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 For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare.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.

High Levels of DEK Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti-Tumor Necrosis Factor Therapy.

OBJECTIVE: The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis (JIA), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA. We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA. METHODS: DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti-tumor necrosis factor (anti-TNF) therapy. Recombinant His-tagged full-length DEK protein (1-375 amino acids [aa]) and the 187-375-aa and 1-350-aa His-tagged DEK fragments made in a baculovirus system were used for enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The C-terminal 25-aa fragment of DEK was expressed in a glutathione S-transferase-tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule. RESULTS: DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA, and were higher in patients with polyarticular JIA who had more active disease after cessation of anti-TNF therapy. Immunoblotting against the C-terminal 25-aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain. CONCLUSION: DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA, and higher in patients who have disease flares after cessation of anti-TNF therapy. The C-terminal 25-aa fragment is the most immunogenic portion of DEK. These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management.

Evidence for Updating the Core Domain Set of Outcome Measures for Juvenile Idiopathic Arthritis: Report from a Special Interest Group at OMERACT 2016.

OBJECTIVE: The current Juvenile Idiopathic Arthritis (JIA) Core Set was developed in 1997 to identify the outcome measures to be used in JIA clinical trials using statistical and consensus-based techniques, but without patient involvement. The importance of patient/parent input into the research process has increasingly been recognized over the years. An Outcome Measures in Rheumatology (OMERACT) JIA Core Set Working Group was formed to determine whether the outcome domains of the current core set are relevant to those involved or whether the core set domains should be revised. METHODS: Twenty-four people from the United States, Canada, Australia, and Europe, including patient partners, formed the working group. Guided by the OMERACT Filter 2.0 process, we performed (1) a systematic literature review of outcome domains, (2) a Web-based survey (142 patients, 343 parents), (3) an idea-generation study (120 parents), (4) 4 online discussion boards (24 patients, 20 parents), and (5) a Special Interest Group (SIG) activity at the OMERACT 13 (2016) meeting. RESULTS: A MEDLINE search of outcome domains used in studies of JIA yielded 5956 citations, of which 729 citations underwent full-text review, and identified additional domains to those included in the current JIA Core Set. Qualitative studies on the effect of JIA identified multiple additional domains, including pain and participation. Twenty-one participants in the SIG achieved consensus on the need to revise the entire JIA Core Set. CONCLUSION: The results of qualitative studies and literature review support the need to expand the JIA Core Set, considering, among other things, additional patient/parent-centered outcomes, clinical data, and imaging data.

Evaluation of quality indicators and disease damage in childhood-onset systemic lupus erythematosus patients.

The aim of this study was to describe compliance with select quality indicators and assess organ-specific dysfunction in a childhood-onset systemic lupus erythematosus population by using a validated damage index and to evaluate associations between compliance with quality indicators and disease damage. A retrospective chart review was performed on patients diagnosed with systemic lupus erythematosus prior to age 18 followed at a single center in the USA from 1999 to 2012 (n = 75). Data regarding quality indicators and outcome variables, including the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, were collected. The median disease duration was 3.8 years. The proportion of patients or patient-years in which care complied with the proposed quality measures was 94.4% for hydroxychloroquine use, 84.3% for vitamin D recommendation,75.8% for influenza vaccination (patient-years), 67.2% for meningococcal vaccination, 49.0% for ophthalmologic examination (patient-years), 31.7% for pneumococcal vaccination, and 28.6% for bone mineral density evaluation. Disease damage was present in 41.3% of patients at last follow-up, with an average damage index score of 0.81. Disease damage at last follow-up was associated with minority race/ethnicity (p = 0.008), bone mineral density evaluation (p = 0.035), and vitamin D recommendation (p = 0.018). Adherence to quality indicators in a childhood-onset systemic lupus erythematosus population is varied, and disease damage is prevalent. This study highlights the importance of quality improvement initiatives aimed at optimizing care delivery to reduce disease damage in pediatric lupus patients.

Improving Pneumococcal Vaccination in Pediatric Rheumatology Patients.

BACKGROUND AND OBJECTIVE: Many pediatric rheumatology patients are at increased risk of pneumococcal disease secondary to a deficient immune system and/or immunosuppressive medications. The goal of this study was to improve pneumococcal vaccination rates in this high-risk population. METHODS: Eligible patients included children at least 2 years old and adults with systemic lupus erythematosus and/or currently on immunosuppressive medication. Interventions included a presentation to rheumatology providers,creation of immunization algorithm, previsit planning, placing reminders on clinic forms, and sending reminder e-mails to providers. Chart reviews were performed, and control charts were established to portray change in immunization rates. RESULTS: The preintervention immunization rates for 90 patient visits compared with the immunization rates for the 53-week postintervention period with 1033 patient visits and 299 separate patients were all statistically significant.The 13-valent pneumococcal conjugate vaccine rate increased from 6.7% to48.4% (x2 = 58.3, P , .001), 23-valent pneumococcal polysaccharide vaccinerate increased from 8.9% to 28.4% (x2 = 16.0, P , .001), and combined rate increased from 0% to 23.2% (x2 = 25.2, P , .001). The improvement was sustained with shifts in the data for each vaccine and combined immunizations for final average rates of 60.9% for 13-valent pneumococcal conjugate vaccine, 39.2% for 23-valent pneumococcal polysaccharide vaccine,and 33.7% for combined. CONCLUSIONS: Pneumococcal vaccination is an important part of the care for systemic lupus erythematosus patients and patients on immunosuppressive medications. Simple interventions through this quality improvement project led to a marked increase in pneumococcal vaccination rates in this vulnerable population.

