Clinical Review - Rheumatoid arthritis

Contributed by Dr Jeffrey Lee, consultant rheumatologist at Barnet General Hospital, north London.

Clinically, RA presents as inflammation in the joints (Photograph: SPL)
Clinically, RA presents as inflammation in the joints (Photograph: SPL)

Section 1: Epidemiology and aetiology
Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects approximately 1 per cent of the UK population.

It is the most common inflammatory joint disease with around 12,000 people diagnosed with new RA in the UK each year. RA also affects more women than men (female to male ratio 3:1) and the prevalence increases with age, presenting most commonly between 50 and 70 years of age.1

The total cost of RA in the UK, including indirect costs, such as loss of productivity, as well as medical costs, is approximately £4 billion per year.2

Aetiology
No known causes or triggers for RA have been identified. It is essentially an autoimmune disorder involving the conversion of synovial membranes of joints into an inflammatory tissue, called pannus, which invades and erodes cartilage and bone.

Clinically, this presents as swelling and inflammation in joints, which, if left uncontrolled, will lead to deformities and marked disability.

However, it is important to point out that RA involves inflammation in more than just joints and is truly a systemic disease.

There is systemic release of inflammatory proteins (for example, TNF-alpha, interleukin(IL)-1 and IL-6) that drive the inflammatory process in not only joints but almost all organs in the body.

Although genetic factors have been shown to influence both susceptibility to and severity of disease, the relationship is not straightforward.

Studies in twins have shown a concordance for RA of only 12-15 per cent in monozygotic twins and 4 per cent in dizygotic twins.3

Section 2: Making the diagnosis
RA is defined using the American Rheumatism Association (ARA) 1987 criteria.4

It is a polyarthritis, which characteristically affects the small joints of the hands and feet (sparing the distal interphalangeal joints) along with other joints as the disease progresses, and is symmetrical.

Although useful for classification, the ARA 1987 criteria should not be used for initial diagnosis as some of these features are found more in advanced disease and patients may have formed irreversible deformities by the time they fulfil it. These include the classic signs of RA, such as Boutonniere, swan-neck and z-thumb deformities.

Initial radiograph (top) and repeat radiograph two years later (below), showing marked joint and bone deformities in the hands of a patient untreated for RA

Early diagnosis
The best practice is to diagnose RA early, even before the development of classic features of RA, and preferably initiate treatment within three months of disease onset (the so called 'window of opportunity').

By doing so, it may be possible to prevent the formation of irreversible damage to joints and organs, reduce disease severity in the long term and, in some mild cases, cure the disease completely after a few years.

Although initial RA joint symptoms usually develop progressively, an acute presentation can occur in 20 per cent of cases.

As we are potentially seeing and treating a group of patients who may not fulfil established criteria for RA, it is important that the physician identifies early symptoms and signs and refers to their local rheumatology department urgently.

Patients should be referred urgently if they present with any of the following:

  • Persistent (more than six weeks) pain or inflammation in the small joints of the hands and feet.
  • Pain or inflammation in more than one joint.
  • Early morning stiffness in joints lasting more than 30 minutes.

Detecting inflammation
Although elevated inflammatory markers, such as CRP, and positive rheumatoid factor (RhF) or anti-cyclic citrullinated peptide (anti-CCP) antibodies, would lend support to the diagnosis, these may be normal early on in the disease.

In fact, both RhF and anti-CCP are found in only 50-60 per cent of confirmed RA cases during the initial presentation.

Anti-CCP is as sensitive as RhF and even more specific for RA (90-95 per cent) and is an indicator of aggressive erosive disease.

In addition, early significant inflammation in the small joints may not present with obvious signs either (joint swelling, erythema).

Rheumatologists may need imaging (ultrasound or MRI) to detect inflammation in joints, which may not be available to primary care physicians. Radiographs may be normal in early cases, as bony deformities appear later and are irreversible.

Therefore negative findings should not deter the primary care physician from referring to secondary care if the history is suggestive of an inflammatory joint disease.

Section 3: Managing the condition
The drug management of RA consists of two categories: pain control, and DMARDs for preventing disease progression.

Often both forms of drugs are used together, particularly in the initial consultation, as most DMARDs are slow to take effect and patients may need further investigations to determine their suitability for such medications.

