CME

Earn Category I CME credit by reading this article and the article beginning on page 42 and successfully completing the posttest on page 48. Successful completion is defined as a cumulative score of at least 70% correct. This material has been reviewed and is approved for 1 hour of clinical Category I (Preapproved) CME credit by the AAPA. The term of approval is for 1 year from the publication date of January 2011.

Learning objectives
Identify risk factors for and prevalence of juvenile idiopathic arthritis Understand the variety of presentations of JIA Review the medical and surgical treatment options Recognize long-term effects of the disease

Juvenile idiopathic arthritis: Can you recognize this complex diagnosis?

The variable manifestations of JIA make diagnosing it a considerable challenge for clinicians, but early, individualized treatment can decrease the long-term sequelae of the disease.
Melissa Isennock, MPAS, PA-C; John M. Grosel, MD

uvenile idiopathic arthritis (JIA)also known as juvenile rheumatoid arthritis (JRA), although JRA is now an outdated termis considered the most common rheumatic disease in children younger than 16 years.1 The condition has a wide variety of manifestations, often making it difcult to identify. A timely diagnosis is important because JIA may cause signicant short- and long-term disability. Since the diagnosis is clinicala diagnosis of exclusionpractitioners who maintain a high index of suspicion are more likely to recognize JIA early. Juvenile idiopathic arthritis is dened as arthritis of unknown etiology with symptoms that persist for at least 6 weeks. The condition is diagnosed before age 16 years, and its symptoms cannot meet the diagnostic criteria for other known conditions. Several classications and presentations of the disorder exist, and treatment varies. JIA may persist into adulthood, and in these cases, clinicians should be prepared to provide long-term care and should consider likely comorbidities.
DIAGNOSTIC CATEGORIES

Normal knee joint

Synovial membrane Synovial fluid Cartilage

Capsule

Inflamed synovial membrane Synovitis Thinned cartilage Bone erosion

The classication criteria developed by the International League of Associations for Rheumatology is the most frequently used system to diagnose juvenile idiopathic arthritis (Table 1). This system identies ve major subtypes of the condition, and an undifferentiated arthritis category if criteria for multiple subtypes or no subtypes are met. Factors common to all the subtypes include joint swelling and gait disturbances.2 Juvenile idiopathic arthritis is the most common systemic disease associated with uveitis in childhood, so patients
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JIA-affected knee joint

Figure 1. Changes associated with JIA

Jennifer N. Gentry

often present with both conditions. Anterior uveitis may occur in patients with all subtypes of JIA who have a positive serum antinuclear antibody (ANA) test result but is most common with oligoarticular JIA.3 Uveitis is initially asymptomatic with permanent damage occurring at the onset of symptoms, so JIA patients benet from an ophthalmologic consultation. Oligoarthritis Up to four joints may be affected at diagnosis; the disease is said to be extended if it progresses to affect more than four joints after the rst 6 months and to be persistent if not more than four joints are affected throughout the course of the disease. The large joints of the lower extremities (the knees and ankles) are most likely to be affected.1 Oligoarthritis is the most common presentation of juvenile idiopathic arthritis.2 Polyarthritis This classication includes rheumatoid factor (RF)-negative or RF-positive arthritis involving ve or more joints in the rst 6 months of disease. Two or more positive RF test results at least 3 months apart in the rst 6 months are required for disease to be classied as RF-positive JIA.2 Systemic-onset juvenile idiopathic arthritis (soJIA) Also known as Still disease , soJIA is dened as 6 weeks of arthritis with intermittent fever that spikes daily or twice daily, usually each evening, for at least 2 weeks. Other symptoms must include at least one of the following: characteristic evanescent erythematous rash, generalized lymphadenopathy, organomegaly, and serositis. Laboratory ndings not required for classication may include neutrophilia, thrombocytosis, and mild anemia, as well as an elevated ESR and elevated levels of C-reactive protein (CRP), liver transaminases, serum ferritin levels, D-dimers, and aldolase. The pattern of arthritis is split equally between oligoarticular and polyarticular, most frequently involving the knee, wrist, and ankle. The sacroiliac joint is least often involved.2 No signicant sex bias has been identied in this subtype, and the age at diagnosis peaks at ages 0 to 5 years, with 2 years being the most common.4 Psoriatic and enthesitis-related arthritis Less common diagnoses include arthritis and enthesitis with two of the following symptoms: sacroiliac (SI) joint tenderness; presence of HLA-B27 antigen; onset of arthritis in a male older than 6 years; acute uveitis or history of ankylosing spondylitis; or sac-

roiliitis with inammatory bowel disease, Reiter syndrome, or acute anterior uveitis in a rst-degree relative. Psoriatic arthritis is arthritis and psoriasis with two of the following: dactylitis, nail pitting, or a rst-degree relative with psoriasis.2
EPIDEMIOLOGY

