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34868357 Comparison of long-term efficacy between biological agents following tumor necrosis factor 2021 BACKGROUND: Currently, there is contradictory evidence regarding the best strategy to follow after discontinuation of a first biological agent in patients with rheumatoid arthritis (RA). We aimed to compare the long-term efficacy of switching to a second tumor necrosis factor inhibitor (TNFi) versus biopharmaceuticals with other mechanisms of action (non-TNFi) in patients with RA who previously failed a first TNFi. METHODS: This prospective cohort study analyzed data from 127 patients who discontinued a previous TNFi between 1999 and 2016. Disease activity was assessed at baseline and at 6, 12, and 24 months (m-6, m-12, m-24) after switching. Primary outcome was the proportion of patients achieving good/moderate EULAR response (E-resp). Factors associated with clinical outcomes were assessed using univariate and multivariate logistic regression models. RESULTS: Seventy-seven (61%) patients received a second TNFi and 50 (39%) switched to a non-TNFi. At m-6 and m-12, no differences were observed between groups; nevertheless, at m-24, the proportion of patients with E-resp was higher in the non-TNFi group (49% TNFi group versus 77% non-TNFi group; p = 0.002). In regression models, switching to a non-TNFi was significantly associated with E-resp at m-24 (odds ratio = 3.21; p = 0.01). When assessing the response to the second biological agent based on the reason for discontinuation of the first TNFi, similar results were obtained; at m-24, patients who discontinued the first TNFi due to inefficacy (either primary or secondary) experienced a better E-resp if they had switched to a non-TNFi (primary inefficacy: 52% TNFi group versus 79% non-TNFi group, p = 0.09; secondary inefficacy: 50% versus 76%, p = 0.03). CONCLUSION: In our cohort of RA patients who discontinued a first TNFi, those who switched to a non-TNFi were three times more likely to attain a sustained clinical response, regardless of whether they had discontinued the first biologic due to a primary or secondary inefficacy.
34676228 Rheumatoid Arthritis and Cardiovascular Risk: Retrospective Matched-Cohort Analysis Based 2021 Background: Rheumatoid arthritis (RA) is associated with an increase in cardiovascular (CV) risk. This issue maybe not only explained by a genetic component, as well as by the traditional CV risk factors, but also by an underestimation and undertreatment of concomitant CV comorbidities. Method: This was a retrospective matched-cohort analysis in the Italian RA real-world population based on the healthcare-administrative databases to assess the CV risk factors and incidence of CV events in comparison with the general population. Persistence and adherence to the CV therapy were also evaluated in both groups. Results: In a RA cohort (N = 21,201), there was a greater prevalence of hypertension and diabetes with respect to the non-RA subjects (N = 249,156) (36.9 vs. 33.4% and 10.2 vs. 9.6%, respectively), while dyslipidemia was more frequent in the non-RA group (15.4 vs. 16.5%). Compared with a non-RA cohort, the patients with RA had a higher incidence of atrial fibrillation (incidence rate ratio, IRR 1.28), heart failure (IRR 1.53), stroke (IRR 1.19), and myocardial infarction (IRR 1.48). The patients with RA presented a significantly lower persistence rate to glucose-lowering and lipid-lowering therapies than the controls (odds ratio, OR 0.73 [95% CI 0.6-0.8] and OR 0.82 [0.8-0.9], respectively). The difference in the adherence to glucose-lowering therapy was significant (OR 0.7 [0.6-0.8]), conversely no statistically significant differences emerged regarding the adherence to lipid-lowering therapy (OR 0.89 [95% CI 0.8-1.0]) and anti-hypertensive therapy (OR 0.96 [95% CI 0.9-1.0]). Conclusion: The patients with RA have a higher risk of developing CV events compared with the general population, partially explained by the excess and undertreatment of CV risk factors.
