Version May 2024
INTRODUCTION — Juvenile idiopathic arthritis (JIA) is a chronic idiopathic inflammatory disorder primarily involving joints. The epidemiology and immunopathogenesis of JIA are reviewed here. Diagnostic criteria and nomenclature of JIA are presented separately. (See "Classification of juvenile idiopathic arthritis".)
Terminology — The older terms, "juvenile rheumatoid arthritis" (JRA; used commonly in the United States) and "juvenile chronic arthritis" (JCA; preferred in Europe), have been replaced by the term "juvenile idiopathic arthritis" (JIA). JIA incorporates all of what was called JRA in the past and also includes all other forms of "idiopathic" arthritis in childhood. The term "JRA" will still be used to describe the general patient population in older studies since JRA is a less inclusive term than JIA (the term "JIA" will be used for these older studies if a specific subgroup is specified [eg, systemic JIA]). However, most clinicians assume that the results of these earlier studies of JRA are generally applicable to all the categories included in JIA, although the precise numbers will be somewhat different. The JIA nomenclature should be regarded as a "work in progress" that will be refined as the genetic and pathophysiologic understanding of arthritis improves. All of the discussion of epidemiology and pathogenesis that follows is complicated by the fact that JIA is not a single disease, but several different diseases. While there are elements common to all of these diseases, some forms of JIA, such as the human leukocyte antigen (HLA) B27-associated diseases and systemic JIA, are clearly distinct entities with differing etiologies and pathogenesis.
EPIDEMIOLOGY
Overall incidence and prevalence — The lack of standard diagnostic criteria has complicated epidemiologic studies. When the revised American College of Rheumatology (ACR; formerly the American Rheumatism Association [ARA]) classification criteria were applied to the Rochester Epidemiology Program Project database, an incidence of 13.9 cases of juvenile rheumatoid arthritis (JRA) per 100,000 per year was reported [1]. A follow-up study utilizing the same database noted a decrease in incidence over a subsequent decade [2].
The results of other population studies are presented in the table (table 1) [3-7]. In the Rochester study, the prevalence rate for JRA was 94 patients per 100,000 children on January 1, 1980 and 86 on January 1, 1990 [2]. An extrapolation to the entire United States population under 16 years of age in the year 2000 suggests that there must be 70,000 to 100,000 cases of JRA (active and inactive). However, the population in the Rochester study was predominantly White. The actual prevalence in the total United States population is probably much lower (15,000 to 36,000 in some estimates [8]) because JRA appears to be less common in African American and Asian American populations [9].
Differences in disease onset among ethnic groups have also been reported [10]. African American children are more likely to have a polyarticular onset than White children, who most often have an oligoarticular onset [11]. Among Japanese children, systemic disease is more common than the oligoarticular form [12]. Genetic factors are likely to contribute to these differences. (See 'Pathogenesis' below.)
Age of onset — In a series from the United States, the peak incidence of JRA occurred at one to three years of age, with a preponderance of girls in this age group [13]. A second, less prominent peak was noted between ages 8 to 10 years; this peak included more boys with oligoarticular JIA. Other investigators have found a mean age of onset of approximately six years for both systemic and polyarticular disease; oligoarticular disease began at a mean age of approximately 4 years in girls and 10 years in boys [14].
Sex differences — In most published series, the female-to-male ratio ranges from 2:1 to 3:1, although equal sex ratios have been described among both Indian and Black South African children [15]. These ratios depend upon the age at onset and the type of disease [16]. As an example, oligoarticular JIA affecting children under eight years old may have a female preponderance as high as 8:1, especially if iridocyclitis is present [17-19]. In contrast, late-onset human leukocyte antigen (HLA) B27-related disease occurs more commonly in males [20,21]. Systemic JIA shows little or no discrimination between sexes.
Secular and seasonal variations — Substantial variations in JIA occurrence over extended (secular trends) and shorter (seasonal) periods have been noted in some populations [2,6]. The possibility of an etiologic link was suggested by a report from the United Kingdom in which an influenza virus epidemic occurred prior to an "outbreak" of JIA [22]. The strongest seasonal variations have been observed with systemic JIA [23,24], although this appears to be true only in some geographic regions.
PATHOGENESIS — The pathogenesis and etiology of JIA are unclear. As with most autoimmune disorders, interactions among genetic factors, immune mechanisms, and environmental exposures are thought to contribute in most cases. Most of the genetic predisposition to JIA is determined by the major histocompatibility complex (MHC) loci. Multiple MHC loci are associated with the development of JIA, and, in general, these associations are markedly distinct from those seen in adult rheumatoid arthritis (RA). The spectrum of non-human leukocyte antigen (HLA) genes that are associated with JIA is expanding rapidly, but their contribution to the risk of JIA appears to be less significant, and their effects may be shared between JIA and other autoimmune diseases including RA.
Familial predisposition — Patterns of inheritance consistent with Mendelian or monogenic inheritance have not been observed in JIA. The level of risk to family members of a proband appears to be only mildly increased [25,26], and families with multiple affected members are uncommon. As examples:
●In the United States, the juvenile rheumatoid arthritis (JRA) Affected Sib Pairs Research Registry in Cincinnati estimated the total number of affected sib pairs at 300 in a population of approximately 250 million [27]. Almost 80 percent of the pairs and 100 percent of twin pairs were concordant for disease type. Among twins, disease onset was separated by a mean of approximately three months. In a subsequent study that included an additional 94 affected pairs, the mean difference in age of onset of non-twin pairs was approximately three years, and concordance of disease type was 73 percent for the two cohorts combined (120 of 164 non-twin affected sib pairs) [28].
●In Europe, only 12 affected sib pairs were found among over 3000 patients [29].
Anecdotal evidence suggests that families with JRA probands have an increased risk of other nonrheumatic autoimmune diseases [30,31].
Predisposing major histocompatibility complex genes — Multiple HLA loci are associated with the development of JIA, with specific disease subtypes being linked to specific HLA alleles [26,32]. Genes that do not encode classic HLA proteins but lie within the MHC may also predispose to JIA. (See "Human leukocyte antigens (HLA): A roadmap".)
