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BACKGROUND: Sjögren's disease is a chronic autoimmune disease with an unmet need for targeted therapies. The aim of the TWINSS study is to evaluate the safety and efficacy of iscalimab, a monoclonal antibody against CD40, in patients with active Sjögren's disease. METHODS: This randomised, double-blind, placebo-controlled, phase 2b study, conducted at 71 sites in 23 countries, enrolled patients aged 18 years or older fulfilling the American College of Rheumatology/European Alliance of Associations for Rheumatology (EULAR) 2016 criteria. In the dose-ranging cohort 1, patients with a EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score of 5 or higher and a EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score of 5 or higher were randomly assigned (1:1:1:1) to subcutaneous iscalimab 150 mg, 300 mg, 600 mg, or placebo. In the proof-of-concept cohort 2, patients with an ESSDAI score of less than 5, ESSPRI (dryness or fatigue) score of 5 or higher, and Impact of Dry Eye on Everyday Life score of 30 or higher were randomly assigned (1:1) to iscalimab 600 mg or placebo. The sponsor, investigator, site personnel, and patients were masked to the treatment assignment. The primary objectives were to demonstrate a dose-response relationship of iscalimab based on the change in ESSDAI from baseline to week 24 in cohort 1 by Multiple Comparison Procedure-Modelling (MCP-Mod), and to assess the effect of iscalimab 600 mg on ESSPRI at week 24 in cohort 2. All the efficacy analyses included all patients who were randomly assigned, and safety analysis included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03905525), and is complete. FINDINGS: Between Oct 1, 2019, and Feb 28, 2022, 460 patients were screened; 173 patients were assigned to cohort 1 (44 to iscalimab 150 mg, 43 to 300 mg, 43 to 600 mg, and 43 to placebo) and 100 to cohort 2 (50 to each group). In cohort 1, the MCP step showed a significant dose-response relationship for placebo-adjusted ESSDAI change from baseline in one of four models (Linlog model, one-sided p=0·0041). ESSDAI decreased from baseline to week 24 with all three doses of iscalimab; 150 mg and 600 mg doses showed statistically significant improvement (placebo-adjusted least squares [LS] mean difference -3·0 [95% CI -4·9 to -1·1]; p=0·0025 for 150 mg and -2·9 [-4·9 to -1·0]; p=0·0037 for 600 mg). In cohort 2, ESSPRI showed a trend towards improvement with iscalimab 600 mg (placebo-adjusted LS mean change from baseline -0·57 points [95% CI -1·30 to 0·15]; p=0·12). Serious adverse events were reported in nine patients in cohort 1 (one [2%] of 43 in the placebo group, one [2%] of 44 in the iscalimab 150 mg group, three [7%] of 42 in the 300 mg group, four [9%] of 44 in the 600 mg group) and four patients in cohort 2 (two [4%] of 50 in each group). No deaths occurred over the 24-week period. INTERPRETATION: The study met the primary objective of demonstrating a significant dose-response relationship with iscalimab in terms of disease activity at week 24. Iscalimab was well tolerated and showed initial clinical benefit over placebo in two distinct populations of patients with Sjögren's disease, to be confirmed in larger trials. FUNDING: Novartis Pharma.
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Relação Dose-Resposta a Droga , Síndrome de Sjogren , Humanos , Método Duplo-Cego , Feminino , Masculino , Pessoa de Meia-Idade , Síndrome de Sjogren/tratamento farmacológico , Injeções Subcutâneas , Adulto , Resultado do Tratamento , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , Idoso , Índice de Gravidade de Doença , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêuticoRESUMO
OBJECTIVES: Sjögren disease (SjD) diagnosis often requires either positive anti-SSA antibodies or a labial salivary gland biopsy with a positive focus score (FS). One-third of patients with SjD lack anti-SSA antibodies (SSA-), requiring a positive FS for diagnosis. Our objective was to identify novel autoantibodies to diagnose 'seronegative' SjD. METHODS: IgG binding to a high-density whole human peptidome array was quantified using sera from SSA- SjD cases and matched non-autoimmune controls. We identified the highest bound peptides using empirical Bayesian statistical filters, which we confirmed in an independent cohort comprising SSA- SjD (n=76), sicca-controls without autoimmunity (n=75) and autoimmune-feature controls (SjD features but not meeting SjD criteria; n=41). In this external validation, we used non-parametric methods for binding abundance and controlled false discovery rate in group comparisons. For predictive modelling, we used logistic regression, model selection methods and cross-validation to identify clinical and peptide variables that predict SSA- SjD and FS positivity. RESULTS: IgG against a peptide from D-aminoacyl-tRNA deacylase (DTD2) bound more in SSA- SjD than sicca-controls (p=0.004) and combined controls (sicca-controls and autoimmune-feature controls combined; p=0.003). IgG against peptides from retroelement silencing factor-1 and DTD2 were bound more in FS-positive than FS-negative participants (p=0.010; p=0.012). A predictive model incorporating clinical variables showed good discrimination between SjD versus control (area under the curve (AUC) 74%) and between FS-positive versus FS-negative (AUC 72%). CONCLUSION: We present novel autoantibodies in SSA- SjD that have good predictive value for SSA- SjD and FS positivity.
