Scott Med J OnlineFirst, published on June 29, 2015 as doi:10.1177/0036933015592761
Educational Article
Advances in the management of rheumatoid arthritis
Scottish Medical Journal 0(0) 1–7 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933015592761 scm.sagepub.com
James Dale1,2
Abstract Modern early rheumatoid arthritis strategies are usually based upon a number of important overarching principles: 1. early diagnosis facilitates early commencement of disease modifying anti-rheumatic therapy; 2. early commencement of treatment reduces the long-term risk of erosive damage and functional decline; 3. composite disease activity measures should be used to quantify global rheumatoid arthritis disease activity; and 4. therapy should be intensified until a predefined disease activity target has been achieved. A substantial minority of rheumatoid arthritis patients (approximately 40%) will experience an adequate response to methotrexate monotherapy; however, the remainder may require disease modifying anti-rheumatic combination therapy, and/or biologic therapy, to achieve disease activity targets. Importantly, short term trials of methotrexate monotherapy do not appear to disadvantage outcomes provided treatment continues to be intensified if disease activity targets are not achieved.
Keywords Biologic therapy, disease-modifying anti-rheumatic drugs, disease activity score, rheumatoid arthritis, treat-to-target
Introduction The past 20 years have witnessed a rapid evolution in the breadth and scope of rheumatologists’ ability to treat rheumatoid arthritis (RA). Unlike other chronic conditions, rheumatologists have increasingly been able to select from a wide range of pharmacological therapies in their attempts to relieve the discomfort of active synovitis (the main inflammatory lesion of RA) and prevent irreversible joint damage. Identification of several key immune mediators that drive RA pathogenesis has accelerated expansion of the rheumatologist’s armamentarium by facilitating the development of immune targeted biologic therapy (particularly antitumour necrosis factor (TNF) therapy). In many cases, these new drug classes can produce profound improvements in the symptoms and prognosis of patients who would otherwise be resistant to nonbiologic disease modifying anti-rheumatic drugs (nbDMARDS). However, this has added further complexity to treatment decisions that can often involve several agents with multiple modes of action and there remains an ongoing debate about treatment timing, sequence and cost. Despite such rapid progress, perhaps one of the most important advances in the
management of RA is the realization that patients treatment should be dynamic and responsive to changes in global disease activity and that relatively simple therapeutic interventions can have profound and lasting clinical benefits. The following article will provide an overview of modern RA management strategies by summarizing the evidence underpinning several of the core treatment principles.
The presenting features of newly diagnosed RA may be evolving International treatment guidelines emphasise the need to initiate nbDMARDs or biologic therapy as soon as the diagnosis of RA is confirmed.1,2 In addition, the identification of anti-cyclic citrillunated peptide antibodies (ACPA) has provided rheumatologists with a biological marker that has both important diagnostic and 1
Honorary Consultant Rheumatologist, NHS Greater Glasgow and Clyde, UK 2 Clinical Lecturer, University of Glasgow, UK Corresponding author: James Dale, University of Glasgow, Glasgow G12 8QQ, UK. Email: [email protected]
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prognostic properties being associated with a very high specificity for the diagnosis of RA3 and an increased long term risk of impaired treatment responses and radiological progression.4,5 However, not all patients diagnosed with RA express ACPA (sensitivity approximately 70–80%)6 and ACPA have been identified in the sera of asymptomatic individuals many years before the onset of synovitis.7 Thus relying on ACPA status alone risks under diagnosis of RA in ACPA-negative RA patients and over diagnosis in ACPA-positive individuals who have symptoms of pain and stiffness but have not yet developed synovitis. The 2010 ACR-EULAR RA Classification Criteria8 (Figure 1) were developed to standardise recruitment to RA clinical trials and to facilitate early diagnosis and treatment in patients who present with undifferentiated inflammatory arthritis. However, they also illustrate how rheumatologists’ collective perception of RA has evolved. To differentiate from pre-clinical RA, patients are required to have at least one clinically swollen joint and, in contrast to the 1987 ACR Classification Criteria,9 there is no longer a requirement for symptoms to have lasted longer than six weeks, nor is there such emphasis on the need for patients to display features traditionally associated with established disease, such as, the presence of symmetrical joint involvement, rheumatoid nodules and/or radiographic erosions. Indeed, in head to head comparisons, the 2010 criteria are more sensitive for the diagnosis of RA in patients who are seronegative for RA autoantibodies and/or have asymmetric oligoarthritic presentations.10–12
