Abstract Background Circular RNA (circRNA) plays an important role in the pathogenesis of many diseases and can be used as a biomarker for diagnosis or disease monitoring. However, reports on circRNA in childhood‐onset systemic lupus erythematosus (cSLE) are limited. Therefore, this study aimed to investigate circEPSTI1 expression in cSLE and evaluate its potential as a biomarker for diagnosing cSLE. Methods This study included 70 children diagnosed with cSLE, 20 diagnosed with juvenile idiopathic arthritis (JIA), 20 diagnosed with juvenile dermatomyositis (JDM), and 50 healthy children at the Rheumatology Department of Beijing Children's Hospital from January 2019 to December 2019. Quantitative polymerase chain reaction was used to determine circEPSTI1 expression in the children. Correlations between circEPSTI1 and clinical features were assessed using Spearman's correlation test. Additionally, we calculated the receiver operating characteristic curve to assess the diagnostic efficacy. Results We found that circEPSTI1 expression was higher in children with cSLE (4.62 ± 3.55) than in healthy children (1.00 ± 0.45), those with JDM (1.06 ± 0.76), and those with JIA (0.96 ± 0.48). The area of the curve of circEPSTI1 was 0.892 (95% confidence interval [CI]: 0.832–0.952, p < 0.001) to discriminate children with SLE from healthy children, with a specificity of 0.814 and a sensitivity of 0.922. Children with lupus nephritis showed a higher circEPSTI1 expression than healthy children, those with JDM, and those with JIA. In addition, circEPSTI1 expression in children with SLE showed significant correlations with the SLE Disease Activity Index ( p < 0.0001) and C3 concentrations ( p = 0.001). Conclusion Our study suggests that circEPSTI1 is a promising biomarker for the diagnosis and monitoring of cSLE.
{"title":"CircEPSTI1 in peripheral blood as a novel potential biomarker for childhood‐onset systemic lupus erythematosus","authors":"Xia Wang, Shipeng Li, Jianghong Deng, Weiying Kuang, Junmei Zhang, Xiaohua Tan, Chao Li, Caifeng Li","doi":"10.1002/rai2.12096","DOIUrl":"https://doi.org/10.1002/rai2.12096","url":null,"abstract":"Abstract Background Circular RNA (circRNA) plays an important role in the pathogenesis of many diseases and can be used as a biomarker for diagnosis or disease monitoring. However, reports on circRNA in childhood‐onset systemic lupus erythematosus (cSLE) are limited. Therefore, this study aimed to investigate circEPSTI1 expression in cSLE and evaluate its potential as a biomarker for diagnosing cSLE. Methods This study included 70 children diagnosed with cSLE, 20 diagnosed with juvenile idiopathic arthritis (JIA), 20 diagnosed with juvenile dermatomyositis (JDM), and 50 healthy children at the Rheumatology Department of Beijing Children's Hospital from January 2019 to December 2019. Quantitative polymerase chain reaction was used to determine circEPSTI1 expression in the children. Correlations between circEPSTI1 and clinical features were assessed using Spearman's correlation test. Additionally, we calculated the receiver operating characteristic curve to assess the diagnostic efficacy. Results We found that circEPSTI1 expression was higher in children with cSLE (4.62 ± 3.55) than in healthy children (1.00 ± 0.45), those with JDM (1.06 ± 0.76), and those with JIA (0.96 ± 0.48). The area of the curve of circEPSTI1 was 0.892 (95% confidence interval [CI]: 0.832–0.952, p < 0.001) to discriminate children with SLE from healthy children, with a specificity of 0.814 and a sensitivity of 0.922. Children with lupus nephritis showed a higher circEPSTI1 expression than healthy children, those with JDM, and those with JIA. In addition, circEPSTI1 expression in children with SLE showed significant correlations with the SLE Disease Activity Index ( p < 0.0001) and C3 concentrations ( p = 0.001). Conclusion Our study suggests that circEPSTI1 is a promising biomarker for the diagnosis and monitoring of cSLE.","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135291212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune condition that mainly affects small vessels of the body. AAV is a condition that may have multisystem manifestations and has an increased prevalence among older individuals.1 AAV patients conventionally present with symptoms at 65 years of age or older. Previous studies have demonstrated worse clinical outcomes in the aging population. Many older patients live with various comorbidities in addition to potentially relapsing AAV. Dealing with the pathophysiological impact of AAV can be burdensome, as this multifaceted condition may lead to impairment of physical function and contribute to significant mental and emotional stress. The impact of aging on the pathophysiology of AAV is not fully known. Immune dysregulation induced by cell senescence is hypothesized to be a key factor, alongside a mixture of genetic and environmental factors.2 Frailty, an age-associated syndrome defined as a state of vulnerability to stressor events as the result of cumulative physiological decline, is associated with an increased risk of adverse outcomes—including falls, hospitalization, reduced quality of life (QoL), and earlier-than-expected death.3 Frailty status is independently linked with poor outcomes for a wide range of medical conditions. For aging patients with multimorbidities, the presence of frailty adds toward an already significant health burden. The combination of aging, frailty, and AAV increases the burden of chronic inflammation, with older individuals subject to malnutrition and sarcopenia, impaired mobility due to musculoskeletal and neurological pathology, decline in kidney function, cognitive deficits, and high levels of pain and fatigue affecting QoL (Figure 1). Evaluating the true extent of frailty and AAV disease severity with their variable phenotypical features is challenging for clinicians. It is difficult to identify at presentation what degree of illness is attributed to AAV disease activity or pre-existing frailty. There have been few studies that have investigated the relationship between frailty status and AAV outcomes. The emergence of original data on this topic recently suggests an increased interest and awareness of its clinical significance. We performed a scoping search in PubMed, Web of Science, EMBASE, Medline-ProQuest, and Google Scholar incorporating the keywords “frailty” and “vasculitis” to identify relevant indexed full articles and conference abstracts (Supporting Information: Table S1).4-9 Primarily, published studies aimed to determine the prevalence of frailty among older AAV patients, to address whether a more severe frailty status indicated worse AAV-associated outcomes including complication rates, and to determine if the perceived frailty status of older AAV patients improved with immunosuppressive treatment. These studies utilized various frailty assessment tools, allowing for comparisons to be made in relation to the applicati
{"title":"Frailty and antineutrophil cytoplasmic antibody‐associated vasculitis: What do we know?","authors":"Henry H. L. Wu, Nina Brown, Rajkumar Chinnadurai","doi":"10.1002/rai2.12098","DOIUrl":"https://doi.org/10.1002/rai2.12098","url":null,"abstract":"Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune condition that mainly affects small vessels of the body. AAV is a condition that may have multisystem manifestations and has an increased prevalence among older individuals.1 AAV patients conventionally present with symptoms at 65 years of age or older. Previous studies have demonstrated worse clinical outcomes in the aging population. Many older patients live with various comorbidities in addition to potentially relapsing AAV. Dealing with the pathophysiological impact of AAV can be burdensome, as this multifaceted condition may lead to impairment of physical function and contribute to significant mental and emotional stress. The impact of aging on the pathophysiology of AAV is not fully known. Immune dysregulation induced by cell senescence is hypothesized to be a key