34441756 Assessment of Subclinical Psychotic Symptoms in Patients with Rheumatoid Arthritis and Spo 2021 Aug 4 Inflammatory and autoimmune processes have been associated with the onset of depressive and psychotic symptoms. Rheumatoid arthritis (RA) and spondyloarthritis (SpA) are rheumatic diseases with an inflammatory etiology. A high prevalence of depressive and anxiety-related comorbidity has been reported for both diseases, with no evidence of a greater prevalence of psychosis. The objective of the present study was to evaluate for the first time subclinical psychotic symptoms in patients with RA and SpA. This is a cross-sectional, single-center study including RA and SpA patients, as well as healthy controls. Abnormal psychotic experiences (positive, negative, and depressive symptoms) were evaluated using the Community Assessment of Psychic Experiences (CAPE-42). Functional capacity was evaluated using the Short-Form Health Survey SF-12. We compared the CAPE and SF-12 scores between the three groups. We recruited 385 individuals: 218 with RA, 100 with SpA, and 67 healthy controls. According to the CAPE scale, the frequency of subclinical psychotic symptoms was greater in patients than in healthy controls (RA, 1.90 vs. 1.63, p < 0.001; SpA, 1.88 vs. 1.63, p = 0.001). Distress was also greater in patients than in controls owing to the presence of symptoms. No differences were observed between the three groups for the mental dimension scores in the SF-12 Health Survey (43.75 in RA, 45.54 in SpA, and 43.19 in healthy controls). Our findings point to a greater prevalence of subclinical psychotic symptoms in patients with RA and patients with SpA than in the general population. The results suggest an association between inflammation and depression/subclinical psychotic symptoms.
34089509 Patient Preference for Treatment Mode of Biologics in Rheumatoid Arthritis: A 2020 Web-bas 2021 Sep INTRODUCTION: Although the proportion of patients with rheumatoid arthritis (RA) using biologic disease-modifying antirheumatic drugs (bDMARDs) has increased steadily, the relationship between patient background and preference for bDMARDs has not been fully investigated. METHODS: We conducted a web-based questionnaire survey among patients aged ≥ 20 years with RA receiving bDMARDs. Participants were recruited through an internet research company in Japan. Study endpoints included factors affecting the preferred bDMARD treatment mode, namely, in-hospital intravenous infusion (infusion), in-hospital subcutaneous injection (in-hospital injection), or self-administered subcutaneous injection (self-injection), and discrepancies between the current and preferred treatment mode. RESULTS: Of the 400 patients surveyed for preferred treatment mode, 15.3% preferred infusion, 18.0% preferred in-hospital injection, and 66.8% preferred self-injection. A preference for infusion (odds ratio [OR] 2.218 and 6.165) and in-hospital injection (OR 4.735 and 6.026) versus self-injection was significantly associated with higher current frequency of hospital visits and anxiety or other hurdles related to self-injection. A flexible administration setting was significantly associated with a preference for self-injection versus infusion (OR 0.401) and versus in-hospital injection (OR 0.445). Further, age (< 40 vs. ≥ 60 years) was significantly associated with a preference for self-injection versus in-hospital injection (OR 0.120). Many patients reported no discrepancy between their current and preferred treatment mode (patients receiving infusion, 68.0%; in-hospital injection, 71.2%; and self-injection, 94.0%). However, > 90% of patients responded that they would change their current mode in the future following a recommendation by a medical professional, aging, or a change in RA symptoms. CONCLUSIONS: This web-based survey showed that patient preference for bDMARD treatment mode was significantly associated with age, frequency of hospital visits, flexible administration setting, and anxiety or other hurdles to self-injection. Changes in patient background which affect the preferred treatment mode should be considered in decision-making for RA therapy with bDMARDs. TRIAL REGISTRATION: R000048089 (UMIN-CTR).
33934720 Reported disability in relation to observed activity limitation, grip strength and physica 2021 May 3 BACKGROUND: The self-reported Health Assessment Questionnaire (HAQ) is specifically designed to assess disability in arthritic patients. In many studies women report higher functional disability than men. The reasons for this difference are suggested to be multifactorial. We therefore evaluated functional disability assessed by HAQ in women and men with rheumatoid arthritis (RA) in relation to observed disability, grip force and physical function. METHODS: Patients with RA, 51 women and 49 men, completed the HAQ on three occasions, some weeks apart. Between HAQ1 and HAQ2, all patients performed 17 of the 20 activities (7 domains) included in the HAQ under observation in a specially designed environment, the observed HAQ. During the same day, grip force, measured by GRIPPIT and physical function assessed by the SOFI (Signals of Functional Impairment) index were evaluated. Differences between groups were studied by the chi-square test, Mann-Whitney U test and Wilcoxon Sign Rank test. Correlations were analysed by Spearman rank correlation. Comparisons between repeated measures were performed using Friedman's test. RESULTS: Median (IQR) total HAQ1 score was 0.50 (0.88) for women and 0.25 (0.84) for men, p = 0.038, and the observed HAQ score (7 domains) 0.57 (0.9) for women and 0.43 (0.96) for men, p = 0.292. The correlations between reported HAQ1 score (7 domains) and observed HAQ score were strong, r = 0.860, p < 0.001 in women, and r = 0.820, p < 0.001 in men. For some activities the patients, both women and men, reported lower difficulty than that observed. Women had lower grip force than men, median (IQR), right and left 126 (84) Newton, versus 238 (146), p < 0.001, and there was a negative correlation between grip force and most of the separate activities in HAQ in both genders. SOFI index was similar in women and men, median (IQR) 0 (3.0) versus 0 (2.0), p = 0.277, with a moderate correlation to HAQ. CONCLUSIONS: The results indicate that in well-treated patients with RA the correlations between reported and observed HAQ scores were strong, similarly in women and men. We found no evidence that the patient's opinion was dependent on unawareness of her/his own ability.
