Treatment with disease modifying anti-rheumatic drugs is now recommended at an early stage in the development of rheumatoid arthritis. In this, the last article in our series on musculoskeletal disorders, the use of these drugs is discussed
Although symptomatic relief from the pain and inflammation associated with rheumatoid arthritis can be obtained with non-steroidal anti-inflammatory drugs (NSAIDs), these agents do not retard disease progression.
Nevertheless, until relatively recently, management of rheumatoid arthritis involved a pyramidal approach where initial treatment was with NSAIDs. After several months or years, and radiological evidence of joint damage, a "second-line" agent or disease-modifying anti-rheumatic drug (DMARD), such as gold, hydroxychloroquine or penicillamine, was added. If the selected DMARD failed, another was used until all the "second-line" agents had been tried. Finally, "third line" agents, such as corticosteroids, or cytotoxics, such as cyclophosphamide, were used.1
Over the past few years, as our knowledge of rheumatoid arthritis and its treatment has improved, this approach has effectively been reversed. Currently the early use of one or, in some patients, a combination of DMARDs is recommended before radiologically visible cartilage or bone damage develops. The aim of this apparently aggressive approach is to limit inflammation and prevent long-term joint damage and subsequent disability. In this article, the rationale for this new therapeutic approach is described together with guidance on the selection, use and monitoring of DMARDs. In addition, new developments and possible future directions in rheumatoid arthritis will be discussed.
In patients in whom a firm diagnosis of rheumatoid arthritis has been made and reliable predictors of poor outcome are available (such as a positive rheumatoid factor, high disability scores and early involvement of large joints), immediate treatment with DMARDs is now recommended by rheumatologists in the UK. Similarly, guidelines from the American College of Rheumatology recommend that treatment with DMARDs should not be delayed beyond three months for any patient with an established diagnosis who, in spite of adequate treatment with NSAIDs, has ongoing signs of active disease.2
The development of this new therapeutic approach is based on three factors. The first is that rheumatoid arthritis is an aggressive disease. The results of research show that inflammation, the number of swollen joints and the rate of appearance of radiological erosions are maximal at an early stage.3-5 Indeed, approximately 90 per cent of patients with persistently active synovitis have radiological evidence of joint damage (erosions) within the first two years of onset of their disease, especially when inflammatory markers are persistently raised.6 It is during this "active" phase that inflammation is most amenable to treatment. Therefore, if given early, DMARDs can stabilise joint function at a level which is near to normal, rather than preserving the joint in a state of disability.
Secondly, increased awareness of the toxicity of NSAIDs has led to the conclusion that the relative toxicities of DMARDs and NSAIDs is not dissimilar. In addition, if given early, DMARDs tend to be better tolerated, especially if the patient's general health is good. Finally, newer DMARDs, such as methotrexate and sulphasalazine, have been introduced over the past few years. These agents have a number of advantages over previously available DMARDs as they are less toxic, more effective and require less monitoring. Over 90 per cent of patients are now given DMARDs within three years of the onset of their disease.1
DMARDs are the most important agents used to treat rheumatoid arthritis as they suppress symptoms, delay joint damage and potentially delay deformity. However, since the precise mechanism of action of most DMARDs is uncertain, no consensus exists on the order in which they should be used. Choice tends to be empirical, based on a balance between toxicity, efficacy and to a certain extent on the prescriber's preference.
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Sulphasalazine Sulphasalazine was specifically developed in the 1940s as an anti-rheumatic drug but its actual mechanism of action is unknown. Its onset of action is between six and 12 weeks.7 It comprises anti-inflammatory (5-aminosalicylic acid) and antibacterial (sulphapyridine) moieties with the antibacterial portion probably responsible for efficacy in rheumatoid arthritis.8 Sulphasalazine appears to be comparable to parenteral gold in efficacy but is much better tolerated.
However, one quarter of patients still develop adverse reactions (ADRs) severe enough to discontinue therapy.9 Gastrointestinal intolerance is probably the most common side effect. It may be minimised by starting therapy at a dose of 500mg daily. This is increased by 500mg at weekly intervals to a maintenance dose of between 2g and 3g daily in divided doses.
The most serious side effects include haematological abnormalities (leucopenia and thrombocytopenia). They are relatively rare, usually occur during the first three to six months, and are reversible on cessation of treatment. Hepatic reactions, which include a transient rise in transaminase levels, can normally be managed by dosage reduction.
