Real-World Health Care Outcomes and Costs Among Patients With Juvenile Idiopathic Arthritis in Spain

Direct cost; Family impact; Juvenile arthritisCost directe; Impacte familiar; Artritis juvenilCoste directo; Impacto familiar; Artritis juvenilBackground: Juvenile idiopathic arthritis (JIA) is the most frequent chronic rheumatic disease in children. If inflammation is not adequately treated, joint damage, long-term disability, and active disease during adulthood can occur. Identifying and implementing early and adequate therapy are critical for improving clinical outcomes. The burden of JIA on affected children, their families, and the healthcare system in Spain has not been adequately assessed. The greatest contribution to direct costs is medication, but other expenses contribute to the consumption of resources, negatively impacting healthcare cost and the economic conditions of affected families. Objective: To assess the direct healthcare, indirect resource utilization, and associated cost of moderate-to-severe JIA in children in routine clinical practice in Spain. Methods: Children were enrolled in this 24-month observational, multicentric, cross-sectional, retrospective study (N = 107) if they had been treated with biologic disease-modifying anti-rheumatic drugs (bDMARDs), had participated in a previous study (ITACA), and continued to be followed up at pediatric rheumatology units at 3 tertiary Spanish hospitals. Direct costs included medication, specialist and primary care visits, hospitalizations, emergency visits or consultations, surgeries, physiotherapy, and tests. Indirect costs included hospital travel expenses and loss of caregiver working hours. Unitary costs were obtained from official sources (€, 2020). Results: Overall, children had inactive disease/low disease activity according to JADAS-71 score and very low functional disability as measured by Childhood Health Assessment Questionnaire score. Up to 94.4% of children received treatment, mainly with bDMARDs as monotherapy (84.5%). Among anti-TNFα treatments, adalimumab (47.4%) and etanercept (40.2%) were used in similar proportions. Annual mean (SD) total JIA cost was €7516.40 (€5627.30). Average cost of pharmacological treatment was €3021.80 (€3956.20), mainly due to biologic therapy €2789.00 (€3399.80). Direct annual cost (excluding treatments) was €3654.60 (€3899.00). Indirect JIA cost per family was €747.20 (€1452.80). Conclusion: JIA causes significant costs to the Spanish healthcare system and affected families. Public costs are partly due to the high cost of biologic treatments, which nevertheless remain an effective long-term treatment, maintaining inactive disease/low disease activity state; a very low functional disability score; and a good quality of life

Efectividad y seguridad de los bisfosfonatos en el tratamiento de la osteoporosis infantil secundaria

