Drs Caroline Cardy (left) and Simon Bowman discuss the pharmacological treatment pathway for rheumatoid arthritis based on the recent recommendations from NICE
- Early referral of patients with RA to specialist care is essential to improve outcomes
- Urgent referral of patients with persistent synovitis is indicated if:
- the small joints of the hands and feet are affected
- more than one joint is affected
- there has been a delay in presentation of 3 months or longer
- A step-down approach to treatment is currently advocated with a combination of DMARDs, including methotrexate, recommended as first-line therapy
- Golimumab is the latest TNF-? inhibitor to be approved by NICE for the treatment of RA
- Rituximab is recommended for patients in whom treatment with a TNF-? inhibitor fails
- Switching directly from one TNF-? inhibitor to another is not currently recommended unless rituximab is contraindicated or there are side-effects to the first anti-TNF-? used
- Tocilizumab, an IL-6 inhibitor, has been approved by NICE for the treatment of RA
- Annual review should include assessment of co-morbidities
- Calculations for cardiovascular risk should incorporate RA as an independent risk factor.
Rheumatoid arthritis (RA) is a heterogeneous multisystem inflammatory condition characterised by inflammation of synovial joints. It is associated with significant disability and premature mortality. The latter is due chiefly to an increase in cardiovascular (CV) disease and infections.1 The prevalence of RA in the UK approaches 1% with the ratio of females to males of 2–3:1 affected.2 The incidence of RA is low, with around 1.5 men and 3.6 women developing RA per 10,000 people per year,3 which translates into approximately 12,000 people developing RA each year in the UK. The peak age of incidence is in people in their 70s,3 but the disease can affect all ages. The total cost of RA in the UK, including indirect costs and work-related disability, has been estimated at between £3.8 and £4.8 billion per year.4
A NICE clinical guideline (CG) on the management and treatment of RA in adults (CG79) was published in February 2009.5 This guideline is based upon best published clinical and economic evidence, alongside expert consensus and provides an evidence-based guide for the management of RA in adults in primary and secondary care. This article revisits the NICE guideline and discusses relevant NICE technology appraisals (TA) in this disease area, focusing on the main recommendations relevant to GPs and discusses the potential obstacles to implementation of the guidance.
A considerable body of evidence supports the concept that early initiation of therapy in RA improves outcomes.6,7 Early referral to a specialist is one of the key messages from the NICE guideline.5 Any person with suspected persistent synovitis should be referred for specialist opinion, and urgent referral is indicated if:5
- the small joints of the hands and feet are affected
- more than one joint is affected
- there has been a delay in presentation of 3 months or longer.
The above recommendations present challenges to GPs. Synovitis can be subtle and difficult to detect, particularly if not encountered regularly in clinical practice. A GP with a list size of 2000 patients will see one new case of RA approximately every 2 years while many patients will present with musculoskeletal aches and pains. Many patients with RA will have symptoms and signs that relapse and remit. Finally, it is well-established that patients with inflammatory arthritis put off visiting their GP.8 Early referral to secondary care will remain suboptimal without public-health campaigns promoting increased patient awareness of inflammatory joint disease.
In early arthritis, acute-phase reactants may not be elevated. The NICE guideline recommends that GPs should not avoid urgent referral of any patient with suspected persistent synovitis of undetermined cause, whose blood tests show a normal acute-phase response or negative rheumatoid factor. The measurement of anti-cyclic citrullinated peptide (CCP) antibodies should be considered for patients with suspected RA who are seronegative for rheumatoid factor.5 However, not all GPs will have access to anti-CCP measurements and, although more specific, it is usually a more expensive test than that for rheumatoid factor.
