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Attentional selection in the context of goal-directed behavior involves top-down modulation to enhance the contrast between relevant and irrelevant stimuli via enhancement and suppression of sensory cortical activity. Acetylcholine (ACh) is believed to be involved mechanistically in such attention processes. The objective of the current study was to examine the effects of donepezil, a cholinesterase inhibitor that increases synaptic levels of ACh, on the relationship between performance and network dynamics during a visual working memory (WM) task involving relevant and irrelevant stimuli. Electroencephalogram (EEG) activity was recorded in 14 healthy young adults while they performed a selective face/scene working memory task. Each participant received either placebo or donepezil (5mg, orally) on two different visits in a double-blinded study. To investigate the effects of donepezil on brain network dynamics we utilized a novel EEG-based Brain Network Activation (BNA) analysis method that isolates location-time-frequency interrelations among event-related potential (ERP) peaks and extracts condition-specific networks. The activation level of the network modulated by donepezil, reflected in terms of the degree of its dynamical organization, was positively correlated with WM performance. Further analyses revealed that the frontal-posterior theta-alpha sub-network comprised the critical regions whose activation level correlated with beneficial effects on cognitive performance. These results indicate that condition-specific EEG network analysis could potentially serve to predict beneficial effects of therapeutic treatment in working memory.

Le bimekizumab (BKZ), un anticorps monoclonal IgG1 qui inhibe sélectivement l'IL-17F en plus de l'IL-17A, a démontré son efficacité à long terme chez les patients (pts) atteints de spondyloarthrite axiale radiographique (r-axSpA) à 5 ans [1]. Nous évaluons l'impact du traitement par BKZ sur la progression radiographique rachidienne à 2 ans chez les pts atteints de r-axSpA dans l'étude d'extension en ouvert de phase III BE MOBILE 2. À S52 de l'étude BE MOBILE 2 (NCT03928743 ; plan de l'étude déjà publié), [2] les pts pouvaient participer à l'étude d'extension en ouvert en cours (NCT04436640), où tous ont reçu 160 mg de BKZ/4S. Les radiographies rachidiennes à l'inclusion et à S104 ont été évaluées à l'aide du score mSASSS, par deux lecteurs centralisés, avec un arbitre si les scores différaient de ≥ 5 points ; toutes les lectures ont été faites à l'aveugle lors de la mesure. La moyenne des scores de variation entre les lectures a été déterminée pour chaque radiographie ; trois lectures ont été faites et une moyenne des deux scores les plus proches a été calculée. Nous rapportons la probabilité moyenne et cumulative de variation par rapport à l'inclusion du mSASSS à S104 dans l'étude d'extension en ouvert, ainsi que la proportion de pts n'ayant pas progressé, en utilisant les définitions mSASSS avec une variation par rapport à l'inclusion ≤ 0,5 et une variation par rapport à l'inclusion < 2. Les facteurs prédictifs potentiels de progression radiographique rachidienne (mSASSS avec une variation par rapport à l'inclusion ≥ 2) ont été évalués à l'aide de modèles de régression logistique. Sur 332 pts atteints de r-axSpA, 286 (86,1 %) ont participé à l'étude d'extension en ouvert et 267 (80,4 %) ont terminé la S104. Parmi eux, 71,9 % (192/267) étaient des hommes et 16,1 % (43/267) étaient des pts ayant une réponse inadéquate aux anti-TNF (anti-TNF-IR). À S104, 71,2 % (190/267) des pts atteints de r-axSpA disposaient d'une évaluation mSASSS. Chez ces pts, le score mSASSS moyen (écart-type) à l'inclusion était de 7,3 (13,8) et la variation par rapport à l'inclusion à S104 était de 0,3 (1,9). La plupart des pts (157/190) n'ont pas eu de progression radiographique rachidienne à S104 sous BKZ (Figure 1). À S104, la proportion de pts n'ayant pas progressé, définie par une variation du mSASSS par rapport à l'inclusion ≤ 0,5, était de 85,3 % (162/190) et celle définie par une variation du mSASSS par rapport à l'inclusion < 2 était de 92,1 % (175/190), comprenant 83,1 % (69/83) des pts qui présentaient des lésions structurales existantes (mSASSS ≥ 2) à l'inclusion. Aucun facteur prédictif potentiel n'a été associé à une probabilité significativement accrue de progression radiographique rachidienne (tous les p > 0,05). Une progression radiographique rachidienne minimale et une proportion élevée de pts sans progression, y compris chez ceux qui présentaient des lésions rachidiennes initiales, ont été démontrées après 2 ans de traitement par BKZ chez des pts atteints de r-axSpA. [ABSTRACT FROM AUTHOR]

