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 107-1. 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 colleagues⁶ 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.

Table 107-1 International League of Associations for Rheumatology Classification Criteria for Juvenile Idiopathic Arthritis (JIA)⁴

ERA, enthesitis-related arthritis; RF, rheumatoid factor.

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 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 enthesitis-related 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 rheumatologists, although low white blood cell count, mild 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

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 ANA-negative 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

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 disease-modifying agent as soon as practically possible after the diagnosis has been confirmed. If nonsteroidal anti-inflammatory 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 107-2 for medications, dosing, route, and safety monitoring recommendations.)

Figure 107-1 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.

Table 107-2 Commonly Used Medications in Juvenile Idiopathic Arthritis^9,176

IV, intravenous; SQ, subcutaneous; SR, sustained release.

^* The effectiveness of the 0.8 mg/kg/wk dose has been evaluated in JIA patients.^177,178

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

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 JIA¹⁰ and is more common in girls, with reported female-to-male ratios between 5.7 and 12.8 : 1.0.^46,47 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 extra-articular 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

Treatment

Treatment algorithms and ACR guidelines for patients with all types of polyarthritis are discussed in Figure 107-1. 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

Clinical and Diagnostic Features

Oligoarticular JIA accounts for up to 20% of all new rheumatic diagnoses in the general pediatric rheumatology clinic⁴⁷ 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 : 1.¹⁰ 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 107-3 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.

Table 107-3 American Academy of Pediatrics Recommended Ophthalmologic Screening Frequency for Asymptomatic Uveitis in Juvenile Idiopathic Arthritis (JIA) Patients*⁶⁷

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

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.

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.

Figure 107-2 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 disease-modifying 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.

Concurrent sulfasalazine and hydroxychloroquine have been used with variable success. Sulfasalazine is more typically used with HLA-B27–associated arthritis and ERA.

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 107-3 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.”

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 diagnosis⁶⁶ 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 107-3.⁶⁷ 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