|First line (non Biologic) Disease Modifying Drugs for Rheumatoid Arthritis.|
First line Disease Modifying Drugs
(For Biologics click here - The
by drdoc on-line
In general the
prognosis of rheumatoid arthritis was previously felt to be good, but in fact it has now
been shown that rheumatoid arthritis has a significant morbidity and mortality 1,2,3 Accordingly,
the practices of Rheumatologists have changed and we are now suggesting that we use
disease modifying therapy early in disease. These agents are variably known as disease
modifying antirheumatic drugs DMARDs, slow acting anti rheumatic drugs
SAARDs, or simply as second line agents.
Relative toxicity of NSAIDs and DMARD's:
Therefore we now see an inversion of the "pyramid" approach to therapy, so that DMARDs are used early, rather than later in disease therapy (Figure 1) 8,9
Surveys in the USA confirm that DMARDS are being used early in disease and in 1987 showed DMARDS were used in 85% of respondents within the first 6 months of disease 10. By 1997, 99 % of USA Rheumatologists' were reported to use combination therapy 11. DMARDS should be used before development of erosive disease or deformities develop. Therapy must be initiated if the pain and synovitis persists and especially if function is compromised. Most Rheumatologists do not wait for fulfillment of the criteria for classification of RA as published by the American College of rheumatology (ACR).
Table 2: 1988 revised ACR criteria for classification of RA 12
Other factors that are useful in deciding whether to start DMARD therapy include the prediction of more aggressive disease. Some factors have been identified and can be used as factors that assist in deciding to introduce DMARD's: (Table 3)
Table 3: Factors suggesting poor prognosis 13,14,15
Once the disease is diagnosed the agents for disease modifying therapy include:
New agents recently introduced include:
Response to Therapy:
In the past response was considered a 20 percent improvement and it has been proposed that a 50 percent response be used as the criteria for improvement. Therefore O'Dell and co-workers have suggested that all results should be measured against 50 percent response. 16 Remission remains the ultimate goal of therapy.
Table 4: Criteria for remission
Approximately 2/3 of patients will respond to DMARDS, but this is not predictable from an individual perspective. The main problem with the drugs is fall-off in efficacy over time and non-serious or serious adverse effects requiring drug withdrawal. Only 20-30 percent of patients on gold / sulphasalazine / penicillamine are still taking the drug by 24 months, and approximately 50% of methotrexate patients are still on the drug at 24 months. 17,18
The drugs have relative strengths and toxicity 19:
These are summarized in tables 5 and 6.
Table 5: Relative strengths.
Table 6: Relative drop out rates
Table 7: Measurement of response to therapy
Methotrexate is given as an Injectable or oral preparation. It is
used at night and the usual recommended starting dose is 7.5 - 10 mg per week and
increasing dose versus response to 15 mg / week. The drug takes approximately 4-6 weeks
for a response to start.
The side effects include nausea,
diarrhoea, rashes, alopecia,
mouth ulcers and stomatitis.
The use of folic acid with
the drug is used to reduce side effects. In South Africa, common practice is to use 5mg
per day. Use of folic acid does not interfere with drug activity and is given daily.
Pregnancy: Teratogenicity is reported and therefore, males and females on methotrexate should be taken off the drug for 3 months before conception. The drug is also contraindicated in lactation.
Sulphasalazine has been used for many years in the rheumatic diseases and in fact was invented the 1930' s at Karolinska Institute by Prof. Nanna Svartz. It consists of two agents -- a sulfur (sulfapyridine) and a salicylate component, 5 amino salicylic acid. The drug is introduced slowly over the first month to avoid problems of nausea and gastrointestinal irritability - starting 0.5 g daily for one week, then 1 g daily for one week, then 1.5 g daily for one week, and thereafter 2 g per day. Response takes between 1-6 months. The dose can be increased to 3 g if inadequate response. An enteric form is advised to further reduce gastric side effects. A reduction in erosions has been reported with sulphasalazine 25.
Adverse events are reported more in the first three months of use and have a generally low profile with no long term effects reported 21. The drug is generally well tolerated. Dose reductions are usually effective for minor side effects.
Mild side effects include:
Rare severe problems requiring drug withdrawal include:
Monitoring requires baseline blood count and liver function assessment including especially AST, ALT, GGT and Urine analysis. The monitoring must be done monthly for 3 months and then every three - six monthly. Despite low toxicity, only 40-70% of patients are still on the drug at 2 years, and 20 % at 5 years, due to efficacy and side effect related difficulty.
