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Secular variation in the heritability of educational attainment are proposed to be due to the implementation of more egalitarian educational policies leading to increased equality in educational opportunities in the second part of the 20th century. The action of effect is hypothesized to be a decrease of shared environmental (e.g., family socioeconomic status or parents' education) influences on educational attainment, giving more room for genetic differences between individuals to impact on the variation of the trait. However, this hypothesis has not yet found consistent evidence. Support for this effect relies mainly on comparisons between countries adopting different educational systems or between different time periods within a country reflecting changes in general policy. Using a population-based sample of 1271 pairs of adult twins, we analyzed the effect of the introduction of a specific educational policy in Spain in 1970. The shared-environmental variance decreased, leading to an increase in heritability in the post-reform cohort (44 vs. 67%) for males. Unstandardized estimates of genetic variance were of a similar magnitude (.56 vs. .57) between cohorts, while shared environmental variance decreased from .56 to .04. Heritability remained in the same range for women (40 vs. 34%). Our results support the role of educational policy in affecting the relative weight of genetic and environmental factors on educational attainment, such that increasing equality in educational opportunities increases heritability estimates by reducing variation of non-genetic familial origin.

There is a lack of information on the psychophysiological response of pilots under hypoxic conditions. The study of the physiological, psychological, cardiorespiratory, neurological, behavioural, sensory, and cognitive symptoms that may appear during training in hypobaric chambers is essential to optimize the training processes of aircrew members. Thus, the present study is aimed at analyzing the psychophysiological responses of aircrew members in an incremental hypoxia training protocol. Psychophysiological responses of 44 aircrew members (34 males and 10 females) in an incremental hypoxia training protocol (3 minutes at 0 meters, 8 minutes at 5,000 meters, and maximum time at 7500 meters) were measured. Results suggested that the incremental hypoxia training protocol did not affect cortical arousal and handgrip strength; however, it increased the sympathetic tone, perceived stress, perceived effort, and heart rate and decreased forced expiratory volume and blood oxygen saturation. Thus, we concluded that acute hypoxic hypobaric exposure leads to decreased parasympathetic tone, blood oxygen saturation, and maximal spirometry values, without negatively affecting handgrip strength and cortical arousal. This information will lead to find specific training systems that meet the real needs of aircrew.

Background:MSB11022 is a biosimilar of adalimumab that has been shown to have comparable bioequivalence, safety, tolerability, and immunogenicity profiles to the reference drug in healthy volunteers, patients with psoriasis, or patients with moderate-severe rheumatoid arthritis. This is the first study conducted under clinical practice conditions evaluating the switch from adalimumab to MSB11022 in patients with rheumatoid arthritis.Objectives:The primary objective was to evaluate the composite Disease Activity Score 28 with C-reactive protein (DAS28-CRP) in patients with rheumatoid arthritis who have switched from the original adalimumab or another biosimilar to MSB11022. Secondary objectives were to assess the Clinical Disease Activity Index (CDAI) after switching; the rates of remission and low disease activity according to DAS28-PCR (remission < 2.6, low activity < 3.2) and CDAI (remission < 2.8, low activity < 10.0); and the safety of MSB11022.Methods:Retrospective and multicenter study with data from the medical records of patients with rheumatoid arthritis who switched from the original adalimumab or another biosimilar to MSB11022, and maintained this treatment for at least 6 months. Patients with psoriasis and/or inflammatory bowel disease were excluded. Information was recorded from both the baseline visit at the moment of the switch and the follow-up visits after the switch.Results:Data from 86 patients were evaluated: median age 63.5 years (53;73), 75.6% female, 71.4% Caucasian, 73.3% non-smokers, BMI 27.2 kg/m2 (23.1;30.5). The median time since diagnosis of rheumatoid arthritis was 12 years (8;18) and 44.2% had erosive rheumatoid arthritis. The most common comorbidities in this population were hypertension (32.6%), cardiovascular disease (12.8%), and diabetes mellitus (9.3%). At the time of switching, most patients were on combined biologic therapy with DMARDs (54.7%). Only 3.5% of the patients received biologic therapy prior to adalimumab; among them, the pre-adalimumab biologic treatments prescribed were certolizumab-pegol (66.7%) and tocilizumab (33.3%). At baseline, the median DAS28-CRP was 1.77 (80.2% in remission and 96.5% with low disease activity) and the median CDAI was 4.00 (44.2% in remission and 90.7% with low disease activity). After a median follow-up of 8 months (5.7;13.0), the median DAS28-CRP was 1.87 (86.0% in remission and 94.2% with low disease activity) and the median CDAI was 4.00 (38.5% in remission and 95.3% with low disease activity) (Table 1). Only three patients experienced pain, swelling and stinging at the injection site or a locally extensive hematoma in the area of administration.Conclusion:The adalimumab biosimilar MSB11022 not only maintained the benefits provided by previous adalimumab treatments, but in some cases led to an improvement of these benefits, maintaining a safety profile in line with that already described for other biosimilars.Table 1.Clinical outcomes after switching from original or other biosimilars to MSB11022VariableBasalLast follow-up available(median 8 months)DAS28-PCR, median (P25;P75)1.77 (1.24;2.34)1.87 (1.22;2.29)• Remission, n (%)• Low disease activity, n (%)69 (80.2%)83 (96.5%)74 (86.0%)81 (94.2%)CDAI, median (P25;75)4.00 (1.00;5.00)4.00 (1.00;5.00)• Remission, n (%)• Low disease activity, n (%)38 (44.2%)78 (90.7%)34 (39.5%)82 (95.3%)Rheumatoid factor, median (P25;75)19.0 (6.00;172:00)22.0 (6.00;64.5)Antibodies anti-CCP, median (P25;75)74.9 (1.50;278.00)14.5 (1.50;78.2)CCP: cyclic citrullinated peptides; CDAI: Clinical Disease Activity Index; DAS28-PCR: Disease Activity Score 28 for rheumatoid arthritis with C-reactive protein.REFERENCES: NIL.Acknowledgements:The authors thank Content Ed Net, Madrid (Spain), for writing and editorial assistance. The support has been funded by Fresenius Spain.Disclosure of Interests:None declared.

