective is reached, treat to target based on disease monitoring and prompt treatment adaptation in the case of derailing [1, 4]. Rapid remission induction can be achieved more efficaciously by combining classical DMARDs with potent and fast-acting agents such as glucocorticoids [14, 53] and TNF-a antagonists [9 11], compared with DMARD monotherapy. Until now no differences have been demonstrated between intensive treatment regimens including TNF-a antagonists or glucocorticoids in terms of clinical efficacy and conventional radiological evolution [13, 54]. There is some evidence from MRI studies that structural joint integrity might be better preserved by initial combination therapy with TNF-a antagonists compared with glucocorticoids [53]. On the other hand, it has been demonstrated that, in early RA, long-term outcome is not so much determined by the type of medication used, but rather by the time it takes to bring the disease into remission [43 45]. Moreover, it seems that the introduction of TNF-a antagonists can be postponed for some months without loss of long-term efficacy in terms of disease control and radiographic evolution [55, 56]. Given the important cost of TNF-a antagonists, step-down bridge strategies with glucocorticoids, like the many variants of the Combinatietherapie Bij Reumatoïde Artritis (COBRA) regimen, can be considered effective and safe alternatives for initial remission induction, at least if followed by a treat to target approach [57]. In case remission is not reached within a reasonable time frame using a conventional regimen, for instance 4 6 months, there is still time to switch to an induction strategy based on TNF-a antagonists or perhaps other biological therapies [55, 56]. There is evidence that once remission is reached in the early disease phase, it is possible to discontinue glucocorticoids and step down to a simple maintenance therapy with classical DMARDs [8, 14, 53]; probably also TNF-a antagonists can be discontinued after remission induction in combination with classical DMARDs, although this remains to be investigated further [58, 59]. In certain cases, albeit not more than 18%, all pharmacological treatment can even be discontinued [60 62]. Whatever the initial therapeutic strategy used, the disease course can be improved if, during follow-up, treatment is adjusted based on regular measurements of disease activity, functionality and structural damage [7, 13, 14]. Although tight control and treat to target are often put forward as interchangeable principles, they cannot be considered identical. Treat to target is basically to adopt a certain RA disease activity level as acceptable and intensify (DMARD) treatment following a predefined schedule if during follow-up this target is not reached [63]. Such a system is as simple as it is rigid. It was even shown that the implementation of this kind of strategy could be made easier by a computer model, but it has certainly also many limitations [64]. In practice, we advocate a more flexible tight control principle [14, 65]. This implies that treatment adaptations are more patient centred and based on a more thorough evaluation of the individual clinical picture, with consideration of the potential of the complete therapeutic arsenal. In an era of increasing therapeutic choices, doctors are tempted to use similar standards of evaluation for drugs with totally different pharmacokinetics and incomparable modes of action, leading to precocious decisions to switch to one of the many alternatives [65]. Sometimes decisions on treatment adaptations can better be postponed for strategic reasons, for instance in the case of a clear trend of improvement or flares due to infection or other transient problems. How far are we in clinical practice today? Until now biologicals have not been recommended as initial treatment for RA in most national and international guidelines. Moreover, they are not reimbursed for early RA in most countries. Despite the overwhelming evidence in favour of intensive treatment strategies based on combinations of DMARDs with glucocorticoids, such as the COBRA regimen, they are not often used in daily practice [16, 19]. Doctors fear discussions about complex