Original Article
Methotrexate in Resistant Juvenile Rheumatoid Arthritis — Results of the U.S.A.–U.S.S.R. Double-Blind, Placebo-Controlled Trial
N Engl J Med 1992; 326:1043-1049April 16, 1992
- Abstract
- Abstract
Background.
The antimetabolite methotrexate has been shown in placebo-controlled trials to be effective in adults with rheumatoid arthritis. Methotrexate may also be effective in children with resistant juvenile rheumatoid arthritis, but the supporting data are from uncontrolled trials.
Methods.
Centers in the United States and the Soviet Union participated in this randomized, controlled, double-blind trial designed to evaluate the effectiveness and safety of orally administered methotrexate. Patients received one of the following treatments each week for six months: 10 mg of methotrexate per square meter of body-surface area (low dose), 5 mg of methotrexate per square meter (very low dose), or placebo. The use of prednisone (≤10 mg per day) and two nonsteroidal antiinflammatory drugs was also allowed.
Results.
The 127 children (mean age, 10.1 years) had a mean duration of disease of 5.1 years; 114 qualified for the analysis of efficacy. According to a composite index of several response variables, 63 percent of the children who received low-dose methotrexate improved, as compared with 32 percent of those in the very-low-dose group and 36 percent of those in the placebo group (P = 0.013). As compared with the placebo group, the low-dose group also had significantly larger mean reductions from base line in the number of joints with pain on motion (—11.0 vs. —7.1), the pain-severity score (—19.0 vs. —11.5), the number of joints with limited motion (—5.4 vs. —0.7), and the erythrocyte sedimentation rate (—19 vs. —6 mm per hour). In the methotrexate groups only three children had the drug discontinued because of mild-to-moderate side effects; none had severe toxicity.
Conclusions.
Methotrexate given weekly in low doses is an effective treatment for children with resistant juvenile rheumatoid arthritis, and at least in the short term this regimen is safe. (N Engl J Med 1992;326:1043–9.)
Media in This Article
Figure 1
Physicians' Global Assessment of Patients' Response to Therapy.Figure 2
Mean (±SE) Change from Base Line in the Articular-Severity Score.Article Activity
- Article
JUVENILE rheumatoid arthritis is the most common rheumatic condition of childhood, with an annual incidence of about 1.4 cases per 10,000 children under the age of 16 years in the United States, and a prevalence of roughly 1 per 1000.1 , 2 Three types of onset of juvenile rheumatoid arthritis are recognized, each of which has a characteristic clinical, epidemiologic, and genetic pattern.3 The systemic-onset form produces a rheumatoid rash and intermittent fever (temperature, >39.4°C, with daily return to normal); anemia, pericarditis, and hepatosplenomegaly are common. The arthritis usually involves multiple joints. Polyarticular onset is characterized by arthritis in five or more joints, and oligoarticular onset (also referred to as pauciarticular) is characterized by arthritis in fewer than five joints. Rheumatoid rash and intermittent fever are absent in the polyarticular and oligoarticular forms, although other systemic manifestations may occasionally be present.
Approximately one third of all patients with juvenile rheumatoid arthritis achieve adequate control of their disease with nonsteroidal antiinflammatory drugs; the remainder are candidates for more aggressive therapy with second-line agents. In large randomized trials in adults with refractory rheumatoid arthritis, the antimetabolite methotrexate has had therapeutic advantage over placebo, with an acceptable safety profile.4 , 5 Long-term studies have shown that the therapeutic effect of methotrexate may persist for extended periods.6 7 8 9 10 11 Anecdotal reports and the results of uncontrolled trials of the efficacy and safety of low-dose methotrexate in juvenile rheumatoid arthritis have been encouraging.12 13 14 15 16 17 For these reasons the Pediatric Rheumatology Collaborative Study Group (PRCSG), in conjunction with colleagues in the then Soviet Union, conducted this double-blind, randomized, placebo-controlled trial to assess the therapeutic effects of two different doses of methotrexate in children with resistant juvenile rheumatoid arthritis.
Methods
The study was conducted under the Cooperation in Medical Science and Public Health Agreement (signed on May 23, 1972, in Moscow) and was a collaborative effort between physicians and scientists in the United States and the Soviet Union. A total of 23 pediatric rheumatology centers in the two countries participated (18 in the United States and 5 in the Soviet Union).
Study Design
The investigation was designed as a prospective, parallel, multi-center, placebo-controlled, randomized, double-blind clinical trial of six months' duration. Randomization was in blocks of three within each center, with no a priori stratification of the patients at entry. All centers followed an identical clinical protocol and used standardized case-report forms.
Patients
Previous collaborative studies between the United States and the Soviet Union involving children with arthritis have shown that the disease is similar in demographic and clinical characteristics in the two countries.18 19 20 21
To be eligible for enrollment, the patients had to meet the criteria for juvenile rheumatoid arthritis of the American College of Rheumatology22 or the criteria used in the Soviet Union and Eastern Europe.23 In addition, patients had to have a minimum of three joints with active arthritis (as defined by the American College of Rheumatology24) that was not adequately controlled by nonsteroidal or second-line agents. Patients had to be at least 18 months and less than 18 years of age. Patients were excluded if any other clinically important severe or chronic disease was present. Girls who might become pregnant (those who were postpubertal and, if sexually active, not practicing effective birth control) were also excluded.
The use of antirheumatic medication was restricted in that patients who had received penicillamine, hydroxychloroquine, oral or parenteral gold, or intraarticular or long-acting parenteral steroids within three months before randomization were excluded. Patients who had previously received methotrexate were also excluded.
Monitoring of Efficacy and Safety
The patients were followed and monitored according to the guidelines of the PRCSG for the conduct of studies of antirheumatic medications in children with juvenile rheumatoid arthritis.25 In brief, after consent was obtained from the patient or parent (or both) and eligibility was verified, each patient was randomly assigned to treatment and scheduled to be examined during seven visits over a six-month period. Visits to the rheumatologist were scheduled at the start of the study and then monthly thereafter. Physical and laboratory assessments of rheumatologic disease activity and drug safety were completed at each visit. For a given patient, all rheumatologic examinations and assessments of laboratory results were performed by the same physician. Four clinical indexes of articular inflammation were used: joint swelling (graded as 0, or none; 1+, or mild — definite swelling but with no blurring of normal skeletal outlines; 2+, or moderate — definite obscuring of skeletal landmarks; or 3+, or severe — no discernible skeletal landmarks); pain on motion and joint tenderness (each graded as 0, or none; 1+, or mild — patient complains on joint movement or palpation; 2+, or moderate — patient withdraws or changes facial expression on movement or palpation; or 3+, or severe — patient responds markedly to movement or palpation); and limitation of motion (0, full range; 1+, 25 percent limitation, 2+, 50 percent limitation; 3+, 75 percent limitation; or 4+, no motion possible).