Bisfosfonatos; Efectividad; NiñoBisfosfonats; Efectivitat; NenBisphosphonates; Effectiveness; ChildIntroduction There are few studies on effectiveness and safety of bisphosphonate therapy in secondary osteoporosis in children. The aim of this research was to analyse effectiveness and safety of bisphosphonates in secondary osteoporosis in children. Patients and methods Multicentre retrospective study in patients younger than 18 suffering from secondary osteoporosis and who have received bisphosphonates. Clinical data were recorded. Bone mineral density (BMD) was assessed in terms of BMD Z-score in lumbar spine (ZBMDls) measured by dual-energy X-ray absorptiometry (DXA). Effectiveness was valued at changes in ZBMDls one and two years after the onset of bisphosphonates and at the decrese in the number of fractures a year. Adverse events reported were recorded. Descriptive and bivariant analysis was performed. Results 32 patients were recruited. ZBMDls increased one year after the onset of treatment ((−2.46 ± 0.96) vs. (−1.54 ± 1.38); p < .001). Fractures a year dicreased significantly (1 (1–2) vs. 0 (0–0.61); p < .001). ZBMDls increase was higher in patients who were able to walk (1.88 ± 0.72 vs. 0.55 ± 0.82; p = .07) and correlated positively with body mass index (BMI)- for- age percentile (rho: 0.564; p < .001). The decrease in the number of fractures a year was higher in patients with lower initial fracture rate (rho: −0,47; p = .006) and with higher initial ZBMDls (rho: −0.47; p = .07). 10 adverse events were reported in 7 patients (22%), all of them intravenous bisphosphonates related. No association was found between adverse events and studied variables. Conclusions Bisphosphonates are effective in secondary osteoporosis in children. Response seems to be better in patients who are able to walk, well-nourished and in the early stages of the disease. Adverse events were frequent but mild.Introducción Los estudios sobre efectividad y seguridad de los bisfosfonatos en osteoporosis infantil secundaria (OIS) son escasos. El objetivo fue analizar efectividad y seguridad de los bisfosfonatos en OIS. Pacientes y métodos Estudio multicéntrico retrospectivo en <18 años afectos de OIS tratados con bisfosfonatos. Se recogieron variables clínicas. Se valoró densidad mineral ósea (DMO) mediante el Z-score de DMO en columna lumbar (ZDMOcl) medido por absorciometría de rayos X de doble energía (DXA). Valoramos efectividad en función del cambio del ZDMOcl al año y a los dos años de su inicio y del descenso del número de fracturas/año. Los eventos adversos reportados fueron recogidos. Se realizó análisis descriptivo y bivariante. Resultados Se reclutaron 32 pacientes. El ZDMOcl se incrementó al año del inicio del tratamiento ((−2,46 ± 0,96) vs. (−1,54 ± 1,38); p < 0,001). El número de fracturas/año disminuyó significativamente (1 (1–2) vs. 0 (0–0,61); p < 0,001). El cambio en el ZDMOcl fue mayor en los pacientes deambulantes (1,88 ± 0,72 vs. 0,55 ± 0,82; p = 0,07) y se correlacionó positivamente con el percentil del IMC (rho: 0,564; p < 0,001). El descenso del número de fracturas/año fue mayor en los pacientes con menor tasa inicial de fracturas (rho: −0,47; p = 0,006) y cuanto mayor era el Z-score inicial (rho: −0,47; p = 0,07). Se reportaron 10 eventos adversos leves en 7 pacientes (22%), todos con bisfosfonatos intravenosos. No se halló relación entre eventos adversos y las variables estudiadas. Conclusiones Los bisfosfonatos son efectivos en OIS. La respuesta parece ser mejor en pacientes deambulantes, bien nutridos y en estadios precoces de la enfermedad. Resultan seguros, siendo los efectos adversos leves, aunque frecuentes

Expert panel consensus recommendations for diagnosis and treatment of secondary osteoporosis in children

Background: Osteoporosis incidence in children is increasing due to the increased survival rate of patients suffering from chronic diseases and the increased use of drugs that can damage bones. Recent changes made to the definition of childhood osteoporosis, along with the lack of guidelines or national consensuses regarding its diagnosis and treatment, have resulted in a wide variability in the approaches used to treat this disease. For these reasons, the Osteogenesis Imperfecta and Childhood Osteoporosis Working Group of the Spanish Society of Pediatric Rheumatology has sounded the need for developing guidelines to standardize clinical practice with regard to this pathology. Methods: An expert panel comprised of 6 pediatricians and 5 rheumatologists carried out a qualitative literature review and provided recommendations based on evidence, when that was available, or on their own experience. The level of evidence was determined for each section using the Oxford Centre for Evidence-based Medicine (CEBM) system. A Delphi survey was conducted for those recommendations with an evidence level of IV or V. This survey was sent to all members of the SERPE. All recommendations that had a level of agreement higher or equal to 70% were included. Results: Fifty-one recommendations, categorized into eight sections, were obtained. Twenty-four of them presented an evidence level 4 or 5, and therefore a Delphi survey was conducted. This was submitted electronically and received a response rate of 40%. All recommendations submitted to the Delphi round obtained a level of agreement of 70% or higher and were therefore accepted. Conclusion: In summary, we present herein guidelines for the prevention, diagnosis and treatment of secondary childhood osteoporosis based on the available evidence and expert clinical experience. We believe it can serve as a useful tool that will contribute to the standardization of clinical practice for this pathology. Prophylactic measures, early diagnosis and a proper therapeutic approach are essential to improving bone health, not only in children and adolescents, but also in the adults they will become in the future