33535498 The Key Comorbidities in Patients with Rheumatoid Arthritis: A Narrative Review. 2021 Feb 1 Comorbidities in patients with rheumatoid arthritis (RA) are often associated with poor health outcomes and increased mortality. Treatment decisions should take into account these comorbidities due to known or suspected associations with certain drug classes. In clinical practice, it is critical to balance potential treatment benefit against the possible risks for comorbidities as well as the articular manifestations of RA. This review summarises the current literature relating to prevalence and risk factors for the important comorbidities of cardiovascular disease, infections, lymphomas and nonmelanoma skin cancers in patients with RA. The impact on patient outcomes and the interplay between these comorbidities and the therapeutic options currently available, including tumour necrosis factor inhibitors and newer biological therapies, are also explored. As newer RA therapies are developed, and patients gain wider and earlier access to advanced therapies, in part due to the emergence of biosimilars, it is important to consider the prevention or treatment of comorbidities as part of the overall management of RA.
33442298 Chronic Inflammatory Diseases - Diabetes Mellitus, Rheumatoid Arthritis, Coeliac Disease, 2021 BACKGROUND: Chronic inflammatory diseases (CIDs) may share aetiological factors across diseases. We used registry data to evaluate the risk of developing five common childhood CIDs dependent on the parents' disease status. METHODS: We performed a national population-based registry study by linking data from the national Danish health registers from January 1973 to March 2016 to evaluate any potential associations between parents' disease and development of CIDs among the offspring. Results were adjusted for parental age at birth, the decade of birth, gender of the child, and type of birth. A cohort of 2,699,449 liveborn children was established for investigating the primary outcome measures: diabetes mellitus (DM), rheumatoid arthritis (RA), coeliac disease, Crohn's disease (CD), and ulcerative colitis (UC) and all diseases combined (CID). RESULTS: Children with one CID affected parent (Hazard ratio (HR), 95% confidence interval (95% CI)=1.75 (1.72-1.79, p<0.001)), one multiple CID affected parent (HR=2.23 (2.11-2.34), p<0.001), and both parents affected (HR=3.10 (2.98-3.22), p<0.001) were at higher risk than children without CID affected parents. Children with DM, RA, and COE affected parents were at increased risk of three specific diseases (DM, RA and COE), whereas children with CD and UC affected parents were at increased risk of two specific diseases (CD and UC). CONCLUSION: Children with CID affected parents were at increased risk of the same CID as their parents as well as other specific CIDs dependent on the parents' CID. Future studies should address the aetiology underlying these findings to support the development of new strategies for prevention, treatment, and cure.
33676818 Therapy of antigen-induced arthritis of the temporomandibular joint via platelet-rich plas 2021 Aug The aim of this animal study was to investigate the effect of platelet-rich plasma (PRP) injections into the temporomandibular joint (TMJ) to treat antigen-induced arthritis AIA. AIA was induced via the application of bovine serum albumin (BSA) into the TMJ. Clear histological signs and protein analysis results indicating inflammation of the TMJ were observed. Afterwards, two PRP injections were performed over an interval of 2 weeks. Concentration levels of the proinflammatory cytokines IL-1β (PRP: 33.7 ± 5.6 pg/mg, untreated: 50.0 ± 2.9 pg/mg; p = 0.04) and TNF-α (PRP: 20.7 ± 2.5 pg/mg, untreated: 31.4 ± 2.7 pg/mg; p = 0.03) were significantly decreased in the PRP-treated joints. A significant reduction in signs of histological inflammation, such as hyperplasia of the synovial membrane, leucocyte infiltration, cartilage surface alterations, and an increase in cartilage-specific glycosaminoglycan content, was observed. This animal study supports the understanding of the underlying effects of PRP treatment in the TMJ, and may enhance novel PRP therapies in the future.
