Juvenile Rheumatoid Arthritis

By admin On Dec 15, 2022

Ovid: Pediatrics

Editors: Tornetta, Paul; Einhorn, Thomas A.; Cramer, Kathryn E.; Scherl, Susan A.

Title: Pediatrics, 1st Edition

> Table of Contents > Section III: – Specialty Clinics > 21 – Juvenile Rheumatoid Arthritis

Juvenile Rheumatoid Arthritis

Kosmas J. Kayes

Suzanne Bowyer

Thomas F. Kling, Jr.

Juvenile rheumatoid arthritis (JRA) is one of the most
common rheumatic disorders of childhood. Although the term JRA is often
used to refer to one disease, there are three variants with related
host responses, which may have the same or different etiologies. All
types are characterized by the insidious onset of idiopathic
(nontraumatic) arthritis, often in the lower extremity, due to an
immunoinflammatory process which may be activated by external antigens
in children with a specific, although as yet undefined, genetic
predisposition. Early diagnosis of JRA is facilitated by recognition of
the three major variants, including oligoarthritis, polyarthritis, and
systemic-onset arthritis. Each type is defined by a distinct
constellation of clinical signs and symptoms, which present during the
first 6 months of disease. Interestingly, JRA and adult rheumatoid
arthritis rarely occur in the same family.

TABLE 21-1 CHARACTERISTICS OF JUVENILE RHEUMATOID ARTHRITIS BY ONSET TYPE

Characteristic		Oligoarthritis (Pauciarticular)	Polyarthritis	Systemic Onset
Number of involved joints		≤4	≥5	Variable
Frequency of cases		60%	30%	10%
Age at onset		Early childhood Peak at 1-2 yr	Childhood Peak at 1-3 yr	Throughout childhood
Female to male ratio		5:1	3:1	1:1
Occurrence of uveitis		20%	5%	Rare
Systemic manifestations		None except uveitis	Moderate involvement	Always involved
Seropositivity
	ANA	75%-85% in girls with uveitis	40%-50%	10%
	Rheumatoid factor	Rare	10%—increases with age	Rare
Prognosis	Excellent except for eyes	Fair	50% Excellent 50% Poor
ANA, antinuclear antibody.
Adapted from Cassidy JT, Petty RE. Juvenile rheumatoid arthritis. In: Textbook of pediatric rheumatology.
Philadelphia: WB Saunders, 2001:218-321.

PATHOGENESIS

Classification

Table 21-1 describes a classification of JRA based on the types of onset.

Etiology

JRA is an autoimmune disease. The pathologic
characteristics of chronic synovitis and T-cell abnormalities suggest a
cell-mediated pathogenesis. In addition, multiple autoantibodies,
complement activation, and immune complexes, suggest humoral
abnormalities. It is also clear that JRA is associated with a complex
genetic predisposition. Specific genetic traits occur in children with
oligoarticular and polyarticular

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onset.
Interaction of multiple genes is likely, given the non-Mendelian
inheritance pattern displayed in the various types of JRA. Many of the
identified genes are on the histocompatibility complex of chromosome 6.
Elevated levels of pre-inflammatory (TH- 1) cytokines characterize all
types of JRA. High levels of circulating tumor necrosis factor (TNF)
are found in all types. Children with systemic-onset JRA have unusually
high levels of interleukin-6 (IL-6). The correlation of IL-6 levels
with disease manifestations of systemic JRA have fueled suspicion that
cytokine plays a role in the pathogenesis of this condition.

Epidemiology

The incidence of JRA varies in the literature from 2 to
20 per 100,000 of the susceptible population per year. The incidence
varies from country to country, and between different ethnic groups.
Some authors have identified seasonal variations in incidence. JRA has
been described in all races and geographic areas although its
prevalence varies throughout the world. Data from North America
indicate that children with African and Chinese ancestry have a lower
incidence of JRA than Caucasian children. In addition, oligoarthritis
is the least common type of arthritis observed in Africa.

The onset of JRA before 6 months of age is rare,
although the age of onset is typically quite young, with a peak
incidence occurring between 1 and 3 years. This peak age distribution
is most evident in girls with oligoarthritis and less so in those with
polyarthritis. Systemic onset has no increased frequency at any age.

