Arthritis, which includes osteoarthritis, inflammatory arthritis and gout, affects about 10 per cent of the adult UK population, although estimates of prevalence are made difficult by diagnostic uncertainties.1,2,3
Osteoarthritis (OA) is most common and affects as many as 10-20 per cent of those aged >64 years.4
Inflammatory arthritic conditions, which include rheumatoid arthritis (RA), juvenile chronic arthritis, psoriatic arthritis and ankylosing spondylitis, tend to be diagnosed earlier and affect about 2 per cent of the population5
|Table 1: Forms of arthritis|
Prevalence (per cent)
Degenerative damage and loss of articular cartilage, especially in the weight bearing joints and hypertrophy in the subchondral (to which the joint is attached) bone
Chronic systemic inflammatory disease characterised by potentially deforming symmetrical polyarthritis and extra-articular features
Juvenile chronic arthritis
Inflammatory joint disease with chronic synovitis in children in whom the onset of disease occurred before the age of 16
Peripheral inflammatory polyarthritis with presence of psoriasis without rheumatoid nodules
Progressive, chronic, systemic inflammatory rheumatic disease with involvement of sacroiliac joints and spine, absence of microbial infection and various extra-articular manifestations
Abnormality of urate metabolism resulting in deposition of monosodium urate monohydrate crystals in the synovial fluid, soft tissue and urinary tract, causing an inflammatory response
The high prevalence of OA makes it the most common single cause of arthritic disability in the population, with chronic pain, social isolation and depression contributing to reduced quality of life. The burden of OA management falls largely within primary care services.
Surgery and joint replacement offer suitable treatment options for localised joint involvement. However for most patients, management of arthritis relies on optimising the use of pharmacotherapy. Long term outcomes rely on an integration of drug treatment with exercise, lifestyle adjustment and physiotherapy. Pharmaceutical care is therefore central to the treatment of these patient groups.
Public health implications of arthritis
Arthritis and its associated conditions are the most frequent self-reported chronic illnesses in Britain. Approximately one in eight of the adult UK population report themselves to be disabled and almost 50 per cent of these individuals report a musculoskeletal complaint, of which arthritis is the most common.6
A true understanding of the impact of arthritic conditions depends on an interpretation of the meaning and the severity of disability. When surveyed, the elderly are inclined to under-report the physical restrictions in daily activities, and hence the importance of arthritis within the population is probably underestimated.
A large survey in one NHS area using questionnaires and interview assessments reported that 5-8 per cent of the adult population suffered disability associated with an arthritic condition. Most sufferers reported “difficulties” in six activities of daily living connected with functional mobility and dressing, while about 2 per cent of the population reported “dependency” in relation to help being required to get in or out of bed, dressing, getting to and using the toilet and getting out of the house.7,8
In a recent Scottish survey, half the sampled adult population reported chronic pain and about one-third of those (equivalent to 16 per cent of the general population) gave arthritis (excluding back pain) as the cause.9
One-third of the arthritic population are middle-aged adults (aged 44-65) and one in six is a young adult (under 44 years).9,10
Therefore, half the arthritic population is under 65 years old. OA of the knee is twice as prevalent in women as in men and is increased by female obesity. OA of the hip affects 10 per cent of persons aged >80 years and has been linked to occupation.11
In the UK, treatment of musculoskeletal disorders formed 6 per cent of hospital expenditure and 15 per cent of primary care and social service expenditure in 1996.4
The cost of treating arthritis was estimated in 1990 to be approximately 4 per cent of the total UK NHS budget.12
In 1998, approximately 5 per cent of prescriptions (by volume and by cost) dispensed in Scotland were for musculoskeletal and joint disorders.13
Pharmaceutical care should therefore be considered in terms of economic value as well as clinical outcomes.
Panel 1: Profile of arthritis in the population of a pharmacy serving 5,000 patients*
- 800 people self report “chronic pain due to arthritis”
- 400 people have a diagnosis of some form of arthritis
- 175 self report that they are “disabled” (rely on aid to help them dress, go to the toilet or to bed, get out of the house)??
- 13 “disabled” patients have rheumatoid arthritis??
- 140 have “unspecified arthritis”? ??
- 22 have other forms of rheumatic disease **
- 325 patients diagnosed with osteoarthritis, leading to 125 GP consultations annually
- 12 new cases of osteoarthritis annually
- 75 patients with inflammatory arthritis as diagnosis ??
- 2 new cases of inflammatory arthritis annually??
- 40 patients with rheumatoid arthritis, leading to 30 GP consultations annually??
- 20 patients with gout, leading to 15 GP consultations annually ??
- 2 cases of gout due to diuretic use??
- 10 patients with ankylosing spondylitis (AS)
- 5 patients with other forms of arthritis, including “juvenile chronic” and “psoriatic” arthritis
- Estimated types of self reported “disabled” arthritic patients by age
- 140 arthritis unspecified? (36 male, 104 female)
- Age <64 – 23 plus 6 with rheumatoid arthritis
- >64 – 117 plus 7 with rheumatoid arthritis
- Age 65-74 – 54 plus 4 with rheumatoid arthritis
- >74 – 63 plus 3 with rheumatoid arthritis
- 3 patients are on the waiting list for hip/knee replacement at any point in time
- 5 patients >64 years will receive their operation during the course of the year
?Arthritis unspecified: diffuse connective tissue disorders, arthropathy associated with infections, crystal arthropathies, osteoarthritis and allied disorders and unspecified arthropathies.
** Other forms include rheumatic disorders of the “back or neck” and “soft tissue” and “other joint disease”
Disease symptoms and joint involvement
OA may be a primary degenerative disease of the articular cartilage or secondary to injury, trauma and infection, or to congenital, systemic, metabolic and endocrine disorders. Increasing age, family history, obesity, work-related repetitive injury, trauma and osteoporosis are contributing risk factors.
RA, the most common chronic systemic inflammatory disease, is characterised by potentially deforming polyarthritis associated with extra-articular features such as rheumatoid nodules, vasculitis, eye inflammation, neurological complications, cardiopulmonary disease, lymphadenopathy and splenomegaly.
