Department Pharmacology Continuing Education
Juvenile Idiopathic
Arthritis: A Focus on
Pharmacologic
Management
Jessica L. Jacobson, PharmD, BCPS, BCPPS, &
Jennifer T. Pham, PharmD, BCPS, BCPPS
ABSTRACT
Juvenile idiopathic arthritis is a chronic condition that affects
many pediatric patients. It is a prevalent disease and has
become the most common rheumatologic disease of child-
hood. The condition encompasses multiple different forms
of chronic arthritides classified based on the location and
number of joints affected as well as the presence or lack of
a number of different inflammatory markers. The exact eti-
ology is unknown but is thought to be multifactorial with
genetic, humoral, and environmental factors playing a key
role. Many pharmacologic agents are available for use in the
treatment of juvenile idiopathic arthritis, with management
involving the use of symptom-reducing agents and disease-
modifying antirheumatic drugs. Treatment is not without
adverse events, with many of the agents require monitor-
ing regimens and patient education. Without treatment, the
progression and chronicity of the disease can result in sig-
nificant morbidity, with the potential for devastating
consequences on the child’s quality of life. J Pediatr Health
Care. (2018) 32, 515-528.
Jessica L. Jacobson, Clinical Pharmacy Specialist-PICU/Pediatrics,
Department of Pharmacy, Rush University Medical Center, Chicago,
IL.
Jennifer T. Pham, Clinical Pharmacist–Neonatal/Pediatrics and Clini-
cal Assistant Professor, Department of Pharmacy Practice, University
of Illinois at Chicago, Chicago, IL.
Conflicts of interest: None to report.
Correspondence: Jennifer T. Pham, PharmD, BCPS, BCPPS,
Department of Pharmacy Practice, University of Illinois at
Chicago, College of Pharmacy, 833 S. Wood St., M/C 886,
Room 164, Chicago, IL 60612; e-mail: Tran@uic.edu
0891-5245/$36.00
Copyright © 2018 by the National Association of Pediatric Nurse
Practitioners. Published by Elsevier Inc. All rights reserved.
https://doi.org/10.1016/j.pedhc.2018.02.005
www.jpedhc.org
KEY WORDS
Juvenile idiopathic arthritis, pediatrics, pharmacotherapy
OBJECTIVES
1. Describe the pathophysiology, clinical presentation and
diagnosis of juvenile idiopathic arthritis (JIA).
2. Discuss the use of nonsteroidal anti-inflammatory drugs,
glucocorticoids, and non-biologic disease modifying anti-
rheumatic drugs in the management of JIA.
3. Explain the role of biologic disease modifying anti-
rheumatic drugs in the management of JIA.
4. Recommend a treatment plan based on classifica-
tion of JIA and disease activity.
5. Identify monitoring parameters and adverse effects as-
sociated with pharmacologic treatment.
INTRODUCTION
Juvenile idiopathic arthritis (JIA) is the most common
rheumatologic disease and has the potential to cause
long-term morbidity and physical disability. Older terms,
including juvenile rheumatoid arthritis, which is used
more commonly in the United States, and juvenile
chronic arthritis, which is preferred in Europe, were
replaced by the term JIA at the meeting of the Inter-
national League of Association for Rheumatology (ILAR)
in the late 1990s (European League Against Rheumatism,
1977). The ILAR highlighted the onset of JIA that begins
during childhood and provided a clear distinction from
adult-onset rheumatoid arthritis. JIA in itself is not a
disease but rather a term that encompasses all forms
of arthritides. It is defined as arthritis of unknown eti-
ology that begins before the 16th birthday and persists
for at least 6 weeks.
September/October 2018 515
 JIA is a diagnosis of exclusion, so other conditions
that present with similar clinical manifestations need
to be ruled out, including connective tissue diseases
(e.g., systemic lupus erythematosus), trauma, infec-
tion (e.g., septic joints, osteomyelitis, viral illnesses, Lyme
disease), and malignancies. Therefore, the diagnosis
of JIA is usually prolonged, which can delay the ini-
tiation of treatment, resulting in devastating consequences
such as permanent joint destruction, joint contractures,
leg-length discrepancies, and blindness secondary to
chronic uveitis. Recent advances in pharmacologic treat-
ment have significantly improved the outcome of JIA
in children.
EPIDEMIOLOGY
JIA is the most common pediatric autoimmune mus-
culoskeletal condition. Although the exact incidence
of JIA in the United States is unknown, the incidence
is estimated to be about 2 to 20 per 100,000 children;
the prevalence is about 16 to 150 per 100,000 chil-
dren in Europe and North America (Giancane et al.,
2016). Oligoarthritis is the most common subtype of
JIA in North America, with rheumatoid factor–positive
(Rf+) polyarthritis being the least common subtype
(Giancane et al., 2016). The disease more commonly
affects females than males (> 2:1); however, sex dis-
tribution varies with disease subtype (Giancane et al.,
2016; Minden et al., 2002). Age at onset of disease also
differs among subtypes, with a median age of onset
of 4 years in oligoarthritis, 11 years in enthesitis-
related arthritis (ERA), and 12 years in Rf+ polyarthritis
(Minden et al., 2002). In addition, ethnicity can affect
the prevalence of disease subtype, highlighting the po-
tential for involvement of genetic predisposition
(Schwarz, Simpson, Kerr, & Jarvis, 1997). For example,
African Americans are more likely to develop polyar-
ticular and Rf+ disease (Espinosa & Gottlieb, 2012),
oligoarthritis is the most common JIA subtype in White
children of European descent, and enthesitis-related
arthritis tends to be more prevalent in children of
Mexican and Asian descent (Woo & Colbert, 2009).
PATHOPHYSIOLOGY The exact etiology
The exact etiology and
pathogenesis of JIA are
and pathogenesis
unknown, although of JIA are
genetic, environmen- unknown, although
tal, and autoimmune
factors are thought to
genetic,
play a role in the de- environmental, and
velopment of this autoimmune
disease. A genetic pre-
disposition for JIA has
factors are thought
been suggested through to play a role in the
concordance rates of development of
25% to 40% in mono-
zygotic twins and
this disease.
516 Volume 32 • Number 5
siblings having a 15- to 30-fold higher prevalence of
JIA compared with the normative population (Woo &
Colbert, 2009). The IL2RA/CD25 and VTCN1 genes have
been proposed to confer susceptibility toward the de-
velopment of JIA (Hinks et al., 2009). In patients with
ERA, test results for human leukocyte antigen (HLA)-
B27 are commonly positive, and HLA-B27 has been
correlated with the development of inflammation of
the axial skeleton, specifically involving the hip (Woo
& Colbert, 2009). Several environmental factors, in-
cluding breastfeeding and vitamin D and sun exposure,
have been identified as having a protective effect against
the development of JIA. In contrast, environmental
factors such as infection and maternal smoking may
increase the risk of developing or worsening the disease
(Ellis, Munro, & Ponsonby, 2010). Further studies are
needed to comprehensively examine these environ-
mental hypotheses.
Humoral and cell-mediated immunity are involved
in the pathogenesis of JIA. Cell-mediated release of
proinflammatory cytokines, such as tumor necrosis
factor–alpha (TNF-α), interleukin (IL)-6, and IL-1 sec-
ondary to T-cell activation, continues to be the best
described pathogenesis of JIA and is the focus of many
newer pharmacologic agents. Radiographic models have
confirmed this etiology by evidence of a higher per-
centage of activated T cells in the synovium of patients
with JIA. In addition, diagnostic tests show that pa-
tients with polyarticular and systemic JIA (SJIA) have
higher levels of TNF-α, IL-6, and IL-1 compared with
other JIA subtypes (Borchers et al., 2006; Espinosa &
Gottlieb, 2012). Activation of the humoral immune re-
sponse is evident through the production of
autoantibodies such as antinuclear antibodies (ANA),
as well as complement activation and an increase in
serum immunoglobulins (Igs), such as IgM rheuma-
toid factor. It is estimated that ANAs are detected in
30% to 50% of patients with JIA, and detection has a
positive correlation with development of uveitis, a com-
plication of JIA (Borchers et al., 2006).
CLINICAL PRESENTATION AND DIAGNOSIS
The clinical manifestation and treatment algorithms of
JIA depend on the subtype of arthritis that is present.
Arthritis must be present for 6 weeks before the di-
agnosis of JIA can be made. Morning stiffness or gelling
phenomenon (i.e., stiffness after long periods of sitting
or inactivity) are common complaints. Arthralgia often
occurs during the morning, with improvements through-
out the day. Different classifications of JIA have been
developed by organizations including the American
College of Rheumatology (ACR), EULAR, and ILAR
(Beukelman et al., 2011; EULAR, 1977; Petty et al., 2004;
Ringold et al., 2013). The progression of the disease
nomenclature and their differing classifications are sum-
marized in Table 1. The ILAR 2001 classification was
developed in response to a need for a more consis-
Journal of Pediatric Health Care
 TABLE 1. Progression of characteristics/classification systems of JIA
Characteristics ACR (1977) EULAR (1978) ILAR (1997, 2001) ACR (2011)
Nomenclature Juvenile rheumatoid arthritis Juvenile chronic arthritis Juvenile idiopathic arthritis Juvenile idiopathic arthritis
Age at onset <16 years <16 years <16 years <16 years
Duration of arthritis ≥6 weeks ≥3 months ≥6 weeks ≥6 weeks
Classifications Systemic Systemic Systemic Arthritis of ≤ 4
Polyarticular Polyarticular Oligoarticular joints
Pauciarticular Juvenile rheumatoid arthritis (persistent/extended) Arthritis of ≥ 5 joints
Pauciarticular Polyarticular (Rf+/Rf–) Active sacroiliac arthritis
Juvenile psoriatic arthritis Psoriatic arthritis Systemic arthritis (without
Juvenile spondylitis ERA active systemic features)
Undifferentiated Systemic arthritis with active
systemic features (without
active arthritis)
Note. Data from EULAR (1977), Beukelman et al. (2011), and Ringold et al. (2013). ACR, American College of Rheumatology; ERA, enthesitis-
related arthritis; EULAR, European League Against Rheumatism; ILAR, International League of Associations for Rheumatology; Rf+, rheumatoid
factor positive; Rf–, Rheumatoid factor negative.

