A Smartphone App to Support Self-Management for People Living With Sjögren's Syndrome: Qualitative Co-Design Workshops.

BACKGROUND: Sjögren's syndrome (SS) is the second most common autoimmune rheumatic disease, and the range of symptoms includes fatigue, dryness, sleep disturbances, and pain. Smartphone apps may help deliver a variety of cognitive and behavioral techniques to support self-management in SS. However, app-based interventions must be carefully designed to promote engagement and motivate behavior change. OBJECTIVE: We aimed to explore self-management approaches and challenges experienced by people living with SS and produce a corresponding set of design recommendations that inform the design of an engaging, motivating, and evidence-based self-management app for those living with SS. METHODS: We conducted a series of 8 co-design workshops and an additional 3 interviews with participants who were unable to attend a workshop. These were audio recorded, transcribed, and initially thematically analyzed using an inductive approach. Then, the themes were mapped to the Self-Determination Theory domains of competency, autonomy, and relatedness. RESULTS: Participants experienced a considerable demand in the daily work required in self-managing their SS. The condition demanded unrelenting, fluctuating, and unpredictable mental, physical, and social efforts. Participants used a wide variety of techniques to self-manage their symptoms; however, their sense of competency was undermined by the complexity and interconnected nature of their symptoms and affected by interactions with others. The daily contexts in which this labor was occurring revealed ample opportunities to use digital health aids. The lived experience of participants showed that the constructs of competency, autonomy, and relatedness existed in a complex equilibrium with each other. Sometimes, they were disrupted by tensions, whereas on other occasions, they worked together harmoniously. CONCLUSIONS: An SS self-management app needs to recognize the complexity and overlap of symptoms and the complexities of managing the condition in daily life. Identifying techniques that target several symptoms simultaneously may prevent users from becoming overwhelmed. Including techniques that support assertiveness and communication with others about the condition, its symptoms, and users' limitations may support users in their interactions with others and improve engagement in symptom management strategies. For digital health aids (such as self-management apps) to provide meaningful support, they should be designed according to human needs such as competence, autonomy, and relatedness. However, the complexities among the 3 Self-Determination Theory constructs should be carefully considered, as they present both design difficulties and opportunities.

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.

Estimated prevalence, incidence and healthcare costs of Sjögren's syndrome in France: a national claims-based study.

OBJECTIVES: To estimate prevalence, incidence and mortality rates, and annual healthcare costs of primary Sjögren's syndrome (pSS) and SS associated with other autoimmune disorders (SS+AID) in France. METHODS: French national healthcare claims-based study within the prospective Système National des Données de Santé database that includes the majority of the French population. An algorithm was developed to identify patients with SS and SS-related healthcare claims were analysed between 2011 and 2018. RESULTS: Overall, 23 848 patients with pSS and 14 809 with SS+AID were identified. From 2011 to 2018, the prevalence rate increased slightly for pSS (23-32 per 100000) and SS+AID (16-20 per 100 000), with females comprising 90%-91% and 92%-93% of cases, respectively. The incidence rate of SS per 100 000 persons decreased from 2012 (pSS: 4.3; SS+AID: 2.0) to 2017 (pSS: 0.7; SS+AID: 0.3). Mortality rates per 100 000 persons increased from 2012 to 2018 in patients with pSS (0.2-0.8) or SS+AID (0.1-0.5); mean age of death also increased. Artificial tears and hydroxychloroquine were the most common drug reimbursements. Less than half of patients received annual specialist care from a dentist or ophthalmologist. Healthcare costs associated with SS increased from 2011 to 2018 and exceeded the national estimate of expected costs for chronic diseases. CONCLUSION: In this large French population database study, the low prevalence of pSS confirms that it is an orphan disease. SS is clinically and economically burdensome; these findings may help clinicians better understand routine healthcare received by patients.

Manifestations and management of Sjögren's disease.

Sjögren's disease is a heterogeneous autoimmune disorder that may be associated with systemic manifestations such as pulmonary or articular involvement. Systemic complications have prognostic implications and need to be identified and managed in a timely manner. Treatment should be tailored to the type and severity of organ involvement, ideally based on multidisciplinary evaluation.

