Safety and effectiveness of abatacept in juvenile idiopathic arthritis: results from the PRINTO/PRCSG registry.

OBJECTIVE: To report the interim 5-year safety and effectiveness of abatacept in patients with juvenile idiopathic arthritis (JIA) in the PRINTO/PRCSG registry. METHODS: The Abatacept JIA Registry (NCT01357668) is an ongoing observational study of children with JIA receiving abatacept; enrolment started in January 2013. Clinical sites enrolled patients with JIA starting or currently receiving abatacept. Eligible patients were assessed for safety (primary end point) and effectiveness over 10 years. Effectiveness was measured by clinical 10-joint Juvenile Arthritis Disease Activity Score (cJADAS10) in patients with JIA over 5 years. As-observed analysis is presented according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. RESULTS: As of 31 March 2020, 587 patients were enrolled; 569 are included in this analysis (including 134 new users) with 1214.6 patient-years of safety data available. Over 5 years, the incidence rate (IR) per 100 patient-years of follow-up of serious adverse events was 5.52 (95% confidence interval [CI]: 4.27, 7.01) and of events of special interest was 3.62 (95% CI: 2.63, 4.86), with 18 serious infections (IR 1.48 [95% CI: 0.88, 2.34]). As early as month 3, 55.9% of patients achieved cJADAS10 low disease activity and inactive disease (20.3%, 72/354 and 35.6%, 126/354, respectively), sustained over 5 years. Disease activity measures improved over 5 years across JIA categories. CONCLUSION: Abatacept was well tolerated in patients with JIA, with no new safety signals identified and with well-controlled disease activity, including some patients achieving inactive disease or remission. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01357668.

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy.

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease.

OBJECTIVE: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease. METHODS: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified.

Genome-Wide Association Meta-Analysis Reveals Novel Juvenile Idiopathic Arthritis Susceptibility Loci.

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is the most common childhood rheumatic disease and has a strong genomic component. To date, JIA genetic association studies have had limited sample sizes, used heterogeneous patient populations, or included only candidate regions. The aim of this study was to identify new associations between JIA patients with oligoarticular disease and those with IgM rheumatoid factor (RF)-negative polyarticular disease, which are clinically similar and the most prevalent JIA disease subtypes. METHODS: Three cohorts comprising 2,751 patients with oligoarticular or RF-negative polyarticular JIA were genotyped using the Affymetrix Genome-Wide SNP Array 6.0 or the Illumina HumanCoreExome-12+ Array. Overall, 15,886 local and out-of-study controls, typed on these platforms or the Illumina HumanOmni2.5, were used for association analyses. High-quality single-nucleotide polymorphisms (SNPs) were used for imputation to 1000 Genomes prior to SNP association analysis. RESULTS: Meta-analysis showed evidence of association (P < 1 × 10-6 ) at 9 regions: PRR9_LOR (P = 5.12 × 10-8 ), ILDR1_CD86 (P = 6.73 × 10-8 ), WDFY4 (P = 1.79 × 10-7 ), PTH1R (P = 1.87 × 10-7 ), RNF215 (P = 3.09 × 10-7 ), AHI1_LINC00271 (P = 3.48 × 10-7 ), JAK1 (P = 4.18 × 10-7 ), LINC00951 (P = 5.80 × 10-7 ), and HBP1 (P = 7.29 × 10-7 ). Of these, PRR9_LOR, ILDR1_CD86, RNF215, LINC00951, and HBP1 were shown, for the first time, to be autoimmune disease susceptibility loci. Furthermore, associated SNPs included cis expression quantitative trait loci for WDFY4, CCDC12, MTP18, SF3A1, AHI1, COG5, HBP1, and GPR22. CONCLUSION: This study provides evidence of both unique JIA risk loci and risk loci overlapping between JIA and other autoimmune diseases. These newly associated SNPs are shown to influence gene expression, and their bounding regions tie into molecular pathways of immunologic relevance. Thus, they likely represent regions that contribute to the pathology of oligoarticular JIA and RF-negative polyarticular JIA.

