Juvenile Idiopathic Arthritis

Practice Essentials

Juvenile rheumatoid arthritis (JRA) is the most common chronic rheumatologic disease in children and is one of the most common chronic diseases of childhood (see the image below). The etiology is unknown, and the genetic component is complex, making clear distinctions between the various subtypes difficult. A new nomenclature, juvenile idiopathic arthritis (JIA), is being increasingly used to provide better definition of subgroups.

View Image

Eighteen-month-old girl with arthritis in her right knee. Note the flexion contracture of that knee.

Signs and symptoms

History findings in children with JIA may include the following:

• Arthritis present for at least 6 weeks before diagnosis (mandatory for diagnosis of JIA)
• Either insidious or abrupt disease onset, often with morning stiffness or gelling phenomenon and arthralgia during the day
• Complaints of joint pain or abnormal joint use
• History of school absences or limited ability to participate in physical education classes
• Spiking fevers occurring once or twice each day at about the same time of day
• Evanescent rash on the trunk and extremities
• Psoriasis or more subtle dermatologic manifestations

Physical findings are important to provide criteria for diagnosis and to detect abnormalities suggestive of alternative etiologies, as well as to indicate disease subtypes. Such findings include the following:

• Arthritis: Defined either as intra-articular swelling on examination or as limitation of joint motion in association with pain, warmth, or erythema of the joint; physical findings in JIA reflect the extent of joint involvement
• Synovitis: Characterized by synovial proliferation and increased joint volume; the joint is held in a position of maximum comfort, and range of motion often is limited only at the extremes

Types of JIA include the following:

• Systemic-onset juvenile idiopathic arthritis
• Oligoarticular juvenile idiopathic arthritis
• Polyarticular juvenile idiopathic arthritis
• Psoriatic arthritis
• Enthesitis-related arthritis
• Undifferentiated arthritis

See Clinical Presentation for more detail.

Diagnosis

Diagnosis of JIA is based on the history and physical examination findings. When physical findings do not document definite arthritis, further evaluation is warranted. Laboratory studies that may be considered include the following:

• Inflammatory markers: Erythrocyte sedimentation rate (ESR) or CRP level
• Complete blood count (CBC) and metabolic panel
• Liver function tests and assessment of renal function with serum creatinine levels
• Antinuclear antibody (ANA) testing
• Rheumatoid factor (RF) and anti–cyclic citrullinated peptide (CCP) antibody
• Additional studies: Total protein, albumin, fibrinogen, ferritin, D-dimer, angiotensin-converting enzyme (ACE), antistreptolysin 0 (AS0), anti-DNAse B, urinalysis

When only a single joint is affected, radiography is important to exclude other diseases. Basic radiographic changes in JIA include the following:

• Soft tissue swelling
• Osteopenia or osteoporosis
• Joint-space narrowing
• Bony erosions
• Intra-articular bony ankylosis
• Periosteitis
• Growth disturbances
• Epiphyseal compression fracture
• Joint subluxation
• Synovial cysts

Other imaging modalities that may be helpful include the following:

• Computed tomography
• Magnetic resonance imaging
• Ultrasonography and echocardiography
• Nuclear imaging

Other studies and procedures that may be considered include the following:

• Dual-energy radiographic absorptiometry (DRA)
• Arthrocentesis and synovial biopsy
• Pericardiocentesis

See Workup for more detail.

Management

A team-based approach to the treatment of JIA can be helpful. Management may include 1 or all of the following areas:

• Pharmacologic therapy with nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), biologic agents, or intra-articular and oral corticosteroids
• Psychosocial interventions
• Measures to enhance school performance (eg, academic counseling)
• Improved nutrition
• Physical therapy
• Occupational therapy

American College of Rheumatology (ACR) criteria for complete remission are as follows^[1] :

• No inflammatory joint pain
• No morning stiffness
• No fatigue
• No synovitis
• No progression of damage, as determined in sequential radiographic examinations
• No elevation of the ESR and CRP level

The ACR recommends treatment approaches to JIA on the basis of the following 5 treatment groups^[2] :

• A history of arthritis in 4 or fewer joints
• A history of arthritis in 5 or more joints
• Active sacroiliac arthritis
• Systemic arthritis without active arthritis
• Systemic arthritis with active arthritis

Within each group, choice of therapy is guided by the severity of disease activity and the presence or absence of features indicating a poor prognosis.

Advances in medical treatment have reduced the need for surgical intervention. Procedures that may be considered in specific circumstances include the following:

• Synovectomy
• Osteotomy and arthrodesis
• Hip and knee replacement

See Treatment and Medication for more detail.

• References

Background

Juvenile rheumatoid arthritis (JRA) is the most common chronic rheumatologic disease in children and is one of the most common chronic diseases of childhood. It represents a group of disorders that share the clinical manifestation of chronic joint inflammation.

The etiology is unknown, and the genetic component is complex, making clear distinctions between the various subtypes difficult. As a result, the various sets of classification criteria that have been recognized have different benefits and limitations. A new nomenclature, juvenile idiopathic arthritis (JIA), is being increasingly used in order to better define subgroups.

Go to Osteoarthritis, Pediatric Osteoarthritis, and Rheumatoid Arthritis for complete information on these topics.

Criteria and classification

Three groups have developed sets of criteria to classify children with arthritis: the American College of Rheumatology (ACR), the European League Against Rheumatism (EULAR), and the International League of Associations for Rheumatology (ILAR).^{[3, 4, 5]}

The ACR criteria define juvenile rheumatoid arthritis (JRA) by age limit (< 16 y) and the duration of disease (>6 weeks). (See Table.) The organization recognizes the following 3 subtypes:

• Polyarticular
• Pauciarticular
• Systemic

Other forms of childhood arthritis, such as juvenile ankylosing spondylitis and psoriatic arthritis, are classified under spondyloarthropathies.

The ILAR classification of JIA includes the following categories:

• Systemic-onset JIA
• Persistent or extended oligoarthritis
• Rheumatoid factor (RF)–positive polyarthritis
• RF-negative polyarthritis
• Psoriatic JIA
• Enthesitis-related arthritis
• Undifferentiated - The disease does not meet criteria for any of the other subgroups, or it meets more than 1 criterion (and therefore could be classified in a number of subgroups).

The EULAR proposed the term juvenile chronic arthritis (JCA) for the heterogeneous group of disorders that manifest as juvenile arthritis. The diagnosis requires that the arthritis begins before age 16 years and lasts for at least 3 months. The EULAR criteria for JCA recognize the following subtypes, based on characteristics at onset:

• Pauciarticular (1-4 joints)
• Polyarticular (≥5 joints)
• Presence of RF (2 positive tests at least 3 months apart)
• Systemic onset with characteristic features
• Positivity for rheumatoid factor
• Juvenile ankylosing spondylitis
• Juvenile psoriatic arthritis

This article will use the ILAR nomenclature unless differentiation is required between JIA and JRA or JCA.

Table. Comparison of Classification Criteria for Chronic Childhood Arthritis

View Table

See Table

• References

Etiology and Pathophysiology

The etiology and pathogenesis of JIA are not completely understood. Genetic susceptibility plays a major role, but there is significant overlap between loci associated with JIA and those associated with other autoimmune diseases.^[6]

JIA is a genetically complex disorder in which multiple genes are important for disease onset and manifestations. The IL2RA/CD25 gene has been implicated as a JIA susceptibility locus, as has the VTCN1 gene.^[7] Associations have been found between specific HLA alleles and clinical subtypes of JIA (eg, HLA-A(*)02:06 with susceptibility to JIA accompanied by uveitis, and HLA-DRB1(*)04:05 with polyarticular JIA, in a Japanese cohort).^[8]  

A study by Ombrello examined the MHC locus in a large collection of systemic juvenile idiopathic arthritis patients and verified the relationship between the class II HLA region and systemic juvenile idiopathic arthritis, implicating adaptive immune molecules in the pathogenesis of the disease.^[9]

Humoral and cell-mediated immunity are involved in the pathogenesis of JIA. T lymphocytes have a central role, releasing proinflammatory cytokines (eg, tumor necrosis factor–alpha [TNF-α], interleukin [IL]-6, IL-1) and favoring a type-1 helper T-lymphocyte response. A disordered interaction between type 1 and type 2 T-helper cells has been postulated.

