Incidence and Prevalence

Incidence and prevalence data vary widely because of differences in case ascertainment, diagnostic and classification criteria applied, accessibility to care, and genetic and ethnic characteristics of the respective populations. The estimated incidence of chronic childhood arthritis varies from 7 to 21 per 100,000 in North American and Northern European studies. Prevalence rates of 121 to 220 per 100,000 have been reported; meta-analysis indicates a chronic childhood arthritis prevalence of 132 (95% confidence interval [CI] 119 to 145) per 100,000 from population studies. Estimating that 20% of JIA popu­lations have polyarthritis and 85% of the polyarthritis populations are RF-negative, the annual incidence and prevalence for RF-negative polyarthritis can be estimated as 1 to 4 per 100,000 and 21 to 37 per 100,000, respectively.

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 ages 1 to 3 years and another encompassing later childhood and adolescence. RF-negative polyarthritis affects girls four times more frequently than boys. The predominance of females is greater in those with an 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 iridocyclitis. 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 prior to the era of biological therapies.

Geographic and Racial Distribution

JIA occurs worldwide but prevalence varies widely among geographic regions. 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 white 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, the North American Indian population had a high relative risk (3.2) of developing RF-negative polyarthritis.

HLA Genes

Genes both within and outside the major histocompatibility complex (MHC) contribute to genetic susceptibility to JIA. The HLA class I A2 allele confers susceptibility in RF-negative polyarthritis as do the class II alleles DRB1*08, DQAI*04, and DPB1*03. These HLA-related profiles are distinct from those characterizing RF-positive polyarthritis, supporting the view that children without RF have a disease different, at least genetically, from children with RF. Further, certain HLA alleles that confer susceptibility to RF-negative polyarthritis (A2, DRB1*08, and DQA1*04) also confer susceptibility to the oligoarthritis JIA subtype, suggesting that RF-negative polyarthritis is more allied genetically with oligoarticular JIA than with RF-positive polyarthritis. The association of HLA-DRB1 is similar between oligoarticular JIA and the younger onset subgroup of polyarticular JIA; the HLA-DRB1*1103/1104 haplotype is found in the oligoarticular cohort and the younger polyarticular group in contrast with the HLA-DRB1*08 susceptibility haplotype found in the older polyarticular JIA group.

In the MHC of children with oligoarticular JIA and, to a somewhat lesser extent with RF-negative polyarticular JIA, a single nucleotide polymorphism (SNP), rs7775055, which tags the HLA-DRB1*0801–HLA-DQA1*0401–HLA-DQB1*0402 haplotypes, is frequently found, again suggesting these two JIA subsets tend to share common genetic influences.

Non-HLA Genes

The TRAF1/C5 region on chromosome 9 encodes the tumor necrosis factor (TNF)-receptor-associated factor 1 and the complement component 5. In polyarticular JIA there is an increase in the A allele of an SNP in the TRAF1/C5 region when compared with controls.

The protein tyrosine phosphatase nonreceptor type 22 (PTPN22) gene codes for lymphoid-specific phosphatase, which modulates antibody-mediated T-cell activation. A missense SNP in the PTPN22 gene reduces the ability to downregulate T-cell activation and has been associated with JIA. There is an association of this PTPN22 SNP and RF-negative polyarthritis ; however, the association has not been found consistently, possibly reflecting ethnic differences in the populations studied. Certain PTPN22 SNPs, although found with significant frequency in RF-negative polyarthritis, are not specific for this JIA subtype, as the same markers are found in RF-positive and oligoarticular JIA.

Continued mining of JIA genome-wide scans is expected to expose additional susceptibility genes allowing for more precise biologically based categorization of JIA, providing insight into mechanisms of disease and informing new treatment strategies.

