Key learning points
- RA is a common form of inflammatory arthritis
- Patients may not present with classical features of RA
- NICE guidance on rheumatoid arthritis has recently been produced
- GPs should refer patients with suspected RA promptly
- Anti-CCP is more specific than rheumatoid factor
- DMARDs should be started within 12 weeks
- Some patients may benefit from biological drugs
- Patients with RA have a higher risk of CVD, depression and osteoporosis
Rheumatoid arthritis (RA) is the most common type of inflammatory arthritis, affecting up to 1 per cent of the UK population. It affects two to four times more women than men and although generally presents between the ages of 30 and 60, it can present at any age. There are approximately 400,000 people with RA in the UK.
The total costs of RA in the UK, including indirect costs and work-related disability, have been estimated at between £3.8 billion and £4.7 billion per year.
It is very important that GPs can recognise and diagnose RA promptly because early treatment has been shown to result in better outcomes1. There are now numerous effective treatments available for RA. The outlook for patients with RA is much improved with the advent of newer, more effective drugs.
The NICE guidance on the management of rheumatoid arthritis in adults was published in April 2009. Its content will be discussed in this article.
Clinical features
Rheumatoid arthritis is an inflammatory disease affecting the joints and tendons and any tissues with synovial membranes. 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. Some patients may, however, present with an abrupt onset. The pain can spread to involve more joints or seem to move from joint to joint.
Although classical presentation of RA is with symmetrical arthopathy with early morning stiffness, many patients present with more vague symptoms. RA affects much more than the joints, and is a systemic disease. The release of large concentrations of proteins that drive inflammatory processes (e.g. tumour necrosis factor-α (TNF-α)) lead to symptoms of profound fatigue, flu-like symptoms and weight loss. Other inflammatory manifestations may lead to fibrosis in the lungs, pleural and pericardial effusions or vasculitis.
Figure 1: Typical appearance of a patient with rheumatoid hands.
Figure 2: A patient with rheumatoid arthritis with a left sided pleural effusion.
Investigations
There is no single diagnostic test to either confirm or exclude RA. Although inflammatory markers such as CRP and ESR can be raised, they can also be normal. A patient with a normal CRP or ESR should still be referred urgently if there is clinical suspicion of RA.
Although rheumatoid factor should be performed in patients with suspected RA, it is only positive in less than half of RA patients at presentation. If available, anti-cyclic citrullinated peptide (CCP) antibodies should be measured in patients with suspected RA if they are negative for rheumatoid factor. This is a more specific test for RA and can be present ten years before the development of clinical disease. However, this test is much more expensive than rheu¬matoid factor and is still not widely available. Further, anti-CCP antibodies are no more sensitive than rheumatoid factor, and are frequently negative in confirmed cases of RA.
The NICE guidelines also recom¬mend X-rays of hands and feet early in the disease, so this may be important for GPs to arrange at the same time as referral. Although they are often normal in early RA, there are occasions when erosive damage will be detected when all other tests are normal. In addition, x-rays can also be used as base -line for future determinations of disease progression.
Note: normal investigations should not deter a GP from referring patients urgently to secondary care.
Diagnosis
NICE has stated that undue emphasis should not be placed on the 1987 ARA classification criteria, as some patients with early disease will not fulfil these criteria. Therefore a clinical diagnosis should prompt referral.
This is because an early persistent synovitis in which other pathologies have been ruled out should be treated as if it is RA to try to prevent damage to joints. International committees are addressing the diagnostic criteria for early RA.
The diagnosis of RA is therefore largely a clinical one, with tests (blood or imaging) sometimes helping.
The American College of Rheumatology classification criteria for rheumatoid arthritis.
Four of the following seven criteria must be met:
- Morning stiffness in and around joints lasting 1 hour or more before maximal improvement*
- Soft tissue swelling (arthritis) of three or more joint areas*
- Swelling (arthritis) of the proximal interphalangeal, metacarpophalangeal, or wrist joints*
- Symmetrical arthritis*
- Subcutaneous nodules
- Positive test for rheumatoid factor
- Radiographic erosions and/or periarticular osteopenia in hand and/or wrist joints
*must have been present for at least 6 weeks
Furthermore, RA can be categorised into two categories of disease duration: ‘recent-onset’ (disease duration of ≤2 years) and ‘established disease’ (disease duration of >2 years).
Figure 3: A male patient with rheumatoid nodules on an arm.
Referral guidelines
The new NICE guideline recom¬mends that GPs refer for special¬ist opinion any case of suspected persistent synovitis of undeter¬mined 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.
