Disease phenotype and outcome depending on the age at disease onset in patients carrying the R92Q low-penetrance variant in TNFRSF1A gene

BACKGROUND: Tumor necrosis factor receptor-associated periodic syndrome (TRAPS) is an autosomal-dominant autoinflammatory disease caused by mutations in the TNFRSF1A gene. R92Q, a low-penetrance variant, is usually associated with a milder TRAPS phenotype than structural or pathogenic mutations. No studies differentiating R92Q-related disease in patients with pediatric and adult onset have been performed to date. OBJECTIVE: To analyze clinical features and disease outcomes in patients diagnosed with TRAPS associated with R92Q variant and to investigate differences between patients with pediatric and adult disease onset. METHODS: A retrospective review of patients with R92Q-related disease from four reference centers for autoinflammatory diseases was performed. Clinical and laboratory features, family history of autoinflammatory diseases, treatments received, and outcomes during follow-up were recorded and separately analyzed in pediatric and adult patients. Our results were included in the analysis with other reported pediatric and adult R92Q-related disease series. RESULTS: Our series encompassed 18 patients (9 females and 9 males) with R92Q variant. In 61% of patients, disease onset occurred during infancy and in 39%, during adulthood, with a median diagnostic delay of 5 years and a follow-up of 5.4 years. A positive family history of autoinflammatory disease was detected in 28% of patients. All patients presented with febrile recurrent episodes. Other common symptoms included arthralgia/arthritis (61%), myalgia (39%), asthenia/fatigue (44%), abdominal pain (39%), headache (33%), odynophagia (33%), skin rash (28%), and chest pain (22%). During attacks, 80% of patients increased acute phase reactants levels. No patient had developed amyloidosis during the study period. At the end of follow-up, 28% of patients were asymptomatic and treatment free, 50% were receiving non-steroidal anti-inflammatory drugs or glucocorticoids on demand, and 22% were being treated with biologic agents. When differences between pediatric and adult patients were globally analyzed, adults tended to have longer attacks duration and presented more frequently with chest pain and headache, while abdominal pain, vomiting, cervical adenitis, and pharyngitis predominated in pediatric patients. No differences in outcomes and treatment requirements were observed in both age groups. CONCLUSION: This study has contributed to characterize R92Q-related disease by identifying trends in disease phenotypes depending on the age at disease onset

The incidence of clinical fractures in adults aged 50 years and older in Spain

Objective. The aim of this study was to quantify the incidence of all clinical fractures, including traumatic and fragility fractures, in patients aged 50 years and older, and to describe their distribution by fracture location, sex and age. Methods. The incidence of clinical fractures at 10 hospitals in Catalonia, with a reference population of 3 155 000 inhabitants, was studied. For 1 week, from 30 May to 5 June 2016, we reviewed the discharge reports of the Traumatology section of the Emergency Department to identify all fractures diagnosed in patients ≥50 years of age. As a validation technique, data collection was carried out for 1 year at one of the centres, from 1 December 2015 to 30 November 2016. The fracture incidence, including the 95% CI, was estimated for the entire sample and grouped by fracture type, location, sex and age. Results. A total of 283 fractures were identified. Seventy per cent were in women, with a mean age of 72 years. The overall fracture incidence was 11.28 per 1000 person-years (95% CI: 11.10, 11.46), with an incidence of traumatic and fragility fractures of 4.15 (95% CI: 4.04, 4.26) and 7.13 per 1000 person-years (95% CI: 6.99, 7.28), respectively. The incidence of fractures observed in the validation sample coincided with that estimated for the whole of Catalonia. The most common fragility fractures were of the hip, forearm, humerus and vertebrae. Conclusion. The results of this study are the first to estimate the incidence of clinical fragility fractures in Spain, grouped by location, age and sex

High incidence of clinical fragility fractures in postmenopausal women with rheumatoid arthritis. A case-control study.