Studies of T-cell receptor expression confirm recruitment of T-lymphocytes specific for synovial nonself antigens. Evidence for abnormalities in the humoral immune system include the increased presence of autoantibodies (especially antinuclear antibodies), increased serum immunoglobulins, the presence of circulating immune complexes, and complement activation.

Chronic inflammation of synovium is characterized by B-lymphocyte infiltration and expansion. Macrophages and T-cell invasion are associated with the release of cytokines, which evoke synoviocyte proliferation. A study by Scola et al found synovium to contain messenger ribonucleic acid (mRNA) for vascular endothelial growth factor and angiopoietin 1, as well as for their receptors, suggesting that induction of angiogenesis by products of lymphocytic infiltration may be involved in persistence of disease.^[10]

Some pediatric rheumatologists view systemic-onset JIA as an autoinflammatory disorder, such as familial Mediterranean fever (FMF) or cryopyrin-associated periodic fever syndromes, rather than a subtype of JIA. This theory is supported by work demonstrating similar expression patterns of a phagocytic protein (S100A12) in systemic-onset JIA and FMF, as well as the same marked responsiveness to IL-1 receptor antagonists.^[11]

FMF is associated with mutations in the MEFV gene; these mutations are associated with activation of the IL-1b pathway, resulting in inflammation. A study by Ayaz et al found an increased frequency of MEFV mutations in Turkish children who were diagnosed with systemic JIA^[12] ; this study has not been replicated in other populations.

In a nested case–control study of 153 children with juvenile arthritis and 1,530 matched controls, researchers found that exposure to antibiotics during childhood significantly increased the risk for developing JIA (adjusted odds ratio = 2.6) in a dose-dependent manner. Compared with those with no exposure, the odds ratio for developing JIA was 3.1 for children exposed to one or two courses of antibiotics, and for those exposed to three to five courses the odds ratio was 3.8.^[13]  The association between antibiotic exposure and JIA was similar for different classes of antibiotics. No association was found between exposure to nonbacterial antimicrobial agents and JIA. Adjustment for the number and type of infections and age at antibiotic exposure did not change the associations significantly.^[13]

• References

Epidemiology

United States statistics

Approximately 300,000 children in the United States are estimated to have some type of arthritis. The incidence rate estimates for JIA range from 4-14 cases per 100,000 children annually; for JRA, the prevalence has ranged from 1.6 to 86.1 cases per 100,000.^[14] These wide-ranging numbers are attributable to differing definitions and criteria for childhood arthritis; population differences, including environmental exposure and immunogenetic susceptibility; and difficulty in case ascertainment and lack of population based data.

International statistics

Worldwide, JIA appears to occur more frequently in certain populations (eg, indigenous peoples) from such disparate areas as British Columbia and Norway. A study in Sweden found the prevalence of JIA there to be similar to that in Minnesota, approximately 85 cases per 100,000 population, with an incidence of 11 cases per 100,000 population. A study from Germany found a prevalence rate of 20 cases per 100,000 population, with an incidence rate of 3.5 cases per 100,000 population.

Estimates from Norway include a prevalence rate of 148 cases per 100,000 population with an incidence rate of 22 cases per 100,000 population. The incidence of JIA in Japan has been reported to be low.

Disease-associated mortality for JIA is difficult to quantify, but it is estimated to be less than 1% in Europe and less than 0.5% in North America. Most deaths associated with JIA in Europe are related to amyloidosis, and most in the United States are related to infections.

The approximate frequencies of the various forms of JRA are as follows:

• Oligoarticular - 30%
• Polyarticular RF negative - 20%
• Polyarticular RF positive – 5%
• Systemic-onset – 5%
• Psoriatic - 5%
• Enthesitis Related – 25%
• Undifferentiated – 10%

Sexual differences in frequency

Girls with an oligoarticular onset outnumber boys by a ratio of 3:1. In children with uveitis, the ratio of girls to boys is 5-6.6:1, and in children with polyarticular onset, girls outnumber boys by 2.8:1. In striking contrast, systemic-onset occurs with equal frequency in boys and girls. Boys outnumber girls with enthesitis-related arthritis.^[15]

Age-related differences in frequency

Although JIA is defined as arthritis beginning before age 16 years, the age at onset is often much lower, with the highest frequency occurring in children aged 1-3 years.^[16] This age distribution is most evident in girls with oligoarticular JIA and psoriatic arthritis.

Polyarticular RF-negative JIA has a biphasic peak of onset; the first is at a young age (1-4 y), similar to oligoarticular JIA, and the second peak is at age 6-12 years. RF-positive disease is more common in adolescents. Systemic-onset JIA is not characterized by a peak age of onset; it is spread across the childhood years. The usual age of onset of enthesitis-related arthritis is 10-12 years.^[15]

• References

Prognosis

Advances in treatment over the last 20 years—especially the introduction of early use of intra-articular steroids, methotrexate, and biologic medications—have dramatically improved the prognosis for children with arthritis. Almost all children with JIA lead productive lives. However, many patients, particularly those with polyarticular disease, may have problems with active disease throughout adulthood, with sustained remission attained in a minority of patients.

Early hip or wrist involvement, symmetrical disease, the presence of RF, and prolonged active systemic disease have been associated with poor long-term outcomes. Compared with adults with RF-positive rheumatoid arthritis, however, children are at less risk for rheumatoid lung involvement and vasculitis. The anti – cyclic citrullinated peptide antibodies (CCP) antibodies test may be more specific than the RF test, but it is not as well studied in children.

Children with systemic-onset disease tend to either respond completely to medical therapy or develop a severe polyarticular course that tends to be refractory to medical treatment, with disease persisting into adulthood.

Most children with oligoarticular disease demonstrate eventual permanent remission, although a small number progress to persisting polyarticular disease.

Concern has been raised that the use of biologics may increase cancer risk among patients with JIA; however, lack of data on the baseline risk of cancer in this population has made it difficult to determine whether the concern is justified. A review of a large cohort of patients from the Swedish registry found an increased risk of cancer in patients who had not been on biologic therapies and had been diagnosed with JIA in the last 20 years. However, this risk was not found if the analysis was extended to patients diagnosed between 1969 and 1987.^{[17, 18]}

The results of this study were not statistically significant. Nevertheless, they may have implications for interpretation of cancer signals in patients with JIA, particularly those who are on ongoing therapy with biologic agents, such as TNF-alpha inhibitors.

• References

Patient Education

Educating the patient, family, and school personnel (eg, classroom teachers, physical education teachers, nurses) about JIA and its presentation, treatment, and potential effects is continually necessary. Members of the pediatric rheumatology team in pediatric rheumatology clinics are the best educators about JIA. Another important source of information is the American Juvenile Arthritis Organization, a council of the Arthritis Foundation.

For patient education information, see the Arthritis Center, as well as Juvenile Rheumatoid Arthritis and Juvenile Rheumatoid Arthritis Treatment.

• References

History

Arthritis must be present for 6 weeks before the diagnosis of juvenile idiopathic arthritis (JIA) can be made. Disease onset is either insidious or abrupt, with morning stiffness or gelling phenomenon (ie, stiffness after long periods of sitting or inactivity) being a frequent complaint and arthralgia occurring during the day. A morning limp that improves with time may be noted, and a toddler may no longer stand in the crib in the morning or after naps.

Complaints of joint pain may not be predominant in the patients’ history, however; children often stop using joints normally (eg, develop contractures of joints, decreased wrist range, limp) rather than complain of pain. Up to a quarter of children with oligoarticular JIA have no pain.

Individuals with JIA may have a history of school absences, and their ability to participate in physical education classes reflects the severity of the disease or acute flares.

Systemic-onset JIA is characterized by spiking fevers, typically occurring once or twice each day, at about the same time of day, with temperature returning to normal or below normal. The fever pattern is very useful because infections, Kawasaki disease, and malignancy usually do not have such a predictable pattern.

Systemic-onset JIA is usually accompanied by an evanescent rash (lasting a few hours), which is typically nonpruritic, macular, and salmon colored on the trunk and extremities. Occasionally, the rash is extremely pruritic and resistant to antihistamine treatment.

Children with psoriatic arthritis may have typical psoriasis but dermatological manifestations may be subtle; careful attention should be paid to looking for nail pits. Dactylitis is characteristic of psoriatic arthritis.

Enthesitis-related arthritis frequently presents as evening and post-exercise pain. Attention should be given to buttock pain and back pain that improves with activity (inflammatory back pain). These children cannot lie in bed all morning but have to get up due to back pain.