Joint Disease

Onset of arthritis may be acute, but it is more often insidious, with progressive accumulation of additional joints. Morning stiffness, indicative of active arthritis, may persist for hours or occasionally all day. The arthritis may be remittent or indolent. Joint swelling is a result of synovial hypertrophy and/or intraarticular fluid. Joints may be warm but are generally not tender or red. Hot, red, tender joints suggest infection or malignancy rather than JIA. Among children with RF-negative polyarthritis knees, wrists and ankles are most commonly affected. Small joint involvement of the hands or feet may occur early or late in the course of the disease; distal interphalangeal joints are seldom affected at onset ( Fig. 17-1 ). The temporomandibular joint (TMJ) is commonly affected in children with a polyarticular disease course regardless of onset subtype, but those with RF-negative polyarthritis are more likely to have TMJ involvement, particularly at long-term follow-up, than those who are RF-positive. 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 radiographically evident destruction in the RF-negative group. Advances in TMJ imaging, including computed tomography and magnetic resonance imaging (MRI), demonstrate that TMJ arthritis is more common and the severity more variable than can be discerned by clinical assessment alone; TMJ arthritis can be present even in the absence of clinical symptoms or signs. In experienced hands ultrasonography can be a suitable method for detecting and monitoring TMJ arthritis. Joint damage associated with TMJ arthritis can result in altered physiognomy, including micrognathia, retrognathia, malocclusion, and facial asymmetry ( Fig. 17-2 ).

Images of an 18-month-old boy with seronegative polyarticular JIA. Swelling of the right thumb was associated with clinical signs of intraarticular fluid and synovial hypertrophy ( A ) and radiographic evidence ( B ) of soft tissue swelling, bony overgrowth of the first metacarpal ( thick arrow ), and premature ossification of the proximal phalanx growth center ( thin arrow ). Similarly, the right foot and ankle show swelling due to fluid and synovial hypertrophy ( C ) and accelerated bone growth on the affected side ( D ; arrows ).

Retrognathia in a 12-year-old girl who had onset of RF-negative polyarticular JIA at 3 years of age.

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 decreased range of motion can ensue. More sensitive imaging modalities, such as MRI, reveal that cervical spine involvement is more common than is generally appreciated even in asymptomatic patients. Atlantoaxial subluxation ( Fig. 17-3 ), erosion of the odontoid process, and vertebral ankylosis can occur ( Fig. 17-4 ).

Flexion ( A ) and extension ( B ) radiographs of the cervical spine of a child with RF-negative polyarthritis. The increased distance between the posterior surface of the anterior arch of the first cervical vertebra and the anterior margin of the odontoid ( arrows ) in flexion suggest mild atlantoaxial subluxation in this patient.

Lateral radiograph of the cervical spine of a child with RF-negative polyarthritis showing bony ankylosis of the second and third cervical vertebrae.

In RF-negative polyarthritis the number of affected joints tends to be less and the pattern of involvement more asymmetric than in RF-positive polyarthritis ( Fig. 17-1 ). In RF-negative disease involvement of wrists and small joints of the hands is less frequent in RF-positive disease. Clinical signs of hip involvement are present in fewer than 20% with RF-negative polyarthritis at first presentation, but progressive hip abnormalities become evident with longer term follow-up. 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 abnormalities identified during childhood in the seronegative group. Wrist and ankle involvement at first presentation has been suggested as a predictor of progression to polyarthritis in those first presenting with oligoarthritis.

A small subset of RF-negative children have “dry synovitis,” a condition characterized by polyarthropathy, minimal or absent clinical signs of joint effusion or synovial hypertrophy, joint stiffness, limited range of motion, and joint contractures associated with laboratory indicators of inflammation. This uncommon subset of polyarthritis can be considered a variant of RF-negative polyarthritis although it has also been suggested to be a forme fruste of scleroderma.

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 lower scores in all domains compared with controls. Fatigue in JIA is significantly 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 does not appear to be 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 less marked and less prolonged than 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 and colleagues 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 arthritis (ERA). Predominant involvement of large joints of the lower extremities and the presence of enthesitis supports the diagnosis of ERA although enthesitis can occur, albeit uncommonly, in other types of JIA.

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 they can be distinguished from those with JIA by clinical manifestations such as typical rash and muscle weakness.

Infections

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 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 clinical manifestations. Acute rheumatic fever following group A beta-hemolytic streptococcal pharyngitis is characterized by acute, painful, nonerosive, migratory polyarthritis (see Chapters 43 and 44 ).

