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Juvenile Idiopathic Arthritis – Changing Times,

Changing Terms, Changing Treatments


Susan Shenoi, MBBS, MS*
*Department of Pediatrics, Division of Rheumatology, University of Washington School of Medicine & Seattle Children’s Hospital, Seattle, WA

Education Gap
The management of juvenile idiopathic arthritis (JIA) has changed
radically over the last few decades. This article provides an update on
identification of JIA, complications of the condition, and common
management strategies to help practitioners treat affected children in
conjunction with other specialists as part of a multidisciplinary team.

AUTHOR DISCLOSURE Dr Shenoi has Objectives After completing this article, readers should be able to:
disclosed that she has been a speaker for
Novartis. This commentary does contain a 1. Recognize the clinical findings associated with the various categories of
discussion of an unapproved/investigative
use of a commercial product/device.
juvenile idiopathic arthritis (JIA).
2. Recognize the laboratory findings associated with the different
ABBREVIATIONS
ALT alanine aminotransferase categories of JIA and its complications.
ANA antinuclear antibody
3. Formulate a differential diagnosis for children with joint pain.
AST aspartate aminotransferase
CARRA Childhood Arthritis and 4. Recognize the long-term complications associated with JIA.
Rheumatology Research Alliance
CBC complete blood cell 5. Plan the appropriate management of JIA while recognizing adverse
CRP C-reactive protein effects of some therapies.
DMARD disease-modifying antirheumatic
drug
ERA enthesitis-related arthritis
ESR erythrocyte sedimentation rate
FDA Food and Drug Administration INTRODUCTION
HLA human leukocyte antigen
IAS intraarticular corticosteroid
Arthritis is a common cause of disability in childhood. In children, the condi-
injection tion previously was known as juvenile chronic arthritis or juvenile rheumatoid
IL interleukin arthritis. Currently, the preferred name for childhood arthritis is juvenile idio-
ILAR International League of pathic arthritis (JIA) because this term denotes the idiopathic or unknown cause
Associations for Rheumatology
of the condition. The exact incidence and prevalence of JIA is unknown and
IV intravenous
likely varies across the world. The estimated incidence and prevalence of JIA
JIA juvenile idiopathic arthritis
MAS macrophage activation syndrome in the United States is approximately 14 per 100,000 children (95% confidence
NSAID nonsteroidal anti-inflammatory interval: 10–18) and 113 per 100,000 (95% confidence interval: 55–155), respec-
drug tively. (1) JIA is believed to have a multifactorial etiology, with both genetic and
PVNS pigmented villonodular synovitis nongenetic (ie, environmental) contributing causes. Due to the paucity of practicing
RF rheumatoid factor
pediatric rheumatologists, pediatricians or family practice physicians often are
SJIA systemic juvenile idiopathic
arthritis
“on the front line” for initial identification and treatment of JIA. This article
TMJ temporomandibular joint focuses on key points for diagnosis and initial evaluation of JIA and provides an
TNF tumor necrosis factor overview of treatment.

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CLASSIFICATION AND CATEGORIES OF JIA based on the number of joints involved, extra-articular fea-
tures, and serology identified in the first 6 months of dis-
According to the International League of Associations for
ease presentation (Table 1). This categorization attempts
Rheumatology criteria (ILAR), JIA is defined as chronic
arthritis (‡6 weeks duration) with no known cause occur- to cluster similar JIA presentations into distinct categories
ring in children before the 16th birthday. (2) The 6-week to improve research into etiology, disease course, long-
minimum duration to define chronicity and onset before term outcomes, response to treatment, and development of
the 16th birthday to define “juvenile” are based on expert future therapies. This classification system will likely evolve
opinion rather than derived from data. The ILAR classifi- and be refined over the next few decades as knowledge of
cation categorizes JIA into 7 mutually exclusive categories this disease increases.

TABLE 1. Categories of Juvenile Idiopathic Arthritis (2)


PREVIOUS
ILAR CATEGORY NOMENCLATURE ILAR DEFINITION EXCLUSION* ADULT EQUIVALENT

Systemic-onset Systemic-onset juvenile Arthritis and fever (‡2 weeks, documented 1, 2, 3, 4 Adult Still disease
JIA rheumatoid arthritis quotidian  3þ days)
Plus 1 or more:
• Evanescent erythematous rash
• Generalized lymphadenopathy
• Hepatosplenomegaly
• Serositis

Polyarticular Arthritis ‡5 joints during the first 6 months 1, 2, 3, 4, 5


RF-negative of disease and RF-negative
Polyarticular Arthritis ‡5 joints during the first 6 months of disease 1, 2, 3, 5 Rheumatoid arthritis
RF-positive and RF-positive  2 at least 3 months apart (RF-positive)
Oligoarthritis Pauciarticular juvenile Arthritis £4 joints during the first 6 months of disease; 1, 2, 3, 4, 5
rheumatoid arthritis 2 subtypes are identified:
• Persistent OJIA affecting no more than 4 joints
• Extended OJIA, affecting a total of >4 joints after
the first 6 months of disease
ERA Seronegative enthesitis Arthritis and enthesitis 1, 4, 5 Ankylosing spondylitis
and arthritis syndrome or (if bilateral sacroiliitis)
Spondyloarthropathy Arthritis or enthesitis
Plus 2 of:
• Sacroiliac joint tenderness or inflammatory
lumbosacral pain
• HLA-B27þ
• Onset of arthritis in a male older than age 6 years
• Acute anterior uveitis
• History of ankylosing spondylitis, ERA, sacroiliitis
with inflammatory bowel disease, reactive
arthritis, or acute anterior uveitis in first-degree
relative
Psoriatic arthritis Arthritis and psoriasis or Arthritis plus 2 of: 2, 3, 4, 5 Psoriatic arthritis
• Dactylitis
• Nail pitting or onycholysis
• Psoriasis in a first-degree relative

