Advances in JDM:biomarker and MRI sensitivity, outcomes and steroid management in a Dutch national prospective cohort

Objectives JDM is a rare chronic inflammatory disorder of childhood. The aim of this prospective study was to describe the characteristics and outcomes of the Dutch JDM population.Methods Demographics, clinical features, diagnostic test results and treatment were prospectively evaluated at diagnosis and during follow-up visits in JDM patients diagnosed between 2007 and 2024 in the study-coordinating centre and between 2015 and 2024 in five other tertiary referral hospitals.Results A total of 83 patients were included (65% female). Median age at diagnosis was 6.0 years (IQR 4-9). Median follow-up was 3.2 years (IQR 1.4-5.8). The most common features at diagnosis were proximal muscle weakness (94.9%) and Gottron's papules/sign (79.7%). While CK was abnormal in 73.1%, IFN-related biomarkers Galectin-9 and CXCL10 were elevated in 98.3% and 93.3% at diagnosis, respectively. Whole-body MRI showed muscle oedema in 30/33 (90.9%) patients. Corticosteroids could be tapered to 0.2 mg/kg at 6 months in 41.5%. Of all patients, 27 (32.5%) experienced one or more flares and 24 (28.9%) had a refractory disease course. Calcinosis occurred in 12 patients (14.5%). At last follow-up, 28.9% of patients had clinically inactive disease without medication. No patient died.Conclusion This study demonstrates the superior diagnostic sensitivity of Galectin-9 and CXCL10 over CK, the high sensitivity of MRI and the frequent occurrence of refractory disease and flares despite treatment. Reliable predictors are needed to identify patients who can safely taper immunosuppressants versus those needing continued treatment, and who may benefit from targeted therapies initiated upfront

Curation and expansion of the Human Phenotype Ontology for systemic autoinflammatory diseases improves phenotype-driven disease-matching

INTRODUCTION: Accurate and standardized phenotypic descriptions are essential in diagnosing rare diseases and discovering new diseases, and the Human Phenotype Ontology (HPO) system was developed to provide a rich collection of hierarchical phenotypic descriptions. However, although the HPO terms for inborn errors of immunity have been improved and curated, it has not been investigated whether this curation improves the diagnosis of systemic autoinflammatory disease (SAID) patients. Here, we aimed to study if improved HPO annotation for SAIDs enhanced SAID identification and to demonstrate the potential of phenotype-driven genome diagnostics using curated HPO terms for SAIDs. METHODS: We collected HPO terms from 98 genetically confirmed SAID patients across eight different European SAID expertise centers and used the LIRICAL (Likelihood Ratio Interpretation of Clinical Abnormalities) computational algorithm to estimate the effect of HPO curation on the prioritization of the correct SAID for each patient. RESULTS: Our results show that the percentage of correct diagnoses increased from 66% to 86% and that the number of diagnoses with the highest ranking increased from 38 to 45. In a further pilot study, curation also improved HPO-based whole-exome sequencing (WES) analysis, diagnosing 10/12 patients before and 12/12 after curation. In addition, the average number of candidate diseases that needed to be interpreted decreased from 35 to 2. DISCUSSION: This study demonstrates that curation of HPO terms can increase identification of the correct diagnosis, emphasizing the high potential of HPO-based genome diagnostics for SAIDs

Endothelial and Inflammation Biomarker Profiles at Diagnosis Reflecting Clinical Heterogeneity and Serving as a Prognostic Tool For Treatment Response in Two Independent Cohorts of Patients With Juvenile Dermatomyositis

Objective: Juvenile dermatomyositis (DM) is a heterogeneous systemic immune-mediated vasculopathy. This study was undertaken to 1) identify inflammation/endothelial dysfunction–related biomarker profiles reflecting disease severity at diagnosis, and 2) establish whether such biomarker profiles could be used for predicting the response to treatment in patients with juvenile DM. Methods: In total, 39 biomarkers related to activation of endothelial

Curation and expansion of Human Phenotype Ontology for defined groups of inborn errors of immunity.

BACKGROUND: Accurate, detailed, and standardized phenotypic descriptions are essential to support diagnostic interpretation of genetic variants and to discover new diseases. The Human Phenotype Ontology (HPO), extensively used in rare disease research, provides a rich collection of vocabulary with standardized phenotypic descriptions in a hierarchical structure. However, to date, the use of HPO has not yet been widely implemented in the field of inborn errors of immunity (IEIs), mainly due to a lack of comprehensive IEI-related terms. OBJECTIVES: We sought to systematically review available terms in HPO for the depiction of IEIs, to expand HPO, yielding more comprehensive sets of terms, and to reannotate IEIs with HPO terms to provide accurate, standardized phenotypic descriptions. METHODS: We initiated a collaboration involving expert clinicians, geneticists, researchers working on IEIs, and bioinformaticians. Multiple branches of the HPO tree were restructured and extended on the basis of expert review. Our ontology-guided machine learning coupled with a 2-tier expert review was applied to reannotate defined subgroups of IEIs. RESULTS: We revised and expanded 4 main branches of the HPO tree. Here, we reannotated 73 diseases from 4 International Union of Immunological Societies-defined IEI disease subgroups with HPO terms. We achieved a 4.7-fold increase in the number of phenotypic terms per disease. Given the new HPO annotations, we demonstrated improved ability to computationally match selected IEI cases to their known diagnosis, and improved phenotype-driven disease classification. CONCLUSIONS: Our targeted expansion and reannotation presents enhanced precision of disease annotation, will enable superior HPO-based IEI characterization, and hence benefit both IEI diagnostic and research activities