Sulphasalazine also induces a variable degree of reversible male infertility.
Over the past 10 years, sulphasalazine has emerged as the first choice and most widely used of the DMARDs in the UK as a result of reasonable efficacy and low rates of serious adverse reactions.
However, its use first-line has probably been superseded by methotrexate in many rheumatology units.
Methotrexate Methotrexate is probably the most effective DMARD currently available and for this reason, and the convenience of its once weekly dosing regimen, its use is increasing rapidly in the UK. Its onset of action (about one month) is shorter than most other DMARDs which may take up to six months to have an effect.7-10 It is often used after failure or intolerance of sulphasalazine and is chosen by some consultants as their first-line DMARD, especially if disease is severe, progressing quickly and/or the patient cannot tolerate sulphasalazine. Methotrexate is well tolerated, especially when compared to other DMARDs of a similar potency.
Although methotrexate acts as an inhibitor of dihydrofolate reductase (DHFR) when used in cancer chemotherapy, this is probably not the way it acts in rheumatoid arthritis. Recent studies have demonstrated an anti-inflammatory effect that is mediated through adenosine and appears to decrease the secretion of pro-inflammatory cytokines, such as tumour necrosis factor (TNF), while increasing the secretion of the inhibitory cytokine interleukin-10 (IL-10).11
Methotrexate is started at a dose of 7.5mg orally once weekly and this is increased slowly to a maximum of 20mg once weekly, subject to regular monitoring and response. In patients who fail to respond to oral therapy, administration by the intramuscular route may be a useful alternative.
Nausea and stomatitis are relatively common with methotrexate and appear to be dose related but may be successfully managed with folic acid supplementation without the need for dosage reduction. There appears to be no clear guidance on the optimal dosage regimen of folic acid. Some rheumatologists recommend a dose of 5mg daily, some use 5mg once weekly (72 hours after the methotrexate) and others advocate 5mg daily for six days each week, with the dose withheld on the day methotrexate is taken.
Haematological toxicity with methotrexate occurs but is rarely a problem at the doses used for rheumatoid arthritis. Of greater concern are hepatic and pulmonary ADRs. Elevation of liver transaminases is common but progression to hepatic fibrosis or cirrhosis is rare in the absence of previously abnormal liver function tests. The risk of hepatic toxicity is also greater if there is an excess alcohol intake. Pulmonary complications, in the form of pneumonitis (inflammation of the lung), are rare idiosyncratic reactions and are potentially lethal. The classical presentation is with rapid onset dyspnoea (shortness of breath) which may result in death after a few days.1 Therefore, patients should be advised to stop methotrexate if they experience dyspnoea or cough and to seek immediate medical attention.
Methotrexate is also teratogenic to ova and sperm. For this reason, it is recommended that reliable contraception is taken during therapy and that conception is avoided for at least six months after stopping methotrexate.
While co-prescription of NSAIDs has been shown to increase the toxicity of methotrexate, it is usually necessary (and is safe) to continue NSAIDs in patients with rheumatoid arthritis provided that careful monitoring is undertaken when methotrexate or NSAIDs are initiated or when the dosage of methotrexate is increased.7
Cyclosporin Cyclosporin is the most recently licensed of the DMARDs and its use is increasing. It is a fungal peptide which impairs the function of B and T lymphocytes by suppressing the synthesis and release of interleukin-1 and interleukin-2 (IL-1 and IL-2).12 It appears to have an efficacy comparable to other DMARDs but it is less well tolerated because of hypertension and nephrotoxicity which are common and dose related.9 Hypertension can be controlled conventionally but if it remains a problem then the cyclosporin should be stopped. Renal impairment is usually reversed by a decrease in dose.
Cyclosporin is usually started at a dose of 2.5mg/kg daily in two divided doses. This is increased gradually after six weeks to a maximum of 4mg/kg daily, according to tolerance and response. A full clinical response is not expected until 12 weeks after starting therapy.