Different forms of arthritis produce particular patterns of pain, swelling, tenderness and stiffness around affected joints, leading to limitation in movement. Symptoms vary in terms of their intensity, localisation and duration. Constitutional symptoms such as malaise, fatigue, loss of appetite, anxiety and depression are associated with arthritis (Table 2).
|Table 2: Signs and symptoms of arthritic conditions|
Other forms of arthritis
Commonly affects large joints (knee, hip, hand and spine)
Commonly affects small joints (hands and wrist), particularly peripheral joints of the fingers. Also affects elbow, shoulder, knee, ankles, toes and jaw
Asymmetrical and affects fewer joints than rheumatoid arthritis
Characteristic distribution, for example, the spine and the sacroiliac joints (ankylosing spondylitis), distal interphalangeal joints (psoriatic arthritis, gout)
Gout may have tophaceous deposits
Worsens with activity (especially in knees and hips)
Moves from joint to joint
Increases with immobility and remains when at rest
Ankylosing spondylitis has gradual onset:
Often poorly localised and rather diffuse in location
Worsens with immobility
Improves with activity and tends to recur after rest
In morning – less than 30 minutes
Transient joint stiffness occurs after rest
In morning – often exceeds 30 minutes
Relieved by modest activity
In ankylosing spondylitis:
In morning – affects low back, buttocks and back of the upper thighs
Relieved by modest activity
Recurs following inactivity
Constitutional symptoms (such as malaise, loss of appetite and depression)
Fatigue, weight loss, dry eye (Sjogren’s syndrome), episcleritis, cardiopulmonary diseases, haematological complications, rheumatoid nodules, vasculitis
Ankylosing spondylitis: Anterior uveitis, aortic valve disease (aortitis and valvulitis), cardiopulmonary disease
Psoriatic arthritis: Ocular inflammation
Gout: Nephropathy, nephrolithiasis
Pain is the most common symptom and can be differentiated as articular pain (mechanical or inflammatory involvement of the joint) or periarticular pain (emanating for instance from the bursa, tendon or ligament). Patients with osteoarthritis suffer from localised pain that worsens with activity (especially in weight-bearing joints) and is relieved by rest; in patients with inflammatory arthritis, pain remains at rest and increases with immobility.
The duration of stiffness, which commonly occurs in all types of arthritis in the morning, reflects the degree of local inflammation. In rheumatoid arthritis, morning stiffness may remain throughout the day. Swelling of joints is caused by fluid accumulation, proliferation of soft tissues or enlargement of bone. Localised inflammatory involvement may cause joints and soft tissues to be red and warm. Joint movement is generally painful. Chronic inflammation, biomechanical changes and failure to maintain exercise result in limitation of motion, compounded by muscle atrophy, weakness and deformity.
In osteoarthritis, there is asymmetrical and monoarticular joint involvement which commonly includes knee, hip and hand joints and the spine. Extra-articular manifestations are limited to constitutional symptoms. Frequently affected joints are the distal interphalangeal (DIP), proximal interphalangeal (PIP) and metacarpophalangeal (MCP) joints in the hand and first metatarsophalangeal (MTP) joints in the feet. Bony enlargements (Heberden’s nodes in the DIP joints and Bouchard’s deformity in the PIP joints) are more common in women than men. These enlargements develop slowly, at first painlessly, before becoming red, warm, swollen and painful. Involvement of the knee may be complicated by muscle atrophy and transient joint effusion.
Eighty per cent of patients with gout have an acute attack in the large toe, although initial presentation of disease may be polyarticular and affect the small joints of the feet, ankles and hands as well as the knees. Gout produces severe pain with hot, red, swollen and tender joints. In chronic disease, crystal aggregates, called tophi, can be associated with cardiovascular disease and nephropathy.
Panel 2: General symptoms and signs of arthritis
- Limitation of movement
- Joint instability
- Multisystem disease
Pathogenesis and disease markers
In OA, there is damage and degradation of articular cartilage which results in loss of biomechanical properties and joint function. This can occur on its own or as a final pathway after inflammatory disease. Damaged cartilage fibres split and are weakened by loss of proteoglycan aggregates which normally retain water within the collagen matrix. The cartilage loses its elastic properties and severe disease is associated with a loss of collagen as the cartilage fails to repair itself. Continued wear and tear of the joint leads to erosion of the upper layers of cartilage and there is focal exposure of the lower layers of calcified cartilage and bone. Changes also occur in the synovium, subchondral bone and other soft tissue and the joint ultimately fails to resist the consequences of weight bearing.
In RA, there is inflammation in both joints and their surrounding structure. Hypertrophy of the synovium can occur, which can diffuse to cause erosive destruction of the cartilage and bone. Genetic and environmental trigger factors are thought to be important. Biochemical, inflammatory and immunological effects play a role in cartilage destruction and loss of joint space. The damage is further complicated by tendon involvement and ligament damage, leading to chronic deformity, particularly in the cervical spine.
Diagnosis in arthropathies depends on clinical assessment (Table 3). Radiological investigation is limited by a lack of sensitivity to identify early changes in joints. Laboratory tests are also not specific enough to discriminate between different types of arthritis. Inflammatory arthritis, including rheumatoid arthritis and other spondylarthropathies (ankylosing spondyl-itis and psoriatic arthritis), tend to cluster in families. Certain types of human lymphocyte antigens (HLAs) such as HLA-DR1, HLA-DR4 and HLA-B27 subtypes are found more frequently in patients with inflammatory arthritis. Most patients with rheumatoid arthritis have HLA antigen serotypes HLA-DR1 or HLA-DR4. HLA-DR4 serotype is associated with more severe cases of rheumatoid arthritis (70 per cent of severe cases) and especially Felty’s syndrome (splenomegaly and leucopenia associated with rheumatoid arthritis) (90 per cent). HLA B27 is found in 6-8 per cent of the general population but in 90 per cent of patients with ankylosing spondylitis.
|Table 3: American Rheumatism Association criteria and definitions for rheumatoid arthritis (1987)|
1. Morning stiffness
Morning stiffness lasting at least one hour before maximal improvement
2. Arthritis of three or more joint areas
At least three joint areas are swollen including PIP, MCP, wrist, elbow, knee, ankle and MTP joints
3. Arthritis of hand joints
At least one area swollen in a wrist, MCP or PIP joint
4. Symmetrical arthritis
Bilateral joint involvement of PIPs, MCPs or MTPs is acceptable without absolute symmetry
5. Rheumatoid nodules
Subcutaneous nodules, over bony prominences, or extensor surfaces, or in juxta-articular regions
6. Serum rheumatoid factor
Demonstration of abnormal amounts of serum rheumatoid factor
7. Radiographic changes of RA
Radiographic changes typical of RA on hand and wrist radiographs
Adapted from reference 20
In general, acute phase reactants such as C-reactive protein (CRP) and the erythrocyte sedimentation rate (ESR) or serum viscosity are increased in inflammatory arthritis and can be used to evaluate disease activity. Rheumatoid factor (RF) is an autoantibody (usually of the IgM class) found in the serum and directed against human IgG. RF is a non-specific indicator present in 60-70 per cent of patients with RA. In other forms of inflammatory arthritis, including ankylosing spondylitis, patients are usually seronegative for RF.
As a result of the severe inflammation in arthritis, haematological white cell and platelet counts are increased. In inflamed joints, the synovial fluid often has a raised white cell count of 5000-50,000/mm3 (normal joints contain <2,000/mm3) and is turbid, yellow or green in colour, showing a high protein content and lower viscosity than is normal.
Osteoarthritis usually shows a non-inflammatory pattern without any increases in acute phase reactants, although findings associated with inflammation can be seen in progressive stages of osteoarthritic disease. Table 3 summarises the diagnostic criteria for rheumatoid arthritis.
Progression of arthritic disease and complications16-19
OA morbidity and disability tend to be worse if the weight-bearing joints or spine are affected.
