Offering a comprehensive review of this condition, this author examines the various subtypes of juvenile idiopathic arthritis, identifies pertinent clinical characteristics and discusses current treatment approaches.

Juvenile idiopathic arthritis (JIA) is the most common rheumatic disorder in children. It is defined as persistent arthritis for more than six weeks with an onset occurring in patients younger than 16 years of age. Early recognition and treatment of JIA is essential in order to prevent irreversible joint damage. Childhood disease is both distinct and comparable to adult onset arthritis and children have benefited from the remarkable progress that has been made over the last 10 to 15 years in the management of chronic arthritis.

Juvenile idiopathic arthritis is the preferred term now for a group of disorders previously called juvenile rheumatoid arthritis (JRA). The International League of Associations for Rheumatology (ILAR) established a new classification system to accompany the change in nomenclature. These changes were needed to further enhance homogeneity and delineate mutually exclusive categories.

Patients with systemic JIA may have a temporary rash that often occurs at the time of fever. The rash is polymorphic and patchy. It is primarily central in location, favoring the medial upper arms and thighs.

The ILAR classification system for JIA includes the following seven subtypes of JIA: systemic; oligoarticular; polyarticular rheumatoid factor negative; polyarticular rheumatoid factor positive; enthesitis-related arthritis; psoriatic arthritis; and undifferentiated or other arthritis. Clinicians can differentiate and recognize the various subtypes based upon the clinical characteristics that emerge during the first six months of disease.

What You Should Know About Systemic JIA

Systemic JIA is characterized by significant extraarticular manifestations such as fever, rash, hepatosplenomegaly, lymphadenopathy and serositis, predominantly pericardial or pleural. Initially, some of these children may just experience extraarticular manifestations with subsequent development of arthritis several months later. These children appear very ill. However, when they are between febrile episodes, they are often well and asymptomatic.

The characteristic fever pattern usually includes two daily peaks. This double quotidian fever is quite suggestive of systemic JIA. These patients may have a temporary rash that often occurs at the time of fever. The rash is polymorphic and patchy, and is primarily central in location, favoring the medial upper arms and thighs. Some lesions have a linear quality known as the Koebner phenomenon, which is likely elicited when the child scratches the skin. The rash is not pruritic.

Arthritis usually has a polyarticular distribution that involves both the large and small joints. However, a small percentage of children may have an oligoarticular pattern. Laboratory assessment shows extremely elevated acute phase reactants with the erythrocyte sedimentation rate (ESR) often being more than 100 mm/hour. A multifactorial anemia develops rather quickly with the hemoglobin approaching 7 to 8 g/dl within three to four weeks after onset. Leukocytosis is universal and most children also have a significant thrombocytosis. Sometimes, one may also note mild transaminase elevations. Both the antinuclear antibody (ANA) and rheumatoid factor are negative.

A Note About Undifferentiated Arthritis

- In spite of the recent improvements in the classification of children with chronic arthritis, a certain percentage still remain unclassified during the first six months of disease and remain so for several years after. This is called undifferentiated or other arthritis. By definition, children with conditions in this category of undifferentiated or other arthritis do not fulfill the criteria for any subtype or fit into two or more subtypes. Future clinical, epidemiologic and genetic studies hopefully will further clarify this group in the future.

However, a rare, life-threatening complication of systemic JIA is the macrophage activation syndrome. Macrophages, particularly those in the bone marrow, ingest multiple blood elements leading to leucopenia, further anemia and thrombocytopenia. Macrophage activation syndrome is accompanied by multiple organ dysfunction including hepatopathy and encephalopathy. Additional laboratory findings include significant elevation of blood ferritin, d-dimer levels, and hypertriglyceridemia. The most common trigger appears to be intercurrent infection but this may be caused by certain medications as well. The etiology is unclear but the pathogenesis appears to be the dysfunction of natural killer cells (NK cells).

While the course of systemic onset JIA is variable, up to 40 percent of children develop aggressive and destructive polyarthritis. Systemic features most often remit but some children exhibit continued episodes of fever and rash many years after the onset of disease. This is the only subtype of juvenile idiopathic arthritis in which mortality may occur. In Europe, there is a higher prevalence of amyloidosis in those children with recurrent active inflammatory disease whereas in the United States, mortality is most often associated with the macrophage activation syndrome.