tent classification system than what had been previously
defined in the ACR 1977 and EULAR 1978 classifications.
The ILAR 2001 classification identified six distinct
subtypes of JIA based on the pattern and number of
joints involved at onset of illness, specific serologic
markers, and systemic manifestations present during
the first 6 months of illness (Petty et al., 2004). The
ILAR classifications of JIA include systemic, oligoarticular,
polyarticular, enthesitis-related, psoriatic, and undif-
ferentiated arthritis. Diagnosis of JIA is typically based
on the presence of clinical symptoms and serologic
markers associated with each classification. Accurate
classification within a subtype is important because it
offers insight to prognostic factors, outcomes, and pre-
ferred treatment regimens.
Systemic Juvenile Idiopathic Arthritis
SJIA is described as a triad of arthritis, remittent fever,
and typical rash (Dannecker & Quartier, 2009; Petty
et al., 2004). The child appears systematically ill with
generalized arthralgia and myalgia. Arthritis is defined
as the presence of joint effusion alone or two or more
of the following symptoms: decreased range of motion,
pain or tenderness during movement, and/or in-
creased heat on palpation in one or more joint(s). Fever
is typically present for at least 2 weeks’ duration with
a daily quotidian pattern for at least 3 days, and ar-
thritis is present in one or more joint(s) accompanied
by one or more of the following criteria: evanescent
erythematous rash, generalized lymph node enlarge-
ment, hepatomegaly and/or splenomegaly, or serositis
(Petty et al., 2004). Muscle tenderness to palpation may
be observed. The classic triad does not need to occur
at the same time, with fever and rash oftentimes oc-
curring weeks before the onset of arthritis (Dannecker
& Quartier, 2009; Petty et al., 2004). The characteris-
tic macular, nonpruritic, salmon-colored rash (linear
macular rash) is most commonly present at time of fever
and is typically distributed over the trunk and extremi-
ties. Patients with SJIA are more likely to develop
macrophage activation syndrome (MAS) and im-
paired growth velocity.
Oligoarthritis
Oligoarthritis is defined as arthritis affecting four or fewer
joints during the first 6 months of disease (Dannecker
& Quartier, 2009; Petty et al., 2004). This subtype is
further classified as persistent (affecting four or fewer
joints throughout the disease) or extended (affecting
more than 4 joints after the first 6 months of disease).
Compared with the other subtypes, oligoarthritis appears
to have an earlier onset of illness and is more preva-
lent in females (Dannecker & Quartier, 2009). Children
generally appear well despite ambulating with a limp.
Most patients with oligoarthritis present with unilat-
eral pain and swelling of one joint (typically larger,
lower extremity joints). Elevated erythrocyte sedimen-
tation rate (ESR) and ANA levels are common diagnostic
criteria in this subtype of JIA. Compared with other
subtypes, oligoarthritis is associated with the devel-
opment of iridocyclitis. Therefore, these patients should
undergo ophthalmologic examinations more fre-
quently than what is recommended for other patients
with JIA.
Polyarticular JIA (Rheumatoid Factor–Negative
[Rf–]/Positive [Rf+] Polyarthritis)
Polyarticular JIA is defined as arthritis affecting five or
more joints during the first 6 months of disease (Petty
et al., 2004). This subtype is further classified as Rf+
(two positive Rf test results at least 3 months apart during
the first 6 months of disease) or Rf– (a test result for