35493315 Anti-rheumatoid activity of a hexane-insoluble fraction from Plantago major in female Wist 2022 May BACKGROUND AND AIM: Plantago major has long been used for medical purposes in Indonesia. However, reports on the anti-arthritic activities of P. major are limited. EXPERIMENTAL PROCEDURE: The anti-arthritic properties of an n-hexane-insoluble fraction of dichloromethane extracts of P. major (IPM) were evaluated using Complete Freund's Adjuvant (CFA)-induced arthritis induced in female Wistar rat by CFA. Diclofenac was used as a positive control. The volume of paw oedema, white blood cell count, lymphocytes, neutrophils, expression of TNF-α and Interleukin-6 and the histopathological features of the joint tissues were assessed to characterise IPM activity. RESULTS: The IPM extract at doses of 280 and 420 mg/kg BW and diclofenac inhibited paw oedema by 15.70 %, 15.94 % and 19.71 % respectively. IPM also reduced the incidence of arthritis and arthritic index. Unlike untreated rats, animals treated with IPM showed a significant decrease in the number of neutrophils and decreased expression of TNF-α and Interleukin-6. Histopathological examination showed a reduction in the number of inflammatory cells and hyperplasia of the synovium after IPM treatment. CONCLUSION: This study showed that P. major displays anti-rheumatoid arthritis activity.
34575873 Defective Efferocytosis in a Murine Model of Sjögren's Syndrome Is Mediated by Dysfunctio 2021 Sep 8 Sjögren's syndrome (SjS) is a chronic autoimmune disease primarily involving the exocrine glands in which the involvement of the innate immune system is largely uncharacterized. Mer signaling has been found to be protective in several autoimmune diseases but remains unstudied in SjS. Here, we investigated the role of Mer signaling in SjS. Mer knockout (MerKO) mice were examined for SjS disease criteria. SjS-susceptible (SjS(S)) C57BL/6.NOD-Aec1Aec2 mice were assessed for defective Mer signaling outcomes, soluble Mer (sMer) levels, A disintegrin and metalloprotease 17 (ADAM17) activity, and Rac1 activation. In addition, SjS patient plasma samples were evaluated for sMer levels via ELISA, and sMer levels were correlated to disease manifestations. MerKO mice developed submandibular gland (SMG) lymphocytic infiltrates, SMG apoptotic cells, anti-nuclear autoantibodies (ANA), and reduced saliva flow. Mer signaling outcomes were observed to be diminished in SjS(S) mice, as evidenced by reduced Rac1 activation in SjS(S) mice macrophages in response to apoptotic cells and impaired efferocytosis. Increased sMer was also detected in SjS(S) mouse sera, coinciding with higher ADAM17 activity, the enzyme responsible for cleavage and inactivation of Mer. sMer levels were elevated in patient plasma and positively correlated with focus scores, ocular staining scores, rheumatoid factors, and anti-Ro60 levels. Our data indicate that Mer plays a protective role in SjS, similar to other autoimmune diseases. Furthermore, we suggest a series of events where enhanced ADAM17 activity increases Mer inactivation and depresses Mer signaling, thus removing protection against the loss of self-tolerance and the onset of autoimmune disease in SjS(S) mice.
33790617 BT2 Suppresses Human Monocytic-Endothelial Cell Adhesion, Bone Erosion and Inflammation. 2021 INTRODUCTION: Inflammation and bone erosion are processes key to the pathogenesis of rheumatoid arthritis, a systemic autoimmune disease causing progressive disability and pain, impacting around 1.3 million people in the United States alone. However, many patients do not respond sufficiently to existing therapies or benefit is not sustained and alternate therapeutic approaches are lacking. We recently identified the dibenzoxazepinone BT2, which inhibits ERK phosphorylation, from a high-throughput chemical screen and identified its ability to inhibit angiogenesis and vascular leakiness. METHODS: Here we evaluated BT2 for potential anti-inflammatory activity in in vitro models of human monocytic-endothelial cell adhesion, monocytic cell extravasation and collagen antibody-induced arthritis in mice. RESULTS: BT2 inhibits human monocytic cell adhesion to IL-1ß-treated human endothelial cells and inhibits monocytic transendothelial migration toward MCP-1. In mice rendered arthritic, single systemic administration of BT2 prevented footpad swelling, bone destruction and TRAP(+) cells in the joints. BT2 suppressed inducible circulating levels of IL-1ß, IL-2 and IL-6 to normal levels without affecting levels of IL-4 or IL-10 among other cytokines. BT2 also inhibited the expression of pro-inflammatory adhesion molecules ICAM-1 and VCAM-1 in arthritic joints. There was no evidence of toxicity following intraperitoneal, gavage or intraarticular administration of BT2. CONCLUSION: BT2 is a novel small molecule inhibitor of joint inflammation, bone erosion, pro-inflammatory cytokine and adhesion molecule expression. This suggests the potential clinical utility of BT2 as a new anti-inflammatory agent.