Human umbilical cord mesenchymal stem cells improve disease characterization of Sjogren's syndrome in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.

BACKGROUND: For the unclear pathogenesis of Sjogren's syndrome (SS), further exploration is necessary. Mesenchymal stem cells (MSCs) and derived exosomes (MSCs-exo) have exhibited promising results in treating SS. OBJECT: This study aimed to investigate the effect and mechanism of human umbilical cord MSCs (UC-MSCs) on SS. METHODS: Nonobese Diabetic (NOD) mouse splenic T cells were co-cultured with UC-MSCs and UC-MSCs-exo, and interferon-gamma (IFN-γ), interleukin (IL)-6, IL-10, prostaglandin E2 (PGE2), and transforming growth factor-ß1 (TGF-ß1) levels in the supernatant were assessed by quantitative real-time polymerase chain reaction and enzyme-linked immunosorbent assay. Co-cultured T cells were injected into NOD mice via the tail vein. The inflammatory cell infiltration in the intestine and the submandibular gland was characterized by hematoxylin-eosin staining. Treg/Th17 homeostasis within the spleen was determined by flow cytometry. Gut microbiota was detected by 16S rRNA sequencing, and the relationship between differential microbiota and Treg/Th17 cytokines was analyzed by the Pearson correlation coefficient. RESULTS: UC-MSCs, UC-MSCs-exo, and NOD mouse splenic T cells were successfully cultured and identified. After T cells were co-cultured with UC-MSCs and UC-MSCs-exo, both IFN-γ and IL-6 were decreased while IL-10, PGE2, and TGF-ß1 were increased in transcriptional and translational levels. UC-MSCs and UC-MSCs-exo partially restored salivary secretion function, reduced Ro/SSA antibody and α-Fodrin immunoglobulin A levels, reduced inflammatory cell infiltration in the intestine and submandibular gland, raised proportion of Treg cells, decreased IFN-γ, IL-6, IL-2, IL-17, lipopolysaccharide, and tumor necrosis factor-alpha levels, and raised IL-10, Foxp3, and TGF-ß1 levels by affecting co-cultured T cells. The intervention of UC-MSCs and UC-MSCs-exo improved intestinal homeostasis in NOD mice by increasing microbiota diversity and richness. Additionally, differential microbiota was significantly associated with Treg/Th17 cytokine levels. CONCLUSION: Human UC-MSCs and UC-MSCs-exo improved disease characterization of SS in NOD mice through regulation of gut microbiota and Treg/Th17 cellular immunity.

Sjögren's syndrome.

Sjögren's syndrome (SS) is characterised as keratoconjunctivitis sicca (dry eyes), xerostomia (dry mouth) commonly associated with salivary gland enlargement, and is referred to as Primary Sjögren's syndrome. It is known as Secondary Sjögren's syndrome when it occurs in patients, with connective tissue disease, such as rheumatoid arthritis, systemic lupus erythematosus, polyarthritis nodosa, polymyositis, and systemic sclerosis. SS has also been associated with chronic graft-versus-host disease after allogeneic bone marrow transplantation, human immunodeficiency syndrome (AIDS), hepatitis C infection (HCV), chronic biliary cirrhosis, neoplastic and myeloplastic syndromes, fibromyalgia, and chronic fatigue syndrome.

Allogeneic mesenchymal stem cell therapy for dry eye disease in patients with Sjögren's syndrome: A randomized clinical trial.

