Version May 2024
INTRODUCTION — Polyarticular juvenile idiopathic arthritis (formerly called polyarticular-onset juvenile rheumatoid arthritis [JRA]) is a subset of juvenile idiopathic arthritis (JIA) that is defined by the presence of more than four affected joints during the first six months of illness [1]. In the revised nomenclature, this disease, which comprises 20 to 30 percent of patients with JIA, is included in the group termed "childhood polyarthritis." (See "Classification of juvenile idiopathic arthritis".)
The clinical manifestations, diagnosis, course, complications, and prognosis of polyarticular JIA are reviewed here. The treatment of polyarticular JIA is discussed separately. (See "Polyarticular juvenile idiopathic arthritis: Treatment".)
EPIDEMIOLOGY — Polyarticular JIA is more frequent in females than males. There is a bimodal distribution of the age at onset. The first peak is between the ages of two and five years, and the second is between 10 and 14 years. This age distribution suggests that two or more distinct diseases may be included in this classification. The classification, epidemiology, and immunopathogenesis of JIA are reviewed in greater detail separately. (See "Classification of juvenile idiopathic arthritis" and "Juvenile idiopathic arthritis: Epidemiology and immunopathogenesis".)
CLINICAL PRESENTATION — The clinical presentation of polyarticular JIA is varied, although it tends to fall into patterns based upon the age of onset.
Younger children — In children less than 10 years of age, polyarticular JIA often begins similarly to oligoarticular disease, with one or two joints affected [2]. The development of the disease is often indolent until an intercurrent infection precipitates a dramatic increase in symptoms. The disease then becomes relentlessly progressive, spreading to involve five or more joints within the first six months after disease onset. Joint involvement is symmetric, with the knees, wrists, and ankles most frequently affected [2]. There are typically periods of apparent response to therapy followed by relapses with an increasing number of involved joints. Polyarticular JIA may go unrecognized at first because of its initial indolent course. This failure to recognize the initial symptoms may make it appear that the disease had a sudden onset and rapid progression.
Older children and adolescents — These patients usually have a relatively rapid onset of inflammation in multiple joints, including involvement of the many small joints of the hands and feet, within two to three months of disease onset [2]. Pain in the small joints is a common manifestation of polyarticular JIA and initially may be out of proportion to the degree of inflammation and stiffness. The joints of the fingers, wrists, elbows, hips, knees, and ankles are most commonly affected.
LABORATORY FINDINGS — The following laboratory tests may be helpful in initial evaluation and to exclude other diagnoses: complete blood count (CBC), comprehensive metabolic panel (CMP), inflammatory markers (erythrocyte sedimentation rate [ESR], C-reactive protein [CRP]), antinuclear antibody (ANA), rheumatoid factor (RF), antibodies to cyclic citrullinated peptide (CCP), and human leukocyte antigen (HLA) B27:
●An elevated ESR (≥40 mm/hour), anemia (hemoglobin concentration ≤11 g/dL), and hypergammaglobulinemia may be present in polyarticular JIA as well as other diagnoses that cause inflammation.
●Many children in the younger age group are ANA positive. The ANA is often low in titer and homogeneous in pattern. The presence of ANA is unrelated to the severity of arthritis and is meaningful only as a marker for an increased risk of developing uveitis. Other autoantibodies are not usually seen in patients with polyarticular JIA, and their presence should prompt evaluation for other rheumatologic disorders. (See "Measurement and clinical significance of antinuclear antibodies" and 'Ocular' below and 'Differential diagnosis' below.)
●Antibodies to double-stranded deoxyribonucleic acid (dsDNA), Smith (Sm), Sjögren's disease-related antigen A (SSA or Ro), Sjögren's disease-related antigen B (SSB or La), or ribonucleoprotein (RNP) are not expected in children with polyarticular JIA.
●A positive RF is uncommon in children <10 years of age. Positive results should be confirmed three months after the original test [1].
