Biologic DMARDs vs. Conventional treatment with or without Methotrexate
Abatacept
One good-quality randomized discontinuation study evaluated abatacept in children with persistent oligoarthritis, extended oligoarthritis, polyarthritis, or systemic JIA [6]. During the 6-month double-blind period of this study, there was statistically significant improvement compared to placebo in the active joint count (4.4 vs. 6; p = 0.02), CHAQ score (0.8 vs. 0.7; p = 0.04), physician global assessment (14.7 vs. 12.5; p < 0.01), and ACR Pediatric 90 response (40% vs. 16%; p < 0.01). There was no statistically significant improvement in parent or patient global assessment (17.9 vs. 23.9; p = 0.70) or erythrocyte sedimentation rate (ESR; 25.1 vs. 30.7; p = 0.96).
Adalimumab
One good-quality randomized discontinuation trial compared adalimumab to conventional therapy among children with polyarticular JRA [7]. The results were stratified by use of methotrexate. At the end of the 48-week double-blind phase, fewer patients treated with adalimumab and methotrexate had flares than those treated with placebo plus methotrexate (43% vs. 71%; p = 0.03). Similarly, the proportion of patients who had a flare of disease in the adalimumab without methotrexate group was lower than in the placebo group without methotrexate (37% vs. 65%; p = 0.02). The ACR Pediatric 50 response in the adalimumab without methotrexate group was higher than in the placebo without methotrexate group (53% vs. 32%; p = 0.01), and higher than in those groups that received methotrexate (63% vs. 38%; p = 0.03). Although the ACR Pediatric 90 response was higher in the adalimumab without methotrexate group than in the placebo without methotrexate group (30% vs. 18%), the difference was not statistically significant (p = 0.28). Similarly, the ACR Pediatric 90 response among those who also received methotrexate was higher in the adalimumab group than in the placebo group, but did not achieve statistical significance (42% vs. 27%; p = 0.17).
Anakinra
One poor-quality randomized discontinuation trial compared anakinra to conventional therapy among children with polyarticular, pauciarticular, or systemic JIA [8]. The main goal of the study was to evaluate safety. By week 28 of blinded treatment, 16% who received anakinra and 40% who received placebo had had a flare (p = 0.11). There was improvement in the CHAQ score in the anakinra group compared to placebo (-0.25 vs. 0.13; no p-value reported). Similarly, there was improvement in the ESR among those who were treated with anakinra (-2.21 vs. 13.73; no p-value reported). The quality was rated poor because the study did not have a sufficient sample size to assess efficacy and there was insufficient reporting of randomization and concealment.
Etanercept
Two studies evaluated etanercept versus placebo. One good-quality randomized discontinuation trial evaluated children with a polyarticular, pauciarticular, or systemic JRA [9]. In the double-blind component, fewer patients who received etanercept had a flare (28% vs. 81%; p = 0.003). There was also an improvement in the CHAQ score (-0.8 vs. -0.1). Overall, there was a 54% median improvement among those who received etanercept compared to no median change in the placebo group. There was an overall improvement in the number of active joints (7 vs. 13; no p-value reported), physician global assessment (2 vs. 5; no p-value reported), parent global assessment (3 vs. 5; no p-value reported), ESR (18 vs. 30; no p-value reported), and the ACR Pediatric 50 response (72% vs. 23%; no p-value reported).
The other study of etanercept was a fair-quality randomized controlled trial (RCT) that evaluated efficacy for the treatment of uveitis among children with JRA [10]. During the study, 6 of 12 subjects in the test treatment arm and 2 of 5 subjects in the conventional treatment arm improved. This was described by study investigators as no apparent difference.
Infliximab
One fair-quality RCT compared infliximab to conventional treatment among 121 children with polyarticular, pauciarticular, or systemic JRA [11]. The study did not find statistically significant differences between infliximab and conventional treatment in the ACR Pediatric 50 response at 14 weeks (50% vs. 33.9%, respectively; p = 0.13) or the rate of clinical remission at 52 weeks (44.1% vs. 43.1%, respectively).