Evidence suggests that children of European ancestry are at an increased risk of developing all subtypes of juvenile idiopathic arthritis except rheumatoid factor-positive polyarticular and systemic arthritis; the risk is highest for the extended oligoarticular and psoriatic subtypes. Compared to children of European descent, black and Indian children are at a lower risk of all but RF-positive polyarthritis; those of Asian origin are less likely to develop all but enthesitis-related arthritis; and American Indians are at an increased risk of developing polyarthritis and extended oligoarticular subtypes. Females of European descent and non-European descent were more likely than males to have JIA.5 A 2007 CDC study found that approximately 294,000 US children had some form of JIA or another rheumatologic condition, which translates to 1 in 250 children younger than 18 years. Juvenile idiopathic arthritis incidence varies by place and time, suggesting a possible environmental component.6 Estimates of JIA incidence range from 4 to 14 per 100,000 children per year, and prevalence ranges from 9 to 113 per 100,000 population. Such a wide range is attributable to a lack of population-based studies, population differences, and environmental factors.7 Mortality is an average of one death per million people per year.6
DIAGNOSIS

Juvenile idiopathic arthritis is a clinical diagnosis. The chief symptoms are varied, and primary care providers (PCPs) frequently refer children with JIA and soJIA (enthesitis-related and psoriatic not included) to orthopedic surgeons based on the symptoms that manifest.8 Thus, orthopedic surgeons are more likely to refer these patients to a rheumatologist for further evaluation. Health care providers should be cognizant of the variety and onset of symptoms in order to better understand which referral each patient requires. A retrospective chart review conducted by McGhee and colleagues found musculoskeletal pain to be the most common presenting complaint in children referred to rheuma-

Key Points
Juvenile idiopathic arthritis (JIA) is arthritis of unknown etiology that must be diagnosed by age 16 years. Symptoms must be present

for at least 6 weeks.

JIA has five subtypes: oligoarticular, polyarticular, systemic, enthesitis-related, and psoriatic arthritis. Each subtype has varying

presentations and lifelong sequelae.

Joint swelling and gait disturbances are strongly correlated presenting complaints in patients with JIA. Laboratory values are not

specific and serve only a supportive role in diagnosis.

Treatment may include exercise therapy, NSAIDs, corticosteroids, disease-modifying antirheumatic drugs, tumor necrosis factor

blockers, and even surgery. Many new treatments are currently under investigation, including interleukin receptor antagonists.

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CME Juvenile arthritis

TABLE 1. Classification of juvenile idiopathic arthritis2,13 Oligoarthritis Arthritis in 1-4 joints during first 6 mo Persistent: not more than 4 joints throughout disease course Extended: more than 4 joints after first 6 mo Exclusions: 1-5 Polyarthritis Arthritis in 5 or more joints during first 6 mo Rheumatoid factor (RF)-positive or negative Exclusions: RF-positive, 1-3,5; RF-negative, 1-5 Systemic-onset juvenile idiopathic arthritis Arthritis in 1 or more joints for 6 wk 2 wk of fever with at least 3 d of quotidian pattern  One or more of the following: evanescent erythematous rash, generalized lymphadenopathy, hepatomegaly and/or splenomegaly, serositis Psoriatic arthritis Arthritis and psoriasis OR  Arthritis and at least 2 of the following: dactylitis, nail pitting or onycholysis, psoriasis in first-degree relative Exclusions: 2-5 Enthesitis-related arthritis Arthritis and enthesitis, OR  Arthritis or enthesitis with at least two of the following: sacroiliac joint tenderness and/or inflammatory lumbosacral pain; HLA-B27 positive; arthritis in a male >6 y; acute symptomatic anterior uveitis; history of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter syndrome, or acute anterior uveitis in firstdegree relative Exclusions: 1, 4-5 Undifferentiated arthritis Arthritis fulfilling criteria in none of above categories, OR Arthritis fulfilling criteria in 2 or more above categories Exclusions 1. Psoriasis or history of psoriasis in first-degree relative 2. Arthritis in HLA-B27-positive male beginning after 6th birthday 3.  Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter syndrome, or acute anterior uveitis in a first-degree relative 4. IgM rheumatoid factor on 2 or more occasions 3 mo apart 5. Systemic juvenile idiopathic arthritis in the patient