Pain control
Pain control drugs include analgesics as well as NSAIDs for general pain. Although corticosteroids can be considered as a DMARD, they also have a quick onset of action for relief of signs and symptoms of inflammation including pain.

Preventing disease progression
The most important development in the management of RA in the past decade is the use of DMARDs early in the disease before the onset of deformities.

Ulnar deviation: begin treatment before irreversible joint damage occurs (Photograph: SPL)

The rationale behind this is to suppress inflammation effectively enough to prevent the development of complications. DMARDs can also be further subdivided into the following groups:

Conventional DMARDs
Conventional DMARDs include methotrexate, sulfasalazine, hydroxychloroquine, leflunomide and corticosteroids.

These are often used as either a single agent or in combination depending on the rheumatologist's judgment on severity and prognosis.

The patient's general health and comorbidities, along with their perceived views on lifestyle, and potential side-effects will also influence the choice of drugs.

It is important to stress that all these drugs have potential life-threatening side-effects requiring long-term blood and clinical monitoring.

The main side-effects to be aware of relate to bone marrow suppression, deranged LFTs, interstitial lung disease (particularly with methotrexate) and risk of infection.

Biologics
Biologics are a group of drugs that include monoclonal antibodies against TNF-alpha (infliximab, adalimumab), IL-6 (tocilizumab), B-cells (rituximab) and T-cells (abatacept).

NICE recommends their use in patients whose disease has failed to be adequately controlled with conventional DMARDs.

These drugs have made a significant impact on the lives of many patients with severe RA, but their side-effects can be greater than those associated with conventional DMARDs.

This is particularly so with regard to risk of infection, reactivation of latent TB, inflammatory lung disease, exacerbation of congestive heart failure and MS.

As they have been in widespread use for only 10 years, we cannot be certain of their long-term safety profile, particularly in patients with a history of malignancy and pregnant women.

The crucial point about DMARDs and biologics is that they are effective in stopping progression of disease but will not significantly change bony deformities that have already developed.

Therefore, in patients with marked structural problems, such as hand deformities that reduce function, surgery may be required.

A multidisciplinary team approach is usually adopted by rheumatology centres managing RA patients. These teams will include nurse specialists, who have a clinical as well as educational role, physiotherapists, occupational therapists and podiatrists.

There is no strong evidence that any dietary or complementary treatments can suppress inflammation in RA.

Section 4: Prognosis
There are a few factors associated with severe RA during initial presentation.5 These include:

  • Positive RhF and/or anti-CCP.
  • Elevated CRP/ESR.
  • Number of swollen/tender joints.
  • Radiographic evidence of joint erosions.

These factors and others will influence the rheumatologist's choice on DMARDs, biologics and escalation of treatment.

It is important that patients are aware they have a chronic disease and medication is for long-term control of the disease and inflammation, and is not a cure.

RA may become less active in terms of inflammation in some patients after many years. However, if the inflammation is not controlled using a long-term DMARD during the active years, patients may be left with deformities that cannot be altered by any medication.

From an occupational perspective, approximately one third of RA patients cease work because of the disease within two years of onset and prevalence increases thereafter.2

Life expectancy is also reduced in RA patients. A woman of 50 years with RA is expected to die four years earlier than a similarly aged woman without the disease.

Increased cardiovascular risk
Although RA is associated with a large number of extra-articular complications, including lung fibrosis, Sjogren's syndrome, vasculitis, peripheral neuropathy and osteoporosis, the commonest cause of death is cardiovascular disease.


RA patients have an increased risk of cardiovascular disease (Photograph: SPL)

Large epidemiological studies have consistently found that RA patients have a 1.5 to three-fold increased risk for cardiovascular events compared with non-RA controls.6,7

Although there is evidence of an increased risk of traditional cardiovascular risk factors,8 the increased rate of cardiovascular disease cannot be explained by these factors alone.

Currently, there is increasing evidence that persistent inflammation is an independent risk factor for cardiovascular events, which may be reduced once disease activity is controlled.9


X-ray showing erosion of both knees joints due to RA

Section 5: Case study
A 45-year-old female was referred to the rheumatology department with a six-week history of pain in her hands and feet. She also noted morning stiffness that eased after mobilising for around an hour.

