British Society for Rheumatology guideline on management of adult and juvenile onset Sjögren disease.

Sjögren disease (SD) is a chronic, autoimmune disease of unknown aetiology with significant impact on quality of life. Although dryness (sicca) of the eyes and mouth are the classically described features, dryness of other mucosal surfaces and systemic manifestations are common. The key management aim should be to empower the individual to manage their condition-conserving, replacing and stimulating secretions; and preventing damage and suppressing systemic disease activity. This guideline builds on and widens the recommendations developed for the first guideline published in 2017. We have included advice on the management of children and adolescents where appropriate to provide a comprehensive guideline for UK-based rheumatology teams.

What can patients tell us in Sjögren's syndrome?

In Sjögren's Syndrome (SS), clinical heterogeneity and discordance between disease activity measures and patient experience are key obstacles to effective therapeutic development. Patient reported outcome measures (PROMs) are useful tools for understanding the unmet needs from the patients' perspective and therefore they are key for the development of patient centric healthcare systems. Initial concern about the subjectivity of PROMs has given way to methodological rigour and clear guidance for the development of PROMs. To date, several studies of patient stratification using PROMs have identified similar symptom-based subgroups. There is evidence to suggest that these subgroups may represent different disease endotypes with differing responses to therapeutic interventions. Stratified medicine approaches, alongside sensitive outcome measures, have the potential to improve our understanding of SS pathobiology and therapeutic development. The inclusion of PROMs is important for the success of such approaches. In this review we discuss the opportunities of using PROMs in understanding the pathogenesis of and therapeutic development for SS.

Fatigue-Related Changes of Daily Function: Most Promising Measures for the Digital Age.

Background: Fatigue is a prominent symptom in many diseases and is strongly associated with impaired daily function. The measurement of daily function is currently almost always done with questionnaires, which are subjective and imprecise. With the recent advances of digital wearable technologies, novel approaches to evaluate daily function quantitatively and objectively in real-life conditions are increasingly possible. This also creates new possibilities to measure fatigue-related changes of daily function using such technologies. Summary: This review examines which digitally assessable parameters in immune-mediated inflammatory and neurodegenerative diseases may have the greatest potential to reflect fatigue-related changes of daily function. Key Messages: Results of a standardized analysis of the literature reporting about perception-, capacity-, and performance-evaluating assessment tools indicate that changes of the following parameters: physical activity, independence of daily living, social participation, working life, mental status, cognitive and aerobic capacity, and supervised and unsupervised mobility performance have the highest potential to reflect fatigue-related changes of daily function. These parameters thus hold the greatest potential for quantitatively measuring fatigue in representative diseases in real-life conditions, e.g., with digital wearable technologies. Furthermore, to the best of our knowledge, this is a new approach to analysing evidence for the design of performance-based digital assessment protocols in human research, which may stimulate further systematic research in this area.

Identification of distinct subgroups of Sjögren's disease by cluster analysis based on clinical and biological manifestations: data from the cross-sectional Paris-Saclay and the prospective ASSESS cohorts.

