Key points
Rheumatoid arthritis (RA) can lead to significant long-term morbidity and mortality
It is important to aim for early diagnosis to limit the structural damage that occurs with prolonged inflammation
Commencing disease-modifying anti-rheumatic drugs (DMARD) therapy and glucocorticoids as early as possible and titrating therapy as appropriate improves clinical outcomes
Patients must be closely monitored for inflammatory disease with regular clinical assessments and treated to a target of clinical remission
If low disease activity or clinical remission cannot be achieved with standard DMARDs biological therapies can be initiated
Rheumatoid arthritis (RA) is an autoimmune condition characterised by a chronic inflammatory arthritis. If inadequately treated it results in joint destruction with subsequent deformity, disability and substantial socio-economic costs. RA affects 0.5–1% of the population in the UK and healthcare costs reach an estimated £560 million annually (National Audit Office). Fortunately, the overall prognosis for RA has improved dramatically in recent years owing to innovative research and advances in available therapies.
Historically, non-steroidal anti-inflammatory drugs (NSAIDs) were the mainstay of treatment, followed by glucocorticoids and finally disease-modifying anti-rheumatic drugs (DMARDS) such as gold, sulphasalazine and penicillamine. Although this treatment strategy managed the symptoms of RA, delay in initiation of DMARDS resulted in persistent inflammation with subsequent joint destruction and long-term disability. A different approach was therefore imperative.
This article will focus on the concept of a therapeutic window for managing RA and the treatment strategies now recommended, with an indication of how the treatment paradigm continues to evolve.
Therapeutic window in rheumatoid arthritis
Since the 1990s rheumatologists have been exploring the concept of a ‘window of opportunity’ in the treatment of RA.1 To explain this concept, comparisons can be drawn from other diseases such as cancer, where treating the disease from the onset equates to less disease burden and leads to maximum effect of therapy. In RA this translates to suppressing the inflammation before the irreversible joint damage occurs. Evidence to support this theory in RA is derived from studies which have demonstrated that early intervention results in optimal clinical outcomes.2–4 This has been further validated by radiographic data illustrating that early treatment equates to less erosive disease.3,5
Principles to treating rheumatoid arthritis
The recognition of a ‘window of opportunity’ has led to a paradigm shift in the management of RA. DMARDS, in particular methotrexate, now form the cornerstone of treatment. Therapies are frequently ‘stepped up’ and used in combination to achieve disease control. Pivotal trials have provided insight into drug efficacy and treatment strategies, culminating in key principles for the modern management of RA.
Aim for early diagnosis
We know from longitudinal studies that functional capacity in patients with RA deteriorates with time.6 Long-term disability is primarily caused by joint damage that occurs subsequent to ongoing inflammation and disease activity. In early RA with high disease activity it is possible to detect changes in joint damage within 3 months using plain radiographs.7 Therefore, early diagnosis and immediate intervention with disease-modifying therapy is vital to prevent disability. The heterogeneity in presentation of RA can lead to delays in diagnosis, and previous criteria for RA have demonstrated low sensitivity and specificity for early disease.8 In recognition of this, the American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) collaborated in 2010 to define a new classification criteria for RA to allow diagnosis at the earliest possible stage (Box 1).9 Referral to a rheumatologist by general practitioners and other physicians is recommended when there is any clinical suspicion (symptoms +/− signs) of an inflammatory arthritis.10 This new criteria combined with prompt referral is paramount in preventing the undesirable sequelae of RA.