In addition to these indexes, the total number of joints with active arthritis, the sum of all the severity ratings (referred to as the articular-severity score), and the mean duration of morning stiffness were calculated and recorded. At each follow-up visit, the examining physician and a parent of the patient each recorded a categorical global rating of the child's condition in relation to the base-line disease status.
Paulus et al.26 have shown the advantage of using a composite index to describe improvement in individual patients during trials of antirheumatic agents in adults with rheumatoid arthritis. Their index, however, is not completely applicable to children with juvenile rheumatoid arthritis, and we modified it to create the composite index used in this study. For treatment to be classified as successful on this more rigorous index of improvement, patients had to have a reduction of ≥25 percent from base line in the articular-severity score and be classified as improved according to the physician's and the parent's final global assessments.
Drug safety was monitored monthly by laboratory tests that included a complete blood count, urinalysis, blood chemistry, and test for fecal occult blood. Ophthalmologic examinations and assessments of pulmonary function were performed at the Start of the study and again at its completion or on withdrawal from the trial.
Study Drugs, Dosages, and Monitoring of Compliance
Methotrexate was provided in 2.5-mg tablets that were physically indistinguishable from the placebo tablets. Methotrexate and placebo tablets were produced and provided by Lederle Laboratories (Pearl River, N.Y.).
Medication was given on the basis of body-surface area. Patients were randomly assigned to one of three treatment groups: placebo, very-low-dose methotrexate (5 mg per square meter of body-surface area per week), or low-dose methotrexate (10 mg per square meter per week). The maximal dose of methotrexate was 15 mg per week. The categories of body-surface area in square meters were 0.5 to 0.75, 0.76 to 1.25, and ≥1.26. All the patients in each category received an equal number of tablets per week. Children in the very-low-dose group thus received a mixture of methotrexate and placebo tablets. Medication was administered in blinded fashion as a single oral dose once per week, with no specification about the time of day the tablets should be taken. Compliance was verified by tablet counts.
Investigators were instructed not to break the code until the completion of the study in their country, unless medical emergency or parental insistence made it necessary.
Concurrent Medications and Therapy
Patients were allowed to take a maximum of two nonsteroidal antiinflammatory drugs and prednisone at a dosage not exceeding 0.5 mg per kilogram of body weight per day (maximum, 10 mg per day) concurrently with the study medication. The dosage of these drugs had to have been constant for at least one month before randomization and could not be changed during the trial. Other concurrent medications that were allowed included antibiotics for infection and acetaminophen (for brief periods) to control fever.
The patients were instructed to continue their programs of physical and occupational therapy during the study.
Response Variables
The primary response (outcome) variables on the basis of which decisions about efficacy were made included the physician's global assessment of the patient's response, the articular-severity score, and the composite index. Secondary variables included the number of joints with swelling, pain on motion, tenderness, and limitation of motion, the severity of the conditions, and the duration of morning stiffness. Elements of the hemogram and the erythrocyte sedimentation rate were also considered secondary measures of outcome. Changes in the titers of rheumatoid factor and antinuclear antibodies are not useful outcome measures in therapeutic trials among children with juvenile rheumatoid arthritis. Because the trial was short, the evaluation of roentgenographic changes was not considered.
Data Management and Statistical Analysis
In the United States, on-site quality assurance and the retrieval of completed case-report forms were performed by clinical-research associates from Lederle Laboratories. Case-report forms from the Soviet Union were reviewed and gathered during periodic visits by the principal investigators. All forms were sent to the coordinating center in Cincinnati, where the data were analyzed.
Statistical analysis was carried out in accordance with the standardized guidelines of the PRCSG.27 For prestudy statistics and estimates of placebo response we used data from previous randomized, controlled trials of other second-line agents undertaken by the PRCSG with the Soviet Union.19 , 21 The physician's global assessment of the patient's response to therapy was used as the primary outcome variable on which the calculation of sample size was based. This variable was dichotomized for the purposes of data analysis. Patients assessed as much better or better were classified as improved; those assessed as the same, worse, or much worse were classified as not improved. The alpha and beta levels were set at 0.05 and 0.2, respectively (power, 80 percent). A difference as small as 40 percent in the rate of response between the active drug and placebo was considered important to detect as statistically significant. We estimated that approximately 30 percent of the patients given placebo would be classified as improved. According to the tables presented by Gehan and Schneiderman,28 and assuming the use of two-tailed tests, a minimum of 30 patients were required in each group.
We tested proportional data for significance using the chi-square test or, where appropriate, Fisher's exact test. Statistical significance by the chi-square test was required for tables with more than 1 degree of freedom before partitioning. For continuous variables, mean values were compared by one-way analysis of variance. When multiple-range tests became appropriate, Dunnett's method for making multiple comparisons with a placebo29 was used. Two-way analysis of variance was used to test for the effects of drug and country on the change in articular indexes. The Bonferroni correction was used to adjust for the testing of multiple hypotheses (n = 12) among secondary variables and in the analysis of response in subgroups of patients. Both unadjusted and adjusted values are shown, however, if a P value was significant (≤0.05) before correction, and the results are referred to as statistically significant.
Emphasis was placed on the intention-to-treat analysis rather than the analysis of those who completed the entire six-month trial. The intention-to-treat technique used the values of response variables at the final visit, whether or not the patient completed the entire trial. This approach offered several advantages: more patients were available for the analysis of efficacy, data on those who dropped out before completion could be included, and it more closely reflected how physicians evaluate a therapeutic agent in the clinical setting, outside an experimental protocol.
Results
A total of 127 patients (96 girls and 31 boys) were enrolled in the trial (66 in the United States and 61 in the Soviet Union). Age and duration of disease at entry averaged 10.1 and 5.1 years, respectively. The disease course was systemic in 32 patients (25 percent), all of whom also had polyarthritis. Forty-six children received low-dose methotrexate, 40 received very-low-dose methotrexate, and 41 were given placebo. Randomization worked well; there were no significant differences among the treatment groups in any of the demographic or disease characteristics shown in Table 1Table 1
Demographic and Clinical Characteristics of the Patients at Entry, According to Study Group.. Patients from the two countries were distributed about equally among the three treatment groups. Those from the United States had a higher mean (±SE) number of joints with active arthritis (27±2 vs. 20±2, P<0.046), but the mean articular-severity score (112) was the same for the two countries.Indomethacin was the most frequently used concurrent nonsteroidal drug (26 percent), followed by naproxen (18 percent), tolmetin sodium (17 percent), diclofenac sodium (16 percent), aspirin (16 percent), and other agents (6 percent).
Efficacy
Patients were included in the analysis of efficacy if they met all eligibility criteria, received the study drug in blinded fashion for a minimum of one month, were 100 percent compliant with the prescribed regimen during at least 80 percent of the follow-up period, and complied with the other specifications of the protocol regarding restrictions on other medications and return visits to the clinic.
