Definition
Oligoarticular juvenile idiopathic arthritis (JIA) is defined as a chronic inflammatory arthritis of unknown origin that begins before the age of 16 and persists for at least 6 weeks ( Box 18-1 ). It is further characterized as being either persistent (if no more than four joints are affected during the disease course) or extended (if, after the initial 6-month period, the total number of affected joints exceeds four). The International League of Associations for Rheumatology (ILAR) classification also requires that patients who otherwise fulfill these criteria be excluded from the category if the patient has psoriasis, or if there is a history of psoriasis or a disease associated with the human leukocyte antigen (HLA) allele HLA-B27 in a first-degree relative; if the disease began in a male older than 6 years of age; or if two positive tests for rheumatoid factor (RF) were obtained at least 3 months apart. Such exclusions do not apply to the European League Against Rheumatism (EULAR) criteria for oligoarticular juvenile chronic arthritis or American College of Rheumatology (ACR) criteria for pauciarticular juvenile rheumatoid arthritis, terms that are of historic significance and refer to diseases that are very similar to oligoarticular JIA (see Chapter 15 ). Oligoarthritis is a distinctly, if not uniquely, pediatric disease, and it is the most commonly diagnosed category of chronic arthritis among children in North America and Europe. In these classifications, the words oligoarticular and pauciarticular have the same meaning: few joints (≤4).
Arthritis in four or fewer joints during the first 6 months of disease
Persistent oligoarthritis: Never more than four joints affected
Extended oligoarthritis: More than four joints affected after the first 6 months of disease
Exclusions:
- •
Psoriasis or a history of psoriasis in the patient or a first-degree relative
- •
Arthritis in an HLA-B27–positive male beginning after the sixth birthday
- •
Ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter syndrome, or acute anterior uveitis, or a history of one of these disorders in a first-degree relative
- •
Presence of IgM RF on at least two occasions at least 3 months apart
- •
Presence of systemic arthritis
Epidemiology
Oligoarthritis accounts for 50% to 80% of all children with chronic arthritis, at least in North American and European white populations. Oen and Cheang noted that the proportion of all children with chronic arthritis who had oligoarthritis (ACR or EULAR criteria) was higher in North American and European children (58%) than in East Indian (25%), North American Indian (26%), or other racial groups (31%). A study of a multiethnic cohort of Canadian children with JIA (ILAR criteria) confirmed the relatively low proportion of non-European children with either persistent or extended oligoarticular JIA, compared with children of European ancestry seen in the same clinic. Several reviews of incidence and prevalence studies have been published.
Incidence
Reports of the incidence of oligoarthritis are difficult to interpret because of the variation in criteria used to classify the patients. Using information from hospitals and community physicians, Andersson-Gare and colleagues determined an annual incidence of oligoarthritis (EULAR criteria) of 7 per 100,000 children younger than 16 years of age in Sweden. Using the same criteria, a Norwegian study reported a somewhat higher incidence of 11.2 per 100,000 per year. It should be noted that 42% of these children were HLA-B27–positive, strongly suggesting that children with enthesitis-related arthritis (ERA) or juvenile ankylosing spondylitis (JAS), which can also present with fewer than four active joints at onset, were included in the group. In studies that used the ACR criteria, estimates of the incidence have ranged from less than 1 per 100,000 per year in Japan to more than 18 per 100,000 per year in Finland.
Prevalence
The prevalence of oligoarthritis in reported studies varies greatly depending on the diagnostic criteria used; whether the study was hospital, clinic, or community based; and the geographic location of the study. Using information from hospitals and community physicians, Andersson-Gare and associates found 146 children with oligoarthritis (EULAR) in a population of 400,600 children younger than 16 years of age, a prevalence of 36 per 100,000. In the study by Manners and Diepeveen, oligoarthritis fulfilling the EULAR criteria for juvenile chronic arthritis (JCA) was found in 9 of 2241 12-year-old school children who were examined by the authors of the study. This prevalence (4 per 1000) is markedly higher than that reported in other studies but may be closest to reality, because it was community based and verified by physical examination by a pediatric rheumatologist. It is possible that this high prevalence is not representative of the disease worldwide, however.