BACKGROUND: Sjögren's disease is a heterogenous autoimmune disease with a wide range of symptoms-including dryness, fatigue, and pain-in addition to systemic manifestations and an increased risk of lymphoma. We aimed to identify distinct subgroups of the disease, using cluster analysis based on subjective symptoms and clinical and biological manifestations, and to compare the prognoses of patients in these subgroups. METHODS: This study included patients with Sjögren's disease from two independent cohorts in France: the cross-sectional Paris-Saclay cohort and the prospective Assessment of Systemic Signs and Evolution of Sjögren's Syndrome (ASSESS) cohort. We first used an unsupervised multiple correspondence analysis to identify clusters within the Paris-Saclay cohort using 26 variables comprising patient-reported symptoms and clinical and biological manifestations. Next, we validated these clusters using patients from the ASSESS cohort. Changes in disease activity (measured by the European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI]), patient-acceptable symptom state (measured by the EULAR Sjögren's Syndrome Patient Reported Index [ESSPRI]), and lymphoma incidence during follow-up were compared between clusters. Finally, we compared our clusters with the symptom-based subgroups previously described by Tarn and colleagues. FINDINGS: 534 patients from the Paris-Saclay cohort (502 [94%] women, 32 [6%] men, median age 54 years [IQR 43-64]), recruited between 1999 and 2022, and 395 patients from the ASSESS cohort (370 [94%] women, 25 [6%] men, median age 53 years [43-63]), recruited between 2006 and 2009, were included in this study. In both cohorts, hierarchical cluster analysis revealed three distinct subgroups of patients: those with B-cell active disease and low symptom burden (BALS), those with high systemic disease activity (HSA), and those with low systemic disease activity and high symptom burden (LSAHS). During follow-up in the ASSESS cohort, disease activity and symptom states worsened for patients in the BALS cluster (67 [36%] of 186 patients with ESSPRI score <5 at month 60 vs 92 [49%] of 186 at inclusion; p<0·0001). Lymphomas occurred in patients in the BALS cluster (five [3%] of 186 patients; diagnosed a median of 70 months [IQR 42-104] after inclusion) and the HSA cluster (six [4%] of 158 patients; diagnosed 23 months [13-83] after inclusion). All patients from the Paris-Saclay cohort with a history of lymphoma were in the BALS and HSA clusters. This unsupervised clustering classification based on symptoms and clinical and biological manifestations did not correlate with a previous classification based on symptoms only. INTERPRETATION: On the basis of symptoms and clinical and biological manifestations, we identified three distinct subgroups of patients with Sjögren's disease with different prognoses. Our results suggest that these subgroups represent different heterogeneous pathophysiological disease mechanisms, stages of disease, or both. These findings could be of interest when stratifying patients in future therapeutic trials. FUNDING: Fondation pour la Recherche Médicale, French Ministry of Health, French Society of Rheumatology, Innovative Medicines Initiative 2 Joint Undertaking, Medical Research Council UK, and Foundation for Research in Rheumatology.

The Sjögren's Working Group: The 2023 OMERACT meeting and provisional domain generation.

Sjögren's disease (SjD) is a systemic autoimmune exocrinopathy with key features of dryness, pain, and fatigue. SjD can affect any organ system with a variety of presentations across individuals. This heterogeneity is one of the major barriers for developing effective disease modifying treatments. Defining core disease domains comprising both specific clinical features and incorporating the patient experience is a critical first step to define this complex disease. The OMERACT SjD Working Group held its first international collaborative hybrid meeting in 2023, applying the OMERACT 2.2 filter toward identification of core domains. We accomplished our first goal, a scoping literature review that was presented at the Special Interest Group held in May 2023. Building on the domains identified in the scoping review, we uniquely deployed multidisciplinary experts as part of our collaborative team to generate a provisional domain list that captures SjD heterogeneity.

Examining the biological pathways underlying clinical heterogeneity in Sjogren's syndrome: proteomic and network analysis.

OBJECTIVES: Stratification approaches are vital to address clinical heterogeneity in Sjogren's syndrome (SS). We previously described that the Newcastle Sjogren's Stratification Tool (NSST) identified four distinct clinical subtypes of SS. We performed proteomic and network analysis to analyse the underlying pathobiology and highlight potential therapeutic targets for different SS subtypes. METHOD: We profiled serum proteins using O-link technology of 180 SS subjects. We used 5 O-link proteomics panels which included a total of 454 unique proteins. Network reconstruction was performed using the ARACNE algorithm, with differential expression estimates overlaid on these networks to reveal the key subnetworks of differential expression. Furthermore, data from a phase III trial of tocilizumab in SS were reanalysed by stratifying patients at baseline using NSST. RESULTS: Our analysis highlights differential expression of chemokines, cytokines and the major autoantigen TRIM21 between the SS subtypes. Furthermore, we observe differential expression of several transcription factors associated with energy metabolism and redox balance namely APE1/Ref-1, FOXO1, TIGAR and BACH1. The differentially expressed proteins were inter-related in our network analysis, supporting the concept that distinct molecular networks underlie the clinical subtypes of SS. Stratification of patients at baseline using NSST revealed improvement of fatigue score only in the subtype expressing the highest levels of serum IL-6. CONCLUSIONS: Our data provide clues to the pathways contributing to the glandular and non-glandular manifestations of SS and to potential therapeutic targets for different SS subtypes. In addition, our analysis highlights the need for further exploration of altered metabolism and mitochondrial dysfunction in the context of SS subtypes.