factor, alongside a mixture of genetic and environmental factors.2 Frailty, an age-associated syndrome defined as a state of vulnerability to stressor events as the result of cumulative physiological decline, is associated with an increased risk of adverse outcomes—including falls, hospitalization, reduced quality of life (QoL), and earlier-than-expected death.3 Frailty status is independently linked with poor outcomes for a wide range of medical conditions. For aging patients with multimorbidities, the presence of frailty adds toward an already significant health burden. The combination of aging, frailty, and AAV increases the burden of chronic inflammation, with older individuals subject to malnutrition and sarcopenia, impaired mobility due to musculoskeletal and neurological pathology, decline in kidney function, cognitive deficits, and high levels of pain and fatigue affecting QoL (Figure 1). Evaluating the true extent of frailty and AAV disease severity with their variable phenotypical features is challenging for clinicians. It is difficult to identify at presentation what degree of illness is attributed to AAV disease activity or pre-existing frailty. There have been few studies that have investigated the relationship between frailty status and AAV outcomes. The emergence of original data on this topic recently suggests an increased interest and awareness of its clinical significance. We performed a scoping search in PubMed, Web of Science, EMBASE, Medline-ProQuest, and Google Scholar incorporating the keywords “frailty” and “vasculitis” to identify relevant indexed full articles and conference abstracts (Supporting Information: Table S1).4-9 Primarily, published studies aimed to determine the prevalence of frailty among older AAV patients, to address whether a more severe frailty status indicated worse AAV-associated outcomes including complication rates, and to determine if the perceived frailty status of older AAV patients improved with immunosuppressive treatment. These studies utilized various frailty assessment tools, allowing for comparisons to be made in relation to the applicati","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135392349","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Shengxiao Zhang, Yige Feng, Xinyu Yin, Qinyi Su, Yujia Xi, Ting Cheng, Heyi Zhang, Yulong Xue, Caihong Wang, Xiaofeng Li
Abstract Background Epidemiological studies have shown a close association between osteoarthritis (OA) and cardiovascular disease (CVD), but reliable evidence needs to be provided. We performed a two‐sample Mendelian randomization (MR) study to examine the potential causal effect between OA and CVD. Methods Exposures were self‐reported OA, knee osteoarthritis (KOA), and hip osteoarthritis (HOA). The outcomes were 12 CVDs, including heart failure, atrial fibrillation, coronary artery disease, pulmonary embolism, stroke and its subtypes, myocardial infarction, coronary heart disease, and primary hypertension. All outcomes were obtained from published genome‐wide association studies. The inverse‐variance weighted method was used as the primary MR analysis. Heterogeneity tests and sensitivity analyses were conducted to validate the accuracy of the MR results. Results Self‐reported OA increased the incidence of small vessel stroke (odds ratio [OR] = 1.25, 95% confidence interval [CI]: 1.02–1.52, p = 0.03) and primary hypertension (1.01 [1.00–1.02], p < 0.01). HOA increased the incidence of stroke (1.06 [1.01–1.11], p = 0.02) and two subtypes (cardioembolic stroke: 1.12 [1.02–1.23], p = 0.02; ischemic stroke: 1.06 [1.01–1.11], p = 0.03). Patients with KOA had an increased risk of heart failure (1.10 [1.04–1.16], p < 0.01), atrial fibrillation (1.08 [1.02–1.13], p < 0.01), small vessel stroke (1.21 [1.06–1.39], p = 0.01), and primary hypertension (1.01 [1.01–1.02], p < 0.01). Conclusions Patients with OA have an increased risk of several CVDs. The causality of this relationship may have clinical implications for improving the quality of prevention and treatment.