Early-onset oligoarticular JIA — Patients with early-onset oligoarticular JIA, which has a relatively high concordance among siblings [27], constitute the subtype with the most distinctive HLA associations. Correlations with various HLA class II DR and DP alleles include:
●HLA-DR8 [33,34]
●HLA-DR11 [35-37]
●HLA-DR13 [38]
●HLA-DPw2 [39,40]
DNA sequence-dependent methodologies have defined more precisely the HLA alleles associated with oligoarticular JIA. Disease susceptibility correlates with particular alleles of each serologically or cellularly defined specificity, such as HLA-DRB1*0801 of DR8 and HLA-DPB1*0201 of DPw2 [32]. Although most associations are with HLA class II, a consistent increase in risk with the HLA class I A2 allele has been reported in females with early-onset oligoarticular JIA [41]. (See "Human leukocyte antigens (HLA): A roadmap".)
In contrast to these findings, some HLA class II alleles occur with decreased frequency in affected children, suggesting a protective effect. Examples include HLA-DR4 and HLA-DR7 [32].
Determination of HLA specificities using DNA-based methodologies has also better defined the genetic markers of disease outcome in early-onset oligoarticular JIA. Haplotypes carrying HLA-DRB*0801, HLA-DRB*1301, and HLA-DP*0201 alleles appear to predispose to oligoarticular JIA in general. In contrast, other alleles may contribute to the risk for other clinical manifestations. As examples:
●HLA-DRB1*1104 predisposes to eye disease [42].
●HLA-DQA1*0101 predisposes to evolution from oligoarticular to polyarticular, erosive disease but is associated with a reduced risk of eye disease [43].
●HLA-DRB1*0101 has been associated with polyarticular disease [44].
Whether the HLA-DQA*0101 or the HLA-DRB*0101 allele is a better marker for the haplotype is uncertain, but there are data that are compatible with either possibility.
The fact that HLA genes from four loci (HLA-A, HLA-DR, HLA-DQ, and HLA-DP) are involved in inherited predisposition to oligoarticular JIA raises the possibility that these genes make up a potential susceptibility haplotype. However, the absence of linkage disequilibrium between these genes indicates that there are independent genetic effects at three loci. This is illustrated in the table (table 2), which demonstrates the odds ratio obtained by the cumulative addition of risk factors. Such interactions have been demonstrated in other populations [45].
In a significant proportion of patients with early-onset oligoarticular JIA, especially those with uveitis, the development of the disease may be associated with the presence of two susceptibility alleles of either the HLA-DR or HLA-DQ loci. Patients who are heterozygous for HLA-DR5/HLA-DR8 have a particularly increased risk for developing eye disease [46]. An HLA-DP gene and the class I HLA-A2 gene also contribute, appearing as independent risk factors. Class II gene homozygosity is not increased in the oligoarticular JIA patient population, suggesting that a dosage effect of any individual gene does not increase risk [46].
Other types — HLA associations with clinical forms other than early-onset oligoarticular JIA are less strong. In addition to the previously mentioned increased risk of late-onset oligoarticular JIA associated with HLA-B27 [20,21], the following associations have been reported:
●Polyarticular, rheumatoid factor (RF) negative JIA susceptibility with HLA-DPw3 [47].
●RF-positive, polyarticular JIA has the same HLA-DR4 associations as does adult RA: HLA-DRB1*0401 and HLA-DRB1*0101 [48]. (See "HLA and other susceptibility genes in rheumatoid arthritis".)
●Systemic JIA with HLA-DRB1*11 and MHC class II locus variants [49], HLA-DR4 in Northern but not Southern European populations [32], and MHC complex, chromosome 1, and other novel loci [50].
HLA-DR1/DR4 shared epitope hypothesis — RA in adults is associated with the presence of the DNA sequence common to human leukocyte antigen (HLA) DR1 and some HLA-DR4 specificities [51,52]. However, the shared epitope hypothesis as applied to adults is not useful for oligoarticular JIA, in which HLA-DR4 is protective and HLA-DR1 haplotypes predispose to a polyarticular outcome. Similarly, patients with seronegative polyarticular JIA do not carry the appropriate epitopes. The only JIA group in which the shared epitope hypothesis may hold is in older children with polyarticular disease who are immunoglobulin M (IgM) RF positive. These patients have the childhood equivalent of adult RA; they represent fewer than 10 percent of all patients with JIA. (See "HLA and other susceptibility genes in rheumatoid arthritis", section on 'Individual alleles and the shared epitope'.)
Age-specific effects — There is new evidence that some genes operative in JIA appear to have a "window-of-effect," during which time they may contribute risk of disease but be neutral or even protective at other times [53]. This appears to be particularly true in the oligoarticular groups, in which HLA-related risks clearly differ with age. For example, 50 percent of children carrying at least one of the susceptibility MHC alleles have disease onset prior to their third birthday, suggesting that the period of susceptibility to early-onset oligoarticular JIA is limited to the first years of life. In contrast, HLA-B27 and DR-4 appear to be associated with the protection against early-onset oligoarticular JIA early in life but with the increased risk for other forms of JIA later in childhood (figure 1).
Predisposing non-HLA genes — Increasing evidence supports the concept that the occurrence of JIA and its phenotype is determined by complex genetic traits with "genetic interplay" between human leukocyte antigen (HLA) and non-HLA predisposing alleles [54]. The spectrum of non-HLA genes that may be associated with JIA is expanding rapidly, as illustrated in the table (figure 2) [18,35,55-67]. However, their contribution to the risk of JIA appears to be less significant than that of HLA genes, and their effects may not be specific to JIA. In general, the odds ratios are low, and distinguishing between founder effects (the incomplete mixing of genetically disparate populations) and associations that relate to pathogenesis has been difficult. Reproducible associations with odds ratios greater than two have been noted with interleukin (IL) 6 and macrophage migration inhibitory factor (MIF) promoter polymorphisms [68]. The IL-6 promoter (-174G) allele is significantly associated with systemic disease in children older than the age of five years but not in younger children [69].
The use of genetic markers, such as microsatellite polymorphisms, suggests the presence of other, as yet unknown genes, which are associated with JIA. As an example, the marker D6S265*5, which is in proximity to, but distinct from, the HLA-A locus, is more commonly found in Norwegian children with seronegative forms of JIA than controls [70].
Initial genome-wide scanning using polymorphic markers on all the chromosomes in 121 families with a pair of affected children has confirmed the linkage of JIA to the HLA region on chromosome 6 and identified several other sites of interest [71]. Evidence for linkage to sites on chromosome 1, 19, and 20 was noted. When affected children were stratified by the type of disease onset, evidence of linkage was found at different chromosomal locations (eg, early-onset polyarticular and oligoarticular disease with chromosomes 7 and 19, respectively), and, when children carrying the HLA-DR8 allele were selected, strong evidence of linkage to a site on chromosome 2 was noted.
