107 Treatment of Juvenile

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1 107 Treatment of Juvenile Idiopathic Arthritis JOYCE J. HSU TZIELAN CHANG LEE CHRISTY I. SANDBORG KEY POINTS Juvenile idiopathic arthritis (JIA) is the umbrella term for the family of childhood arthritides of unknown cause. JIA affects at least 1 in 1000 children. Before wide use of methotrexate and biologic therapies, 50% of children with JIA would reach adulthood with significant disabilities. The goals of treatment in JIA are complete suppression of inflammation on medications and remission when possible. Oligoarticular JIA, characterized by early age of onset, female predominance, antinuclear antibody positivity, and frequent subacute anterior uveitis, occurs only in childhood. Systemic JIA is distinct from other subgroups of JIA in its equal sex distribution, lack of autoantibodies and human leukocyte antigen associations, and increased responsiveness to interleukin (IL)-1 and IL-6 inhibition compared with tumor necrosis factor inhibition. Enthesitis-related arthritis typically occurs in children greater than 6 years of age, but sacroiliitis may not develop until adolescence. Arthritis in a child can result in overgrowth (in the knee causing length discrepancy) and undergrowth (in the temporomandibular joint causing micrognathia) of joints. Because bone erosions on conventional radiographs are late radiographic findings in growing children, early joint damage may require different imaging modalities. Considerable progress in understanding the genetics and pathogenesis of JIA has revealed subtype-specific associations, as well as some common mechanisms of disease that will translate to more effective and targeted therapies. Juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in childhood, but actual estimates of prevalence and incidence vary remarkably in different geographic regions, ranging from 7 to 400 per 100,000 children, reflecting variations in disease reporting, classification, and ethnic and environmental differences in disease expression. 1 Reasonable working estimates are 150 per 100,000 children, which makes JIA one of the most common chronic diseases of childhood. There are significant differences in the disease manifestations in children compared with adults, with some types occurring exclusively in children. This chapter discusses the current understanding of the key clinical features of the various forms of JIA, differential diagnoses, treatment approaches, prognosis, and outcomes. The rapid growth in understanding the biologic basis for JIA and 1752 the ongoing development of targeted therapies for rheumatic diseases are likely to lead to enhancements in these recommendations. Data concerning long-term disease course and outcome in children with JIA in this modern treatment era remain limited, and there are international prospective inception cohorts of children with arthritis designed to address these gaps in knowledge. 2,3 CLASSIFICATION CRITERIA FOR JUVENILE IDIOPATHIC ARTHRITIS Differential Diagnosis In the past, different groups had used various types of nomenclature to classify children with persistent arthritis including juvenile rheumatoid arthritis (American College of Rheumatology [ACR]) and juvenile chronic arthritis (European League Against Rheumatism), which created problems in comparing research studies and outcomes. The goal of the International League of Associations for Rheumatology (ILAR) is to identify subtypes of JIA for research purposes that are homogeneous and mutually exclusive. JIA classification is currently based on predominant clinical and laboratory features and the number of involved joints at disease onset. 4 There is a continual renewal process, with the second revision occurring in Edmonton in 2001, which is presented in Table However, classification systems are ever evolving, and categorization may evolve to more biologically and genetically similar subgrouping, especially with recent advances in etiology and pathogenesis. For example, age of onset may be a more biologically relevant parameter to distinguish between subtypes of JIA than classification based on number of involved joints. PBMC gene expression analysis reveals biologic differences between patients with early-onset (<6 years) and late-onset (>6 years) JIA, which was independent of oligoarthritis or polyarthritis subtype. 5 Ravelli and colleagues 6 provided clinical support for this approach, showing that antinuclear antibody (ANA)-positive patients with oligoarthritis and rheumatoid factor (RF)-negative polyarthritis were similar in terms of early age at onset, female predilection, increased frequency of asymmetric arthritis, and increased frequency of uveitis. Pattern recognition is perhaps the most significant skill needed by clinicians in the diagnostic evaluation of patients. The usual patterns in children with rheumatic diseases often overlap with malignancies, infection, and trauma (especially nonaccidental). Therefore it is crucial to evaluate these diagnostic possibilities first before accepting the diagnosis of JIA. The ILAR categories are meant to simplify classification and are useful for typical presentations of

2 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis 1753 Table International League of Associations for Rheumatology Classification Criteria for Juvenile Idiopathic Arthritis (JIA) 4 General definition of JIA: arthritis of unknown etiology that begins before the sixteenth birthday and persists for at least 6 wk; other known conditions are excluded Subcategory Definition Exclusions Oligoarthritis 1. Persistent oligoarthritis: Affecting 4 joints throughout the disease course 2. Extended oligoarthritis: affecting a total of >4 joints after the first 6 mo of disease RF-Negative Polyarthritis RF-Positive Polyarthritis Psoriatic Arthritis Enthesitis-Related Arthritis Systemic JIA Undifferentiated Arthritis ERA, enthesitis-related arthritis; RF, rheumatoid factor. Arthritis affecting 1-4 joints during the first 6 mo of disease 1. Arthritis affecting 5 joints during the first 6 mo of disease and 2. Test for RF is negative 1. Arthritis affecting 5 joints during the first 6 mo of disease, and 2. 2 positive RF tests (as routinely defined in an accredited laboratory), at least 3 mo apart during the first 6 mo of disease 1. Arthritis and psoriasis, or 2. Arthritis and at least 2 of the following: 1. Dactylitis 2. Nail pitting (minimum of 2 pits on 1 or more nails at any time) or onycholysis 3. Psoriasis in a first-degree relative 1. Arthritis and enthesitis, or 2. Arthritis or enthesitis, with at least 2 of the following: a. The presence of or a history of sacroiliac joint tenderness and/or inflammatory lumbosacral pain b. The presence of HLA-B27 c. Onset of arthritis in a male >6 yr of age d. Acute (symptomatic) anterior uveitis e. History of ankylosing spondylitis, ERA, sacroiliitis with inflammatory bowel disease, reactive arthritis, or acute anterior uveitis in a first-degree relative Arthritis in 1 or more joints with, or preceded by, fever of at least 2 weeks duration that is documented to be daily and quotidian (fever that rises to 39 C once a day and returns to 37 C between fever peaks) for at least 3 days, and accompanied by 1 or more of the following: 1. Evanescent (nonfixed) erythematous rash 2. Generalized lymph node enlargement 3. Hepatomegaly and/or splenomegaly 4. Serositis Arthritis that fulfills criteria in no category or in 2 of the above categories a. Psoriasis or a history of psoriasis in the patient or first-degree relative b. Arthritis in an HLA-B27 positive male beginning after the sixth birthday c. Ankylosing spondylitis, ERA, sacroiliitis with inflammatory bowel disease, reactive arthritis, acute anterior uveitis, or a history of one of these disorders in a first-degree relative d. The presence of IgM RF on at least 2 occasions at least 3 mo apart e. The presence of systemic JIA in the patient a, b, c, d, e a, b, c, e b, c, d, e a, d, e a, b, c, d disease. However, if a patient does not easily fit into the ILAR classification system, clinicians must carefully consider all other possibilities, rheumatologic and nonrheumatologic. To this end, ILAR recommends the following descriptors in order to obtain more clinical information: age at onset; characteristics of articular involvement; serologies (ANA, RF, anticitrullinated protein antibody [ACPA]); uveitis; and the human leukocyte antigen (HLA) allelic associations. For example, a 2-year-old girl who wakes up crying at night from back or hip pain should immediately trigger alarms of infection or malignancy rather than a rheumatic condition. This case is different from a 12-year-old boy with back stiffness and hip and entheseal pain, which would be a classic presentation of enthesitisrelated arthritis (ERA) in this age group. Among patients with acute lymphocytic leukemia (ALL), 15% to 30% present with musculoskeletal symptoms and may be misdiagnosed as JIA. 7 Up to 75% of children ultimately diagnosed with ALL presenting with musculoskeletal complaints did not have blasts in the peripheral blood at the time of evaluation by pediatric rheuma - tologists, although low white blood cell count, mild

3 1754 PART 16 RHEUMATIC DISEASES OF CHILDHOOD thrombocytopenia, and nighttime pain were early indicators of ALL. ANA status, rash, radiographic abnormalities, and objective signs of arthritis were not helpful in distinguishing between ALL and JIA because they occurred at similar rates in both groups. 8 Each subcategory is discussed later, focusing on clinical manifestations, diagnostic features, treatment, outcome, and prognosis. Treatment recommendations are discussed later for each of the subtypes of JIA on the basis of current available evidence including the recently developed ACR recommendations for the treatment of JIA. 9 RHEUMATOID FACTOR NEGATIVE POLYARTHRITIS Clinical Manifestations and Diagnostic Features RF-negative polyarthritis makes up 10% to 30% of all JIA cases, with a bimodal distribution of age of onset with the first peak at 1 to 4 years of age and the second peak at 10 to 12 years. Girls are more commonly affected than boys with a ratio of 3.2 : 1, and subacute anterior uveitis occurs in 4% to 25%. 10 Any joint may be affected in RF-negative polyarthritis JIA, with more involvement of hip, shoulder, cervical spine, and distal interphalangeal joints than in adults. The arthritis is often usually insidious and can be symmetric or asymmetric, affecting both large and small joints. Some authors distinguish between two clinical subgroups on the basis of ANA status: (1) an ANA-positive form that resembles oligoarthritis, except for the number of joints affected in the first 6 months of disease, consisting of young girls (younger than age 6) with an asymmetric-onset arthritis and at a high risk of uveitis, and (2) an ANAnegative form that is similar to adult-onset RF-negative rheumatoid arthritis (RA), characterized by symmetric synovitis of large and small joints, with onset in a slightly older age group (ages 7 to 9). The similarities between ANA-positive, RF-negative polyarthritis and oligoarthritis have led to the hypothesis that these two entities are actually in the same disease spectrum. 6 RF-negative polyarthritis may be associated with elevated acute phase reactants, mild anemia, and ANA positivity in up to 40%. Even though RF is negative, 50% to 80% of patients are ACPA positive, 10 using high-sensitivity (but low-specificity) testing methods. 11 Differential Diagnosis The differential diagnosis of RF-negative polyarthritis includes the other JIA subtypes including ERA, which should be considered particularly in boys older than 6 years of age because sacroiliac involvement may not occur until adolescence. Other major diagnostic considerations include other rheumatic conditions such as lupus, especially in an older girl who is ANA positive; lymphoma; and leukemia. Neisseria gonorrhoeae and Lyme disease can present as an acute polyarthritis. Treatment With the current development of increasingly more effective biologic treatment for arthritis, pediatric rheumatologists now aim to achieve complete disease remission as early as possible in the disease course. Several studies support the paradigm of treating aggressively to reach inactive disease as early as possible, which may ultimately lead to better outcome such as improved quality of life, shorter periods of time spent in active disease, and less long-term joint damage. Active disease in the first 2 years was significantly associated with the duration of active disease in the following 3 years, 12 and conversely, improved disease control with disease-modifying antirheumatic drugs (DMARDs) and/or biologics was associated with improved outcomes. 13 To this end, children with polyarthritis require a diseasemodifying agent as soon as practically possible after the diagnosis has been confirmed. If nonsteroidal antiinflammatory drugs (NSAIDs) are initially used as monotherapy, with or without intra-articular steroids (IASs), continued disease activity at no more than 2 months should prompt escalation of therapy. 9 As shown in Figure 107-1, methotrexate (MTX) is the first DMARD of choice, but if there is an inadequate response to MTX by 2 months, anti tumor necrosis factor (TNF) agents should be initiated. 14,15 The different TNF inhibitors have not been directly compared against each other, so it is not possible to determine which might be most effective and safe in a given patient. Switching between TNF inhibitors in children has not been well studied. Sulfasalazine and leflunomide can still be used before an anti-tnf agent in mild disease, although evidence suggests that leflunomide may be slightly less effective than MTX. 16 Polyarticular disease course of any type, which does not respond well to MTX or anti-tnf agents, is now increasingly being treated with a range of newer biologics. Physiotherapy (PT) is important for all children with JIA, for stretching, muscle building, and consequent joint protection. Children with hand involvement need occupational therapy (OT) assessment and input regarding writing and school accommodations. The following paragraphs summarize specific information about different therapies used in children and may be applied to all types of JIA as appropriate. (See Table for medications, dosing, route, and safety monitoring recommendations.) Nonsteroidal Anti-inflammatory Drug Use in Children NSAIDs may help control symptoms but do not alter the natural history of JIA. In general, NSAIDs should only be considered as monotherapy in initial therapy in low disease activity. If control is not achieved in 1 to 2 months, additional therapy should be considered. 9 NSAIDs are frequently used for symptom control as an adjunctive therapy to more definitive therapies. Gastric protection with H 2 blockers or proton pump inhibitors may be required. Intra-articular Steroid Injections The use of intra-articular triamcinolone hexacetonide (THA), 1 mg/kg in large joints such as the knee and 0.5 mg/ kg in smaller joints such as the ankle, has been found to be superior to triamcinalone acetonide, betamethasone, and methylprednisolone acetate in randomized controlled trials Early treatment is associated with better outcome, 23 and IASs are expected to result in clinical improvement of

