Hypergammaglobulinemia in the pediatric population as a marker for underlying autoimmune disease: a retrospective cohort study

Background: The significance of hypergammaglobulinemia as a marker of immune activation is unknown, as a differential diagnosis for hypergammaglobulinemia in children has not been adequately established. The goal of this study was to identify conditions associated with hypergammaglobulinemia in children, with the hypothesis that elevated immunoglobulin levels may precede or predict the development of autoimmune conditions. Methods: We reviewed the medical records for all children with IgG level ≥2000 mg/dL treated at a tertiary care children’s hospital from January 1, 2000 through December 31, 2009. We compared clinical and laboratory features of these patients, and developed an algorithm to predict the likelihood of underlying autoimmunity based on these characteristics. Results: After excluding children who had received IVIG, a total of 442 patients with hypergammaglobulinemia were identified. Of these, nearly half had autoimmune conditions, most frequently systemic lupus erythematosus and lupus-related disorders. Autoimmune gastrointestinal disorders such as inflammatory bowel disease were also common. Infectious diseases were the next largest category of diseases, followed with much less frequency by malignant, drug-related, and other conditions. In comparison with non-autoimmune conditions, patients with autoimmune disease had higher IgG levels, lower white blood cell counts, lower hemoglobin values, and lower C-reactive protein (CRP) levels. Multivariable logistic regression confirmed that CRP (P = 0.002), white blood cell count (P < 0.001), hemoglobin (P = 0.015), and female gender (P < 0.001) are independent risk factors for autoimmune disease in patients with high IgG levels. Conclusions: In a cohort of pediatric patients at a tertiary care children’s hospital, hypergammaglobulinemia was most commonly associated with autoimmune diseases. In female patients with hypergammaglobulinemia, the presence of leukopenia, anemia, and normal CRP was 95% predictive of underlying autoimmune disease

Risk Model Development and Validation for Prediction of Coronary Artery Aneurysms in Kawasaki Disease in a North American Population.

Background Accurate prediction of coronary artery aneurysms ( CAAs ) in patients with Kawasaki disease remains challenging in North American cohorts. We sought to develop and validate a risk model for CAA prediction. Methods and Results A binary outcome of CAA was defined as left anterior descending or right coronary artery Z score ≥2.5 at 2 to 8&nbsp;weeks after fever onset in a development cohort (n=903) and a validation cohort (n=185) of patients with Kawasaki disease. Associations of baseline clinical, laboratory, and echocardiographic variables with later CAA were assessed in the development cohort using logistic regression. Discrimination (c statistic) and calibration (Hosmer-Lemeshow) of the final model were evaluated. A practical risk score assigning points to each variable in the final model was created based on model coefficients from the development cohort. Predictors of CAAs at 2 to 8&nbsp;weeks were baseline Z score of left anterior descending or right coronary artery ≥2.0, age &lt;6&nbsp;months, Asian race, and C-reactive protein ≥13&nbsp;mg/ dL (c=0.82 in the development cohort, c=0.93 in the validation cohort). The CAA risk score assigned 2 points for baseline Z score of left anterior descending or right coronary artery ≥2.0 and 1 point for each of the other variables, with creation of low- (0-1), moderate- (2), and high- (3-5) risk groups. The odds of CAA s were 16-fold greater in the high- versus the low-risk groups in the development cohort (odds ratio, 16.4; 95% CI , 9.71-27.7 [ P&lt;0.001]), and &gt;40-fold greater in the validation cohort (odds ratio, 44.0; 95% CI, 10.8-180 [ P&lt;0.001]). Conclusions Our risk model for CAA in Kawasaki disease consisting of baseline demographic, laboratory, and echocardiographic variables had excellent predictive utility and should undergo prospective testing

Gene-expression patterns reveal underlying biological processes in Kawasaki disease

Background: Kawasaki disease (KD) is an acute self-limited vasculitis and the leading cause of acquired heart disease in children in developed countries. No etiologic agent(s) has been identified, and the processes that mediate formation of coronary artery aneurysms and abatement of fever following treatment with intravenous immunoglobulin (IVIG) remain poorly understood. Results: In an initial survey, we used DNA microarrays to examine patterns of gene expression in peripheral whole blood from 20 children with KD; each was sampled during the acute, subacute, and convalescent phases of the illness. Acute KD was characterized by increased relative abundance of gene transcripts associated with innate immune and proinflammatory responses and decreased abundance of transcripts associated with natural killer cells and CD8+ lymphocytes. There was significant temporal variation in transcript levels during the acute disease phase and stabilization thereafter. We confirmed these temporal patterns in a second cohort of 64 patients, and identified additional inter-individual differences in transcript abundance. Notably, higher levels of transcripts of the gene for carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1) were associated with an increased percentage of unsegmented neutrophils, fewer days of illness, higher levels of C-reactive protein, and subsequent non-response to IVIG; this last association was confirmed by quantitative reverse transcription PCR in a third cohort of 33 patients, and was independent of day of illness. Conclusion: Acute KD is characterized by dynamic and variable gene-expression programs that highlight the importance of neutrophil activation state and apoptosis in KD pathogenesis. Our findings also support the feasibility of extracting biomarkers associated with clinical prognosis from gene-expression profiles of individuals with systemic inflammatory illnesses