Children with onset of polyarticular disease may be divided by the presence or absence of RF (eg, polyarthritis RF negative and polyarthritis RF positive) (see "Classification of juvenile idiopathic arthritis"):
•Most children with polyarticular-onset disease are RF negative, and it is rare for these children to have antibodies to CCP [3-5]. Their disease is probably not etiologically similar to adult-onset rheumatoid arthritis (RA).
•Older children with RF are more likely to be female and tend to have more severe disease, mimicking their adult counterparts with RA. Some of these children may be HLA-DR4 positive and/or have anti-CCP antibodies, which put them at risk for an aggressive disease course in the absence of appropriate therapy [3,6]. (See 'Differential diagnosis' below and "Clinical manifestations of rheumatoid arthritis".)
DIAGNOSIS — The diagnosis of polyarticular JIA requires the development of arthritis in more than four joints during the first six months of disease. Other causes of arthritis must be excluded, primarily based upon clinical history and exam findings [1]. There are no specific diagnostic tests to confirm the diagnosis. Rather, it is a clinical diagnosis. (See "Classification of juvenile idiopathic arthritis" and 'Differential diagnosis' below.)
DIFFERENTIAL DIAGNOSIS — Polyarticular JIA must be distinguished from a variety of illnesses that may be self-limited or chronic in nature.
Reactive arthritis — Children with serum sickness, viral infections, and many other forms of reactive arthritis may have polyarthritis. These conditions are excluded by recognition of the associated events and by their generally self-limited nature. The rapidity of the onset of polyarticular disease in these conditions often helps to distinguish them from true JIA. A rapid onset of polyarthritis within a period of days to weeks is more characteristic of reactive arthritis in childhood, although some children with polyarticular JIA present with a history of apparent sudden-onset disease due to a failure to recognize the initial symptoms of the arthritis. (See "Reactive arthritis" and "Serum sickness and serum sickness-like reactions" and 'Younger children' above and "Viral arthritis: Causes and approach to evaluation and management".)
Psoriatic JIA — Patients with early-onset psoriatic arthritis can present with polyarthritis. The asymmetric pattern of joint involvement, the presence of a positive family history of psoriasis, axial symptoms, and/or the presence of prominent enthesitis (inflammation at tendon, ligament, and/or joint capsule insertion sites) are features that differentiate psoriatic JIA from polyarticular JIA. Dactylitis (uniform swelling of a single digit, sometimes referred to as a sausage digit) is a common finding in patients with psoriatic JIA, but it is also reported in nonpsoriatic JIA. Children with dactylitis followed by progression to polyarticular disease and a family history of psoriasis or psoriatic arthritis are often suspected to have psoriatic JIA, but there are not always sufficient criteria for that classification [7]. Thus, they are given the diagnosis of polyarticular JIA. However, many go on to develop psoriasis and are reclassified. (See "Psoriatic juvenile idiopathic arthritis: Pathogenesis, clinical manifestations, and diagnosis".)
Enthesitis related JIA — The spondyloarthropathies may also be difficult to differentiate from polyarticular JIA. Similar to psoriatic JIA, the asymmetric pattern of joint involvement, the presence of a positive family history of spondylitis, axial symptoms, and/or the presence of prominent enthesitis are useful distinguishing features. Distinguishing between these two forms of JIA is important because methotrexate is ineffective for axial manifestations of spondyloarthropathies [8] but is recommended for JIA before anti-tumor necrosis factor (TNF) agents. Anti-TNF agents are effective for spondyloarthropathies [9-11]. (See "Spondyloarthritis in children".)
Systemic JIA — Children with systemic JIA may also present with polyarthritis. Higher elevations of inflammatory markers, fevers, and the characteristic salmon-colored evanescent rash are useful distinguishing features. (See "Systemic juvenile idiopathic arthritis: Clinical manifestations and diagnosis".)