Pregnancy: No teratogenicity is reported from over 2000 reports of pregnancy on the drug, mainly in inflammatory bowel disease patients, but it is generally advised that the drug be discontinued in pregnancy unless considered essential because of severe disease. The drug is considered safe in lactation, with little sulphasalazine in the milk, and sulfapyridine levels 40% of plasma levels22,23,24.
These are Chloroquine salts / Hydroxychloroquine. They are generally seen as milder drugs. The use of Chloroquine is generally for milder disease or in combination therapy and it takes about three to six months to demonstrate efficacy. Double blind studies show efficacy in 60-80 percent of patients. There is no influence on erosion progression compared to sulphasalazine 25. Hydroxychloroquine has on meta-analysis review been shown to be slightly weaker, but less side effect prone than chloroquine 19.
Minor side effects include:
Serious side effects:
The main problems are ophthalmologic. Prolonged therapy has been associated with fundal defects with maculopathy, especially peripheral vision and reduced night vision. Therefore regular ophthalmologic assessment is required on a six monthly to yearly basis. Baseline assessment is required within the first six months. Early examination may reveal dose related corneal deposits, necessitating dose reduction. Retinal changes are a consequence of excessive daily dose and not thought to be from accumulation.
Dose recommendations -
Chloroquine - 4mg / kg. Hydroxychloroquine - 6.0-6.5 mg/kg 24.
Monitoring - regular 6 - 12 monthly eye checks for field-testing.
Little information is available, as fewer than 100 reports exist of pregnancy in rheumatoid arthritis patients on antimalarials. However, amongst these there are no reports of adverse fetal effect, and therefore the advisory, is that the drug should be stopped, unless absolutely necessary 26,27.
4. Arava / Leflunomide
Arava is a drug that works in a similar fashion to methotrexate and is similar in both response, and potential side effect. It inhibits the inflammatory cascade. It has similar precautions, especially against use in pregnancy, or for several months before planning on pregnancy. It also has some problems associated with liver toxicity and requires monitoring. The drug however is effective with response over 3-4 weeks, and has been shown to reduce erosions of the bone and joints. It reduces structural deterioration. This is therefore a major advantage in management of RA. Dose requires a loading dose of 100mg daily for 3 days and then a maintenance of 20mg per day.
Monitoring requires at minimum baseline FBC, AST, ALT, GGT and pregnancy testing as required. The bloods should be repeated at 1 month then two monthly. Overdose or side effect may be treated using cholestyramine.
Main side effects include
5.. Sodium aurothiomalate / auranofin - NOW ESSENTIALLY OBSOLETE
Gold has been shown to improve symptoms and signs of Rheumatoid arthritis, but toxicity is common, especially with injectable form 19,28.
Injectable gold is given in increasing doses over several weeks. Doses are started with a test dose of 25 mg, followed by 50 mg per week to a total of 1g or 6 months therapy. Thereafter a maintenance dose of 50 mg is continued 2 - 4 weekly. Response may take between 3 - 6 months to occur. Monitoring of injectable gold therapy requires blood count and urinalysis weekly prior to each injection for the first month, then 4 weekly.
Main side effects include:
Auranofin is used in mild disease, and has a high incidence of side effects including diarrhea nausea and skin rashes. The more serious side effects on the marrow and kidney are uncommon.
In the case of a rash - discontinue the drug, and allow the rash to settle. However rechallenge with the drug is often not associated with recurrence of the rash.
Pregnancy: There is little available data, with fewer than 100 cases of pregnancies on gold therapy. However there are no reported cases of teratogenicity. It is considered advisable to start the gold injections on the day of menses, to minimize risk of pregnancies on the drug 26. The drug must be stopped if pregnant.
6. D-Penicillamine.- NOW ESSENTIALLY OBSOLETE
D-Penicillamine is also shown in trials to be effective in rheumatoid arthritis 19,28,29. Response takes 3-6 months to see. Approximately 60 percent respond, but there is no effect on radiological progression and toxicity profile is significant.
Main side effects include:
Doses recommended include starting at 150 mg for 3 months and if no response, increasing by 150 mg every 4 - 8 weeks to a maximal dose of 750 mg per day if no response. Do not use concurrently with meals and in particular, not with iron or antacid preparations. It is generally recommended to take it in the evening.