4 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis 1755 Escalation of therapy due to ongoing disease activity Moderate to severe disease activity and/or high-risk features (RF or ACPA +, erosions, narrowing, hip or neck involvement) NSAID, IAS, and MTX Add TNF inhibitor 1-2 months 1-2 months Change TNF inhibitor or Change to abatacept Other; e.g., rituximab, IL-6 or IL-1 inhibitor Mild disease activity NSAID, IAS Add MTX Add TNF inhibitor Figure Polyarticular-course juvenile idiopathic arthritis treatment algorithm including rheumatoid factor (RF)-negative, RF-positive, extended oligoarticular, and psoriatic arthritis treatment. The treatment goal is remission of disease activity and is stratified by severity of disease. More disease activity or high-risk features should prompt disease-modifying antirheumatic drug use as initial therapy, whereas nonsteroidal anti-inflammatory drug (NSAID) monotherapy could be used initially for 1 to 2 months. If NSAID monotherapy is ineffective, treatment should be escalated. ACPA, anticitrullinated protein antibody; IAS, intra-articular steroid; IL, interleukin; MTX, methotrexate; TNF, tumor necrosis factor. arthritis for at least 4 months. Therefore if arthritis recurs, joint injections can be repeated up to three times in a 12-month period. Difficult-to-reach joints such as the hip, sacroiliac (SI) joint, temporomandibular joint (TMJ), and subtalar joint may be injected using ultrasound or fluoroscopy. IASs should be administered under sedation or general anesthesia for the young. The use of IASs for active arthritis has been recommended by the ACR guidelines regardless of concurrent therapy, JIA subtype, disease activity, prognostic features, or joint contracture. If the duration of clinical improvement is shorter than 4 months, systemic treatment (e.g., MTX) may be indicated. 9 Corticosteroid Use in Children with Juvenile Idiopathic Arthritis In general, systemic corticosteroids should be used sparingly in the treatment of any subgroup of JIA because of the severe morbidity associated with chronic use, even at low doses. Newer therapeutic modalities such as biologics reduce the dependence for any corticosteroids and/or limit the doses needed. The evidence for use of corticosteroids for the synovitis of JIA is controversial and conflicting, and the ACR recommendations for JIA treatment were unable to make any recommendations for corticosteroid use, except in systemic juvenile idiopathic arthritis (sjia) for severe systemic features. 9 However, in some cases, low doses of corticosteroids (<0.1 mg prednisone equivalent/kg/day) or brief high-dose regimens (intravenous methylprednisolone 30 mg/kg/day for 1 to 3 days) may be used in polyarticular JIA, in order to bridge constitutional features of pain and fatigue while waiting for DMARDs or biologic therapies to reach their therapeutic effect. Local use of corticosteroids for uveitis is discussed later in Uveitis. Methotrexate MTX is the most commonly used DMARD in JIA. 24 In a retrospective cohort study involving all JIA subtypes, the strongest predictor of response to MTX at 6 months of treatment was the time from diagnosis to start of MTX, suggesting that starting MTX early will lead to a better response. 25 The ACR guidelines support a maximum dose of 0.6 mg/kg once weekly (equivalent to 15 mg/m 2 /week, maximal 25 mg/week) of parenteral MTX. 9 In patients with lower disease severity, lower doses (8 to 12.5 mg/m 2 /week oral or parenteral) may be effective, and these doses are similar in safety. 15 Most pediatric rheumatologists start folic acid at 1 mg/day, but daily folate supplementation remains controversial. Routine monitoring of liver enzyme tests should be done as noted in Table 107-2, but liver biopsies are not indicated except in unusual circumstances. Some children develop an intolerance to MTX, and leflunomide may be used as an alternative. 16,26 Both MTX and leflunomide are associated with teratogenic effects. Tumor Necrosis Factor Inhibitors Anti-TNF agents are effective in many children with polyarticular-course JIA of any onset type who fail to respond fully to MTX. The first TNF inhibitor to be studied in JIA, etanercept, demonstrated efficacy and safety in a novel randomized withdrawal trial design in patients with polyarticular JIA, in which the study design was based on an open-label period, followed by randomization of responders to placebo or study drug with the primary endpoint being time to flare. 14 Since that initial randomized control study in 2000, long-term studies and registries have continued to demonstrate the safety and efficacy of etanercept in children

5 1756 PART 16 RHEUMATIC DISEASES OF CHILDHOOD Table Commonly Used Medications in Juvenile Idiopathic Arthritis 9,176 Medication Typical Maximum Dose Typical Frequency Abatacept 10 mg/kg (max 1000 mg) IV Load at 0, 2, 4 wk, then every 4 wk Adalimumab 24 mg/m 2 Every 2 wk <30 kg: 20 mg SQ >30 kg: 40 mg SQ Anakinra 2 mg/kg (max 100 mg) SQ Daily Cyclosporine 6 mg/kg/day orally Divided twice a day Diclofenac (SR preparation available) 1-3 mg/kg/day (max 150 mg/day) Divided 1-3 times a day Etanercept 0.8 mg/kg/wk (max 50 mg)* SQ 0.4 mg/kg/dose (max 25 mg) SQ Once weekly 2 /wk Ibuprofen 6 mo of age: mg/kg/day Divided 3-4 times a day Indomethacin (SR preparation available) >1 mo of age: 1-2 mg/kg/day (max 50 mg/day) Divided 1-2 times a day Infliximab 10 mg/kg/dose IV Load at 0, 2, 6 wk, then every 4 wk Intravenous immunoglobulin 2 g/kg/dose IV Every 2 wk Leflunomide <40 kg: 10 mg orally Daily >40 kg: 20 mg orally Methotrexate 15 mg/m 2 /dose SQ Weekly (0.6 mg/kg; max 25 mg) Naproxen >2 yr of age: mg/kg/day (max 1 g/day) Divided twice a day Piroxicam <15 kg: 5 mg orally Daily kg: 10 mg orally kg: 15 mg orally >46 kg: 20 mg orally Rilonacept mg/kg SQ Once weekly Rituximab 750 mg/m 2 (max 1000 mg) IV Twice 2 wk apart Sulfasalazine 50 mg/kg/day (max 2 g) orally Divided twice a day Tacrolimus 0.2 mg/kg/day orally Divided twice a day Thalidomide 5 mg/kg/dose orally Daily Tocilizumab <30 kg: 12 mg/kg IV >30 kg: 8 mg/kg IV Every 2 wk *The effectiveness of the 0.8 mg/kg/wk dose has been evaluated in JIA patients. 177,178 Medication IV, intravenous; SQ, subcutaneous; SR, sustained release. Typical Maximum Dose Typical Frequency Summary of Recommendations for Medication Safety Monitoring Nonsteroidal Anti-inflammatory Drugs Complete blood count, liver enzymes, serum creatinine Before or soon after initiation of routine use Repeat approximately twice yearly for chronic daily use Repeat approximately once yearly for routine use (3-4 days/wk) Methotrexate Complete blood count, liver enzymes, serum creatinine Before initiation Approximately 1 mo after initiation Approximately 1-2 mo after increase in dose Repeat approximately every 3-4 mo if prior results normal and dose stable Tumor Necrosis Factor Inhibitors Complete blood count, liver enzymes, serum creatinine Before initiation Repeat approximately every 3-6 mo Tuberculosis screening Before initiation Repeat approximately once yearly with polyarthritis, with and without MTX The frequency of major serious adverse events (SAEs) have been low, with adjusted rates of 0.12 events per patient year and 0.03 medically important infections per patient year in open-label extensions. 30 Importantly, no cases of lupus, demyelinating disorders, malignancies, opportunistic infections, or tuberculosis were seen. Although there have been several long-term studies of etanercept with international registries, the total number of patient-years available for evaluation is still too small to be able to detect rare long-term SAEs such as malignancy or demyelinating diseases. A 1-year prospective, observational study to compare combination etanercept and MTX with etanercept monotherapy demonstrated that the likelihood of achieving 70% disease control (ACR Pedi 70) was increased with combination therapy (odds ratio of 2.1, 95% CI 1.2 to 3.5) as compared with etanercept monotherapy. 27 In this cohort, there were 24 infectious SAEs and 23 noninfectious SAEs including three malignancies in 496 patients over 12 months. Growth delay in JIA was improved and reversed with the use of etanercept. 33 An international, multicenter, randomized, doubleblind, placebo-controlled trial of infliximab provided