Additional loci and genes associated with adult RA have also been identified in genome-wide association studies (GWAS) of RA, including IL-2 receptor alpha (IL2RA), protein tyrosine phosphatase nonreceptor-type 2 (PTPN2), PTPN22, signal transducer and activator of transcription 4 (STAT4), angiopoietin 1 (ANGPT1), and component of oligomeric Golgi complex 6 (COG6) [72,73]. The latter study also found associations with loci at 3q13 and 10q21 that may be unique to JIA [73]. Dense mapping of suspected loci in 2816 patients with oligoarticular or polyarticular JIA confirmed associations with the HLA region, PTPN2, PTPN22, STAT4, IL2RA, and COG6 [74]. Additional regions were also identified, including several loci involved in the IL-2 pathway, which is important for T cell activation and overall regulation of the immune system. Some examples include IL2, IL21, IL-2 receptor subunit beta (IL2RB), and SH2B adaptor protein 3 (SH2B3) regions. Additionally, when subtype-specific association testing was performed, one region (interferon regulatory factor 1 [IRF1]) differed between oligo- and polyarticular JIA. This region was strongly associated only with oligoarticular JIA. IRF1 is a transcription factor that binds to a number of genes that contain an interferon (IFN) stimulated response element, and it is therefore an important regulator of the immune response.
Genetic associations in RF-positive polyarticular JIA are strikingly similar to those in adult RA. Combined with the fact that RF-positive polyarticular JIA typically occurs in older children, this type of JIA may represent early-onset RA [75].
Environmental factors — Although at least some genetic component is evident in all clinical forms of JIA, the environmental component appears to be stronger for some forms [76]. Potential environmental influences that may improve or worsen disease include infection, antibiotic use, breastfeeding, maternal smoking, and vitamin D/sun exposure [77].
Infection — An infectious etiology has been suspected for a long time [78]. However, classical epidemiologic studies have not generally shown clustering of JIA that would imply a definite infectious etiology, although some seasonality in systemic disease has been noted [23,24]. In addition, changes in the incidence of JIA over time may reflect an environmental or infectious rather than a genetic effect [2,6]. Several potential pathogens have been proposed, but none have been definitely shown to be casual. The following are of interest:
●A transient arthritis can develop after rubella virus infection or rubella virus vaccine. In addition, limited data suggest that rubella may play a role in JIA. Mean rubella antibody levels were significantly elevated in young children with JIA in one series but were no different to only mildly elevated in two other studies [79-81]. Rubella virus antigen and rubella virus in lymphoreticular cells have been identified in the synovial fluid in some children with JIA [79,82]. The abrupt nature of a relapse of systemic JIA after primary rubella vaccination in one case report suggests that this event was due to molecular mimicry between rubella and JIA rather than directly due to the infection [83]. However, the majority of these references are more than 20 years old, and the question has not been readdressed with modern techniques. (See "Oligoarticular juvenile idiopathic arthritis", section on 'Immunizations'.)
●An Epstein-Barr virus protein has sequence similarities to HLA-DR8, DR11, and DPw2, all of which are associated with oligoarticular JIA [84]. This and the finding of cross-reactive T cell-mediated cytotoxicity stimulated by HLA and viral-derived peptides suggests a role for molecular mimicry [85].
●Chlamydia has been identified in the joints of some children with arthritis, although the significance of this in the context of JIA is uncertain. The clinical presentation of chlamydial arthritis can be similar to JIA, including the development of iridocyclitis [86].
●Influenza A infection in pregnancy was associated with the subsequent development of polyarticular JIA in childhood in a study from South Wales [22].
●An evaluation of long-term trends in Canada found that Mycoplasma pneumoniae infections had incidence peaks that coincided with incidence peaks for JRA [6]. Peaks in JRA incidence over years of observation have been noted in other studies but have not been correlated with specific infectious agents [2].
●Recovery of parvovirus B19 DNA from synovial fluid or serum was higher in 74 patients with various types of JIA than in children without arthritis (35 versus 7 percent, respectively) [87]. There was little difference in the rates of prior infection with parvovirus B1 as estimated by the prevalence of immunoglobulin G (IgG) antibodies to viral proteins (62 versus 52 percent, respectively).
●HLA-B27 associated forms of JIA can be triggered by bacterial infections [88], as is the case with HLA-B27-associated disease in adults. An immunodominant epitope of Escherichia coli heat shock proteins (HSPs) is a potential target in HLA-B27-positive JIA [89]. (See "Pathogenesis of spondyloarthritis".)
Antibiotics — A few studies have found a link between antibiotic use and the development of JIA. The potential underlying mechanism is unknown, but alteration of the intestinal microbiome with subsequent immune dysregulation is postulated [90]. Alternative explanations of the findings include the possibility that these patients develop more frequent infections due to some intrinsic abnormalities in the immune system that may also predispose them to JIA.
●One study examined antibiotic use in all children born in Finland between 2000 and 2010 and diagnosed with JIA by the end of 2012 (n = 1298) and matched controls (n = 5179) [91]. Purchase of one or more courses of antibiotics from birth to the time of diagnosis was associated with an increased risk of JIA (odds ratio [OR] 1.6, 95% CI 1.3-1.9). The risk increased with the number of prescriptions filled.
●Previous antibiotic prescriptions were compared in a second case-control study of 152 children newly diagnosed with JIA and 1520 controls in the United Kingdom [90]. This study also found that any use of antibiotics was associated with an increased risk of JIA (OR 2.1, 95% CI 1.2-3.5), and the risk was dose dependent. The timing of first antibiotic exposure did not influence the risk, but the risk was greatest for antibiotic exposures that occurred within one year of diagnosis. No appreciable change in risk was seen after adjusting for specific types or numbers of infections. In secondary analyses, having multiple antibiotic-treated upper respiratory tract infections (URIs) was associated with an increased risk of JIA, but having untreated URIs was not. No differences in risk were seen when specific antibiotic types and functions were evaluated. Antiviral and antifungal antimicrobial drugs were not associated with an increased risk of JIA.
PATHOBIOLOGY — The major clinical manifestation of JIA is persistent joint swelling that results from the combination of synovial fluid accumulation and synovial thickening. Such swelling may cause deformities of affected joints due to stretching of periarticular ligaments and tendons. In addition, enzymes released by inflammatory cells within the synovium or synovial fluid may result in degradation of the collagen and proteoglycan matrix of the articular cartilage. Activation of osteoclasts resulting from the production of cytokines by cells within the mass of inflammatory tissue is probably the final pathway of juxta-articular bone demineralization and bone erosions.
