Dvergsten, Jeffrey

ObjectiveThe study objective was to identify differences in gene expression between treatment responders (TRs) and treatment non‐responders (TNRs) diagnosed with juvenile dermatomyositis (JDM).MethodsGene expression analyses were performed using whole blood messenger RNA sequencing in patients with JDM (n = 17) and healthy controls (HCs; n = 10). Four analyses were performed (A1‐4) comparing differential gene expression and pathways analysis exploiting the timing of sample acquisition and the treatments received to perform these comparative analyses. Analyses were done at diagnosis and follow‐up, which averaged 7 months later in the cohort.ResultsAt diagnosis, the expression of 10 genes differed between TRs and TNRs. Hallmark and canonical pathway analysis revealed 11 and 60 pathways enriched in TRs and 3 and 21 pathways enriched in TNRs, respectively. Pathway enrichment at diagnosis in TRs was strongest in pathways involved in metabolism, complement activation, and cell signaling as mediated by IL‐8, p38/microtubule associated protein kinases (MAPK)/extracellular signal‐regulated kinases (ERK), Phosphatidylinositol 3 Kinase Gamma (PI3Kγ), and the B cell receptor. Follow‐up hallmark and canonical pathway analysis showed that 2 and 14 pathways were enriched in TRs, whereas 24 and 123 pathways were enriched in treatment TNRs, respectively. Prior treatment with glucocorticoids significantly altered expression of 13 genes in the analysis of subjects at diagnosis with JDM as compared with HCs.ConclusionNumerous genes and pathways differ between TRs and TNRs at diagnosis and follow‐up. Prior treatment with glucocorticoids prior to specimen acquisition had a small effect on the performed analyses.

ObjectiveOur aim was to identify cytokines and chemokines in patients with adult dermatomyositis (DM) and juvenile dermatomyositis (JDM) that predict changes in disease activity.MethodsMultiplexed immunoassays (Meso Scale Discovery) enabled simultaneous measurement of interferon (IFN)‐regulated chemokines and other pro‐ and anti‐inflammatory cytokines specific to differentiation of specific T‐cell and innate pathways. Cytokine scores were computed for IFNCK (IP‐10, MCP‐1), Th1 (IFNɣ, TNFα, and IL2), Th2 (IL4, IL10, IL12, and IL 13), Th17 (IL6, IL17, IL1β), macrophage (MIP‐1α, MIP‐1β, IL8), and regulatory (IL10, TNFα) factors. Spearman correlation and mixed models were used to examine whether cytokines at a previous visit predict change in disease activity at the next visit.ResultsThe study included 36 patients (16 DM and 20 JDM) with at least two visits (87 patient intervals between two visits). Mean age (SD) at inclusion was 56.9 (18.4) years for DM and 10.8 (6.6) years in JDM, 67% of patients were female, 89% Caucasian. The mean (SD) physician global, muscle and extra‐muscular disease activity Visual Analog Scale scores at inclusion were 41 (26), 36 (30), and 34 (21) mm, respectively. The change in IFN score from one visit to the next was associated with the change in physician global (P = 0.010) and extramuscular (P < 0.001) disease activity scores. Preliminary results revealed significant correlations of previous IFNCK score and IL‐6 with subsequent disease activity measures, but after adjustment for multiple visits per patient, these associations did not reach statistical significance.ConclusionThere is a potential relationship between IFNCK and other cytokine scores seen in adult and juvenile DM with future disease states.

ObjectiveCD8+ T cells lacking CD28 were originally reported to be a characteristic feature of juvenile idiopathic arthritis (JIA), but the relevance of these unusual cells to this disease remains to be elucidated. Because of recent evidence that loss of CD28 cells is typical of terminally differentiated lymphocytes, the aim of this study was to examine functional subsets of CD8+ T cells in patients with JIA.MethodsBlood and/or waste synovial fluid samples were collected from children with a definite diagnosis of JIA (n = 98). Deidentified peripheral blood (n = 33) and cord blood (n = 13) samples from healthy donors were also collected. CD8+ and CD4+ T cells were screened for novel receptors, and where indicated, bioassays were performed to determine the functional relevance of the identified receptor.ResultsJIA patients had a naive T cell compartment with shortened telomeres, and their entire T cell pool had reduced proliferative capacity. They had an overabundance of CD31+CD28nullCD8+ T cells, which was a significant feature of oligoarticular JIA (n = 62) as compared to polyarticular JIA (n = 36). CD31+ CD28nullCD8+ T cells had limited mitotic capacity and expressed high levels of the senescence antigens histone γH2AX and/or p16. Ligation of CD31, which was independent of the T cell receptor (TCR), sufficiently induced tyrosine phosphorylation, vesicle exocytosis, and production of interferon‐γ and interleukin‐10.ConclusionThese data provide the first evidence of cell senescence, as represented by CD31+CD28null CD8+ T cells, in the pathophysiology of JIA. Activation of these unusual cells in a TCR‐independent manner suggests that they are maladaptive and could be potential targets for immunotherapy.