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Antioxidants (Basel, Switzerland) Aug 2022Genetic association studies have discovered the intergenic region as a strong susceptibility locus for multiple autoimmune disorders, with the missense mutation... (Review)
Review
Genetic association studies have discovered the intergenic region as a strong susceptibility locus for multiple autoimmune disorders, with the missense mutation rs201802880 as the causal polymorphism. In this work, we aimed to perform a comprehensive meta-analysis of the association of the locus with various autoimmune diseases and to provide a systemic review on potential mechanisms underlying the effect of the causal risk variants. The frequencies of the two most extensively investigated polymorphisms within the locus, rs117026326 and rs201802880, vary remarkably across the world, with the highest frequencies in East Asian populations. Meta-analysis showed that the locus is significantly associated with primary Sjögren's syndrome, systemic lupus erythematosus, systemic sclerosis, and neuromyelitis optica spectrum disorder. The causal rs201802880 polymorphism leads to an amino acid substitution of p.Arg90His in the p47phox subunit of the phagocyte NADPH oxidase. The autoimmune disease risk His90 variant results in a reduced ROS production in phagocytes. Clinical and experimental evidence shows that the hypoactive His90 variant might contribute to the development of autoimmune disorders via multiple mechanisms, including impairing the clearance of apoptotic cells, regulating the mitochondria ROS-associated formation of neutrophil extracellular traps, promoting the activation and differentiation of autoreactive T cells, and enhancing type I IFN responses. In conclusion, the identification of the association of with autoimmune disorders demonstrates that ROS is an essential regulator of immune tolerance and autoimmunity mediated disease manifestations.
PubMed: 36009308
DOI: 10.3390/antiox11081589 -
Annals of Hepatology 2022We performed a systematic review and meta-analysis to evaluate the prevalence of concomitant Sjögren's syndrome (SS) with primary biliary cholangitis (PBC) in adults... (Meta-Analysis)
Meta-Analysis
INTRODUCTION AND OBJECTIVES
We performed a systematic review and meta-analysis to evaluate the prevalence of concomitant Sjögren's syndrome (SS) with primary biliary cholangitis (PBC) in adults and quantify the impact of SS on PBC.
METHODS
PubMed, Web of Science and Cochrane library were searched using subject terms and predefined inclusion and exclusion criteria.
RESULTS
Seventeen articles were included. The prevalence of SS in PBC patients ranged from 3.5 to 73% (35% pooled) (95% CI: 28-41%; p < 0.01). Seven studies included various biochemical indicators, including alanine transaminase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), γ-glutamyltransferase (γ-GT), total bilirubin (TBiL), albumin (ALB) and platelet (PLT), and immunological indexes including IgG, IgM, antinuclear antibody (ANA), anti-mitochondrial antibody (AMA), AMA-M2 and anti-Ro/Sjögren's syndrome antigen A (SSA) antibodies. Meta-analysis showed that there were no significant differences in ALT, AST, ALP, γ-GT, TBiL and IgM levels between PBS and PBC with SS. Pooled analysis showed that ALB (MD=0.82; 95% CI: 0.08-1.56) and PLT (MD=30.41; 95% CI: 10.16-50.66) levels were lower, IgG levels (MD=-1.55; 95% CI: -2.39 to -0.72) were higher, and the positive ratios of ANA (RR=0.92; 95% CI: 0.87-0.98), AMA (RR=0.94; 95% CI: 0.89-0.98), AMA-M2 (RR=0.77; 95% CI: 0.70-0.85) and anti-Ro/SSA antibodies (RR=0.29; 95% CI: 0.08-1.01) were significantly higher in PBC patients with SS than in PBC patients.
CONCLUSIONS
Our study confirms that SS is common in PBC. Comorbid SS appears to influence the clinical phenotype of PBC and may therefore influence the management of PBC.
Topics: Humans; Sjogren's Syndrome; Liver Cirrhosis, Biliary; Autoantibodies; Prevalence; Antibodies, Antinuclear; gamma-Glutamyltransferase; Alkaline Phosphatase; Alanine Transaminase; Immunoglobulin M; Immunoglobulin G
PubMed: 35970319
DOI: 10.1016/j.aohep.2022.100746 -
Frontiers in Immunology 2022To explore the efficacy and safety of Iguratimod intervention in Primary Sjogren's syndrome (pSS). (Meta-Analysis)
Meta-Analysis
OBJECTIVE
To explore the efficacy and safety of Iguratimod intervention in Primary Sjogren's syndrome (pSS).