While some mechanisms of disease are likely shared by children with JIA and adults with rheumatoid arthritis (RA), there may be some that are unique to childhood disease. The pathobiology of RA in adults is discussed separately. (See "Pathogenesis of rheumatoid arthritis" and "Synovial pathology in rheumatoid arthritis".)
Synovial fluid — Synovial fluid in affected joints is increased in amount and decreased in viscosity. Various inflammatory cells are found in the fluid, including neutrophils, plasma cells, dendritic cells, and T cells expressing markers of activation [92]. Mediators of inflammation such as cytokines and cleavage products of the complement system are also abundant [93].
Synovial tissue — One of the hallmarks of the pathology of both JIA and RA is the tumor-like expansion of inflamed synovial tissue, or pannus, which causes much of the joint damage [94,95]. As the disease progresses, pannus spreads over the synovial space and adheres to intra-articular cartilage. It is in the areas of pannus-cartilage junction where the cartilage eventually degrades.
Pannus results from the proliferation of synoviocytes and invasion of the synovial tissue by inflammatory cells recruited from the peripheral circulation. Mitotic figures are rarely seen in synovial histopathology, suggesting that ongoing recruitment of inflammatory cells from peripheral circulation is a major pathway of pannus expansion [96]. Pannus growth is also supported by extensive formation of new blood vessels that provide both a source of nutrients for growing pannus and access for inflammatory cells to infiltrate the synovium.
The increased angiogenic activity appears to be mediated by growth factors derived from monocytic cells recruited to the synovium in patients with JIA [97-99]. These factors include vascular endothelial growth factors (VEGF), angiopoietin 1 (Ang 1), and osteopontin. In one study, expression of VEGF and Ang and their receptors correlated with the inflammatory activity in the tissues [97]. Another study showed a strong correlation between increased serum levels of VEGF and disease activity in polyarticular JIA [98].
Cellular infiltrate — Light and electron microscopic studies of the synovium in JIA reveal prominent infiltration with lymphocytes, plasma cells, and macrophages as well as proliferation of fibroblast- and macrophage-like synoviocytes. Infiltration with inflammatory cells is inhomogeneous: lightly infiltrated areas alternate with areas of dense cell aggregates [94].
Inflammatory cell aggregates are usually seen around or near blood vessels and are comprised of clusters of CD4-positive cells surrounded by a mantle of mixed CD4- and CD8-positive cells and B cells. In one small series of newly diagnosed, untreated patients, those with polyarthritis had significantly higher numbers of CD4- and CD8-positive T cells and B cells than patients with oligoarthritis [100]. Patients with persistent oligoarthritis had fewer CD3- and CD4-positive T cells and B cells than those who went on to develop extended oligoarthritis. CD68-positive cells of monocyte/macrophage lineage are numerous and are typically found in the cell aggregates. This pattern of findings resembles that of classic delayed-type hypersensitivity reactions [101]. In general, tissues from patients with the polyarticular form of JIA appear to have somewhat larger mononuclear cell foci as compared with oligoarticular JIA patients. However, the tissues cannot be reliably distinguished solely on this basis [102]. The meaning of these findings in relation to disease pathogenesis remains unclear.
Dendritic cells appear in increased numbers within the synovial membrane and fluid. Dendritic cells from the synovial compartment are larger than most of those from peripheral blood and have a more extensive Golgi complex [94]. They are often found near T cells [103]. A distinctive feature of such synovial dendritic cells is their high level of human leukocyte antigen (HLA) DQ and DR expression.
Dendritic cells are particularly potent antigen-presenting cells [104]. Since their main function is to present antigens, it is reasonable to believe that antigen presentation is taking place in inflamed synovium. This notion is supported by the demonstration that dendritic cells from joints of some patients with JIA stimulate autologous lymphocytes in a mixed lymphocyte reaction [105].
Most of the T cells infiltrating synovium are of a memory phenotype. T cell activation levels vary among different areas in synovium. Most interleukin (IL) 2 receptor-positive cells are found in the "mantle" surrounding the inflammatory cell aggregates or in interaggregate areas [9]. DNA-synthesizing T cell blasts represent no more than 5 percent of all synovial compartment mononuclear cells [11], suggesting that most of these cells are recruited from the peripheral circulation. Among the small proportion of radiolabeled blast cells, CD4+ lymphocytes are the dominant cell population [106].
Recruitment of cells into synovium — Infiltration into the synovium depends upon an interplay of vascular factors, cytokines, adhesion molecules, and chemokines.
Vascular factors — Mononuclear cell aggregates are found predominantly around blood vessels, particularly postcapillary venules that have distinct morphology [94]. These venules are lined by tall, metabolically active endothelial cells that express high levels of adhesion molecules, features similar to those observed in venules of lymphoid organs. Some of the postcapillary venules in lymphoid organs are specialized to facilitate the transendothelial migration of circulating lymphocytes [96,107]. These specialized high endothelial venules (HEV) may play a similar role in JIA synovium. As an example, CD4+, HLA-DR+ lymphocytes from peripheral blood of children with JIA adhere to human umbilical vein endothelial cells that have been activated by tumor necrosis factor (TNF) alpha [108].
Cytokines promoting immune cell recruitment into synovium — Given the abundance of TNF-alpha in juvenile rheumatoid arthritis (JRA) synovial tissues and the high levels of the p55 TNF receptor on the synovial endothelial cells [109], it is likely that TNF-alpha plays a pivotal role in the enhancement of inflammatory cell trafficking into inflamed synovium. IL-15 is another cytokine that enhances the transendothelial migration of lymphocytes to RA synovium [110]. IL-15 appears to be one of the most highly expressed cytokines in JRA synovium [111].
Macrophage migration inhibitory factor (MIF) may also play a role in JIA. Both serum and synovial fluid levels of this cytokine may be elevated in children with systemic disease [112]. Other evidence for a contribution of MIF in this subset is the correlation between increased disease severity, as estimated from swollen joint counts and duration of corticosteroid therapy, and the presence of a single nucleotide polymorphism in the promoter (noncoding) region of the MIF gene [113,114].
Adhesion molecules — Trafficking into synovium may also be enhanced by overexpression on lymphocytes of very late activation antigen (VLA-1), a surface protein from the integrin family of adhesion molecules that mediates leukocyte adhesion to matrix proteins [115]. The recruitment of proinflammatory cells into synovium does not appear to be random. Selection of predominantly T helper cell type 1 (Th1) lymphocytes may be dependent upon various chemokines and be both antigen specific and antigen nonspecific [116,117].
