Methotrexate was first introduced in 1955 for leukemia and in 1986 became FDA approved for the treatment of adults with severe, active, rheumatoid arthritis or children with active polyarticular-course juvenile RA.

In rheumatology, MTX has been the first-line drug against which all other agents are judged. It is the preferred agent in early and late disease and has been the anchor drug to all combination therapies that have revolutionized antirheumatic therapy.

Although MTX has become the drug that rheumatologists love, it is the drug patients often have an aversion to. Patient reluctance or reactions to MTX are based largely on toxicity – some read on the internet and others experienced after a trial of MTX. Effective utilization of MTX requires a plan for risk communication and toxicity prevention and management.

Risk communication is the art of informing patients of the likely and unlikely or most dangerous side effects associated with a particular drug. The risk factors for MTX toxicity include improper instruction, wrongful dosing, not monitoring labs for renal insufficiency, hypoalbuminemia or dropping cell counts and lastly, concurrent use of drugs known to interact with MTX. Below is a review of the management and prevention of common/nuisance toxicities of MTX. Additionally, pearls of prevention and wisdom from the products package insert are found at the end of this article.

Common Mistakes and Myths in MTX Management.

Changing from oral to parenteral or changing from single weekly to split doses to lessen (GI) toxicity. The literature and research is clear that toxicity is related to MTX levels and that parenteral dosing yields higher MTX levels than oral and that split doses results in more MTX absorbtion. Thus split doses or parenteral doses will cause more toxicity, not less.

Using Folate to manage fatigue or oral ulcers. See vitamin A and dextromethorphan below.

Higher doses (above 15 or 20 mg per week) yields greater efficacy. The truth is that as you increase the dose, toxicity is more likely than efficacy. Moreover, recent studies like JESMR, CONCERTO and MUSICA have shown that lower doses (7.5-10mg) may be as effective as higher doses (15-20mg).

Nuisance Side Effects. The usual list here includes post-dosing painful oral ulcers, nausea, vomiting, GI discomfort, diarrhea, hair thinning, minor hepatic enzyme elevations and drug interactions. Rarely MTX causes colonic ulcerations.

The avoidance of many of these common nuisance side-effects was largely taught to me by a world-class pediatric oncologist, Dr. Bart Kamen (see end of article dedication). For these you need only rely upon the use of folate supplementation, vitamin A and dextromethorphan.

Folate Benefits : The utility and safety of folate supplementation with MTX use was reviewed by a Cochrane analysis that showed folate supplementation (low doses of ≤ 7 mg weekly) to be effective at lowering the frequency of GI side effects, protective against hepatic enzyme elevations and reduces the frequency of MTX discontinuations. Folates were not shown to have a significant effect on oral ulcerations due to MTX (although a protective “trend” was mentioned). Although I believe that folate supplementation may protect against the rare instance of MTX induced hypersensitivity pneumonitis, I can find no evidence to back this observation. For many leucovorin is given post MTX dosing as a means of preventing myelosuppression, GI toxicity, and neurotoxicity. Leucovorin is usually given within 24 to 36 hours of MTX to prevent toxicity.

: The utility and safety of folate supplementation with MTX use was reviewed by a Cochrane analysis that showed folate supplementation (low doses of ≤ 7 mg weekly) to be effective at lowering the frequency of GI side effects, protective against hepatic enzyme elevations and reduces the frequency of MTX discontinuations. Folates were not shown to have a significant effect on oral ulcerations due to MTX (although a protective “trend” was mentioned). Although I believe that folate supplementation may protect against the rare instance of MTX induced hypersensitivity pneumonitis, I can find no evidence to back this observation. For many leucovorin is given post MTX dosing as a means of preventing myelosuppression, GI toxicity, and neurotoxicity. Leucovorin is usually given within 24 to 36 hours of MTX to prevent toxicity. Vitamin A and Oral Ulceration : while the package insert for MTX states “…certain side effects such as mouth sores may be reduced by folate supplementation”, my experience suggests this is rarely so and the Cochrane review supports this non-association. Dr. Kamen taught me that when rats are given oral MTX, a severe enterocolitis ensues. However when these same rats are pre-treated with vitamin A – no such GI toxicity was observed. This led to our clinic study that showed Vitamin A given as 8,000 IU day was effective in nearly two-thirds of patients in reducing oral ulcerations and post-MTX nausea. It was less effective, but worthwhile, in reducing the diarrhea sometimes seen.

