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Objective: To estimate cut-off points and to establish response criteria for the Hospital Universitario La Princesa Index (HUPI) in patients with chronic polyarthritis. Methods: Two cohorts, one of early arthritis (Princesa Early Arthritis Register Longitudinal [PEARL] study) and other of long-term rheumatoid arthritis (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide [EMECAR]) including altogether 1200 patients were used to determine cut-off values for remission, and for low, moderate and high activity through receiver operating curve (ROC) analysis. The areas under ROC (AUC) were compared to those of validated indexes (SDAI, CDAI, DAS28). ROC analysis was also applied to establish minimal and relevant clinical improvement for HUPI. Results: The best cut-off points for HUPI are 2, 5 and 9, classifying RA activity as remission if ≤2, low disease activity if >2 and ≤5), moderate if >5 and <9 and high if ≥9. HUPI’s AUC to discriminate between low-moderate activity was 0.909 and between moderate-high activity 0.887. DAS28’s AUCs were 0.887 and 0.846, respectively; both indices had higher accuracy than SDAI (AUCs: 0.832 and 0.756) and CDAI (AUCs: 0.789 and 0.728). HUPI discriminates remission better than DAS28-ESR in early arthritis, but similarly to SDAI. The HUPI cut-off for minimal clinical improvement was established at 2 and for relevant clinical improvement at 4. Response criteria were established based on these cut-off values. Conclusions: The cut-offs proposed for HUPI perform adequately in patients with either early or long term arthritis. [ABSTRACT FROM AUTHOR]

Background: A promising approach for treating Alzheimer's disease relies on the net efflux of the amyloid-β (Aβ) peptide from the brain to peripheral plasma, as a result of plasma Aβ clearance promoted by plasma removal and therapeutic albumin replacement. Objective: To assess the binding of therapeutic albumin (Albutein®, Grifols) to monomeric and aggregated Aβ according to methods previously tested on the interactions between Aβ and research-grade albumin. Methods: Albumin integrity and the interactions with albumin stabilizers (octanoic acid and N-Ac-Trp) were assessed through one-dimensional (1D) 1H-NMR and saturation transfer difference (STD) NMR spectra. The interactions between monomeric Aβ1-40 and albumin were probed by 2D 1H-15 N HSQC spectra of labeled Aβ1-40. The formation of cross-β structured Aβ1-42 assemblies was monitored by ThT fluorescence. The interactions between self-assembled Aβ1-42 and albumin were probed by Trp fluorescence. Results: NMR spectra indicated that both therapeutic and research-grade albumin are similarly well-folded proteins. No significant changes in either HSQC peak position or intensity were observed upon addition of albumin to 15N-labeled Aβ1-40, which rules out binding of albumin to monomeric Aβ with dissociation constant in the μM or lower range. When aggregated Aβ1-42 was added to albumin, quenching of Trp fluorescence was observed, which indicates albumin binding to Aβ1-42 aggregates. The relative potency of therapeutic albumin as an Aβ self-association inhibitor was in the same order of magnitude as research-grade albumin. Conclusions: Albutein® inhibited Aβ self-association by selectively binding Aβ aggregates rather than monomers and by preventing further growth of the Aβ assemblies. [ABSTRACT FROM AUTHOR]

Given the role of CD247 in the response of the T cells, its entailment in autoimmune diseases and in order to better clarify the role of this gene in RA susceptibility, we aimed to analyze CD247 gene variants previously associated with other autoimmune diseases (rs1052237, rs2056626 and rs864537) in a large independent European Caucasian population. However, no evidence of association was found for the analyzed CD247 single-nucleotide polymorphisms (SNPs) with RA and with the presence/absence of anti-cyclic citrullinated polypeptide. We performed a meta-analysis including previously published GWAS data from the rs864537 variant, revealing an overall genome-wide significant association between this CD247 SNP and RA with anti-CCP (OR = 0.90, CI 95% = 0.87–0.93, Poverall = 2.1×10−10). Our results show for first time a GWAS-level association between this CD247 polymorphism and RA risk. [ABSTRACT FROM AUTHOR]