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textabstractIntroduction: Approximately 30 % of juvenile idiopathic arthritis (JIA) patients fail to respond to anti-TNF treatment. When clinical remission is induced, some patients relapse after treatment has been stopped.We tested the predictive value of MRP8/14 serum levels to identify responders to treatment and relapse after discontinuation of therapy.Methods: Samples from 88 non-systemic JIA patients who started and 26 patients who discontinued TNF-blockers were analyzed.MRP8/14 serum levels were measured by in-house MRP8/14 ELISA and by Bühlmann Calprotectin ELISA at start of anti-TNF treatment, within 6 months after start and at discontinuation of etanercept in clinical remission.Patients were categorized into responders (ACRpedi ≥ 50 and/or inactive disease) and non-responders (ACRpedi < 50) within six months after start, response was evaluated by change in JADAS-10.Disease activity was assessed within six months after discontinuation.Results: Baseline MRP8/14 levels were higher in responders (median MRP8/14 of 1466 ng/ml (IQR 1045-3170)) compared to non-responders (median MRP8/14 of 812 (IQR 570-1178), p < 0.001).Levels decreased after start of treatment only in responders (p < 0.001).Change in JADAS-10 was correlated with baseline MRP8/14 levels (Spearman's rho 0.361, p = 0.001).Patients who flared within 6 months after treatment discontinuation had higher MRP8/14 levels (p = 0.031, median 1025 ng/ml (IQR 588-1288)) compared to patients with stable remission (505 ng/ml (IQR 346-778)).Results were confirmed by Bühlmann ELISA with high reproducibility but different overall levels.Conclusion: High levels of baseline MRP8/14 are associated with good response to anti-TNF treatment, whereas elevated MRP8/14 levels at discontinuation of etanercept are associated with higher chance to flare

Clinical exome sequencing data from patients with inborn errors of immunity:Cohort level diagnostic yield and the benefit of systematic reanalysis

While next generation sequencing has expanded the scientific understanding of Inborn Errors of Immunity (IEI), the clinical use and re-use of exome sequencing is still emerging. We revisited clinical exome data from 1300 IEI patients using an updated in silico IEI gene panel. Variants were classified and curated through expert review. The molecular diagnostic yield after standard exome analysis was 11.8 %. Through systematic reanalysis, we identified variants of interest in 5.2 % of undiagnosed patients, with 76.7 % being (candidate) disease-causing, providing a (candidate) diagnosis in 15.2 % of our cohort. We find a 1.7 percentage point increase in conclusive molecular diagnoses. We find a high degree of actionability in patients with a genetic diagnosis (76.4 %). Despite the modest absolute diagnostic gain, these data support the benefit of iterative exome reanalysis in IEI patients, conveying the notion that our current understanding of genes and variants involved in IEI is by far not saturated.</p

Opportunistic infections in immunosuppressed patients with juvenile idiopathic arthritis: Analysis by the Pharmachild Safety Adjudication Committee

Background: To derive a list of opportunistic infections (OI) through the analysis of the juvenile idiopathic arthritis (JIA) patients in the Pharmachild registry by an independent Safety Adjudication Committee (SAC). Methods: The SAC (3 pediatric rheumatologists and 2 pediatric infectious disease specialists) elaborated and approved by consensus a provisional list of OI for use in JIA. Through a 5 step-procedure, all the severe and serious infections, classified as per MedDRA dictionary and retrieved in the Pharmachild registry, were evaluated by the SAC by answering six questions and adjudicated with the agreement of 3/5 specialists. A final evidence-based list of OI resulted by matching the adjudicated infections with the provisional list of OI. Results: A total of 772 infectious events in 572 eligible patients, of which 335 serious/severe/very severe non-OI and 437 OI (any intensity/severity), according to the provisional list, were retrieved. Six hundred eighty-two of 772 (88.3%) were adjudicated as infections, of them 603/682 (88.4%) as common and 119/682 (17.4%) as OI by the SAC. Matching these 119 opportunistic events with the provisional list, 106 were confirmed by the SAC as OI, and among them infections by herpes viruses were the most frequent (68%), followed by tuberculosis (27.4%). The remaining events were divided in the groups of non-OI and possible/patient and/or pathogen-related OI. Conclusions: We found a significant number of OI in JIA patients on immunosuppressive therapy. The proposed list of OI, created by consensus and validated in the Pharmachild cohort, could facilitate comparison among future pharmacovigilance studies. Trial registration: Clinicaltrials.gov NCT 01399281; ENCePP seal: awarded on 25 November 2011