Management of Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic disease that affects the synovial joints.

The management of RA has changed completely in recent years. An increasing range of disease-modifying anti-rheumatic drugs (DMARDs) is available.^1,2 New NICE guidance in February 2009 reflects recent advances and highlights important recommendations for decreasing the mortality and morbidity from RA.³

Once mechanical damage has occurred, pain and joint deformity often require aids and appliances and, eventually, surgery. Better management should avoid complications and reduce morbidity and mortality.

The British Society for Rheumatology (BSR) has published standards of care which patients with rheumatoid arthritis should expect to receive.^1,4,5,6

There have been a number of new and comprehensive guidelines. In the past, guidelines emphasised the use of medication but more recent guidelines have reviewed all treatment options and placed them in context.

It is clear from all of these and new NICE guidance that to improve care of patients and to allow for planning of resources, management of RA should follow guidance based on evidence and increasing use of DMARDs.

Detailed algorithms covering a wide range of different management options are included within these guidelines. The main outline of these guidelines is summarised in the boxes below to demonstrate the range and scope, together with some key points for general practice.

The importance of early diagnosis in RA has been compared to that in diabetes. Late diagnosis of RA greatly increases the risk of erosive joint damage.⁵Current guidance is that patients with suspected RA should be referred to a rheumatologist as soon as possible so that disease-modifying agents can be started early in the condition.⁷ However, studies suggest there is room for improvement in this respect.⁸ The window of opportunity in which disease-modifying drugs can prevent joint damage is only a few months.⁹ The BSR standard is for a rheumatologist to see the patient within twelve weeks of onset.

Early detection is now possible by laboratory diagnosis. Antibodies called anti-cyclic citrullinated peptides occur 10 years before the development of clinical disease. Unlike the rheumatoid factor test they are highly specific and if the test is available to GPs locally it should be performed before referral to secondary care.¹⁰
NICE recommends:

• Rheumatoid factor in people with suspected RA and synovitis
• Measuring anti-cyclic citrullinated peptide (CCP) antibodies in people with suspected RA if:
  • Negative for rheumatoid factor
  • Combination therapy is being considered
• X-rays of the hands and feet early in the course of the disease in people with persistent synovitis in these joints

• The patient should be fully involved in the MDT of their condition and given information on self-management of their symptoms and the existence of any local support groups.
• Good communication and education are essential in management of RA:³
  • Explain risks and benefits of treatments clearly to patients.
  • Give verbal and written information (addressing their ideas, concerns and expectations).
  • Offer education and involvement in self-management programmes.
  • Gain the patient's agreement on all aspects of treatments.
• The psychological, emotional, employment and social issues relevant to the patient also need to be addressed.
• The needs of carers should also be considered.

Whilst waiting for specialist review, non-drug measures and symptomatic treatment - such as simple analgesics and non-steroidal anti-inflammatories (NSAIDs) - can be instituted.

Non-drug management

The importance of the MDT is emphasised in the NICE guidance:³

• RA patients should have access to a named member of the MDT who is responsible for coordinating their care (often a specialist nurse).
• RA patients should have easy access to physiotherapy, occupational therapy, psychological services and podiatry. There should be regular review particularly with physiotherapy and occupational therapy.
• The core members of the MDT will be the GP, the rheumatologist, physiotherapists and occupational therapists. Other specialties that may need to be involved include podiatrists, orthotists, dieticians, pharmacists and neurologists.
• Exercise has been found to reduce bone loss in pre-menopausal women with RA.¹¹
• Pain clinic specialists may be able to advise on non-drug management options such as transcutaneous electrical nerve stimulation (TENS) and behavioural approaches.⁴
• Non-clinical issues may need the assistance of social workers, voluntary organisations and wheelchair services.

Drug management

Recent trends in drug treatment

Treatment has shifted to earlier and more intense use of disease-modifying agents. The aim of treatment is to improve symptoms and reduce the later complications and disability. RA is an independent risk factor for cardiovascular disease and suppressing disease activity may reduce co-morbidity.^12,13 Combinations of different classes of drugs are being investigated for the treatment of early RA. One small trial, looking at a combination of sulfasalazine, methotrexate, prednisolone and hydroxychloroquine, showed promising results.¹⁴

At any stage the use of simple analgesia should be considered as an adjunct. Drugs to suppress neuropathic pain, such as carbamazepine or amitriptyline, may also be beneficial.

Non-steroidal anti-inflammatory drugs

For example: ibuprofen, diclofenac, naproxen.

• NICE recommends prescribing with a suitable PPI.³
• NSAIDs improve symptoms and signs of RA. They are highly effective and many RA patients rely on them, but they do not slow progression or long-term disability.
• NSAIDs have a rapid onset of action, but their beneficial effects are unfortunately offset by toxicity.¹⁵
• There are more than 30 available. The problem is deciding which preparation will be best for which patient, in terms of side-effects and potential benefits, e.g. the greater cardioprotective effects of standard NSAIDs compared to COX-2 drugs.¹⁶ The most commonly used NSAIDs are ibuprofen, diclofenac and naproxen.
• NSAIDs can interact with diuretics (reduced effect in renal toxicity), warfarin (risk of bleeding), lithium (toxicity) and methotrexate (marrow toxicity). See individual drug monographs.