tology. In order of frequency, other complaints included abnormal laboratory test results, joint swelling, fever, gait disturbance, rash, fatigue, and morning stiffness. No patient with isolated musculoskeletal pain had juvenile idiopathic arthritis, thus making such pain a poor diagnostic criterion; especially as an isolated complaint, it generally was caused by mechanical or overuse syndromes instead. The most reliable manifestations of JIA include joint swelling and gait disturbances, usually a limp most prominent after periods of rest that improves with activity.8 Laboratory values were nonspecic. Neither ANA nor rheumatoid factor tests had the ability to identify patients with juvenile idiopathic arthritis, and though the ESR seemed to be more specic, the positive predictive value was low.8 Overall, the timely diagnosis of JIA is most likely with a good history and physical examination, while laboratory tests should serve merely a supportive role. Imaging studies, including conventional radiography and MRI, are useful for ruling out other possible diagnoses and monitoring the progression of the disease or response to treatment. In general, however, ndings on imaging are nonspecic and are not considered diagnostic in JIA.9
TREATMENT

Oligoarticular arthritis often responds to NSAIDs and glucocorticoid intra-articular injections. Polyarticular arthritis often requires the use of disease-modifying antirheumatic drugs (DMARDs), injections, and/or tumor necrosis factor (TNF) blockers. Systemic onset often requires oral glucocorticoids and a DMARD. Several new and alternate agents are available.1 A generalized approach to treatment that can help the health care provider to identify when further treatment changes are best left to a rheumatologist while still maintaining an active role in patient care is shown in
An approach to the treatment of rheumatoid arthritis.10

Certain patients are best managed by a team that may include several specialists, including a rheumatologist, orthopedist, occupational therapist, physical therapist, psychiatrist, and others as indicated by the patients specic symptoms. Exercise therapy Patients with juvenile idiopathic arthritis tend to be less active than healthy children, leading to deconditioning and functional deterioration. Exercise programs for these patients are varied and may include endurance training, strength training, or a combination of both.11 Although very few controlled trials on exercise therapy exist, an exercise regimen, tailored to the patients capabilities, is generally recognized as an integral part of the overall treatment plan. None of the studies found that exercise therapy exacerbated arthritis.11 NSAIDs These agents work by inhibiting the cyclooxygenase (COX) pathway of arachidonic acid metabolism and thus prevent formation of inammatory prostaglandins. In oligoarticular JIA, NSAIDs may be used as monotherapy. A recent survey of 129 pediatric rheumatologists found that 72% would use an NSAID as rst-line treatment.12 Many NSAIDs are available in