34881869 In Situ Synthesis of Natural Antioxidase Mimics for Catalytic Anti-Inflammatory Treatments 2022 Jan 12 Mimicking the coordination geometry of the active metal sites of natural enzymes is an efficient strategy in designing therapeutic chemicals with enzymelike in vivo reaction thermodynamics and kinetics. In this study, this chemical concept has been applied for the in situ synthesis of natural antioxidase mimics for catalytic anti-inflammatory treatment by using rheumatoid arthritis, a common and hardly curable immune-mediated diseases, as an example. Briefly, a composite nanomedicine has been first constructed by loading cationic porphyrin ligands into a manganese-engineered mesoporous silica nanocarrier, which can respond to a mildly acidic environment to concurrently release manganous ions and porphyrin ligands, enabling their subsequent coordination and synthesis of manganese porphyrin with a coordination environment of an active Mn site similar to those of the metal sites in natural superoxide dismutase (SOD) and catalase. Due to the strong metal-ligand exchange coupling enabled by the N-ethylpyridinium-2-yl groups tetrasubstituted in the meso positions of N(4)-macroheterocycles, such a manganese porphyrin presents the SOD-like activity of disproportionating superoxide anions via outer-sphere proton-coupled one-electron transfer (diaquamanganese(III)/monoaquamanganese(II) cycling), as well as the catalase-like activity of disproportionating hydrogen peroxide via inner-sphere proton-coupled two-electron transfer (diaquamanganese(III)/dioxomanganese(V) cycling). Cellular experiments demonstrated the high antioxidative efficacy of the composite nanomedicine in M1 macrophages by promoting their polarization shift to the anti-inflammatory M2 phenotype. Equally importantly, the silicon-containing oligomers released from the manganese silicate nanocarrier can act as heterogeneous nucleation centers of hydroxyapatite for facilitating biomineralization by bone mesenchymal stem cells. Finally, an in vivo adjuvant-induced arthritis animal model further reveals the high efficacy of the nanomedicine in treating rheumatoid arthritis.
34857786 Integrative epigenomics in Sjögren´s syndrome reveals novel pathways and a strong intera 2021 Dec 2 Primary Sjögren's syndrome (SS) is a systemic autoimmune disease characterized by lymphocytic infiltration and damage of exocrine salivary and lacrimal glands. The etiology of SS is complex with environmental triggers and genetic factors involved. By conducting an integrated multi-omics study, we confirmed a vast coordinated hypomethylation and overexpression effects in IFN-related genes, what is known as the IFN signature. Stratified and conditional analyses suggest a strong interaction between SS-associated HLA genetic variation and the presence of Anti-Ro/SSA autoantibodies in driving the IFN epigenetic signature and determining SS. We report a novel epigenetic signature characterized by increased DNA methylation levels in a large number of genes enriched in pathways such as collagen metabolism and extracellular matrix organization. We identified potential new genetic variants associated with SS that might mediate their risk by altering DNA methylation or gene expression patterns, as well as disease-interacting genetic variants that exhibit regulatory function only in the SS population. Our study sheds new light on the interaction between genetics, autoantibody profiles, DNA methylation and gene expression in SS, and contributes to elucidate the genetic architecture of gene regulation in an autoimmune population.