Undifferentiated Arthritis that fulfills criteria for:


arthritis • No category
or
• Two or more categories

ERA¼enthesitis-related arthritis, ILAR¼International League of Associations for Rheumatology, HLA¼human leukocyte antigen, JIA¼juvenile idiopathic
arthritis, OJIA¼oligoarticular juvenile idiopathic arthritis, RF¼rheumatoid factor.
*Exclusion definitions: 1. Psoriasis in patient or first-degree relative; 2. HLA-B27þ male older than age 6 years; 3. Ankylosing spondylitis, ERA, sacroiliitis with
inflammatory bowel disease, Reiter syndrome, or acute anterior uveitis in a first-degree relative; 4. RF-positive in 2 assessments 3 months apart; 5. Systemic-
onset JIA in patient.
Reproduced with permission from inPractice.com, Essentials of Juvenile Idiopathic Arthritis for the Adult Rheumatologist/Internist.

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KEY CLINICAL PRESENTING FEATURES

JIA is diagnosed clinically because no laboratory results can


uniquely distinguish JIA from other diseases. A thorough
history and physical examination are the key elements to
making the diagnosis. Important features of the history that
are suggestive of JIA include presence of morning stiffness/
achiness for at least 15 minutes (in toddlers this is often
described as a grumpy or limping child in the mornings
or after naps), improvement in stiffness/pain with activity
or as the day progresses, presence of gelling (joint stiff-
ness after prolonged periods of inactivity), and swelling or
decreased range of motion of the joints. Often pain is not
the primary symptom of JIA, and occasionally arthritis or
synovitis can be painless. During a clinic visit, several clues
can be inferred by observing how a child positions and
uses extremities, gets on or off the examination table, and Figure 1. Knee in juvenile arthritis patient showing active arthritis of left
walks/runs in the hallway. All joints must be examined for the knee (red arrow) and the positions for checking enthesitis (2, 6, and 10
o’clock, black arrows).
presence of arthritis (ie, swelling, warmth, restricted range
of motion or tenderness with range of motion). Other ex-
amination clues that may signify chronic arthritis (usually Systemic JIA (SJIA) is a unique form of JIA, with a
seen several months later) include the presence of muscle clinical presentation that is remarkably distinct from the
weakness or atrophy (due to disuse), bony overgrowth other JIA categories. The typical SJIA presentation is daily
(commonly seen at the affected knee), leg length discrep- (or quotidian) intermittent fever, with temperatures as high
ancy (the affected leg may be longer due to overgrowth), as 102.2 to 104°F (39-40°C), with or without classic evanes-
and micro- or retrognathia (due to temporomandibular cent (transient) salmon-pink, macular rash. Other features
joint [TMJ] arthritis). Although TMJ disease may present of SJIA include lymphadenopathy, hepatosplenomegaly,
as jaw pain or difficulty chewing, it is often asymptomatic. and serositis (such as pericarditis, pleuritis, or peritonitis).
Jaw involvement can be evaluated by measuring the inter- A subset of SJIA patients can present with or later develop
macrophage activation syndrome (MAS). MAS is a life-
incisor mouth opening (normal ‡4 cm) or assessing for devi-
threatening complication characterized by persistent fe-
ation of the jaw to the affected side with mouth opening.
vers, fixed rash, cytopenias, elevated liver enzymes, elevated
Enthesitis is inflammation of the entheses, which are
D-dimers, low fibrinogen and dropping erythrocyte sedi-
the sites at which tendons or ligaments insert onto bone.
mentation rate (ESR), elevated triglycerides, and coagulop-
Enthesitis can occur in several categories of JIA and should
athy. Affected patients may develop abnormal bleeding and
be assessed for during the physical examination. Common
cardiac, liver, or renal failure.
locations include the Achilles tendons, around the knees
(at the 2, 6, and 10 o’clock positions) (Fig 1), greater
trochanter, metatarsal heads, and planter fascia insertion Oligoarticular JIA
on the feet. The presence of psoriasis, nail pits, and ony- Oligoarticular JIA is the most common category of JIA and
cholysis may favor a diagnosis of psoriatic arthritis. by definition involves fewer than 5 joints. The disease in
Uveitis (inflammation of the eyes) may be associated with some affected children progresses after the first 6 months to
several categories of JIA. Presence of synechiae (abnormal/ involve additional joints and then is classified as “extended
distorted pupillary shape due to presence of uveitis) signi- oligoarticular JIA.” The typical phenotype of oligoarticular
fies long-standing uveitis requiring immediate evaluation JIA is a well-appearing 2- to 4-year-old girl presenting with
by an ophthalmologist (which should include a slit lamp ex- morning limp and swelling of 1 of the lower extremity
amination) and treatment. Because ocular inflammation in joints, most commonly the knees. Laboratory evaluation
JIA is often asymptomatic, children with JIA must be re- often yields normal results, including complete blood cell
gularly screened for uveitis by an ophthalmologist based (CBC) count with differential count, ESR, and C-reactive
on the current American Academy of Pediatrics guidelines protein (CRP). Up to 70% of these children may have a
(Table 2). (3) positive antinuclear antibody (ANA) and need to be screened

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TABLE 2. Initial Screening Frequency Recommendations for Patients
Without Known Iridocyclitis (3)
DISEASE FEATURES* ONSET AGE YOUNGER THAN 7 YEARS ONSET AGE 7 YEARS OR OLDER

