Systemic lupus erythematosus (SLE) is a chronic autoimmune disease whose onset and progression are affected by genetic and environmental factors. The purpose of this study is to identify the ...influence of gut microbiota in the pathogenesis of SLE, and to investigate the mechanism involved.
Fecal microbiota from C57/BL6 mice and SLE prone mice were examined using next-generation sequencing (NGS). Germ free mice were given fecal microbiota transplantation (FMT), and their gut microbiome and gene expression in recipients' colons were examined by NGS. The anti-double stranded DNA (anti-dsDNA) antibodies in recipients were determined using an enzyme-linked immunosorbent assay (ELISA). The immune cell profiles of mice were analyzed by flow cytometry at the 3rd week after FMT, and the expression of genes associated with SLE after FMT was determined using quantitative real-time PCR (qRT-PCR).
The fecal microbiota of SLE mice had lower community richness and diversity than healthy mice. Fecal microbiota of recipient mice were similar to their donors. Fecal microbiome from SLE mice could lead to a significant increase of anti-dsDNA antibodies and promote the immune response in recipient mice. Our results also indicated that fecal microbiome from SLE mice resulted in significant changes in the distribution of immune cells and upregulated expression of certain lupus susceptibility genes.
SLE is associated with alterations of gut microbiota. Fecal microbiome from SLE mice can induce the production of anti-dsDNA antibodies in germ free mice and stimulate the inflammatory response, and alter the expression of SLE susceptibility genes in these mice.
The dysregulation of the JAK–STAT pathway is associated with various immune disorders. Four JAK inhibitors have been approved for rheumatoid arthritis (RA), and numerous JAK inhibitors are currently ...being tested in phase II and III trials for the treatment of various autoimmune inflammatory diseases. In this narrative review, we elucidate the involvement of the JAK–STAT signaling pathway in the pathogenesis of connective tissue diseases (CTDs). We also discuss the efficacy of the first- and second-generation JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib, filgotinib, upadacitinib, solcitinib, itacitinib, decernotinib, R333, and pf-06651600) for CTDs including RA, systemic lupus erythematosus, dermatomyositis, systemic sclerosis, Sjögren’s syndrome, and vasculitis, based on laboratory and clinical research findings. JAK inhibitors have great potential for the treatment of various CTDs by reducing multiple cytokine production and suppressing inflammation, with the advantages of rapid onset in an oral formulation and decreased corticosteroid dependence and the associated adverse events, especially in refractory cases. We also highlight the safety of novel JAK inhibitors, which can cause opportunistic infections, especially viral infections. Being a very recent therapeutic option, information regarding the safety of JAK inhibitors during pregnancy and for pediatric use is limited. However, it is recommended that JAK inhibitors should be avoided in pregnant and breastfeeding women. More clinical data, especially on highly selective inhibitors, are required to judge the efficacy and safety of JAK inhibition in CTDs.
Pulmonary arterial hypertension (PAH) and interstitial lung disease (ILD) are leading causes of systemic sclerosis (SSc)-related death. In this study, we aimed to identify biomarkers for detecting ...SSc pulmonary complications that are mild and in the early stages to improve the prognosis.
We screened for serum biomarkers using a proteomic antibody microarray that simultaneously assessed 1000 proteins. Differentially expressed proteins were further verified using ELISA. Finally, we performed a correlation analysis using clinical data.
We identified 125 differentially expressed proteins, of which calcitonin, sclerostin (SOST), CD40, and fibronectin were selected for further verification. Serum calcitonin and SOST levels were significantly elevated in all SSc pulmonary complication subgroups, whereas serum calcitonin levels were higher in the SSc with PAH subgroup than in the SSc without PAH and ILD subgroup. Serum SOST levels were possibly associated with the presence of ILD and positively related to the presence of cardiac and gastrointestinal involvement. Serum CD40 and calcitonin levels appeared to be positively related to the presence of renal involvement, and serum calcitonin was also positively related to the presence of gastrointestinal involvement.
This study indicated that serum calcitonin and SOST levels may be promising biomarkers for SSc-related PAH and ILD, respectively. Further research is needed to verify this result and understand the underlying mechanisms.
