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Published: May 1999

Disease-modifying Anti-rheumatic Drugs (DMARDs) for Rheumatoid Arthritis: Benefits and Risks

Prescriber Update 18: 4-12
May 1999

Dr Andrew Harrison, Rheumatologist, Senior Lecturer in Medicine, Wellington School of Medicine, New Zealand

Rheumatologists and general practitioners have a shared responsibility for the care of rheumatoid arthritis (RA) patients taking disease-modifying anti-rheumatic drugs (DMARDs). Assessment by a rheumatologist is recommended within 3 months of the patient developing symptoms of RA. As DMARDs can be toxic, a risk/benefit analysis should be undertaken prior to commencing therapy. A meta-analysis has shown methotrexate and sulphasalazine have relatively high efficacy and low toxicity, anti-malarials have moderate efficacy and low toxicity, and intramuscular gold has moderate efficacy but relatively high toxicity. Current practice favours the use of methotrexate, sulphasalazine and hydroxychloroquine (given as monotherapy or in combination) over other agents such as d-penicillamine, azathioprine and gold salts.
Methotrexate: Adverse effects - nausea & stomatitis (common), bone marrow suppression, liver disease & interstitial pneumonitis (rarer but potentially serious). Monitoring – baseline CXR, CBC, LFTs and serum creatinine, repeat CBC, LFTs and serum creatinine every 4-8 weeks.
Sulphasalazine: Adverse effects - nausea, skin rash, Stevens-Johnson syndrome, neutropenia (2%) & aplastic anaemia. Monitoring - baseline CBC & LFTs. Repeat CBC every 2-4 weeks for first three months, then every three months.
Hydroxychloroquine: Adverse effects - nausea, rash, bone marrow suppression, agranulocytosis, aplastic anaemia, and corneal and retinal damage at higher doses. Monitoring - baseline serum creatine. Routine review by an opthalmologist every 6-12 months in those taking > 6.5mg/kg/day and/or the elderly, those with renal impairment, or duration of treatment greater than 10 years.

Predicting RA outcome important for optimal management
Benefits include inflammation suppression & minimising loss of function
Individual drugs: benefits and risks
    Sulphasalazine
    Methotrexate
    Anti-malarials
    Gold compounds
    Azathioprine
    D-Penicillamine
    Cyclosporin A

Relative efficacy and toxicity of DMARDs
Treatment strategies and combination therapy
Conclusion
References

This article reviews the benefits and risks of disease-modifying anti-rheumatic drugs (DMARDs) taken for rheumatoid arthritis (RA). While rheumatologists initiate DMARD therapy, general practitioners need to be aware of potential adverse reactions and to share the responsibility of monitoring patients.

Predicting RA outcome important for optimal management

RA is a heterogeneous disease which may run a benign course with little or no long term loss of function, or at the other extreme, may lead to serious morbidity with rapid loss of function. RA causes an increase in mortality. Overall, the survival from onset of RA is similar to coronary artery disease and Hodgkin’s lymphoma.1 Since the tendency for joint destruction is greatest in the early stages of disease2, it is desirable to commence treatment as early as possible. On the other hand, the unnecessary exposure of patients with the likelihood of a more benign outcome to the risks of DMARD therapy should, if possible, be avoided.

In order to optimise the intensity of treatment based on the individual’s likely outcome, prescribing decisions should take into account an assessment of predictors of outcome.2 Numerous predictors of adverse outcome in RA have been identified, including high markers of disease activity, seropositivity for rheumatoid factor, the presence of an epitope shared by HLA DR1 and DR4, poor functional status and radiographic abnormalities.3 The individual’s risk profile for adverse outcome is also valuable in deciding who receives low toxicity therapy with the aim of symptomatic relief, and who is treated aggressively with a potentially toxic combination regimen of one or more DMARDs, corticosteroids and NSAIDs. This decision is best left to the rheumatologist. As the potential for damage is greatest in the early stages of the disease, it is recommended that all patients with suspected RA be referred to a rheumatologist for assessment within three months of first developing symptoms.