The trend in RA management has shifted in recent years towards the use of earlier more aggressive therapy. The use of a combination of disease-modifying anti-rheumatic drugs (DMARDs) including methotrexate as first-line treatment is now recommended, beginning ideally within 3 months of the onset of persistent symptoms. When combination therapy is not appropriate (e.g. if the patient is methotrexate intolerant), DMARD monotherapy with rapid escalation to a clinically effective dose is recommended. Once sustained and satisfactory levels of disease control have been achieved, a cautious stepping down in therapy is advocated.5
This more intensive treatment approach has implications for GPs. One of the key roles of primary care in the management of a patient with RA is to offer regular medication reviews, check concordance, and assess for adverse events. General practitioners need to be aware that patients may be started on a combination of DMARDs and they should be ready to support patients in this initial phase. Although GPs may have very few patients taking any particular DMARD, they still need to be familiar with each of the commonly used drugs, side-effects, and monitoring requirements for toxicity.To support them in this role, specialist units should make themselves accessible to answer questions from primary care.
The NICE guideline recommends that in patients with established RA, prolonged treatment with glucocorticoids should only be continued when the long-term complications have been fully discussed, and all other treatment options (including biological drugs) have been offered.5 It is acceptable to use short-term steroids to control flares of disease, but ideally patients should no longer be managed in primary care on steroids alone. Referral to specialist care for assessment or reassessment should be considered for patients who are being maintained on long-term steroids as attempts should always be made to replace steroids with other DMARDs.
Guidance for the use of biological drugs in RA has become increasingly complex as the number of available agents has increased. Since the publication of CG79 on the management of RA in 2009, four NICE TAs have been released:
- TA186 on certolizumab pegol9
- TA195 on the use of adalimumab, etanercept, infliximab, rituximab, and abatacept after the failure of a tumour necrosis factor-alpha (TNF-?) inhibitor10
- TA198 on tocilizumab11
- TA225 on golimumab.12
A brief summary of the NICE recommendations on the sequential use of biological therapies is shown in Figure 1 (see p.23).
Tumour necrosis factor-? inhibitors
Tumour necrosis factor-? inhibitors remain the first-line biological therapy following the failure of traditional DMARDs. There are now five TNF-? inhibitors approved by NICE for use in RA. In addition to adalimumab, etanercept, and infliximab, certolizumab pegol (a humanised antibody Fab fragment to TNF-?) was approved in 2010,9 and golimumab (a human monoclonal antibody that prevents the binding of TNF to its receptors) was approved in 2011.9,12
Tumour necrosis factor-? inhibitors in combination with methotrexate are recommended for the treatment of active RA following the failure of two conventional DMARDs, including methotrexate. Adalimumab, etanercept, and certolizumab pegol may be given as monotherapy if treatment with methotrexate is not tolerated or is inappropriate.9,10 Certolizumab pegol is only recommended if the manufacturer provides the first 12 weeks of treatment free of charge9 and, similarly, golimumab is only recommended if the manufacturer provides the 100 mg dose at the same cost as the 50 mg dose (agreed as part of the patient access scheme).12
While many patients respond well to TNF-? inhibitors, others may never respond, stop responding over time, or develop tolerability issues. A recent advance in the treatment of RA has been the introduction of B-cell depletion as a therapeutic modality. Rituximab is a chimeric monoclonal antibody that depletes the B-cell population by targeting cells bearing the CD20 surface marker. Rituximab in combination with methotrexate is recommended following the failure of other DMARDs, including at least one TNF-? inhibitor. If rituximab is contraindicated or withdrawn, an alternative TNF inhibitor or abatacept (a selective T-cell co-stimulation modulator), each in combination with methotrexate, are now recommended as treatment options.10 If methotrexate is contraindicated or withdrawn because of an adverse event, adalimumab or etanercept monotherapy is recommended.10
Tocilizumab is another biological therapy that has been approved for the treatment of RA. It is a humanised monoclonal antibody against interleukin-6, a pleiotropic pro-inflammatory cytokine. Tocilizumab in combination with methotrexate is recommended for the treatment of active RA following the failure of one or more TNF inhibitors and rituximab, or if rituximab is contraindicated or withdrawn.11
Implications of biological therapy
General practitioners treating patients with RA need to have knowledge of an ever-expanding number of biological agents. The algorithms for treatment are becoming increasingly complex and keeping pace with a fast-moving field will prove challenging. The cost implications of biological therapy are huge. In the 12 months preceding August 2009, the prescribing of biological drugs in primary care was £1,524,891, an increase of 50% compared with the previous 12 months.13 This figure is likely to continue to rise as increasing numbers of biological agents become available. Cost-saving incentives such as those with certolizumab pegol and golimumab are likely to rise and have a greater influence on prescribing.