www.jpedhc.org September/October 2018 517

Rf is negative), depending on presence of the auto-
antibody within the bloodstream. Rf+ disease is thought
to have a more aggressive disease course character-
ized by a higher incidence of joint deformities because
of the development of erosive joints and rheumatoid
nodules (Espinosa & Gottlieb, 2012; Petty et al., 2004).
The onset of Rf+ disease tends to occur later com-
pared with other subtypes and predominantly affects
females in late childhood to early adolescence (Espinosa
& Gottlieb, 2012).
Enthesitis-Related Arthritis
ERA is described as the presence of arthritis and enthesitis
(inflammation of tendons and ligaments where they
attach to bone) or as the presence of arthritis or enthesitis
with at least two of the following: (a) presence of or
history of sacroiliac joint tenderness and/or inflamma-
tory lumbosacral pain; (b) presence of the HLA-B27
antigen; (c) onset of arthritis in males older than 6 years;
(d) acute (symptomatic) anterior uveitis; or (e) first-
degree relative with a history of ankylosing spondylitis,
ERA, sacroiliitis with inflammatory bowel disease, Reiter’s
syndrome, or acute anterior uveitis (Petty et al., 2004).
The most common symptoms include pain, swelling,
and tenderness with a higher incidence in males older
than 8 years of age (Espinosa & Gottlieb, 2012).
Psoriatic Arthritis
Psoriatic arthritis in children is usually mild. Patients
are classified as having psoriatic arthritis if there is pres-
ence of arthritis and psoriasis or the presence of arthritis
and at least two additional criteria: dactylitis (diffuse
swelling of fingers extending beyond the joint margin),
nail pitting or onycholysis, or psoriasis in a first-
degree relative (Dannecker & Quartier, 2009). Children
with psoriatic arthritis are often found to have posi-
tive test results for ANAs and HLA-B27 and therefore
are at a higher risk for development of uveitis
(Dannecker & Quartier, 2009; Espinosa & Gottlieb, 2012).
Undifferentiated Arthritis
Undifferentiated arthritis is the least common type of
JIA and is described as the presence of arthritis that
does not fit into any of the other five ILAR subtypes
or fits the descriptions of at least two or more of the
other five subtypes (Petty et al., 2004).
DISEASE MANAGEMENT
Although the ILAR classifications of JIA continued to
be the most widely used classification system, vali-
dated guidelines providing recommendations for the
treatment of JIA were still lacking. This deficiency led
to the development of the 2011 ACR Recommenda-
tions for the Treatment of JIA, with revision in 2013
(Beukelman et al., 2011; Ringold et al., 2013). The ACR
guidelines do not follow the six distinct ILAR classi-
fications, which can lead to a lack of consistency in
518 Volume 32 • Number 5
management. To minimize the number of treatment
algorithms and attempt to simplify recommendations
for providers, the ACR task force developed their own
JIA treatment groups based on the number of joints
affected and classifications of prognosis (features of
poor prognosis) and disease level activity (low, mod-
erate, high; Beukelman et al., 2011; Table 2).
The development of risk stratification through the
use of outcomes variables provides a more objective
guide to treatment and an objective method for moni-
toring response to therapy. The six outcomes variables
in the ACR guidelines include (a) the physician global
assessment of disease activity, which is a subjective
assessment made by the provider measured on a 10-
point visual analog scale; (b) parent/patient global
assessment of well-being (mimics the same 10-point
visual analog scale but is completed by the patient/
parent); (c) functional assessment; (d) active joint counts;
(e) restrictive joint counts; and (f) presence of acute
phase reactants such as ESR or C-reactive protein (CRP;
Beukelman et al., 2011). Recommendations/treatment
algorithms for initiation of pharmacologic agents in JIA
based on treatment group, prognosis, and disease ac-
tivity can be found in the ACR guidelines and will be
discussed in this review.
Although this is not part of the ACR guidelines, the
ACR Pedi 30 (Consolaro et al. 2016), which is a tool
to assess response to treatment regimens, has been
widely used throughout many clinical trials and clini-
cal practice. This tool incorporates the six ACR outcome
variables as part of the assessment. A response is defined
as a minimum of 30% improvement from baseline in
at least three of the six ACR outcome variables and
no more than one remaining outcome variable wors-
ening by greater than 30%. Similarly, ACR Pedi 50, 70,
90, and 100 responses are often reported, and these
definitions require 50%, 70%, 90%, or 100% improve-
ment, with no more than one variable worsening by
30%.
The goal of therapy in JIA is to treat the disease
by decreasing pain and limiting disability, to mini-
mize adverse effects, and to prevent disease progression
(Harris, Kessler, & Verbsky, 2013). The goal is to achieve
clinical remission, defined by the ACR as satisfaction
of clinical inactive disease for at least 6 continuous
months while taking medication or for at least 12 con-
tinuous months while not taking medication (Lovell,
Ruperto, Giannini, & Martini, 2013; Wallace, Giannini,
Huang, Itert, & Ruperto, 2011). The ACR defines clini-
cal inactive disease as the lack of active arthritis, fever,
rash, serositis, splenomegaly, or generalized lymph-
adenopathy attributable to JIA; no active uveitis; normal
ESR or CRP levels; and no damage progression deter-
mined by radiographic examination.
A systematic treatment approach begins with a
simpler, conservative modality and escalates to more
complex therapies if treatment fails (Harris et al., 2013).
Journal of Pediatric Health Care
www.jpedhc.org

TABLE 2. ACR treatment groups and classifications of prognosis and disease level activity
Features of poor
Treatment group ILAR classifications prognosisa LDAb MDA HDAc
Arthritis of ≤ 4 joints Persistent oligoarthritis Arthritis of hip or cervical AJC ≤ 1 ≥1 features greater than AJC ≥ 2
Psoriatic arthritis spine Normal ESR or CRP level LDA ESR/CRP = 2 × ULN
ERA Arthritis of the ankle or wrist PhysGA: <3 of 10 <3 features of HDA PhysGA: ≥7 of 10
Undifferentiated arthritis and inflammatory marker ParGE: <2 of 10 ParGE: ≥4 of 10
elevation
Radiographic damage
Arthritis of ≥ 5 joints Extended oligoarthritis Arthritis of hip or cervical AJC ≤ 4 ≥1 features greater than AJC ≥ 8
Rf– polyarthritis spine Normal ESR or CRP level LDA ESR/CRP = 2 × ULN
Rf+ polyarthritis Rf+ PhysGA: <4 of 10 <3 features of HDA PhysGA: ≥7 of 10
Psoriatic arthritis Radiographic damage ParGE: <2 of 10 ParGE: ≥5 of 10
ERA
Undifferentiated arthritis
Active sacroiliac arthritis ERA or psoriatic arthritis with Radiographic damage of Normal back flexion ≥1 features greater than ESR/CRP = 2 × ULN
clinical and imaging any joint Normal ESR or CRP level LDA PhysGA: ≥7 of 10
evidence of active PhysGA: <4 of 10 <2 features of HDA ParGE: ≥4 of 10
sacroiliac arthritis ParGE: <2 of 10
Systemic arthritis with active Systemic arthritis (active 6 months of significant Two levels of disease activity:d
systemic features (without fever, SJIA, no arthritis) active systemic Active fever and PhysGA: <7 of 10
active arthritis) disease (fever, elevated Active fever and systemic features of HDA that result in PhysGA: ≥7 of 10
inflammatory markers, or
requirement for treatment
with systemic
glucocorticoids)
Systemic arthritis with active Systemic arthritis (with active Arthritis of hip AJC ≤ 4 ≥1 features greater than AJC ≥ 8
arthritis (without active arthritis) Radiographic damage Normal ESR or CRP level LDA ESR/CRP = 2 × ULN
systemic features) PhysGA: <4 of 10 <3 features of HDA PhysGA: ≥7 of 10
September/October 2018

ParGE: <2 of 10 ParGE: ≥5 of 10

Note. Data from Beukelman et al. (2011).