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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.
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Síndrome de Sjogren , Humanos , Resultado do Tratamento , Síndrome de Sjogren/terapia , Dor , FadigaRESUMO
OBJECTIVES: Sjögren's disease (SjD) is a heterogenous disease with a wide range of manifestations, ranging from symptoms of dryness, fatigue, and pain, to systemic involvement. Considerable advances have been made to evaluate systemic activity or patient-reported outcomes, but most of the instruments were not able to assess all domains of this multifaceted disease. The aim of this scoping review was to generate domains that have been assessed in randomized controlled trials, as the first phase of the Outcome Measures in Rheumatology (OMERACT) process of core domain set development. METHODS: We systematically searched Medline (Pubmed) and EMBASE between 2002 and March 2023 to identify all randomized controlled trials assessing relevant domains, using both a manual approach and an artificial intelligence software (BIBOT) that applies natural language processing to automatically identify relevant abstracts. Domains were mapped to core areas, as suggested by the OMERACT 2.1 Filter. RESULTS: Among the 5,420 references, we included 60 randomized controlled trials, focusing either on overall disease manifestations (53%) or on a single organ/symptom: dry eyes (17%), xerostomia (15%), fatigue (12%), or pulmonary function (3%). The most frequently assessed domains were perceived dryness (52% for overall dryness), fatigue (57%), pain (52%), systemic disease activity (45%), lacrimal gland function (47%) and salivary function (55%), B-cell activation (60%), and health-related quality of life (40%). CONCLUSION: Our scoping review highlighted the heterogeneity of SjD, in the study designs and domains. This will inform the OMERACT SjD working group to select the most appropriate core domains to be used in SjD clinical trials and to guide the future agenda for outcome measure research in SjD.
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Qualidade de Vida , Síndrome de Sjogren , Humanos , Inteligência Artificial , Fadiga/etiologia , Dor , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: We used the University of Wisconsin cohort to determine the extent to which the EULAR Sjögren's syndrome disease activity index (ESSDAI) was associated with comorbidities that contribute to mortality. METHODS: Our University of Wisconsin, Madison cohort had 111 patients with Sjögren's Disease (SjD) by 2016 ACR/EULAR criteria and 194 control patients with sicca. Our study was performed from March 1st, 2020 through April 1st, 2023. We collected data using a standardized collection tool, including components of the Charlson Comorbidity Index (CCI). Stratifying our SjD patients by ESSDAI < 5 and ESSDAI ≥ 5, we assessed differences in comorbidities associated with mortality. RESULTS: At time of SjD diagnosis, the ESSDAI ≥ 5 group had increased odds of peripheral vascular disease compared to controls (OR 10.17; 95% CI 1.18-87.87). Patients with a current ESSDAI ≥ 5 were more likely to have a myocardial infarction compared to controls (OR 9.87; 95% CI 1.17-83.49). SjD patients had increased prevalence of monoclonal gammopathy compared to controls (9.3% vs 0.5%, p < 0.001). SjD patients with high ESSDAI at diagnosis had greater prevalence of monoclonal gammopathy compared to the SjD patients with a low ESSDAI (16% vs 5%, p = .04). As reported elsewhere, the ESSDAI ≥ 5 group had increased odds of chronic pulmonary disease (OR 4.37; 95% CI 1.59-11.97). CONCLUSION: We found high ESSDAI scores were associated with worse cardiovascular outcomes, specifically peripheral vascular disease and myocardial infarction. Furthermore, monoclonal gammopathy was more frequent in SjD patients compared to sicca controls, supporting screening for monoclonal gammopathy in the appropriate clinical scenario. Key Points ⢠High ESSDAI scores are associated with worse cardiovascular outcomes, specifically peripheral vascular disease and myocardial infarction. ⢠Monoclonal gammopathy is more frequent in SjD patients than sicca controls, supporting screening for monoclonal gammopathy in the appropriate clinical scenario.