NICE CG79 recommends that all patients with RA are offered an annual review, which includes:
- assessment of disease activity and damage
- checking for complications
- screening for the development of co-morbidities.
Although annual review for most patients with RA is likely to take place in secondary care, the GP is ideally placed to monitor potential co-morbidities, particularly CV risk, osteoporosis, and depression. It is vital that GPs are aware of the increased CV risk associated with RA and incorporate this as a risk factor when using risk assessment tools. In contrast to the Framingham risk assessment tables commonly used in primary care, the CV risk calculator, QRISK2, incorporates other factors such as RA, social deprivation, and ethnicity. It may, therefore, provide a more accurate estimate of the CV risk for patients with RA.14
The successful management of patients with RA relies on liaison between healthcare professionals of different disciplines. NICE CG79 recommends that people with RA should have ongoing access to a multidisciplinary team incorporating various healthcare professionals such as specialist nurses, physiotherapists, occupational therapists, and podiatrists.5 Many of the team members are likely to be based in secondary care, but primary care led services may play an integral role in management, and liaison between primary and secondary care is crucial.
It is recommended that people with RA should have access to a named member of the multidisciplinary team who is responsible for coordinating care. It is important that this named professional is made known to the relevant GP.5
Role of the GP
The role of the GP in early referral is critical to optimal outcomes for patients with RA. If the GP can recognise the early signs and symptoms of RA and facilitate early diagnosis, referral to a rheumatologist, and treatment, the result will be a decrease in disease severity, disability, mortality, and complications.
The NICE guideline on the management and treatment of RA acknowledges the role that primary care plays in the management of RA and, in particular, provides GPs with detailed guidance on when to refer patients with suspected RA. Inclusion of musculoskeletal disorders in the quality and outcomes framework is the next step in recognising progress in management and further improving standards of care.
Developments in RA
In clinical practice many rheumatologists are choosing to commence patients with newly diagnosed RA on DMARD monotherapy, using a step-up approach in patients who fail to respond. There are several recent studies comparing this step up with the recommended parallel treatment approach.15,16 Current results suggest that the two approaches are equivocal and amendments to the current NICE recommendations may be proposed.
The number of therapeutic options available for the treatment of RA continues to grow. New molecules targeting different aspects of the inflammatory cascade are continually being developed. Initial trial results for two such agents, tofacitinib (a Janus kinase inhibitor) and fostamatinib (a spleen tyrosine kinase inhibitor), are promising.17,18 Head-to-head trials will eventually be required to establish the best treatment options for individual patients.
Rheumatoid arthritis is a disease associated with significant disability, premature mortality and major economic burden. General practitioners can have a significant impact on these factors by identifying patients early in the disease course, referring promptly for specialist care, and by closely monitoring co-morbidities such as CV risk.
|Figure 1: An algorithm on the recommended sequential use of biological therapies in active rheumatoid arthritis*9–12|
*Please refer to the relevant NICE technology appraisal for further information on the use of these agents
†Certolizumab pegol and golimumab are recommended as treatment options only if they are used as described for other TNF-? inhibitors in TA130 and if the manufacturers provide certolizumab pegol and golimumab as agreed under the patient access schemes (see TA186 and TA225, respectively)
‡Golimumab is recommended as a treatment option only if it is used as described for other TNF-? inhibitors in TA195 and if the manufacturer provides golimumab as agreed under the patient access scheme (see TA225)
DMARD=disease-modifying anti-rheumatic drug; TNF-?=tumour necrosis factor-alpha; TA=technology appraisal
- The NICE guideline emphasises that early accurate diagnosis and treatment with DMARDs can prevent later disability in RA. As a result of this guidance, commissioners should plan for the increased demand for referrals to rheumatology specialists
- Much of the follow-up care of patients with RA can be undertaken by specialist nurses; commissioners should look to commission these as a community service and not at full PbR tariff rates
- Biological agents are usually prescribed by secondary care and are not included in the PbR tariff outpatient costs
- Commissioners should agree rational use of biological agents with local secondary care trusts and aim to use the most cost-effective agents and discount schemes available to hospitals, and ensure any discounts are passed on to commissioners in the ´follow-through price´
- Essential blood monitoring for patients receiving DMARDs and biological agents is a considerable extra amount of work for primary care, but can be commissioned with built-in quality standards as a local enhanced service or by using the 2004 national enhanced service template
- Tariff prices for rheumatology outpatients = £260 (new), £107 (follow up)a
DMARD=disease-modifying anti-rheumatic drug; RA=rheumatoid arthritis; PbR=payment by results
- Symmons D, Jones M, Scott D, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998; 25 (6): 1072–1077.