SLE and mixed connective tissue disease — The presence of autoantibodies other than antinuclear antibodies (ANAs), including to double-stranded DNA (dsDNA), Smith (Sm), Sjögren's disease-related antigen A (SSA or Ro), Sjögren's disease-related antigen B (SSB or La), or ribonucleoprotein (RNP), should prompt consideration of systemic lupus erythematosus (SLE) or mixed connective tissue disease. Additional features that differentiate SLE and mixed connective tissue from polyarticular JIA are the involvement of other organs, especially the skin, and hematologic abnormalities including leukopenia, lymphopenia, or thrombocytopenia. (See "Childhood-onset systemic lupus erythematosus (SLE): Clinical manifestations and diagnosis".)
Systemic vasculitis — Systemic vasculitis also may manifest with polyarthritis. Evidence of a vasculitic rash or additional end-organ involvement (especially kidney or pulmonary) may help to identify children with vasculitis. As an example, two girls who were initially diagnosed with polyarticular JIA subsequently developed antineutrophil cytoplasmic antibody (ANCA) positive glomerulonephritis, consistent with an ANCA-associated vasculitis [12]. (See "Vasculitis in children: Incidence and classification".)
Sarcoidosis — Sarcoidosis is an infrequent cause of polyarticular arthritis in both young and older children [13]. Significant hilar adenopathy is not common in children with sarcoid arthritis and therefore cannot be relied upon to confirm the diagnosis. However, hypercalcemia and/or recurrent, unexplained liver enzyme elevations are suggestive of sarcoid arthritis. In addition, angiotensin-converting enzyme levels are often elevated in children with sarcoid, especially those with pulmonary involvement. Uveitis, including inflammation of the posterior pole that is distinct from the anterior uveitis seen in juvenile arthritis, is another characteristic feature of juvenile sarcoidosis. Radiographically, sarcoid arthritis is unusually destructive. (See "Clinical manifestations and diagnosis of sarcoidosis" and "Overview of extrapulmonary manifestations of sarcoidosis".)
Juvenile systemic granulomatosis (Blau syndrome) — Juvenile systemic granulomatosis may present with polyarthritis. The associated rash is sometimes only exhibited transiently. Granulomatous uveitis may also occur. This syndrome is distinguished from polyarticular JIA by the presence of synovial granulomas and confirmed by identification of nucleotide-binding oligomerization domain-containing 2 (NOD2) mutations [14]. (See "Autoinflammatory diseases mediated by NFkB and/or aberrant TNF activity", section on 'Blau syndrome'.)
Inflammatory bowel disease — Inflammatory bowel disease (IBD) is commonly associated with arthralgia and/or enthesitis in adolescents [15,16]. Approximately one-third develop arthritis, which can be polyarticular. In some children, arthritis may precede the onset of gastrointestinal symptoms [17]. Even in a child who has previously been evaluated by gastroenterology, continued complaints of stomach discomfort, weight loss or failure to gain weight, microcytic anemia, hypoalbuminemia, or an elevated fecal calprotectin should prompt further investigation by a gastroenterologist. The diagnosis is confirmed with small bowel imaging and endoscopy with biopsies. (See "Clinical presentation and diagnosis of inflammatory bowel disease in children".)
Epiphyseal dysplasia — Epiphyseal dysplasia may cause joint pain and visible joint deformity and enlargement but is characteristically not associated with inflammatory markers. It is usually easily distinguished from JIA radiographically. Progressive pseudorheumatoid arthropathy of childhood (MIM #208230) is a form of epiphyseal dysplasia that results in oligo- or polyarticular joint pain and stiffness beginning at approximately age three years and is associated with vertebral flattening seen on lateral spinal radiographs [18]. Mutations causing the disorder map to 6q22 and affect the WNT1-inducible signaling pathway protein 3 (WISP3) gene [19], which plays a role in regulation of chondrocyte production of matrix proteins [20].