PURPOSE: This double-blinded randomized clinical trial aimed to evaluate the efficacy of injecting allogeneic adipose-derived mesenchymal stem cells (ASCs) into the lacrimal gland (LG) for the treatment of dry eye disease (DED) secondary to Sjögren's syndrome (SS). METHODS: Fifty-four participants with severe DED secondary to SS were included and allocated to either ASCs (n = 20), vehicle (n = 20), or a non-randomized observation group (n = 14). The intervention groups received a single injection of either ASCs or an active comparator (vehicle, Cryostor® CS10) into the LG in one eye, while the observation group received lubricating eye drops only. The primary outcome measure was changes in Ocular Surface Disease Index (OSDI) score and secondary outcome measures were non-invasive tear break-up time, tear meniscus height, Schirmer's test, and Oxford score within a 12-month follow-up. RESULTS: A significant reduction in OSDI score was observed in the ASCs and vehicle groups compared to the observation group. In addition, the ASCs group demonstrated a significant increase in non-invasive tear break-up time compared to the vehicle group at the 4-week follow-up and to the observation group at the 12-month follow-up. A significant improvement in ocular surface staining, tear osmolarity, and Schirmer test score from baseline was also observed in the ASCs group; however, these changes were not significant compared to the other groups. CONCLUSION: Improvement of subjective and objective signs and symptoms of DED was observed in both intervention groups following injection into the LG compared to the observation group. Future studies should investigate the mode-of-action of both injection treatments.

Evaluation and management of dry mouth and its complications in rheumatology practice.

INTRODUCTION: The symptom of dry mouth has multiple potential etiologies and can be a diagnostic clue to the presence of common systemic diseases encountered in rheumatology practice. The presence of decreased saliva flow (i.e. salivary hypofunction) defines a subset of dry mouth patients in whom there may be reversible drug effects, an iatrogenic insult such as head and neck irradiation, or a disease that directly involves the salivary glands (e.g. Sjögren's disease). The assessment of salivary hypofunction includes sialometry, salivary gland imaging, salivary gland biopsy, and an assessment for relevant systemic diseases. Optimal management of dry mouth requires accurate definition of its cause, followed by general measures that serve to alleviate its symptoms and prevent its complications. AREAS COVERED: Through a literature search on xerostomia and salivary hypofunction, we provide an overview of the causes of dry mouth, highlight the potential impact of salivary hypofunction on oral and systemic health, detail routine evaluation methods and treatment strategies, and emphasize the importance of collaboration with oral health care providers. EXPERT OPINION: Our Expert Opinion is provided on unmet needs in the management of dry mouth and relevant research progress in the field.

Sjogren's syndrome meets Meige's syndrome.

This report details a rare case where a patient simultaneously suffered from Sjogren's syndrome (SS) and Meige's syndrome (MS). SS, an autoimmune disorder, and MS, a rare neurological condition characterized by involuntary eyelid closure, presented in a 73-year-old male. The patient had been experiencing dry eye symptoms for the past 5 years, with the onset of eyelid spasms and tetanic eye closure occurring 3 years ago. Traditional treatments, including subthalamic nucleus deep brain stimulation, provided only temporary relief. Diagnostic evaluations, including blood tests and imaging, confirmed SS and MS coexistence. Treatment involved a combination of steroids, immunosuppressants, and immunoglobulin, leading to significant symptom relief. This case suggests a potential association between SS and the development of MS, highlighting the importance of immunomodulatory therapy in managing neurological symptoms. Further research is needed to explore the relationship between these two conditions and to develop more effective treatment strategies.

Impact of sex differences on the clinical presentation, pathogenesis, treatment and prognosis of Sjögren's syndrome.

Sjögren's syndrome is a common chronic autoimmune disease that manifests as dry mouth, dry eyes and systemic complications. There are sex differences in the clinical manifestations between men and women, with the average age of onset being around 55 years and the majority of female patients developing the disease during the menopausal years. Understanding the impact of sex differences on SS may help in the treatment and prognosis of patients. Studies have confirmed that a number of factors are associated with the onset of SS, but the exact mechanisms are not fully understood. Sex hormones (especially oestrogens and androgens) play a very important role, and the balance of sex hormone levels in the body is crucial for maintaining homeostasis in the acinar cells of the lacrimal and salivary glands. In addition, chromosomes play a very important role in the sex differences in SS. The gut microbiota also has some influence on sex differences in SS. In this review, we focus on oestrogens and androgens, which are important in the pathogenesis of SS, and summarize the progress of non-clinical studies. Sex differences may influence differences in individualized treatment regimens and further studies are needed.

