Rheumatoid Arthritis: Nistala K

Nistala K, Wedderburn LR. · Rheumatology Unit, Institute of Child Health, University College London, London, UK. · Rheumatology (Oxford). · Pubmed #19269955 No free full text.

Abstract: Inflammatory T cells are thought to be central to the pathology of autoimmune arthritis. Th17 cells, CD4 T cells that secrete the pro-inflammatory cytokine IL-17 play a critical role in murine models of arthritis. Recent evidence from human studies suggests that Th17 cells may be important players in several autoimmune diseases, including seronegative arthritis in adults, childhood arthritis [juvenile idiopathic arthritis (JIA)]. It was surprising to find that the development of Th17 cells is closely related to that of an immunoregulatory subset called regulatory T cells (Tregs). Tregs are important in the maintenance of immune homeostasis. Defects in Treg function or reduced numbers have been documented in several human autoimmune diseases, including RA and JIA. Conditions that typically favour the development of Tregs and promote tolerance can be subverted by inflammatory signals towards supporting the generation of Th17 cells. In animal models, the enhancement of Th17 cell differentiation is at the expense of Tregs, and these combined changes trigger autoimmunity. Several mechanisms have come to light that control this reciprocal relationship between Tregs and Th17 cells, including the action of pro-inflammatory cytokines such as IL-1beta. Anti-rheumatic biologic therapies may offer a means of restoring the Th17/Treg balance in favour of Tregs and thereby re-establishing immune tolerance.

Nistala K, Moncrieffe H, Newton KR, Varsani H, Hunter P, Wedderburn LR. · University College London, London, UK. · Arthritis Rheum. · Pubmed #18311821 links to  free full text

Abstract: OBJECTIVE: To identify interleukin-17 (IL-17)-producing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship to Treg cells at sites of inflammation, as well as to test the hypothesis that IL-17+ T cell numbers correlate with clinical phenotype in childhood arthritis. METHODS: Flow cytometry was used to analyze the phenotype, cytokine production, and chemokine receptor expression of IL-17-producing T cells in peripheral blood and synovial fluid mononuclear cells from 36 children with JIA, in parallel with analysis of forkhead box P3 (FoxP3)-positive Treg cells. Migration of IL-17+ T cells toward CCL20 was assessed by a Transwell assay. Synovial tissue was analyzed by immunohistochemistry for IL-17 and IL-22. RESULTS: IL-17+ T cells were enriched in the joints of children with JIA as compared with the blood of JIA patients (P = 0.0001) and controls (P = 0.018) and were demonstrated in synovial tissue. IL-17+ T cell numbers were higher in patients with extended oligoarthritis, the more severe subtype of JIA, as compared with patients with persistent oligoarthritis, the milder subtype (P = 0.046). Within the joint, there was an inverse relationship between IL-17+ T cells and FoxP3+ Treg cells (r = 0.61, P = 0.016). IL-17+,CD4+ T cells were uniformly CCR6+ and migrated toward CCL20, but synovial IL-17+ T cells had variable CCR4 expression. A proportion of IL-17+ synovial T cells produced IL-22 and interferon-gamma. CONCLUSION: This study is the first to define the frequency and characteristics of "Th17" cells in JIA. We suggest that these highly proinflammatory cells contribute to joint pathology, as indicated by relationships with clinical phenotypes, and that the balance between IL-17+ T cells and Treg cells may be critical to outcome.

Nistala K, Babar J, Johnson K, Campbell-Stokes P, Foster K, Ryder C, McDonagh JE. · Paediatric Rheumatology Department, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, UK. · Rheumatology (Oxford). · Pubmed #17158211 links to  free full text

Abstract: OBJECTIVES: To compare the diagnostic performance of clinical assessment against magnetic resonance imaging (MRI) diagnosed hip arthritis in a juvenile idiopathic arthritis (JIA) population. To determine the clinical and serological predictors of MRI diagnosed hip arthritis. METHODS: A total of 34 JIA patients with established disease (mean disease duration 6.3 yrs) had their hip MRIs scored for features of active hip arthritis and hip damage. Results were compared with clinical variables (disease subtype, history of hip pain, core outcome variables (COV)) and the clinician's assessment of active hip arthritis. RESULTS: MRI features of active hip arthritis were found in 45 hips (70%) and hip damage in 36 hips (56%). Clinical assessment had fair agreement with MRI scoring of active arthritis in patients with disease duration <4 yrs (kappa score 0.38, P = 0.045). Clinical assessment had a sensitivity of 25.7% and specificity of 91% for detecting MRI diagnosed arthritis. Of the core outcome variables only erythrocyte sedimentation rate predicted inflammation detected on MRI (r = 0.44, P = 0.014). CONCLUSIONS: The association between the clinician's assessment, core outcome variables and MRI findings in this study was limited. This indicates that clinical and laboratory findings are inadequate diagnostic tools for the assessment of hip arthritis when compared with MRI as the gold standard.

Nistala K, Murray KJ. · Paediatric Rheumatology Unit, Great Ormond Street Hospital, London, England. · J Rheumatol. · Pubmed #11550986 No free full text.

Abstract: We describe 2 pediatric patients with sickle cell disease (SCD) who developed seropositive juvenile rheumatoid arthritis (JRA). Both patients have severe joint damage, the compound effect of both disease processes. The bone and cartilage destruction, which poses serious therapeutic challenges, highlights the difficulty of making a diagnosis of chronic inflammatory disease in the setting of SCD. There may be a correlation between increased levels of tumor necrosis factor-alpha in the synovial tissue of joints damaged by arthritis and local sickling. The resultant ischemia and corresponding inflammatory infiltrates could in turn worsen existing synovial proliferation and cartilage destruction as well as trigger further sickling.