Polyarticular Juvenile Idiopathic Arthritis

Incidence and Prevalence

Incidence and prevalence data vary because of differences in diagnostic and classification criteria applied, inconsistency in case ascertainment methods, accessibility to care, and genetic and ethnic characteristics of the respective populations. ^, Global incidence rates of chronic childhood arthritis range from 0.8 to 23 per 100,000 children. The incidence rate of RF-negative polyarticular disease has been reported as ranging from 0.3 to 6.5 per 100,000. The prevalence of RF-negative polyarticular JIA varies from 1.64 to 33.4 per 100,000. ^,

Age at Onset and Sex Ratio

RF-negative polyarticular JIA can begin at any age before 16 years, but onset age displays a biphasic trend with a peak at age 1 to 3 years and another between ages 9 and 14 years. ^{, ,} RF-negative polyarthritis affects girls four times more frequently than boys. The predominance of females is greater in those with onset during adolescence (female-to-male ratio 10:1) compared with those with a younger onset age (female-to-male ratio 3:1). ^, Younger-onset RF-negative polyarthritis patients are more likely to be antinuclear antibody (ANA) positive and are at greater risk for developing chronic iridocyclitis, much like oligoarticular JIA. A young onset age of RF-negative polyarthritis is associated with a less favorable long-term outcome. Greenwald et al. found 2-year outcomes in an older onset, RF-negative JIA subgroup to be generally favorable even before the era of biological therapies.

Geographical and Racial Distribution

JIA occurs worldwide, but prevalence varies widely among geographical regions. ^, RF-negative polyarticular JIA is the second most prevalent category of JIA (after oligoarticular JIA) in all regions of the world except in Southeast Asia where systemic JIA and enthesitis-related JIA are most frequently reported. Oen and Cheang reported that polyarthritis accounted for a higher proportion of East Indian (61%) and North American Indian (64%) children with chronic arthritis compared with Caucasian children (27%). Saurenmann et al. analyzed ethnicity as a risk factor for JIA in a multiethnic cohort; among 223 children with RF-negative polyarthritis, no significant differences among European and non-European patients were found. However, there are some reports that at least some North American Indigenous populations had a high relative risk (3.2) of developing RF-negative polyarthritis.

Genetic Background

Genetic influence in the pathogenesis of JIA is indicated by ethnic variability in the incidence of certain JIA subsets, female preponderance, increased sibling recurrence rates, and associations with both human leukocyte antigen (HLA) and non-HLA genes.

Environmental Influences

Maternal smoking and infection during pregnancy have been invoked as risk factors for the development of polyarticular JIA in the offspring. ^, A role of stressful life events before the onset of RF-negative polyarticular JIA has been highlighted. A proposed protective role for breast-feeding has not been well established in polyarticular JIA. ^,

Joint Disease

The onset of arthritis may be acute, but it is more often insidious, with progressive accumulation of additional affected joints. Morning stiffness, indicative of active arthritis, may persist for hours or occasionally all day. Arthritis may be remittent or indolent. Joint swelling is a result of synovial hypertrophy with or without intraarticular fluid. Joints may be tender and slightlly warm but are not red. Hot, red, and very tender joints suggest infection or malignancy rather than JIA. Stress pain is often identified in active joints. Among children with RF-negative polyarthritis, knees, wrists, and ankles are most commonly affected. Small joint involvement of the hands and feet may occur early or late in the course of the disease; distal interphalangeal joints are seldom affected at onset ( Fig. 18.1 ).

In RF-negative polyarthritis, the number of affected joints tends to be less and the pattern of involvement more asymmetrical than in RF-positive polyarthritis ( Fig. 18.1 ). In RF-negative disease, involvement of wrists and small joints of the hands is less frequent than in those with RF. Clinical signs of hip involvement are present in fewer than 20% with RF-negative polyarthritis at first presentation, but progressive hip abnormalities become evident in the longer term. Oen et al. reported that radiological signs of hip joint involvement during childhood were more likely to occur in RF-negative than RF-positive polyarthritis; the tendency for RF-negative polyarthritis to have its onset at a younger age compared with RF-positive disease might be a factor contributing to the higher frequency of radiographic abnormalities identified during childhood in the seronegative group. Wrist and ankle involvement at first presentation predicts progression to polyarthritis in those first presenting with oligoarthritis.