T cell contribution — T cell receptor (TCR) alpha-beta-T cells are the predominant cell population in the JIA synovium and exhibit phenotypic and functional characteristics of cells that have undergone prior activation in vivo. These characteristics include expression of IL-2 receptors (CD25) [118], early activation antigen CD69, CD45RO (memory phenotype), VLA-1 [115], and HLA class II antigens [92,119]. These activated effector T cells have impaired sensitivity to immunoregulation by regulatory T cells (CD4+CD25+FoxP3+ Tregs) in synovial fluid [120]. (See "Normal B and T lymphocyte development".)
A theory that such activation might be induced by an autoantigen located in the inflamed joints prompted a search for clonally expanded synovial T cell populations, an approach that had been successfully utilized in experimental allergic encephalomyelitis [121]. In this model, a known autoantigen (eg, myelin basic protein) stimulates expansion of T cells with receptor specificity for this particular antigen. Furthermore, clonally expanded T cells utilize a limited number of V-beta segments in their TCRs. It was anticipated that, if detected in the JIA synovium, such populations might provide a clue to the identification of the antigens driving the immune response in JIA.
Clonal expansion of alpha-beta-T cells in both CD4+ and CD8+ populations can be detected in the synovium of the vast majority of JRA patients [122-125]. Identical clones with the same receptor specificity are present in multiple joints of the same individual and persist over a long period of time [123,125]. Some clones can be detected in peripheral blood as well, although there is preferential accumulation of these clonally expanded populations in inflamed synovial tissues [123,124].
These findings were thought to be consistent with the concept of persistent antigenic stimulation of T cells in the synovial compartment of JIA patients. However, the discovery of similar clonally expanded CD8+ populations in peripheral blood of healthy adults (usually older than 35 years of age) [126] made some investigators question this concept.
Further studies were focused on the analysis of the TCR complementarity determining region 3 (CDR3), the site of specific interaction of the TCR with unique peptide-HLA complexes. It was anticipated that expansion of structurally identical clones would be indicative of an ongoing antigen-driven immune response in the joint. Since the CDR3 region is encoded by the variable diversity joining (V-D-J) segments, several studies were carried out to determine whether oligoclonal T cell populations preferentially utilized particular V-alpha or V-beta chain TCR segments. Initially, fewer V-beta families were found in fresh T cells from the synovial fluid than from the peripheral blood [122]. These differences were more obvious when IL-2 receptor-positive T cells were isolated [122]. Restricted usage of V-alpha segments by synovial fluid T cells was also seen. (See "T-B-NK+ SCID: Pathogenesis, clinical manifestations, and diagnosis", section on 'T cell receptor generation'.)
A more comprehensive study of synovial fluid samples obtained from 36 patients with different forms of JRA revealed that the vast majority of JRA patients had multiple synovial T cell clones utilizing a wide variety of different TCR V-beta segments [124]. However, some differences in patterns of TCR V-beta utilization between clinical subtypes of JRA were noted, suggesting that different antigens might be involved in different clinical forms of JRA.
Subsequently, extensive DNA sequencing efforts showed that, despite the wide diversity of CDR3 motifs, certain similarities between multiple synovial T cell clones derived from an individual patient could be found [127]. These data provided indirect support for the concept that the persistent synovial inflammation in JIA is antigen driven. However, the wide variety of both V-alpha and V-beta segments and CDR3 motifs utilized by clonally expanded T cell populations precludes their use as potential targets for specific immunotherapy.
Gamma-delta-T cells — A clonal analysis of JRA synovial T cells responding to IL-2 revealed the presence of a distinct T cell population with a CD3+ CD4-, CD8- phenotype [118]. These cells have gamma-delta (instead of alpha-beta) TCRs and comprise approximately 5 to 10 percent of T cells infiltrating the JRA synovial membrane [128-130]. In most cases, gamma-delta T cells are clustered in lymphoid follicle-like structures [130]. In approximately 30 percent of patients with JRA, the proportions of gamma-delta T cells were increased in synovial fluid relative to peripheral blood [131]. A high proportion of synovial gamma-delta T cells express CD25, CD69, and HLA-DR [129].
Although the specificity and function of human gamma-delta T cells are unknown, at least some of these cells, including those in JRA synovial fluid, appear to respond to mycobacterial antigens and stress proteins (in particular heat shock protein 65 [hsp65]) [89,132,133]. Heat shock proteins (HSPs) are constitutively expressed in practically all organisms, and increased synthesis can be induced by a variety of stress conditions including inflammation. Utilizing monoclonal antibodies that recognize human hsp60, high levels of expression were demonstrated within synovial lining cells in JRA synovial tissue [134].
Heat shock protein-related T cells — There is a high degree of homology between bacterial and mammalian Hep2-derived HSPs. During infection, the synthesis of HSP is elevated in both the microorganism and host cells. If crossreactivity occurs between these, it can be inferred that the immune response to HSP would be potentially autoreactive [135]. On the other hand, HSP have been shown to stimulate local expansion of T cells secreting antiinflammatory cytokines such as IL-4 or IL-10 [136,137]. These T cells appear to have a phenotype of so-called immunoregulatory T cells that appear to provide protection against autoimmunity [138]. Indeed, an inverse relationship may hold between high immune responses to human hsp60 and the severity of arthritis in patients with JIA [137,139].
This is illustrated by the following studies [140,141]:
●In the first study, 13 of15 patients with oligoarticular JIA had peripheral blood T cells that demonstrated reactivity to HSP 60 [140]. Only 1 of 20 patients with polyarticular JIA had a similar finding. HSP reactivity was associated with disease remission by 12 weeks.
●In contrast, a study of 57 patients with oligoarticular or polyarticular JIA demonstrated an enhanced proliferative response of peripheral blood T cells when exposed to five of eight selected HSP epitopes. This response was absent in both of the control groups (healthy children and children with type 1 diabetes). The relative response of T regulatory and T helper cells was also measured by comparing cytokine production of IL-10 (immunosuppressive cytokine) to interferon (IFN) gamma (proinflammatory cytokine). Only patients with active oligoarticular JIA produced increased levels of IL-10 compared with IFN-gamma. These results suggest that, in patients with active oligoarticular JIA, there is a greater response in the T regulatory cells than in T helper cells.
