Table 12, Summary of the evidence on comparative effectiveness and harms of DMARDs for childhood JIA - Disease-Modifying Antirheumatic Drugs (DMARDs) in Children With Juvenile Idiopathic Arthritis (JIA)

Key question	Strength of evidence	Conclusions
1. In children with JIA, does treatment with DMARDs, compared to conventional treatment:
a. Improve laboratory measures of inflammation?	Low	Trials of DMARDs usually report changes in laboratory measures of inflammation (e.g., ESR). However, ESR is inconsistently associated with treatment. This conclusion is based on 14 studies of 1060 subjects.
b. Improve radiological progression?	Insufficient	Insufficient data are available to evaluate the impact of DMARDs on radiological progression. Only one cohort study of 63 subjects reported data on radiological progression.
c. Improve symptoms?	Moderate	Among children who have responded to a biologic DMARD, randomized discontinuation trials show that continued treatment for from 4 months to 2 years decrease the risk of having a flare (RR 0.46, 95% CI 0.36 to 0.60). This conclusion is based on four studies of 322 subjects. Among the non-biologic DMARDs, there is some evidence that methotrexate is superior to conventional therapy and oral corticosteroids, based on two randomized trials of 215 subjects.
d. Improve health status?	Low	Changes in health status were reported in 12 studies involving 927 subjects. Health status improved inconsistently with treatment with DMARDs.
2. In children with JIA, what are the comparative effects of DMARDs on:
a. Laboratory measures of inflammation?	Low	Trials of DMARDs usually report changes in laboratory measures of inflammation (e.g., ESR). However, ESR is inconsistently associated with treatment. This is based on 4 RCTs of 448 subjects and 1 cohort study of 72 subjects.
b. Radiological progression?	Insufficient	No study addressed radiologic progression.
c. Symptoms?	Low	The non-biologic DMARDs that were compared directly (penicillamine vs. hydroxychloroquine, sulfasalazine vs. hydroxychloroquine, and leflunomide vs. methotrexate) had similar efficacy. Changes in symptoms between the treatment arms were not measured with significant precision to detect a difference. This is based on 4 RCTs of 448 subjects and 1 cohort study of 72 subjects. One poor-quality RCT of 94 subjects found that etanercept was similar to infliximab.
d. Health status?	Low	The non-biologic DMARDs that were compared directly (penicillamine vs. hydroxychloroquine, sulfasalazine vs. hydroxychloroquine, and leflunomide vs. methotrexate) had similar efficacy. Changes in health status between the treatment arms were not measured with significant precision to detect a difference. This is based on 4 RCTs of 448 subjects and 1 cohort study of 72 subjects. One poor quality RCT of 94 subjects found that etanercept was similar to infliximab.
3. In children with JIA, does the rate and type of adverse events differ between:
a. The various DMARDs?	Insufficient	Three RCTs directly compared two DMARDs; two compared penicillamine to hydroxychloroquine, and one compared leflunomide to methotrexate. The rate and type of adverse events did not differ between treatment groups in these studies. High variability across studies in the ascertainment and reporting of adverse events preclude valid comparisons of the rate and type of adverse events among the various DMARDs. Recently published studies of adverse event reporting databases provide indirect evidence that suggests a possible relationship between cancer and exposure to tumor necrosis factor α blockers.
b. DMARDs and conventional treatment with or without methotrexate?	Insufficient	No RCT directly compared a DMARD to conventional treatment. Thirteen trials directly compared a DMARD to placebo. The rate and type of adverse events were generally similar between intervention and placebo groups, with the notable exceptions of infliximab plus methotrexate being associated with more serious adverse events (32% vs. 5% over differing lengths of followup), and methotrexate being associated with higher rates of laboratory abnormalities (35% vs. 13%).
4. How do the efficacy, effectiveness, safety, and adverse effects of treatment with DMARDs differ among the various categories of JIA?	Insufficient	Only one study – an RCT of methotrexate versus placebo in which each group could also receive oral corticosteroids, intra-articular corticosteroids, and NSAIDs – evaluated efficacy by JIA category. No difference was found among those with extended oligoarticular JIA (n = 43) and systemic JIA (n = 45). We did not identify any studies that provide reliable information on the comparative safety or rates or types of adverse events among the various categories of JIA.
5. What are the validity, reliability, responsiveness, and feasibility of the clinical outcome measures for childhood JIA that are commonly used in clinical trials or within the clinical practice setting?	Insufficient	Most of the studies examining the psychometric properties of the instruments used in JIA were fair-quality cross-sectional or longitudinal non-randomized controlled trials. No one instrument or outcomes measure appeared superior in measuring disease activity or functional status. The current response criteria of the ACR Pediatric 30, a composite measure that includes articular indices, functional status, laboratory measure, and global assessments, takes into account the various measures most commonly used. However, the responsiveness of several of these measures, including functional status and parent/patient global assessment, are poor to moderate, and they may not adequately reflect changes in disease state. Furthermore, given that the ACR Pediatric 30 is a relative measure of disease activity, the impact of JIA category on percent improvement is unclear, as certain instruments, such as the CHAQ, appear to have differential responsiveness depending on extent of disease at baseline. The ACR Pediatric 30 is also a relative measure of disease activity and not a measure of current disease state.

Key question

Strength of evidence

Conclusions

1. In children with JIA, does treatment with DMARDs, compared to conventional treatment:

a. Improve laboratory measures of inflammation?