Early initiation of treatment can improve longterm outcomes Patients’ greatest exposure to active disease occurs during the period leading up to diagnosis and starting any immune therapy has consistently been shown to be the single intervention that has the biggest impact on disease activity levels. In addition, persistently active disease and an increased cumulative exposure to active synovitis are important predictors of future functional decline and progressive joint damage.13–15 In this area, several studies have demonstrated that minimizing the period of time from symptom onset to commencement of therapy has a positive impact on outcomes. An additional analysis of the Finnish Rheumatoid Arthritis Combination Therapy (FinRACo) trial reported that patients with symptom durations of greater than four months were less likely to attain clinical remission with sequential monotherapy than patients with shorter durations.16 Interestingly, this temporal relationship was not apparent in patients treated with combination nbDMARD therapy, suggesting that any negative impact of delayed
therapy may be attenuated by the use of more aggressive strategies. Nell has compared the clinical and radiological outcomes of cohorts of newly diagnosed RA patients with either early (10 joints (at least one small joint) B. Serology – at least one result is needed for classification
0
Negative RF and ACPA
2
Low positive RF or low positive ACPA (≤ 3 times ULN)
3
High positive RF or high positive ACPA (>3 times ULN) C. Acute-phase reactants – at least one result is needed for
0
classification
1
Normal CRP and normal ESR Abnormal CRP or abnormal ESR D. Duration of symptoms
0
< 6 weeks
1
≥ 6 weeks A total score ≥ 6/10 is needed to classify a patient as definite RA
Figure 1. Classification criteria for RA.
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replicated by a number of subsequent treatment strategy studies21,22 and now, intensive early treatment strategies that target attainment of a predefined disease activity state (usually either low disease activity or clinical remission) are important components of most modern RA treatment guidelines.23,24 The introduction of biologic drugs has encouraged rheumatologists to choose from an increasingly narrow range of nbDMARD agents. In the pre-biologic era, important studies by O’Dell and colleagues demonstrated that combinations that comprised methotrexate, sulphasalazine and hydroxychloroquine produced significantly better clinical outcomes than monotherapy with any of the agent or any two agents used in combination.25,26 Thus, triple therapy with all three agents has become many rheumatologist’s preferred nbDMARD combination since it is the most rigorously studied nbDMARD combination, has proven clinical efficacy and, if ineffective, satisfies many countries biologic prescribing guidelines. In early RA, combination nbDMARD therapy can be introduced using either step-up, whereby additional agents are added if the treatment target is not achieved, or parallel, whereby all agents are commenced at the same time, treatment strategies. However, approximately 30–40% of newly diagnosed RA patients will experience an adequate clinical response to methotrexate monotherapy27,28 and in these patients initial triple combination therapy would be needlessly complex and excessive. Two randomised clinical trials, which both targeted attainment of low clinical disease activity, have compared the relative efficacies of step-up and parallel nbDMARD intensive treatment protocols in newly diagnosed RA patients. In the BehandelStrategieen (BeST) study, 508 newly diagnosed RA patients were randomised to treatment with either: (1) sequential monotherapy, (2) step-up combination therapy, (3) parallel nbDMARD therapy with tapering corticosteroids and (4) combination nbDMARD and antiTNF therapy.21 After 12 months follow-up, all treatment groups exhibited similar levels of disease activity and functional ability. However, over the preceding follow-up period the most intensively treated groups (groups 3 and 4) had experienced faster improvements in disease activity and functional ability, higher rates of clinical remission and a lesser rate of radiographic progression, once again suggesting that cumulative exposure to active synovitis may be an important predictor of future joint damage. In the Triple Therapy in Early Rheumatoid Arthritis Study (TEAR), 96 patients with newly diagnosed RA and high disease activity (DAS28 > 5.1) were randomised to be treated with either step-up nbDMARD or low dose triple nbDMARD parallel therapy. In both groups, therapy was intensified by either adding additional agents (step-