Of the 127 enrolled patients, 114 (90 percent) qualified for the analysis of efficacy, including 38 (83 percent) of the 46 in the low-dose group, 37 (92 percent) of the 40 in the very-low-dose group, and 39 (95 percent) of the 41 who took placebo. Among the 13 patients excluded from the efficacy analysis, 8 violated the specified doses for concurrent nonsteroidal agents, 3 violated the prednisone regimen, 1 was noncompliant in taking the study medication, and 1 was discovered to have had fewer than three joints that met the criteria for active arthritis at the base-line visit.
Only 11 of the 114 children in the efficacy subgroup took two concurrent nonsteroidal agents during the trial. These patients were equally divided among the treatment groups, and their data were not considered separately. A total of 40 patients in the efficacy subgroup received low-dose prednisone during the trial, including 14 who were given low-dose methotrexate and 13 in each of the other two groups. Since the numbers were small and the dose low and constant, data for those who received prednisone were not analyzed separately.
Among the 127 randomized patients, 108 completed the entire six-month trial, including 97 (85 percent) of the 114 in the efficacy subgroup.
Global Assessment
Figure 1Figure 1
Physicians' Global Assessment of Patients' Response to Therapy. shows the percentages of patients at each return visit who had clinical improvement from their base-line condition, according to the physician's global assessment. Both methotrexate groups had consistently higher proportions of patients with improvement than the placebo group. According to the physician's final global assessment, a significantly higher proportion of patients improved in the low-dose group than in the placebo group (χ2 with 2 df = 7.53, P = 0.023). Those in the very-low-dose group did not have a statistically greater frequency of improvement than those in the placebo group (χ2 = 3.4, P = 0.062). In general, the results of the parent's global assessment of the child's response were nearly identical with those of the physician's.Changes in Indexes of Articular Disease
Table 2Table 2
Changes in the Indexes of Articular Disease at the Final Visit, According to Study Group. shows the changes between base line and the final study visit for each index of articular disease. The low-dose group had numerically greater mean and median changes in all variables than either of the other groups. When data on those who completed the entire six months of therapy were analyzed separately, the results were the same. Mean changes in the number of joints with pain on motion, the severity of the pain, and the number of joints with limitation of motion were significantly larger in the low-dose group. When Dunnett's multiple-range test was used to compare each of the methotrexate groups with the placebo group, the only significant difference was between placebo and low-dose methotrexate with respect to the number of joints with limitation of motion (Dunnett's q = 2.15, P<0.05 unadjusted and P>0.30 adjusted).Changes in the articular-severity score over time are illustrated in Figure 2Figure 2
Mean (±SE) Change from Base Line in the Articular-Severity Score.. The low-dose group showed numerically greater improvement than the other groups after about the first month of treatment.Response in Individual Patients
Twenty-four (63 percent) of the patients in the low-dose group were classified as improved according to the composite index, as compared with only 12 (32 percent) in the very-low-dose group and 14 (36 percent) in the placebo group (χ2 with 2 df = 8.71, P= 0.013).
Response among Subgroups of Patients
We classified patients on the basis of independent variables that might have influenced outcome, including the severity of disease at base line, the type of disease the patient had during the first six months of illness (systemic, polyarticular, or oligoarticular in onset), and the country of residence. We then analyzed responses among the subgroups of patients.
Each patient was classified as having either severe or less severe arthritis, according to whether the initial articular-severity score was above or below the median value (87.5) for the efficacy subgroup. Among the 57 children classified as having severe disease, 17 (68 percent) of the 25 in the low-dose group were classified as improved according to the physician's final global assessment, as were 10(77 percent) of the 13 in the very-low-dose group and 11 (58 percent) of the 19 in the placebo group (P>0.05 by chi-square test). Also, the mean changes in the articular-severity scores (— 82 in the low-dose group, —75 in the very-low-dose group, and —66 in the placebo group) were not significantly different (F = 0.19, P>0.3).
Among the 57 children whose articular disease was less severe at base line, significantly more patients who received low-dose methotrexate improved, as compared with the other groups. Ten of 13 (77 percent) in the low-dose group improved, as compared with 11 of 24 (46 percent) in the very-low-dose group and 5 of 20 (25 percent) in the placebo group (χ2 with 2 df = 8.56, P = 0.014 unadjusted and P = 0.168 adjusted). In addition, the mean decrease in the articular-severity score was larger in the low-dose group (—25.6) than in the very-low-dose (—2.4) and placebo (—8.0) groups (F = 3.1, P = 0.05 unadjusted and P≥0.3 adjusted).
In juvenile rheumatoid arthritis the type of disease during the first six months of illness may serve as a predictor of prognosis and response to therapy.3 , 17 Among the 114 patients we studied in the analysis of efficacy, 58 (51 percent) had a polyarticular onset, 33 (29 percent) a systemic onset, and 23 (20 percent) an oligoarticular onset. The onset types were divided about equally among the three treatment groups. Although the numbers were small, the frequency of response did not appear to be strongly influenced by type of onset.
We investigated the relation between response and country of residence in each of the three treatment groups. In neither of the methotrexate groups was there a significant association between the physician's final global assessment and the country. However, patients given placebo in the Soviet Union were more likely to be classified as improved (according to the physician's final global assessment) than were patients given placebo in the United States. Specifically, 5 of 21 patients given placebo in the United States were classified as improved, as compared with 11 of 18 in the Soviet Union (P = 0.025 by Fisher's exact test). The country of residence was not predictive of the reduction from base line in the articular-severity score.
Effect on Systemic Manifestations
Thirty-three children who had disease of systemic onset were in the efficacy subgroup, and 24 had one or more systemic manifestations (intermittent fever, lymphadenopathy, organomegaly, and rheumatoid rash) at base line. All systemic manifestations resolved by the final visit in 3 of the 5 given low-dose methotrexate, in 2 of the 11 given very-low-dose methotrexate, and in 3 of the 8 given placebo. In two children (one in each methotrexate group), systemic signs first developed during the trial. The mean decrease from base line in the number of systemic manifestations was 0.83 in the low-dose group, 1.57 in the very-low-dose group, and 0.9 in the placebo group (P>0.05).
Laboratory Indexes of Disease Activity
The erythrocyte sedimentation rate was elevated (greater than 20 mm per hour by the modified Westergren method) at entry in about 80 percent of the patients in each group. Repeat values were obtained at the final visit in 93 percent of the patients. Among those given low-dose methotrexate, 13 of 28 with an elevated value at base line had a normal value by the final visit, as did 7 of 28 in the very-low-dose group and 8 of 27 in the placebo group. The mean change in the erythrocyte sedimentation rate was statistically greater in the low-dose group (—19 mm per hour) than in the very-low-dose group (—6 mm per hour) and the placebo group (—6 mm per hour; F = 4.1, P = 0.02 unadjusted and P = 0.24 adjusted).