A Closer Look At Oligoarticular JIA

Oligoarticular JIA is defined as arthritis in four joints or less during the first six months of disease. The most commonly involved joints are the knees, ankles and elbows. However, the most frequent presentation is monoarticular, which occurs in up to 50 percent of children. Morning stiffness is common and joint contractures tend to appear reasonably quickly in spite of limited discomfort.

Chronic uveitis develops in approximately 20 percent of children with oligoarticular JIA. This variety of oligoarticular JIA tends to be more prevalent among younger females. One may note a positive ANA in up to 50 percent of patients with oligoarticular JIA and at an even higher percentage among children who develop chronic uveitis. After six months of disease, some children experience swelling in additional joints and their conditions are subsequently reclassified as extended oligoarticular JIA.

Usually, acute phase reactants are only mildly elevated with the sedimentation rate ranging from 25 to 40 mm/hour among children with oligoarticular JIA. However, be aware that sedimentation rate and c-reactive protein are normal in some children.

Here one can notice polyarticular rheumatoid factor negative JIA. This patient has bilateral knee and ankle arthritis.

The prognosis for oligoarticular JIA is generally favorable with up to 50 percent of children having complete remission. Those children with extended oligoarticular JIA are less likely to have a lasting remission.

A Guide To Key Characteristics Of Polyarticular JIA

Polyarticular JIA involves five or more joints, often presents in a symmetrical fashion and occurs during the first six months of disease. This subtype is further divided into rheumatoid factor negative and rheumatoid factor positive subgroups. Both of these subgroups seem to occur three to five times more often among females.

Children with rheumatoid factor negative polyarticular JIA usually present early in childhood whereas the rheumatoid factor positive conditions often occur during the early teenage years. Rheumatoid factor positivity (two positive tests at least three months apart during the first six months of disease) is a marker for a more aggressive disease course that is sometimes accompanied by rheumatoid nodules.

The evolution of erosive joint disease is common. Both rheumatoid factor negative and positive children may develop chronic uveitis but usually at a much lower rate (~10 percent) than the oligoarticular JIA group. Symmetric involvement of both large and small joints is common as is involvement of the the cervical spine and temporomandibular joints. One will note moderately elevated acute phase reactants among these patients. The sedimentation rate often reaches 50 mm/hour but rarely climbs up to 100 mm/hour. Between 30 to 40 percent of these children may also have a positive ANA.

Getting A Handle On Enthesitis-Related Arthritis

Enthesitis-related arthritis is more diverse and includes children with evolving ankylosing spondylitis, reactive arthritis and undifferentiated spondyloarthropathy. Peripheral arthritis is often asymmetric and often involves the joints of the lower extremities. Isolated hip disease may occur and one may sometimes note intertarsal joint inflammation. Spine changes are a relatively late finding in the course of the disease but clinicians may see sacroiliac inflammation earlier.

Enthesitis, which is defined as inflammatory changes at the sites of attachment of tendons, ligaments and fascia to bone, is characteristic and clinicians most commonly see this at the insertion of the Achilles tendon and at sites of plantar fascial insertion. These children are often males and have a high frequency of the HLA-B27 antigen. They will have a negative ANA and rheumatoid factor. There are usually increased indices of inflammation along with a mild leukocytosis and anemia.

Extraarticular manifestations may include uveitis, low-grade fever and aortic insufficiency. The uveitis is acute and characterized by a painful, red and photophobic eye.

When Psoriatic Arthritis Occurs In The Pediatric Population

Psoriatic arthritis most often presents in children from 6 to 11 years of age. Arthritis may develop before the evolution of the typical skin changes of psoriasis. This makes it more difficult to diagnose psoriatic arthritis early in its course since it resembles oligoarticular JIA.

In regard to patients with psoriatic arthritis, the involvement at onset is often asymmetric with a small number of joints affected. An asymmetric, polyarticular pattern is the most common long-term manifestation. Dactylitis is common as well. Nail pits occur in up to one-third of children with psoriatic arthritis and a few of these patients may have onycholysis. Clinicians may also note the development of chronic uveitis, similar to that which one might see with oligoarticular JIA.

Here one can see polyarticular rheumatoid factor positive JIA. Note the severe destructive changes of the wrist with subluxation of the radius and carpal bones.

One will note mildly elevated acute phase reactants along with a slight thrombocytosis. While the rheumatoid factor is negative, the ANA may be positive in 30 to 60 percent of children with this condition. The course is variable but some children have progressive disease.

