“Methotrexate polyglutamates can tell us something and make us a little bit smarter in how we handle this drug clinically,” said Dr. Kremer. These metabolites both increase and decrease slowly in cells, reaching a steady state of concentration at about 28 weeks after initiation in most RA patients. Intracellular elimination half-life of methotrexate polyglutamates takes a little over four weeks. “If your patient misses his dose and says to you, ‘Doc, I feel great! The methotrexate must not be working,’ it is actually just slowly decreasing within cells, and not yet at the threshold of a diminished therapeutic effect.”
Oral absorption of methotrexate is highly variable and may drop off as much as 30% when increasing the dose from 7.5 mg to 15 mg due to bioavailability. “Switching to parenteral methotrexate can be highly effective, because the bioavailability changes,” said Dr. Kremer. “The patient’s intracellular levels of methotrexate polyglutamates are simply greater because they are seeing more drug.”
Methotrexate polyglutamates determine dosing rates, said Dr. Weinblatt. The optimal dose for most patients is between 18 mg and 25 mg per week. “It is important to get your methotrexate dose up when you treat patients with RA. Using too low a dose and then adding another therapy because a patient is just a ‘methotrexate nonresponder’ is not justified by the data,” he said.
RA patients whose disease is well controlled typically flare between four and six weeks after they discontinue methotrexate, so it’s preferable to either lower the dose or stretch out the duration between doses to every two weeks in these patients rather than completely stopping therapy, he said.
Tolerability Issues
Most RA patients who stop using methotrexate do so due to tolerability issues, such as nausea, stomatitis, diarrhea, vomiting and weight loss. Folic acid supplementation at 1 mg to 5 mg per day or folinic acid at 5 mg to 20 mg per week may reduce these events. Patients could take leucovorin (folinic acid), which is biologically active, if folic acid is not successful. Leucovorin should not be taken within eight hours of the methotrexate dose since it may block the efficacy of methotrexate if taken in this time frame. If leucovorin is dosed 48 hours after methotrexate, it may not reduce toxicities. Dr. Weinblatt said. Switching to subcutaneous methotrexate or using antiemetics may help relieve nausea, as well.
Fatigue is another common complaint, said Dr. Weinblatt. “Many patients simply do not feel well. We call this the ‘postmethotrexate blah.’” Increasing caffeine intake the day before or after treatment may blunt this effect. Painful skin nodules on the soles of the feet, palms or even the lungs may affect some patients. Local steroid injections may help treat nodules, or rheumatologists may switch to synthetic DMARDs or biologics in these patients.