Cyclosporin was originally used in patients with severe disease who failed on other treatments or were unsuitable for other DMARDs. It is now used much earlier as a second-line DMARD by some rheumatologists and by others as a third-line drug, after sulphasalazine and methotrexate have been tried, or where the latter cannot be used. Cyclosporin is particularly valuable when used together with methotrexate in patients with very active early disease.10
Chloroquine and hydroxychloroquine The antimalarials chloroquine and hydroxychloroquine may exert a beneficial effect in rheumatoid arthritis by suppression of lysosomal enzymes and inhibition of interleukin-1 (IL-1) release.9 They have a weaker DMARD effect than either sulphasalazine or methotrexate but are generally well tolerated, with few patients discontinuing therapy because of adverse effects. Clinical response usually occurs after six to 12 weeks.10
Hydroxychloroquine is started at a dose of 400mg daily in two divided doses. The maintenance dose is usually between 200mg and 400mg daily. Although there is concern over irreversible retinopathy, it occurs rarely provided that the daily dose of hydroxychloroquine does not exceed 6.5mg/kg (or 400mg daily), the lifetime dose does not exceed 200g and ophthalmological screening is undertaken.7
In younger patients, ophthalmological screening involves initial screening prior to commencing therapy to establish baseline (Table 1). If baseline is normal, patients are told to report any changes in vision and no further monitoring is generally undertaken. In elderly patients, because age-related macular degeneration may mimic antimalarial-induced retinopathy, twice yearly assessments have been recommended by some rheumatologists.7 Advice is provided in the British National Formulary by the College of Ophthalmologists.
Chloroquine is used less frequently than hydroxychloroquine. The recommended dose of chloroquine base is 150mg daily or 2.5mg/kg daily. Gastrointestinal toxicity is the main problem with the antimalarials, although headache and skin rashes are also relatively common. Rarely, blood disorders (such as thrombocytopenia, agranulocytosis and aplastic anaemia) may occur. Ocular toxicity is rare if the dose of chloroquine does not exceed 2.5mg/kg/day of chloroquine base but, as for hydroxychloroquine, ophthalmological screening should be undertaken.
Antimalarials are no longer used commonly. They are usually restricted to patients with mild, non-erosive disease or to those in whom more powerful DMARD therapy is felt to be too risky. They may also be useful when used in combination with other agents but they should be used with caution if a concurrent ophthalmological condition exists which might obscure early retinal toxicity.
Gold Gold may be given by intramuscular injection or by the oral route as auranofin. The metabolism of auranofin is complex and yields several metabolites which vary in concentration in different tissues but no specific site of action has been conclusively identified. Parenteral gold has been demonstrated to affect the function of B and T lymphocytes as well as polymorphonuclear leucocyte function. Compared with parenteral gold, auranofin is less toxic but is probably less efficacious. The time to response with auranofin (between three to six months) is also longer than with parenteral gold, where a response is usually seen after eight to 16 weeks. Diarrhoea is a common problem with auranofin. For these reasons it is seldom used.9
Patients starting parenteral gold are given a test dose of 10mg followed by weekly doses of 50mg until there is definite evidence of remission. Benefit is not expected until 300mg to 500mg has been given. If there is no remission after 1g of gold has been given, the drug should be discontinued. In patients who do respond, the interval between injections is then gradually increased to four weeks. Treatment is continued for up to five years after complete remission. If relapse occurs, dosage may be immediately increased to 50mg weekly; and once control has been regained, the dosage should again be reduced. It is important to avoid complete relapse since second courses of gold are not usually effective.
Toxicity with gold is a problem, affecting a wide range of systems including the skin, kidney, blood, lungs and liver. Eczematous reactions and mouth ulcers are common but normally resolve rapidly on discontinuation. These occur with a similar frequency in patients treated with oral or parenteral gold. Bone marrow dysfunction, resulting in leucopenia and thrombocytopenia, as well as proteinuria, also occur but are less common with auranofin. While these more serious toxicities, as well as stomatitis and rash, limit the number of patients who can tolerate long-term parenteral gold (two years after starting therapy only 20-25 per cent of patients are still on treatment), parenteral gold is still a useful option in patients who cannot tolerate sulphasalazine or methotrexate.1
Penicillamine Penicillamine is a chelator of divalent cations which is structurally similar to cysteine. While it has been shown to impair antigen presentation, to diminish globulin synthesis and to inhibit polymorphonuclear leucocyte myeloperoxidase, its mechanism of action is not certain.10 Penicillamine is started at a dose of 125mg to 250mg daily. After two weeks this is increased by 125mg daily each month until remission is achieved. This usually takes between eight and 16 weeks. The maintenance dose is between 250mg and 1g daily and the maximum daily dosage recommended is 1g daily. If remission is sustained for six months, reduction of the daily dosage by 125mg to 250mg every 12 weeks may be attempted.