AJC, active joint count; ACR, American College of Rheumatology; CRP, C-reactive protein; ERA, enthesitis-related arthritis; ESR, erythrocyte sedimentation rate; HDA, high disease activity; ILAR,
International League of Associations for Rheumatology; LDA, low disease activity; MDA, moderate disease activity; ParGE, patient/parent general evaluation of overall well-being; PhysGA, physi-
cian global assessment of disease activity; Rf–, rheumatoid factor negative; Rf+, rheumatoid factor positive; SJIA, systemic juvenile idiopathic arthritis; ULN, upper limit of normal.
a
Must satisfy one criterion.
b
Must satisfy all criteria.
c
Must satisfy three criteria.
d
This criteria applies to all three (LDA, MDA, and HDA).
519
There are four main pharmacologic classes that can
be used in the management of JIA. These include non-
steroidal anti-inflammatory drugs (NSAIDs),
glucocorticoids (intra-articular and systemic), nonbiologic
disease-modifying antirheumatic drugs (DMARDs), and
biologic DMARDs (bDMARDs). This review will provide
a thorough discussion of each pharmacologic drug class
and its place in therapy, dosing regimens, adverse effects,
and monitoring parameters (Tables 3 and 4).
Nonpharmacologic Treatment
The management of JIA involves a multidisciplinary
approach. Nonpharmacologic therapy such as physi-
cal, occupational, and
psychosocial (e.g., The management
mental health, psychi-
atric) therapies have all
of JIA involves a
been used to help multidisciplinary
manage the disease approach.
process in conjunction
with pharmacologic
agents (Giancane et al., 2016; Ostring & Singh-Grewal,
2013). Assistive device (wheelchairs, walkers), aerobic
conditioning, and splinting are all techniques used to
help maintain physical functioning and prevent de-
velopment of disability. Psychiatric counseling has also
proven beneficial, because many children with JIA suffer
from anxiety and/or depression secondary to chronic
pain and emotional distress due to decreased ability
to perform normal childhood activities. Initiation of phar-
macologic therapy and education on the disease should
include the child to ensure optimal medication com-
pliance. Providers and parents should work to create
an environment that minimizes time away from school.
Surgery may be indicated in patients who are unre-
sponsive to pharmacologic treatment.
Pharmacologic Treatment
Nonsteroidal anti-inflammatory drugs
NSAIDs remain first-line therapy (approved by the U.S.
Food and Drug Administration [FDA]) and the most
commonly used agents in the treatment of JIA. NSAIDs
provide both anti-inflammatory and analgesic proper-
ties by blocking the production of prostaglandins through
cyclooxygenase-1 and cyclooxygenase-2 enzyme in-
hibition. Dosing for anti-inflammatory effects is often
twice the manufacturer recommended analgesia dose;
however, the lowest possible dose should be used to
minimize adverse effects (Giancane et al., 2016). Com-
monly used NSAID regimens include naproxen, 10 to
15 mg/kg/day divided twice daily (range = 7-20 mg/
kg/day, maximum = 1,000 mg/day); ibuprofen, 30 to
40 mg/kg/day divided 3 to 4 times daily (maximum
= 2,400 mg/day); and indomethacin, 1 to 2 mg/kg/
day divided 2 to 4 times daily (maximum = 4 mg/kg/
day or 150-200 mg/day; Taketomo, Hodding, & Kraus,
520 Volume 32 • Number 5
2017). Aspirin is not recommended for treatment of
JIA because of its association with Reye syndrome.
Cyclooxygenase-2 inhibitors (celecoxib) may be con-
sidered for patients with severe gastrointestinal adverse
effects. A 2-month trial of NSAID monotherapy is in-
dicated for patients with low-disease-activity (LDA)
arthritis in fewer than four joints, without joint con-
tracture, and without features of poor prognosis
(Beukelman et al., 2011). Some experts suggest that
a lack of response to one NSAID does not confer re-
sponse to all agents in the class; a trial of an alternate
NSAID may be warranted (Harris et al., 2013).
Because NSAIDs provide only symptomatic relief from
pain and stiffness associated with arthritis and do not
stop the destructive inflammatory process associated
with this illness, most patients inflicted with moder-
ate to severe JIA receive NSAIDs as adjunctive therapy.
Adverse reactions associated with NSAID use include
abdominal discomfort, gastritis/peptic ulcer disease, and
thrombocytopenia. Long-term use may result in renal
toxicity such as renal papillary necrosis (Taketomo et al.,
2017). A complete blood count (CBC), liver function
tests (LFTs), and serum creatinine should be com-
pleted before initiation and at least twice yearly for
chronic daily use and once yearly for routine use (3-4
days per week; Beukelman et al., 2011).
Intra-articular glucocorticoid injections
Intra-articular glucocorticoid injections are reserved for
patients with localized disease. Triamcinolone
hexacetonide ([TH], available as a 5 mg/ml and 20 mg/
ml injection) and triamcinolone acetonide ([TA], available
as a 10 mg/ml and 40 mg/ml injection) have both been
used in the treatment of JIA. TH is the more com-
monly used agent because it has shown superior efficacy
(e.g., longer time to relapse) because of its lower solu-
bility, resulting in slower absorption from the injected
joint and a longer duration of action compared with
TA (Eberhard, Sison, Gottlieb, & Ilowite, 2004). These
are considered first-line therapies in patients with mod-
erate disease activity (MDA) or high disease activity
(HDA) arthritis in fewer than four joints and those who
failed a trial of NSAIDs (Beukelman et al., 2011). The
typical dosage of TH is based on the size of the child
and the affected joint. Those with larger joints typi-
cally receive TH at 10 to 20 mg/dose, and those with
smaller joints receive 2 to 6 mg/dose every 3 to 4 weeks
(Taketomo et al., 2017). Previous studies in children
have used a TH dose of 1 mg/kg (maximum = 40 mg/
dose or 2 ml using 20 mg/ml injection) and a TA dose
of 2 mg/kg (maximum = 80 mg/dose or 2 ml using
40 mg/ml solution; Zulian et al., 2004). Clinical im-
provement should last at least 4 months after joint
injection (Beukelman et al., 2011). Improvement for
less than 4 months may indicate the need for escala-
tion of therapy. Common adverse events include skin
Journal of Pediatric Health Care
hypopigmentation and subcutaneous (SC) skin atrophy
(Harris et al., 2013; Taketomo et al., 2017).
Systemic glucocorticoids
Systemic glucocorticoids, prednisone and methylpred-
nisolone, are potent anti-inflammatory drugs that were
historically used as a bridge therapy until DMARDs
became effective. Because of the adverse event profile
and the advent of newer therapeutic options, sys-
temic glucocorticoids have fallen out of favor. The ACR
guidelines do not include recommendations for use of
systemic glucocorticoids (Beukelman et al., 2011).
However, they remain a therapeutic option for treat-
ment of systemic arthritis with active systemic features
(Beukelman et al., 2011). Glucocorticoids can be given
as high-dose “pulse” intravenous (IV) methylpredniso-
lone at 15 to 30 mg/kg/day up to 1,000 mg/day for 1
to 3 days (Taketomo et al., 2017). However, because
of the short duration of action, some patients may
require chronic oral prednisolone at 1 to 2 mg/kg/
day in 1 to 2 divided doses (maximum = 60 mg/day;
Giancane et al., 2016; Taketomo et al., 2017). Common
adverse effects associated with long-term use include
weight gain, growth suppression, osteoporosis, acne,
and adrenal suppression (Taketomo et al., 2017).
Nonbiologic disease-modifying antirheumatic drugs
DMARDs are medications that slow the progression of
JIA and prevent long-term morbidity by controlling
disease before irreversible damage occurs. Treatment
with DMARD therapy may eliminate the need for anti-
inflammatory drugs. Because DMARDs do not provide
immediate symptom reduction, with benefits typi-
cally evident weeks to months after initiation, bridging
therapy may be necessary until the full onset occurs.
Although DMARDS are considered first-line disease-
modifying therapy, long-term outcomes in children with
JIA are limited because of the change in the defini-
tion of JIA, different patient characteristics, and variations
in comparator. Table 3 provides an overview of
DMARDs, including their mechanism of action, ap-
proved indications, detailed dosing information, adverse
effects, and monitoring parameters.
Methotrexate
Methotrexate (MTX) has an unknown mechanism of
action as an anti-inflammatory agent. MTX affects the
immune function and is a folic acid analog that in-
hibits dihydrofolate reductase, interfering with purine
synthesis and DNA replication. MTX is recommended
as the first-line nonbiologic DMARD for patients with
HDA and features of poor prognosis; for patients with
joint arthritis involving fewer than four joints; and for
patients with HDA, irrespective of prognosis, with in-
volvement of five or more joints (Beukelman et al.,
2011). MTX dosages in the range of 10 to
15 mg/m2/week are commonly used (Giancane et al.,
www.jpedhc.org
2016; Taketomo et al., 2017). At this relatively lower
dose, MTX functions as an anti-inflammatory agent rather
than a cytotoxic drug. It is typically administered orally
initially, but may be given intramuscularly or SC in in-
stances of non-compliance, intolerance, or poor response
to oral therapy given the lower oral bioavailability of
70%. Higher dosages of 30 mg/m2/week did not show
improved therapeutic response in patients with poly-
articular JIA for whom 6 months of standard MTX doses
failed (Giancane et al., 2016). Clinical improvement
should be seen 6 to 12 weeks after initiation of therapy,
but it could take up to 6 months to see maximal benefit.
Gastrointestinal (GI) adverse effects are the most
prominent, with abdominal pain and nausea occur-
ring within the first 24 to 36 hours after administration
(Taketomo et al., 2017). Other adverse events include
oral ulcers, infection, and hematologic and liver tox-
icity. Transient transaminitis usually resolves upon
discontinuation of MTX; no reports of irreversible liver
fibrosis have occurred. Glossitis and macrocytic anemia
are thought to be due to folate antagonism, and there-
fore folate supplementation with folic acid or folinic
acid may be considered. A retrospective, noncontrolled
study of pediatric patients showed a reduction in the
mean number of episodes per patient–year of hepatic
and GI toxicities after folinic acid supplementation
(Ravelli et al., 1999). Further studies are needed to assess
the efficacy of folic acid/folinic acid and to develop
an appropriate dosing regimen. Monitoring param-
eters include a CBC, LFTs, and serum creatinine before
initiation, 1 month after initiation, 1 to 2 months after
dose escalation, and every 3 to 4 months once the
patient stable receiving a dosing regimen with prior
normal laboratory test values (Beukelman et al., 2011).
Methotrexate is contraindicated in pregnant pa-
tients (because of the teratogenic potential) when used
for the management of arthritis, mainly because there
are many other therapies available. Fetal anomalies and
congenital malformations have been reported in preg-
nant patients exposed to methotrexate. Pregnancy should
be excluded in all patients of childbearing age before
the initiation of therapy and should be avoided for at
least 3 months after treatment in males and at least
one ovulatory cycle in females (Taketomo et al., 2017).
Leflunomide
Leflunomide is an immunomodulatory drug that in-
hibits the mitochondrial enzyme dihydroorotate
dehydrogenase, reversibly inhibiting de novo pyrimi-
dine synthesis (Harris et al., 2013; Taketomo et al., 2017).
It is recommended as a second-line nonbiologic DMARD
in patients mainly because of the greater degree of clini-
cal experience associated with MTX (Beukelman et al.,
2011). In patients with arthritis in five or more joints,
leflunomide may be considered as an approach to initial
treatment for patients with HDA and features of poor
prognosis. Leflunomide is a prodrug that is rapidly
September/October 2018 521
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Volume 32 • Number 5