Low

Trials of DMARDs usually report changes in laboratory measures of inflammation (e.g., ESR). However, ESR is inconsistently associated with treatment. This conclusion is based on 14 studies of 1060 subjects.

b. Improve radiological progression?

Insufficient

Insufficient data are available to evaluate the impact of DMARDs on radiological progression. Only one cohort study of 63 subjects reported data on radiological progression.

c. Improve symptoms?

Moderate

Among children who have responded to a biologic DMARD, randomized discontinuation trials show that continued treatment for from 4 months to 2 years decrease the risk of having a flare (RR 0.46, 95% CI 0.36 to 0.60). This conclusion is based on four studies of 322 subjects. Among the non-biologic DMARDs, there is some evidence that methotrexate is superior to conventional therapy and oral corticosteroids, based on two randomized trials of 215 subjects.

d. Improve health status?

Low

Changes in health status were reported in 12 studies involving 927 subjects. Health status improved inconsistently with treatment with DMARDs.

2. In children with JIA, what are the comparative effects of DMARDs on:

a. Laboratory measures of inflammation?

Low

Trials of DMARDs usually report changes in laboratory measures of inflammation (e.g., ESR). However, ESR is inconsistently associated with treatment. This is based on 4 RCTs of 448 subjects and 1 cohort study of 72 subjects.

b. Radiological progression?

Insufficient

No study addressed radiologic progression.

c. Symptoms?

Low

The non-biologic DMARDs that were compared directly (penicillamine vs. hydroxychloroquine, sulfasalazine vs. hydroxychloroquine, and leflunomide vs. methotrexate) had similar efficacy. Changes in symptoms between the treatment arms were not measured with significant precision to detect a difference. This is based on 4 RCTs of 448 subjects and 1 cohort study of 72 subjects. One poor-quality RCT of 94 subjects found that etanercept was similar to infliximab.

d. Health status?

Low

The non-biologic DMARDs that were compared directly (penicillamine vs. hydroxychloroquine, sulfasalazine vs. hydroxychloroquine, and leflunomide vs. methotrexate) had similar efficacy. Changes in health status between the treatment arms were not measured with significant precision to detect a difference. This is based on 4 RCTs of 448 subjects and 1 cohort study of 72 subjects. One poor quality RCT of 94 subjects found that etanercept was similar to infliximab.

3. In children with JIA, does the rate and type of adverse events differ between:

a. The various DMARDs?

Insufficient

Three RCTs directly compared two DMARDs; two compared penicillamine to hydroxychloroquine, and one compared leflunomide to methotrexate. The rate and type of adverse events did not differ between treatment groups in these studies. High variability across studies in the ascertainment and reporting of adverse events preclude valid comparisons of the rate and type of adverse events among the various DMARDs. Recently published studies of adverse event reporting databases provide indirect evidence that suggests a possible relationship between cancer and exposure to tumor necrosis factor α blockers.

b. DMARDs and conventional treatment with or without methotrexate?

Insufficient

No RCT directly compared a DMARD to conventional treatment. Thirteen trials directly compared a DMARD to placebo. The rate and type of adverse events were generally similar between intervention and placebo groups, with the notable exceptions of infliximab plus methotrexate being associated with more serious adverse events (32% vs. 5% over differing lengths of followup), and methotrexate being associated with higher rates of laboratory abnormalities (35% vs. 13%).

4. How do the efficacy, effectiveness, safety, and adverse effects of treatment with DMARDs differ among the various categories of JIA?

Insufficient

Only one study – an RCT of methotrexate versus placebo in which each group could also receive oral corticosteroids, intra-articular corticosteroids, and NSAIDs – evaluated efficacy by JIA category. No difference was found among those with extended oligoarticular JIA (n = 43) and systemic JIA (n = 45). We did not identify any studies that provide reliable information on the comparative safety or rates or types of adverse events among the various categories of JIA.

5. What are the validity, reliability, responsiveness, and feasibility of the clinical outcome measures for childhood JIA that are commonly used in clinical trials or within the clinical practice setting?

Insufficient

Most of the studies examining the psychometric properties of the instruments used in JIA were fair-quality cross-sectional or longitudinal non-randomized controlled trials. No one instrument or outcomes measure appeared superior in measuring disease activity or functional status. The current response criteria of the ACR Pediatric 30, a composite measure that includes articular indices, functional status, laboratory measure, and global assessments, takes into account the various measures most commonly used. However, the responsiveness of several of these measures, including functional status and parent/patient global assessment, are poor to moderate, and they may not adequately reflect changes in disease state. Furthermore, given that the ACR Pediatric 30 is a relative measure of disease activity, the impact of JIA category on percent improvement is unclear, as certain instruments, such as the CHAQ, appear to have differential responsiveness depending on extent of disease at baseline. The ACR Pediatric 30 is also a relative measure of disease activity and not a measure of current disease state.

From: Summary and Discussion

Cover of Disease-Modifying Antirheumatic Drugs (DMARDs) in Children With Juvenile Idiopathic Arthritis (JIA)

Disease-Modifying Antirheumatic Drugs (DMARDs) in Children With Juvenile Idiopathic Arthritis (JIA) [Internet].

Comparative Effectiveness Reviews, No. 28.

Kemper AR, Coeytaux R, Sanders GD, et al.

Rockville (MD): Agency for Healthcare Research and Quality (US); 2011 Sep.

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Table 12Summary of the evidence on comparative effectiveness and harms of DMARDs for childhood JIA