Objectives: To estimate the incidence of clinical fragility fractures in postmenopausal women with rheumatoid arthritis (RA) and analyze risk factors for fracture. Methods: Incidence of clinical fragility fractures in 330 postmenopausal women with RA was compared to that of a control population of 660 age-matched postmenopausal Spanish women. Clinical fractures during the previous five years were recorded. We analyzed associations with risk factors for fracture in both populations and with disease-related variables in RA patients. Results: Median age of RA patients was 64 years; median RA duration was eight years. Sixty-nine percent were in remission or on low activity. Eighty-five percent had received glucocorticoids (GCs); 85 %, methotrexate; and 40 %, ≥1 biologic DMARD. Fifty-four patients and 47 controls had ≥1 major osteoporotic fracture (MOF). Incidence of MOFs was 3.55 per 100 patient-year in patients and 0.72 in controls (HR: 2.6). Risk factors for MOFs in RA patients were age, previous fracture, parental hip fracture, years since menopause, BMD, erosions, disease activity and disability, and cumulative dose of GCs. Previous fracture in RA patients was a strong risk for MOFs (HR: 10.37). Conclusion: Of every 100 postmenopausal Spanish women with RA, 3-4 have a MOF per year. This is more than double that of the general population. A previous fracture poses a high risk for a new fracture. Other classic risk factors for fracture, RA disease activity and disability, and the cumulative dose of GCs are associated with fracture development

Centrality evolution of the charged-particle pseudorapidity density over a broad pseudorapidity range in Pb-Pb collisions at root s(NN)=2.76TeV

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Anticuerpos frente a péptidos carbamilados en la artritis reumatoide: Papel en el reumatismo palindrómico, la enfermedad pulmonar intersticial y la respuesta terapéutica

