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Oligoarticular juvenile idiopathic arthritis

Oligoarticular juvenile idiopathic arthritis
Literature review current through: Sep 2023.
This topic last updated: Feb 22, 2023.

INTRODUCTION — Oligoarticular juvenile idiopathic arthritis (formerly called pauciarthritis or pauciarticular-onset juvenile rheumatoid arthritis) is defined as juvenile idiopathic arthritis (JIA) involving fewer than five joints. It is the most common subgroup, constituting approximately 50 percent of cases of JIA (table 1). This subgroup of JIA is further divided into persistent oligoarthritis, in which there is no additional joint involvement after the first six months of illness, and extended oligoarthritis, in which there is involvement of additional joints after the first six months such that more than four joints are ultimately affected [1]. Approximately 50 percent of children with oligoarticular disease go on to have extended oligoarticular disease [2]. (See "Classification of juvenile idiopathic arthritis".)

The clinical issues related to oligoarticular JIA are discussed in this topic review. Systemic JIA, polyarticular JIA, and psoriatic JIA are discussed separately. The epidemiology, classification, and immunopathogenesis of JIA are also discussed separately. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis" and "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications" and "Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis" and "Classification of juvenile idiopathic arthritis" and "Juvenile idiopathic arthritis: Epidemiology and immunopathogenesis".)

CLINICAL PRESENTATION — Oligoarticular JIA affects females more often than males, as does polyarticular disease. The peak incidence of oligoarticular JIA is in the second and third years of life. It is less common over five years of age and rarely begins after age 10 years.

The typical child with oligoarticular JIA is a toddler girl who is noticed to be limping without complaint. Often, the caregiver notices that the child "walks funny" in the morning, but after a little while seems fine. In many cases, the child has never complained of pain; the caregiver seeks medical advice only because the knee is swollen. It is unusual for the caregiver to be able to specify exactly when the illness started.

Oligoarticular JIA affects the large joints (typically knees and ankles, sometimes also wrists and elbows, but rarely the hips). Systemic manifestations (other than uveitis) are characteristically absent. Thus, fever, rash, or other constitutional symptoms suggest a different diagnosis. (See 'Differential diagnosis' below.)

The involved joints in a child with oligoarticular JIA are typically swollen and tender. Involved joints are usually warm, but erythema is characteristically absent. Young children normally have a much greater range of motion than adults. As a result, limitation of motion may not be recognized unless the involved joint is compared with the opposite side.

Several long-term complications may occur in oligoarticular JIA. The most frequent and significant complications are uveitis and leg-length discrepancy. (See 'Complications' below.)

LABORATORY FINDINGS — There are no diagnostic laboratory tests for oligoarticular JIA. Antinuclear antibodies (ANAs) are frequently present and are associated with an increased risk of iridocyclitis/uveitis. (See "Measurement and clinical significance of antinuclear antibodies" and 'Uveitis' below.)

Laboratory abnormalities other than ANAs are typically absent, including rheumatoid factor (RF) and antibodies to double-stranded deoxyribonucleic acid (dsDNA), Sjögren-syndrome-related antigen A (SSA or Ro), Sjögren-syndrome-related antigen B (SSB or La), Smith (Sm), and ribonucleoprotein (RNP). The erythrocyte sedimentation rate (ESR) is generally normal or mildly elevated. The presence of anemia, an elevated ESR or C-reactive protein (CRP), or two or more involved joints at presentation is associated with an increased risk of progression to extended oligoarthritis or polyarticular disease [3,4]. (See 'Diagnosis' below.)

DIAGNOSIS — The diagnosis of oligoarticular JIA is made in the presence of arthritis in four or fewer joints during the first six months of disease after ruling out other causes [1]. The onset of arthritis is usually established from the history. (See 'Differential diagnosis' below.)

Children with oligoarticular arthritis but an otherwise unexplained elevated erythrocyte sedimentation rate (ESR; >40 mm/hour) or anemia (hemoglobin <11.0 g/dL) fulfill the International League of Associations for Rheumatology (ILAR) criteria for a diagnosis of oligoarticular JIA. However, this subgroup is far more likely to have recurrent disease and ultimately evolve into extended oligoarticular JIA with widespread joint involvement [3,4]. Particular attention should be paid to children within this subgroup since their course, prognosis, and optimal therapy appear to differ from typical oligoarticular JIA. (See 'Course and prognosis' below and 'Management' below and 'Differential diagnosis' below.)

The evaluation of the child with a limp, joint pain, and/or joint swelling is reviewed in detail separately. (See "Evaluation of limp in children" and "Overview of the causes of limp in children" and "Evaluation of the child with joint pain and/or swelling".)