treatment schedules and the use of glucocorticoids [15]. Patients often have preconceived ideas about glucocorticoids and tend to prefer newer drugs that are being advertised in the media, but interestingly, they do not seem to object to complex strategies if these can be simplified during the further course of treatment [17, 66]. There is also evidence that once they have experienced the positive effect, their opinion about glucocorticoids improves [66]. Interestingly, patients and doctors also have different views on the side effects of glucocorticoid treatment [67], which illustrates the need for more education/information of the general public, and certainly also health-care professionals about this kind of medication [68]. Apart from patient- and physician-related psychological hurdles, practical objections can also hinder the prescription of intensive induction regimens, many of them related to a lack of time [69]. Recognizing the disease, making a correct diagnosis and informing the patient about the need for lifelong treatment can indeed take quite some time at a busy outpatient clinic. Some educative steps can certainly be postponed, but at least a synopsis of the most important facts about the disease and its treatment should be given as soon as possible. The need to find time for an appropriate patient intake causes logistic problems because many outpatient clinics are overbooked and extra appointments are not easily created. These practical problems certainly have to do with the fact that in most countries rheumatologists daily income is primarily based on the number of patient contacts and only marginally on the delivered quality of care. As a consequence, the cost-effectiveness of implementing

4 Optimal care for early RA time-consuming treatment strategies remains low, at least from the individual doctor s point of view. There is evidence that patients treated in a multidisciplinary ambulatory care programme, coordinated by nurse specialists, have a better disease outcome than patients receiving standard rheumatologist s care [16]. This advantage certainly has to do with the facilitation of early intensive treatment initiation thanks to structured teamwork, systematic patient education and monitoring of treatment adherence. Also, different aspects of care not immediately related to pharmacological treatment seem to play a role, although it remains uncertain which components are essential for an effective ambulatory care programme. Unfortunately, in many countries, including Belgium, there is still no structured financial support from the health authorities for models of care in which rheumatologists work closely together with nurse specialists [16]. As a consequence, until now rheumatologistcentred care remains the standard and the basics of the present treatment paradigm for early RA, early intensive remission induction therapy followed by a treat to target approach, are seldom put into practice [16]. How can we proceed? Improvement of the implementation of intensive conventional treatment strategies could lead to a better outcome of early RA at the population level, without necessarily creating extra costs for society [15, 70]. A positive effect on the budget can even be expected, as a consequence of improved socio-professional participation [16, 43]. The minority of patients that cannot be brought into remission with a conventional remission induction regimen can be rapidly recognized and treated with biological therapy if necessary, but in the majority of early RA patients the use of these expensive agents could be avoided or at least postponed [55]. In Belgium, the application of the treat to target principle in RA is already successfully stimulated by a financial incentive from the social security system, but there is still a need for support in the critical early phase of the disease. Promoting the role of nurse specialists for that purpose could even be cost saving [49, 71, 72]. Apart from financial incentives, obviously, the development of local treatment guidelines might be considered, reinforcing existing recommendations from international organizations. In practice, unfortunately such guidelines do not always work appropriately [73]. The research agenda The place of biologicals at the frontline of early RA treatment remains to be determined. Improved knowledge of the pathophysiology could lead to the recognition of more reliable and practical predictors of the disease course and treatment response. Certain individuals might benefit from an earlier introduction of biologics in their treatment regimen without necessarily increasing the cost to society in the long run, provided the duration of treatment could also be limited. Unfortunately, until now we are in need of scientific data supporting such an approach and this evidence will be needed to convince the payers. Today it is still unclear whether there is an ideal sequence for the use of the different biological therapies we have at our disposal. Apart from new insights in the pathophysiology, we would need cleverly designed strategy trials respecting the different modes of action of these targeted therapies to answer this important question. For the time being, treatment regimens based on combinations of conventional DMARDs and glucocorticoids seem the most effective initial treatment choice for RA, also at the macro-economic level. However, it remains to be proved that the current high dosages of glucocorticoids and the addition of SSZ, such as in the original COBRA regimen, are essential for optimal efficacy. Perhaps, other combinations of DMARDs could be even more efficacious. On top of that, there is a need to further analyse in more detail the reasons why COBRA-like treatment strategies are not put into practice more frequently. Does maximal practical support, for instance with preprinted prescription orders, indeed have a favourable effect on COBRA prescription in practice [69]? What is the real extra time investment needed and are there indeed reasons to believe that financial support for a restructuring of time slots for initial patient visits would be helpful? Many of these questions are addressed in the CareRA trial running in various Flemish rheumatology centres with the support of government [Agentschap voor Innovatie door Wetenschap en Technologie (IWT)]. Research in rheumatology has benefited a lot from the support of the pharmaceutical industry over the past decade, but it is clear that this type of strategic investigator-initiated research project cannot and will not be organized without the financial support of the public health authorities. Rheumatology key messages. Promoting integrated RA care programmes could improve implementation of intensive treatment strategies.. Until further research allows more personalized treatment choices, initiation of classical combination therapy with glucocorticoids should be stimulated. Disclosure statement: R.W. holds the UCB chair for RA care at the KU Leuven and acts as a consultant for BMS, Roche and Centocor. P.V. holds the Wyeth chair of early RA management at the KU Leuven and acts as a consultant for UCB, Roche and Pfizer. References 1 Smolen JS, Landewe R, Breedveld FC et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs. Ann Rheum Dis 2010;69:

5 Patrick Verschueren and René Westhovens 2 Walker D, Hall S. NICE guidance on rheumatoid arthritis: implications and challenges for rheumatologists. Rheumatology 2010;49: Deighton C, O Mahony R, Tosh J, Turner C, Rudolf M. Management of rheumatoid arthritis: summary of NICE guidance. Br Med J 2009;338:b Combe B, Landewe R, Lukas C et al. EULAR recommendations for the management of early arthritis: report of a task force of the European Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2007;66: Boers M, Verhoeven AC, Markusse HM et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350: Mottonen T, Hannonen P, Leirisalo-Repo M et al. Comparison of combination therapy with single-drug therapy in early rheumatoid arthritis: a randomised trial. FIN-RACo trial group. Lancet 1999;353: Grigor C, Capell H, Stirling A et al. Effect of a treatment strategy of tight control for rheumatoid arthritis (the TICORA study): a single-blind randomised controlled trial. Lancet 2004;364: Goekoop-Ruiterman YP, de Vries-Bouwstra JK, Allaart CF et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): a randomized, controlled