Rheumatoid arthritis (RA) is a chronic systemic disease. Early diagnosis of RA and effective treatment with disease-modifying anti-rheumatic drugs (DMARDs) is essential to reduce joint destruction and disability.¹ An increasing range of DMARDs is now available.² Once mechanical damage has occurred, pain and joint deformity often require aids and appliances and, eventually, surgery.

Early detection and referral

Late diagnosis of RA greatly increases the risk of erosive joint damage.¹ Current 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.³ The window of opportunity in which disease-modifying drugs can prevent joint damage is only a few months.⁴ The British Society for Rheumatology (BSR) standard is for a rheumatologist to see the patient within twelve weeks of onset.

• The National Institute for Health and Clinical Excellence (NICE) recommends referral of any person with suspected persistent synovitis of undetermined cause for specialist opinion. Refer urgently if any of the following apply:⁵
  • The small joints of the hands or feet are affected.
  • More than one joint is affected.
  • There has been a delay of three months or longer between onset of symptoms and seeking medical advice.

• Do not avoid referring urgently any person with suspected persistent synovitis of undetermined cause whose blood tests show a normal C-reactive protein (CRP) and ESR or a negative rheumatoid factor.

Investigation

See separate Rheumatoid Arthritis article.

Management

• Whilst waiting for specialist assessment, nondrug measures and symptomatic treatment - such as simple analgesics and non-steroidal anti-inflammatory drugs (NSAIDs) - can be instituted. 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.
• Management should include a multidisciplinary team (MDT). All patients should have access to a range of professionals, including GP, rheumatologist, nurse specialist, physiotherapist, occupational therapist, dietitian, podiatrist, pharmacist, and social worker.⁶

Referral for specialist treatment⁵

Refer for specialist opinion any person with suspected persistent synovitis of undetermined cause. Refer urgently if any of the following apply:

• The small joints of the hands or feet are affected.
• More than one joint is affected.
• There has been a delay of three months or longer between onset of symptoms and seeking medical advice.

Monitoring disease⁵

• In people with recent-onset active RA, measure CRP and key components of disease activity (using a composite score such as DAS28) monthly until treatment has controlled the disease to a level previously agreed with the person with RA.
• The DAS28 is a measure of disease activity in RA. The score is calculated by a complex mathematical formula, which includes the number of tender and swollen joints (out of a total of 28 - shoulders, elbows, wrists, metacarpophalangeal joints, proximal interphalangeal joints and the knees), the ESR, and the patient's 'assessment of global health'. A DAS28 score greater than 5.1 implies active disease, less than 3.2 well-controlled disease, and less than 2.6 remission.⁷
• Screen for comorbid conditions, e.g. osteoporosis, depression, infection and cardiovascular disease (CVD).⁸

Nondrug management

The importance of the MDT is emphasised in the NICE guidance:⁵

• RA patients should have access to a named member of the MDT who is responsible for co-ordinating 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 premenopausal women with RA.⁹
• Pain clinic specialists may be able to advise on nondrug management options, such as transcutaneous electrical nerve stimulation (TENS) and behavioural approaches.¹⁰
• Non-clinical issues may need the assistance of social workers, voluntary organisations and wheelchair services.

Analgesics⁵

Analgesics (e.g. paracetamol, codeine or compound analgesics) should be offered to people with RA whose pain control is not adequate, to potentially reduce their need for long-term treatment with NSAIDs or cyclo-oxygenase-2 (COX-2) inhibitors.

NSAIDs

For example: ibuprofen, diclofenac, naproxen.

• NICE recommends prescribing with a suitable proton pump inhibitor (PPI).⁵
• 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.¹¹
• 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 inhibitor drugs.¹² 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.⁵
• COX-2 selective drugs have very similar efficacy to standard NSAIDs, although patients report individual differences. COX-2 selective NSAIDs are more expensive.
• The Committee on Safety of Medicines 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).¹³ 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.

Corticosteroids⁶

• Low-dose oral corticosteroids can be used in combination with DMARD therapy for short-term relief of signs and symptoms, and in the medium to long term to minimise radiological damage.
• Short-term treatment with glucocorticoids (oral, intramuscular or intra-articular) to rapidly improve symptoms should be considered in people with newly diagnosed RA if they are not already receiving glucocorticoids as part of DMARD combination therapy.⁵
• Intra-articular corticosteroid injections can be used to:
  • Provide symptomatic relief pending the onset of DMARD effect.
  • Alleviate symptoms in particularly troublesome joints where the overall disease control is good.
  • Deal with monoarthritis/oligoarthritis in instances when DMARDs are deemed inappropriate.

