+++
Oligoarticular,Polyarticular, and Systemic Categories: Introduction
++
Arthritis is a clinical finding of persistent
joint swelling or painful restriction of joint movement. Arthralgia is
pain in a joint, with or without inflammation. Thus, a patient with
arthralgia will not necessarily have arthritis, nor does a patient
with arthritis always have arthralgia. There are many causes of
arthritis and arthralgia in childhood, and this section will be
limited to the chronic arthritides of childhood that have no known
cause.
++
Terminology for this category of disease is problematic: In ongoing
attempts to rationalize the nomenclature, at least three different
classification schemes have been used during the past 20 years (see eTable 201.1). Without a clear-cut understanding
of the pathogenesis or biologic variability of arthritis in children,
however, these systems have often served more to confuse than to
elucidate. Idiopathic arthritis lasting for at least 6 weeks; with
onset before age 16; and not the result of infections, neoplasms,
orthopedic disorders, chronic inflammatory or autoimmune conditions,
or metabolic inherited and endocrine diseases, will be referred
to as juvenile idiopathic arthritis (JIA) in this section. This term
is increasingly used internationally to describe this group of conditions.
Details of the definitions and subcategories within this system are
shown in Table 201-1. The Juvenile Rheumatoid
Arthritis system still used by most caregivers in the United States
is shown in Table 201-2.
++
++
++
+++
Comparing Systems of
Nomenclature and Classification
++
Diagnosis, stratification, and study of arthritis in children
are all dependent on a consistent and agreed on system for classifying
and naming disease subsets. In the absence of a clear understanding
of the etiology and pathogenesis of arthritis, however, criteria
must be based on demographic, clinical, and laboratory factors,
and consequently they are bound to be imperfect. Over time, the
features that are thought to distinguish apparently discrete types
of arthritis have changed, and so classification systems have changed
as well. The most recent modification of the classification criteria
for childhood arthritis was published by the International League
of Associations for Rheumatology (ILAR) in 2001. Although childhood
arthritis in the United States generally continues to be known as
juvenile rheumatoid arthritis, after a previous classification system,
the ILAR criteria have gained widespread acceptance in most other
countries and in most medical journals. Thus, in order to allow
clinicians from around the world to communicate using common terminology,
this edition of Pediatrics utilizes the ILAR classification
of juvenile idiopathic arthritis (JIA).
++
Criteria to classify chronic arthritis in childhood as JIA were
first proposed by the Pediatric standing committee of ILAR in 1993
and subsequently revised in 2001. Arthritis of childhood had previously
been characterized on different sides of the Atlantic in the 1970s by
a committee of the American College of Rheumatology (ACR), and by
the European League against Rheumatism (EULAR). They respectively
coined the terms juvenile rheumatoid arthritis (JRA)
and juvenile chronic arthritis (JCA) but confusingly,
within the EULAR classification one of the categories of arthritis
describing patients with rheumatoid factor positive disease was
also called JRA. The systems of nomenclature of the ACR, EULAR,
and ILAR are compared in Table 201-1. These
classifications share some common features: They all refer to patients
whose disease onset was before age 16; they require a minimum period
of duration of arthritis–6 weeks for ACR and ILAR, and
6 months for EULAR; they all use terms to describe the pattern of
disease during the first 6 months from onset—oligoarticular (or
pauciarticular) arthritis occurring in 4 or fewer joints and polyarticular, defining arthritis
occurring in 5 or more joints. Systemic in all
schemes refers to arthritis in association with characteristic fever
and other extra-articular features, including rash, lymphadenopathy,
hepatosplenomegaly, or serositis. The presence of rheumatoid factor has
also been recognized as a defining feature for subclassification, and
in the EULAR system, patients with rheumatoid factor are described
as having JRA, whereas in the ILAR system a subclass of JIA is described
as rheumatoid factor positive polyarthritis.
++
A major deficiency of the ACR, EULAR, and current ILAR classification
systems is in how they deal with childhood spondyloarthropathies.
They are respectively not included, incompletely included, or inadequately
described in the context of adult disease. These deficiencies are
further discussed in the section on enthesitis-related arthritis
and the spondyloarthropathies (Chapter 229).