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liquid form for children who cannot swallow pills. The efcacy of NSAIDs is not known to be high, however, and many children experience side effects, most often abdominal pain. Recent studies have shown that celecoxib, a COX-2 inhibitor, may prevent COX-1 inhibition-related side effects such as GI ulcers, upset, and bleeding without lessening efcacy. Research has shown that chronic use is safe in children.12 Although NSAIDs can be useful in JIA, especially the oligoarticular form, they are often not effective as the sole therapy. Additionally, if the disease is progressive at diagnosis, which may include joint contractures or muscle atrophy, initiation of more aggressive therapy is advisable.13 Glucocorticoids Oral steroids remain a powerful antiinammatory option, but their large side-effect prole warrants caution when using them. While they are excellent for controlling systemic manifestations in patients with systemic-onset juvenile idiopathic arthritis, glucocorticoids should be avoided for patients in other classications unless being used as a bridge to new treatment or for patients who are experiencing terrible pain and functional restriction.1 Once improvement is seen, oral steroids should be tapered to the lowest effective dose or discontinued completely as quickly as safety allows. Intra-articular corticosteroid injections are a common treatment method for adult rheumatoid arthritis (RA), but they are not typically used in children because of concern about effects on cartilage and local suppression of limb growth.13 Recent understanding that intra-articular steroids are safe and well-tolerated may increase their use in children. Patients with oligoarticular JIA are most likely to use injections, especially if NSAIDs fail to provide complete symptom control. Triamcinolone hexacetonide, a longacting preparation, is the drug of choice. Injections can be used as often as every 3 months but should not be admin istered more than three times per year per joint.1 Disease-modifying antirheumatic drugs The most commonly used DMARD is methotrexate, but sulfasalazine and leunomide are also used. Methotrexate, a folate antagonist, is often the second-line agent in JIA after NSAID failure. Supplementation with folic acid may lessen GI upset, the most common side effect, without altering efcacy.1 Methotrexate has proven to be both safe and efcacious, and those patients who have a 70% response rate to treatment tend to continue to have the best 5-year disease control.13 Although maximum doses have increased over time, higher doses of the drug do not show an increase in efcacy or adverse effects.14 Tumor necrosis factor blockers Etanercept, iniximab, and adalimumab comprise the TNF blockers. Etanercept has been proven to be effective in controlling pain and swelling, especially in patients with disease that was unresponsive to other therapies; it may also delay radiologic progression of the disease.1 This drug has demonstrated sustained improvement in signs and symptoms of juvenile idiopathic arthritis and maintains its safety prole over time. A recent study found that the risk of severe adverse effects 8 years into therapy was no higher than at the beginning of treatment.15

Iniximab is a chimeric monoclonal anti-TNF-alpha antibody.1 Although adults with rheumatoid arthritis are currently treated with iniximab, further studies of the risks and benets in pediatric patients are required. Adalimumab is a fully human monoclonal anti-TNF-alpha antibody administered by SC injection every 2 weeks. Studies show that adalimumab improves signs and symptoms of the disease and can be given with or without methotrexate to achieve these improvements. The combination of adalimumab plus methotrexate exhibited the most desirable end point. The most common side effects include infections and injection-site reactions, although the size and length of the study were not sufcient to identify the risk of rare adverse events.16 Interleukin receptor antagonists Interleukin-1 (Il-1) has been linked to the pathogenesis of JIA. Thus anakinra, a recombinant Il-1 receptor antagonist, is being investigated for safety and efcacy. It has been shown to reduce the symptoms of RA in adults, especially when disease-modifying antirheumatic drugs do not offer adequate control. One study found 58% of patients showed a greater than 30% disease improvement when anakinra was given in daily SC injections. The highest improvements were seen in patients with systemic onset, followed by those with oligoarticular and polyarticular subtypes. Fewer patients in the treatment group had disease ares compared to those in the placebo group. The most common adverse effects were injection-site reactions, headache, and upper respiratory tract infections.17 Research remains preliminary for anakinra in the treatment of juvenile idiopathic arthritis, but it does seem to produce improvements and short-term adverse effects are minimal. However, more research is necessary before the drug will be added to the formulary for JIA. Surgery Some patients will have progressive joint degeneration, and in such cases medication may no longer be enough to prevent disability or pain. Surgery has been a possible treatment for some time, but the efcacy of each option differs. Nonarthroplasty choices such as synovectomy or osteotomy are no longer indicated, as they have produced inconsistent results. The hip is a frequently affected and problematic joint in JIA, and bone sparing strategies like bipolar hemiarthroplasty have been suggested and tried. Although these methods provide clinically signicant improvement for patients, they have not been shown to be as effective or durable as total hip arthroplasty. This procedure is proven to provide relief from unremitting pain for most patients, and the outcomes are better than with hemiarthroplasty. Although there is concern for acetabular component loosening and failure, for some patients there may be no other choice to relieve pain.18
LONG-TERM SEQUELAE

Patients with juvenile idiopathic arthritis, especially soJIA, develop chronic impairment. The disease course may be monophasic, meaning one episode that lasts less than 24 months. Other possible courses are polycyclic, relapsingwww.jaapa.comjanuary 201124(1)JAAPA 25

CME Juvenile arthritis

algorithM. An approach to the treatment of rheumatoid arthritis Establish diagnosis early Document baseline disease activity and damage Estimate prognosis
Primary care physician