Objective
To understand the epidemiology, current treatment, and disease burden of systemic lupus erythematosus (SLE) in the Asia Pacific (APAC) region.
Methods
A targeted literature review of ...published evidence on SLE in the APAC region was conducted, using the Medline database (2008–2018), conference proceedings, and other supplementary sources.
Results
The current review identified 70 studies conducted in China (n = 15), Japan (n = 13), Taiwan (n = 12), Korea (n = 9), Australia (n = 7), Hong Kong (n = 6), Singapore (n = 4), and multiple places within the APAC region (n = 4). Incidence rates (per 100,000 persons per year) ranged from 0.9–8.4, while prevalence rates ranged from 3.7–127 (per 100,000 persons); however, recent data were limited. Asian patients with SLE were reported to have higher disease severity, disease activity (higher SLE disease activity index scores), and organ damage accrual, along with increased morbidity, mortality, and susceptibility to renal involvement compared with other ethnicities in the APAC region. The risk of developing SLE is higher in the Asian population. Routinely used SLE therapies included belimumab, hydroxychloroquine, cyclophosphamide, tacrolimus, azathioprine, mycophenolate mofetil, and glucocorticoids; however, prescribing patterns varied across the region. Increased disease activity was associated with high economic burden and poor quality of life for SLE patients in the APAC region.
Conclusion
SLE remains a disease with a significant unmet medical need for an innovative therapy that is well‐tolerated and effective for patients in the APAC region. Further evidence is required to better characterize the disease and fully capture the burden and impact of SLE in the APAC region. This review has highlighted where there is a paucity of data from patients across the APAC region.
The PD-1/PD-L pathway in rheumatic diseases Zhang, Shuo; Wang, Li; Li, Mengtao ...
Journal of the Formosan Medical Association,
January 2021, 2021-Jan, 2021-01-00, 20210101, 2021-01-01, Letnik:
120, Številka:
1
Journal Article
Recenzirano
Odprti dostop
Autoimmune diseases are diseases in which the body produces an abnormal immune response to self-antigens and damages its own tissues. Programmed death-1 (PD-1) and its ligands (PD-Ls) have been ...discovered to be important negative regulators of the immune system, playing crucial roles in autoimmunity.
We analyzed the existing scientific literature dealing with this issue. In this review, the PD-1/PD-L pathway in the genetic susceptibility to and pathogenesis of rheumatic diseases is discussed. The PD-1/PD-L pathway might be helpful for diagnosing, evaluating the disease activity of and treating rheumatic diseases.
PD-1/PD-L gene polymorphisms are associated with a genetic predisposition to rheumatic disorders, which can provide reference information for diagnosis and disease activity. The conclusion of the crucial role of the PD-1/PD-L pathway in the pathogenesis of rheumatic diseases is consistent, but the details remain controversial. In some animal models, manipulating the PD-1/PD-L pathway could decrease disease severity. PD-1/PD-Ls may enable us to develop new therapeutics for patients with rheumatic diseases in the future.
The PD-1/PD-L pathway plays crucial roles in rheumatic disease. More work is needed to provide a better mechanistic understanding of the PD-1/PD-L pathway and to facilitate the precise therapeutic manipulation of this pathway.
Abstract
Background
Pulmonary arterial hypertension (PAH) is a rare complication of primary Sjögren’s syndrome (pSS). Several genes have proven to be associated with pSS and PAH. However, there is no ...study specifically addressing the genetic susceptibility in pSS combined with PAH.
Methods
Thirty-four unrelated patients with pSS-PAH were recruited from April 2019 to July 2021 at Peking Union Medical College Hospital. Demographic and clinical data were recorded in detail, and peripheral blood samples were collected for whole-exome sequencing (WES). Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to predict the functional effect of mutant genes. Genetic variants identified by WES were confirmed by polymerase chain reaction (PCR)-Sanger sequencing.