Transcriptional profiles of JIA patient blood with subsequent poor response to methotrexate.

Objective: The mechanisms that determine the efficacy or inefficacy of MTX in JIA are ill-defined. The objective of this study was to identify a gene expression transcriptional signature associated with poor response to MTX in patients with JIA. Methods: RNA sequencing was used to measure gene expression in peripheral blood mononuclear cells collected from 47 patients with JIA prior to MTX treatment and 14 age-matched controls. Differentially expressed baseline genes between responders and non-responders were evaluated. Biological differences between all JIA patients and controls were explored by constructing a signature of differentially expressed genes. Unsupervised clustering and pathway analysis was performed. Results: A signature of 99 differentially expressed genes (Bonferroni-corrected P < 0.05) capturing the biological differences between all JIA patients and controls was identified. Unsupervised clustering of samples based on this list of 99 genes produced subgroups enriched for MTX response status. Comparing this gene signature with reference signatures from sorted cell populations revealed high concordance between the expression signatures of monocytes and of MTX non-responders. CXCL8 (IL-8) was the most significantly differentially expressed gene transcript comparing all JIA patients with controls (Bonferroni-corrected P = 4.12 × 10-10). Conclusion: Variability in clinical response to MTX in JIA patients is associated with differences in gene transcripts modulated in monocytes. These gene expression profiles may provide a basis for biomarkers predictive of treatment response.

Impact of bone-targeted therapies in chemotherapy-naïve metastatic castration-resistant prostate cancer patients treated with abiraterone acetate: post hoc analysis of study COU-AA-302.

BACKGROUND: Metastatic castration-resistant prostate cancer (mCRPC) often involves bone, and bone-targeted therapy (BTT) has become part of the overall treatment strategy. OBJECTIVE: Investigation of outcomes for concomitant BTT in a post hoc analysis of the COU-AA-302 trial, which demonstrated an overall clinical benefit of abiraterone acetate (AA) plus prednisone over placebo plus prednisone in asymptomatic or mildly symptomatic chemotherapy-naïve mCRPC patients. DESIGN, SETTING, AND PARTICIPANTS: This report describes the third interim analysis (prespecified at 55% overall survival [OS] events) for the COU-AA-302 trial. INTERVENTION: Patients were grouped by concomitant BTT use or no BTT use. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Radiographic progression-free survival and OS were coprimary end points. This report describes the third interim analysis (prespecified at 55% OS events) and involves patients treated with or without concomitant BTT during the COU-AA-302 study. Median follow-up for OS was 27.1 mo. Median time-to-event variables with 95% confidence intervals (CIs) were estimated using the Kaplan-Meier method. Adjusted hazard ratios (HRs), 95% CIs, and p values for concomitant BTT versus no BTT were obtained via Cox models. RESULTS AND LIMITATIONS: While the post hoc nature of the analysis is a limitation, superiority of AA and prednisone versus prednisone alone was demonstrated for clinical outcomes with or without BTT use. Compared with no BTT use, concomitant BTT significantly improved OS (HR 0.75; p=0.01) and increased the time to ECOG deterioration (HR 0.75; p<0.001) and time to opiate use for cancer-related pain (HR 0.80; p=0.036). The safety profile of concomitant BTT with AA was similar to that reported for AA in the overall intent-to-treat population. Osteonecrosis of the jaw (all grade 1/2) with concomitant BTT use was reported in <3% of patients. CONCLUSIONS: AA with concomitant BTT was safe and well tolerated in men with chemotherapy-naïve mCRPC. The benefits of AA on clinical outcomes were increased with concomitant BTT. PATIENT SUMMARY: Treatment of advanced prostate cancer often includes bone-targeted therapy. This post hoc analysis showed that in patients with advanced prostate cancer who were treated with abiraterone acetate and prednisone in combination with bone-targeted therapy, there was a continued trend in prolongation of life when compared with patients treated with prednisone alone. TRIAL REGISTRATION: ClinicalTrials.gov NCT00887198.

