Abstract
Developments in the understanding of the pathogenesis of rheumatoid arthritis (RA) and the introduction of targeted biologic therapies have greatly advanced the management of RA in clinical practice. The management of RA is now aimed at achieving remission, to prevent joint damage and disability. In particular, a critical period early in disease is recognised, in which early aggressive treatment with disease-modifying therapy is advocated. Although a state of remission is the ideal, this chapter discusses the difficulties which may arise in achieving this goal in patients with established disease.
The evidence for best management, aimed at achieving clinical remission in established disease, is reviewed. The consequences of incomplete control of chronic inflammation in established disease, including pain, disability and co-morbidities (such as cardiovascular disease and osteoporosis), also pose a significant clinical challenge. The rationale for a multidisciplinary team approach in reducing the associated morbidity and mortality of the disease are examined.
In recent years, the focus of the management of rheumatoid arthritis (RA) has changed, with the aim of identifying patients with ‘early disease’ and commencing treatment as soon as possible with disease-modifying anti-rheumatic drugs (DMARDs) and, if inadequate, biologic therapy. Radiographic joint damage occurs more rapidly in early disease , and superior outcomes have been achieved with early, aggressive treatment strategies. Initial combination DMARD therapy was first shown to be favourable to initial DMARD monotherapy in a randomised study design in the COBRA trial (comparing the combination of sulphasalazine, methotrexate and prednisolone with sulphasalazine alone) , and later in the FIN-RACo study (comparing combination of sulphasalazine, methotrexate, hydroxychloroquine and prednisolone with initial sulafasalazine and prednisolone) . Tight control of disease, with frequent monitoring and escalation of treatment according to a target of disease activity, has proved advantageous in several pragmatic studies. For example, in the TICORA study intensive management (involving monthly assessment and step-up to combination DMARD therapy according to a target of low disease activity) was compared to three-monthly monitoring without use of a formal measure of disease activity . At 18 months, clinical remission was achieved in 65% of the intensive therapy group, compared to 16% of the routine treatment group. This step-up approach to treatment is currently the most widely practised strategy in RA, with extensive data supporting the addition of non-biologic or biologic DMARDs over sequential DMARD monotherapy in early disease, and the benefits of this approach over initial combination therapy in terms of risks of toxicity . There is increasing evidence demonstrating that commencement of tumour necrosis factor inhibitor (TNFi) therapy at an early stage may result in complete suppression of inflammation and allow withdrawal of biologic therapy without relapse of disease . Furthermore, in line with the apparent benefits of early treatment, new classification criteria have recently been developed with the aim of identifying disease at an earlier stage allowing intervention in a timelier manner: the 2010 American College of Rheumatology (ACR) and European League Against Rheumatism (EULAR) rheumatoid arthritis classification criteria . Despite advances in the management of early RA, however, a large proportion of current clinical practice in rheumatology involves the assessment and management of patients with established disease.
‘Early’ versus ‘established’ RA
There is, at present, no accepted consensus on the precise definition of ‘early’ or ‘established’ RA. Previously, clinical trials have classified patients with disease duration of less than 2 years as having early RA. However, studies of synovial histology demonstrate that pathological changes in the synovium in patients with disease duration of less than 1 year, or even 6 months, are no different to those seen in patients with disease of longer duration . Patients with established RA vary between patients with long-standing, destructive RA, who have failed to respond to several DMARDs (characterised by disability and deformity), and patients who were treated with DMARDs at an early stage but have not reached sustained remission.
Principles in the management of established RA
Management of established RA involves a multidisciplinary approach aiming to optimise drug therapy to reduce disease activity, with input from allied health professionals to optimise and preserve patients’ functional ability. The recently published European guidelines, ‘Treating Rheumatoid Arthritis to Target’, recommend that a target of disease activity should be set for any individual patient in consultation with the patient . The ideal target for the treatment of all patients with RA is clinical remission, defined as the absence of signs and symptoms of significant inflammation. Remission is associated with less disability and improved quality of life in comparison to even low disease activity states, and disease activity has been shown to be the strongest predictor of disability in established RA . It is recognised that in patients with long-standing disease or in those with co-morbidities, a state of low disease activity may be a more appropriate target, as the risk of increasing DMARD therapy may outweigh potential benefits . Remission may also be more difficult to achieve in established disease, with studies suggesting that there may be a ‘window of opportunity’ in very early RA when higher rates of remission with TNFi therapies can be attained (70% of patients commencing TNFi within 4 months of symptom onset achieved remission, in comparison to 40% of those with a symptom duration of 4–24 months) .
Another challenge in the management of established RA is posed by the functional disability caused by irreversible damage, and the progressive disability which may be observed in the absence of synovitis, for example, in non-inflammatory pain syndromes such as fibromyalgia. In this patient group, non-pharmacologic management can play a vital role in improving quality of life and preserving joint function. However, these treatment modalities should not be overlooked in the care of any RA patient, including those recently diagnosed.
Other considerations in established disease include an increased risk of infection, cardiovascular disease and osteoporosis, and the high incidence of depression amongst persons with RA. Consideration of these aspects of the disease should form part of routine management, for example, pneumococcal and influenza vaccinations are advised. Despite recent advances in the control of inflammatory disease, including the development of several biologic therapies, there is a relative paucity of evidence for the effect of therapy on these outcomes; however, initial data from long-term follow-up studies is beginning to emerge (discussed later with the management of co-morbidities).
Principles in the management of established RA
Management of established RA involves a multidisciplinary approach aiming to optimise drug therapy to reduce disease activity, with input from allied health professionals to optimise and preserve patients’ functional ability. The recently published European guidelines, ‘Treating Rheumatoid Arthritis to Target’, recommend that a target of disease activity should be set for any individual patient in consultation with the patient . The ideal target for the treatment of all patients with RA is clinical remission, defined as the absence of signs and symptoms of significant inflammation. Remission is associated with less disability and improved quality of life in comparison to even low disease activity states, and disease activity has been shown to be the strongest predictor of disability in established RA . It is recognised that in patients with long-standing disease or in those with co-morbidities, a state of low disease activity may be a more appropriate target, as the risk of increasing DMARD therapy may outweigh potential benefits . Remission may also be more difficult to achieve in established disease, with studies suggesting that there may be a ‘window of opportunity’ in very early RA when higher rates of remission with TNFi therapies can be attained (70% of patients commencing TNFi within 4 months of symptom onset achieved remission, in comparison to 40% of those with a symptom duration of 4–24 months) .
Another challenge in the management of established RA is posed by the functional disability caused by irreversible damage, and the progressive disability which may be observed in the absence of synovitis, for example, in non-inflammatory pain syndromes such as fibromyalgia. In this patient group, non-pharmacologic management can play a vital role in improving quality of life and preserving joint function. However, these treatment modalities should not be overlooked in the care of any RA patient, including those recently diagnosed.
Other considerations in established disease include an increased risk of infection, cardiovascular disease and osteoporosis, and the high incidence of depression amongst persons with RA. Consideration of these aspects of the disease should form part of routine management, for example, pneumococcal and influenza vaccinations are advised. Despite recent advances in the control of inflammatory disease, including the development of several biologic therapies, there is a relative paucity of evidence for the effect of therapy on these outcomes; however, initial data from long-term follow-up studies is beginning to emerge (discussed later with the management of co-morbidities).
Strategies for optimal treatment of established RA in clinical practice
The efficacy of early aggressive therapy in patients with early RA has been demonstrated in multiple clinical trials . While no data exist regarding the role of aggressive treatment strategies in established RA, it is feasible to extrapolate data from early RA and hypothesise that more complete suppression of disease activity would be associated with less progression of pre-existent joint damage and therefore less functional disability. The EULAR ‘treat to target’ guidelines recommend remission as the target of therapy in all patients with RA, that is, those with early or established disease . These guidelines do however recognise that a state of low disease activity might be an alternative target especially in patients with established disease or those with co-morbidities precluding aggressive use of DMARDs either as monotherapy or combination therapy as discussed above.
Multiple measures of disease activity are used in clinical practice to assess response to therapy . The level of disease activity reached is an important indicator of future disability and radiographic progression . In established RA, the addition of imaging modalities, such as ultrasound (US) and magnetic resonance imaging (MRI), to clinical examination can aid assessment of response to therapy particularly in patients with chronic deformity. In these patients resolution of chronic swelling might not be expected to occur following treatment, whereas the presence of active synovitis (e.g., as evidenced by presence of power Doppler on US) would be more indicative of suboptimal response to therapy, and hence increased likelihood of progression of radiographic damage, especially in patients treated with traditional DMARDs .
The average patient with RA has 1.6 co-morbidities, and risk of co-morbidity increases with age . This increases the complexity of caring for patients with RA especially with respect to prescribing DMARDs and biological therapies. Furthermore, outcomes of co-morbidities including myocardial infarction is worse in patients with RA compared to those without RA and therefore screening and management of co-morbidities should be an important part of the overall care package for these patients .
Achieving clinical remission in patients with established RA: disease activity measures
The acute phase response
The acute phase response describes the local and systemic inflammatory and repair processes that accompany inflammation. The acute phase markers most commonly used in assessment of disease activity in RA are the C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), both of which are used in composite scores for the assessment of disease activity. ESR and CRP have been shown to correlate with radiographic progression. CRP is now considered the preferential acute phase marker as it is standardised across centres allowing data comparison and, unlike ESR measurement, does not vary depending on patient sex or age.
Composite measures of disease activity
‘Treating Rheumatoid Arthritis to Target’ recommendations advise the use of disease-assessment tools such as those which incorporate joint assessment for swelling and tenderness in clinical practice . Many validated clinical scores are available for the assessment of disease activity in patients with RA in clinical practice; these are summarised in Table 1 . The modified disease activity score, DAS28, has been validated in the assessment of disease activity in RA for use in clinical trials , and can be used by assessors with varying levels of experience in clinical practice . The Simplified Disease Activity Index (SDAI) was developed in an attempt to simplify assessment of disease activity in day-to-day practice: variables are added together to calculate the score avoiding the use of formulae; however, it requires the value of CRP, which may not be immediately available in clinic. In this instance, the Clinical Disease Activity Index (CDAI), being calculated from only clinical variables, may be useful. Both of these indices correlate with DAS28 as well as patients’ physical function (assessed by the Health Assessment Questionnaire, HAQ) .
| Method of assessment | Definition of clinical remission | |
|---|---|---|
| Disease Activity Score (DAS) | Calculated using a mathematical formula comprising 3 variables:
| Score < 1.6 |
| DAS using 4 variables may also be calculated, incorporating patient global health assessment (recorded on a visual analogue scale). | ||
| DAS based on 28 joints (DAS28) | Calculated using a mathematical formula comprising:
| Score < 2.6 |
| Clinical Disease Activity Index (CDAI) | The sum of 4 variables:
| Score ≤ 2.8 |
| Simplified Disease Activity Index (SDAI) | The sum of CDAI plus CRP (in mg dl −1 ). | Score ≤ 3.3 |
With multiple measures of disease activity available, a provisional ACR/EULAR definition of remission, which can be applied uniformly in clinical trials, has recently been published . In an analysis of the performance of clinical scores to predict stability in terms of radiographic joint damage and physical function (as assessed by the Health Assessment Questionnaire, HAQ), SDAI and CDAI remission performed better than DAS28 remission (which did not correspond with radiographic stability). Use of one of two stringent definitions for remission in clinical trials has been proposed: either SDAI remission or a score of 1 or less in tender joint count (out of 28), swollen joint count (out of 28), patient global assessment (on a visual analogue scale of 0–10) and CRP (in mg dl −1 ).
Achieving clinical remission in patients with established RA: radiological assessment
Plain radiography
When treating patients with RA, it is important to consider radiological and functional outcome as well as clinical outcome measures. Joint damage in patients with RA is related to disease activity and correlates with disability; correlation coefficients between 0.3 and 0.7 have been described, with a strong relationship seen between joint damage and disability in established RA and a weaker relationship in early disease . Conventional radiography is a widely available resource and radiographs of hand and feet are recommended annually to assess for progression of joint damage. Radiographic progression can occur in patients even in clinical remission ; therefore, even if low disease activity or clinical remission has been achieved, alteration of disease-modifying medication may be considered if there is evidence of radiographic progression. However, a significant time lag may exist between insufficient disease control and the development of X-ray features of disease.
Numerous scoring methods have been developed for the assessment of joint damage in RA such as the modified Sharp Scoring method for hands and wrists (assesses 17 areas in the hand for erosion and 18 areas for joint space narrowing) . These scoring systems are mainly employed in clinical trials and, as they are time consuming, are not carried out in routine clinical practice where an estimation of joint progression by an experienced radiologist is sufficient to make decisions regarding treatment alterations.
Ultrasound (US)
US has many advantages; it is cheap, portable, does not use ionising radiation and displays images in real-time; therefore, it can be helpful in the assessment of patients in the out-patient setting. The advent of Power Doppler US (PDUS) allows haemodynamic evaluation of synovitis which can be helpful in determining ‘activity’ in joints with chronic deformities, whereas US synovial hypertrophy (grey scale) may reflect chronic changes from previous inflammatory activity and may not be expected to resolve completely despite effective disease control. US has been shown to be more sensitive than clinical examination in the detection of synovitis , and more sensitive than conventional radiology in the detection of erosions (detecting 6.5-fold more erosions in early disease) .
There is emerging evidence that US may be a useful tool in the assessment of patients achieving clinical remission. In a study of patients receiving DMARD therapy, subclinical synovitis was detected by US in the majority of patients with physician-determined remission . As presence of PD is associated with progression of joint damage in patients in clinical remission , this implies that decisions regarding continuation and discontinuation of therapy should not be based purely on clinical measures of disease activity.
Magnetic resonance imaging
Due to cost considerations and limited availability, MRI is rarely used in clinical practice for the assessment of RA. However, MRI is superior to conventional radiography in the assessment of bone erosion in both early and established RA and is considered the gold standard in the assessment of synovitis. MRI is the only radiographic assessment that can assess bone oedema. Increased numbers of osteoclasts are seen in the presence of bone oedema, associated with increased inflammatory cell infiltrate of the bone marrow. This is thought to contribute to the development of erosions . The Outcome Measures in RA studies (OMERACT) group have developed a standardised scoring system for the assessment of bone erosion, synovitis and bone oedema in RA known as the RA MRI scoring system (RAMRIS) .
Achieving clinical remission in patients with established RA: therapeutic options
Non-biologic DMARDs
Methotrexate (MTX) is a folate antimetabolite and is the most commonly used DMARD. It is recommended by EULAR as first-line therapy unless contraindications are present , and is regarded as the anchor drug in RA; it is effective as monotherapy, but also widely used in combination with other non-biologic or biologic DMARDs (in the knowledge that its combination with biologic therapies increases the efficacy of these agents). Results of a systematic review suggest that predictive factors for achieving a good clinical response to MTX include being female, having previously demonstrated an inadequate response to an alternative DMARD and having lower disease activity at commencement of MTX . Disease duration does not appear to influence response to MTX; however, Anderson et al. demonstrated that increasing disease duration was associated with a poor clinical response to DMARDs including MTX: approximately 50% of patients with disease duration of less than 1 year demonstrated a clinical response compared to 35% of those with disease duration of 10 years or more . DMARDs may lose efficacy over time or patients may develop intolerance; MTX has the longest ‘survival’ of approximately 5 years compared to 2 years for sulphasalazine and other agents .
Combination DMARD therapy
While there is evidence of efficacy of combination treatment strategies in the treatment of early RA , there is very little data to support the addition of or switching between non-biologic DMARDs in patients with established RA. The ACR recommends the use of combination DMARD therapy in patients with established disease with poor prognostic indicators (such as high disease activity, positivity for rheumatoid factor or anti-cyclic citrullinated protein, or presence of radiographic erosions); however, these guidelines focus on the commencement of non-biologic DMARDs and not on the management of patients following failure of monotherapy . There are numerous potential DMARD combination strategies using either two or three DMARDs. Most treatment strategies used include MTX, if tolerated, in combination with another DMARD such as sulphasalazine, hydroxychloroquine or leflunomide.
Corticosteroids
Corticosteroids have been used for over 50 years in the treatment of inflammatory conditions. They rapidly suppress inflammation and are often used to control symptoms and signs in patients commencing DMARDs as they can take up to 12 weeks to affect a clinical response. The benefit of corticosteroids in suppressing inflammation and reducing progression of radiographic change has been demonstrated in early RA . The effects of corticosteroids on radiographic progression in established disease is unknown. In clinical practice, corticosteroids are weaned as quickly as possible in the majority of patients, and used as sparingly as possible in established RA due to their significant side effects .
Biological therapies
Tumour necrosis factor inhibitors
Five TNFi therapies are currently licensed for the treatment of RA after the failure of conventional DMARD therapy: three monoclonal antibodies (infliximab, adalimumab and golimumab), a TNF receptor fusion protein (etanercept) and a pegylated antibody-binding fragment (certolizumab). All have demonstrated efficacy in the treatment of RA refractory to non-biologic DMARDs . Direct clinical trials comparing TNFi have not been performed; however, they appear to have similar clinical and radiological efficacy, as well as similar safety profiles .
B cell targeted therapy
Rituximab is a chimeric monoclonal antibody against CD20, a cell-surface marker present on B cells from the pre-B cell to mature B cell stage of development. It is efficacious in the treatment of RA refractory to MTX and after TNFi failure . Rituximab is currently licensed in combination with MTX for the treatment of RA refractory to TNFi. Rituximab is more likely to be effective in patients that are rheumatoid factor (RF) and/or anti-cyclic citrullinated protein (anti-CCP) positive . A good clinical response is also associated with effective depletion of B cells in the peripheral circulation 2 weeks after initial rituximab infusion . It follows that non-responders, with persistence of high-level circulating B cells, may benefit from re-treatment if B cell depletion can be improved with a second treatment course: a repeat infusion of rituximab at 6 months, prior to total B cell repopulation, led to clinical response in 72% of previous non-responders . Repeated treatment courses are effective and well tolerated. Improvement in functional status and inhibition of structural damage has also been demonstrated following treatment with rituximab .
T cell co-stimulation blockade
Abatacept is a fusion protein composed of cytotoxic T lymphocyte antigen-4 (CTLA4) linked to a modified Fc portion of human immunoglobulin G. It selectively blocks the CD80/CD86:CD28 co-stimulatory signal which is required for full T cell activation, that is, it works upstream from the inflammatory cytokine cascade. Abatacept has demonstrated clinical efficacy in MTX inadequate responders and after TNFi failure , and is licensed in both of these groups of patients. Ability of abatacept to inhibit radiographic progression has also been demonstrated .
Interleukin-6 receptor inhibition
Tocilizumab is a fully human IL-6 receptor antibody licensed to treat RA refractory to TNFi and, in Europe, also in RA refractory to conventional DMARDs. Clinical and functional improvements have been demonstrated with tocilizumab monotherapy and with use in combination with MTX, in MTX and TNFi inadequate responders . Moreover, its ability to inhibit radiographic progression in monotherapy as well as in combination with MTX has been proven in patients with an inadequate response to DMARDs .
Clinical use of biologic therapy
Available evidence suggests that the efficacy of the various biologic agents is similar although head-to-head trials are limited; the first trial to directly compare biologic agents resulted in abatacept demonstrating similar efficacy to infliximab in MTX inadequate responders . TNFi are predominantly the first biologics prescribed, with greatest experience and the largest amount of long-term follow-up data available for this drug class. Exceptional circumstances where TNFi are avoided include patients with a history of malignancy within the previous 10 years or history of demyelinating illness. Rituximab is usually commenced in these cases .
Data from clinical trials and registries demonstrates that approximately 20–30% of patients with established RA achieve clinical remission; whilst up to one-third of patients fail to obtain any significant benefit with TNFi. Non-response may also manifest as a loss of response over time (secondary non-response). In the case of non-response or intolerance to initial TNFi therapy, the decision of which second line biologic to prescribe is usually left to the discretion of the attending physician. Prior to the development of alternative biologic treatment strategies, it was common practice to switch to an alternate TNFi in either of these events; numerous observational studies report benefits , in addition to randomised controlled trial (RCT) evidence of the efficacy of golimumab after TNFi which supports this practice . Data from biologic registries suggest that patients who have failed two TNFi are unlikely to respond to a third . In RF and anti-CCP negative patients, in whom rituximab is less effective, the use of alternate biologic agent (TNFi, abatacept or tocilizumab) is appropriate; however, other biomarkers of response which could guide treatment decisions are, at present, lacking.
Cessation of DMARD therapy in remission
EULAR guidelines suggest that in patients with sustained remission, following tapering of corticosteroid, titration of DMARD can be considered . It has been demonstrated that in the event of a patient’s disease flaring, resumption of DMARD therapy is effective and tolerated .
Despite success seen in remission induction and withdrawal of TNFi therapy in patients with early disease , successful withdrawal of TNFi therapy in patients with established RA has largely been unsuccessful . In a cohort of 20 patients with established disease (median disease duration 120 months) achieving clinical remission, sustained for at least 6 months, only three patients (15%) remained in remission after cessation of TNFi; these three patients had shorter disease duration and less functional impairment (lower HAQ scores) . Similar to a cohort with early disease, successful withdrawal of TNFi therapy was associated with several immunological parameters including higher levels of naïve T cells, lower levels of inflammation-related cells and higher CD62L + T regulatory cells. Further research in this area, and in the use of US as discussed previously, may lead to the development of clinical and laboratory biomarkers which, in the future, could aid physicians in deciding when it may be appropriate to trial withdrawal of therapy.
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