One interpretation of these data is that upregulation of the T regulatory cells in patients with oligoarticular JIA decreases inflammation, leading to less severe disease in these patients compared with those with polyarticular JIA [141,142]. The data also suggest that increased T regulatory cell activity might contribute to better clinical outcomes with early remission of disease [140,142].
T cell-derived cytokines — In adults with RA, T cell-derived cytokines are usually undetectable despite heavy T cell infiltration of the synovium. In contrast, T cells in JIA appear to be more actively producing cytokines [102].
Th1 cytokines such as IFN-gamma or TNF-beta are found in most of the synovial tissue and fluid samples of children with JRA [93,143]. Increased TNF-beta expression correlates with the occurrence of lymphocytic aggregates [109]. The in vitro production of cytokines by T cell clones derived from synovial fluids of oligoarticular JIA were of Th1/Th0 type in one report [144]. Thus, a Th1 cytokine response may be disease promoting. Consistent with this notion, one study showed that higher levels of IFN-gamma and a strong IFN-induced transcriptional signature in synovial fluid mononuclear cells were predictive of progression from oligoarticular to polyarticular disease [145].
In a subsequent study, synovial fluid CD4+ T cells displayed an overall Th1 phenotype, although scRNA-Seq uncovered heterogeneous effector and regulatory subpopulations, including IFN-induced regulatory T (Treg) cells, peripheral helper T cells, and cytotoxic CD4+ T cells [146].
Th2 cytokines, such as IL-4 and IL-10, may be produced as well. IL-4 has mainly been demonstrated in tissue and fluid samples obtained from patients with more restricted disease, particularly oligoarticular JIA [143]. IL-10 is more consistently found in JRA tissues [143]. Preliminary evidence suggests that at least some of these cytokines are derived from the immunoregulatory T cells [138,147], which are found in the CD25+ T cell population in both peripheral blood and synovial compartments.
T cells infiltrating the inflamed synovium in children with JIA may have a skewed cytokine phenotype, which may be due to selective recruitment of cells expressing chemokine receptors characteristic of Th1 cells. This hypothesis is supported by the demonstration of enrichment of synovial fluid lymphocytes for T cells expressing chemokine receptors cysteine-cysteine chemokine receptor (CCR) 5 and cysteine-X-cysteine motif chemokine receptor (CXCR) 3, which are markers for the Th1 phenotype [148,149]. Enrichment of synovial fluid CCR4-bearing T cells, when compared with similar cells in peripheral blood, has also been noted [150].
JIA synovial tissues are also enriched by chemokines capable of stimulating CCR5 and CXCR3 receptors (eg, interferon inducible protein 10 [IP-10] and RANTES) [151]. I-309 (or CCL1) is also abundant.
Results from one study suggest that the highly proinflammatory Th17 cells also contribute to joint pathology in JIA [152]. IL-17+ T cells were increased in the joints of children with JIA compared with levels in the blood of JIA patients and controls and were also demonstrated in synovial tissue. IL-17+ T cell numbers were higher in patients with extended oligoarthritis compared with patients with persistent oligoarthritis. Within the joint, there was an inverse relationship between IL-17+ T cells and forkhead box P3-positive (FoxP3+) Treg cells. A higher proportion of Th17 cells is also seen in the peripheral blood of patients with systemic JIA compared with normal controls [153].
Natural killer cells — Natural killer (NK) cells in JIA have been assessed in several studies with somewhat contradictory results. No significant differences in the distribution of cells bearing CD16+, a surface marker for cytotoxic T lymphocytes was noted in one report [115]. However, decreased NK cell numbers and an inverse correlation between disease activity and NK cell content has been described by others [154]. Profoundly decreased NK cytolytic activity often associated with abnormal levels of perforin expression may be a distinguishing feature of the systemic form of JIA that puts these patients at risk for the development of macrophage activation syndrome (MAS) [155]. (See 'Macrophage activation syndrome' below.)
Macrophages/fibroblasts — Increased numbers of macrophages, dendritic cells, and synoviocytes of both fibroblast-like and macrophage-like phenotype are typical features of JIA synovium [94]. The abundance of cytokines secreted by these cells (such as IL-1, IL-6, IL-12, and TNF-alpha) provides further evidence for a major role in perpetuation of the synovial inflammation.
Evidence of the importance of inflammatory mediators released from such cells includes the following:
●High spontaneous production of IL-1 by mononuclear cells derived from peripheral blood of JRA patients and abundance of IL-1 producing macrophages in inflamed JRA synovium [156].
●A correlation between levels of IL-6 expression in the serum, the extent of joint involvement, and degree of thrombocytosis in systemic JIA [157].
●Serum from patients with systemic JIA induced the transcription of IL-1 in healthy peripheral blood mononuclear cells [158].
●Elevation of IL-12 in the serum and TNF-alpha, TNF-beta, and IL-6 in synovial fluids of a large proportion of JRA patients [93,109].
●Increased circulating levels of IL-18 in children with systemic disease were not seen in other JIA subtypes or Kawasaki disease [159].
Role of tumor necrosis factor alpha — In the majority of JRA synovial tissue samples, cells staining for TNF-alpha are found within dense cellular aggregates and in the "mantle" of cells surrounding the aggregates [109]. The pattern of distribution of TNF-alpha staining is similar in nature to the pattern observed with CD68 staining. The level of expression of TNF-alpha correlates closely with the degree of inflammatory infiltration of synovia.
High levels of TNF expression are associated with wide distribution of TNF receptors in the vast majority of tissues. As an example, staining with antibodies specific for the p55 and p75 TNF receptors revealed that cells with diverse morphology expressed TNF receptors on their surfaces. Higher numbers of positive cells were observed in the areas of cellular aggregates adjacent to synovial venules, with the most intense staining seen on the endothelial cells lining the synovial blood vessels [109]. Serum levels of the soluble forms of both the p55 and p75 TNF receptors are elevated in the majority of children with active systemic JIA but only in minority of those with polyarticular or oligoarticular disease [160].
Activated lymphocytes from peripheral blood of children with JRA adhere to vascular endothelial cells stimulated with TNF-alpha in vitro [108]. In vivo, this would be expected to lead to the extravasation of such cells and their accumulation at the site of inflammation. These observations suggest that one of the mechanisms by which TNF-alpha amplifies inflammation in JIA is its ability to promote trafficking of the inflammatory cells from peripheral circulation into synovium.
The proinflammatory role of TNF-alpha in rheumatoid disease does not appear to be limited to only synovium. TNF-alpha is a major proinflammatory cytokine with both local and systemic effects [161]:
●At low concentrations, it acts locally, mostly as a paracrine and autocrine regulator of leukocytes and vascular endothelial cells. These actions contribute to the accumulation of inflammatory cells at local site of inflammation.