Only 19 children had a hemoglobin value of ≤6.2 mmol per liter (10 g per deciliter) at base line, and 17 of these were retested at the final visit. Two of five who received low-dose methotrexate, six of eight given very-low-dose methotrexate, and one of four given placebo had hemoglobin levels above 6.2 mmol per liter (10 g per deciliter) at their final visit. Eight children who began the study with hemoglobin values above 6.2 mmol per liter (10 g per deciliter) had values below that level at the final visit, but in only two of them (both in the very-low-dose group) did the decrease represent a change of more than 0.9 mmol per liter (1.5 g per deciliter). All other blood-count indexes were normal in these two children, and the change in hemoglobin level was attributed to disease activity.
Safety
Clinical Evidence of Toxicity
All the patients who received medication in blinded fashion were included in the analysis of safety. Side effects judged by the examining physician to be both clinically important and definitely, probably, or possibly related to the study medication occurred in 19 (15 percent) of the 127 patients enrolled. Six of the 46 patients who took low-dose methotrexate (13 percent) had adverse events (3 had gastrointestinal problems alone, 1 had ulceration of mucous membranes, 1 had headache alone, and 1 had headache and abdominal problems). Eight of the 40 given very-low-dose methotrexate (20 percent) had side effects, including 4 who had gastrointestinal complaints alone, 2 who had headache or dizziness alone, and 2 who had inflammation of the oral mucosa accompanied by headache and gastrointestinal problems. Five of the 41 patients who took placebo (12 percent) had side effects, all of which were gastrointestinal. All side effects were graded as either mild or moderate in severity, except for two episodes of stomach pain graded as severe in a patient receiving placebo. No patient had evidence of methotrexate-induced pulmonary disease during the trial.
Laboratory Evidence of Toxicity
Patients who received methotrexate had more abnormal results on laboratory tests that were judged to be clinically important and possibly, probably, or definitely related to the study medication than those given placebo. Fifteen patients who received low-dose methotrexate, 15 who were given very-low-dose methotrexate, and 5 who were given placebo had such results. Among the patients given methotrexate, the most frequent abnormal results were alterations in the differential white-cell count, hematuria, pyuria, and the elevation of serum aminotransferase levels. Elevations of aminotransferase levels and anemia were the most frequent abnormal results among the patients given placebo. Other clinical-chemistry data were unremarkable.
Dropouts
A total of 19 patients (10 in the United States and 9 in the Soviet Union) discontinued therapy before completing the six-month trial (Table 3Table 3
Reasons Patients Left the Study, According to Study Group.). Two patients in the low-dose group dropped out because of adverse effects: persistent elevations of serum aspartate and alanine aminotransferase (levels up to 120 IU per liter) in one and persistent hematuria in the other. Both problems resolved quickly after the discontinuation of the study medication. One patient given very-low-dose methotrexate had a persistent skin rash and was dropped from the study one month after entry. The total numbers of dropouts were not significantly different among the groups.Discussion
The results of this trial confirm anecdotal reports and evidence from uncontrolled trials that low-dose methotrexate has antiinflammatory activity and clinical effectiveness in resistant juvenile rheumatoid arthritis. We also found a trend toward a dose–response relation in the low-dose and very-low-dose methotrexate groups, similar to that reported by Furst et al.30 in adult rheumatoid arthritis. The favorable findings from the present study should be encouraging news for clinicians faced with managing a child's disease that has failed to respond adequately to nonsteroidal drugs. Methotrexate has distinct advantages over other second-line agents, including its oral route of administration, once-a-week dosage, lack of known oncogenicity, and lack of long-term effects on fertility. The choice of which second-line agent to use initially has become more difficult in recent years, after controlled trials and long-term prospective studies showed a lack of efficacy among the agents in common use.19 20 21 , 31 Parenteral gold remains a therapeutic option, but its considerable toxicity32 and inconvenience must be considered. Furthermore, injectable gold salts have never been assessed in a controlled trial in children with arthritis. Thus, the tendency among pediatric rheumatologists to consider the use of methotrexate earlier in the disease, and before other second-line agents, is likely to continue.
There was a consistent trend in this study toward greater improvement in the low-dose group across all indexes of articular disease; some of the mean changes were not statistically significant, however. The variability of the changes within the treatment groups, the limited sample size, the corrections for testing of multiple hypotheses, and the high rate of response to placebo in all previous PRCSG studies undoubtedly affected our ability to detect some changes as statistically significant. The recent development of a childhood health-assessment questionnaire and functional-ability tool may provide more sensitive measures of response in future trials.33 , 34 Nevertheless, the results obtained here represent by far the most encouraging data from a trial of a second-line agent undertaken by the PRCSG.
The equality of response across treatment groups in the subgroup of patients with severe disease is unexplained. Since all three groups showed dramatic improvement in the articular-severity score, it is possible that there was a greater regression toward the mean in these children with severe disease that effectively blurred any difference in response produced by methotrexate.
The concurrent administration of aspirin is known to slow systemic and renal clearance and increase the unbound fraction of methotrexate, perhaps resulting in greater toxicity.35 We did not observe such an association among the 20 children (16 percent) who took aspirin. Among the 14 children who had clinically important physical adverse effects while receiving methotrexate, 2 (14 percent) were taking aspirin. Among the 30 children treated with methotrexate who had substantial abnormalities in laboratory indexes of toxicity, 4 (13 percent) were receiving aspirin.
Although mild elevations of serum aminotransferase levels were common in all the study groups, only four children in the low-dose group, one in the very-low-dose group, and one in the placebo group had markedly elevated (more than two times the upper limit of normal) enzyme levels (range, 85 to 134 IU per liter). Possible explanations for the lack of hepatotoxic effects include the duration of the trial, the administration schedule of a single dose per week, and the low cumulative doses to which the children had been exposed. Also, previous concern about the hepatic toxicity of methotrexate may have been exaggerated.36 A prospective study of the children who received methotrexate during this study is now under way to evaluate long-term outcome and safety.
In conclusion, methotrexate at a dose of 10 mg per square meter per week appears to have greater clinical effectiveness than placebo in children with juvenile rheumatoid arthritis. The short-term safety profile is acceptable. Given the results of previous trials by the PRCSG, the use of methotrexate as the initial second-line agent in resistant juvenile rheumatoid arthritis appears to be justified.
Supported by a grant (FD-R-000032) from the Office of Orphan Products Development of the Food and Drug Administration, by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, by a Clinical Projects Grant from the National Arthritis Foundation, by the Children's Hospital Research Foundation, Cincinnati, and by Lederle Laboratories, Pearl River, N.Y.
We are indebted to Academician Valentina A. Nassonova, M.D., of the Academy of Medical Sciences, Moscow; John Kuppel, M.D., and Lawrence E. Shulman, M.D., Ph.D., of the National Institutes of Health, Bethesda, Md.; Marlene Haffner, M.D., John Harter, M.D., and Kent Johnson, M.D., of the Food and Drug Administration, Washington, D.C.; and Dick Ryan, Harriet Kiltie, M.D., and Margaret Gandt, M.D., of Lederle Laboratories, Pearl River, N.Y., for their assistance in organizing and conducting this study.
