Traditional Disease modifying anti-rheumatic drugs

Disease-modifying anti-rheumatic drugs (DMARDs) are effective at reducing inflammation associated with RA and slowing or preventing damage to joints and enabling a patient to maintain function and quality of life. This is why they are called “disease-modifying,” because they can interrupt the processes that cause damage in rheumatic diseases. The introduction of DMARDs for the treatment of RA has significantly changed and improved the prospects for patients with RA. Before the availability of drugs like methotrexate, damage to joints and related structures from chronic inflammation associated with RA was inevitable for many patients.1

The most widely used traditional or conventional DMARDs (newer biologics are also considered DMARDs, so the words “traditional” and “conventional” refer to non-biologics) recommended for RA treatment by the American College of Rheumatology (ACR) (2012 Treatment Guidelines) include methotrexate, sulfasalazine (Azulfidine), leflunomide (Arava), and hydroxychloroquine (Plaquenil). Other conventional DMARDs that are less widely used and for which there is limited recent data on efficacy and safety (these do not appear in the ACR 2012 Treatment Guidelines) include minocycline (Minocin), D-penicillamine (Cuprimine, Depen), auranofin (Ridaura), sodium aurothiomalate, azathioprine (Imuran), and cyclosporine (Neoral).2-4

Conventional DMARD treatments for RA: dosing, comparative efficacy, and safety

Drug (brand names)
Dosing and admin
Comparison with other conventional DMARDs (AHRQ)
Side effects and safety issues

Conventional DMARDs included in ACR 2012 Recommendations

  • 7.5-25 mg weekly
  • Oral or subcutaneous
  • ACR20 (disease control), x-ray evidence of progression, functional capacity equal to LEF and SULF
  • Decreased quality of life vs LEF
  • Similar tolerability with LEF, SULF, and TNF-inhibitors
  • Liver toxicity
  • Lung (alveoli) inflammation
  • Suppresses production of immune cells by bone marrow suppression
  • More patients able to use long-term vs SULF
Leflunomide (Arava)
  • 10-20 mg daily
  • Oral
  • ACR20 (disease control) equal to MTX
  • X-ray evidence of progression equal to MTX and SULF
  • Functional capacity equal to MTX, better than SULF
  • Improved quality of life vs MTX
  • Similar tolerability with MTX and SULF
  • Liver toxicity
  • Suppresses production of immune cells by bone marrow suppression
  • Hypertension
Sulfasalazine (Azulfidine)
  • 1000-1500 mg twice daily
  • Oral
  • ACR20 (disease control) and x-ray evidence of progression equal to MTX and LEF
  • Functional capacity less effective than LEF
  • Similar tolerability with MTX and LEF
  • More patients able to use long-term vs LEF
  • Liver toxicity
  • Suppresses production of immune cells by bone marrow suppression
  • Hypersensitivity (allergic) reactions
Hydroxychloroquine (Plaquenil)
  • 200-400 mg daily
  • Oral
  • Not studied by AHRQ
Minocycline (Minocin)
  • 100 mg twice daily
  • Oral
  • Not studied by AHRQ
  • Not studied by AHRQ
Auranofin (Ridaura)
  • 3-6 mg daily
  • Oral
  • Not studied by AHRQ
  • Diarrhea
  • Hypersensitivity (allergic) reactions
  • Not studied by AHRQ
Azathioprine (Imuran)
  • 50-200 mg daily
  • Oral
  • Not studied by AHRQ
  • Liver toxicity
  • Suppresses production of immune cells by bone marrow suppression
  • Gastrointestinal toxicity
  • Not studied by AHRQ
Cyclosporine (Neoral)
  • 2.5-5 mg/kg daily
  • Oral
  • Not studied by AHRQ
  • Hypertension
  • Kidney toxicity
  • Not studied by AHRQ
D-penicillamine (Cuprimine, Depen)
  • 250-1000 mg per day
  • Oral
  • Not studies by AHRQ
  • Significant toxicity
  • Rash, oral ulcers
  • Proteinuria
  • Hematologic side effects
  • Autoimmune syndrome
Sodium aurothiomalate
  • 50 mg weekly
  • Injection
  • Not studied by AHRQ
  • Hypersensitivity (allergic) reactions
  • Kidney inflammation
  • Lung inflammation
  • Not studied by AHRQ

ACR20=American College of Rheumatology 20% improvement; AHRQ=Agency for Healthcare Research and Quality; DMARD=disease-modifying antirheumatic drug; LEF=leflunomide; MTX=methotrexate; SULF=sulfasalazine.



Methotrexate is called an antimetabolite and an antifolate. It inhibits the metabolism of folic acid, which is necessary in the production of key immune system cells. Therefore, it results in a dampening of immune processes at work in RA. It has become the cornerstone of RA treatment since it was first introduced over five decades ago as an anti-cancer drug. In RA, methotrexate is given at a low dose and has been shown to be effective in controlling inflammation and related symptoms, while slowing or preventing damage to joints and related structures. Additionally, with experience in over half a million patients with RA, methotrexate has a strong safety record when monitored appropriately.5

Learn more about methotrexate


Leflunomide (Arava) is an immunodulatory drug that inhibits the production of immune system cells. It was introduced about two decades ago and is considered a second choice to methotrexate. It provides efficacy similar to methotrexate, including similar ACR20 disease control, slowing of disease progression (as shown by x-ray), and improvement of physical functioning. Additionally, it is associated with greater improvements in quality of life compared with methotrexate.3,6