Benefits include inflammation suppression & minimising loss of function

The value of a DMARD is measured by its ability to suppress inflammatory activity over a long time-frame thus improving day to day function, and on the ability to prevent, lessen or delay destructive changes which may result in permanent loss of function. A DMARD may also benefit the patient by reducing the need for other medications, e.g. corticosteroids and NSAIDs, which may have a greater potential for toxicity than the DMARD.4

In clinical trials of DMARDs in RA, outcome is usually measured by clinical (e.g. number of tender or swollen joints), laboratory (e.g. ESR, CRP) and radiographic (e.g. number of erosions) parameters.5 For various reasons, it is usual to observe that approximately 30% of subjects in the placebo arm of such trials show an improvement in clinical parameters.6 The value of a DMARD cannot, therefore, be adequately assessed with trials which do not have placebo or alternative treatment controls.

Individual drugs: benefits and risks

Unless otherwise indicated, the monitoring recommendations given in this section are those of the American College of Rheumatology Clinical Guidelines Committee.7

Sulphasalazine

Placebo-controlled trials have demonstrated that sulphasalazine is an efficacious DMARD in the treatment of RA. In addition to suppressing markers of inflammatory activity, it has been shown to slow the progression of erosive changes on X-ray.

Minor side-effects include nausea, which is often transient during the first few days of treatment. This can be minimised by introducing the drug in low doses and increasing to the usual maintenance dose of two to three grams daily in a twice daily regimen (Salazopyrin-EN). Skin rash, typically maculo-papular and pruritic, occurs in 4-5% of patients. Stevens-Johnson syndrome has been reported. Reversible oligospermia may result in reduced fertility. More serious side effects, including potentially fatal neutropenia or aplastic anaemia, are rare. The incidence of sulphasalazine-induced neutropenia has been estimated to be as high as 2% in rheumatoid arthritis patients but most cases are reversible on withdrawal of the drug.8 The Centre for Adverse Reactions Monitoring has 3 reports of leukopenia with sulphasalazine (one fatal) and the WHO database has approximately 700 reports of blood dyscrasias with this drug.

Monitoring recommendations: Baseline CBC and LFTs. CBC every 2 to 4 weeks for the first three months, then every three months.

Methotrexate

Several randomised placebo-controlled trials have shown that methotrexate has a significant beneficial effect on disease activity in RA. Methotrexate has also been shown to slow the rate of progression of erosions and joint space narrowing in radiographic studies.9

Many of the side effects are due to the inhibition of folate metabolism (e.g., nausea, stomatitis, bone marrow suppression). As the beneficial effects of methotrexate in RA are largely unrelated to folate inhibition, the administration of a single weekly dose of folic acid, 5 to 10mg, can result in a significant reduction in toxicity without loss of efficacy.10

Methotrexate outperformed other DMARDs in a meta-analysis of studies comparing efficacy with toxicity11, and more patients remained on methotrexate after five years than on other DMARDs.12 However, enthusiasm for the use of methotrexate is limited by two potentially serious adverse reactions which may not resolve with cessation of treatment:

Liver disease : Methotrexate-induced liver disease is characterised by fibrotic changes which may progress to cirrhosis. Initial studies overestimated the incidence and seriousness of methotrexate induced liver disease. The incidence of real toxicity is probably in the order of 1 in 1000 RA patients over a five year treatment period.13 While routine liver biopsy is not recommended, patients who have persistent elevation of AST may require a liver biopsy to ensure that continuation of treatment is not harmful.13

Interstitial pneumonitis : This is an uncommon but potentially fatal complication of methotrexate treatment. The risk factors for methotrexate lung are not well understood, but may include pre-existing lung disease or an abnormal chest radiograph. Patients taking methotrexate who present with dry cough, shortness of breath on exertion, malaise, fever and diffuse crackles on auscultation should discontinue taking methotrexate until evaluated further. The chest X-ray may be normal. The differential diagnosis includes Pneumocystis carinii pneumonia, and bronchoscopy may be required to exclude this. Corticosteroids are frequently given for methotrexate-induced interstitial pneumonitis, although it remains to be proven whether this is of value.10 In the event of a patient developing symptoms suggestive of methotrexate pneumonitis, the patient or GP should contact the rheumatologist who will arrange the appropriate investigations.