: while the package insert for MTX states “…certain side effects such as mouth sores may be reduced by folate supplementation”, my experience suggests this is rarely so and the Cochrane review supports this non-association. Dr. Kamen taught me that when rats are given oral MTX, a severe enterocolitis ensues. However when these same rats are pre-treated with vitamin A – no such GI toxicity was observed. This led to our clinic study that showed Vitamin A given as 8,000 IU day was effective in nearly two-thirds of patients in reducing oral ulcerations and post-MTX nausea. It was less effective, but worthwhile, in reducing the diarrhea sometimes seen. Dextromethorphan and the “Blahs” : Neurotoxicity is quite common with high-dose MTX chemotherapy (10% seizures) and more frequent than most realize with low-dose weekly MTX. A survey of my clinic patients showed that nearly 50% of my MTX patients admitted to some neurologic manifestations – usually manifest as post-MTX somnolence/fatigue or “the Blahs”, but may also include headache, cognitive dysfunction, impotence, blindness or numbness. Usually such symptoms last for 24-36 hours. Again, it was Dr. Kamen who taught me that the metabolism of MTX leads to excess homocysteine and that homocysteine leads to a number of excitogenic amines that includes homocyteic acid, amongst others. Interestingly these amines will noncompetitively bind NMDA receptors in the brain and presumeably mediate the neurotoxicities seen. NDMA binding can be noncompetitively inhibited by dextromethorphan. Dr. Kamen often related stories of children with leukemia who were receiving intrathecal MTX and would go into a coma. He would then perform his magic by taking a bottle of Robitussin DM and pouring down the NG tube so that his residents and fellows could watch the child awaken from the drug induced coma. This led to our study in 1999 that was published as an ACR abstract wherein we treated our MTX patients who had the “blahs” and showed again that two-thirds promptly responded and had less or no CNS symptoms. Hence we now recommend the use of dextromethorphan (20-50mg) be given weekly with the MTX dose and again 8-12 hours later. We usually prescribe this as a tablet (Mucinex DM).

: Neurotoxicity is quite common with high-dose MTX chemotherapy (10% seizures) and more frequent than most realize with low-dose weekly MTX. A survey of my clinic patients showed that nearly 50% of my MTX patients admitted to some neurologic manifestations – usually manifest as post-MTX somnolence/fatigue or “the Blahs”, but may also include headache, cognitive dysfunction, impotence, blindness or numbness. Usually such symptoms last for 24-36 hours. Again, it was Dr. Kamen who taught me that the metabolism of MTX leads to excess homocysteine and that homocysteine leads to a number of excitogenic amines that includes homocyteic acid, amongst others. Interestingly these amines will noncompetitively bind NMDA receptors in the brain and presumeably mediate the neurotoxicities seen. NDMA binding can be noncompetitively inhibited by dextromethorphan. Dr. Kamen often related stories of children with leukemia who were receiving intrathecal MTX and would go into a coma. He would then perform his magic by taking a bottle of Robitussin DM and pouring down the NG tube so that his residents and fellows could watch the child awaken from the drug induced coma. This led to our study in 1999 that was published as an ACR abstract wherein we treated our MTX patients who had the “blahs” and showed again that two-thirds promptly responded and had less or no CNS symptoms. Hence we now recommend the use of dextromethorphan (20-50mg) be given weekly with the MTX dose and again 8-12 hours later. We usually prescribe this as a tablet (Mucinex DM). Hepatic enzymes and Hepatotoxicity. As mentioned above the evidence shows that daily or weekly folate supplementation has a protective effect against hepatic enzyme elevation with an overall 77% relative risk reduction. Avoidance of hepatotoxicity is best accomplished by proper patient selection and prescribing and monitoring. This was first highlighted by the seminal 1994 paper wherein Kremer et al published the recommended guidelines for monitoring of MTX toxicity. They and others have pointed out that regular monitoring of hepatic enzymes is necessary and will show that hepatic enzyme elevations during MTX therapy is a frequent and transient problem, but that persistent elevations may indicate liver pathology and the need for further evaluation.