Malignancy

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

Other Inflammatory 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, mucopolysaccharidosies, familial hypertrophic synovitis, familial arthritis and camptodactyly, familial osteochondritis dissecans, Stickler’s syndrome, velocardial facial syndrome, Turner’s syndrome, and relapsing polychondritis 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 erythrocyte sedimentation rate (ESR) and C-reactive protein, and may have elevated white blood cell and platelet counts and a normocytic, hypochromic anemia associated with chronic inflammation.

Autoantibodies

Medical Management

An initial trial of nonsteroidal antiinflammatory drugs (NSAIDs) is appropriate. The trend to more aggressive treatment at first presentation of polyarthritis has resulted in the early use of a disease-remitting agent, usually methotrexate, often in combination with an NSAID; earlier initiation of biological therapies has also been advocated.

American College of Rheumatology (ACR) guidelines for treating JIA promote early treatment of JIA with rapid escalation of therapies as required in accord with responses. In RF-negative polyarthritis the aggressiveness of therapy can be guided by prognostic and disease activity indicators. Unfavorable prognostic indicators, which would prompt more aggressive early treatment, include hip and cervical spine involvement, radiographic evidence of joint space narrowing and/or bone erosions, and the presence of ACPA. Indicators of moderate to severe disease activities, judged by the number of active joints, levels of inflammatory markers, and poor physician and patient/parent global assessments would also prompt aggressive, early treatment.

There are no established guidelines for stopping drug therapy in JIA. Once disease remission is induced with a remittive agent, NSAIDs can often be discontinued without exacerbation of disease activity. In any event, even in polyarthritis with a favorable prognostic profile and low disease activity score, failure of NSAIDs to control the disease within 6 weeks should prompt the addition of methotrexate. Methotrexate is usually given by mouth initially, in doses of 10-15 mg/m ² /week. In the absence of an adequate response the dose can be increased to 15-20 mg/ m ² /week, preferably administered subcutaneously. The response to methotrexate is usually excellent. Nonresponse to methotrexate in RF-negative polyarthritis, as in other JIA subtypes, might be predicted by considering SNPs of genes involved in methotrexate metabolic pathways. For patients who are unresponsive to or intolerant of methotrexate, leflunomide is an option, although there is insufficient information to evaluate leflunomide’s role in RF-negative polyarthritis specifically. Treatment approaches that include use of biologically based anti-TNF agents at first presentation either in combination with a DMARD or alone have been suggested.

Anti-TNF agents are effective in treating children with polyarthritis who are unresponsive to methotrexate or leflunomide alone although there is little information to indicate that RF status correlates with responsiveness. Anti-TNF therapy should be considered in any child with polyarticular JIA with moderate or high disease activity who has not responded to methotrexate or leflunomide by 3 months or, for those with low disease activity, by 6 months. Biologically based therapies targeting proinflammatory cytokines other than TNF, including IL-6 as an example (tocilizumab), are emerging as treatment options. When patient-specific biomarker profiling becomes more clinically accessible, the selection of specific anticytokine therapies can be more biologically based.

Glucocorticoids are important as intraarticular therapy. Breit and colleagues reported a longer median duration of response to intraarticular triamcinolone hexacetonide in children with juvenile chronic arthritis who were RF negative (105 weeks) than in those who were RF positive (63 weeks). Glucocorticoids have a limited role as systemic therapy in polyarthritis although judicious use of systemic steroids as a bridging agent can be considered until disease-modifying agents become effective. Gold compounds and penicillamine are seldom used since the advent of generally safer and more efficacious pharmacotherapeutic options. Although hydroxychloroquine is at times used in RF-negative polyarthritis as an adjunctive and relatively safe agent, often in combination with methotrexate, there is no substantive evidence reported to support its efficacy.

There are no established guidelines to direct when pharmacotherapies can be safely discontinued in RF-negative polyarthritis. Although there is no evidence-based rationale for continuing treatment beyond the point of clinical remission, there is accumulating concern that clinical remission might not always reflect actual biologic remission. Both magnetic resonance and ultrasound imaging indicate that synovial inflammation can persist even in patients in whom clinical remission is achieved. Undetected, subclinical inflammation leads to joint damage and disability. Persistent biologic activity is evidenced by expression of TNF-α and IL-4-regulated genes and elevated levels of S100 proteins in patients in apparent clinical remission. In the future it is expected that incorporation of clinical, imaging, and biomarker indicators will be possible and will help identify true disease remission and thus guide the timing of when to safely stop treatment.

