Rheumatoid arthritis

Contributed by Dr Edith Villeneuve, rheumatology research fellow, and Professor Paul Emery, professor of rheumatology, at Leeds Teaching Hospitals.

Section 1 Epidemiology and aetiology
Rheumatoid arthritis (RA) is the most common type of inflammatory arthritis, affecting up to 1 per cent of the UK population.1 It affects twice as many women as men and generally presents between the ages of 30 and 60.2

Early recognition of the disease by GPs is crucial, because many effective therapies are now available and early treatment has been shown to result in better outcomes.3

Autoimmune disease
RA is an autoimmune disease in which the immune system attacks the synovium. This results in synovial cell hyperplasia, inflammatory cell infiltration and formation of new blood vessels.

This inflammation leads to destruction of cartilage, periarticular osteoporosis, bone erosion, joint misalignment and deformity, with subsequent weakness of surrounding tissues and muscles. Patients experience pain and loss of function. As a systemic disorder, it can lead to multiple organ system complications and increased mortality, predominantly due to accelerated cardiovascular disease (CVD).4 The aetiology of this inflammatory process is unknown.

As with other autoimmune diseases, RA may develop in three phases. The first phase represents the genetic risk or susceptibility of an individual. The second, or preclinical, phase is one where, because of an environmental trigger, the immune system enters a state of auto-reactivity with autoantibody production but no clinically apparent disease. The third phase is the development of the disease itself.

Risk factors
The shared epitope is the most studied associated genetic factor. It represents a common sequence found on the beta chains of certain HLA-DR haplotypes, the most common ones being HLA-DR1 and HLA-DR4. Other genetic factors have also been associated with RA, and susceptibility is likely polygenic.5

Environmental factors with the strongest association are smoking and infections. In patients who are homozygous for the shared epitope alleles, smoking increases the risk of developing RA up to 20 times compared with a shared epitope negative non-smoker.

Female sex is also associated with an increased risk of developing RA, and disease onset has been often reported after pregnancy.

Silicate exposure and decaffeinated coffee consumption may also be contributing factors. High vitamin D intake, tea consumption and oral contraceptive use are in contrast associated with a decreased risk of developing RA.

Section 2 Diagnosis
The classic presentation of RA is the insidious and progressive onset of pain and swelling involving small joints of the hands and feet in a symmetrical fashion. The pain can spread to involve more joints or seem to move from joint to joint.

Key points to look for when taking a history are the pattern of joint involvement; classically, the involvement of the hand, either the wrist, metacarpophalangeal (MCP) or proximal interphalangeal (PIP) joints is present in the majority of cases, with distal interphalangeal (DIP) joints usually spared; duration of early morning stiffness for more than an hour; and the relationship of symptoms to use (inflammatory pain tends to improve with activity).

On examination, the presence of synovitis can be recognised as a joint that is boggy, tender and may have limited active and passive range of motion.

Synovitis, however, is not always easy to detect. A technique that may be very helpful in identifying patients with early disease is the MCP or metatarsophalangeal (MTP) squeeze test.

This is performed by placing one's thumb and index finger across the MCP joint line of the hand or the MTPs of the foot and squeezing across those joints.

The test is considered positive if it reproduces pain.

Investigations
No diagnostic test alone can absolutely confirm or exclude RA, but baseline investigations are very helpful to assess prognosis and comorbidities and allow monitoring of disease progression.

Baseline workup should include inflammatory markers, (ESR or CRP), FBC, transaminases, urine analysis, rheumatoid factor and anti-cyclic citrullinated peptide (anti-CCP) antibodies, when available, as well as antinuclear antibodies.6

X-rays of hands and feet are often normal in early disease and therefore usually unhelpful for diagnosis.

Diagnosis
Although often used as diagnostic criteria, the American College of Rheumatology (ACR) criteria7 were developed as classification criteria and are not sensitive enough to be used to diagnose RA. Diagnosis should be made by a rheumatologist and rapid referral, ideally within six weeks of onset, is advised.

