A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate

Authors


Abstract

Objective

To compare the safety and efficacy of parenteral methotrexate (MTX) at an intermediate dosage (15 mg/m2/week) versus a higher dosage (30 mg/m2/week) in patients with polyarticular-course juvenile idiopathic arthritis (JIA) who failed to improve while receiving standard dosages of MTX (8–12.5 mg/m2/week).

Methods

In the screening phase, 595 patients who were newly started on a standard dose of MTX were followed up for 6 months. Subsequently, the nonresponders, defined according to the American College of Rheumatology (ACR) pediatric 30% improvement criteria (pediatric 30), were randomized to receive an intermediate dose or higher dose of parenteral MTX for an additional 6 months. Improvement in the screening and randomization phase was defined by the ACR pediatric 30 response, as well as by the 50% and 70% response levels (ACR pediatric 50 and ACR pediatric 70, respectively).

Results

In the screening phase, after receiving standard doses of MTX, 430 patients (72%) improved according to the ACR pediatric 30, while 360 (61%) met the ACR pediatric 50 and 225 (38%) met the ACR pediatric 70; among these patients, 69 (12%) also met the definition of complete disease control. Of the 133 nonresponders, 80 were randomized to receive an intermediate dose or higher dose of MTX. In the randomization phase, the ACR pediatric 30 response rate was 25 of 40 children (62.5%) in the intermediate-dose group versus 23 of 40 children (57.5%) in the higher-dose group. An ACR pediatric 50 response rate was attained by 23 patients (57.5%) receiving an intermediate dose versus 22 (55%) in the higher-dose group. An ACR pediatric 70 response rate was seen in 18 children (45%) receiving an intermediate dose versus 19 (47.5%) receiving a higher dose. Five children (12.5%) in the intermediate-dose group versus 4 (10%) receiving the higher dose of MTX also met the definition of complete disease control. None of the intergroup differences in response rate were significant. There were no significant differences in the frequency of adverse events or laboratory abnormalities between the 2 randomized groups.

Conclusion

This study shows that the plateau of efficacy of MTX in JIA is reached with parenteral administration of 15 mg/m2/week and that a further increase in dosage is not associated with any additional therapeutic benefit. MTX should be administered for up to 9–12 months to appreciate its full therapeutic effect.

Juvenile idiopathic arthritis (JIA) encompasses a heterogeneous group of disorders involving chronic arthritis, disease onset before 16 years of age, and unknown etiology. With a reported prevalence of 86.1–94 per 100,000 children (1), JIA is the most common chronic rheumatic disease in childhood and one of the leading causes of pediatric acquired disability (2, 3).

Methotrexate (MTX) is the disease-modifying agent of first choice for the treatment of polyarticular-course JIA. At a dosage of 10 mg/m2/week, MTX has been shown to have a significant therapeutic advantage over placebo and an acceptable safety profile (4). Subsequently, a higher dosage of MTX, up to 30 mg/m2/week, has been suggested as a therapeutic option for patients whose condition remains resistant to the standard dosage, but no randomized trial has ever confirmed this hypothesis (5). Although anti–tumor necrosis factor (anti-TNF) agents (6) have become available in recent years for the treatment of MTX-resistant patients, these medications are expensive and not available to all patients. Therefore, the definition of the optimal dosage of MTX in terms of efficacy and safety remains central to disease management.

For these reasons, the Pediatric Rheumatology International Trials Organization (known as PRINTO), which is supported by the European Union, conducted a 20-country randomized, open-label, standard-of-care trial to evaluate the efficacy and safety profile of MTX at an intermediate dose versus a higher dose in patients with polyarticular-course JIA who failed to improve while receiving a standard dosage of MTX.

PATIENTS AND METHODS

Patients.

A total of 633 children with polyarticular-course JIA were enrolled from January 1998 to May 2001. These children were recruited from pediatric rheumatology tertiary care units in 20 countries: Austria (n = 2), Belgium (n = 17), Brazil (n = 49), Bulgaria (n = 5), Czech Republic (n = 18), Finland (n = 9), Germany (n = 12), Israel (n = 10), Italy (n = 175), Korea (n = 2), Mexico (n = 17), The Netherlands (n = 42), Norway (n = 19), Slovakia (n = 16), Spain (n = 26), Sweden (n = 6), Switzerland (n = 19), Turkey (n = 16), UK (n = 165), and the US (n = 8).

Study design.

The study was divided into 2 phases (Figure 1). The initial phase was the screening phase. This was followed by the randomization phase.

Figure 1.

Flow diagram of the patients with juvenile idiopathic arthritis participating in a randomized trial of parenteral methotrexate (MTX) at an intermediate dose versus a higher dose as compared with a standard dose. po = by mouth; sc = subcutaneously; im = intramuscularly.

