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ID PMID Title PublicationDate abstract
34948236 Akt Signaling Pathway Is Activated in the Minor Salivary Glands of Patients with Primary S 2021 Dec 14 Primary Sjögren's syndrome (pSS) is an autoimmune exocrinopathy of mainly the salivary and lacrimal glands associated with high prevalence of lymphoma. Akt is a phosphoinositide-dependent serine/threonine kinase, controlling numerous pathological processes, including oncogenesis and autoimmunity. Herein, we sought to examine its implication in pSS pathogenesis and related lymphomagenesis. The expression of the entire and activated forms of Akt (partially and fully activated: phosphorylated at threonine-308 (T308) and serine-473 (S473), respectively), and two of its substrates, the proline-rich Akt-substrate of 40 kDa (PRAS40) and FoxO1 transcription factor has been immunohistochemically examined in minor salivary glands (MSG) of pSS patients (n = 29; including 9 with pSS-associated lymphoma) and sicca-complaining controls (sicca-controls; n = 10). The entire and phosphorylated Akt, PRAS40, and FoxO1 molecules were strongly, uniformly expressed in the MSG epithelia and infiltrating mononuclear cells of pSS patients, but not sicca-controls. Morphometric analysis revealed that the staining intensity of the fully activated phospho-Akt-S473 in pSS patients (with or without lymphoma) was significantly higher than sicca-controls. Akt pathway activation was independent from the extent or proximity of infiltrates, as well as other disease features, including lymphoma. Our findings support that the Akt pathway is specifically activated in MSGs of pSS patients, revealing novel therapeutic targets.
34861168 Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sjögren's 2022 Jan 8 BACKGROUND: Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome. METHODS: VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18-75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895. FINDINGS: Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline -1·92 points (95% CI -4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group). INTERPRETATION: The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future. FUNDING: Novartis.
34208077 The Association of ATG16L1 Variations with Clinical Phenotypes of Adult-Onset Still's Dise 2021 Jun 11 Adult-onset Still's disease (AOSD) is a rare autoinflammatory disease, which has elevated autophagosome levels regulated by autophagy-related gene (ATG) expression. We investigated the associations of ATG polymorphisms with AOSD susceptibility, clinical manifestations, and disease course. The six-candidate single-nucleotide polymorphisms (SNPs) involved in autophagy were genotyped using direct sequencing on samples from 129 AOSD patients and 129 healthy participants. The differentially expressed gene products were quantified using PCR and ELISA. Significant linkage disequilibrium was noted in three SNPs of autophagy-related 16-like 1 (ATG16L1) gene (rs10210302, rs2241880, and rs1045100). Although the AA/CC/TT haplotype of ATG16L1 was not associated with the susceptibility of our AOSD patients compared with other haplotypes, those carrying this haplotype had lower mRNA expression levels of LC3-II, reflecting by autophagosome formation (p = 0.026). Patients carrying AA/CC/TT haplotype also have a significantly higher proportion of skin rash and a lower proportion of arthritis compared with other haplotypes. The AA/CC/TT haplotype was significantly associated with systemic pattern (odds ratio, 3.25; 95% confidence interval, 1.15-9.14; p = 0.026). In summary, the AA/CC/TT haplotype encoded lower levels of autophagosome formation and was associated with a higher proportion of skin rash and systemic pattern of AOSD compared with other haplotypes.
32669446 Axial Articular Manifestations in Primary Sjögren Syndrome: Association With Spondyloarth 2021 Jul OBJECTIVE: To assess the prevalence of axial articular manifestations (AAMs) in patients with primary Sjögren syndrome (pSS), to investigate whether these symptoms reveal an associated spondyloarthritis (SpA), and to assess their therapeutic management. METHODS: Among 148 consecutive patients with pSS fulfilling European League Against Rheumatism (EULAR)/American College of Rheumatology 2019 classification criteria followed between 2010 and 2018, we selected those who presented with AAMs. The association with SpA was retained when patients fulfilled Assessment of SpA international Society criteria. RESULTS: A total of 29 patients (20%, 28 women) with a median age of 43 years (range 15-65 yrs), were identified. The main extraglandular features were peripheral arthralgia and arthritis in 93% and 90% of patients, respectively. Positive anti-Ro/SSA (anti-SSA) antibody was reported in 62%. AAMs were inaugural in 7%, delayed from the diagnostic of pSS in 7%, and occurred concomitantly in 86% of patients. AAMs were not associated to multisystemic involvement of pSS. Radiographic sacroiliitis was mentioned in 65%, and HLA-B27 was positive in 13%. The diagnosis of SpA was retained in 23/29 patients (79%), among which 74% and 26% fulfilled psoriatic arthritis and ankylosing spondylitis criteria, respectively. There was no phenotypic difference according to the anti-SSA antibody status. With a median follow-up of 60 months (range: 5-96), 61% of patients with associated SpA required biotherapies, mainly of anti-tumor necrosis factor-α or anti-interleukin 17A molecules with a good clinical outcome in 64% and no effect on pSS. CONCLUSION: AAMs are not uncommon in patients with pSS and may reveal an associated SpA. Treatment of AAMs, especially when clearly associated with SpA, may necessitate biologics, following SpA-management therapeutic guidelines.