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of oligoarticular JIA principally includes the other subtypes of JIA, particularly polyarticular JIA, psoriatic JIA, and spondyloarthritis (enthesitis related JIA). There should not be any systemic complications of oligoarticular JIA other than uveitis. If there is evidence of systemic illness, the diagnosis of oligoarticular JIA is in doubt, and complete investigation to exclude malignancy, infection (particularly Lyme disease in endemic regions), or other diseases should be undertaken.

Polyarticular JIA – In children less than 10 years of age, polyarticular JIA often begins similarly to oligoarticular disease, with one or two joints affected. Antinuclear antibody (ANA) is often positive on presentation in this age group. Polyarticular JIA involves five or more joints during the first six months after disease onset. In addition, joint involvement is symmetric, and an elevated erythrocyte sedimentation rate (ESR), anemia, and hypergammaglobulinemia may be present. (See "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications".)

Psoriatic JIA Dactylitis (a swollen finger or toe, sometimes referred to as a sausage digit) may be present in a child with fewer than five inflamed joints, but it is more typical of psoriatic arthritis, a distinct category of JIA. (See "Clinical manifestations and diagnosis of psoriatic arthritis" and "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications".)

Spondyloarthritis/enthesitis related arthritis (ERA) – Children older than six years of age with arthritis involving large joints (hips or knees) and enthesopathy (pain at the insertions of muscle tendons into bones) also do not have oligoarticular JIA. Rather, these manifestations are indicative of ERA (spondyloarthritis). Spondyloarthritis is an umbrella term for children with arthritis and varying degrees of enthesitis (inflammation where the tendons attach to the bone). Most children with spondyloarthritis are classified as having ERA, psoriatic arthritis, or undifferentiated arthritis [1]. (See "Spondyloarthritis in children" and "Classification of juvenile idiopathic arthritis".)

Lyme disease – Oligoarticular arthritis is one of the most common late manifestations of Lyme disease, a tickborne illness. The knee is the most commonly affected joint, but almost any joint can be affected. Typically, the large joints are preferentially affected, and fewer than five joints in total are involved. The knee effusion is characteristically quite large. Unlike other infectious arthritides, Lyme arthritis is not usually very painful. Diagnosis is based on serologic testing with an enzyme-linked immunosorbent assay (ELISA) for screening and a Western blot for confirmatory testing. (See "Musculoskeletal manifestations of Lyme disease" and "Lyme disease: Clinical manifestations in children".)

Inflammatory bowel disease (IBD) – Elevated inflammatory markers, anemia, history of loose stools/diarrhea, poor weight gain, and/or a family history of IBD in a child with oligoarticular disease should raise suspicion for IBD. One-third of children with IBD develop arthritis, and the arthritis may precede the onset of gastrointestinal symptoms by months to years. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)

Pigmented villonodular synovitis – Episodic swelling of a single joint should raise suspicion for pigmented villonodular synovitis, which is inflammation and overgrowth of the synovium [5]. It most often occurs in the large joints and is more common in males than females. Patients present with joint swelling and pain. The synovial fluid is often bloody. Pigmented villonodular synovitis can be distinguished from inflammatory arthritis on magnetic resonance imaging (MRI).

Malignancy – Neoplastic diseases may present with musculoskeletal pain but are an infrequent cause of monoarticular pain in childhood [6]. Both acute lymphocytic leukemia (ALL) and neuroblastoma may present with joint pain in the same age group as oligoarticular JIA. In general, these children are in more severe pain and sicker in appearance. In addition, these entities are associated with marked periarticular pain, which is not present in oligoarticular JIA. The presence of night sweats or monoarticular hip involvement should also raise suspicion for malignancy [7]. (See "Overview of the clinical presentation and diagnosis of acute lymphoblastic leukemia/lymphoma in children" and "Epidemiology, pathogenesis, and pathology of neuroblastoma".)

Anemia or marked elevation of the ESR is unusual in oligoarticular JIA but is often present in children with malignancies. Additionally, thrombocytopenia, leukopenia, anemia, elevated lactate dehydrogenase (LDH), and elevated uric acid should raise suspicion for malignancy [6]. Except for neoplastic cells in the peripheral smear, no single laboratory test may be relied upon for differentiating malignancy from JIA.

Radiologic evaluation may reveal bony metastases in neuroblastoma or metaphyseal rarefaction ("leukemic lines") in ALL.

Other inflammatory and/or infectious disorders – Children with plant thorn synovitis, septic arthritis, osteomyelitis, or tuberculosis are sometimes mistakenly diagnosed with oligoarticular JIA. These conditions may be associated with elevated acute phase reactants, acute onset of moderate-to-severe pain, erythema of the overlying skin, or fever that should alert the clinician to look for a diagnosis other than oligoarticular JIA. (See "Bacterial arthritis: Clinical features and diagnosis in infants and children" and "Hematogenous osteomyelitis in children: Clinical features and complications" and "Lyme disease: Clinical manifestations in children", section on 'Arthritis'.)