In the screening phase, eligible patients were children who had a diagnosis of JIA with a polyarticular disease course as defined according to the Durban criteria (7), and who were newly started on MTX at a standard dose. A baseline evaluation was performed on the day of initiation of MTX therapy. To make the sample more pathophysiologically homogeneous, we excluded from the screening phase patients with rheumatoid factor (RF)–positive JIA, psoriatic arthritis, and enthesitis-related arthritis. Children with RF-positive JIA were excluded because this subset of JIA is considered the equivalent, in childhood, of adult RF-positive rheumatoid arthritis (8). Those with psoriatic arthritis were excluded because, at the time of the study, there was still concern about the increased hepatotoxicity of MTX in patients with psoriatic arthritis (9). Finally, those with enthesitis-related arthritis were excluded because this type of arthritis is considered to belong to the spondylarthropathies, and MTX is not considered the second-line drug of first choice for its treatment (10).

In order to be randomized to receive a higher dose of MTX, eligible patients had to have at least 5 joints with active arthritis plus abnormal results for at least 2 of any of the 5 remaining JIA core set criteria (11, 12). Other eligibility criteria for the randomization phase were treatment with standard-dose MTX for 6 months (screening phase period), a stable dose of no more than 1 nonsteroidal antiinflammatory drug for at least 1 month prior to randomization, and a stable, low dosage of prednisone (≤0.2 mg/kg/day or 10 mg/day, whichever was less) for at least 1 month prior to randomization, as well as administration of adequate birth control methods in patients who were sexually active (the decision about which birth control methods should be used was left to the attending physician, family, and patient), and the ability of the patient to communicate meaningfully with the medical staff.

Exclusion criteria for the randomization phase included treatment in the screening phase with any other second-line agents or intravenous immunoglobulin, a white blood cell count ≤3,000/mm3, a platelet count ≤50,000/mm3, levels of serum glutamic oxaloacetic transaminase/asparagine aminotransferase (SGOT/AST) or serum glutamic pyruvic transaminase/alanine aminotransferase (SGPT/ALT) above the upper limit of normal, creatinine levels above the upper limit of normal, chronic proteinuria or hematuria (2–4+/4 on dipstick on 2 consecutive tests), known positive serologic findings of hepatitis B or C, immunization with a live-virus vaccine within the 2 weeks prior to randomization, presence of any other concomitant disease (arthritis associated with inflammatory bowel disease, neonatal-onset multisystem inflammatory disease, periodic syndrome, acute or chronic infection, insulin-dependent diabetes mellitus, malignant disease within the previous 5 years, interstitial pneumonitis by history, or other medical conditions considered to preclude adequate evaluation of drug safety or efficacy). The patients who, at the end of the screening phase, were classified as treatment responders according to the American College of Rheumatology (ACR) pediatric 30% improvement criteria (ACR pediatric 30) were no longer followed up.

Patients were dropped from the trial, but included in the efficacy analysis, if any of the following occurred during the randomization phase of the trial: enrollment in other therapeutic trials, receipt of more than 3 intraarticular steroid injections (in the same or different joints) during the randomization phase (these joints were considered to be failure joints in the analysis), an increase in the steroid dose higher than the entry dose at any time during the randomization phase of the trial, development of significant proteinuria (2–4+/4 on dipstick on 2 consecutive tests), and an elevation in the levels of SGOT/AST and/or SGPT/ALT above the normal limits in at least 3 of 6 monthly determinations (modified from the method described by Kremer et al [13]). The protocol was approved by an independent ethics committee at each center, and written informed consent was obtained from the patient's parent or legal guardian at the beginning of the screening phase or before randomization, according to the requirements of the local ethics committee. The trial was built on the current standard of care in such a way that insurance coverage, medications, clinic visits, and laboratory tests were paid by the usual method of reimbursement for care in each country (14).

In the screening phase, all patients were treated with a standard dosage of MTX at 8–12.5 mg/m2/week by mouth, intramuscularly, or subcutaneously for 6 months. In the randomization phase, children were randomly assigned, in an open manner, to receive either an intermediate dosage (15 mg/m2/week, maximum 20 mg/week) or a higher dosage (30 mg/m2/week, maximum 40 mg/week) of MTX subcutaneously or intramuscularly for an additional 6 months. Medication was administered as a single dose once per week.

Physical examinations and evaluations of the JIA core set variables were performed at baseline, at the end of the screening phase, and then, for the randomized patients, at month 3 and month 6. For drug safety, standard laboratory tests (hematology with differential cell counts, measurements of SGOT/AST, SGPT/ALT, and serum creatinine, and examination of urine) and evaluations of adverse events were performed at the end of the screening phase and then monthly during the randomization phase. Data were collected via fascimile, and queries were resolved immediately.

Measures.