Minocycline-induced autoimmunity — Minocycline-induced autoimmunity (systemic drug-induced lupus) may present as polyarthritis or polyarthralgia, primarily affecting the hands and feet in adolescents [21]. Although this is a rare complication of minocycline therapy, it has increased in frequency because minocycline is commonly used in the treatment of acne. (See "Drug-induced lupus".)
Malignancy — Malignancy may cause polyarthritis or migratory polyarthralgias. Low leukocyte and platelets counts and a history of nighttime pain may help differentiate children with malignancy from JIA [22].
Pachydermodactyly — Pachydermodactyly is a rare and benign condition characterized by symmetric periarticular soft tissue swelling of the proximal interphalangeal joints. The etiology is unknown, but repetitive trauma may be contributory. Adolescent males are the most commonly affected. Magnetic resonance imaging (MRI) demonstrates soft tissue swelling without evidence of synovitis [23].
Pachydermoperiostosis — Pachydermoperiostosis, also known as primary hyperostosis, is a rare, autosomal-dominant condition caused by mutations in the 15-hydroxyprostaglandin dehydrogenase (HPGD) or solute carrier organic anion transporter family member 2A1 (SLCO2A1) genes, characterized by periarticular soft tissue swelling and subperiosteal new bone formation. Adolescent males are primarily affected. Adolescents with this condition may also have digital clubbing, subtle joint effusions, skin thickening on the face and scalp, and periodontal disease. Radiographs demonstrate new bone formation along the affected extremities [24].
COMPLICATIONS
Musculoskeletal — The most common complications of polyarticular JIA are related to arthritis.
●Bony erosions and joint destruction – Bony erosions and joint destruction can occur if therapy is inadequate to fully control the synovitis. The wrist and hips are most vulnerable to erosion, but any joint can be affected [25]. In one study, the hamate and capitate bones of the wrist had erosions in 12.9 and 16.1 percent, respectively, of children with polyarticular-course JIA [25]. Rarely, despite optimal therapy, arthritis progresses to the point at which a joint is severely damaged and becomes nonfunctional. This state is usually but not always accompanied by significant pain. Joint replacement is indicated in children of any age who are nonambulatory or severely limited in ambulation as a result of arthritis. Nonetheless, preservation of the native joint is preferable, particularly in young patients, because the functional life expectancy of an artificial articulation is only 10 to 15 years and joint replacement can affect long bone growth due to loss of the growth plate.
●Osteopenia and osteoporosis – Osteopenia and osteoporosis may occur among those with polyarticular JIA, even in the absence of glucocorticoid exposure [26]. In one study of 103 adolescents with JIA who underwent total body imaging, 41 and 34 percent had low total body bone mineral content and bone mineral density, respectively [27]. Vertebral compression fractures can occur, particularly in patients with refractory disease. In one series of patients with severe JIA, risk factors for vertebral compression fractures included high disease activity, body mass index, and recent cumulative glucocorticoid dose [28]. There was no association with bone mineral density or disease duration.
●Temporomandibular joint involvement – Involvement of the temporomandibular joint (TMJ) may lead to micrognathia even in the absence of symptoms. Predictors of radiographic damage of the TMJ are pain with TMJ motion and the finding of limited forward movement of the mandibular condyle (limited translation) with mouth opening [4]. The evolution of TMJ involvement is often slow and virtually imperceptible. In one study of 32 patients, magnetic resonance imaging (MRI) often demonstrated TMJ involvement, even in patients who were asymptomatic and had normal examinations [29]. TMJ abnormalities were found in 70 percent of adults with JIA assessed with MRI or computed tomography (CT) imaging, including 8 of 21 patients with polyarthritis [30].
TMJ involvement is treated in the same way as other joint disease. However, if significant micrognathia develops, surgical correction may be required. This intervention is not undertaken until the facial bones are fully developed.