DMARDs

See also separate Disease-modifying Anti-rheumatic Drugs (DMARDs) article.

• DMARDs include azathioprine, ciclosporin, d-penicillamine, hydroxychloroquine, leflunomide, methotrexate, mycophenolate mofetil (MMF), sodium aurothiomalate, sulfasalazine.²
• Early initiation of treatment with DMARDs is recommended to control the symptoms and signs of RA as well as limiting radiological damage.⁶
• Methotrexate and sulfasalazine are the DMARDs of choice, due to their more favourable efficacy and toxicity profiles. DMARD therapy should be sustained in patients with early RA, to control the signs and symptoms of disease. A combination DMARD strategy, rather than sequential monotherapy, should be considered in patients with an inadequate response to initial DMARD therapy.⁶
• 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.¹⁴
• In people with newly diagnosed active RA, offer a combination of DMARDs (including methotrexate and at least one other DMARD, plus short-term glucocorticoids) as first-line treatment as soon as possible, ideally within three months of the onset of persistent symptoms.⁵
• In people with newly diagnosed RA for whom combination DMARD therapy is not appropriate, start DMARD monotherapy, placing greater emphasis on fast escalation to a clinically effective dose rather than on the choice of DMARD.⁵
• In people with recent-onset RA receiving combination DMARD therapy and in whom sustained and satisfactory levels of disease control have been achieved, cautiously try to reduce drug doses to levels that still maintain disease control.⁵

Biological therapies

Biological therapies (cytokine modulators) have been shown to be effective in the treatment of RA, including patients resistant to methotrexate.¹⁵ The following are approved for treatment of RA:¹⁶

• Tumour necrosis factor (TNF) inhibitors: adalimumab, certolizumab pegol, etanercept, golimumab, infliximab.
• Anti-interleukin-1 therapy: anakinra.
• T-cell co-stimulator modulator: abatacept.
• Anti-CD20 therapy: rituximab.
• Anti-interleukin-6 receptor therapy: tocilizumab.

NICE recommends that in addition to low-dose glucocorticoids, two trials of six months of traditional DMARD monotherapy or combination therapy (at least one including methotrexate) should fail to control symptoms or prevent disease progression before a biological therapy be recommended. A trial of a DMARD is defined as being normally of six months, with two months at standard dose, unless significant toxicity has limited the dose or duration of treatment.⁵

• The TNF-alpha inhibitors adalimumab, etanercept, infliximab and certolizumab pegol are recommended as options for the treatment of adults who have severe active RA and have undergone trials of two DMARDs, including methotrexate (unless contra-indicated).^17,18
• Treatment with adalimumab, etanercept, infliximab, abatacept and certolizumab pegol should be continued only if there is an adequate response six months after initiation of therapy. Treatment should be monitored at least every six months and continued only if an adequate response is maintained.^17,18
• Following failure of TNF inhibitor treatment:
  • Rituximab in combination with methotrexate is recommended as an option for the treatment of adults with severe active RA who have had an inadequate response to, or are intolerant of, other DMARDs, including at least one TNF inhibitor. Treatment with rituximab should be given no more frequently than every six months.¹⁹
  • Adalimumab, etanercept, infliximab and abatacept, each in combination with methotrexate, are recommended as treatment options for adults with severe active RA who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab.¹⁹
  • Adalimumab monotherapy and etanercept monotherapy are recommended as treatment options for adults with severe active RA who have had an inadequate response to, or have an intolerance of, other DMARDs, including at least one TNF inhibitor, and who cannot receive rituximab therapy because they are unable to be treated with methotrexate.¹⁹
  • Tocilizumab, in combination with methotrexate, is recommended for the treatment of moderate-to-severe active RA in people whose RA has responded inadequately to one or more TNF-alpha inhibitors and whose RA has responded inadequately to rituximab or in whom rituximab is contra-indicated.²⁰
• Abatacept in combination with methotrexate is not recommended for the treatment of moderate-to-severe active RA in adults whose disease has responded inadequately to one or more conventional non-biological DMARDs, including methotrexate.²¹

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).⁵
• 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.