As primary outcome measures, we used the validated ACR pediatric 30 definition of improvement (11, 12, 15). According to the ACR pediatric 30, patients were considered to be responders to treatment with MTX if they demonstrated at least 30% improvement from baseline in at least 3 of any 6 JIA core set variables with no more than 1 of the remaining variables worsening by more than 30% (11, 12). The ACR pediatric 30 allows researchers or clinicians to dichotomize patients into responders or nonresponders. Patients were also evaluated by ACR response levels of at least 50% and at least 70% (ACR pediatric 50 and ACR pediatric 70, respectively) in at least 3 of any 6 JIA core set variables with no more than 1 of the remaining variables worsening by >30%. Complete disease control was defined as an erythrocyte sedimentation rate (ESR) of <20 mm in the first hour in the absence of any active arthritis (16).

As secondary outcomes measures, we used the individual validated JIA core set variables (11, 12), which include the number of joints with active arthritis (defined as a joint with swelling or a joint with pain and limitation on movement) (range 0–71) (17), the number of joints with limited range of motion (range 0–67) (18), the physician's global evaluation of disease activity on a double-anchored 10-cm visual analog scale (VAS) (anchoring words 0 = inactive, 10 = very severe), the parent's global assessment of the child's overall well-being on a double-anchored 10-cm VAS (anchoring words 0 = very well, 10 = very poor) as reported on the Childhood Health Assessment Questionnaire (CHAQ) (19, 20), the disability index of the CHAQ, and the Westergren ESR. All measures related to assessment of the joints are reported as a joint count only, to avoid redundancy with the scoring method for joint evaluation (18, 21). The CHAQ (19, 20) is a validated disease-specific instrument for JIA adapted from the adult Health Assessment Questionnaire. It measures functional ability in 8 activities of daily living: dressing and grooming, arising, eating, walking, hygiene, reach, grip, and activities. These 8 domains are then averaged into a summary score ranging from 0 to 3, with higher scores meaning higher disability. The CHAQ also provides an assessment of discomfort using a 10-cm VAS for the evaluation of pain and a 10-cm VAS for the evaluation of overall well-being (this is part of the JIA core set).

As additional assessments, we reported the number of joints with swelling (range 0–62), the number of joints with tenderness and/or pain on motion (range 0–75), the parent's evaluation of the child's pain on a double-anchored 10-cm VAS (anchoring words 0 = no pain, 10 = very severe pain) as reported on the CHAQ, and the physical summary score (PhS) and psychosocial summary score (PsS) of the Child Health Questionnaire (CHQ) (20, 22). The CHQ (20) is a generic health instrument designed to record the physical and psychosocial well-being of children 5 years of age and older. In the parent's version used in this study, parents are instructed to take into consideration the 4-week period preceding the date that the questionnaire was completed. The CHQ measures 50 items/questions comprising 15 health concepts, 10 of which are then used to obtain the 2 final grouping scores, the PhS and the PsS. The PhS and the PsS are norm-based scores (obtained with comparison against healthy children) with a mean of 50 and a standard deviation of 10 (higher scores indicate better health). Both the CHAQ and the CHQ have been fully validated and translated in all of the languages of the countries participating in this MTX trial (20).

Statistical analysis.

Analyses were completed according to the recommendation of the Consolidated Standards of Reporting Trials statement, using the intention-to-treat principle with a last-observation-carried-forward approach for missing data and for patients who withdrew before the end of the randomization phase (23). Descriptive statistics were used for reporting demographics, clinical characteristics, efficacy variables, and adverse events. Data analysis included Student's t-test, analysis of variance with Scheffé test for post hoc comparisons, Mann-Whitney U test, and chi-square test or Fisher's exact test as appropriate. Repeated-measures analysis of variance was performed in order to test differences at various time points for the secondary continuous outcome measures. Confidence intervals were expressed with limits of 95% (95% CI).

For the randomization phase, a sample size of 115 patients per treatment group was necessary, with the alpha error level set at 0.05, power of 80%, delta of 20% (Δ20% = 70% expected response rate in the MTX higher-dose group minus 50% expected response rate in the intermediate-dose group), and an estimated dropout rate of 20% (24, 25). With a reported nonresponder rate to standard-dose MTX of 27% (27% nonresponder rate = 1 minus 63% responder rate reported in the literature) (4), we estimated that up to 650 patients had to be enrolled in the screening phase to be able to randomize the required 230 patients.

Patients were centrally randomized, with a unique list of random numbers that were valid for all centers (no stratification per center), into 2 nonstratified independent groups using the random number selection function of Epistat 4.5 (Sigma Services, Richardson, TX). Physicians and patients were unaware of the patients' assigned treatment group until randomization occurred. Data were entered in an Access XP database and analyzed with Excel XP (Microsoft, Redmond, WA), Statistica 6.0 (StatSoft, Tulsa, OK), and Stata 7.0 (Stata Corporation, College Station, TX) by 2 of the authors (NR and AP).

RESULTS

Baseline characteristics.