TABLE 3. Disease-modifying antirheumatic drugs used in the treatment of JIA

FDA-approved Common adverse Serious adverse Monitoring
Agent Mechanism of action indication Dosing regimen effects effects parameters
Methotrexate Inhibits dihydrofolate Polyarticular JIA 10–15 mg/m2/dose PO/SQ/IM weekly N/V Infection Platelets
reductase, interferes with Maximum = 30 mg/m2/dose Abdominal pain Cirrhosis CBC
purine synthesis and DNA Pulmonary toxicity LFTs
replication SCr
PFT
Leflunomide Inhibits dihydroorotate Off-label use for JIA ≥ 3 Loading dose: 100 mg PO × 1–3 days N/D Hepatic toxicity CBC
dehydrogenase, reversibly years of age (duration based on patient’s weight) Headache LFTs
inhibiting de novo Maintenance: 10–20 mg PO daily Rash
pyrimidine synthesis Maximum = 20 mg/dose Alopecia
Sulfasalazine Inhibits multiple inflammatory JIA ≥ 6 years of age Usual dose = 30–50 mg/kg/day PO in N/V/D Hepatitis CBC
pathways including 2 divided doses Hematologic effects Skin reactions (SJS, LFTs
leukotrienes, Maximum = 2,000 mg/day drug-induced SLE)
prostaglandins, and
possibly TNF-α
Thalidomide Multiple immunomodulatory Off-label use for SJIA ≥ 3 Initial dosage of 2 mg/kg/day PO, Drowsiness Teratogenicity CBC
characteristics, may years of age increased at 2-week intervals to Neutropenia Peripheral neuropathy CPK
suppress TNF-α and IL-6 3–5 mg/kg/day Somnolence
Myalgias
Cyclosporine Inhibits the production and Off-label use for JIA 2–5 mg/kg/day PO BID N/V Renal fibrosis BP
release of IL-2→ inhibition Maximum = 5 mg/kg/day Hypertension Hepatic toxicity SCr
of IL-2–induced Hirsutism Infection LFTs
T-lymphocyte activation Gingival hyperplasia CBC
Hydroxychloroquine Anti-inflammatory effects may Off-label use for JIA 3–5 mg/kg/day (as sulfate) PO in Agranulocytosis Ocular Ophthalmic
be due to the inhibition of 1–2 divided doses examination
migration of neutrophils/ Maximum = 7 mg/kg/day or Leukopenia Dermatologic (alopecia) CBC
eosinophils and 400 mg/day Thrombocytopenia LFT
prostaglandin inhibition Aplastic anemia
Cyclophosphamide Alkylating agent that interferes Not approved 500 mg/m2/dose IV monthly N/V Hemorrhagic cystitis CBC
Journal of Pediatric Health Care

with normal function of Maximum = 1,000 mg/m2/dose Anorexia Sterility LFTs

DNA Bone marrow toxicity SCr
Azathioprine Prevents purine metabolism, Off-label use for JIA and JIA: 2–2.5 mg/kg/dose PO once daily N/D Bone marrow CBC
inhibiting synthesis of DNA, JIA-associated uveitis Uveitis: Initial 2.4 mg/kg/dose PO once suppression
RNA, and proteins daily (range = 1.4–3.2 mg/kg/day) Pancytopenia

