Methotrexate is the most common disease-modifying antirheumatic drug (DMARD) used to treat juvenile idiopathic arthritis (JIA). However, only about half the children treated with methotrexate respond to it. Among rheumatologists, questions about methotrexate use in children remain.
Mara Becker, MD, director of the division of rheumatology at Children's Mercy Hospital in Kansas City, Mo., and a methotrexate expert, says uncertainty exists because methotrexate studies yield conflicting results and ideas about JIA treatment are changing rapidly.
Pill or injection?
Initially, almost all children took methotrexate by mouth (oral methotrexate) because that's how it was administered to adults. Also, there were no specific guidelines for children. In the United States, that changed when JIA treatment approaches became more aggressive.
"We were no longer satisfied with partial improvement; we wanted kids to be in remission. Instead of waiting for a pill to work, many doctors stared using injections right away, knowing the drug would be absorbed completely," Dr. Becker explains. "There was also a sense that side effects such as nausea and vomiting were worse with oral medication."
However, European studies and registry data have found that methotrexate pills and shots are equally effective and have similar side effects.
Norman Ilowite, MD, chief of the division of rheumatology at The Children's Hospital at Montefiore and professor of pediatrics at Albert Einstein College of Medicine in the Bronx, New York, agrees with those findings.
"Both ways of giving methotrexate are good," he says. "There is a slightly higher level of methotrexate in the blood after an injection but, in studies, the overall amount absorbed in most children is the same. [Furthermore], the idea that injecting methotrexate reduces the frequency and severity of side effects was based on studies in adults; that doesn't seem to be true in children."
Dr. Becker thinks otherwise. At the 2014 Pediatric Rheumatology Symposium in Florida, she presented results of a study showing that children treated with injectable methotrexate achieved better and faster results than those who took the medicine by mouth.
"There isn't a lot of great data to guide treatment, and giving the drug in an injection takes some of the guesswork out. I also believe the side effects are diminished," she says.
What about dosing?
Methotrexate is prescribed based on a child's weight. The American College of Rheumatology recommends 15 milligrams per square meter of body surface area (15 mg/m2) per week a dose used by many pediatric rheumatologists.
"Some studies have looked at regimens of 25 to 30 mg/m2 per week for children who don't respond to lower doses, but that seems to be the highest dose that should be tried," Dr. Ilowite says. "Beyond that, there is evidence of increased toxicity. If you've pushed the dose as high as a child can tolerate and there's no response, it's probably time to add a biologic." (Biologics are another class of drugs that target various inflammatory proteins).
Dr. Becker uses a similar step-wise approach in treating non-systemic subtypes of JIA. "I start with a standard dose of methotrexate, then live with it a few months to see if it's working before adding a biologic," she says.
Dr. Ilowite notes that some doctors are "going straight to biologics" for kids with polyarticular JIA, but adds, "That's not in the guidelines, and it's not what the FDA approved for children. On the other hand, there is no nausea, vomiting or fatigue with biologic medications, and some people feel they're more effective and less toxic. But I don't use them as a first-line therapy for polyarticular-course patients. Methotrexate has been around much longer than biologics, it's much cheaper and insurance will cover it. These are all things families need to discuss with their doctor."
Folic acid or leucovorin for side effects?
Nausea and vomiting are the most common short-term side effects of methotrexate; some kids also feel sleepy, fatigued and generally unwell after taking it.
"About 15 to 20 percent of kids just don't feel great for 24 hours after a dose," Dr. Becker says. "If they take [methotrexate] on Friday, they may feel yucky on Saturday, but then the rest of the week, they're feeling pretty good."
The most common way to help prevent these and other side effects, including mouth sores and hair loss, is with folic acid, a synthetic form of the B vitamin folate. Methotrexate interferes with the body's ability to use folate and can deplete it over time.
"Folate is important for rapidly dividing cells [such as red blood cells], so I prescribe daily folic acid. It helps nausea and mouth sores. It's an important and easy adjunct to methotrexate therapy," Dr. Becker explains.
Dr. Ilowite doesn't dispute the effectiveness, ease and reasonable cost of folic acid. But he notes that some studies suggest folic acid may make methotrexate less effective. For that reason, the drug leucovorin is sometimes prescribed instead. Leucovorin, also called folinic acid, is used to treat nausea during chemotherapy.
The most important thing, Dr. Ilowite says, is to supplement with folic acid or leucovorin as soon as methotrexate is prescribed in order to help minimize side effects.
When to stop methotrexate?
Once the arthritis is well controlled, there are few clear guidelines about when to discontinue therapy. The risk of a disease flare, which occurs in up to 50 percent of kids who stop medication, must be balanced against the increased risk of side effects and toxicity.
Dr. Becker tends to wait one to two years after remission (complete absence of symptoms) before discontinuing treatment.
"We don't have the ability to know when the disease is really inactive, but we know through registry data that it tends to last longer than we thought," she says.
But Dr. Ilowite points to a 2004 European study that showed extending medication use for more than six months after remission did not prevent long-term flares.
"We always thought if kids were treated longer they would end up with fewer relapses, but that may not be the case," he notes.
The debate about the timing of methotrexate discontinuation may eventually be resolved using laboratory tests to measure inflammatory markers in the blood. In studies, a substance called myeloid-related protein (MRP)-8/14 accurately predicted which children were likely to relapse after stopping medication.
Each child with JIA is unique and will have a treatment plan customized for his or her needs. Dr. Ilowite encourages parents to ask their child's rheumatologist about all these issues. Unfortunately, he says, "There's no good answer because the studies are contradictory."