RA progression is characterised by progressive X-ray changes and then irreversible joint deformities such as ulnar deviation of the fingers (the drift of the fingers in the direction of the ulna bone in the forearm and away from the thumb), boutonniere deformities (hyperextension of the DIP joint and flexion of the PIP joint) or swan neck deformities (hyperextension of the PIP joint and flexion of the DIP joint). Extra-articular symptoms are associated with disease progression and particular types of inflammatory arthritic conditions. They include skin and mucous membrane changes, eye complications and gastrointestinal, cardiopulmonary, genito-urinary, neurological and haematological disorders. Subcutaneous nodules are hallmarks of rheumatoid arthritis.
Rheumatoid nodules occur in 20-30 per cent of patients with RA. The nodules are asymptomatic and mostly occur on the extensor surfaces of the elbows, forearms, hands and the sacral areas but can also be found in other tissues including the eye, pleura, pericardium, lung and heart.
Eye involvement is common in RA and in other forms of inflammatory arthritis. Episcleritis is a painless, self-limiting, often transient lesion associated with vasculitis. In contrast, scleritis is a painful, less common but more serious condition which may lead to perforation of the eyeball. Dry, itchy eyes are found in 20 per cent of patients with rheumatoid arthritis and result from reduced tear formation (keratoconjunctivitis sicca or Sjogren’s syndrome). Uveitis is a common condition in the other spondyl-arthropathies, especially in AS. It is found in 20 per cent of patients with AS and 60 per cent of those have recurrent attacks. Ocular inflammation is seen in 30 per cent of patients with psoriatic arthritis.
Vasculitis occurs in about 25 per cent of patients with long-standing RA. It is due to inflammatory cell infiltration and necrosis of blood vessel walls and it may be complicated by skin ulceration. Vasculitis most commonly involves the ends of the fingers or toes, especially around the nail beds, as well as the lower extremities. Extensive arterial involvement of larger vessels may produce life-threatening complications such as ischaemia and may provide a portal of entry for infection.
Pulmonary fibrosis causes progressive dyspnoea, inspiratory crepitations and clubbing of the fingers. Pulmonary fibrosis is seen in 2 per cent of patients with RA and 1 per cent of patients with advanced ankylosing spondylitis. The risk is increased by smoking. Cardiopulmonary involvement may reduce life expectancy. Ankylosing spondylitis is associated with a threefold excess in respiratory disease mortality.
Aortic regurgitation has been found in 1 per cent of patients with ankylosing spondylitis. Cardiac involvement is more common in men and is usually subclinical; valvulitis occurs in 20 per cent of cases of rheumatoid arthritis but is rarely symptomatic.
Lymphadenopathy affects 2 per cent of RA cases and is more common in patients with Felty’s syndrome. Anaemia, thrombocytopenia, persistent vasculitic leg ulceration, weight loss and recurrent infection are other frequently presented features in rheumatoid arthritis.
Other manifestations of RA include peripheral neuropathy and carpal tunnel syndrome, which is caused by local pressure on the median nerve at the wrist. Dysphagia may occur in Sjogren’s syndrome, secondary to dry mouth. Later in rheumatoid disease, cervical myelopathy is a significant neurological complication caused by damage to the upper cervical spine.
Guidelines for the management of arthritis
In the UK, the Royal College of Physicians has published guidelines on rheumatoid arthritis (1992) and on osteoarthritis of the hip and knee (1993).21,22
The American College of Rheumatology has issued guidelines for osteoarthritis (1995)23,24
and for rheumatoid arthritis (1996).25,26,27
However, those guidelines do not reflect the findings of recent studies that have prompted new strategies for the treatment of rheumatoid arthritis, in particular trends in the use of disease modifying drugs. Guidelines for management of early rheumatoid arthritis from the Scottish Intercollegiate Guidelines Network (SIGN) are awaited.
The evidence base for treatment of arthritis is summarised in Table 4. Pain relief in OA starts with simple analgesics (such as paracetamol) which can be given in combination with opioid or non-opioid analgesics if necessary. Non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, should be considered as alternatives or adjuncts for pain relief in those who do not respond adequately to simple analgesics. Topical anti-inflammatory agents may be used for pain localised to specific joints, although their effectiveness is limited and they are overprescribed. NSAIDs constitute 5 per cent of NHS prescriptions in the UK, with ibuprofen, naproxen and diclofenac being the most commonly prescribed in general practice.28,29
|Table 4: Arthritis treatment evidence base|
Summary of findings
In inflammatory arthritis, NSAIDs are more effective than simple analgesics. Differences in efficacy between most NSAIDs are small but responses show high individual patient variation. NSAID-gastrointestinal toxicity is dose related; ibuprofen has the lowest risk of GI complications. Recent meta-analysis shows that rofecoxib has a lower incidence of upper GI effects, including perforation, ulcer and bleeding than NSAIDs
Sulphasalazine is as effective as injectable gold, penicillamine and methotrexate and is significantly better than antimalarials, oral gold and azathioprine. It has a better effect on disease progression than hydroxychloroquine. Triple combinations with a steroid plus methotrexate are more effective than sulphasalazine alone
Meta-analysis demonstrates a relatively high efficacy:toxicity ratio compared with other DMARDs. Hydroxychloroquine (rather than chloroquine) tends to be used in practice
Combination of chloroquine and methotrexate is more effective than methotrexate alone. Triple therapy with hydroxychloroquine, sulphasalazine and methotrexate is more effective than either hydroxychloroquine/ sulphasalazine or methotrexate alone
Methotrexate is probably the most effective and most rapidly acting DMARD. Combinations of methotrexate with cyclosporin and with sulphasalazine and hydroxychloroquine show better clinical outcomes than methotrexate alone
Combination with corticosteroids increases effectiveness of oral or IM gold. Oral gold (auranofin) is significantly less effective than methotrexate, sulphasalazine, penicillamine and injectable gold
As effective as IM gold, methotrexate and sulphasalazine. The penicillamine/oral gold combination shows improved outcomes compared with penicillamine alone. However, there is lack of evidence for long-term efficacy and poor long-term tolerance
Meta-analysis of studies of oral prednisolone 2.5-12.5mg/day confirms effectiveness in symptomatic control. Addition of prednisolone 7.5mg to other DMARD regimen shows short-term rather than long-term effects
Doctors should be aware of the consequences of overconsumption and risks of toxicity of NSAIDs, especially when they are prescribed on an “as required” basis.29
Annually, 12,000 hospitalisations and about 2,000 deaths have been attributed to NSAID use in the UK.30
Patients who are taking NSAIDs have a three-to-five fold risk increased of GI complications compared with non-users. Misoprostol and proton pump inhibitors may be prescribed to reduce GI complications but prophylaxis with those agents is not cost-effective except in targeted high risk groups. Recent studies indicate that omeprazole 20mg once daily is effective and well tolerated in the prevention of both gastric and duodenal ulcer in patients receiving NSAIDs. Misoprostol is also effective in prevention of gastric and duodenal ulceration, whereas the use of H2 antagonists is limited since they only prevent duodenal ulceration.31
Side effects of misoprostol, such as diarrhoea and abdominal pain – which occur approximately twice as frequently as with omeprazole – sometimes limit its use.