Serum and Tissue Biomarkers Associated With Composite of Relevant Endpoints for Sjögren Syndrome (CRESS) and Sjögren Tool for Assessing Response (STAR) to B Cell-Targeted Therapy in the Trial of Anti-B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS).

OBJECTIVE: This study aimed to identify peripheral and salivary gland (SG) biomarkers of response/resistance to B cell depletion based on the novel concise Composite of Relevant Endpoints for Sjögren Syndrome (cCRESS) and candidate Sjögren Tool for Assessing Response (STAR) composite endpoints. METHODS: Longitudinal analysis of peripheral blood and SG biopsies was performed pre- and post-treatment from the Trial of Anti-B Cell Therapy in Patients With Primary Sjögren Syndrome (TRACTISS) combining flow cytometry immunophenotyping, serum cytokines, and SG bulk RNA sequencing. RESULTS: Rituximab treatment prevented the worsening of SG inflammation observed in the placebo arm, by inhibiting the accumulation of class-switched memory B cells within the SG. Furthermore, rituximab significantly down-regulated genes involved in immune-cell recruitment, lymphoid organization alongside antigen presentation, and T cell co-stimulatory pathways. In the peripheral compartment, rituximab down-regulated immunoglobulins  and auto-antibodies together with pro-inflammatory cytokines and chemokines. Interestingly, patients classified as responders  according to STAR displayed significantly higher baseline levels of C-X-C motif chemokine ligand-13 (CXCL13), interleukin (IL)-22, IL-17A, IL-17F, and tumor necrosis factor-α (TNF-α), whereas a longitudinal analysis of serum T cell-related cytokines showed a selective reduction in both STAR and cCRESS responder patients. Conversely, cCRESS response was better associated with biomarkers of SG immunopathology, with cCRESS-responders showing a significant decrease in SG B cell infiltration and reduced expression of transcriptional gene modules related to T cell costimulation, complement activation, and Fcγ-receptor engagement. Finally, cCRESS and STAR response were associated with a significant improvement in SG exocrine function linked to transcriptional evidence of SG epithelial and metabolic restoration. CONCLUSION: Rituximab modulates both peripheral and SG inflammation, preventing the deterioration of exocrine function with functional and metabolic restoration of the glandular epithelium. Response assessed by newly developed cCRESS and STAR criteria was associated with differential modulation of peripheral and SG biomarkers, emerging as novel tools for patient stratification.

Identification of Fatigue and Sleepiness in Immune and Neurodegenerative Disorders from Measures of Real-World Gait Variability.

Current assessments of fatigue and sleepiness rely on patient reported outcomes (PROs), which are subjective and prone to recall bias. The current study investigated the use of gait variability in the "real world" to identify patient fatigue and daytime sleepiness. Inertial measurement units were worn on the lower backs of 159 participants (117 with six different immune and neurodegenerative disorders and 42 healthy controls) for up to 20 days, whom completed regular PROs. To address walking bouts that were short and sparse, four feature groups were considered: sequence-independent variability (SIV), sequence-dependant variability (SDV), padded SDV (PSDV), and typical gait variability (TGV) measures. These gait variability measures were extracted from step, stride, stance, and swing time, step length, and step velocity. These different approaches were compared using correlations and four machine learning classifiers to separate low/high fatigue and sleepiness.Most balanced accuracies were above 50%, the highest was 57.04% from TGV measures. The strongest correlation was 0.262 from an SDV feature against sleepiness. Overall, TGV measures had lower correlations and classification accuracies.Identifying fatigue or sleepiness from gait variability is extremely complex and requires more investigation with a larger data set, but these measures have shown performances that could contribute to a larger feature set.Clinical relevance- Gait variability has been repeatedly used to assess fatigue in the lab. The current study, however, explores gait variability for fatigue and daytime sleepiness in real-world scenarios with multiple gait-impacted disorders.