The temporomandibular joint (TMJ) is commonly affected in children with a polyarticular disease course regardless of onset subtype. However, those with RF-negative polyarthritis are more likely to have TMJ involvement, particularly at long-term follow-up, than those who are RF-positive. Growth disturbances of the TMJs are more likely to occur when inflammation starts before the age of 8 years. The earlier age of onset, when the TMJ might be more vulnerable to damage, is thought to be a reason for the greater prevalence of involvement in the RF-negative group. ^, TMJ arthritis can be present even in the absence of clinical symptoms or signs. As clinical examination has poor sensitivity and specificity to detect TMJ inflammation, delay in diagnosis or overdiagnosis of TMJ arthritis can occur. ^, Advances in TMJ imaging, including computed tomography and magnetic resonance imaging (MRI), support the view that TMJ arthritis is more common, and the severity more variable, than can be discerned by clinical assessment alone. In experienced hands, ultrasonography can be a suitable method for detecting and monitoring TMJ arthritis, but, as reflected in a meta-analysis of ultrasound as a method to detect TMJ arthritis, further standardization and validation of ultrasonography for assessing TMJs is required. TMJ MRI with contrast remains the gold standard for detection of active inflammation. ^, Joint damage associated with TMJ arthritis can result in altered physiognomy, including micrognathia, retrognathia, malocclusion, and facial asymmetry ( Fig. 18.2 ). ^{, ,}

Cervical spine involvement is not commonly recognized early in the course of RF-negative polyarthritis, either clinically or by conventional radiography, but with longer-term follow-up, a decreased range of motion can ensue. ^, More sensitive imaging modalities, such as contrast-enhanced MRI, reveal that cervical spine involvement is more common than is generally appreciated even in asymptomatic patients. Atlantoaxial subluxation ( Fig. 18.3 ), erosion of the odontoid process, and vertebral ankylosis can occur ( Fig. 18.4 ).

A palindromic course in polyarticular JIA, characterized by episodic arthritis, is not common in children; only 10% of children with a palindromic pattern at onset will progress to persistent, chronic JIA. Some patients can have an oligoarticular onset that progresses to polyarthritis; patients with symmetrical arthritis, wrist and ankle involvement, and elevated erythrocyte sedimentation rate (ESR) are most likely to progress to polyarticular involvement. The term polygoJIA has been proposed as a category to include children with RF-negative arthritis regardless of the number of involved joints, thus incorporating RF-negative polyarthritis and oligoarthritis into one category.

Systemic Manifestations

Systemic manifestations in seronegative polyarticular JIA are unusual but can include fatigue and growth failure. Fever seldom occurs and when present is low grade.

Fatigue in children with polyarthritis can be present even in the absence of active joint disease. Ringold et al. studied fatigue in 60 children with polyarthritis, of whom 24 (61.2%) were RF-negative, using a survey tool that includes assessment of general fatigue, sleep/rest fatigue, and cognitive fatigue domains. Both JIA children and their parent/proxies reported less favorable scores in all domains compared with controls. Fatigue in JIA is associated with poor functional ability. Factors contributing to fatigue can include pain and stress, decreased muscle mass, low aerobic and anaerobic capacity, and anemia. ^, Sleep disturbance is not a common factor contributing to fatigue in JIA.