Penicillamine was thought to be as efficacious as gold but a recent study in early rheumatoid arthritis found improvements in clinical variables but not in radiographic features.10 In addition, its use is often limited by side effects such as rashes and nausea. Early rashes (occurring in the first few months of treatment) disappear when the drug is stopped and treatment may then be re-introduced at a lower dosage and gradually increased. However, late rashes are more resistant and often necessitate permanent discontinuation of treatment.
Nausea may occur but is not usually a problem provided that penicillamine is taken before food or on retiring and that low initial doses are used and are only gradually increased. Loss of taste may occur about six weeks after treatment is started but taste usually returns six weeks later, irrespective of whether or not treatment is discontinued; mineral supplements are not recommended. Leucopenias and thrombocytopenias are normally reversible but bone marrow aplasia can occur and carries a high mortality. The use of penicillamine has decreased considerably over the past 15 years as the usage of agents such as methotrexate and sulphasalazine, which have comparable potency and better tolerability, has increased.
Azathioprine Azathioprine is an oral purine analogue that inhibits lymphocyte proliferation, presumably by disrupting the incorporation of adenosine and guanine in DNA synthesis. It becomes biologically active after metabolism in the liver to 6-thioinosinic acid and 6-thioguanylic acid. It is renally excreted.10 The drug is usually given at a dose of 1.5 to 2.5mg/kg daily in divided doses and has an efficacy comparable to that of gold and penicillamine but it has greater toxicity.
Nausea, vomiting and diarrhoea are relatively common and bone marrow suppression and liver toxicity are also a problem. The most serious concerns, however, are the potential for development of lymphoproliferative cancers (although the actual risk is unclear) and its potential to cause infertility. Therefore, most rheumatologists prefer to reserve azathioprine for patients with progressive disease which is refractory to other DMARDs of comparable potency or as a steroid-sparing agent.10
Cyclophosphamide Cyclophosphamide interrupts DNA and RNA metabolism, resulting in cell death and decreased numbers of B and T lymphocytes. Although clinical improvements may be dramatic, side effects can be severe. These include bone marrow suppression, increased risk of infection and disruption of gonadal function which may lead to infertility. Therefore, its use is restricted to patients presenting with life-threatening complications of rheumatoid arthritis such as vasculitis.9 Cyclophosphamide is used orally at a dosage of 1 to 1.5mg/kg daily or as a course of pulse therapy (eg, every week for six weeks) by intravenous infusion over 30 to 60 minutes at a dose of 10 to 15mg/kg (usually 500mg, 750mg or 1g) with prophylactic mesna. In patients with renal impairment the dosage should be reduced. The use of mesna with IV therapy helps to reduce the risk of haemorrhagic cystitis which is a recognised side effect caused by acrolein, the active metabolite of cyclophosphamide. The use of cyclophosphamide in rheumatoid arthritis is currently unlicensed.
Table 1: Typical monitoring parameters and schedules for commonly used DMARDs |
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| Drug | Parameter | Schedule |
| Methotrexate | FBC | Baseline, then fortnightly for one month (or until dose stable) then monthly |
| RF | Baseline | |
| LFT | Baseline, then fortnightly for one month (or until dose stable) then monthly | |
| CXR | Baseline | |
| Sulphasalazine | FBC | Baseline, monthly for three months, then every three months |
| RF | Baseline | |
| LFT | Baseline, monthly for three months, then every three months | |
| Cyclosporin | RF | Baseline (average of two), then every two weeks for three months then monthly |
| LFT | Monitor regularly if co-administering NSAID | |
| BP | Baseline, every two weeks for three months, then monthly | |
| U | Baseline, every two weeks for three months, then monthly | |
| Parenteral gold | FBC | Prior to each injection |
| RF | Baseline | |
| U | Prior to each injection | |
| LFT | Baseline | |
| Penicillamine | FBC | Baseline, every one to two weeks for eight weeks, then in the week after any dose increase. Monthly thereafter |
| RF | Baseline | |
| P | Baseline, every one to two weeks for eight weeks, then in the week after any dose increase. Monthly thereafter | |
| Antimalarials | Eye | Baseline, data sheets recommend three to six monthly follow-up |
| Azathioprine | FBC | Baseline, weekly for eight weeks then at least every three months |
| LFT | Baseline, weekly for eight weeks then at least every three months | |
| RF | Baseline | |
| Key: FBC=full blood count (haemoglobin, white cell count including differential, platelets); RF=renal function (serum creatinine, urea, electrolytes); LFT=liver function tests (alkaline phosphatase, g-glutamyltrans ferase, alanine/aspartate aminotransferase); U=urinalysis for blood and protein; BP=blood pressure; CXR=chest X-ray | ||
Corticosteroids produce rapid relief from inflammatory symptoms in rheumatoid arthritis. Their mode of action is not fully understood; however, they selectively inhibit the pro-inflammatory response of cytokines, including interleukin-8 (IL-8) and leucocyte adhesion molecules. Their major role in recent years has been as "bridge therapy" to reduce symptoms and disease activity in the interval between starting DMARDs and the time until onset of their effect.10,13 Steroids may also have a role in disease modification but this remains controversial, as the dosage, duration and the stage of disease where they should be used is still under debate.1
The major limiting factor with steroids is their side effects, which include osteoporosis, peptic ulceration, diabetes mellitus and hypertension, rather than a lack of effect. In addition, once started, it is often difficult to withdraw steroids as the disease may flare when their dosage is reduced.