COX-1 is the constitutive isoform of cyclo-oxygenase and it is responsible for production of physiological prostaglandins which protect gastric, small and large bowel mucosa and maintain renal blood flow. COX-2 is an inducible isoform and is localised mainly to inflammatory sites; it is induced by cytokines. Recently developed NSAIDs, meloxicam, rofecoxib and celecoxib have demonstrably marked COX-2 selectivity which may be expected to reduce NSAID gastrointestinal complications.32,33,34
Their clinical value is still being assessed. Currently, meloxicam and rofecoxib are licensed in the UK, although in the case of rofecoxib, only for OA.
Although NSAIDs are effective in ameliorating the symptoms of rheumatoid arthritis, they have no effects on progression of the disease. Remission or control of inflammatory joint disease requires the use of disease-modifying antirheumatic drugs (DMARDs). In UK practice, sulphasalazine is most popular (80 per cent of patients with rheumatoid arthritis receive it in the first year), followed by methotrexate, gold and penicillamine, which are the most commonly preferred second line drugs. Assessments by meta-analysis have suggested that methotrexate and hydroxychloroquine have the highest efficacy/toxicity ratio.35
Some 90 per cent of patients with RA take a DMARD at some stage of their disease. DMARDs have conventionally been used in patients with radiological evidence of erosive disease, or in rapid functional decline,36
but they are increasingly being used earlier and more intensively in RA.37,38
The shift towards more widespread use of methotrexate places increasing responsibility on primary care services for patient education and monitoring for dose-related toxicity (Panel 3).
Panel 3: Methotrexate (MTX)
Individualised oral dose
Starting with 5mg/week and increasing at 2.5mg monthly increments until the patient is stabilised. The usual dose is 7.5-10mg/week orally and may be increased up to 20mg/week. MTX is given as a single dose. Younger patients may require doses higher in the range or a switch to the parenteral route
Since MTX is virtually completely eliminated unchanged in the urine, dosage requires to be adjusted in accordance with the patient’s renal function (proportional to ClCr). The half life of MTX is normally 4-10 hours and is extended in patients with impaired renal function
Nausea, stomatitis, diarrhoea and risk of infection. Blood dyscrasias, hepatotoxicity, pulmonary fibrosis, renal toxicity and teratogenesis
Hepatotoxicity is more likely in the presence of excessive alcohol intake, diabetes, obesity, impaired renal function and previous liver abnormalities
- Mild renal impairment
- Respiratory disease
- Haematological disorders
- Very elderly patients
- Contraindicated in pregnancy
Cautions in co-prescribing
NSAIDs affect gastrointestinal tolerance and renal elimination. Diuretics and ACE inhibitors can reduce renal elimination
Folic acid 5mg/week, 3-4 days after MTX dose administration. Folic acid supplementation is required to minimise adverse effects, particularly stomatitis
Avoid co-prescribing trimethoprim, co-trimoxazole or phenytoin
Full blood count, urea and electrolytes, plasma creatinine and liver function tests every 4-8 weeks
Discontinue MTX when:
- Hb <9g/dl
- WCC <4×109/L
- Platelets <150×109/L
- Raised LFTs
- Urea or creatinine increasing
|Table 5: Drug treatment in arthritis|
Identify and discontinue drugs that can interact with current drug treatment or add to the toxicity of required treatment. Avoid the combination of two or more NSAIDs and rationalise combination of analgesics to minimise unwanted effects, address diurnal fluctuation in pain control and maximise patient compliance
Simple analgesics (mainly paracetamol alone or in combination) are the first choice for pain relief in osteoarthritis; NSAIDs are used as alternatives or adjuncts for those with indequate response to simple analgesics. Analgesic effect of NSAIDs can be achieved within a week whereas three to four weeks are required for anti-inflammatory effect. Risk factors for upper GI symptoms are: age >65, history of peptic ulcer disease, concomitant use of oral corticosteroids and anticoagulants, recent upper abdominal pain, previous GI intolerance to aspirin or NSAIDs. Misoprostol and proton pump inhibitors, and to a lesser extent H2 antagonists, reduce the risk of peptic ulcers and they may be co-prescribed with NSAIDs. Renal adverse effects are the next most common side effects. NSAIDs may also provoke bronchoconstriction. If possible, avoid chronic use of NSAIDs
Sulphasalazine is now more commonly used early in the treatment of arthritis. Adverse effects are GI or central nervous system complications, neutropenia, skin rashes and hepatotoxicity. Full blood count should be undertaken every two to four weeks for three months and every three months thereafter; liver function tests should be checked monthly for the first three months and every three to six months thereafter. The drug should be stopped if the white cell count <3.5×109/L or platelets <120×109/L and if liver function tests increase to three times the baseline value
These drugs tend to be reserved for patients with mild, slowly progressive arthritis or in those in whom disease overlaps with connective tissue disorders. They are relatively well tolerated compared with other DMARDs. GI symptoms can be avoided by starting with low doses and increasing gradually. The major side effect is ocular toxicity which is dose related and may produce corneal or retinal deposits. Although visual field problems are rare with hydroxychloroquine, early detection of retinopathy is necessary. Ophthalmologic examination every six to 12 months is recommended
Methotrexate is increasingly being used in a weekly individualised dose regimen, although careful use is required to avoid toxicity. Adverse effects have previously limited its use in long-term treatment. However, recent studies indicate that discontinuation of therapy due to side effects is less than with other DMARDs and more patients have remained on methotrexate than other DMARDs at three years and five years. Caution is required in co-prescribing NSAIDs with methotrexate because of GI toxicity and reduced renal elimination of methotrexate
Gold (IM, oral)
Intramuscular gold is given weekly, initially, followed by fortnightly or monthly maintenance. Haematological, renal and pulmonary side effects can occur. Recommendations for monitoring are full blood count before each injection, liver function tests and plasma creatinine every three months, urine dipstick for protein every one to two weeks for the first 20 weeks, then before every injection. The oral route is associated with reduced effectiveness and greater delay in onset of gold treatment. Diarrhoea also limits the use of oral gold (auranofin)
Side effects are generally dose-dependent but do limit its usefulness. Haemoglobin, full blood count and urine dipstick for protein should be done every two weeks until dosage is stable, then every one to three months. Oral iron and antacids impair absorption and should be given two hours before or after penicillamine. A common reason for discontinuation is drug toxicity such as mucocutaneous reactions and haematological, GI and renal complications (proteinuria)