Identification of a novel C16orf57 mutation in Athabaskan patients with Poikiloderma with Neutropenia.

Poikiloderma with Neutropenia (PN), Clericuzio-Type (OMIM #604173) is characterized by poikiloderma, chronic neutropenia, recurrent sinopulmonary infections, bronchiectasis, and nail dystrophy. First described by Clericuzio in 1991 in 14 patients of Navajo descent, it has since also been described in non-Navajo patients. C16orf57 has recently been identified as a causative gene in PN. The purpose of our study was to describe a spectrum of C16orf57 mutations in a cohort of PN patients including five patients of Athabaskan (Navajo and Apache) ancestry. Eleven patients from eight kindreds were enrolled in an IRB-approved study at Baylor College of Medicine. Five patients were of Athabaskan ancestry. PCR amplification and sequencing of the entire coding region of the C16orf57 gene was performed on genomic DNA. We identified biallelic C16orf57 mutations in all 11 PN patients in our cohort. The seven new deleterious mutations consisted of deletion (2), nonsense (3), and splice site (2) mutations. The patients of Athabaskan ancestry all had a common deletion mutation (c.496delA) which was not found in the six non-Athabaskan patients. Mutations in the C16orf57 gene have been identified thus far in all patients studied with a clinical diagnosis of PN. We have identified seven new mutations in C16orf57 in PN patients. One of these is present in all patients of Athabaskan descent, suggesting that c.496delA represents the PN-causative mutation in this subpopulation.

Treatment approaches to juvenile dermatomyositis (JDM) across North America: The Childhood Arthritis and Rheumatology Research Alliance (CARRA) JDM Treatment Survey.

OBJECTIVE: There are a number of different approaches to the initial treatment of juvenile dermatomyositis (JDM). We assessed the therapeutic approaches of North American pediatric rheumatologists to inform future studies of therapy in JDM. METHODS: A survey describing clinical cases of JDM was sent to pediatric rheumatologists. The cases described children with varying severity of typical disease, disease with atypical features, or refractory disease. Three open-ended questions were asked following each case: (1) What additional investigations would you order; (2) What medicine(s) would you start (dose, route, frequency, adjustment over time); and (3) What nonmedication treatment(s) would you start. RESULTS: The response rate was 84% (141/167). For typical cases of JDM, regardless of severity, almost all respondents used corticosteroids and another medication, methotrexate (MTX) being the most commonly used. The route and pattern of corticosteroid administration was variable. Intravenous immunoglobulin (IVIG) was used more frequently for more severe disease, for refractory disease, and for prominent cutaneous disease. Hydroxychloroquine was often used in milder cases and cases principally characterized by rash. Cyclophosphamide was reserved for ulcerative disease and JDM complicated by lung disease. CONCLUSION: For the majority of North American pediatric rheumatologists, corticosteroids and MTX appear to be the standard of care for typical cases of JDM. There is variability, however, in the route of administration of corticosteroids and use of IVIG and hydroxychloroquine.

Biologic similarities based on age at onset in oligoarticular and polyarticular subtypes of juvenile idiopathic arthritis.