+++
Principles and
Unique Features of the Ilar (JIA) System
++
The philosophy of the ILAR system of classification was to describe
categories and subcategories of JIA that apart from the presence
of arthritis are clinically distinct, with the assumption that the
homogeneity of each subgroup reflects an underlying biological or pathophysiological
homogeneity. Thus, the results of research into the causes of arthritis, assessments
of disease outcomes, and evaluation of new drugs and treatment strategies
are intended to be not only clinically useful, but also biologically
relevant. To achieve this, the ILAR classification system is unique
because categories of JIA are defined by specific inclusion criteria
as well as by exclusion criteria. These are designed so that patients
who fulfill criteria for more than one category of arthritis will
be relegated to the undifferentiated JIA category. For example,
a patient whose disease is characterized by enthesitis, and who also
has a persistently positive rheumatoid factor, would fit within
the category of undifferentiated JIA. Although it is acknowledged that
this principle of mutual exclusivity will result in many patients
being included in the undifferentiated category, it is hoped that those
patients within each category (or subcategory) will have as homogeneous
a disease as possible. In practice, this is useful if the categories
truly represent biologically discrete conditions, but it is not
clear that this is the case.1 Unfortunately, those
patients remaining within the undifferentiated category have a condition
that is difficult to explain to families, and are usually excluded
from clinical trials. Nonetheless, the ILAR system has gained a
great deal of international acceptance to replace the two previous
parallel systems, although its scientific merits and consistency have
not been confirmed. The ILAR system is complicated to use and is
decidedly imperfect, but it appears to be the preferred system for most
of the world, giving it a cache lacking in the previous systems.
+++
Interchangeability of
Terminology
++
It is tempting to use similarly named subcategories within each
of the classification systems interchangeably. Because of the very exclusive
ILAR definitions, it is likely that most patients with JIA-oligoarthritis,
for example, could also be classified as either oligoarticular JRA
or oligoarticular JCA. However, the converse is not true. The categories
of oligoarticular JRA or oligoarticular JCA also include patients
that might better be described as having the enthesitis-related
arthritis, or psoriatic arthritis. In the clinical setting this
may not always be critical, but there is a need to be careful in
extrapolating the results of clinical or biological studies back
to the context of a specific patient. There is a wealth of literature
on JRA and JCA that cannot be ignored and that must be applied to
patients within the new ILAR classifications. However, going forward,
studies will enroll patients according to the ILAR criteria, so eventually
the transition in nomenclature must be made.2 It
is hoped that the next modification in terminology will be based
firmly on genetic and pathogenic data, and subsequent changes will
not be necessary.
++
In the United States, the prevalence of juvenile idiopathic arthritis
is 1 in 1000 and the incidence is 1.4 in 10,000. JIA is subdivided
into seven categories based on the number of joints involved and
other identified features present within the first 6 months of disease
onset (rather than on the biology of the disease). Consequently,
etiologic and prognostic differences between the oligoarticular,
polyarticular, and psoriatic categories are not striking. As fundamental
genetic and pathogenic information about these disorders increases,
the manner in which we describe, categorize, understand, and treat
childhood arthritis will likely undergo dramatic changes.
+++
Pathophysiology and
Genetics
++
A disease of persistent inflammation of the synovium, JIA has
long been considered a manifestation of autoimmunity; however, intense investigation
has failed to identify autoantibodies or target antigens. The contribution
of Human Leukocyte Antigens (HLA) alleles in persistent oligoarticular
JIA (DRB1* 1301, 0801) and polyarticular JIA (DPB1* 0301)
is emerging as important, possibly through their effect on T-lymphocyte
receptor function. Current thinking is leading toward understanding
these heretogeneous categories of JIA as autoinflammatory, rather
than autoimmune, diseases. It is postulated that persistence of
microbial antigens initiates synovial inflammation through the action
of antibodies against microbial antigens that cross-react with self
(molecular mimicry). Another line of investigation presents evidence
that an infection promotes the presentation of self–HLA
peptides to T cells.
++
Evidence for an infectious initiation of synovial inflammation
includes the persistent arthritis seen after a variety of infections, including
rubella and parvovirus. The clinical features (abrupt onset, high-spiking
fever, rash, hepatosplenomegaly, lymphadenopathy, and serositis)
and a clustering of cases in the autumn also suggest infection as
an inflammatory trigger. Further, polymerase chain reaction has
allowed identification of microbes and their antigens in synovial
tissue in some arthritides not previously thought to be owing to
infection.