BackgroundSeveral case reports published in the 2000’s indicated that demyelinating diseases could be a serious adverse event following TNF inhibitors (TNFi) treatment. However, initial data from biological therapy registries did not bring enough clarification.ObjectivesTo investigate whether treatment with biologics or targeted synthetic DMARDs is associated with an increased risk of demyelinating events among patients with rheumatoid arthritis (RA)MethodsA systematic search was performed in MEDLINE, EMBASE (up to Oct 2022), and by manual references. Selection criteria: (population) patients with RA; (intervention) treatment with any biologic including TNFi and synthetic DMARDs, (outcome) demyelinating event; (study design) observational studies and randomised clinical trials. Titles and abstracts were screened and data were extracted from the selected studies including quality evaluation, and outcomes of interest.ResultsFrom 368 identified studies, 4 cohorts and 3 nested case-control studies reported risk of demyelinating events following treatment with biologics, mainly TNFi and anakinra, in one study. Most studies included mixed populations of inflammatory arthritis and patients with RA were analysed as a separate subgroup. Two nested case-control reported an increased risk, but in a mixed population, with no analysis of a subgroup of RA. In general, demyelinating events were very uncommon in patients receiving TNFi, with a marginal increased risk in males with RA in 2 studies (Table 1).Table 1.Characteristics and incidence rates of demyelinating events in the included studiesStudyDesignPopulationOutcomeLingyi 2022 (1)Nested case-controlCanadian healthcare databasesN= 462/296,918Rheumatic diseases, mixed populationCase = multiple sclerosisPooled IRR (95% CI): 2.05 (1.13-3.72)Taylor 2021 (2)Prospective CohortBritish Society for Rheumatology Biologics RegisterN= 35/13,489Mixed population of inflammatory arthritisIncidence (95% CI):19.7/100,000 pts-years (13.7-27.3)SIR (95% CI): 1.38 (0.96-1.92)Definite cases: 0.83 (0.51-1.26)Males: 2.75 (1.31-5.06)Kunchok 2020 (3)Nested case-control Medical records at Mayo Clinic (USA)N=106 cases/106 controlsAutoimmune diseasesCase = Any inflammatory CNS eventOR 4.82 (95%CI 1.62-14.36)Koop 2020 (4)Combined biologic registers in Sweden and DenmarkN=271 and 51/111,455 RA ptsIncidence Rate: 0.37-0.39/1000 pt-yrsHR (95% CI) TNFi exposed vs non:Sweden: 0.97 (0.72 to 1.33)Denmark: 1.45 (0.74 to 2.81)Dreyer 2016 (5)Register-based cohort study DANBION= 27,880 patients with arthritis and TNFi therapySIR 1.11 (95% CI 0.63-1.93)RA: 0.65 (95% CI 0.24–1.72)Males: 3.48 (95% CI 1.45–8.37)Fernandez-Espartero 2011 (6)BIOBADASER-SpainN= 9/13,075 RA pts-yearsIncident rate in RA: 0.69 (95% CI: 0.36-1.32)MS 0.05 (95% CI: 0.01-0.33), vs Spanish population 0.02-0.04*1000Bernatsky 2010 (7)Nested case-control Administrative data in CanadaN= 104,958 RA pts81 cases and 810 controlsAdjusted rate ratios (95% CI):TNFi 1.31 (0.68 - 2.50)Anakinra 0.80 (0.29 - 2.24)MTX 1.09 (0.63 - 1.89)Abbreviations: RA, rheumatoid arthritis; SIR, standardized incidence rate; CI, confidence interval; CNS, central nervous system; HR, hazard ratio; OR, odds ratio; MTX, methotrexate; MS, multiple sclerosis; TNFi, tumour necrosis factor inhibitor.ConclusionNo consistent and significant risk of demyelinating disease following TNFi treatment was found in RA patients. A marginal and slight increase of risk was found in male RA patients. The small number of events is reassuring when considering the use of TNFi. A careful consideration is recommended in individuals at highest risk of demyelinating diseases.References[1] Neurology. 2022 Oct 28:10.1212.[2] Neurol Neuroimmunol Neuroinflamm. 2021;8(3).[3] JAMA Neurol. 2020;77(8):937-46.[4] Ann Rheum Dis. 2020;79(5):566-72.[5] Ann Rheum Dis. 2016;75(4):785-6.[6] Semin Arthritis Rheum. 2011;41(3):524-33.[7] Ann Rheum Dis. 2010;69(9):1691-3.AcknowledgementsIC received partial funding from the Spanish Society of Rheumatology (SER).Disclosure of InterestsNone Declared.