Initial symptoms in the hip should be regarded with great concern since oligoarticular JIA rarely begins in the hip joint. Most such patients have a different diagnosis. As an example, toxic synovitis is a transient condition that may affect the hip in young children. Other disorders to consider include Legg Calve Perthes disease, osteoid osteoma, neoplasm, or infectious diseases. In older children, ERA (spondyloarthropathy) and slipped capital femoral epiphysis may also cause symptoms beginning in the hip. (See "Evaluation and management of slipped capital femoral epiphysis (SCFE)" and "Approach to hip pain in childhood", section on 'Common causes of hip pain in children'.)

COURSE AND PROGNOSIS — Twenty-five to 35 percent of children with oligoarticular JIA extend to involve five or more joints within several years of diagnosis (extended oligoarthritis) [8-10]. In one study, 70, 65, and 50 percent of children with oligoarticular JIA achieved an American College of Rheumatology (ACR) Pediatric 30, 50, or 70 response, respectively, approximately six months after diagnosis [11]. In this same cohort, 86 percent of patients with oligoarticular JIA attained inactive disease within two years, and 58 percent achieved remission within five years [8].

In comparison to children with extended oligoarthritis, those children with persistent typical oligoarthritis that involves fewer than five joints have a better chance of achieving remission. In one longitudinal study with follow-up a median of 98 months after diagnosis, 69 percent of children with persistent oligoarthritis attained remission (66 and 3 percent off and on medication, respectively) [9]. In that same study, only 37 percent of children with extended oligoarthritis attained remission (21 and 16 percent on and off medication, respectively).

MANAGEMENT — Oligoarticular JIA is usually responsive to intraarticular glucocorticoids [12]. Methotrexate and other immunosuppressive drugs are recommended for children with disease that extends to involve five or more joints or require repeat injections. Biologic agents are typically reserved for patients with uveitis and are also used in some patients with extended oligoarticular JIA.

The approach to the treatment of oligoarticular JIA is reviewed here and is consistent with the approach outlined in the 2011 American College of Rheumatology (ACR) Juvenile Arthritis Treatment Recommendations [12]. The choice of treatment depends upon disease activity and whether features of poor prognosis are present.

Determining disease activity — Disease activity should be determined before the initiation of therapy and periodically thereafter at the decision branch points discussed below [12]:

Low disease activity is defined by the 2011 ACR Juvenile Arthritis Treatment Recommendations as meeting all of the following criteria: ≤1 active joint, normal inflammatory markers (erythrocyte sedimentation rate [ESR] or C-reactive protein [CRP]), physician global disease activity assessment of <3 (0 to 10 scale), and patient and parent/caregiver global assessment of overall well-being of less than <2 (0 to 10 scale).

High disease activity is defined as meeting at least three of the following criteria: ≥2 active joints, inflammatory markers greater than twice the upper limit of normal, physician global disease activity assessment ≥7 (0 to 10 scale), and patient and parent/caregiver overall well-being assessment ≥4 (0 to 10 scale).

Moderate disease activity does not satisfy criteria for low or high disease activity.

Prognostic markers — Patients should also be evaluated for the presence of features associated with poor prognosis prior to starting treatment and periodically thereafter at the decision branch points discussed below [12]. (See 'Initial therapy' below.)

If at least one of the following features is present, the patient is considered to have a poor prognosis:

Hip or cervical spine arthritis

Ankle or wrist arthritis and marked or prolonged elevation of ESR or CRP

Radiographic evidence of joint damage

Initial therapy — There are several options for initial therapy in patients with low disease activity, no poor prognosis risk factors, and no joint contractures, including intraarticular glucocorticoid injection(s), nonsteroidal antiinflammatory drugs (NSAIDs), or a combination thereof [12]. Intraarticular injection of a joint or joints with long-acting glucocorticoids typically provides relief of symptoms within days. Treatment with NSAID monotherapy is another option for these patients. NSAIDs usually start to relieve symptoms within two weeks [13]. In patients who respond, NSAIDs are continued until there has been a minimum of six months of disease inactivity. A different NSAID can be tried if no response is seen within the first two weeks of therapy, or, alternatively, the patient can be treated with glucocorticoid injection. Patients who do not respond to NSAID therapy within a few weeks should be treated with glucocorticoid injection of the affected joint(s). Infectious etiologies (including tuberculosis) must be excluded prior to injecting glucocorticoids. Patients who have persistent symptoms despite treatment with NSAIDs and intraarticular glucocorticoids should be treated with methotrexate [14]. (See 'Differential diagnosis' above.)