Check glucose and blood pressure every three to six months. Sudden withdrawal may cause resurgence of RA. In combination with other treatments, corticosteroids reduce disease progression in early active RA. Long-term adverse effects such as osteoporosis limit their routine use. To avoid long term toxicity, IV administration is used as pulse treatment; intra-articular injections are also used in acute episodes of RA. Pulse therapy may be safer than long-term oral corticosteroid therapy and is given as IV methylprednisolone 400-1000mg repeated on three consecutive days, or on three alternate days, or once a month for six months. Intra-articular injection should be considered in patients with effusion in the joint (although it provides temporary benefits only). To avoid joint erosion and risk of infection, local injection into the same joint is preferably limited to no more than once every three months
Azathioprine is used mainly in patients with progressive disease who have failed to respond to either methotrexate or gold. Methotrexate plus azathioprine combination therapy is not better than either methotrexate or azathioprine alone. In aggressive therapy, the triple combination of methotrexate, hydroxychloroquine and azathioprine shows good clinical response. Common side effects are nausea, vomiting, diarrhoea, mouth ulcers, rash, bone marrow suppression and liver toxicity. Full blood counts are required every one to two weeks with changes in dosage and every one to three months thereafter. Liver function tests should be checked at least every three months. Avoid concomitant use with allopurinol
Cyclosporin has been introduced as a DMARD for patients with severe, progressive disease in whom most other DMARDs have failed. It is less well tolerated because of hypertension and nephrotoxicity, which are common and dose-related side effects. Combination with methotrexate increases effectiveness of therapy. It should be used cautiously in patients aged >65 years, and in those with hypertension, active infection, on anti-epileptic treatment and/or undergoing surgery. If a good clinical response is achieved within three months, the dose can be reduced by 0.5mg/kg/day every month to achieve the lowest effective dose. If plasma creatinine rises >30 per cent, the dose should be reduced for one month and the drug plasma concentration measured every two weeks until stable, and monthly thereafter. Serum creatinine, urea, electrolytes, blood pressure and urinalysis should be checked every two weeks for three months and monthly thereafter. Periodic monitoring of liver function tests recommended
New treatment approaches
A wider range of agents are now used as DMARDs in the treatment of RA. Although the relative effectiveness of different strategic approaches to DMARD treatment is at present unclear, the increase in treatment options for RA requires general practitioners to refer patients to specialists early in the disease. DMARDs are also being used in combination in order to make the best use of individual components. Combination therapy has been studied and the results are inconclusive. Emphasis is placed on systematic monitoring of disease progression to signal the need to make changes in the DMARD regimen.39
The strategy of using changes in treatment regimens to achieve greater individualisation of the treatment course (“saw tooth” strategy) challenges the notion of comparing individual regimens in clinical trials and makes evaluation of treatments difficult (Panel 4).
Panel 4: DMARD “saw tooth” strategy
- Use DMARDs early
- Use one or more DMARDs continuously
- Monitor disability and other outcomes
- Set ceilings of acceptable disability in order to define decision points for the need to change treatment
- Modify treatment systematically, by changing DMARD treatment at each decision point
- Use analgesic/NSAIDs as adjunctive (symptomatic) treatment only
A “step down” approach has also been advocated. In such cases, DMARD combinations are first used intensively to achieve “remission” of disease activity and then the more toxic components(s) are gradually withdrawn with the aim of limiting toxicity while maintaining disease control. Corticosteroids and NSAIDs are used as adjunctive agents to provide what has been termed “bridge therapy” while DMARDs take effect.40
Minocycline has been found to be useful in the treatment of RA. This drug has antibacterial, antimetalloproteinase and immunomodulating effects and evidence suggests that it is effective for controlling disease activity in seropositive RA within the first year of disease, although the evidence comes from limited controlled trials (conducted in patients with seropositve RA). The main problem with minocycline has been local hyperpigmentation.41
Leflunomide is a newly licensed DMARD affecting pyrimidine synthesis through an effect on dihydro-orotate dehydrogenase. It has a relatively rapid onset of action, usually within four weeks. However, leflunomide exerts its effect through an active metabolite with a long half-life (15-18 days) which undergoes enterohepatic circulation. Side effects are wide-ranging, and include a variety of skin disorders, diarrhoea, abdominal pain, alopecia, dizziness and hypertension. Liver function should also be monitored during therapy. There is potential additive toxicity in combination with other DMARDs. Combination of methotrexate may be useful in RA patients who do not respond adequately to methotrexate alone but increased hepatotoxic effects can be seen.
42,43,44 The summary of product characteristics for leflunomide says that combinations should be avoided.
Biological modulators include agents acting on T-cells and cytokines, such as tumour necrosis factor alpha (TNFa) and interleukin 1 (IL-1). Alteration of cytokine function can be achieved by use of local or systemic monoclonal antibodies (such as infliximab), soluble cytokine receptors (such as etanercept), cytokine receptor antagonists and the administration of cytokines which have opposing effects on the targeted cytokines.45,46,47
Etanercept is licensed in the US for patients who have failed on other DMARDs and is likely to be launched shortly in the UK. The drug reduces inflammation by blocking TNF and therefore the production of pro-inflammatory cytokines (IL-1). It is administered subcutaneously twice a week and clinical response has been achieved after two weeks. The main problems with etanercept therapy are increased risk of infection and injection site reactions such as erythema, itching, pain or swelling. However, absence of tachyphylaxis with prolonged use, apparent lack of anti-etanercept antibodies and a better tolerability profile suggest that it has advantages over infliximab in the treatment of RA.48
Infliximab reduces inflammation by binding to and neutralising TNF on the cell membrane and in the blood. It is approved for treatment of Crohn’s disease in the UK and is being considered for the treatment of RA. It has a rapid and long duration of action but multiple infusions may cause the development of anti-infliximab antibodies in long-term therapy. The most common adverse effects with infliximab are upper respiratory tract infections, headache, nausea, sinusitis, rash and cough.
Combination with oral methotrexate has significantly reduced the proportion of patients with anti-infliximab antibodies and prevented tachyphylaxis. The Food and Drug Administration has approved the combination with methotrexate therapy for RA.
Studies currently indicate that the main effects of these new biological products may be short-lived and that their place in the treatment of RA is likely to be in combination with DMARDs such as methotrexate.