++
The
immunologic cascade involved in JIA appears to be initiated by presentation
of antigen(s) to T lymphocytes by antigen-presenting cells (macrophages,
B cells, dendritic cells, fibroblasts, and endothelial cells). Subsequent
T-cell activation, development of specific subsets of CD4+ lymphocytes
(including the newly-described Th17 lineage), and production of
IL-17 stimulates cell activation and release of cytokines such as
TNF-α, IL-1, and IL-6. These then trigger polyclonal
T-cell expansion and production of a variety of additional inflammatory
mediators including prostaglandins, complement proteins, kinins, proteases,
matrix metalloproteases, and lysosomal enzymes. The result is migration
of additional inflammatory cells into the synovial tissue and fluid,
increased vascular permeability, and damage to cartilage and bone
(see Chapter 198).
++
The histology of the inflamed synovium in all categories of JIA
is identical to that of adult rheumatoid arthritis and is characterized
by lymphocytic and plasma cell infiltration and later villous hypertrophy
and hyperplasia of the synovial lining. This is accompanied by prominent
vascular endothelial cell hyperplasia and angiogenesis resulting
in the secretion of large amounts of protein-rich synovial fluid and
the migration of neutrophils, lymphocytes, and macrophages into
the joint. Synovial fluid white cell counts usually range from 2000
to 30,000/mL. However, even counts exceeding 100,000/mL
may be seen in patients with systemic JIA.
++
An exuberant inflammatory process leads to aggressive expansion
of the synovium onto the articular cartilage (pannus formation).
++
An exuberant inflammatory process leads to aggressive expansion
of the synovium onto the articular cartilage (pannus formation).
Lysosomal hydrolyses that break down proteoglycans and collagen
facilitate invasion of the avascular cartilage by the pannus. Prolonged
synovial inflammation causes irreparable damage to the cartilage,
as well as erosion and destruction of subchondral bone. Formation
of synovial-lined bony cysts can occur. New investigations have
documented migration of activated macrophages into subchondral bone
with activation of osteoclasts, further contributing to chronic
erosive changes.
++
Small areas of bone at the margins of articular cartilage (bare
areas) are exposed directly to the inflamed synovium; erosions at
these sites provide an early radiographic clue to bony destruction
in inflammatory arthritis.
+++
Clinical Presentations
++
In the absence of laboratory tests specific for the diagnosis
of JIA, patient history and physical examination assume critical
importance. A cardinal feature of inflammatory synovitis is morning
stiffness of at least 30 minutes, with improvement over time or
following movement and warming of the joint. Parents and other caregivers
may observe changes in walking, running, climbing stairs, or eagerness
to play. Children may need help with dressing, eating, bathing,
toileting, and other activities that were previously performed independently.
Enuresis may recur in a recently toilet-trained child, and developmental
milestones may be lost. Children not old enough to describe stiffness
or pain may be cranky in the morning or have generally decreased
activity.
++
On physical examination all joints must be thoroughly assessed
for swelling, motion, tenderness, pain, and bony enlargement. Muscles should
be examined for strength and possible atrophy. In addition, extra-articular
signs of juvenile arthritis should be sought, including abnormal
pupils, rash, lymphadenopathy, organomegaly, and pericardial and
pleural rubs. Occasionally, synovitis may be painless, but the diagnosis
requires the physical finding of swelling resulting from inflammation.
Indirect evidence of synovitis in those joints where swelling cannot
be visualized (ie, spine, hip, and shoulder) is decreased of motion
of the joint with associated pain or tenderness. Observing the child
moving about in the exam room can be as important as direct examination,
which may be difficult in an uncooperative, frightened toddler or
infant.
+++
Oligoarticular Category
++
Oligoarticular JIA, defined as synovitis in four or fewer joints
over the first 6 months of symptoms, occurs in about 40% of
children with JIA. The ratio of males to females is 1:6.5; the usual
age of onset is 1 to 3 years. Typically, the arthritis is minimally
symptomatic and has an insidious onset. Many of these children will
report no pain and come to medical attention after joint swelling
is found incidentally. The knee is most frequently involved, followed
by the ankle and then the small joints of the hand or the wrist,
but almost any joint may be affected. Isolated hip or neck arthritis
occurs rarely, although it may also portend evolution into enthesitis-related
arthritis, ankylosing spondylitis or psoriatic arthritis. Involvement
of only the temporomandibular joints has been described. Children
with oligoarticular JIA are systemically well—without fever,
rash, lymphadenopathy or organomegaly.
