A better knowledge of the different subtype diseases by the search of homogeneity for each diagnostic category is necessary for conducting research. Assessing inflammatory changes is crucial for developing a better control of inflammation and evaluating the effectiveness of therapeutic interventions for JIA children. To our knowledge, this study is first evaluating the laboratory parameters involvement among different JIA subtype, in particularly analyzing the relationship between laboratory inflammatory and immunological parameters with semi-quantitative MR imaging score.
In our study, oligoarthritis onset JIA was a major proportion, which was the most frequent chronic inflammatory rheumatic condition in childhood with approximately 27-60% 10. The sex distribution varied with disease subtype, with a striking female predominance in the oligoarthritis and polyarticular onset groups, and male predominance in enthesitis related arthritis, which was similar with other studies 11,12. The age of onset also differed, with a median 10 years of age in RF+ polyarticular arthritis, slightly older than in systemic and seronegative polyarticular arthritis, and even higher in enthesitis related arthritis. The median age of onset may be slight difference with other studies, in general, two major peaks in JIA onset were observed at 1-2 years and between the ages of 9 and 15 years 13.
Markedly distinct pathogenesis of JIA subtypes implies that there are different presentations on laboratory characteristics, which may represent useful tools to distinguish systemic JIA from other JIA subtypes. Our study illustrated the differences in clinical laboratory variables among JIA onset subtypes, and abnormalities were most frequent in those with systemic JIA. Laboratory investigations showed high levels of inflammatory markers including ESR, CRP and PCT, which were present at very higher circulating levels in systemic JIA and at lower levels in oligoarthritis than in other JIA subtypes, these conventional parameters of inflammation could be useful in monitoring of JIA activity. The time of disease duration prior to first admission may be responsible for these adverse findings, each subtype differs with respect to presentation and anticipated disease course for first admission. Another reason may be that the uncomfortable symptom of affected joints may be difficult to assess in young children, particularly toddlers with limited expressive skills. In fact, swelling is a complaint specific, and as a major characteristic for active arthritis, which is often not correctly identified by families. Oligoarthritis has long been considered as a benign disease14, and oligo/polyarticular JIA is an antigen-driven lymphocyte-mediated autoimmune disease with abnormality in the adaptive immune system, while systemic JIA is demonstrated to be an autoinflammatory disease with abnormality in the innate immune system, and the classic form of systemic JIA is characterized by fevers accompanied associated lymphadenopathy, serositis, and markedly increased acute phase reactants, these symptom is easily assess by families. The values of IL-6 and IL-10 were significantly higher than those of other of JIA subtypes. Aberrant activation of phagocytes leads to the release of pro-inflammatory cytokines including IL-6 in both peripheral blood and synovial fluid, which contribute to the multisystem inflammation of systemic JIA. IL-6 as a cytokine with many biological activities have been implicated in most inflammatory diseases15, and regulated immune responses and acute-phase reactions, which is correlated with spikes of fever, thrombocytosis, and joint involvement. while decreased anti-inflammatory cytokine IL-10 leads to the failure of T cell tolerance to self-antigens, which contributes to the synovial inflammation of oligo/polyarticular JIA. There appear to be complex interactions between disease subtypes and other incompletely defined factors. The most important findings of this work were the clear differences in pattern of complement activation among oligoarthritis JIA, systemic JIA and polyarticular JIA. Circulating immune complexes are elevated in JIA. In work using a qualitative test for C3 and C4 values, higher concentrations of C3 and C4 values have been described in systemic JIA than in oligoarthritis JIA. Immune complexes containing RF were detectable in synovial fluid of patients with polyarticular RF+ JIA. The reason may be that complement-mediated tissue damage was induced by the classical complement activation pathway in JIA. The precise pathogenesis still remained unknown, however, the occurrence of autoantibodies in a significant proportion of patients suggested involvement of autoimmune mechanisms. In population-based studies, ANA were not specific and present in 16-44% of patients16, but the positivity has been reported to be an independent risk factor for a longer duration of active disease, which itself was a risk factor for increased disability. In this study, only rare patients had positive antinuclear antibody test, we found that the positive rates in patients with whole JIA (24.24%), oligoarticular JIA (18.36%), and polyarticular JIA (26.15%) were lower than those reported by previous literatures 17. False positivity and transient positivity of the ANA were common occurrences. Furthermore, the criterion for defining ANA positivity differently should be also considered when comparing results.