Age at Onset
Oligoarthritis has a striking age at onset distribution, with a peak incidence between 1 and 3 years of age ( Fig. 18-1 ). A small proportion of children with oligoarthritis have disease onset after this time, but when this occurs it raises the possibility of alternative diagnoses, such as ERA, JAS, psoriatic arthritis, or developing polyarthritis.
Sex Ratio
In North America and Europe, oligoarthritis is predominantly a disease of girls, with a female-to-male ratio of approximately 3 : 1. In children with oligoarthritis and uveitis, the ratio of girls to boys is even higher: 5 : 1 to 6.6 : 1. In parts of Asia and Africa, however, oligoarthritis occurs predominantly in boys, and uveitis is reported to be rare.
Genetics
Oligoarthritis is seldom familial. When sibling pairs both have arthritis, however, three quarters are concordant for onset type (most commonly oligoarthritis). Early-onset oligoarthritis, particularly if it is complicated by uveitis, appears to be very uncommon in populations of non-European origin. It is likely that oligoarthritis, like other types of childhood arthritis, is a multigenic disease.
HLA Genes
For the sake of clarity, the classification system (ACR—JRA; EULAR—JCA; ILAR—JIA) employed in studies cited in this section is indicated.
There are quite characteristic associations of oligoarthritis, or subsets of oligoarthritis, with some HLA genes. The unusual disease association of an A locus antigen, A2, has been reported and confirmed in children with JRA (ACR criteria) in general and in early-onset pauciarticular JRA in girls in particular.
An increase in the HLA-B27 allele in early studies reflects the inclusion of children with juvenile ankylosing spondylitis (similar to ERA of the ILAR classification). Later investigations documented inconsistent increases in the frequency of this antigen in subgroups of children with JRA.
Among the class II alleles, the most consistent association has been with the DRB1*08-DQA1*04-DQB1*04 haplotype encoding DR8 and DQ4. These two alleles are in strong linkage disequilibrium, but Smerdel et al. showed that it was DR8, not DQ4, that was associated with JIA. DR8, DR5, DR6, DPB1*0201, and certain DQ alleles are also reportedly more frequent in children with early-onset oligoarthritis and in pauciarticular JRA, with relative risks in the range of 2 to 13. Linkage disequilibrium probably accounts for some of the reported associations. The transmission disequilibrium test was used by Moroldo and colleagues to examine linkage and association in 101 white families who had a child with oligoarthritis. DR8 and DR5 (as well as A2, B27, and B35) had significantly higher frequencies of transmission to the affected child; DR4 and DR7 were found less often. These data suggest that these numerous HLA associations partly reflect linkage between the HLA gene region in children with JRA and a population stratification effect. However, age and sex influenced these effects. Prahalad and colleagues studied sibling pairs with arthritis to confirm the linkage of pauciarticular JRA with the HLA-DR region, especially DR8 and DR11. Using restriction fragment length polymorphisms, Morling and colleagues found that children with pauciarticular JRA had increased frequencies of DRB1*08; DRB3*01/02/03 (DRw52); DQA1*0401 and 0501; DQB1*0301; DPA1*0201; and DPB1*02, compared with healthy controls. Both subtypes of DR5 (DR11 and DR12) and DR8 (DRB1*0801) contributed to susceptibility to early-onset oligoarticular disease. DR11, DR12, and DR8 haplotypes share similar DQA1 alleles: DQA1*0401, *0501, and *0601. These three DQ alleles have a common motif in exon 2 at the 42 to 53 positions, which was present in 86% of children with JCA but in only 36% of controls. Haas and colleagues demonstrated that distinct differences in the DQA1 promoter are strongly associated with susceptibility to early-onset disease. Nepom and associates identified a 13-nucleotide region of sequence identity in the first hypervariable region of DR5, DR6, and DR8 alleles, which is a possible “shared epitope” that could be important in antigen recognition.
DR1 and DR4 are present in lower frequency in young girls with persistent pauciarticular JRA and antinuclear antibody (ANA) seropositivity, compared with the normal population. However, DR1 is a risk factor for extended oligoarthritis as well as for polyarthritis in older children. It is in linkage disequilibrium with DQA*0101, which was associated in one study with progressive erosive disease in children with early-onset pauciarticular JRA and was negatively associated with the presence of uveitis. This DQA gene, although not present in all children with the disease, may be critically important in the development of this onset type. DQA*0101 and A2*0101 are also binding sites for the 45-kD DEK proto-oncogene. Anti-DEK antibodies are characteristic of oligoarticular-onset disease (78% positive), especially in children who are ANA positive and have a history of uveitis, and may negate the regulatory function of the gene, or they may simply be a reflection of autoimmunity. One study associated ANA positivity in early-onset disease with DQB1*0603.