Annual review

Patients should be offered an annual review by a hospital specialist or GP with special interest to:⁵

• 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 MDT whenever appropriate.
• Assess the need for referral for surgery.
• Also, review the effectiveness and adverse effects of medication.
• 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).

Surgery

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

NICE guidance on referral for surgery⁵

Refer people with RA for an early specialist surgical opinion if the following do not respond to optimal nonsurgical management:

• Persistent pain (from, for example, joint damage or other soft tissue cause).
• Worsening joint function.
• Progressive deformity.
• Persistent localised synovitis.

Refer people with complications for a specialist surgical opinion before damage or deformity becomes irreversible:

• Imminent or actual tendon rupture.
• Nerve entrapment (for example, carpal tunnel syndrome).
• Any stress fracture.

• Suspected or proven septic arthritis (especially in a prosthetic joint).
• Any symptoms or signs that suggest cervical myelopathy.

Do not let concerns about the long-term durability of prosthetic joints influence decisions to offer joint replacements to younger people with RA.⁵

Document references

1. Guideline for the management of rheumatoid arthritis (first 2 years), British Society for Rheumatology (July 2006)
2. Guideline for disease-modifying anti-rheumatic drug (DMARD) therapy, British Society for Rheumatology and British Health Professionals in Rheumatology (2008)
3. 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]
4. Valesini G, Di Franco M, Spinelli FR, et al; Induction of remission in rheumatoid arthritis: criteria and opportunities. Rheumatol Int. 2008 Dec;29(2):131-9. Epub 2008 Sep 21. [abstract]
5. Rheumatoid arthritis, NICE Clinical Guideline (February 2009); Rheumatoid arthritis: the management of rheumatoid arthritis in adults
6. Management of early rheumatoid arthritis, Scottish Intercollegiate Guidelines Network - SIGN (February 2011)
7. National Rheumatoid Arthritis Society; Disease Activity Score.
8. Guideline for the management of rheumatoid arthritis (after the first 2 years), British Society for Rheumatology and British Health Professionals in Rheumatology (January 2009)
9. Tourinho TF, Capp E, Brenol JC, et al; Physical activity prevents bone loss in premenopausal women with rheumatoid arthritis: a cohort study. Rheumatol Int. 2008 Aug;28(10):1001-7. Epub 2008 Mar 4. [abstract]
10. Guidelines on standards of care for persons with Rheumatoid Arthritis, British Society for Rheumatology (2004)
11. Singh G, Triadafilopoulos G; Epidemiology of NSAID induced gastrointestinal complications; J Rheumatol Suppl. 1999 Apr;56:18-24. [abstract]
12. Juni P, Rutjes AW, Dieppe PA; Are selective COX 2 inhibitors superior to traditional non steroidal anti-inflammatory drugs?; BMJ. 2002 Jun 1;324(7349):1287-8.
13. Action on Cox II - European Medicines Agency - Press Release (27 June 2005)
14. Bakker MF, Jacobs JW, Verstappen SM, et al; Tight control in the treatment of rheumatoid arthritis: efficacy and feasibility. Ann Rheum Dis. 2007 Nov;66 Suppl 3:iii56-60. [abstract]
15. 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]
16. Tugwell P, Singh JA, Wells GA; Biologicals for rheumatoid arthritis. BMJ. 2011 Jul 28;343:d4027. doi: 10.1136/bmj.d4027.
17. Rheumatoid arthritis - adalimumab, etanercept and infliximab, NICE Technology Appraisal (October 2007); Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis
18. Rheumatoid arthritis - certolizumab pegol, NICE Technology Appraisal (February 2010); Certolizumab pegol for the treatment of rheumatoid arthritis
19. Rheumatoid arthritis - drugs for treatment after failure of a TNF inhibitor, NICE Technology Appraisal Guideline (August 2010); Adalimumab, etanercept, infliximab, rituximab and abatacept for the treatment of rheumatoid arthritis after the failure of a TNF inhibitor
20. Rheumatoid arthritis - tocilizumab, NICE Technology Appraisal Guideline (August 2010); Tocilizumab for rheumatoid arthritis
21. Rheumatoid arthritis - abatacept (2nd line), NICE Technology Appraisal (August 2011)

Internet and further reading

• 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]
• 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)
• Rheumatoid arthritis, Prodigy (June 2009)