34660815 Advances in Pathogenesis of Sjögren's Syndrome. 2021 Sjögren's syndrome (SS) is a chronic autoimmune disease of unknown etiology that mainly involves exocrine glands. Patients present with dry mouth and eyes, fever, arthralgia, and other systemic symptoms. In severe cases, the quality of life of patients is affected. At present, there is no cure for SS, and the treatment options are extremely limited. In recent years, studies of patients and animal models have identified abnormalities of immune cell function and cytokines to be involved in SS. A systematic review of the literature may clarify the etiology and pathogenesis of SS, as well as provide a theoretical basis for the development of new drugs for the treatment of SS.
34868062 Development and Application of the Placebo Response Model in Clinical Trials for Primary S 2021 This study aimed to develop a placebo response model for pharmaceutical clinical trials of primary Sjogren's syndrome,and to quantitatively analyze the distribution and related factors influencing the placebo response to further optimize the design of clinical trials and evaluate the results of single-arm clinical trials. Public databases, including PubMed, Embase, and Cochrane Library were searched for reports on randomized placebo-controlled trials for Sjögren's syndrome which used the change from baseline in ESSDAI score as the primary outcome. The model-based meta-analysis method was used to evaluate the time course and the related influencing factors of the placebo response for ESSDAI in such clinical trials. A virtual placebo control group was constructed based on the final placebo response model to determine the treatment efficacy of belimumab and cyclosporine A for primary Sjögren's syndrome in a single-arm study. A total of 12 studies involving 450 subjects were included in the analysis. The established model described the time-course characteristics of the changes in ESSDAI score from the baseline in the 48 weeks placebo group. We found that the onset time of placebo response was approximately 12 weeks, and its efficacy plateaued at 48 weeks. The baseline ESSDAI score had a significant effect on the maximum value of the placebo response; the maximum value of the placebo response decreased by 0.552 for every 1 score rise in the baseline ESSDAI score. The efficacy of belimumab and cyclosporine A in the single-arm trial was comparable to that of the placebo response at the same baseline; no significant therapeutic advantage was observed. The placebo response model established in this study could provide a basis for designing clinical trials for primary Sjogren's syndrome in the future. It may also provide a reliable external efficacy control standard for single-arm clinical trials.
33488608 Transcriptomic and Network Analysis of Minor Salivary Glands of Patients With Primary Sjö 2020 Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease characterized primarily by immune-mediated destruction of exocrine tissues, such as those of the salivary and lacrimal glands, resulting in the loss of saliva and tear production, respectively. This disease predominantly affects middle-aged women, often in an insidious manner with the accumulation of subtle changes in glandular function occurring over many years. Patients commonly suffer from pSS symptoms for years before receiving a diagnosis. Currently, there is no effective cure for pSS and treatment options and targeted therapy approaches are limited due to a lack of our overall understanding of the disease etiology and its underlying pathology. To better elucidate the underlying molecular nature of this disease, we have performed RNA-sequencing to generate a comprehensive global gene expression profile of minor salivary glands from an ethnically diverse cohort of patients with pSS. Gene expression analysis has identified a number of pathways and networks that are relevant in pSS pathogenesis. Moreover, our detailed integrative analysis has revealed a primary Sjögren's syndrome molecular signature that may represent important players acting as potential drivers of this disease. Finally, we have established that the global transcriptomic changes in pSS are likely to be attributed not only to various immune cell types within the salivary gland but also epithelial cells which are likely playing a contributing role. Overall, our comprehensive studies provide a database-enriched framework and resource for the identification and examination of key pathways, mediators, and new biomarkers important in the pathogenesis of this disease with the long-term goals of facilitating earlier diagnosis of pSS and to mitigate or abrogate the progression of this debilitating disease.
34638813 Treatment of Sjögren's Syndrome with Mesenchymal Stem Cells: A Systematic Review. 2021 Sep 28 Mesenchymal stem cells (MSCs) are ubiquitous in the human body. Mesenchymal stem cells were initially isolated from bone marrow and later from other organs such as fatty tissues, umbilical cords, and gingiva. Their secretory capacities give them interesting immunomodulatory properties in cell therapy. Some studies have explored the use of MSCs to treat Sjögren's syndrome (SS), a chronic inflammatory autoimmune disease that mainly affects exocrine glands, including salivary and lacrimal glands, although current treatments are only palliative. This systematic review summarizes the current data about the application of MSCs in SS. Reports show improvements in salivary secretions and a decrease in lymphocytic infiltration in salivary glands in patients and mice with SS after intravenous or infra-peritoneal injections of MSCs. MSC injections led to a decrease in inflammatory cytokines and an increase in anti-inflammatory cytokines. However, the intrinsic mechanism of action of these MSCs currently remains unknown.
