Parenteral MTX in Children With JIA Questioned

Janis C. Kelly

May 30, 2012

May 30, 2012 — Data from the German Methotrexate Registry showed no advantage to subcutaneous (SC) methotrexate (MTX) compared with oral MTX for children with juvenile idiopathic arthritis (JIA). Ariane Klein, MD, from Asklepios Klinik in Augustin, Germany, and colleagues suggest that SC MTX can probably be avoided in favor of oral MTX "without consequences" in patients with JIA. However, pediatric rheumatology specialists not involved in the newly published study have raised methodological questions about the work.

Dr. Klein and colleagues describe their results in an article published online May 30 in Arthritis Care and Research.

Unexpected Results

Senior author Gerd Horneff, MD, director of the Center of General Pediatrics and Neonatology and chief of Pediatric Rheumatology at the Asklepios Clinic, told Medscape Medical News, "Indeed, our results were unexpected. When we decided to make the analysis, we expected to observe superiority of parenteral MTX over oral MTX, as has been shown in adults.... However, in this study on rheumatoid arthritis patients, the number needed to treat for 1 superior result is about 12 patients ([American College of Rheumatology 20 criteria] was 78% vs 70% of patients). This number already would argue more against injecting children because you may need to inject 12 children to have 1 in who [the drug] has an advantage."

The investigators used data collected by the German Methotrexate Registry since 2005 to identify JIA patients who were treated with MTX for at least 6 months and who did not receive additional biologic therapies. The researchers excluded patients who changed their MTX approach during the observation period. The study groups consisted of 259 (63%) patients who received oral MTX and 152 (32%) patients who received SC MTX. In both groups, patients had a median age of 10 years, two thirds were girls, and all received a comparable weekly dose of MTX (0.4 - 0.42 mg/kg). Patients in the SC MTX group were significantly less likely that those receiving oral MTX to have received folic acid supplements (32% vs 46%; P = .002), were more likely to have rheumatoid factor (RF)-positive arthritis (9% vs 2%; P < .001), and had shorter disease duration (0.8 vs 1.1 years; P = .033).

The primary outcome measure was efficacy, defined as the number of patents who reached American College of Rheumatology Pediatric Score (PedACR) 30 criteria after 6 months of treatment. The researchers report that 72% of patients receiving oral MTX and 73% of patients receiving SC MTX achieved this outcome.

At least 1 adverse event was reported in 22% of patients receiving oral MTX and in 27% of patients receiving SC MTX. Significantly more patients receiving SC MTX injections discontinued treatment because of adverse events compared with those receiving oral treatment (11% vs 5%; P = .02).

Dr. Klein said in a press statement, "Our analysis found that efficacy and tolerability of MTX was similar in both delivery methods. The often unpopular MTX injection did not appear to be superior to oral administration and may likely be spared without clinical consequences."

Avoiding the unpleasant injections would appeal to many clinicians and to patients with JIA and their families, who must either give the injections themselves at home or visit a clinic weekly. Dr. Horneff said, "Since I know about these data, I have changed my behavior and am prescribing the oral dosing more often. Only few patients still receive injections, typically because they refuse to swallow the pills."

However, 2 pediatric rheumatologists consulted by Medscape Medical News are less convinced that the retrospective registry analysis adequately supports routine avoidance of SC MTX in patients with JIA.

"Interesting but Not Definitive"

"The study by Klein et al is interesting but not definitive," said Matthew Stoll, MD, assistant professor of pediatric rheumatology at the University of Alabama, Birmingham. "I have several concerns with the study. As the authors acknowledged, there is the possibility for confounding by indication, in that the patients started on SC MTX may have had more active disease. There is some indication that this was the case, in that patients started on SC MTX had more RF-positive polyarticular JIA and less extended oligoarticular JIA."

Dr. Stoll continued, "The authors limited the study to patients who were on MTX for 6 months and did not start a biologic medicine, such as etanercept. In so doing, they may have selected for a group of patients who would do well on MTX, since patients who showed minimal improvement after 3 months may have been more likely to be started on a biologic."

Dr. Stoll also questioned the low MTX dose used in both groups. "Tukova et al. showed that increases of MTX beyond 10 mg/m2 lead to increased blood levels if given SC, but not by mouth. Thus, it is possible that they might have detected larger differences between the groups if they had used higher doses," he said.

When asked about this dosing, Dr. Horneff countered that the mean dosage in adults on a fixed dosing regimen of 15 mg/week without adjustment for weight is much lower than in the patients with JIA in this study. "It has been shown previously that higher dosages are not very valuable. Higher bioactivity reached by SC injection [with a drug that achieves maximum effect at lower dosages] is of no advantage for the patient."

Heather Van Mater, MD, assistant professor of pediatrics at Duke University School of Medicine, Durham, North Carolina, also reviewed the study for Medscape Medical News. Dr. Van Mater agreed with Dr. Stoll that the data do not support the authors' conclusion that "[t]he often unpopular and more expensive parenteral application could probably be spared without consequences."

Results Biased?

Dr. Van Mater said, "They excluded patients who switched from 1 route to the other, which in my opinion biases their results. The most common reason for changing from oral to SC MTX is ineffectiveness of the oral drug. Patients doing well may be switched from SC to oral. It also seems the patient started on SC MTX had higher physician and parent global assessments and ESR.... The difference in RF-positive disease is significant, given how much more aggressive and difficult to control RF-positive disease is."

Dr. Stoll agreed that the increased incidence of RF-positive polyarticular JIA in the SC MTX group could have influenced the outcome, and that higher use of folic acid supplementation in the oral MTX group could have affected the incidence of adverse events.

"Because of the concerns listed above, I am not convinced by the data," Dr. Stoll said. He also noted that although the authors acknowledge the need for randomized trials of SC MTX vs oral MTX in patients with JIA and of the effects of switching from oral MTX to SC MTX, such studies are unlikely.

Dr. Horneff would like to see a head-to-head double-placebo trial with 2 placebos. "I am wondering if there would be a financial support for this in the area of biologics," he said.

"I doubt that a randomized trial in JIA will be performed," Dr. Stoll said. "Not only would it be expensive, but I don't think many pediatric rheumatologists in the United States would tolerate maintaining children on MTX as monotherapy for a period of 6 months, unless they demonstrated an excellent response."

Dr. Van Mater added, "We have to be careful drawing conclusions from registry data, especially when you exclude the very population that may provide some of the most useful information; ie, those who start on oral but change to SC due to ineffectiveness of the oral drug. I also am not convinced that the initial selection of SC MTX wasn't because those patients had worse disease. This [study] will not change my practice, which is to use oral MTX initially on kids with milder disease and SC MTX on kids with more severe disease. While a randomized clinical trial would be great, I don't see that study being funded."

The German Methotrexate Registry is sponsored by Wyeth Biopharma. Dr. Horneff has been a member of the advisory boards for Wyeth Biopharma, Abbott Pharma, Novartis Pharma, Roche Pharma, and Essex Pharma and is conducting clinical studies sponsored by Wyeth Biopharma and Abbott Pharma. Dr. Stoll And Dr. Van Mater have disclosed no relevant financial relationships.

Arthritis Care Res. Published online May 30, 2012. Abstract

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