Among the arthritic conditions, relative consulting rates for osteoarthritis, rheumatoid arthritis and gout are 21 per cent, 4 per cent and 2 per cent, respectively.69
A combination of pharmacological and non-pharmacological approaches for managing joint disease is required, the latter including physiotherapy, occupational therapy, podiatry, encouragement to exercise and weight control. Concomitant disorders, polypharmacy and repeat prescriptions, combined with possible advanced age, also contribute to the need for individualisation of care (Table 6).
|Table 6: Pharmaceutical care of arthritis|
Stage of treatment
Points to consider at each stage
Patient comprehension/active participation
Indication (the need for each drug)
Choice of medication
Conformity to guidelines
Continuity of care
Verify the plan in respect of:
Patient’s needs for education
Concordance and agreed expectations
Radiographic/symptomatic type of arthritis
Patient’s health beliefs, understanding of their condition, treatment goals, complications and the impact on their quality of life
Health advice regarding diet, exercise, smoking, alcohol consumption
Modify the plan to address:
Specific educational needs
Need for individualisation of treatment plan
Motivation of the patient and their family with respect to self care, lifestyle modification and treatment goals
Presence of risk factors such as obesity, trauma, infectious disease, diabetes
Concomitant therapy or pregnancy which may influence drug choice
Reasons for drugs withdrawn in the past
Selection of appropriate NSAIDs with regard to risk factors for toxicity, such as known cardiac, respiratory or renal disease, concomitant therapy and previous response to NSAIDs
Need for appropriate co-prescription with misoprostol or proton pump inhibitors
Other co-morbidities present that influence treatment choice, eg, hypertension, upper GI disease, COPD
Renal function assessment and implications for drug choice and dosage individualisation
Shared care arrangements and support available
Monitor the patient for:
Continuing suitability of drug/dose regimen
Signs/symptoms of effectiveness and toxicity
Patient compliance and the need to re-inforce health messages
Adjust choice of oral dose forms to help patients with swallowing difficulties
Frequency and timing of analgesics/anti-inflammatory agents
Advice/discouragement about over-consumption of OTC medicines
Adjust the process by:
Further individualisation in response to monitoring
Achievement of regular exercise and adherence to advice on self care
Monitoring of laboratory (erythrocyte sedimentation rate, C-reactive protein, creatinine, urea and electrolytes, chest X ray) and clinical markers (cough, fever, shortness of breath, duration of stiffness, pain, swollen joints) in the initiation of DMARDs and NSAIDs
Ensure adequate dietary intake of calcium to protect against osteoporosis, especially in patients receiving corticosteroids, who may require appropriate prophylaxis
Recorded adverse reaction
Confirm evidence of treatment success:
Seek and provide reassurance that treatment expectations are being achieved
Attainment of treatment goals with pain relief, mobility, functional ability and improved quality of life
Unwanted symptoms from medication (steroid-induced osteoporosis, worsening of sleep disturbances, gastrointestinal complications, toxicity of DMARDs)
Prompt a review from:
Identification of treatment failure
Newly identified patient’s needs
Sharing information and discussion of implications with the prescriber and other team members
Documentation of unexpected or serious adverse effects
Changes in the patient’s needs after pharmacotherapy
Indications for treatment plan revisions, such as persistent symptoms and progression of disease, complicating features such as co-morbidity and polypharmacy
Co-morbidity, especially chest disease, cardiovascular disease and obesity, commonly complicates OA. In a Scottish GP electronic questionnaire of 2,646 patients in 1998 the estimated major co-morbidities reported in RA patients were hypertension (20 per cent), respiratory disease (16 per cent), depression (15 per cent), ischaemic heart disease (13 per cent), anxiety (12 per cent) and duodenal ulcer (10 per cent). Mortality due to co-morbid conditions may be increased because of increased risk of infection, cardiopulmonary disease and gastrointestinal complications.70,71
The aims of therapy are pain control and reduction of progression of joint damage in order to minimise disability and maximise quality of life. While OA is mainly treated in primary care, inflammatory arthritis is usually treated by specialist rheumatologists as part of shared care arrangements with GPs. Control of disease progression in OA may be affected by a patient’s general lack of knowledge and misunderstandings about the nature of the disease, the causes of symptoms, disability and handicap. Patients’ beliefs and expectations tend to affect their motivation to use other, non-prescribed medicines. Approximately half of patients with RA have been estimated to self-medicate without informing medical staff. In a European survey of arthritis patients, 18 per cent were found to be taking simultaneously both prescribed and over-the-counter NSAIDs. The reasons for using self-medication include the search for better pain relief, maintenance of energy level, reduction of sleep disturbances and continuation of daily activities.72,73
Patients with all forms of arthritis are likely to benefit from health care practitioners developing an integrated care approach. In particular, educational programmes should form part of agreed shared care arrangements. Improving the patient’s participation in treatment, through improved education and better self-management, has recently been shown to produce positive effects on outcomes.74-77
In patients with arthritis, physiotherapy and regular mild exercise can be helpful to improve functional ability, relieve pain during the day, promote self-confidence and decrease the risk of depression and anxiety.78
Weight-bearing exercise helps to maintain bone mass and prevent osteoporotic fractures.
In the arthritic population, the main reported problem is pain, followed by functional limitations, deformities and stiffness, which are much more common in RA patients than OA patients.73
Joint pain is the most common reason for referral to hospital and the British Society for Rheumatology has estimated that approximately one-third of people in general with arthritis are in pain all the time and more than half have disturbed sleep as a result.
In the general arthritic population, the prevalence of joint problems, dependency and difficulty in daily living activities increases with age, particularly in those aged over 65 years. Patients with problems related to advancing age, persistent pain and worsening disability need to be identified for further referral. Questionnaires that research into quality of life in arthritis patients include the AIMS (Arthritis Impact Measurement Scales) for functional assessment and HAQ (Health Assessment Questionnaire) for the assessment of the wider impact of the arthritic condition.79,80
In RA, approximately 25 per cent of patients are severely disabled after 10 years. Anxiety and depression might be seen in arthritic patients due to pain and/or disability. Depression associated with chronic pain or disability may require specialist care, especially in RA. Obesity is associated with pain in the knee and hip joints so that weight loss should be considered in obese patients. Eliminating obesity in osteoarthritic patients reduces the incidence of knee OA by 25-50 per cent and hip OA by 26 per cent.81,82
Attention to achieving a good diet and regular mild exercise, such as swimming, to strengthen the muscles, are helpful.
Regular assessments of disease activity, drug interactions and side effects, laboratory markers and physical signs are required. Arthritis is a major public health concern which remains an important cause of disability in the general population. Its associated co-morbid conditions, such as anxiety, depression and chronic pain, can reduce life expectancy as well as result in poor quality of life. Multidisciplinary teamwork and co-operation between primary and secondary care services is essential to provide the necessary educational and social support to patients and their families.
Case 1 – Pharmaceutical Care Plan
Ms Bayraktar is research pharmacist and Professor Hudson is Boots professor of pharmaceutical care in the pharmaceutical care health service unit, University of Strathclyde; Ms Watson is lecturer in clinical practice in the pharmaceutical care health service unit and Southern General hospital NHS trust, and Dr Fraser is consultant rheumatologist, Southern General hospital NHS trust
Other articles in the series
1. Steven MM. Prevalence of chronic arthritis in four geographical areas of Scottish Highlands. Ann Rheum Dis 1992;51:186-94.
2. Symmons D, Bankhead C. Health care needs assessment for musculoskeletal diseases. The first step - estimating the number of incidence and prevalent cases. ARC Epidemiology Research Unit, University of Manchester, 1994 and ARC web site report.
3. Rowan K, Doyle D, Griffiths I. Arthritis: Standards of care: Towards meeting people’s needs. British League Against Rheumatism, 1997.
4. Scott DL, Shipley M, Dawson A, Edwards S, Symmons DPM, Woolf AD. The clinical management of rheumatoid arthritis and osteoarthritis: strategies for improving clinical effectiveness. Br J Rheumatol 1998; 37: 546-54.