Learn more about Arava/leflunomide


Sulfasalazine is made up of two components, aspirin (5-aminosalicyclic acid) and sulfapyridine. It is unclear how these work together to provide benefit in RA, but we think sulfasalazine may act in a way similar to methotrexate, as an antimetabolite, interfering with the production of key immune system cells. It also appears to inhibit tumor necrosis factor (TNF), which plays an important role in the immune response. In terms of ACR20 disease activity and disease progression (as shown by x-ray), it has similar efficacy to both leflunomide and methotrexate. However, it appears to be less effective than leflunomide in improving functional capacity.3,4

Learn more about sulfasalazine


Hydroxychloroquine (Plaquenil) is an antimalarial drug that changes or modulates the immune system response. The exact mechanism of action for hydroxychloroquine and another antimalarial drug chloroquine in RA is not known, but we think that these drugs decrease production of a number of different chemicals that are important to the immune response. Hydroxychloroquine has been shown to reduce RA symptoms, including pain, swelling, and tenderness, and improve physical functioning in many patients (up to 80% in clinical trials). Antimalarials are generally well tolerated, with gastrointestinal side effects occurring in about 10% of patients. Serious adverse effects, such as toxicity affecting the eyes, are rare, occurring in less than 2% of patients.3,4

Learn more about hydroxychloroquine


Other conventional DMARDs

Other conventional DMARDs that are less widely used and for which there is less efficacy and safety data include the tetracycline (a type of antibiotic) minocycline (Minocin), the chelator D-penicillamine (Cuprimine, Depen), gold salts including auranofin (Ridaura) and sodium aurothiomalate, which were a cornerstone in RA treatment before 1990, and the immunosuppressive drugs azathioprine (Imuran) and cyclosporine (Neoral).4


Is it important to begin DMARD treatment immediately after diagnosis?

There is a growing body of evidence supporting the benefits of early aggressive treatment of RA using DMARDs and other drug treatment to achieve early control of RA disease activity. In fact, much of the joint damage that happens with RA which results in disability begins early in the course of the disease. So, early detection, diagnosis, and treatment are important. Many doctors recommend that patients with RA begin treatment with a DMARD as soon as possible after diagnosis. Choice of drug treatment and the intensity of treatment will depend on the level of disease activity.5

In patients with mild disease, initial treatment with an non-steroidal anti-inflammatory drug (NSAID) for relief of symptoms and control of minor inflammation, while simultaneously starting a DMARD, such as sulfasalazine or hydroxychloroquine (DMARDs typically take 4 to 6 weeks to achieve full effect), may result in control of disease activity.5

With moderate to severe disease activity, initial anti-inflammatory treatment with an NSAID or glucocorticoid as a “bridge” therapy while starting methotrexate may result in control of disease activity.5

If a patient is resistant to initial DMARD treatment with an agent such as methotrexate, combination DMARD treatment may be used, adding one or more conventional DMARDs (leflunomide, hydroxychloroquine, sulfasalazine) or a newer biologic treatment to methotrexate. Recent research suggests that combinations of conventional DMARDs may be effective as an early treatment approach to RA, as well as following inadequate response to methothrexate. Additionally, anti-inflammatory treatment (with an NSAID or glucocorticoid) can be used to control active inflammation.5


How will I select a conventional DMARD treatment?

Your doctor will work closely with you to select the right DMARD treatment based on several different factors, including5:

  • Your level of disease activity
  • Your previous treatment history
  • Your preferences, including how a drug is taken, cost considerations, and monitoring requirements
  • Your other diagnoses or comorbidities


Since DMARDs are associated with side effects and safety concerns (many of these safety concerns only affect a minority of patients), your doctor will screen you carefully to minimize risk for side effects when selecting a DMARD. Before choosing a DMARD, your doctor will give you several screening tests. Some of these tests apply to specific DMARDs). They include5:

  • General laboratory tests, including complete blood count, serum creatinine, liver function tests
  • Hepatitis test (for methotrexate, leflunomide, and newer biologic treatments)
  • Ophthalmologic screening (for hydroxychloroquine)
  • Tuberculosis screening (for methotrexate and newer biologic treatments)


Your doctor may also test your blood for immune responses to common childhood vaccinations, and then suggest that you receive recommended vaccinations prior to starting a DMARD.


Combining treatments to minimize inflammation and protect against joint damage

There is substantial evidence showing that early aggressive treatment of RA to control disease activity can protect against joint damage and preserve function. Many doctors will begin DMARD treatment immediately following diagnosis and may combine that treatment with NSAIDs or glucocorticoids, as well as newer biologic treatments, all with the goal of bringing RA disease activity under control as quickly as possible.5

You and your doctor will select an RA treatment approach that is appropriate to your level of disease activity. However, for many patients, aggressive control of disease activity involves using different drugs in combination. For instance, because the DMARD methotrexate may take 4 to 6 weeks to improve RA symptoms and hydroxychloroquine 2 to 3 months, glucocorticoids are often used in concert with DMARDs during RA flares for acute (short-term) control of inflammation and associated symptoms.5


What are the monitoring requirements with conventional DMARDs?

Your monitoring requirements will vary according to the specific drug treatment or treatments that you receive. In general, your doctor will want to see you on a regular basis to check for drug toxicities, as well as to monitor disease activity and how well your treatment is keeping RA under control. Regular monitoring for treatment response may include:

Written by: Jonathan Simmons | Last reviewed: September 2013.
View References