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CHAPTER 11
|
Juvenile Idiopathic Arthritis
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
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