Patients with RA should be offered verbal and written information to improve their understanding of the condition and its management, and counter possible misconceptions.
At the time of initial specialist referral, it should be normal practice to give patients some information about what to expect when they are seen at the hospital and what the course of their disease is likely to be.
Many people still do not have adequate knowledge about rheumatoid arthritis and can present, even to their GP, late when they have had swollen joints for many months2. It is therefore important that the general public are aware of the symptoms and signs of synovitis so that they can attend their GP early. In addition, GPs need to consider prompt referral in patients with suspected RA.
Management
The aim of management is to achieve disease remission, or to minimise disease activity if remission cannot be achieved, in order to optimise the chances of preventing progressive damage to joints with subsequent disability. The longer the remission period, or the least amount of disease activity that can be achieved, the better the long-term outcome.
Management can be divided into non-drug and drug management.
Non-drug management
- The core members of the multidisciplinary team will be the GP, the rheumatologist, the rheumatology nurse specialist, physiotherapists and occupational therapists. Other specialties that may need to be involved include podiatrists, orthotists, psychologists, dieticians, pharmacists, orthopaedic surgeons.
- People with RA should have access to specialist physiotherapy. This will improve general fitness and encourage regular exercise, enhance joint flexibility, muscle strength and managing other functional impairments.
- Pain clinic specialists may be able to advise on non-drug management options such as transcutaneous electrical nerve stimulation (TENS) and behavioural approaches.
Although some studies have shown that modifications in diet can be beneficial in some people with RA, NICE recommend that people with RA should be informed that there is no strong evidence that their arthritis will benefit with changing their diet.
NICE state that patients should be offered verbal and written information about RA. If they wish to know more about their disease and its management then they should be offered the opportunity to take part in existing educational activities, including self management programmes.
Drug management
Drug management has two main aims: pain relief and modification of the disease process.
DMARDS (Disease-modifying anti-rheumatic drugs)
Given appropriate information, people with RA may prefer one DMARD over another, because of mode or frequency of administration, lifestyle and perceived side effect profiles and other considerations (e.g. comorbidities, pregnancy).
Disease-modifying anti-rheumatic drugs (DMARDs) should be started, ideally within 12 weeks of disease onset, as early treatment has been shown to slow disease progression and even lead to benefits up to five years after the drugs are introduced.
In addition, early introduction of these drugs results in fewer adverse reactions and withdrawals.
Patients with newly diagnosed active RA should be offered a combination of DMARDs (including methotrexate and at least one other, plus short-term glucocorticoids) as first-line treatment as soon as possible. This should ideally be within three months of the onset of persistent symptoms.
Patients who are started on more than one DMARD as part of more aggressive therapy for RA have be shown to have better outcomes of their disease3.
Methotrexate is the most commonly used DMARD and is generally used first. Sulfasalazine and leflunomide are considered the best alternatives. The effects of the DMARDs usually take several weeks.
Once sustained and satisfactory levels of disease control have been achieved, their medication may be cautiously reduced to levels that still maintain disease control. However, the dose should be promptly increased at the first sign of a flare.
Steroids
Patients are often given short-term treatment with glucocorticoids for managing flares with recent-onset disease. These rapidly decrease inflammation and also have a disease modifying effect when used in early disease.
Patients should not be left on steroids for the long term. In recent-onset RA, low dose oral steroid regimes have been shown to give symptomatic and quality of life benefit for up to three months.
In established RA, knee joint injections of steroid can be beneficial. However the evidence that steroids may be disease modifying in patients with established RA is still conflicting and is not as strong as the evidence base for recent-onset RA.
Any patients who are being maintained on long-term steroids should be referred to spe¬cialist care for assessment or reassessment. Osteoporosis risk factors should be addressed and a treatment should be initiated, if appropriate.
Biological drugs
Biological drugs are substantially more expensive than conventional DMARDs. However, studies have shown that in patients with established active disease despite conventional disease modifying drugs, the addition of a biological drug adds significant benefits for symptom control, function and quality of life.
The combination of methotrexate and biological agents has been shown to be superior to methotrexate alone. Widespread use of these combinations has been restricted by the increased cost and worries of potential toxicity of biological agents.
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. They are recommended as options for the treatment of adults who have both of the following characteristics:
- Active rheumatoid arthritis as measured by disease activity score (DAS28 – see later) greater than 5.1 confirmed on at least two occasions, one month apart.