up) or increasing nbDMARD doses (parallel).29 In contrast to the BeST study, after 12 months follow-up, patients in both TEAR study treatment groups exhibited similar improvements in measures of disease activity and functional ability, similar rates of clinical remission and similar, albeit small, rates of radiographic progression. Exposing all RA patients to a potentially ineffective trial of nbDMARDs therapy may be inappropriate if those with nbDMARD resistant disease would have been better served by starting biologic therapy from diagnosis. However, in many settings it is not practical to commence all newly diagnosed RA patients on biologic therapy, and many patients will experience an adequate response to nbDMARDs. Several recent treatment strategy studies have investigated whether patients who ultimately require anti-TNF therapy are disadvantaged if they initially receive treatment with methotrexate monotherapy and/or combination nbDMARD therapy. In the Swedish Pharmacotherapy Trial (SWEFOT), 258 early patients with an inadequate response to methotrexate monotherapy (DAS28 > 3.2) were randomised to receive either triple nbDMARD therapy or methotrexate and anti-TNF therapy.27 After 24 months follow-up, there were no significant between group differences in overall response rates; however, the methotrexate and antiTNF therapy group did demonstrate faster early treatment responses and lower overall rates of radiographic damage progression. Similarly, the RA: Comparison of Active Therapies (RACAT) study has demonstrated that triple nbDMARD therapy is not inferior to treatment with methotrexate and anti-TNF therapy in patients who experience an initial inadequate response to methotrexate monotherapy.30 Importantly, patients who failed to respond to their initial treatment allocation experienced improved overall responses if they switched to the alternative treatment arm after 24 weeks and all groups had similar levels of disease activity, functional ability and radiographic damage at the completion of follow-up (48 weeks). The same investigators have also compared whether immediate treatment with triple nbDMARD therapy or anti-TNF therapy was superior to methotrexate monotherapy with the option to progress to triple nbDMARD therapy or anti-TNF therapy if low disease activity was not attained after 24 weeks.28 Patients who received initial combination therapy with either triple nbDMARDs or anti-TNF experienced greater early (24 weeks) improvements in disease activity compared than those who received methotrexate monotherapy. However, once the subset of methotrexate nonresponders had progressed to treatment with either triple nbDMARDS or anti-TNF, there was no significant between group differences in subsequent disease
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activity levels for the remainder of the follow-up period (102 weeks). Taken together, these results emphasise that modern RA treatment strategies should be dynamic and proactive and that rheumatologists should be prepared to continue regularly reassessing disease activity and adjusting therapy until an acceptable level of disease control is attained.
Intensive early treatment strategies may also improve long-term outcomes Few of the previously described intensive treatment strategy studies have reported the impact of early intensive treatment on long-term outcomes. The FINRACo Study has suggested that a favourable early response to combination nbDMARD therapy (triple nbDMARDs with corticosteroids) is associated with better long-term outcomes than treatment with sequential nbDMARD monotherapy.31 Patients who received combination therapy were more likely to attain clinical remission over the first two years of follow-up,31 exhibited lesser rates of radiographic damage progression after five years32 and higher rates of remission after 11 years of follow-up.33 Similarly, ongoing follow-up of patients recruited to the BeST study has demonstrated that continuing to monitor disease activity and adjust immune therapy to maintain low disease activity stabilizes functional decline and minimises further progression of radiological damage.34 Patients who were initially treated with sequential monotherapy (Group 1) or step-up combination therapy (Group 2) experienced a slower initial treatment response, and required more treatment adjustments, than patients who were treated with either parallel combination therapy (Group 3) or anti-TNF therapy (Group 4). However, after seven years followup, patients in all treatment groups had similar levels of functional ability and clinical remission. Further, whilst Groups 3 and 4 showed statistically lesser rates of radiographic progression overall, much of this could be attributed to progression in the first two years of follow-up when the greatest between group difference in treatment response was evident, and, in fact there was no significant between group differences in rates of radiographic progression after this point. Importantly, the BeST study has also demonstrated that a subset of patients may eventually be able to reduce the cost and burden of their longterm therapy through the stepwise reduction and withdrawal of nbDMARD and/or biologic therapy once they attain stable clinical remission
Key points summary 1. Early diagnosis and commencement of therapy delivers long-term clinical and radiological benefits.
2. Management strategies that quantify disease activity and seek to suppress disease activity below a pre-specified lower threshold achieve better short and long term clinical and functional outcomes than strategies that are driven by clinician’s instinct. 3. Step-up and parallel nbDMARD strategies produce similar short-term clinical and radiological outcomes. 4. Combination therapy with either triple nbDMARDs or anti-TNF therapy may not be necessary in the subset of patients who respond adequately to methotrexate monotherapy. 5. Step-up DMARD strategies that incorporate initial short periods of methotrexate monotherapy, and/ or triple nbDMARD combination therapy, do not appear to disadvantage newly diagnosed RA patient’s short term outcomes, provided they are responsive to the patient’s disease activity state and therapy continues to be escalated until a pre-specified disease activity state has been achieved. 6. Long term stable low disease activity is associated with stabilization of functional decline and minimal further radiological damage progression. 7. Attainment of stable low disease activity, and/or remission, may allow some patients to taper their biologic therapy and/or nbDMARDs. Declaration of conflicting interests None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Singh JA, Furst DE, Bharat A, et al. 2012 Update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying antirheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012; 64: 625–639. 2. Smolen JS, Landewe R, Breedveld FC, et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update. Ann Rheum Dis 2014; 73: 492–509. 3. Schellekens GA, Visser H, de Jong BA, et al. The diagnostic properties of rheumatoid arthritis antibodies recognizing a cyclic citrullinated peptide. Arthritis Rheum 2000; 43: 155–163. 4. van der Helm-van Mil AHM, Verpoort KN, Breedveld FC, et al. Antibodies to citrullinated proteins and differences in clinical progression of rheumatoid arthritis. Arthritis Res Ther 2005; 7: R949–R958.
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5. Ronnelid J. Longitudinal analysis of citrullinated protein/peptide antibodies (anti-CP) during 5 year follow up in early rheumatoid arthritis: anti-CP status predicts worse disease activity and greater radiological progression. Ann Rheum Dis 2005; 64: 1744–1749. 6. Hani El-Gabalawy MD FPOMAI. The preclinical stages of RA: lessons from human studies and animal models. Best Pract Res Clin Rheumatol 2009; 23: 49–58. 7. Nielen MMJ, van Schaardenburg D, Reesink HW, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004; 50: 380–386. 8. Aletaha D, Neogi T, Silman AJ, et al. 2010 Rheumatoid arthritis classification criteria: An American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum 2010; 62: 2569–2581. 9. Arnett F, Edworthy S, Bloch D, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1987; 31: 315–324. 10. Fautrel B, Combe B, Rincheval N, et al ESPOIR Scientific Committee. Level of agreement of the 1987 ACR and 2010 ACR/EULAR rheumatoid arthritis classification criteria: an analysis based on ESPOIR cohort data. Ann Rheum Dis 2012; 71: 386–389. 11. Radner H, Neogi T, Smolen JS, et al. Performance of the 2010 ACR/EULAR classification criteria for rheumatoid arthritis: a systematic literature review. Ann Rheum Dis, Epub ahead of print 16 April 2013. 12. Luchikhina EL, Karateev DE, Novikov AA, et al. Performance and predictive value of ACR/EULAR 2010 rheumatoid arthritis classification criteria in different groups of patients with early arthritis. Ann Rheum Dis 2011; 70(Suppl3): 285. 13. Wick MC. Relationship between inflammation and joint destruction in early rheumatoid arthritis: a mathematical description. Ann Rheum Dis 2004; 63: 848–852. 14. Conaghan PG, Hensor EMA, Keenan AM, et al the YEAR Consortium. Persistently moderate DAS-28 is not benign: loss of function occurs in early RA despite step-up DMARD therapy. Rheumatology 2010; 49: 1894–1899. 15. Salaffi F, Carotti M, Ciapetti A, et al. Relationship between time-integrated disease activity estimated by DAS28-CRP and radiographic progression of anatomical damage in patients with early rheumatoid arthritis. BMC Musculoskelet Disord 2011; 12: 120. 16. Mo¨tto¨nen T, Hannonen P, Korpela M, et al. Delay to institution of therapy and induction of remission using single-drug or combination-disease-modifying antirheumatic drug therapy in early rheumatoid arthritis. Arthritis Rheum 2002; 46: 894–898. 17. Nell VPK. Benefit of very early referral and very early therapy with disease-modifying anti-rheumatic drugs in patients with early rheumatoid arthritis. Rheumatology 2004; 43: 906–914. 18. van der Linden MPM, le Cessie S, Raza K, et al. Longterm impact of delay in assessment of patients with early arthritis. Arthritis Rheum 2010; 62: 3537–3546.