Intravenous Immunoglobulin (IVIG)
Three studies compared IVIG to conventional treatment. One fair-quality randomized discontinuation trial [12] of 19 patients who had polyarticular JRA found a 3% decrease in the active joint count among those who were treated compared to a 30% increase in the placebo group. Physician global assessment improved for 3% of patients in the treatment group and worsened for 91% in the placebo group. Another, poor-quality study [13] compared IVIG to methylprednisolone among 20 subjects with JCA. Investigators found no statistically significant difference between the IVIG and methylprednisolone groups for ESR (59 at baseline and 21 at 6 months vs. 61 at baseline and 24 at 6 months, respectively). This study was rated poor because it was an open-label trial with no randomization, the subjects were incompletely described, and the analyses were not adjusted for baseline differences.
A poor-quality RCT [14] that included 31 subjects with systemic JRA found that IVIG compared to conventional therapy was associated with a non-statistically significant improvement in the median change in active joint count (-2 vs. -1) and in physician global assessment of improvement (50% improvement vs. 27% improvement; p > 0.3). This study was rated poor because the sample size was small, there was a high dropout rate.
Tocilizumab
One fair-quality randomized discontinuation trial of 43 subjects with JIA evaluated tocilizumab [15]. From the RCT component, the active joint count in the tocilizumab group decreased from 3.5 to 0. Similarly, in the conventional treatment group it decreased from 4 to 0. There was improvement in the CHAQ score for each group (-0.5 vs. -0.25). Both physician global assessment (51.0 to 5.5 vs. 51 to 14) and parent global assessment (51.0 to 4.5 vs. 55 to 39) improved. The ESR decreased for both the tocilizumab and conventional treatment group (35 to 0.1 vs. 38 to 15, respectively). The ACR Pediatric 70 response increased in the tocilizumab group from approximately 70% to approximately 80%, but decreased in the conventional treatment group from approximately 80% to approximately 30%.
Non-biologic DMARDs vs. Conventional treatment with or without Methotrexate
Azathioprine
One fair-quality RCT evaluated azathioprine among 32 subjects with polyarticular-onset, pauciarticular-onset, or systemic-onset JRA [16]. At 16 weeks of treatment, this study found non-statistically significant improvements with azathioprine in the number of active joints (-7 vs. -1; p = 0.45), physician global assessment (-5 vs. -2; p = 0.12), and the proportion with 50% improvement in ESR (4/13 subjects vs. 2/11 subjects; p = 0.36).
Hydroxychloroquine
Two RCTs evaluated hydroxychloroquine. One good-quality trial of 162 subjects with polyarticular, pauciarticular, or systemic JRA (described in two publications [17, 18]) found no significant difference in the change in mean active joint count compared to placebo after 12 months (6.7 [95% confidence interval (CI) -9.4 to -4] vs. -5.4 [95% CI -8 to -2.8]). The physician global assessment appeared slightly better for hydroxychloroquine than for placebo (70% better, 26% same, 2% worse compared to 53% better, 41% same, 6% worse; no p-value reported). There was no difference in the mean ESR decrease at 12 months (10 each).
The other study was a poor-quality, open-label RCT of 72 subjects with polyarticular or pauciarticular JRA that compared hydroxychloroquine to gold [19]. At 50 weeks, there were no statistically significant differences in the active joint count (-4 vs. -5), median change in the physician global assessment (-8 vs. -9), or change in the ESR (-12 vs. -11). Similarly, the physician overall assessment of at least 50% improvement was not statistically significantly different between the hydroxychloroquine group and the gold group (12 of 17 improved vs. 10 of 15 improved, respectively). This study was rated poor because allocation concealment was not specified, there were important differences in baseline characteristics, it was unclear if outcomes were assessed blinded to the intervention, and the outcomes were incompletely described.