Objectives: To describe the long-term effectiveness and safety of certolizumab pegol in patients with moderate-to-severe rheumatoid arthritis (RA) in a real-world setting in France., Methods: ECLAIR was a 3-year longitudinal, prospective, observational, multicentre study. The primary objective was to describe the EULAR response after 1 year of certolizumab pegol treatment. Other endpoints included DAS28, clinical disease activity index, health assessment questionnaire disability index, fatigue assessment scale, patient's assessment of arthritis pain, patient and physician global assessments of disease activity, patient quality of life, and long-term safety., Results: A total of 792 patients were enrolled, of whom 776 comprised the safety set, and 733 the full analysis set. In the full analysis set, 559, 469 and 430 patients had a 12-, 24- and 36-month visit, respectively. This included 378, 296 and 246 patients still receiving certolizumab pegol at these visits. The percentage of EULAR responders was 75.3% (305/405 patients with an available EULAR response) at 12, 76.5% (261/341) at 24, and 79.6% (226/284) at 36 months. Among those still receiving certolizumab pegol, the percentage of EULAR responders was 81.7% (237/290) at 12, 81.1% (185/228) at 24, and 87.3% (158/181) at 36 months. Sustained improvements were observed in other effectiveness outcomes. Overall, 45.1% (350/776) of patients experienced 776 adverse drug reactions. No new safety signals were identified., Conclusions: This is the first prospective, observational study of an anti-TNF treatment in France. The results confirm the effectiveness and safety profile of certolizumab pegol treatment in patients with RA in a real-world setting.

Objective: To evaluate the performance of clinical criteria for predicting late treatment failure in patients with early non-response to certolizumab pegol (CZP)., Methods: A protocol-specified analysis of interim data from ECLAIR, a 3-year longitudinal, prospective, observational, multicentre study of patients with active rheumatoid arthritis (RA) initiating CZP treatment in France, was conducted. Clinical measures assessed were Clinical Disease Activity Index (CDAI), Disease Activity Score-28 with erythrocyte sedimentation rate (DAS28(ESR)) and Health Assessment Questionnaire Disability Index (HAQ-DI). Early non-response was measured at 3 months (M3) and failure to achieve low disease activity (LDA) at 12 months (M12)., Results: 574/792 enrolled patients were treated at M3. The numbers available for predictability analyses were 532 (CDAI), 434 (DAS28(ESR)) and 496 (HAQ-DI). Of the three indices evaluated, the highest predictor of non-response value was observed for the CDAI (88.8% (95% CI 81.0 to 94.1)), indicating that up to 88% of patients identified as non-responders at M3 failed to achieve LDA at M12, regardless of baseline disease severity or treatment history. The specificity for this measure was also very high (96.0%), indicating that less than 5% of patients who achieved CDAI response at M12 had not responded at M3. Similar predictability was observed for DAS28(ESR), but only in patients with high disease activity at baseline and/or those previously treated by a biological disease-modifying antirheumatic drug., Conclusion: CDAI non-response at M3 is a predictor of failure to achieve the therapeutic target of LDA at M12 in patients with RA initiating treatment with CZP., Competing Interests: Competing interests: BC, AS and R-MF received honoraria from AbbVie, BMS, Lilly, Merck, Pfizer, Roche-Chugai, Sanofi, UCB Pharma. AS, R-MF, FF, JM, PH-M and BC were members of the scientific committee. GC and J-MJ are employed by UCB Pharma., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objectives: To estimate the number of patients with severe spondyloarthritis (SpA) in France, describe their comorbidities and document and value their healthcare resource consumption., Methods: Data were retrieved from an insurance claims database covering a 1/97 random sample of the French population. All patients benefiting from full insurance coverage ("ALD") for severe SpA in 2012 (including cases with structural damage and/or frequent flares) were identified, together with a control group frequency-matched by age and gender. Severe comorbidities were documented through ALD categories. Healthcare resource consumption was documented and valued from the payer's perspective. Rates of comorbidities and costs were compared in SpA patients versus controls using non-parametric testing., Results: Overall, 827 patients with ALD status for severe SpA were identified (control group: n=2.481), corresponding to a prevalence rate of 0.18% [0.17-0.19] for SpA with ALD in the general population. Severe comorbidities more frequent in patients with SpA than in controls included inflammatory bowel disorders (odds ratio: 15.0 [6.2-36.2]), hypertension (2.5 [1.6-3.9]), atrial fibrillation (4.3 [1.9-9.6]) and major depressive disorder (2.1 [1.3-3.6]). Mean per capita annual direct healthcare expenditure was 3.6 [3.2-4.1]-fold higher in SpA patients (€6,122 [€5,838-€6,406]) than in controls (€1,682 [€1,566-€1,798]). Extrapolating to all patients in France, total healthcare cost attributable to severe SpA patients was €391 [€355-€426] million, with medication accounting for 53.8% of this cost., Conclusions: The burden of severe SpA in France is substantial, due to the high prevalence, high direct costs and associated comorbidities., (Copyright © 2018. Published by Elsevier Masson SAS.)