Results
We totally identified 141 pathogenic variant loci of 129 genes in these 34 pSS-PAH patients, using WES analysis. Patients with a family history of rheumatic diseases are more likely to carry
FLG
mutations or carry gene variations related to the biosynthesis of the amino acids pathway (
p
< 0.05). According to Sanger sequencing confirmation and pathogenicity validation, we totally identified five candidate pathogenic variants including
FLG
c.12064A > T,
BCR
c.3275_3278dupCCGG,
GIGYF2
c.3463C > A,
ITK
c.1741C > T, and
SLC26A4
c.919-2A > G.
Conclusion
Our findings provide preliminary data of exome sequencing to identify susceptibility loci for pSS-PAH and enriched our understanding of the genetic etiology for pSS-PAH. The candidate pathogenic genes may be the potential genetic markers for early warning of this disease.
Thoracic ossification of the ligamentum flavum (TOLF) is characterized by ectopic bone formation in the ligamentum flavum and is considered to be a leading cause of thoracic spinal canal stenosis and ...myelopathy. However, the underlying etiology is not well understood. An iTRAQ proteomics was used to reveal the involvement of inflammation factors in TOLF. TNF-α is a pro-inflammatory cytokine implicated in the pathogenesis of many human diseases. Protein profiling analysis showed that the protein level of TNF-α increased in the ossified ligamentum flavum of TOLF, which was confirmed by western blot. The effects of TNF-α on primary ligamentum flavum cells was examined. Cell proliferation assay demonstrated that primary cells from the ossified ligamentum flavum of TOLF grew faster than the control. Flow cytometry assay indicated that the proportions of cells in S phase of cell cycle of primary cells increased after TNF-α stimulation. To address the effect of TNF-α on gene expression, primary cells were derived from ligamentum flavum of TOLF patients. Culture cells were stimulated by TNF-α. RNA was isolated and analyzed by quantitative RT-PCR. G1/S-specific proteins cyclin D1 and c-Myc were upregulated after TNF-α stimulation. On the other hand, osteoblast differentiation related genes such as Bmp2 and Osterix (Osx) were upregulated in the presence of TNF-α. TNF-α activated Osx expression in a dose-dependent manner. Interestingly, a specific mitogen-activated protein kinase ERK inhibitor U0126, but not JNK kinase inhibitor SP600125, abrogated TNF-α activation of Osx expression. This suggests that TNF-α activates Osx expression through the mitogen-activated protein kinase ERK pathway. Taken together, we provide the evidence to support that TNF-α involves in TOLF probably through regulating cell proliferation via cyclin D1 and c-Myc, and promoting osteoblast differentiation via Osx.
Systemic sclerosis is a disease that has significant clinical heterogeneity. This study aims to determine the causes and risk factors of death in a single center European League Against Rheumatism ...Scleroderma Trials and Research Group (EUSTAR) cohort at the Peking Union Medical College Hospital (PUMCH) in China.
Patients clinically diagnosed with systemic sclerosis (SSc) between Feb 2009 and Dec 2015 were prospectively recruited from the EUSTAR database and Chinese Rheumatism Data Center (CRDC) of the PUMCH. Baseline and follow-up data were collected. Kaplan-Meier analysis was used to estimate survival, and Cox proportional hazards regression analysis was used to identify factors associated with mortality.
A total of 448 patients were included in the cohort, of whom 56.7% had limited cutaneous systemic sclerosis (lcSSc). The average age at diagnosis was 42.8 ± 12.1 years. The prevalence of interstitial lung disease (ILD) was 382/447 (85.5%). Among 402 patients, 348 of them took glucocorticoid during the disease course; 374 patients received immunosuppressors. Across 2167 patient-years, 40 patients died. Of these, 27 deaths were attributable to SSc, with pulmonary arterial hypertension (PAH) being the leading cause of death. The median survival time was 53 months. Survival rates from disease diagnosis were 97.0%, 94.6%, 91.1% and 87.8% at 1, 3, 5 and 10 years, respectively. Independent prognostic factors for mortality were PAH (HR 6.248, 95% CI 2.855, 13.674) and arrhythmia (HR 4.729, 95% CI 1.588, 14.082). Tripterygium wilfordii Hook F (TwHF) (log-rank test 7.851, p 0.005) and methotrexate (MTX) (log-rank test 7.925, p = 0.005) were found in survival analysis to be protective treatments against mortality. Patients who used cyclophosphamide (CTX) during the disease course had poorer prognosis (log-rank test 5.177, p = 0.023).