METHODS
Many databases were searched to collect the RCTs. Three independent reviewers extracted data and assessed the quality of the studies based on the Cochrane Handbook. The statistical analysis was done by RevMan 5.3 and STATA. The quality of evidence was evaluated by GRADE tool.
RESULTS
Twenty-nine RCTs with 2258 participants were included in this review. The meta-analysis shows that: iguratimod experiment group can reduce the ESSPRI score (WMD -1.93 [-2.33, -1.52], P<0.00001), ESSDAI score (WMD -1.39 [-1.81, -0.98], P<0.00001), Schirmer's test (WMD 1.77 [0.85, 2.70], P=0.0002), RF (WMD -5.78 [-7.59, -3.97], P<0.00001), and decrease the ESR level (WMD -7.05 [-9.84, -4.26], P<0.00001). Meanwhile, the summary result showed the addiction of Iguratimod may not increase the adverse events. The adverse events were mainly gastrointestinal discomfort, abnormal liver function, and rash and itching. The quality of evidence of adverse events was moderate. Referring to minimal clinically important difference (MCID), the improvement of ESSPRI is clinically significant, and the improvement of ESSDAI for patients older than 60 years old may be clinically significant.
CONCLUSION
Based on current evidence, iguratimod can effectively reduce ESSPRI score, ESSDAI score, Schirmer's test score and decrease systemic inflammatory response (such as ESR level and RF level) without increasing the probability of adverse events. The recommended course of treatment is at least 12 weeks.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/prospero/display_record.php?, identifier CRD42020220770.
Topics: Chromones; Humans; Middle Aged; Randomized Controlled Trials as Topic; Sjogren's Syndrome; Sulfonamides
PubMed: 35967307
DOI: 10.3389/fimmu.2022.924730 -
Frontiers in Immunology 2022The cytokine interleukin (IL)-1 plays a pivotal role in immune-mediated disorders, particularly in autoinflammatory diseases. Targeting this cytokine proved to be...
BACKGROUND
The cytokine interleukin (IL)-1 plays a pivotal role in immune-mediated disorders, particularly in autoinflammatory diseases. Targeting this cytokine proved to be efficacious in treating numerous IL-1-mediated pathologies. Currently, three IL-1 blockers are approved, namely anakinra, canakinumab and rilonacept, and two additional ones are expected to receive approval, namely gevokizumab and bermekimab. However, there is no systematic review on the safety and efficacy of these biologics in treating immune-mediated diseases.
OBJECTIVE
To evaluate safety and efficacy of anakinra, canakinumab, rilonacept, gevokizumab, and bermekimab for the treatment of immune-mediated disorders compared to placebo, standard-of-care treatment or other biologics.
METHODS
The PRISMA checklist guided the reporting of the data. We searched the PubMed database between 1 January 1984 and 31 December 2020 focusing on immune-mediated disorders. Our PubMed literature search identified 7363 articles. After screening titles and abstracts for the inclusion and exclusion criteria and assessing full texts, 75 articles were included in a narrative synthesis.
RESULTS
Anakinra was both efficacious and safe in treating cryopyrin-associated periodic syndromes (CAPS), familial Mediterranean fever (FMF), gout, macrophage activation syndrome, recurrent pericarditis, rheumatoid arthritis (RA), and systemic juvenile idiopathic arthritis (sJIA). Conversely, anakinra failed to show efficacy in graft-versus-host disease, Sjögren's syndrome, and type 1 diabetes mellitus (T1DM). Canakinumab showed efficacy in treating CAPS, FMF, gout, hyper-IgD syndrome, RA, Schnitzler's syndrome, sJIA, and TNF receptor-associated periodic syndrome. However, use of canakinumab in the treatment of adult-onset Still's disease and T1DM revealed negative results. Rilonacept was efficacious and safe for the treatment of CAPS, FMF, recurrent pericarditis, and sJIA. Contrarily, Rilonacept did not reach superiority compared to placebo in the treatment of T1DM. Gevokizumab showed mixed results in treating Behçet's disease-associated uveitis and no benefit when assessed in T1DM. Bermekimab achieved promising results in the treatment of hidradenitis suppurativa.
CONCLUSIONS
This systematic review of IL-1-targeting biologics summarizes the current state of research, safety, and clinical efficacy of anakinra, bermekimab, canakinumab, gevokizumab, and rilonacept in treating immune-mediated disorders.
SYSTEMATIC REVIEW REGISTRATION
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021228547.
