I’m Confused About All The Medicines Used To Treat Rheumatoid Arthritis… Can You Explain Them To Me? Part 2- The Disease-modifying Anti-rheumatic Drug (DMARD) Group

Rheumatoid arthritis (RA) is a chronic, potentially destructive, systemic, autoimmune form of arthritis. It affects roughly 2 million Americans and has been the subject of intense research, particularly in recent years.

The goal of treatment is to induce remission.

In a previous article I discussed the use of non-steroidal anti-inflammatory drugs (NSAIDS) and glucocorticoids in rheumatoid arthritis (RA). In this article I will discuss disease-modifying anti-rheumatic drugs. (DMARDS).

Although non-steroidal anti-inflammatory drugs (NSAIDs) and glucocorticoids (“steroids”) may alleviate symptoms, joint damage can progress in patients with active rheumatoid arthritis (RA). Disease-modifying anti-rheumatic drugs (DMARDs) can reduce or prevent joint damage, preserve joint integrity and function, and maintain the economic productivity of the patient with RA.

DMARD therapy should be considered in all patients with active RA. DMARD therapy should be started immediately- certainly within 3 months of diagnosis- in any patient, who has persistent joint pain, significant morning stiffness or fatigue, active joint inflammation, persistent elevation of the ESR (sed rate) or CRP level (these latter two are blood tests that measure inflammation), or x-ray joint damage.

For any untreated patient with persistent joint inflammation and joint damage, DMARD treatment should be started to prevent or slow further damage. Unfortunately, all DMARDS including methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), leflunomide, azathioprine, cyclophosphamide and cyclosporine require several weeks to months before improvement begins to occur.

Most rheumatologists select MTX as their initial DMARD of choice, particularly for patients where the RA is active. Because of its efficacy, relatively low toxicity, and low cost, MTX has become the standard by which all DMARDs are compared.

Controlled clinical trials have established the efficacy of MTX in RA, particularly in patients with severe disease. MTX slows the progression of x-ray damage, and more than 50% of patients who take MTX continue the drug beyond 3 years. Mouth sores, nausea, diarrhea, fatigue, and hair loss caused by MTX can be reduced by treating the patient with folic acid supplementation.

Relative contraindications for MTX therapy are pregnancy (MTX is a potent teratogen, meaning it causes severe birth defects), preexisting liver disease -especially infectious hepatitis, kidney function impairment, significant lung disease, and alcohol abuse.

A liver biopsy should be considered in patients who develop abnormal findings on blood liver function tests that persist during treatment or after discontinuation of MTX where no other cause for the abnormalities are found.

MTX can be used either by itself (monotherapy) or in combination with another DMARD.

In some patients, as described above, MTX is contraindicated. Not all people respond to MTX and some people are unable to tolerate it.

In that case, other DMARDs can be used.

Hydroxychloroquine (Plaquenil) is a mild DMARD that may decrease the pain and swelling of arthritis as well as reduce the risk for long-term disability. It can be used early in the course of RA and is often used in combination with other DMARDs. Taking a high dose for prolonged periods has been associated with damage to the retina, and an eye examination is recommended for most patients every 6-12 months.

Sulfasalazine (SSZ) is a sulfa-based DMARD. It acts more quickly than hydroxychloroquine, sometimes as early as 4 weeks. SSZ can slow x-ray progression of RA and is usually well tolerated. Most adverse effects (nausea and stomach discomfort) occur in the first few months of therapy. Starting low and gradually increasing the dosage lessens the incidence of these adverse effects. Low white blood cell counts can occur and may be serious. Periodic laboratory monitoring is necessary. Clinical response should be apparent within 3 months.

Leflunomide (Arava) has a slightly different mechanism of action than MTX and is taken in pill form once a day. It can be used alone or with MTX, although the risk for adverse effects (including liver problems) is greater with this combination. The reduction in disease activity and in the rate of x-ray progression by leflunomide alone is equal to that of MTX. As with MTX, liver tests must be monitored closely. Five percent of patients receiving leflunomide and up to 60% of patients receiving MTX plus leflunomide have elevated liver enzyme levels.

Leflunomide is a potent teratogen- it causes severe birth defects. If a patient is planning pregnancy, the drug should be stopped and cholestyramine elimination performed (cholestyramine 8 g 3 times daily by mouth for 11 days).

Adherence to the package insert on ridding leflunomide from the system is mandatory before pregnancy is considered.

Other DMARDs occasionally used in RA include azathioprine (Imuran), cyclosporine (Sandimmune), and gold therapy (Solganol, Myochrisine). Azathioprine and cyclosporine are immunosuppressant drugs taken in pill form. The usual dose for azathioprine is once daily, whereas cyclosporine is generally started at twice daily. Intramuscular gold injection is typically initiated as a low test dose followed by a higher weekly dose over 5-6 months.

While many rheumatologists select hydroxychloroquine or sulfasalazine first, MTX is usually preferred.

After 5 years, only 60% of patients remain on MTX, the best-tolerated traditional DMARD. Joint damage by x-ray is found in 30% of patients after 1 year of therapy with traditional DMARDs and in 70% of patients after 2 years of therapy. Joint damage by x-ray is closely correlated with subsequent disability. In addition, significant numbers of patients on DMARD therapy may still have progressive x-ray damage and disability.

Numerous studies have established the importance of aggressive DMARDs as single-drugs and as combination agent treatments. The existence of a window of opportunity is now a well-accepted concept in RA therapeutics. This window consists of the first 3-6 months of disease and is the optimal time to initiate therapy to prevent x-ray damage and subsequent disability. A number of controlled studies have advocated the use of early aggressive DMARD therapy either alone or in combination.

In another article- Part 3- I will discuss the role of biologic therapies.