Twice as many girls as boys develop JRA. Girls with
oligoarthritis outnumber boys by 3:1. In patients with uveitis, the
ratio of girls to boys is higher at 5 or 6:1. Girls with polyarthritis
outnumber boys in a ratio of 2.8:1. Systemic-onset JRA occurs with
equal frequency in girls and boys although there is a seasonal
variation in frequency. These differences in sex ratios suggest that
the disease expression is modified by sex chromosome factors.

Pathophysiology

The final pathway in all forms of JRA is arthritis
associated with abnormalities of the immune system. Synovial
proliferation and increased fluid production cause reduced joint
activity that results in decreased range of motion and strength, as
well as potential for development of flexion contractures. Ultimately,
cartilage erosion and bony destruction occur as the result of a
long-standing, active, or uncontrolled inflammatory process with
persistent pannus formation.

DIAGNOSIS

The diagnosis of JRA is clinical and based on knowledge
of each onset type and a high index of suspicion. No laboratory tests
are pathognomonic for JRA. However, the laboratory does provide support
for the diagnosis of JRA by providing evidence of inflammation in an
appropriate clinical setting for each onset type.

TABLE 21-2 LABORATORY FINDINGS IN JUVENILE RHEUMATOID ARTHRITIS BY ONSET TYPE

Laboratory Test	Oligoarthritis	Polyarthritis	Systemic Onset
Elevated ESR	+	++	+++
Elevated CRP	+	++	+++
Anemia	No	+	+++
Leukocytosis	No	+	+++
Thrombocytosis	No	+	+++
ANA	++	+	No
Rheumatoid factor	No	+	No
Increased hepatic enzymes	No	+	++
ANA, antinuclear antibody; CRP, C-reactive protein; ESR, erythrocyte sedimentation rate.
Adapted from Cassidy JT, Petty RE. Juvenile rheumatoid arthritis. In: Textbook of pediatric rheumatology. Philadelphia: WB Saunders, 2001:218-321.

Useful laboratory tests vary by onset type and are presented in Table 21-2.
It is appropriate to order complete blood count with differential,
erythrocyte sedimentation rate, and antinuclear antibody (ANA) testing
when considering the diagnosis of JRA. Interestingly, rheumatoid
factors (RFs) are unusual in normal children under the age of 7 years
and are seldom helpful in the diagnosis at onset of disease. Thus, as a
diagnostic aid, RF is of little value. However, children with a high
titer of RF likely represent a subgroup of those with polyarthritis who
have a later age of onset, are older, and typically have a poor
functional outcome.

Clinical Features

The common clinical manifestations of JRA are specific
to the onset type, the duration, pattern, and number of joints involved
and the presence of associated organ disease. These features are
summarized in Tables 21-3 and 21-4.

The arthritis in JRA is usually insidious in onset and
is associated with a gait abnormality or limb movement abnormality that
is not described as painful. Morning stiffness and gelling after
inactivity of the involved joint are common. Stiffness is infrequently
mentioned by the child but frequently reported by parents as morning
slowness or stiffness. Fatigue is rare in oligoarthritis but is common
in children with polyarthritis and systemic onset, especially at onset.
It may be expressed as a lack of energy, increased sleep requirement,
or increased irritability. Children with oligoarticular onset are not
ill while those with systemic onset appear quite ill. Those with
polyarthritis may appear ill at onset when a large number of joints are
involved.

The affected joint is swollen and warm but usually not
erythematous, tender, or painful with gentle movement. If the disease
has been present for several weeks, then there is usually mild to
moderate muscle atrophy and a mild joint

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flexion contracture. These changes can best be observed when the joint involvement is asymmetric.

TABLE 21-3 CLINICAL FINDINGS IN JUVENILE RHEUMATOID ARTHRITIS BY ONSET TYPE

Finding	Oligoarthritis	Polyarthritis	Systemic Onset
Number of joints involved (during 1st 6 mo)	≤4	≥5	Variable
Distribution of joint involvement	Lower extremity Large joints	Lower and upper extremities Large and small joints	Variable
Frequency of involved joints	Knees, ankles, elbows Hips almost always spared	Knees, wrists, elbows, ankle	Variable
Pattern of joint involvement	Usually unilateral Knee most common	Tends to be symmetric	Systemic symptoms often proceed arthritis by weeks or months
Small joints of hands and feet	No	IP joint of thumb; 2nd and 3rd MCP and PIP	May be involved
Cervical spine	Rare	Frequent	Frequent
Temporomandibular joints		Often develops later
Systemic illness	No	Mildly	Pronounced
Adapted from Cassidy JT, Petty RE. Juvenile rheumatoid arthritis. In: Textbook of pediatric rheumatology.
Philadelphia: WB Saunders, 2001:218-321.
IP, interphalangeal; MCP, metacarpal phalangeal; PIP, proximal interphalangeal.