6 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis 1757 important lessons regarding dosing in children. 34 The initial dose of 3 mg/kg/infusion based on adult studies did not demonstrate efficacy at 3 months compared with placebo; however, a separate arm suggested that 6 mg/kg/infusion had better pharmacokinetics leading to better effectiveness. In a 4-year, long-term, open-label extension, 14% of patients dis continued infliximab due to SAEs including six infectious SAEs in 120 patients over 52 weeks. 35 Significant infusion reactions associated with infliximab antibodies and asymptomatic development of antinuclear antibodies were observed. Adalimumab was shown to be efficacious and safe in a randomized placebo-controlled withdrawal trial in patients with moderately to severely active polyarticular JIA with or without MTX, and there was a trend toward more improvement with combination therapy, although the study was not statistically powered to measure this difference. 36 The dose used was adalimumab 24 mg/m 2 (maximum dose, 40 mg) subcutaneously every other week. SAEs possibly related to adalimumab occurred in 14 patients (total 177), seven of which were serious infections. In August 2009, the U.S. Food and Drug Administration issued a black box warning on the increased risk of cancer, particularly lymphoma, in children and adolescents receiving TNF inhibitors for arthritis or inflammatory bowel disease (IBD). 37 The other adverse events involved with TNF inhibitors are similar to that of adults and have been reported in children as well including serious infections, demyelinating processes, optic neuritis, injection site reactions or infusion reactions, and development of autoimmune conditions. Because of the voluntary nature of reporting rare adverse drug events in the United States, the actual risk of any of these rare events is not known. Abatacept The T cell co-stimulatory inhibitor, CTLA4-Ig (abatacept), was studied in an international placebo-controlled randomized withdrawal trial in 190 patients with active polyarthritis regardless of onset type who had inadequate response or intolerance to one DMARD in the past including TNF inhibitors. 38 Concurrent MTX was allowed. Thirty-percent improvement (ACR Pedi 30) response rates were 76% in biologic-naïve patients and 39% in patients with prior biologic therapy. Abatacept continued to be clinically significant with durable efficacy in patients with JIA, and some patients require longer periods for optimal response (>3 to 4 months) compared with TNF inhibitors. 39 No cases of tuberculosis or malignancy were detected, but patient numbers were small and follow-up time was limited. Other Biologics The ACR guidelines recommend consideration of rituximab as a treatment option for patients who have received TNF inhibitor and abatacept sequentially and have high disease activity. 9 IL-6 and IL-1 inhibition are discussed in more detail later in Systemic Juvenile Idiopathic Arthritis but have not been specifically studied in polyarticular disease. The use of nonbiologic DMARD combinations (such as MTX plus sulfasalazine and/or hydroxychloroquine) has not been studied in children. Outcome Early response to treatment was an important predictor of long-term outcome. 13 Symmetric arthritis and early hand involvement predicted future disability and poorer overall well-being. 40 The ACR guidelines for JIA treatment also consider the following as poor prognostic factors in patients with RF-negative polyarthritis: arthritis of hip or cervical spine; positive ACPAs; and radiographic damage (erosions or joint space narrowing by radiograph). 9 RF-negative polyarthritis has a variable outcome, which shows the heterogeneity of the subtype, 41 but the overall prognosis appears to be better than RF-positive polyarticular JIA. 42 Approximately 30% of children will go into long-term remission off medication, with the chance of remission being highest in the first 5 years of disease. 43,44 However, flare of disease 2 years after reaching clinical remission off medication had occurred in 69% of patients. 43 RHEUMATOID FACTOR POSITIVE POLYARTHRITIS Clinical Manifestations and Diagnostic Features RF-positive polyarthritis is a well-characterized JIA subcategory and is part of the same disease spectrum as adult RF-positive RA, 45 sharing immunogenetic and serologic factors. This subcategory makes up 5% to 10% of cases of JIA 10 and is more common in girls, with reported femaleto-male ratios between 5.7 and 12.8 : ,47 Age of onset occurs in late childhood or adolescence and typically is an aggressive, symmetric polyarthritis affecting the small joints of the hands, as well as large joint involvement in a pattern that resembles RA. These children frequently have more than 30 joints with arthritis. Hip involvement is common and may be debilitating. The arthritis can be quite severe, often resulting in bony erosions and joint destruction. Radiologic changes tend to take place early, 42 especially in hands and feet. With active disease, patients may occasionally have mild systemic signs and symptoms such as weight loss, low-grade fever, malaise, mild hepatosplenomegaly, or lymphadenopathy. Rheumatoid nodules occur in up to 10% of cases, most frequently around the elbow. Other extraarticular manifestations are reported less often than in adults. Uveitis is an unusual feature of this subtype, occurring in only about 0% to 2% of patients. 10 Polyarthritis may be associated with mild to moderate inflammation such as elevated acute-phase reactants and a normocytic, normochromic anemia. By definition, all patients have IgM-anti-IgG RF. The ANA test is positive in about 55% of patients, 10 and ACPAs have been reported in 57% to 73%. 48,49 Differential Diagnosis The differential diagnosis of RF-positive polyarthritis includes other JIA subcategories, especially when there is no confirmed RF-positive test on two occasions. Such cases are frequently unclassified in the JIA system; however, management and therapy remain similar.

7 1758 PART 16 RHEUMATIC DISEASES OF CHILDHOOD Treatment Treatment algorithms and ACR guidelines for patients with all types of polyarthritis are discussed in Figure However, because children with RF-positive polyarthritis are at higher risk of prolonged erosive arthritis compared with other types of JIA, these children should be considered to be in the more severe disease category, requiring rapid escalation of treatment if even mild disease activity persists. Rather than an initial period of NSAID monotherapy, RF-positive polyarthritis patients should receive MTX, at the time of diagnosis, with rapid addition of a TNF inhibitor if response is not adequate. 9 Some children benefit from multiple joint injections to maintain control of the arthritis. Outcome Children with RF-positive polyarthritis have a poorer long-term prognosis than the other JIA subcategories. 42,50 Inactive disease is difficult to achieve with 84% of the disease course consisting of active disease, and only 5% of patients were able to maintain remission after cessation of therapy. 43 OLIGOARTICULAR JUVENILE IDIOPATHIC ARTHRITIS Clinical and Diagnostic Features Oligoarticular JIA accounts for up to 20% of all new rheumatic diagnoses in the general pediatric rheumatology clinic 47 and is the most prevalent of all the JIA subcategories, comprising 30% to 60% of all JIA patients in North America and Europe. 41 Oligoarticular JIA has no adult equivalent. The peak age of onset occurs in Caucasian children ages 2 to 4 years from the United States and Europe. 10 Females are affected more commonly than males, 3 : Two general subgroups are recognized within oligoarticular JIA: extended oligoarticular involvement, in which many additional joints develop arthritis after the initial 6 months, as contrasted to persistent oligoarticular JIA, in which the number of joints affected remains less than 5. Currently, there is no single reliable predictor of extension, but symmetric disease, ankle and/or wrist involvement, and an elevated erythrocyte sedimentation rate (ESR) in the first 6 months of disease may indicate likelihood of extension. 51,52 Disease extension to the extended subtype has been reported to be 30% to 50% at 4 to 6 years after disease onset. 51,53 Oligoarticular JIA usually presents as an asymmetric arthritis affecting one or two large joints, especially of the lower extremities, with the knee being the most commonly affected, followed by the ankle, wrist, and digits. Hand involvement is the third most commonly affected location, but this pattern may portend the later onset of psoriatic arthritis. 54 Involvement of the hip and back, especially in young children, is so unusual that extensive evaluation is warranted to rule out other conditions such as infection or tumors. Significant constitutional and systemic symptoms are unusual in oligoarticular JIA and, if present, should raise concern regarding the accuracy of the initial diagnosis. Pain in an obviously inflamed joint is surprisingly minimal compared with septic arthritis, and in up to 25% of cases the symptoms may be subtle with parents only noticing a limp and joint swelling. In a young child there is reluctance to walk and bear weight with a return to crawling. There is a high risk for developing a relatively asymptomatic chronic uveitis, especially in ANA-positive individuals, requiring regular ophthalmology examinations to detect early changes. (See Table for guidelines and Uveitis later for treatment.) Other complications that can be prevented in most patients with proper treatment include growth discrepancies in muscle tone and bulk, leg length, and the development of micrognathia and joint contractures. Among children with oligoarthritis, 75% to 85% have a positive ANA (70% to 80% in persistent oligoarticular JIA and 80% to 95% in extended oligoarticular JIA), 10 with low to moderate titers (1 : 40 to 1 : 320). The rate of ANA positivity is even higher in girls with an early onset. 55 Patients are RF negative, although ACPAs have been detected in some patients with oligoarticular JIA, depending on the enzyme-linked immunoreceptor assay (ELISA) method used for screening. 11 Some suggest that ANA serology should delineate a homogeneous group of arthritis patients, independent of the course of arthritis and number of joints involved. 6 Table American Academy of Pediatrics Recommended Ophthalmologic Screening Frequency for Asymptomatic Uveitis in Juvenile Idiopathic Arthritis (JIA) Patients* 67 JIA Subtype Antinuclear Antibody Status Age of JIA Onset (yr) Duration of Disease (yr) Uveitis Risk Category Eye Examination Frequency (mo) Oligoarthritis or High 3 polyarthritis + 6 >4 Moderate >7 Low 12 + >6 4 Moderate 6 + >6 >4 Low Moderate 6 6 >4 Low 12 >6 NA Low 12 Systemic JIA NA NA NA Low 12 *Several investigators have recommended the most intensive screening ophthalmologic exams in ANA-positive girls with JIA onset <7 yr of age independent of JIA subtype. Patients with JIA onset <5 yr should have eye exams every 3 mo until 7 yr after JIA diagnosis. 64 On the other hand, in a large, German, population-based study using the International League of Associations for Rheumatology classification system of JIA, certain modifications were proposed that were less conservative than the American Academy of Pediatrics in terms of frequency of eye exams, so the timing of screening exams remains unclear. 65 NA, not applicable.

8 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis 1759 The typical child with oligoarticular JIA will have normal white blood counts, normal or mild to moderately elevated acute-phase reactants, and in some cases, mild anemia. Elevated acute-phase reactants may suggest other conditions with inflammatory features such as IBD or malignancy. Differential Diagnosis The differential diagnosis of oligoarticular JIA includes other JIA subtypes, especially ERA and psoriatic JIA; other rheumatic diseases of childhood; and nonrheumatic causes of joint pain and swelling such as septic arthritis, benign or malignant tumors, reactive arthritis, foreign body synovitis, pigmented villonodular synovitis, arterial-venous malformation, bleeding disorders (such as hemophilia), or severe trauma including nonaccidental injury. Mild trauma such as from a fall does not cause persistent joint swelling, and trauma is rarely a cause of joint swelling unless there is an internal derangement seen in older, not younger, children. Children with hypermobility can develop transient joint effusions after exercise, 56 but this should not be long-lasting swelling. Lyme disease (in an endemic area) can cause recurrent monoarticular arthritis (typically involving the knee and often popliteal cysts), usually for less than 6 weeks. As described earlier, ALL may present with bone and joint pain and swelling, often monoarticular. If there is any concern of malignancy or infection, a complete blood count with manual differential and peripheral smear is crucial and bone marrow examination should be performed if indicated. A common initial response by general pediatricians when evaluating children with joint pain or swelling is to believe the problem is mechanical. However, in young children and toddlers, orthopedic problems such as meniscal tears or ligamentous injury are exceedingly rare because of the nature of pediatric musculoskeletal development and anatomy. In general, ligaments and tendons are stronger than growing bone in children, and the bone-ligament or bone-tendon junction is the weakest link. Therefore fractures are more common in children than adults, but nonaccidental trauma should always be considered, especially in children younger than 3 years. Treatment The treatment strategies for extended versus persistent oligoarticular JIA differ in both the approach to therapy and the intensity of escalating treatment on the basis of the number of joints at risk for significant damage. For extended oligoarticular JIA, treatment approaches are similar to RF-positive or RF-negative polyarticular JIA because these subtypes all have polyarticular involvement (see Figure 107-1). Treatment of persistent oligoarticular JIA is usually approached in a stepwise fashion (Figure 107-2). For these patients with a history of arthritis in four or fewer joints, the initial treatment is an NSAID, with or without an adjunctive IAS, followed by MTX if there is an inadequate response to one or more IASs. Initiation of MTX was recommended in the ACR guidelines for JIA as initial treatment for children with oligoarticular JIA with high disease activity and poor prognostic features, defined as involvement of hip, cervical spine, ankle or wrist, high inflammatory markers, or radiologic changes. 9 Partial or complete remission on MTX can be induced in 60% to 70% with extended oligoarticular JIA. 15,57,58 TNF inhibition should be considered in resistant cases, often in combination with MTX. Concurrent sulfasalazine and hydroxychloroquine have been used with variable success. Sulfasalazine is more typically used with HLA-B27 associated arthritis and ERA. Escalation of therapy due to ongoing disease activity Moderate to severe disease activity and/or high-risk features (neck, hip, wrist, ankle involvement, erosions, or joint space narrowing) NSAID, IAS, and MTX Add TNF inhibitor 2-3 months 2-3 months Change TNF inhibitor or Change to abatacept Mild disease activity NSAID, IAS (repeat as needed) Add MTX 3 months Add TNF inhibitor Figure Persistent oligoarticular juvenile idiopathic arthritis (JIA) treatment algorithm including oligoarticular course psoriatic JIA. The treatment goal is remission of disease activity and is stratified by severity of disease. More disease activity or high-risk features should prompt diseasemodifying antirheumatic drug use as initial therapy, whereas nonsteroidal anti-inflammatory drug (NSAID) monotherapy could be used initially for 2 to 3 months. If NSAID monotherapy is ineffective, therapy should be escalated. IAS, intra-articular steroid; MTX, methotrexate; TNF, tumor necrosis factor.