Intra-articular corticosteroids The role of intra-articular steroids, such as methylprednisolone, triamcinolone acetonide or triamcinolone hexacetonide, in rheumatoid arthritis is clear. They provide effective symptomatic relief by reducing inflammation in patients who have one or few joints affected. Triamcinolone and methylprednisolone tend to be used most commonly in large joints as they remain in situ longer than other agents (about two to three weeks). This is because of their insolubility, which means that they produce a more sustained response.14
However, in practice, selection is based more on the personal preference of the prescriber than on experimental proof. The dosage is dependent on the size of the joint, according to the information provided by each manufacturer. Lignocaine may be mixed with these agents immediately prior to injection to reduce the pain of any acute inflammatory reaction caused by the suspension itself. Patients should be instructed to rest the limb for 24 hours after injection and will usually notice a benefit within 48 hours. Benefit may persist for several months.10
The frequency with which joint injections can be repeated remains controversial but injections repeated at intervals of one to five weeks or more may be given, depending on patient benefit. However, as data have suggested that intra-articular corticosteroids impede cartilage metabolism and accelerate cartilage breakdown, it is generally recommended that injections into a single joint are restricted to four or fewer per year.7,10,14
Intramuscular and intravenous corticosteroids Methylprednisolone is also available for intramuscular or intravenous injection. For very severe disease, especially with extra-articular manifestations, pulses of 1g of intravenous methylprednisolone are sometimes given as a short infusion (over 30 to 60 minutes) every other day for three days. This pulse therapy may be safer than long term oral steroids as the overall dosage is lower and the frequency of injections can be controlled.
Oral corticosteroids Over the past 30 years rheumatologists have tried to avoid the use of oral steroids because of long term side effects, such as osteoporosis. Deflazacort, an oxazoline derivative of prednisolone, was promoted on the basis that it had a lower risk of producing osteoporosis but equal efficacy to prednisolone and methylprednisolone. However, the manufacturer has recently withdrawn this claim at the request of the Medicines Control Agency.
Studies suggest that using low dose oral steroids may reduce the development and progression of radiographic erosions in patients with early stages of rheumatoid arthritis.13,15 In addition, a recent meta-analysis of 10 randomised trials comparing oral steroids with placebo or an NSAID showed that low dose prednisolone (15mg daily or less) had a marked effect over placebo on joint tenderness and grip strength. It had a greater effect than NSAIDs on joint tenderness and pain whereas the difference in grip strength was not significant. The authors felt that the risk of adverse effects during moderate and long-term treatment seemed to be acceptable. They concluded that low dose prednisolone may be used intermittently in patients with rheumatoid arthritis, particularly if the disease cannot be controlled by other means.16 Further work is needed to clarify the use of low dose oral steroids with DMARDs in early rheumatoid arthritis as many rheumatologists currently feel that their use cannot routinely be recommended.
Interest in this area has increased as single agent DMARD therapy often fails to induce remission in a significant number of patients. The selection of appropriate combinations, however, is largely empirical. Numerous combinations have been tried but many have been in small, uncontrolled studies. The better established combinations are: methotrexate and sulphasalazine; methotrexate, sulphasalazine and antimalarials; and methotrexate and cyclosporin.