- Symmons D, Turner G, Webb R et al. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology 2002; 41 (7): 793–800.
- Symmons D, Barrett E, Bankhead C et al. The incidence of rheumatoid arthritis in the United Kingdom: Results from the Norfolk Arthritis Register. Br J Rheumatol 1994; 33 (8): 735–739.
- Pugner K, Scott D, Holmes J et al. The costs of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum 2000; 29 (5): 305–320.
- National Institute for Health and Care Excellence. Rheumatoid arthritis: national clinical guideline for management and treatment in adults. Clinical Guideline 79. London: NICE, 2009. Available at: www.nice.org.uk/CG79
- Landewe R, Boers M, Verhoeven A et al. COBRA combination therapy in patients with early rheumatoid arthritis: long-term structural benefits of a brief intervention. Arthritis Rheum 2002; 46 (2): 347–356.
- 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 (7): 2072–2081.
- Kumar K, Daley E, Carruthers D et al. Delay in presentation to primary care physicians is the main reason why patients with rheumatoid arthritis are seen late by rheumatologists. Rheumatology 2007; 46 (9): 1438–1440.
- National Institute for Health and Care Excellence. Certolizumab pegol for the treatment of rheumatoid arthritis. Technology Appraisal 186. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA186
- National Institute for Health and Care Excellence. Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor. Technology Appraisal 195. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA195
- National Institute for Health and Care Excellence. Tocilizumab for the treatment of rheumatoid arthritis. Technology Appraisal 198. London: NICE, 2010. Available at: www.nice.org.uk/guidance/TA198
- National Institute for Health and Care Excellence. Golimumab for the treatment of rheumatoid arthritis after the failure of previous disease-modifying anti-rheumatic drugs. Technology Appraisal 225. London: NICE, 2011. Available at: www.nice.org.uk/guidance/TA225
- National Institute for Health and Care Excellence. NICE implementation uptake report. Rheumatoid arthritis: the management of rheumatoid arthritis in adults. London: NICE, 2009. Available at: www.nice.org.uk/media/B30/34/UptakeReportRA1.pdf
- Collins G, Altman D. An independent and external validation of QRISK2 cardiovascular disease risk score: a prospective open cohort study. BMJ 2010; 340: c2442.
- Saunders S, Capell H, Stirling A et al. Triple therapy in early active rheumatoid arthritis: a randomized, single-blind, controlled trial comparing step-up and parallel treatment strategies. Arthritis Rheum 2008; 58: 1310–1317.
- Moreland L, O’Dell J, Paulus H et al. TEAR: Treatment of early aggressive RA: a randomized, double-blind, 2-year trial comparing immediate triple DMARD versus MTX plus etanercept to step-up from initial MTX monotherapy. Arthritis Rheum 2009; 60 (Suppl 10): 1895.
- Tanaka Y, Suzuki M, Nakamura H et al; the Tofacitinib Study Investigators. Phase 2 study of tofacitinib (CP-690,550) combined with methotrexate in patients with rheumatoid arthritis and inadequate response to methotrexate. Arthritis Care Res 2011; doi: 10.1002/acr.20494 (Epub ahead of print).
- Genovese M, Kavanaugh A, Weinblatt M et al. An oral Syk kinase inhibitor in the treatment of rheumatoid arthritis: a three-month randomized, placebo-controlled, phase II study in patients with active rheumatoid arthritis that did not respond to biologic agents. Arthritis Rheum 2011; 63 (2): 337–345. G