Misinterpretation of patient beliefs may complicate shared decision-making in rheumatoid arthritis (RA) or axial spondyloarthritis (axSpA). The objective of this study was to develop a questionnaire to assess patients' beliefs about their disease and its treatment, and to identify patient characteristics associated with these beliefs. All beliefs reported by > 5% of 50 patients in a previous study were reformulated with a partnering patient organization into statements with which participants could rate their agreement on a scale of 0-10 (totally disagree to totally agree). The resulting Questionnaire for Arthritis Dialogue (QuAD) was made available to patients with RA or axSpA. A score ≥ 7 was considered a strongly held belief. Associations between patient characteristics and individual lifestyle beliefs were assessed using multiple logistic regression. The 21-item QuAD was completed by 672 patients (432 RA, 240 axSpA; mean [±SD] age 54.2 [± 14.2]; 63.7% female). The most widely held beliefs were related to uncertainty about progression (n = 354, 54.0%), heredity (n = 309, 47.8%), and flare triggers (n = 283, 42.7%). The unwarranted belief that physical activity is deleterious to disease activity was associated with markers of psychological distress and lower educational levels. The beliefs of patients with RA or axSpA about their disease are wide-ranging. Since these may be unwarranted and may lead to inappropriate behaviors, physicians should discuss these beliefs with their patients. The QuAD may facilitate this dialogue, and may also be useful in population studies to standardize the assessment and evolution of beliefs over time. People with long-term inflammatory conditions such as rheumatoid arthritis (RA; inflammation of the joints) and axial spondyloarthritis (axSpA; inflammation of the spine) may hold a number of beliefs about their disease, including some that are not supported by current scientific evidence (e.g., "I think that my disease was triggered by a vaccination"). Some beliefs, especially those relating to the role of lifestyle factors (such as exercise, diet, smoking, and drinking alcohol), may encourage people living with severe diseases to change their behavior in a way that has an effect on their disease. Within this project, we developed a questionnaire to identify the most common beliefs held by people living with RA or axSpA, which is called the "Questionnaire for Arthritis Dialogue (QuAD)." We also examined whether certain characteristics (or traits) of people living with RA or axSpA are linked to beliefs not currently supported by scientific evidence. A total of 672 people living with RA or axSpA in France were asked to complete the questionnaire (QuAD). The questionnaire included 21 opinion statements that they scored from 0 (totally disagree) to 10 (totally agree). A score of more than 7 was interpreted to mean that the person significantly agreed with the opinion. Based on the responses to specific opinion statements in the questionnaire, we were able to identify possible links between beliefs that are not supported by scientific evidence (e.g., "I think that flare-ups of my disease are triggered by physical effort"), and characteristics of people living with severe diseases. Our findings suggested that beliefs about lifestyle and inflammatory diseases varied from person to person, were sometimes inconsistent (the most widely held beliefs were sometimes contradictory), and were often not supported by scientific evidence. The belief that physical activity had negative effects on the disease was linked to poor education and psychological issues (such as anxiety and helplessness). People living with axSpA were more likely to believe their disease was a result of their genetic make-up, whereas those with RA more often believed their disease was caused by emotional issues. People living with axSpA were also more likely to believe that physical activity could be beneficial for their disease, and less likely to believe that their disease was caused by smoking. Our results suggest that doctors need to discuss with their patients how they might believe lifestyle is associated with their disease. This will help to dispel any unnecessary concerns, and to encourage their patients to take up healthy lifestyles and habits that are beneficial for their disease management. It may also be beneficial for health care providers to discuss the beliefs identified in this study during educational programs about inflammatory diseases, for the benefit of people living with RA or axSpA.