There have been a number of approaches to the use of combination therapy. In the "step-down" approach, DMARDs are initially given in combination in an attempt to secure rapid suppression of severe, active disease. Treatment is later reduced to a minimum that maintains control (eg, one agent is stopped or two are given at lower doses).
In the "step-up" approach, treatment is started with a single DMARD and a second agent is added if the first fails or ceases to be effective. A slightly different approach is to overlap two treatments when transferring from one DMARD to another. With this approach, any residual affect of the first drug is maintained while the second DMARD begins to work. Over the next few years more information will hopefully become available on effective combinations of DMARDs.17
Although DMARDs modify disease activity they do not abolish it and a true remission that allows withdrawal of therapy is rare. Several measures have been identified which can be used to assess therapeutic response. The American College of Rheumatology has recommended specific criteria for defining improvement.18
Improvement should be demonstrable both in the number of swollen and tender joints and in at least five other measures of disease activity: global assessments by the patient and physician; scores for pain and disability; and serum levels of acute phase reactants (erythrocyte sedimentation rate [ESR] and c-reactive protein [CRP]). While improvement of 20 per cent in clinical endpoints has often been taken to indicate a "significant" response to treatment, improvement of at least 50 per cent on the American College of Rheumatology criteria is a more appropriate goal if complete suppression of disease activity is the aim.17
As outlined earlier, DMARDs do not produce an immediate therapeutic effect but take between four weeks and six months to produce a response, depending on the agent used. In addition, DMARDs do not have analgesic properties and therefore patients still require NSAIDs or other analgesics to ensure adequate pain control.
The details of monitoring DMARDs differs to some extent with each drug because of their different patterns of toxicity. The frequency of monitoring also differs between different rheumatology units and even different rheumatologists. The British Society for Rheumatology19 and the American College of Rheumatology20 have both published recommendations on monitoring for DMARDs. Typical parameters and monitoring schedules for commonly used agents are shown in Table 1. Suggested actions to be taken for patients whose monitoring parameters are outside the recommended limits are provided in Table 2.
Table 2: Suggested action on detection of abnormal monitoring parameters with DMARDs27 |
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| Parameter | Suggested action |
| Full blood count | Discontinue drug and refer for investigation if white cell count <4x109/L, neutrophils <2x109/L or platelets <150x109/L. If macrocytosis occurs with sulphasalazine check B12 and folate |
| Liver function tests | Discontinue drug and refer for investigation if liver transaminases or alkaline phosphatase increase more than twofold |
| Renal function | If serum creatinine remains increased by more than 30 per cent above baseline on more than one occasion, dosage should be reduced. A dosage reduction of 50 per cent is mandatory if the serum creatinine rises by 50 per cent. If dosage reduction is not successful within one month, treatment should be discontinued |
| Proteinuria | If persistent (proteinuria or haematuria on two occasions), test mid-stream urine for infection and undertake 24 hour urinary protein collection. If clinically significant (>300mg/L without other cause) treatment should be discontinued |
Rheumatoid arthritis is a heterogeneous disease with manifestations ranging from mild articular symptoms to life threatening complications. Although there have been substantial changes in practice over the past 10 years, treatment for rheumatoid arthritis is still selected empirically.
In the future, as our understanding of the disease process in rheumatoid arthritis improves, it may be possible to select treatment(s) in relation to the pathogenesis of this disease. In the meantime, patients with a suspected diagnosis of rheumatoid arthritis should be referred promptly to a specialist centre where their diagnosis can be confirmed and appropriate treatment started without delay, based on a careful evaluation of efficacy and potential toxicity in the individual patient. For example, seronegative patients with mild disease and little evidence of inflammation may be treated initially with NSAIDs, with DMARDs being used if there is evidence of persistent disease activity. Patients with persistently active disease, swollen joints and a positive rheumatoid factor tend to be treated from the outset with both a DMARD and an NSAID, and parenteral steroids may also be used to cover the interval between starting the DMARD and its expected onset of action. Finally, patients with very active disease and poor predictive outcomes, such as high inflammatory markers, large joint involvement and strong seropositivity, may be treated with combination therapy from the outset, for example, parenteral pulse methylprednisolone, oral weekly methotrexate, and daily cyclosporin as well as intra-articular steroid injections to all their inflamed large joints. All regimes should be combined with physiotherapy, occupational therapy and education about the disease and its management.
New developments and future directions in therapyNew DMARDS
Biologicals
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Mrs Wood is head of pharmacy at North Manchester General Hospital