Pain hypersensitivity in juvenile idiopathic arthritis: a quantitative sensory testing study

Background: Juvenile Idiopathic Arthritis (JIA) is the most common cause of non-infectious joint inflammation in children. Synovial inflammation results in pain, swelling and stiffness. Animal and adult human studies indicate that localized joint-associated inflammation may produce generalized changes in pain sensitivity. The aim was to characterize pain sensitivity in children with JIA to mechanical and thermal stimulus modalities using quantitative sensory testing (QST) at an affected inflamed joint, and compare to children in clinical remission. Generalized hypersensitivity was evaluated by comparing QST measures at the thenar eminence between JIA and healthy control children. Methods: 60 children aged 7–17 years with JIA participated. QST assessed sensory detection threshold and pain threshold at two sites: (1) affected joint (clinically active or inactive), (2) contralateral thenar eminence. Joint site included finger, wrist, knee and ankle. Clinical status was measured using objective and subjective markers of disease severity. Questionnaires assessed pain intensity and frequency, functional disability, anxiety, pain catastrophization and fatigue. QST data collected from joints were compared within JIA patients: active vs. inactive inflammation; and data from the contralateral thenar eminence were compared between JIA and healthy control cohorts in Europe [EU, (n = 151)] and the US (n = 92). Statistical analyses were performed using Kruskal-Wallis with Dunn’s post-hoc comparison, Mann-Whitney or Fisher’s exact test, where appropriate. Results: Overall, children with JIA reported low pain scores and low degrees of functional disability. Sensory detection thresholds and pain thresholds were similar in “active” compared to “inactive” joints. Despite this, children with JIA had generalized hypersensitivity at the thenar eminence when compared to healthy children for pressure (vs. EU p < 0.001), light touch (vs. EU p < 0.001), cold (vs EU, p < 0.01; vs US, p < 0.001) and heat pain (vs EU, p < 0.05; vs US p < 0.001). Conclusions: JIA is associated with increased sensitivity to painful mechanical and thermal stimuli, even in absence of pain reports, or markers of disease activity. Future research investigating mechanisms underlying pain hypersensitivity in JIA is warranted; this will in turn guide pharmacologic and non-pharmacologic interventions to prevent or reverse these processes. Electronic supplementary material The online version of this article (doi:10.1186/1546-0096-12-39) contains supplementary material, which is available to authorized users

Urine proteomics for discovery of improved diagnostic markers of Kawasaki disease

Kawasaki disease (KD) is a systemic vasculitis of unknown etiology. Absence of definitive diagnostic markers limits the accuracy of clinical evaluations of suspected KD with significant increases in morbidity. In turn, incomplete understanding of its molecular pathogenesis hinders the identification of rational targets needed to improve therapy. We used high-accuracy mass spectrometry proteomics to analyse over 2000 unique proteins in clinical urine specimens of patients with KD. We discovered that urine proteomes of patients with KD, but not those with mimicking conditions, were enriched for markers of cellular injury such as filamin and talin, immune regulators such as complement regulator CSMD3, immune pattern recognition receptor muclin, and immune cytokine protease meprin A. Significant elevations of filamin C and meprin A were detected in both the serum and urine in two independent cohorts of patients with KD, comprised of a total of 236 patients. Meprin A and filamin C exhibited superior diagnostic performance as compared to currently used markers of disease in a blinded case-control study of 107 patients with suspected KD, with receiver operating characteristic areas under the curve of 0.98 (95% confidence intervals [CI] of 0.97–1 and 0.95–1, respectively). Notably, meprin A was enriched in the coronary artery lesions of a mouse model of KD. In all, urine proteome profiles revealed novel candidate molecular markers of KD, including filamin C and meprin A that exhibit excellent diagnostic performance. These disease markers may improve the diagnostic accuracy of clinical evaluations of children with suspected KD, lead to the identification of novel therapeutic targets, and allow the development of a biological classification of Kawasaki disease

Evidence-based decision support for pediatric rheumatology reduces diagnostic errors.