5. Klippel JH, Dieppe PA. Practical Rheumatology, London: Mosby, 1995.
6. Martin J, Meltzer H, Elliot D. OPCS 1988 Survey of physical disability in Great Britain. Report 1. The prevalence of disability among adults.
7. Badley EM, Tennant A. Impact of disablement due to rheumatic disorders in a British population: estimates of severity and prevalence from the Calderdale rheumatic disablement survey. Ann Rheum Dis 1993;52:6-13.
8. Badley EM, Tennant A. Changing profile of joint disorders with age: findings from postal survey of the population of Calderdale, West Yorkshire, United Kingdom. Ibid 1992;51:366-71.
9. Elliott AM, Smith BH, Penny KI, Smith WC, Chambers WA. The epidemiology of chronic pain in the community. Lancet 1999;354:1248-52.
10. British Society for Rheumatology. Musculoskeletal disorders: providing for the patient’s needs no 3. A basis for planning a rheumatology service.
11. Murray CJL, Lopez AD. Global Health Statistics. Boston: Harvard University Press, 1996.
12. Wyles M. Arthritis. London: Office of Health Economics, 1992.
13. Scottish Health Statistics 1998. Information and statistics division. National Health Service in Scotland. Edinburgh, 1999.
14. Fry J, Sandler G. Common Diseases. Their nature, presentation and care. 5th ed. Dordrecht, London, Boston: Kluwer Academic Publishers, 1993.
15. Croft P. Review of UK data on the rheumatic diseases - 3. Osteoarthritis. Br J Rheumatol 1990;29:391-5.
16. Weatherall DJ, Ledingham JJG, Warell DA, editors. Oxford textbook of medicine. 3rd ed. Oxford: Oxford University Press, 1996.
17. Akil M, Amos RA. Rheumatoid arthritis - I: Clinical features and diagnosis. BMJ 1995;310:587-90.
18. Keat A. Spondyloarthropathies. Ibid 1995;310:1321-4.
19. Watts RA, Scott DGI. Rashes and vasculitis. Ibid 1995;310:1128-32.
20. Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 315-324.
21. Report of a joint working group of the British Society for Rheumatology and the research unit of the Royal College of Physicians. Guidelines and audit measures for the specialist supervision of patients with rheumatoid arthritis. J Roy Coll Phys London 1992;26:76-81.
22. Scott DL. Guidelines for diagnosis, investigation and management of osteoarthritis of the hip and knee. Report of a joint working group of the British Society for Rheumatology and research unit of the Royal College of Physicians. Ibid 1993; 27: 391-96.
23. Hochberg MC, Altman RD, Brandt KD, Clark BM, Dieppe PA, Griffin MR et al. Guidelines for the medical management of osteoarthritis. Part 1. Osteoarthritis of the hip. Arthritis Rheum 1995;38:1535-40.
24. Hochberg MC, Altman RD, Brandt KD, Clark BM, Dieppe PA, Griffin MR et al. Guidelines for the medical management of osteoarthritis. Part 2. Osteoarthritis of the knee. Ibid 1995;38: 1541-6.
25. American College of Rheumatology ad hoc committee on clinical guidelines. Guidelines for the management of rheumatoid arthritis. Ibid 1996;39:713-22.
26. American College of Rheumatology ad hoc committee on clinical guidelines. Guidelines for the initial evaluation of the adult patient with acute musculoskeletal symptoms. Ibid 1996;39:1-8.
27. American College of Rheumatology ad hoc committee on clinical guidelines. Guidelines for the monitoring drug therapy in rheumatoid arthritis. Ibid 1996;39:723-31.
28. A prescription for improvement. Towards more rational prescribing in general practice. Audit commission, health and personal social services report no 1, London: HMSO, 1994.
29. Eccles M, Freemantle N, Mason J for the north of England non-steroidal anti-inflammatory drug guideline development group. North of England evidence based guideline development project: summary guideline for non-steroidal anti-inflammatory drugs versus basic analgesia in treating the pain of degenerative arthritis. BMJ 1998;317:526-30.
30. Blower AL. Consideration for nonsteroidal anti-inflammatory drug therapy: safety. Scand J Rheumatol 1996; 25 (suppl 105): 13-26.
31. Hawkey CJ. Progress in prophylaxis against nonsteroidal anti-inflammatory drug-associated ulcers and erosions. Am J Med 1998; 104 (3A):67-74.
32. Kaplan-Machlis B, Klostermeyer BS. The cyclooxygenase-2 inhibitors: safety and effectiveness. Ann Pharmacother 1999;33:979-88.
33. Donnelly MT, Hawkey CJ. Review article: COX-II inhibitors - a new generation of safer NSAIDs? Aliment Pharmacol Ther 1997;11:227-36.
34. Langman MJ, Jensen DM, Watson DJ, Harper SE, Zhao PL, Quan H et al. Adverse upper gastrointestinal effects of rofecoxib compared with NSAIDs. JAMA 1999;282:1929-33.
35. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A meta-analysis of published clinical trials. Arthritis Rheum 1992;35:1117-25.
36. Emery P. Therapeutic approaches for early rheumatoid arthritis. How early? How aggressive? Br J Rheumatol 1995;34 (suppl 2):87-90.
37. Ward MM, Fries JF. Trends in antirheumatic medication use among patients with rheumatoid arthritis, 1981-1996. J Rheumatol 1998;25:408-16.
38. Horsfall MWJ, Shaw JP, Highton J, Cranch PJ. Changing patterns in the use of slow acting antirheumatic drugs for the treatment of rheumatoid arthritis. New Zealand Med J 1998;111:200-3.
39. Fries JF. Reevaluating the therapeutic approach to rheumatoid arthritis: “Sawtooth” strategy. J Rheumatol 1990;17 (supplement 22):12-5.
40. Dahl SL. Advances and issues in the pharmacotherapy of rheumatoid arthritis. J Clin Pharm Ther 1995;20:131-47.
41. O’Dell JR, Paulsen G, Haire CE, Blakely K, Palmer W, Wees S et al. Treatment of early seropositive rheumatoid arthritis with minocycline. Arthritis Rheum 1999;42:1691-5.
42. Choy EHS, Scott DL. Drug treatment of rheumatic diseases in the 1990s. Drugs 1997;53:337-48.
43. Weinblatt ME, Kremer JM, Coblyn JS, Maier AL, Helfgott SM, Morrell M et al. Pharmacokinetics, safety, and efficacy of combination treatment with methotrexate and leflunomide in patients with active rheumatoid arthritis. Arthritis Rheum 1999;42:1322-8.
44. Smolen JS, Kalden JR, Scott DL, Rozman B, Kvien TK, Larsen A et al and European Leflunomide Study Group. Efficacy and safety of leflunomide compared with placebo and sulphasalazine in active rheumatoid arthritis: a double-blind, randomised, multicentre trial. Lancet 1999;353:259-66.