Note. Data from Harris et al. (2013), Taketomo, Hodding, and Krause (2017), and Brent (2001).
BID, twice daily; BP, blood pressure; CBC, complete blood count; CPK, creatinine phosphokinase; D, diarrhea; FDA, U.S. Food and Drug Administration; IL, interleukin; IM, intramuscular; IV,
intravenous; JIA, juvenile idiopathic arthritis; LFT, liver function test; N, nausea; PFT, pulmonary function test; PO, by mouth; SCr, serum creatinine; SJS, Stevens–Johnson syndrome; SLE, sys-
temic lupus erythematosus; SQ, subcutaneous; TNF-α, tumor necrosis factor-α; V, vomiting.
converted to its active plasma metabolite, teriflunomide
(Sanofi-Aventis, 2016; Taketomo et al., 2017).
Teriflunomide is highly protein bound, with a pro-
longed half-life of approximately 18 days. Given the
prolonged half-life and time to reach steady state, some
experts consider the administration of loading doses
of 100 mg orally for the first 3 days of therapy. However,
loading doses may precipitate GI effects. Because of
the lower steady state plasma concentration of the active
metabolite of leflunomide in children less than 40 kg,
as reported in pharmacokinetic studies, the FDA does
not recommend its use for the treatment of JIA (Sanofi-
Aventis U.S., 2016; Silverman et al., 2005).
Because leflunomide has been shown to be
embryotoxic and teratogenic, the FDA considers this
drug to be contraindicated in pregnancy (Sanofi-
Aventis U.S., 2016; Taketomo et al., 2017). Women of
childbearing potential must have a negative preg-
nancy test result before initiation of leflunomide therapy,
and contraceptive practices of patients should be docu-
mented. In addition, women who wish to conceive while
taking leflunomide must complete an enhanced drug
elimination procedure using cholestyramine 8 g three
times a day for 11 days. This will reduce the half-life
of teriflunomide to about 1 day (Brent, 2001). They
should also have two separate documented teriflunomide
drug levels of less than 0.02 µg/ml at least 2 weeks
before trying to conceive (Taketomo et al., 2017). The
most common adverse effects include GI symptoms,
headache, and dermatologic symptoms (i.e., alope-
cia, skin rash; Taketomo et al., 2017). In addition,
patients should be monitored for hepatotoxicity, because
this drug can cause severe liver injury and is contra-
indicated in hepatic failure. Liver enzyme level and CBC
should be obtained every 4 to 12 weeks. Monitoring
of serum teriflunomide trough levels may be consid-
ered when evaluating therapeutic efficacy; however,
therapeutic trough concentrations have not been es-
tablished for the treatment of JIA (Taketomo et al., 2017).
Sulfasalazine
Sulfasalazine is a 5-aminosalicyclic acid analog that in-
terferes with several inflammatory pathways, including
leukotriene and prostaglandin production. It is a com-
bination of sulfonamide (an antibiotic) and
5-aminosalicyclic acid (anti-inflammatory agent). The
ACR guidelines recommend sulfasalazine for treat-
ment of ERA in patients with a history of arthritis of
fewer than four joints with MDA or HDA after a trial
of NSAIDs and/or glucocorticoid joint injections
(Beukelman et al., 2011). Because of conflicting results,
the ACR guidelines do not recommend its use in non-
ERA patients. Some literature recommends reserving
sulfasalazine as an add-on therapy for patients with
refractory disease receiving combination therapy because
of conflicting results and adverse effects. Van Rossum
et al. (1998) reported that 31% of children with JIA dis-
www.jpedhc.org
continued sulfasalazine therapy because of drug toxicity.
Adverse effects include nausea, vomiting, diarrhea, an-
orexia, rash, bone marrow suppression, and hepatitis.
Because sulfasalazine inhibits dihydrofolate reduc-
tase, it may cause folate deficiency and megaloblastic
anemia. Because the data on FA or FLA supplemen-
tation in those who are taking sulfasalazine are limited,
it is not commonly prescribed compared with MTX.
Some clinicians may initiate therapy at half to one third
of the maintenance dose with weekly dose titrations
to decrease GI effects. Patients with a sulfa allergy should
avoid sulfasalazine because of the possible develop-
ment of Stevens–Johnson syndrome. CBC and liver
enzyme level should be periodically monitored.
Other nonbiologic disease-modifying antirheumatic
agents
Other nonbiologic DMARDs, including thalidomide,
cyclosporine, tacrolimus, hydroxychloroquine, cyclo-
phosphamide, and azathioprine, have been previously
described in the treatment of JIA (Harris et al., 2013).
These agents are not included in the ACR guidelines,
because there are no clear recommendations as to where
they fit within the disease subtypes and treatment
groups. These agents may play a role in refractory
disease.
Combination therapy involving multiple nonbiologic
DMARDs has also been studied; however, with com-
bination therapy there is a risk of additive
immunosuppression and adverse effects. Thalido-
mide is one agent that should be used with extreme
caution because of its potent teratogenic potential. All
patients, male and female, should receive birth control
while receiving thalidomide therapy, and additional
caution should be taken in adolescents and those of
childbearing potential. Permanent peripheral neuropa-
thy may occur with prolonged thalidomide exposure,
and patients should be monitored with regular neu-
rologic examinations (Taketomo et al., 2017).
Thalidomide use has been described in children with
systemic JIA irresponsive to other therapies; however,
published data are limited to case series and small
sample sizes. (Lehman et al., 2004). Cyclosporine and
tacrolimus are drugs with a narrow therapeutic index
and, therefore, require therapeutic drug monitoring.
Hydroxychloroquine can cause ocular abnormality and
bone marrow suppression; ophthalmologic examina-
tions and periodic CBC should be monitored.
Cyclophosphamide may cause hemorrhagic cystitis; a
urine analysis and chemistries should be monitored.
There are limited data for azathioprine in the pediat-
ric population for treatment of JIA, and it is considered
a last-line nonbiologic DMARD therapy.
Biologic disease-modifying antirheumatic drugs
The development of biologic agents has greatly changed
the outcomes and morbidity associated with this disease.
September/October 2018 523
Biologic agents are substances that are made from a
living organism or its products and may include mono-
clonal antibodies, receptor antagonists, or soluble
cytokine receptors that target specific proteins in-
volved in the inflammatory cascade. Biologic agents
are administered via the IV or SC routes, which may
be more challenging and can affect medication com-
pliance. The financial implications associated with these
agents are substantial, and pharmacoeconomic
analyses evaluating the cost per treatment among regi-
mens are lacking. Costs associated with these agents
must include IV administration and the requirement
for infusion clinics.
Before initiation of these therapies, providers should
take into consideration insurance coverage and the fi-
nancial impact that will be placed on the patient and
family. Because of their relatively new advent in the
1990s, long-term outcomes and safety data are sparse.
Biologic agents also carry the risk of severe immuno-
suppression, and routine monitoring and close follow-
up are extremely important. Table 4 provides a detailed
review of biologic agents that have been used in the
treatment of JIA.
TNF-α inhibitors
TNF-α inhibitors (TNFi) remain the most commonly
prescribed biologic agents for the treatment of JIA. El-
evated levels of the proinflammatory cytokine TNF-α
are found in children with JIA, and therefore inhibi-
tors of these cytokines play an important role in
modifying the inflammatory disease progression. Avail-
able agents in this class include etanercept, adalimumab,
and infliximab. Although all three agents target TNF-
α, they differ slightly in the manner in which they
achieve inhibition. Adalimumab and infliximab are
monoclonal antibodies, whereas etanercept is a soluble
receptor antagonist. The monoclonal antibodies differ
in terms of their antibody type: adalimumab is a fully
humanized monoclonal antibody, whereas infliximab
is a chimeric monoclonal antibody, thus resulting in
a potentially higher immunogenicity. Other differ-
ences include their route of administration. Infliximab
is given via IV infusion, whereas etanercept and
adalimumab are SC injections. Given the concern for
the risk of infusion-related reactions associated with
infliximab, etanercept and adalimumab may be the more
preferable agents. Etanercept was the first biologic agent
approved in the treatment of moderate to severe poly-
articular JIA in children 2 years of age and older in
1999. In 2008, adalimumab received FDA approval for
use in children 4 years of age and older with polyar-
ticular JIA (Taketomo et al., 2017). Currently, clinical
trials on the use of other TNFi agents such as golimumab
and certolizumab, both approved for adult rheuma-
toid arthritis, for the treatment of JIA are underway.
Golimumab and certolizumab are currently not ad-
dressed in the ACR guidelines (Beukelman et al., 2011).
524 Volume 32 • Number 5
In patients with arthritis of fewer than four joints,
TNFi agents are indicated after a 3-month trial of MTX
plus glucocorticoid joint injections in patients with MDA
or HDA with poor prognosis or after a 6-month trial of
MTX plus glucocorticoid joint injections for patients with
HDA without features of poor prognosis (Beukelman
et al., 2011). Furthermore, in patients with arthritis of
five or more joints, a TNFi may be consider after 3
months of MTX or leflunomide in patients with MDA
or had, irrespective of poor prognosis, or after 6 months
of MTX or leflunomide in patients with LDA, irrespec-
tive of poor prognosis. Additionally, they can be used
in patients with systemic arthritis with active arthritis
(without active systemic features) after 3 months of MTX
in patients with MDA or had, irrespective of poor prog-
nosis. Because response is delayed, a 4-month trial of
a TNFi is indicated. If response is not optimal after the
initial bDMARD trial, it is reasonable to try a different
TNFi or switch to a different bDMARD. Infliximab did
not show a statistically significant benefit compared with
placebo in its primary endpoint (ACR Pedi 30) at week
14 of therapy in a Phase 3 study, and therefore it is
not FDA approved for JIA treatment (Ruperto et al.,
2007). The ACR guidelines, however, do acknowl-
edge infliximab as an available TNFi option. Currently,
there are no clinical trials comparing TNFi agents head
to head for the treatment of JIA.
Abatacept
Abatacept is a soluble fusion protein that is a selec-
tive co-stimulation modulator. It inhibits T-cell activation
by binding to CD80 or CD86 on antigen-presenting cells,
preventing interaction of the antigen-presenting cells
with CD28 (Harris et al., 2013). Abatacept is typically
reserved for patients for whom therapy with a TNFi
has failed, which highlights the potential for other in-
flammatory mediators and cytokines playing a role in
the pathogenesis of JIA. Clinical trials showed that of
patients who discontinued a TNFi, 25% achieved an
ACR Pedi 50 after 4 months of abatacept therapy
(Ruperto et al., 2008). Initial improvement in clinical
symptoms is typically seen by the third or fourth dose;
however, response may be delayed in some patients.
Abatacept is recommended for the following pa-
tients: (a) patients with arthritis in five or more joints
and who have received a TNFi for 4 months who and
have HDA, irrespective of poor prognosis, or MDA with
features of poor prognosis; (b) patients with arthritis
in five or more joints who have received more than
one TNFi and have MDA or HAD, irrespective of poor
prognostic features, or LDA with poor prognosis; and
(c) patients who have received MTX and a TNFi who
have HAD, irrespective of poor prognosis, or MDA with
features of poor prognosis (Beukelman et al., 2011).
Abatacept is administered as an IV infusion every 2
weeks for the first month and monthly thereafter because
of its long half-life of 8 to 25 days (Taketomo et al.,
Journal of Pediatric Health Care
www.jpedhc.org