BACKGROUND: The number of trained specialists world-wide is insufficient to serve all children with pediatric rheumatologic disorders, even in the countries with robust medical resources. We evaluated the potential of diagnostic decision support software (DDSS) to alleviate this shortage by assessing the ability of such software to improve the diagnostic accuracy of non-specialists. METHODS: Using vignettes of actual clinical cases, clinician testers generated a differential diagnosis before and after using diagnostic decision support software. The evaluation used the SimulConsult® DDSS tool, based on Bayesian pattern matching with temporal onset of each finding in each disease. The tool covered 5405 diseases (averaging 22 findings per disease). Rheumatology content in the database was developed using both primary references and textbooks. The frequency, timing, age of onset and age of disappearance of findings, as well as their incidence, treatability, and heritability were taken into account in order to guide diagnostic decision making. These capabilities allowed key information such as pertinent negatives and evolution over time to be used in the computations. Efficacy was measured by comparing whether the correct condition was included in the differential diagnosis generated by clinicians before using the software ( unaided ), versus after use of the DDSS ( aided ). RESULTS: The 26 clinicians demonstrated a significant reduction in diagnostic errors following introduction of the software, from 28% errors while unaided to 15% using decision support (p \u3c 0.0001). Improvement was greatest for emergency medicine physicians (p = 0.013) and clinicians in practice for less than 10 years (p = 0.012). This error reduction occurred despite the fact that testers employed an open book approach to generate their initial lists of potential diagnoses, spending an average of 8.6 min using printed and electronic sources of medical information before using the diagnostic software. CONCLUSIONS: These findings suggest that decision support can reduce diagnostic errors and improve use of relevant information by generalists. Such assistance could potentially help relieve the shortage of experts in pediatric rheumatology and similarly underserved specialties by improving generalists\u27 ability to evaluate and diagnose patients presenting with musculoskeletal complaints. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02205086

Predicting Coronary Artery Aneurysms in Kawasaki Disease at a North American Center: An Assessment of Baseline z Scores

Background: Accurate risk prediction of coronary artery aneurysms (CAAs) in North American children with Kawasaki disease remains a clinical challenge. We sought to determine the predictive utility of baseline coronary dimensions adjusted for body surface area (z scores) for future CAAs in Kawasaki disease and explored the extent to which addition of established Japanese risk scores to baseline coronary artery z scores improved discrimination for CAA development. Methods and Results: We explored the relationships of CAA with baseline z scores; with Kobayashi, Sano, Egami, and Harada risk scores; and with the combination of baseline z scores and risk scores. We defined CAA as a maximum z score (zMax) ≥2.5 of the left anterior descending or right coronary artery at 4 to 8 weeks of illness. Of 261 patients, 77 patients (29%) had a baseline zMax ≥2.0. CAAs occurred in 15 patients (6%). CAAs were strongly associated with baseline zMax ≥2.0 versus <2.0 (12 [16%] versus 3 [2%], respectively, P<0.001). Baseline zMax ≥2.0 had a C statistic of 0.77, good sensitivity (80%), and excellent negative predictive value (98%). None of the risk scores alone had adequate discrimination. When high‐risk status per the Japanese risk scores was added to models containing baseline zMax ≥2.0, none were significantly better than baseline zMax ≥2.0 alone. Conclusions: In a North American center, baseline zMax ≥2.0 in children with Kawasaki disease demonstrated high predictive utility for later development of CAA. Future studies should validate the utility of our findings

Disordered T cell-B cell interactions in autoantibody-positive inflammatory arthritis

T peripheral helper (Tph) cells, identified in the synovium of adults with seropositive rheumatoid arthritis, drive B cell maturation and antibody production in non-lymphoid tissues. We sought to determine if similarly dysregulated T cell-B cell interactions underlie another form of inflammatory arthritis, juvenile oligoarthritis (oligo JIA). Clonally expanded Tph cells able to promote B cell antibody production preferentially accumulated in the synovial fluid (SF) of oligo JIA patients with antinuclear antibodies (ANA) compared to autoantibody-negative patients. Single-cell transcriptomics enabled further definition of the Tph gene signature in inflamed tissues and showed that Tph cells from ANA-positive patients upregulated genes associated with B cell help to a greater extent than patients without autoantibodies. T cells that co-expressed regulatory T and B cell-help factors were identified. The phenotype of these Tph-like Treg cells suggests an ability to restrain T cell-B cell interactions in tissues. Our findings support the central role of disordered T cell-help to B cells in autoantibody-positive arthritides

American College of Rheumatology Provisional Criteria for Clinically Relevant Improvement in Children and Adolescents With Childhood-Onset Systemic Lupus Erythematosus

10.1002/acr.23834ARTHRITIS CARE & RESEARCH715579-59