OBJECTIVE: To explore biologic correlates to age at onset in patients with juvenile idiopathic arthritis (JIA) using peripheral blood mononuclear cell (PBMC) gene expression analysis. METHODS: PBMCs were isolated from 56 healthy controls and 104 patients with recent-onset JIA (39 with persistent oligoarticular JIA, 45 with rheumatoid factor-negative polyarticular JIA, and 20 with systemic JIA). RNA was amplified and labeled using NuGEN Ovation, and gene expression was assessed with Affymetrix HG-U133 Plus 2.0 GeneChips. RESULTS: A total of 832 probe sets revealed gene expression differences (false discovery rate 5%) in PBMCs from children with oligoarticular JIA whose disease began before age 6 years (early-onset disease) compared with those whose disease began at or after age 6 years (late-onset disease). In patients with early-onset disease, there was greater expression of genes related to B cells and less expression of genes related to cells of the myeloid lineage. Support vector machine analyses identified samples from patients with early- or late-onset oligoarticular JIA (with 97% accuracy) or from patients with early- or late-onset polyarticular JIA (with 89% accuracy), but not from patients with systemic JIA or healthy controls. Principal components analysis showed that age at onset was the major classifier of samples from patients with oligoarticular JIA and patients with polyarticular JIA. CONCLUSION: PBMC gene expression analysis reveals biologic differences between patients with early-and late-onset JIA, independent of classification based on the number of joints involved. These data suggest that age at onset may be an important parameter to consider in JIA classification. Furthermore, pathologic mechanisms may vary with age at onset, and understanding these processes may lead to improved treatment of JIA.

Immature cell populations and an erythropoiesis gene-expression signature in systemic juvenile idiopathic arthritis: implications for pathogenesis.

INTRODUCTION: Previous observations suggest that active systemic juvenile idiopathic arthritis (sJIA) is associated with a prominent erythropoiesis gene-expression signature. The aim of this study was to determine the association of this signature with peripheral blood mononuclear cell (PBMC) subpopulations and its specificity for sJIA as compared with related conditions. METHODS: The 199 patients with JIA (23 sJIA and 176 non-sJIA) and 38 controls were studied. PBMCs were isolated and analyzed for multiple surface antigens with flow cytometry and for gene-expression profiles. The proportions of different PBMC subpopulations were compared among sJIA, non-sJIA patients, and controls and subsequently correlated with the strength of the erythropoiesis signature. Additional gene-expression data from patients with familial hemophagocytic lymphohistiocytosis (FHLH) and from a published sJIA cohort were analyzed to determine whether the erythropoiesis signature was present. RESULTS: Patients with sJIA had significantly increased proportions of immature cell populations, including CD34+ cells, correlating highly with the strength of the erythropoiesis signature. The erythropoiesis signature strongly overlapped with the gene-expression pattern in purified immature erythroid precursors. The expansion of immature cells was most prominently seen in patients with sJIA and anemia, even in the absence of reticulocytosis. Patients with non-sJIA and anemia did not exhibit the erythropoiesis signature. The erythropoiesis signature was found to be prominent in patients with FHLH and in a published cohort of patients with active sJIA, but not in patients with inactive sJIA. CONCLUSIONS: An erythropoiesis signature in active sJIA is associated with the expansion of CD34+ cells, also is seen in some patients with FHLH and infection, and may be an indicator of ineffective erythropoiesis and hemophagocytosis due to hypercytokinemia.

Unexpected role for the immunoproteasome subunit LMP2 in antiviral humoral and innate immune responses.

Proteasomes are multisubunit proteases that initiate degradation of many Ags presented by MHC class I molecules. Vertebrates express alternate forms of each of the three catalytic proteasome subunits: standard subunits, and immunosubunits, which are constitutively expressed by APCs and are induced in other cell types by exposure to cytokines. The assembly of mixed proteasomes containing standard subunits and immunosubunits is regulated in a tissue specific manner. In this study, we report that the presence of mixed proteasomes in immune cells in LMP2(-/-) mice compromises multiple components that contribute to the generation of antiviral Ab responses, including splenic B cell numbers, survival and function of adoptively transferred B cells, Th cell function, and dendritic cell secretion of IL-6, TNF-alpha, IL-1beta, and type I IFNs. These defects did not result from compromised overall protein degradation, rather they were associated with altered NF-kappaB activity. These findings demonstrate an important role for immunoproteasomes in immune cell function beyond their contribution to Ag processing.