ANA-positive (OJIA and PJIA) Every 3-4 months Every 6 months


ANA-negative (OJIA and PJIA) Every 6 months
SJIA and ERA Every 12 months

ANA¼antinuclear antibody, ERA¼enthesitis-related arthritis, OJIA¼oligoarticular juvenile idiopathic arthritis, PJIA¼polyarticular juvenile idiopathic
arthritis, SJIA¼systemic juvenile idiopathic arthritis.
*Once uveitis is detected, the treating ophthalmologist determines the frequency of screening to ensure the inflammation is responding appropriately to
the therapy. Patients with JIA onset of age <7 years who reach age 7 years or those with JIA onset of age ‡7 years who are 4 years into their diagnosis are
considered to be at lower risk for uveitis and can transition to annual ophthalmologic examinations going forward.
Reproduced with permission from inPractice.com, Essentials of Juvenile Idiopathic Arthritis for the Adult Rheumatologist/Internist.

frequently (every 3 months) for uveitis. The long-term prog- before being diagnosed with SJIA. Occult MAS can occur in
nosis is usually good if they do not develop extended disease. up to one-third of children and must be recognized and
treated promptly. Clinicians should not be reassured by a
Polyarticular JIA decreasing ESR in an ill-looking patient because this may
By ILAR definition, children who have polyarticular JIA have signify MAS. MAS is considered a secondary form of he-
more than 4 joints involved in the first 6 months of disease mophagocytic lymphohistiocytosis and is a life-threatening
onset. Depending on the presence or absence of rheumatoid condition that involves rapid expansion of macrophages
factor (RF), the disease is classified further as RF-positive or and T cells, leading to massive overproduction of cytokines.
-negative. Because RF is transiently positive in other con- Among the JIA categories, this complication appears to be
ditions such as infections, its positivity should be confir- unique to SJIA. Features of MAS include persistent fevers,
med by repeating RF evaluation 3 months later. There are bleeding diathesis, central nervous system involvement with
typically 2 peaks of presentation: ages 1 to 3 years and dur- drowsiness or seizures, fixed rashes, decreasing white blood
ing adolescence. Fig 2 shows a teenage girl with polyarti- cell and platelet counts, decreasing fibrinogen, elevated
cular JIA and arthritis of several proximal interphalangeal D-dimer, elevated triglycerides, and abnormal liver function
joints bilaterally and flexion contractures with boutonniere tests (aspartate aminotransferase [AST], alanine aminotransfer-
deformity (proximal interphalangeal joint flexion and distal ase [ALT]). Hyperferritinemia (ferritin levels are often >5,000
interphalangeal joint hyperextension) of bilateral fifth fingers. ng/mL [11,235 pmol/Lng/mL]) and hemophagocytosis
(often seen in bone marrow or other tissues such as lymph
Systemic JIA node or spleen) are hallmarks of MAS.
Children who have SJIA must undergo complete infec-
tious and malignancy evaluation for their fevers, including Psoriatic JIA
cultures, serology, imaging, and/or bone marrow examination Children may present with classic psoriasis, nail changes
suggestive of psoriasis, or family history of psoriasis in a
first-degree relative in addition to arthritis. Affected chil-
dren often present with “sausage digits” or dactylitis.

Enthesitis-related Arthritis
Enthesitis-related arthritis (ERA) is more common in boys
and usually presents with enthesitis and arthritis. Axial
involvement of the spine or sacroiliac joints with back pain
is common. This is the only category of JIA that can present
with an “acute painful red eye” rather than asymptomatic
Figure 2. Arthritis of several proximal interphalangeal joints bilaterally
and flexion contractures with boutonniere deformity of bilateral fifth
uveitis. Some children may have the acute iritis months to
fingers in a child who has polyarticular juvenile idiopathic arthritis. years before joint symptoms develop.