Genome-wide pathway analysis identifies VEGF pathway association with oral ulceration in systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) is a genetically complex rheumatic disease characterized by heterogeneous clinical manifestations of unknown etiology. Recent studies have suggested the existence of a genetic basis for SLE heterogeneity. The objective of the present study was to identify new genetic variation associated with the clinically relevant phenotypes in SLE. Methods: A two-stage pathway-based approach was used to identify the genetic variation associated with the main clinical phenotypes in SLE. In the discovery stage, 482 SLE patients were genotyped using Illumina Human Quad610 microarrays. Association between 798 reference genetic pathways from the Molecular Signatures Database and 11 SLE phenotypes was tested using the set-based method implemented in PLINK software. Pathways significantly associated after multiple test correction were subsequently tested for replication in an independent cohort of 425 SLE patients. Using an in silico approach, we analyzed the functional effects of common SLE therapies on the replicated genetic pathways. The association of known SLE risk variants with the development of the clinical phenotypes was also analyzed. Results: In the discovery stage, we found a significant association between the vascular endothelial growth factor (VEGF) pathway and oral ulceration (P value for false discovery rate (P FDR) < 0.05), and between the negative regulation signaling pathway of retinoic acid inducible gene-I/melanoma differentiation associated gene 5 and the production of antinuclear antibodies (P FDR < 0.05). In the replication stage, we validated the association between the VEGF pathway and oral ulceration. Therapies commonly used to treat mucocutaneous phenotypes in SLE were found to strongly influence VEGF pathway gene expression (P = 4.60e-4 to 5.38e-14). Analysis of known SLE risk loci identified a strong association between PTPN22 and the risk of hematologic disorder and with the development of antinuclear antibodies. Conclusions: The present study has identified VEGF genetic pathway association with the risk of oral ulceration in SLE. New therapies targeting the VEGF pathway could be more effective in reducing the severity of this phenotype. These findings represent a first step towards the understanding of the genetic basis of phenotype heterogeneity in SLE

Effectiveness and safety of bisphosphonates therapy in secondary osteoporosis in children Efectividad y seguridad de los bisfosfonatos en el tratamiento de la osteoporosis infantil secundaria

Introduction: There are few studies on effectiveness and safety of bisphosphonate therapy in secondary osteoporosis in children. The aim of this research was to analyse effectiveness and safety of bisphosphonates in secondary osteoporosis in children. Patients and methods: Multicentre retrospective study in patients younger than 18 suffering from secondary osteoporosis and who had received bisphosphonates. Clinical data were recorded. Bone mineral density was assessed in terms of bone mineral density Z-score in lumbar spine (ZBMDls) measured by dual-energy X-ray absorptiometry (DXA). Effectiveness was valued at changes in ZBMDls one and two years after the onset of bisphosphonates and at the decrease in the number of fractures a year. Adverse events reported were recorded. Descriptive and bivariant analysis were performed. Results: 32 patients were recruited. ZBMDls increased one year after the onset of treatment ([−2.46 ± 0.96] vs. [−1.54 ± 1.38]; p <.001). Fractures a year decreased significantly (1 [1-2] vs. 0 [0-0.61]; p <, 001). ZBMDls increase was higher in patients who were able to walk (1.88 ± 0.72 vs. 0.55 ± 0.82; p =.07) and correlated positively with body mass index (BMI) for age percentile (rho: 0.564; p <.001). The decrease in the number of fractures a year was higher in patients with lower initial fracture rate (rho: −0.47; p =.006) and with higher initial ZBMDls (rho: −0.47; p =.07). 10 adverse events were reported in 7 patients (22%), all of them intravenous bisphosphonates related. No association was found between adverse events and studied variables. Conclusions: Bisphosphonates are effective in secondary osteoporosis in children. Response seems to be better in patients who are able to walk, well-nourished and in the early stages of the disease. Adverse events were frequent but mild

Effectiveness and safety of bisphosphonates therapy in secondary osteoporosis in children.

There are few studies on effectiveness and safety of bisphosphonate therapy in secondary osteoporosis in children. The aim of this research was to analyse effectiveness and safety of bisphosphonates in secondary osteoporosis in children. Multicentre retrospective study in patients younger than 18 suffering from secondary osteoporosis and who have received bisphosphonates. Clinical data were recorded. Bone mineral density (BMD) was assessed in terms of BMD Z-score in lumbar spine (ZBMDls) measured by dual-energy X-ray absorptiometry (DXA). Effectiveness was valued at changes in ZBMDls one and two years after the onset of bisphosphonates and at the decrese in the number of fractures a year. Adverse events reported were recorded. Descriptive and bivariant analysis was performed. 32 patients were recruited. ZBMDls increased one year after the onset of treatment ((-2.46 ± 0.96) vs. (-1.54 ± 1.38); p Bisphosphonates are effective in secondary osteoporosis in children. Response seems to be better in patients who are able to walk, well-nourished and in the early stages of the disease. Adverse events were frequent but mild