The participating clinical investigators in the United States were (in alphabetical order) Bram H. Bernstein, M.D., Harry L. Gewanter, M.D., Jerry C. Jacobs, M.D., Deborah W. Kredich, M.D., Robert N. Lipnick, M.D., Daniel J. Lovell, M.D., M.P.H., Lauren M. Pachman, M.D., Murray H. Passo, M.D., Donald A. Person, M.D., Jane G. Schaller, M.D., Charles H. Spencer, M.D., Ilona Szer, M.D., and Carolyn L. Yancey, M.D. In the Soviet Union the participating clinical investigators were Danute Astrauskene, M.D., Ludmila Isaeva, M.D. (deceased), Nina Letenkova, M.D., Eliana Puogienene, M.D., Inessa Shakhbazyan, M.D., Marina Stcherbakova, M.D., Alexandra Yakovleva, M.D., and Seraphima Yandashevskaya, M.D. The senior scientist in the Soviet Union was Boris Shokh, M.D.
Source Information
From the Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati (E.H.G.); the Department of Pediatrics, Baylor College of Medicine, Houston (E.J.B.); the Institute of Rheumatology, Academy of Medical Sciences, Moscow, Russia (N.K., A.S., A.M.); the Department of Child Diseases, St. Petersburg Pediatric Institute, St. Petersburg, Russia (I.V.); the Department of Pediatrics, University of Texas Southwestern Medical School, Dallas (C.W.F.); Rainbow Babies and Children's Hospital, Cleveland (A.J.N.); the Department of Child Health, University of Missouri, Columbia (J.T.C.); and the Department of Rheumatology, Newington Children's Hospital, Newington, Conn. (L.S.Z.). Address reprint requests to Dr. Giannini at the Children's Hospital Medical Center, Pavilion Bldg., 1st Fl., Elland and Bethesda Aves., Cincinnati, OH, 45229–2899.
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Giannini
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Brewer
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Howe
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Stewart
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Kaplan
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- Citing Articles (122)
Citing Articles
1
Thomas Broughton, Kate Armon. (2012) Defining Juvenile Idiopathic Arthritis Remission and Optimum Time for Disease-Modifying Anti-Rheumatic Drug Withdrawal. Pediatric Drugs 14:1, 7-12
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Jennifer Goldman, Mara L Becker, Bridgette Jones, Mark Clements, J Steven Leeder. (2011) Development of biomarkers to optimize pediatric patient management: what makes children different?. Biomarkers in Medicine 5:6, 781-794
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A. Heiligenhaus, H. Michels, C. Schumacher, I. Kopp, U. Neudorf, T. Niehues, H. Baus, M. Becker, B. Bertram, G. Dannecker, C. Deuter, I. Foeldvari, M. Frosch, G. Ganser, M. Gaubitz, G. Gerdes, G. Horneff, A. Illhardt, F. Mackensen, K. Minden, U. Pleyer, M. Schneider, N. Wagner, M. Zierhut. (2011) Evidence-based, interdisciplinary guidelines for anti-inflammatory treatment of uveitis associated with juvenile idiopathic arthritis. Rheumatology International
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Jun-ichi Kawada, Naomi Iwata, Yoshiro Kitagawa, Hiroshi Kimura, Yoshinori Ito. (2011) Prospective monitoring of Epstein–Barr virus and other herpesviruses in patients with juvenile idiopathic arthritis treated with methotrexate and tocilizumab. Modern Rheumatology
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Teruyuki Nakatani, Toru Maekawa, Shinsuke Ishii. (2011) A case of juvenile idiopathic arthritis exhibiting repair of systemic bone erosion in response to continuation of MTX therapy after achievement of clinical remission. Modern Rheumatology 21:5, 514-517
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Gregor Dueckers, Nihal Guellac, Martin Arbogast, Guenther Dannecker, Ivan Foeldvari, Michael Frosch, Gerd Ganser, Arnd Heiligenhaus, Gerd Horneff, Arnold Illhardt, Ina Kopp, Ruediger Krauspe, Barbara Markus, Hartmut Michels, Matthias Schneider, Wolfram Singendonk, Helmut Sitter, Marianne Spamer, Norbert Wagner, Tim Niehues. (2011) Evidence and consensus based GKJR guidelines for the treatment of juvenile idiopathic arthritis. Clinical Immunology
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P. Woo, R. E. Petty. (2011) Looking at paediatric rheumatology over the past 50 years. Rheumatology 50:9, 1533-1536
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Nicolino Ruperto, Alberto Martini. (2011) Emerging drugs to treat juvenile idiopathic arthritis. Expert Opinion on Emerging Drugs 16:3, 493-505
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Tomoyuki Imagawa, Shumpei Yokota, Masaaki Mori, Takako Miyamae, Syuji Takei, Hiroyuki Imanaka, Yasuhito Nerome, Naomi Iwata, Takuji Murata, Mari Miyoshi, Norihiro Nishimoto, Tadamitsu Kishimoto. (2011) Safety and efficacy of tocilizumab, an anti-IL-6-receptor monoclonal antibody, in patients with polyarticular-course juvenile idiopathic arthritis. Modern Rheumatology
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Michael W. Beresford. (2011) Juvenile Idiopathic Arthritis. Pediatric Drugs 13:3, 161-173
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Gerd Horneff. (2011) Treatment options with biologics for juvenile idiopathic arthritis. International Journal of Clinical Rheumatology 6:3, 305-323
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Timothy Beukelman, Nivedita M. Patkar, Kenneth G. Saag, Sue Tolleson-Rinehart, Randy Q. Cron, Esi Morgan DeWitt, Norman T. Ilowite, Yukiko Kimura, Ronald M. Laxer, Daniel J. Lovell, Alberto Martini, C. Egla Rabinovich, Nicolino Ruperto. (2011) 2011 American College of Rheumatology recommendations for the treatment of juvenile idiopathic arthritis: Initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features. Arthritis Care & Research 63:4, 465-482
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Viera Kalinina Ayuso, Evelyne Leonce van de Winkel, Aniki Rothova, Joke Helena de Boer. (2011) Relapse Rate of Uveitis Post-Methotrexate Treatment in Juvenile Idiopathic Arthritis. American Journal of Ophthalmology 151:2, 217-222
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Tomoharu Yokooji, Nobuhiro Mori, Teruo Murakami. (2011) Modulated pharmacokinetics and increased small intestinal toxicity of methotrexate in bilirubin-treated rats. Journal of Pharmacy and Pharmacology 63:2, 206-213
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Alan M. Rosenberg, Kiem G. Oen. 2011. POLYARTHRITIS. , 249-261.
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G. Horneff, I. Foeldvari, K. Minden, D. Moebius, T. Hospach. (2011) Report on malignancies in the German juvenile idiopathic arthritis registry. Rheumatology 50:1, 230-236
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Norman T. Ilowite, Ronald M. Laxer. 2011. PHARMACOLOGY AND DRUG THERAPY. , 71-126.