34706972 Small Fiber Neuropathy Incidence, Prevalence, Longitudinal Impairments, and Disability. 2021 Nov 30 BACKGROUND AND OBJECTIVES: There are limited population-based data on small fiber neuropathy (SFN). We wished to determine SFN incidence, prevalence, comorbid conditions, longitudinal impairments, and disabilities. METHODS: Test-confirmed patients with SFN in Olmsted, Minnesota, and adjacent counties were compared 3:1 to matched controls (January 1, 1998-December 31, 2017). RESULTS: Ninety-four patients with SFN were identified, with an incidence of 1.3/100,000/y that increased over the study period and a prevalence of 13.3 per 100,000. Average follow-up was 6.1 years (0.7-43 years), and mean onset age was 54 years (range 14-83 years). Female sex (67%), obesity (body mass index mean 30.4 vs 28.5 kg/m(2)), insomnia (86% vs 54%), analgesic-opioid prescriptions (72% vs 46%), hypertriglyceridemia (180 mg/dL mean vs 147 mg/dL), and diabetes (51% vs 22%, p < 0.001) were more common (odds ratio 3.8-9.0, all p < 0.03). Patients with SFN did not self-identify as disabled with a median modified Rankin Scale score of 1.0 (range 0-6) vs 0.0 (0-6) for controls (p = 0.04). Higher Charlson comorbid conditions (median 6, range 3-9) occurred vs controls (median 3, range 1-9, p < 0.001). Myocardial infarctions occurred in 46% vs 27% of controls (p < 0.0001). Classifications included idiopathic (70%); diabetes (15%); Sjögren disease (2%); AL-amyloid (1%); transthyretin-amyloid (1%); Fabry disease (1%); lupus (1%); postviral (1%); Lewy body (1%), and multifactorial (5%). Foot ulcers occurred in 17, with 71% having diabetes. Large fiber neuropathy developed in 36%, on average 5.3 years (range 0.2-14.3 years) from SFN onset. Median onset Composite Autonomic Severity Score (CASS) was 3 (change per year 0.08, range 0-2.0). Median Neuropathy Impairment Scale (NIS) score was 2 at onset (range 0-8, change per year 1.0, range -7.9 to +23.3). NIS score and CASS change >1 point per year occurred in only AL-amyloid, hereditary transthyretin-amyloid, Fabry, uncontrolled diabetes, and Lewy body. Death after symptom onset was higher in patients with SFN (19%) vs controls (12%, p < 0.001), 50% secondary to diabetes complications. DISCUSSION: Isolated SFN is uncommon but increasing in incidence. Most patients do not develop major neurologic impairments and disability but have multiple comorbid conditions, including cardiovascular ischemic events, and increased mortality from SFN onsets. Development of large fiber involvements and diabetes are common over time. Targeted testing facilitates interventional therapies for diabetes but also rheumatologic and rare genetic forms.