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Undifferentiated Arthritis IMAGING EVALUATION
This category includes children who meet criteria for 2 or
Imaging is increasingly used in the diagnosis and manage-
more categories or those who do not meet criteria for any
ment of JIA. Point-of-care ultrasonography and magnetic
category. Examples include a child who has involvement of
resonance imaging (with intravenous [IV] gadolinium con-
only 2 joints but is RF-positive on 2 separate tests or a child
trast) can identify active synovitis, particularly in clinically
with arthritis in 3 joints whose mother has psoriasis.
difficult-to-examine joints such as the hips, shoulders, or
TMJ. Imaging is also useful for early identification of joint
LABORATORY EVALUATION damage such as joint space narrowing (indicative of carti-
lage damage) or erosions (bone damage) (Fig 3). Imaging
JIA is a clinical diagnosis. Although no laboratory tests are
modalities are limited by their inability to differentiate the
diagnostic of JIA, such evaluations are helpful for exclud-
underlying cause of arthritis, such as infectious, malignant,
ing other diagnoses. For example, in an acutely (hours to
or inflammatory. Therefore, the onus of determining the
days) swollen, painful joint, synovial fluid analysis may be
correct diagnosis rests with the treating physician.
important to rule out septic arthritis (50,000-300,000 cells
with > 75% neutrophils, low glucose, and positive culture
or Gram stain). Indolent infections such as Lyme disease
DIFFERENTIAL DIAGNOSIS
or tuberculosis should be screened for on history and ap-
propriate testing may include screening enzyme-linked im- The differential diagnosis of JIA is broad because arthritis/
munosorbent assay with confirmatory Western blot for arthralgias can occur in several conditions, including:
suspected Lyme disease or purified protein derivative/ 1) Infections: bacterial, viral, fungal;
interferon-g release assay gold for tuberculosis. 2) Postinfectious conditions: poststreptococcal arthritis,
Clinicians should consider and exclude malignancy, especially rheumatic fever, reactive arthritis (Salmonella sp, Shigella
in the presence of bone pain, pain out of proportion to exami- sp, Campylobacter sp, Clostridium difficile, Chlamydia
nation findings, pain that wakes the child from sleep, and pres- trachomatis, Mycoplasma genitalium, Yersinia sp);
ence of cytopenias or elevated markers of cell turnover (such 3) Malignancies: leukemia, lymphoma, neuroblastoma,
as lactate dehydrogenase and uric acid). Both generalized PVNS;
malignancies (such as leukemia, lymphoma, or neuroblas- 4) Other inflammatory diseases: systemic lupus erythem-
toma) and localized tumors (such as pigmented villonodular atosus, juvenile dermatomyositis, scleroderma, Kawasaki
synovitis [PVNS] or Ewing sarcoma) can mimic JIA. disease, Henoch-Schönlein purpura, vasculitis, sarcoidosis;
Normal values for inflammation markers (ESR or CRP) 5) Gastrointestinal conditions: inflammatory bowel disease,
should not deter a diagnosis of JIA because these may be celiac disease;
normal in localized disease such as oligoarticular JIA. Most 6) Endocrine conditions: thyroid disease;
polyarticular JIA and SJIA (except when in MAS) presents 7) Hematologic diseases: sickle cell, hemophilia, thalassemia;
with elevated values of inflammatory markers (ESR, CRP) 8) Heritable diseases: mucopolysaccharidosis, Fabry dis-
and/or elevated platelet counts. ease, Marfan syndrome, Ehlers-Danlos syndrome;
The ANA is not useful for diagnosis of JIA because 9) Immunodeficiency syndromes: combined variable
40% to 50% of JIA can be ANA-negative. In addition, its util- immunodeficiency, DiGeorge syndrome, autoimmune
ity is limited by frequent low titer positivity (up to 1:160) in lymphoproliferative syndrome; and
healthy children without rheumatic disease. (4) The primary 10) Miscellaneous: toxic synovitis of hip, serum sickness,
utility of ANA testing in children with JIA is to stratify the risk hypertrophic osteoarthropathy. Before diagnosing a
of uveitis. Children with JIA who are ANA-positive are at higher child with JIA, it is crucial to rule out infection, malignancy,
risk for uveitis and need to be screened more frequently by the and other causes of arthritis/arthralgia. Other conditions to
ophthalmologist. The immunofluorescent testing method is consider that present with joint pain (usually without joint
considered the gold standard for ANA testing. swelling) include mechanical conditions such as hyper-
Because only 10% of children with JIA are RF-positive, mobility, trauma, benign nocturnal limb pains of childhood
this test cannot be relied upon to make the diagnosis. Human (growing pains), avascular necrosis conditions (Perthes,
leukocyte antigen (HLA) B27 testing for the ERA category is Sever disease), or slipped capital femoral epiphysis.
limited by its lack of sensitivity and specificity. Children can SJIA fever must be differentiated from infectious or ma-
have ERA in the absence of HLAB27 positivity, and not all lignant fevers as well as other conditions such as Kawa-
HLAB27-positive children meet criteria for ERA. saki disease or periodic fever syndromes (eg, familial

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epiphyseal overgrowth, premature fusion of growth plates
(leading to brachydactyly), subluxed/unstable joints (seen com-
monly at wrists or atlantoaxial joints), or eventual fusion/
ankyloses of joints. Bilateral TMJ involvement can quickly
result in destruction of the growth center for the mandible,
with subsequent micrognathia and retrognathia.

Eyes
Complications of uveitis include posterior synechiae pre-
senting as fixed irregular pupillary margin (due to adhesions
between the iris and lens), glaucoma (related to topical cor-
ticosteroid medication or due to inadequate drainage from
circumferential synechiae), band keratopathy, cataracts (due
to inflammation or topical corticosteroids), and eventual
blindness. Thus, it is important to ensure slit lamp oph-
thalmologic evaluations at diagnosis and regular intervals
thereafter. (3)

MANAGEMENT OF JIA

Over the last few decades, there has been a major paradigm
shift in treatment strategies for JIA. Rather than the previously
recommended step-up approach, current recommenda-
tions suggest rapid and aggressive therapy to control in-
flammation, followed by a gradual taper of medications
once complete remission has been established. The avail-
ability of biologic and targeted therapies for JIA has re-
volutionized its treatment. Goals of therapy include pain relief,
maintenance of function and range of motion of joints,
achievement of remission (either on or off medications),
and minimization of adverse effects of medications. The Child-
hood Arthritis and Rheumatology Research Alliance
(CARRA) has published consensus treatment plans for
polyarticular JIA and SJIA. These are not meant to be guide-
Figure 3. Radiograph of foot showing first metatarsal head erosion in a lines but rather outline the most common treatment strate-
boy with enthesitis-related arthritis.
gies currently used by pediatric rheumatologists. The goal of
establishing these treatment plans is to collect data to enable
Mediterranean fever, PFAPA [periodic fever, aphthous comparative effectiveness studies and identify superior treat-
ulcers, pharyngitis, adenitis], TRAPS [tumor necrosis factor ment strategies through evidence. The American College
[TNF]-associated periodic syndrome], cryopyrinopathies of Rheumatology has published evidence-based recommen-
(familial cold autoinflammatory syndrome, Muckle-Wells dations for JIA treatment.
syndrome), or hyperimmunoglobulin D syndrome.
Oligoarticular JIA
Initial treatment of oligoarticular disease may include anti-
LONG-TERM COMPLICATIONS OF JIA
inflammatory doses of nonsteroidal anti-inflammatory drugs
Joints (NSAIDs) such as ibuprofen 10 mg/kg per dose 3 times a day
Untreated inflammatory arthritis can lead to early (months) to a maximum of 3,200 mg/day or naproxen 10 mg/kg per
or longer-term destruction of the joint, including cartilage dose twice a day to a maximum of 1,000 mg/day or intra-
loss (manifesting as joint space narrowing) and bony erosions. articular corticosteroid injection (IAS) (triamcinolone hex-
Among the other complications are osteopenia/osteoporosis, acetonide is superior to triamcinolone acetonide because of