trial. Arthritis Rheum 2005;52: St Clair EW, van der Heijde DM, Smolen JS et al. Combination of infliximab and methotrexate therapy for early rheumatoid arthritis: a randomized, controlled trial. Arthritis Rheum 2004;50: Breedveld FC, Weisman MH, Kavanaugh AF et al. The PREMIER study: a multicenter, randomized, doubleblind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate treatment. Arthritis Rheum 2006;54: Emery P, Breedveld FC, Hall S et al. Comparison of methotrexate monotherapy with a combination of methotrexate and etanercept in active, early, moderate to severe rheumatoid arthritis (COMET): a randomised, double-blind, parallel treatment trial. Lancet 2008;372: Westhovens R, Robles M, Ximenes AC et al. Clinical efficacy and safety of abatacept in methotrexate-naive patients with early rheumatoid arthritis and poor prognostic factors. Ann Rheum Dis 2009;68: Goekoop-Ruiterman YP, Vries-Bouwstra JK, Allaart CF et al. Comparison of treatment strategies in early rheumatoid arthritis: a randomized trial. Ann Intern Med 2007;146: Verschueren P, Esselens G, Westhovens R. Daily practice effectiveness of a step-down treatment in comparison with a tight step-up for early rheumatoid arthritis. Rheumatology 2008;47: Korthals-de Bos I, Van Tulder M, Boers M et al. Indirect and total costs of early rheumatoid arthritis: a randomized comparison of combined step-down prednisolone, methotrexate, and sulfasalazine with sulfasalazine alone. J Rheumatol 2004;31: Esselens G, Westhovens R, Verschueren P. Effectiveness of an integrated outpatient care programme compared with present-day standard care in early rheumatoid arthritis. Musculoskeletal Care 2009;7: van Tuyl LH, Plass AM, Lems WF et al. Discordant perspectives of rheumatologists and patients on COBRA combination therapy in rheumatoid arthritis. Rheumatology 2008;47: van Tuyl LH, Plass AM, Lems WF, Voskuyl AE, Dijkmans BA, Boers M. Why are Dutch rheumatologists reluctant to use the COBRA treatment strategy in early rheumatoid arthritis? Ann Rheum Dis 2007;66: Kiely P, Williams R, Walsh D, Young A. Contemporary patterns of care and disease activity outcome in early rheumatoid arthritis: the ERAN cohort. Rheumatology 2009;48: Esselens GH, De Brabander A, Ovaere L, De Brabanter G, Moons P, Westhovens R. Personal attributes as determinants of timely care in rheumatoid arthritis. Ann Rheum Dis 2006;65: Kumar K, Daley E, Carruthers DM et al. Delay in presentation to primary care physicians is the main reason why patients with rheumatoid arthritis are seen late by rheumatologists. Rheumatology 2007;46: Sheppard J, Kumar K, Buckley CD, Shaw KL, Raza K. I just thought it was normal aches and pains : a qualitative study of decision-making processes in patients with early rheumatoid arthritis. Rheumatology 2008;47: Lard LR, Huizinga TW, Hazes JM, Vliet Vlieland TP. Delayed referral of female patients with rheumatoid arthritis. J Rheumatol 2001;28: Emery P, Breedveld FC, Dougados M, Kalden JR, Schiff MH, Smolen JS. Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Ann Rheum Dis 2002;61: Gao IK, Haas-Wohrle A, Mueller KG, Lorenz HM, Fiehn C. Determination of anti-ccp antibodies in patients with suspected rheumatoid arthritis: does it help to predict the diagnosis before referral to a rheumatologist? Ann Rheum Dis 2005;64: Raza K, Breese M, Nightingale P et al. Predictive value of antibodies to cyclic citrullinated peptide in patients with very early inflammatory arthritis. J Rheumatol 2005;32: Robinson PC, Taylor WJ. Time to treatment in rheumatoid arthritis: factors associated with time to treatment initiation and urgent triage assessment of general practitioner referrals. J Clin Rheumatol 2010;16: Cush JJ. Early arthritis clinics: if you build it will they come? J Rheumatol 2005;32: McGonagle D, Ash ZR, Hodgson RJ, Emery P, Radjenovic A. MRI for the assessment and monitoring of RA-what can it tell us? Nat Rev Rheumatol 2011;7: Brown AK. Using ultrasonography to facilitate best practice in diagnosis and management of RA. Nat Rev Rheumatol 2009;5: Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31:

6 Optimal care for early RA 32 Aletaha D, Neogi T, Silman AJ et al Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010;62: Nishimura K, Sugiyama D, Kogata Y et al. Meta-analysis: diagnostic accuracy of anti-cyclic citrullinated peptide antibody and rheumatoid factor for rheumatoid arthritis. Ann Intern Med 2007;146: Coenen D, Verschueren P, Westhovens R, Bossuyt X. Technical and diagnostic performance of 6 assays for the measurement of citrullinated protein/peptide antibodies in the diagnosis of rheumatoid arthritis. Clin Chem 2007;53: Skapenko A, Prots I, Schulze-Koops H. Prognostic factors in rheumatoid arthritis in the era of biologic agents. Nat Rev Rheumatol 2009;5: Visser H, le Cessie S, Vos K, Breedveld FC, Hazes JM. How to diagnose rheumatoid arthritis early: a prediction model for persistent (erosive) arthritis. Arthritis Rheum 2002;46: Lindqvist E, Eberhardt K, Bendtzen K, Heinegard D, Saxne T. Prognostic laboratory markers of joint damage in rheumatoid arthritis. Ann Rheum Dis 2005;64: Smolen JS, van der Heijde DM, St Clair EW et al. Predictors of joint damage in patients with early rheumatoid arthritis treated with high-dose methotrexate with or without concomitant infliximab: results from the ASPIRE trial. Arthritis Rheum 2006;54: Wessels JA, van der Kooij SM, le Cessie S et al. A clinical pharmacogenetic model to predict the efficacy of methotrexate monotherapy in recent-onset rheumatoid arthritis. Arthritis Rheum 2007;56: Vastesaeger N, Xu S, Aletaha D, St Clair EW, Smolen JS. A pilot risk model for the prediction of rapid radiographic progression in rheumatoid arthritis. Rheumatology 2009; 48: Durnez A, Vanderschueren G, Lateur L, Westhovens R, Verschueren P. Effectiveness of initial treatment allocation based on expert opinion for prevention of rapid radiographic progression in daily practice of an early RA cohort. Ann Rheum Dis 2011;70: Visser K, Goekoop-Ruiterman YP, Vries-Bouwstra JK et al. A matrix risk model for the prediction of rapid radiographic progression in patients with rheumatoid arthritis receiving different dynamic treatment strategies: post hoc analyses from the BeSt study. Ann Rheum Dis 2010;69: Verschueren P, Esselens G, Westhovens R. Predictors of remission, normalized physical function, and changes in the working situation during follow-up of patients with early rheumatoid arthritis: an observational study. Scand J Rheumatol 2009;38: Aletaha D, Funovits J, Keystone EC, Smolen JS. Disease activity early in the course of treatment predicts response to therapy after one year in rheumatoid arthritis patients. Arthritis Rheum 2007;56: Verstappen SM, Albada-Kuipers GA, Bijlsma JW et al. A good response to early DMARD treatment of patients with rheumatoid arthritis in the first year predicts remission during follow up. Ann Rheum Dis 2005;64: Groarke A, Curtis R, Coughlan R, Gsel A. The role of perceived and actual disease status in adjustment to rheumatoid arthritis. Rheumatology 2004;43: Geuskens GA, Burdorf A, Evers AW, Hazes JM. Clear associations between demographic and psychosocial factors and health-related quality of life in patients with early inflammatory joint complaints. J Rheumatol 2008;35: Scharloo M, Kaptein AA, Weinman J et al. Illness perceptions, coping and functioning in patients with rheumatoid arthritis, chronic obstructive pulmonary disease and psoriasis. J Psychosom Res 1998;44: Hill J. Rheumatology nurse specialists do we need them? Rheumatology 2007;46: Fautrel B, Pham T, Gossec L et al. Role and modalities of information and education in the management of patients with rheumatoid arthritis: development of recommendations for clinical practice based on published evidence and expert opinion. Joint Bone Spine 2005;72: Hill J, Bird H, Johnson S. Effect of patient education on adherence to drug treatment for rheumatoid arthritis: a randomised controlled trial. Ann Rheum Dis 2001;60: Abourazzak F, El Mansouri L, Huchet D et al. Long-term effects of therapeutic education for patients with rheumatoid arthritis. Joint Bone Spine 2009;76: Durez P, Malghem J, Nzeusseu Toukap A et al. Treatment of early rheumatoid arthritis: a randomized magnetic resonance imaging study comparing the effects of methotrexate alone, methotrexate in combination with infliximab, and methotrexate in combination with intravenous pulse methylprednisolone. Arthritis Rheum 2007; 56: Landewe RB, Boers M, Verhoeven AC et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002;46: van Vollenhoven RF, Ernestam S, Geborek P et al. Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial. Lancet 2009;374: Soubrier M, Puechal X, Sibilia J et al. Evaluation of two strategies (initial methotrexate monotherapy vs its combination with adalimumab) in management of early active rheumatoid arthritis: data from the GUEPARD trial. Rheumatology 2009;48: van Tuyl LH, Boers M, Lems WF et al. Survival, comorbidities and joint damage 11 years after the COBRA combination therapy trial in early rheumatoid arthritis. Ann Rheum Dis 2010;69: Quinn MA, Conaghan PG, O Connor PJ et al. Very early treatment with infliximab in addition to methotrexate in early, poor-prognosis rheumatoid arthritis reduces magnetic resonance imaging evidence of synovitis and damage, with sustained benefit after infliximab withdrawal: results from a twelve-month randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2005;52: van der Bijl AE, Goekoop-Ruiterman YP, Vries- Bouwstra JK et al. Infliximab and methotrexate as induction therapy in patients with early rheumatoid arthritis. Arthritis Rheum 2007;56:

7 Patrick Verschueren and René Westhovens 60 van der Kooij SM, Goekoop-Ruiterman YP, Vries- Bouwstra JK et al. Drug-free remission, functioning and radiographic damage after 4 years of response-driven treatment in patients with recent-onset rheumatoid arthritis. Ann Rheum Dis 2009;68: Aletaha D. Therapy: Challenging the course of RA: time for drug-free remission? Nat Rev Rheumatol 2010;6: van der Woude D, Young A, Jayakumar K et al. Prevalence of and predictive factors for sustained disease-modifying antirheumatic drug-free remission in rheumatoid arthritis: results from two large early arthritis cohorts. Arthritis Rheum 2009;60: Smolen JS, Aletaha D, Bijlsma JW et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010;69: Verstappen SM, Jacobs JW, van der Veen MJ et al. Intensive treatment with methotrexate in early rheumatoid arthritis: aiming for remission. Computer Assisted Management in Early Rheumatoid Arthritis (CAMERA). Ann Rheum Dis 2007;66: Keystone EC. Tight control for the management of RA a therapeutic approach worth pursuing. Nat Clin Pract Rheumatol 2008;4: Goekoop-Ruiterman YP, Vries-Bouwstra JK, Allaart CF et al. Patient preferences for treatment: report from a randomised comparison of treatment strategies in early rheumatoid arthritis (BeSt trial). Ann Rheum Dis 2007;66: van der Goes MC, Jacobs JW, Boers M et al. Patient and rheumatologist perspectives on glucocorticoids: an exercise to improve the implementation of the European League Against Rheumatism (EULAR) recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2010;69: Hoes JN, Jacobs JW, Boers M et al. EULAR evidence-based recommendations on the management of systemic glucocorticoid therapy in rheumatic diseases. Ann Rheum Dis 2007;66: van Tuyl LH, Plass AM, Lems WF et al. Facilitating the use of COBRA combination therapy in early rheumatoid arthritis: a pilot implementation study. J Rheumatol 2009;36: Verhoeven AC, Bibo JC, Boers M, Engel GL, Van Der LS. Cost-effectiveness and cost-utility of combination therapy in early rheumatoid arthritis: randomized comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone. COBRA Trial Group. Combinatietherapie Bij Reumatoide Artritis. Br J Rheumatol 1998;37: Tijhuis GJ, Zwinderman AH, Hazes JM, van den Hout WB, Breedveld FC, Vliet Vlieland TP. A randomized comparison of care provided by a clinical nurse specialist, an inpatient team, and a day patient team in rheumatoid arthritis. Arthritis Rheum 2002;47: van den Hout WB, Tijhuis GJ, Hazes JM, Breedveld FC, Vliet Vlieland TP. Cost effectiveness and cost utility analysis of multidisciplinary care in patients with rheumatoid arthritis: a randomised comparison of clinical nurse specialist care, inpatient team care, and day patient team care. Ann Rheum Dis 2003;62: Benhamou M, Rincheval N, Roy C et al. The gap between practice and guidelines in the choice of first-line disease modifying antirheumatic drug in early rheumatoid arthritis: results from the ESPOIR cohort. J Rheumatol 2009;36: