Acupuncture for Primary Sjogren Syndrome (pSS) on symptomatic improvements: study protocol for a randomized controlled trial.
ABSTRACT: Currently, feasible medical treatments are hitherto not satisfying to relieve pSS symptoms, which concerns numbers of clinical doctors. Acupuncture seems to be an alternative to treat pSS and conduces to good symptomatic results. However further research is necessary. This trial is to investigate the efficacy of acupuncture on improving the key symptoms of pSS, which are dryness, pain and fatigue (DPF).The study is designed as a randomized controlled trial of two arms with a single centre. We compare acupuncture with sham acupuncture on symptomatic improvements of pSS. A total of 120 pSS patients, aged at least 18, with DPF, will be randomly assigned to acupuncture or sham acupuncture groups, where they will have needle intervention for 8 weeks with 16 weeks of follow-up. Subjects will be assessed each time before interventions during the 8-week intervention, in week 8 after all interventions and in week 12, 16, 20 and 24 for follow-up with different measurements. The primary outcome are the proportions of subjects that have 30% or greater reduction in at least 2 out of 3 items of DPF in Numeric Analog Scale (NAS) scores (0 = the best, 10 = the severest), calculated between the baseline and the average scores of week 2 to 8. The secondary outcome are related to individual items of NAS scores, EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI), EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI), Schirmer test score and unstimulated salivary flow, serum Immunoglobulin G, A and M levels, Medical Outcome Study Short Form 36 Short-Form Health Survey (SF-36), Salivary glands ultrasounds, Hospital Anxiety and Depression (HAD) scale score. The secondary outcome scores are to be collected at baseline, in week 8, 16, and 24. Besides, individual items of NAS will also be collected in week 12 and 20. Moreover, subjects' satisfaction and the proportion of the subjects who identified their allocation will also be measured and analyzed.This study will be the first randomized and controlled pilot trial of acupuncture on alleviating the symptoms of pSS with relatively long-term follow-up. The result of the study might offer a new option to treat pSS and might be a clinical proof that acupuncture has beneficial effects on pSS.ClinicalTrials.gov: NCT02691377 (February 20, 2016).
Project description:OBJECTIVE:Salivary gland (SG) progenitor cells (SGPCs) maintain SG homeostasis. We have previously shown that in primary Sjögren's syndrome (pSS), SGPCs are likely to be senescent, and may underpin SG dysfunction. This study assessed the extent of senescence of cells in a SGPC niche in pSS patients' SGs, and its correlation with functional and clinical parameters. METHODS:The expression of p16 and p21 as markers of senescence in both total SG epithelium and a SGPC niche (basal striated duct cells, BSD) was examined in SGs of pSS (n?=?35), incomplete pSS (n?=?13) (patients with some signs of pSS, but not fulfilling all classification criteria) and non-SS sicca control (n?=?21) patients. This was correlated with functional and clinical parameters. RESULTS:pSS patient SGs contained significantly more p16+ cells both in the epithelium in general (P <0.01) and in the BSD layer (P <0.001), than non-SS SGs. Significant correlations were found in pSS patients between p16+ BSD cells and secretion of unstimulated whole saliva, stimulated whole saliva, stimulated parotid saliva, CD45+ infiltrate, ultrasound total score and ACR-EULAR classification score, but not with EULAR Sjögren's syndrome disease activity index (ESSDAI) and EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) scores. Correlations with total epithelium p16+ cells were weaker. Incomplete pSS patients also had increased numbers of p16+ epithelial and BSD cells. Based on protein and mRNA expression, p21+ appears not to play a significant role in the SG in pSS. CONCLUSION:These findings suggest SGPC senescence may be an early feature of primary Sjögren's syndrome and may contribute to defective SG function in pSS but not to systemic disease activity.
Project description:OBJECTIVE:To identify numbers of participants in the UK Primary Sjögren's Syndrome Registry (UKPSSR) who would fulfil eligibility criteria for previous/current or potential clinical trials in primary SS (pSS) in order to optimize recruitment. METHODS:We did a retrospective analysis of UKPSSR cohort data of 688 participants who had pSS with evaluable data. RESULTS:In relation to previous/current trials, 75.2% fulfilled eligibility for the Belimumab in Subjects with Primary Sjögren's Syndrome study (Belimumab), 41.4% fulfilled eligibility for the Trial of Remicade in primary Sjögren's syndrome study (Infliximab), 35.4% for the Efficacy of Tocilizumab in Primary Sjögren's Syndrome study (Tocilizumab), 31.6% for the Tolerance and Efficacy of Rituximab in Sjögren's Disease study (Rituximab), 26.9% for the Trial of anti-B-cell therapy in pSS study (Rituximab) and 26.6% for the Efficacy and Safety of Abatacept in Patients With Primary Sjögren's Syndrome study (Abatacept). If recent measures of outcome, such as the EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) score ?5 (measure of patient symptoms) and the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) score ?5 (measure of systemic disease activity) are incorporated into a study design, with requirements for an unstimulated salivary flow >0 and anti-Ro positivity, then the pool of eligible participants is reduced to 14.3%. CONCLUSION:The UKPSSR identified a number of options for trial design, including selection on ESSDAI ?5, ESSPRI ?5 and serological and other parameters.
Project description:B-cell activating factor (BAFF), ?-2 microglobulin (?2M) and serum free light chains (FLCs) are elevated in primary SS (pSS) and associated with disease activity. We aimed to investigate their association with the individual disease activity domains of the EULAR Sjögren's Syndrome Disease Activity Index (ESSDAI) in a large well-characterized pSS cohort.Sera from pSS patients enrolled in the UK Primary Sjögren's Syndrome Registry (UKPSSR) (n = 553) and healthy controls (n = 286) were analysed for FLC (? and ?), BAFF and ?2 M. Pearson correlation coefficients were calculated for patient clinical characteristics, including salivary flow, Schirmer's test, EULAR Sjögren's Syndrome Patient Reported Index and serum IgG levels. Poisson regression was performed to identify independent predictors of total ESSDAI and ClinESSDAI (validated ESSDAI minus the biological domain) scores and their domains.Levels of BAFF, ?2M and FLCs were higher in pSS patients compared to controls. All three biomarkers associated significantly with the ESSDAI and the ClinESSDAI. BAFF associated with the peripheral nervous system domain of the ESSDAI, whereas ?2M and FLCs associated with the cutaneous, biological and renal domains. Multivariate analysis showed BAFF, ?2M and their interaction to be independent predictors of ESSDAI/ClinESSDAI. FLCs were also shown to associate with the ESSDAI/ClinESSDAI but not independent of serum IgG.All biomarkers were associated with total ESSDAI scores but with differing domain associations. These findings should encourage further investigation of these biomarkers in longitudinal studies and against other disease activity measures.
Project description:<h4>Objectives</h4>To evaluate efficacy and safety of abatacept in adults with active primary Sjögren's syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial.<h4>Methods</h4>Eligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren's Syndrome Disease Activity Index [ESSDAI] ?5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125?mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren's Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored.<h4>Results</h4>Of 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI -3.2 abatacept vs -3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified.<h4>Conclusions</h4>Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.
Project description:<h4>Objective</h4>To determine the prevalence of upregulation of interferon (IFN) type I inducible genes, the so called 'IFN type I signature', in CD14 monocytes in 69 patients with primary Sjögren's syndrome (pSS) and 44 healthy controls (HC) and correlate it with disease manifestations and expression of B cell activating factor (BAFF).<h4>Methods</h4>Expression of IFI44L, IFI44, IFIT3, LY6E and MX1 was measured using real time quantitative PCR in monocytes. Expression values were used to calculate IFN type I scores for each subject. pSS patients positive for the IFN type I signature (IFN score?10) and patients negative for the signature (IFN score<10) were then compared for clinical disease manifestations and BAFF expression. A bioassay using a monocytic cell line was performed to study whether BAFF mRNA expression was inducible by IFN type I activity in serum of patients with pSS.<h4>Results</h4>An IFN type I signature was present in 55% of patients with pSS compared with 4.5% of HC. Patients with the IFN type I signature showed: (a) higher EULAR Sjögren's Syndrome Disease Activity Index scores; higher anti-Ro52, anti-Ro60 and anti-La autoantibodies; higher rheumatoid factor; higher serum IgG; lower C3, lower absolute lymphocyte and neutrophil counts; (b)higher BAFF gene expression in monocytes. In addition, serum of signature-positive patients induced BAFF gene expression in monocytes.<h4>Conclusions</h4>The monocyte IFN type I signature identifies a subgroup of patients with pSS with a higher clinical disease activity together with higher BAFF mRNA expression. Such patients might benefit from treatment blocking IFN type I production or activity.
Project description:BACKGROUND:We reported that the production of BAFF (B cell-activating factor) and IL-6, both of which are involved in survival and differentiation of B cells, is dysregulated in monocytes of patients with primary Sjögren's syndrome (pSS). In this study, we investigate the relationship between possible aberrations of pSS monocytes and clinical features of pSS patients and the contribution of monocytes to B cell activation, a mechanism involved in the pathogenesis of pSS. METHODS:Expression of BAFF-receptor (BR3) on peripheral monocytes from patients with pSS (n?=?67) and healthy controls (HC: n?=?37) was analyzed by FACS. Peripheral monocytes were stimulated with BAFF, and IL-6 production by the cells was measured by ELISA. Peripheral B cells were cultured with BAFF-stimulated monocytes in the presence or absence of anti-IL-6 receptor antibody, and IgG production by the cells was measured by ELISA. Patients' serological data were collected from their clinical records. Patients' disease activity was quantified based on their EULAR Sjögren's syndrome disease activity index (ESSDAI) scores. RESULTS:The proportion of peripheral BR3-positive monocytes (BR3+/CD14+) was significantly increased in pSS patients compared to HC. Moreover, IL-6 production by BAFF-stimulated monocytes was remarkably higher than HC and was significantly correlated with BR3+/CD14+ ratios of patients. In addition, BR3 expression on pSS monocytes was elevated in anti-Ro/SSA and/or anti-La/SSB positive compared to negative patients. Remarkably, BR3 expression on peripheral monocytes was positively and significantly correlated with patients' serum IgG and IgM levels and ESSDAI scores. Moreover, the amount of IgG produced by B cells was markedly higher in pSS patients compared to HC when the cells were co-cultured with BAFF-stimulated autologous monocytes in vitro. Notably, addition of anti-IL-6 receptor antibody into the co-culture system led to inhibition of IgG production by B cells. CONCLUSIONS:Our data suggest that elevated BR3 expression in monocytes is associated with clinical features in pSS patients and that enhanced production of IL-6 by BAFF-stimulated monocytes plays a part in the overproduction of IgG by B cells in pSS. These results suggest that BAFF signaling pathways through BR3 in monocytes are possible therapeutic targets for pSS.
Project description:OBJECTIVE: To establish an easy and practical assay for identifying systemic interferon (IFN) type I bioactivity in patients with primary Sjögren's syndrome (pSS). The IFN type I signature is present in over half of the pSS patients and identifies a subgroup with a higher disease activity. This signature is currently assessed via laborious expression profiles of multiple IFN type I-inducible genes. METHODS: In a cohort of 35 pSS patients, myxovirus-resistance protein A (MxA) was assessed as a potential biomarker for type I IFN activity, using an enzyme immunoassay (EIA) on whole-blood and flow cytometric analyses (fluorescence-activated cell sorting, FACS) of isolated CD14 monocytes. In addition, potential biomarkers such as CD64, CD169 and B cell-activating factor (BAFF) were simultaneously analysed in CD14 monocytes using FACS. The IFNscore, a measure for total type I IFN bioactivity, was calculated using expression values of the IFN type I signature genes--IFI44, IFI44L, IFIT3, LY6E and MX1--in CD14 monocytes, determined by real-time quantitative PCR. RESULTS: IFNscores correlated the strongest with monocyte MxA protein (r=0.741, p<0.001) and whole-blood MxA levels (r=0.764, p<0.001), weaker with CD169 (r=0.495, p<0.001) and CD64 (r=0.436, p=0.007), and not at all with BAFF protein. In particular, whole blood MxA levels correlated with EULAR Sjögren's Syndrome Disease Activity Index scores and numerous clinical pSS parameters. Interestingly, patients on hydroxychloroquine showed reduced MxA levels (EIA, p=0.04; FACS p=0.001). CONCLUSIONS: The MxA assays were excellent tools to assess IFN type I activity in pSS, MxA-EIA being the most practical. MxA levels associate with features of active disease and are reduced in hydroxychloroquine-treated patients, suggesting the clinical applicability of MxA in stratifying patients according to IFN positivity.