[spa] INTRODUCCIÓN: La artritis reumatoide (AR) es una de las enfermedades autoinmunes más frecuentes y la forma de artritis inflamatoria más común afectando en torno al 1% de la población mundial. Además, es una enfermedad sistémica de naturaleza autoinmune, que se caracteriza por inflamación articular y la presencia de autoanticuerpos, como los anticuerpos contra péptidos citrulinadas (ACPA). Los ACPA constituyen un biomarcador de mal pronóstico. La AR es un síndrome heterogéneo, con diferentes mecanismos patogénicos involucrados entre individuos con el mismo diagnóstico. De hecho, aunque los autoanticuerpos son una característica importante de la AR, hasta en un 30% de individuos no se detectan autoanticuerpos. Los anticuerpos contra proteínas carbamiladas (anti-CarP), son una nueva familia de anticuerpos, presentes en el 50% aproximadamente de pacientes con AR, incluso en aquellos negativos para otros anticuerpos. También, los anti-CarP se relacionan con un peores desenlaces de la enfermedad. Es probable que existan factores pronósticos relacionados con los anti-CarP aún no establecidos que podrían tener relevancia para la población con AR. En esta tesis doctoral hipotetizamos que los anti- CarP se detectan en formas tempranas de AR, como en el reumatismo palindrómico (RP), que su presencia en la AR establecida puede condicionar a complicaciones tales como la enfermedad pulmonar intersticial (EPI), y que podría ser un biomarcador de buena respuesta para agentes como el Abatacept (ABA). OBJETIVOS: Los objetivos de esta tesis son: 1) Analizar la prevalencia de anti-CarP en pacientes con RP y comparar su respuesta inmune contra a proteínas carbamiladas frente a la de la AR establecida; 2) Analizar la relación entre los anti-CarP y la enfermedad pulmonar intersticial en pacientes con A; 3) Determinar el papel de los anti-CarP como biomarcador de respuesta terapéutica a ABA en pacientes con AR. METODOLOGÍA Y RESULTADOS: Para responder todos estos objetivos, se diseñaron 4 estudios. En el primer trabajo realizamos un estudio transversal para determinar la presencia de anti-CarP en una cohorte de pacientes con RP. En esta cohorte, los anti-CarP fueron positivos en el 24% los pacientes con RP. Al comparar con la AR, observamos que todas las proporciones de isotipos anti-CarP fueron significativamente más bajas en RP. En cuanto a la distribución de los isotipos, la respuesta de IgG anti-CarP fue similar en ambos grupos (100% en RP vs 79% en AR), pero la respuesta de isotipos fue significativamente menor en la IgA (31% vs 53%) e IgM (31% vs 56%) en pacientes con RP. En el segundo trabajo, analizamos la presencia de RP preexistente en una cohorte de AR establecida, y analizamos si existe un perfil de anticuerpos distintivos en estos pacientes. Encontramos que el 18% de los pacientes con AR presentaban una historia compatible de RP previo al debut de su enfermedad. Al analizar el perfil serológico, la positividad de anticuerpos fue numéricamente más alta para los pacientes con RP preexistente, incluido los Anti-CarP (52% vs 45%) aunque las diferencias no fueron estadísticamente significativas. En el tercer trabajo, realizamos en un estudio transversal sobre una cohorte de paciente con AR con y sin EPI, además de una serie de replicación de otro centro hospitalario. Observamos que todas la especificidades de anti-CarP medidas eran frecuentes en el grupo EPI-AR (Anti-FCS 70% vs.43%; Anti-Fib 73% vs.51%; Anti-CFFHP 38% vs.19%; Anti-CarP- IgA 51% vs.20%, p <0.05). El análisis de regresión logística multivariante demostró que todas las especificidades de anti-CarP mostraron un efecto robusto para aumentar las probabilidades de EPI tanto en la cohorte principal como en la serie de replicación. Para el cuarto trabajo, realizamos un estudio prospectivo, sobre una cohorte multicéntrica de paciente con AR tratados con ABA. Entre los 65 pacientes que fueron analizados, 43% de ellos eran anti-CarP positivos. A los tres meses de seguimiento, observamos que los pacientes positivos para los anti-CarP mostraron una reducción significativa en la actividad de la enfermedad, medida por δ-DAS28 (- 1,904 vs -0,212) en comparación con los anti-CarP negativos. Además, aquellos pacientes catalogados como respondedores presentaban niveles de anti-CarP basales más altos, y se observó una reducción significativa de dichos anticuerpos tras 3 meses de tratamiento. CONCLUSION: Con estos estudios hemos logrado avanzar un poco en el conocimiento del papel de los anti-CarP en el RP, EPI relacionada a la AR y en la respuesta terapéutica del ABA.[eng] INTRODUCTION: Rheumatoid arthritis (RA) is one of the most common autoimmune diseases, characterized by joint inflammation and the presence of autoantibodies, such as antibodies against citrullinated peptides (ACPA). ACPAs are a poor prognostic biomarker. RA is a heterogeneous syndrome, with different pathogenic mechanisms involved between individuals with the same diagnosis. Antibodies against carbamylated proteins (anti-CarP) are a new family of antibodies, present in approximately 50% of patients. OBJECTIVES: 1) To analyze the prevalence of anti-CarP in patients with palindromic rheumatism (PR) and to compare their immune response against that of established RA; 2) To analyze the relationship between anti-CarP and interstitial lung disease(ILD); 3) To determine the role of anti-CarP as a biomarker of therapeutic response to abatacept (ABA). METHODOLOGY AND RESULTS: To answer these objectives, 4 studies were designed. In the first, a cross-sectional study to determine the presence of anti-CarP in a cohort of patients with PR. Anti-CarP were positive in 24% of PR patients. When comparing with RA, all the proportions of Anti-CarP isotypes were significantly lower in PR. Regarding the isotypes distribution, IgG anti-CarP was similar in both groups (100% vs 79%) but was significantly lower in IgA (31% vs 53% ) and IgM (31% vs 56%) in patients with RP. In the second study, we analyzed the presence of pre-existing RP in an established RA cohort, and whether they had a distinctive antibody profile. 18% of patients had a compatible history of PR prior to RA diagnosis. Antibody positivity was numerically higher for patients with pre-existing PR, including Anti-CarP (52% vs 45%). In the third study, we conducted a cross-sectional study on two cohorts of patients with RA with and without ILD. All Anti-CarP specificities were more frequent in the ILD-RA group (Anti-FCS 70% vs. 43%; Anti- Fib 73% vs. 51%; Anti-CFFHP 38% vs. 19%; Anti -CarP-IgA 51% vs. 20%, p <0.05). Multivariate analysis demonstrated that all Anti-CarP had a robust effect towards increasing the odds of ILD. For the fourth work, was a prospective study of RA patients treated with ABA. 43% of them were Anti-CarP positive. After 3 months of follow-up, patients positive for anti-CarP showed a significant reduction in disease activity compared to negative anti-CarP. Also, those patients classified as responders had higher baseline anti-CarP levels, and a significant reduction in these antibodies was observed after 3 months of treatment