Monitoring of D-Penicillamine therapy requires blood count and urinalysis two weekly for the first month, then 4 weekly.
Pregnancy: Data in pregnancy is limited. Teratogenicity is not confirmed but the drug should ideally be stopped 1 month before the planning of any pregnancy.
Antibiotic therapy especially Minocycline has been controversial but some studies now suggest that there is a response to Minocycline. It is seen as an option in milder disease. Use of the drug has been based on the theory that the disease may have an infective aetiology. Trials have been contradictory 30, but the balance of early trials showed benefit 31,32. Response included clinical as well as improvement in acute phase response. The MIRA study group (Minocycline in rheumatoid arthritis) showed an improvement in moderate severity RA, with modest, but significant benefit in RA. O'Dell has published recent data on the early use of minocycline in Rheumatoid arthritis, and reported a greater remission rate in patients treated early within the first year with minocycline 33. Radiological progression has not been slowed by use of the drug 34
Dose recommended is 100mg twice a day.
Effectiveness takes approximately 3-6 months.
Pregnancy and lactation: contraindicated.
Cyclosporine is considered a more toxic drug and has largely been used with combination therapy with methotrexate. It as major side effect problems include hypertension and renal toxicity. It requires careful monitoring of the drug level. But cyclosporine is limited by cost factors that make it impractical for general use. It's only role in this country would be that of patients with drug resistance and in severe intractable disease.
Azathioprine (AZA) is a purine antagonist and is used in resistant disease.
Dose: 1.5-3 mg/kg/day
Side effects include:
Side effects require drug withdrawal, and are usually reversible.
Reproductive failure is not a problem with AZA.
Pregnancy : Teratogenicity is not seen, although use in pregnancy remains undesirable.
Monitoring: A full blood count is recommended 1-2 weekly
initially and then monthly once disease stable.
10. Combination therapy
It is being suggested by several centers that combination therapy is the best form of therapy with better response rates compared to individual therapy. Combinations have been used in different formats, including "step-down models", starting with several drugs and then dropping agents consecutively, eventually maintaining a mild DMARD long-term 35. "Saw-tooth" models are also proposed. These entail early use of DMARD, with replacement of each in turn by another as the efficacy of the respective drug subsides 36. The standard practice with RA management however, remains initial treatment with single drug therapy. If patients do not show an adequate response, then the drug may either be substituted or a second DMARD drug added. A number of combinations have been shown to be potentially superior to monotherapy with respect to both efficacy and toxicity. These should de done under Rheumatologist supervision, especially in cases of resistance to monotherapy.
O'Dell recommends continuation of triple therapy with methotrexate, sulphasalazine and hydroxychloroquine, thereby increasing remissions and reducing / preventing recurrence of disease 37. Initiation of combination therapy as the initial therapy may be indicated in severe disease but long term data is still required.Recommendations for primary care practitioners:
1. Confirm the diagnosis as early as
11. Anti- TNF therapy - Infliximab and Etanercept.
The use of biological agents is increasing with tumor necrosis factor receptor antagonist - Remicaide/Infliximab, being the first to register for use in RA, and now Spondyloarthropathies, and juvenile arthritis also being treated. The Medication is given as a infusion, dose determined by weight and given at baseline, 2 weeks , 6 weeks then 2 monthly. It is used with methotrexate to prevent antibody production to the drug itself (which is a chimeric antibody - part mouse, part human). The drug response is dramatic with reduction in inflammatory markers and reduction in swollen and tender joint counts. The drug however requires ongoing use and withdrawal results in the resurgence of disease.
Enbrel / Etanercept is a fusion protein of Tumour necrosis factor soluble i.e. circulating receptor. It is given as a subcutaneous injection twice a week at 25mg per injection for a normal adult. It has similar profile to infliximab, but is a pure human form and not susceptible to the antibody response to itself. It can be given with or without methotrexate.
Both drugs are used in resistant therapy rather than ab-initio. This is related to price constraints and also side effect potential. Major side effects are infection risk, and infliximab has been found to reduce defenses against tuberculosis, hence making use in Africa more difficult.
Other biological therapies include
Adalimumab an anti TNF human
...and many more in pipeline development.
My recommendation for DMARD use
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This article is Copyright
Dr David Gotlieb