Topics: Arthritis, Juvenile; Arthritis, Rheumatoid; Biological Products; Cryopyrin-Associated Periodic Syndromes; Diabetes Mellitus, Type 1; Familial Mediterranean Fever; Gout; Humans; Immune System Diseases; Interleukin 1 Receptor Antagonist Protein; Interleukin-1; Pericarditis
PubMed: 35874710
DOI: 10.3389/fimmu.2022.888392 -
Frontiers in Big Data 2022Despite decades of research, systemic autoimmune diseases (SADs) continue to be a major global health concern and the etiology of these diseases is still not clear. To...
INTRODUCTION
Despite decades of research, systemic autoimmune diseases (SADs) continue to be a major global health concern and the etiology of these diseases is still not clear. To date, with the development of high-throughput techniques, increasing evidence indicated a key role of oral microbiome in the pathogenesis of SADs, and the alterations of oral microbiome may contribute to the disease emergence or evolution. This review is to present the latest knowledge on the relationship between the oral microbiome and SADs, focusing on the multiomics data generated from a large set of samples.
METHODOLOGY
By searching the PubMed and Embase databases, studies that investigated the oral microbiome of SADs, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and Sjögren's syndrome (SS), were systematically reviewed according to the PRISMA guidelines.
RESULTS
One thousand and thirty-eight studies were found, and 25 studies were included: three referred to SLE, 12 referred to RA, nine referred to SS, and one to both SLE and SS. The 16S rRNA sequencing was the most frequent technique used. HOMD was the most common database aligned to and QIIME was the most popular pipeline for downstream analysis. Alterations in bacterial composition and population have been found in the oral samples of patients with SAD compared with the healthy controls. Results regarding candidate pathogens were not always in accordance, but and were found significantly increased in three SADs, and was significantly decreased in the SADs compared with controls.
CONCLUSION
A large amount of sequencing data was collected from patients with SAD and controls in this systematic review. Oral microbial dysbiosis had been identified in these SADs, although the dysbiosis features were different among studies. There was a lack of standardized study methodology for each study from the inclusion criteria, sample type, sequencing platform, and referred database to downstream analysis pipeline and cutoff. Besides the genomics, transcriptomics, proteomics, and metabolomics technology should be used to investigate the oral microbiome of patients with SADs and also the at-risk individuals of disease development, which may provide us with a better understanding of the etiology of SADs and promote the development of the novel therapies.
PubMed: 35844967
DOI: 10.3389/fdata.2022.927520 -
Frontiers in Immunology 2022Primary Sjögren's syndrome (pSS) and breast cancer are a highly prevalent autoimmune disease and malignancy, respectively, both occurring predominantly in females.... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Primary Sjögren's syndrome (pSS) and breast cancer are a highly prevalent autoimmune disease and malignancy, respectively, both occurring predominantly in females. Whether there is a link between these two diseases is uncertain. We conducted a systematic review and meta-analysis to investigate the risk, incidence, and mortality of breast cancer in patients with pSS.
METHODS
We systematically searched Embase, PubMed, and Web of Science on January 31, 2022 to identify the study that assessed risk, incidence, or mortality of breast cancer in pSS. The fixed or random-effects models were applied to pool the effect estimates based on heterogeneity measured by Cochran's Q-test and Higgins' I.
RESULTS
Ten studies involving 725,805 participants and 64,836 pSS patients were included in our analysis. The pooled result showed that, overall, pSS was not associated with the risk (SIR=0.92, 95%CI: 0.66-1.29, =0.646) and mortality (HR = 0.78, 95%CI: 0.26-2.34, = 0.664) of breast cancer; however, when stratified by geographic region, we found that patients with pSS in Asian countries (SIR=1.32, 95%CI: 1.10-1.58, =0.003) and Argentina (SIR=3.76, 95%CI: 1.04-9.45, =0.019) had an elevated risk of breast cancer, while pSS in Europe was associated with a reduced risk (SIR=0.61, 95%CI: 0.51-0.73, <0.001). The pooled result from 28,635 female pSS patients indicated that the incidence of breast cancer was 2.15 (95% CI: 1.33-3.50) per 1000 person/years.
CONCLUSION
This study suggests that there may be geographical differences in the association between pSS and breast cancer risk; patients with pSS in European countries are associated with a lower risk of breast cancer, while Asia and Argentina are the opposite. Future research is needed to further characterize the effect of pSS on breast cancer risk and the pathophysiological mechanisms underlying this association to unravel the complex relationship between the two.