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Doenças Cardiovasculares , Gamopatia Monoclonal de Significância Indeterminada , Infarto do Miocárdio , Paraproteinemias , Doenças Vasculares Periféricas , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/complicações , Síndrome de Sjogren/epidemiologia , Síndrome de Sjogren/diagnóstico , Estudos de Coortes , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/epidemiologia , Universidades , Índice de Gravidade de Doença , Comorbidade , Paraproteinemias/complicações , Paraproteinemias/epidemiologia , Gamopatia Monoclonal de Significância Indeterminada/complicações , Gamopatia Monoclonal de Significância Indeterminada/epidemiologiaRESUMO
Rheumatoid factors (RFs), polyreactive antibodies canonically known to bind two conformational epitopes of IgG Fc, are a hallmark of rheumatoid arthritis but also can arise in other inflammatory conditions and infections. Also, infections may contribute to the development of rheumatoid arthritis and other autoimmune diseases. Recently, RFs only in rheumatoid arthritis were found to bind novel linear IgG epitopes as well as thousands of other rheumatoid arthritis autoantigens. Specific epitopes recognized by infection-induced polyreactive RFs remain undefined but could provide insights into loss of immune tolerance. Here, we identified novel linear IgG epitopes bound by RFs in COVID-19 but not rheumatoid arthritis or other conditions. The main COVID-19 RF was polyreactive, binding two IgG and multiple viral peptides with a tripeptide motif, as well as IgG Fc and SARS-CoV-2 spike proteins. In contrast, a rheumatoid arthritis-specific RF recognized IgG Fc, but not tripeptide motif-containing peptides or spike. Thus, RFs have disease-specific IgG reactivity and distinct polyreactivities that reflect the broader immune response. Moreover, the polyreactivity of a virus-induced RF appears to be attributable to a very short peptide motif. These findings refine our understanding of RFs and provide new insights into how viral infections may contribute to autoimmunity.
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Artrite Reumatoide , Doenças Autoimunes , COVID-19 , Humanos , Epitopos , SARS-CoV-2 , Fator Reumatoide/metabolismo , Peptídeos , Imunoglobulina GRESUMO
ABSTRACT: Rheumatologists have never been reluctant to adopt procedures that might enhance their diagnostic or therapeutic powers. Their propensity to penetrate the joints of the patients they were treating set them apart from the general internist. Since the 1980s, when a chance to look inside the joints they were treating attracted a few rheumatologists, other things that could be done at the bedside emerged with now an array of bedside procedures that could be part of a rheumatologist's skill set. Besides gains in diagnosis and/or therapy, each constitutes a chance to restore the physical contact between physician and patient, riven by factors of the last decade, such as electronic medical records and COVID. With such contact so important to satisfaction of the patient and physician alike, acquisition of proficiency in certain technical procedures described herein offers one path to begin restoring rheumatology to the richly fulfilling practice it once was.