COX-2 drugs

For example: celecoxib, etoricoxib.

• NICE recommends prescribing with a suitable PPI.³
• COX-2 selective drugs have very similar efficacy to standard NSAIDs, although patients report individual differences.
• COX-2 selective NSAIDs are more expensive and they should only be considered in patients at significant risk of gastro-intestinal bleeding with standard NSAIDS.¹⁷
• The CSM and European Medicines Agency have recommended that COX-2s should not be used in patients with established ischaemic heart disease, heart failure or cerebrovascular disease (and switch to alternative therapy).¹⁸ Care should be taken when they are used with patients with any CVD risk factors and the drugs should be used at the lowest effective dose for the shortest period possible.

Disease-modifying anti-rheumatic drugs

For example: auranofin (oral gold), azathioprine, ciclosporin, d-penicillamine, hydroxychloroquine, leflunomide, methotrexate, mycophenolate mofetil (MMF), sodium aurothiomalate, sulfasalazine.¹

• Early intervention with DMARDs produces better outcomes, in the short-term at least.¹⁹ They require 4 to 6 months for a full response.
• The primary aim is to establish a tolerable and effective drug regimen for each patient. Sulfasalazine or methotrexate are often used first because they may be better tolerated. If one drug does not lead to objective benefit within 3 months a different drug is tried. This was confirmed by the CORRONA database study which found that an improvement in functional ability was associated with a change of drug.²⁰
• They are instituted by specialists as soon as diagnosis, progression and severity of the disease have been confirmed. "Tight control" is the aim, which means increasing the therapy whenever the disease is not fully suppressed. Several studies have now shown this gives a significant improvement in symptoms and signs.²¹
• Methotrexate - this is a first line DMARD with advantage of known effectiveness and long-term safety.
• Sulfasalazine - this significantly reduces disease activity and joint inflammation and parenteral gold reduces disease activity and joint inflammation and slows radiological progression.
• Oral gold (auranofin) - this is also used but is less effective.
• All the DMARDs have potentially serious adverse effects which limit their usefulness.
• Contra-indications - see individual drug monographs.

Monoclonal antibodies

For example: infliximab, etanercept, anakinra, adalimumab, rituximab.^22,23

• A revolution has occurred in treating RA due to the realisation that the pro-inflammatory cytokine TNF-alpha plays a central role. In the last 10 years several agents have been developed that block this molecule and TNF inhibitors significantly improve symptoms and reduce disease activity and joint inflammation.
• The initiation and monitoring of these drugs is very much the province of the specialist. However it is important for generalists and members of the MDT to be aware of the how they are used and monitoring issues.
• Infliximab (Remicade®) and etanercept (Enbrel®) are very effective in reducing the symptoms and signs of RA in patients who fail to respond to DMARDs and both reduce joint swelling, radiological erosions, malaise and fatigue.²⁴
• Clinical effectiveness and side-effect profiles are similar for all these drugs. All have rapid onsets of action - days to weeks.
• A meta-analysis has concluded that this group of drugs are very effective in the treatment of RA, both in treatment-naive and methotrexate resistant patients.²⁵
• Contra-indications and monitoring - see individual drug monographs.
• Initiation of treatment - Patients at risk of infection (those on high-dose steroids or with uncontrolled diabetes), are excluded from treatment. See also individual drug monographs.
• Complications and reasons to discontinue drug - side-effects are generally minor and tolerable and monitoring is not required to the degree necessary with DMARDs. Severe adverse events are unusual but have been reported. TNF is a key regulator of immunity and opportunistic infections, such as tuberculosis (TB), have been reported. Reactivation of TB, worsening of demyelinating disease, suppression of bone marrow and a variety of unusual idiosyncratic side effects can occur.

Corticosteroids²⁶

• Oral corticosteroids may be offered for symptom control, particularly if the disease is widespread, whilst waiting for DMARDs to take effect.
• There is radiographic evidence that intra-articular steroids help to limit the progression of erosive arthritis.

Diet and complementary therapies

• There is no strong evidence that patients with RA will benefit from changes in diet.
• A Mediterranean diet should be encouraged (more bread, fruit, vegetables and fish; less meat; and replace butter and cheese with products based on vegetable and plant oils).³
• Complementary therapies may provide short-term symptomatic benefit but there is little or no evidence of long-term benefit.
  Advise RA patients who wish to try complementary therapies:
  • That they should not replace conventional treatment.
  • That this should not affect the care offered by any member of the MDT.