19. Deighton C, Hyrich K, Ding T, et al. BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. Rheumatology, Epub ahead of print 22 March 2010. 20. 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. The Lancet 2004; 364: 263–269. 21. Goekoop-Ruiterman YPM, 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: 3381–3390. 22. Verstappen SMM, Jacobs JWG, 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, an open-label strategy trial). Ann Rheum Dis 2007; 66: 1443–1449. 23. 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: 964–975. 24. Smolen JS, Aletaha D, Bijlsma JWJ, et al. Treating rheumatoid arthritis to target: recommendations of an international task force. Ann Rheum Dis 2010; 69: 631–637. 25. O’Dell J, Haire C and Erikson N. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. N Engl J Med 1996; 334: 1287–1291. 26. O’Dell JR, Leff R, Paulsen G, et al. Treatment of rheumatoid arthritis with methotrexate and hydroxychloroquine, methotrexate and sulfasalazine, or a combination of the three medications: results of a two-year, randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2002; 46: 1164–1170. 27. van Vollenhoven RF, Geborek P, Forslind K, et al. Conventional combination treatment versus biological treatment in methotrexate-refractory early rheumatoid arthritis: 2 year follow-up of the randomised, nonblinded, parallel-group Swefot trial. Lancet, Epub ahead of print 28 March 2012. 28. Moreland LW, O’Dell JR, Paulus HE, et al. A randomized comparative effectiveness study of oral triple therapy versus etanercept plus methotrexate in early aggressive rheumatoid arthritis: The Treatment of Early Aggressive Rheumatoid Arthritis trial. Arthritis Rheum 2012; 64: 2824–2835. 29. Saunders SA, Capell HA, Stirling A, et al. Triple therapy in early active rheumatoid arthritis: a randomized, singleblind, controlled trial comparing step-up and parallel treatment strategies. Arthritis Rheum 2008; 58: 1310–1317. 30. O’Dell JR, Mikuls TR, Taylor TH, et al. Therapies for active rheumatoid arthritis after methotrexate failure. N Engl J Med, Epub ahead of print 2013. DOI: 130611150115007.
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31. 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: 1568–1573. 32. Korpela M, Laasonen L, Hannonen P, et al. Retardation of joint damage in patients with early rheumatoid arthritis by initial aggressive treatment with disease-modifying antirheumatic drugs: five-year experience from the FIN-RACo study. Arthritis Rheum 2004; 50: 2072–2081.
33. Rantalaiho V, Korpela M, Hannonen P, et al. The good initial response to therapy with a combination of traditional disease-modifying antirheumatic drugs is sustained over time: the eleven-year results of the Finnish Rheumatoid Arthritis Combination Therapy Trial. Arthritis Rheum 2009; 60: 1222–1231. 34. van den Broek M, Lems WF and Allaart CF. BeSt practice: the success of early-targeted treatment in rheumatoid arthritis. Clin Exp Rheumatol 2012; 30: S35–S38.
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Educational Article
Advances in the management of rheumatoid arthritis
Scottish Medical Journal 0(0) 1–7 ! The Author(s) 2015 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0036933015592761 scm.sagepub.com
James Dale1,2
Abstract Modern early rheumatoid arthritis strategies are usually based upon a number of important overarching principles: 1. early diagnosis facilitates early commencement of disease modifying anti-rheumatic therapy; 2. early commencement of treatment reduces the long-term risk of erosive damage and functional decline; 3. composite disease activity measures should be used to quantify global rheumatoid arthritis disease activity; and 4. therapy should be intensified until a predefined disease activity target has been achieved. A substantial minority of rheumatoid arthritis patients (approximately 40%) will experience an adequate response to methotrexate monotherapy; however, the remainder may require disease modifying anti-rheumatic combination therapy, and/or biologic therapy, to achieve disease activity targets. Importantly, short term trials of methotrexate monotherapy do not appear to disadvantage outcomes provided treatment continues to be intensified if disease activity targets are not achieved.