Gene Expression Profiles from Peripheral Blood Mononuclear Cells Are Sensitive to Short Processing Delays.

In the analysis of peripheral blood gene expression, timely processing of samples is essential to ensure that measurements reflect in vivo biology, rather than ex vivo sample processing variables. The effect of processing delays on global gene expression patterns in peripheral blood mononuclear cells (PBMCs) was assessed by isolating and stabilizing PBMC-derived RNA from 3 individuals either immediately after phlebotomy or after a 4 h delay. RNA was labeled using NuGEN Ovation labeling and probed using the Affymetrix HG U133 Plus 2.0 GeneChip(®). Comparison of gene expression levels (≥2-fold expression change and P < 0.05) identified 307 probe sets representing genes with increased expression and 46 indicating decreased expression after 4 h. These differentially expressed genes include many that are important to inflammatory, immunologic, and cancer pathways. Among others, CCR2, CCR5, TLR10, CD180, and IL-16 have decreased expression, whereas VEGF, IL8, SOCS2, SOCS3, CD69, and CD83 have increased expression after a 4 h processing delay. The trends in expression patterns associated with delayed processing were also apparent in an independent set of 276 arrays of RNA from human PBMC samples with varying processing times. These data indicate that the time between sample acquisition, initiation of processing, and when the RNA is stabilized should be a prime consideration when designing protocols for translational studies involving PBMC gene expression analysis.

Gene expression signatures in polyarticular juvenile idiopathic arthritis demonstrate disease heterogeneity and offer a molecular classification of disease subsets.

OBJECTIVE: To determine whether peripheral blood mononuclear cells (PBMCs) from children with recent-onset polyarticular juvenile idiopathic arthritis (JIA) exhibit biologically or clinically informative gene expression signatures. METHODS: Peripheral blood samples were obtained from 59 healthy children and 61 children with polyarticular JIA prior to treatment with second-line medications, such as methotrexate or biologic agents. RNA was extracted from isolated mononuclear cells, fluorescence labeled, and hybridized to commercial gene expression microarrays (Affymetrix HG-U133 Plus 2.0). Data were analyzed using analysis of variance at a 5% false discovery rate threshold after robust multichip analysis preprocessing and distance-weighted discrimination normalization. RESULTS: Initial analysis revealed 873 probe sets for genes that were differentially expressed between polyarticular JIA patients and healthy controls. Hierarchical clustering of these probe sets distinguished 3 subgroups within the polyarticular JIA group. Prototypical patients within each subgroup were identified and used to define subgroup-specific gene expression signatures. One of these signatures was associated with monocyte markers, another with transforming growth factor beta-inducible genes, and a third with immediate early genes. Correlation of gene expression signatures with clinical and biologic features of JIA subgroups suggested relevance to aspects of disease activity and supported the division of polyarticular JIA into distinct subsets. CONCLUSION: Gene expression signatures in PBMCs from patients with recent-onset polyarticular JIA reflect discrete disease processes and offer a molecular classification of disease.

Subtype-specific peripheral blood gene expression profiles in recent-onset juvenile idiopathic arthritis.