OBJECTIVES: To analyse the differences in the clinical features and characteristics of 123I-labelled 2ß-carbomethoxy-3ß-(4-iodophenyl)-N-(3-fluoropropyl) nortropane (123I-FP-CIT) single photon emission CT (SPECT) imaging among patients with vascular parkinsonism (VP) and Parkinson's disease (PD). METHODS: We performed a case-control study to compare clinical features and qualitative and semi-quantitative analyses of 123I-FP-CIT SPECT images between 106 patients with VP and 280 patients with PD. A case series study was used to search for clinical features related to SPECT or neuroimaging findings among patients with VP. RESULTS: Patients with VP had a higher age at symptom onset and lower disease duration than patients with PD. The most frequent symptom at onset was gait disorder in VP and tremor in PD. Gait disorder, postural instability and falls were more frequent in VP. Rest and mixed tremor were more prevalent in PD. Of the patients who received levodopa treatment in the VP group, only about half had a good response. Qualitatively 123I-FP-CIT SPECT images were normal in 32.5% of patients with VP and abnormal in all patients with PD. The use of different visual score patterns showed higher ability to differentiate VP from PD. Semi-quantitative analysis showed significantly higher uptake in the striatum, caudate and putamen in VP. The asymmetry index was higher in patients with PD. Among patients with VP, falls were the only clinical feature that demonstrated a correlation with the SPECT visual pattern. CONCLUSION: Our data contribute to the confirmation that VP and PD are two different clinical entities. Neurological signs, response to treatment and qualitative and semi-quantitative 123I-FP-CIT SPECT analyses may help to make the diagnosis. [ABSTRACT FROM AUTHOR]

Objective The p38 MAPK is important in the pathogenic immune response in rheumatoid arthritis (RA). The p38 molecule can be activated through phosphorylation on Thr [ABSTRACT FROM AUTHOR]