Project description:Aims:Interstitial lung disease (ILD) is the most common type of pulmonary involvement of extraglandular complication in patients with primary Sjögren's syndrome (pSS), but the diagnosis of pSS-associated ILD (pSS-ILD) is still challenging. This study aimed to investigate the levels of serum tumor markers in pSS patients with or without ILD (pSS-non-ILD) and explore its diagnostic value for pSS-ILD. Methods:A total of 168 pSS-ILD patients and age- and sex-matched 538 pSS-non-ILD were recruited. The levels of peripheral tumor markers, including carbohydrate antigen (CA)153, CA125, CA19-9, carcinoembryonic antigen (CEA), neuron-specific enolase (NSE), ?-human chorionic gonadotropin, alpha fetoprotein, CA724, and complexed prostate specific antigen, the clinical manifestations, and general laboratory indicators were measured and collected. Results:Compared with pSS-non-ILD, pSS-ILD patients had higher levels of disease activity indicators, such as EULAR Sjögren's syndrome disease activity index, ESR, and CRP, and elevated serum levels of tumor markers: NSE, CEA, CA125, and CA153. The serum levels of CA153 [odds ratio (OR)?=?4.521, 95% confidence interval (CI)?=?[1.871, 10.928)] and CEA [OR?=?2.879, 95% CI?=?(1.305, 6.353)] were significantly correlated with the onset of SS-ILD. CA153 was the only tumor marker with area under receiver operating characteristic curve (AUC) over 0.7 [AUC?=?0.743, 95% CI?=?(0.70, 0.79)]. Conclusion:Tumor markers increased in serum of pSS-ILD patients. Higher CA153 levels are significantly correlated to the increased risk of ILD in patients with pSS and may be directly involved in the pathogenesis of pSS-ILD. Serum CA153 had the best diagnostic value in those tumor markers for pSS-ILD without malignancy.
Project description:OBJECTIVE:To assess whether the addition of salivary gland ultrasonography (SGUS) or replacement of current criteria items by SGUS influences the performance of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) criteria for primary Sjögren's syndrome. METHODS:Included were consecutive patients with complete data on all ACR/EULAR items (n = 243) who underwent SGUS in our primary Sjögren's syndrome expertise center. Clinical diagnosis by the treating physician was used as the gold standard. Separate analyses were performed for patients who underwent labial or parotid gland biopsies. The average score for hypoechogenic areas in 1 parotid and 1 submandibular gland was determined (range 0-3). Next, performance of the ACR/EULAR criteria was evaluated after addition of SGUS or replacement of current items by SGUS. RESULTS:Receiver operating characteristic analysis showed an optimal cutoff value of ?1.5 for SGUS. The optimal weight for SGUS positivity was 1. Cutoff for ACR/EULAR fulfilment remained ?4. In patients who underwent a labial gland biopsy (n = 124), the original criteria showed an area under the curve (AUC) of 0.965, sensitivity of 95.9%, and specificity of 92.2%. After the addition of SGUS, the AUC was 0.966, with a sensitivity of 97.3% and specificity of 90.2%. In patients who underwent a parotid gland biopsy (n = 198), similar results were found. Sensitivity of the criteria decreased substantially when SGUS replaced salivary gland biopsy or anti-SSA antibodies, while performance remained equal when SGUS replaced the ocular staining score, Schirmer's test, or unstimulated whole saliva flow. CONCLUSION:Validity of the ACR/EULAR criteria remains high after incorporation of SGUS. With SGUS, clinicians are offered a larger array of tests to evaluate fulfillment of the ACR/EULAR criteria.
Project description:<h4>Background</h4>Primary Sjögren's syndrome (pSS) is an autoimmune disease characterized by a lymphocytic infiltrate in salivary glands driving to epithelial damage. The pSS patients present heterogenic clinical and serological characteristics. This heterogenicity could be due to the cytokine microenvironment. Cytokine levels have been analyzed and reported individually, showing controversial results; for that reason, we considered essential to evaluate a cluster of cytokines and relate them with antibody levels and clinical characteristics to find pSS subgroups.<h4>Methods</h4>Ninety-nine pSS patients, diagnosed by the 2016 ACR/EULAR classification criteria, and 76 control subjects (CS) were included. Cytokine quantification was performed by Multiplex assay. Principal component analysis (PCA) was realized, and the K-mean test was used to identify clusters/groups. Groups were analyzed by the Kruskal-Wallis test and the Bonferroni test.<h4>Results</h4>Higher IFN-?, IL-17F, IL-21, IL-23, IL-4, and IL-31 levels were observed in pSS patients in comparison with control subjects. PCA analysis showed three groups. The severe group was characterized by higher cytokine concentrations as well as an increase in clinical parameters such as antibody levels, damage index score, and others. The moderate group presented intermediate severity; meanwhile, the mild group presented the lowest severity.<h4>Conclusion</h4>Cluster analysis revealed three groups that were different in cytokine levels and clinical parameters in which the mild group was defined by lower severity, the moderate group with intermediate severity, and the severe group with higher severity. This analysis could help subclassify the primary Sjögren syndrome patients for a better understanding of the clinical phenotype that impacts the treatment approach.