Pauciarticular JRA is also associated with DP2 (DPB1*0201), which in one study was present in 67% of patients but only 34% of controls. It has been suggested that this DP allele increases the risk conferred by DR alleles but is not sufficient in itself to increase susceptibility to pauciarticular JRA. A number of studies have discussed the role of interactions among alleles at different loci in producing susceptibility to disease. Interactions between class I and class II genes led to the hypothesis that at least two genetic loci are involved in the predisposition to oligoarthritis. Zeggini and co-workers demonstrated linkage to HLA-A, -B, and -DRB1 in girls with persistent and extended oligoarticular JIA. They suggested that linkage appeared to be attributable to preferential maternal transmission of these alleles. HLA associations are summarized in Table 18-1 .
| HLA GENE | CRITERIA | ASSOCIATIONS | REFERENCE NO. |
|---|---|---|---|
| A2 | ACR | Young age, female sex | |
| B27 | ACR | Oligoarthritis | |
| DR 6 | ACR | Oligoarthritis | |
| DRB1*08 | ACR | Oligoarthritis | |
| EULAR | Early onset | ||
| ACR | Persistent disease | ||
| DRB3*01/2/3 | ACR | Oligoarthritis | |
| DPA*0101 | ACR | Progressive erosive disease | |
| ACR | Decreased in uveitis | ||
| DPA1*0201 | ACR | Oligoarthritis | |
| DPB1*0201 | EULAR | Oligoarthritis | |
| ACR | Oligoarthritis | ||
| DR 1 | ACR | Extended oligoarthritis | |
| ACR | Decreased in persistent oligoarthritis | ||
| DR 4 | ACR | Decreased in persistent oligoarthritis | |
| DR11 (DR5) | EULAR | Early onset | |
| DR12 (DR5) | EULAR | Early onset | |
| DQA1*0401 | ACR | Oligoarthritis | |
| DQA1*0501 | ACR | Oligoarthritis | |
| DQB1*0301 | ACR | Oligoarthritis | |
| DQB1*0603 | EULAR | Early onset, ANA positive |
Non-HLA Genes
A number of genes involved in antigen presentation or cytokine expression may be important in either a predisposition to JCA or its pathogenesis. IL-1A2, a variant of the IL-1β gene, is associated with early-onset oligoarthritis. Children with extended oligoarthritis (ILAR criteria) were shown to have a high frequency of the interleukin (IL)-1 receptor antagonist gene IL1RN*2; this was also observed, to a lesser extent, in children with ERA. The gene for the cytokine IL-1β, or a gene for which its polymorphism is a marker, may contribute risk for early-onset disease and uveitis.
Crawley and colleagues found a decrease in the IL-10 phenotype associated with low IL-10 production in children with arthritis affecting fewer than five joints, compared with those with more than four affected joints. The frequency of the tumor necrosis factor (TNF)-α2 microsatellite allele was significantly increased in Latvian children with oligoarticular JCA, and the frequency of TNF-α9 was significantly decreased in this population. The TNF-α2 allele is associated with high TNF-α production. Zeggini and colleagues reported an increased frequency of the intronic +851 TNF single nucleotide polymorphism (SNP) in persistent oligoarticular JIA (odds ratio, 3.86; 95% confidence interval [CI], 1.6 to 9.2). Kaalla et al. have performed a meta-analysis of data regarding four SNPs in loci that had previously been associated with JIA: MIF (G173C), TNFA (G308A and G238A), and PTPN22 (C1858T). They confirmed the association of the PTPN22 SNP and TNFA G238A, but not MIF G173C with oligoarticular JIA. Genome-wide association studies have been recently published.