Although she had no obvious joint swelling, she was particularly tender in her knuckles and wrists. Her GP had requested blood tests, which showed CRP 6 and ESR 32. She was negative for RhF and her serum urate was normal.

Tenderness in small joints
On her first consultation with the rheumatologist at week seven, her examination revealed tenderness in the small joints of her hands, particularly the metacarpophalangeal joints but sparing the distal interphalangeal joints.

There was no significant soft tissue swelling or erythema in her joints, although she could no longer remove her wedding ring. Further blood tests were requested, along with radiographs, and she was given an intramuscular injection of corticosteroids.

She had complete resolution of her pain and morning stiffness 24 hours after her corticosteroid injection. A follow-up appointment was arranged for four weeks' time.

During that time, she noticed the morning stiffness was slowly recurring. She was also found to be positive for anti-CCP antibodies.

The radiographs of her hands and feet were normal.

A combination of methotrexate and hydroxychloroquine was discussed as a potential long-term treatment.

The drugs were initiated by the department's nurse practitioner whom she would have direct access to for both advice and review.

Section 6: Evidence base
Guidelines

  • NICE. Rheumatoid arthritis: The management of rheumatoid arthritis in adults. CG79. London, NICE, 2009.
  • British Society for Rheumatology. RA guidelines on safety of anti-TNF therapies. Oxford, Oxford University Press, 2010.
  • British Society for Rheumatology. Management of rheumatoid arthritis. Oxford, Oxford University Press, 2009.
  • British Society for Rheumatology. Disease modifying anti-rheumatic drug (DMARD) therapy. Oxford, Oxford University Press, 2008.

Key text

  • Hochberg MC, Silman AJ, Smolen JS et al. Rheumatology. Vol 1. 3rd edition. Mosby. 2003.

Curriculum

The RCGP covers this topic in statement 15.9 Rheumatology and Musculoskeletal.

Online

  • British Society for Rheumatology. www.rheumatology.org.uk Contains information for rheumatologists and patients and has the above guidelines.

References
1. Symmons D, Turner G, Webb R et al. The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. Br J Rheumatol 1994; 33(8): 735-9.

2. Pugner KM, Scott DI, Holmes JW et al. The cost of rheumatoid arthritis: an international long-term view. Semin Arthritis Rheum 2000; 29(5): 305-20.

3. Silman AJ, MacGregor AJ, Thomson W et al. Twin concordance rates for rheumatoid arthritis. Br J Rheumatol 1993; 32: 903-7.

4. Arnett FC, Edworthy SM, Bloch DA et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31(3): 315-24.

5. Machold KP, Stamm TA, Eberl GJM et al. Very recent onset arthritis-clinical, laboratory, and radiological findings during the first year of disease. J Rheumatol 2002; 29(11): 2278-87.

6. Solomon DH, Goodson NJ, Katz JN et al. Patterns of cardiovascular risk in rheumatoid arthritis. Ann Rheum Dis 2006; 65: 1608-12.

7. Wolfe F, Freundlich B, Straus WL. Increase in cardiovascular and cerebrovascular disease prevalence in rheumatoid arthritis. J Rheumatol 2003; 30: 36-40.

8. Dessein PH, Joffe BI, Veller MG et al. Traditional and non-traditional cardiovascular risk factors are associated with atherosclerosis in rheumatoid arthritis. J Rheumatol 2005; 32: 435-42.

9. Dixon WG, Watson KD, Lunt M et al. British Society for Rheumatology Biologics Register Control Centre Consortium; British Society for Rheumatology Biologics Register. Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti-tumour necrosis factor alpha therapy: results from the British Society for Rheumatology Biologics Register. Arthritis Rheum 2007; 56: 2905-12.

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 CPD IMPACT: EARN MORE CREDITS

These further action points may allow you to earn more credits by increasing the time spent and the impact achieved.

  • Ensure all staff are aware of the increased risk of osteoporosis, cardiovascular disease and depression in patients with RA.
  • Consider holding a meeting with your local rheumatologist to discuss urgent referral guidelines, use of anti-CCP in your region, accessibility to clinics for patients with flare-ups and preference of DMARD in their practice.
  • Consider reviewing all of your patients taking DMARDs and ensure they are having their regular blood tests.

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