{"title":"Genetic evidence suggesting the predicted causality between osteoarthritis and cardiovascular diseases","authors":"Shengxiao Zhang, Yige Feng, Xinyu Yin, Qinyi Su, Yujia Xi, Ting Cheng, Heyi Zhang, Yulong Xue, Caihong Wang, Xiaofeng Li","doi":"10.1002/rai2.12097","DOIUrl":"https://doi.org/10.1002/rai2.12097","url":null,"abstract":"Abstract Background Epidemiological studies have shown a close association between osteoarthritis (OA) and cardiovascular disease (CVD), but reliable evidence needs to be provided. We performed a two‐sample Mendelian randomization (MR) study to examine the potential causal effect between OA and CVD. Methods Exposures were self‐reported OA, knee osteoarthritis (KOA), and hip osteoarthritis (HOA). The outcomes were 12 CVDs, including heart failure, atrial fibrillation, coronary artery disease, pulmonary embolism, stroke and its subtypes, myocardial infarction, coronary heart disease, and primary hypertension. All outcomes were obtained from published genome‐wide association studies. The inverse‐variance weighted method was used as the primary MR analysis. Heterogeneity tests and sensitivity analyses were conducted to validate the accuracy of the MR results. Results Self‐reported OA increased the incidence of small vessel stroke (odds ratio [OR] = 1.25, 95% confidence interval [CI]: 1.02–1.52, p = 0.03) and primary hypertension (1.01 [1.00–1.02], p < 0.01). HOA increased the incidence of stroke (1.06 [1.01–1.11], p = 0.02) and two subtypes (cardioembolic stroke: 1.12 [1.02–1.23], p = 0.02; ischemic stroke: 1.06 [1.01–1.11], p = 0.03). Patients with KOA had an increased risk of heart failure (1.10 [1.04–1.16], p < 0.01), atrial fibrillation (1.08 [1.02–1.13], p < 0.01), small vessel stroke (1.21 [1.06–1.39], p = 0.01), and primary hypertension (1.01 [1.01–1.02], p < 0.01). Conclusions Patients with OA have an increased risk of several CVDs. The causality of this relationship may have clinical implications for improving the quality of prevention and treatment.","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-11-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135725143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Marco Krasselt, Jeanette Henkelmann, Matthias Pierer
A 25-year-old man with known dermatomyositis was admitted to the University of Leipzig Medical Centre for the first time. The diagnosis was originally made abroad years ago. Current laboratory studies showed elevated C-reactive protein and creatine kinase. Antinuclear antibodies, anti-Mi-2 antibodies, anti-Jo-1 antibodies, and anti-Scl-70 antibodies were negative, and the rheumatoid factor was positive. Nailfold video capillaroscopy (NVC) revealed numerous arborized (or “bushy”) capillaries reflecting dermatomyositis-typical neoangiogenesis. Physical examination showed extensive calcinosis cutis on arms, legs, and trunk. Impressively, we found numerous painful nodules and subsequent scars all over his body (exemplarily demonstrated on the right arm, Figure 1A). He reported these lesions were repeatedly associated with surrounding skin inflammation. Additional complaints were generalized myalgia and symmetrical proximal muscle weakness of the upper legs. X-ray of the affected right arm shows multiple nodular, partly confluent calcifications affecting the cutis and the subcutis (Figure 1B). The only treatment for the patient's dermatomyositis was daily administration of prednisolone up to 50 mg for several years. For steroid-sparing reasons, we initiated an immunosuppressive treatment with azathioprine (125 mg daily). The prednisolone dose could be reduced to 2.5 mg hereafter. To treat the calcinosis cutis, minocycline was prescribed.1, 2 Additionally, iloprost was administered to improve a secondary Raynaud's phenomenon. Unfortunately, none of these treatment approaches led to a relevant improvement of the calcinosis cutis. In general, calcinosis cutis seems to be more common in juvenile dermatomyositis than in adult patients.3, 4 Our patient was diagnosed during adolescence. Calcinosis cutis, in the context of rheumatic diseases, is usually dystrophic and characterized by tissue deposition of calcified material without elevated serum calcium or phosphate levels. The exact causes are not known, but recurrent trauma, vascular hypoxemia, and chronic inflammation are theorized to be involved.2 Pharmacologic treatment options are limited and data is scarce. Possible pharmacotherapies include minocycline, diltiazem, bisphosphonates, colchicine, the anti-CD20 antibody rituximab, or intravenous immunoglobulins. Surgical excision of the lesions is possible but should be restricted to selected (i.e., large or particularly painful) lesions since impaired wound healing and infections are not uncommon.2 Marco Krasselt: Conceptualization; data curation; project administration; resources; supervision; visualization; writing and review of the original draft. Jeanette Henkelmann: Data curation; validation; visualization; writing and review of the original draft. Matthias Pierer: Data curation; resources; validation; writing and review of the original draft. The authors have nothing to report. The authors declare no conflict of interest. The authors certify that t
