MonitoringMTX


	Methotrexate Methotrexate (MTX) was approved by the FDA for the treatment of RA in 1988 and to this day remains the ‘anchor’ drug in the treatment of RA and other types of inflammatory arthritis. Several randomized placebo-controlled trials have shown that MTX has a significant beneficial effect on disease activity in RA and slows the rate of bone erosion. It can be used alone or in combination with other DMARDs, except azathioprine where evidence suggests no incremental benefit from the combination. MTX may also be used safely in combination with NSAIDs. Be aware though that many pharmacists warn patients that this combination is contraindicated, presumably due to potential for reduction in GFR and therefore MTX excretion. This interaction is not of clinical concern to Rheumatologists. Note: Methotrexate is given as a weekly dose (up to 30mg/week) in RA. There have been overseas reports of patients who have died following the inadvertent administration of methotrexate as a daily dose. Although, better known for its effects as a folate inhibitor, the mechanism of action in RA is most probably through promotion of adenosine release by immune cells. However, many of the side effects are due to the inhibition of folate metabolism (e.g., nausea, stomatitis, bone marrow suppression). The administration of a single weekly dose of folic acid, 5 to 10mg, can result in a significant reduction in toxicity without loss of efficacy and increasing the frequency of folic acid administration can alleviate some of these AEs. MTX is cleared from the body by the kidney and any deterioration in renal function may precipitate toxicity. Monitoring recommendations Baseline: CBC, LFTs, serum creatinine, hepatitis B & C serology and chest x-ray. Monitoring: CBC, LFTs and serum creatinine every 4 weeks initially. For patients on stable doses, monitoring frequency may be reduced to every 12 weeks. Consideration should be given to skin checks for melanoma and non-melanoma skin cancers annually or biannually. Clinical AE’s The GP may encounter several scenarios in patients receiving MTX: 1. Nausea – This is probably the most frequent AE associated with MTX. Nocturnal dosing or an increase in the frequency of folic acid administration can assist. 2. Headache – May respond to the measures above. 3. Rash – Usually mild and transient. If severe may require cessation and notification of the rheumatologist. 4. Stomatitis – patients present with a painful mouth with multiple oral ulcers. This suggests MTX toxicity. Mild cases may respond to an increase in the frequency of folic acid; more severe cases may require discontinuation of MTX. 5. Pneumonitis - This is an uncommon but potentially fatal complication of MTX treatment. The risk factors for MTX lung are not well understood, but may include pre-existing lung disease, smoking or an abnormal chest radiograph. Patients taking MTX who present with dry cough, shortness of breath on exertion, malaise, fever and diffuse crackles on auscultation should discontinue taking MTX until evaluated further. The chest X-ray may be normal. The differential diagnosis includes Pneumocystis jiroveci pneumonia, and bronchoscopy may be required to exclude this. Corticosteroids are frequently given for MTX-induced interstitial pneumonitis, although it remains to be proven whether this is of value. In the event of a patient developing symptoms suggestive of MTX pneumonitis, the patient or GP should contact the rheumatologist who will arrange the appropriate investigations. Laboratory AE’s Associated with MTX Liver disease: Methotrexate-induced liver disease is characterized by fibrotic changes that may progress to cirrhosis. Initial studies overestimated the incidence and seriousness of methotrexate induced liver disease. The incidence of real toxicity is probably in the order of 1 in 1000 RA patients over a five-year treatment period. While routine liver biopsy is not recommended, patients who have persistent elevation of AST may require a further investigation to ensure that continuation of treatment is not harmful. For patients with psoriasis, the incidence of LFT abnormalities is higher than for those with RA. For all cases of abnormal LFTs, consider concomitant medications, especially NSAIDs, which can also cause liver function abnormalities. Abnormal LFTs are encountered frequently, even in those receiving placebo treatments in clinical trials. A single abnormal result (AST or ALT <3x ULN) should not therefore cause alarm. As a guiding principal, MTX should be withheld if the AST or ALT rise to >3x ULN and the rheumatologist notified. LFT abnormalities usually settle promptly with cessation of MTX and this may be re-initiated at lower dose. It is unusual for MTX to affect GGT and ALP. Abnormalities of these enzymes can be seen in those with active inflammatory disease but consideration should also be given to biliary pathology. Haematologic Abnormalities: Macrocytosis is a frequent finding in patients on MTX and is not necessarily a sign of toxicity. The development of sore throat or abnormal bruising may herald the development of a cytopenia. Cytopenias are important to recognize promptly and frequently respond to cessation of MTX if stopped early. Recommendations for withholding MTX are the presence of: neutrophil count below 1x10⁹/L platelet count below 100x10⁹/L Lesser falls in haematologic indices could be managed by repeating the blood count to exclude laboratory error and reducing the MTX dose. The rheumatologist should also be informed. Sepsis in this setting may require the use of Folinic acid or GCSF. 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