32613392 Characteristics of primary Sjögren's syndrome related lymphocytic interstitial pneumonia. 2021 Feb OBJECTIVE: This paper is aimed at investigating the clinical characteristics of primary Sjogren's syndrome (pSS) with lymphocytic interstitial pneumonia (LIP). METHODS: The demographic data, clinical manifestations, laboratory and radiological findings, treatment, and prognosis from 15 cases of pSS-LIP patients were retrospectively analyzed. The data were compared with t test, χ (2) test, and Pearson/Spearman correlation analysis. RESULTS: (1) Fifteen cases of patients with pSS-LIP are all females (100%). Compared with pSS with interstitial lung disease(pSS-ILD) patients, the incidence of dry cough, dental caries is higher in pSS-LIP patients. The incidence of shortness of breath, weight loss, and crackles is lower in pSS-LIP patients than that of pSS-ILD patients. (2) Compared with pSS-ILD patients, pSS-LIP patients had higher percentage of patients with ANA, anti-SSA52KD antibody, anti-SSA60KD antibody, and anti-SSB antibody, and the higher concentration of serum globulin. (3) Compared with pSS-ILD patients, the frequency of obstructive ventilation dysfunction is significantly higher and the frequency of diffusion dysfunction is significantly lower in pSS-LIP patients. (4) The most frequent HRCT findings in patients with pSS-LIP is cysts (100%), followed by ground-glass opacities (73.3%), nodular shadow (73.3%) among the pSS-LIP patients. Compared with PSS-ILD patients, the incidence of pulmonary nodule shadow is significantly higher in PSS-LIP patients, while that of grid shadow was significantly lower. (5) Compared with the baseline, the sum of the number, maximum diameter, and diameter of cysts in three levels of pSS-LIP patients showed an increasing trend after treatment. (6) Correlation analysis: The changes of ground-glass opacities were positively correlated with using GC or not, and those were negatively correlated with the dose of GC treatment. Besides, there is a positive correlation between the annual change rate of the maximum diameter of cysts (△Ømax1/t) and the use of CTX; there is a positive correlation between the annual change rate of the total diameter of cysts (△Øsum1/t) and the use of CTX. CONCLUSION: To the patients of pSS-LIP, female were more common than male, and the onset of LIP was usually more insidious. Hyperglobulinemia and anti-SSA antibody were more prominent in patients with pSS-LIP. Pulmonary function showed the higher rate of obstructive ventilation dysfunction and the lower rate of diffusion dysfunction. The appearance of ground-glass opacities in pSS-LIP patients suggests that the infiltration of inflammatory cells increases, which may cause airway compression, the expansion of terminal bronchioles, and the formation of cysts. The more ground-glass opacities appear earlier, and the more appearance of new cysts later. Therapy with glucocorticoid may be effective on the ground-glass opacity during acute stage, and therapy with cyclophosphamide may be effective on the cysts during chronic stage. The heavier ground-glass opacity is at baseline, the more likely it will recur during maintenance treatment. So follow-up closely is needed. Key Points • It is the first clinical study with more cases of patients with pSS-LIP. • Female and hyperglobulinemia and anti-SSA antibody were more prominent in patients with pSS-LIP. • Pulmonary function showed the higher rate of obstructive ventilation dysfunction and the lower rate of diffusion dysfunction. • Therapy with glucocorticoid may be effective on the ground-glass opacity during acute stage, and therapy with cyclophosphamide may be effective on the cysts during chronic stage.
34393240 [Effect of topical injection of cyclosporine A on saliva secretion and inflammation in the 2021 Aug 18 OBJECTIVE: To investigate the effects of topical administration of cyclosporine A (CsA) on salivary secretion and inflammation of the submandibular glands in non-obese diabetic (NOD) mice. METHODS: Female NOD mice, 21 aged 14 weeks and 18 aged 21 weeks were selected and randomly divided into low-dose group, high-dose group and control group on average. CsA was injected into submandibular glands. One week later the saliva stimulated by pilocarpine was collected and measured. The submandibular glands were collected to make paraffin sections. The lymphocyte infiltration in submandi-bular gland was observed by microscope after hematoxylin-eosin (HE) staining. The number of lymphocyte infiltration foci was counted to calculate the focus sore and the ratio of lymphocyte infiltration area to total gland area was figured up by Leica image analysis system. The expressions of inflammatory cytokines tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-4 (IL-4), IL-13, IL-17F, IL22 and IL-23a in the submandibular glands of the NOD mice were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Cell apoptosis in the submandibular gland was detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The levels of serum creatinine (Scr), blood urea nitrogen (BUN), uric acid (UA), alanine aminotransferase (ALT), aspertate aminotransferase (AST), alkaline phosphatase (ALP), albumin (ALB) and γ-glutamyl transferase (GGT) were measured by automatic biochemical analyzer to evaluate liver and kidney functions. RESULTS: After topical injection of CsA in the submandibular gland, the stimulated salivary flow rate of the 14- and 21-week-old NOD mice significantly increased compared with the control group (P < 0.01 or P < 0.05), and the number and area of lymphocyte infiltration foci in the 14-week-old NOD mice low-dose group significantly decreased compared with the control group (P < 0.01). Low and high dose of CsA had similar effects on reducing inflammation and improving salivary secretion. The overall level of inflammatory cytokines in the submandibular gland did not decrease significantly. The number of cell apoptosis of submandibular gland in the NOD mice treated with CsA decreased compared with the control group, but there was no statistically significant difference. Topical injection of CsA had no adverse effect on liver and kidney function in the NOD mice. CONCLUSION: Topical injection of CsA can reduce lymphocyte infiltration in submandibular gland of NOD mice and improve salivary secretion.