Recent progress in regenerative therapy for damaged salivary glands: From bench to bedside.

OBJECTIVE: For functional restoration of salivary glands (SGs) injured by radiation therapy or Sjögren's syndrome (SS), various experimental approaches, such as gene therapy, tissue engineering, and cell-based therapy, have been proposed. This narrative review summarized recent progresses in research using cell-based therapies, including promising trials that could lead to bench-to-clinic applications. METHODS: A literature review based on PubMed publications in the last two decades was performed to summarize progresses in cell-based therapies for SG dysfunction. RESULTS: Over 100 experimental studies have shown the therapeutic potential of several types of cells, such as SG stem cells and mesenchymal stem cells, as well as effectively conditioned mononuclear cells, in both radiation injury and SS animal models. These therapies affect to slow fibrosis progression and stimulate tissue regeneration in atrophic glands. However, to date, only a total of seven studies have been developed to the stage of clinical study, showing the safety and preliminary efficacy. CONCLUSION: To lead the radical effectiveness expected in cell-based therapy, advances in reverse translational research and in innovative experimental research, based on the findings of recent clinical studies, will be critical in the next decade.

Sjögren's syndrome: one year in review 2023.

Primary Sjögren's syndrome (pSS) is a systemic autoimmune disorder characterised by the T-cell-mediated hyperactivation of B-cells and cytokine production. The condition may evolve from an asymptomatic, indolent course, with glandular involvement, to extra-glandular systemic manifestations up to lymphoma development. On tissue level, the typical feature is the lymphocytic infiltration of the salivary gland by B-, T- and antigen presenting cells, as mirrored by the diagnostic cornerstone role of minor salivary gland (MSG) biopsy. Recently, increasing research focused on the investigation of mechanisms underlying the complex pathogenesis of the disease and highlighted the multi-factorial nature of SS consisting of concomitant involvement of environmental, genetic, neuroendocrine and immune factors. In particular, many aspects have been investigated regarding genetic and epigenetics, the role of specific B- and T-cell phenotypes and the investigation of disease-specific biomarkers as predictors of disease development, activity, and lymphomagenesis. Surely, a deeper understanding of these multiple mechanisms may facilitate earlier diagnosis, enable subphenotyping of patients and open novel therapeutic possibilities to address the unmet needs of the disease in the upcoming years.In this review, following the others of this series, we will summarise the most recent literature on pSS pathogenesis and clinical features focusing in particular on new insights into pSS molecular stratification and therapeutic advances in the era of precision medicine.

Impact of gender and age at onset on Sjögren's syndrome presentation and outcome: state of the art.

Sjögren's syndrome (SS) is a complex and heterogeneous disease that typically affects middle-aged women. However, while it is rare, the disease may occur in male patients and in females during their childhood/adolescence or in the elderly. Contrasting data have been reported on these three subgroups clinical features and long-term outcomes. Notably, recent studies have pinpointed the severity of the disease in male patients and in both the early and the late-onset subgroups.The aim of this review is, therefore, to summarise the available evidence from the recent literature on these phenotypes. The focus will be on the clinical and laboratory features, and on the lymphoma risk observed in the three subgroups distinct phenotypes: of male patients as well as young-onset SS and elderly-onset SS. Ultimately, an accurate phenotypic stratification may represent the first step towards individualised medical approaches.

Advances in mesenchymal stem cell-derived extracellular vesicles therapy for Sjogren's syndrome-related dry eye disease.