Abnormalities of growth and development are frequently
associated with JRA. Linear growth is retarded during periods of active
systemic disease. Localized growth disturbance results from accelerated
development of ossification centers of long bones or premature fusion
of the physis. During active disease the growth and development of the
epiphysis is accelerated related to the hyperemia of inflammation. When
this occurs in the knee of a young child, it may result in overgrowth
of the involved leg, which can be a long-term problem.

TABLE 21-4 FREQUENCY OF EXTRAARTICULAR JUVENILE RHEUMATOID ARTHRITIS FINDINGS BY ONSET TYPE

Finding	Oligoarthritis	Polyarthritis	Systemic Onset
Fever	No	30%	100%
Rheumatoid rash	No	2%	95%
Hepatosplenomegaly	No	10%	85%
Lymphadenopathy	No	5%	70%
Pericarditis	No	5%	35%
Pleuritis	No	1%	20%
Rheumatoid nodules	No	10%	5%
Uveitis	20%	5%	1%
Adapted from Cassidy JT, Petty RE. Juvenile rheumatoid arthritis. In: Textbook of pediatric rheumatology. Philadelphia: WB Saunders, 2001:218-321.

Radiographic Features

Plain films of the affected joint are the best
investigation in most situations. Early radiographic changes reflect
inflammation and include periarticular soft tissue swelling, and
sometimes widening of the joint space secondary to synovial
hypertrophy. Juxtaarticular localized osteoporosis, growth arrest
lines, and advanced epiphyseal ossification center development are
often seen within weeks of the onset of disease. These findings are
most obvious when the disease is asymmetric. Overtubulation often
accompanies linear overgrowth of long bones. Periosteal new bone
formation

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and metaphyseal rarefaction are found in some children with polyarticular- and systemic-onset disease.

Later radiographic changes include joint space
narrowing, marginal joint erosion, joint subluxation, ankylosis, and
aseptic necrosis of the femoral head and dome of the talus in those
with severe polyarticular- and systemic-onset disease. These late
changes are unusual in oligoarticular disease.

Radionuclide scans show early evidence of joint
inflammation with increased uptake on both sides of the joint with
increased uptake on the early blood flow phase. Unfortunately, they
cannot differentiate JRA from septic arthritis or other causes of joint
arthritis.

Differential Diagnosis

The differential diagnosis is different for each onset
type. In monoarthritis of recent onset (within 72 hours), the diagnosis
must include septic arthritis, trauma, and hemolytic disease, including
hemophilia, leukemia, and malignancy. If a joint is acutely
erythematous and painful, especially with movement, in a febrile child,
then septic arthritis is most likely the cause. Immediate joint
aspiration is always indicated to rule out septic arthritis.

Juvenile Rheumatoid Arthritis

The most common cause of chronic arthritis, particularly in girls younger than 6 years of age.
Psoriatic arthritis and Lyme disease may also present in a similar fashion.
Rare causes of monoarthritis include
juvenile ankylosing spondylitis, villonodular synovitis, and
seronegative spondyloarthropathy.

Polyarticular-Onset JRA

Differential diagnosis is different from oligoarthritis.
Septic polyarthritis is rare, although Neisseria gonorrhoeae may have an early polyarticular phase.
Lyme disease may be polyarticular, but
can be differentiated from JRA by its intermittent pattern of activity
and preceding cutaneous, neuralgic, and cardiac findings.

Systemic Lupus Erythematosus

Can present as polyarthritis in a preadolescent or adolescent girl and mimic JRA.
Difficult to distinguish the two without
serologic studies and the later onset of the characteristic clinical
features of systemic lupus erythematosus (SLE) including butterfly
rash, alopecia, nephritis, central nervous system disease, Raynaud
phenomenon, leukopenia, and hemolytic anemia.
Presence of an active urinary sediment or Raynaud phenomenon strongly suggests the diagnosis of SLE.