Growth disturbances are common in JIA. In children with polyarthritis, height-for-age Z scores (reflecting the number of standard deviations from the normal mean) may decline in the first several years of disease but tend to return to normal. In those children without RF, the negative deviation is negligible compared with those with RF, particularly with longer disease duration. ^, Low growth velocity tends to correlate with disease severity and activity, and with the number of involved joints. ^{, ,}

Extraarticular Manifestations

Rheumatic Diseases

The onset of polyarthritis in a girl later in childhood or during adolescence could suggest the possible diagnosis of systemic lupus erythematosus (SLE). The arthritis of SLE may mimic that of JIA, although it is nonerosive and less likely to be deforming; the presence of other clinical hallmarks and a positive test for anti–double-stranded DNA (anti-dsDNA) antibodies establishes the diagnosis of SLE. Ragsdale et al. described nine children (six of whom were RF-negative) who developed SLE years after an initial diagnosis of polyarticular juvenile arthritis.

The differential diagnosis of RF-negative polyarthritis also includes enthesitis-related JIA. Predominant involvement of large joints of the lower extremities and the presence of enthesitis supports the diagnosis of enthesitis-related JIA, although enthesitis can occur, albeit uncommonly, in other types of JIA. RF-negative polyarticular JIA might be the initial diagnosis when the articular manifestations of psoriatic arthritis appear before skin rash develops.

Scleroderma begins insidiously with joint contractures of the small joints of the hands mimicking features of polyarthritis but ordinarily without associated signs of intraarticular swelling. Children with dermatomyositis may have polyarthritis but can be distinguished from those with JIA by clinical manifestations such as rash and muscle weakness.

Sarcoidosis, Blau syndrome, Sjӧgren syndrome, ^, and mixed connective tissue disease are additional differential diagnostic considerations for the child presenting with polyarthritis. The early phases of these respective conditions can mimic polyarticular JIA before discriminating clinical, laboratory, and pathological features become evident.

Infection

Septic arthritis affecting multiple joints is unusual; only 3% of the 65 children with septic arthritis reported by Al Saadi et al. had more than one involved joint. Lyme disease, typically manifesting as one swollen knee, may be polyarticular but it can usually be differentiated from RF-negative polyarthritis by its intermittent pattern of arthritis activity and accompanying extraarticular abnormalities. Arthritis caused by Neisseria gonorrhoeae may have an early migratory polyarticular phase.

Reactive polyarthritis in response to infection in the respiratory, gastrointestinal, or genitourinary tracts ordinarily can be distinguished from polyarticular JIA by a limited duration of the disease and associated manifestations of the inciting infection. Acute rheumatic fever after group A beta-hemolytic streptococcal pharyngitis is characterized by acute, painful, nonerosive, and migratory polyarthritis, although atypical presentations in which monoarthritis or nonmigratory arthritis of large and small joints can occur. ^, Poncet disease (reactive polyarthritis with tuberculosis) can sometimes mimic seronegative polyarticular JIA.

Malignancy

Malignant infiltration of bone or synovium can mimic polyarthritis, although in most instances the malignant focus is in juxta-articular bone rather than in the joint. However, joint swelling can occur in lymphoblastic leukemia as a result of leukemic infiltration into the synovium. Joint involvement in malignancy tends to be oligoarticular rather than polyarticular and associated with systemic and laboratory manifestations of malignancy.

Other Conditions

Arthritis associated with inflammatory bowel disease or sarcoidosis should be considered in the differential diagnosis of RF-negative polyarthritis. Sickle cell disease causes diffuse, symmetrical swelling of the hands and feet that may mimic true arthritis. Hypermobility syndromes, mucopolysaccharidosis, familial hypertrophic synovitis, ^{, , ,} familial arthritis and camptodactyly, familial osteochondritis dissecans, Stickler syndrome, velocardiofacial syndrome, Turner syndrome, relapsing polychondritis, idiopathic multicentric osteolysis, Farber disease, familial hypertrophic synovitis, pseudorheumatoid dysplasia, and pachydermodactyly are rare causes of disease that may suggest polyarticular JIA. Scurvy should be considered in the differential diagnosis of polyarthropathy in children at risk for nutritional deficiencies, including those with autism and other developmental disorders.

Indicators of Inflammation

Children with polyarthritis typically have moderate elevations of the ESR and C-reactive protein (CRP) and may have elevated white blood cell and platelet counts. Normocytic, hypochromic anemia indicative of chronic inflammatory disease can be seen.

Autoantibodies