Polyarticular Forms Of Juvenile Idiopathic Arthritis Research Articles

Renal Lesions of Juvenile Idiopathic Arthritis in Children: A Literature Review

The literature review presents current data on the frequency, mechanisms of development, clinical manifestations, diagnosis and treatment of renal AA-amyloidosis and describes different forms of glomerulonephritis (GN) in children with juvenile idiopathic arthritis (JIA). The frequency of AA renal amyloidosis in JIA in children ranges from 0.8% to 2%, in adults with JIA duration of 28.3 years - 8.9%. In recent years, against the background of immunobiological therapy, the incidence of AA-amyloidosis of the kidneys in adults has decreased to 2%. AA-amyloidosis of the kidneys most often develops in children with the systemic form, in adults - with systemic and polyarticular forms of JIA. The first symptom of AA-amyloidosis of the kidneys is isolated proteinuria, which transforms into nephrotic syndrome. The peculiarity of the nephrotic syndrome is the absence of hypercholesterolemia in most cases, combined in some patients with arterial hypertension, hematuria, and impaired renal function. The available literature presents clinical cases of renal GN in children with JIA, viz: ANCA-associated GN, mesangioproliferative GN, including IgA- and IgM-nephropathy, membranous nephropathy, focal-segmental glomerulosclerosis, minimal change disease, extracapillary GN. Most publications are devoted to ANCA-associated HN, which developed in patients with a torpid course and a high degree of activity of polyarticular and systemic forms of JIA. The peculiarity of ANCA-associated HN was the presence of hypercreatininemia and, in almost half of cases, the development of terminal renal failure, despite the ongoing immunosuppressive therapy. The main method confirming the diagnosis of AA-amyloidosis and renal HN is the intravital renal morphological study. The use of immunobiological drugs in renal AA-amyloidosis and HN in children with JIA has therapeutic efficacy.

Aberrant expression of shared master-key genes contributes to the immunopathogenesis in patients with juvenile spondyloarthritis.

Association of juvenile spondyloarthritis (jSpA) with the HLA-B27 genotype is well established, but there is little knowledge of other genetic factors with a role in the development of the disease. To date, only a few studies have tried to find those associated genes by obtaining expression profiles, but with inconsistent results due to various patient selection criteria and methodology. The aim of the present study was to identify and confirm gene signatures and novel biomarkers in highly homogeneous cohorts of untreated and treated patients diagnosed with jSpA and other forms of juvenile idiopathic arthritis (JIA) according to ILAR criteria. For the purposes of the research, total RNA was isolated from whole blood of 45 children with jSpA and known HLA genotype, 11 children with oligo- and polyarticular forms of JIA, as well as 12 age and sex matched control participants without diagnosis of inflammatory disease. DNA microarray gene expression was performed in 11 patients with jSpA and in four healthy controls, along with bioinformatical analysis of retrieved data. Carefully selected differentially expressed genes where analyzed by qRT-PCR in all participants of the study. Microarray results and bioinformatical analysis revealed 745 differentially expressed genes involved in various inflammatory processes, while qRT-PCR analysis of selected genes confirmed data universality and specificity of expression profiles in jSpA patients. The present study indicates that jSpA could be a polygenic disease with a possible malfunction in antigen recognition and activation of immunological response, migration of inflammatory cells and regulation of the immune system. Among genes involved in these processes TLR4, NLRP3, CXCR4 and PTPN12 showed almost consistent expression in study patients diagnosed with jSpA. Those genes and their products could therefore potentially be used as novel biomarkers, possibly predictive of disease prognosis and response to therapy, or even as a target for new therapeutic approaches.

A115: Deep Immunophenotyping in the Identification of Clinically Meaningful Immune Signatures in Juvenile Idiopathic Arthritis

Background/Purpose:The evolution of molecular immunology has made available high‐throughput tools which can provide an entirely new, comprehensive and multidimensional picture of the immune system. We have applied a combination of deep phenotyping by cytometry, multiplex expression and functional assays, to identify immunological signatures which could associate with, and perhaps contribute to, lack of responsiveness to treatment in juvenile idiopathic arthritis (JIA).Methods:We developed a platform of deep immunophenotyping to identify immune signatures on a variety of blood cell types with special focus given to CD4+ effector and regulatory T cells (Teff and Treg, respectively).Results:Analysis of samples from the NIH funded TREAT JIA study showed there were no significant changes between R and NR when Teff and Treg functions were analyzed as a whole. However, in‐depth characterization of the two cell subsets led to the identification of specific phenotypical differences at both time points. Strikingly, the combination of a restricted set of CD4+ T cell markers was able to segregate R and NR with up to 87.5% accuracy. Importantly, our analysis identified a population of cells significantly more represented in NR and characterized by an activated phenotype, expressing pro‐inflammatory markers and chemokine receptors targeting cells to inflammatory sites, and bearing signs of recent antigen recognition, possibly indicating their direct involvement in autoimmunity. Our approach will be greatly benefitted by the addition of recent advances in flow cytometry, with the development of the mass cytometer CyTOF, which dramatically improves single cell multiplexing. These methods are currently being applied to the analysis of samples from 137 subjects enrolled from 16 sites in a prospective multicenter NIH funded study who had Polyarticular forms of JIA (extended oligoarticular, Poly RF+, Poly RF/‐) who had reached clinical inactive disease (CID) for /G6 months at the time the anti‐TNF agent was withdrawn and followed for at least /G8 months to determine if they do or do not meet a validated definition of disease “flare”. Samples for immunophenotyping were obtained at baseline, time of stopping anti‐TNF therapy and last study visit (i.e. time of flare or at least 8 months of CID off anti‐TNF therapy). Duration of CID at baseline was mean/median/range of 1.2/0.5/1 day‐12.1 yrs. 106 (77%) subjects maintained CID for the first 6 months and stopped anti‐TNF as per protocol. 67/106 (63%) maintained CID for ≥8 mos off anti‐TNF while 39 (37%) flared. The mean/median/range for time to flare was 108/105/7–271 days.Conclusion:Immunophenotyping, when performed as an integrated analysis of immune signatures, has demonstrated effectiveness in identifying immune signatures that have excellent accuracy in segregating and predicting clinical disease states and responses. These methods are currently being analyzed in these study populations.