●Problems related to mobility – While flexion contractures, weakness, and difficulty with ambulation were frequent complications of polyarticular JIA prior to the introduction of biologic agents, severe mobility problems are rare with adequate treatment [31]. Children presenting with these problems should be referred for physical therapy in addition to reevaluating their treatment regimen. (See "Polyarticular juvenile idiopathic arthritis: Treatment".)
Ocular — Uveitis is seen in polyarticular JIA, although it is less common than in oligoarticular JIA (14 versus 20 percent in one series) [32]. The uveitis is typically isolated to the anterior chamber and is completely asymptomatic. Periodic slit-lamp ophthalmic examination is required for screening and detection. Screening for uveitis in children with JIA is discussed in greater detail separately. (See "Oligoarticular juvenile idiopathic arthritis", section on 'Uveitis'.)
The serologic marker most strongly associated with uveitis is antinuclear antibodies (ANAs) [32-35]. Thus, children who are ANA positive are screened more often than those who are ANA negative, although children with polyarticular JIA who are ANA negative are still at risk. In contrast to ANA, children with rheumatoid factor (RF) negative polyarticular JIA are more likely to develop uveitis than those who are RF positive [31,32,35]. The risk is further increased in children with RF-negative polyarticular JIA who are diagnosed at a young age (less than six years) [32].
Visceral — Internal organ involvement is rare. Although many of these children suffer from chronic anemia and malaise, these symptoms typically resolve with successful control of the underlying synovitis. Similarly, systemic complications that may occur in adult rheumatoid arthritis (RA), such as vasculitis and pneumonitis, are uncommon in children with polyarthritis.
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: Juvenile idiopathic arthritis" and "Society guideline links: Uveitis".)
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
●Epidemiology – The age at onset of polyarticular juvenile idiopathic arthritis (JIA) has a bimodal distribution. The first peak in incidence is between the ages of two and five years, and the second peak is between 10 and 14 years. It is more common in females than males at all ages. (See 'Epidemiology' above.)
●Clinical presentation – The clinical presentation of polyarticular JIA is varied and tends to fall into patterns based upon the age of onset. In children less than 10 years of age, polyarticular JIA often begins similarly to oligoarticular disease, with one or two joints affected. The development of the disease is often indolent until an intercurrent infection precipitates a dramatic increase in symptoms. The disease then becomes relentlessly progressive, spreading to involve five or more joints during the first six months after disease onset. Joint involvement is typically symmetrical. Older children and adolescents usually have a relatively rapid onset of inflammation in multiple joints, including involvement of the many small joints of the hands and feet, within two to three months of disease onset. (See 'Clinical presentation' above.)
●Laboratory findings – There are no diagnostic laboratory findings for polyarticular JIA. However, patients often have a positive antinuclear antibody (ANA), and an elevated erythrocyte sedimentation rate (ESR; ≥40 mm/hour), anemia (hemoglobin concentration ≤11 g/dL), and hypergammaglobulinemia may be present. Other autoantibodies are not usually seen in patients with polyarticular JIA. (See 'Laboratory findings' above.)
●Diagnosis – The diagnosis is made in children with arthritis in more than four joints during the first six months of disease and in whom other causes of polyarthritis have been excluded. (See 'Diagnosis' above.)
●Differential diagnosis – The differential diagnosis includes a number of illnesses that may be self-limited or chronic in nature, including other forms of JIA (eg, psoriatic, systemic, enthesitis related), reactive arthritis, systemic lupus erythematosus (SLE), systemic vasculitis, sarcoidosis, inflammatory bowel disease (IBD), epiphyseal dysplasia, and minocycline-induced autoimmunity. (See 'Differential diagnosis' above.)
●Complications – Complications include debilitating arthritis, uveitis, and osteoporosis. These complications may require additional therapies. (See 'Complications' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Thomas JA Lehman, MD, who contributed to earlier versions of this topic review.
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