Key Insights For Managing Systemic JIA

The goals of JIA therapy include maintaining normal growth and development, controlling pain and preserving normal joint function. Prompt referral to a physical or occupational therapist or both is essential to maintain range of motion and muscle strength. Night splints are encouraged when clinicians note joint contractures. One should encourage the patient’s family to maintain a regular home physical therapy/occupational therapy regimen between visits to the physical therapist.

Pharmacologic choices for management have expanded significantly during the last 10 to 15 years. Management decisions are guided by the disease subtype, the onset of the condition and the clinical interpretation of articular changes. With this in mind, let us consider the current concepts in treating the various forms of JIA.

Systemic JIA is the most problematic condition to manage. Systemic features often do not respond initially to non-steroidal antiinflammatory medications (NSAIDs). One often needs to administer corticosteroids intravenously or as a daily or alternate day oral dosage. Progressive polyarthritis develops in more than half of these children but methotrexate and anti-TNF inhibitors appear to be less effective in suppressing systemic JIA than in the other subtypes of JIA. There may be some benefits for the systemic features with intravenous gamma globulin (IVIG) but this treatment is expensive and requires a lengthy intravenous infusion every two to four weeks.

Other hopeful therapeutic agents for systemic onset JIA include thalidomide and several anti IL-1 (interleukin 1) agents. The anti IL-6 (interleukin 6) receptor antibody also shows great promise but currently remains under clinical investigation.

Clinicians have treated severe systemic JIA with various combinations of methotrexate, intravenous corticosteroids and intravenous cyclophosphamide. The evolution of macro-phage activation syndrome is a true emergency and requires high doses of corticosteroids with the addition of cyclosporine if there is an inadequate early response.

How To Address Oligoarticular JIA

Initial management of oligoarticular JIA includes NSAID medications such as naproxen, tolmetin sodium and ibuprofen, which are formally approved for the treatment of JIA. One may also use other non-steroidal agents such as diclofenac or nabumetone. Clinicians often make these choices based on the availability of liquid or long-acting preparations and each child’s tolerance.

Indomethacin is a very potent antiinflammatory medication that is sometimes effective in managing systemic JIA. However, this nonsteroidal agent has a somewhat increased gastrointestinal toxicity profile and also may cause headaches. Naproxen is currently the most popular medication due to its twice daily dosing and the availability of a liquid preparation. However, fair-skinned children may develop a photosensitive rash leading to heightened skin fragility and scarring, particularly over the face.

Additional or alternative therapy for oligoarticular JIA includes the use of intraarticular corticosteroids. Indeed, one intraarticular injection may be curative in a child with involvement of a single large joint. If there is persistent synovitis after treatment with both non-steroidal medications and intraarticular therapy, one should consider further management with methotrexate. However, it is not common to require remissive agents for the management of oligoarticular JIA.

Pertinent Treatment Tips For Polyarticular JIA

One would initially manage polyarticular rheumatoid factor negative JIA with NSAID medications. However, if you have not achieved symptom control after four to eight weeks, proceed to initiate methotrexate at a dose of 10 mg/m each week and increase it to a maximum of 15 mg/m. At the higher dose range, methotrexate is more effective with parenteral administration. If articular disease is only partially controlled but does not seem to be particularly progressive, one may use sulfasalazine prior to methotrexate. Leflunomide is an alternative therapeutic choice although it is not yet formerly approved for use in treating children. A recent large study of leflunomide demonstrated comparable benefits to methotrexate.

This patient has psoriatic arthritis and dactylitis of the second, third and fourth digits.

One may also employ intraarticular corticosteroid injections for selectively affected large or small joints. Clinicians may use short courses of oral corticosteroids to treat acute flares or as a bridging therapy for initiating additional agents. The anti-TNF agent etanercept is approved for use in treating children with polyarticular JIA and one may add this to or substitute it for methotrexate. Other anti-TNF agents such as infliximab or adalimumab are currently under investigation in the treatment of this condition. In several uncontrolled studies, infliximab has shown equal efficacy to etanercept.

Children presenting with polyarticular rheumatoid factor positive JIA have a close clinical presentation to adult rheumatoid arthritis and most often require more aggressive therapy at the onset. In these cases, one would start methotrexate very early and adding anti-TNF agents is often necessary. Combination therapy has been effective in treating adult rheumatoid arthritis but has not been adequately studied in treating children. However, a combination of etanercept and methotrexate appears to be safe.

What About Treating Enthesitis-Related Arthritis And Psoriatic Arthritis?