Etiology and Pathogenesis
Environmental Factors
The etiology of oligoarticular JIA is unknown. The narrow age-at-onset profile suggests the possibility of exposure at a time of immunological immaturity to a ubiquitous environmental agent, possibly a virus, but none has been consistently identified. In a study of six twin pairs with pauciarticular JRA, there was an average of approximately 3 months (range, 0 to 12 months) separating disease onset in each twin, again raising the question of an environmental agent as an initiating event. One study alleged that breast-feeding has a protective effect on the development of JRA, especially oligoarticular disease; however, a strong relationship was not confirmed in another investigation. Radon et al. found no association of urban versus rural residence or exposure to farm animals or pets with development of oligoarticular JIA. Neufeld and colleagues have reported a significant increase in a serious psychological upset, illness in the family, or difficulties with interpersonal interactions in children prior to the onset of oligoarticular JIA, compared to healthy age-matched controls.
Immunological Factors
T Lymphocytes
Although it is generally agreed that the pathogenesis of oligoarticular JIA involves abnormalities in the adaptive immune system, studies of lymphocytes have yielded inconsistent results. The synovial infiltrate predominantly comprises an oligoclonal population of CD4+ and CD8+ T lymphocytes that differ functionally from those in the peripheral blood. High frequencies of different T-cell receptor alleles (TCR Vβ6.1) and TCR Vβ20 have been reported in some studies but not confirmed in others. The degree of activation of synovial T cells (CD3+ IL-2R+) and the CD4/CD8 ratio were significantly higher in oligoarthritis. CD4+ cells that lack CD28 are more frequent in oligoarticular JIA than in polyarticular JIA. CD4+CD28 null T cells are markers of immunological aging and have shortened telomeres consistent with cells that are senescent. Such cells are activated in a TCR-independent manner.
There is a high frequency of the highly proinflammatory Th17 cells in synovial tissue of children with JIA. The importance of Th17 cells in synovial fluid in the pathogenesis of oligoarticular JIA was investigated by Cosmi et al. There was a shift from Th17 to Th17/Th1 or Th1 phenotype in synovial fluid, which correlated with parameters of inflammation.
B Lymphocytes
The high frequency of autoantibodies to nuclear antigens indicates a break in immunological tolerance, but there is no evidence that autoantibodies participate directly in disease pathogenesis. The identity of the specificities of the antigens to which ANAs react in children with oligoarthritis is still largely unknown. Antibodies to an epitope on the high-mobility group (HMG)-17 protein are increased in JRA, and antibodies to an HMG-2 protein are increased in oligoarticular disease. In a study searching for IgG antibodies to a large number of autoantigens in children with oligoarticular JIA, Stoll and colleagues identified two groups of patients, one with elevated autoantibody production, who were relatively resistant to therapy, and a second group with lower autoantibody production who were treatment responsive. It is not certain whether the differences reflect predispositions to treatment-resistant disease or the results of effective therapy. Further studies are required to determine the significance of these findings.
Humoral and cellular immune responses to highly conserved bacterial heat shock proteins (HSPs) are present in children with chronic arthritis. In 13 of 15 children with oligoarthritis, T-lymphocyte proliferative responses to HSP-60 were detected an average of 12 weeks before remission of the inflammatory disease. The investigators hypothesized that induction of tolerance to specific T-cell epitopes of HSP-60 by nasal administration may be a promising route of immunotherapy for childhood arthritis.
Other Factors
Finnegan et al. compared the proteomic profile of synovium from children with oligoarticular JIA (n = 7) and those with polyarticular JIA (n = 8) using two-dimensional (2D) difference gel electrophoresis (DIGE) and matrix-assisted laser desorption ionization tandem time of flight analysis and Western blotting. All patients were studied within 2 years of disease onset, and none had received corticosteroids or disease-modifying agents. Analysis of variance revealed 26 differentially expressed proteins. Proteins overexpressed in the oligoarticular group included type VI collagen alpha 2, integrin alpha 2b, and fibrinogen fragments. These proteins were not overexpressed in the polyarticular group. Some of these proteins are potential autoantigens and may participate in the initiation or perpetuation of joint inflammation.
Serum prolactin levels were increased in children with JRA and were associated with ANA seropositivity. Modest hyperprolactinemia was also identified in prepubertal girls who were ANA seropositive and had oligoarthritis. The prolactin concentration correlated with levels of IL-6 and with a chronic course of the disease.