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its longer-lasting effect in the joint). IAS can be performed compared the efficacy of infliximab þ methotrexate versus
under anesthesia (conscious sedation, nitrous oxide, or gen- methotrexate alone versus methotrexate þ sulfasalazine þ
eral anesthesia) for younger children or in the outpatient hydroxychloroquine (combination triple therapy) in very
clinic setting under local anesthesia (lidocaine or J-tip) for early polyarticular JIA and showed significantly better
the cooperative older child. Increasingly, pediatric rheu- response rates at 12 months for those receiving infliximab
matologists are favoring use of ultrasonography to ensure and methotrexate (100% response versus 50% response for
appropriate needle placement for IAS. Failure to achieve methotrexate only versus 65% response for combination
inactive disease, frequent need for joint injections (‡3 in a triple therapy). Table 3 lists the common biologic agents
year), or extension of disease to involve additional joints currently in use. Common adverse effects of the biologic
warrants systemic therapy with disease-modifying anti- agents include increased risk for infection (especially oppor-
rheumatic drugs (DMARDs) such as methotrexate or bio- tunistic infections, screen for tuberculosis before use),
logics such as TNF inhibitors. elevated liver enzymes, local injection site reactions or
infusion reactions, cytopenias (neutropenia with tocilizu-
Polyarticular JIA mab, rituximab), and hypogammaglobulinemia (seen with
Treatment of this condition usually involves rapid initia- rituximab). Currently, biologic agents carry a warning label
tion of methotrexate with or without a biologic agent and for the potential of lymphoproliferative malignancies with
with or without a brief course of oral prednisone and/or IAS. use. Several recent studies have indicated that an in-
Methotrexate is used at 0.3 to 1 mg/kg per dose once weekly creased risk of malignancy might be due to JIA itself rather
(maximum dose 25 mg/week) either orally or subcutane- than therapy (including biologics), as is being found in
ously. The subcutaneous route is preferred due to supe- adults with rheumatoid arthritis. (7) Careful monitoring and
rior bioavailability. Because methotrexate can take up to 3 caution with use are advised. It is important to avoid
months to achieve full effect, some clinicians use cortico- live vaccines while a patient is receiving methotrexate or bio-
steroids as a bridge while the methotrexate is building up to logic therapy.
full effect (prednisone 0.1 to 1 mg/kg per day; maximum 60
mg/day), with subsequent taper for rapid symptom control.
ERA/Psoriatic JIA
Common adverse effects of methotrexate are nausea, eme-
Treatment of these diseases is similar to that for polyartic-
sis, oral ulcers, decreased appetite (addition of daily oral folic
ular JIA. Axial involvement in ERA is more likely to respond
acid at 1 mg/day may alleviate some of the gastrointestinal
to anti-TNF inhibitors, although specific studies on this
adverse effects), and elevated liver enzymes (usually tran-
topic in pediatric patients are lacking.
sient). Unfortunately, similar adverse effects can be seen
with NSAIDs, so determining causality if these problems
occur may be challenging. Adolescent girls should be Systemic JIA
counseled about the teratogenic effects of methotrexate and Because the clinical presentation of SJIA is extremely vari-
may need a referral for birth control. Laboratory tests that able, treatment depends on the severity of involvement.
should be monitored after 1 month on therapy and subse- About 33% of SJIA-related MAS requires intensive care
quently every 3 months include CBC count with differential unit-level care and carries an 8% mortality risk. (8) Mild
count, AST, ALT, blood urea nitrogen, and creatinine. With disease may be treated with NSAIDs, corticosteroids, meth-
the advent of several biologic medications (that are either otrexate (better for arthritis than for the systemic features of
approved by the Food and Drug Administration [FDA] or the disease such as rash and fever), or biologic agents (anti-
used off-label), previously used DMARDs such as hydroxy- interleukin [IL]1 and anti-IL6 agents are preferred). MAS
chloroquine, leflunomide, sulfasalazine, and azathioprine should be treated aggressively with IV pulse methylpred-
have fallen out of favor and are not commonly used. nisolone (usually 30 mg/kg per day to a maximum of
Recent trials demonstrate that aggressive initial therapy 1,000 mg/day for 1-3 consecutive days), high-dose anakinra
improves outcomes in polyarticular JIA. The Trial of Early (2-10 mg/kg per day either once or several times daily
Aggressive Therapy (TREAT) study randomized patients subcutaneous or IV), and/or cyclosporine (3-5 mg/kg
with severe polyarticular JIA (<1 year duration) to receive per day). Anti-IL1 and anti-IL6 therapies have drastically
methotrexate þ placebo or methotrexate þ etanercept þ changed the management and outcomes for SJIA and have
prednisolone. (5) For each month earlier that a patient was been demonstrated to be extremely effective in SJIA manage-
treated, the odds of achieving inactive disease by 6 months ment in randomized, controlled trials. There are no trials
of treatment increased by 1.32 (P ¼ .01). Tynjälä et al (6) directly comparing IL1 to IL6 therapy for SJIA.

