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Methotrexate (MTX) was an effective treatment of resistant juvenile rheumatoid arthritis (JRA) in a double blind, placebo controlled study.1 Its advantages over other second line agents,2 include oral administration, once a week dose, fewer side effects than parenteral gold,3 no known oncogenicity4 or long term effects on fertility.5 Therefore, paediatric rheumatologists tend to consider the use of MTX as a first choice for children with refractory JRA.6 7
We considered the duration of MTX therapy required for the achievement of partial and total clinical remission of JRA, and conducted a prospective open trial of all patients with JRA who were given MTX treatment at the Paediatric Rheumatology Clinic of the Rambam Medical Centre, between January 1994 and January 1997.
The patients had active JRA according to American College of Rheumatology (ACR) criteria8 and had failed to respond to adequate courses of non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroids or disease modifying drugs (DMARDs). All the patients who had been previously treated with a DMARD stopped taking the drug at least three months before starting MTX; patients who had previously received MTX were excluded.
Seventeen patients were eligible for inclusion in the study; eight had a polyarticular, five systemic, and four pauciarticular disease onset.
MTX was given orally, in a total weekly dose of 0.2 mg/kg. Although additional prednisone in doses below 10 mg/day and NSAIDs were permitted, no patient received DMARDs or higher dose corticosteroids during the study period.
A partial response to MTX was defined as a 25% reduction of the active joint count or articular severity score, or both, as defined by the Pediatric Rheumatology Collaborative Study Group.1Remission criteria for JRA were applied as in adult rheumatoid arthritis.9
Seventeen patients were enrolled in the trial (nine girls and eight boys). Mean (SD) age and duration of disease activity at entry were 11.4 (5.4) and 4.5 (3.7) years, respectively. Nine patients had previously received other DMARDs.
Ten patients were taking low dose prednisone. The dose of MTX ranged from 7–15 mg/m2/wk. Two patients required an increase of the dose to 15 mg after six months of treatment.
Fourteen of 17 patients (82%) displayed a 25% reduction in joint activity after six weeks to four months (median; nine weeks) of treatment; 10 patients (59%) went into full clinical remission after five to 26 months (median 15 months); three patients (18%) relapsed after an initial favorable response, and four (23%) did not respond to MTX.
Laboratory parameters of activity improved in 12 patients (70%).
Disease activity decreased in 15 patients (88%). The mean (SD) number of joints affected with active arthritis at the beginning of the trial was 12.2 (9.3), and decreased to 5.2 (7.1) at its completion. Duration of morning stiffness decreased by more than 50% in 10 patients (59%).
Of 10 patients who had initially been taking low dose prednisone, six (60%) were able to reduce the dose or stop taking corticosteroids altogether.
Seven (41%) patients did not respond to treatment; these were mainly children who required the higher dose of corticosteroids (p<0.001). Table 1 shows the clinical characteristics of responders and non-responders.
MTX is being increasingly used by paediatric rheumatologists as a first choice agent in the treatment of children with resistant JRA,6 7 but prospective studies regarding remission of JRA with MTX are lacking. Two retrospective reports described the clinical characteristics of patients with JRA experiencing remission10 and the frequency of relapse after discontinuation of MTX treatment.11 The dose of MTX in those two studies was in the same range that we used in our group.
The remission rate we observed was similar to that reported in the retrospective studies, as well as the mean time to achieve clinical remission: 15 months in our study, compared with 13 months and 11 months in the Wallace10 and Ravelli11studies, respectively, although some of the patients in the study conducted by Wallace received various DMARDs concomitantly with MTX.11
Fourteen of our patients experienced a partial remission after a median of nine weeks of treatment, but three did not sustain their remission; four others did not respond to MTX treatment at all. These patients did not differ from the responders as regards duration of disease before starting MTX, disease onset type, previous treatment with DMARDs, or severity of disease activity.
In conclusion, MTX seems to be an effective and safe drug for patients with resistant JRA. An initial favourable response can be expected in most children, and nearly two thirds of our patients experienced good clinical remission after a median treatment period of 15 months.
In view of the limited numbers of patients who have been studied so far, further prospective controlled studies are necessary to confirm the the value of MTX in the treatment of refractory JRA.
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