Peptides Bearing Multiple Post-Translational Modifications as Antigenic Targets for Severe Rheumatoid Arthritis Patients

Rheumatoid arthritis (RA) is characterized by the presence of autoantibodies that are of paramount importance for the diagnosis and prognosis of the disease and have been implicated in its pathogenesis. Proteins resulting from post-translational modifications (PTMs) are capable of triggering autoimmune responses important for the development of RA. In this work, we investigate serum antibody reactivity in patients with an established RA against a panel of chimeric peptides derived from fibrin and filaggrin proteins and bearing from one to three PTMs (citrullination, carbamylation and acetylation) by home-designed ELISA tests (anti-AMPA autoantibodies). The role of anti-AMPAs as biomarkers linked to the presence of a more severe RA phenotype (erosive disease with radiological structural damage) and to the presence of interstitial lung disease (ILD), a severe extra-articular manifestation in RA patients entailing a high mortality, was also analyzed. In general, the association with the clinical phenotype of RA was confirmed with the different autoantibodies, and especially for IgA and IgM isotypes. The prevalence of severe joint damage was only statistically significant for the IgG isotype when working with the peptide bearing three PTMs. Furthermore, the median titers were significantly higher in patients with RA-ILD, a finding not observed for the IgG isotype when working with the single- and double-modified peptides.This research was funded by the Spanish Ministry of Economy, Industry and Competitiveness, and the European Regional Development Fund (Grant No. RTI2018-094120-B-I00)Peer reviewe

Anti-carbamylated proteins antibody repertoire in rheumatoid arthritis: Evidence of a new autoantibody linked to interstitial lung disease

Objective: To analyse the association between anti-carbamylated protein antibodies (Anti-CarP) and interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients. Methods: Cross-sectional study including RA patients fulfilling the 2010 ACR/EULAR criteria. The main population comprised two groups: (1) RA patients diagnosed with RA-ILD (RA-ILD group); (2) RA patients without ILD (non-ILD RA group). Non-ILD RA patients in whom ILD was suspected underwent a diagnostic work-up and, if ILD was diagnosed, were switched to the RA-ILD group. ILD was diagnosed by high-resolution computed tomography and confirmed by a multidisciplinary committee. An independent replication sample was also obtained. Three Anti-CarP IgG autoantibodies against fetal calf serum (Anti-FCS), fibrinogen (Anti-Fib) and chimeric fibrine/filagrine homocitrullinated peptide (Anti-CFFHP) and one Anti-CarP IgA against FCS (Anti-FCS-IgA) were determined by home-made ELISA. Associations between Anti-CarP and ILD were analysed using multivariable logistic regression adjusted by smoking, sex, age, RA disease duration, rheumatoid factor and anticitrullinated protein antibodies. Results: We enrolled 179 patients: 37 (21%) were finally diagnosed with RA-ILD. Anti-CarP specificities were more frequent in RA-ILD patients (Anti-FCS 70% vs 43%; Anti-Fib 73% vs 51%; Anti-CFFHP 38% vs 19%; Anti-CarP-IgA 51% vs 20%, p<0.05 for all comparisons). Serum titers of Anti-CarP were significantly higher in RA-ILD patients. Anti-CarP specificities showed a robust effect towards increasing the odds of ILD in the multivariate analysis (Anti-FCS (OR: 3.42; 95% CI: 1.13 to 10.40), Anti-Fib (OR: 2.85; 95% CI: 0.83 to 9.70), Anti-CFFHP (OR: 3.11; 95% CI: 1.06 to 9.14) and Anti-FCS-IgA (OR: 4.30; 95% CI: 1.41 to 13.04)). Similar findings were observed in the replication sample. Conclusions: Anti-CarP were strongly associated with ILD. The role of homocitrullination in RA-ILD merits further investigation. © Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.Financial support from the Hospital Clinic of Barcelona, Research, Innovation and Education Department (Grant # 37 933 to RC-M and the Spanish Ministry of Economy, Industry and Competitiveness and the European Regional Development Fund (Grant # RTI2018-094120-B-I00 to IH).Peer reviewe

