The continuation of methotrexate therapy for 12 months after a child with juvenile idiopathic arthritis has achieved remission did not decrease the relapse rate, compared with treatment for 6 months, according to a report in JAMA.
Longer continuation of methotrexate also failed to extend the duration of remission, said Dr. Dirk Foell of the University of Muenster (Germany) and his associates. “Therefore, it cannot be recommended that methotrexate therapy be continued in all patients for longer than 6 months after remission is induced,” an approach that has been advocated even though no controlled prospective studies have examined the issue until now.
Approximately half of patients with JIA experience disease flares after they discontinue methotrexate.
The researchers assessed 364 patients who were treated at rheumatology centers in 29 countries in a randomized, prospective, open-label trial.
Patients with all subtypes of JIA were included, and all subjects had achieved remission with methotrexate therapy. The children were about 11 years old at enrollment; they had been about 5.5-6 years old at JIA onset.
Group 1 (183 children) was randomly assigned to continue the drug for 6 months, whereas group 2 (181) was assigned to continue methotrexate for 12 months. They were then followed every 3 months for at least 1 year (median follow-up, 34 months).
Approximately equal numbers of children in groups 1 and 2 had persistent oligoarthritis (30% and 23%, respectively), extended oligoarthritis (19% and 12%), polyarthritis that was negative for rheumatoid factor (30% and 45%), polyarthritis that was positive for rheumatoid factor (5% and 4%), systemic onset JIA (8% and 12%), enthesitis-related arthritis (4% and 2%), and psoriatic arthritis (6% and 2%).
The relapse rate at 1 year was about 57% in the children who discontinued methotrexate at 6 months, which was not significantly different from the rate of 56% in the group that prolonged methotrexate for 12 months. The median relapse-free intervals were 21 months and 23 months, respectively—a difference that also was not significant, the investigators said (JAMA 2010;303:1266–73). These findings were consistent across all subtypes of JIA, they added.
“Our data are of general relevance because many chronic inflammatory diseases regularly take a relapsing course,” including rheumatoid arthritis, inflammatory bowel disease, and pediatric autoimmune hepatitis, Dr. Foell and his associates noted.
“In clinical practice, physicians are frequently faced with the question of what to do with patients who are clinically well after induction of remission. Physicians have to decide whether continuation of drug therapy is meaningful, because it may maintain inactive disease and induce a more stable remission” but also is likely to induce more adverse effects, they said.
The investigators found that serum concentrations of myeloid-related proteins 8 and 14 helped identify which patients in remission had subclinical disease activity and were at risk for relapse. Study subjects with levels less than 690 ng/mL were unlikely to have a disease flare during follow-up, whereas those with higher levels were at increased risk.
This finding suggests that relapses after methotrexate is withdrawn result from a local disease process that has not been completely resolved by the therapy, even though the clinical impression and standard laboratory testing both indicate that there is remission, Dr. Foell and his colleagues added.
Disclosures: This study was supported by the Paediatric Rheumatology International Trials Organization, a nonprofit group, and the Deutsche Rheuma-Liga. Wyeth Pharmaceuticals funded the patients' insurance in Germany. No other potential financial conflicts of interest were reported.
My Take
When Can We Stop Methotrexate?
The most common question posed by the parents of a child with JIA who has “gone into remission” has always been, “When can we stop giving these drugs?” Any parent who has read the list of warnings and side effects included on the methotrexate package insert is understandably anxious to discontinue therapy. Findings from the research by Dr. Foell and his associates begin to answer this question. When all the patients who were diagnosed as having JIA were randomly mixed, researchers found no difference in the rate of recurrence when therapy was continued for either 6 or 12 months after remission. The significance of this interesting finding is unclear. Although the treatment groups were balanced for JIA subtypes, the researchers do not discuss which subtypes the children who flared belonged to. The investigators clearly state in the methods section that “biased results due to differences between JIA subtypes were excluded by Cox models.” However, because the subtypes were evenly balanced between the two groups, this provides no information about which subgroups were most at risk.