The first-line approach for patients with moderate-to-high disease activity is intraarticular glucocorticoid injection, with NSAIDs as needed [12,15,16]. Methotrexate, a disease-modifying antirheumatic drug (DMARD), is also part of initial therapy in patients with high disease activity and risk factors for poor prognosis [14]. Whether methotrexate should be used in patients with moderate disease activity was examined in a randomized, open-label trial of children with oligoarticular JIA and at least two swollen joints or one swollen joint (shoulder, elbow, wrist, ankle, or knee) if injected with glucocorticoid in the prior 12 months [17]. There was no significant difference in the proportion of children who achieved inactive disease or clinical remission by the Wallace criteria and the clinical Juvenile Arthritis Disease Activity Score (cJADAS) at 12 months between those who underwent glucocorticoid injections alone versus glucocorticoid injections plus oral methotrexate. There was, however, a significantly increased time to flare (approximately four months; hazard ratio [HR] 0.67) in those treated with glucocorticoid injections plus oral methotrexate compared with those treated with injections alone. The addition of methotrexate was not protective for the development of new-onset uveitis. Further research is needed to determine whether methotrexate should be used in patients with moderate disease activity. Use of methotrexate in patients with JIA is discussed in greater detail separately. (See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Methotrexate'.)

Several NSAIDs have been approved for use in children with JIA, including naproxen, meloxicam, celecoxib, and ibuprofen. Many other NSAIDs are routinely used by pediatric rheumatologists but have not been specifically approved for use in children. Concerns regarding potential adverse effects, especially cardiovascular events that may not appear until adulthood, exist for all NSAIDs. (See "Nonselective NSAIDs: Overview of adverse effects" and "NSAIDs: Adverse cardiovascular effects" and "Overview of COX-2 selective NSAIDs", section on 'Toxicities and possible toxicities'.)

Benefits resulting from intraarticular glucocorticoid injection were verified in a study of 43 patients with oligoarticular JIA [15]. Remission lasting more than six months was achieved in 82 percent of injections (115 of 141 injections), discontinuation of all oral medications occurred in 74 percent of patients (32 patients), correction of joint contracture was observed in 55 joints, and complete remission was achieved among all 11 patients with Baker's cysts and all 12 with tenosynovitis. No infections or other serious complications were noted in this study.

The dose of intraarticular glucocorticoid used depends upon both the size of the child and the size of the affected joint. Joint injection, including glucocorticoid choice and dosing, is discussed in greater detail separately. (See "Joint aspiration or injection in children: Indications, technique, and complications" and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)

Escalation of therapy — Intraarticular glucocorticoid injection should improve arthritis for at least four months. A trial of a DMARD, usually methotrexate, is recommended if a patient with severe disease activity, or moderate disease activity and poor prognosis, does not respond to joint injection therapy [12,14]. Sulfasalazine and leflunomide are alternate DMARDs available if the child has contraindications or intolerance to methotrexate [18,19]. If a patient responds to intraarticular glucocorticoids but requires repeated injections due to disease flares, the patient also becomes a candidate for DMARD therapy. This latter group includes both those with moderate disease activity and no features of poor prognosis as well as those with low disease activity and poor prognostic features.

Methotrexate is also used in patients who develop additional joint involvement (extended oligoarthritis) [12,14]. As an example, a randomized trial in 43 children with extended oligoarticular JIA reported significantly greater improvement in children administered methotrexate as determined by parent/caregiver and clinician global assessments [20]. There was also a greater decline in both the mean ESR and CRP levels in the methotrexate-treated children.

Patients are advanced to a tumor necrosis factor (TNF) inhibitor (adalimumab, etanercept, or infliximab) if they continue to have moderate-to-high disease activity after three months of a nonbiologic DMARD and have poor prognostic features [12,21]. The patient may be tapered off the DMARD once disease control is attained on a TNF inhibitor, although there is large practice variation regarding when to stop the DMARD. A TNF inhibitor is also started in patients who continue to have high disease activity without poor prognostic features after six months of methotrexate therapy. TNF-alpha is more likely to play a significant role in the disease process in patients with persistent disease activity. These patients are more likely to have extended oligoarthritis. (See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Tumor necrosis factor inhibitors'.)

Infliximab and adalimumab are routinely used to treat uveitis in children who have progression or persistence of ocular inflammation despite the use of topical ophthalmic glucocorticoids and/or systemic medications such as methotrexate [22-25]. (See 'Uveitis' below.)

Duration of therapy for methotrexate and for TNF inhibitors is similar to the approach used for polyarticular JIA and is discussed in detail separately. (See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Duration of therapy'.)

Medication safety monitoring in patients on DMARDs (methotrexate or TNF inhibitor) is discussed in detail separately. (See "Polyarticular juvenile idiopathic arthritis: Treatment", section on 'Monitoring on DMARD therapy'.)

Immunizations

Rationale for and concerns regarding vaccination in JIA – Prevention of infection is important in children with JIA because of the increased risk of infection due to treatment with immunosuppressive medications [26]. Historically, however, immunizations, particularly with live-virus vaccines such as the measles-mumps-rubella (MMR) and varicella vaccines, have been avoided in patients with JIA for several reasons. First, there is some question about the impact of immune stimulation from immunizations on JIA, both with regards to induction of arthritis and as a cause of disease flares, although data are limited and conflicting [27-30]. Patients on immunosuppressive therapy may develop infections from live-virus vaccines and may not develop protective responses to killed vaccines. Thus, the rate completion of vaccination according to schedule and administration of the MMR vaccine in particular is still low in this population [31].