45. Breedveld FC. Future treatment. Bailliere’s Clinical Rheumatology 1997;11:83-96.
46. Wood J. Rheumatoid arthritis: management with DMARDs. Pharm J 1999;263:162-7.
47. O’Dell JR. Anticytokine therapy - a new era in the treatment of rheumatoid arthritis? New Engl J Med 1999;340:310-2.
48. Jarvis B, Faulds D. Etanercept a review of its use in rheumatoid arthritis. Drugs 1999;57:945-66.
49. Tannenbaum H, et al. An evidence based approach to prescribing NSAIDs in musculoskeletal disease: a Canadian consensus. Can Med Assoc J 1996;155:77-88.
50. Brooks PM, Day RO. Nonsteroidal anti-inflammatory drugs - differences and similarities. New Engl J Med 1991;324:1716-25.
51. Fries JF, Williams CA, Bloch DA. The relative toxicity of nonsteroidal anti-inflammatory drugs. Arthritis Rheum 1991;34:1353-60.
52. Langman MJS, Weil J, Wainwright P, Lawson DH, Rawlins MD, Logan RFA et al. Risk of bleeding peptic ulcer associated with individual non-steroidal anti-inflammatory drugs. Lancet 1994;343:1075-8.
53. Lanas A, Hirschowitz BI. Toxicity of NSAIDs in the stomach and duodenum. Eur J Gastroenterol Hepatol 1999;11:375-81.
54. Henry D, Lim LL, Rodriguez LAG, Gutthann SP, Carson JL, Griffin M et al. Variability in risk of gastrointestinal complications with individual non-steroidal anti-inflammatory drugs: results of a colloborative meta-analysis. BMJ 1996;312:1563-6.
55. Boers M, Verhoeven AC, Markusse HM, Van de Laar MAFJ, Westhovens R, Van Denderen JC et al. Randomised comparison of combined step-down prednisolone, methotrexate and sulphasalazine with sulphasalazine alone in early rheumatoid arthritis. Lancet 1997;350:309-18.
56. Box SA, Pullar T. Sulphasalazine in the treatment of rheumatoid arthritis. Br J Rheumatol 1997;36:382-6.
57. Felson DT, Anderson JJ, Meenan RF. The comparative efficacy and toxicity of second-line drugs in rheumatoid arthritis. Two meta-analysis. Arthritis Rheum 1990;33:1449-61.
58. Cash JM, Klippel JH. Second-line drug therapy for rheumatoid arthritis. New Engl J Med 1994;330:1368-75.
59. Verhoeven AC, Boers M, Tugwell P. Combination therapy in rheumatoid arthritis: updated systematic review. Br J Rheumatol 1998;37:612-9.
60. Rynes RI. Antimalarial drugs in the treatment of rheumatological diseases. Ibid 1997;36:799-805.
61. Tugwell P, Pincus T, Yocum D, Stein M, Gluck O, Kraag G et al. Combination therapy with cyclosporine and methotrexate in severe rheumatoid arthritis. New Engl J Med 1995;333:137-41.
62. Furst DE. The rationale use of methotrexate in rheumatoid arthritis and other rheumatic diseases. Br J Rheumatol 1997;36:1196-204.
63. O’Dell JR, Haire CE, Erikson N, Drymalski W, Palmer W, Eckhoff PJ et al. Treatment of rheumatoid arthritis with methotrexate alone, sulfasalazine and hydroxychloroquine, or a combination of all three medications. New Engl J Med 1996;334:1287-91.
64. Munro R, Capell HA. Penicillamine. Br J Rheumatol 1997;36:104-9.
65. Laan RFJM, Jansen TLTA, van Riel PLCM. Glucocorticosteroids in the management of rheumatoid arthritis. J Rheumatol 1999;38:6-12.
66. Kirwan JR. The effect of glucocorticoids on joint destruction in rheumatoid arthritis. New Engl J Med 1995;333:142-6.
67. Hickling P, Jacoby RK, Kirwan JR and Arthritis and Rheumatism Council Low Dose Glucocorticoid Study Group. Joint destruction after glucocorticoids are withdrawn in early rheumatoid arthritis. Br J Rheumatol 1998;37:930-6.
68. Gotzsche PC, Johansen KH. Meta-analysis of short term low dose prednisolone versus placebo and non-steroidal anti-inflammatory drugs in rheumatoid arthritis. BMJ 1998;316:811-8.
69. Spector TD. Epidemiology of rheumatic diseases. In: Snaith ML, editor. ABC of Rheumatology. London: BMJ Publishing Group, 1995.
70. Wolfe F, Mitchell DM, Sibley JT, Fries JF, Bloch DA, Williams CA et al. The mortality of rheumatoid arthritis. Arthritis Rheum 1994;37:481-94.
71. Symmons DPM, Jones MA, Scott DL, Prior P. Longterm mortality outcome in patients with rheumatoid arthritis: early presenters continue to do well. J Rheumatol 1998;25:1072-77.
72. Cronan TA, Kaplan RM, Kozin F. Factors affecting unprescribed remedy use among people with self-reported arthritis. Arthritis Care Res 1993;6:149-55.
73. Emery P. Consideration for nonsteroidal anti-inflammatory drug therapy: benefits. Scand J Rheumatol 1996;25(suppl 105):5-12.
74. Lorig KR, Mazonson PD, Holman HR. Evidence suggesting that health education for self-management in patients with chronic arthritis has sustained benefits while reducing health care cost. Arthritis Rheum 1993;36:439-46.
75. Cabuslay ES, Ward MM, Lorig KR. Patient education interventions in osteoarthritis and rheumatoid arthritis: a meta-analytic comparison with nonsteroidal anti-inflammatory drug treatment. Arthritis Care Res 1996;9:292-301.
76. Mazzuca SA, Brandt KD, Katz BP, Chambers M, Byrd D, Hanna M. Effects of self-care education on the health status of inner-city patients with osteoarthritis of the knee. Arthritis Rheum 1997;40:1466-74.
77. Weinberger M, Tierney WM, Booher P, Katz BP. Can the provision of information to patients with osteoarthritis improve functional status? Ibid 1989;32:1577-83.
78. Van Baar ME, Assendelft WJJ, Dekker J, Oostendorp RAB, Bijlsma JWJ. Effectiveness of exercise therapy in patients with osteoarthritis of the hip or knee. Ibid 1999; 42:1361-69.
79. Meenan RF, Gertman PM, Mason JH. Measuring health status in arthritis. The Arthritis Impact Measurement Scales. Ibid 1980;23:146-52.
80. Spilker B. Quality of life and pharmacoeconomics in clinical trials. Second edition. Philadelphia: Lippincott-Raven, 1996;1029.
81. Felson DT, Chaisson CE. Understanding the relationship between body weight and osteoarthritis. Bailliere’s Clinical Rheumatology 1997;11:671-81.
82. Felson D, Zhang Y. An update on the epidemiology of knee and hip osteoarthritis with a view to prevention. Arthritis Rheum 1996;41:1343-55.