It may be just as safe and effective to treat children with juvenile idiopathic arthritis, or JIA, using oral methotrexate as it is to give them injectable methotrexate, according to a retrospective analysis of a Germany database. But the authors of the study caution that a randomized, clinical trial is needed to compare these two routes of administration before either one can be established as superior. The study was recently published online in Arthritis Care & Research.

Methotrexate is a cornerstone of treatment for JIA, a term used to describe several different categories of arthritis in children less than the age of 16 years. “The question of how to start treatment with methotrexate in children with JIA – orally or via subcutaneous injections – is of great importance. There is no common consensus,” says lead author Ariane Klein, MD, Askelapios Klinik in Sankt Augustin, Germany.

The study notes that methotrexate injections tend to have better response rates than oral methotrexate in adults with rheumatoid arthritis, or RA. But the authors write that injections may be especially painful for pediatric patients. This can “pose a significant burden for the patients and their families, and result in more consultations with physicians and health professionals if parents feel unable to give the injections themselves,” says Dr. Klein.

In the United States, injectable methotrexate is often given to JIA patients at the start of treatment to achieve maximum effects, and once the disease is brought under control, the patient is switched to oral methotrexate, according to pediatric rheumatologist Carol Wallace, MD. Dr. Wallace is past chair of CARRA – the Childhood Arthritis and Rheumatology Research Alliance – professor and division chief of rheumatology at the University of Washington Seattle Children’s Hospital, and has authored several studies on methotrexate use in JIA.

The retrospective analysis was based on data from the German Methotrexate Registry, which was started in 2005. The study group included 411 children with JIA (average disease duration about one year) who were newly treated with either oral methotrexate (259 patients) or injectable methotrexate (152 patients) for at least six months. The method of methotrexate delivery was not assigned randomly; it was chosen by each child’s doctor.
 

Children taking injectable methotrexate had more severe disease activity when they entered the study than those in the oral group. Despite this difference, patients in both groups got a similar dose of methotrexate, about 0.4 mg/kg.

Both oral and injections of methotrexate were similarly effective, with 73 percent of the oral group and 72 percent of the injectable group achieving at least a 30 percent improvement in signs and symptoms of JIA after 6 months of treatment. A similar percentage of patients in both groups achieved a 50 percent and a 70 percent improvement in signs and symptoms of disease at 6 months.

Safety data showed that 22 percent of the oral group and 27 percent of subcutaneous group experienced at least one documented side effect (including gastrointestinal symptoms, infectious events, fatigue, blood abnormalities, uveitis). But significantly more injection patients (11 percent) discontinued methotrexate due to side effects than patients taking oral methotrexate (5 percent).

Folic acid supplementation, which is used to prevent side effects of methotrexate – such as gastrointestinal distress and elevation of liver enzymes – was given to 46 percent of the oral group and only to 32 percent of the injectable group. (Dr. Wallace notes that in the US, folic acid is typically given to all patients on methotrexate.) But there were no difference in the frequency of discontinuation in those patients who did and did not receive folic acid.

Dr. Wallace calls this study provocative and interesting – but interprets the results of this report cautiously. “Registry studies may have missing data that can be a potential problem,” she says, pointing out that the study’s safety data are difficult to interpret, details on corticosteroid use (oral and injected) was not provided, and whether patients were on nonsteroidal anti-inflammatory drugs, or NSAIDs, when they experienced an adverse event was not reported. Many of the side effects attributed to methotrexate may also occur with NSAIDs, she says.

She, like the study authors, says that a clinical trial comparing the two different routes of methotrexate administration in JIA patients would be “incredibly helpful.”

And Dr. Wallace – whose research has focused on early and aggressive treatment for JIA, including the use of a biologic in addition to methotrexate – says she would be interested in a follow up of this group of patients. “Treatment of JIA is an evolving area. It would be interesting to know how many patients from this 2005 to 2009 cohort continued on methotrexate alone after six months with achieving inactive disease,” she says. “Currently, most patients would be started on methotrexate earlier in [the course of the] disease than the average disease duration of 1 year in this report. Earlier treatment may provide different efficacy between the routes of treatment.”