In the screening phase, 633 patients with JIA who were newly started on standard dosages of MTX were enrolled; 38 patients were excluded from further consideration because 35 of them were RF positive, 2 had psoriatic arthritis (1 was RF positive), and 2 had enthesitis-related arthritis (Figure 1). The remaining 595 patients with JIA (325 with polyarthritis, 183 with extended oligoarthritis, and 87 with systemic-onset arthritis) were treated for a mean (±SD) of 5.6 ± 1.5 months. MTX was administered orally in 463 children (78%), subcutaneously in 101 children (17%), and intramuscularly in 31 children (5%) at a mean ± SD dose of 10.0 ± 2.3 mg/m2/week.

At the end of the screening phase, after treatment with the standard dosages of MTX, 430 children (72%) improved in accordance with the ACR pediatric 30, 133 (23%) did not improve, and 32 (5%) were lost to followup. Of the 133 nonresponders, 53 were not eligible for randomization (Figure 1). The reasons for not randomizing these 53 patients were as follows: 29 children had <5 joints with active arthritis, 10 parents refused to allow randomization, 7 children had drug-related reasons (4 were receiving a higher-than-allowed dose of prednisone, 1 was receiving a higher-than-allowed dose of MTX, 1 was receiving salazopyrine, and 1 was receiving cyclosporine), 4 children had laboratory-related reasons (3 experienced an increase in transaminase levels, 1 had leukopenia), and 3 children had other reasons (1 had a seizure, 1 developed proteinuria, and 1 showed noncompliance with MTX administration). Some of the noneligible patients had more than 1 criteria for exclusion from randomization. The remaining 80 patients were equally randomized to receive either intermediate-dose MTX or higher-dose MTX.

In the randomization phase, the 2 groups of patients (40 in each group) were well balanced with respect to their demographic and disease characteristics (Table 1). All of the randomized patients were switched to parenteral MTX (79% subcutaneous and 21% intramuscular). The mean ± SD dosage of MTX was 14.5 ± 1.3 mg/m2/week in the intermediate-dose group and 28.5 ± 2.5 mg/m2/week in the higher-dose group.

Table 1. Demographic characteristics and disease history of the study patients at baseline*
CharacteristicScreening phase, standard-dose MTX (n = 595)Randomization phase
Intermediate- dose MTX (n = 40)Higher-dose MTX (n = 40)
  • *

    Percentages were calculated based on valid data (i.e., missing data were excluded). MTX = methotrexate; JIA = juvenile idiopathic arthritis.

Demographics, mean ± SD years   
 Age at onset5.5 ± 4.05.5 ± 3.95.7 ± 4.1
 Age at visit8.2 ± 4.68.8 ± 4.88.3 ± 4.3
 Disease duration2.7 ± 3.33.2 ± 3.72.6 ± 2.1
Age group, no. (%)   
 ≤4 years139 (23)7 (17.5)6 (15)
 >4 and ≤8 years164 (28)14 (35)15 (38)
 >8 and ≤12 years173 (29)7 (17.5)12 (30)
 >12 years119 (20)12 (30)7 (17)
Sex, no. (%)   
 Female428 (72)31 (78)32 (80)
 Male167 (28)9 (22)8 (20)
JIA subtype, no. (%)   
 Polyarthritis325 (54)24 (60)20 (50)
 Extended oligoarthritis183 (31)9 (23)14 (35)
 Systemic-onset arthritis87 (15)7 (17)6 (15)
Clinical and laboratory characteristics, no. (%)   
 Antinuclear antibody positive269 (47)12 (31)16 (41)
 Chronic iritis74 (13)1 (3)4 (10)
Concomitant therapy, no. (%)   
 Folic acid289 (55)30 (75)33 (83)
 Folinic acid108 (20)8 (20)5 (13)
 Prednisone145 (27)15 (38)14 (35)

Screening phase.

As shown in Figure 2, at the end of the screening phase (month 6) among the 595 patients enrolled, 430 patients met the ACR pediatric 30 (response rate 72%, 95% CI 68–76%), whereas 360 met the ACR pediatric 50 (response rate 61%, 95% CI 56–64%) and 225 met the ACR pediatric 70 (response rate 38%, 95% CI 34–42%); 69 of these patients also met the definition of complete disease control (12%, 95% CI 9–14%). There was no statistically significant difference in the response rate, according to the ACR pediatric 30, when the patients treated orally (response rate 76%, 95% CI 72–80%) were compared with the patients treated intramuscularly or subcutaneously (response rate 77%, 95% CI 69–83%) (P = 0.90).

Figure 2.