++
Asymptomatic uveitis (inflammation of the uveal tract—iris,
ciliary body, and choroid) develops in approximately 20% of
children with oligoarticular JIA, and 80% of these will have a
positive antinuclear antibody (ANA) test. Prompt diagnosis and treatment
of uveitis is critical to prevent later cataracts and glaucoma,
and potential loss of vision. Consequently, ophthalmologic screening
by slit-lamp examination every 3 to 4 months is essential for these
high-risk children. In fact, persistent or difficult-to-treat uveitis
becomes the most prominent chronic feature in a subset of children
with JIA. Less frequent screening is adequate in other forms of
arthritis that carry a lower risk of uveitis. Guidelines for ophthalmologic
screening for children with different JRA subtypes are shown in eTable 201.2.
++
++
Over time, about 80% of children with oligoarthritis
will continue to have episodes of arthritis with 4 or fewer joints
involved (persistentoligoarthritis),
whereas 20% will have extension of synovitis into additional joints
and become the group labeled as extended oligoarthritis.
++
Seventy percent of children with oligoarticular JIA are ANA-positive,
usually in low titer (⩽1:320). Mild elevation of erythrocyte sedimentation
rate (ESR) or C-reactive protein (CRP) and mild thrombocytosis with
a slight decrease in hemoglobin may be found, but these tests are
usually normal, as are other laboratory tests. The rheumatoid factor
test is rarely positive, but if it is, it often portends conversion
to a polyarticular course. Fever, rash, night pain, weight loss,
thrombocytopenia, or leukopenia are not seen in this disease, and
should prompt further investigations for alternative diagnoses.
++
Polyarticular JIA, defined as involvement of at least 5 joints
during the first 6 months of illness, is found in about 25% of
children with JIA. This group is further split into the categories
of RF– and RF+ disease. Those children who are considered
to be RF+ must have this test confirmed with repeat testing
at least 3 months from the initial test. Females predominate with two
peak ages of onset: 1 to 3 years, and again during early adolescence.
Both large and small joints may be affected; presentations vary
from scattered joint involvement to symmetric synovitis of nearly
all joints in the body. Involvement of the cervical spine, hips,
shoulders, and temporomandibular joints (TMJ) is common. In most
patients, the onset is insidious and accompanied by fatigue. Additionally,
some patients have low-grade fever, weight loss, rheumatoid nodules,
hepatosplenomegaly, lymphadenopathy, pleuritis, pericarditis and pneumonitis.
These patients are more likely to have elevated acute phase reactants,
including ESR, CRP and platelet counts, and they will often have
mild anemia of chronic disease. White blood cells counts should
be normal.
++
The disease of those children with a positive rheumatoid factor
closely resembles adult rheumatoid arthritis, including occasional
development of rheumatoid nodules, vasculitis and Felty syndrome
(splenomegaly and leukopenia). Antibodies to cyclic citrullinated
peptide (anti-CCP) are found in many of the same patients, though
they may develop earlier than the rheumatoid factor and may be a
more sensitive marker of severe disease.4 Other
serologic markers are generally negative; about 30% of patients
with polyarticular JIA have positive ANA test results. Five percent
of patients with polyarticular JIA develop asymptomatic chronic
uveitis, but in general children with more than 5 involved joints
are at less risk to do so than are children with oligoarticular
disease.
++
Systemic onset juvenile idiopathic arthritis , defined as the
occurrence of high-spiking daily fevers and arthritis in one or
more joints (often with other systemic findings), affects about 10% of
children with JIA. Males and females are affected equally. The age
of onset peaks at 5 to 10 years but spans infancy through adulthood.
The characteristic finding is daily fever, which, although erratic,
usually spikes once or twice a day, rising above 39.3°C (103�F)
and then spontaneously falling to or below normal. The peak of the
fever curve is often in the evening and may be accompanied by intense arthralgia
and myalgia. When the temperature is normal, the child may feel
quite well only to appear ill again when the fever spikes. Often the
fever and other systemic features will precede the development of
arthritis, so in general systemic onset JIA is a diagnosis of exclusion. Such
patients must have an extensive evaluation to rule out other sources
of fever, especially infections and malignancies.