A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA. Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses. Results: A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response (P < 0.05). At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (P = 0.0015) and infliximab (P = 0.021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (P = 0.0019). The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (P = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (P = 0.041). Conclusions: These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA

A combined transcriptomic and genomic analysis identifies a gene signature associated with the response to anti-TNF therapy in rheumatoid arthritis

Background: Rheumatoid arthritis (RA) is the most frequent autoimmune disease involving the joints. Although anti-TNF therapies have proven effective in the management of RA, approximately one third of patients do not show a significant clinical response. The objective of this study was to identify new genetic variation associated with the clinical response to anti-TNF therapy in RA. Methods: We performed a sequential multi-omic analysis integrating different sources of molecular information. First, we extracted the RNA from synovial biopsies of 11 RA patients starting anti-TNF therapy to identify gene coexpression modules (GCMs) in the RA synovium. Second, we analyzed the transcriptomic association between each GCM and the clinical response to anti-TNF therapy. The clinical response was determined at week 14 using the EULAR criteria. Third, we analyzed the association between the GCMs and anti-TNF response at the genetic level. For this objective, we used genome-wide data from a cohort of 348 anti-TNF treated patients from Spain. The GCMs that were significantly associated with the anti-TNF response were then tested for validation in an independent cohort of 2,706 anti-TNF treated patients. Finally, the functional implication of the validated GCMs was evaluated via pathway and cell type epigenetic enrichment analyses. Results: A total of 149 GCMs were identified in the RA synovium. From these, 13 GCMs were found to be significantly associated with anti-TNF response (P < 0.05). At the genetic level, we detected two of the 13 GCMs to be significantly associated with the response to adalimumab (P = 0.0015) and infliximab (P = 0.021) in the Spain cohort. Using the independent cohort of RA patients, we replicated the association of the GCM associated with the response to adalimumab (P = 0.0019). The validated module was found to be significantly enriched for genes involved in the nucleotide metabolism (P = 2.41e-5) and epigenetic marks from immune cells, including CD4+ regulatory T cells (P = 0.041). Conclusions: These findings show the existence of a drug-specific genetic basis for anti-TNF response, thereby supporting treatment stratification in the search for response biomarkers in RA

Genome-wide association study meta-analysis identifies five new loci for systemic lupus erythematosus

Background: Systemic lupus erythematosus (SLE) is a common systemic autoimmune disease with a complex genetic inheritance. Genome-wide association studies (GWAS) have significantly increased the number of significant loci associated with SLE risk. To date, however, established loci account for less than 30% of the disease heritability and additional risk variants have yet to be identified. Here we performed a GWAS followed by a meta-analysis to identify new genome-wide significant loci for SLE. Methods: We genotyped a cohort of 907 patients with SLE (cases) and 1524 healthy controls from Spain and performed imputation using the 1000 Genomes reference data. We tested for association using logistic regression with correction for the principal components of variation. Meta-analysis of the association results was subsequently performed on 7,110,321 variants using genetic data from a large cohort of 4036 patients with SLE and 6959 controls of Northern European ancestry. Genetic association was also tested at the pathway level after removing the effect of known risk loci using PASCAL software. Results: We identified five new loci associated with SLE at the genome-wide level of significance (p < 5 × 10− 8): GRB2, SMYD3, ST8SIA4, LAT2 and ARHGAP27. Pathway analysis revealed several biological processes significantly associated with SLE risk: B cell receptor signaling (p = 5.28 × 10− 6), CTLA4 co-stimulation during T cell activation (p = 3.06 × 10− 5), interleukin-4 signaling (p = 3.97 × 10− 5) and cell surface interactions at the vascular wall (p = 4.63 × 10− 5). Conclusions: Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci.This study was funded by the Spanish Ministry of Economy and Competitiveness (grant numbers: PSE-010000-2006-6 and IPT-010000-2010-36). This work has been also sponsored by the grant SEV-2011-00067 of Severo Ochoa Program, awarded by the Spanish Government. This work was supported by an EFSD/Lilly research fellowship. Josep M. Mercader was supported by Sara Borrell Fellowship from the Instituto Carlos III. Sílvia Bonàs was awarded an FI-DGR Fellowship from FI-DGR 2013 from Agència de Gestió d’Ajuts Universitaris i de Recerca (AGAUR, Generalitat de Catalunya)