Clinical Manifestations
The first 6 months of disease is characterized by inflammation in four or fewer joints. These children are not systemically ill, and, except for chronic uveitis, extraarticular manifestations are distinctly unusual. In the child with oligoarthritis, the affected joint is swollen and often warm, but usually not very painful or tender, and almost never red. Varying degrees of effusion may be present involving either the joint space, suprapatellar or prepatellar bursa, or both. The ambulatory child with lower extremity arthritis can usually bear weight but often limps. Oligoarticular JIA is predominantly a disease of the lower extremities. In a study of 64 children with pauciarticular JRA, one or both knees were most commonly affected at disease onset (89%), followed by the ankles (36%). Arthritis affecting small joints of the fingers and toes occurred in only 6% of the children, and arthritis in elbows, hips, wrists, or temporomandibular joints in 3%. Although it is the authors of the study’s impression that wrists and small joints of the hands or feet are seldom affected in oligoarticular JIA at onset, others disagree. In at least half of the reported cases, only a single joint is affected (monarticular onset), usually the knee. Uveitis may be present at onset of the disease; it eventually affects up to 20% of children and is usually asymptomatic (see Chapter 22 ).
Growth abnormalities may be generalized or limited to one limb. Generalized growth retardation is becoming much less frequent with the availability of effective treatment, although Padeh et al. reported short stature in approximately one third of children with oligoarticular JIA. Localized growth abnormalities are particularly common when one knee is affected, with the leg on the affected side usually becoming longer. The opposite effect is seen with unilateral temporomandibular joint disease in which the ramus of the affected mandible is shorter. Muscles around inflamed joints may quite quickly become atrophic: muscles of the thigh may atrophy in the child with arthritis in the knee, those of the calf in ankle joint disease, and of the forearm when the wrist is inflamed.
Laboratory Evaluation
Laboratory indicators of inflammation may be normal in children with oligoarthritis, although mild to moderate elevation of the erythrocyte sedimentation rate (ESR) and elevation of C-reactive protein levels may occur. Hemoglobin levels and white blood cell and platelet counts are usually normal, and the presence of marked abnormalities in these parameters should suggest a diagnosis other than oligoarticular JIA.
Tests for RF are almost always negative, although occasionally children with a single affected joint (often the wrist) have RF. These children may progress to have RF-positive polyarthritis. In contrast, tests for ANAs are positive in low to moderate titer (1 : 160 to 1 : 640) in 62% to 65% of children with oligoarthritis, particularly in girls and in those with uveitis. Antibodies to double-stranded DNA and the extractable nuclear antigens are rarely detectable and should raise the possibility of an alternative diagnosis such as systemic lupus erythematosus. Antibodies to histones have been described in 6% of children with oligoarticular JIA, 12% in those with uveitis.
Antibodies that react with citrullinated peptides have rarely been demonstrated in children with oligoarthritis, their frequency depending to some extent on the antigen used. Syed and colleagues noted that IgA anticyclic citrullinated peptide (anti-CCP) antibodies were more common than other isotypes in children with JIA. Anticardiolipin antibodies were reported in up to 46% of children with oligoarthritis. They are usually transient and do not appear to be associated with intravascular thrombosis, however.
Elevated concentrations of activated C3 (C3c, C3d) were demonstrated in about one third of children with active oligoarthritis (a lower frequency than in children with systemic arthritis or polyarthritis), possibly the result of activation of the alternative pathway. Circulating immune complexes are not characteristic of oligoarthritis.
Routine synovial fluid analysis does not distinguish one type of JIA from another. The fluid is usually moderately inflammatory, with a cell count of 5 to 20,000 cells/mm 3 , mostly polymorphonuclear leukocytes. CD8+ cells constitute the predominant lymphocyte population. Specialized studies of the synovial fluid proteome have identified differences between JIA subtypes with elevations of antichymotrypsin, ceruloplasmin, Apo A-1, and haptoglobin in oligoarthritis, as compared with polyarthritis.
Radiographic Evaluation
The radiographic changes in oligoarthritis are similar to those seen on other kinds of arthritis, although often less frequent and less severe (see Chapter 9 ). In a follow-up study of 97 children with pauciarticular JRA, joint space narrowing was present in only 5% of children early in the disease course, increasing to approximately 15% at a median of 6.2 years after disease onset. Erosions were seen in 10% of children with early disease, and in approximately 25% of children 6 years later. Bone overgrowth was more common; it occurred in more than 20% of children early in the disease and slightly more frequently later in the disease course. Not surprisingly, overgrowth was most common at the knee ( Figs. 18-2 and 18-3 ). Advanced maturation, particularly at the wrist, may also occur.