34058801 Wnt signaling pathway activities may be altered in primary Sjogren’s syndrome. 2021 Aug 30 BACKGROUND/AIM: Sjögren’s syndrome (SS) is an autoimmune disease and its pathogenesis is still not completely clear. The wingless (Wnt)/β-catenin pathway has recently been shown to play an important role in inflammation. This study aims to determine the serum and saliva levels of Dickkopf (DKK)1 and sclerostin and to evaluate Wnt-1 and Wnt-3a expression in the salivary gland in patients with primary SS. MATERIALS AND METHODS: This study included 30 patients diagnosed with SS, 30 patients diagnosed with systemic lupus erythematosus (SLE), and 29 healthy controls. Serum and saliva levels of DKK1 and sclerostin were measured and the expressions of Wnt1 and Wnt3a in the salivary gland were measured immunohistochemically. RESULTS: Serum DKK1 and sclerostin levels were lower in the SS and SLE groups compared to the control group (both p < 0.001). Saliva DKK1 levels were higher in the SS group compared to the control and SLE groups (p = 0.004 and p = 0.009, respectively). Wnt1 and Wnt3a expression were found in salivary gland tissue samples in 71.4% of primary SS patients and relatively frequent than control group. CONCLUSIONS: Serum DKK1 and sclerostin levels in primary SS and SLE were decreased. Moreover, levels of Wnt1 and Wnt3a expression in the salivary gland were also elevated in primary SS. Therefore, it can be concluded that the Wnt/β-catenin pathway activities may be altered in case of glandular inflammation.
33561833 [A Case of Immune-Mediated Necrotizing Myopathy Associated with Primary Sjögren Syndrome] 2021 Feb A 66-year-old woman visited our hospital complaining of shortness of breath during exertion and progressive weakness in all her limb muscles. On admission, we noted muscle weakness in her trunk and in her proximal limb muscles, although, her muscle MRI showed no remarkable findings. However, her serum CK level (2,747U/L) was above the normal range. Histopathological examination of muscle biopsy, performed from the left biceps brachii muscle, revealed immune-mediated necrotizing myopathy (IMNM). Her serum samples were negative for myositis-associated autoantibodies (MAAs), anti-SRP, and HMGCR antibodies. However, as the anti-SS-A antibody level in her serum was high (53.2U/mL), we conducted the salivary gland biopsy and the Schirmer test on her eyes. We found lymphocytes infiltration in her salivary gland tissue, and thus, she was diagnosed with primary Sjögren syndrome (SjS). We also observed necrotizing myopathy associated with the SjS. Following her treatment with oral steroids, her symptoms and CK level improved. Although, inflammatory myositis frequently occurs in association with general collagen diseases, necrotizing myopathy has rarely been observed secondary to SjS. We report here this rare case study along with the review of the relevant literature. (Received June 24, 2020; Accepted October 12, 2020; Published February 1, 2021).
33405348 Haematologic indices and disease activity index in primary Sjogren's syndrome. 2021 Mar BACKGROUND: The present study was conducted to investigate the association between haematologic indices, neutrophil/lymphocyte ratio (NLR), mean platelet volume (MPV), platelet/lymphocyte ratio (PLR), disease activation, organ involvement, and inflammatory markers in the SS. METHODS: The study was conducted with newly diagnosed and treatment-naive 41 primary SS patients who met ACR-2012 criteria and 96 healthy volunteers. Blood tests obtained before treatment were evaluated. Lymphocyte, neutrophil and platelet counts, mean corpuscular volume (MCV), platelet distribution width (PDW), plateletcrit (PCT), haematocrit (HCT), MPV, white blood cell count (WBC) values were harvested from CBC of the subjects and NLR, PLR were calculated over these values. The values were compared between groups and correlation with EULAR SS disease activity index (ESSDAI) was evaluated. RESULTS: The study included a total of 41 patients with a mean age of 40.73 ± 12.0 years and 96 healthy subjects with a mean age of 40.0 ± 9.2 years. In inter-group comparisons, lymphocyte, platelet counts, and MPV values were significantly lower in the SS group compared with the control group (P < .01), and NLR was significantly higher in the SS group (P = .026). The mean ESSDAI scores in SS patients were 5.65 ± 0.86 SE. These scores were significantly higher in patients with neurological involvement. There was a positive correlation between ESSDAI and PLR. CONCLUSION: NLR, PLR, and MPV may be used as indicators or with activity index in SS. ESSDAI scores were found to be high in patients with neurological involvement, and it was also found to be correlated with PLR.