The original version of this article was revised due to a retrospective Open Access order.

Objectives: To develop and validate an outcome measure for assessing fears in patients with rheumatoid arthritis (RA) and axial spondyloarthritis (axSpA)., Methods: Fears were identified in a qualitative study, and reformulated as assertions with which participants could rate their agreement (on a 0-10 numeric rating scale). A cross-sectional validation study was performed including patients diagnosed with RA or axSpA. Redundant items (correlation >0.65) were excluded. Internal consistency (Cronbach's α) and factorial structure (principal component analysis) were assessed. Patients were classified into fear levels (cluster analysis). Associations between patient variables and fear levels were evaluated using multiple logistic regression., Results: 672 patients were included in the validation study (432 RA, 240 axSpA); most had moderate disease activity and were prescribed biologics. The final questionnaire included 10 questions with high internal consistency (α: 0.89) and a single dimension. Mean scores (±SD) were 51.2 (±25.4) in RA and 60.5 (±22.9) in axSpA. Groups of patients with high (17.2%), moderate (41.1%) and low (41.7%) fear scores were identified. High fear scores were associated with high Arthritis Helplessness Index scores (OR 6.85, 95% CI (3.95 to 11.87)); high Hospital Anxiety and Depression Scale anxiety (OR 5.80, 95% CI (1.19 to 4.22)) and depression (OR 2.37, 95% CI (1.29 to 4.37)) scores; low education level (OR 3.48, 95% CI (1.37 to 8.83)); and high perceived disease activity (OR 2.36, 95% CI (1.10 to 5.04))., Conclusions: Overall, 17.2% of patients had high fear scores, although disease was often well controlled. High fear scores were associated with psychological distress. This questionnaire could be useful both in routine practice and clinical trials., Competing Interests: Competing interests: LG, PC, AS, CH, CD, ST, FB: no competing interests.GC and J-MJ are employees of UCB Pharma; TdC was an employee of UCB Pharma at the time of the study; VS and FR-M are employees of Fondation Arthritis., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Desmoplasia, a fibrotic mass including cancer-associated fibroblasts (CAFs) and self-sustaining extracellular matrix (D-ECM), is a puzzling feature of pancreatic ductal adenocarcinoma (PDACs). Conflicting studies have identified tumor-restricting and tumor-promoting roles of PDAC-associated desmoplasia, suggesting that individual CAF/D-ECM protein constituents have distinguishable tumorigenic and tumor-repressive functions. Using 3D culture of normal pancreatic versus PDAC-associated human fibroblasts, we identified a CAF/D-ECM phenotype that correlates with improved patient outcomes, and that includes CAFs enriched in plasma membrane-localized, active α 5 β 1 -integrin. Mechanistically, we established that TGFβ is required for D-ECM production but dispensable for D-ECM-induced naïve fibroblast-to-CAF activation, which depends on α v β 5 -integrin redistribution of pFAK-independent active α 5 β 1 -integrin to assorted endosomes. Importantly, the development of a simultaneous multi-channel immunofluorescence approach and new algorithms for computational batch-analysis and their application to a human PDAC panel, indicated that stromal localization and levels of active SMAD2/3 and α 5 β 1 -integrin distinguish patient-protective from patient-detrimental desmoplasia and foretell tumor recurrences, suggesting a useful new prognostic tool., Competing Interests: The authors declare that no competing interests exist.