34319596 Circulating regulatory T cells in adult-onset Still's disease: Focusing on their plasticit 2021 Nov We investigated the characteristics of regulatory T cells in adult-onset Still's disease (AOSD) with a focus on their plasticity, stability and relationship to disease severity. The proportion of circulating CD4(+) CD25(+) forkhead box protein 3 (FoxP3(+) ) cells (T(regs) ) and intracellular expression of effector cytokines, including interferon (IFN)-γ, interleukin (IL)-17 and IL-4, was analysed in 27 untreated patients with AOSD (acute AOSD), 11 of the 27 patients after remission and 16 healthy controls (HC) using flow cytometry. The suppressive ability of T(regs) was also evaluated. Regression analyses of the results were performed. The proportion of T(regs) was significantly lower in patients with acute AOSD than in the HC. The expression levels of IFN-γ, IL-17 and IL-4 in T(regs) were significantly increased in patients with acute AOSD. IFN-γ and IL-4 expression levels were inversely correlated with the proportion of T(regs) and positively correlated with serum ferritin levels. Decreased expression of FoxP3 in CD4(+) CD25(+) cells, which was correlated with increased expression of IL-17, and impaired suppressive function were observed in T(regs) in acute AOSD. However, these aberrant findings in T(regs) , including the reduced circulating proportion and functional ability and altered intracellular expression levels of cytokines and FoxP3, were significantly improved after remission. In acute AOSD, T(regs) show plastic changes, including effector cytokine production and reductions in their proportion and functional activity. IFN-γ and IL-4 expression levels in T(regs) may be associated with disease severity. Also, down-regulation of FoxP3 may be related to IL-17 expression in T(regs) . Importantly, the stability of T(regs) can be restored in remission.
34177936 Association Between Minor Salivary Gland Biopsy During Sjӧgren's Syndrome and Serologic B 2021 OBJECTIVE: Patients with primary Sjögren's syndrome (pSS) may develop a potentially severe disease with extra-glandular involvement and lymphoma insurgence. Minor salivary gland biopsy is routinely used in the disease diagnosis, but its potential role as a biomarker for clinical disease presentation and prognosis is still poorly understood. METHODS: We performed a systematic review and meta-analysis on clinical presentation and prognosis in pSS patients who underwent minor salivary gland biopsy at diagnosis according to the PRISMA guidelines. RESULTS: We included five retrospective studies and 589 pSS patients. Ectopic GCs presence was not associated with a significant increase in the odds ratio for the clinical variables explored such as salivary gland swelling, arthritis, and Raynaud's phenomenon. As far as serological features are concerned, ectopic GCs presence accounted for an increased ratio of antibodies anti-SSA (OR = 3.13, 95% CI: 1.25-7.85, p = 0.02, I(2) = 79%), anti-SSB (OR = 3.94, 95% CI: 1.50-10.37, p = 0.0005, I(2) = 80%), and RFs presence (OR = 3.12, 95% CI: 1.94-5.00, p < 0.00001, I(2) = 0%). CONCLUSIONS: This study showed that the association between ectopic GC in salivary glands identifies a clinical subset characterized by autoantibodies presence, and probably pSS patients affected from a more severe disease.
33801157 SMADS-Mediate Molecular Mechanisms in Sjögren's Syndrome. 2021 Mar 21 There is considerable interest in delineating the molecular mechanisms of action of transforming growth factor-β (TGF-β), considered as central player in a plethora of human conditions, including cancer, fibrosis and autoimmune disease. TGF-β elicits its biological effects through membrane bound serine/threonine kinase receptors which transmit their signals via downstream signalling molecules, SMADs, which regulate the transcription of target genes in collaboration with various co-activators and co-repressors. Until now, therapeutic strategy for primary Sjögren's syndrome (pSS) has been focused on inflammation, but, recently, the involvement of TGF-β/SMADs signalling has been demonstrated in pSS salivary glands (SGs) as mediator of the epithelial-mesenchymal transition (EMT) activation. Although EMT seems to cause pSS SG fibrosis, TGF-β family members have ambiguous effects on the function of pSS SGs. Based on these premises, this review highlights recent advances in unravelling the molecular basis for the multi-faceted functions of TGF-β in pSS that are dictated by orchestrations of SMADs, and describe TGF-β/SMADs value as both disease markers and/or therapeutic target for pSS.