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

Characterization of pathogenic immune mechanisms in oligoarticular juvenile idiopathic arthritis applying single-cell transcriptomics and proteomics

L'artritis idiopàtica juvenil (AIJ) és una malaltia reumàtica prevalent en nens, que comprèn set subtipus diferents. El subtipus més comú és l'AIJ oligoarticular (AIJo), que representa entre el 30 i el 60% de tots els casos, depenent de les sèries estudiades. Els pacients amb AIJo solen presentar artritis asimètrica i un risc elevat de desenvolupar uveïtis (AIJo-U), un fenotip greu i únic que poques vegades s'observa a l'artritis de l'adult. Mentre que els estudis sobre les cèl·lules T a l'oJIA s'han centrat principalment en les cèl·lules T CD4+ a causa de la seva forta associació amb els al·lels majors d'histocompatibilitat de classe II, la investigació sobre el paper de les cèl·lules T CD8+ a l'oJIA ha estat limitada. A més, cada cop es reconeix més la contribució dels membres del sistema immunitari innat a la patogènesi de l'oJIA. Per caracteritzar quines cèl·lules patògenes del sistema immunitari estan implicades en el desenvolupament de l'oJIA, realitzem anàlisi de seqüenciació de scRNA-Seq i TCR, examinant 132.824 cèl·lules mononuclears (CM) de sang perifèrica (SP) i líquid sinovial (SF) de tres pacients amb oJIA recent diagnosticada. També analitzem PBMC de quatre pacients amb oJIA-U i quatre controls sans (HC) a nivell unicel·lular. Utilitzant seqüenciació d'ARNm unicel·lular encapsulat en perles Chromium 10x Genomics (scRNA-seq), dilucidem diferents clústers cel·lulars no identificats prèviament en aquesta entitat. En una segona etapa, caracteritzem el perfil proteòmic del plasma de pacients amb oJIA recent diagnosticada, oJIA-U, HC i individus amb altres condicions relacionades amb el tractament, l'activitat de la malaltia i malalties com l'AR. Analitzem 235 proteïnes mitjançant l'assaig d'extensió de proximitat (PEA). Les nostres troballes van revelar la presència de monòcits intermedis, cèl·lules T reguladores, cèl·lules T CD8+ activades i cèl·lules T CD8+ de memòria efectores NKG2C+ a l'SF de pacients amb oJIA, cèl·lules no esperades en condicions normals. Es van observar diferències transcripcionals significatives a les cèl·lules T CD8+ de memòria efectores activades ia les cèl·lules T CD8+ de memòria efectores NKG2C+ del SL i la PB dels pacients amb oJIA en comparació amb els HC, mostrant una sobreexpressió dels gens CCL5, GMZA, GZMK, CXCL13, CXCR6, S100A6 i S100A11. En els pacients amb oJIA-U, observem una presència més gran de cèl·lules dendrítiques circulants dels tipus 1 i 4, així com de cèl·lules NK madures, en comparació tant amb els pacients amb oJIA sense uveïtis com amb els controls sans. En concret, les NK madures CD56+ dels pacients amb oJIA-U en comparació amb els pacients sense uveïtis i els HC sobreexpressen PRF1, FECR1G, CCL4 (MIP-1[Beta]) i B2M. L'anàlisi de les proteïnes plasmàtiques mitjançant l'assaig PEA va revelar un augment dels nivells de proteïnes crucials del sistema immunitari innat com FGF-23, TRAIL, C2, IL-18R1 i IL-6 als oJIA en comparació amb els HC. El perfil d'expressió proteica observat és coherent amb la implicació de cèl·lules del sistema immunitari innat com les NK a l'oJIA-U o els monòcits intermedis a l'oJIA. Els pacients en tractament amb antiTNF alfa presentaven majors nivells de TNF alfa. Aquest estudi representa el primer atles unicel·lular d'aquest tipus i proporciona coneixements valuosos sobre la dinàmica cel·lular i els possibles impulsors cel·lulars en el context de l'oJIA i l'oJIA-U. La investigació d'aquestes poblacions cel·lulars pot contribuir a una millor comprensió dels mecanismes subjacents i, en darrer terme, a la millora de les estratègies terapèutiques per a aquestes afeccions.La artritis