Several algorithms and screening tools have been devised to help identify individuals who should be referred.8 GPs should refer their patients to a specialist as soon as possible on the basis of the history and not wait for test results.

ACR classification criteria
1. Morning stiffness (lasting more than an hour before symptoms ease off).

2. Arthritis of 3 or more joint areas (the 14 possible joint areas are right or left proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee, ankle, and metatarsophalangeal joints).

3. Arthritis of hand joints (wrist, proximal interphalangeal or metacarpophalangeal joints).

4. Symmetric swelling (arthritis), by area.

5. Subcutaneous rheumatoid nodules.

6. Positive rheumatoid factor.

7. Radiographic changes (hand and wrist, showing erosions of joints or unequivocal demineralisation around joints).

Criteria 1,2,3 and 4 must be present for at least six weeks.

At least four criteria out of seven are needed for diagnosis.

Tools to identify inflammatory arthritis early

  • Joint swelling and pain of three or more joints.
  • Metacarpal or metatarsal joint involvement (positive squeeze test).
  • Morning stiffness lasting more than 30-60 minutes.
  • Elevated ESR or CRP.
  • Positive rheumatoid factor or anti-CCP antibody.
  • Characteristic joint distribution of inflammatory arthritis.
  • First-degree relative with inflammatory arthritis.
  • Erosions on hands or feet X-ray.
  • Benefit from NSAID or steroids.

Section 3 Management
The ultimate goal of treatment is to achieve a state of remission with no apparent disease activity or inflammation. This will arrest joint damage, preserve function and quality of life, and prevent the systemic complications of RA.

There is now increasing evidence that the best way to achieve this is to start treatment as early as possible, and to assess disease activity on a frequent basis to achieve tight control.3,9

That means that therapy is increased if disease activity is not suppressed below a predefined level.

Current treatments
Management should include patient education, physical/occupational therapy and lifestyle measures such as smoking cessation and regular exercise.2

Early institution of a disease-modifying antirheumatic drug (DMARD) is the cornerstone of treatment. It should be started in every patient once the diagnosis has been confirmed.

Methotrexate (MTX) is the most commonly used DMARD and is generally used first. Sulfasalazine and leflunomide are considered the best alternatives. NSAIDs and/or steroids are helpful for symptomatic relief while awaiting the effect of the disease-modifying therapy, which can take several weeks.

Combinations of DMARDs are often used in patients not adequately controlled with one agent alone. Patients with significant disease activity and/or poor prognostic factors can also benefit from a more intensive therapy at baseline.

However, there is no clear evidence of the superiority of one combination over another. Biologics represent the latest family of agents that have been developed to treat RA.

Anti-tumour necrosis factor (TNF) agents act by inhibiting TNF-alpha, a cytokine that plays a central role in the inflammatory process in RA. These include etanercept, infliximab and adalimumab.

Approved agent
Rituximab is the only other biological agent currently approved by NICE for the treatment of RA. It acts by depleting B cells and has proven efficacy in patients with RA who have failed to respond to DMARDs and anti-TNF agents.

The combination of MTX and biological agents has been shown to be superior to MTX alone. Widespread use of these combinations has been restricted by the increased cost and worries of potential toxicity of biological agents.

At present, their use has been limited to RA patients who have failed to respond to a combination of conventional DMARDs.

Recent developments
Developments have shown that patients with RA should be started on treatment as soon as possible and the goal of treatment should be remission.

There is accumulating evidence to support the concept of a 'window-of-opportunity',3 a timeframe early in the course of the disease where there may be a disproportionate response to therapy. Early treatment may alter the long-term disease process and perhaps even cure it, but many issues still need to be addressed, such as best choice of initial therapy as well as best timing, criteria for initiation and duration of treatment with combination therapy.

Abatacept and tocilizumab are two new biologic agents. Abatacept has been licensed for the treatment of RA, but is yet to be approved by NICE. Tocilizumab is under evaluation to be licensed. This will bring research questions such as when to best use those therapies and what the best treatment is in patients.