Keywords Biologic therapy, disease-modifying anti-rheumatic drugs, disease activity score, rheumatoid arthritis, treat-to-target
Introduction The past 20 years have witnessed a rapid evolution in the breadth and scope of rheumatologists’ ability to treat rheumatoid arthritis (RA). Unlike other chronic conditions, rheumatologists have increasingly been able to select from a wide range of pharmacological therapies in their attempts to relieve the discomfort of active synovitis (the main inflammatory lesion of RA) and prevent irreversible joint damage. Identification of several key immune mediators that drive RA pathogenesis has accelerated expansion of the rheumatologist’s armamentarium by facilitating the development of immune targeted biologic therapy (particularly antitumour necrosis factor (TNF) therapy). In many cases, these new drug classes can produce profound improvements in the symptoms and prognosis of patients who would otherwise be resistant to nonbiologic disease modifying anti-rheumatic drugs (nbDMARDS). However, this has added further complexity to treatment decisions that can often involve several agents with multiple modes of action and there remains an ongoing debate about treatment timing, sequence and cost. Despite such rapid progress, perhaps one of the most important advances in the
management of RA is the realization that patients treatment should be dynamic and responsive to changes in global disease activity and that relatively simple therapeutic interventions can have profound and lasting clinical benefits. The following article will provide an overview of modern RA management strategies by summarizing the evidence underpinning several of the core treatment principles.
The presenting features of newly diagnosed RA may be evolving International treatment guidelines emphasise the need to initiate nbDMARDs or biologic therapy as soon as the diagnosis of RA is confirmed.1,2 In addition, the identification of anti-cyclic citrillunated peptide antibodies (ACPA) has provided rheumatologists with a biological marker that has both important diagnostic and 1
Honorary Consultant Rheumatologist, NHS Greater Glasgow and Clyde, UK 2 Clinical Lecturer, University of Glasgow, UK Corresponding author: James Dale, University of Glasgow, Glasgow G12 8QQ, UK. Email: [email protected]
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prognostic properties being associated with a very high specificity for the diagnosis of RA3 and an increased long term risk of impaired treatment responses and radiological progression.4,5 However, not all patients diagnosed with RA express ACPA (sensitivity approximately 70–80%)6 and ACPA have been identified in the sera of asymptomatic individuals many years before the onset of synovitis.7 Thus relying on ACPA status alone risks under diagnosis of RA in ACPA-negative RA patients and over diagnosis in ACPA-positive individuals who have symptoms of pain and stiffness but have not yet developed synovitis. The 2010 ACR-EULAR RA Classification Criteria8 (Figure 1) were developed to standardise recruitment to RA clinical trials and to facilitate early diagnosis and treatment in patients who present with undifferentiated inflammatory arthritis. However, they also illustrate how rheumatologists’ collective perception of RA has evolved. To differentiate from pre-clinical RA, patients are required to have at least one clinically swollen joint and, in contrast to the 1987 ACR Classification Criteria,9 there is no longer a requirement for symptoms to have lasted longer than six weeks, nor is there such emphasis on the need for patients to display features traditionally associated with established disease, such as, the presence of symmetrical joint involvement, rheumatoid nodules and/or radiographic erosions. Indeed, in head to head comparisons, the 2010 criteria are more sensitive for the diagnosis of RA in patients who are seronegative for RA autoantibodies and/or have asymmetric oligoarthritic presentations.10–12
Early initiation of treatment can improve longterm outcomes Patients’ greatest exposure to active disease occurs during the period leading up to diagnosis and starting any immune therapy has consistently been shown to be the single intervention that has the biggest impact on disease activity levels. In addition, persistently active disease and an increased cumulative exposure to active synovitis are important predictors of future functional decline and progressive joint damage.13–15 In this area, several studies have demonstrated that minimizing the period of time from symptom onset to commencement of therapy has a positive impact on outcomes. An additional analysis of the Finnish Rheumatoid Arthritis Combination Therapy (FinRACo) trial reported that patients with symptom durations of greater than four months were less likely to attain clinical remission with sequential monotherapy than patients with shorter durations.16 Interestingly, this temporal relationship was not apparent in patients treated with combination nbDMARD therapy, suggesting that any negative impact of delayed
therapy may be attenuated by the use of more aggressive strategies. Nell has compared the clinical and radiological outcomes of cohorts of newly diagnosed RA patients with either early (10 joints (at least one small joint) B. Serology – at least one result is needed for classification
0
Negative RF and ACPA
2
Low positive RF or low positive ACPA (≤ 3 times ULN)
3
High positive RF or high positive ACPA (>3 times ULN) C. Acute-phase reactants – at least one result is needed for
0
classification
1
Normal CRP and normal ESR Abnormal CRP or abnormal ESR D. Duration of symptoms
0
< 6 weeks
1
≥ 6 weeks A total score ≥ 6/10 is needed to classify a patient as definite RA
Figure 1. Classification criteria for RA.