Exposure to air pollution as an environmental determinant of how Sjögren's disease is expressed at diagnosis.

OBJECTIVES: To analyse how the potential exposure to air pollutants can influence the key components at the time of diagnosis of Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease). METHODS: For the present study, the following variables were selected for harmonization and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Air pollution indexes per country were defined according to the OECD (1990-2021), including emission data of nitrogen and sulphur oxides (NO/SO), particulate matter (PM2.5 and 1.0), carbon monoxide (CO) and volatile organic compounds (VOC) calculated per unit of GDP, Kg per 1000 USD. RESULTS: The results of the chi-square tests of independence for each air pollutant with the frequency of dry eyes at diagnosis showed that, except for one, all variables exhibited p-values <0.0001. The most pronounced disparities emerged in the dry eye prevalence among individuals inhabiting countries with the highest NO/SO exposure, a surge of 4.61 percentage points compared to other countries, followed by CO (3.59 points), non-methane (3.32 points), PM2.5 (3.30 points), and PM1.0 (1.60 points) exposures. Concerning dry mouth, individuals residing in countries with worse NO/SO exposures exhibited a heightened frequency of dry mouth by 2.05 percentage points (p<0.0001), followed by non-methane exposure (1.21 percentage points increase, p=0.007). Individuals inhabiting countries with the worst NO/SO, CO, and PM2.5 pollution levels had a higher mean global ESSDAI score than those in lower-risk nations (all p-values <0.0001). When systemic disease was stratified according to DAS into low, moderate, and high systemic activity levels, a heightened proportion of individuals manifesting moderate/severe systemic activity was observed in countries with worse exposures to NO/SO, CO, and PM2.5 pollutant levels. CONCLUSIONS: For the first time, we suggest that pollution levels could influence how SjD appears at diagnosis in a large international cohort of patients. The most notable relationships were found between symptoms (dryness and general body symptoms) and NO/SO, CO, and PM2.5 levels.

Influence of exposure to climate-related hazards in the phenotypic expression of primary Sjögren's syndrome.

OBJECTIVES: To analyse how the key components at the time of diagnosis of the Sjögren's phenotype (epidemiological profile, sicca symptoms, and systemic disease) can be influenced by the potential exposure to climate-related natural hazards. METHODS: For the present study, the following variables were selected for harmonisation and refinement: age, sex, country, fulfilment of 2002/2016 criteria items, dry eyes, dry mouth, and overall ESSDAI score. Climate-related hazards per country were defined according to the OECD and included seven climate-related hazard types: extreme temperature, extreme precipitation, drought, wildfire, wind threats, river flooding, and coastal flooding. Climatic variables were defined as dichotomous variables according to whether each country is ranked among the ten countries with the most significant exposure. RESULTS: After applying data-cleaning techniques and excluding people from countries not included in the OECD climate rankings, the database study analysed 16,042 patients from 23 countries. The disease was diagnosed between 1 and 3 years earlier in people living in countries included among the top 10 worst exposed to extreme precipitation, wildfire, wind threats, river flooding, and coastal flooding. A lower frequency of dry eyes was observed in people living in countries exposed to wind threats, river flooding, and coastal flooding, with a level of statistical association being classified as strong (p<0.0001 for the three variables). The frequency of dry mouth was significantly lower in people living in countries exposed to river flooding (p<0.0001) and coastal flooding (p<0.0001). People living in countries included in the worse climate scenarios for extreme temperature (p<0.0001) and river flooding (p<0.0001) showed a higher mean ESSDAI score in comparison with people living in no-risk countries. In contrast, those living in countries exposed to worse climate scenarios for wind threats (p<0.0001) and coastal flooding (p<0.0001) showed a lower mean ESSDAI score in comparison with people living in no-risk countries. CONCLUSIONS: Local exposure to extreme climate-related hazards plays a role in modulating the presentation of Sjögren across countries concerning the age at which the disease is diagnosed, the frequency of dryness, and the degree of systemic activity.