Interactions between rheumatoid arthritis antibodies are associated with the response to anti-tumor necrosis factor therapy

Background Blocking of the Tumor Necrosis Factor (TNF) activity is a successful therapeutic approach for 50–60% of rheumatoid arthritis (RA) patients. However, there are yet no biomarkers to stratify patients for anti-TNF therapy. Rheumatoid factor (RF) and anti-cyclic-citrullinated antibodies (anti-CCP) have been evaluated as biomarkers of response but the results have shown limited consistency. Anti-carbamylated protein (anti-CarP) and anti-peptidylarginine deiminase type 4 (anti-PAD4) antibodies have been much less studied. Despite being linked to common immune processes, the interaction between these markers has not been evaluated yet. Our aim was to analyze the interaction between these four antibodies in relation to the response to anti-TNF therapy. Methods For this objective, a prospective cohort of n = 80 RA patients starting anti-TNF therapy was recruited. Serum determinations at baseline were performed for RF, anti-CCP, anti-CarP and anti-PAD4 antibodies using enzyme-linked immunosorbent assays (ELISA). The clinical response to anti-TNF therapy was determined at week 12 using the change in DAS28 score. Association was performed using multivariate linear regression adjusting for baseline DAS28, sex and age. Results The interaction between pairs of antibodies was tested by the addition of an interaction term. We found two highly significant antibody interactions associated with treatment response: anti-CarP with anti-PAD4 (p = 0.0062), and anti-CCP with RF (p = 0.00068). The latter antibody interaction was replicated in an independent retrospective cohort of RA patients (n = 199, p = 0.04). Conclusions The results of this study suggest that antibody interaction effects are important factors in the response to anti-TNF therapy in RA.This project was supported by UCB Pharma. The funders had no role in the study design, data analysis, data interpretation or writing the manuscript.Peer reviewe

Measurement of Λ(1520) production in pp collisions at √s = 7 TeV and p–Pb collisions at √sNN = 5.02 TeV

The production of the Λ(1520) baryonic resonance has been measured at midrapidity in inelastic pp collisions at s√ = 7 TeV and in p-Pb collisions at sNN−−−√ = 5.02 TeV for non-single diffractive events and in multiplicity classes. The resonance is reconstructed through its hadronic decay channel Λ(1520) → pK− and the charge conjugate with the ALICE detector. The integrated yields and mean transverse momenta are calculated from the measured transverse momentum distributions in pp and p-Pb collisions. The mean transverse momenta follow mass ordering as previously observed for other hyperons in the same collision systems. A Blast-Wave function constrained by other light hadrons (π, K, K0S, p, Λ) describes the shape of the Λ(1520) transverse momentum distribution up to 3.5 GeV/c in p-Pb collisions. In the framework of this model, this observation suggests that the Λ(1520) resonance participates in the same collective radial flow as other light hadrons. The ratio of the yield of Λ(1520) to the yield of the ground state particle Λ remains constant as a function of charged-particle multiplicity, suggesting that there is no net effect of the hadronic phase in p-Pb collisions on the Λ(1520) yield