OBJECTIVE: To identify differences in peripheral blood gene expression between patients with different subclasses of juvenile idiopathic arthritis (JIA) and healthy controls in a multicenter study of patients with recent-onset JIA prior to treatment with disease-modifying antirheumatic drugs (DMARDs) or biologic agents. METHODS: Peripheral blood mononuclear cells (PBMCs) from 59 healthy children and 136 patients with JIA (28 with enthesitis-related arthritis [ERA], 42 with persistent oligoarthritis, 45 with rheumatoid factor [RF]-negative polyarthritis, and 21 with systemic disease) were isolated from whole blood. Poly(A) RNA was labeled using a commercial RNA amplification and labeling system (NuGEN Ovation), and gene expression profiles were obtained using commercial expression microarrays (Affymetrix HG-U133 Plus 2.0). RESULTS: A total of 9,501 differentially expressed probe sets were identified among the JIA subtypes and controls (by analysis of variance; false discovery rate 5%). Specifically, 193, 1,036, 873, and 7,595 probe sets were different in PBMCs from the controls compared with those from the ERA, persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA patients, respectively. In patients with persistent oligoarthritis, RF-negative polyarthritis, and systemic JIA subtypes, up-regulation of genes associated with interleukin-10 (IL-10) signaling was prominent. A hemoglobin cluster was identified that was underexpressed in ERA patients but overexpressed in systemic JIA patients. The influence of JAK/STAT, ERK/MAPK, IL-2, and B cell receptor signaling pathways was evident in patients with persistent oligoarthritis. In systemic JIA, up-regulation of innate immune pathways, including IL-6, Toll-like receptor/IL-1 receptor, and peroxisome proliferator-activated receptor signaling, were noted, along with down-regulation of gene networks related to natural killer cells and T cells. Complement and coagulation pathways were up-regulated in systemic JIA, with a subset of these genes being differentially expressed in other subtypes as well. CONCLUSION: Expression analysis identified differentially expressed genes in PBMCs obtained early in the disease from patients with different subtypes of JIA and in healthy controls, providing evidence of immunobiologic differences between these forms of childhood arthritis.

Pathogenesis of myositis in children.

PURPOSE OF REVIEW: There is increasing evidence for involvement of innate immune mechanisms in the pathogenesis of idiopathic inflammatory myopathies. This review focuses on recent advances in understanding these mechanisms in juvenile dermatomyositis, the most common form of childhood inflammatory myopathy. RECENT FINDINGS: Type I interferon activity in juvenile dermatomyositis has been demonstrated by both global gene expression profiling and immunohistochemical analysis of affected tissues. Most recently, expression of interferon-inducible genes in peripheral blood cells has shown promise as a biomarker for disease activity. The possible pathogenic actions of type I interferons include induction and maintenance of major histocompatibility complex class I expression in affected myofibers, and promotion of local pro-inflammatory cytokine and chemokine production. The cellular source of type I interferons is not clearly defined, though plasmacytoid dendritic cells that constitute a significant component of the inflammatory cell infiltrate are obvious candidates. These cells likely contribute to pathogenesis not only via type I interferon production, but also by regulating other infiltrating inflammatory cells. SUMMARY: Type I interferons and plasmacytoid dendritic cells appear to make important contributions to the pathogenesis of juvenile dermatomyositis. Understanding the role of the innate immune system in childhood myositis may lead to novel treatment strategies.

Differential intra-proteasome interactions involving standard and immunosubunits.

Animals with immune systems have two types of proteasomes, "standard proteasomes" and "immunoproteasomes" that respectively contain constitutively expressed catalytic subunits or interferon-gamma-inducible catalytic subunits. Interestingly, proteasome assembly is biased against formation of most mixed proteasomes containing combinations of standard subunits and immunosubunits. We previously demonstrated that catalytic subunit propeptide differences contribute to this assembly specificity. In the current study, we investigated the contributions of catalytic subunit propeptides and C-terminal extensions to intra-proteasome protein-protein interactions that are potentially involved in mediating biased assembly of human proteasomes, and we found a number of interactions that differentially depended on these structures. For example, the C-terminal extension of standard subunit beta2 is required for beta2's interaction with adjacent beta3, whereas the C-terminal extension of immunosubunit beta2i is dispensable for beta2i's interaction with beta3. Taken together, our results suggest mechanisms whereby differential intra-proteasome interactions could contribute to proteasome assembly specificity.

T cells lacking immunoproteasome subunits MECL-1 and LMP7 hyperproliferate in response to polyclonal mitogens.