Juvenile Ankylosing Spondylitis

Should be considered in a boy older than
10 years with a family history of ankylosing spondylitis who develops
lower extremity arthritis.
The HLA-B-27 antigen is present in 92% of these children.
Firm diagnosis of juvenile ankylosing
spondylitis depends on the characteristic x-ray findings in the
sacroiliac joint, which is observed later in the disease.

Systemic-Onset JRA

Can be difficult to diagnose early in its
course in a child with a high-spiking fever and evidence of systemic
infection but no arthritis.
Arthritis may not be present initially in this onset type.
The differential diagnosis is that of
fever of unknown origin and includes sepsis, malignancy, inflammatory
bowel disease, polyarteritis nodosa, SLE, and juvenile dermatomyositis.
Infectious mononucleosis and other viral illnesses may have transient arthritis.
Documenting a rheumatoid rash and the presence of arthritis helps to make the diagnosis of JRA.
Laboratory tests are of little value in
systemic-onset JRA, which is often a diagnosis of exclusion when the
associated features are observed in the ensuing weeks or months.

TREATMENT

JRA cannot yet be cured, but spontaneous remission
eventually occurs in many children and, in the interim, disease control
can be achieved in many with vigorous treatment. Most children with
chronic arthritis require a combined regimen of pharmacologic,
physical, and psychosocial treatment. The goals of treatment are as
follows:

Preserve range of motion and muscle strength.
Restore function.
Prevent deformity.
Control pain if present.
Diagnose and manage associated manifestations, particularly uveitis.
Facilitate normal growth and psychological development.

Since it is not usually possible at outset to predict
which child will recover and which will have unremitting disease, it is
therefore prudent to initiate vigorous treatment in all children.

All children should be referred to an
ophthalmologist for slit-lamp examination to look for uveitis, which
can be present at onset and is often asymptomatic.
- □ Most children develop uveitis within 5 to 7 years of onset, making regular ophthalmologic exams mandatory.
- □ Slit-lamp exams should be done every 3
  months for the first 2 years in children in the high-risk group (early
  age of onset, oligoarthritis, female sex, ANA-positive) and every 4 to
  6 months thereafter for at least 7 years.
- □ The exam can be done every 4 to 6 months in children with polyarthritis.

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Inflammatory arthritis should initially be treated with nonsteroidal antiinflammatory drugs (NSAIDs).
- □ Naproxen is effective in managing joint inflammation in a dose of 15 to 20 mg per kg per day given with food twice daily.
- □ Available in a b.i.d. liquid.
- □ Tolmetin in a dose of 25 to 30 mg per
  kg per day given in three divided doses with food is also effective,
  although it causes slightly more frequent gastric irritation.
- □ Clinical response to NSAIDs is variable and relatively unpredictable.
- □ Approximately 65% of children respond within 4 weeks of onset of treatment.
Analgesia with acetaminophen given two to three times a day is useful to control pain and fever in systemically ill children.
- □ Acetaminophen should not be used long term with NSAIDs, since it may contribute to interstitial nephritis.
If NSAIDs are not effective in
controlling the inflammatory arthritis after 1 to 2 months, second-line
drugs such as methotrexate, sulfasalazine, or lefluramide can be used.
- □ Glucocorticoid drugs are indicated in
  children with uncontrolled or life-threatening systemic disease, in the
  treatment of chronic uveitis, and as an intraarticular agent.
- □ Chronic oral glucocorticoid therapy is to be avoided if at all possible.
Physical therapy should be initiated early if there is any muscle atrophy or joint contracture.
- □ Atrophy of the extensor muscles begins
  early and active exercise must be instituted to maintain strength and
  prevent contracture.
- □ During periods of active inflammation,
  warming the joint with a hot bath in the morning and heat before
  physical therapy can reduce joint pain and stiffness.
- □ Passive stretching is usually necessary to regain lost extension.
- □ For resistant contractures, particularly of the wrist, elbows, or knees, serial casts or splints may be beneficial.
- □ The maintenance of normal range of motion often requires long-term gentle stretching and the use of resting splints.
- □ During periods of remission, an active exercise program to maintain range of motion and strength is recommended.
- □ This exercise program also helps to alert parents of recurrent arthritis if atrophy or contracture intervenes.
- □ It is usually not necessary to limit
  play since children determine their own level of activity and normal
  play is vital to the psychosocial development of the child.
- □ Sports that place excessive stress on
  affected joints, particularly in the lower extremities of older
  children, should be avoided.
- □ Physical therapy is critical to the
  total management program and should be a regular component of follow-up
  in children with JRA.
Biologic medications became commercially available in November 1998 and have greatly benefited children with JRA.
- □ Given by injection (etanercept) or
  intravenously (infliximab), these medications lead to remission in most
  of the children treated.
- □ Etanercept (Enbrel) is given by subcutaneous injections twice a week.
  - □ In a study of children with JRA who were started on etanercept, approximately 70% responded favorably.
  - □ These patients had all failed treatment with methotrexate.
- □ Infliximab (Remicade) is given intravenously on a monthly basis.
- □ Newer biologics like anti-IL-1 (Anakinra) and anti-IL-6 should be available for children within the next few years.
  - □ The major side effect of this class of
    medication is decreased resistance to infection, especially infections
    such as tuberculosis and endemic fungi (histoplasmosis,
    coccidiomycosis).
It is unclear whether these medications need to be discontinued prior to orthopaedic procedures such as total hip arthroplasty.
Depot glucocorticoid can be very
beneficial when injected into joints that have not responded to NSAIDs
or as an aid to physical therapy of inflamed contracted joints.
- □ Triamcinolone hexacetonide is the drug of choice in a dose of 20 to 40 mg for large joints.
- □ Aseptic technique is necessary to prevent infection, and anesthesia or conscious sedation is often helpful.
- □ Almost all patients respond favorably
  in 2 to 4 days and the effect lasts for 6 months in 60% of patients and
  for 1 year in almost 45%.
- □ Side effects are uncommon.
- □ Subcutaneous atrophy at the injection
  site can be avoided or minimized by careful prevention of leakage
  around the needle tract.
Orthopaedic surgery to equalize leg
lengths, relieve long-standing joint contractures, and joint
replacement of the hip and knee are beneficial in older children with
disability.
- □ Synovectomy does not alter the
  long-term arthritis of JRA, although it can be beneficial to relieve
  mechanical blocks to joint motion secondary to chronic synovial
  hypertrophy.
- □ Preservation of muscle strength in
  anticipation of surgery requires rehabilitation over many years and
  greatly improves the results of surgery.
- □ Total joint replacement can be successful only if muscle strength and range of motion have been preserved through the years.