Exercise and Physical and Occupational Therapy

Regular participation in physical activity by children with JIA is beneficial. Functional impairment generally correlates with the extent and severity of articular disease, but poor fitness also occurs even in those with mild symptoms and persists even after disease remission. Both aerobic and anaerobic exercise capacity are decreased in children with polyarthritis compared with those with oligoarticular disease; those with RF-positive polyarthritis are somewhat more limited than those with RF-negative disease. Notwithstanding the advantages of active exercise, it is important to have a carefully designed passive therapy program. Children tend to function within the range of motion they have, not the range they should be trying to achieve. Focused physical therapy should be instituted as soon as inflammation subsides sufficiently to facilitate the child’s cooperation. Physical therapy aimed at restoration of range of motion can be facilitated by pretreatment with an analgesic or application of heat. Major contractures are often more amenable to therapy after intraarticular triamcinolone hexacetonide (see Chapter 14 ).

Surgery

The need for surgical management is now less common as a consequence of more effective medical management. Nonetheless, some children with resistant or untreated disease will require joint replacement of hips, knees, or, less commonly, other joints. Prior to surgical procedures the child with polyarthritis should be evaluated for conditions that might present added anesthesia and surgery risk, including cervical spine and TMJ damage, immunosuppression that heightens infection risk, and poor bone quality that can compromise the integrity of joint implants.

Incidence and Prevalence

There is limited published information about incidence and prevalence rates for the RF-positive polyarthritis onset subtype. Estimated incidence rates of 0.3 to 0.7 per 100,000 person-years at risk have been reported or can be calculated from publications from Europe and the United States. In comparison, incidence estimates as high as 12.3 can be calculated from published data for East Coast Alaskan Indian children, and 8.1 per 100,000 person-years at risk for Native Canadian Indian children in Manitoba. Similarly, estimates of point prevalence of 0 to 6.7 per 100,000 in Europe and the United States, and 54 per 100,000 at risk for Manitoba Canadian Indian children, can be calculated from published data.

Age at Onset and Sex Ratio

The mean age at juvenile onset of RF-positive polyarthritis is 9 to 11 years, and the range is 1.5 to 15 years. Affected girls outnumber boys from 4 : 1 to 13 : 1 in large series.

Geographic and Racial Distribution

RF-positive polyarthritis is one of the least frequent JIA subtypes in white children but occurs at higher relative frequencies in non-white children. Reported frequencies range from 51% in a series of Native Canadian Indian children to 18% of Hispanic-American children, 7% to 17% of East Indian children, 14% of African-American children, and 12.5% of Japanese children, and 0.2% to 6% in European and US children and adolescents with chronic arthritis.

HLA Genes

Distinct from RF-negative polyarticular JIA, RF-positive polyarticular JIA shares genetic predispositions with adult RA. The shared epitope (SE), a specific sequence present on a number of HLA-DRB1 antigens, is associated with increased risk of both RF-positive polyarthritis and adult RA. The SE is found on HLA-DRB1*04 (0401, 0404, 0408, or 0405), DRB1*01 (0101), and DRB1*14 (1402) alleles. Population frequencies of the SE and particular SE-bearing HLA alleles vary in different ethnic groups. Thus, RF-positive polyarthritis and RA are associated with DRB1*04 alleles, mainly DRB1*0401 and *0404, in white populations. The relative risk of RF-positive polyarthritis attributable to DRB1*0401 is 3.2 to 7.2, and to DRB1*0404, 3.8 to 8.9. Double doses of the SE further increase the relative risk of the disease. The associated allele is DRB1*0405 in Asian (i.e., Japanese, Chinese, Korean) populations. In Native North American Indian tribes the SE is represented by DRB1*04 alleles and DRB1*1402 and is associated with RA. In some tribes the population frequency of DRB1*1402 is so high that no significant increase is found in patients with RA. In Native Canadian Indian children, the situation is more complex when both the SE and DRB1*0901 occurring together as a genotype are associated with RF-positive polyarthritis. This dual association supports the suggestion that earlier age at onset is associated with a greater genetic influence.