In china, although there is a high prevalence of ILD in patients with SSc (85.5%), most of them have reserved pulmonary function, which means that interstitial lung disease (ILD) is not the most important factor in the death of patients with SSc and also is not a risk factor for poor prognosis. Only ILD with pulmonary dysfunction is associated with poor outcome. The 10-year cumulative rate (87.8%) in patients with SSc in China is slightly lower than the Europe, and pulmonary arterial hypertension (PAH) and arrhythmia at baseline are independent prognostic factors, whereas PAH instead of ILD is the leading cause of death in patients with SSc. Interestingly, the Chinese traditional medicine TwHF, as a protective factor for survival deserves further study.
Background The effectiveness and safety of sirolimus for the treatment of systemic lupus erythematosus (SLE) and lupus nephritis (LN) have been shown in some studies. However, a comparison of ...sirolimus with standard of care (SoC) for LN patients has not been reported. We conducted the study to compare the efficiency and safety of sirolimus versus mycophenolate mofetil (MMF) for LN treatment. Methods A real-world cohort study based on the Chinese SLE Treatment and Research (CSTAR) registry was conducted. LN patients who were prescribed sirolimus or MMF were enrolled. Patients who achieved LLDAS (lupus low disease activity state) or remission at baseline were excluded. Propensity score matching was used to ensure equivalent disease conditions and background medications. SLE disease activity indices, serological parameters, steroid doses, renal efficacy, and adverse events were compared between the two groups at 3-month, 6-month, and 12-month follow-up visits. Results Data from 53 patients in each group were analyzed. The clinical effectiveness of sirolimus, including the proportion of patients with LLDAS/remission, or clinical response (SLEDAI-2K reduction≥4 and PhGA increase <0.3), the change of Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K) scores, physician’s global assessment (PhGA) scores, the remission of lupus nephritis, the change of 24 hours urine protein level, and the steroid tapering effect, were equivalent to those of MMF at all follow-up timepoints (all P≥0.05). Greater improvements in complement levels were observed in the sirolimus group than the MMF group at 3, 6, and 12 months. Ten adverse events in the sirolimus group and one in the MMF group were recorded. None was severe or led to drug discontinuation. Conclusions Sirolimus was as effective as MMF in the treatment of LN and glucocorticoid tapering. Sirolimus had better effects on serological improvement. Sirolimus was well tolerated in LN patients.
Rheumatoid arthritis patients are at higher risk of developing comorbidities. The main objective of this study was to evaluate the prevalence of major comorbidities in Chinese rheumatoid arthritis ...patients. We also aimed to identify factors associated with these comorbidities.
Baseline demographic, clinical characteristics and comorbidity data from RA patients enrolled in the Chinese Registry of rhEumatoiD arthrITis (CREDIT) from Nov 2016 to August 2017 were presented and compared with those from five other registries across the world. Possible factors related to three major comorbidities (cardiovascular disease, fragility fracture and malignancy) were identified using multivariate logistic regression analyses.
A total of 13,210 RA patients were included (80.6% female, mean age 52.9 years and median RA duration 4.0 years). Baseline prevalence rates of major comorbidities were calculated: CVD, 2.2% (95% CI 2.0-2.5%); fragility fracture, 1.7% (95% CI 1.5-1.9%); malignancy, 0.6% (95% CI 0.5-0.7%); overall major comorbidities, 4.2% (95% CI 3.9-4.6%). Advanced age was associated with all comorbidities. Male gender and disease duration were positively related to CVD. Female sex and longer disease duration were potential risk factors for fragility fractures. Ever use of methotrexate (MTX) was negatively related to baseline comorbidities.
Patients with rheumatoid arthritis in China have similar prevalence of comorbidities with other Asian countries. Advanced age and long disease duration are possible risk factors for comorbidities. On the contrary, MTX may protect RA patients from several major comorbidities, supporting its central role in the management of rheumatoid arthritis.
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