Minimal clinically important differences of disease activity indices in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To determine the minimal clinically important differences (MCIDs) of validated measures of systemic lupus erythematosus (SLE) disease activity in childhood-onset SLE. METHODS: Childhood-onset SLE patients (n = 98) were followed every 3 months for up to 7 visits (n = 623 total visits). Disease activity measures (European Consensus Lupus Activity Measure, Systemic Lupus Erythematosus Disease Activity Index, Systemic Lupus Activity Measure, British Isles Lupus Assessment Group, and Responder Index for Lupus Erythematosus [RIFLE]) were completed at the time of each visit. Physician-rated changes in the disease course (clinically relevant improvement, no change, clinically relevant worsening) between visits served as the criterion standard. RESULTS: MCIDs defined by mean change scores with improvement and worsening, or those based on the standard error of measurement with stable disease, were both small and did not discriminate well between disease courses (detection rates for improvement or worsening were all <55%). MCIDs based on discriminant and classification analyses yielded similar results. Alternative MCIDs, defined by a 70% predicted probability of improvement or worsening as per the discrimination analysis, were larger but underestimated the proportion of patients with change. The RIFLE only correctly identified 26% and 8% of episodes of clinically important worsening and improvement of childhood-onset SLE, respectively. CONCLUSION: The MCIDs of childhood-onset SLE disease activity measures are often small but similar to those reported for adults with SLE. Therefore, even small changes in disease activity scores can be clinically relevant. Low correct detection rates of these MCID thresholds for changes in disease course support the notion that worsening and improvement with childhood-onset SLE, or its response to therapy, is unlikely to be captured adequately by validated measures of disease activity alone.

Toward the development of criteria for global flares in juvenile systemic lupus erythematosus.

OBJECTIVE: To develop a definition of global flare in juvenile systemic lupus erythematosus (SLE) and derive candidate criteria for measuring juvenile SLE flares. METHODS: Pediatric rheumatologists answered 2 Delphi questionnaires to achieve consensus on a common definition of juvenile SLE flare and identify variables for use in candidate flare criteria. The diagnostic accuracy of these candidate flare criteria was tested with data from juvenile SLE patients (n = 98; 623 visits total). Physician-rated change in the juvenile SLE course (worsening, yes/no) between visits served as the criterion standard. RESULTS: There was 96% consensus that a "a flare is a measurable worsening of juvenile SLE disease activity in at least one organ system, involving new or worse signs of disease that may be accompanied by new or worse SLE symptoms. Depending on the severity of the flare, more intensive therapy may be required." Variables suggested for use in flare criteria were: physician-rated disease activity (V1), patient well-being, protein:creatinine ratio, a validated disease activity index (V2), the Child Health Questionnaire physical summary score (V3), anti-double-stranded DNA antibodies, erythrocyte sedimentation rate, and complement levels. Using multiple logistic regression, several candidate flare criteria were derived with area under the receiver operating characteristic curve (AUC) as high as 0.92 (sensitivity >or=85%, specificity >or=85%); classification and regression tree analysis suggested that V1, V2, and V3 suffice to identify juvenile SLE flares (AUC 0.81; sensitivity = 64%, specificity = 86%). CONCLUSION: Consensus about a definition of global disease flare for juvenile SLE has been obtained and promising candidate flare criteria have been developed. These will need further assessment of their ease of use and accuracy in prospective study.