Regulatory Qualification of a Cross-Disease Digital Measure: Benefits and Challenges from the Perspective of IMI Consortium IDEA-FAST.

Background: Innovative Medicines Initiative (IMI) consortium IDEA-FAST is developing novel digital measures of fatigue, sleep quality, and impact of sleep disturbances for neurodegenerative diseases and immune-mediated inflammatory diseases. In 2022, the consortium met with the European Medicines Agency (EMA) to receive advice on its plans for regulatory qualification of the measures. This viewpoint reviews the IDEA-FAST perspective on developing digital measures for multiple diseases and the advice provided by the EMA. Summary: The EMA considered a cross-disease measure an interesting and arguably feasible concept. Developers should account for the need for a strong rationale that the clinical features to be measured are similar across diseases. In addition, they may expect increased complexity of study design, challenges when managing differences within and between disease populations, and the need for validation in both heterogeneous and homogeneous populations. Key Messages: EMA highlighted the challenges teams may encounter when developing a cross-disease measure, though benefits potentially include reduced resources for the technology developer and health authority, faster access to innovation across different therapeutic fields, and feasibility of cross-disease comparisons. The insights included here can be used by project teams to guide them in the development of cross-disease digital measures intended for regulatory qualification.

Depression in Sjögren's syndrome mediates the relationship between pain, fatigue, sleepiness, and overall quality of life.

Objectives: Sjögren's syndrome (SS) includes many extra-glandular symptoms such as fatigue, pain, sleepiness and depression, which impact on quality of life (QoL). These symptoms also influence each other and could be linked by autonomic nervous system (ANS) dysregulation. Our aim was to model the role of putative predictive variables, including depression in the relationships between ANS function, fatigue, and QoL in SS. Methods: Cross-sectional analysis of self-reported data from the multicentre UK primary SS registry. The Composite Autonomic Symptom Scale (COMPASS) was used to assess autonomic function, the Hospital Anxiety and Depression Scale (HADS) to assess anxiety and depression and the EuroQol-5 Dimension (EQ-5D) to assess QoL. Validated scales were used for other clinical variables. Using multiple regression analysis and structural equation modelling (SEM), we investigated how the QoL of people with SS is impacted by the direct and indirect effects of fatigue, sleepiness, depression, symptom burden and ANS function, and their interactions. Results: Data was obtained for 1046 people with SS, 56% COMPASS completers. Symptoms of ANS dysregulation were common. Participants with ANS dysregulation had more severe depression, anxiety, dryness, fatigue, pain, sleepiness and QoL (P < 0.01 for all). Depression, anxiety, dryness, and pain were independent predictors of ANS function in the multiple regression model (P < 0.05 for all). ANS function could not be included in the SEM. The SEM model had good fit to the data (comparative fit index = 0.998) and showed that, in people with SS, depression mediates the effects of pain, fatigue and sleepiness on QoL. Conclusion: Our results show that diagnosing and treating depression in people with SS could have direct positive impact on QoL, and significantly ameliorate the impact of fatigue and pain.

Digital endpoints in clinical trials of Alzheimer's disease and other neurodegenerative diseases: challenges and opportunities.