33074391 The validity of salivary gland scintigraphy in Sjögren's syndrome diagnosis: comparison o 2021 May OBJECTIVES: The diagnostic validity of salivary gland scintigraphy in Sjögren's syndrome (SS) has not been conclusively defined. Whether a quantitative (excretion fraction) interpretation of scintigraphy is superior to a qualitative one (visual analysis) remains a matter of debate. We sought to determine whether the diagnostic discrimination of excretion fraction is higher compared to that obtained by visual analysis. METHODS: Diagnostic test validity study that encompassed 137 suspected SS subjects who underwent scintigraphy for diagnostic purposes. Patients were diagnosed as SS and non-SS according to the rheumatologist's clinical judgment, and by using the American-European Consensus Group (AECG) and American College of Rheumatology (ACR) classification criteria. Visual analysis (normal vs. abnormal and Schall's classification grade) and excretion fraction scores were calculated. The diagnostic discrimination of these methods was compared through the area under the curve (AUC) analysis. Scintigraphy associations with SS clinical and laboratory features were assessed through multivariable regression analysis. RESULTS: Schall's classification AUC reached statistical significance in its diagnostic discrimination for SS clinical judgment (0.704 [95%CI 0.597-0.811]) and AECG criteria (0.764 [95%CI 0.641-0.886]). Similarly, submandibular excretion fraction was associated with SS diagnosis based on ACR (0.737 [95%CI 0.546-0.931]) and AECG criteria (0.715 [95%CI 0.597-0.833]). However, AUC comparisons between qualitative and quantitative methods did not yield statistically significant values. Both interpretation modalities were associated with SS serological features. Moreover, excretion fraction was also associated with salivary gland biopsy. CONCLUSIONS: SS diagnostic discrimination of excretion fraction is not superior to that obtained by qualitative visual analysis. Both qualitative and quantitative scintigraphy methods are associated with SS clinical and laboratory characteristics.
33004530 Clinical Phenotyping of Primary Sjögren Syndrome Patients Using Salivary Gland Ultrasonog 2021 May OBJECTIVE: To investigate salivary gland ultrasound (SGUS) abnormalities in relation to clinical phenotype and patient characteristics, disease activity, and disease damage in patients with primary Sjögren syndrome (pSS). METHODS: Consecutive outpatients included in our REgistry of Sjögren Syndrome LongiTudinal (RESULT) cohort were selected. Patients with pSS who were included were classified according to the American College of Rheumatology/European League Against Rheumatism (EULAR) criteria and underwent full ultrasonographic examination (Hocevar score 0-48) at baseline. Total SGUS scores of ≥ 15 were considered positive. Patient characteristics, disease activity, and disease damage were compared between the different SGUS groups. RESULTS: In total, 172 of 186 patients with pSS were eligible, of whom 136 (79%) were SGUS positive. Compared with patients who were SGUS negative, SGUS-positive patients had significantly longer disease duration, higher EULAR Sjögren Syndrome Disease Activity Index, higher Sjögren Syndrome Disease Damage Index, and were more likely to have a positive parotid gland biopsy, anti-SSA/SSB antibodies, and abnormal unstimulated whole saliva (UWS) and ocular staining score (OSS), and higher levels of IgG and rheumatoid factor. Regarding patient-reported outcome measurements (PROM), patients who were SGUS positive scored significantly lower on the EULAR Sjögren Syndrome Patient-Reported Index for fatigue and pain, and more often found their disease state acceptable compared with patients who were SGUS negative. SGUS total score showed significant associations with various clinical and serological variables, and with PROM. Highest associations were found for UWS (ρ = -0.551) and OSS (ρ = 0.532). CONCLUSION: Patients who were SGUS positive show a distinct clinical phenotype in all aspects of the disease compared with patients who were SGUS negative: clinical, functional, serological, and PROM. SGUS could be a helpful tool in selecting patients for clinical trials and estimating treatment need.