Prospective validation of the provisional criteria for the evaluation of response to therapy in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To prospectively validate the provisional criteria for the evaluation of response to therapy in children with systemic lupus erythematosus (SLE). METHODS: In this multicenter study, childhood-onset SLE patients (n = 98; 81 girls, 17 boys, 50% white, 88% non-Hispanic) were followed every 3 months for up to 7 visits (total number of visits 623). The 5 childhood-onset SLE core response variables were obtained at the time of each visit: 1) physician assessment of overall disease activity, 2) parent assessment of patient well-being, 3) Child Health Questionnaire, 4) proteinuria, and 5) global disease activity measure score, as measured by the European Consensus Lupus Activity Measure (ECLAM), the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), or the Systemic Lupus Activity Measure (SLAM). Physician-rated relevant changes in the disease course (clinically relevant improvement, no change in disease, or worsening) between visits served as the criterion standard. Mixed models were used to assess the diagnostic accuracy of the 4 highest-ranked provisional definitions of response to therapy. RESULTS: There were 89 episodes of clinically relevant improvement between 2 consecutive visits, and 448 episodes without improvement. Irrespective of the choice of the global disease activity measure (ECLAM, SLAM, SLEDAI), sensitivities of all 4 highest-ranked definitions were low (all < or =31%), whereas their specificities were excellent (all >88%). Using logistic models, alternative definitions can be developed with both 80% sensitivity and specificity. CONCLUSION: The provisional criteria of response to therapy in childhood-onset SLE may have considerably lower sensitivity than previously reported. Additional validation in clinical trials is necessary to further evaluate the measurement properties of the provisional Paediatric Rheumatology International Trials Organisation/American College of Rheumatology criteria for response to therapy in children with SLE.

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.

Health-related quality of life and its relationship to patient disease course in childhood-onset systemic lupus erythematosus.

OBJECTIVE: To (1) estimate the health-related quality of life (HRQOL) of children with childhood-onset systemic lupus erythematosus (cSLE) and compare it to that of normative cohorts; (2) assess the relationship of HRQOL with cSLE disease activity and damage; and (3) determine the effects of changes of disease activity on HRQOL. METHODS: Patients with cSLE (n = 98) followed every 3 months completed HRQOL measures, the Pediatric Quality of Life Inventory Generic Core scale (PedsQL-GC), the Rheumatology Module (PedsQL-RM), and the Child Health Questionnaire (CHQ). The British Isles Lupus Activity Group Index (BILAG) was used to measure organ-system-specific disease activity. Physicians rated the course of cSLE between visits. RESULTS: At baseline, mean (standard deviation, SD) score [parent report] of the PedsQL-GC and the PedsQL-RM was 75 (17) and 79 (14), respectively; the mean (SD) of the CHQ physical summary score (CHQ-PHS) was 49 (7) and that of the CHQ psychological summary score was 42 (12). Higher BILAG scores, especially in the general, musculoskeletal, neurological, and vascular, but not the mucocutaneous, renal, cardiovascular, or hematological BILAG domains, were associated with a significantly lower HRQOL. Patients with damage had lower HRQOL than those without damage. All HRQOL measures included were at most modestly responsive to clinically important changes with cSLE. CONCLUSION: HRQOL with cSLE is significantly lower than that reported in healthy populations. Organ-specific involvement with cSLE has a differential effect on HRQOL. Higher disease activity and damage are associated with significantly lower HRQOL as measured by the PedsQL-RM and the CHQ-PHS, and worsening of cSLE leads to a further decline.

Long-term efficacy and safety of etanercept in children with polyarticular-course juvenile rheumatoid arthritis: interim results from an ongoing multicenter, open-label, extended-treatment trial.

OBJECTIVE: To evaluate the long-term efficacy and safety of etanercept in children with juvenile rheumatoid arthritis (JRA) participating in an ongoing multicenter, open-label, extended-treatment trial. All patients had been participants in an initial randomized efficacy and safety trial of etanercept. METHODS: Etanercept was administered at a dosage of 0.4 mg/kg (maximum 25 mg) subcutaneously twice each week. Safety and efficacy evaluations were performed every 3-4 months. The JRA 30% definition of improvement (DOI) was defined as improvement of > or =30% in at least 3 of 6 response variables used to assess disease activity, with no more than 1 variable worsening by more than 30%. RESULTS: At the time of analysis, 48 of the 58 patients (83%) were still enrolled in the study; 43 of them (74%) had completed 2 years of treatment. Of these 43 patients, 81% met the JRA 30% DOI, 79% met the JRA 50% DOI, and 67% met the JRA 70% DOI. Ten children started low-dose methotrexate after year 1. Of the 32 children taking prednisone, the dosage was decreased to <5 mg/day in 26 (81%). Two children had serious infections (varicella with aseptic meningitis in one and complicated sepsis in the other). In general, adverse events were of the types seen in a general pediatric patient population. CONCLUSION: Children with severe, longstanding, methotrexate-resistant polyarticular JRA demonstrated sustained clinical improvement with >2 years of continuous etanercept treatment. Etanercept was generally well-tolerated. There were no increases in the rates of adverse events over time. However, children taking etanercept should be monitored closely for infections.

Juvenile idiopathic arthritis: an update.

Juvenile idiopathic arthritis (JIA) is the most common chronic arthropathy of childhood. Previous terminology identified this entity as juvenile rheumatoid arthritis. The 7 subsets of JIA identified under the new classification system are discussed, as are current treatments. A differential diagnosis of JIA is included as this condition continues to be diagnosed by exclusion. Recent studies, which discuss the outcome of adults with previous childhood arthritis, are reviewed.