++
Patients with systemic JIA may have a wide variety of systemic
manifestations. Among these is a macular, evanescent, salmon-colored rash
(Fig. 201-1). It typically exhibits discrete borders
with or without central clearing, and is often best seen during
the fever. The rash may be raised, is usually nonpruritic, and is
migratory, appearing anywhere, but most commonly over the trunk,
thighs, and axillae. It may be induced by mild trauma (Koebner phenomenon). Other
common systemic manifestations include pericarditis, myocarditis,
pleuritis, lymphadenopathy, hepatosplenomegaly, abdominal pain,
fatigue, anorexia, weight loss, and, rarely, asymptomatic iritis.
With time a few or many inflamed joints will appear. These tend
to be markedly swollen and more painful than the arthritis of other
subgroups. Nighttime pain and awakening are not unusual, but they nonetheless
should prompt investigation for underlying malignancy or infection.
++
++
The child with typical fever and rash but without arthritis may
be treated empirically for probable systemic JIA after other diagnoses
are exhaustively excluded. The diagnosis is not firm until synovitis
appears, and other potential causes of the child’s symptoms
have been duly considered. Many of these children will require bone marrow
aspiration and/or lymph node biopsy to exclude malignant
diseases. Laboratory abnormalities of systemic JIA are often dramatic, including
significant leukocytosis (>40,000), thrombocytosis (>1 million),
and elevated inflammatory markers (eg, CRP > 20 mg/dl and ESR
> 100 mm/hour). Elevated transaminases, anemia, and low
serum albumin levels are found frequently, but urinalysis is normal
and rheumatoid factor and DNA are rarely positive. During the acute
phase of disease, some children become severely ill with development
of leukopenia, thrombocytopenia, profound anemia, and hypofibrinoginemia,
and an acute decrease in the sedimentation rate. In addition, D-dimer
and ferritin levels may rise dramatically, and prothrombin time
and partial thromboplastin time become prolonged, consistent with
disseminated intravascular coagulation. This crisis is called macrophage
activation syndrome (MAS) and it appears to be related
to hereditary lymphohistiocytiosis. As it progresses, serum transaminases may
abruptly increase to greater than 1000 U/l, the bone marrow
may exhibit hemophagocytosis, and further sequelae of DIC and cytokine storm
may develop. With delayed or inappropriate management, MAS carries
a 10% to 20% mortality rate, but severe sequellae
largely may be avoided with prompt recognition and treatment with
pulse IV methylprednisone and further immunosuppression (for example,
with IV cyclosporine).
+++
Laboratory Evaluation
++
As described for each category of JIA, there is no test or combination
of tests that can differentiate JIA from other diseases. JIA remains
a clinical diagnosis dependent on the finding of unexplained synovitis.
The major role of laboratory tests is to exclude other potential
diagnoses, particularly infection and/or malignancy, and
to stratify patients’ risk of disease sequelae.
++
There is no imaging study that can definitively diagnose JIA
unless the disease is so advanced that characteristic erosions and
joint destruction have occurred. In general, imaging studies demonstrate
joint inflammation, but they do not distinguish JIA from infectious
or proliferative conditions. Thus, plain radiographs may rule out
diseases that mimic JIA, such as leukemia, tumors or chronic recurrent
multifocal osteomyelitis. The earliest changes are soft tissue swelling
and periarticular osteopenia, though this latter finding is only
visible on plain radiographs when 50% of the bone mineral
content has been lost because of inflammation. The intense inflammation
of the tendon sheath, joint, and tendon attachments can stimulate
periosteal new bone formation in the tubular bones of the phalanges,
metacarpals, and metatarsals, and occasionally long bones. A characteristic radiographic
finding in children with JIA involving a finger is widening of the
mid-portion of a phalange from periosteal new bone formation. Plain
radiographs are also useful for monitoring chronic joint changes
and effectiveness of treatment, but CT and/or MRI evaluations are
more sensitive. In young children, joint space widening can initially
be seen because of increased intra-articular fluid or synovial hypertrophy.
The hypervascularity of involved joints may stimulate adjacent growth plates
and result in bony enlargement, (knee or ankle), or epiphyseal advancement
or closure (often seen in the wrist or hip).