One study suggested that cod liver oil could be used as a NSAID-sparing agent in RA patients.²⁶

Patients should be offered an annual review by a hospital specialist or GP with special interest to:³

• Assess disease activity and damage, and measure functional ability - using, for example, the Health Assessment Questionnaire (HAQ).
• Check for the development of comorbidities, such as hypertension, ischaemic heart disease, osteoporosis and depression.
• Assess for complications, such as vasculitis and disease of the cervical spine, lung or eyes.
• Organise appropriate referrals within the multidisciplinary team whenever appropriate.
• Assess the need for referral for surgery.
• The effectiveness and adverse effects of medication should also be reviewed.
• Assess the effect the disease is having on the patient's personal life (for example the capacity to work, study, mix socially and remain financially viable).

The opinion of an orthopaedic surgeon with a special interest in rheumatoid arthritis should be sought in patients who are on maximum tolerated therapy but have uncontrollable pain and/or significant restrictions of joint movement.

Pre-pregnancy counselling

Both male and female patients require a review of their medication, as many anti-rheumatic drugs are teratogenic.

Young patients

There should be a smooth transition from paediatric to adult services, with assessment provided by specialists in paediatric and adolescent rheumatology according to the standards laid down by the British Society of Paediatric and Adolescent Rheumatology.²⁷ Do not let concerns about the long-term durability of prosthetic joints influence decisions to offer joint replacements to younger people with RA.³

These may serve as a prompt for a number of initiatives. For example:

• Practice audit (for example of PPI usage with NSAIDs)
• Practice policies (for example on referrals and early diagnosis)
• Practice screening for co-morbid conditions (for example cardiovascular disease in RA patients)
• Better liaison with hospital specialists and other MDT members

1. Guideline for disease-modifying anti-rheumatic drug (DMARD) therapy, British Society for Rheumatology and British Health Professionals in Rheumatology (2008)
2. Disease-modifying anti-rheumatic drugs (DMARDs), Clinical Knowledge Summaries (2008)
3. Rheumatoid arthritis, NICE Clinical Guideline (February 2009); Rheumatoid arthritis: the management of rheumatoid arthritis in adults
4. Guidelines on standards of care for persons with Rheumatoid Arthritis, British Society for Rheumatology (2004)
5. Guideline for the management of rheumatoid arthritis (first 2 years), British Society for Rheumatology (July 2006)
6. Guideline for the management of rheumatoid arthritis (after the first 2 years), British Society for Rheumatology and British Health Professionals in Rheumatology (January 2009)
7. Kremers HM, Nicola P, Crowson CS, et al; Therapeutic strategies in rheumatoid arthritis over a 40-year period. J Rheumatol. 2004 Dec;31(12):2366-73. [abstract]
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17. Osteoarthritis and rheumatoid arthritis - cox II inhibitors, NICE Technology Appraisal (2001)
18. Action on Cox II - European Medicines Agency - Press Release (27 June 2005)
19. van der Heide A, Jacobs JW, Bijlsma JW, et al; The effectiveness of early treatment with "second-line" antirheumatic drugs. A randomized, controlled trial.; Ann Intern Med. 1996 Apr 15;124(8):699-707. [abstract]
20. Ranganath VK, Paulus HE, Onofrei A, et al; Functional improvement after patients with rheumatoid arthritis start a new disease modifying antirheumatic drug (DMARD) associated with frequent changes in DMARD: the CORRONA database. J Rheumatol. 2008 Oct;35(10):1966-71. Epub 2008 Sep 1. [abstract]
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25. Venkateshan SP, Sidhu S, Malhotra S, et al; Efficacy of Biologicals in the Treatment of Rheumatoid Arthritis. A Meta-Analysis. Pharmacology. 2008 Oct 28;83(1):1-9. [abstract]
26. Rheumatoid arthritis, Clinical Knowledge Summaries (June 2009)
27. British Society of Paediatric and Adolescent Rheumatology 2002; Standard Assessment for Juvenile Idiopathic Arthritis; Link to pdf file

• Alonso-Ruiz A, Pijoan JI, Ansuategui E, et al; Tumor necrosis factor alpha drugs in rheumatoid arthritis: systematic review and metaanalysis of efficacy and safety. BMC Musculoskelet Disord. 2008 Apr 17;9:52. [abstract]
• Donahue KE, Gartlehner G, Jonas DE, et al; Systematic review: comparative effectiveness and harms of disease-modifying medications for rheumatoid arthritis. Ann Intern Med. 2008 Jan 15;148(2):124-34. Epub 2007 Nov 19. [abstract]
• Management of early rheumatoid arthritis, SIGN (2004)
• Guidelines on standards of care for persons with Rheumatoid Arthritis, British Society for Rheumatology (2004)
• Guideline for the management of rheumatoid arthritis (first 2 years), British Society for Rheumatology (July 2006)
• Guideline for disease-modifying anti-rheumatic drug (DMARD) therapy, British Society for Rheumatology and British Health Professionals in Rheumatology (2008)
• Guideline for the management of rheumatoid arthritis (after the first 2 years), British Society for Rheumatology and British Health Professionals in Rheumatology (January 2009)