34538269 Longitudinal analysis of symptom-based clustering in patients with primary Sjogren's syndr 2021 Sep 19 BACKGROUND: Sjogren's syndrome (SS) is a heterogenous disease with various phenotypes. We aimed to provide a relevant subclassification based on symptom-based clustering for patients with primary (p) SS. METHODS: Data from patients in a prospective pSS cohort in Korea were analysed. Latent class analysis (LCA) was performed using patient reported outcomes, including pain, fatigue, dryness, and anxiety/depression. Clinical and laboratory differences between the classes were analysed. Latent transition analysis (LTA) was applied to the longitudinal data (annually for up to 5 years) to assess temporal stability of the classifications. RESULTS: LCA identified three classes among 341 patients with pSS (i.e., 'high symptom burden', 'dryness dominant', 'low symptom burden'). Each group had distinct laboratory and clinical phenotypes. LTA revealed that class membership remained stable over time. Baseline class predicted future salivary gland function and damage accrual represented by a Sjogren's syndrome disease damage index. CONCLUSION: Symptom-based clustering of heterogenous patients with primary Sjogren's syndrome provided a relevant classification supported by temporal stability over time and distinct phenotypes between the classes. This clustering strategy may provide more homogenous groups of pSS patients for novel treatment development and predict future phenotypic evolvement.
33878179 Mortality in patients with primary Sjögren's syndrome: a systematic review and meta-analy 2021 Sep 1 OBJECTIVE: It remains debated whether patients with primary Sjögren's syndrome (pSS) are at greater risk of mortality. We aimed to determine the magnitude of all-cause mortality risk in patients with pSS compared with the general population through a systematic review and meta-analysis. METHODS: We searched PubMed, EMBASE and Cochrane Library for studies published from inception to October 2020. Stata meta-analysis software was used to calculate the pooled risk estimates for mortality (standardized mortality ratio, SMR). RESULTS: Our search identified 2796 articles, of which 14 studies with 14 584 patients were eventually included for the analysis. A total of 902 deaths were observed. Overall, we found a 1.46-fold increased risk of death in pSS patients when compared with the general population [meta-standardized mortality ratio (SMR): 1.46, 95% CI: 1.10, 1.93]. Subgroup analyses showed that mortality risks were higher in European countries (meta-SMR: 1.55, 95% CI: 1.04, 2.33), in retrospective studies (meta-SMR: 1.50, 95% CI: 1.09, 2.05), in studies based on referral cohorts (meta-SMR: 1.55, 95% CI: 1.04, 2.30), in studies that enrolled >500 patients (meta-SMR: 1.70, 95% CI: 1.11, 2.61) and in studies with follow-up time longer than 8 years (meta-SMR: 1.55, 95% CI: 0.87, 2.77). Significantly greater mortality risk was found in patients with older age, male gender, vasculitis, interstitial lung disease, low complements, positive anti-La/SSB and cryoglobulinaemia. CONCLUSION: The existing data indicated ∼50% increase of mortality among patients with pSS compared with the general population. More attention should be paid to those patients with poor prognostic factors.
33509710 Traditional Chinese medicine is a useful and promising alternative strategy for treatment 2021 May Primary Sjogren's syndrome (pSS) is a chronic autoimmune disease involving exocrine glands. Current studies have found that the occurrence of the disease is closely related to genetic, environmental and neuroendocrine factors, as well as abnormal activation of T and B lymphocytes. The etiology and pathogenesis of pSS is complex, and there is a lack of specific targeted drugs. Traditional Chinese medicines (TCMs) have been comprehensively investigated for their treatment effects on pSS. Through a systematic review of the literature, we summarized the TCMs used to treat pSS, and find that there are four major ways that TCMs are used, including upregulation of aquaporin proteins, suppression of cell apoptosis, suppression of the abnormal activation of B lymphocytes and suppression of the abnormal activation of T lymphocytes (balancing T helper type [Th]1/Th2 & Th17/Treg and suppressing follicular helper T [Tfh] cells). However, there are not enough data about the active constituents, quality control, pharmacokinetics, toxicity and modern preparations of these TCMs; therefore, more investigations are needed. This paper highlights the importance of TCMs for treating pSS and provides guidance for future investigations.