++
Bone scans may be
normal or reveal increased uptake on both sides of an affected joint
during the flow phase, indicative of increased synovial vascularity.
Increased uptake on just one side of a joint would suggest another
diagnosis. MRI with IV gadolinium contrast can highlight inflamed
synovium and increased joint fluid along with bone edema. It is
also a sensitive means of identifying early cartilage damage and
erosions. Ultrasound can identify synovial expansion, increased
synovial fluid and bony erosions, but is highly dependent on the
skill of the sonographer and the radiologist involved.
++
Computerized
tomography (CT) is best for identifying bony abnormalities and erosions. Joint
space narrowing on plain radiographs and CT scanning is only detectable
after a significant amount of cartilage has been destroyed. This
typically takes longer in children than in adults because of the
relative thickness of cartilage during growth and it may first become
manifest in the temporomandibular joint (TMJ). The TMJ is at particular
risk for destruction because the epiphysis is immediately adjacent
to a thin fibrocartilage, which is not as robust as true articular
cartilage. When the epiphysis is destroyed, micrognathia because of
lack of mandibular growth becomes evident. Coronal CT of the TMJ
currently provides the best images for evaluation of joint damage
in the TMJ, whereas MRI with IV gadolinium can detect active synovitis.
As arthritis progresses, further erosions become evident radiographically
when inflamed synovium and activated osteoclasts and macrophages
destroy cartilage and bone. Cysts can be formed when the inflamed
synovium invades subchondral bone. In late stages, these cysts may
collapse, leading to marked joint irregularity. Fibrous ankylosis
and bony fusion can occur and are not uncommon in JIA, particularly
in the wrist, cervical spine and tarsal areas. Erosion of the odontoid
process can lead to subluxation of C1 on C2. Children with JIA involving
the neck should be followed with flexion and extension lateral radiographs
of the cervical spine to assess the stability of C1 and C2 movement.
Repeat films should be obtained before general anesthesia and if
children are involved in gymnastics and contact sports.
+++
Differential Diagnosis
++
A thorough and diligent evaluation to exclude other processes
such as infection and malignancy must be emphasized. The diagnoses
of oligoarticular, polyarticular, or systemic juvenile idiopathic
arthritis require swollen joints or evidence of synovitis (see Table 201-1). A well child with joint pain
but no swelling may have an orthopedic condition (avascular necrosis, slipped
femoral epiphysis, benign joint tumor, Osgood-Schlatter disease),
so-called growing pains (benign nocturnal limb pains of childhood),
hypermobility, or a pain syndrome. An ill child may have infection
(of joints, bone or generalized), postinfectious arthritis, a metastatic
tumor, leukemia, lymphoma, or multifocal osteomyelitis. Thus, a
thorough workup is mandatory.
++
Goals of treatment are to minimize symptoms, prevent joint destruction,
maintain normal growth and development, and achieve inactive disease.
Inactive disease is defined as no joints with active arthritis;
no fever, rash, serositis, splenomegaly, or generalized lymphadenopathy
attributable to JIA; no uveitis; normal
physician global evaluation; and normalization of inflammatory markers
such as ESR or CRP. The pillars of treatment are patient/family
education, early aggressive medical management, and physical and occupational
therapy.4
++
Patient and family education is a critical component of treatment;
in order to achieve an optimal outcome, children and their caregivers must
be active partners in the treatment plan. Knowledge about the disease,
understanding of the goals of treatment, and realistic expectations
regarding the medications used are necessary to promote adherence
to therapeutic regimens. Patients and families must be provided
with careful, detailed explanations about joint functioning, the
effects of untreated inflammation on growing joints, the need for
early aggressive therapy, the goals of therapy, and potential side
effects of treatments. These topics need to be reviewed repeatedly
during the treatment course to make sure that the family’s
goals remain congruent with those of the caregiving team. The Arthritis
Foundation is an excellent source for additional information and
peer support. The emotional impact of this chronic, often painful,
and disabling disease on the child, siblings, and parents should
not be underestimated. The unpredictable course of JIA, including
the potential for exacerbations of disease after a long period of
remission, are particularly stressful for most patients and families.
The majority of children and parents do not need long-term counseling, but
many benefit from short-term family or individual treatment.