9 1760 PART 16 RHEUMATIC DISEASES OF CHILDHOOD Special Considerations: Knee Monoarthritis Because knee monoarthritis is the most common presentation of oligoarticular JIA, specific management is discussed here. The two treatments to be considered are NSAIDs and IASs, with evidence that IASs may be more effective even though most pediatric rheumatologists use NSAIDs before IASs. 59 An initial trial of NSAIDs may be conducted with the hopes of avoiding IASs in some patients, but the risk of IASs must be weighed against the cost of continued active arthritis. Choosing among treatment strategies involves a tradeoff between several different outcomes including duration of active arthritis, potential for long-term complications, adverse effects of therapies, discomfort of daily medications or potentially painful procedures and anesthesia, as well as parental preferences. Synovectomy is not indicated in oligoarticular JIA. Outcome Long-term studies of adults treated before the use of biologic agents have shown that up to 50% of adults who had oligoarticular JIA may have ongoing active disease or functional problems in adulthood, 60 and the rate of remission after 6 to 10 years from onset of disease ranges only from 23% to 47%. 51,61 Ongoing disease activity and extension of joint involvement is related to a poor outcome and radiographic damage, 62 and therefore emphasis on control of disease activity is critical. Morbidity from long-term inflammation can cause problems as well such as leg-length discrepancy with knee arthritis, muscle atrophy, bony overgrowth, and joint contractions (Figure 107-3), as well as other growth abnormalities such as micrognathia. Figure Radiograph of a young girl with oligoarticular juvenile idiopathic arthritis involving the right knee, demonstrating bony hypertrophyof the affected knee, with leg-length discrepancy and flexion contracture. Patients with persistent oligoarthritis generally have the best outcome with 68% of patients achieving clinical remission off medication. 43,51 Patients with an extended oligoarticular JIA have higher cumulative duration of active arthritis, 43 more erosive disease, and a higher risk of chronic disability. 51 Only 31% of children with extended oligoarticular JIA achieved remission after discontinuing their medication. 43 Relapses occur, and within 2 years after clinical remission off medication, flares occurred in 47% of patients with persistent oligoarthritis and 67% of patients with extended oligoarthritis. 43 Diligence regarding ophthalmologic screening for asymptomatic uveitis needs to continue as described in Uveitis. UVEITIS Clinical Manifestations and Diagnostic Features Chronic anterior uveitis, defined as inflammation involving the anterior uveal tract including the iris and ciliary body, is the most frequent extra-articular manifestation of JIA. Uveitis is most common in oligoarticular JIA and RF-negative polyarticular JIA, with a prevalence ranging from 17% to 26% and 4% to 25%, respectively. It is rare in RF-positive polyarticular JIA and sjia. 10 Risk factors for uveitis include ANA positivity, being younger than 6 years of age at JIA onset, female sex, and oligoarticular subtype. 63 These risk factors of developing uveitis are larger influences in girls but not boys. 64 The interval from diagnosis of JIA to the development of uveitis is longer the younger the age at onset of JIA, especially in ANA-positive patients. 64 Overall, uveitis is observed in 30% of ANA-positive patients with JIA. 65 Chronic anterior uveitis is typically nongranulomatous and asymptomatic at onset, and if unrecognized it can lead to serious visual deficits. Because of its insidious onset, regularly scheduled screening by an experienced ophthalmologist with slit lamp examination is required for early diagnosis and treatment. Newly diagnosed patients are ideally screened within 6 weeks of diagnosis 66 because in 5% of cases, uveitis occurs before diagnosis of JIA. 67 The highest risk period for uveitis development is the first 4 years after arthritis onset, although the risk is never completely eliminated. 67 The frequency of ophthalmologic screening according to the American Academy of Pediatrics guidelines is determined by the degree of risk such as ANA status, age of JIA onset, and duration of disease shown in Table In children with HLA-B27 related disease, anterior uveitis occurs in 10% to 15% but is usually highly symptomatic and therefore does not require routine screening. 63 The severity of chronic anterior uveitis associated with JIA is unrelated to the severity of the underlying joint disease, and the clinical course of the uveitis and arthritis may not parallel one another. Disease is eventually bilateral in nearly two-thirds of patients, but both eyes are not always inflamed at the same time. 68 Treatment Differential Diagnosis When evaluating the etiology of uveitis, it is important to consider infectious causes, such as tuberculosis,

10 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis 1761 toxoplasmosis, cytomegalovirus, herpes simplex virus, syphilis, human immunodeficiency virus, Lyme disease, cat scratch disease, and fungus. Uveitis can be confined primarily to the eye or occur secondary to a systemic illness, such as in Behçet s disease, sarcoidosis, autoinflammatory syndromes, multiple sclerosis, TINU (tubulointerstitial nephritis and uveitis syndrome), and Vogt-Koyanagi-Harada syndrome. Although the cause of uveitis often remains idiopathic, it is important to not miss a malignancy such as lymphoma or retinoblastoma. 63 Uveitis is initially treated with topical corticosteroids and mydriatics, although in approximately 30% of patients the uveitis remains active even with topical or local treatment with subtenon corticosteroid injections, and immunosuppressive medications are indicated to attempt to aggressively control the inflammation and prevent poor visual outcomes. Although there are no prospective randomized controlled studies on the use of immunosuppressive medications in children with uveitis, several observational studies suggest the effectiveness of these treatments. MTX, either oral or parenteral, is usually the first choice of treatment and is also used as a steroid-sparing agent Other effective immunosuppressives include mycophenolate mofetil 72 and azathioprine, while cyclosporine has limited value. 73 Treatment of uveitis requires close collaboration between the affected child s rheumatologist and ophthalmologist. In cases of refractory inflammation, biologic agents should be considered. TNF inhibitors are the most commonly used, specifically infliximab and adalimumab, which appear to be more effective than etanercept The dosing range and frequency of infliximab varies widely when used for uveitis, and up to 10 mg/kg/month are often required for control and should be used with MTX to prevent development of anti-infliximab antibodies. Adalimumab is given 20 to 40 mg subcutaneously every 2 weeks, and when ineffective, it can be administered weekly. 78 A case series reported remission with the administration of abatacept 10 mg/kg intravenously monthly in six of seven patients refractory to immunosuppressives and TNF inhibition. 82 High-dose intravenous daclizumab, a humanized monoclonal antibody against IL-2 receptor, has been reported to be effective but is no longer available in the United States. 83 In the past, ophthalmologists were concerned about primary placement of intraocular lens in JIA patients with history of uveitis with subsequent formation of cataracts. 84 Now, with the more widespread practice of strict control of uveitis, good visual outcomes with cataract surgery and intraocular lens placement can be achieved using aggressive systemic immunomodulatory therapy perioperatively. 85 The general expert opinion among uveitis specialists is to try to taper immunomodulatory therapy after 12 to 24 months of quiescence of uveitis; however, this has not been studied. 86 Outcome Complications resulting from uveitis include posterior synechiae, cataract, band keratopathy, glaucoma, papillitis, or cystoid macular edema. Posterior synechiae (fibrous bands adhering the iris to the lens, Figure 107-4) result in a distorted papillary border. Band keratopathy (a layer of calcium deposited in Bowman s membrane of the cornea), is not Figure Chronic anterior uveitis associated with oligoarticular and polyarticular rheumatoid factor negative juvenile idiopathic arthritis, demonstrating posterior synechiae and absence of significant sclera inflammation. uncommon. Cataracts and glaucoma may develop as a complication of the uveitis or its treatment, so chronic monotherapy with topical corticosteroids should be avoided. The reported rate of visual loss due to JIA-related uveitis has decreased from 22% to 66% in studies before 1990 to 3% to 25% in newer studies, suggesting that newer and more aggressive approaches are effective. 87 Ongoing active intraocular inflammation with greater than or equal to 0.5+ cells was associated with increased risk of visual impairment and blindness. Prognostic factors in JIA-associated uveitis are not clearly identified, and the results of the studies are often controversial. Different studies have revealed the following as potential factors associated with poor prognosis: short intervals between the diagnosis of arthritis and uveitis, severity of uveitis at first examination, 91,92 signs of anterior chamber involvement (cells and flare), 92 and male gender JUVENILE PSORIATIC ARTHRITIS Clinical Manifestations and Diagnostic Features Juvenile psoriatic arthritis (JPsA) was initially defined as juvenile-onset arthritis associated with psoriasis occurring at some point during the disease course. This definition has been expanded to include not only patients with overt psoriatic lesions but also arthritis who only have nail abnormalities or a first-degree relative with overt psoriasis. 94,95 JPsA represents 2% to 15% of all JIA with slight female preponderance and a bimodal pattern of onset (2 to 4 years and 7 to 10 years). 94,96,97 The psoriasis typically occurs within

11 1762 PART 16 RHEUMATIC DISEASES OF CHILDHOOD 2 years of the onset of arthritis, and for the majority of children the skin symptoms follow the arthritis symptoms. 98 Up to 80% of children have a classic psoriatic vulgaris or plaque psoriasis characterized by well-demarcated erythematous scaly lesions occurring over extensor surfaces (elbows and knees), scalp, and trunk However, in small children younger than the age of 2, the most common finding is psoriatic diaper rash. 100 Additional areas that should be evaluated include the hairline behind the ears, the navel, the groin region, and superior to the gluteal cleft. 98 Because JPsA shares similar manifestations with multiple subtypes of juvenile arthritis, there is not one specific articular presentation. Patterns of joint involvement can be similar to both oligoarticular or polyarticular JIA with 60% to 70% of JPsA patients having an oligoarticular onset (<5 joints). 101 There were no differences in ANA or HLA-B27 positivity, or frequency of uveitis between oligoarticular JIA and JPsA with fewer than 5 joints at onset, although dactylitis was more frequent, reported in 15% to 37% of JPsA. 54,94,102 When JPsA subjects who had a polyarticular type course were compared with polyarticular JIA subjects, there was also no difference seen in ANA positivity, HLA-B27 positivity, and dactylitis. JPsA is associated with subacute anterior uveitis and ANA positivity in 15% to 20% of children with JPsA. 102 A recent study of childhood psoriatic arthritis argued for two distinct subpopulations: (1) a younger group (median age, 2.7 years), ANA positive, with a female preponderance, all of whom had dactylitis and more persistent disease, and (2) an older group (median age 9.5 years), more likely to be oligoarticular, have axial disease and enthesitis, and have higher remission rates. 94 Children with psoriatic arthritis may have mild elevated acute-phase reactants (ESR, C-reactive protein [CRP], and platelets) and a mild anemia of chronic disease. However, up to one-third have no laboratory evidence of inflammation. Serologies and HLA associations are noted earlier. Treatment To date there have been no controlled studies examining the efficacy of antirheumatic medications in JPsA. A recent study compared treatment regimens of JPsA patients versus olgioarticular and polyarticular JIA patients and found no difference in use of NSAIDs, MTX, and TNF inhibitors. 102 In general, the treatment of JPsA should follow the treatment approaches for oligoarticular or RF-negative polyarticular JIA (see Figures and 107-2) depending on the patient s pattern of joint involvement. MTX is of benefit for both the skin psoriasis and arthritis and, when used in children, is recommended as a single weekly dose rather than split doses. 99 In children with more aggressive disease, TNF inhibitors (which have also been successful in treating psoriasis) are indicated and may significantly limit bony destruction. 100,103,104 Regular screening for uveitis is required, especially in ANA-positive patients with both oligoarticular and polyarticular courses, with monitoring and management as described later in Uveitis. Outcome Because of the heterogeneity in the patterns of arthritis in JPsA, the outcomes are variable and tend to track with the pattern of joint involvement. Although in one study erosions were less common in JPsA compared with polyarticular JIA (23% vs. 46%, respectively), there appears to be more persistent disease activity and more evidence of physical limitations and ongoing disease activity continuing into adulthood in patients with JPsA compared with oligoarticular and polyarticular JIA patients. 95,105 The uveitis of psoriatic arthritis, like that of oligoarticular disease, can lead to blindness if untreated. ENTHESITIS-RELATED ARTHRITIS/ JUVENILE SPONDYLOARTHROPATHY Clinical Manifestations and Diagnostic Features The current ILAR category of ERA is a spectrum that includes spondyloarthropathies, juvenile ankylosing spondylitis, and SEA (spondylitis enthesitis and arthritis). ERA accounts for about 20% of JIA in one U.S. study, 47 but previous classification schemas have included JPsA within spondyloarthropathies resulting in variability in incidence and prevalence data. 106 In some cases, patients are first diagnosed as oligoarticular JIA, but characteristics of ERA later evolve. ERA occurs after age 6 and is more common in boys (maleto-female ratio of 7 : 1), although it may be under-recognized in symptomatic girls who can have milder disease with less axial skeleton involvement. 107 The typical feature of ERA is the presence of enthesitis, or inflammation of the tendons and ligaments where they attach to bone (or enthesis). It is an early manifestation and occurs more frequently in children than in adult-onset ankylosing spondylitis (AS). 98 The typical enthesitis sites are around the patella (at the 2, 6, and 10 o clock positions); Achilles tendon; plantar fascia insertions into the calcaneus and metatarsal heads, greater trochanter, tibial tuberosity, and the base of the fifth metatarsal. Children may report vague buttock pain, groin pain, or heel pain, and a classic finding is of tarsitis with inflammation of the subtalar joint and surrounding tendon sheaths. At onset spinal symptoms are rare, but a subgroup of children with ERA will progress to features more typical of adult AS with SI joint and spinal inflammation during adolescence. This progression is more likely in boys who are HLA-B27 positive and have spinal or sacroiliac pain within 1 year of diagnosis. 108 The modified Schober s test can be used to evaluate lower lumbar flexibility with a change less than 6 cm being abnormal. 109 Because thoracic excursion varies greatly in a growing child, only performing sequential measurements are helpful. In the adolescent, any thoracic excursion less than 5 cm should be regarded as abnormal. 98 ERA is associated with an acute anterior uveitis (AAU) in 6% to 27% of children, which typically presents as an acutely red, painful eye that needs immediate medical attention to avoid blindness. 98,110,111 Cardiovascular disease, although uncommon, can be severe in patients with ERA that has evolved into juvenile ankylosing spondylitis, with inflammatory aortic regurgitation reported in up to 10% of patients. 112 Restrictive pulmonary disease has been seen in juvenile spondyloarthritis without clinical or radiologic findings. Reactive arthritis is categorized under ERA, following infection with organisms from the gastrointestinal tract