• References

Physical Examination

JIA is a clinical diagnosis. A complete physical examination is critical for the diagnosis. Physical findings are important to provide criteria for diagnosis and to detect abnormalities suggestive of alternative etiologies. The diagnosis of JIA is based on the physical finding of arthritis in at least 1 joint that has persisted for at least 6 weeks, with other causes excluded, in an individual younger than 16 years.

No diagnostic serologic tests for JIA are recognized, aside from rheumatoid factor assay for subclassification of polyarticular disease. Other tests, such as antinuclear antibody and HLA-B27 assays, may help further define diagnosis and risk of complications.

Arthritis is defined as either intra-articular swelling on examination or as limitation of joint motion in association with pain, warmth, or erythema of the joint. The hips, temporomandibular joint, and small joints in the spine do not demonstrate swelling when affected by synovitis but demonstrate the combination of loss of motion and pain. The physical findings in JIA are a reflection of the extent of joint involvement.^[19]

In synovitis, in which there is synovial proliferation and an increase in joint volume, the joint is held in a position of maximum comfort. Limbs with synovitis are generally held in flexion. Range of motion often is limited only at the extremes.

In synovitis, the fingers may appear swollen, and the range of motion becomes painful. The wrist goes into flexion. In the knee, the parapatellar fossae often are obliterated, and a doughy synovium may be palpable. A soft, boggy swelling is appreciated in the popliteal fossa.

The hip is held in an attitude of flexion, abduction, and external rotation. Attempted range of motion will be painful to a varying degree. Guarding is an early sign of synovitis.

Cutaneous erythema is extremely rare in JIA. Its presence should alert one to look for another diagnosis.

• References

Systemic-Onset Juvenile Idiopathic Arthritis

A definite diagnosis of systemic-onset JIA must await the development of arthritis. This may occur at onset of the fever and rash or may lag by months or, rarely, years.

Physical examination findings include the following:

• The child appears systemically ill
• Arthralgia is often present
• The child may have generalized myalgia
• Evanescent, salmon-pink, macular rash (often linear) is found, predominantly on the trunk and the extremities; this rash, seen in the image below, is associated with fever spikes

  View Image

  Systemic juvenile idiopathic arthritis (JIA) rash.

   

  

   
• Hepatosplenomegaly is often present
• Lymphadenopathy is sometimes present, especially the axillary lymph nodes
• Muscle tenderness to palpation may be observed
• Serositis, including pleural and pericardial effusions, may be present, as is noted in the image below

  View Image

  Child with pericardial effusion due to systemic onset juvenile idiopathic arthritis (JIA).

   

  

   
• Chest pain or shortness of breath may be a sign of pericarditis or pleuritis
• Friction rub may occur in pericarditis but can be absent with a large pericardial effusion
• S₃, basilar rales, and hepatomegaly suggestive of heart failure may rarely be observed when myocarditis occurs in individuals with systemic-onset JIA

• References

Oligoarticular Juvenile Idiopathic Arthritis

Characteristics of oligoarticular JIA include the following:

• In individuals with oligoarticular JIA, 4 or fewer joints (and in many cases, only 1 joint) are affected
• Large, weight-bearing joints, such as the knees and ankles, are typically affected, as seen in the image below

  View Image

  Eighteen-month-old girl with arthritis in her right knee. Note the flexion contracture of that knee.

   

  

   
• Children appear to be well, despite ambulating with a limp
• In cases of asymmetrical arthritis, chronic inflammation-related hyperemia in a knee or ankle may lead to overgrowth of that limb with subsequent leg-length discrepancy
• Muscle atrophy, often of extensor muscles (eg, vastus lateralis, quadriceps when the knee is affected), may occur
• Flexion contractures in the knees and, less commonly, the wrists are found

Involvement of a few small joints in the hands is atypical and suggests eventual development of polyarticular JIA or psoriatic arthritis. Dactylitis, or diffuse tenosynovitis of a finger or toe, also called a "sausage digit," is more typical of psoriatic arthritis or enthesitis-related arthritis.

Anterior uveitis (seen in the image below) is present in as many as 20% of children with oligoarticular and polyarticular JIA, especially those who are antinuclear antibody (ANA) positive. The uveitis is typically asymptomatic at onset and must be screened for with an ophthalmologic slit lamp examination.

Generally, children who were 6 years of age or younger at onset (especially of oligoarticular and psoriatic arthritis) and have a positive ANA test are screened by slit lamp exam every 3 months for 4 years or more and then every 6 months until at least 7 years after diagnosis.^[20] Thereafter they are screened yearly for life.

Children who are at lesser risk (ie, have polyarticular disease and are ANA negative), are screened every 6 months for 7 years and then yearly. Children with systemic JIA are at very low risk and are screened yearly.

Acute anterior uveitis is one of the diagnostic criteria for enthesitis-related arthritis. These children with are screened initially and if symptomatic.

Older children with RF-positive polyarticular JIA should probably be screened yearly. There are few data on these children regarding their risk for uveitis.

View Image

Sequelae of chronic anterior uveitis. Note the posterior synechiae (weblike attachments of the pupillary margin to the anterior lens capsule) of the r....

• References

Polyarticular Juvenile Idiopathic Arthritis

In polyarticular juvenile idiopathic arthritis, 5 or more joints are affected in the first 6 months after disease onset, weight-bearing joints are affected, rheumatoid nodules may be seen in patients with RF-positive disease, and symmetrical involvement of small joints in the hands is often found, as seen in the images below.

View Image

Patient with active polyarticular arthritis. Note swelling (effusions) of all proximal interphalangeal (PIP) joints in addition to boney overgrowth. A....

View Image

Wrist radiographs of the patient with active polyarticular arthritis shown in Media file 2. Note severe loss of cartilage in the intercarpal spaces an....

View Image

Close-up of the proximal interphalangeal (PIP) effusions in the patient with active polyarthritis shown in Media files 2 and 3. Synovial thickening an....

View Image

Patient with inactive polyarticular arthritis. Long-term sequelae of polyarticular disease includes joint subluxation (note both wrists and thumbs), j....

View Image

Hand and wrist radiographs of the patient with inactive polyarticular arthritis shown in Media file 5. Long-term sequelae of polyarticular disease inc....

Decreased extension of the cervical spine is often asymptomatic. It is indicative of arthritis of the cervical spine and can lead to subluxation, typically of the C2 vertebra on C3. Fusion of the posterior elements of the vertebra may occur. (See the image below.)

View Image

Flexion and extension views of C-spine in child with poorly controlled polyarticular juvenile idiopathic arthritis (JIA).

Arthritis of the temporal-mandibular joint (TMJ) may lead to micrognathia. TMJ arthritis is typically asymptomatic; decreased mouth aperture, lateral deviation of the jaw gait, or auscultatory abnormalities over the TMJ are signs of underlying arthritis (see the image below).

View Image

Temporal-mandibular joint (TMJ) MRI postgadolinium infusion. Abnormal increased uptake indicative of synovitis in child with polyarticular juvenile id....

• References

Psoriatic Arthritis

Psoriatic arthritis in children is usually mild. Onset of arthritis precedes that of psoriasis in approximately half of children.

Characteristics of psoriatic arthritis include the following:

• Monoarticular arthritis (50% of children)
• DIP joint involvement (50%)
• Tenosynovitis (30%)
• Nail involvement(71%) - pitting is the most common but least specific finding
• Disordered bone growth with resultant shortening (47%)
• Sacroiliitis (28%)

For further discussion of this disorder, see Psoriatic Arthritis.

• References

Enthesitis-Related Arthritis

Enthesitis-related arthritis, or pediatric spondyloarthropathy, is characterized by periods of inflammation of tendons and ligaments, particularly at the area of insertion into bone (entheses). Often, children and adolescents with spondyloarthropathy present with arthritis, making the distinction between subtypes difficult. Furthermore, children occasionally develop a disease that appears to be a combination of the 2 diseases.