Severe Toxicity Management: MTX is dialyzable – hence hemodialysis and hemoperfusion have been successfully used in patients with toxic MTX levels. Maintenance of renal function, hydration, leucovorin rescue, G-CSF, transfusions and/or alkalinization of the urine may also be necessary in some patients. Plasmapheresis has less and limited value.

Package Insert Exerpts

- Methotrexate elimination is reduced in patients with impaired renal function, ascites, or pleural effusions. Such patients require especially careful monitoring for toxicity, and require dose reduction or, in some cases, discontinuation of methotrexate administration.

- Unexpectedly severe (sometimes fatal) bone marrow suppression, aplastic anemia, and gastrointestinal toxicity have been reported with concomitant administration of methotrexate (usually in high dosage) along with some non-steroidal anti-inflammatory drugs (NSAIDs). Despite the potential interactions, studies of methotrexate in patients with rheumatoid arthritis have usually included concurrent use of constant dosage regimens of NSAIDs, without apparent problems. It should be appreciated, however, that the doses used in rheumatoid arthritis (7.5 to 20 mg/week) are somewhat lower than those used in psoriasis and that larger doses could lead to unexpected toxicity.

- Patients with psoriasis or rheumatoid arthritis with alcoholism, alcoholic liver disease or other chronic liver disease should not receive methotrexate.

- Patients with psoriasis or rheumatoid arthritis who have overt or laboratory evidence of immunodeficiency syndromes should not receive methotrexate.

- Patients with psoriasis or rheumatoid arthritis who have preexisting blood dyscrasias, such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anemia, should not receive methotrexate.

- Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides. Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored. Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria.

- Drug interaction with trimethoprim/sulfamethoxazole (Bactrim) may rarely lead to bone marrow suppression, probably from an additive anti-folate effect and displacement of MTX binding to albumin.

- Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with methotrexate. Use of methotrexate with penicillins should be carefully monitored.

- The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases. Therefore, patients receiving concomitant therapy with methotrexate and other potential hepatotoxins (eg, azathioprine, retinoids, sulfasalazine) should be closely monitored for possible increased risk of hepatotoxicity.

- Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate.

- Pregnancy should be avoided if either partner is receiving methotrexate; during and for a minimum of three months after therapy for male patients, and during and for at least one ovulatory cycle after therapy for female patients

This article is dedicated to the brilliance of Dr. Barton Kamen (1949-2012) – a pediatric oncologist who taught me and thousands of physician about the art of medicine and specifically, about the safe use of methotrexate. Bart invented the infusion pump, was an exceptional pediatrician and magician, and a giant of a translational researcher and folate scientist. You can read more about him here.

Dr. Barton Kamen

References

Drachtman RA, Cole PD, Golden CB, James SJ, Melnyk S, Aisner J, Kamen BA. Dextromethorphan is effective in the treatment of subacute methotrexate neurotoxicity. Pediatr Hematol Oncol. 2002 Jul-Aug;19(5):319-27

Shea B, et al. Folic acid and folinic acid for reducing side effects in patients receiving methotrexate for rheumatoid arthritis. Cochrane Database Syst Rev. 2013 May 31