Objectives: To evaluate the impact of rheumatoid arthritis (RA) on career, productivity, and employability., Methods: A retrospective cross-sectional survey was conducted in 2012-2013 in France among patients with RA who were younger than 60 years of age and employed or unemployed. Patients were either recruited during a rheumatologist visit or among members of a nationwide patient-support organization (ANDAR). They completed a questionnaire on the functional impact of RA evaluated by the Health Assessment Questionnaire (HAQ) and on the impact of their disease on work ability., Results: Of 488 surveyed patients, 364 (74.6%) were actively employed, 31 (6.4%) were job seekers, and 93 (19.1%) had left the workforce. In the employed group, mean age was 48.9 years; 82.1% of patients were women; mean RA duration was 11.6 years; and the HAQ score correlated strongly with various markers for decreased productivity including sick leaves, temporary or permanent work discontinuation, and having unwillingly downgraded from a full-time to a part-time work schedule or changed to a different job. Among job seekers, 54% had lost their previous job because of their RA., Conclusion: RA is associated with various forms of work disability, which are directly related to the severity of disease-related functional impairments., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

Objective: To estimate healthcare service utilisation costs of patients with rheumatoid arthritis in France and to estimate the fraction of these costs attributable to RA., Method: The "Échantillon généraliste des bénéficiaires" (EGB) is a 1/97 random sample of the main national claims database covering the French population. A cohort of patients with rheumatoid arthritis was constituted of all adults benefiting from full coverage for rheumatoid arthritis (ICD-10 M05-06) on 1st january 2009. A control group matched for age and gender was identified. Health expenditures were assessed from the payer's perspective for the year 2010., Results: The annual per capita reimbursed total health expenditure was €6,404 in 2010, an amount around two times higher than in the control group €3,095 (P<0.0001). The main contributors to this extra cost were outpatient care (+€2,407; 72.7%), including medication (+€1,686; 50.0%), and inpatient care (+€903; 27.3%). Patients treated by biological agents generated an age-adjusted per capita annual expenditure about three times higher than untreated patients (€15,757 versus €4,640)., Conclusion: Only half of medical expenditure by patients with rheumatoid arthritis is attributable to their disease and use of biological agents has become a major driver of cost., (Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.)

The overarching goal of this event-related potential (ERP) study was to examine the effects of scopolamine on the dynamics of brain network activation using a novel ERP network analysis method known as Brain Network Activation (BNA). BNA was used for extracting group-common stimulus-activated network patterns elicited to matching probe stimuli in the context of a delayed matching-to-sample task following placebo and scopolamine treatments administered to healthy participants. The BNA extracted networks revealed the existence of two pathophysiological mechanisms following scopolamine, disconnection, and compensation. Specifically, weaker frontal theta and parietal alpha coupling was accompanied with enhanced fronto-centro-parietal theta activation relative to placebo. In addition, using the characteristic BNA network of each treatment as well as corresponding literature-guided selective subnetworks as combined biomarkers managed to differentiate between individual responses to each of the treatments. Behavioral effects associated with scopolamine included delayed response time and impaired response accuracy. These results indicate that the BNA method is sensitive to the effects of scopolamine on working memory and that it may potentially enable diagnosis and treatment assessment of dysfunctions associated with cholinergic deficiency.