Clinicians would initially treat enthesitis-related arthritis with NSAID medications. Indomethacin appears to be quite effective and is likely the most effective NSAID agent for this category of JIA. Non-controlled studies also indicate that sulfasalazine offers significant therapeutic benefit. One may add methotrexate but there are also no controlled studies available. Early experience indicates that anti-TNF agents are effective in refractory cases.

When it comes to psoriatic arthritis, there are no treatment efficacy studies for this condition in children. Since the disease expression may be oligoarticular or polyarticular, one should tailor treatment to these presentations. Research has shown that both methotrexate and anti-TNF agents are effective for treating psoriatic arthritis in adults.

Addressing Other Key Clinical Considerations

Growth delay. Children with oligoarticular JIA may develop a localized bone disturbance characterized by early, accelerated bone growth and subsequent premature epiphyseal closure at the affected joint. This phenomenon occurs often with arthritis of the knee. Intraarticular corticosteroid injections appear to be effective in limiting the consequences of localized disturbances of bone growth. Keep in mind that mandibular growth may be affected by polyarticular JIA and can lead to micrognathia.

Generalized growth retardation is common in patients with both polyarticular and systemic JIA. This growth reduction is accentuated by systemic corticosteroids, particularly at doses of more than 0.3 mg/kg/day. Growth hormones may be effective in limiting growth retardation in some severely affected children.
Osteoporosis. Children with significant JIA, particularly those who require treatment corticosteroids, are at increased risk for both osteoporosis and osteopenia. Dual energy, X-ray photon absorptiometry scans are available for children but it is important to use adequate comparative pediatric controls.

Reduced levels of physical activity often associated with severe JRA correlate with osteopenia as well as a younger age of onset, increased severity of disease and reduced intake of calcium and vitamin D. One should pay particular attention to adolescent female patients in order to ensure their calcium intake is sufficient enough to facilitate adequate bone stock in later life.

Basic management of significant JIA in these patients includes adequate control of disease activity, improved calcium intake through dietary measures and consistent attempts to promote physical activity. Those children who require long-term maintenance corticosteroids should receive supplemental calcium and vitamin D. Once you have established a diagnosis of osteoporosis, you may consider using bisphosphonates although long-term safety studies of these agents in children are lacking.

Here one can see polyarticular rheumatoid factor negative JIA. Note the dorsal synovial cyst of the wrist.

Chronic uveitis. This condition predominantly occurs in association with oligoarticular JIA and, in some reported series, may affect up to 21 percent of patients in that subgroup. Approximately 10 percent of children with polyarticular JIA develop uveitis but one does not see this with increased frequency in systemic JIA. Most children are asymptomatic without photophobia or ocular injection. Formal ophthalmology assessment is mandatory for those children with oligoarticular or polyarticular JIA. In those children with an onset of oligoarticular JIA at less than 7 years of age and a positive ANA, there is a high risk for uveitis and eye examinations are required every three to four months.

With polyarticular onset JIA, a positive ANA is also an increased risk factor for uveitis and mandates an examination every three to four months. Those with ANA negative oligoarticular or polyarticular JIA are at medium risk and require examinations every six months.

When patients older than the age of 7 experience the onset of disease, they are considered at medium risk and require ocular examination every six months. Cataracts, band keratopathy, anterior and posterior synechiae, and glaucoma are complications of uveitis. All of these complications have the potential to cause visual impairment.

Initial management of uveitis includes topical ophthalmic mydriatics and corticosteroids. A short course of systemic corticosteroids is also sometimes needed to suppress significant inflammatory changes that do not respond to topical therapy. Within the last five to 10 years, clinicians have employed other systemic medications including methotrexate, cyclosporine and mycophenolate mofetil to manage chronic uveitis. The anti-TNF agent infliximab may also be beneficial. However, the most optimal systemic medication for uveitis is unknown at this time.

Cardiovascular disease. It is known that the chronic inflammation associated with arthritis in adults is linked to an increased risk of cardiovascular disease. Children with JIA sometimes have elevated levels of plasma homocysteine and increased aortic stiffness as measured by phase-contrast MRI. This data suggests that early vascular changes may occur in children with JIA. It is likely that improved control of inflammation in children with JIA will help to limit future cardiovascular disease.

In Conclusion

Juvenile idiopathic arthritis is an aggregation of disorders linked by the common thread of persistent arthritis. However, each subtype is characterized by several unique clinical markers. Earlier recognition of each subtype is needed to forestall long-term sequela and current therapeutic guidelines include many of the pharmacologic agents recently developed for the treatment of chronic arthritis. n