Course of Disease and Outcome

The course of JRA is unpredictable at the outset of
disease since the arthritis is typically remitting and relapsing over a
period of time. As a group, it is estimated that 70% to 85% of children
have a good prognosis for recovery from

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their
arthritis without serious disability. Some 10% to 17% of children with
JRA have moderate to severe functional disabilities in adulthood.
Children who have many involved joints or unremitting arthritis over a
long period of time have a poor prognosis. As expected, there are
differences in the course and prognosis for each onset type. However,
even with group statistics, it is not possible to predict the outcome
in any individual child.

Oligoarticular-Onset JRA

Course is variable.
Most children go into remission, although flares of arthritis may occur years later.
A few have persistent arthritis, which can lead to cartilage erosion.
Children with oligoarthritis fare best from the standpoint of joint disease and worst from the risk of uveitis.
Because of the limited extent of joint involvement, serious functional disability is uncommon.
Correct responce to intraarticular glucocorticoid injection.

Polyarticular-Onset JRA

The prognosis is not nearly as good as in oligoarticular-onset disease due to the greater number of involved joints.
Factors that correlate with an unsatisfactory course:
- □ Older age at onset
- □ Long duration of unremitting inflammatory activity
- □ Early involvement of the small joints of the hands and feet
- □ Rapid appearance of erosions
- □ Positive RF
Largest number of involved joints, often 20 or more
Long-term disability is related to the extent of articular involvement.
Limited range of motion often develops early, and remission is unlikely if the arthritis persists longer than 7 years.
Hip disease occurs in 50% of sufferers
and is almost always accompanied by persistent inflammation, which
leads to abnormal development and distortion of the femoral head.
Involvement of the small joints of the
hands and feet is characteristically associated with polyarthritis and
with a more guarded outlook.

Systemic-Onset JRA

Acute manifestations vary in duration from weeks to months.
About half the children eventually
recover almost completely, usually after a pattern of oligoarticular
disease for a variable period of time.
The rest of affected children continue to
show progressive involvement of more and more joints, which results in
moderate to severe disability.
Eventual outcome depends more on the
number of involved joints and on the persistence of inflammatory
activity in the joints than on the nature of the systemic disease.