TABLE 4. Biologic disease-modifying antirheumatic drugs used in the treatment of JIA

Common adverse Serious adverse Monitoring
Medication Mechanism of action FDA-approved indication Dosing regimen effects effects parameters

TNF-α inhibitors
Etanercept (Enbrel; Amgen, Soluble, dimeric, fusion Moderate to severe PJIA ≥ 2 years of age Weekly: 0.8 mg/kg/dose SC once weekly; maximum = 50 mg/dose Injection site reaction Infection HBsAg
Thousand Oaks, CA) protein that binds to Twice weekly: 0.4 mg/kg/dose given 72–96 hours apart; maximum = 25 mg/ URI Anaphylaxis PPD
TNF-α preventing binding dose twice weekly Urticaria Autoantibodies Dermatologic
to cell-surface receptors Malignancy examination
TB reactivation
Adalimumab (Humira; Abbvie, North Fully humanized Moderate to severe PJIA ≥ 2 years of age PJIA Injection site reaction Infection HBsAg
Chicago, IL) recombinant IgG Off-label use for JIA-associated uveitis 10 to <15 kg: 10 mg SC every other week URI Anaphylaxis PPD
monoclonal Ab that 15 to <30 kg: 20 mg SC every other week Urticaria Autoantibodies
binds to TNF-α ≥30 kg: 40 mg SC every other week Malignancy
Uveitis TB reactivation
<30 kg: 20 mg every other week
≥30 kg: 40 mg every other week
Infliximab (Remicade; Janssen, Monoclonal Ab that binds to Off-label use for JIA and uveitis Age ≥ 4 years: 3 mg/kg/dose IV at 0, 2, and 6 weeks, then 3–6 mg/kg/dose Injection site reaction Infection HBsAg
Raritan, NJ) both soluble and every 8 weeks + MTX Myalgia Anaphylaxis PPD
membrane-bound TNF-α URI Autoantibodies
Urticaria PNA
Malignancy
TB reactivation
T-cell co-stimulation blocker
Abatacept (Orencia; Bristol-Myers T-cell co-stimulator inhibitor Moderate to severe PJIA ≥6 years of age <75 kg: 10 mg/kg/dose Headache Varicella CBC
Squibb, New York, NY) through binding to CD80/ 75–100 kg: 750 mg/dose Nausea Anaphylaxis PPD
CD86 >100 kg: 1,000 mg/dose URI TB reactivation
IV at 0, 2, and 4 weeks, then every 4 weeks thereafter Ovarian cyst
ALL
IL-1 inhibitors
Anakinra (Kineret; Swedish Orphan Human recombinant IL-1 Off-label use for SJIA and PJIA SJIA Injection site reaction Hepatitis SCr
Biovitrum, Stockholm, Sweden) receptor antagonist Initial: 1–2 mg/kg/dose SC daily (maximum = 100 mg/day); may increase to URI Infections ANC
4 mg/kg/day at 2-week intervals (maximum = 200 mg/day) Headache Secondary malignancies CBC
PJIA: Nausea
1 mg/kg/dose SC daily; Max 100 mg/day Diarrhea
Neutropenia
Arthralgia
Rilonacept (Arcalyst; Regeneron, Binds to IL-1 receptor Not approved Age 12–17 years Injection site reaction Serious infections CBC
Tarryton, NY) preventing interaction Loading dose: 4.4 mg/kg/dose SC (maximum = 320 mg/dose) URI
with cell surface May divide into 1–2 injections (maximum injection volume = 2 ml)
receptors Maintenance: 2.2 mg/kg/dose SC weekly (maximum = 160 mg/dose)
Canakinumab (Ilaris; Novartis, East Humanized monoclonal Ab SJIA ≥2 years of age Age ≥ 2 years: 4 mg/kg/dose SC every 4 weeks URI Serious infections CBC
Hanover, NY) that selectively blocks Maximum = 300 mg/dose Abdominal pain
IL-1β
September/October 2018

Injection site reaction

IL-6 inhibitor
Tocilizumab (Actemra; Genetech, Anti–IL-6 receptor SJIA and PJIA ≥2 years SJIA: URI Serious infections BP
South San Francisco, CA) monoclonal Ab <30 kg: 12 mg/kg/dose IV every 2 weeks Headache (PNA, UTI, herpes CBC
≥30 kg: 8 mg/kg/dose IV every 2 weeks HTN zoster) PPD
Maximum = 800 mg/dose Increased ALT GI perforation LFT
PJIA: Anaphylaxis ANC
<30 kg: 10 mg/kg/dose IV every 4 weeks TB Lipid panel
≥30 kg: 8 mg/kg/dose IV every 4 weeks
Maximum = 800 mg/dose
Other drug
Rituximab (Rituxan; Biogen, Anti-CD20 B-cell depleting Off-label use for refractory PJIA and SJIA 375 mg/m2/dose IV infusion once weekly for 2–4 weeks Infusion reactions Neuropathy CBC
Cambridge, MA) monoclonal Ab Maximum = 1,000 mg/dose HTN Tumor lysis syndrome ECG
Increased ALT SJS HBsAg

Ab, antibody; ALL, acute lymphocytic leukemia; ALT, alanine aminotransferase; ANC, absolute neutrophil count; BP, blood pressure; CBC, complete blood count; ECG, electrocardiography; FDA, U.S. Food and Drug Administration; GI, gastrointestinal; HBsAg,
525