ObjectiveThis study aimed to evaluate the effectiveness of computed tomography and positron emission tomography-computed tomography prior to salvage surgery after head and neck carcinoma treated with bioradiotherapy and to look at the role of neck dissection in this setting.MethodThis study was a retrospective chart review of a series of consecutive patients with locally advanced head and neck squamous cell carcinoma treated with bioradiotherapy. Radiological and pathological stages were compared to evaluate the accuracy of computed tomography and positron emission tomography-computed tomography in detecting occult neck metastasis in the context of recurrence of primary tumour. In order to assess the impact of neck dissection on survival, Kaplan–Meier survival curves after salvage surgery with and without neck dissection were derived.ResultsA total of 268 patients were identified, of which 22 underwent salvage surgery. The negative predictive value of computed tomography and positron emission tomography-computed tomography was excellent. Neck dissection did not represent an improvement on overall, disease specific and regional recurrence free survival (p = 0.67, p = 0.91 and p = 0.62, respectively) amongst clinically and radiologically negative necks.ConclusionConservative treatment of the neck should be considered when dealing with patients with primary site recurrence or persistent disease after bioradiotherapy without evidence of neck disease.

Background:Primary Sjögren’s Syndrome (pSS) shares with SLE and RA a variety of features including their predominance in women, immunological characteristics and genetic risk background. For these reasons, to dissect the heterogeneity across these IMIDs is paramount to design precision medicine strategies. Single cell transcriptomics allows the interrogation of patients’ samples at great resolution to inform on both common and specific pathogenic molecular mechanisms that drive disease. This is particularly relevant not only for the discovery of potentially actionable targets, but also to identify which patients could benefit from such novel therapeutic interventions. Despite pathogenic mechanisms can be organ-specific, immune cells are mobilized via peripheral blood and many inflammatory responses are initiated by blood cells. In that respect, the profiling of peripheral blood mononuclear cells (PBMCs) is important since PBMCs may show cell-type signatures that can define disease specific pathogenesis, with the advantage of being an easily accessible tissue.Objectives:To study peripheral blood cells on pSS, SLE and RA patients one cell at the time, and to decipher the immune cell landscape in the peripheral blood underlying disease.Methods:PBMCs from 8 pSS and 5 healthy (H) donors were isolated in Ficoll gradient, to generate a suspension of viable single cells that were processed with Chromium Single Cell 3’ kit v3 (10X Genomics). A median of 8,008 cells per sample were profiled. Raw sequences were demultiplexed and mapped against the genome using Cellranger. Downstream analyses, including QC filtering, normalization, and integration were done with Seurat. Immune cell types were automatically annotated using Azimuth. Single cell data from 6 RA patients (71,224 cells) and 8 SLE patients (71,224 cells), was obtained from the DoCTIS Consortium project.Results:A total of 110,378 single cells (67,192 from pSS and 43,186 from HC) passed QC and were analyzed. Differential cell abundance analysis among the 4 groups (H, pSS, SLE and RA) showed a significant increment in the CD8 lymphocyte population with CD8TEM features, that is specific to pSS. In turn, reduced numbers of circulating CD8 naïve T