Pain and tenderness at the enthesis is the most common manifestation, but swelling may also be seen. In children, the initial manifestations involve mainly the peripheral joints (eg, dactylitis) with asymmetric oligoarticular arthritis of the lower limbs; axial involvement (eg, sacroiliitis) tends to appear later in the disease course.^[15]

Diagnostic criteria for enthesitis-related JIA are the presence of both arthritis and enthesitis, or the presence of arthritis or enthesitis along with any 2 of the following 5 manifestations^[21] :

• Sacroiliac tenderness and/or inflammatory lumbosacral pain
• Positive human leukocyte antigen B27 (HLA-B27) test
• Onset of arthritis in a male 6 years old or older
• Acute symptomatic anterior uveitis
• Presence in a first-degree relative of ankylosing spondylitis, enthesitis-related arthritis, inflammatory bowel disease with sacroiliitis, reactive arthritis, or acute anterior uveitis

Although enthesitis can be observed in persons with oligoarticular and polyarticular JIA, the eventual development of arthritis into a predominant enthesitis is more characteristic of spondyloarthropathy. The radiographic changes observed in adults (eg, sclerosis of the sacroiliac joints, bamboo spine) are rare in childhood and adolescence.

• References

Undifferentiated Arthritis

Undifferentiated JIA is diagnosed if the patient’s manifestations either do not fulfill the criteria for any one category or fulfill the criteria for more than one.

Most often, children in the latter category fulfill the criteria for polyarticular RF-negative JIA and either enthesitis-related JIA or psoriatic JIA.^[21]

• References

Complications of Disease

Systemic-onset juvenile idiopathic arthritis

The complications that may occur in systemic-onset JIA are pericarditis, hemolytic anemia, macrophage activation syndrome (MAS), and endarteritis. Patients with pericarditis often present with orthopnea and respond to intravenous (IV) corticosteroid treatment.

MAS is a rare, but important, complication, in which all 3 bloodlines become rapidly decreased. Hypofibrinogenemia, thrombocytopenia, and elevated aspartate aminotransferase levels and markedly elevated ferritin levels are hallmarks. Hypotension, central nervous system (CNS) disease, and marked hepatosplenomegaly may be noted as complications of a release of massive amounts of cytokines.

Children with limited arthritis

Complications of oligoarticular JIA and psoriatic arthritis include joint contractures, uveitis, and leg-length discrepancy. Uveitis is almost always asymptomatic and more frequent in young girls who have positive levels of antinuclear antibody. Evaluation with a slit-lamp every 4 months by a pediatric ophthalmologist can detect early disease to prevent permanent eye damage and even blindness.

Leg-length discrepancy may complicate unilateral knee involvement. In young children, it may result from neovascularization of growth plates, so the involved limb is longer. In early puberty, unilateral arthritis can lead to premature fusion of the epiphysis, in which case the short limb is on the affected side. The problem may not be detected in patients with a knee flexion contracture until the contracture is corrected. Both flexion contractures and leg-length discrepancies are much less frequent with early intervention.

Children with widespread arthritis

Complications of polyarticular JIA include skeletal abnormalities such as increased size of epiphyses, accelerated bone age, narrowed joint spaces, swan-neck and/or boutonniere deformities, joint subluxation, and cervical spine involvement.

Difficulty extending the spine may create a problem for intubation prior to surgery, so anesthesiologists need to be informed of the patient's diagnosis. Cervical spine radiography (in flexion and extension) may help to screen for potential difficulties during induction of anesthesia. High-level subluxation is a potential complication.

Enthesitis-related arthritis

Complications of enthesitis-elated arthritis are rare but can include restrictive lung disease and aortic insufficiency. These children are at risk for symptomatic iritis with acute photophobia and conjunctivitis but only rarely does it lead to visual impairment.

• References

Approach Considerations

The diagnosis of juvenile idiopathic arthritis (JIA) is based on the history and physical examination findings. No laboratory studies are diagnostic for JIA, and indeed, all laboratory study findings may be normal in children with this disorder. However, laboratory studies help to exclude other underlying disorders, classify the type of arthritis, and evaluate for extra-articular manifestations of JIA. Imaging of affected joints is usually indicated.

When physical findings do not document definite arthritis, further evaluation is warranted. The choice of studies varies on the basis of the specific circumstances.

Go to Imaging in Juvenile Rheumatoid Arthritis for complete information on this topic.

• References

Inflammatory Markers

The erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) level is usually elevated in children with systemic-onset JIA (with a disproportionate increase in the CRP) and may be elevated in those with polyarticular disease; however, it is often within the reference range in those with oligoarticular disease. When elevated, inflammatory markers can be used to monitor disease activity.

Other markers of inflammation include thrombocytosis, leukocytosis, complement, and, in a reverse fashion, albumin and hemoglobin.

In a study that examined whether the risk of JIA relapse can be identified by biomarkers in the absence of clinical signs of disease activity, Gerss et al found that 35 of 188 patients with JIA experienced a flare within 6 months.^[22] Myeloid-related proteins 8/14 (MRP8/14) and S100A12 levels were significantly higher in subjects who developed flares than in those with stable remission. The best single biomarker for predicting flare was S100A12. Predictive performance of this biomarker may be improved by combining it with high-sensitivity C-reactive protein (CRP).

• References

Complete Blood Count and Metabolic Panel

Lymphopenia is not uncommon because of emigration of activated lymphocytes out of the circulation into synovium. However, neutropenia is uncommon and, particularly with lymphocytosis or thrombocytopenia, raises the possibility of acute lymphocytic leukemia.

A complete blood count, liver function tests (to exclude the possibility of viral or autoimmune hepatitis), and assessment of renal function with serum creatinine levels should be done before starting treatment with nonsteroidal anti-inflammatory drugs (NSAIDs), methotrexate (MTX), or tumor necrosis factor–alpha inhibitors.

• References

Antinuclear Antibody Testing

As many as 70% of children with oligoarticular JIA have positive ANA assays. However, a positive ANA should also raise suspicion of systemic lupus erythematosus (SLE). Overlap between the manifestations of the two disorders may lead to initial misdiagnosis of SLE as JIA.

A positive ANA is a marker for increased risk of anterior uveitis. Children younger than 6 years at arthritis onset with a positive ANA finding are in the highest risk category for development of uveitis and need slit lamp screening every 3-4 months. Titers do not correlate with disease activity.

• References

Additional Laboratory Tests

In systemic-onset JIA, total protein and albumin levels are often decreased during active disease, and fibrinogen, ferritin and D-dimer levels are often elevated. Laboratory results that can help to rule out JIA include angiotensin-converting enzyme (ACE) elevation, which may be indicative of sarcoidosis, and antistreptolysin 0 (AS0) and anti-DNAse B elevations, which may indicate acute rheumatic fever or poststreptococcal arthritis.

Perform a urinalysis to exclude the possibility of infection (as a trigger for JIA or transient postinfectious arthritis). Proteinuria (>0.5 g/d or 3+ positive on dipstick testing) or cellular casts is consistent with renal involvement in SLE.

In patients with systemic-onset JIA, the following test results are indicative of the development of macrophage-activating syndrome (MAS):

• Falling ESR
• Normalization or decrease in white blood cell (WBC) count
• Low platelets
• Elevated liver enzymes
• Increased ferritin
• Increased triglycerides
• Low fibrinogen
• Erratic fevers
• Hemorrhages (disseminated intravascular coagulation–like pattern)

• References

Radiography

When only a single joint is affected, radiography is important to exclude other diseases, such as osteomyelitis. Basic radiographic changes in JIA (see the images below) include the following:

• Soft tissue swelling
• Osteopenia and/or osteoporosis
• Joint-space narrowing
• Bony erosions
• Intra-articular bony ankylosis
• Periosteitis
• Growth disturbances
• Epiphyseal compression fracture
• Joint subluxation
• Synovial cysts

  View Image

  Ankylosis in the cervical spine at several levels due to long-standing juvenile rheumatoid arthritis (also known as juvenile idiopathic arthritis).

  View Image

  Widespread osteopenia, carpal crowding (due to cartilage loss), and several erosions affecting the carpal bones and metacarpal heads in particular in ....

   

  

   

The main limitation of conventional radiography is that it does not allow direct examination of the articular cartilage, synovium, and other important noncalcified structures in a joint.

Go to Imaging in Juvenile Rheumatoid Arthritis for complete information on this topic.

• References

Computed Tomography and Magnetic Resonance Imaging

CT scanning is the best method for analyzing bony abnormalities, but it has been largely superseded by MRI in the overall assessment of JIA. The major disadvantage of CT scanning is that it involves a substantial radiation dose. Perform CT scanning of the long bones when considering osteoid osteoma is suspected.

MRI is helpful when considering trauma in the differential diagnosis. In addition, imaging of the TMJ, sacroiliac joint, cervical spine, midfoot, hip, or shoulder is useful in diagnosing inflammatory arthritis. (See the image below.)