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TABLE 3. Biologic Therapies for JIA
BIOLOGIC AGENT/ OFF-LABEL
BRAND NAME ROUTE/DOSE FDA-APPROVED INDICATIONS USES MECHANISM OF ACTION

Etanercept SC Moderately to severely active PJIA Inhibits the action of TNF by


Enbrel Once weekly: 0.8 mg/kg per in patients age ‡2 years binding to TNF-a and
Amgen, Thousand dose (maximum dose: preventing its interaction
Oaks, CA 50 mg) with the receptor

Adalimumab SC Moderately to severely active Anterior uveitis Recombinant human


Humira For patients ages 4-17 years: PJIA in children age ‡4 years monoclonal antibody
AbbVie Inc, North Weight 15-30 kg: 20 mg every Noninfectious intermediate, against TNF-a
Chicago, IL other week posterior, and panuveitis
Weight ‡30 kg:
40 mg every other week
Weight <15 kg: limited data
Infliximab IV infusion Children ages ‡6 years with JIA (in Chimeric monoclonal
Remicade Author-recommended dose: pediatric Crohn disease or combination antibody against TNF-a
Janssen 6-15 mg/kg per dose IV at 0, 2, pediatric ulcerative colitis with
Biotech, Titusville, NJ 6 weeks then every 4-8 weeks Adults with AS and PsA methotrexate)
Uveitis
Certolizumab SC Moderately to severely active JIA in older Recombinant humanized
Cimzia RA: 400 mg/dose at 0, 2, 4 Crohn disease in adults with children pegylated monoclonal
UCB, Inc, Smyrna, GA weeks, then 200 mg every inadequate response to antibody against TNF-a;
2 weeks conventional therapy the pegylated structure
Alternative dosing: Moderately to severely active RA allows for longer duration
400 mg/dose at 0, 2, 4 weeks, in adults of action
then 400 mg every 4 weeks
Golimumab SC Active AS, PsA in adults JIA in older Recombinant human
Simponi RA, PsA, AS: 50 mg once/month Moderately to severely active RA children monoclonal antibody
Janssen Biotech, Inc, in adults (in combination with against TNF-a.
Titusville, NJ methotrexate)
Moderately to severely active
ulcerative colitis in adults with
corticosteroid dependence or
who are refractory/intolerant
to oral aminosalicylates, oral
corticosteroids, azathioprine,
or 6-mercaptopurine
Tocilizumab IV infusion Age ‡2 years: SJIA or PJIA Uveitis Humanized monoclonal
Actemra SJIA: Older than 2 years with (monotherapy or in antibody against IL-6
Genentech USA, active disease combination with receptor
Inc, South Weight <30 kg: 12 mg/kg per methotrexate)
San Francisco, CA dose every 2 wks
Weight ‡30 kg: 8 mg/kg per
dose every 2 weeks
(maximum: 800 mg)
PJIA: Older than 2 years with
active disease
Weight <30 kg: 10 mg/kg per
dose every 4 weeks
Weight ‡30 kg: 8 mg/kg per
dose every 4 weeks
Abatacept IV infusion Age ‡6 years: moderately to CTLA4-IgFCg costimulation
Orencia JIA: Age ‡6 years severely active PJIA blocker binding to CD80/
Bristol-Myers Weight <75 kg: 10 mg/kg at 0, 2, (monotherapy or with CD86 on antigen-
Squibb Company, 4 weeks and every 4 weeks methotrexate) presenting cells and
New York, NY Weight 75-100 kg: 750 mg/dose preventing interaction
at 0, 2, 4 weeks and every with CD28, resulting in
4 weeks dampened T-cell activity
Weight >100 kg: 1,000 mg/dose at
0, 2, 4 weeks and every 4 weeks
Continued

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TABLE 3. (Continued )

BIOLOGIC AGENT/ OFF-LABEL


BRAND NAME ROUTE/DOSE FDA-APPROVED INDICATIONS USES MECHANISM OF ACTION

Rituximab IV infusion Adults with moderately to severely Refractory PJIA Chimeric cytolytic
Rituxan Refractory PJIA: 375 mg/m2 IV active RA who have inadequate SJIA monoclonal antibody to
Genentech USA, weekly  4 weeks, repeated response to 1 or more TNF Uveitis CD20 (on pre-B and
Inc, South course every 6 months or 750 inhibitors (use in combination mature B cells)
San Francisco, CA mg/ m2 IV on days 1 and 14 with methotrexate)
SJIA uveitis: 375-500 mg/m2 IV
weeks 0 and 2 (with
methotrexate)
Subsequent courses can be
administered every 24 weeks
(based on clinical
examination findings)
Anakinra SC Moderately to severely active SJIA Fully human recombinant
Kineret 1-4 mg/kg SC daily (maximum: DMARD-refractory RA SJIA with MAS IL-1RA (receptor antagonist)
Sobi, Inc, 100 mg/day); best studied at NOMID Competes with IL-1 for
Waltham, MA 1 mg/kg per day (Note: can binding of the receptor
be used as IV or IV continuous so that it is unavailable to
infusion off-label; 1-10 mg/kg bind with IL-1
over 4 hours has been used in
severe MAS with SJIA)
Canakinumab Active SJIA: Age ‡2 years: 4 mg/kg Cryopyrin-associated periodic Fully human anti-IL-1b
Ilaris per dose (maximum dose: 300 syndromes (including familial monoclonal antibody
Novartis mg) for patients with weight cold autoinflammatory
Pharmaceuticals ‡7.5 kg; repeat dose for disease syndrome, Muckle-Wells
Corp, East relapse approximately every syndrome) for patients age
Hanover, NJ 4 weeks ‡4 years
Cryopyrin-associated periodic Tumor Necrosis Factor Receptor-
syndromes: Weight 15-40 kg: Associated Periodic Syndrome
2 mg/kg per dose (can (TRAPS)
increase to 3 mg/kg if Hyperimmunoglobulin D
unresponsive) Syndrome (HIDS)/Mevalonate
Weight >40 kg: 150 mg/dose; Kinase Deficiency (MKD)
SC dose every 8 weeks Familial Mediterranean Fever
(FMF)
SJIA ‡2 years
Rilonacept SC Cryoprin-associated periodic SJIA IL-1 trap agent acts as a
Arcalyst Loading dose 4.4 mg/kg syndromes for patients age Age ‡4 years: soluble decoy receptor
Regeneron, (maximum: 320 mg) in 1-2 SC ‡12 years 4.4 mg/kg and consequently blocks
Tarrytown, NY injections (same day, different per week IL-1 signaling
sites), maximum volume
2 mL/injection; maintenance
dosing 2.2 mg/kg per dose
(maximum: 160 mg) weekly

AS¼ankylosing spondylitis, DMARD¼disease-modifying antirheumatic drug, FDA¼US Food and Drug Administration, IL¼interleukin, IV¼intravenous,
MAS¼macrophage activation syndrome, NOMID¼neonatal-onset multisystem inflammatory disease, PJIA¼polyarticular juvenile idiopathic arthritis,
PsA¼psoriatic arthritis, RA¼rheumatoid arthritis, SC¼subcutaneous, SJIA¼systemic juvenile idiopathic arthritis, TNF¼tumor necrosis factor. Reproduced
with permission from inPractice.com, Essentials of Juvenile Idiopathic Arthritis for the Adult Rheumatologist/Internist.