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replicated by a number of subsequent treatment strategy studies21,22 and now, intensive early treatment strategies that target attainment of a predefined disease activity state (usually either low disease activity or clinical remission) are important components of most modern RA treatment guidelines.23,24 The introduction of biologic drugs has encouraged rheumatologists to choose from an increasingly narrow range of nbDMARD agents. In the pre-biologic era, important studies by O’Dell and colleagues demonstrated that combinations that comprised methotrexate, sulphasalazine and hydroxychloroquine produced significantly better clinical outcomes than monotherapy with any of the agent or any two agents used in combination.25,26 Thus, triple therapy with all three agents has become many rheumatologist’s preferred nbDMARD combination since it is the most rigorously studied nbDMARD combination, has proven clinical efficacy and, if ineffective, satisfies many countries biologic prescribing guidelines. In early RA, combination nbDMARD therapy can be introduced using either step-up, whereby additional agents are added if the treatment target is not achieved, or parallel, whereby all agents are commenced at the same time, treatment strategies. However, approximately 30–40% of newly diagnosed RA patients will experience an adequate clinical response to methotrexate monotherapy27,28 and in these patients initial triple combination therapy would be needlessly complex and excessive. Two randomised clinical trials, which both targeted attainment of low clinical disease activity, have compared the relative efficacies of step-up and parallel nbDMARD intensive treatment protocols in newly diagnosed RA patients. In the BehandelStrategieen (BeST) study, 508 newly diagnosed RA patients were randomised to treatment with either: (1) sequential monotherapy, (2) step-up combination therapy, (3) parallel nbDMARD therapy with tapering corticosteroids and (4) combination nbDMARD and antiTNF therapy.21 After 12 months follow-up, all treatment groups exhibited similar levels of disease activity and functional ability. However, over the preceding follow-up period the most intensively treated groups (groups 3 and 4) had experienced faster improvements in disease activity and functional ability, higher rates of clinical remission and a lesser rate of radiographic progression, once again suggesting that cumulative exposure to active synovitis may be an important predictor of future joint damage. In the Triple Therapy in Early Rheumatoid Arthritis Study (TEAR), 96 patients with newly diagnosed RA and high disease activity (DAS28 > 5.1) were randomised to be treated with either step-up nbDMARD or low dose triple nbDMARD parallel therapy. In both groups, therapy was intensified by either adding additional agents (step-
up) or increasing nbDMARD doses (parallel).29 In contrast to the BeST study, after 12 months follow-up, patients in both TEAR study treatment groups exhibited similar improvements in measures of disease activity and functional ability, similar rates of clinical remission and similar, albeit small, rates of radiographic progression. Exposing all RA patients to a potentially ineffective trial of nbDMARDs therapy may be inappropriate if those with nbDMARD resistant disease would have been better served by starting biologic therapy from diagnosis. However, in many settings it is not practical to commence all newly diagnosed RA patients on biologic therapy, and many patients will experience an adequate response to nbDMARDs. Several recent treatment strategy studies have investigated whether patients who ultimately require anti-TNF therapy are disadvantaged if they initially receive treatment with methotrexate monotherapy and/or combination nbDMARD therapy. In the Swedish Pharmacotherapy Trial (SWEFOT), 258 early patients with an inadequate response to methotrexate monotherapy (DAS28 > 3.2) were randomised to receive either triple nbDMARD therapy or methotrexate and anti-TNF therapy.27 After 24 months follow-up, there were no significant between group differences in overall response rates; however, the methotrexate and antiTNF therapy group did demonstrate faster early treatment responses and lower overall rates of radiographic damage progression. Similarly, the RA: Comparison of Active Therapies (RACAT) study has demonstrated that triple nbDMARD therapy is not inferior to treatment with methotrexate and anti-TNF therapy in patients who experience an initial inadequate response to methotrexate monotherapy.30 Importantly, patients who failed to respond to their initial treatment allocation experienced improved overall responses if they switched to the alternative treatment arm after 24 weeks and all groups had