++
The medical treatment of JIA is hampered by incomplete understanding
of the etiology of arthritis, and by the nonspecific actions of many
key medications. Further, many medications that are effective in
adult arthritis have not been approved by the FDA for use in children,
generally because of a lack of pivotal studies. Despite this deficiency,
with the limited armamentarium of approved medications for JIA,
many agents without FDA indications for JIA (eg, leflunomide, infliximab)
may still have a place in the treatment of JIA.
++
Our current understanding of how quickly synovitis can cause
joint destruction, coupled with the traditionally poor long-term
outcome of JIA, have led to earlier and more aggressive treatment
over the past decade (Fig. 201-2). (An algorithm
for the treatment of systemic-onset JIA is not presented because
the treatment varies considerably depending on individual factors;
agents ranging from nonsteroidal anti-inflammatory drugs (NSAIDs) to
high-dose methylprednisolone, IV cyclosporine,5 and
experimental drugs all may be considered in specific cases.) NSAIDs
are no longer the mainstay of treatment for arthritis, but they
can be useful for mild reduction of pain and as a mild anti-inflammatory
agent. Intra-articular injections of triamcinolone hexacetamide,
in place of or in addition to systemic therapies, can be particularly
effective in quickly suppressing inflammation in a limited number
of joints.6 Depending on the age of the child and
the number and location of joints to be injected, brief general
anesthesia may be necessary for the injections. Repeat injections
(up to 3/joint) can be an important treatment strategy.
++
++
For those patients with polyarthritis or persistent or extended
oligoarthritis, methotrexate should be started as early as possible.7,8 Although
this drug can be administered orally once weekly (0.3/kg/week),
SQ injections of 0.5 to 1.0 mg/kg/week (40 mg
maximum) are more effective. Daily folate (1 mg) is usually given
for its demonstrated reduction of side effects in adults with rheumatoid
arthritis who are treated with methotrexate, though comparable data
in children are not available.
++
Short-term daily oral prednisone (0.5–2 mg/kg/day)
and/or weekly IV pulse methylprednisolone (30 mg/kg,
1 gram maximum), followed by low-dose daily prednisone (0.15 mg/kg/day)
for several months, may be very helpful in quickly reducing synovitis,
joint symptoms and systemic features of disease. Adult data indicate
that this treatment strategy may persistently decrease the likelihood
of joint damage when begun early in the course of the disease. Although
there is concern for potential side effects from the use of corticosteroids,
the benefits of better disease control and improved physical activity
may be tremendous. Weight gain is temporary, and many patients on
0.15 mg/kg/day or less grow normally and have
normal bone density studies.
++
In tandem with methotrexate, tumor necrosis factor antagonists
(etanercept,9 infliximab, and adalimumab), anti-IL-1
medications (anakinra, rilonacept), and costimulatory blocking agents (abatacept)
have greatly increased the ability to achieve complete disease control
in the majority of children with JIA. Other new biologic medications
(anti-IL 6 agents, longer-acting anti-TNF preparations, etc) are
becoming available, and treatment of JIA is evolving rapidly. Initially, these
medications were reserved as “the last treatment”;
however, accumulating data suggest that their effectiveness in preventing
joint damage is even greater when used early in the disease course,
rather than after other treatments have failed.
++
All of the medications mentioned here (including NSAIDs) have
potential side effects and require ongoing laboratory monitoring.
Cytopenias and liver function abnormalities are seen most commonly.
For patients on methotrexate, complete blood count (CBC), aspartate
aminotransterase (AST), blood urea nitrogen (BUN), and creatinine
are recommended after one month of treatment and then every 2 to
3 months. For NSAID use, the same monitoring (with a urinalysis)
should be done 1 month after starting the medication, and then every
4 months thereafter. Similar monitoring is recommended for most
biologic response modifiers.
++
Clinical follow-up of children with active JIA should occur every
1 to 3 months to allow for thorough evaluations and medication adjustments,
with the goal of achieving disease remission. After inactive disease
is achieved, medications are kept stable for 6 months to several
years before they are gradually tapered and discontinued. Evolving
management strategies may be similar to cancer protocols, with induction
regimens utilizing many medications together early in the disease
course followed by milder maintenance regimens aimed at maintaining
remission.