Topics: Autoimmune Diseases; Breast Neoplasms; Female; Humans; Incidence; Risk; Sjogren's Syndrome
PubMed: 35844507
DOI: 10.3389/fimmu.2022.904682 -
Stem Cell Research & Therapy Jun 2022Primary Sjögren's syndrome (pSS) is a diffuse connective tissue disease characterized by the invasion of exocrine glands such as lacrimal and salivary glands, abnormal... (Review)
Review
Primary Sjögren's syndrome (pSS) is a diffuse connective tissue disease characterized by the invasion of exocrine glands such as lacrimal and salivary glands, abnormal proliferation of T and B lymphocytes, and infiltration of tissue lymphocytes. With the development of modern medicine, although research on the pathogenesis, diagnosis, and treatment of pSS has made significant progress, its pathogenesis has not been fully understood. Meanwhile, in the era of individualized treatment, it remains essential to further explore early diagnosis and treatment methods. Exosomes, small vesicles containing proteins and nucleic acids, are a subtype of extracellular vesicles secreted by various cells and present in various body fluids. Exosomes contribute to a variety of biological functions, including intercellular signal transduction and pathophysiological processes, and may play a role in immune tolerance. Therefore, exosomes are key to understanding the pathogenesis of diseases. Exosomes can also be used as a therapeutic tool for pSS because of their biodegradability, low immunogenicity and toxicity, and the ability to bypass the blood-brain barrier, implying the prospect of a broad application in the context of pSS. Here, we systematically review the isolation, identification, tracing, and mode of action of extracellular vesicles, especially exosomes, as well as the research progress in the pathogenesis, diagnosis, and treatment of pSS.
Topics: B-Lymphocytes; Exosomes; Extracellular Vesicles; Humans; Salivary Glands; Sjogren's Syndrome
PubMed: 35659085
DOI: 10.1186/s13287-022-02912-1 -
EBioMedicine Jun 2022Emerging evidence suggests that dysbiosis in gut microbiota may contribute to the occurrence or development of several rheumatic diseases. Since gut microbiota dysbiosis... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Emerging evidence suggests that dysbiosis in gut microbiota may contribute to the occurrence or development of several rheumatic diseases. Since gut microbiota dysbiosis is potentially modifiable, it has been postulated to be a promising preventive or therapeutic target for rheumatic diseases. However, the current understanding on the potential associations between gut microbiota and rheumatic diseases is still inadequate. Therefore, we aimed to synthesise the accumulating evidence for the relation of gut microbiota to rheumatic diseases.
METHODS
The PubMed, Embase and Cochrane Library were searched from inception to March 11, 2022 to include observational studies evaluating the associations between gut microbiota and rheumatic diseases. Standardised mean difference (SMD) of α-diversity indices between rheumatic diseases and controls were estimated using random-effects model. β-diversity indices and relative abundance of gut microbes were summarised qualitatively.
FINDINGS
Of the included 92 studies (11,998 participants), 68 provided data for α-diversity. Taken together as a whole, decreases in α-diversity indices were consistently found in rheumatic diseases (observed species: SMD = -0.36, [95%CI = -0.63, -0.09]; Chao1: SMD = -0.57, [95%CI = -0.88, -0.26]; Shannon index: SMD = -0.33, [95%CI = -0.48, -0.17]; Simpson index: SMD = -0.32, [95%CI = -0.49, -0.14]). However, when specific rheumatic diseases were examined, decreases were only observed in rheumatoid arthritis (observed species: SMD = -0.51, [95%CI = -0.78, -0.24]; Shannon index: SMD = -0.31, [95%CI = -0.49, -0.13]; Simpson index: SMD = -0.31, [95%CI = -0.54, -0.08]), systemic lupus erythematosus (Chao1: SMD = -1.60, [95%CI = -2.54, -0.66]; Shannon index: SMD = -0.63, [95%CI = -1.08, -0.18]), gout (Simpson index: SMD = -0.64, [95%CI = -1.07, -0.22]) and fibromyalgia (Simpson index: SMD = -0.28, [95%CI = -0.44, -0.11]), whereas an increase was observed in systemic sclerosis (Shannon index: SMD = 1.25, [95%CI = 0.09, 2.41]). Differences with statistical significance in β-diversity were consistently reported in ankylosing spondylitis and IgG4-related diseases. Although little evidence of disease specificity of gut microbes was found, shared alterations of the depletion of anti-inflammatory butyrate-producing microbe (i.e., Faecalibacterium) and the enrichment of pro-inflammatory microbe (i.e., Streptococcus) were observed in rheumatoid arthritis, Sjögren's syndrome and systemic lupus erythematosus.
INTERPRETATION
Gut microbiota dysbiosis was associated with rheumatic diseases, principally with potentially non-specific, shared alterations of microbes.