Uveitis necessitates the use of systemic medications, including meth-


Collaboration between pediatric rheumatology and ophthal- otrexate, adalimumab, infliximab, tocilizumab, cyclosporine,
mology for management of this condition is imperative. Slit or mycophenolate mofetil.
lamp examination to determine extent and severity of in-
volvement is required at regular intervals. (3) Most ophthal- Other Considerations for Management
mologists treat mild disease with topical corticosteroids The presence of active disease should not be tolerated.
and mydriatic agents. Lack of response to this initial therapy Treatment should aim to achieve inactive disease, defined

Vol. 38 No. 5 MAY 2017 229


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as absence of arthritis, rash, serositis, splenomegaly, lymph- era of biologics are needed. CARRA has developed a North
adenopathy due to JIA, and uveitis, as well as 15 min/day American registry to specifically examine the long-term
or less of morning stiffness, normal ESR and CRP, and outcomes and potential medication adverse effects of treat-
physician global assessment of disease activity as zero (best ment for children with JIA.
score on scale used). Clinical remission either on or off
medications is the ultimate goal of therapy and is defined
ACKNOWLEDGMENTS
as inactive disease for 6 months while receiving therapy
and inactive disease for 12 months after discontinuation of The author would like to thank Dr Carol Wallace and Dr
therapy, respectively. (9) How, when, and whether medica- Alexandra Aminoff for reading the article and providing
tions should be tapered/discontinued after a child achieves comments.
inactive disease/remission is currently controversial, and
there are no data to guide physicians on these important deci-
sions. Most treating physicians continue medications in inac- Summary
tive disease/remission for several months or years before • On the basis of expert opinion, case reports, or reasoning (level of
considering taper or withdrawal. Data are emerging that pa- evidence D), juvenile idiopathic arthritis (JIA) is defined as chronic
tients with some categories of JIA may need to continue low- arthritis (‡6 weeks duration) without known cause occurring in
children younger than age 16 years and consists of 7 mutually
dose therapy over the long term to prevent return of disease.
exclusive categories of arthritis. (2)
Multidisciplinary team treatment is important to achieve
• JIA is a clinical diagnosis of exclusion; laboratory test results are
the best possible outcomes for every child. This includes only supportive and may yield normal results in some cases.
family-centered care involving the pediatric rheumatologist
• Early identification and referral to a pediatric rheumatologist
and other specialties, including: enables early aggressive management that is likely to result in
• occupational and physical therapy to maintain/improve improved outcomes. (5)(6)
range of motion and strength; • Because uveitis is usually asymptomatic (except in enthesitis-
• behavioral health for counseling and teaching coping related arthritis), regular ophthalmologic screenings with slit
strategies to children and their families; lamp evaluation are essential.
• social work to help liaise with schools for potential • Management includes anti-inflammatory therapies such as
accommodations or financial assistance; nonsteroidal anti-inflammatory drugs, corticosteroids,
methotrexate, and biologic agents and depends on the number
• primary care physician for routine well-child visits,
of joints involved and presence of systemic features. The goal of
anticipatory guidance, and immunizations; therapy is to achieve inactive disease and remission (on or off
• ophthalmologist for iritis screening; and surgeons/ medications).
orthopedic physicians for deformity corrections such • On the basis of randomized, controlled studies or supportive
as micrognathia or leg length discrepancies. observational studies (level of evidence B), both methotrexate
and biologic therapies are extremely effective for JIA and require
regular laboratory and clinical monitoring for safety.
OUTCOMES IN JIA • On the basis of randomized, controlled studies or supportive
Although long-term data are lacking at this time, improved observational studies as well as case reports or cohort studies
(level of evidence B and C), anti-interleukin (IL)1 and anti-IL6
recognition, early identification, and early aggressive treat-
therapies are the preferred biologics for systemic JIA. It is
ment of JIA should result in lower JIA-related morbidity important to suspect, recognize, and treat developing
and mortality, as has been well demonstrated in adults with macrophage activation syndrome rapidly and aggressively.
rheumatoid arthritis. A Canadian cohort study (ReACCh-
Out) noted that children with JIA can achieve inactive
disease, with the likelihood of achieving remission at about
50% in 5 years for all categories except polyarticular disease. References and Suggested Readings for this article are at http://
(10) More studies to characterize long-term outcomes in this pedsinreview.aappublications.org/content/38/5/221.