●When production of TNF-alpha is increased significantly, it is released into peripheral circulation causing a number of systemic effects. As an example, TNF-alpha acts on hypothalamic regulatory systems to induce fever and stimulate hepatocytes to produce proteins that constitute the acute phase response. (See "Acute phase reactants".)
●When TNF-alpha is produced at high levels over a long period of time, it also suppresses the bone marrow and may cause metabolic alterations leading to cachexia.
Although similar symptoms and signs are often observed in JIA, particularly in the systemic form, it is not clear to which extent they can be attributed to TNF-alpha. The beneficial clinical experience with anti-TNF-alpha treatment strategies supports a critical role of TNF-alpha in both local and systemic features of pauci- and polyarticular JIA. (See "Polyarticular juvenile idiopathic arthritis: Clinical manifestations, diagnosis, and complications" and "Systemic juvenile idiopathic arthritis: Treatment", section on 'Biologic disease-modifying antirheumatic drug (DMARD) therapy'.)
Surprisingly, the same strategy appears to be less effective in the systemic form of JIA. Preliminary clinical experience, however, suggests that patients with systemic JIA may show a much better response to therapy directed toward IL-1 or IL-6. In fact, good clinical response to the inhibition of IL-6 and/or IL-1 in systemic JIA is similar to that seen in autoinflammatory diseases with a known genetic cause, such as neonatal-onset multisystem inflammatory disease, in which the inflammatory response is triggered by the abnormalities in the innate immunity [158]. It has been suggested that the role of the adaptive immune response in systemic JIA may be rather limited compared with the other clinical forms of JIA. In contrast, the contribution of the innate immunity may be much more prominent, and systemic JIA should be viewed as an autoinflammatory syndrome. (See "Cryopyrin-associated periodic syndromes and related disorders", section on 'Neonatal-onset multisystem inflammatory disease' and "Systemic juvenile idiopathic arthritis: Treatment", section on 'Biologic disease-modifying antirheumatic drug (DMARD) therapy'.)
Macrophage activation syndrome — Massive expansion of macrophages exhibiting hemophagocytic activity is the central feature of so-called "macrophage activation syndrome" (MAS), occasionally seen in patients with predominantly systemic JIA. The expansion of macrophages in this condition is associated with the uncontrolled proliferation of activated CD8+ T cells. Clinically, MAS shares strong similarities with familial hemophagocytic lymphohistiocytosis (FHLH), a usually fatal heritable disorder. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis" and "Systemic juvenile idiopathic arthritis: Course, prognosis, and complications", section on 'Macrophage activation syndrome'.)
Neutrophils — Numbers of circulating neutrophils may be very high in patients with systemic JIA, and these cells may contribute to the amplification of the inflammatory response in this form of JIA. Neutrophil gene profiling in polyarticular JIA suggests an important role for neutrophils in disease pathogenesis of this subtype as well [162]. Evidence of the importance of inflammatory mediators released from neutrophils includes:
●Elevation of serum levels of a pair of calcium-binding S100 molecules (the myeloid-related proteins 8 and 14) by 120-fold and approximately 12-fold from children with systemic disease when compared with healthy children or those with other inflammatory diseases or infections, respectively [163].
●Increased serum levels of the calcium binding protein S100A12 (also called p6 or calgranulin C), a ligand for the receptor for advanced glycation end products (RAGE) and a mediator of inflammation are often present in untreated patients; average levels are much higher in those with systemic disease than in children with polyarticular or oligoarticular disease (mean serum concentrations of 3700 ng/mL, versus 395 and 325 ng/mL, respectively) [164].
B cells — Although T cells are usually more numerous in inflamed synovial tissue, B cell activity appears to be enhanced in both peripheral blood and the synovial compartment. Synovial tissue specimens from JIA patients have significant numbers of immunoglobulin-synthesizing cells [103]. These cells tend to be focally aggregated. An increased number of B cells spontaneously producing immunoglobulins are also seen in the peripheral blood [165,166]. In addition, memory B cells in the synovium of JIA patients express costimulatory molecules (CD80/CD86) and may function as antigen-presenting cells and activate T cells [167].
Increased expression of genes related to B cells and decreased expression of genes related to cells of the myeloid compartment are seen in patients with oligoarticular JIA who had disease onset before age six years compared with those with a later age of onset [168]. These findings suggest that oligoarticular JIA with onset before six years of age may ultimately be determined to be a distinct disease.
Immunoglobulins — The serum levels of immunoglobulins are elevated in a large proportion of patients with JRA [169,170]. In one series, for example, 37 percent of patients with JRA exhibited hyperglobulinemia in at least one immunoglobulin class, and elevation of globulins correlated with the activity of the disease [170]. Differences in immunoglobulin levels among different JIA clinical subgroups were also noted: Children with polyarticular and systemic disease had mean immunoglobulin levels that were higher than those with oligoarticular JIA. Elevated immunoglobulin A (IgA) levels were associated with the appearance of cartilage erosions.
Conversely, hypoglobulinemia has also been associated with JRA, and a selective decrease in serum IgA concentrations has been described in some patients [170,171].
Rheumatoid factors — Rheumatoid factors (RFs) are only rarely detected in patients with JIA by the classic Rose-Waller reaction or latex-fixation method; the probability of RF positivity increases with the child's age and the duration of the disease. (See "Rheumatoid factor: Biology and utility of measurement".)
Allen and Kunkel demonstrated a so-called hidden RF, defined as IgM 19S antiglobulin [172]. This antiglobulin is "hidden" because of its occupied binding sites. Gel filtration at acid pH dissociates IgM from IgG and allows IgM RF to fix complement in the hemolytic assay. Hidden RFs have been correlated with clinically active disease in approximately two-thirds of patients with JRA [173,174].
Antinuclear antibodies — The reported incidence of antinuclear antibodies (ANAs) in patients with JRA varies from 4 to 88 percent depending upon the clinical subtype and the laboratory technique used [175]. ANAs are uncommon in systemic disease but are present in more than one-half of children with oligoarticular JIA. ANAs are occasionally found in patients with polyarticular disease, most often in those who are RF positive. (See "Measurement and clinical significance of antinuclear antibodies".)
Children who are ANA positive carry an especially high risk of chronic anterior uveitis [175,176]. Local synthesis of ANA in the eyes of patients with chronic iridocyclitis has been noted [177].