Sjogren's syndrome (SS) is a chronic autoimmune disorder that affects exocrine glands, particularly lacrimal glands, leading to dry eye disease (DED). DED is a common ocular surface disease that affects millions of people worldwide, causing discomfort, visual impairment, and even blindness in severe cases. However, there is no definitive cure for DED, and existing treatments primarily relieve symptoms. Consequently, there is an urgent need for innovative therapeutic strategies based on the pathophysiology of DED. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic tool for various autoimmune disorders, including SS-related DED (SS-DED). A particularly intriguing facet of MSCs is their ability to produce extracellular vesicles (EVs), which contain various bioactive components such as proteins, lipids, and nucleic acids. These molecules play a key role in facilitating communication between cells and modulating a wide range of biological processes. Importantly, MSC-derived EVs (MSC-EVs) have therapeutic properties similar to those of their parent cells, including immunomodulatory, anti-inflammatory, and regenerative properties. In addition, MSC-EVs offer several notable advantages over intact MSCs, including lower immunogenicity, reduced risk of tumorigenicity, and greater convenience in terms of storage and transport. In this review, we elucidate the underlying mechanisms of SS-DED and discuss the relevant mechanisms and targets of MSC-EVs in treating SS-DED. In addition, we comprehensively review the broader landscape of EV application in autoimmune and corneal diseases. This review focuses on the efficacy of MSC-EVs in treating SS-DED, a field of study that holds considerable appeal due to its multifaceted regulation of immune responses and regenerative functions.

Treatment with a Lactococcus lactis that chromosomally express E. coli cfaI mitigates salivary flow loss in a Sjögren's syndrome-like disease.

Sjögren's Syndrome (SjS) results in loss of salivary and lacrimal gland excretion due to an autoimmune attack on these secretory glands. Conventional SjS treatments address the symptoms, but not the cause of disease. Recognizing this deficit of treatments to reverse SjS disease, studies were pursued using the fimbriae from enterotoxigenic E. coli, colonization factor antigen I (CFA/I), which has anti-inflammatory properties. To determine if CFA/I fimbriae could attenuate SjS-like disease in C57BL/6.NOD-Aec1Aec2 (SjS) females, the Lactococcus lactis (LL) 301 strain was developed to chromosomally express the cfaI operon. Western blot analysis confirmed CFA/I protein expression, and this was tested in SjS females at different stages of disease. Repeated dosing with LL 301 proved effective in mitigating salivary flow loss and in reducing anti-nuclear antibodies (ANA) and inflammation in the submandibular glands (SMGs) in SjS females and in restoring salivary flow in diseased mice. LL 301 treatment reduced proinflammatory cytokine production with concomitant increases in TGF-ß+ CD25+ CD4+ T cells. Moreover, LL 301 treatment reduced draining lymph and SMG follicular T helper (Tfh) cell levels and proinflammatory cytokines, IFN-γ, IL-6, IL-17, and IL-21. Such evidence points to the therapeutic capacity of CFA/I protein to suppress SjS disease and to have restorative properties in combating autoimmune disease.

Efficacy and safety of platelet-rich plasma and autologous-serum eye drops for dry eye in primary Sjögren's syndrome: a randomized trial.

We compared the efficacy and safety of autologous-serum (AS) and platelet-rich plasma (PRP) eye drops for dry eye (DE) treatment in primary Sjögren's syndrome (SS). This prospective, randomized, double-blinded clinical study included patients diagnosed with primary SS DE. Thirty-eight participants were randomly assigned to the AS or PRP groups. Corneal and conjunctival staining scores, Schirmer I test, tear film break-up time (TBUT), and ocular surface disease index (OSDI) scores were evaluated at 4 and 12 weeks. Conjunctival impression cytology (CIC) metaplasia grade and goblet cell density grade at 12 weeks were compared with those at baseline. Corneal and conjunctival staining scores and TBUT significantly improved at 4 and 12 weeks in both groups (all p < 0.005). No significant difference between the AS and PRP groups was observed at 4 and 12 weeks. The Schirmer I values, OSDI scores, CIC metaplasia grade, and goblet cell density grade did not significantly change at 4 and 12 weeks in either group. Both AS and PRP eye drops are effective for primary SS DE without a significant difference. Considering that the preparation time of PRP is shorter than that of AS, PRP can be a good alternative treatment for primary SS DE.

Association of Ocular Surface Immune Cells With Dry Eye Signs and Symptoms in the Dry Eye Assessment and Management (DREAM) Study.