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Nicolino Ruperto, Daniel J. Lovell, Tracy Li, Flavio Sztajnbok, Claudia Goldenstein-Schainberg, Morton Scheinberg, Inmaculada Calvo Penades, Michael Fischbach, Javier Orozco Alcala, Philip J. Hashkes, Christine Hom, Lawrence Jung, Loredana Lepore, Sheila Oliveira, Carol Wallace, Maria Alessio, Pierre Quartier, Elisabetta Cortis, Anne Eberhard, Gabriele Simonini, Irene Lemelle, Elizabeth Candell Chalom, Leonard H. Sigal, Alan Block, Allison Covucci, Marleen Nys, Alberto Martini, Edward H. Giannini. (2010) Abatacept improves health-related quality of life, pain, sleep quality, and daily participation in subjects with juvenile idiopathic arthritis. Arthritis Care & Research 62:11, 1542-1551
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Nicolino Ruperto, Edward H. Giannini, Angela Pistorio, Hermine I. Brunner, Alberto Martini, Daniel J. Lovell. (2010) Is it time to move to active comparator trials in juvenile idiopathic arthritis?: A review of current study designs. Arthritis & Rheumatism 62:11, 3131-3139
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G. Horneff. (2010) Juvenile Arthritiden. Zeitschrift für Rheumatologie 69:8, 719-737
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D. Holzinger, M. Frosch, D. Föll. (2010) Methotrexat bei der Therapie der juvenilen idiopathischen Arthritis. Zeitschrift für Rheumatologie 69:6, 496-504
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G. Horneff. (2010) Malignome und Tumor-Nekrose-Faktor-Inhibitoren bei der juvenilen idiopathischen Arthritis. Zeitschrift für Rheumatologie 69:6, 516-526
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Nicolino Ruperto, Daniel J. Lovell, Pierre Quartier, Eliana Paz, Nadina Rubio-Pérez, Clovis A. Silva, Carlos Abud-Mendoza, Ruben Burgos-Vargas, Valeria Gerloni, Jose A. Melo-Gomes, Claudia Saad-Magalhães, J. Chavez-Corrales, Christian Huemer, Alan Kivitz, Francisco J. Blanco, Ivan Foeldvari, Michael Hofer, Gerd Horneff, Hans-Iko Huppertz, Chantal Job-Deslandre, Anna Loy, Kirsten Minden, Marilynn Punaro, Alejandro Flores Nunez, Leonard H. Sigal, Alan J. Block, Marleen Nys, Alberto Martini, Edward H. Giannini. (2010) Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis. Arthritis & Rheumatism 62:6, 1792-1802
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Hobart W. Walling, Pedram Gerami, Richard D. Sontheimer. (2010) Juvenile-Onset Clinically Amyopathic Dermatomyositis. Pediatric Drugs 12:1, 23-34
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Mary Beth F. Son, Robert P. Sundel. 2010. Juvenile Arthritis. , 70-82.
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Silvia Magni-Manzoni, Oscar Epis, Angelo Ravelli, Catherine Klersy, Chiara Veisconti, Stefano Lanni, Valentina Muratore, Carlo Alberto Scir
, Silvia Rossi, Carlomaurizio Montecucco. (2009) Comparison of clinical versus ultrasound-determined synovitis in juvenile idiopathic arthritis. Arthritis & Rheumatism 61:11, 1497-1504
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Manfred Zierhut, Deshka Doycheva, Sabine Biester, Nicole Stübiger, Jasmin Kümmerle-Deschner, Christoph Deuter. (2009) Therapy of Uveitis in Children. International Ophthalmology Clinics 48:3, 131-152
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Ryoko Yumoto, Shota Hamada, Kaori Okada, Yuki Kato, Mika Ikehata, Junya Nagai, Mikihisa Takano. (2009) Effect of ursodeoxycholic acid treatment on the expression and function of multidrug resistance-associated protein 2 in rat intestine. Journal of Pharmaceutical Sciences 98:8, 2822-2831
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G. Horneff, A. Ebert, S. Fitter, K. Minden, I. Foeldvari, J. Kummerle-Deschner, A. Thon, H. J. Girschick, F. Weller, H. I. Huppertz. (2009) Safety and efficacy of once weekly etanercept 0.8 mg/kg in a multicentre 12 week trial in active polyarticular course juvenile idiopathic arthritis. Rheumatology 48:8, 916-919
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Tomoharu Yokooji, Nobuhiro Mori, Teruo Murakami. (2009) Site-specific contribution of proton-coupled folate transporter/haem carrier protein 1 in the intestinal absorption of methotrexate in rats. Journal of Pharmacy and Pharmacology 61:7, 911-918
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Miloš Hroch, Jana Tuková, Pavla Doležalová, Jaroslav Chládek. (2009) An improved high-performance liquid chromatography method for quantification of methotrexate polyglutamates in red blood cells of children with juvenile idiopathic arthritis. Biopharmaceutics & Drug Disposition 30:3, 138-148
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Hoda Y. Tomoum, Gehan A. Mostafa, Esraa M. F. El-Shahat. (2009) Autoantibody to heterogeneous nuclear ribonucleoprotein-A2 (RA33) in juvenile idiopathic arthritis: Clinical significance. Pediatrics International 51:2, 188-192
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Lovell, Daniel J., Ruperto, Nicolino, Goodman, Steven, Reiff, Andreas, Jung, Lawrence, Jarosova, Katerina, Nemcova, Dana, Mouy, Richard, Sandborg, Christy, Bohnsack, John, Elewaut, Dirk, Foeldvari, Ivan, Gerloni, Valeria, Rovensky, Jozef, Minden, Kirsten, Vehe, Richard K., Weiner, L. Wagner, Horneff, Gerd, Huppertz, Hans-Iko, Olson, Nancy Y., Medich, John R., Carcereri-De-Prati, Roberto, McIlraith, Melissa J., Giannini, Edward H., Martini, Alberto, . (2008) Adalimumab with or without Methotrexate in Juvenile Rheumatoid Arthritis. New England Journal of Medicine 359:8, 810-820
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Nicolino Ruperto, Daniel J Lovell, Pierre Quartier, Eliana Paz, Nadina Rubio-Pérez, Clovis A Silva, Carlos Abud-Mendoza, Ruben Burgos-Vargas, Valeria Gerloni, Jose A Melo-Gomes, Claudia Saad-Magalhães, Flavio Sztajnbok, Claudia Goldenstein-Schainberg, Morton Scheinberg, Immaculada Calvo Penades, Michael Fischbach, Javier Orozco, Philip J Hashkes, Christine Hom, Lawrence Jung, Loredana Lepore, Sheila Oliveira, Carol A Wallace, Leonard H Sigal, Alan J Block, Allison Covucci, Alberto Martini, Edward H Giannini. (2008) Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled withdrawal trial. The Lancet 372:9636, 383-391
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Tim Bongartz. (2008) Tocilizumab for rheumatoid and juvenile idiopathic arthritis. The Lancet 371:9617, 961-963
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Angelo Ravelli, Alberto Martini. 2008. Juvenile idiopathic arthritis. , 789-801.