Alzheimer's disease (AD) and other neurodegenerative diseases such as Parkinson's disease (PD) and Huntington's disease (HD) are associated with progressive cognitive, motor, affective and consequently functional decline considerably affecting Activities of Daily Living (ADL) and quality of life. Standard assessments, such as questionnaires and interviews, cognitive testing, and mobility assessments, lack sensitivity, especially in early stages of neurodegenerative diseases and in the disease progression, and have therefore a limited utility as outcome measurements in clinical trials. Major advances in the last decade in digital technologies have opened a window of opportunity to introduce digital endpoints into clinical trials that can reform the assessment and tracking of neurodegenerative symptoms. The Innovative Health Initiative (IMI)-funded projects RADAR-AD (Remote assessment of disease and relapse-Alzheimer's disease), IDEA-FAST (Identifying digital endpoints to assess fatigue, sleep and ADL in neurodegenerative disorders and immune-mediated inflammatory diseases) and Mobilise-D (Connecting digital mobility assessment to clinical outcomes for regulatory and clinical endorsement) aim to identify digital endpoints relevant for neurodegenerative diseases that provide reliable, objective, and sensitive evaluation of disability and health-related quality of life. In this article, we will draw from the findings and experiences of the different IMI projects in discussing (1) the value of remote technologies to assess neurodegenerative diseases; (2) feasibility, acceptability and usability of digital assessments; (3) challenges related to the use of digital tools; (4) public involvement and the implementation of patient advisory boards; (5) regulatory learnings; and (6) the significance of inter-project exchange and data- and algorithm-sharing.

Technology acceptance of digital devices for home use: Qualitative results of a mixed methods study.

Objective: Digital devices have demonstrated benefits to patients with chronic and neurodegenerative diseases. But when patients use medical devices in their homes, the technologies have to fit into their lives. We investigated the technology acceptance of seven digital devices for home use. Methods: We conducted 60 semi-structured interviews with participants of a larger device study on their views on the acceptability of seven devices. Transcriptions were analysed using qualitative content analysis. Results: Based on the unified theory of acceptance and use of technology, we evaluated effort, facilitating conditions, performance expectancy and social influence of each device.In the effort category, five themes emerged: (a) the hassle to use the device; (b) its usability; (c) comfort; (d) disturbance to daily life; and (e) problems during usage. Facilitating conditions consisted of five themes: (a) expectations regarding a device; (b) quality of the instructions; (c) insecurities with usage; (d) possibilities of optimization; and (e) possibilities to use the device longer. Regarding performance expectancy, we identified three themes: (a) insecurities with the performance of a device; (b) feedback; and (c) motivation for using a device. In the social influence category, three themes emerged: (a) reactions of peers; (b) concerns with the visibility of a device; and (c) concerns regarding data privacy. Conclusions: We identify key factors that determine the acceptability of medical devices for home use from the participants' perspective. These include low effort of use, minor disruptions to their daily lives and good support from the study team.

Reverse Engineering of Digital Measures: Inviting Patients to the Conversation.

Background: Digital measures offer an unparalleled opportunity to create a more holistic picture of how people who are patients behave in their real-world environments, thereby establishing a better connection between patients, caregivers, and the clinical evidence used to drive drug development and disease management. Reaching this vision will require achieving a new level of co-creation between the stakeholders who design, develop, use, and make decisions using evidence from digital measures. Summary: In September 2022, the second in a series of meetings hosted by the Swiss Federal Institute of Technology in Zürich, the Foundation for the National Institutes of Health Biomarkers Consortium, and sponsored by Wellcome Trust, entitled "Reverse Engineering of Digital Measures," was held in Zurich, Switzerland, with a broad range of stakeholders sharing their experience across four case studies to examine how patient centricity is essential in shaping development and validation of digital evidence generation tools. Key Messages: In this paper, we discuss progress and the remaining barriers to widespread use of digital measures for evidence generation in clinical development and care delivery. We also present key discussion points and takeaways in order to continue discourse and provide a basis for dissemination and outreach to the wider community and other stakeholders. The work presented here shows us a blueprint for how and why the patient voice can be thoughtfully integrated into digital measure development and that continued multistakeholder engagement is critical for further progress.

The Effects of Noninvasive Vagus Nerve Stimulation on Fatigue in Participants With Primary Sjögren's Syndrome.

