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CHAPTER 11  |  Juvenile Idiopathic Arthritis

of 3 to 10 mg/kg/dose; higher doses are often used for the treatment of refractory uveitis. Higher doses ( ≥ 6 mg/kg/dose) are also associated with less frequent adverse events, infusion reactions, and induced antibodies to the drug itself, ANA and double-stranded DNA (149). Adalimumab (Humira) is a fully human monoclonal anti–TNF- a antibody that binds soluble and membrane- bound TNF- a . Adalimumab alone or in combination with methotrexate was well tolerated and effective in treatment- refractory RA (152), juvenile arthritis (153), and treatment- refractory JIA-associated uveitis (154). Adalimumab is given subcutaneously at a dose of 24 mg/m 2 (maximum dose 40 mg) every other week (153). The major adverse events associated with the use of anti– TNF- a agents are an increased risk of infection, coccidiomycosis, and reactivation of latent tuberculosis (155). Prior to the onset of therapy, patients should have a documented negative PPD. Sulfasalazine.  Sulfasalazine has been used extensively in Europe, and increasingly in North America for the treatment of JIA. It was developed on the idea that RA was caused by an infec- tion; therefore, it has both antibacterial and anti-­inflammatory properties. A randomized, double-blind, placebo-controlled trial showed that sulfasalazine is both safe and effective for the treatment of oligo- and polyarticular juvenile arthritis (156). It is typically given in an enteric-coated form at a dose of 50 mg/kg/d in two divided doses. Serious side effects have been noted in children with systemic arthritis, and the rou- tine use of sulfasalazine is not recommended for this subgroup (157, 158). Side effects occur in up to 30% of patients (159) and include cytopenias, severe allergic reactions such as Stevens Johnson syndrome, hypogammaglobulinemia, and IgA defi- ciency. Children taking sulfasalazine should have a complete blood count, liver function tests, and urinalysis at baseline and every 2 to 3 months thereafter. Immunoglobulin levels should be monitored every 6 months. Abatacept.  Abatacept (Orencia) is a fully human mono- clonal antibody (MRA) that consists of the extracellular domain of the CTLA-4 receptor attached to the Fc portion of the immunoglobulin receptor. CTLA-4 competitively binds CD-80/86 and blocks T-cell co-stimulation. Abatacept is efficacious and safe in TNF-resistant adult RA (160). In a double-blinded, randomized controlled trial, children with methotrexate-resistant or TNF-resistant JIA who were treated with abatacept had a statistically significant decrease in the occurrence of and increased time to disease flare (161). Abatacept is given at a dose of 10 mg/kg every 4 weeks. The major adverse events are infusion reactions and infection (161). Anti-Interleukin 1 Agents.  Anakinra (kineret) is an IL-1 receptor antagonist. It has been shown to be safe and efficacious in combination with methotrexate for adult RA (162). A recent randomized, placebo-controlled trial showed that anakinra was safe and well tolerated at a dose of

6.7 months of active arthritis (141). Further, early intra-articular corticosteroid injections are associated with less leg-length ­discrepancy (LLD) in young children with oligoarthritis (142). Triamcinolone hexacetonide (1 mg/kg for large joints and 0.5 mg/kg for medium joints) is the most commonly used agent and often provides long-term control of inflammation. The most frequent adverse consequence of intra-articular corticoste- roids is the development of subcutaneous atrophy at the site of injection. Other side effects of intra-articular injections include infection, chemical irritation, and periarticular calcifications. Systemic corticosteroids can be used for rapid control of severe arthritis. However, long-term use should be restricted to those children who have severe arthritis or systemic features that do not respond to other interventions. Methotrexate.  The efficacy of methotrexate in JIA is well established (143, 144). It is a folic aid analogue, a competi- tive inhibitor of dihydrofolate reductase, and an inhibitor of purine biosynthesis. Methotrexate is typically given at a dosage of 0.5 to 1 mg/kg/wk or 15 mg/m 2 /wk (with a maximum of 25 mg) once weekly, either orally or by subcutaneous injection (145, 146). The most common side effects of methotrexate are nausea, fatigue, and liver transaminitis. Supplementation with folic acid (1 mg/d) can usually prevent gastrointestinal complications. Subcutaneous methotrexate should be considered for children who require doses > 20 mg or who have significant gastrointes- tinal toxicity with the oral formulation. The average timecourse for clinical response to methotrexate is 6 to 8 weeks. Children on methotrexate should have a complete blood count and liver function tests at baseline, within 6 weeks of therapy initiation and then every 2 to 3 months thereafter. Antitumor Necrosis Factor Agents.  Although the etiology and pathogenesis of juvenile arthritis are still unclear, macrophage-derived cytokines, such as tumor necrosis factor- a , appear to play a critical role in the induction and perpetuation of the chronic inflammatory process in JIA. Etanercept (Enbrel) is a soluble protein containing the extracellular domains of a p75 human TNF receptor attached to the Fc portion of a type 1 human immunoglobulin. Etanercept binds TNF- a in circu- lation and prevents subsequent cell activation. A multicenter placebo-controlled, double-blinded trial showed it to be effec- tive in the treatment of juvenile arthritis that was resistant to initial therapy with methotrexate (147, 148). Further, the safety and efficacy of etanercept is maintained for up to 8 years (149). Etanercept is given subcutaneously at a dose of 0.8 mg/kg/wk. Infliximab (Remicade) is a chimeric, monoclonal anti– TNF- a antibody that binds both soluble and membrane-bound TNF- a . Infliximab has been shown to be efficacious in combi- nation with methotrexate for the treatment of refractory juve- nile arthritis (150) and chronic inflammatory uveitis (151). However, recently, a double-blinded, randomized trial did not show a statistically significant difference between children treated with methotrexate plus placebo versus methotrexate plus infliximab (149). Infliximab is given intravenously at a ­dosage