Section 4 Prognosis
Although rheumatologists now aim to get their patients into remission and not only control their disease, RA still has to be considered a lifelong illness. Only 10 per cent of patients will have a spontaneous remission.

Untreated, in the majority of cases, persistent synovitis will lead to cartilage damage, bone erosion, joint destruction and loss of function.

Active inflammation is also associated with increased morbidity and mortality mainly due to CVD.

Remission
Most patients have a chronic waxing and waning course and need long-term treatment.

However, there is now accumulating evidence that with early therapeutic intervention and tight control of the disease activity, a significant proportion of patients with RA can achieve remission, a state with no apparent disease activity and absence of joint damage.

With the availability of new therapies and new treatment strategies, studies have even demonstrated the possibility of drug-free remission in some patients. Hopefully, as more patients achieve remission, RA prognosis will improve.

However, despite intervention, a proportion of patients are still experiencing persistent disease activity requiring more intensive therapy, and there is still a need for new therapies.

Factors that have been commonly associated with a worse prognosis are female gender, high tender and swollen joint count, high health assessment questionnaire score, raised inflammatory markers, raised rheumatoid factor and anti-CCP antibodies, positivity for the shared epitope and erosions on X-rays.

Regular follow-up of patients is essential to achieve tight control with the aim of remission. Patients need to be evaluated regularly to assess their disease activity and functional capacity so that treatment changes can be made accordingly if needed.

Assessment
Assessment of disease activity can be by various methods, including tender and swollen joint count, patient and physician visual analogue scales, inflammatory markers and various composite measures. Annual hand and feet radiographs are also recommended.2

As RA is a multisystem disease and treatment has many potential side-effects, teamwork between GPs and rheumatologists is essential for optimal management of the disease.

Patients must have ongoing surveillance for medication side-effects and TB. Cardiovascular risk reduction is an issue that must be addressed as studies have shown that RA patients are at increased risk of IHD.

They also need age-appropriate screening for malignancies and osteoporosis as well as appropriate immunisations including influenza and pneumococcal vaccines.

Resources
Websites
Primary Care Rheumatology Society, www.pcrsociety.org.uk
Arthritis Care, www.arthritiscare.org.uk.
Arthritis Foundation www.arthritis.org.
NICE guidelines www.nice.org.uk.

References

1. Symmons D, Turner G, Webb R. The prevalence of rheumatoid arthritis in the United Kingdom: new estimates for a new century. Rheumatology (Oxford) 2002; 41: 793-800.

2. American College of Rheumatology Subcommittee on Rheumatoid Arthritis Guidelines. Guidelines for the management of rheumatoid arthritis: 2002 Update. Arthritis Rheum 2002; 46: 328-46.

3. Cush J. Early rheumatoid arthritis - is there a window of opportunity? J Rheumatol Suppl 2007; 80: 1-7.

4. Bacon P, Townend J. Nails in the coffin: increasing evidence for the role of rheumatic disease in the cardiovascular mortality of rheumatoid arthritis. Arthritis Rheum 2001; 44: 2,707-10.

5. Firestein G. Etiology and pathogenesis of rheumatoid arthritis. In: Kelley's textbook of Rheumatology, 7th ed. Philadelphia: WB Saunders 2005, 996-1,042.

6. Combe B, Landewe R, Lukas C et al. EULAR recommendations for the management of early arthritis. Ann Rheum Dis 2007; 66: 34-45.

7. Arnett F, Edworthy S, Bloch D et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-24.

8. Emery P, Breedveld F, Dougados M et al. Early referral recommendation for newly diagnosed rheumatoid arthritis: evidence based development of a clinical guide. Ann Rheum Dis 2002; 61: 290-7.

9. Saleem B, Nizam S, Emery P. Can remission be maintained with or without further drug therapy in rheumatoid arthritis? Clin Exp Rheumatol 2006; 24: 33-6.

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