Frequency of treatment response as determined by the American College of Rheumatology (ACR) pediatric 30%, 50%, and 70% definitions of improvement (Ped 20%, Ped 50%, and Ped 70%, respectively), as well as those achieving complete disease control among the 595 patients enrolled in the screening phase (standard doses [S] of methotrexate [MTX]) and among the 80 patients randomized to receive an intermediate (I) dose of MTX (n = 40) or a higher (H) dose of MTX (n = 40). Bars show the mean and 95% confidence intervals. In the randomization phase, all comparisons between MTX intermediate dose versus higher dose were statistically not significant at any point in time irrespective of the ACR pediatric definition used.

Significant mean improvement was observed in all of the JIA core set variables (Table 2 and Figure 3). As an exploratory analysis, we also evaluated the response rate among the 3 JIA onset subtypes of the study patients (polyarthritis, extended oligoarthritis, and systemic-onset arthritis) in the screening phase. We found no statistically significant difference in the response rates between subtypes according to the ACR pediatric 30, pediatric 50, and pediatric 70.

Table 2. Measures of disease activity and improvement from baseline*
MeasureEnrolled in screening phase (n = 595)Randomized to receive intermediate-dose MTX (n = 40)Randomized to receive higher-dose MTX (n = 40)
Month 0Month 6Month 0Month 6Month 12Month 0Month 6Month 12
  • *

    Values are the mean ± SD. Month 0 is baseline at the screening phase. Month 6 is the end of the screening phase and baseline at the time of randomization. Month 12 is at the end of the randomization phase. All comparisons are versus baseline. MTX = methotrexate; JIA = juvenile idiopathic arthritis; VAS = visual analog scale; CHAQ = Childhood Health Assessment Questionnaire; CHQ = Child Health Questionnaire.

  • P < 0.0001.

  • P < 0.001.

  • §

    P < 0.05.

  • P not significant.

JIA core set measures        
 No. of active joints (0–71 joints)12.0 ± 9.25.4 ± 7.214.7 ± 9.213.4 ± 7.75.7 ± 7.414.7 ± 9.514.3 ± 9.85.4 ± 11.3
 No. of limited joints (0–67 joints)10.6 ± 9.16.1 ± 7.812.3 ± 10.712.3 ± 9.16.3 ± 8.611.4 ± 10.914.2 ± 12.48.5 ± 13.1
 Physician's global assessment of disease activity, by VAS (0–10 cm)5.2 ± 2.02.4 ± 2.15.0 ± 1.94.9 ± 1.91.8 ± 2.05.4 ± 2.05.3 ± 2.01.7 ± 2.0
 Erythrocyte sedimentation rate, mm/hour45.0 ± 29.324.2 ± 22.241.6 ± 29.834.2 ± 29.421.6 ± 21.5§42.9 ± 24.837.7 ± 25.120.1 ± 16.4
 Parent's global assessment of overall well-being, by VAS (0–10 cm)4.4 ± 2.62.3 ± 2.43.9 ± 2.74.3 ± 2.52.8 ± 3.04.5 ± 2.34.7 ± 2.22.4 ± 2.0
 Disability index of the CHAQ (0–3 points)1.2 ± 0.80.8 ± 0.71.4 ± 0.81.4 ± 0.70.9 ± 0.81.5 ± 0.71.4 ± 0.70.9 ± 0.8
Additional measures        
 No. of swollen joints (0–62 joints)9.8 ± 8.04.4 ± 6.212.2 ± 8.611.1 ± 7.95.1 ± 6.511.7 ± 8.310.9 ± 8.42.2 ± 2.3
 No. of painful joints (0–75 joints)10.5 ± 10.33.7 ± 6.910.9 ± 8.29.7 ± 9.13.5 ± 8.013.7 ± 13.211.5 ± 12.14.9 ± 12.6
 Parent's evaluation of pain, by VAS (0–10 cm)4.6 ± 2.72.1 ± 2.44.7 ± 2.54.6 ± 2.42.4 ± 2.74.9 ± 2.64.3 ± 2.72.1 ± 2.0
 Physical summary score on the CHQ (normal 50 ± 10)38.5 ± 10.746.2 ± 9.739.6 ± 10.239.2 ± 9.046.5 ± 10.437.0 ± 9.838.9 ± 10.546.6 ± 8.7
 Psychosocial summary score on the CHQ (normal 50 ± 10)44.6 ± 9.248.1 ± 8.544.4 ± 10.045.6 ± 8.547.1 ± 9.445.2 ± 8.545.8 ± 8.849.9 ± 9.4
Figure 3.

Analysis of variance for repeated measures for the 6 individual variables included in the juvenile idiopathic arthritis core set of outcome measures, evaluating outcomes among the 595 patients enrolled in the screening phase (screened) and the 80 patients in the randomization phase (intermediate-dose and higher-dose methotrexate groups, each n = 40). Bars show the mean and 95% confidence interval for each evaluation time point in the trial (0, 6, 9, and 12 months). The physician's and the parent's global evaluations were assessed on 10-cm visual analog scales. The erythrocyte sedimentation rate (ESR) is in mm/hour. P values refer to the comparison of the intermediate-dose and higher-dose groups (by repeated-measures analysis of variance). CHAQ = Childhood Health Assessment Questionnaire (scale 0–3 points).