OBJECTIVES: Fatigue is one of the most important symptoms needing improvement in Primary Sjögren's syndrome (PSS). Previous data from our group suggest that noninvasive stimulation of the vagus nerve (nVNS) may improve symptoms of fatigue. This experimental medicine study uses the gammaCore device (electroCore) and a sham device to investigate the relationship between nVNS and fatigue in PSS, and to explore potential mechanisms involved. MATERIALS AND METHODS: Forty participants with PSS were randomly assigned to use active (n = 20) or sham (n = 20) nVNS devices twice daily for 54 days in a double-blind manner. Patient-reported measures of fatigue were collected at baseline and day 56: Profile of Fatigue (PRO-F)-Physical, PRO-F-Mental and Visual Analogue Scale of abnormal fatigue (fVAS). Neurocognitive tests, immunologic responses, electroencephalography alpha reactivity, muscle acidosis, and heart rate variability were compared between devices from baseline to day 56 using analysis of covariance. RESULTS: PRO-F-Physical, PRO-F-Mental, and fVAS scores were significantly reduced at day 56 in the active group only (p = 0.02, 0.02, and 0.04, respectively). Muscle bioenergetics and heart rate variability showed no change between arms. There were significant improvements in digit span and a neurocognitive test (p = 0.03), and upon acute nVNS stimulation, frontal region alpha reactivity showed a significant negative relationship with fatigue scores in the active group (p < 0.01). CONCLUSIONS: We observed significant improvements in three measures of fatigue at day 56 with the active device but not the sham device. Directly after device use, fatigue levels correlate with measures of alpha reactivity, suggesting modulation of cholinergic system integrity as a mechanism of action for nVNS.

Assessing fatigue and sleep in chronic diseases using physiological signals from wearables: A pilot study.

Problems with fatigue and sleep are highly prevalent in patients with chronic diseases and often rated among the most disabling symptoms, impairing their activities of daily living and the health-related quality of life (HRQoL). Currently, they are evaluated primarily via Patient Reported Outcomes (PROs), which can suffer from recall biases and have limited sensitivity to temporal variations. Objective measurements from wearable sensors allow to reliably quantify disease state, changes in the HRQoL, and evaluate therapeutic outcomes. This work investigates the feasibility of capturing continuous physiological signals from an electrocardiography-based wearable device for remote monitoring of fatigue and sleep and quantifies the relationship of objective digital measures to self-reported fatigue and sleep disturbances. 136 individuals were followed for a total of 1,297 recording days in a longitudinal multi-site study conducted in free-living settings and registered with the German Clinical Trial Registry (DRKS00021693). Participants comprised healthy individuals (N = 39) and patients with neurodegenerative disorders (NDD, N = 31) and immune mediated inflammatory diseases (IMID, N = 66). Objective physiological measures correlated with fatigue and sleep PROs, while demonstrating reasonable signal quality. Furthermore, analysis of heart rate recovery estimated during activities of daily living showed significant differences between healthy and patient groups. This work underscores the promise and sensitivity of novel digital measures from multimodal sensor time-series to differentiate chronic patients from healthy individuals and monitor their HRQoL. The presented work provides clinicians with realistic insights of continuous at home patient monitoring and its practical value in quantitative assessment of fatigue and sleep, an area of unmet need.

Sjögren's syndrome: shedding light on emerging and key drug targets.

INTRODUCTION: Sjögren's syndrome (SS) is an immune-mediated inflammatory condition characterized by sicca syndrome, musculoskeletal pain, and fatigue. Extra-glandular manifestations are common and there is a markedly increased risk of lymphoma development. SS is associated with high health-economic burden driven largely by the symptom burden on patients. Currently, there is no approved disease-modifying treatment and management is based on empirical evidence. Progress in the understanding of SS pathogenesis has led to an expanding portfolio of more targeted therapies under development. AREAS COVERED: This review summarizes the key development in targeted biological therapies in SS including emerging targets. It also highlights the challenges in therapeutic development in SS such as disease heterogeneity and defining appropriate disease assessment tools to evaluate therapeutic efficacy. EXPERT OPINION: Early trials in SS failed to meet their primary outcomes which may in part due to the use of inappropriate or insensitive study endpoints. Recent trials targeting B-cells, B-T cell co-stimulation and IFN signaling have shown promising results. Development of composite endpoints including patient reported outcomes and objective disease measure may provide a more holistic approach to disease assessment. The impact of these new tools on therapeutic development that benefit patients remains to be fully evaluated.