PHILADELPHIA — Extending methotrexate for more than 6 months after remission had no added benefit for preventing long-term flares in a randomized study of more than 300 patients with juvenile idiopathic arthritis.
The findings also showed that measuring serum levels of the inflammatory marker myeloid-related protein (MRP)8/14 predicted which patients in remission would experience flares off treatment and which would not.
Based on these results, MRP8/14 now is routinely used at the University of Muenster, Germany, to guide withdrawal of methotrexate from juvenile idiopathic arthritis (JIA) patients in remission, Dr. Dirk Foell said at the annual meeting of the American College of Rheumatology, More work is needed to refine use of prognostic, inflammatory markers in these patients, he added.
Some patients may reach an unstable remission on medication, giving them a status of clinical but not immunologic remission. “MRP8/14, a marker of phagocyte activity, indicates subclinical inflammation and identified patients with an increased risk of relapse in whom therapy may not be safely stopped,” said Dr. Foell.
Dr. Foell and his associates proposed a MRP8/14 cutoff of 690 ng/dL because they found it combined the best level of specificity and sensitivity for predicting relapse. But they recognize that the cutoff is a statistical number that is not ideal for all cases.
A multicenter collaboration of the Paediatric Rheumatology International Trials Organization (PRINTO), randomized 364 JIA patients with clinical remission on methotrexate. (The average age of the patients was 11 years, about two-thirds were girls, nearly 90% were white, and their median disease duration at enrollment was 3 years). The researchers took patients off of their methotrexate regimen after either 6 or 12 months of remission. They took serum specimens just before methotrexate stopped to measure MRP8/14, which is very stable in the serum. Specimens came from 188 of the patients (52%). Follow-up continued for at least 12 months following the withdrawal.
In an intention to treat analysis, the rate of relapse flares during the first year of follow-up was virtually identical in the two treatment arms: a rate of 40.2 flares/1,000 patient-months of follow-up in 183 patients withdrawn after 6 months, and 40.3 flares/1,000 patient-months in 181 patients withdrawn after 12 months. During 2 years of follow-up, the rates were 33 flares/1,000 patient-months and 29 flares/1,000 patient-months, respectively, also not a statistically significant difference.
An analysis of patients based on their MRP8/14 levels showed a dramatic difference in flare rates. Those with a level of less than 690 ng/dL just before cessation of methotrexate had a flare rate of 26/1,000 patient-months during the first year of follow-up, and 20/1,000 patient months through 2 years of follow-up. Patients with a MRP8/14 level of 690 ng/dL or more had rates of 57 flares/1,000 patient-months and 48 flares/1,000 patient-months, respectively, a statistically significant difference between the two arms, according to the investigators.
Dr. Foell said that he has been a scientific adviser to Wyeth, Regeneron Pharmaceuticals Inc., and CisBio International.