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Tomoharu Yokooji, Ryoko Yumoto, Junya Nagai, Mikihisa Takano, Tomoharu Yokooji, Teruo Murakami. (2007) Role of intestinal efflux transporters in the intestinal absorption of methotrexate in rats. Journal of Pharmacy and Pharmacology 59:9, 1263-1270
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Nicolino Ruperto, Daniel J. Lovell, Ruben Cuttica, Nick Wilkinson, Patricia Woo, Graciela Espada, Carine Wouters, Earl D. Silverman, Zsolt Balogh, Michael Henrickson, Maria-Teresa Apaz, Eileen Baildam, Anders Fasth, Valeria Gerloni, Pekka Lahdenne, Anne-Marie Prieur, Angelo Ravelli, Rotraud K. Saurenmann, Maria Luz Gamir, Nico Wulffraat, Laszlo Marodi, Ross E. Petty, Rik Joos, Francesco Zulian, Deborah McCurdy, Barry L. Myones, Kalman Nagy, Peter Reuman, Ilona Szer, Suzanne Travers, Anna Beutler, Greg Keenan, Jason Clark, Sudha Visvanathan, Adedigbo Fasanmade, Aparna Raychaudhuri, Alan Mendelsohn, Alberto Martini, Edward H. Giannini, , . (2007) A randomized, placebo-controlled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis. Arthritis & Rheumatism 56:9, 3096-3106
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Angelo Ravelli, Maka Ioseliani, Ximena Norambuena, Juliana Sato, Angela Pistorio, Federica Rossi, Nicolino Ruperto, Silvia Magni-Manzoni, Nicola Ullmann, Alberto Martini. (2007) Adapted versions of the Sharp/van der Heijde score are reliable and valid for assessment of radiographic progression in juvenile idiopathic arthritis. Arthritis & Rheumatism 56:9, 3087-3095
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Angelo Ravelli, Alberto Martini. (2007) Juvenile idiopathic arthritis. The Lancet 369:9563, 767-778
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C. Job-Deslandre. (2007) Artritis idiop
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GERD HORNEFF,, MICHAEL BORTE,, PETER MATZEN, WOLFGANG HIRSCH. 2007. Rheumatische Krankheiten und Arthropathie bei Hämophilie. , 401-435.
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Bridgette Guthrie, Kelly A. Rouster-Stevens, Sally L. Reynolds. (2007) Review of Medications Used in Juvenile Rheumatoid Arthritis. Pediatric Emergency Care 23:1, 38-46
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Richard Mier. (2006) Recent therapeutic advances in the care of children with chronic arthritis. Current Opinion in Orthopaedics 17:6, 526-530
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Federica Rossi, Fiorella Di Dia, Olivia Galipò, Angela Pistorio, Maura Valle, Silvia Magni-Manzoni, Nicolino Ruperto, Paolo Tomà, Alberto Martini, Angelo Ravelli. (2006) Use of the sharp and larsen scoring methods in the assessment of radiographic progression in juvenile idiopathic arthritis. Arthritis & Rheumatism 55:5, 717-723
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Manfred Zierhut, Hartmut Michels, Nicole St??biger, Dorothea Besch, Christoph Deuter, Arnd Heiligenhaus. (2006) Uveitis in Children. International Ophthalmology Clinics 45:2, 135-156
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A. Lurati, I. Pontikaki, B. Teruzzi, F. Desiati, V. Gerloni, M. Gattinara, R. Cimaz, F. Fantini. (2006) A comparison of response criteria to evaluate therapeutic response in patients with juvenile idiopathic arthritis treated with methotrexate and/or anti–tumor necrosis factor α agents. Arthritis & Rheumatism 54:5, 1602-1607
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Andrea T. Borchers, Carlo Selmi, Gurtej Cheema, Carl L. Keen, Yehuda Shoenfeld, M. Eric Gershwin. (2006) Juvenile idiopathic arthritis. Autoimmunity Reviews 5:4, 279-298
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Petros E. Carvounis, David C. Herman, Stephen Cha, James P. Burke. (2006) Incidence and outcomes of uveitis in juvenile rheumatoid arthritis, a synthesis of the literature. Graefe's Archive for Clinical and Experimental Ophthalmology 244:3, 281-290
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Tim Niehues, Petra Lankisch. (2006) Recommendations for the Use of Methotrexate in Juvenile Idiopathic Arthritis. Pediatric Drugs 8:6, 347-356
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Masaaki Mori, Syuji Takei, Tomoyuki Imagawa, Hiroyuki Imanaka, Nobuaki Maeno, Rumiko Kurosawa, Yoshifumi Kawano, Shumpei Yokota. (2005) Pharmacokinetics, efficacy, and safety of short-term (12 weeks) etanercept for methotrexate-refractory polyarticular juvenile idiopathic arthritis in Japan. Modern Rheumatology 15:6, 397-404
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G. Ted Brown, F. Virginia Wright, Bianca A. Lang, Nina Birdi, Kim Oen, Derek Stephens, Joan McComas, Brian M. Feldman. (2005) Clinical responsiveness of self-report functional assessment measures for children with juvenile idiopathic arthritis undergoing intraarticular corticosteroid injections. Arthritis & Rheumatism 53:6, 897-904
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A. V. Ramanan, N. Campbell-Webster, S. Ota, S. Parker, D. Tran, P. N. Tyrrell, B. Cameron, L. Spiegel, R. Schneider, R. M. Laxer, E. D. Silverman, B. M. Feldman. (2005) The effectiveness of treating juvenile dermatomyositis with methotrexate and aggressively tapered corticosteroids. Arthritis & Rheumatism 52:11, 3570-3578
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JANE G. SCHALLER. (2005) The History of Pediatric Rheumatology. Pediatric Research 58:5, 997-1007
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Gaëlle Chédeville, Pierre Quartier, Marta Miranda, Raja Brauner, Anne-Marie Prieur. (2005) Improvements in growth parameters in children with juvenile idiopathic arthritis associated with the effect of methotrexate on disease activity. Joint Bone Spine 72:5, 392-396
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Marion A. J. van Rossum, Maarten Boers, Aeilko H. Zwinderman, Renée M. van Soesbergen, Helen Wieringa, Theo J. W. Fiselier, Marcel J. A. M. Franssen, Rebecca ten Cate, Lisette W. A. van Suijlekom-Smit, Nico M. Wulffraat, Wilma H. J. van Luijk, Johanna C. M. Oostveen, Wietse Kuis, Ben A. C. Dijkmans, . (2005) Development of a standardized method of assessment of radiographs and radiographic change in juvenile idiopathic arthritis: Introduction of the Dijkstra composite score. Arthritis & Rheumatism 52:9, 2865-2872
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F. Weller, H.-I. Huppertz. (2005) Die Behandlung des kindlichen Rheumas: Pharmakotherapie. Zeitschrift für Rheumatologie 64:5, 308-316
