Drugs, Treatment
Comments 2

The Four Non-biologic DMARDs

The Four Non-biologic DMARDs,

Disease Modifying Anti-Rheumatic Drugs,

in common use are


MTX, Rheumatrex, Trexall, Otrexup

Methotrexate has become the most frequently used DMARD in the world.  It reduces the inflammation of RA by suppressing the immune system.  It does not induce remission, but it does slow the progression of joint damage.

Aminopterin, an earlier form of methotrexate was used successfully in a 1951 study to treat RA. In the 1960s methotrexate was extensively studied but its success in treating RA was overshadowed by the popularity of corticosteroids.

In 1972 rheumatologist Rex Hoffmeister reported success with IM injections of methotrexate. After a 15-year study, his 1983 report encouraged other rheumatologists to study the use of methotrexate. After two pivotal studies, the FDA approved methotrexate as a therapy for RA in 1988. By the mid-1990s methotrexate (MTX) becomes the drug of choice for RA.

It usually takes 3-6 weeks to see improvement in symptoms. It takes12 weeks to see the full effect oh MTX.; Folic acid is usually prescribed along with MTX to replace a nutrient depleted during treatment.

Methotrexate is frequently used in combination with other traditional drugs as in triple therapy of methotrexate, sulfasalazine, and hydroxychloroquine. It is also used in combination with most of the biologics.  This combination improves the effectiveness of the drugs.

Gi symptoms such as stomach upset, and diarrhea are quite bothersome for some. These side effects disappear with time. If they don’t, switching to an injection form of MTX instead of a pill will help.

Regular lab work is ordered to monitor any effects on the liver and kidneys.


HCQ, Plaquenil

This was the drug Donald Trump said would cure the covid virus.

Hydroxychloroquine was developed as an anti-malarial drug. It is one of several 4-aminoquinolines. Introduced in 1955, it was found to also reduce symptoms in RA and Lupus. Eventually, it was approved for use in those autoimmune diseases.  For rheumatoid arthritis, it is prescribed for mild, slowly progressive disease.

Plaquenil is also used in combination with other DMARDs for the control of more aggressive RA. For example, it is combined with methotrexate and sulfasalazine to provide a stronger response.

It is important to have regular eye exams as a rare eye disorder can occur while on Hydroxychloquine. The risk can be compounded when a person is also on Tamoxifen for breast cancer.

Hydroxychloroquine is considered safe during pregnancy by the American College of Rheumatology, ACR.



SSZ, Azulfidine

 It is a combination of salicylate (anti-inflammatory)) and sulfa (antibiotic). Sulfasalazine was developed in the 1930’s to treat Rheumatoid Arthritis. It was popular in the 40’s but then fell out of favor with the discovery of the new miracle drug, cortisone. It is now back in favor and is frequently prescribed for RA even though not approved by the FDA for RA use. It has become a substitute for those unable to tolerate methotrexate.


LEF, Arava

Leflunomide is a DMARD and immunosuppressant.  The usual dose is 20mg. It was approved in 1998 for the treatment of RA.  Leflunomide is an alternative when methotrexate is not tolerated.  Alternately, it may also be combined with methotrexate. The half-life is long. Onset takes 4-8 weeks. Side effects: GI upsets, diarrhea. Hair loss in 10% of those on Arava.  

Leflunomide is contraindicated in pregnancy. Leflunomide is capable of damaging a fetus.   For a couple planning pregnancy, it is necessary for both partners to take cholestyramine to eliminate the active metabolites of leflunomide completely.

My view

I have been on all these drugs at one time or another. I was on methotrexate for seven years. The last few years I was on the injectable form. Initially, I did have a problem with diarrhea, but it passed. It helped me about 50%. Significant. I had to stop it when I developed necrosis in radiated breast tissue.

My RA treatment is complicated by my history of three different cancers. My symptoms have worsened. I have used Medrol to see me through until Orencia starts helping which it is at three months. Medrol has been a life saver but it has its own problems.

Hydroxychloquine was not helpful either alone or in combination with other drugs. Sulfasalazine made me sick. I think the sulfa didn’t agree with me. Leflunomide was no help either.


Next topic will be on the TNF inhibitors. This class of biologic drugs is usually the first biologic giver to a patient.

Reliable resources

American College of Rheumatology                

American College of Rheumatology

Johns Hopkins Arthritis Center                             

Johns Hopkins Arthritis Center

Creaky Joints                          

CreakyJoints – Arthritis Support, Education, Advocacy and Research


  1. Kari says

    Your blog is super helpful! I am sorry you have suffered so much, I am beginning the journey. Thank you for all of the great information!


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