Among the whole cohort of the patients, the limb joints of ankle and wrist were also preferentially involved in our study, particularly the ankle. The ankle was also the second most frequently affected joint after the large joint of knee in children with JIA 18, 19, which has been relatively ignored. The ankle examination is difficult in small children because of anatomically and mechanically complex. The wrist joint was less commonly affected but was one of the most vulnerable site of structural damage and was associated with a more severe progressive disease course 20, 21. Synovial thickening, joint effusions, and bone marrow edema were the most prevalent disease features 22. The importance of synovial hypertrophy as the hallmark of arthritis was again underscored by our imaging study because it was the most frequent MRI abnormality in the affected joints for all JIA subtypes. Synovial proliferation and infiltration by inflammatory cells could result in increased secretion of synovial fluid and synovial hypertrophy. Persistent synovitis may eventually lead to articular cartilage lesions and bone erosions that are responsible for disability and reduced quality of life in JIA. According to the prevalence and predominant of synovitis in all kinds of JIA, enhanced MRI was essential, while whole body MRI was not sufficient because of unachievable enhancement23. In our study, there were two patients respectively presented with ankle articular cartilage damage and iliac erosion. Erosive changes in affected joints are rare among patients with JIA nowadays and are seen only in very advanced cases as a late complication. Owing to the incompleteness of ossification, the articular cartilage is thicker in growing children than in adults. Importantly, articular cartilage of growing children has a distinctive regenerative capacity. This attribute might explain the rare presentation of joint cartilage damage on conventional MR imaging in those with JIA.
We identified several predictive factors of severity in synovitis-onset JIA that could help to select high-risk subgroups of children who might possibly benefit from earlier and more aggressive therapeutic strategies. The number of joints involved with synovitis was correlated with the ESR and CRP, higher CRP value was a predictive factor according to the multivariate analyses, but without the inflamed parameter of ESR in our study. In contrast, higher ESR values on first MRI examination predicted the development of joint erosions on oligoarthritis JIA by Guillaume, et al 24. Furthermore, young age of onset and gender were risk factors for a poor prognosis in our study. While, gender, as well as age at disease onset, were not identified as predictive factors of poor joint outcome in other studies. The overall seroprevalence of RF in patients with JIA was found very low, and the multivariate analyses showed that it may be not related to the severity of synovitis. Patients2 with RF+ polyarticular JIA were at higher risk of a more aggressive disease course and bone erosion than JIA patients without RF+. In fact, RF was a non-specifically positive indicator for JIA severity, because it can also be abnormal in other autoimmune disorders such as acute rheumatic fever and SLE, as well as in otherwise healthy individuals. The variation in results may have been influenced by differences in patient selection, methods for assessing outcome, and criteria for remission. The positive results of the multivariate analyses were limited because some of the predictive factors had an OR close to one per unit change or a wide CI. The variance explained by the models was low, indicated that there were still other factors than those identified here were important determinants for outcome in JIA. Furthermore, as the laboratory parameters could not fully explain and predict the severity on MRI, timely baseline and follow-up MRI should be carried out for observing the involvement of symptomatic joints, synovitis especially. Interpretation of thus-far-published prognostic studies of JIA patients was difficult because of the heterogeneity of the populations studied, which have been constituted not only of oligoarthritis-onset JIA patients, but also of polyarticular-and systemic onset JIA patients. Prospective testing of these predictors is needed to establish a set of reliable criteria for the early recognition of children with severe JIA who need aggressive management.
We acknowledged that our research had some limitations. This study was limited by its retrospective nature, which led to incomplete data collection for some items such as HLA-B27 level retrieved from medical record. Second, though ANAs were directed against a variety of components of the cell nucleus, we only performed the overall ANA positivity or negativity, and did not pursue fine specificities of ANA for subgroups of autoantibodies in present study. In addition to these, a limited sample size and a bias on selection of clinically suspected affected joints for imaging, especially in oligoarthritis patients, may underestimate the severity of JIA imaging, as it was known that some authors had found a high prevalence of subclinical synovitis.