Initiate therapy Begin patient education Start DMARD therapy within 1 mo Consider NSAID Consider local or low-dose systemic corticosteroids Start physical therapy or occupational therapy

Periodically assess disease activity

Rheumatologist

Adequate response with decreased disease activity

Inadequate response (ongoing active disease after 3 mo of maximal therapy)

Change or add DMARDs

No previous MTX treatment

Suboptimal response to MTX

MTX

Other monotherapy

Combination therapy

Combination therapy

Other monotherapy

Biologic DMARDs

Monotherapy

Combination therapy

Failure of DMARDs Symptomatic or structural joint damage

Surgery
Key: DMARD, disease-modifying antirheumatic drug; MTX, methotrexate. Adapted with permission from ODell JR. Therapeutic strategies for rheumatoid arthritis. N Engl J Med. 2004;350(25):2591-2602.

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remitting, or persistent. A polycyclic course is uncommon. Patients who had a polyarticular onset are more likely to have a persistent disease course. Patients at higher risk for persistent diseasewho were thus likely to have a poorer outcomehad active arthritis and persistent fever at 3 months from diagnosis and an elevated ESR with corticosteroid treatment at 6 months from diagnosis.19 These predictors are useful because such patients require more aggressive treatment to avoid disability; they can also provide patients and families with a better idea of the likely individual disease course. JIA is not solely a disease of childhood, and 31% to 55% of patients have active disease 10 years after diagnosis. Adults with the condition have been found to have higher levels of physical disability, pain, fatigue, and unemployment.20 Psychosocial effects Chronic pain and illness are wellknown to cause depression and anxiety. Juvenile idiopathic arthritis can affect physical growth; furthermore, many of these patients are on long-term steroid therapy, which also causes impaired development. Short stature is often considered a disadvantage in social and psychological realms. Patients with long-term disease may have lower academic or employment levels, are more likely to be single, and exhibit delayed independence. Severity of illness does not necessarily predict level of disability. Boys, children from single-parent or low-income families, and children who are older at diagnosis are at greatest risk. The quality of a patients social support network correlates with psychosocial outcome.21 Transition from pediatric to adult care is an important consideration, and delay of this transfer may affect entry into adulthood. The practitioner may wish to foster the patients personal responsibility for health care in order to promote independence. Although chronic illness and JIA do not guarantee psychosocial disability, it is important to consider the psychological effects of long-term disease. A less obvious effect of the illness, it is no less important for the long-term health of the patient. Mortality Patients with juvenile idiopathic arthritis have increased mortality compared to the general population. One study found a fourfold increase in its cohort of JIA patients, none of whose deaths occurred in childhood. Deaths occurred from complications of other autoimmune diseases, especially in patients with polyarticular or systemic onset JIA.20 This suggests that JIA is involved in broader immune system dysregulation in some patients; therefore, a higher index of suspicion for related diagnoses in JIA patients is warranted.
CONCLUSION

out other diagnoses. Treatment is varied. An individualized care plan must be developed by determining the most effective agents and modalities for the patient and, if the disease course progresses, by implementing more aggressive approaches to treatment. JIA is a chronic illness, so the practitioner can better serve patients by remaining aware of the diseases potential effects on quality of life both physically and mentally. Being cognizant of such effects allows for a better overall treatment plan and may make a difference in a patients current and future health. JAAPA
Melissa Isennock was a student in the Marietta College PA program when this article was written. John Grosel is an assistant professor in the Marietta PA program and a staff radiologist for Marietta Imaging, Inc, Marietta, Ohio. The authors have indicated no relationships to disclose relating to the content of this article. DRUGS MENTIONED Adalimumab (Humira) Anakinra (Kineret) Celecoxib (Celebrex) Etanercept (Enbrel) Infliximab (Remicade)

Leflunomide (Arava, generics) Methotrexate (Rheumatrex, Trexall, generics) Sulfasalazine (Azulfidine, Azulfidine EN-tabs, generics) Triamcinolone hexacetonide injection (Aristospan)

Juvenile idiopathic arthritis is a more common illness than may be expected, and it can be a difcult diagnosis for clinicians to make. Given the wide range of manifestations, a thorough history and physical examination to determine the likelihood of JIA in a patient with suspicious complaints is invaluable. Laboratory values act as a supportive measure or tool to rule

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