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Objectives: Sjâ¡gren's disease (SjD) diagnosis requires either positive anti-SSA antibodies or a labial salivary gland biopsy with a positive focus score (FS). One-third of SjD patients lack anti-SSA antibodies (SSA-), requiring a positive FS for diagnosis. Our objective was to identify novel autoantibodies to diagnose 'seronegative' SjD. Methods: IgG binding to a high density whole human peptidome array was quantified using sera from SSA- SjD cases and matched non-autoimmune controls. We identified the highest bound peptides using empirical Bayesian statistical filters, which we confirmed in an independent cohort comprising SSA- SjD (n=76), sicca controls without autoimmunity (n=75), and autoimmune controls (SjD features but not meeting SjD criteria; n=41). In this external validation, we used non-parametric methods for peptide abundance and controlled false discovery rate in group comparisons. For predictive modeling, we used logistic regression, model selection methods, and cross-validation to identify clinical and peptide variables that predict SSA- SjD and FS positivity. Results: IgG against a peptide from D-aminoacyl-tRNA deacylase (DTD2) was bound more in SSA- SjD than sicca controls (p=.004) and more than combined controls (sicca and autoimmune controls combined; p=0.003). IgG against peptides from retroelement silencing factor-1 (RESF1) and DTD2, were bound more in FS-positive than FS-negative participants (p=.010; p=0.012). A predictive model incorporating clinical variables showed good discrimination between SjD versus control (AUC 74%) and between FS-positive versus FS-negative (AUC 72%). Conclusion: We present novel autoantibodies in SSA- SjD that have good predictive value for SSA- SjD and FS-positivity. KEY MESSAGES: What is already known on this topic - Seronegative (anti-SSA antibody negative [SSA-]) Sjögren's disease (SjD) requires a labial salivary gland biopsy for diagnosis, which is challenging to obtain and interpret. What this study adds - We identified novel autoantibodies in SSA- SjD that, when combined with readily available clinical variables, provide good predictive ability to discriminate 1) SSA- SjD from control participants and 2) abnormal salivary gland biopsies from normal salivary gland biopsies. How this study might affect research, practice or policy - This study provides novel diagnostic antibodies addressing the critical need for improvement of SSA- SjD diagnostic tools.
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ABSTRACT: The hands-on aspect of rheumatologic practice serves to balance its more cerebral features with the everyday necessity to touch patients to assess their condition, obtain samples for diagnosis, and deliver therapy, all cementing the important bond between patient and physician. Factors over recent years, ranging from the intercession of the electronic medical record to COVID, have weakened this bond, which we must restore if the practice of rheumatology is to return to previous levels of satisfaction. We review herein, in 2 parts, the many ways rheumatologists may interact physically with patients, with hope that pursuit of these measures can enhance satisfaction of physician and patient alike. This first installment reviews those simple skills in place before more involved technical bedside skill began to evolve over the last half century.
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Retrieval of minor salivary glands from a labial submucosal site through a minimally invasive bedside procedure was first described nearly 60 years ago and remains an attractive alternative to more invasive surgical procedures to obtain salivary gland tissue for pathologic examination. Examination of glands for features of Sjögren's has constituted the primary use of this procedure but other systemic disorders can affect minor salivary glands and their diagnoses can be supported by biopsy. Performance of the procedure does not require specialized training in head and neck surgery or dentistry, only simple wound closure skills. Skill in performing the procedure enables the clinician to acquire potentially diagnostic material without the need for referral while offering immediate expert feedback to the patient being biopsied. Material obtained at biopsy can also be the focus of research investigations.
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Glândulas Salivares Menores , Síndrome de Sjogren , Humanos , Glândulas Salivares Menores/patologia , Síndrome de Sjogren/diagnóstico , Lábio/patologia , Reumatologistas , BiópsiaRESUMO
INTRODUCTION: Sjögren's Disease, SjD, is a systemic autoimmune disorder characterized by reduced function of the salivary and lacrimal glands. Patients suffer from dryness, fatigue, and pain and may present with or without extra-glandular organ involvement. Symptoms limit SjD patients' quality of life and are the most difficult to improve with therapy. SjD patients are heterogeneous and clustering them into biologically similar subgroups might improve the efficacy of therapies. The need for therapies that address both the symptoms and extra glandular organ involvement of SjD presents an unmet opportunity that has recently attracted a growing interest in the pharmaceutical industry. AREAS COVERED: The goal of this report is to review recent phase II/III studies in SjD. To accomplish our goal, we performed a literature search for phase II/III studies and abstracts recently presented at conferences. EXPERT OPINION: This review allows updates the reader on the multitude of recent phase II/III clinical trials. We speculate on how subtypes of SjD will drive future therapeutic targeting and inform pathogenesis.