FUNDING
National Natural Science Foundation of China (81930071, 81902265, 82072502 and U21A20352).
Topics: Dysbiosis; Gastrointestinal Microbiome; Humans; Lupus Erythematosus, Systemic; Rheumatic Diseases; Sjogren's Syndrome
PubMed: 35594658
DOI: 10.1016/j.ebiom.2022.104055 -
Corneal Confocal Microscopy for Assessment of Non-Neurological Autoimmune Diseases: A Meta-Analysis.Frontiers in Medicine 2022This study aimed to evaluate the features of corneal nerve with confocal microscopy (IVCM) among patients with non-neurological autoimmune (NNAI) diseases.
PURPOSE
This study aimed to evaluate the features of corneal nerve with confocal microscopy (IVCM) among patients with non-neurological autoimmune (NNAI) diseases.
METHODS
We systematically searched PubMed, Web of Science, and Cochrane Central Register of Controlled Trials for studies published until May 2021. The weighted mean differences (WMDs) of corneal nerve fiber length (CNFL), corneal nerve fiber density (CNFD), corneal nerve branch density (CNBD), tortuosity, reflectivity, and beadings per 100 μm with a 95% CI between NNAI and control group were analyzed using a random-effects model.
RESULTS
The results showed 37 studies involving collective totals of 1,423 patients and 1,059 healthy controls were ultimately included in this meta-analysis. The pooled results manifested significantly decreased CNFL (WMD: -3.94, 95% CI: -4.77--3.12), CNFD (WMD: -6.62, 95% CI: -8.4--4.85), and CNBD (WMD: -9.89, 95% CI: -14--5.79) in NNAI patients. In addition, the NNAI group showed more tortuous corneal nerve (WMD: 1.19, 95% CI:0.57-1.81). The comparison between NNAI patients and healthy controls in beadings per 100 μm corneal nerve length was inconsistent. No significant difference was found in the corneal nerve fiber reflectivity between NNAI and the control group (WMD: -0.21, 95% CI: -0.65-0.24, = 0.361).
CONCLUSIONS
The parameters and morphology of corneal nerves observed by IVCM proved to be different in NNAI patients from healthy controls, suggesting that IVCM may be a non-invasive technique for identification and surveillance of NNAI diseases.
PubMed: 35372389
DOI: 10.3389/fmed.2022.809164 -
Clinical and Experimental Rheumatology May 2022To perform a systematic literature review (SLR) on the association of common variable immunodeficiency (CVID) and rare and complex connective tissue and musculoskeletal...
OBJECTIVES
To perform a systematic literature review (SLR) on the association of common variable immunodeficiency (CVID) and rare and complex connective tissue and musculoskeletal diseases, namely systemic lupus erythematosus (SLE), Sjögren's syndrome (SS), idiopathic inflammatory myopathies (IIM), systemic sclerosis (SSc), relapsing polychondritis, antiphospholipid syndrome, immunoglobulin (Ig) G4-related disease, as well as undifferentiated and mixed connective tissue disease.
METHODS
An SLR on studies and cases about the association of CVID and rare and complex connective tissue and musculoskeletal diseases was performed. Animal studies were excluded.
RESULTS
170 publications fulfilled the inclusion criteria. Sjögren's syndrome was the most frequent connective tissue disease in CVID-patients. Most case reports exist on SLE and CVID with SLE mostly preceding the manifestation of CVID. Multiple cases were published reporting the concurrence of CVID and inclusion body myositis and single cases were found on CVID and antisynthetase syndrome, polymyositis, limited SSc and relapsing polychondritis, respectively. There are no cases of CVID and antiphospholipid syndrome, IgG4-related disease, as well as undifferentiated and mixed connective tissue disease.
CONCLUSIONS
The concurrence of CVID and complex connective tissue and musculoskeletal diseases, especially SS, IIM, SSc and relapsing polychondritis is rare but relevant. The measurements of Ig-levels should be performed before the initiation of immunosuppressive therapy to allow for the differentiation of primary and secondary Ig-deficiency and substitute IG if necessary.
Topics: Antiphospholipid Syndrome; Common Variable Immunodeficiency; Connective Tissue; Connective Tissue Diseases; Humans; Lupus Erythematosus, Systemic; Mixed Connective Tissue Disease; Musculoskeletal Diseases; Polychondritis, Relapsing; Scleroderma, Systemic; Sjogren's Syndrome
PubMed: 35349404
DOI: 10.55563/clinexprheumatol/bbuvih