hepatitis B surface antigen; HTN, hypertension; Ig, immunoglobulin; IL, interleukin; IV, intravenous; LFT, liver function test; MTX, methotrexate; PJIA, polyarticular juvenile idiopathic arthritis; PNA, pneumonia; PPD, purified protein derivative of tuberculin; SC,
subcutaneous; SJIA, systemic juvenile idiopathic arthritis; SJS, Stevens–Johnson Syndrome; TB, tuberculosis; TNF-α, tumor necrosis factor-α; URI, upper respiratory infection; UTI, urinary tract infection.
2017). Adverse events were common and included head-
ache, nausea, diarrhea, cough, and upper respiratory
infection (Taketomo et al., 2017). Serious adverse effects
such as arthritis flare, varicella, ovarian cyst, and acute
lymphocytic leukemia were seen in 3% of patients
(Ruperto et al., 2008). Because abatacept can alter the
immune response against infections and malignan-
cies because of T-cell inhibition, consideration should
be made to hold abatacept doses in patients with sus-
pected infection. Absence of latent or active tuberculosis
should be documented before initiation of therapy, with
periodic monitoring of CBC and LFTs every 4 to 12
weeks while taking abatacept (Taketomo et al., 2017).
Providers should be educated that glucose readings on
the day of infusion may be falsely elevated because
the powder for reconstitution contains maltose
(Taketomo et al., 2017).
IL-1 inhibitors
IL-1 inhibitors include anakinra, canakinumab, and
rilonacept; anakinra and rilonacept are IL-1 receptor
antagonists, and canakinumab is an anti-IL-1 mono-
clonal antibody (Espinosa & Gottlieb, 2012). All three
agents were evaluated for the treatment of JIA by the
current ACR guidelines (Beukelman et al., 2011). IL-1
inhibitors are indicated for patients with systemic ar-
thritis with active systemic features who have fever and
features of poor prognosis (irrespective of current
therapy level) or those with ongoing disease activity
while receiving systemic glucocorticoids. It is also in-
dicated in patients with systemic arthritis with active
arthritis and MDA or HDA, irrespective of features of
poor prognosis, after an unsuccessful 3-month trial of
MTX or a 4-month trial of a TNFi (Beukelman et al.,
2011). Anakinra should not be used in combination
with a TNFi because of the risk of severe neutrope-
nia. A CBC with differential should be obtained before
initiation, monthly for 3 months and then quarterly there-
after while receiving therapy (Taketomo et al., 2017).
IL-1 inhibitors are administered SC, and their fre-
quency is drug dependent. Anakinra has a short half-
life of 4 to 7 hours and thus requires daily injections.
Rilonacept has a half-life of approximately 8 days and
therefore can be administered once a week.
Canakinumab has a prolonged half-life of 23 to 26 days
and therefore can be administered every 4 weeks
(Taketomo et al., 2017).
IL-6 inhibitors
Tocilizumab is a recombinant humanized monoclonal
antibody approved for the treatment of JIA and is cur-
rently the only agent that functions as an IL-6 receptor
antagonist. Tocilizumab received FDA approval for the
treatment of SJIA and polyarticular JIA in patients 2
years of age or older (Frampton, 2013). It is indicated
in patients with continued disease activity after glu-
cocorticoid monotherapy, MTX, leflunomide, or anakinra
526 Volume 32 • Number 5
(Frampton, 2013). Tocilizumab is administered as a
1-hour infusion every 2 weeks for SJIA and every 4
weeks for polyarticular JIA. Adverse effects include neu-
tropenia, thrombocytopenia, liver transaminitis,
hypertriglyceridemia, hypercholesterolemia, and GI per-
foration (Taketomo et al., 2017). Tocilizumab should
not be initiated in patients with an active infection, ab-
solute neutrophil count less than 2,000/mm3, platelet
count less than 100,000/mm3, or alanine aminotrans-
ferase or aspartate aminotransferase level more than
1.5 times the upper limit of normal. LFT and CBC should
be monitored before therapy initiation, with the second
infusion, and every 2 to 4 weeks (for SJIA) or every 4
to 8 weeks (for polyarticular). A lipid panel should also
be obtained before therapy, about 4 to 8 weeks after
initiation and every 6 months thereafter while receiv-
ing therapy (Taketomo et al., 2017).
Rituximab
Rituximab is a monoclonal antibody directed against
the CD20 antigen on the B-lymphocyte surface, which
thereby inhibits the inflammatory cascade. The ACR
guidelines suggest that rituximab may be used in pa-
tients with fewer than five joints involved for whom
both an IL-1 inhibitor and tocilizumab sequentially or
a DMARD plus IL-1 inhibitor or tocilizumab failed. In
addition, it can also be used in patients with five or
more joints involved for whom both an IL-1 inhibitor
and tocilizumab or a DMARD plus IL-1 inhibitor,
tocilizumab, TNFi, or abatacept failed (Beukelman et al.,
2011). Furthermore, rituximab use has also been re-
ported in limited case reports for refractory JIA (Giancane
et al., 2016). Boxed warnings include severe and oc-
casionally fatal infusion-related reactions. Pretreatment
with acetaminophen, an antihistamine, and methyl-
prednisolone should be considered, and medications
for the treatment of hypersensitivity reactions (e.g., epi-
nephrine, bronchodilators) should be available for
immediate use. Other boxed warnings include severe
mucocutaneous reactions such as Stevens–Johnson syn-
drome, the development of progressive multifocal
leukoencephalopathy, and the potential for reactiva-
tion of hepatitis B (Taketomo et al., 2017). Because
of significant adverse events, the use of rituximab in
the management of JIA has decreased significantly. Pa-
tients should be watched closely for infusion-related
reactions and should receive continuous electrocar-
diographic and vital sign monitoring during and
immediately after infusion. B-cell levels should be evalu-
ated before and 1 month after infusion, with quantitative
immunoglobulin levels assessed every 3 months. Clini-
cal improvement with rituximab is typically seen within
1 month of the initial infusion.
Adverse effects/monitoring parameters for bDMARDs
The risk of infection is one of the most serious adverse
effects associated with bDMARDs. Concerns regard-
Journal of Pediatric Health Care
ing serious infection risks including the development MAS is a rare but potentially life-threatening syn-
of opportunistic infections secondary to immunosup- drome that most frequently occurs in SJIA patients. It
pression, hepatitis B and tuberculosis reactivation, and is thought to be secondary to organ infiltration by
a decreased response to vaccination (Taketomo et al., activated macrophages due to a cytokine storm. Pa-
2017). Patients should be screened for hepatitis B surface tients with MAS present with fever, pancytopenia,
antigen, hepatitis B core antibody, and tuberculosis using liver failure, coagulopathy with hemorrhage or throm-
chest radiography and/or purified protein derivative bophilia, encephalopathy, and seizures. Treatment of
testing and/or tuberculosis blood tests (interferon-γ MAS typically requires admission to an intensive care
release assay) before initiation of therapy (Taketomo unit and administration of immunosuppressive agents
et al., 2017). Patients should be monitored for symp- (Brent, 2001).
toms of hepatitis B virus reactivation during treatment
and for several months after therapy. Purified protein SUMMARY
derivative testing should be repeated yearly through- JIA is a chronic, debilitating childhood condition with
out therapy. All efforts should be made to ensure that many long-term consequences. The development of
patients are fully vaccinated before the initiation of the ILAR classification
therapy. As with all forms of immunosuppression, live system and ACR treat- The development
vaccines should be avoided concurrently and for 3 ment guidelines better
months after biologic therapy. Secondary malignan- define this childhood
of the ILAR
cies have also been associated with the use of bDMARDs disease and provide a classification
and are therefore contraindicated in patients with active more objective manner system and ACR
malignancy. Further studies are needed to address this in which to treat and
associated risk, because many of these cases may have monitor patients with
treatment
been compounded by concomitant immunosuppres- JIA. Diagnosis is based guidelines better
sion use and underlying illnesses. mainly on clinical define this
symptoms, and accu-
COMPLICATIONS rate classification of
childhood disease
Untreated or inadequately treated JIA can result in many JIA disease subtype is and provide a more
long-term consequences such as anemia, pericarditis, extremely important. objective manner in
chronic pain, slow rate of growth, and uveitis. Irido- Chronic pain and
cyclitis, a chronic anterior uveitis, is one of the most inflammation are hall-
which to treat and
common complications of JIA occurring in approxi- mark characteristics of monitor patients
mately 15% to 20% of children inflicted with this disease this disorder, and with JIA.
(Espinosa & Gottlieb, 2012). If left untreated, uveitis without treatment many
can result in cataracts, glaucoma, and blindness. Pa- patients will develop
tients with ANA-positive titer results have been found disability. Many pharmacotherapeutic agents are avail-
to be at a higher risk for development of uveitis and able for the management of JIA. DMARDs have been
should undergo monitoring with slit lamp examina- shown to be the most effective in preventing long-
tions by an ophthalmologist more frequently than term consequences of this disease. MTX continues to
children with JIA who have negative ANA titer results. be a preferred agent because of its affordability, proven
Primary treatment of uveitis involves the use of topical efficacy, safety, and tolerability. bDMARDs have revo-
ocular corticosteroid drops; however, some patients may lutionized treatment of JIA, having shown promise in
require systemic or intraocular corticosteroid injec- promoting disease remission, but they are associated
tions (Borchers et al., 2006; Ostring & Singh-Grewal, with high costs and many safety concerns. Clinicians
2013). should evaluate the efficacy and safety of all avail-
Chronic, persistent arthritis in the knee can also lead able treatment options and tailor each medication
to growth disturbances, specifically leg length distur- regimen to the individual patient. The importance of
bances, secondary to accelerated growth in affected routine monitoring and close follow-up should be em-
joints (Borchers et al., 2006; Espinosa & Gottlieb, 2012). phasized, given the complexity of the regimens at hand.
Growth retardation may be seen in patients with per- More studies are needed to assess the long-term safety
sistent arthritis in the wrist and ankles. A higher incidence and efficacy of the bDMARDs for JIA. In addition, the
of osteopenia and osteoporosis have been seen in pa- completion of head-to-head comparative trials of dif-
tients with JIA, possibly secondary to bone loss and ferent treatment options could help identify preferred
reduced bone density (due to corticosteroid treat- drug therapy.
ment), decreased weight-bearing activity, and
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