General guidance for all patients with JIA – The European Alliance of Associations for Rheumatology (EULAR)/Paediatric Rheumatology European Society (PRES) recommendations for vaccination of children with autoimmune inflammatory rheumatic diseases such as JIA include several overarching principles [26]:

Assess vaccination status and indications/contraindications for additional vaccines yearly.

If possible, administer vaccines two to four weeks before starting immunosuppressive therapy, but do not delay necessary treatment for vaccines.

Vaccination in patients with JIA not on immunosuppression – In the absence of immunosuppression, routine childhood vaccines should be administered to all children with JIA, regardless of disease activity. (See "Standard immunizations for children and adolescents: Overview", section on 'Routine schedule'.)

Vaccination in patients with JIA on immunosuppression:

Non-live vaccines, including the seasonal influenza, pneumococcal conjugated, and human papillomavirus vaccines, may be given and are recommended for JIA patients, even if on conventional or biologic DMARD therapy and regardless of disease activity [26,32].

Deferment of all non-live vaccines, with the exception of influenza, is conditionally recommended for adults with rheumatic disease who are taking ≥20 mg daily of glucocorticoid. For adults taking ≤10 mg of daily glucocorticoids, all non-live vaccines are recommended. For adults taking between 10 and 20 mg of daily glucocorticoids, non-live vaccinations are conditionally recommended [32]. Specific recommendations for children taking glucocorticoids have not been released.

For adults with rheumatic disease, holding DMARD therapy for two weeks after influenza vaccination in recommended while other immunosuppressive medications can be continued [32]. Specific recommendations for children have not been released.

For adults with rheumatic disease, continuation of immunosuppression is conditionally recommended around vaccinations other than influenza [32]. Specific recommendations for children have not been released.

Live vaccines (table 2) should not be given to children who are receiving systemic immunosuppression, although some emerging data suggest that certain vaccinations may be safe. Further studies are needed before recommendations are likely to change. (See specific vaccines below.)

Specific live vaccines:

MMR and MMR/V – Data from a small, open-label trial and observational studies suggest that a booster MMR vaccine is safe to administer and immunogenic in patients with JIA on methotrexate. No increase in JIA disease activity or medication use after MMR vaccination was seen in several observational studies, which included patients on methotrexate with or without etanercept [33,34], nor were overt measles, mumps, or rubella infections reported. These findings were confirmed in a randomized, open-label trial of MMR booster vaccination in 137 patients (131 analyzed) in which a normal immunologic response and no significant increase in JIA disease activity were seen [35]. This study included 15 patients on biologic agents (discontinued prior to vaccination) and 60 patients on methotrexate. Sixty-five percent of patients in this study had oligoarticular JIA, and most patients had low disease activity. Further studies are needed in this area, particularly regarding the safety of primary immunization with live-virus vaccines in patients with all types of JIA who have inactive disease and are not on immunosuppressants, and booster vaccination in patients who have other forms of JIA, who have moderate-to-high disease activity, and/or who are on biologic agents. (See "Juvenile idiopathic arthritis: Epidemiology and immunopathogenesis", section on 'Environmental factors' and "Secondary immunodeficiency induced by biologic therapies".)

VZV – Limited observational data suggest that primary vaccination with the varicella zoster virus (VZV) vaccine may be safe and immunogenic in children with JIA. In one case-control study of 49 children with rheumatic disease (39 with JIA) treated with methotrexate and, in some patients, also glucocorticoids or biologics, antibody response was similar in patients and controls, and no disease flares after vaccination were reported [36]. Further studies on the safety of VZV in children with JIA on immunosuppressants are needed.

COMPLICATIONS — The most common complications associated with oligoarticular JIA are temporomandibular joint (TMJ) arthritis, uveitis, leg-length discrepancy, and short stature.

Temporomandibular joint arthritis — Arthritis of the TMJ is present in greater than 75 percent of children with JIA [37,38]. The clinical importance of these findings is unclear since not all children go on to develop micrognathia and condylar alterations can improve in some children [39]. Clinical findings that may indicate TMJ involvement include crepitus, pain with TMJ motion, limited maximal incisal opening, and limited forward movement of the mandibular condyle (limited translation) with mouth opening [40]. TMJ arthritis, however, can also be asymptomatic [37].

TMJ arthritis is concerning in children who are actively growing since the mandibular growth plate is located in close proximity to the fibrocartilage of the joint. Damage to this growth plate from uncontrolled inflammation may lead to jaw undergrowth or micrognathia [38]. Patients are monitored for this complication by physical examination, with imaging performed if there are concerning findings on exam. (See "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications", section on 'Musculoskeletal'.)