Background: Deeper insight is needed on how monoclonal antibodies (mAbs) affect vaccine-mediated immune responses when targeting the same protein. We describe the first prospective randomised trial designed to understand mAb-mediated alterations in vaccine-induced immune responses to SARS-CoV-2 spike protein epitopes., Methods: This randomised, open-label, parallel-group study assessed the potential interaction of a mAb combination, casirivimab and imdevimab, with a vaccine, Moderna's mRNA-1273, in healthy SARS-CoV-2 immunologically naive, seronegative adults at six centres in the USA. Participants were randomly assigned (per prespecified randomisation ratios within enrolment waves) according to a computer-generated randomisation scheme, stratified by age (<65 years and ≥65 years), to various intravenous or subcutaneous doses of casirivimab and imdevimab before, after, or at the same time as mRNA-1273 or to mRNA-1273 only. The doses of casirivimab and imdevimab were chosen to mimic various time intervals between receipt of 1200 mg of the mAb and the first dose of a primary series with mRNA-1273. The primary endpoint was vaccine-induced 50% inhibitory dilution neutralising antibody titres to SARS-CoV-2 spike protein, 56 days after the first vaccination. Secondary endpoints included vaccine-induced total antibodies to SARS-CoV-2 antigens and incidence of treatment-emergent adverse events. Exploratory endpoints included blood-derived T-cell and B-cell responses. The per-protocol set was used for the analysis of the primary endpoint and included all randomly assigned participants who received both doses of the vaccine and completed the injection or infusion of casirivimab and imdevimab per protocol, had no evidence of SARS-CoV-2 infection in the past or in the 56 days after the first dose of vaccine, and did not receive any intervention outside of the study that could alter the immune response. Safety was assessed in the safety analysis set, which included all randomly assigned participants who had received one or more doses of mRNA-1273 or any study drug, and analysed based on treatment received. The study is registered with ClinicalTrials.gov, NCT04852978, and is complete., Findings: Between April 29, 2021, and Nov 21, 2022, 807 participants were assessed for eligibility and 295 were randomly assigned. 293 participants were included in the safety analysis set and 260 were included in the per-protocol set. All vaccinated participants developed neutralising antibodies to SARS-CoV-2, with median titres above the published protective threshold (100 IU/mL) against the SARS-CoV-2 D614G variant (considered a reference strain at the time the initial COVID-19 vaccines were developed). Titres were decreased up to 4-fold (median titres 280-450 IU/mL for casirivimab and imdevimab vs 1160 IU/mL for vaccine only on day 56) when casirivimab and imdevimab was given 85 days or less before vaccination (150-1200 mg intravenously) or co-administered subcutaneously (600 mg or 1200 mg) with vaccination. Minimal reduction in neutralisation titres was observed in the 48 mg and 12 mg intravenous groups, corresponding to receipt of casirivimab and imdevimab 113 days and 169 days, respectively, before vaccination, and when administering the vaccine 6 days before the mAb. Across all groups, mAbs had a minimal effect on vaccine-induced total antibodies and T-cell responses to the spike protein. Casirivimab and imdevimab plus mRNA-1273 was generally well tolerated; a slight increase in treatment-emergent adverse events was observed in the casirivimab and imdevimab plus vaccine groups versus the vaccine-only group., Interpretation: Casirivimab and imdevimab administration before or at the time of COVID-19 vaccination reduced the elicitation of SARS-CoV-2 neutralising antibodies, but minimal effect was observed when vaccination occurred before mAb administration. Although the clinical significance of this decrease in neutralisation is unclear, this evidence suggests that further investigation of potential interactions could be warranted before concurrent clinical use of mAbs and vaccines targeting the same viral proteins as their main modes of action for the prevention or treatment of infectious diseases., Funding: Regeneron Pharmaceuticals and F Hoffmann-La Roche., Competing Interests: Declaration of interests FI and JDH are employees and stockholders of Regeneron Pharmaceuticals, and report having patents pending, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. AMGO, BAO, TB, SG, LF, SCI, MT, GPG, and BM are employees and stockholders of Regeneron Pharmaceuticals. JM is an employee of Regeneron Pharmaceuticals. EF-N is a former employee and current stockholder of Regeneron Pharmaceuticals, and reports patents pending, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. IH is an employee and stockholder of Regeneron Pharmaceuticals, and a stockholder of Merck & Co. ATH is an employee and stockholder of Regeneron Pharmaceuticals, is a stockholder of Pfizer, and reports a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals. AB, CAK, and GDY are employees and stockholders of Regeneron Pharmaceuticals and report having issued patents (US patent numbers 10 787 501, 10 954 289, and 10 975 139) and pending patents, which have been licensed and receiving royalties, with Regeneron Pharmaceuticals. CDP is an employee and stockholder of Regeneron Pharmaceuticals and reports a patent pending with Regeneron Pharmaceuticals. MJM reports funding from Regeneron Pharmaceuticals, paid to her institution, and grants from the US National Institute of Allergy and Infectious Diseases, the Biomedical Advanced Research and Development Authority, Moderna, Sanofi Pasteur, and Janssen, paid to her institution. SCDR reports grants from the National Institutes of Health and the Bill & Melinda Gates Foundation awarded to his institution, and contracts from Regeneron Pharmaceuticals, The Henry M Jackson Foundation, Johnson & Johnson Innovative Medicine (formerly Janssen Pharmaceuticals), Gates Medical Research Institute, Paul G Allen Family Foundation, and Battelle, awarded to his institution. KWC reports funding from Regeneron Pharmaceuticals, paid to her institution, and is an employee and stockholder of Moderna. LDW CAH, AJO, AHP, and GDT report funding and provision of study materials from Regeneron Pharmaceuticals, paid to their institution. GAH is an employee and stockholder of Regeneron Pharmaceuticals and reports having a patent pending, which has been licensed and receiving royalties, with Regeneron Pharmaceuticals, as well as a pending patent application. MM, JH, LP, and FAF declare no competing interests., (Copyright © 2024. Elsevier Ltd. 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The Covid-19 pandemic has been responsible for millions of deaths worldwide. Patients with comorbidities- such as those on peritoneal dialysis (PD)- present higher morbidity and mortality than the general population. We prospectively evaluated all Chilean patients on PD (48 centres) and followed those who had Covid-19 from the beginning of the Covid-19 pandemic in Chile (March 2020) to January 2021 (start of vaccination campaign). We described demographic history, comorbidities, factors related to infection, need for hospitalisation and death due to Covid-19. During the study period, 106 adults on PD were infected by SARS-CoV-2, with a mean age of 53.1 (±16.3) and of which 53.9% were female. From that group, 54.8% required hospitalisation and 24.5% ( n = 26) died due to Covid-19. Most of the patients (63.4%) were infected at home and 22.8% during hospitalisation for other reasons. There was a significant association for Covid-19 mortality with: being ≥60 years old, diabetes, time on PD ≥5 years, need for hospitalisation and hospital-acquired infection. At 90 days of follow-up, all deaths associated to Covid-19 occurred before 40 days. We conclude that patients on PD without Covid-19 vaccination have a high mortality and need for hospitalisation associated to Covid-19. To avoid this negative outcome, it is necessary to intensify strategies to avoid contagion, especially in those ≥60 years old, with diabetes and/or ≥5 years spent on PD.