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Silverman, Earl, Mouy, Richard, Spiegel, Lynn, Jung, Lawrence K., Saurenmann, Rotraud K., Lahdenne, Pekka, Horneff, Gerd, Calvo, Immaculada, Szer, Ilona S., Simpson, Karen, Stewart, John A., Strand, Vibeke, . (2005) Leflunomide or Methotrexate for Juvenile Rheumatoid Arthritis. New England Journal of Medicine 352:16, 1655-1666
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Tim Niehues, Gerd Horneff, Hartmut Michels, Michaela Sailer H
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Janine A. Smith, Darby J. S. Thompson, Scott M. Whitcup, Eric Suhler, Grace Clarke, Susan Smith, Michael Robinson, Jonghyeon Kim, Karyl S. Barron. (2005) A randomized, placebo-controlled, double-masked clinical trial of etanercept for the treatment of uveitis associated with juvenile idiopathic arthritis. Arthritis & Rheumatism 53:1, 18-23
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Earl Silverman, Lynn Spiegel, David Hawkins, Ross Petty, Donald Goldsmith, Laura Schanberg, Ciaran Duffy, Paul Howard, Vibeke Strand. (2005) Long-term open-label preliminary study of the safety and efficacy of leflunomide in patients with polyarticular-course juvenile rheumatoid arthritis. Arthritis & Rheumatism 52:2, 554-562
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Gijs Teklenburg, Salvatore Albani. (2004) The role of immune tolerance in preventing and treating arthritis. Current Rheumatology Reports 6:6, 434-441
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Daniel J. Lovell, Theoklis E. Zaoutis, Kathleen Sullivan. (2004) Immunosuppressants, infection, and inflammation. Clinical Immunology 113:2, 137-139
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Dagnachew W. Workie, Bernard J. Dardzinski, T. Brent Graham, Tal Laor, Wendy A. Bommer, Kendall J. O'Brien. (2004) Quantification of dynamic contrast-enhanced MR imaging of the knee in children with juvenile rheumatoid arthritis based on pharmacokinetic modeling. Magnetic Resonance Imaging 22:9, 1201-1210
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U. Neudorf, A. Heiligenhaus. (2004) Uveitis bei juveniler idiopathischer Arthritis. Monatsschrift Kinderheilkunde 152:11, 1240-1249
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Nicolino Ruperto, Alberto Martini. (2004) International research networks in pediatric rheumatology: the PRINTO perspective. Current Opinion in Rheumatology 16:5, 566-570
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Nora G Singer, Lisabeth V Scalzi. (2004) Remittive agents in pediatric rheumatology. Current Opinion in Rheumatology 16:5, 571-576
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Nicolino Ruperto, Kevin J. Murray, Valeria Gerloni, Nico Wulffraat, Sheila Knupp Feitosa De Oliveira, Fernanda Falcini, Pavla Dolezalova, Maria Alessio, Ruben Burgos-Vargas, Fabrizia Corona, Richard Vesely, Helen Foster, Joyce Davidson, Francesco Zulian, Line Asplin, Eileen Baildam, Julia Garcia Consuegra, Huri Ozdogan, Rotraud Saurenmann, Rik Joos, Angela Pistorio, Pat Woo, Alberto Martini, . (2004) 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. Arthritis & Rheumatism 50:7, 2191-2201
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Lucila M. A. Agle, Liza B. Vazquez-Cobian, Thomas J. A. Lehman. (2003) Clinical trials in pediatric uveitis. Current Rheumatology Reports 5:6, 477-481
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MP Iqbal, M Ahmed, M Umer, N Mehboobali, AA Qureshi. (2003) Effect of methotrexate and folinic acid on skeletal growth in mice. Acta Paediatrica 92:12, 1438-1444
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Gary N Holland, E.Richard Stiehm. (2003) Special considerations in the evaluation and management of uveitis in children. American Journal of Ophthalmology 135:6, 867-878
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M. BALLMANN, S. JUNGE, H. VON DER HARDT. (2003) Low-dose methotrexate for advanced pulmonary disease in patients with cystic fibrosis. Respiratory Medicine 97:5, 498-500
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Johanna C. Escher, Jan A. J. M. Taminiau, Edward E. S. Nieuwenhuis, Hans A. B??ller, Richard J. Grand. (2003) Treatment of Inflammatory Bowel Disease in Childhood: Best Available Evidence. Inflammatory Bowel Diseases 9:1, 34-58
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Nadia Khalida Waheed, Elisabetta Miserocchi, C. Stephen Foster. (2002) Ocular Concerns in Juvenile Rheumatoid Arthritis. International Ophthalmology Clinics 41:4, 223-234
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Kevin J Murray, Daniel J Lovell. (2002) Advanced therapy for juvenile arthritis. Best Practice & Research Clinical Rheumatology 16:3, 361-378
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Luis Carre??o, Francisco Javier L??pez-Longo, Carlos Manuel Gonz??lez, Indalecio Monteagudo. (2002) Treatment Options for Juvenile-Onset Systemic Lupus Erythematosus. Pediatric Drugs 4:4, 241-256
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Tim Takken, Janjaap J van der Net, Paul PJM Helders, Tim Takken. 2001. Methotrexate for treating juvenile idiopathic arthritis. .
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Donald T. Kulas, Laura Schanberg. (2001) Juvenile idiopathic arthritis. Current Opinion in Rheumatology 13:5, 392-398
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Brian Feldman, Elaine Wang, Andrew Willan, John Paul Szalai. (2001) The randomized placebo-phase design for clinical trials. Journal of Clinical Epidemiology 54:6, 550-557
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Douglas A. Jabs, James T. Rosenbaum, C.Stephen Foster, Gary N. Holland, Glenn J. Jaffe, James S. Louie, Robert B. Nussenblatt, E.Richard Stiehm, Howard Tessler, Russell N. Van Gelder, Scott M. Whitcup, David Yocum. (2000) Guidelines for the use of immunosuppressive drugs in patients with ocular inflammatory disorders: recommendations of an expert panel. American Journal of Ophthalmology 130:4, 492-513
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Anne-Marie Prieur, Pierre Quartier. (2000) Comparative Tolerability of Treatments for Juvenile Idiopathic Arthritis. BioDrugs 14:3, 159-183
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P. Woo, T. R. Southwood, A.-M. Prieur, C. J. Doré, J. Grainger, J. David, C. Ryder, N. Hasson, A. Hall, I. Lemelle. (2000) Randomized, placebo-controlled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis. Arthritis & Rheumatism 43:8, 1849-1857
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David D. Sherry. (2000) What's New in the Diagnosis and Treatment of Juvenile Rheumatoid Arthritis. Journal of Pediatric Orthopaedics 20:4, 419-420
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