12 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis 1763 (e.g., Salmonella, Shigella, Yersinia, Campylobacter, Clostridium difficile) or genitourinary tract (i.e., Chlamydia or Ureaplasma) without actual infection in the joint tissues. Usually self-limited, the arthritis can persist and transform into a more chronic arthropathy. 113 In addition to the arthritis, urethritis and uveitis have been documented in children to complete the classic triad for reactive arthritis. The clinical infection usually precedes the arthritis, enthesitis, or extraarticular disease by 1 to 4 weeks. Arthritis associated with IBD (Crohn s disease or ulcerative colitis) is seen in children, and two distinct patterns of joint involvement are noted: (1) peripheral arthritis and (2) sacroiliitis and spondylitis, with the former more common than the latter. Additional clinical manifestations unique to arthritis associated with IBD include clubbing, periostitis, erythema nodosum, pyoderma gangrenosum, osteoporosis, and rarely hypertrophic osteoarthropathy. The peripheral arthritis activity has been shown to correlate with gut disease activity unlike the SI joint activity, which tends not to correlate. 109 Compared with adults, in whom radiologic evidence of sacroiliitis is the diagnostic hallmark of ankylosing spondylitis, radiologic evaluation in children with ERA is less often diagnostic because sacroiliitis is rare as a presenting symptom. Magnetic resonance imaging (MRI) with contrast is being increasingly used to detect evidence of acute sacroiliitis without chronic changes in children. MRI has also been used to evaluate enthesitis. 114 HLA-B27 is present in 80% to 90% of cases depending on ethnicity. The ESR may be mildly or markedly raised, and there may be a mild anemia, but these should also raise the suspicion that the child may have subclinical IBD. RF is negative, and ANA may be positive. Differential Diagnosis Children with true infectious arthritides (viral, rheumatic fever, poststreptococcal, Lyme) can present with similar manifestations as ERA patients. More benign entities such as toxic synovitis and benign limb pains of childhood (growing pains), as well as more concerning entities such as malignancies and solid tumors, should be considered. Orthopedic diagnoses such as Legg-Calvé-Perthes disease, slipped capital femoral epiphyses disease, and Osgood- Schlatter disease and less common rheumatologic diseases such as SAPHO (synovitis, acne, pustulosis, hyperostosis, and osteomyelitis), Kawasaki s syndrome, and vasculitis can share similar articular and extra-articular manifestations with ERA. Lastly, children with widespread amplified musculoskeletal pain may have tender entheses that can be mistaken for enthesitis. Treatment Treatment of ERA ranges from NSAIDs to DMARDs with the use of biologics in the most aggressive cases. To date there have been few randomized controlled trials in this population. One study of sulfasalazine showed no significant effects in juvenile spondyloarthropathy, whereas another showed good response in oligoarticular- and polyarticularonset JIA patients. 115,116 Most respond well to intra-articular corticosteroid injections, but many may need a DMARD. For severe symptoms or evidence of potential joint damage (such as erosive sacroiliitis), the use of TNF inhibitors has been effective on the basis of small pediatric studies. 117,118 Outcome Long-term outcome of ERA is unknown, but a proportion of these children may progress to the adult form of AS. Predictors of sacroiliitis were HLA-B27 positivity, absence of DPB1*02, hip joint involvement within the first 6 months, and disease onset after age 8 years. 119 When compared with adult-onset ankylosing spondylitis, juvenileonset ankylosing spondylitis had less severe axial involvement but worse hip involvement, and in some studies, worse functional impairment. 120,121 The probability of remission remains low with remission rates reported ranging from 17% to 44%. Predictors for failure to achieve remission include family history of AS in first-degree relative, female sex, younger age at disease onset, arthritis in ankle joint within 6 months of disease onset, and HLA- DRB1* Minden and colleagues 50 showed that if ERA persisted for more than 5 years, the chance of remission was only 17%. SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS Clinical Manifestations and Diagnostic Features sjia, which makes up 10% of all JIA, has unique characteristics that include fever, specific rash, and significantly elevated inflammatory markers in addition to arthritis. Recent research has identified biologic differences between sjia and the other subcategories including prominent involvement of components of the innate immune system (in particular, inflammatory cytokines IL-1, IL-6, IL-18, neutrophils, and monocytes/macrophages), suggesting that sjia may be in the autoinflammatory disease spectrum. 123 sjia occurs at any age with a tendency toward younger than 5 years peaking around 2 years of age. 124,125 Rarely it occurs in adults and is called adult-onset Still s disease. The gender predilection has stayed neutral, and some studies have suggested that sjia may be relatively more frequent in Asian countries. 125 The systemic features of this disease are striking and are always present at onset, often predominating the clinical presentation. The arthritis may not be clinically present at onset, although arthralgias and myalgias are almost universally present at onset. 98 The fever is typically spiking in character with a peak of at least 39 C daily, occurring once or twice a day. Interestingly, the temperatures can become subnormal between fevers. The child is usually unwell and irritable during the fever but often recovers in between. In 80% of patients, the fevers are accompanied by an evanescent, migratory, salmon pink, and sometimes urticarial macular rash (Figure 107-5). 124 The rash typically spares the face and can occur without specific pattern on any part of the trunk or extremities. It can be subtle and scattered or diffuse and almost confluent. A helpful diagnostic feature is that the rash can be elicited by the Koebner phenomenon in which rubbing or scratching the skin elicits the rash. Other systemic features include lymphadenopathy, hepatosplenomegaly, serositis (pleural/pericardial involvement/

13 1764 PART 16 RHEUMATIC DISEASES OF CHILDHOOD the clinician to a different diagnosis. Other childhood rheumatic diseases should be considered such as systemic lupus erythematosus, Behçet s syndrome, and others. Figure Typical rash of systemic juvenile idiopathic arthritis, with small 1- to 5-mm flat or slightly raised salmon pink macules. abdominal pain), headaches, and sore throat. sjia has the most common and severe cardiac presentations of all the subtypes of JIA. Pericarditis and pericardial effusions are the most common organ system manifestations, occurring in up to 10% of the presentations. 124 A serious lifethreatening systemic manifestation called macrophage activation syndrome (MAS) is discussed in more detail later. The arthritis in sjia can be varied from minimal to oligoarticular to polyarticular presentation 124 and typically does not correlate with the severity of the systemic manifestations. 126 Tenosynvositis and synovial cyst formation can also be seen. Although the systemic manifestations can be serious initially, the long-term morbidity is due to articular disease and adverse effects of medications, especially chronic corticosteroids. There are no diagnostic tests for sjia, but there are characteristic patterns of laboratory abnormalities including high inflammatory markers (CRP, ESR), significant leukocytosis with neutrophilia and bandemia, thrombocytosis, and anemia. Liver transaminases, aldolase, ferritin, fibrin split products, and coagulation screen may be abnormal in severe cases and can be signs of early or impending macrophage activation syndrome (MAS). ANA or other autoantibodies are rarely present. Inflammatory cytokine gene expression profiles have been shown to distinguish sjia from other febrile inflammatory diseases seen in children and may lead to more specific tests in the future. 127 Differential Diagnosis Due to the nonspecific nature of the characteristics of sjia, the diagnosis can be difficult and should be approached as a diagnosis of exclusion. Infections, Kawasaki s syndrome, malignancy, and other autoimmune diseases can present with similar symptoms; therefore it is necessary to screen for infectious agents and neoplasia, especially leukemia and neuroblastoma with appropriate tests including cultures, bone marrow aspiration and biopsy, and urinary vanillylmandelic acids. Some physicians do these tests routinely because malignancies are often close mimics to the early stages of sjia. The recurrent fever syndromes are often mistaken for sjia, but the character of the fevers and the fixed rashes associated with these syndromes should alert Special Considerations: Macrophage Activation Syndrome About 10% of the sjia patients will develop overt lifethreatening MAS, and up to 30% will develop a milder form, which if inadequately treated could lead to full-blown MAS MAS is a form of secondary or acquired hemophagocytic lymphohistiocytosis (HLH) seen within rheumatic disease. Two-thirds of the mortality seen in all patients with JIA are due to this entity. 131 The main manifestations include unrelenting high fevers, hepatosplenomegaly, lymphadenopathy, severe cytopenias, liver dysfunction, central nervous system (CNS) involvement (seizures/ coma), and coagulopathy (Table 107-4). The ferritin often exceeds 10,000 ng/ml, and coagulopathy can be impressive with elevated prothrombin and partial thrombin times, hypofibrinogenemia, petechiae, mucosal bleeding, epistaxis, Table Preliminary Diagnostic Guidelines for Macrophage Activation Syndrome (MAS) Complicating Systemic Juvenile Idiopathic Arthritis (sjia) 179 Laboratory Criteria Decreased platelet count ( /L) Elevated levels of aspartate aminotransferase (>59 U/L) Decreased white blood cell count ( /L) Hypofibrinogenemia ( 2.5 g/l) Clinical Criteria Central nervous system dysfunction (irritability, disorientation, lethargy, headache, seizures, coma) Hemorrhages (purpura, easy bruising, mucosal bleeding) Hepatomegaly ( 3 cm below the costal arch) Histopathologic Criterion Evidence of macrophage hemophagocytosis in the bone marrow aspirate Diagnostic Rule The diagnosis of MAS requires the presence of any 2 or more laboratory criteria or of any 2 or 3 or more clinical and/or laboratory criteria. A bone marrow aspirate for the demonstration of hemophagocytosis may be required only in doubtful cases. Recommendations The aforementioned criteria are of value only in patients with active sjia. The thresholds of laboratory criteria are provided by way of example only. Comments The clinical criteria are probably more useful as classification criteria rather than as diagnostic criteria because they often occur late in the course of MAS and therefore may be of limited value for the early suspicion of the syndrome. Other abnormal clinical features in sjia-associated MAS, not aforementioned, may include nonremitting high fever, splenomegaly, generalized lymphadenopathy, and paradoxical improvement of signs and symptoms of arthritis. Other abnormal laboratory findings in sjia-associated MAS, not aforementioned, may include anemia, erythrocyte sedimentation rate fall, elevated levels of alanine aminotransferase, increased bilirubin, presence of fibrin degradation products, elevated lactate dehydrogenase, hypertriglyceridemia, low sodium levels, decreased albumin, and hyperferritinemia.