TMJ arthritis can be treated with intraarticular joint injections (typically performed by interventional radiologists) with or without initiation of systemic therapy. If significant micrognathia develops, surgical correction is an option once the facial bones are fully developed.

Uveitis — The most serious complication of oligoarticular JIA, occurring in approximately 20 to 25 percent of children, is the development of uveitis or iridocyclitis (inflammation of the anterior uveal tract and the adjacent ciliary body) (figure 1) [41-43]. The uveitis is typically isolated to the anterior chamber and is completely asymptomatic. Periodic slit-lamp ophthalmic examination is required for screening and detection. (See "Uveitis: Etiology, clinical manifestations, and diagnosis" and "Uveitis: Treatment".)

The serologic marker most strongly associated with uveitis is antinuclear antibodies (ANA) [41-44]. Thus, children who are ANA positive are screened more often than those who are ANA negative. Diagnosis at a young age (less than six years) increases the risk of uveitis [41].

Screening — The sections on ophthalmology and rheumatology of the American Academy of Pediatrics developed a schedule for ophthalmologic examination based upon the age of onset, JIA category, duration of disease, and the presence of ANA [44]. These guidelines were modified in 2007 for application to the JIA classification criteria [42]. The 2019 American College of Rheumatology (ACR)/Arthritis Foundation guidelines suggest a simplified approach of ophthalmologic screening every three months for all children and adolescents at high risk of uveitis. This includes patients with oligoarticular, polyarticular (rheumatoid factor [RF] negative), psoriatic, or undifferentiated JIA who are also ANA positive, had disease onset at <7 years of age, and have disease duration of ≤4 years [45]. Screening every 6 to 12 months is suggested for all other patients with JIA.

The rationale for frequent screening examinations is to minimize the risk of ocular complications due to late diagnosis and treatment of uveitis in children with JIA. As an example, approximately one-third of patients with JIA and uveitis (53 of 142) in a Canadian study developed ocular complications [41]. The most common sequelae were cataracts (n = 33) and synechiae (n = 31), followed by glaucoma (n = 22), band keratopathy (n = 20), and macular edema (n = 7). After a mean follow-up time of 6.9 years, 10 patients developed legal blindness in 10 eyes, and 4 patients developed impaired vision in 6 eyes. The importance of appropriate screening must be emphasized to caregivers if the frequency of complications is to be reduced. (See "Uveitis: Etiology, clinical manifestations, and diagnosis".)

Treatment — Uveitis is initially treated with topical corticosteroids [45]. According to the Single Hub and Access Point for Pediatric Rheumatology in Europe (SHARE) recommendations, systemic immunosuppression should be initiated if uveitis is still active after three months or reactivation occurs with tapering of topical corticosteroids [46]. Methotrexate is the first-line steroid-sparing agent for chronic uveitis [14,47,48]. Anti-tumor necrosis factor (TNF) alpha monoclonal antibodies, specifically adalimumab [49-51], infliximab [52,53], or golimumab [46], are typically added if the inflammatory process does not abate or are included as part of initial systemic therapy in patients with severe active uveitis and sight-threatening complications due to uveitis or topical corticosteroid treatment. Another option is systemic glucocorticoids [47,54]. There are case reports of successful use of cyclosporine [55], rituximab [56], abatacept [57,58], tocilizumab [59], or golimumab (another TNF inhibitor) [60] in especially severe, treatment-resistant disease. Mycophenolate mofetil may be beneficial in children who have not responded to these therapies [61]. Etanercept, however, does not seem to benefit ocular inflammation [62]. (See "Uveitis: Treatment", section on 'Noninfectious uveitis'.)

Topical corticosteroids, typically prednisolone acetate 1% or dexamethasone 0.1%, are the first line of treatment for JIA-associated uveitis [47,54]. Topical corticosteroids were first shown to be efficacious for uveitis in a randomized trial published in 1979 [63]. The frequency of drops varies greatly (hourly to daily) depending upon the severity of inflammation. Adverse effects of ophthalmic corticosteroids that occur with chronic use include increased intraocular pressure and cataracts. Cycloplegic topical drops (usually muscarinic receptor blockers) are usually also used to help treat synechiae. Systemic therapy is used if inflammation is not adequately controlled or the patient is unable to wean off of topical therapy. For severe, vision-threatening inflammation, systemic therapy can be used as part of initial therapy [54].

Methotrexate is typically the first corticosteroid-sparing agent used in the treatment of JIA-associated uveitis [47,48,64]. In a retrospective study of 38 children with JIA-associated uveitis, 25 received methotrexate (subcutaneous or oral) at a mean dose of 15 mg/m2 [48]. Of these 25 patients, one discontinued therapy due to intolerance, and four had an inadequate response and required escalation of therapy. In the 20 methotrexate responders, remission occurred at a mean of four months after initiation. In another study of 35 children, 17 attained inactive uveitis on methotrexate with or without escalation of topical corticosteroid therapy [64]. Eight achieved inactive disease with systemic glucocorticoids, seven required additional immunosuppression for adequate control, and three had active inflammation at the end of the study.