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Qualidade de Vida , Síndrome de Sjogren , Humanos , Síndrome de Sjogren/tratamento farmacológico , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: Sjögren's disease (SjD), a highly female predominant systemic autoimmune disease, peaks in perimenopause. Prior studies lack details on timing or type of sex hormone exposure. We examined SjD risk using endogenous and exogenous hormone exposure and related comorbidities. METHODS: We performed a retrospective case-control study of adult women, nested within a population cohort. Cases had SjD diagnosed by a rheumatology provider or two SjD diagnoses from a non-rheumatology provider with a positive anti-SSA antibody or salivary gland biopsy. Cases were age-matched to three SjD-free controls. We calculated modified composite estrogen scores (mCES) and collected demographics, comorbidities, and endogenous and exogenous hormone exposures. Risk ratios were adjusted for demographics. RESULTS: Of 546 SjD cases and 1637 age-matched controls, mCES was not significantly associated with SjD in adjusted models. The top individual hormone exposures associated with SjD included estrogen replacement therapy (ERT; RR 1.78 [95% CI 1.47-2.14]), polycystic ovarian syndrome (1.65 [1.28-2.12]), and hysterectomy without bilateral oophorectomy (1.51 [1.13-2.03]). We identified comorbidities preceding SjD including fibromyalgia, pulmonary disease, diabetes, lymphoma, osteoporosis, peripheral vascular disease, and renal disease. Taking comorbidities into account, we developed a predictive model for SjD that included fibromyalgia (2.50 [1.93-3.25]), osteoporosis (1.84 [1.27-2.66]), hormone replacement therapy (HRT) (1.61 [1.22-2.12]), diabetes (0.27 [0.13-0.50]), and body mass index (BMI) (0.97 [0.95-0.99]). CONCLUSIONS: We report a novel algorithm to improve identifying patients at risk for SjD and describe sex hormone association with SjD. Finally, we report new comorbidities associated with SjD decrease, BMI and diabetes, and increase, lymphoma and osteoporosis.. Key Points â¢Given female predominance and typical perimenopausal onset, sex hormones should be considered when studying comorbidities in Sjögren's disease. â¢The top exposures associated with developing Sjögren's disease included fibromyalgia, osteoporosis, and use of hormone replacement therapy. Possible protective factors included prior diabetes and higher body mass index. â¢We used our newly identified exposures to generate a predictive algorithm, which has potential to improve diagnosis and pathogenic insights into Sjögren's disease.
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Fibromialgia , Osteoporose , Síndrome de Sjogren , Adulto , Índice de Massa Corporal , Estudos de Casos e Controles , Estrogênios , Feminino , Fibromialgia/epidemiologia , Hormônios Esteroides Gonadais , Humanos , Masculino , Osteoporose/complicações , Estudos Retrospectivos , Síndrome de Sjogren/complicaçõesRESUMO
BACKGROUND: The consequences of past coronavirus disease 2019 (COVID-19) infection for personal and population health are emerging, but accurately identifying distant infection is a challenge. Anti-spike antibodies rise after both vaccination and infection and anti-nucleocapsid antibodies rapidly decline. METHODS: We evaluated anti-membrane antibodies in COVID-19 naive, vaccinated, and convalescent subjects to determine if they persist and accurately detect distant infection. RESULTS: We found that anti-membrane antibodies persist for at least 1 year and are a sensitive and specific marker of past COVID-19 infection. CONCLUSIONS: Thus, anti-membrane and anti-spike antibodies together can differentiate between COVID-19 convalescent, vaccinated, and naive states to advance public health and research.
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COVID-19 , Humanos , COVID-19/diagnóstico , Vacinação , Saúde Pública , Vírion , Anticorpos Antivirais , Glicoproteína da Espícula de CoronavírusRESUMO
OBJECTIVE: Although symptom relief is a critical aspect for successful drug development in Sjögren's disease, patient experiences with Sjögren's-related symptoms are understudied. Our objective was to determine how pain, dryness, and fatigue, the cardinal symptoms of Sjögren's disease, drive cluster phenotypes. METHODS: We used data from the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry and a Sjögren's Foundation survey. We performed hierarchical clustering of symptoms by levels of dryness, fatigue, and pain. Using international and US cohorts, we performed multiple logistic regression analysis to compare the clusters, which included comparisons of differences in symptoms, quality of life (QoL), medication use, and systemic manifestations. RESULTS: Four similar clusters were identified among 1,454 SICCA registrants and 2,920 Sjögren's Foundation survey participants: 1) low symptom burden in all categories (LSB); 2) dry with low pain and low fatigue (DLP); 3) dry with high pain and low to moderate fatigue (DHP); and 4) high symptom burden in all categories (HSB). Distribution of SICCA registrants matching the symptom profile for each cluster was 10% in the LSB cluster, 30% in the DLP cluster, 23% in the DHP cluster, and 37% in the HSB cluster. Distribution of survey participants matching the symptom profile for each cluster was 23% in the LSB cluster, 14% in the DLP cluster, 21% in the DHP cluster, and 42% in the HSB cluster. Individuals in the HSB cluster had more total symptoms and lower QoL but lower disease severity than those in the other clusters. Despite having milder disease as measured by laboratory tests and organ involvement, individuals in the HSB cluster received immunomodulatory treatment most often. CONCLUSION: We identified 4 symptom-based Sjögren's clusters and showed that symptom burden and immunomodulatory medication use do not correlate with Sjögren's end-organ or laboratory abnormalities. Findings highlight a discordance between objective measures and treatments and offer updates to proposed symptom-based clustering approaches.
