Nonsteroidal anti-inflammatory drugs (NSAIDs) have traditionally been the mainstay treatment for all forms of JIA. However, their use as monotherapy for more than 2 months is discouraged if arthritis is still active [
88]. NSAIDs are not disease modifying, but merely symptomatic medications. Only a few NSAIDs are approved for use in children: the most common are naproxen, ibuprofen, and indomethacin. They are usually better tolerated by children than adults, and the role of antiacids and proton pump inhibitors to reduce gastrointestinal complications in pediatric subjects is unclear. Experience with cyclooxygenase (COX)-2 inhibitors in children is scarce [
89,
90]. Meloxicam, an inhibitor of both COX-1 and COX-2, has proven to be effective and safe in a controlled trial [
89].
Intra-articular corticosteroid (IAC) injections are widely used in the management of children with JIA, particularly in those with oligoarthritis, to induce rapid relief of inflammatory symptoms and for functional improvement as well as to obviate the need for regular systemic therapy [
65,
91]. The strategy of performing multiple IAC injections is used by some pediatric rheumatologists in children with polyarticular JIA to induce prompt remission of synovitis, while simultaneously initiating therapy with disease-modifying antirheumatic drugs (DMARDs) and/or a biologic agent [
92,
93]. Triamcinolone hexacetonide (TH) is the medication of choice in JIA [
65]. Although there are no established guidelines for this practice, most rheumatologists will limit the frequency of reinjections to three times per year. Subcutaneous atrophic skin changes at the site of injection, periarticular calcifications, crystal-induced synovitis, and septic arthritis are potential complications of IACs. The potential role of IAC injections in the hip in causing avascular necrosis of the femoral head is uncertain [
94,
95].
Conventional DMARDs
Methotrexate (MTX) remains the most widely used conventional DMARD in the management of JIA because of its effectiveness at achieving disease control and acceptable toxic effects [
98,
99]. Its efficacy was established in a controlled trial in 1992 at a dosage of 10 mg/m
2 per week given orally [
100]. A subsequent randomized study has shown that MTX exerts its maximum therapeutic effect with parenteral administration of 15 mg/m
2 per week. There was no additional advantage in giving higher doses up to 30 mg/m
2 per week [
101]. MTX can be given both orally and subcutaneously, with some studies reporting no differences in effectiveness [
102]. However, there is an increased bioavailability of the subcutaneous route at higher doses [
103], and other investigators have found increased efficacy after switching from oral to subcutaneous administration [
104]. The greatest efficacy of MTX has been seen in patients with extended oligoarthritis. A decrease in the rate of radiographic progression has been reported in two small uncontrolled studies [
105,
106]. Recently, no advantage in prolonging MTX administration for 12 instead of 6 months after the achievement of disease remission was seen [
77]. Tests to monitor complete blood counts, liver enzymes, and renal function are recommended during MTX treatment, although the optimal frequency of testing is not established [
107]. The supplementation of folic or folinic acid may help to prevent the occurrence of liver enzyme abnormalities, oral ulcerations, and nausea [
108].
Leflunomide may have similar effectiveness and safety as MTX and is an alternative option to it in case of intolerance [
109]. However, experience with this medication in childhood arthritis is still limited.
Biologic DMARDs
Etanercept, a fully human TNF inhibitor, is the first biologic agent registered for use in JIA. Its efficacy at a dosage of 0.8 mg/kg weekly was demonstrated in a controlled trial on 69 patients refractory or intolerant to MTX [
110]. Long-term extension studies of the original trial cohort and several national registries have subsequently confirmed the sustained clinical benefit and acceptable safety profile of the drug [
111‐
113]. Etanercept in JIA has been demonstrated to improve ability and quality of life [
114], growth velocity and bone status [
115,
116] and reduce the progression of radiographic joint damage [
117]. Complete disease quiescence can be achieved in half of the patients [
118,
119].
Infliximab, a chimeric TNF-α inhibitor, failed to show a statistically significant difference in its primary outcome at 3 months in a placebo-controlled trial [
120]. However, after 1 year the response to infliximab was comparable to that observed with etanercept. Paradoxically, despite similar efficacy, patients treated with 3 mg/kg of infliximab experienced a greater frequency of serious adverse events and autoantibodies than those given 6 mg/kg. Infliximab is not approved for use in JIA.
The efficacy of adalimumab, a recombinant human anti-TNF agent, was established in a controlled trial including patients who were either MTX naive, resistant, or intolerant [
121], with 94% of patients treated with MTX responding at week 16, versus 74% who did not receive concomitant MTX. Recently, adalimumab was found to be highly effective in children and adolescents with JIA who had been previously treated with other biologic agents [
122]. Adalimumab is registered for use in JIA both in the USA, at a fixed dosage of 20 or 40 mg every 2 weeks for children less than 30 kg or at least 30 kg, respectively, and in Europe, at a dosage of 24 mg/m
2 (maximum 40 mg) every 2 weeks.