The specificity of these antibodies remains to be determined. Some studies indicate that ANAs in JRA are directed against a ribonucleoprotein that requires both RNA and protein components for antigenic integrity [178]. Others dispute this and find that ANA specificity profiles are highly individual and do not correlate with disease subtype or activity [179].
Antibodies to many antigens typical for other rheumatic diseases (eg, the extractable nuclear protein, centromere proteins, topoisomerase [Scl-70], Ro, La, and double-stranded DNA) are generally absent in JIA. Antibodies to the 45 kDa DEK nuclear antigen, a putative oncoprotein, have been associated with the oligoarticular type of JIA, particularly in patients with a history of iridocyclitis [180]. However, these antibodies are present in other rheumatic diseases [181]. Anticollagen [182], antiretinal [183-185], and anti-T cell antibodies have been described, but their relevance to the pathogenesis of JIA is uncertain [186-188].
Immune complexes — Abnormal antibody production and defects in clearance by the reticuloendothelial system may result in an increased concentration of circulating immune complexes in serum and synovial fluid.
Attempts at quantitating immune complexes in serum have yielded conflicting results:
●Using a C1q binding assay, 22 percent of patients with JRA have elevated levels of circulating immune complexes, and the concentration of circulating immune complexes may correlate with the severity of the disease [189].
●Using the polyethylene glycol precipitation method, circulating immune complexes were found in the serum of only 1 out of 13 children with JRA [190].
●Using four different techniques, elevated levels of circulating immune complexes were demonstrated in 79 percent of patients with JRA by at least one method [191].
Findings in synovial fluid have also been inconsistent:
●Using the C1q binding assay, elevated levels of immune complexes were found in joint fluid from some children, but the results varied substantially among patients [192].
●Using the Raji cell method, normal levels of circulating immune complexes have been found in synovial fluids of patients with oligoarticular JIA [141].
A general impression is that circulating immune complexes may contribute to the perpetuation of chronic inflammation in JIA but do not play a major role in its pathogenesis.
Complement activation — Despite these conflicting results, many investigators think that deposition of circulating immune complexes in synovial compartments may result in complement system activation, which in turn causes tissue damage. Some evidence to support this hypothesis has been obtained.
●In one report, complement degradation products C3c and C3d were elevated in the serum of 7 of 10 patients with active systemic disease, in 16 of 29 with active polyarthritis, in 7 of 20 with active pauciarthritis, but in only 2 of 20 with inactive disease [193]. C3c and C3d were not increased in synovial fluid. Elevated serum C3d has also been described in other studies [192].
●Systemic and, to a lesser degree, polyarticular subgroups may have elevations of both C4d/C4 and C3d/C3 ratios, while only the C3d level may be increased in oligoarticular disease [194].
The complement activation cascade (C1-C5) participates in inflammatory reactions mostly by releasing anaphylatoxins, while the terminal cascade results in the formation of the cytolytic macromolecular complex. The entire cascade is involved in the activation process both in peripheral blood and the synovial compartment in patients with JRA [195]. Weak staining for deposits of C3b, C3dg, and the membrane attack complex has also been noted. However, no association was noted between clinical activity and the degree of complement activation. This may in part be due to complement activation by C-reactive protein, a process that is not antigen specific, rather than by immune complexes [195]. (See "Complement pathways".)
Systemic JIA — Data suggest that the underlying pathogenesis of systemic JIA is based upon an uncontrolled innate immune system that results in an autoinflammatory disease. In this disease, there is activation of the vascular endothelium with expression of leucocyte adhesion molecules (E-selectin, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1), subsequent recruitment of neutrophils, and monocytes, and secretion of proinflammatory cytokines (TNF-alpha, IL-1, and IL-6) and S100 proteins [196]. (See 'Recruitment of cells into synovium' above and 'Macrophages/fibroblasts' above and 'Neutrophils' above.)
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".)
SUMMARY
●The lack of standard diagnostic criteria for juvenile idiopathic arthritis (JIA; which includes the previous grouping of juvenile rheumatoid arthritis [JRA] or juvenile chronic arthritis [JCA]) has complicated epidemiologic studies, including the determination of incidence and prevalence (table 1). JIA appears to be less common in African American and Asian American populations in the United States. In most populations, the female-to-male ratio ranges from 2:1 to 3:1. However, these ratios depend upon the age at onset and the type of the disease. The peak incidence is one to three years of age, although this varies depending upon sex and type of disease. (See 'Epidemiology' above.)
●The pathogenesis and etiology of JIA are unclear. As with most autoimmune disorders, interactions among genetic factors, immune mechanisms, and environmental exposures are thought to contribute in most cases. (See 'Pathogenesis' above.)
●Patterns of inheritance consistent with Mendelian or monogenic inheritance have not been observed in JIA. The level of risk to family members of a proband appears to be only mildly increased in most cases. Multiple human leukocyte antigen (HLA) loci are associated with the development of JIA, with specific disease subtypes being linked to specific HLA alleles. Patients with early-onset oligoarticular JIA, which has a relatively high concordance among siblings, constitute the subtype with the most distinctive HLA associations. Some genes operative in JIA appear to have a "window-of-effect," during which time they may contribute risk of disease but be neutral or even protective at other times. (See 'Predisposing major histocompatibility complex genes' above.)
●The major clinical manifestation of JIA is persistent joint swelling that results from the combination of synovial fluid accumulation and synovial thickening. Such swelling may cause deformities of affected joints due to stretching of periarticular ligaments and tendons. In addition, enzymes released by inflammatory cells within the synovium or synovial fluid may result in degradation of the collagen and proteoglycan matrix of the articular cartilage. Activation of osteoclasts resulting from the production of cytokines by cells within the mass of inflammatory tissue is probably the final pathway of juxtaarticular bone demineralization and bone erosions. (See 'Pathobiology' above.)
●One of the pathologic hallmarks of JIA is the tumor-like expansion of inflamed synovial tissue, or pannus, which causes much of the joint damage. Pannus results from the proliferation of synoviocytes and invasion of the synovial tissue by inflammatory cells, including lymphocytes, macrophages, and dendritic cells, recruited from the peripheral circulation. Infiltration into the synovium depends upon the interplay of vascular factors, cytokines, adhesion molecules, and chemokines. Various inflammatory cells are also found in the synovial fluid. As the disease progresses, pannus spreads over the synovial space and adheres to intraarticular cartilage. It is in the areas of pannus-cartilage junction where the cartilage eventually degrades. (See 'Pathobiology' above.)
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