View Image

(A) T2-weighted MRI shows high signal in both hips, which may be due to hip effusions or synovitis. High signal intensity in the left femoral head ind....

MRI provides the most sensitive radiologic indicator of disease activity. The modality can depict synovial hypertrophy, define soft tissue swelling, and demonstrate excellent detail of the status of articular cartilage and overall joint integrity.^{[23, 24, 25, 26, 3, 4, 5, 27, 28]}

To improve visualization of synovial hypertrophy and improve detection of cartilaginous erosions when an inflammatory arthritis is suspected, contrast-enhanced sequences should be performed.

Synovitis and a joint effusion may have similar hyperintensity on T2-weighted (T2W) and short-tau inversion recovery (STIR) images. Therefore, gadolinium-enhanced T1-weighted (T1W) MRIs are necessary to accurately define active synovitis.

Note that gadolinium-based contrast agents (gadopentetate dimeglumine [Magnevist], gadobenate dimeglumine [MultiHance], gadodiamide [Omniscan], gadoversetamide [OptiMARK], gadoteridol [ProHance]) have been linked to the development of nephrogenic systemic fibrosis (NSF) or nephrogenic fibrosing dermopathy (NFD). For more information, see the Medscape Reference topic Nephrogenic Systemic Fibrosis.

Go to Imaging in Juvenile Rheumatoid Arthritis for complete information on this topic.

• References

Ultrasonography

On ultrasonograms, inflamed synovium can appear as an area of mixed echogenicity lining the articular cartilage; the vascularity of the synovium can be assessed with Doppler flow studies. Serial measurements of synovial thickness and effusion volumes have been used to monitor disease progression.^[29] It can be helpful to evaluate joints that are difficult to palpate, such as the hip and shoulder.

Some researchers claim that ultrasonography is more sensitive than plain radiography in the detection of cartilage erosions and effusions. Ultrasound has the advantages of no exposure to ionizing radiation; it can be done in the clinic is an awake, moving child; and it can help guide injections.

Go to Imaging in Juvenile Rheumatoid Arthritis for complete information on this topic.

• References

Nuclear Imaging

Bone scanning, which can be used in the assessment of JIA, is characterized as follows:

• This modality can be used when physical findings do not document definite arthritis.
• It can also be used to identify a potential focus of osteomyelitis, osteoid osteoma or other abnormality.
• Bone scanning is characterized by high sensitivity and low specificity
• It may be combined with single-photon emission CT (SPECT) scanning to increase sensitivity in the 1 or more foci of abnormal isotopic accumulation.
• Bone scintigraphy is primarily used in the determination of the distribution of JIA, but the substantial radiation dose from this modality is a major disadvantage

Go to Imaging in Juvenile Rheumatoid Arthritis for complete information on this topic.

• References

Echocardiography

In a child who has nonspecific rash, adenopathy, and possible mucocutaneous changes, perform echocardiography to exclude coronary arterial dilation resulting from Kawasaki disease. In an individual who has findings suggestive of SLE (eg, nephritis, pleuritic chest pain, thrombocytopenia), perform echocardiography to exclude valvular disease, although mild dilation may be seen in some patients with systemic-onset JIA.

• References

Other Studies and Procedures

Perform dual energy radiographic absorptiometry (DRA) scanning to document osteopenia in children with JIA, especially in children requiring long-term steroids (systemic JIA) or with prolonged widespread arthritis.

Perform arthrocentesis to exclude septic arthritis in a child with monoarticular swelling. Synovial biopsy may be helpful to exclude other diagnoses, particularly when the knee is affected (eg, villonodular synovitis, granulomatous arthritis, foreign body synovitis). Synovial biopsy may reveal synovial infiltration with plasma cells, mature B lymphocytes, and T lymphocytes, with areas of synovial thickening and fibrosis.

Pericardiocentesis is used in an intensive care unit (ICU) setting to treat severe pericarditis.

• References

Approach Considerations

The ultimate goals in managing rheumatoid arthritis are to prevent or control joint damage, to prevent loss of function, and to decrease pain.^[1] These goals are particularly important in juvenile idiopathic arthritis (JIA), in which the rate of progression and the onset of debility can be rapid. JIA is a chronic disease characterized by periods of remission and flare. Treatment is aimed at inducing remission with the least toxicity from medications with hopes of inducing a permanent remission.

The success of therapy is monitored best with repeated physical examinations and history. The number of joints involved and the duration of morning stiffness should demonstrate continued decrease, with elimination reflecting success. Surgery may be indicated in patients who are unresponsive to medical therapy.

A team-based approach can be helpful. Management may include one or all of the following areas:

• Pharmacologic management consisting of nonsteroidal anti-inflammatory drugs (NSAIDs), disease-modifying antirheumatic drugs (DMARDs), biologic agents,^[30] and intra-articular and oral steroids
• Psychosocial factors, including counseling for patients and parents
• School performance, such as academic counseling, school-life adjustments, and physical education adjustments
• Nutrition, particularly to address anemia and generalized osteoporosis; often microcytic, anemia is refractive to treatment with iron
• Physical therapy to relieve pain and to address range of motion, muscle strengthening, activities of daily living, and conditioning exercises
• Occupational therapy, including joint protection, a program to relieve pain, range of motion, and attention to activities of daily living

American College of Rheumatology (ACR) criteria for complete remission are as follows^[1] :

• No inflammatory joint pain
• No morning stiffness
• No fatigue
• No synovitis
• No progression of damage, as determined in sequential radiographic examinations
• No elevation of the erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels

The ACR issued recommendations for the treatment of JIA on the basis of the following 5 treatment groups^[2] :

• History of arthritis in 4 or fewer joints
• History of arthritis in 5 or more joints
• Active sacroiliac arthritis
• Systemic arthritis without active arthritis
• Systemic arthritis with active arthritis

Within each treatment group, choice of therapy is guided by the severity of disease activity and the presence or absence of features indicating a poor prognosis.

In September 2013, the ACR released updated guidelines for the treatment of systemic JIA, which included the medications canakinumab, rilonacept, and tocilizumab.^{[31, 32]} These guidelines include the following treatment recommendations:

• For systemic JIA with active systemic features and varying degrees of synovitis, initial treatment for most patients should consist of anakinra with systemic glucocorticoids
• For systemic JIA without active systemic features and with varying degrees of active synovitis, initial treatment should be methotrexate or leflunomide for an active joint count higher than 4, with a change to abatacept, anakinra, a tumor necrosis factor (TNF)-α inhibitor, or tocilizumab if disease activity continues after 3 months; for patients with 4 or fewer active joints, NSAID monotherapy or intra-articular glucocorticoid injections should be initial treatment
• For systemic JIA with features suggesting macrophage activation syndrome (MAS), initial treatment should include anakinra, a calcineurin inhibitor, or systemic glucocorticoid monotherapy for up to 2 weeks

• References

History of Arthritis in 4 or Fewer Joints

According to ACR guidelines, the treatment group that comprises patients who have developed active arthritis in only 4 or fewer joints total throughout their disease course includes patients in the International League of Associations for Rheumatology (ILAR) categories of persistent oligoarthritis, as well as patients with psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis.^[2]

In this treatment group, escalation of therapy typically proceeds from NSAIDs to intra-articular glucocorticoid injections to methotrexate to TNF-α inhibitors.

NSAIDs alone may be adequate for patients with involvement of a single joint and other indications of low disease activity (eg, normal inflammatory marker levels); response should be evident within 2 months. For other patients, NSAIDs may be used as adjunctive treatment, as needed.

Intra-articular injections of triamcinolone can be used for any joint involved with active arthritis, and should provide clinical relief for at least 4 months. If so, the injections can be repeated as needed.

Methotrexate can be instituted in patients who fail to show adequate response to NSAIDs and/or joint injections. Alternatively, methotrexate is recommended as initial treatment for patients in this treatment group who have high disease activity and features indicating poor prognosis. In patients with enthesitis-related JIA, sulfasalazine rather than methotrexate is recommended for patients who have an inadequate response to joint injection or an adequate trial of NSAIDs.

Patients in this treatment group who fail to respond adequately to joint injections and to 3-6 months (depending on disease characteristics and severity) of methotrexate are candidates for TNF-α treatment. The same is true of patients with enthesitis-related JIA who receive sulfasalazine.