++
Physical and occupational therapies are an important component
of the treatment for JIA. Therapeutic goals include improving range
of motion, strength, and functioning when possible, otherwise at
least preventing further deterioration. Because loss of age-appropriate
developmental skills can occur, functional skills should to be monitored
by a therapist experienced in working with children with arthritis.
Frequency of therapy visits varies considerably, but all therapy
is based on a daily home program done by the child and parent. With
severe ongoing disease, long-term cooperation with physical and
occupational therapy can be difficult but is enhanced if the therapist
tailors the home program to take into account age, extent of disease,
school activities, sports, hobbies, and family dynamics. An active
lifestyle is important for maintaining bone and joint health; low-impact exercises
such as swimming are preferable when disease is active.
++
Nighttime splinting of the wrist, hand, knee, elbow, or ankle
may decrease morning stiffness and help to prevent flexion contractures
during active disease. Loss of extension can often be improved after
corticosteroid injection followed by serial casting of a knee, ankle,
wrist, finger, or elbow. Ice, heat, ultrasound, or a combination
of these modalities may help restore motion and decrease pain due
to muscle spasm. When a leg-length difference is present, a shoe
lift for the short limb will help to prevent contralateral knee
or hip flexion contractures. Children with arthritis of the tarsal
and metatarsal joints may ambulate more easily with shoe splints
(soft orthotics).
++
School can present a particular challenge for children with arthritis.
Morning stiffness may make a timely arrival difficult, and stiffness
from prolonged sitting may make moving between classes problematic.
Daytime stiffness can be ameliorated by allowing the child to get
up and move about the classroom, and some children may need extra
time to pass from class to class. Upper-extremity involvement may
make writing, drawing, working on the blackboard, and participating
in class difficult. An extra set of books at home greatly lessens
the load that needs to be carried to and from home. Physical education
and sports can be a challenge when arthritis is active; most children
do well when allowed to participate as much as they are able. Exercise
and nonimpact sports will not damage joints or worsen arthritis
if bony destruction is not present. Rarely, a child may need a shortened
school day, but home tutoring is almost never indicated.
++
In the United States, Public Law 94-142 (the Education for All
Handicapped Children Act of 1975) mandates that public schools provide
transportation to and from school and therapy for those individuals
with disabilities that affect their education. This applies to many
children with JIA who have limitations of range, strength, and coordination
that alter their functioning at school. Physical and occupational
therapists are available in the school to treat severely involved
children whose disease precludes them from meeting their educational
goals in a timely fashion. All therapists, whether at home, in school,
or at a hospital, can be the most helpful when they work in conjunction
with the other members of the patient’s rheumatology team.
++
The outcome of juvenile rheumatoid arthritis is variable for
all categories. Some patients may experience a single episode of
disease lasting 6 to 12 months, whereas others are afflicted with continuous
chronic inflammation, progressive joint destruction, and chronic
disability. Children do not outgrow JIA nor does puberty predictably
alter its course. Outcome can be measured by functional ability,
persistence of synovitis, or radiographic findings. Most long-term
outcome studies report cross-sectional information on patients at
defined time points in the disease course rather than characterizing the
longitudinal course of patients. One recent investigation described
the entire course of each of 437 patients followed 4 to 22 years
with respect to time spent with active or inactive disease, and
on or off medications. This investigation revealed that although
the majority of patients with oligoarticular JIA spent nearly 60% of
their disease course with inactive disease, 64% of patients
with RF– polyarticular JIA and 84% of children
with RF+ polyarticular JIA spent 60% or more of
the time with active disease.10 Although overall,
44% of patients achieved clinical remission off medications, only
18% remained in that state for more than 2 years and only
4% for 5 years. Thus, many patients begin their adult life
with ongoing joint inflammation, and they remain at risk for all
of the potential complications that this can cause.
++
Radiographic changes are yet another measure of arthritis severity
and outcome. All patients with JIA are at risk for joint damage—it is
common and can occur early in disease. Twenty-eight percent of pauciarticular-onset patients
develop radiologic evidence of joint damage at a median time of
5 years, whereas half of those with polyarticular- and systemic-onset
JIA develop joint damage within 2 years of onset of disease.
++
Despite these challenges, mortality from JIA in North America
is very rare, largely confined to children with systemic-onset disease.
It is calculated at 0.29% of all patients with JIA; although
a low number, this rate greatly exceeds overall mortality rates
for American children.11