Purpose: Dry eye disease (DED) is a multifactorial, heterogeneous disease of the ocular surface with one etiology being ocular surface inflammation. Studies using animal models demonstrate the role of ocular surface immune cells in the inflammatory pathway leading to DED, but few have evaluated humans. This study described the white blood cell population from the ocular surface of patients with DED and assessed its association with DED signs and symptoms in participants of the Dry Eye Assessment and Management (DREAM) study. Methods: Participants were assessed for symptoms using the Ocular Surface Disease Index, signs via corneal staining, conjunctival staining, tear break-up time, and Schirmer test, and Sjögren's syndrome (SS) based on the 2012 American College of Rheumatology classification criteria. Impression cytology of conjunctival cells from each eye was evaluated using flow cytometry: T cells, helper T cells (Th), regulatory T cells (Tregs), cytotoxic T cells, and dendritic cells. Results: We assessed 1049 eyes from 527 participants. White blood cell subtype percentages varied widely across participants. Significant positive associations were found for Th and conjunctival staining (mean score of 2.8 for 0% Th and 3.1 for >4.0% Th; P = 0.007), and corneal staining (mean score of 3.5 for 0% Th and 4.3 for >4.0% Th; P = 0.01). SS was associated with higher percent of Tregs (median 0.1 vs. 0.0; P = 0.01). Conclusions: Th were associated with more severe conjunctival and corneal staining, possibly indicating their role in inflammation leading to damage of the ocular surface. There is no consistent conclusion about Tregs in SS, but these results support that Tregs are elevated in SS.

Effect of adipose tissue-derived stem cells therapy on clinical response in patients with primary Sjogren's syndrome.

The purpose of this trial was to clinically assess the effect and safety of Adipose Tissue-derived Stem Cells (ADSCs) treatment on primary Sjogren's Syndrome (pSS). In this 6-month randomized, triple-blind, placebo-controlled clinical trial, pSS patients were randomly assigned to two groups. After demographic characteristics and clinical examination were achieved, local injection of ADSCs into bilateral glands was performed with patients in ADSCs group (n = 35) and placebo solution was used for another group (n = 39) at three time points. Patients were followed up at 1-, 3- and 6-month. At each visit, studies of clinical and laboratory outcomes, as well as subjective symptoms, were conducted. A total of 74 subjects who met the including criteria were allocated in two groups and eventually 64 subjects (86.5%) completed the treatments and the follow-up assessments. Secretion of salivary and lachrymal glands were significantly improved in 3-month (P < 0.05). A great improvement of European League Against Rheumatism Sjögren's Syndrome Disease Activity Index (ESSDAI) was found after ADSCs treatment with intergroup comparison from baseline to follow-up (P < 0.05). There is also a significant difference of European Alliance of Associations for Rheumatology SS Patient Reported Index (ESSPRI) between the two groups in the follow-up (P < 0.05). A significant abatement of IgG, IgM, C3, C4 and ESR between two groups was observed in part of follow-up time points (P < 0.05). The ADSCs therapy can provide relief of oral and eye's dryness in our trial in a short time and has potential improvement of subjective and systemic syndromes of pSS.

[Recommendations for the diagnosis and treatment of Sjögren's syndrome in China].

Sjögren's syndrome (SS) is a chronic systemic autoimmune disease characterized by lymphocyte proliferation and progressive exocrine gland damage. In addition to the impairment of salivary and lacrimal gland function, SS can present with multi-system and multi-organ involvement, accompanied by autoantibodies in serum and hyperimmunoglobulinemia. SS can be divided into primary and secondary forms based on the absence or presence, respectively, of concurrent connective tissue diseases such as systemic lupus erythematosus and rheumatoid arthritis. Based on evidence and guidelines from China and other countries, the Chinese Rheumatology Association drafted standardized criteria for the diagnosis and treatment of primary SS. The objectives were to standardize the detection and interpretation of key indicators for the diagnosis of SS, including serum anti-SSA antibody and labial gland pathology, suggest the use of the widely accepted European League Against Rheumatism (EULAR)-SS disease activity index for the evaluation of the disease, and standardize the rational management of SS patients with topical and systemic therapies.