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Qualidade de Vida , Síndrome de Sjogren , Análise por Conglomerados , Estudos de Coortes , Fadiga/etiologia , Humanos , Dor/etiologia , Índice de Gravidade de Doença , Síndrome de Sjogren/tratamento farmacológicoRESUMO
Many autoimmune diseases exhibit a strikingly increased prevalence in females, with primary Sjögren's syndrome (pSS) being the most female-predominant example. However, the molecular basis underlying the female-bias in pSS remains elusive. To address this knowledge gap, we performed genome-wide, allele-specific profiling of minor salivary gland-derived mesenchymal stromal cells (MSCs) from pSS patients and control subjects, and detected major differences in the regulation of X-linked genes. In control female MSCs, X-linked genes were expressed from both paternal and maternal X chromosomes with a median paternal ratio of ~ 0.5. However, in pSS female MSCs, X-linked genes exhibited preferential expression from one of the two X chromosomes. Concomitantly, pSS MSCs showed decrease in XIST levels and reorganization of H3K27me3+ foci in the nucleus. Moreover, the HLA-locus-expressed miRNA miR6891-5p was decreased in pSS MSCs. miR6891-5p inhibition in control MSCs caused XIST dysregulation, ectopic silencing, and allelic skewing. Allelic skewing was accompanied by the mislocation of protein products encoded by the skewed genes, which was recapitulated by XIST and miR6891-5p disruption in control MSCs. Our data reveal X skewing as a molecular hallmark of pSS and highlight the importance of restoring X-chromosomal allelic balance for pSS treatment. KEY MESSAGES: X-linked genes exhibit skewing in primary Sjögren's syndrome (pSS). X skewing in pSS associates with alterations in H3K27me3 deposition. pSS MSCs show decreased levels of miR6891-5p, a HLA-expressed miRNA. miR6891-5p inhibition causes H3K27me3 dysregulation and allelic skewing.
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Genes Ligados ao Cromossomo X , MicroRNAs , Síndrome de Sjogren , Feminino , Histonas/genética , Humanos , MicroRNAs/genética , Síndrome de Sjogren/genéticaRESUMO
To gain insight into the Sjögren's disease (SjD) patient experience using a survey generated by patients and providers. We evaluated the results of the 2016 Sjögren's Foundation survey, with 25 questions designed in a collaborative effort between the Foundation, patients with SjD, SjD provider experts, and a marketing research company. We used descriptive statistics to provide a thorough understanding of SjD demographics, symptoms, quality of life (QoL), cost, and treatments. Analyses revealed high symptoms, QoL, and financial burdens in SjD. Dry mouth and eye were the most commonly reported symptoms (94 and 93%, respectively). The most frequent extra-glandular symptoms included fatigue, dry or itchy skin, and morning stiffness. The top three aspects of QoL most impaired included (i) sex life (53%), (ii) participating in hobbies/social activities/extracurricular activities (52%), and (iii) job/career or ability to work (49%). SjD respondents commonly reported taking health food supplements/remedies, vitamin D, and exercising, in addition to taking treatments for symptomatic dryness. SjD costs were high, including a total yearly cost, on average, of $2026 for dental care. SjD respondents reported that dryness and risk factors for lymphoma and fatigue are essential to address with new therapies. In this comprehensive overview of the SjD experience, we demonstrated a high burden of disease to SjD respondents, including symptoms, QoL, and financial burden. We also identify the top goals of therapy for new systemic SjD therapies. Key Points ⢠The top three symptoms or signs that patients with Sjögren's hope new treatments will address are dryness, fatigue, and reduction in lymphoma or blood cancer risk ⢠The top aspects of quality of life reported to be impaired by Sjögren's are sex life, hobbies, social activities and extracurricular activities, job/career or ability to work, and finding the correct word during conversations ⢠Patients with Sjögren's have a yearly mean dental cost of $2026 but also have high costs associated with prescription medications, healthcare appointments, over-the-counter medications, alternative therapies, and medical equipment.