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PIR Quiz
There are two ways to access the journal CME quizzes:
1. Individual CME quizzes are available via a handy blue CME link under the article title in the Table of Contents of any issue.
2. To access all CME articles, click “Journal CME” from Gateway’s orange main menu or go directly to: http://www.aappublications.
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1. A 3-year-old child is evaluated for 7 weeks of morning stiffness and pain in her knees REQUIREMENTS: Learners
that improves as the day progresses. The joint stiffness seems to worsen again if the can take Pediatrics in Review
child tries to rest for prolonged periods. The parents have also noted swelling in quizzes and claim credit
both knees. There has been no fever or rash. On physical examination, the child clearly online only at: http://
has decreased range of motion in the knees bilaterally as well as swelling and pedsinreview.org.
warmth of both joints. Laboratory studies are ordered. Which of the following is the
To successfully complete
single most helpful finding in establishing the diagnosis of juvenile idiopathic arthritis
2017 Pediatrics in Review
(JIA) in this child?
articles for AMA PRA
A. Cartilage biopsy. Category 1 CreditTM, learners
B. Characteristic clinical findings. must demonstrate a minimum
C. Elevated antinuclear antibody. performance level of 60% or
D. Elevated erythrocyte sedimentation rate. higher on this assessment,
E. Elevated rheumatoid factor. which measures achievement
2. A 3-year-old child has been diagnosed with oligoarticular JIA. During the discussion about of the educational purpose
long-term care and follow-up, the family is told that frequent visits to an ophthalmologist and/or objectives of this
are particularly important. Which of the following is the most appropriate rationale for the activity. If you score less than
importance of the frequent visits to the ophthalmologist? 60% on the assessment, you
A. Children frequently complain of eye pain. will be given additional
B. Children with JIA need frequent changes in their corrective lenses. opportunities to answer
C. Eye exercises can substantially decrease the rate of complications. questions until an overall 60%
D. Ocular inflammation in JIA is often asymptomatic. or greater score is achieved.
E. Children with JIA require vision correction early in their lives. This journal-based CME
3. A 14-year-old girl with systemic JIA who is taking methotrexate presents to the emergency activity is available through
department with the acute onset of fever, bleeding from the gums, seizures, decreased Dec. 31, 2019, however, credit
white blood cell and platelet counts, elevated D-dimer, and elevated aspartate will be recorded in the year in
aminotransferase and alanine aminotransferase. Her erythrocyte sedimentation rate today which the learner completes
is lower than it was 2 weeks ago during a regular follow-up visit. Which of the following is the quiz.
the most likely diagnosis in this patient?
A. Autoimmune hemolysis.
B. Macrophage activation syndrome.
C. Methotrexate overdose.
D. Overwhelming sepsis.
E. Secondary leukemia. 2017 Pediatrics in Review now
is approved for a total of 30
4. A 3-year-old girl with oligoarticular JIA presents to the clinic with a limp on the
Maintenance of Certification
right side associated with spiking fevers. Her right knee and ankle appear
(MOC) Part 2 credits by the
normal on physical examination, with no redness, warmth, or swelling. You
American Board of Pediatrics
order point-of-care right hip ultrasonography. Which of the following is the
through the AAP MOC
most important information that this imaging study will provide you in this
Portfolio Program. Complete
patient?
the first 10 issues or a total of
A. Confirm the presence of late ischemic changes of the joint. 30 quizzes of journal CME
B. Diagnose malignant bone tumors in deep-seated joint spaces. credits, achieve a 60% passing
C. Distinguish between inflammatory and infectious arthritis. score on each, and start
D. Evaluate the integrity of the lymphatic drainage of the affected limb. claiming MOC credits as early
E. Identify active synovitis of the hip joint. as October 2017.

Vol. 38 No. 5 MAY 2017 231


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5. A 6-year-old child is recently diagnosed with severe polyarticular JIA. The treating
rheumatologist discusses with the family the optimal treatment course. The family is
concerned about the potential adverse effects of the medications used. Which of the
following is the best early treatment regimen that is more likely to achieve the highest rate
of remission in this patient?
A. High-dose nonsteroidal anti-inflammatory drug.
B. Hydroxychloroquine and prednisolone combination.
C. Intravenous pulse methylprednisolone.
D. Intra-articular corticosteroid injections and nonsteroidal anti-inflammatory drug
combination.
E. Methotrexate and etanercept combination.

Additional Resources for Pediatricians


AAP Textbook of Pediatric Care, 2nd Edition
• Chapter 324: Rheumatologic Diseases - https://pediatriccare.solutions.aap.org/chapter.aspx?
sectionId¼124995829&bookId¼1626&resultClick¼1#139997278
Point-of-Care Quick Reference
• Juvenile Idiopathic Arthritis - https://pediatriccare.solutions.aap.org/Content.aspx?gbosid¼165535

Parent Resources from the AAP at HealthyChildren.org


• Juvenile Idiopathic Arthritis: https://www.healthychildren.org/English/health-issues/conditions/orthopedic/Pages/Juvenile-Idiopathic-
Arthritis.aspx
For a comprehensive library of AAP parent handouts, please go to the Pediatric Patient Education site at http://patiented.aap.org.

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Juvenile Idiopathic Arthritis − Changing Times, Changing Terms, Changing
Treatments
Susan Shenoi
Pediatrics in Review 2017;38;221
DOI: 10.1542/pir.2016-0148

Updated Information & including high resolution figures, can be found at:
Services http://pedsinreview.aappublications.org/content/38/5/221
References This article cites 15 articles, 3 of which you can access for free at:
http://pedsinreview.aappublications.org/content/38/5/221#BIBL
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_cme
Rheumatology/Musculoskeletal Disorders
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tology:musculoskeletal_disorders_sub
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n_vascular_-_other_multisystem_disorders_sub
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Juvenile Idiopathic Arthritis − Changing Times, Changing Terms, Changing
Treatments
Susan Shenoi
Pediatrics in Review 2017;38;221
DOI: 10.1542/pir.2016-0148

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://pedsinreview.aappublications.org/content/38/5/221

Data Supplement at:


http://pedsinreview.aappublications.org/content/suppl/2017/04/27/38.5.221.DC1

Pediatrics in Review is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1979. Pediatrics in Review is owned,
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Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2017 by the American Academy of
Pediatrics. All rights reserved. Print ISSN: 0191-9601.

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