35039264 Toxicity studies and anti-arthritic effect of mandelic acid (2-hydroxy -2-phenyl acetic ac 2021 Nov The major concern to search for new anti-arthritic drugs is primarily to prevent systemic complications and to maintain quality of life. As these drugs are prescribed for long duration so the objective is to ensure their safety in terms of toxicity. By keeping in view this concept, the present study was investigated to determine new anti-arthritic potential using in-vitro and in-vivo methods. The in-vitro tests comprised of protein denaturation (BSA and egg albumin) and Human Red Blood cell (HRBC) membrane stabilization assays at 50-6400μg/mL, for in-vivo testing, formaldehyde-induced arthritic rats were treated with 40, 80 and 160mg/kg mandelic acid. Mandelic acid (MA) inhibited the protein denaturation and stabilized the membrane of HRBC in a concentration dependent manner. Likewise, mandelic acid exhibited dose dependent reduction in paw volume induced by formaldehyde. For acute and sub-acute treatment, MA did not show any sign of toxicity and mortality in each rat and LD50 might be greater than 2000mg/kg. In addition, histopathological assessment presented slight increased interstitial spaces in the kidney, disorganization of glomerulus, dilated sinusoids at highest dose 800mg/kg which were not observed in sub-chronic therapy. Hence, these results conclude that mandelic acid has the potential to treat rheumatoid arthritis with observed no significant signs of toxicity and should be tested further to determine anti-arthritic mechanism of drug action at cellular level.
35110180 Ginger extract suppresses the activations of NF-κB and Wnt pathways and protects inflamma 2021 Oct OBJECTIVE: Rheumatoid arthritis (RA) is a disabling inflammatory disorder. Ginger is used for food and medicine to treat arthralgia, sprains, and muscle aches. Anti-inflammatory effects of ginger have been observed. The aim of our study was to detect the effects of ginger on experimentally induced inflammatory arthritis. METHODS: Female Wistar albino rats (n = 21) were randomly separated into three groups (control, arthritis, and arthritis + ginger). Arthritis was generated by an appropriate method using type 2 collagen and Freund's adjuvant (collagen-induced arthritis model). The ginger group was treated starting at the first collagen injection with ginger root extract for 32 days by oral gavage (50 mg/kg/daily). Interleukin (IL)-6, IL-17, tumor necrosis factor-α (TNF-α), sclerostin, dickkopf-related protein-1 (DKK-1), and obestatin serum levels were studied by enzyme-linked immunosorbent assay method. Tissue TNF-α, IL-17, cyclooxygenase-2 (COX-2), and nuclear factor kappa B (NF-κB) levels were detected using the Western blot method. RESULTS: Mean arthritis score and serum levels of TNF-α, IL-6, and IL-17 were significantly decreased in ginger group than in the arthritis group. Increased sclerostin serum level and decreased DKK-1 serum levels were detected in ginger group compared with arthritis group. The decreases of IL-17, TNF-α, COX-2, and NF-κB tissue levels were statistically significant in the ginger group compared with arthritis group. Histopathological evaluation of the ginger group showed a decrease in the inflammation score compared to arthritis group. CONCLUSION: It can be concluded that ginger has protective properties in the development of inflammatory arthritis. The antiarthritic acts of ginger are related to NF-κB activity and Wnt pathway. Thus, it may be suggested that ginger is a candidate to research in human RA treatment.
34784311 miR-544-3p mediates arthritis pain through regulation of FcγRI. 2021 Nov 12 Chronic joint pain is a major symptom in rheumatoid arthritis (RA) and its adequate treatment represents an unmet medical need. Noncoding microRNAs (miRNAs) have been implicated in the pathogenesis of RA as negative regulators of specific target mRNAs. Yet, their significance in RA pain is still not well defined. We and other groups recently identified neuronally expressed FcγRI as a key driver of arthritis pain in mouse RA models. Thus, we tested the hypothesis that miRNAs that target and regulate neuronal FcγRI attenuate RA pain. Here, we show that miR-544-3p was robustly downregulated, whereas FcγRI was significantly upregulated in the dorsal root ganglion (DRG) in mouse RA models. Intrathecal injection of miR-544-3p mimic attenuated established mechanical and heat hyperalgesia partly through the downregulation of FcγRI in the DRG in a mouse model of collagen II-induced arthritis. Moreover, this effect was likely mediated, at least in part, by FcγRI because miR-544-3p mimic downregulated Fcgr1 mRNA expression in the DRG during arthritis and genetic deletion of Fcgr1 produced similar antihyperalgesic effects in the collagen II-induced arthritis model. This notion was further supported by a dual luciferase assay showing that miR-544-3p directly targeted Fcgr1 3'UTR. In naïve mice, miR-544-3p mediated acute joint pain hypersensitivity induced by IgG immune complex through the regulation of FcγRI. These findings suggest that miR-544-3p causally participates in the maintenance of arthritis pain by targeting neuronal FcγRI, and thus define miR-544-3p as a new potential therapeutic target for treating RA pain.