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Síndrome de Sjogren , Xerostomia , Fadiga/etiologia , Humanos , Qualidade de Vida , Síndrome de Sjogren/diagnóstico , Inquéritos e Questionários , Xerostomia/etiologiaRESUMO
OBJECTIVES: Sjögren's disease (SjD) is a systemic autoimmune disease characterized by focal lymphocytic infiltrate of salivary glands (SGs) and high SG IFNγ, both of which are associated with elevated lymphoma risk. IFNγ is also biologically relevant to mesenchymal stromal cells (MSCs), a SG resident cell with unique niche regenerative and immunoregulatory capacities. In contrast to the role of IFNγ in SjD, IFNγ promotes an anti-inflammatory MSC phenotype in other diseases. The objective of this study was to define the immunobiology of IFNγ-exposed SG-MSCs with and without the JAK1 & 2 inhibitor, ruxolitinib. METHODS: SG-MSCs were isolated from SjD and controls human subjects. SG-MSCs were treated with 10 ng/ml IFNγ +/- 1000 nM ruxolitinib. Experimental methods included flow cytometry, RNA-sequencing, chemokine array, ELISA and transwell chemotaxis experiments. RESULTS: We found that IFNγ promoted expression of SG-MSC immunomodulatory markers, including HLA-DR, and this expression was inhibited by ruxolitinib. We confirmed the differential expression of CXCL9, CXCL10, CXCL11, CCL2 and CCL7, initially identified with RNA sequencing. SG-MSCs promoted CD4+ T cell chemotaxis when pre-stimulated with IFNγ. Ruxolitinib blocks chemotaxis through inhibition of SG-MSC production of CXCL9, CXCL10 and CXCL11. CONCLUSIONS: These findings establish that ruxolitinib inhibits IFNγ-induced expression of SG-MSC immunomodulatory markers and chemokines. Ruxolitinib also reverses IFNγ-induced CD4+ T cell chemotaxis, through inhibition of CXCL9, -10 and -11. Because IFNγ is higher in SjD than control SGs, we have identified SG-MSCs as a plausible pathogenic cell type in SjD. We provide proof of concept supporting further study of ruxolitinib to treat SjD.
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Glândulas Salivares , Síndrome de Sjogren , Quimiotaxia , Antígenos HLA-DR/metabolismo , Humanos , Interferon gama/metabolismo , Nitrilas , Pirazóis , Pirimidinas , RNA , Glândulas Salivares/patologiaRESUMO
OBJECTIVE: Rheumatoid arthritis (RA) patients often develop rheumatoid factors (RFs), antibodies that bind IgG Fc, and anti-modified protein antibodies (AMPAs), multireactive autoantibodies that commonly bind citrullinated, homocitrullinated, and acetylated antigens. Recently, antibodies that bind citrulline-containing IgG epitopes were discovered in RA, suggesting that additional undiscovered IgG epitopes could exist and that IgG could be a shared antigen for RFs and AMPAs. This study was undertaken to reveal new IgG epitopes in rheumatic disease and to determine if multireactive AMPAs bind IgG. METHODS: Using sera from patients with RA, systemic lupus erythematosus, Sjögren's disease (SjD), or spondyloarthropathy, IgG binding to native, citrulline-containing, and homocitrulline-containing linear epitopes of the IgG constant region was evaluated by peptide array, with highly bound epitopes further evaluated by enzyme-linked immunosorbent assay (ELISA). Binding of monoclonal AMPAs to IgG-derived peptides and IgG Fc was also evaluated by ELISA. RESULTS: Seropositive RA sera showed high IgG binding to multiple citrulline- and homocitrulline-containing IgG-derived peptides, whereas anti-SSA+ sera from SjD patients showed consistent binding to a single linear native epitope of IgG in the hinge region. Monoclonal AMPAs bound citrulline- and homocitrulline-containing IgG peptides and modified IgG Fc. CONCLUSION: The repertoire of epitopes bound by AMPAs includes modified IgG epitopes, positioning IgG as a common antigen that connects the otherwise divergent reactivities of RFs and AMPAs.