Dr Aneela Mian (left) and Prof David L. Scott highlight recent EULAR guidance updates in the care of people with RA and the importance of prompt referral from primary care
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Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that primarily affects synovial joints. In most patients, RA involves the small joints of the hands and feet in a symmetrical distribution. It can also involve shoulders, elbows, hips, knees, and the cervical spine. Rheumatoid arthritis affects all ethnic groups. Its UK prevalence is approximately 1% of adults.1 Most RA patients are women. Interactions between many genetic and environmental factors trigger RA, including female gender, family history,2,3 smoking,4 and increasing age.5
Impacts of rheumatoid arthritis
heumatoid arthritis causes substantial disability and reduced quality of life. This is as a result of joint inflammation, progressive joint damage, and associated comorbid disorders like depression. Historically, patients have experienced progressive problems due to their RA: disability worsened annually,6 with 30% of patients being disabled 10 years after diagnosis,7 and over 80% being disabled after 20 years.8 Modern treatment is designed to limit this disease progression.
Identifying patients with poor outcomes, who need the most intensive treatments, remains challenging. Patients who are seropositive for rheumatoid factor and anti-citrullinated peptide antibody have worse outcomes than patients who are seronegative.9,10 Less is known about other predictors.
Rheumatoid arthritis is costly for individual patients, healthcare providers, and the overall economy. Many patients with RA are unable to remain in paid work, with major financial consequences. One-third of patients with RA may stop working within the first years of their disease.7,11,12 In 2010, The National Rheumatoid Arthritis Society put the annual cost to the UK economy of productivity losses due to RA at £8 billion,13 while in 2009 NICE stated that the estimated total costs of RA in the UK, including indirect costs and work-related disability, were between £3.8 and £4.75 billion per year.14
Current management of RA
Modern RA management focuses on reducing synovitis using disease-modifying anti-rheumatic drugs (DMARDs). Methotrexate has become the most widely used DMARD. Every effort is made to avoid treatment delay so as to minimise the risks of joint damage and disability. 8,15
When DMARDs are insufficient, or cause unacceptable adverse reactions, patients with ongoing active disease need biological therapies. These include:
- tumour necrosis factor (TNF) inhibitors (e.g. etanercept and adalimumab)
- alternative biological agents (e.g. tocilizumab, which targets interleukin 6, abatacept, which targets lymphocytes, and rituximab, which targets B cells).
Several other treatments complement DMARDs. Additional drug treatments include:
- oral or injectable steroids to reduce inflammation
- non-steroidal anti-inflammatory drugs and analgesics to control pain
- drugs like bisphosphonates to prevent complications such as osteoporosis.
Supportive treatments include:
- providing education and advice
- encouraging exercise
- offering access to psychological support
- encouraging self-management.
Some useful online sources of information for patients and GPs can be found at:
- NICE Clinical Guideline 79:16 see Rheumatoid arthritis in adults.
- European League against Rheumatism (EULAR) website: Questions and answers on rheumatic diseases.17 See: www.eular.org/myUploadData/files/Q&A%20on%20RD.pdf
- Arthritis Research UK website: Rheumatoid arthritis.18 See:
- National Rheumatoid Arthritis Society website. Publications.19 See: www.nras.org.uk/publications
Managing RA is complex and there have been substantial changes over recent years. Many guidelines have been developed to ensure patients receive the best possible care. The ever-changing evidence base for managing RA has meant that there has been a steady renewal of historical guidelines.
Some guidelines deal with specific issues, in particular when to use high-cost biological agents. This is exemplified by the NICE technology appraisals (TAs) (e.g. TA195,20 TA24721). Most guidelines deal with overall RA management. Some were developed by specialist societies like the British Society for Rheumatology11 and American College of Rheumatology.22 Others are from national bodies like NICE.14 There are also guidelines from international groups like EULAR; the recently updated EULAR guideline, EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2013 update,23 (‘the EULAR guideline’) is the focus of this article and is freely available at: ard.bmj.com/content/73/3/492.full.pdf+html
The EULAR guideline
The initial EULAR guideline for managing RA with synthetic and biological DMARDs was published in 201024 and updated in 2013.23 It is based on reviews of the published literature on drug efficacy and safety, and also covers some health economic aspects. Healthcare varies across Europe and the guideline provides advice that is sufficiently general to be applicable across the continent.
The EULAR guideline incorporates three underlying principles (see Box 1, below), which highlight the need for rheumatologists to work with patients so that they receive the care they want and need. There are 14 specific recommendations (see Box 2 here), which encompass four broad themes:
- early diagnosis and DMARD initiation
- monitoring and treat-to-target
- treatment strategies
- remission and reducing therapy.
The guideline classifies immunosuppressive drugs (with the exception of glucocorticoids) as DMARDs. These include:
- synthetic DMARDs (sDMARDs), which include conventional synthetic DMARDs (csDMARDs) (e.g. methotrexate) and targeted synthetic DMARDs (tsDMARDs) (e.g. tofacitinib. NB At the time of the guideline’s Task Force’s meeting in April 2013, tofacitinib had not been approved or used in practice in Europe or North America)
- biological DMARDs (bDMARDs), which include biological originator DMARDs (boDMARDs) (e.g. etanercept, a TNF inhibitor), and biosimilar DMARDs (bsDMARDs), which are now available for infliximab.
Early diagnosis and initiation of treatment
There are new RA classification criteria to help diagnose the disease early,25 allowing patients to be readily identified and referred for rheumatology specialist care as soon as possible. The clinical features of early RA can be subtle, and inflammatory markers may not be elevated. Low referral thresholds are crucial. Disease-modifying anti-rheumatic drugs should be initiated by rheumatologists as soon as the diagnosis is made so as to:
- control inflammation
- prevent joint damage
- limit disability.
This early treatment is crucial, because patients are most at risk of irreversible erosive damage shortly after the onset of disease.26
Box 1: Three principles of care in the EULAR 2013 updated guideline23
- Treatment of patients with rheumatoid arthritis should aim at the best care and must be based on a shared decision between the patient and the rheumatologists
- Rheumatologists are the specialists who should primarily care for patients with rheumatoid arthritis
- Rheumatoid arthritis incurs high individual, societal, and medical costs, which should be considered in its management by the treating rheumatologist.
- Adapted from Table 1 in: Smolen J, Landewé R, Breedveld F 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 (3): 492–509. By kind permission.
Box 2: Fourteen key recommendations in the EULAR 2013 updated guideline23
- Therapy with DMARDs should be started as soon as the diagnosis of RA is made
- Treatment should be aimed at reaching a target of remission or low disease activity in every patient
- Monitoring should be frequent in active disease (every 1–3 months): if there is no improvement by at most 3 months after the start of treatment or the target has not been reached by 6 months, therapy should be adjusted
- Methotrexate should be part of the first treatment strategy in patients with active RA
- In cases of methotrexate contraindications (or early intolerance), sulfasalazine or leflunomide should be considered as part of the (first) treatment strategy
- In DMARD-naïve patients, irrespective of the addition of glucocorticoids, csDMARD monotherapy or combination therapy of csDMARDs should be used
- Low-dose glucocorticoids should be considered as part of the initial treatment strategy (in combination with one or more csDMARDs) for up to 6 months, but should be tapered as rapidly as clinically feasible
- If the treatment target is not achieved with the first DMARD strategy, in the absence of poor prognostic factors, change to another csDMARD strategy should be considered; when poor prognostic factors are present, addition of a bDMARD should be considered
- In patients responding insufficiently to methotrexate and/or other csDMARD strategies, with or without glucocorticoids, bDMARDs (TNF inhibitors,* abatacept or tocilizumab, and, under certain circumstances, rituximab†) should be commenced with methotrexate
- If a first bDMARD has failed, patients should be treated with another bDMARD; if a first TNF inhibitor therapy has failed, patients may receive another TNF inhibitor* or a biological agent with another mode of action
- Tofacitiniba may be considered after biological treatment has failed
- If a patient is in persistent remission after having tapered glucocorticoids, one can consider tapering‡ bDMARDs§, especially if this treatment is combined with a csDMARD
- In cases of sustained long-term remission, cautious reduction of the csDMARD dose could be considered, as a shared decision between patient and physician
- When therapy needs to be adjusted, factors apart from disease activity, such as progression of structural damage, comorbidities and safety issues, should be taken into account.
- * TNF inhibitors: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab, biosimilars (as approved according to a thorough approval process, such as by EMA and/or FDA)
- † The ‘certain circumstances’, which include history of lymphoma or a demyelinating disease, are detailed in the text [of the source material]
- ‡ Tapering is seen as either dose reduction or prolongation of intervals between applications § Most data are available for TNF inhibitors, but it is assumed that dose reduction or interval expansion is also pertinent to biological agents with another mode of action.
- DMARD=disease-modifying antirheumatic drug; RA=rheumatoid arthritis; csDMARD=conventional synthetic disease-modifying antirheumatic drug; bDMARD=biological disease-modifying antirheumatic drug; TNF=tumour necrosis factor; EMA=European Medical Agency; FDA=Food and Drug Administration
- a At the time of the guideline’s task force’s meeting in April 2013, tofacitinib had not been approved or used in practice in Europe or North America.
- Adapted from Table 1 in: Smolen J, Landewé R, Breedveld F 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 (3): 492–509. By kind permission.
Monitoring and treat-to-targetComposite measures of disease activity should be used to help patients achieve predetermined targets, and patients should be seen every 1–3 months for close monitoring. Disease Activity Score based on 28 joint counts (DAS28) is widely used for monitoring disease in clinical practice.27 DAS28 is easily used, reproducible, and represents the best available measure. It incorporates tender and swollen joint counts, patients’ self-reported global scores, and erythrocyte sedimentation rate or C-reactive protein levels.
The best treatment target is to achieve remission of RA within 6 months. The DAS28 is the most widely used disease-monitoring tool used for this, with a score of <2.6 indicating clinical remission. Patients in DAS28 remission have been shown to have active disease and ongoing structural damage. Consequently, some experts prefer more stringent remission definitions.
Methotrexate is the ‘anchor’ DMARD.29-31 It is effective in monotherapy and combinations.30,32 Co-prescribing folic acid minimises toxicity.33 The conventional starting dose is 15 mg/week, increased monthly to 20–25 mg weekly.32 Maximal effects are achieved after 4–6 months.34,35 Methotrexate has blood, hepatic, renal, and lung toxicities. Consequently, it is best started and supervised by rheumatologists and needs frequent safety monitoring.
Sulfasalazine and leflunomide are alternative DMARDs with comparable efficacy to methotrexate. As they can be combined with biological agents36,37 they can be used as initial treatment when methotrexate causes side-effects or is contraindicated. The optimal doses are 3–4 g/day for sulfasalazine and 20 mg/day for leflunomide. Sulfasalazine is the only DMARD that is safe for use in pregnancy.38
Hydroxychloroquine, an antimalarial, is often used in combination with methotrexate and sulfasalazine. It can also be used as monotherapy in mild disease and can be used safely in pregnancy.23 Finally, gold injections remain effective but concerns about toxicity have curtailed their use.39
Glucocorticoids give clinical, functional, and structural benefits when combined with conventional DMARDs.40-43 Low-dose steroids are often used within the initial treatment strategy,25 but doses should be tapered as soon as possible to minimise long-term toxicity.
Treatments may be prescribed in primary care when a patient is on a stable dose. Treatment should be guided by the specialist centre and only initiated by the rheumatologist.
If initial treatment does not achieve remission, alternative strategies are needed. In the absence of poor prognostic factors (see Box 3, below), an alternative conventional DMARD should be used. Where there are poor prognostic factors, intensive treatment is needed. There is debate about the relative benefits of using step-up DMARDs, or adding a biological agent to methotrexate.44-47 EULAR preferred initiating a biological agent in patients with poor prognostic indicators.23
If one biological DMARD is not effective, an alternative biological agent should be used. The EULAR task-force felt that there is currently insufficient evidence to suggest that any particular biological agent is better than another.
Remission and reducing therapy
When patients have achieved remission, most current data suggest that withdrawing TNF inhibitors in patients with established RA causes flares.48-51 The effects of withdrawal of TNF inhibitors in patients with early disease are less clear. There is growing evidence that biological dose reduction may maintain good control in both early52 and established RA.53,54
Withdrawing conventional DMARDs when patients have achieved remission results in many flares in established RA.55,56 Most experts therefore recommended dose reductions rather than withdrawal of DMARDs in patients who have achieved remission.57
Treatment decisions need to be tailored to individual patients. Achieving remission or low disease activity may not always be best for patients, particularly when treatment risks (e.g. increased risk of infection) are taken into account. Decisions must take account of comorbidities and other safety issues. In addition, some patients with low disease activity and remission have been found to have progression of bone erosions on X-ray;58 it is not always sensible to taper treatment.
Box 3: Poor prognostic factors
- High disease activity score
- Rheumatoid factor and/or citrullinated protein antibodies
- Early presence of joint damage.
The challenges for primary care
The proportion of patients with RA being seen by a rheumatologist within 12 weeks of symptom onset varies in Europe from 8% to 42%.59 Delays reflect the variable impacts of patient, professional, and healthcare systems issues. Recent European research found delays from symptom onset to treatment initiation to be over 20 weeks. Most of these delays were due to patient-related factors.60,61 Educating both the public and healthcare professionals is essential to ensure that patients are recognised and referred early. Close collaboration between primary care and local rheumatology services is vital to ensure patients with possible early RA are seen promptly. Clear pathways need to be developed for these patients to ensure that they receive the best possible care and can experience better outcomes in the future.
In the last two decades, RA management has increasingly focused on early intensive treatment with DMARDs. As new cases of RA are relatively uncommon, and therefore encountered infrequently in practice, this creates substantial challenges across primary and secondary care. It is better to refer too many patients, who can be screened and returned to primary care with ease, rather than risk delaying treatment in patients who may have unrecognised active disease. The outstanding challenge is not to help GPs recognise early RA, since most GPs do now refer patients they see with early RA to specialists; rather, it is to educate the public in recognising the early features of RA, so that people will seek medical advice sooner rather than later.
- Both this EULAR guideline23 and NICE CG7914 emphasise the need for early referral to specialist services for people with suspected RA
- Commissioners should ensure that there is a rapid referral route to secondary care and capture this within a local care pathway, which should also detail what investigations should be performed in primary care before patients are referred
- In their contracts with acute providers, commissioners could apply a CQUIN reward scheme for the percentage of newly referred patients with RA reaching remission within 6 months of first being seen in secondary care
- As the diagnosis of RA is not always straighforward, and delays in presentation are common, educational programmes aimed at patients and primary care professionals could be effective at reducing delay in diagnosis:
- pharmacies would be a good place for RA information campaigns for the public, as patients will often look to buy analgesics for joint pains before seeking medical advice
- Commissioners should ensure that biological drugs are prescribed in secondary care in line with NICE guidance and, where possible, drugs of lower acquisition price are used, as these drugs are excluded from the PbR tariff and the cost passes through to commissioners
- Tariff costs for rheumatology outpatients: £214 (new), £99 (follow up).a
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- Stahl E, Raychaudhuri S. Evidence for a genetic component to disease severity in RA. Nat Rev Rheumatol 2012; 8 (6): 312–313.
- Arend W, Firestein G. Pre-rheumatoid arthritis: predisposition and transition to clinical synovitis. Nature Review Rheumatology 2012; 8 (10): 573–586.
- Humphreys J, Verstappen S, Hyrich K et al. The incidence of rheumatoid arthritis in the UK: comparisons using the 2010 ACR/EULAR classification criteria and the 1987 ACR classification criteria. Results from the Norfolk Arthritis Register. Ann Rheum Dis 2013; 72 (8): 1315–1320.
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- Pugner K, Scott D, Holmes J, Hieke K. The costs of RA: an international long-term view. Semin Arthritis Rheum 2000; 29 (5): 305–320.
- Choy E, Panayi G. Cytokine pathways and joint inflammation in rheumatoid arthritis. N Eng J Med 2001; 344 (12): 907–916.
- Goronzy J, Matteson E, Fulbright J et al. Prognostic markers of radiographic progression in early rheumatoid arthritis. Arthritis Rheum. 2004; 50 (1): 43–54.
- Kroot E, de Jong B, van Leeuwen M et al. The prognostic value of anti-cyclic citrullinated peptide antibody in patients with recent-onset rheumatoid arthritis. Arthritis Rheum 2000; 43 (8): 1831–1835.
- Deighton C, Hyrich K, Ding T et al. BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy. Rheumatology (Oxford) 2010; 49 (6): 1197–1199.
- National Rheumatoid Arthritis Society. I want to work: a self-help guide for people with Rheumatoid Arthritis. London: NRAS, 2007. Available at: www.nras.org.uk/includes/documents/cm_docs/2011/e/employee_guide_feb_2011.pdf
- National Rheumatoid Arthritis Society. The Economic Burden of RA. NRAS, 2010.
- NICE. Rheumatoid arthritis: The management of rheumatoid arthritis in adults. Clinical Guideline 79. NICE, 2009. Available at: www.nice.org.uk/guidance/cg79
- Scott D, Pugner K, Kaarela K et al. The links between joint damage and disability in rheumatoid arthritis. Rheumatology (Oxford) 2000; 39 (2): 122–132.
- NICE. Rheumatoid arthritis in adults. Information for the public. Clinical Guideline 79. NICE, 2009. Available at: publications.nice.org.uk/rheumatoid-arthritis-in-adults-ifp79
- The European League Against Rheumatism. Questions and answers on rheumatic diseases. EULAR Secretariat. Available at: www.eular.org/myUploadData/files/Q&A%20on%20RD.pdf
- Arthritis Research UK website. Rheumatoid arthritis. www.arthritisresearchuk.org/arthritis-information/conditions/rheumatoid-arthritis.aspx
- National Rheumatoid Arthritis Society website. Publications. www.nras.org.uk/publications
- NICE. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. Technology Appraisal 195. NICE, 2010. Available at: www.nice.org.uk/guidance/TA195
- NICE. Tocilizumab for the treatment of rheumatoid arthritis (rapid review of technology appraisal guidance 198). Technology Appraisal 247. NICE, 2012. Available at: www.nice.org.uk/guidance/TA247
- Singh J, Furst D, Curtis J et al. 2012 update of the 2008 American College of Rheumatology recommendations for the use of disease-modifying anti-rheumatic drugs and biologic agents in the treatment of rheumatoid arthritis. Arthritis Care Res 2012; 64 (5): 625–639.
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