The anti-TNF biologic agents, infliximab, adalimumab, and golimumab, are options for uveitis not adequately controlled with topical corticosteroids and methotrexate. In a retrospective, multicenter study of children with noninfectious uveitis, 56 children (half with JIA) with active uveitis despite therapy with glucocorticoids (topical therapy with or without oral therapy) and other disease-modifying antirheumatic drugs (DMARDs; methotrexate, azathioprine, mycophenolate mofetil, cyclosporine) were treated with an anti-TNF agent (infliximab n = 42, adalimumab n = 3, etanercept n = 11) [23]. Forty-seven and 59 percent achieved quiescence of uveitis at three and six months, respectively. Forty-two (75 percent) achieved inactive uveitis within 12 months, 36 of whom were also able to discontinue all glucocorticoids.

In one trial, 90 children with active uveitis and JIA (mostly oligoarticular) on a stable dose of methotrexate were continued on their current therapy and also randomly assigned to adalimumab (20 or 40 mg based upon body weight, administered subcutaneously every two weeks) or placebo for 18 months or until treatment failure, based upon a multicomponent intraocular inflammation score [51]. Treatment failure was observed in 16 of 60 patients (27 percent) on adalimumab compared with 18 of 30 (60 percent) in the placebo group, with a significant delay in time to treatment failure in the adalimumab group (hazard ratio [HR] 0.25, 95% CI 0.12-0.49). In addition, more patients in the adalimumab group compared with placebo were able to taper or discontinue topical corticosteroids, and they also had a longer mean duration of sustained inactive disease (no cells seen on slit-lamp exam). However, side effects, including serious adverse events, were more common in the adalimumab group. The trial was stopped early (90 rather than 114 patients enrolled), which can lead to an overestimation of treatment effect. Although the trial enrolled patients with more severe disease, limiting the generalizability of the results, the beneficial effect on less severe cases may be even greater. The efficacy of adalimumab monotherapy was not examined nor was the ability to taper other medications.

Monitoring — Once uveitis is diagnosed, the frequency of subsequent examinations is based upon the response to therapy, changes in therapy, and presence of complications [45].

Ocular complications — Approximately one-third to one-half of patients with uveitis will have ocular complications, highlighting the importance of frequent screening and aggressive therapy [41,42]. A retrospective review of patients with JIA and uveitis from a single, Canadian tertiary center reported complications in 53 of the 142 patients with uveitis [41]. The most common complications were cataracts (n = 33) and synechiae (n = 31), followed by glaucoma (n = 22), band keratopathy (n = 20), and macular edema (n = 7). After a mean follow-up time of 6.9 years, 10 patients developed legal blindness in 10 eyes, and 4 patients developed impaired vision in 6 eyes. Another retrospective review found that male sex was a risk factor for a more complicated course of uveitis and poorer visual outcome [65,66]. However, severe disease is also seen in females.

Leg-length discrepancy — Leg-length discrepancy is the second common complication of oligoarticular JIA. There can be significant asymmetric bony overgrowth in both length and width when a single knee joint is involved, resulting in a leg-length discrepancy over time.

Joint injection with glucocorticoids early in the course of oligoarticular JIA may prevent leg-length discrepancies. A retrospective study compared the development of leg overgrowth among a cohort of children with oligoarticular JIA who received intraarticular glucocorticoids with a similar group of patients followed at a different center who did not receive such injections [67]. Although not a randomized trial, both groups had similar clinical characteristics. None of those who received glucocorticoid injections of the knee or ankle developed a significant leg-length discrepancy or required a lift. By comparison, among those who did not receive injections, 50 percent had leg-length discrepancies, averaging approximately 1 percent of total leg length.

Leg-length discrepancies of less than 1 cm are not clinically significant and are present in up to 70 percent of the population [68-70]. When they become greater, however, they are associated with gait abnormalities and increased strain on the shorter leg [71,72]. Proper gait can be maintained in children with mild leg-length discrepancies (1 to 2 cm) by placing an appropriate lift in the opposite shoe. An absolute discrepancy of great than 2 to 2.5 cm should prompt orthopedic evaluation for possible surgical management [73]. Orthopedic consultation should be obtained before the child reaches skeletal maturity. By using radiographic standards to forecast the remaining growth, it is possible to surgically close the distal tibial epiphysis in the leg that is longer and allow catch-up growth on the opposite side [73]. This is a minor surgical procedure (stapling) that usually has a good outcome. Similar discrepancies of bone growth may occur in other affected joints, but the knee is most common since two-thirds of longitudinal growth occurs around this joint.