similar levels of disease activity, functional ability and radiographic damage at the completion of follow-up (48 weeks). The same investigators have also compared whether immediate treatment with triple nbDMARD therapy or anti-TNF therapy was superior to methotrexate monotherapy with the option to progress to triple nbDMARD therapy or anti-TNF therapy if low disease activity was not attained after 24 weeks.28 Patients who received initial combination therapy with either triple nbDMARDs or anti-TNF experienced greater early (24 weeks) improvements in disease activity compared than those who received methotrexate monotherapy. However, once the subset of methotrexate nonresponders had progressed to treatment with either triple nbDMARDS or anti-TNF, there was no significant between group differences in subsequent disease
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activity levels for the remainder of the follow-up period (102 weeks). Taken together, these results emphasise that modern RA treatment strategies should be dynamic and proactive and that rheumatologists should be prepared to continue regularly reassessing disease activity and adjusting therapy until an acceptable level of disease control is attained.
Intensive early treatment strategies may also improve long-term outcomes Few of the previously described intensive treatment strategy studies have reported the impact of early intensive treatment on long-term outcomes. The FINRACo Study has suggested that a favourable early response to combination nbDMARD therapy (triple nbDMARDs with corticosteroids) is associated with better long-term outcomes than treatment with sequential nbDMARD monotherapy.31 Patients who received combination therapy were more likely to attain clinical remission over the first two years of follow-up,31 exhibited lesser rates of radiographic damage progression after five years32 and higher rates of remission after 11 years of follow-up.33 Similarly, ongoing follow-up of patients recruited to the BeST study has demonstrated that continuing to monitor disease activity and adjust immune therapy to maintain low disease activity stabilizes functional decline and minimises further progression of radiological damage.34 Patients who were initially treated with sequential monotherapy (Group 1) or step-up combination therapy (Group 2) experienced a slower initial treatment response, and required more treatment adjustments, than patients who were treated with either parallel combination therapy (Group 3) or anti-TNF therapy (Group 4). However, after seven years followup, patients in all treatment groups had similar levels of functional ability and clinical remission. Further, whilst Groups 3 and 4 showed statistically lesser rates of radiographic progression overall, much of this could be attributed to progression in the first two years of follow-up when the greatest between group difference in treatment response was evident, and, in fact there was no significant between group differences in rates of radiographic progression after this point. Importantly, the BeST study has also demonstrated that a subset of patients may eventually be able to reduce the cost and burden of their longterm therapy through the stepwise reduction and withdrawal of nbDMARD and/or biologic therapy once they attain stable clinical remission
Key points summary 1. Early diagnosis and commencement of therapy delivers long-term clinical and radiological benefits.
2. Management strategies that quantify disease activity and seek to suppress disease activity below a pre-specified lower threshold achieve better short and long term clinical and functional outcomes than strategies that are driven by clinician’s instinct. 3. Step-up and parallel nbDMARD strategies produce similar short-term clinical and radiological outcomes. 4. Combination therapy with either triple nbDMARDs or anti-TNF therapy may not be necessary in the subset of patients who respond adequately to methotrexate monotherapy. 5. Step-up DMARD strategies that incorporate initial short periods of methotrexate monotherapy, and/ or triple nbDMARD combination therapy, do not appear to disadvantage newly diagnosed RA patient’s short term outcomes, provided they are responsive to the patient’s disease activity state and therapy continues to be escalated until a pre-specified disease activity state has been achieved. 6. Long term stable low disease activity is associated with stabilization of functional decline and minimal further radiological damage progression. 7. Attainment of stable low disease activity, and/or remission, may allow some patients to taper their biologic therapy and/or nbDMARDs. Declaration of conflicting interests None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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