34880764 Delanzomib, a Novel Proteasome Inhibitor, Combined With Adalimumab Drastically Ameliorates 2021 Delanzomib is a novel proteasome inhibitor initially developed for treating multiple myeloma. It was found to inhibit the expression of tumor necrosis factor alpha (TNF-α). This study aimed to investigate the ameliorating effect of delanzomib on collagen-induced arthritis (CIA) and to explore the pharmacodynamics and pharmacokinetics (PK) interactions between delanzomib and adalimumab. Rats with CIA were randomly assigned to receive the treatment with delanzomib, adalimumab, delanzomib combined with adalimumab, or placebo. Visual inspection and biochemical examinations including TNF-α, interleukin 6, and C-reactive protein were performed to assess arthritis severity during the treatment. The adalimumab concentration in rats was determined to evaluate the PK interaction between delanzomib and adalimumab. Also, the levels of neonatal Fc receptor (FcRn) and FcRn mRNA were measured to explore the role of FcRn in the PK interaction between delanzomib and adalimumab. As a result, delanzomib combined with adalimumab exhibited stronger anti-arthritis activity than a single drug because both drugs synergistically reduced TNF-α level in vivo. Delanzomib also decreased adalimumab elimination in rats by increasing the level of FcRn. The slower elimination of adalimumab in rats further prolonged the anti-TNF-α effect of adalimumab. Moreover, FcRn level was increased by delanzomib via suppressing FcRn degradation rather than promoting FcRn production. In conclusion, delanzomib combined with adalimumab may be a potential therapeutic approach for treating rheumatoid arthritis. The initial finding that the PK interaction occurred between delanzomib and adalimumab may have clinical relevance for patients who simultaneously take proteasome inhibitors and anti-TNF-α therapeutic proteins.
34881329 Suppression of epithelial abnormalities by nintedanib in induced-rheumatoid arthritis-asso 2021 Oct Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is relevant for the prognosis in patients with RA. Nintedanib, which inhibits both receptor and non-receptor type tyrosine kinases, is an antifibrotic drug for the treatment of progressive fibrosing ILDs, such as idiopathic pulmonary fibrosis and systemic sclerosis-associated interstitial lung disease. Little is known about the effects of nintedanib on RA-ILD. We examined the characteristics of a novel induced RA-ILD (iRA-ILD) mouse model and the effects of nintedanib on the model. D1CC×D1BC mice are highly susceptible to arthritogenic antigens, such as bovine type II collagen, resulting in severe inflammatory arthritis. ILD develops after joint inflammation is alleviated. Serum surfactant protein D levels were monitored as an ILD marker. Nintedanib was orally administered to iRA-ILD mice for 2 months. The iRA-ILD model showed similar symptoms to those in patients with RA-ILD. The histopathological features of pulmonary disorder resembled nonspecific interstitial pneumonia, but with metaplastic epithelium. Histopathological analysis revealed that in addition to reducing fibrosis, nintedanib suppressed M2 macrophage polarisation and hyperplasia of Type 2 alveolar epithelial cells. The metaplastic epithelium acquired invasiveness because of the expression of E-cadherin, MMP7, Tgf-β, Col1a1, Padi2 and Padi4. Moreover, citrullinated peptides were detected in these invasive epithelial cells as well as in the bronchiolar epithelium. Administration of nintedanib reduced the expression of Pad4 and citrullinated peptides and eliminated invasive epithelial cells. The broad inhibitory effects of nintedanib on tyrosine kinases may contribute to the overall improvement in RA-ILD, including epithelial abnormalities associated with progressive lung fibrosis.