Objectives: To investigate the role of body mass index (BMI) in the phenotypic and genotypic characteristics of early arthritis patients., Methods: We analysed the clinical and laboratory parameters from the baseline visit of patients (670 patients [78.51% women]) included in the PEARL study. The WHO definition for low weight, normal weight, overweight and obesity (BMI <18.5, 18.5-25, 25-30 or ≥30 kg/m2, respectively) was applied. Anticitrullinated protein antibodies (ACPA) were studied by ELISA and HLA-DRB1* were genotyped by sequence speci c oligonucleotide probes. The relationship between BMI classification and other variables was analysed using Kruskall-Wallis, Anova and Chi-Square tests. Then multivariate logistic regression was performed to establish the role of BMI in ACPA positivity and ordered logistic regression to establish its relationship with ACPA level., Results: Among the patients studied, 255 (38.06%) were considered overweight and 136 (20.3%) obese. High BMI patients had significantly more pain perception and disability than normal weight patients, whereas no clear differences in disease activity were observed between high BMI and normal weight patients. ACPA positivity was significantly less frequent in overweight and obese patients compared to normal BMI patients. This information was confirmed by adjusting for smoking habit and the presence of shared epitope., Conclusions: Our data support the theory that high BMI patients suffer more frequently from ACPA-negative RA. Nevertheless, although no disease activity differences were observed, these patients showed higher pain and disability scores since the beginning of disease.

Objectives: To explore the remission concept in rheumatoid arthritis (RA) and the implications of the existing definitions when applied to clinical practice among rheumatologists with different profiles., Methods: A qualitative study through focus groups was conducted. Three focus groups were organised from February to March 2016. Each group was composed of rheumatologists with extensive clinical experience with different profiles; experts in basic research (RBR), experts in imaging techniques research (RIR), and experts in clinical research (RCR). The data was collected with audio recording. Verbatim transcriptions of the audio files were made, and a subsequent reflexive thematic analysis assisted by ATLAS.ti (GmbH, Berlin, v. 7) software was performed., Results: From the reflexive thematic analysis, three main themes were generated: (1) remission limitations, (2) instruments or measures to assess remission, and (3) a new definition of remission. Rheumatologists mentioned frequently that the following variables should be considered when developing a new remission definition: inflammatory activity, calprotectin, psychological variables, sex, disease stage, and sociocultural factors. Contrary to what could be expected, all groups acknowledged that their research field could contribute with domains for a gold standard remission instrument, but not in a hierarchical arrangement of importance. The dissonance existing in the entire remission evaluation process was outlined: remission in clinical practice versus remission in clinical trials, remission following the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) Boolean versus Musculoskeletal Ultrasound (US) remission, and remission from the rheumatologist's point of view versus the patient's point of view., Conclusions: Currently, rheumatologists would not accept a domain as more important than others in remission. Our suggestion is, not to generate a universal definition of remission - one that could cover all aspects - but rather to develop definitions of remission for the different settings that could be pondered by the patient's perspective.

Objectives: Reconstitution of B-cells after their therapeutic depletion with rituximab mimics the ontogeny of the B-cell linage in patients with rheumatoid arthritis. However, little is known about the effects of multiple cycles of treatment on the repletion kinetics and their long-lasting effects on the B-cell compartment. We therefore compared the recovery capacity of the B cell subpopulations between patients who experienced their first cycle of rituximab and those who experienced successive cycles., Methods: The distribution of the different B-cell subsets was characterised by multiparametric flow cytometry in the peripheral blood of 29 patients in the first rituximab course (naïve cycles) and 40 patients in successive cycles. Samples were obtained at baseline and at 3, 6, and 8 months of each cycle., Results: The baseline percentage of B-cell subsets was similar among successive cycles. Therefore, successive cycles were grouped for comparison with naïve cycles. Patients in naïve cycles had higher percentages at baseline of both total and memory B-cells. However, the recovery of the different B-cell subsets was similar between naïve and successive cycles. In naïve patients the percentage of transitional B-cells significantly correlated with disease activity at baseline., Conclusions: Rituximab induces a long-term reshape of the B-cell compartment while multiple cycles of rituximab do not induce cumulative effects on B-cell subpopulations. Transitional B-cells seem to be associated with higher disease activity, although further studies are needed to determine if they can be used as a biomarker to predict the need for rituximab retreatment.