Short stature — Growth retardation with short stature is seen in 11 to 36 percent of patients with persistent oligoarticular JIA [74-77]. In one series, severe growth retardation was more likely in children who required treatment with DMARDs than those who were treated with intraarticular glucocorticoid injections alone. This difference is most likely due to the latter group having milder disease, rather than any effect of the drugs. Risk factors for growth retardation included younger age at onset and elevated erythrocyte sedimentation rate (ESR).

Amyloidosis — Although the risk of developing secondary (AA) amyloidosis is generally small in patients with JIA, there may be an increased risk in those with extended oligoarticular disease. In one study of 215 children with various subtypes of JIA, only three (1.4 percent) developed amyloidosis, but two of these three had the extended type of oligoarthritis [78]. Nonetheless, amyloidosis is sufficiently rare that most practicing pediatric rheumatologists report never having seen secondary amyloidosis. (See "Pathogenesis of AA amyloidosis" and "Causes and diagnosis of AA amyloidosis and relation to rheumatic diseases".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Uveitis" and "Society guideline links: Juvenile idiopathic arthritis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Juvenile idiopathic arthritis (The Basics)")

SUMMARY AND RECOMMENDATIONS

Definitions – Patients with oligoarticular juvenile idiopathic arthritis (JIA) have involvement of four or fewer joints during the first six months after disease onset (table 1). These patients are subdivided into two groups. Patients with no additional joint involvement after the first six months of illness have persistent oligoarticular JIA. Those who have involvement of four or fewer joints during the first six months of illness, but have additional joints involved over time, resulting in five or more joints ultimately being affected, have extended oligoarticular JIA. (See 'Introduction' above and 'Course and prognosis' above.)

Epidemiology and clinical presentation – Oligoarticular JIA is the most common JIA category, constituting approximately half of cases of JIA. It is more common in females than males, and the peak incidence is two to three years of age. The typical presentation is limping without complaint. The large joints (particularly knees and ankles) are most commonly affected, but the hips are virtually never the first involved joint. Systemic manifestations other than uveitis are characteristically absent. (See 'Clinical presentation' above.)

Diagnosis and differential diagnosis – The diagnosis of oligoarticular JIA is made in children with arthritis in four or fewer joints during the first six months of disease and in whom other causes of oligoarthritis have been excluded. Antinuclear antibodies (ANAs) are frequently present in oligoarticular JIA and are associated with an increased risk of iridocyclitis. Patients with an otherwise unexplained elevated erythrocyte sedimentation rate (ESR) or anemia are more likely to have recurrent disease and evolve into extended oligoarticular JIA. The differential diagnosis of oligoarticular JIA includes Lyme disease, psoriatic arthritis, enthesitis related arthritis (ERA), inflammatory bowel disease (IBD), pigmented villonodular synovitis, and malignancy, all of which may initially involve four or fewer joints. (See 'Diagnosis' above and 'Differential diagnosis' above.)

Course and prognosis – Recurrences occur in approximately one-fifth of children who initially do well. Some cases of oligoarticular disease evolve into chronic destructive arthritis. Features present during the first six months of oligoarticular illness, such as presence of symmetric disease, ankle and/or wrist involvement, and laboratory evidence of inflammation, are indicators of poor prognosis. (See 'Course and prognosis' above and 'Prognostic markers' above.)

Management – Patients with low-to-moderate disease activity, no poor prognosis risk factors, and no joint contractures are usually responsive to intraarticular glucocorticoids and nonsteroidal antiinflammatory drugs (NSAIDs). However, patients with more significant disease who do not respond to initial joint injection therapy or those with initial severe disease activity and poor prognosis risk factors require treatment with methotrexate or other disease-modifying antirheumatic drugs (DMARDs). Biologic agents (tumor necrosis factor [TNF] inhibitors) are used in patients with severe disease, or moderate disease and poor prognostic features, who do not respond to nonbiologic DMARD therapy. TNF inhibitors are also used in patients with extended oligoarticular JIA and in those with uveitis. (See 'Management' above.)

Complications – Uveitis or iridocyclitis is the most serious complication, occurring in approximately one-quarter of children with oligoarticular JIA. Those who have detectable ANAs and are below six years of age at diagnosis are at the greatest risk. Uveitis is often initially silent. Thus, routine screening is necessary. Screening must be performed by an ophthalmologist and includes a complete slit lamp examination; optometric examination or office funduscopy are not adequate substitutes. Complications include cataracts, synechiae, glaucoma, band keratopathy, and macular edema. (See 'Uveitis' above.)

Leg-length discrepancy is the second common complication of oligoarticular JIA. This frequently results in bony overgrowth both in length and in width. Knee and ankle joint injection with glucocorticoids early in the course may prevent leg-length discrepancies. (See 'Leg-length discrepancy' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas JA Lehman, MD, who contributed to earlier versions of this topic review.

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References

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