• References

History of Arthritis in 5 or More Joints

This group comprises patients who have developed active arthritis in 5 or more joints total throughout throughout their disease course. Patients need not currently have active involvement in 5 or more joints. According to ACR guidelines, this group includes patients with the ILAR categories of extended oligoarthritis, rheumatoid factor (RF) negative and RF-positive polyarthritis, psoriatic arthritis, enthesitis-related arthritis, and undifferentiated arthritis.^[2]

Treatment in this group places less emphasis on initial NSAIDs. After 1 month of NSAID treatment in patients with low disease activity, or 1-2 months in those with moderate disease activity but without poor prognostic features (ie, hip or cervical spine involvement, positive RF or anti-cyclic citrullinated peptide antibodies (CCP), radiographic signs of joint damage), it is appropriate to escalate to methotrexate, plus adjunctive NSAIDs and joint injection as needed.

In patients with moderate disease activity and poor prognostic features, as well as in patients with high disease activity, treatment may start with methotrexate.

Leflunomide may be used as an alternative to methotrexate, after a failed NSAID trial, or as initial treatment in patients with high disease activity and poor prognostic features.

The US Food and Drug Administration (FDA) has approved the interleukin (IL)-6 inhibitor tocilizumab for the treatment of polyarticular JIA in children 2 years of age and older with active disease. Tocilizumab can be used alone or in combination with methotrexate.^[33]

Escalation to a TNF-α inhibitor follows if 3-6 months (depending on disease characteristics and severity) of methotrexate or leflunomide provides inadequate control. Patients who show inadequate response after 3-4 months (depending on disease characteristics and severity) of TNF-α inhibitor treatment can be switched to a different TNF-α inhibitor or to abatacept. If these agents prove inadequate, patients may be started on rituximab; this agent may be most appropriate in patients with RF-positive polyarticular JIA.

A study confirmed the acceptable long-term tolerability of etanercept and adalimumab treatment in polyarticular juvenile idiopathic arthritis. However, the authors also add that whether the onset of inflammatory bowel disease and uveitis during etanercept monotherapy is a paradoxical effect or an inadequate response to therapy remains unclear and requires further investigation in this growing cohort.^{[34, 35]}

Another study by Horneff et al that included 577 pediatric patients reported a similar safety profile of adalimumab in pediatric patients with polyarticular juvenile idiopathic arthritis, enthesitis-related arthritis, psoriasis, and Crohn disease. The most common adverse events were infections which occurred in 82% of patients with JIA.^[36]

• References

Active Sacroiliac Arthritis

This group includes all patients with clinical and imaging evidence of active sacroiliac arthritis. It may include patients from any of the ILAR JIA categories.^[2]

Use of a TNF-α inhibitor is recommended more readily for patients in this group. A TNF-α inhibitor may be started after failure of an adequate trial of NSAIDs or after 3-6 months (depending on disease characteristics and severity) of methotrexate or sulfasalazine proves inadequate.

• References

Systemic Arthritis with Active Systemic Features and without Active Arthritis

This group includes all patients who fulfill the ILAR criteria for systemic arthritis and who have active fever of systemic JIA with or without other systemic features, but without active arthritis.^[2] A 2-week trials of NSAIDs may be used in patients who have fever and less severe disease, and have had significant active systemic disease for less than 6 months; after that, patients should be started on systemic glucocorticoids, with adjunct NSAIDs as needed.

Patients with high systemic disease activity (eg, significant serositis) may be started on steroids as a first step. There is virtually no published evidence regarding steroid doses or administration routes in this setting.

Patients who sustain or develop active fever while on systemic steroid therapy can be started on anakinra. This agent may be a first choice in patients who have had significant active systemic disease for at least 6 months.

The FDA has approved tocilizumab for the treatment of systemic JIA. Clinical trials in children with JIA showed significantly fewer disease flares when treated with tocilizumab compared with placebo (26% vs 48%). Additionally, a higher success rate of steroid reduction/discontinuance was achieved in the tocilizumab group (24%) compared with placebo (3%).^[37]

The phase III TENDER study demonstrated that tocilizumab was effective in improving the signs and symptoms of systemic JIA. After 3 months of treatment, 85% of participants who took tocilizumab had a 30% improvement (JIA ACR30+) in the signs and symptoms of systemic JIA and absence of fever, compared with 24% of patients who received placebo.

Further data showed 70% of patients on tocilizumab achieved JIA ACR70+ and 37% achieved JIA ACR90+, compared with 8% and 5% of patients who received placebo, respectively. Additionally, nearly two-thirds of patients in the study were free of rash after 3 months. In this study, the safety profile similar to adults treated with tocilizumab for rheumatoid arthritis.^[38]

The interleukin-1 β inhibitor canakinumab has also been FDA-approved for systemic JIA.^[39] In the beta-SPECIFIC 1 trial, 84% of patients with SJIA treated with canakinumab experienced at least a 30% improvement in symptoms compared with 10% in the placebo group after 15 days of treatment (P< 0.001).^[40]

In the open-label beta-SPECIFIC 2 trial, 45% of canakinumab-treated patients who were prescribed corticosteroids were able to reduce steroid use, and one-third of patients completely discontinued corticosteroids. Additionally, the canakinumab-treated patients were nearly 3 times less likely to experience a new flare, with 74% remaining flare-free compared to 25% with placebo (P = 0.003).^[40]

• References

Systemic Arthritis with Active Arthritis and without Active Systemic Features

This category includes all patients who fulfill the ILAR criteria for systemic arthritis and who have active arthritis, but who do not have active systemic features.^[2] Most of these patients are started on NSAIDs while their diagnostic assessment progresses.

NSAID therapy, with intra-articular joint injections as needed, may be adequate for patients with low disease activity who do not have hip involvement or radiographic signs of joint damage. After up to 1 month, however, methotrexate can be added for patients with any degree of disease severity who continue to have active arthritis.

After 3 months of methotrexate therapy, the next step in escalation is to anakinra or a TNF-α inhibitor, although etanercept is less effective in systemic arthritis than in other forms of JIA.^[41] Patients who show inadequate response to TNF-α inhibitor treatment can be started on abatacept.

• References

Hospital Admission

Inpatient care is required for persisting fevers of unknown origin or when children with known JIA have severe exacerbation of disease.

Admit for evaluation any child who loses the ability to walk for unknown reasons.

The development of pericarditis in children with systemic-onset JIA is usually an indication for admission.

• References

Exercise and Other Nonpharmacologic Therapy

Exercise preserves joint range of motion and muscular strength, and it protects joint integrity by providing better shock absorption. Types of exercises that may be advised include a muscle-strengthening program, range-of-motion activity, stretching of deformities, and endurance and recreational exercises. Hydrotherapy is a good form of exercise that helps achieve the aforementioned objectives.

Rarely, children require splinting or serial casting to help decrease contractures in joints unresponsive to medical treatment.

Leg-length discrepancy can result from neovascularization of growth plates of an affected knee. The problem may not be detected in patients with a knee flexion contracture until the contracture is corrected. Treatment consists of a shoe lift on the contralateral side.

In a single-blind, randomized, controlled trial involving 60 children with JIA, Coda and colleagues found that the use of inexpensive prefabricated fitted foot orthoses reduced pain and improved quality of life compared with use of sham orthoses. Changes in pain were measured with a visual analogue scale and quality of life was measured with the Pediatric Quality of Life questionnaire. The study included 60 children with lower joint involvement beginning at age 5-18 years, previous failure of orthotic management with no use of orthoses for at least 3 months, the ability to walk 15 meters without assistive devices, and a 6-month history of disease-modifying antirheumatic drugs. At 3- and 6-month follow-ups, children in the fitted orthoses group experienced significantly greater pain reduction and improvements in quality of life than controls.^[42]

• References

Surgical Treatment

Advances in medical treatment have reduced the need for surgical intervention in JIA. Possible procedures include synovectomy, osteotomy and arthrodesis, and hip and knee replacement.

Synovectomy

Synovectomy is rarely needed, and long-term outcome is poor; however, it may be used in children in whom a single joint or just a few joints are involved and who have very active, proliferative synovitis.

Osteotomy and arthrodesis

Osteotomy and arthrodesis are salvage procedures for patients whose JIA is associated with severe joint destruction or deformity.

Arthrodesis is superior to arthroplasty for children who have rheumatic disease in the wrist and fingers and in the ankle.

Total hip and total knee replacements

Total hip and knee replacements provide excellent relief of pain and restore function in a functionally disabled child with debilitating disease.

The role of total hip replacement and total knee replacement in JIA is fraught with problems, however. Joint replacement is usually delayed until bone growth has completed, as indicated by epiphyseal closure.