In the screening phase, 25 patients interrupted their MTX treatment temporarily or definitely (Figure 1) for the following reasons: 10 children developed laboratory abnormalities (8 had elevations in transaminase, 2 had leukopenia), 9 developed gastrointestinal symptoms (3 with nausea, 4 with vomiting, 1 with mouth sores, 1 with loss of appetite), 5 had infections (2 with upper respiratory tract infection, 2 with urinary tract infection, 1 with pneumonitis), and 1 had focal seizures.

Randomization phase.

As shown in Figure 2, by the end of the randomization phase (month 12), the response rate according to the ACR pediatric 30 was 25 of 40 patients (62.5%, 95% CI 46–77%) in the intermediate-dose group and 23 of 40 (57.5%, 95% CI 41–73%) in the higher-dose group (P = 0.65). According to the ACR pediatric 50, the response rate was 23 of 40 patients (57.5%, 95% CI 41–73%) in the intermediate-dose group and 22 of 40 patients (55%, 95% CI 38–71%) in the higher-dose group (P = 0.82). Finally, according to the ACR pediatric 70, the response rate was 18 of 40 patients (45%, 95% CI 29–61%) in the intermediate-dose group and 19 of 40 patients (47.5%, 95% CI 32–64%) in the higher-dose group (P = 0.82). Five patients (12.5%) receiving the intermediate dose of MTX, compared with 4 (10%) receiving the higher dose of MTX, also met the definition of complete disease control.

As shown in Table 2 and Figure 3, subjects in both the intermediate- and higher-dose MTX groups showed a statistically significant mean improvement in all 6 JIA core set variables and in all other additional assessments. When the 6 individual JIA core set variables were examined with analysis of variance for repeated measures, no statistically significant differences were found between the intermediate-dose MTX group and the higher-dose MTX group in terms of the response rate according to the ACR pediatric 30, pediatric 50, or pediatric 70 (Figure 3).

As an exploratory analysis, we also evaluated the response rate among the 3 subtypes of JIA onset (polyarthritis, extended oligoarthritis, and systemic-onset arthritis) in the randomization phase. We found no statistically significant difference between subtypes in the response rate according to the ACR pediatric 30, pediatric 50, or pediatric 70.

With regard to adverse events, when the intermediate-dose MTX group was compared with the higher-dose MTX group, there were no statistically significant differences in the frequency of patients with adverse events that were graded as moderate or severe and whose attribution to MTX was judged as either possible or definite, although a trend toward more frequent toxicity was observed in the higher-dose group. The most common adverse events (among the combined group of patients) were nausea in 17 patients (21%), vomiting in 9 (11%), mouth sores in 8 (10%), loss of appetite in 6 (7.5%), hair loss in 4 (5%), and malaise in 4 (5%). No patient experienced diarrhea, pneumonitis, rash, or hepatomegaly. All other adverse events were mild and were considered to be unrelated to the MTX treatment.

There were no statistically significant differences in the frequency of patients with laboratory abnormalities when the intermediate-dose MTX group was compared with the higher-dose MTX group. The most common laboratory abnormalities (among the combined group of patients) were levels of AST and/or ALT greater than twice the upper limit of normal on at least 1 determination in 4 patients (5%) and leukopenia ≤4,000/mm3 on at least 1 determination in 4 children (5%).

The number of patients who dropped out of the study due to MTX-related toxicity was similar between the intermediate-dose group and the higher-dose group (Figure 1) and did not differ from the dropout rate observed in the screening phase. Of the 40 patients who were randomized to receive the intermediate dose of MTX, 34 (85%) completed the trial and 6 (15%) dropped out for the following reasons: 3 experienced a disease flare that required treatment with steroids (1 also required treatment with intravenous immunoglobulin and cyclosporine), 2 had adverse events (1 with severe alopecia and 1 with seizures that were not related to MTX), and 1 dropped out because of the parent's refusal to continue. Of the 40 patients randomized to receive the higher dose of MTX, 29 completed the trial (72.5%) and 11 (27.5%) dropped out for the following reasons: 5 had adverse events (2 with nausea, loss of appetite, and general malaise, 1 with documented acute familial pancreatitis, 1 with dizziness, syncope, and unconsciousness, and 1 with papilloedema for large arterovenous malformation), 3 experienced an insufficient therapeutic effect so that other drugs were required (1 received sulfasalazine, 1 received etanercept, and 1 received prednisone), 2 dropped out because of the parent's refusal to continue, and 1 was lost to followup. Patients could have more than 1 reason for dropping out of the trial.

Early trial termination.

