A young girl with severe polyarteritis nodosa successfully treated with tocilizumab: a case report

Child; Polyarteritis nodosa; TocilizumabNena; Poliarteritis nodosa; TocilizumabNiña; Poliarteritis nodosa; TocilizumabBackground Childhood Polyarteritis nodosa (PAN) is a systemic vasculitis with necrotizing inflammation of medium- and small-sized arteries. Disease evolution may be severe and refractory to standard treatment including prednisone, azathioprine and cyclophosphamide. Case presentation We present the case of a young girl with severe PAN resulting in progressive ischemia and necrosis of fingers and toes. Biological work-up revealed increased acute phase reactants and interleukin-6 levels. She was only partially controlled despite high-dose corticosteroids and cyclophosphamide infusions, and eventually achieved rapid improvement and sustained remission on tocilizumab. Further, we review the current evidence of the interleukin-6-inhibitor tocilizumab for the treatment of PAN. Conclusion Tocilizumab may be an efficient therapeutic option in a subset of treatment-refractory children with PAN

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

Targeting of the CD80/86 proinflammatory axis as a therapeutic strategy to prevent severe COVID-19

Coronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Malalties inflamatòries; Identificació de l'objectiu; Infecció viralCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Enfermedades inflamatorias; Identificación del objetivo; Infección viralCoronavirus SARS-CoV-2; COVID-19; 2019-nCoV; Inflammatory diseases; Target identification; Viral infectionAn excessive immune response known as cytokine storm is the hallmark of severe COVID-19. The cause of this cytokine rampage is yet not known. Based on recent epidemiological evidence, we hypothesized that CD80/86 signaling is essential for this hyperinflammation, and that blocking this proinflammatory axis could be an effective therapeutic approach to protect against severe COVID-19. Here we provide exploratory evidence that abatacept, a drug that blocks CD80/86 co-stimulation, produces changes at the systemic level that are highly antagonistic of the proinflammatory processes elicited by COVID-19. Using RNA-seq from blood samples from a longitudinal cohort of n = 38 rheumatic patients treated with abatacept, we determined the immunological processes that are significantly regulated by this treatment. We then analyzed available blood RNA-seq from two COVID19 patient cohorts, a very early cohort from the epicenter of the pandemic in China (n = 3 COVID-19 cases and n = 3 controls), and a recent and larger cohort from the USA (n = 49 severe and n = 51 mild COVD-19 patients). We found a highly significant antagonism between SARS-CoV-2 infection and COVID-19 severity with the systemic response to abatacept. Analysis of previous single-cell RNA-seq data from bronchoalveolar lavage fluid from mild and severe COVID-19 patients and controls, reinforce the implication of the CD80/86 proinflammatory axis. Our functional results further support abatacept as a candidate therapeutic approach to prevent severe COVID-19.The PACTABA project was funded Bristol-Myers Squibb. We thank all participants from the PACTABA study for their collaboration. AJ and SM are supported by the DoCTIS project funded by the European Union’s H2020 programme (Grant #848028). This work was supported by funds from the Vall d’Hebron Hospital Research Institute and from IMIDomics S.L. We thank Dr Ariel Jaitovich (Albany Medical Centre, USA) for providing additional clinical data on the late COVID-19 cohort

Impact of JAK Inhibitors in Pediatric Patients with STAT1 Gain of Function (GOF) Mutations-10 Children and Review of the Literature.

Since the first description of gain of function (GOF) mutations in signal transducer and activator of transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, their indications, dosing, and monitoring remain to be established. A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Ten children (median age 8.5 years (3-18), receiving JAKinibs (ruxolitinib (n = 9) and baricitinib (n = 1)) with a median follow-up of 18 months (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patients (previous reports) showed partial or complete responses. The median immune deficiency and dysregulation activity scores were 15.99 (5.2-40) pre and 7.55 (3-14.1) under therapy (p = 0.0078). Infection, considered a likely adverse event of JAKinib therapy, was observed in 1/10 patients; JAKinibs were stopped in 3/10 children, due to hepatotoxicity, pre-HSCT, and absence of response. Our study supports the potentially beneficial use of JAKinibs in patients with STAT1 GOF, in line with previously published data. However, consensus regarding their indications and timing, dosing, treatment duration, and monitoring, as well as defining biomarkers to monitor clinical and immunological responses, remains to be determined, in form of international prospective multicenter studies using established IEI registries

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

**Background:** 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

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 x 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 x 10(-6)), CTLA4 co-stimulation during T cell activation (p = 3.06 x 10(-5)), interleukin-4 signaling (p = 3.97 x 10(-5)) and cell surface interactions at the vascular wall (p = 4.63 x 10(-5)). Conclusions: Our results identify five novel loci for SLE susceptibility, and biologic pathways associated via multiple low-effect-size loci