idiopática juvenil (AIJ) es una enfermedad reumática prevalente en niños, que comprende siete subtipos distintos. El subtipo más común es la AIJ oligoarticular (AIJo), que representa entre el 30 y el 60% de todos los casos, dependiendo de las series estudiadas. Los pacientes con AIJo suelen presentar artritis asimétrica y un riesgo elevado de desarrollar uveítis (AIJo-U), un fenotipo grave y único que rara vez se observa en la artritis del adulto. Mientras que los estudios sobre las células T en la oJIA se han centrado principalmente en las células T CD4+ debido a su fuerte asociación con los alelos mayores de histocompatibilidad de clase II, la investigación sobre el papel de las células T CD8+ en la oJIA ha sido limitada. Además, cada vez se reconoce más la contribución de los miembros del sistema inmunitario innato en la patogénesis de la oJIA. Para caracterizar qué células patógenas del sistema inmunitario están implicadas en el desarrollo de la oJIA, realizamos análisis de secuenciación de scRNA-Seq y TCR, examinando 132.824 células mononucleares (CM) de sangre periférica (SP) y líquido sinovial (SF) de tres pacientes con oJIA recién diagnosticada. También analizamos PBMC de cuatro pacientes con oJIA-U y cuatro controles sanos (HC) a nivel unicelular. Utilizando secuenciación de ARNm unicelular encapsulado en perlas Chromium 10x Genomics (scRNA-seq), dilucidamos diferentes clusters celulares no identificados previamente en esta entidad. En una segunda etapa, caracterizamos el perfil proteómico del plasma de pacientes con oJIA recién diagnosticada, oJIA-U, HC e individuos con otras condiciones relacionadas con el tratamiento, la actividad de la enfermedad y enfermedades como la AR. Analizamos 235 proteínas mediante el ensayo de extensión de proximidad (PEA). Nuestros hallazgos revelaron la presencia de monocitos intermedios, células T reguladoras, células T CD8+ activadas y células T CD8+ de memoria efectoras NKG2C+ en el SF de pacientes con oJIA, células no esperadas en condiciones normales. Se observaron diferencias transcripcionales significativas en las células T CD8+ de memoria efectoras activadas y en las células T CD8+ de memoria efectoras NKG2C+ del SL y la PB de los pacientes con oJIA en comparación con los HC, mostrando una sobreexpresión de los genes CCL5, GMZA, GZMK, CXCL13, CXCR6, S100A6 y S100A11. En los pacientes con oJIA-U, observamos una mayor presencia de células dendríticas circulantes de los tipos 1 y 4, así como de células NK maduras, en comparación tanto con los pacientes con oJIA sin uveítis como con los controles sanos. En concreto, las NK maduras CD56+ de los pacientes con oJIA-U en comparación con los pacientes sin uveítis y los HC sobreexpresan PRF1, FECR1G, CCL4 (MIP-1[Beta]) y B2M. El análisis de las proteínas plasmáticas mediante el ensayo PEA reveló un aumento de los niveles de proteínas cruciales del sistema inmunitario innato como FGF-23, TRAIL, C2, IL-18R1 e IL-6 en los oJIA en comparación con los HC. El perfil de expresión proteica observado es coherente con la implicación de células del sistema inmunitario innato como las NK en la oJIA-U o los monocitos intermedios en la oJIA. Los pacientes en tratamiento con anti-TNF alfa presentaban mayores niveles de TNF alfa. Este estudio representa el primer atlas unicelular de este tipo y proporciona valiosos conocimientos sobre la dinámica celular y los posibles impulsores celulares en el contexto de la oJIA y la oJIA-U. La investigación de estas poblaciones celulares puede contribuir a una mejor comprensión de los mecanismos subyacentes y, en última instancia, a la mejora de las estrategias terapéuticas para estas afecciones.Juvenile idiopathic arthritis (JIA) is a prevalent rheumatic disease in children, comprising seven distinct subtypes. The most common subtype is oligoarticular JIA (oJIA), which accounts for 30-60% of all cases depending on the series studied. oJIA patients typically experience asymmetrical arthritis and have an elevated risk of developing uveitis (oJIA-U), a severe and unique phenotype rarely seen in adult arthritis. While studies on T cells in oJIA have mainly focused on CD4+ T cells due to their strong association with major histocompatibility class II alleles, research on the role of CD8+ T cells in oJIA has been limited. Although CD8+ T cells have been described in the synovium of rheumatoid arthritis (RA) and have been implicated in germinal center formation, their role in oJIA remains understudied. In addition, the contribution of members of the innate immune system in the pathogenesis of oJIA is increasingly recognized. To characterize which pathogenic cells of the immune system are involved in the development of oJIA, we performed scRNA-Seq and TCR sequencing analysis, examining 132,824 peripheral blood (PB) and synovial fluid (SF) mononuclear cells (MCs) from three patients with newly diagnosed oJIA. We also analyzed PBMCs from four patients with oJIA-U and four healthy controls (HCs) at the single-cell level. Using single-cell mRNA sequencing encapsulated in Chromium 10x Genomics beads (scRNA-seq), we elucidated different cellular clusters not previously identified in this entity. In a second stage, we characterized the proteomic profile of plasma from patients with newly diagnosed oJIA, oJIA-U, HCs, and individuals with other conditions related to treatment, disease activity, and diseases such as RA. We analyzed 235 proteins using the proximity extension assay (PEA). Our findings revealed the presence of intermediate monocytes, regulatory T cells, activated CD8+ T cells and NKG2C+ effector memory CD8+ T cells in the SF of oJIA patients, cells not expected in normal conditions. Conversely, these cell populations showed reduced levels in the PB of oJIA patients compared to controls. This observation suggests the active recruitment of these cell types from blood into the inflamed synovium of oJIA patients and their importance in the pathology. We observed significant transcriptional differences in activated effector memory CD8+ T cells and NKG2C+ effector memory CD8+ T cells from FS and PB of oJIA patients compared to HCs, showing overexpression of CCL5, GMZA, GZMK, CXCL13, CXCR6, S100A6 and S100A11 genes. In patients with oJIA-U, we observed a higher presence of circulating dendritic cells of types 1 and 4, as well as mature NK cells, compared to both oJIA patients without uveitis and healthy controls. At the transcriptional level, the more abundant cells in PB from oJIA-U patients showed a marked up-regulation of type I and III interferon signaling pathway and antigen processing and peptide antigen presentation through MHC class I. Specifically, CD56+ dim mature NKs from patients with oJIA-U compared to patients without uveitis and HCs overexpress PRF1, FECR1G, CCL4 (MIP-1[Beta]), and B2M. Analysis of plasma proteins by PEA assay revealed increased levels of crucial innate immune system proteins such as FGF-23, TRAIL, C2, IL-18R1 and IL-6 in oJIAs compared to HCs. The observed protein expression profile is consistent with the involvement of innate immune system cells such as NKs in oJIA-U or intermediate monocytes in oJIA. Patients on anti-TNF alpha therapy had increased levels of TNF alpha. This study represents the first single-cell atlas of its kind and provide valuable insights into the cellular dynamics and potential cellular drivers in the context of oJIA and oJIA-U. Investigation of these cell populations may contribute to a better understanding of the underlying mechanisms and, ultimately, to the improvement of therapeutic strategies for these conditions

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