The results presented herein are the consequence of an interim analysis performed when the sample calculated for the screening phase was enrolled. In the screening phase, we enrolled an amount of patients (n = 633) that was very close to the hypothesized sample size needed (n = 650). In the randomization phase, however, we were unable to recruit the calculated number of patients (n = 230) due to a higher-than-expected response rate to standard-dose MTX (72% versus 63% expected) and a high rate of noneligible patients among the nonresponders (53 [40%] of 133) (4).

For the calculation of sample size in the randomization phase, the difference considered clinically important was 20% (that is, the difference calculated between the expected response rate in the higher-dose MTX group of 70% and the expected response rate in the intermediate-dose MTX group of 50%), whereas the observed difference was −5% (higher-dose group response rate 57.5% minus intermediate-dose group response rate 62.5%). Based on these results, the steering committee considered the observed difference to be not clinically relevant, and therefore decided to stop patient enrollment to not unduly expose children to the higher MTX dose.

To confirm the steering committee decision and accept the null hypothesis (response rate in the higher- dose group equal to the response rate in the intermediate-dose group), we performed a conditional power analysis, calculated under a parameter value θ, which falls below a prespecified value γ, or between 0.1 (conservative) and 0.3 (nonconservative) (26). According to this analysis, the conditional power in this study is equal to 0.177, that is, between the conservative and nonconservative prespecified value γ. The conditional power analysis therefore confirmed that the steering committee decision to stop the trial was correct.

DISCUSSION

MTX is the disease-modifying agent of first choice in children with JIA. It is effective, safe, and cheap, and therefore represents an affordable therapy for most patients with JIA all over the world. At the time that our trial was designed, anti-TNF agents were not available, and there were no proven alternatives for children whose condition did not respond to standard-dose MTX (27). In the original controlled trial of MTX, the drug was used at 2 dosages, 5 mg/m2/week and 10 mg/m2/week, and only the 10 mg/m2/week dosage was shown to be superior to placebo. Subsequent studies suggested (5), but did not prove, that higher dosages (of up to 30 mg/m2/week) could be effective in children with JIA resistant to the standard dose of the drug. The protocol of the present study was designed in 1996 after an international survey among pediatric rheumatologists indicated that a trial of MTX at a higher dose would be the most important study to be performed (28). Indeed, when the study started, it was considered standard practice in the international pediatric rheumatology community to increase the MTX dose to a variable degree in patients who were resistant to a standard dose.

In the design of the protocol, it was considered ethical to increase the MTX dosages, in the control group, to 15 mg/m2/week, rather than allow patients to continue to receive the previous low dosages (8–12.5 mg/m2/week) to which they had not responded in the screening phase. MTX was therefore increased by a limited amount in the active control group (intermediate dose), while the higher dose of MTX was considered the experimental arm of the trial. With low-dose MTX, the oral, subcutaneous, and intramuscular routes of administration are interchangeable in terms of bioavailability and efficacy (29–32). However, at higher doses, oral absorption is more variable, and therefore parenteral administration is advised, since it represents at least a 20% increase in the absorbed amount of MTX when compared with the oral dose (31, 33–35). All of the randomized patients who were receiving oral MTX in the screening phase were therefore switched to parenteral administration in the randomization phase.

In the screening phase, we studied more than 600 patients with JIA treated with MTX at standard dosages (mean 10 mg/m2/week). This represents the largest single population of MTX-treated patients with JIA reported and confirms that MTX is an effective and safe drug in this disease. Moreover, for the first time, MTX efficacy has been evaluated using the ACR pediatric 50 and ACR pediatric 70 criteria. By using the ACR pediatric 30, the percentage of responders was similar (72%) to that reported by us in an open-label trial (66%) (12) and to that reported by Giannini et al in their controlled study (63%) (4) that used a different definition of improvement. Interestingly, a high percentage of response was also observed when the clinically more meaningful ACR pediatric 50 and ACR pediatric 70 criteria were applied (61% and 38%, respectively).

In the randomization phase, our study did not show any difference in terms of efficacy or safety between patients treated with MTX at an intermediate dose or those treated with a higher dose for an additional 6 months. However, both treatment groups showed a consistent improvement according to the ACR pediatric 30, ACR pediatric 50, or ACR pediatric 70 definitions.

It is generally assumed that higher doses of second-line agents in immune-mediated diseases should be more effective in comparison with conventional doses, although the limit is the increase in side effects with increasing dosage. In systemic lupus erythematosus, for example, the use of cyclophosphamide at a higher dose has been associated with increased drug efficacy (36). On the contrary, our study shows that doubling the dosage of MTX from 15 mg/m2/week to 30 mg/m2/week in JIA does not lead to any further significant clinical improvement, and therefore the plateau of efficacy of MTX is reached with the parenteral administration of 15 mg/m2/week. Similar results have been obtained recently in a preliminary study involving adult rheumatoid arthritis (37).