- Have undergone trials of two DMARDs, including methotrexate (unless contraindicated). (Adalimumab, etanercept and infliximab for the treatment of rheumatoid arthritis NICE 2007)
Rituximab is a monoclonal antibody which binds to the protein CD20, which is found on B-cells. It has been approved by NICE for the treatment of RA (Rituximab for the treatment of rheumatoid arthritis – NICE 2007) 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.
Abatacept is a selective T-cell co stimulation modulator. It is not recommended (within its marketing authorisation) for the treatment of people with rheumatoid arthritis (Abatacept for the treatment of rheumatoid arthritis NICE 2008).
Anakinra is a recombinant form of human IL-1 receptor antagonist that inhibits the activity of IL-1, thus theoretically protecting both cartilage and bone. However, on the balance of its clinical benefits and cost effectiveness, anakinra is not recommended for the treatment of RA, except in the context of a controlled, long-term clinical study.
Analgesics
Patients with rheumatoid arthritis are often in pain.
NICE recommends that analgesics (for example, paracetamol, codeine or compound analgesics) should be offered to people with rheumatoid arthritis whose pain control is not adequate, to potentially reduce their need for long-term treatment with non-steroidal anti-inflammatory drugs (NSAIDs) or cyclo-oxygenase-2 (COX-2) inhibitors. In patients who do need to take a NSAID or COX-2 inhibitor to control their symptoms, then they should be used with proton pump inhibition. Oral NSAIDs andCox-2 inhibitors should be used at the lowest effective dose for the shortest possible length of time.
Many patients with rheumatoid arthritis have effective symptomatic relief with NSAIDs. Obviously the analgesic effects need to be balanced against the well-recognised toxicity profile; for many patients the balance favours treatment.
Other analgesics should be considered before prescribing NSAIDs or COX-2 inhibitors to those patients also taking aspirin.
Surgery
Surgery may need to be considered for people with RA if they:
- Do not respond to optimal non-surgical management
- Have persistent pain due to joint damage or other identifiable soft tissue cause
- Have worsening joint function
- Have progressive deformity
- Have persistent localised synovitis.
The main expected benefits of surgery are pain relief, improvement or prevention of further deterioration, of joint function and prevention of deformity.
Course of the disease
Most patients have a chronic waxing and waning course and need long-term treatment.
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.
Outcome
Untreated, in the majority of cases, persistent synovitis will lead to cartilage damage, bone erosion, joint destruction and loss of function.
Factors that are associated with a worse prognosis include female gender, the number of joints affected (the more joints the worse the prognosis), the presence of both swelling and tenderness in affected joints, raised rheumatoid factor and anti-CCP antibody levels and erosions on x-rays.
Monitoring disease
The DAS28 is a measure of disease activity in RA as is used by many rheumatologists. The score is calculated by a complex mathematical formula, which includes the number of tender and swollen joints (out of a total of 28), the ESR (or CRP) 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.
NICE recommends that measurement of CRP and key components of disease activity (using a composite score such as DAS28) should be performed regularly in people with RA. This will also help to make decisions regarding increasing treatment to control disease and also cautiously decreasing treatment when the disease is controlled.
In addition, patients with controlled RA should have review appointments at a frequency and location suitable to their needs. They should have access to additional visits for disease flares and have ongoing drug monitoring. All patients with RA should be offered an annual review. This can also be used as an opportunity to screen for the development of co-morbidities, such as hypertension, ischaemic heart disease, osteoporosis and depression.
Co-existing morbidities
Osteoporosis is also more common, due to reduced mobility, inflammation, and sometimes the drugs they are on (particularly steroids). Rheumatoid arthritis is an independent risk factor for osteoporosis.
People with RA are more prone to infections than the rest of the population, probably due to abnormalities in the immune system, and sometimes contributed to by medication (such as the immunosuppressant effects of steroids). Patients with RA should be encouraged to have their annual influenza immunisation.
References
- Cush J. Early rheumatoid arthritis - is there a window of opportunity? J Rheumatol Suppl 2007; 80: 1-7.
- Kumar K, Daley E, Carruthers DM et al. Delay in presentation to primary care physicians is the main reason why patients with rheumatoid arthritis are seen late by rheumatologists. Rheumatology (Oxford) 2007; 46: 1,438-40.
- Lee YH, Woo JH, Rho YH et al. Meta-analysis of the combination of TNF inhibitors plus MTX compared to MTX monotherapy, and the adjusted indirect comparison of TNF inhibitors in patients suffering from active rheumatoid arthritis. Rheumatology International. 2008;28(6):553–559.
Websites
Author and reviewers competing interests: none.
Images: Wellcome.