• References

Treatment of Macrophage Activation Syndrome

MAS) is a rare but important complication of systemic-onset JIA in which numbers of all 3 bloodlines become rapidly decreased. Hypofibrinogenemia, thrombocytopenia, and elevated aspartate aminotransferase levels are hallmarks.

MAS often responds to cyclosporin A, and some case reports have detailed a response to anakinra. Treatment of MAS is a medical emergency and should be performed by physicians familiar with this complication.

• References

Treatment of Uveitis

Uveitis is often asymptomatic. Patients are typically young girls who have positive levels of ANA.

Treatment with topical corticosteroid medication and with mydriatic agents (to prevent closed-angle glaucoma) often can prevent progression of disease to development of calcium deposition in the lens (band keratopathy) and adhesions of the iris to the lens (posterior synechiae), in which an irregular pupillary margin develops. Such complications may herald a chronic active disease in which vision is threatened.

Immunosuppressive agents, such as methotrexate or cyclosporine, may help control chronic uveitis. Infliximab can be effective in some patients who are resistant to immunosuppressive agents.^[43]

A multicenter, double-blind, randomized, placebo-controlled trial by Ramanan et al reported that adalimumab plus methotrexate therapy controlled inflammation and was associated with a lower rate of treatment failure than placebo among children and adolescents with active JIA-associated uveitis. The study observed 16 treatment failures out of 60 patients (27%) in the adalimumab group compared to 18 treatment failures in 30 patients (60%) in the placebo group (hazard ratio, 0.25; 95% confidence interval [CI], 0.12 to 0.49; P< 0.0001). The study also reported a higher rate of adverse events (eg, oropharyngeal pain, cough, arthralgia) in the adalimumab group (10.07 events per patient-year vs. 6.51 events per patient-year) as well as a higher rate of serious adverse events (eg, infections or infestations [0.29 events per patient-year vs. 0.19 events per patient-year]).^[44]

• References

Diet and Activity

No specific diet helps in the treatment of JIA. However, because active JIA has been associated with decreased osteoblastic activity and a risk of osteopenia, encourage the inclusion of at least 3 servings of calcium-rich foods each day. Consider supplementation when poor calcium intake persists. Rarely, overall caloric intake is poor and supplementation is required. TMJ disease may also compromise the child’s diet.

Encourage patients to be as active as possible. Bed rest is not a part of the treatment. In fact, the more active the patient, the better the long-term prognosis. Children may experience increased pain during routine physical activities. As a result, these children must be allowed to self-limit their activities, particularly during physical education classes. A consistent physical therapy program, with attention to stretching exercises, pain modalities, joint protection, and home exercises, can help ensure that patients are as active as possible.

• References

Consultations

Referral to a pediatric rheumatologist may be indicated when the diagnosis is unclear, when information on diagnostic evaluation and long-term management is needed, or because the family requires information from a subspecialist to cope with the patient's disease process, to accept the treatment plan, to allay anxiety, and/or to receive education.^[45]

In addition to a pediatric rheumatologist (when available), the subspecialty team may include a nurse, physical and occupational therapists, social worker, ophthalmologist, and orthopedic surgeon. A nurse may provide patient education through nursing care.

Although at presentation, arthritis may be so active as to preclude the use of an aggressive program of muscle strengthening, physical and occupational therapists are an important part of treatment. The use of pain modalities during this period may permit the gradual introduction of an active program of exercises and stretching.

Social work evaluation helps to determine how well each family is coping with their child's disease in terms of emotional and financial resources. Social workers can offer invaluable guidance that helps children maintain healthy relationships within their families and at school. Transition programs for adolescents with arthritis can help to prepare them for higher education and vocation.

A pediatric ophthalmologist provides slit-lamp examinations to exclude uveitis, and a pediatric orthopedic surgeon is essential when orthopedic diagnoses are being considered.

The spectrum of specialists may be required such as pediatric hematologist for evaluation for malignancy or a pediatric gastroenterologist if inflammatory bowel disease is suspected.

• References

Long-Term Monitoring

A complete blood cell count and measurement of liver enzymes and serum creatinine should be part of routine follow-up in JIA patients. For JIA patients receiving NSAIDs on a long-term daily basis, these tests, plus urinalysis, should be done twice yearly; in patients taking these agents 3-4 days per week, testing should be repeated annually.

In JIA patients taking methotrexate, these tests should be conducted approximately 1 month after initiation of routine use and approximately 1-2 months after any increase in dose. If prior results were normal and the patient is on a stable dose, the tests can be repeated approximately every 3-4 months.

In JIA patients taking TNF inhibitors, these tests should be repeated approximately every 3-6 months. Tuberculosis screening should be repeated approximately once yearly.

• References

Medication Summary

Optimal care of patients with juvenile idiopathic arthritis (JIA) requires an integrated approach of nonpharmacologic and pharmacologic therapies. Classes of medications used include disease-modifying antirheumatic drugs (DMARDs), biologicals, NSAIDs, and corticosteroids.

• References

Meloxicam (Mobic)

• Dosing, Interactions, etc.

Clinical Context:  Meloxicam is a member of the enolic class of NSAIDs and is structurally related to piroxicam. The pediatric dosage is 0.125 mg/kg/d for patients aged 2 years or older, up to 7.5 mg qd.

• References

Naproxen (Aleve, Naprelan, Naprosyn)

• Dosing, Interactions, etc.

Clinical Context:  Naproxen is used for analgesic and anti-inflammatory properties, treating arthralgia and arthritis. It inhibits inflammatory reactions and pain by decreasing activity of cyclooxygenase, which is responsible for prostaglandin synthesis. The pediatric dosage is 7-20 mg/kg/d PO divided bid/tid, not to exceed 1 g/d

• References

Ibuprofen (Advil, Motrin)

• Dosing, Interactions, etc.

Clinical Context:  Ibuprofen inhibits inflammatory reactions and pain by decreasing prostaglandin synthesis. The adult dosage is 400 mg PO q4-6h, 600 mg q6h, or 800 mg q8h while symptoms persist, not to exceed 3.2 g/d; the pediatric dosage is 30-50 mg/kg/d PO divided qid, not to exceed 2.4 g/d.

• References

Diclofenac (Voltaren, Cataflam)

• Dosing, Interactions, etc.

Clinical Context:  This is one of a series of phenylacetic acids that has demonstrated anti-inflammatory and analgesic properties in pharmacological studies. It is believed to inhibit the enzyme cyclooxygenase, which is essential in the biosynthesis of prostaglandins. Diclofenac can cause hepatotoxicity; hence, liver enzymes should be monitored in the first 8 weeks of treatment. It is absorbed rapidly; metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. The delayed-release, enteric-coated form is diclofenac sodium, and the immediate-release form is diclofenac potassium.

• References

Celecoxib (Celebrex)

• Dosing, Interactions, etc.

Clinical Context:  Celecoxib inhibits primarily COX-2. Inhibition of COX-1 may contribute to NSAID GI toxicity. At therapeutic concentrations, COX-1 isoenzyme is not inhibited; thus, incidence of GI toxicity, such as endoscopic peptic ulcers, bleeding ulcers, perforations, and obstructions, may be decreased when compared with nonselective NSAIDs.

Seek the lowest dose for each patient. The adult dosage is 100-200 mg PO bid; the pediatric dosage has not been established for patients younger than 2 years, is 50 mg PO bid for patients 2 years or older whose weight is ≥10 kg to ≤25 kg, and is 100 mg PO bid for patients 2 years or older whose weight is greater than 25 kg.

• References

Tolmetin (Tolectin)

• Dosing, Interactions, etc.

Clinical Context:  Tolmetin inhibits prostaglandin synthesis by decreasing the activity of the enzyme cyclooxygenase, which in turn decreases formation of prostaglandin precursors. The pediatric dosage is 20 mg/kg/d PO divided tid/qid initially, then 15-30 mg/kg/d, not to exceed 30 mg/kg/d

• References

Indomethacin (Indocin)

• Dosing, Interactions, etc.