A clinical trial on a second recombinant human TNF inhibitor, golimumab [
123], in 173 children with active arthritis despite MTX therapy for at least 3 months showed a rapid response to the medication after 16 weeks of open-label treatment, resulting in achievement of an American College of Rheumatology (ACR) Pediatric 30 response and the state of inactive disease in 87.3% and 36.1% of the patients, respectively. However, no differences in flare rates between golimumab and placebo arms were seen from week 16 to 48 among responders to golimumab in the open-label phase, and the primary endpoint of the trial was not met. The safety profile was acceptable and injections were well tolerated. This drug has not yet been approved for use in JIA.
TNF inhibitors are more effective if administered early in the disease [
124], in combination with MTX [
125] and/or prednisone [
126]. Recent data indicate that TNF inhibitors are efficacious and safe in juvenile spondyloarthropathies and PsA [
127,
128].
Abatacept is a soluble, fully human fusion protein that comprises the extracellular portion of human CTLA4 and a fragment of the Fc region of a human IgG1. The binding between abatacept and the CD80/86 molecules prevents their interaction with the CD28 receptor and, therefore, blocks the second signal necessary for T cell activation [
129]. The efficacy of abatacept in JIA has been documented in a double-blind randomized controlled withdrawal trial in 190 patients with polyarticular course JIA and an inadequate response or intolerance to at least one DMARD [
130]. During the double-blind treatment, flares of arthritis were observed in 53% patients on placebo versus 20% of patients on abatacept (
p = 0.0003), who showed a lower risk of flares (hazard ratio 0.31, 95% CI 0.16–0.95). The median time to flare was 6 months for patients given placebo, while insufficient events occurred in the abatacept group (
p = 0.0002). The frequency of adverse events did not differ in the two treatment groups. Drug effectiveness was found to be durable in the long-term open-label extension phase of the trial and was noticed also in patients who were initially nonresponders [
131]. The improvement was also recorded in HRQoL [
132]. Abatacept is registered for JIA patients older than 6 years at the dosage of 10 mg/kg intravenously every 28 days.
A randomized controlled trial on the IL-6 receptor inhibitor tocilizumab in polyarticular-course JIA [
133] has enrolled 188 patients placed on tocilizumab at 10 mg/kg if less than 30 kg or 8 mg/kg if at least 30 kg. In the second part of the study, 163 patients were continued with tocilizumab or switched to placebo. Disease flare occurred in 48.1% of patients on placebo versus 25.6% continuing tocilizumab (
p = 0.0024). At the end of the second part, 64.6% and 45.1% of patients receiving tocilizumab had ACR Pediatric 70 and 90 responses, respectively. Infection was the most common serious adverse event (4.9/100 patient/years). Tocilizumab has been approved by the US Food and Drug Administration (FDA) for the treatment of polyarticular JIA in children aged 2 years and older.
A growing body of evidence suggests that in active systemic JIA the proinflammatory cytokines that play a major pathogenic role are IL-6 [
134,
135] and IL-1 [
136], rather than TNF-α. Excellent responses of patients with the systemic subtype of JIA to the IL-1 receptor antagonist anakinra have been observed in uncontrolled studies [
136,
137]. Despite the efficacy of the drug in the adult equivalent of systemic JIA (Still’s disease), anakinra has not been registered for the treatment of systemic JIA yet. Two double-blind placebo-controlled trials of canakinumab, a novel monoclonal antibody against IL-1, in children with systemic JIA and active systemic features, have been completed, which showed good efficacy and safety [
138,
139]. Canakinumab has been approved for the treatment of active systemic JIA in children aged 2 years and older both in Europe and the USA. A 24-week randomized trial of another IL-1 antagonist, rilonacept, in 71 children with active arthritis in at least two joints demonstrated a shorter time to drug response and good tolerance [
140]. A potential advantage of canakinumab and rilonacept over anakinra, which has a short half-life and requires a daily injection, is a longer half-life, which enables the administration at longer intervals (every 4 weeks and weekly, respectively). A retrospective analysis of 46 patients who received anakinra as first-line therapy led to the conclusion that introduction of anti-IL-1 therapy early in the course of systemic JIA may help to prevent refractory arthritis [
141]. In a prospective cohort study of 20 patients with new-onset systemic JIA, excellent responses were seen in nearly all patients within 3 months of anakinra as first-line therapy. In the majority of responding patients, treatment could be stopped within 1 year, with remission being maintained during follow-up [
80]. Based on these observations as well as on data from animal studies, a biphasic model of systemic JIA has been theorized. It has been speculated that early treatment with biologics may take advantage of this “window of opportunity”, in which disease pathophysiology may be altered to prevent chronic arthritis [
142].
Uncontrolled studies [
143,
144] and a controlled withdrawal trial performed in Japan [
145] have shown impressive clinical responses to the administration of the IL-6 blocker tocilizumab in patients with refractory systemic JIA. These findings were confirmed in a double-blind controlled trial of tocilizumab against placebo in patients with or without systemic manifestations, which showed at the end of the 12-week double-blind phase as an ACR Pediatric 30 response plus absence of fever in 85% of patients on tocilizumab and in 24% of patients on placebo (
p < 0.001) [
146].
Anecdotal studies have reported the effectiveness of rituximab, a humanized chimeric monoclonal antibody to the B lymphocyte CD20 antigen, in severe resistant systemic JIA [
147]. However, so far the information on the use of this agent is very limited.