Monitoring recommendations: Baseline CBC, LFTs, serum creatinine and chest x-ray. CBC, LFTs and serum creatinine every 4 to 8 weeks.

Note: Methotrexate is given as a weekly dose in RA. There have been overseas reports of patients who have died following the inadvertant administration of methotrexate as a daily dose.

Anti-malarials

Chloroquine and hydroxychloroquine have both been used for the treatment of RA, although controlled studies of anti-malarials in RA have almost all involved hydroxychloroquine, and toxicity is thought to be greater with chloroquine. Several randomised controlled trials have shown that hydroxychloroquine is superior to placebo with regard to disease activity in the treatment of RA.14 Hydroxychloroquine and sulphasalazine were found to have similar effects on disease activity, although sulphasalazine was significantly superior to hydroxychloroquine in preventing joint damage measured radiographically.15

Minor side effects include nausea and rash. Bone marrow suppression is rare, but potentially fatal agranulocytosis or aplastic anaemia can occur. Monitoring the blood count is not generally considered necessary. Much attention has been given to the corneal and retinal damage that may occur following treatment with anti-malarials. A recent study has shown that RA patients taking a daily dose less than 6.5 mg/kg of hydroxychloroquine were not at increased risk of ocular complications. The authors concluded that regular ophthalmological monitoring was probably not justified.16

Monitoring recommendations: Baseline serum creatinine. Routine review by an ophthalmologist every 6 to 12 months in those taking >6.5 mg/kg/day hydroxychloroquine, and/or those with renal impairment or in the elderly or duration of treatment greater than ten years.16

Gold compounds

Although auranofin has been shown to be superior to placebo in the treatment of RA, it is less efficacious than injectable gold. Auranofin has a low incidence of serious toxicity, but the overall frequency of side effects (e.g. rash, diarrhoea) is higher with auranofin than any other DMARD. Its usefulness is, therefore, limited by low efficacy and poor tolerability.

Sodium aurothiomalate (Myocrisin) is an injectable gold salt which has been shown to have a similar efficacy to sulphasalazine, d-penicillamine and methotrexate, but with considerably greater toxicity than these drugs.11 There is conflicting data on the question of whether injectable gold prevents progression of radiographic erosions. Side effects may include rash, stomatitis, thrombocytopenia, proteinuria and nephrotic syndrome. Interstitial pneumonitis (gold lung) is a rare but potentially fatal complication of gold treatment.17

Monitoring recommendations: Baseline CBC, creatinine, urine dipstick for protein. CBC and urine dipstick every 1 to 2 weeks for the first 20 weeks then with each injection.

Azathioprine

Azathioprine has been proven to be beneficial in the treatment of RA but does not influence the progression of radiographic changes.17 Its efficacy has been found to be comparable to hydroxychloroquine, d-penicillamine and cyclosporin. In Felson’s meta-analysis, azathioprine had similar toxicity to sulphasalazine and methotrexate, but was less efficacious. Its efficacy was similar to that of anti-malarials, but it had greater toxicity.11

Transient side effects may include nausea, stomatitis and bone marrow suppression. Hepatitis and pancreatitis are uncommon. There has been concern about a potential increased risk of lymphoma. While transplant recipients are at increased risk of lymphoma, there is conflicting evidence for an increased risk of lymphoproliferative malignancy in RA patients.

Monitoring recommendations: Baseline CBC, serum creatinine, LFTs. CBC every 1 to 3 months.

