Disease Modifying Anti-rheumatic Drugs (Agents with Delayed Onset of Action)

Disease Modifying Anti-rheumatic Drugs (Agents with Delayed Onset of Action)
Although both NSAIDs and DMARD agents improve symptoms of active rheumatoid arthritis, only DMARD agents have been shown to alter the disease course and improve radiographic outcomes. DMARDs have an effect upon rheumatoid arthritis that is different and more delayed in onset than either NSAIDs or corticosteroids. Once persistent disease activity (chronic synovitis) is established, a DMARD agent should be considered. The development of erosions or joint space narrowing on x-rays of the involved joints is a clear indication for DMARD therapy, however one should not wait for x-ray changes to occur. The currently available drugs include:

Methotrexate has become the most popular first-line DMARD agent because of its early onset of action (4-6 weeks), good efficacy, favorable toxicity profile, ease of administration, and relatively low cost. Methotrexate is the only conventional DMARD agent in which the majority of patients continue on therapy after 5 years. Methotrexate is effective in reducing the signs and symptoms of RA, as well as slowing or halting radiographic damage. It was as effective as leflunomide and sulfasalazine in one study, and nearly as effective as etanercept in another study.

Mechanism: Although the immunosuppressive and cytotoxic effects of methotrexate are due to the inhibition of dihydrofolate reductase, the anti-inflammatory effects in rheumatoid arthritis appear to be related at least in part to interruption of adenosine and TNF pathways.

Dosage: In a study comparing methotrexate to etanercept in early RA, methotrexate was begun at a dose of 10 mg per week, and increased to 20 mg per week by week 8. This dosing regimen is now fairly well accepted in clinical practice. Maximal dose is usually 25 mg per week. Methotrexate can be given orally or by subcutaneous injection. The latter route of administration can be advantageous for patients who have methotrexate-associated nausea. Patients should be carefully selected not to have renal insufficiency, acute or chronic liver disease, alcohol abuse, leukopenia, thrombocytopenia, or untreated folate deficiency. Obesity, diabetes and history of hepatitis B or C are factors that have been suggested but not confirmed to increase methotrexate hepatotoxicity. Salicylates (and other NSAIDs) and trimethoprim (Bactrim, Septra) block the renal excretion of methotrexate and leads to higher serum levels and potential toxicity. If alternatives exist, concomitant use of methotrexate and trimethoprim is to be avoided. NSAIDs and methotrexate are routinely used together with safety.

Usual Time to Effect: The onset of action is 4 to 6 weeks, with 70% of patients having some response. A trial of 3 to 6 months is suggested.

Side Effects: Fortunately the most serious complications of methotrexate therapy: hepatic cirrhosis, interstitial pneumonitis and severe myelosuppression are rare. Stomatitis, mild alopecia and GI upset may occur and are related to folic acid antagonism and can be improved with folic acid supplementation. Folic acid 1mg daily does not diminish the efficacy of methotrexate and is routinely given. Before starting methotrexate, baseline studies should include complete blood count, liver chemistries, serum creatinine, hepatitis B and C serologies and chest radiography. Routine toxicity monitoring should include a CBC, liver profile, serum albumin and serum creatinine every 4-8 weeks.

Hepatotoxicity has not been significant if patients with pre-existing liver disease, alcohol abuse, or hepatic dysfunction are excluded from treatment. Patients are instructed to limit alcohol containing beverages to no more than two per week. Baseline or surveillance liver biopsies are not indicated unless pre-existing iver disease is suspected. Elevated liver enzymes do not directly correlate with toxicity but therapy should be stopped if transaminases are elevated to 3 times the upper limit of normal. Liver biopsy should be done if elevated liver enzymes persist or if methotrexate therapy is to be continued.

Interstitial pneumonitis is rare (2%), but the clinician should be alert to symptoms of cough or shortness of breath that may herald the onset of this severe complication. Methotrexate pneumonitis may occur at any time during therapy and is not dose related. A baseline chest x-ray is useful for comparison. Patients with poor pulmonary reserve from other causes may be excluded from therapy over concerns of increased morbidity if methotrexate pneumonitis occurs.

Myelosuppression is also rare at the low doses of methotrexate utilized for rheumatoid arthritis. Increased renal insufficiency from other causes or use of trimethoprim (Bactrim, Septra) frequently raises methotrexate levels and may cause myelosuppression.

In the absence of leukopenia, there has not been conclusive information to link methotrexate use in rheumatoid arthritis with increased risk of infection. The exception is a slight increased risk of localized herpes zoster infection.

Although there are case reports of lymphoma associated with methotrexate therapy including a case where the lymphoma resolved after cessation of therapy, increased occurrence of malignancy has not been found in large population based studies. Nor have there been noted effects on sperm production or ovarian function. Women of childbearing potential or men with partners of child bearing potential must understand that methotrexate has potential for teratogenesis and should practice effective birth control. Women must discontinue methotrexate for one ovulatory cycle prior to attempting conception, while men should wait 3 months.

Methotrexate can be combined safely with nearly every other FDA approved DMARD for RA, including sulfasalazine, hydroxychloroquine, TNF inhibitors, anakinra and leflunomide. In all clinical trials combining methotrexate with one of these DMARDs, no unexpected toxicities or synergistic toxicities were observed.