Population frequencies of the SE tend to correlate with frequencies of RA and RF-positive polyarticular JIA. For example, the frequency of the SE in white populations is 27% to 36%, whereas Native North American Indian populations with high incidence and prevalence rates of RA and RF-positive polyarthritis have frequencies of 66% to 98%. As discussed above, the SE is associated specifically with ACPA-positive, rather than RF-positive, disease.

Non-HLA Genes

HLA-DR alone accounts for 17 % of the genetic risk for juvenile rheumatoid arthritis (JRA) and provides the greatest risk with odds ratios (OR) ranging from 3 to 12. Moreover, HLA associations are specific for JRA or JIA subtypes. In contrast, although the remaining genetic risk is large, it is contributed by multiple genes, each providing only modest probabilities with OR values less than 1.5, with the exception of PTPN22. Many associations with non-HLA genes are shared by a number of autoimmune conditions, suggesting common immunopathogenic pathways. The associated genes are often called autoimmune genes and many are involved in T-cell activation and differentiation. Autoimmune genes with replicated associations with JIA include SNPs of TNF-α–induced protein 3 (TNF AIP3), STAT-4, IL-2RA, PTPN22, and PTPN2 genes, whereas associations with TRAF1/C5, IL2RA gene variations are controversial. Not all studies have included patients with RF-positive polyarthritis, and few have stratified patients by JIA subtype. One study showed a suggestive association of RF-positive polyarthritis with a STAT4 SNP and another with a SNP in the MVK gene, the gene for hyper-IgD syndrome. However, as with HLA, it is likely non-HLA gene associations for RA are shared with RF-positive polyarthritis. These associations include all the autoimmune genes mentioned above. In contrast to shared autoimmune genes, the peptidylarginine deiminase 4 (PADI4) gene association is specific for RA, particularly for ACPA-positive RA, but this association is strongest in East Asian populations. The PADI4 genes code for PAD enzymes. There is a possible functional correlation as the associated PADI4 haplotype stabilizes PADI4 messenger RNA (mRNA), allowing increased citrullination. An association of PADI4 polymorphisms specifically with RF-positive polyarthritis has not been investigated.

Joint Disease

Upper and lower extremity large and small joints are affected, as well as the cervical spine and TMJs. The thoracic and lumbar spine and sacroiliac joints are spared. Although large joints are commonly involved, the characteristic pattern is symmetrical arthritis affecting the metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the hands, the wrists, and the metatarsophalangeal (MTP) and PIP joints of the feet. In contrast to RF-negative polyarthritis, micrognathia (TMJ involvement) does not usually occur because of the individual’s older age at onset. Early limited range of motion occurs at the wrists and can eventually progress to more substantial debility and deformity. Deformities that develop at the hands include ulnar drift at the wrists and the MCP joints, and boutonnière and swan neck deformities at the fingers ( Fig. 17-5 ). Deformities that develop at the feet include hallux valgus deformity at the first MTP joints, hammertoe, and cock-up toe deformities.

Hands of children with RF-positive polyarthritis. A , Swan neck deformities in digits 2, 3, and 4 displaying characteristic extension at the proximal interphalangeal joints and flexion at the distal interphalangeal joints. Ulnar deviation at the metacarpophalangeal joints is also demonstrated. B , Boutonnière deformities at digits 4 and 5 displaying characteristic flexion at the proximal interphalangeal joints and extension at the distal interphalangeal joints.

Systemic Manifestations

Fatigue and weight loss may occur with active disease. Fatigue may persist even if disease is inactive. Fever is rare in RF-positive polyarthritis, and a rash does not occur.

Extraarticular Manifestations

Other than nodules, uveitis or extraarticular disease manifestations associated with adult RA (described below) rarely occur in patients with RF-positive polyarthritis, whether during childhood, adolescence, or adulthood.

Indicators of Inflammation

These are identical to those in RF-negative polyarthritis discussed earlier.

Autoantibodies