cells were observed in pSS compared to healthy individuals, a cell abundance change that is also found in RA but not in SLE. Gene expression analysis revealed that CD14+ monocytes are the cell type that shows the highest number of differentially expressed genes (DEGs) in pSS compared to controls. Analysis of these DEGs in CD14+ monocytes from SLE and RA patients showed a significant antagonism, with many genes showing a differential expression in the opposite direction. Second to monocytes, CD4TCM lymphocytes showed also a large number of significant DEGs between pSS patients and controls. In this case, no significant antagonism was found in CD4TCM from RA or SLE. Pathway analysis of the genes exclusive to pSS (i.e. differentially expressed in pSS but not in SLE or RA), identified an association with the regulation of type I interferon and tumor necrosis factor production. Among the former, the family of genes encoding 2′–5′ oligoadenylate synthetases (OAS1 to OAS3) were found to be significantly overexpressed in CD14+ monocytes. OAS1 is a well-known risk gene for pSS associated at a genome-wide level (Thorlacius et al).Conclusion:We have generated a comprehensive map of cells from pSS PBMCs and compared it with healthy donors as well as SLE and RA, covering a total of 241,841 cells. This study provides a valuable resource for further in-depth analysis and reveals relevant disorder and cell-specific transcriptomic changes such as the upregulation of OAS family of IFNI response genes in CD14+ monocytes providing further clues into the pathological mechanisms driving the disease.REFERENCES:[1] Thorlacius, Gudny Ella, Albin Björk, and Marie Wahren-Herlenius. “Genetics and epigenetics of primary Sjögren syndrome: implications for future therapies.” Nature Reviews Rheumatology 19.5 (2023): 288-306.Acknowledgements:NIL.Disclosure of Interests:None declared.

ObjectivesTo prepare recommendations on practical aspects of biological-drug monitoring that may be useful for rheumatologistMethodsA systematic review of the literature was carried out to determine in which patients and in what clinical circumstances may be most beneficial to monitor the levels of biological drugs and their antibodies in patients suffering Rheumatoid Arthritis (RA) and/or Spondyloarthritis (SpA). With the results of the review, a group of experts produced a series of clinical questions, to be answered through the available scientific evidence, and then, subsequently, to make the recommendations and clinical algorithms for instructing the decision-making process.ResultsResults from the systematic review showed that the biological-drug monitoring might be especially useful in two clinical situations; in case of a treatment failure (primary or secondary) and in sustained remission (see figure 1). It was also reviewed which laboratory technique might be better and the optimal time for blood withdrawal. Specific recommendations are given on the interpretation of drug levels and on factors that should be taken into account are given (i.e. body mass index and concomitant medication).Abstract AB1318 – Figure 1ConclusionsInformed algorithms have been developed regarding the optimal time for requesting drug levels and anti- drug antibodies in patients with RA and SpA. This recommendations may help in the decision-making process and could be useful as part of future guidelines in the field.AcknowledgementsThis study was funded by Grifols through the Asociación para la Investigación en Reumatología de la Marina Baixa (AIRE-MB). The content is solely the responsibility of the authors and does not necessarily represent the official views of Grifols.Disclosure of InterestNone declared