14 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis 1765 and hematemesis. Often MAS is heralded by a decrease of the ESR, leukocyte and platelet counts, and liver dysfunction. 132 Histologically, patients with MAS show expansion of well-differentiated macrophages exhibiting hemophagocytosis in the bone marrow, lymph nodes, and other organs such as the liver and lungs. There is no gender, age, or race predilection for MAS in sjia. 132 It often occurs during active systemic disease but has also been seen in the quiescence phase of the disease (no clinical symptoms but still on medications). 133 Triggers for MAS in sjia include bacterial, fungal, and parasitic infections. Epstein-Barr virus, varicella, coxsackie, parvovirus B19, hepatitis A, Salmonella, and Pneumocystis infections have been implicated. Drugs have also been implicated including aspirin, NSAIDs, sulfasalazine, MTX, etanercept, anakinra, and gold salts. One must be cautious to quickly lay blame because many patients who are receiving these medications have active disease and may have been developing MAS despite the medications. 132,134 Most of the time, the trigger is unknown. Poor natural killer cell cytolytic activity leading to low levels of perforin expression has been reported in sjia, a unique finding compared with the other subtypes of JIA. 128,132,135 Soluble IL-2Rα receptors and soluble CD163 are increased severalfold in MAS. 128,136 Treatment sjia is an active area of research with increasing understanding of the autoinflammatory biology and the potential therapeutic roles for targeted biologics. Therapies such as MTX and TNF inhibition are less helpful in sjia compared with other forms of JIA. 45,125,137,138 An approach to treating sjia is shown in Figure 107-6, separating this complex disease into different severities and manifestations. This algorithm is consistent with the recently published ACR guidelines for JIA. 9 Mild sjia, defined as mild systemic symptoms without organ system involvement and synovitis, can be successfully treated with anti-inflammatory doses of NSAIDs. Certain NSAIDs are helpful for different aspects of the disease (e.g., indomethacin can be used for fever control and serositis symptoms). In addition, if there are only a few large joints involved, intra-articular steroid injections are an additional option. In the more severe cases with persistent fevers, cardiopulmonary symptoms, significant anemia, and significantly elevated inflammatory markers, corticosteroids may be used, often given as pulsed intravenous high-dose methlyprednisolone (30 mg/kg/dose) daily for 3 days in a row followed by tapering doses of oral prednisolone. 139 Increasingly, as shown in Figure 107-6, IL-1 or IL-6 inhibition is instituted to avoid steroid toxicity and in some recent studies is being used as initial therapy before corticosteroids. 140 Use of DMARDs and TNF inhibitors may be more helpful for more significant articular disease. TNF inhibition has been shown to be effective in some patients with sjia, though to a lesser extent than in other types of JIA. 137 Similarly, MTX may be helpful in sjia with prominence of articular symptoms over systemic features. 9 Cyclosporine as Rapid escalation of therapy as needed Severe systemic features with or without synovitis MAS/impending MAS Serositis Pulse MP Pred. 2 mg/kg/day IL-1 inhibition or IL-6 inhibition Ongoing MAS CSA, immunosuppressive agents (e.g., VP-16, CYC) Pulse MP Pred. 2 mg/kg/day and/or IL-1 inhibition or IL-6 inhibition Moderate systemic symptoms with or without synovitis NSAID, IAS and Pulse MP or low-dose Pred. and/or IL-1 inhibition or IL-6 inhibition 2 months Increase dose of cytokine inhibitors 2-6 months Synovitis with mild, systemic symptoms NSAID, IAS 1-2 months Add IL-1 inhibition or IL-6 inhibition Increase dose Add methotrexate and/or TNF inhibitors if synovitis predominates Escalation of therapy due to ongoing disease activity Other; e.g., lenalidomide/thalidomide, calcineurin inhibitors, abatacept, stem cell transplant Figure Systemic juvenile idiopathic arthritis treatment algorithm. The treatment goal is remission of disease activity, both systemic and articular, and is stratified by severity of disease. Algorithm is divided into severe systemic disease manifestations (macrophage activation syndrome [MAS], serositis) or synovitis with milder systemic disease. Currently there is significant variability in practice regarding using corticosteroid as initial systemic therapy or moving directly to inflammatory cytokine inhibitors. At the time of this writing, interleukin (IL)-1 inhibition and IL-6 inhibition are currently in trials, and more information is likely to be available in the future. CSA, cyclosporine A; CYC, cyclophosphamide; IAS, intra-articular steroid; MP, methylprednisolone; NSAID, nonsteroidal anti-inflammatory drug; Pred., prednisone; TNF, tumor necrosis factor.

15 1766 PART 16 RHEUMATIC DISEASES OF CHILDHOOD well as monthly intravenous immunoglobulin have shown some benefit in systemic symptoms and can be used for steroid-sparing effects. 140,141 Unfortunately, effectiveness of these DMARDS is much less than in other subtypes of JIA with cyclosporine less than MTX. The newer biologics that block IL-6 and IL-1 signaling are promising according to the recent elucidations in the pathophysiology of sjia, as well as recent clinical trials and studies. Initial reports on IL-1 blockade using anakinra showed rapid and sustained remission within a few days in sjia patients with chronic disease activity resistant to conventional therapy. 142 However, more recently reports have called into question the sustainability of the response using these medications. 140,143,144 Newer IL-1 inhibitors such as rilonacept (currently being studied in a clinical trial, NCT ) and anti-il-1β monoclonal antibody (canakinumab) may shed more light on the effectiveness of these therapies and the biology of the responses. Two phase III placebo-controlled, double-blind trials using the IL-6 receptor antagonist tocilizumab showed significant improvement of ACR Pedi 30, 50, and 70 responses. 145,146 In the TENDER trial, the tocilizumab dose for patients less than 30 kg was 12 mg/kg/dose and for greater than 30 kg was 8 mg/kg/dose every 2 weeks. 145 Thalidomide has also been reported to improve symptoms in refractory sjia patients. 147 The teratogenic potential of thalidomide and its newer analogue lenalidomide limits the usefulness of these medications. 148 Abatacept has been used in sjia patients who have failed previous treatments. In the open-label portion of a doubleblind placebo-controlled trial of abatacept therapy in JIA patients, 24 of 37 (65%) of sjia patients had an ACR Pedi 30 response. This was comparable with the other JIA subtypes evaluated in that study. 38 The 2010 ACR guidelines for JIA treatment divided sjia treatment into two groups: active systemic features and active arthritis. But the guidelines did not include patients with MAS, impending MAS, or life-threatening manifestations (e.g., cardiac tamponade). 9 The algorithm shown in Figure incorporates some of the principles from the guidelines, expanding the area s severe systemic disease and MAS. One difference is that the guideline supports earlier use of methotrexate and TNF inhibition in patients with active sjia with primarily articular manifestations. The optimal treatment for MAS continues to be controversial. Therapy should be aggressive and usually starts with high-dose steroids and disease-modifying agents such as cyclosporine and IL-1 blockade. 149,150 Almost 50% of patients in one study showed response to steroids alone. 134 A consensus treatment protocol for HLH has been published and uses a combination of VP-16 (etoposide), dexamethasone, with or without intrathecal methotrexate, followed by a maintenance with cyclosporine A. 151 This protocol or parts of it have been used with MAS in sjia patients with success. 152 However, the new use of the powerful IL-1 and IL-6 inhibitors may preclude the need for the HLH approach with its potential serious bone marrow suppression. 151 For the severe refractory cases, stem cell transplantation has been done. A recent review of the experience showed favorable response with more than 50% sustained drug-free remission. Early experience demonstrated cases of induction of MAS during transplant conditioning and immediately post-transplant. This early morbidity has improved with less intense conditioning regimen. 153 A follow-up study reported that late relapses were noted with lower percentages for drug-free long-term outcome. The late relapses were often less severe and treated successfully with conventional drugs Outcome sjia is heterogeneous in severity, disease course, and outcome. Studies of the natural history of sjia before biologic therapies demonstrate that the course can be monocyclic, with remission within 2 to 4 years; relapsing, characterized by flares of systemic features with mild arthritis; or continuous with persistent destructive arthritis, often more prominent after the regression of systemic features. 125,157 Patients with severe disease can have flares of extra-articular features at any time and may have active arthritis into adult life despite standard therapies. 157 Emerging evidence suggests that IL-1 and IL-6 inhibitors have permitted significant disease control with no or much lower doses of corticosteroids, which were one of the major causes of morbidity in sjia in the past. Predictors of poor articular outcome in sjia include the systemic features 6 months after onset, thrombocytosis, and the presence of polyarthritis with hip involvement. 126,158,159 The mortality rate for sjia is still perceived to be higher than the mortality rate associated with other subtypes of JIA in clinical practice now, although no formal figures are available. As a result of the inadequate control of the disease with the available therapies, growth failure and osteoporosis are serious and lasting complications. The use of growth hormone (GH) is now more accepted with recent reviews outlining the safety of its use in sjia. Growth hormone therapy can improve linear growth even during active phase of the disease, resulting in an ultimate higher final height. 160 Amyloidosis was previously a major cause of death in sjia but is now less common, most likely due to the use of more aggressive therapy to better control inflammation. Recently MEFV mutations seen in familial Mediterranean fever have been identified in sjia patients, and these patients were noted to have the most resistant disease. 161 Pulmonary hypertension has also been reported in a few case reports and one case series. 162 IMAGING Imaging is important in JIA to confirm the diagnosis; to exclude other diseases such as infection, malignancy, osteoid osteoma, or avascular necrosis; and to monitor therapy. Determining the presence of cartilage loss and erosions are complicated by the anatomically changing joints during the normal growth process. Because children have a large amount of cartilage in their joints, a significant amount of destruction can occur before erosions are identified on plain radiographs (Figure 107-7). Local growth disturbances can also be seen in children including bony overgrowth, particularly in the small joints of the hands and feet and in the knees, likely due to chronic hyperemia. Bony hypertrophy around the knee joints can lead to leg-length discrepancies,