Methotrexate
Three studies compared methotrexate to conventional treatment without methotrexate. One good-quality RCT of 127 subjects with JIA compared low-dose methotrexate, very low-dose methotrexate, and placebo in a 6-month trial [20]. The mean active joint count decreased with low-dose methotrexate (-7.5), very low-dose methotrexate (-5.2), and placebo (-5.2; p > 0.3 overall). Physician global assessment improved with low-dose methotrexate compared to placebo (p = 0.02), but there was no statistically significant difference between the low-dose and very low-dose methotrexate groups for this outcome (p = 0.06). Based on a composite index with at least 25% improvement in articular score and improvement according to physicians and parents, 63% of those in the low-dose methotrexate group improved, compare to 32% in the very low-dose methotrexate group, and 36% in the placebo group (p = 0.013).
Another good-quality study [21] of 88 subjects with extended oligoarticular or systemic JIA compared methotrexate to placebo among children with extended oligoarticular JIA or systemic JIA in a double-blind RCT with crossover. Among those with oligoarticular JIA, there was statistically significant improvement in physician global assessment (p < 0.001) and ESR (p < 0.001) with methotrexate. The change in the number of joints with synovitis (-3) did not achieve statistical significance (p < 0.1). Similarly, among those with systemic JIA, there was improvement in physician global assessment (p < 0.001), but not in ESR (p = 0.06) or in the number of joints with synovitis (p = 0.06) in patients taking methotrexate.
A poor-quality, non-randomized study that included 63 children with JIA compared methotrexate to NSAIDs and to methylprednisolone [22]. In this study, the active joint count improved more in the methylprednisolone group than in either the methotrexate or NSAID groups (-7.1 vs. -4 vs. -0.8, respectively; p = 0.008). This study was rated poor because there was confounding by indication, the analysis did not adjust for potential confounders, outcomes were not assessed blinded to treatment, and subjects were not blinded to treatment assignment.
Penicillamine
Four publications describing three distinct studies evaluated penicillamine. One good-quality RCT [17, 18] among subjects with polyarticular, pauciarticular, or systemic JRA found no statistically significant effect on the mean active joint count with penicillamine compared to placebo after 12 months (-3 [95% CI -4.8 to -1.1] vs. -5.4 [-8 to -2.8]); results were similar for physician global assessment (56% better, 28% same, 16% worse vs. 53% better, 41% same, 6% worse) and mean decrease in ESR (9.4 vs. 10).
A fair-quality RCT [23] of 74 subjects with polyarticular-onset, pauciarticular-onset, or systemic-onset JCA found no statistically significant effect on ESR in a 6-month study in patients treated with penicillamine compared to conventional treatment (-18 vs. -8). However, this study did find a statistically significant decrease in the number of painful joints in patients taking penicillamine (-3 vs. -1.6; p < 0.04).
A previously described poor-quality, open-label RCT [19] that included 74 subjects with polyarticular or pauciarticular JRA found no statistically significant effect for penicillamine compared to gold at 50 weeks in the active joint count (-2.5 vs. -5), median change in the physician global assessment (-7.5 vs. -9), change in ESR (-8 vs. -11), or the proportion of patients who had at least a 50% improvement based on physician assessment (8/12 vs. 10/15).
Sulfasalazine
One good-quality RCT of 69 subjects with polyarticular or oligoarticular JCA evaluated sulfasalazine versus placebo [24]. In this study, it was unclear which time points were compared. However, there was statistically significant improvement with sulfasalazine in active joint count (-5.54 vs. -0.78; p = 0.005), physician global assessment (-1.95 vs. -0.99; p = 0.0002), patient/parent global assessment (-0.98 vs. -0.44; p = 0.01), and decrease in ESR (-0.74 vs. -0.04; p < 0.001). The number of improved joints by x-ray findings was not statistically significantly different (0.71 vs. 0.53).
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