Early initiation of therapy
In clinical practice, the concept of a therapeutic window in RA involves the -immediate initiation of therapy upon diagnosis, with minimum delay. There is unequivocal -evidence to support the early commencement of DMARDs. Individuals assessed and treated with disease duration of <12 weeks have been shown to have better clinical outcomes and less radiographic progression than those presenting with longer disease duration.2 A meta-analysis of 14 randomised control trials confirmed early initiation of therapy in individuals with symptoms of less than a year corresponded to better response to DMARDs.11 In fact, shorter disease duration was the strongest variable associated with improved clinical response. There is a wealth of clinical trial data supporting this approach.12–16
Treat to a target
Treating to a predefined target is undertaken in several pathologies to enable physicians and patients to discuss and adopt therapeutic changes within distinct time frames. Improved clinical outcomes in hypertension and diabetes have been witnessed subsequent to close monitoring and predefined targets in blood pressure and HbA1c levels, respectively. In RA the development of reliable composite measures to assess disease activity, such as the Disease Activity Score 28 (DAS28),17 has allowed the principles of treating to a target to be applied to RA management. Clinical remission – the absence of inflammatory disease – is accepted as the target of treatment of RA. In those individuals where this is not possible, a state of low disease activity is accepted. Attainment of this goal has been demonstrated to halt joint damage and hence improve long-term clinical outcomes.14,18
Monitoring disease and optimising therapy
In order to achieve a treatment target of remission or low disease activity, a structured patient management approach is required. This is supported by trials that compared routine outpatient review vs intensive follow up (defined as frequent visits with prompt titration of drug therapy). Those receiving intensive follow up had significant improvement in clinical outcome, physical function and structural damage.15,16,19,20 Patients treated early and aggressively with DMARDs also had reduced work disability, sick leave and premature retirement rates. The aim is to achieve the predefined target, ideally within 3 months, but at least within 6 months of diagnosis. The interval between assessments should be at least 3 months, but monthly visits may be necessary until a period of sustained low disease activity or remission is achieved. It appears that irrespective of treatment therapy, treating to a target, regular follow up and monitoring of disease activity with responsive drug escalation all lead to sustained clinical and functional benefit.21 The principles described above form the foundations of guidelines recently published for the management of RA.22 ‘Treat to target’ is an international initiative developed from a systematic review of all strategy trials in RA and expert opinion (Box 2). It advocates early diagnosis, immediate implementation of disease modifying therapy, monitoring of disease activity and the optimisation of therapy accordingly.
Treatment strategies
Recommendations for pharmacological therapies in RA have been developed by the National Institute for Health and Care Excellence (NICE) and EULAR.23,24 The clinical efficacy data and safety profile of methotrexate endorse it as the anchor drug of choice. Alternative DMARDs are available for those individuals intolerant of methotrexate. DMARDs can also be added in combination as appropriate. Glu-cocorticoids are recommended as an adjuvant therapy at disease onset due to their disease-modifying and anti-inflammatory properties.19 Clinical trials have consistently demonstrated that tight disease control with appropriate escalation of therapy is fundamental in achieving low disease activity.16,20 Therefore, when synthetic DMARDs fail, escalation to one of the biological therapies is advised (Table 1).
Biological therapies approved by NICE for the treatment of rheumatoid arthritis.
Biological therapies have revolutionised disease outcomes in RA. In active, longstanding disease with an inadequate response to methotrexate the addition of a biological agent has significantly improved clinical and structural outcomes.25 Evaluation of biologicals when initiated early suggests more optimal suppression of inflammation may be achieved, reinforcing the concept of a ‘window of opportunity’. When tumour necrosis factor inhibitors were initiated as first line treatment in early RA, higher rates of low disease activity and remission were achieved.20,26 In the UK, NICE stipulates that treatment with methotrexate and one other DMARD is necessary prior to escalation. With this is mind it is imperative that treatment is regularly reviewed and titrated in order to allow appropriate escalation when standard therapy is not sufficient.
The future of rheumatoid arthritis
Research and clinical experience have provided rheumatologists with effective -therapies and strategies for managing RA. However, the optimum treatment pathway has not yet been established. While a good proportion of patients may achieve clinical remission with synthetic DMARDS alone (particularly with a treatment to target approach), it remains unclear whether an initial period of -aggressive therapy with biological agents would equate to improved clinical outcomes. The possibility of drug-free remission and additional advantages of therapy such as cardiovascular benefits remain areas for further evaluation that will help refine treatment approaches in the future.
It is also important to monitor for structural damage in addition to disease activity. Patients in clinical remission have been observed to continue to show structural progression, attributed to persistent subclinical synovitis.27,28 This has partly driven evaluation of more accurate methods of defining and monitoring disease. Ultrasound has emerged as a useful and practical tool in detecting subclinical inflammation that is not identified -clinically. Similarly, advances in the understanding and methods of analysis of immune dysregulation provide additional disease markers. Targets for remission in subsequent years could include achieving imaging and immunological remission.
The potential for curing RA is a realistic goal in light of the novel drug therapies in development. As our understanding of the pathogenesis of RA expands, the prospect for prevention is also on the horizon. The last 20 years have seen dramatic changes in the way we approach RA; however, the future may hold even greater promise.
Target population: patients who have at least one joint with definite clinical synovitis (swelling), not better explained by another disease, should be tested.9
Ten recommendations on treating rheumatoid arthritis to target based on both evidence and expert opinion.22
- © 2013 Royal College of Physicians
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