16 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis 1767 marrow edema, which has been shown to be an important predictor of erosive joint damage in RA patients, but the connection is not established in JIA patients. For evaluating bony erosions, MRI was found to be the most sensitive imaging modality in wrists of JIA patients, revealing more than twice as many erosions compared with plain radiography and US. 171 Pilot MRI grading scores of hip and knee disease activity and damage in JIA have been proposed but not validated. 164 A recent systematic review of the literature assessed that the overall quality of the reporting of methods in studies on the MRI assessment of JIA is heterogeneous and fair overall. 172 Figure Plain radiograph of a young child with active polyarticular juvenile idiopathic arthritis, demonstrating the challenge in evaluating joint damage in the growing child. Periarticular osteoporosis and early periostitis of the metacarpals are noted. permanent gait disturbances, and secondary scoliosis (see Figure 107-3). In contrast, premature fusion of the epiphyses can lead to shortening of certain joints, most notably the TMJs, leading to micrognathia Interestingly, the articular cartilage of growing children has been shown to have unique regenerative qualities and studies have shown that children with JIA can have improvement in their radiographic joint damage. 165 Plain radiographs in patients with JIA show soft tissue swelling as an early but nonspecific finding. The most common form of radiographic damage in JIA is joint space narrowing due to erosion, thinning, and loss of articular cartilage. 163,165 Periarticular osteopenia due to hyperemia of inflamed joints is frequently seen. Erosions and ankylosis can be seen as late findings in radiographs. 163 Lastly, periostitis along the shafts of the phalanges, metacarpals, and metatarsals and calcifications from steroid joint injections can be seen. The trend toward early aggressive treatment to prevent erosive disease shifts the imaging need away from plain radiographs and toward other imaging modalities that are more sensitive in detecting early disease activity. 164 Therefore MRI and ultrasound (US) are becoming more popular. US is reliable, safe, and relatively inexpensive but not as well standardized in children as in adults. It has been shown to be more sensitive than plain radiography in the detection of effusion, synovial thickening, and synovial cysts. In more experienced hands, cartilage thinning and bone erosions can also be seen. Inflammatory involvement of the hip, shoulder, and elbow is more frequently accurately detected by US compared with clinical examination. 166,167 Color and power Doppler US can facilitate the evaluation of hyperemia and vascular abnormalities in affected joints and tendon involvement. 168 MRI is the most sensitive imaging modality currently available for detecting synovial inflammation; however, its use is limited by expense and the need for anesthesia in young children. With the use of contrast, accurate differentiation between active and inactive states can be established. Synovial enhancement and thickening can easily be seen, 169 and pannus volume measurements can be tracked. 170 MRI is the only technique available to visualize bone SPECIAL CONSIDERATIONS: REHABILITATION IN CHILDREN PT and OT play a crucial role in JIA patients. PT and OT can consult for stretches, range-of-motion evaluation, joint protection, muscle building and strengthening, as well as endurance and graduated aerobic activity. Children who present late in the course of oligoarthritis may already have flexion contractures, which require splinting and serial casting. Serial casting is done two or three times a week for up to a month if necessary and is probably most effective when started just after joint injections. Some children with marked leg-length discrepancy (resulting from overgrowth of the affected knee) may require a shoe lift/raise. Strict limitations from physical education at school and sports are generally not encouraged because physical activity plays an important role in rehabilitation and therapy; however, impact sports should be limited in the presence of joint effusions or when there is a concern for joint instability (e.g., C1/C2 atlantoaxial subluxation). A modified physical education program and sports activities to the patients own tolerance are recommended instead. Orthotics can be helpful in foot involvement in ERA, as well as other types of JIA. Although there is a wide within-patient and betweenpatient variability, children with early-disease onset and a greater number of restricted joints have the highest risk of developing long-term functional physical disability. 173 In addition, health-related quality of life was significantly lower in patients with JIA than in healthy children, and patients with persistent oligoarthritis were less severely affected compared with the other JIA subcategories. 174 Total energy and activity-related energy expenditure, as well as physical activity levels, were significantly lower in JIA patients compared with controls, and only 23% of the JIA patients met the public health guidelines on physical activity compared with 66% in controls. 175 SUMMARY The modern treatment of JIA has significantly decreased the long-term burden of disease but requires early recognition and diagnosis. It also requires aggressive treatment to extinguish disease activity and multidisciplinary approaches to maintain and improve function and quality of life. Pediatric rheumatologists have in their favor the remarkable capacity for childhood growth and development to allow repair and restoration of function, in contrast to adults with

17 1768 PART 16 RHEUMATIC DISEASES OF CHILDHOOD inflammatory arthritis. The advent of new biologic therapies and rapid translation of basic research into therapeutic strategies and an increased willingness on the part of regulatory bodies to make new therapies available to children should combine to continue to improve the outlook for children with arthritis. Selected References 1. Helmick CG, Felson DT, Lawrence RC, et al: Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: part I, Arthritis Rheum 58(1):15 25, Oen K, Duffy CM, Tse SML, et al: Early outcomes and improvement of patients with juvenile idiopathic arthritis enrolled in a Canadian multicenter inception cohort, Arthritis Care Res (Hoboken) 62(4): , Hyrich KL, Lal SD, Foster HE, et al: Disease activity and disability in children with juvenile idiopathic arthritis one year following presentation to paediatric rheumatology. 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juvenile idiopathic arthritis: initiation and safety monitoring of therapeutic agents for the treatment of arthritis and systemic features, Arthritis Care Res 62: , Macaubas C, Nguyen K, Milojevic D, et al: Oligoarticular and polyarticular JIA: epidemiology and pathogenesis, Nat Rev Rheumatol 5(11): , Albers HM, Brinkman DMC, Kamphuis SSM, et al: Clinical course and prognostic value of disease activity in the first two years in different subtypes of juvenile idiopathic arthritis, Arthritis Care Res (Hoboken) 62(2): , Bartoli M, Tarò M, Magni-Manzoni S, et al: The magnitude of early response to methotrexate therapy predicts long-term outcome of patients with juvenile idiopathic arthritis, Ann Rheum Dis 67(3): , Lovell D, Giannini E, Reiff A, et al: Etanercept in children with polyarticular juvenile rheumatoid arthritis, N Engl J Med 342(11): , Ruperto N, Murray KJ, Gerloni V, et al: A randomized trial of parenteral methotrexate comparing an intermediate dose with a higher dose in children with juvenile idiopathic arthritis who failed to respond to standard doses of methotrexate, Arthritis Rheum 50(7): , Albers HM, Wessels JAM, van der Straaten RJHM, et al: Time to treatment as an important factor for the response to methotrexate in juvenile idiopathic arthritis, Arthritis Rheum 61(1):46 51, Horneff G, De Bock F, Foeldvari I, et al: Safety and efficacy of combination of etanercept and methotrexate compared to treatment with etanercept only in patients with juvenile idiopathic arthritis (JIA): preliminary data from the German JIA Registry, Ann Rheum Dis 68(4): , Lovell DJ, Giannini EH, Reiff A, et al: Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multicenter, openlabel, extended-treatment trial, Arthritis Rheum 48(1): , Lovell DJ, Reiff A, Jones OY, et al: Long-term safety and efficacy of etanercept in children with polyarticular-course juvenile rheumatoid arthritis, Arthritis Rheum 54(6): , Lovell DJ, Reiff A, Ilowite NT, et al: Safety and efficacy of up to eight years of continuous etanercept therapy in patients with juvenile rheumatoid arthritis, Arthritis Rheum 58(5): , Southwood TR, Foster HE, Davidson JE, et al: Duration of etanercept treatment and reasons for discontinuation in a cohort of juvenile idiopathic arthritis patients, Rheumatology (Oxford) 50: , Giannini EH, Ilowite NT, Lovell DJ, et al: Long-term safety and effectiveness of etanercept in children with selected categories of juvenile idiopathic arthritis, Arthritis Rheum 60(9): , Vojvodich PF, Hansen JB, Andersson U, et al: Etanercept treatment improves longitudinal growth in prepubertal children with juvenile idiopathic arthritis, J Rheumatol 34(12): , Ruperto N, Lovell DJ, Cuttica R, et al: A randomized, placebocontrolled trial of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis, Arthritis Rheum 56(9): , Ruperto N, Lovell DJ, Cuttica R, et al: Long-term efficacy and safety of infliximab plus methotrexate for the treatment of polyarticular-course juvenile rheumatoid arthritis: findings from an open-label treatment extension, Ann Rheum Dis 69(4): , Lovell D, Ruperto N, Goodman S, et al: Adalimumab with or without methotrexate in juvenile rheumatoid arthritis, N Engl J Med 359(8): , Ruperto N, Lovell DJ, Quartier P, et al: Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebocontrolled withdrawal trial, Lancet 372(9636): , Ruperto N, Lovell DJ, Quartier P, et al: Long-term safety and efficacy of abatacept in children with juvenile idiopathic arthritis, Arthritis Rheum 62(6): , Ravelli A, Martini A: Juvenile idiopathic arthritis, Lancet 369(9563): , Ringold S, Seidel KD, Koepsell TD, Wallace CA: Inactive disease in polyarticular juvenile idiopathic arthritis: current patterns and associations, Rheumatology (Oxford) 48(8): , Wallace CA, Huang B, Bandeira M, et 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Pediatric Rheumatology Database Research Group, J Rheumatol 23(11): , Minden K, Kiessling U, Listing J, et al: Prognosis of patients with juvenile chronic arthritis and juvenile spondyloarthropathy, J Rheumatol 27(9): , Guillaume S, Prieur A, Coste J, Job-Deslandre C: Long-term outcome and prognosis in oligoarticular-onset juvenile idiopathic arthritis, Arthritis Rheum 43(8): , Al-Matar MJ, Petty RE, Tucker LB, et al: The early pattern of joint involvement predicts disease progression in children with oligoarticular (pauciarticular) juvenile rheumatoid arthritis, Arthritis Rheum 46(10): , Huemer C, Malleson PN, Cabral DA, et al: Patterns of joint involvement at onset differentiate oligoarticular juvenile psoriatic arthritis from pauciarticular juvenile rheumatoid arthritis, J Rheumatol 29(7): , Woo P, Southwood TR, Prieur AM, et al: Randomized, placebocontrolled, crossover trial of low-dose oral methotrexate in children with extended oligoarticular or systemic arthritis, Arthritis Rheum 43(8): , Ravelli A, Viola S, Migliavacca D, et al: The extended oligoarticular subtype is the best predictor of methotrexate efficacy in juvenile idiopathic arthritis, J Pediatr 135(3): , Packham JC, Hall MA: Long-term follow-up of 246 adults with juvenile idiopathic arthritis: functional outcome, Rheumatology (Oxford) 41(12): , Oen K, Malleson PN, Cabral DA, et al: Disease course and outcome of juvenile rheumatoid arthritis in a multicenter cohort, J Rheumatol 29(9): , 2002.