D-Penicillamine

In doses greater than 500 mg/day, d-penicillamine has been shown to beneficial in the treatment of RA. It has been shown to have efficacy similar to methotrexate, injectable gold, azathioprine and hydroxychloroquine.17 There is no evidence that d-penicillamine slows the progression of radiographic damage. Adverse effects may include rash, alopecia, altered taste, stomatitis, and gastrointestinal upset. Leukopenia, thrombocytopenia and aplastic anaemia can occur, as can haematuria and the nephrotic syndrome which require monitoring. Rarely, autoimmune syndromes, including SLE, polymyositis, Goodpasture’s syndrome and myasthenia gravis may develop.17

Monitoring recommendations: Baseline CBC, creatinine, urine dipstick for protein. CBC and urine dipstick for protein every 2 weeks until dosage stable, then every 1 to 3 months.

Cyclosporin A

In placebo-controlled trials, cyclosporin has been shown to improve clinical manifestations of RA, and to reduce the progression of radiographic erosions.18 In New Zealand, the microemulsion formulation Neoral is approved and funded for use in severe RA provided certain criteria are met (see the Pharmaceutical Schedule).

The most important adverse effect is nephrotoxicity which must be monitored with blood pressure recordings and serum creatinine measurements. This may be acute, mediated by renal vasoconstriction, or chronic, resulting in permanent damage to the kidneys. The risk of gingival hyperplasia may be lessened with meticulous oral hygiene. Other side effects include hirsutism, tremor, paraesthesia and headache.17

Monitoring recommendations: Baseline CBC, creatinine (on two different occasions), uric acid, LFTs and blood pressure (on two different occasions). Serum creatinine every 2 weeks until dosage stable, then monthly. Periodic CBC, electrolytes and LFTs.

Relative efficacy and toxicity of DMARDs

Life table analysis studies which compare the drop-out rates for the use of DMARDs reflect the efficacy of a drug as perceived by patient and physician, as well as the ability of the patient to tolerate the side effects of that drug. In these studies, the number of patients who continued to benefit from and tolerate methotrexate after five years was approximately two-fold greater than for other DMARDs.19,20 In a meta-analysis based on existing clinical trials which compared efficacy with toxicity, methotrexate and sulphasalazine were found to have relatively high efficacy and low toxicity. Antimalarials had moderate efficacy and low toxicity, but intramuscular gold had moderate efficacy but relatively high toxicity.11 An index of the relative toxicity of DMARDs has been derived from a study of 2,747 RA patients. Hydroxychloroquine was the least toxic with an index of 1.38. Methotrexate had an index of 3.82, and this was lower than several of the NSAIDs studied (e.g. indomethacin 3.99).21 The findings of these studies are in line with current practice which favours the use of methotrexate, sulphasalazine and hydroxychloroquine over other agents such as d-penicillamine, azathioprine and gold salts.

Treatment strategies and combination therapy

Although reports of the treatment of RA with a combination of DMARDs date back nearly 40 years, it is only recently that the practice has become widespread. The recognition of the morbidity and mortality associated with RA, and the ability to predict prognosis has lead to a more aggressive approach to treatment in high risk individuals.

The step down approach has been proposed for the treatment of patients with recent onset RA who have clinical features predictive of an adverse prognosis. This may involve a combination of two or more DMARDs, corticosteroids and NSAIDs given at the onset and then withdrawn in a stepwise fashion once remission is achieved. Others favour the sequential addition of DMARDs to minimise toxicity.22 Numerous DMARD combinations have been evaluated but those involving any two or all three of methotrexate, sulphasalazine and hydroxychloroquine have been particularly effective.23 Surprisingly, the combination of methotrexate and sulphasalazine does not appear to be more toxic than either drug used as monotherapy.22

Conclusion

A cure for RA is yet to be discovered. Although vast resources have been expended in the search for an immunological key to switch off the rheumatoid process, the most significant advances in the treatment of RA in recent times have come from gaining better understanding and skill in the safe use of existing DMARDs. If prescribed appropriately and combined with adequate patient education and monitoring, DMARDs are safe and effective tools in the treatment of rheumatoid arthritis.

Correspondence to Dr Andrew Harrison, Senior Lecturer in Medicine (Rheumatology), Wellington School of Medicine, Wellington. Telephone (04) 566 6999, fax 04 479 8014, e-mail aharrison@wnmeds.ac.nz

References
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