Methotrexate

Methotrexate enters cells through the reduced folate carrier, SLC19A1, the same entry gate as natural vitamin B9. Once inside, it undergoes polyglutamation, which retains it within the cell and strengthens its action. It then inhibits dihydrofolate reductase, the enzyme that converts dihydrofolate into active tetrahydrofolate. Without this tetrahydrofolate, the cell can no longer make the nucleotides of DNA and RNA. In its polyglutamated form, methotrexate also blocks thymidylate synthase, another key enzyme of DNA synthesis.

In autoimmune diseases, at low doses, another mechanism dominates. Methotrexate inhibits AICAR transformylase, which leads to an accumulation of adenosine around cells. This adenosine slows the activation of T lymphocytes and reduces the function of B lymphocytes. It is this pathway that explains the anti-inflammatory effect sought against rheumatoid arthritis, distinct from the antiproliferative effect used in oncology.

Methotrexate occupies two quite different areas depending on the dose. At a low weekly dose, it serves as a disease-modifying treatment for inflammatory conditions: rheumatoid arthritis, juvenile idiopathic arthritis and psoriasis. It calms inflammation and slows joint or skin damage over time.

At a high dose, it becomes a chemotherapy agent. It is then indicated in several leukaemias and lymphomas, breast cancer, head and neck cancers and gestational trophoblastic tumours. The same drug therefore completely changes its role depending on the prescription regimen, which explains why the dose and the timing are set with such precision.

For autoimmune diseases, methotrexate is taken only once a week, as a single dose or split over the day. This weekly rhythm is the most important safety rule of the treatment. People who took it once a day instead of once a week have experienced very serious side effects, sometimes fatal. The day of intake is chosen and kept the same from one week to the next, to anchor the reference point.

The doctor almost always prescribes folic acid alongside it, at a rate of 1 mg per day or 5 to 7 mg per week, in order to prevent bone marrow toxicity and reduce certain side effects. Methotrexate is not stopped on your own, even when symptoms subside: its long-term effect rests on continuity. Any change in the rhythm or the dose goes through the doctor.

The most frequent side effects are digestive: nausea, vomiting, ulceration of the mucous membranes of the mouth and loss of appetite. The liver is the organ to monitor closely. Under a low or medium dose taken over several months, a rise in transaminases, ALT or AST, occurs in 15 to 50% of patients, most often mild and transient; about 5% exceed twice the upper normal limit. Over the longer term, nearly 30% of patients develop mild to moderate histological liver abnormalities and 2 to 20% some degree of fibrosis.

With modern regimens, that is 5 to 15 mg in a single weekly dose with folate supplementation, fibrosis and clinically apparent liver damage remain rare, even over time. The serious effects to be aware of include hepatotoxicity, bone marrow suppression, infections, kidney failure and teratogenicity. Methotrexate is classified as category X and contraindicated during pregnancy because of its effect on the fetus.

Methotrexate is a folate antagonist. By inhibiting dihydrofolate reductase, it reduces the availability of tetrahydrofolate and its derivatives, and thus deprives thymidylate synthase of its substrates. This action is also the source of most of its side effects, because tissues that renew quickly, bone marrow and mucous membranes, depend on folates. The drug is among those that interfere with the use of folates and can contribute to a deficiency.

This is why folic acid supplementation accompanies the treatment. The concomitant administration of about 1 mg per day reduces the frequency of liver enzyme elevations, without reducing the efficacy of methotrexate. In case of toxicity, it is another form, folinic acid or leucovorin, that serves as rescue treatment. Dietary folates are found mainly in green leafy vegetables such as spinach and broccoli, legumes, citrus fruits, liver and eggs.

Several common medicines increase the risk of methotrexate toxicity. NSAIDs, salicylates and proton pump inhibitors modify its renal elimination and can raise its blood concentrations. Drugs strongly bound to plasma proteins can displace it, since it too binds about 50% to these proteins. Methotrexate is eliminated mainly by the kidney, and its half-life ranges from 3 to 10 hours at low doses up to 8 to 15 hours after a high-dose course.

Laboratory monitoring frames the treatment. It combines a blood count, serum creatinine and transaminases, carried out every week during the first 4 weeks, then at least twice a month. This monitoring makes it possible to detect early any damage to the marrow, kidney or liver and to adjust the dose. It is an integral part of the treatment, just like the weekly intake itself.