BackgroundSeveral studies in rheumatic and other inflammatory diseases treated with tumour necrosis factor-alpha inhibitors (TNFi) support the association between clinical response and trough drug levels (DL). The utility of monitoring DL in rheumatoid arthritis (RA) and spondyloarthritis (SpA) patients on biological therapy is not clear, so it is important to identify clinical situations in which, the knowledge of DL, would allow an individualised therapeutic decision in the patient, more cost-effective.ObjectivesTo answer the most relevant clinical questions related to the usefulness of DL measurement in clinical practice: 1) whether, in patients in remission who are candidates for optimisation, DL predict relapse or survival to dose-titration; 2) whether, in patients with primary or secondary failure to biological agents, DL influence prognosis; and 3) whether concomitant use of methotrexate (MTX) influences the association between DL and response.MethodsAn electronic search of the major databases was performed, Medline, Embase and Cochrane Library, from inception to December 2016. We included articles published in English or Spanish on patients with RA, SpA or both, treated with TNFi, tocilizumab or abatacept, and related to answer any of the three questions of the target research. Overall characteristics and outcomes of the studies were collected in a table of evidence and the quality of the studies was assessed with a scale based on the Oxford levels of Evidence.ResultsThe electronic search strategy yielded 1749 articles, twelve of which were included in this systematic review. 2 studies responded the first question, 5 the second, and 7 the third. These studies were mainly observational studies, 6 retrospective and 4 prospective cohort studies, and 2 randomised clinical trials. Sample sized varied from 24 to 395 patients, for a total of 1482 patients analysed. A total of 1281 RA patients were included (64 in the first question, 243 in the second and 1038 in the third) and 201 SpA patients (32 in the first and second questions, 169 in the third). Studies were small and with limitations, but suggest that measurement of DL may be useful in patients in remission, that higher DL predict a longer relapse-free optimisation, and in patients with failure to a biological agent, treatment may need individual adjustment according to the presence of DL or antidrug-antibodies. In addition, MTX influences the association between response and DL in most studies, with greater controversy in tocilizumab and SpA patients.ConclusionsMonitoring DL would allow optimal use of current biological therapies, but more studies and of better quality are needed to draw definitive conclusions. In addition, future research should be performed to determine therapeutic ranges of DL, so that the proposed algorithms can be used in a standardised and reliable manner.Disclosure of InterestNone declared

BackgroundRheumatoid arthritis (RA) is a long-lasting inflammatory autoimmune disorder that ultimately leads to the destruction of joint architecture. The activity of this disease is measured by the assessment of clinical symptoms.ObjectivesTo apply a proteomic strategy to find serum biomarkers able to discriminate patients with different RA activities.MethodsTo facilitate the complex measurement of serum by proteomics, a simple, fast and reproducible albumin-specific depletion method using ethanol was optimised and applied to the samples employed in this study. 80 samples from the IMID consortium, classified according to the DAS28 score into low activity40 and high activity40 were analysed by mass spectrometry. Four independent pools of the high RA activity samples (10 samples per pool) and 4 pools of the low RA activity samples were firstly albumin-depleted, and then the remnant serum proteins were digested and differentially labelled with iTraq 8-plex reagents. Subsequently, the 8 labelled pools were combined and cleaned using StageTips-C18. Finally, the pool mixture was fractionated by HPLC (Zorbax-C18) and the resulting fractions were analysed by nanoLC-MS/MS using MALDI-TOF/TOF, TripleTOF and LTQ-Orbitrap.ResultsThe mass spectrometry analysis led to the identification of 186 proteins. In this screening step, the abundance of 9 proteins was found to be significantly different between patients with high (H) and low (L) RA activity. Orthogonal experiments, using Western Blot, protein bead arrays and Multiple Reaction Monitoring (MRM) with synthetic heavy-labelled peptides, were conducted in order to verify some of these these biomarker candidates of RA activity. The results obtained from the verification phase, conducted by MRM on 50 samples from the same cohort, show a decrease of Apolipoprotein B (ratio H/L=0.84, p=0.00), Histidine Rich Glycoprotein (ratio H/L=0.86, p=0.01) and Plasma protease C1 inhibitor (ratio H/L=0.84, p=0.02). Furthermore, this verification phase shows also an increase of Haptoglobin (ratio H/L=1.34, p=0.01) and Serum Amyloid A1 (ratio H/L=1.64, p=0.05), in accordance with that observed in the screening. These proteins are related with the RA process and the effects caused by this type of disease (inflammation and immune disorder in joints).ConclusionsIn this proteomic study, 5 proteins were found to be quantitatively altered between patients with high and low RA activity using shotgun and targeted mass spectrometry.Disclosure of InterestNone declared

Anti-Tumor Necrosis Factor (anti-TNF) drugs are biologic agents commonly used to treat rheumatoid arthritis (RA). However, anti-TNFs are not effective in approximately one out of four treated patients. We conducted a Genome-Wide Association Study (GWAS) to identify the genetic variation associated with the response to anti-TNF therapy in RA. In the discovery stage, 372 RA patients treated with an anti-TNF agent (infliximab, adalimumab or etanercept) were analyzed and treatment response was defined at 12 weeks of therapy. We found a genome-wide significant association in the MED15 gene with the response to etanercept ( P <1.5e-8). Using an independent cohort of 245 RA patients, we performed a replication study of the most significant GWAS associations. We replicated the association at the MED15 locus and found suggestive evidence of association in the previously associated MAFB locus. The results of this study suggest novel mechanisms associated with the response to anti-TNF therapies.