18 CHAPTER 107 Treatment of Juvenile Idiopathic Arthritis Oen K, Reed M, Malleson PN, et al: Radiologic outcome and its relationship to functional disability in juvenile rheumatoid arthritis, J Rheumatol 30(4): , Wright T, Cron RQ: Pediatric rheumatology for the adult rheumatologist, II: uveitis in juvenile idiopathic arthritis, J Clin Rheumatol 13(4): , Saurenmann RK, Levin AV, Feldman BM, et al: Risk factors for development of uveitis differ between girls and boys with juvenile idiopathic arthritis, Arthritis Rheum 62(6): , Heiligenhaus A, Niewerth M, Ganser G, et al; German Uveitis in Childhood Study Group: Prevalence and complications of uveitis in juvenile idiopathic arthritis in a population-based nation-wide study in Germany: suggested modification of the current screening guidelines, Rheumatology (Oxford) 46(6): , Davies K, Cleary G, Foster H, et al: BSPAR Standards of Care for children and young people with juvenile idiopathic arthritis, Rheumatology 49(7): , Cassidy J, Kivlin J, Lindsley C, Nocton J, the Section on Rheumatology, and the Section on Ophthalmology: Ophthalmologic examinations in children with juvenile rheumatoid arthritis, Pediatrics 117(5): , Biester S, Deuter C, Michels H, et al: Adalimumab in the therapy of uveitis in childhood, Br J Ophthalmol 91(3): , Zulian F, Balzarin M, Falcini F, et al: Abatacept for severe anti-tumor necrosis factor alpha refractory juvenile idiopathic arthritis-related uveitis, Arthritis Care Res (Hoboken) 62(6): , Saurenmann RK, Levin AV, Feldman BM, et al: Prevalence, risk factors, and outcome of uveitis in juvenile idiopathic arthritis: a long-term followup study, Arthritis Rheum 56(2): , Sabri K, Saurenmann RK, Silverman ED, Levin AV: Course, complications, and outcome of juvenile arthritis-related uveitis, J AAPOS 12(6): , Chia A, Lee V, Graham EM, Edelsten C: Factors related to severe uveitis at diagnosis in children with juvenile idiopathic arthritis in a screening program, Am J Ophthalmol 135(6): , Zulian F, Martini G, Falcini F, et al: Early predictors of severe course of uveitis in oligoarticular juvenile idiopathic arthritis, J Rheumatol 29(11): , Edelsten C, Lee V, Bentley CR, et al: An evaluation of baseline risk factors predicting severity in juvenile idiopathic arthritis associated uveitis and other chronic anterior uveitis in early childhood, Br J Ophthalmol 86(1):51 56, Holland GN, Denove CS, Yu F: Chronic anterior uveitis in children: clinical characteristics and complications, Am J Ophthalmol 147(4): e5, Ayuso VK, Ten Cate HAT, van der Does P, et al: Male gender and poor visual outcome in uveitis associated with juvenile idiopathic arthritis, Am J Ophthalmol 149(6): , Stoll ML, Zurakowski D, Nigrovic LE, et al: Patients with juvenile psoriatic arthritis comprise two distinct populations, Arthritis Rheum 54(11): , Flatø B, Lien G, Smerdel-Ramoya A, Vinje O: Juvenile psoriatic arthritis: longterm outcome and differentiation from other subtypes of juvenile idiopathic arthritis, J Rheumatol 36(3): , Cassidy CJ, Petty RE, Laxer RM, Lindsley C: Textbook of pediatric rheumatology, ed 5, Philadelphia, 2005, Elsevier Saunders. 99. Lewkowicz D, Gottlieb AB: Pediatric psoriasis and psoriatic arthritis, Dermatol Ther 17(5): , Southwood TR, Petty RE, Malleson PN, et al: Psoriatic arthritis in children, Arthritis Rheum 32(8): , Butbul YA, Tyrrell PN, Schneider R, et al: Comparison of patients with juvenile psoriatic arthritis and nonpsoriatic juvenile idiopathic arthritis: how different are they? J Rheumatol 36(9): , Hofer M: Spondylarthropathies in children are they different from those in adults? Best Pract Res Clin Rheumatol 20(2): , Burgos-Vargas R, Pacheco-Tena C, Vázquez-Mellado J: Juvenileonset spondyloarthropathies, Rheum Dis Clin North Am 23(3): , Burgos-Vargas R, Vázquez-Mellado J, Cassis N, et al: Genuine ankylosing spondylitis in children: a case-control study of patients with early definite disease according to adult onset criteria, J Rheumatol 23(12): , Burgos-Vargas R, Lardizabal-Sanabria J, Katona G: Anterior spinal flexion in healthy Mexican children, J Rheumatol 12(1): , Kotaniemi K, Arkela-Kautiainen M, Haapasaari J, Leirisalo-Repo M: Uveitis in young adults with juvenile idiopathic arthritis: a clinical evaluation of 123 patients, Ann Rheum Dis 64(6): , Huppertz H, Voigt I, Müller-Scholden J, Sandhage K: Cardiac manifestations in patients with HLA B27-associated juvenile arthritis, Pediatr Cardiol 21(2): , Azouz EM, Duffy CM: Juvenile spondyloarthropathies: clinical manifestations and medical imaging, Skeletal Radiol 24(6): , Burgos-Vargas R, Vázquez-Mellado J, Pacheco-Tena C, et al: A 26 week randomised, double blind, placebo controlled exploratory study of sulfasalazine in juvenile onset spondyloarthropathies, Ann Rheum Dis 61(10): , van Rossum MA, Fiselier TJ, Franssen MJ, et al: Sulfasalazine in the treatment of juvenile chronic arthritis: a randomized, double-blind, placebo-controlled, multicenter study. Dutch Juvenile Chronic Arthritis Study Group, Arthritis Rheum 41(5): , Henrickson M, Reiff A: Prolonged efficacy of etanercept in refractory enthesitis-related arthritis, J Rheumatol 31(10): , Tse SML, Burgos-Vargas R, Laxer RM: Anti-tumor necrosis factor alpha blockade in the treatment of juvenile spondylarthropathy, Arthritis Rheum 52(7): , Flatø B, Smerdel A, Johnston V, et al: The influence of patient characteristics, disease variables, and HLA alleles on the development of radiographically evident sacroiliitis in juvenile idiopathic arthritis, Arthritis Rheum 46(4): , Gensler LS, Ward MM, Reveille JD, et al: Clinical, radiographic and functional differences between juvenile-onset and adult-onset ankylosing spondylitis: results from the PSOAS cohort, Ann Rheum Dis 67(2): , Flatø B, Hoffmann-Vold A, Reiff A, et al: Long-term outcome and prognostic factors in enthesitis-related arthritis: a case-control study, Arthritis Rheum 54(11): , Thompson SD, Barnes MG, Griffin TA, et al: Heterogeneity in juvenile idiopathic arthritis: impact of molecular profiling based on DNA polymorphism and gene expression patterns, Arthritis Rheum 62(9): , Behrens EM, Beukelman T, Gallo L, et al: Evaluation of the presentation of systemic onset juvenile rheumatoid arthritis: data from the Pennsylvania Systemic Onset Juvenile Arthritis Registry (PASOJAR), J Rheumatol 35(2): , Woo P: Systemic juvenile idiopathic arthritis: diagnosis, management, and outcome, Nat Clin Pract Rheumatol 2(1):28 34, Sandborg C, Holmes TH, Lee T, et al: Candidate early predictors for progression to joint damage in systemic juvenile idiopathic arthritis, J Rheumatol 33(11): , Allantaz F, Chaussabel D, Stichweh D, et al: Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade, J Exp Med 204(9): , Grom AA, Mellins ED: Macrophage activation syndrome: advances towards understanding pathogenesis, Curr Opin Rheumatol 22(5): , Sawhney S, Woo P, Murray KJ: Macrophage activation syndrome: a potentially fatal complication of rheumatic disorders, Arch Dis Child 85(5): , Behrens EM, Beukelman T, Paessler M, Cron RQ: Occult macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis, J Rheumatol 34(5): , Behrens EM: Macrophage activation syndrome in rheumatic disease: what is the role of the antigen presenting cell? 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19 1770 PART 16 RHEUMATIC DISEASES OF CHILDHOOD 139. Adebajo AO, Hall MA: The use of intravenous pulsed methylprednisolone in the treatment of systemic-onset juvenile chronic arthritis, Br J Rheumatol 37(11): , Nigrovic PA, Mannion M, Prince FHM, et al: Anakinra as first-line disease modifying therapy in systemic juvenile idiopathic arthritis, Arthritis Rheum 63: , Pascual V, Allantaz F, Arce E, et al: Role of interleukin-1 (IL-1) in the pathogenesis of systemic onset juvenile idiopathic arthritis and clinical response to IL-1 blockade, J Exp Med 201(9): , Lequerré T, Quartier P, Rosellini D, et al: Interleukin-1 receptor antagonist (anakinra) treatment in patients with systemic-onset juvenile idiopathic arthritis or adult onset Still disease: preliminary experience in France, Ann Rheum Dis 67(3): , Woo P: Anakinra treatment for systemic juvenile idiopathic arthritis and adult onset Still disease, Ann Rheum Dis 67(3): , Benedetti F, Brunner HI, Ruperto N, et al: Tocilizumab in patients with systemic juvenile idiopathic arthritis: efficacy data from the placebo-controlled 12 week part of the phase 3 TENDER trial, Arthritis Rheum 62(Suppl 10):1434, Yokota S, Imagawa T, Mori M, et al: Efficacy and safety of tocilizumab in patients with systemic-onset juvenile idiopathic arthritis: a randomised, double-blind, placebo-controlled, withdrawal phase III trial, Lancet 371(9617): , Lehman TJA, Schechter SJ, Sundel RP, et al: Thalidomide for severe systemic onset juvenile rheumatoid arthritis: a multicenter study, J Pediatr 145(6): , Hayward K, Wallace CA: Recent developments in anti-rheumatic drugs in pediatrics: treatment of juvenile idiopathic arthritis, Arthritis Res Ther 11(1):216, Vastert SJ, Kuis W, Grom AA: Systemic JIA: new developments in the understanding of the pathophysiology and therapy, Best Pract Res Clin Rheumatol 23(5): , Miettunen P, Narendran A, Jayanthan A, et al: Successful treatment of severe paediatric rheumatic disease-associated macrophage activation syndrome with interleukin-1 inhibition following conventional immunosuppressive therapy: case series with 12 patients, Rheumatology (Oxford) 50: , Henter J, Samuelsson-Horne A, Aricò M, et al: Treatment of hemophagocytic lymphohistiocytosis with HLH-94 immunochemotherapy and bone marrow transplantation, Blood 100(7): , Filipovich A: Hemophagocytic lymphohistiocytosis and related disorders, Curr Opin Allergy Clin Immunol 6: , Wulffraat NM, van Rooijen EM, Tewarie R, et al: Current perspectives of autologous stem cell transplantation for severe juvenile idiopathic arthritis, Autoimmunity 41(8): , Lomater C, Gerloni V, Gattinara M, et al: Systemic onset juvenile idiopathic arthritis: a retrospective study of 80 consecutive patients followed for 10 years, J Rheumatol 27(2): , Singh-Grewal D, Schneider R, Bayer N, Feldman BM: Predictors of disease course and remission in systemic juvenile idiopathic arthritis: significance of early clinical and laboratory features, Arthritis Rheum 54(5): , Spiegel LR, Schneider R, Lang BA, et al: Early predictors of poor functional outcome in systemic-onset juvenile rheumatoid arthritis: a multicenter cohort study, Arthritis Rheum 43(11): , Simon D, Bechtold S: Effects of growth hormone treatment on growth in children with juvenile idiopathic arthritis, Horm Res 72(Suppl 1):55 59, Ayaz NA, Ozen S, Bilginer Y, et al: MEFV mutations in systemic onset juvenile idiopathic arthritis, Rheumatology (Oxford) 48(1):23 25, Azouz EM: Juvenile idiopathic arthritis: how can the radiologist help the clinician? Pediatr Radiol 38(Suppl 3):S403 S408, Damasio MB, Malattia C, Martini A, Tomà P: Synovial and inflammatory diseases in childhood: role of new imaging modalities in the assessment of patients with juvenile idiopathic arthritis, Pediatr Radiol 40(6): , Ravelli A: The time has come to include assessment of radiographic progression in juvenile idiopathic arthritis clinical trials, J Rheumatol 35(4): , Magni-Manzoni S, Epis O, Ravelli A, et al: Comparison of clinical versus ultrasound-determined synovitis in juvenile idiopathic arthritis, Arthritis Rheum 61(11): , Rooney ME, McAllister C, Burns JFT: Ankle disease in juvenile idiopathic arthritis: ultrasound findings in clinically swollen ankles, J Rheumatol 36(8): , Graham TB, Laor T, Dardzinski BJ: Quantitative magnetic resonance imaging of the hands and wrists of children with juvenile rheumatoid arthritis, J Rheumatol 32(9): , Lamer S, Sebag GH: MRI and ultrasound in children with juvenile chronic arthritis, Eur J Radiol 33(2):85 93, Malattia C, Damasio MB, Magnaguagno F, et al: Magnetic resonance imaging, ultrasonography, and conventional radiography in the assessment of bone erosions in juvenile idiopathic arthritis, Arthritis Rheum 59(12): , Miller E, Roposch A, Uleryk E, Doria AS: Juvenile idiopathic arthritis of peripheral joints: quality of reporting of diagnostic accuracy of conventional MRI, Acad Radiol 16(6): , Magni-Manzoni S, Pistorio A, Labò E, et al: A longitudinal analysis of physical functional disability over the course of juvenile idiopathic arthritis, Ann Rheum Dis 67(8): , Oliveira S, Ravelli A, Pistorio A, et al: Proxy-reported healthrelated quality of life of patients with juvenile idiopathic arthritis: the Pediatric Rheumatology International Trials Organization multinational quality of life cohort study, Arthritis Rheum 57(1):35 43, Gartlehner G, Hansen RA, Jonas BL, et al: Biologics for the treatment of juvenile idiopathic arthritis: a systematic review and critical analysis of the evidence, Clin Rheumatol 27(1):67 76, Ravelli A, Magni-Manzoni S, Pistorio A, et al: Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis, J Pediatr 146(5): , Full references for this chapter can be found on

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