Of interest, although the randomization phase failed to show any difference in efficacy between the 2 MTX doses, it was nevertheless associated with a statistically significant and overlapping improvement in both study arms, as assessed by the ACR pediatric 30, ACR pediatric 50, and ACR pediatric 70 criteria. It is impossible to discern if the observed effect in the intermediate-dose group was due to the small increase in the MTX dosage (from 10 mg/m2/week to 15 mg/m2/week) and/or to the better bioavailability resulting from parenteral administration or to the longer duration of therapy with MTX. Indeed, the only possible way to have answered this question would have been to have a control arm of patients followed up for an additional 6 months with no change in the standard dose of MTX. This possibility had been excluded for ethical reasons, to avoid leaving children on a dose of MTX that had been demonstrated to be ineffective. Nevertheless, patients with JIA who had failed to respond to treatment with MTX at standard doses for 6 months showed a very consistent improvement (up to ∼50% with the clinically very significant ACR pediatric 70 criteria) when treated for a further 6 months with parenterally administered MTX at 15 mg/m2/week. This is in contrast to the previous notion that therapy with 10 mg/m2/week of MTX for 3–6 months is enough to judge the efficacy of the drug.

There are some limitations that need to be taken into account when interpreting the results in the present study. We did not collect information about the racial characteristics of the population studied, but only the country of origin of the patients. Most of the patients were white children from western and eastern European countries, and the second biggest group was from Latin America. Only a few patients from the US were enrolled, the main reasons being the need to increase earlier (within 3–4 months) the dose of MTX in children who appeared resistant to a standard dose, and the earlier availability on the market of etanercept that shifted the attention of North American physicians and parents toward this new drug. Another reason of concern was the relatively small sample of patients randomized; this occurred because there was a high frequency of noneligible patients among the nonresponders in the screening phase, since many of the children who were not eligible for randomization were nonresponders to standard-dose MTX but had <5 joints with active arthritis.

In conclusion, in patients with polyarticular-course JIA who did not respond to the standard dosage of MTX (mean 10 mg/m2/week), the parenteral administration of an intermediate dosage (15 mg/m2/week) for an additional 6 months was associated with a significant clinical improvement in a high proportion of cases, and a good safety profile was developed. In contrast, the administration of higher-dosage MTX (30 mg/m2/week) for the same period was not associated with any further increase in the proportion of patients responding to the drug. Therefore, our study demonstrates that the plateau of efficacy of parenteral MTX in JIA is reached at 15 mg/m2/week, and that a further increase in dose is not associated with any additional therapeutic benefit.

These results suggest that MTX therapy in patients with JIA should be initiated with the parenteral administration of 15 mg/m2/week and should be continued for at least 9–12 months before considering the treatment to be a failure. Future studies are needed to verify whether this new approach is associated with a higher and earlier frequency of response and remission.

Acknowledgements

We are indebted to Drs. Edward H. Giannini, Daniel J. Lovell, and Angelo Ravelli for their assistance in the basic study design, to Professor John R. Whitehead for his methodologic suggestions for the conditional power analysis, and to Drs. Luci Gado-West and Anna Tortorelli for their help in data handling, organization skills, and overall management of the project. We also thank the following members of PRINTO who participated as investigators in the trial and whose enthusiastic effort made this work possible: Christian Huemer, MD (Austria); Carine Wouters, PhD (Belgium); Blanca Bica, MD, Lucia Campos, MD, Claudia Machado, MD, Virginia Ferriani, MD, Flavio Sztajnbok, MD (Brazil); Dimitrina Mihaylova, MD (Bulgaria); Dana Nemcova, MD (Czech Republic); Pekka Lahdenne, MD, PhD (Finland); Frank Dressler, MD, Ivan Foeldvari, MD, Renate Hafner, MD, Hans Iko Huppertz, MD, Kirsten Minden, MD (Germany); Riva Brik, MD, Phil Hashkes, MD, Yoseph Uziel, MD (Israel); Maria Giannina Alpigiani, MD, Antonella Buoncompagni, MD, Elisabetta Cortis, MD, Loredana Lepore, MD (Italy); Rebecca ten Cate, MD, Renée van Soesberger, MD (The Netherlands); Marite Rygg, MD (Norway); Veronika Vargova, MD, PhD (Slovakia); Sang Cheol Bae, MD (South Korea); Boel Andersson-Gäre, MD, Bo Magnusson, MD (Sweden); Immaculada Penades Calvo, MD, María Luz Gamir Gamir, MD, Rosa Merino, MD (Spain); Michael Hofer, MD, Marie-Josephe Sauvain, MD (Switzerland); Aysin Bakkaloglu, MD (Turkey); Jo Walsh, FRCPCH, Ann Hall, FRCP, FRCPCH, Peter Hollingworth, MBBS, FRCPCH, Helen Venning, MBBS, FRCPCH (UK); Yukiko Kimura, MD, Gail Cawkwell, MD (USA).

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