Immunoproteasomes comprise a specialized subset of proteasomes that is defined by the presence of three catalytic immunosubunits: LMP2, MECL-1 (LMP10), and LMP7. Proteasomes in general serve many cellular functions through protein degradation, whereas the specific function of immunoproteasomes has been thought to be largely, if not exclusively, optimization of MHC class I Ag processing. In this report, we demonstrate that T cells from double knockout mice lacking two of the immunosubunits, MECL-1 and LMP7, hyperproliferate in vitro in response to various polyclonal mitogens. We observe hyperproliferation of both CD4(+) and CD8(+) T cell subsets and demonstrate accelerated cell cycling. We do not observe hyperproliferation of T cells lacking only one of these subunits, and thus hyperproliferation is independent of either reduced MHC class I expression in LMP7(-/-) mice or reduced CD8(+) T cell numbers in MECL-1(-/-) mice. We observe both of these latter two phenotypes in MECL-1/LMP7(-/-) mice, which indicates that they also are independent of each other. Finally, we provide evidence of in vivo T cell dysfunction by demonstrating increased numbers of central memory phenotype CD8(+) T cells in MECL-1/LMP7(-/-) mice. In summary, this novel phenotype of hyperproliferation of T cells lacking both MECL-1 and LMP7 implicates a specific role for immunoproteasomes in T cell proliferation that is not obviously connected to MHC class I Ag processing.

Gastrointestinal symptoms and their association with health-related quality of life of children with juvenile rheumatoid arthritis: validation of a gastrointestinal symptom questionnaire.

OBJECTIVES: The objectives of this study were to perform an initial validation of the Gastrointestinal Symptom Scale for Kids (GISSK) in children with juvenile rheumatoid arthritis (JRA); and too evaluate the relationship between gastrointestinal (GI) symptoms and health-related quality of life (HRQOL) in JRA. METHODS: A convenience sample of 77 children (median age, 10 years; range, 2-18 years) with JRA requiring second-line agents and one of their parents were interviewed. GI symptoms during the preceding 1 week were measured using the GISSK, which consists of 2 components, a visual analog scale of GI symptom severity (GISSK-VAS) and an 8-item questionnaire (GISSK-Q; score 0-8; 0= no GI symptoms). Information on medications, joint involvement with arthritis, and a physician rating of disease activity were obtained. Patient-centered outcomes included the Childhood Health Assessment Questionnaire (CHAQ) to assess disability and discomfort. HRQOL was measured by the Pediatric Quality of Life Generic Core Scale (PedsQL-GC) and the Rheumatology Module (PedsQL-RM), as well as a visual analog scale (VAS-health). To determine test-retest reliability, the GISSK was completed by 40 parents twice within a 1- to 2-week period. To determine the quality of parent proxy-reporting, parent ratings were compared with those of their children aged 8 years or older. RESULTS: GI symptoms were present in the majority of the patients with JRA (58%). Compared with other patients with JRA, those with a GISSK-Q score of > or =2 had significantly lower HRQOL (PedsQL-GC: P < 0.04; PedsQL-RM: P < 0.05; VAS-health: P < 0.02) and more disability (CHAQ: P < 0.002), despite similar disease activity and joint findings. Similar relationships were observed for the GISSK-VAS with traditional outcomes and HRQOL. The test-retest reliability of the GISSK was good (ICCGISSK-Q = 0.60; ICCGISSK-VAS = 0.67). The quality of parent proxy-reporting was fair to good (ICCGISSK-Q = 0.47; ICCGISSK-VAS = 0.66). CONCLUSION: GI symptoms are frequent among children with JRA requiring advanced therapies and, if moderate or severe, are associated with significantly lower HRQOL. The GISSK is a reliable and valid measure of GI symptoms and their severity in JRA. This self-administered measure can be used to screen for GI symptoms in clinical practice and may be useful to assess the effects of medication changes on the perceived GI side effects in children with JRA.