Clinical Context:  Indomethacin is rapidly absorbed, and metabolism occurs in the liver by demethylation, deacetylation, and glucuronide conjugation. It inhibits prostaglandin synthesis. The adult dosage is 25-50 mg PO bid/tid, not to exceed 200 mg/d, and the ER product may be administered qd or bid; the pediatric dosage is 1-2 mg/kg/d PO divided bid/qid, not to exceed 4 mg/kg/d or 150-200 mg/d

• References

Class Summary

Nonsteroidal anti-inflammatory drugs (NSAIDs) interfere with prostaglandin synthesis through inhibition of the enzyme cyclooxygenase (COX), thus reducing swelling and pain. NSAIDs are used to treat all subtypes of JIA. They may help with pain and decrease swelling. Commonly used NSAIDs include naproxen, ibuprofen, tolmetin, diclofenac, and indomethacin.

Aspirin is no longer the drug of first choice because of the increased frequency of gastric toxicity and hepatotoxicity when compared to other NSAID medications. The cyclooxygenase 2 (COX-2) inhibitor celecoxib (Celebrex) may have a role in treatment when a bleeding diathesis is a potential problem.

Several dozen NSAIDs are available and can be classified into different groups of compounds. Commonly used NSAIDs include ibuprofen, naproxen, ketoprofen, piroxicam, and diclofenac. Predicting which patient will respond to a particular NSAID is not possible and many children who do not respond to one may benefit by changing to a different NSAID. Indomethacin is particularly effective for fever and pericarditis and is usually preferred for children with active systemic JIA.

• References

Sulfasalazine (Azulfidine, EN-tabs)

• Dosing, Interactions, etc.

Clinical Context:  Sulfasalazine decreases the inflammatory response and systemically inhibits prostaglandin synthesis. The pediatric dosage has not been established for patients younger than 6 years; for patients 6 years or older, the typical dose range is 30-50 mg/kg/d; to lessen GI irritation, start at one half to one third of maintenance dose, increasing the dose weekly, not to exceed 2 g/d.

• References

Methotrexate (Rheumatrex, Trexall)

• Dosing, Interactions, etc.

Clinical Context:  Methotrexate has an unknown mechanism of action in the treatment of inflammatory reactions; it may affect immune function. It ameliorates symptoms of inflammation (eg, pain, swelling, stiffness). Adjust the dose gradually to attain a satisfactory response. Consider SC route for patients who do not respond to PO methotrexate or who have GI intolerance to PO dosing.

The pediatric dosage is 10-25 mg/m2/wk PO/IM/SC as a single dose or divided into 2 doses weekly; many pediatric rheumatologists increase the dose (not to exceed 30 mg/m2, approximately equivalent to 1 mg/kg); administer with folic acid 1-2 mg PO qd or folinic acid 2.5-5 mg PO qwk

• References

Class Summary

Disease-modifying antirheumatic drugs (DMARDs) can retard or prevent disease progression and, thus, joint destruction and subsequent loss of function. Successful DMARD therapy may eliminate the need for other anti-inflammatory or analgesic medications; however, until the full action of DMARDs takes effect, anti-inflammatory or analgesic medications may be required as bridging therapy to reduce pain and swelling.

• References

Methylprednisolone (Solu-Medrol, Medrol, A-Methapred)

• Dosing, Interactions, etc.

Clinical Context:  Methylprednisolone decreases inflammation by suppressing migration of polymorphonuclear leukocytes and reversing increased capillary permeability. It is used temporarily for JIA until longer-term treatment provides effective relief. The pediatric dosage is 15-30 mg/kg IV qd administered over 30-60 min for 2-3 d.

• References

Prednisone

• Dosing, Interactions, etc.

Clinical Context:  Prednisone is an immunosuppressant for treatment of JIA. It may decrease inflammation by reversing increased capillary permeability and suppressing polymorphonuclear neutrophil (PMN) activity, and it stabilizes lysosomal membranes and also suppresses lymphocytes and antibody production. The pediatric dosage is 4-5 mg/m2/d PO; alternatively, the dosage is 0.05-2 mg/kg PO divided bid/qid; taper over 2 wk as symptoms resolve and other antirheumatic drugs take effect.

• References

Triamcinolone (Aristospan, Kenalog)

• Dosing, Interactions, etc.

Clinical Context:  Triamcinolone decreases inflammation by suppressing the migration of polymorphonuclear leukocytes and reversing capillary permeability.

• References

Class Summary

Corticosteroids are potent anti-inflammatory drugs used in patients with JIA to bridge the time until DMARDs are effective. Adverse events associated with long-term steroid use make dose reductions and cessation important in due course.

• References

Adalimumab (Amjevita, Cyltezo, Humira, Hadlima, Hyrimoz, Adalimumab-atto, Adalimumab-adbm, Adalimumab-bwwd, Adalimumab-adaz)

• Dosing, Interactions, etc.

Clinical Context:  Adalimumab is a recombinant human IgG1 monoclonal antibody that is specific for human TNF. It reduces inflammation and inhibits progression of structural damage. The pediatric dosage has not been established for patients younger than 2 years for Humira. FDA approved adalimumab-atto, adalimumab-adbm, adalimumab-adaz, adalimumab-bwwd for patients 4 years or older, as biosimilars and not as interchangeable drugs.

• References

Etanercept (Enbrel)

• Dosing, Interactions, etc.

Clinical Context:  Etanercept acts by binding and inhibiting TNF, a cytokine that contributes to inflammatory and immune response. The pediatric dosage is not established for patients younger than 4 years. For patients 4-17 years, the dosage is 0.4 mg/kg SC 2 times weekly (administered at least 72-96 h apart), not to exceed 25 mg/dose. For patients older than 17 years, the dosage is administered as in adults.

• References

Abatacept (Orencia)

• Dosing, Interactions, etc.

Clinical Context:  Abatacept is a selective costimulation modulator that inhibits T-cell activation by binding to CD80 and CED86, thereby blocking CD28 interaction. It is indicated for reducing signs and symptoms of RA, slowing progression of structural damage and improving physical function in adults with moderate-to-severe RA who have inadequate response to DMARDs, MTX, or TNF antagonists. It is not recommended for concomitant use with anakinra because of insufficient experience.

The pediatric dosage is not established for patients younger than 6 years. For pediatric patients 6-17 years, the dosage is according to body weight, and the drug is administered on days 1, 15, and 29, then q4wk thereafter; infuse IV over 30 min. For pediatric patients less than or equal to 74 kg, use 10 mg/kg IV; for pediatric patients 75-100 kg, use 750 mg IV; and for pediatric patients heavier than 100 kg, use 1000 mg IV.

• References

Anakinra (Kineret)

• Dosing, Interactions, etc.

Clinical Context:  Anakinra competitively and selectively inhibits IL-1 binding to type I receptor (IL-1RI). By blocking IL-1 binding, inflammation and pain associated with rheumatoid arthritis are inhibited. It is indicated for rheumatoid arthritis in patients who have failed 1 or more DMARDs. The dose should be administered at approximately the same time every day. The adult dosage is 100 mg SC qd; the pediatric dosage has not been established.

• References

Tocilizumab (Actemra)

• Dosing, Interactions, etc.

Clinical Context:  Tocilizumab is an IL-6 receptor antagonist that inhibits IL-6 mediated signaling that results in decreased inflammatory cytokine production. It is indicated for systemic JIA and PJIA. The safety and efficacy of tocilizumab has not been established in patients younger than 2 years old.

• References

Canakinumab (Ilaris)

• Dosing, Interactions, etc.

Clinical Context:  Canakinumab is recombinant, human monoclonal antibody that inhibits interleukin-beta1.

• References

Class Summary

The recognition of tumor necrosis factor-alpha (TNF-alpha) and interleukin (IL)–1 as central proinflammatory cytokines has led to the development of agents that block these cytokines or their effects. In addition to improving signs and symptoms and quality of life, all biologic agents significantly retard radiographic progression of joint erosions. The TNF blockers, which bind TNF and thus prevent its interaction with its receptors, include etanercept, infliximab, and adalimumab. Consensus statements do not recommend their use until at least one xenobiotic DMARD, usually methotrexate (MTX), has been administered without sufficient success, although one study reported better results with etanercept in patients with less disability and when used before methotrexate.^[41]

Adverse effects associated with the biologic agents include the generation of antibodies against these compounds, emergence of antinuclear antibodies, occasional drug-induced lupuslike syndromes, and infections. Rarely, demyelinating disorders and bone marrow suppression occur. Acute and chronic infections, demyelinating disorders, class 3 or 4 heart failure, and recent malignancies are contraindications for TNF blockers. Thoroughly searching for latent tuberculosis using chest radiography and/or purified protein derivative (PPD) testing is recommended before these agents are started.^[46]

• References