{"title":"Calcinosis cutis in a young man with dermatomyositis","authors":"Marco Krasselt, Jeanette Henkelmann, Matthias Pierer","doi":"10.1002/rai2.12092","DOIUrl":"https://doi.org/10.1002/rai2.12092","url":null,"abstract":"A 25-year-old man with known dermatomyositis was admitted to the University of Leipzig Medical Centre for the first time. The diagnosis was originally made abroad years ago. Current laboratory studies showed elevated C-reactive protein and creatine kinase. Antinuclear antibodies, anti-Mi-2 antibodies, anti-Jo-1 antibodies, and anti-Scl-70 antibodies were negative, and the rheumatoid factor was positive. Nailfold video capillaroscopy (NVC) revealed numerous arborized (or “bushy”) capillaries reflecting dermatomyositis-typical neoangiogenesis. Physical examination showed extensive calcinosis cutis on arms, legs, and trunk. Impressively, we found numerous painful nodules and subsequent scars all over his body (exemplarily demonstrated on the right arm, Figure 1A). He reported these lesions were repeatedly associated with surrounding skin inflammation. Additional complaints were generalized myalgia and symmetrical proximal muscle weakness of the upper legs. X-ray of the affected right arm shows multiple nodular, partly confluent calcifications affecting the cutis and the subcutis (Figure 1B). The only treatment for the patient's dermatomyositis was daily administration of prednisolone up to 50 mg for several years. For steroid-sparing reasons, we initiated an immunosuppressive treatment with azathioprine (125 mg daily). The prednisolone dose could be reduced to 2.5 mg hereafter. To treat the calcinosis cutis, minocycline was prescribed.1, 2 Additionally, iloprost was administered to improve a secondary Raynaud's phenomenon. Unfortunately, none of these treatment approaches led to a relevant improvement of the calcinosis cutis. In general, calcinosis cutis seems to be more common in juvenile dermatomyositis than in adult patients.3, 4 Our patient was diagnosed during adolescence. Calcinosis cutis, in the context of rheumatic diseases, is usually dystrophic and characterized by tissue deposition of calcified material without elevated serum calcium or phosphate levels. The exact causes are not known, but recurrent trauma, vascular hypoxemia, and chronic inflammation are theorized to be involved.2 Pharmacologic treatment options are limited and data is scarce. Possible pharmacotherapies include minocycline, diltiazem, bisphosphonates, colchicine, the anti-CD20 antibody rituximab, or intravenous immunoglobulins. Surgical excision of the lesions is possible but should be restricted to selected (i.e., large or particularly painful) lesions since impaired wound healing and infections are not uncommon.2 Marco Krasselt: Conceptualization; data curation; project administration; resources; supervision; visualization; writing and review of the original draft. Jeanette Henkelmann: Data curation; validation; visualization; writing and review of the original draft. Matthias Pierer: Data curation; resources; validation; writing and review of the original draft. The authors have nothing to report. The authors declare no conflict of interest. The authors certify that t","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136034008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Researchers have identified a new interaction mode between gut microbiota and immune homeostasis of the synovium in modulating autoimmune responses in rheumatoid arthritis (RA), according to a new study published in Cell Host & Microbe.1 The study findings provide valuable information and insights into the causes of inflammation of RA and suggest Fusobacterium nucleatum (F. nucleatum) and its outer membrane vesicles (OMVs) as promising therapeutic targets for clinically ameliorating RA. The gut microbiota is gaining increasing attention as it plays essential but complex roles in maintaining host immune homeostasis of RA. However, due to physical and chemical restrictions, the gut microbiota can hardly translocate into distant organs intercellularly but primarily by secreting metabolites, proteins, and OMVs. “Accumulating evidence shows that microbiota-derived OMVs induce immune responses by carrying molecules including peptidoglycans, lipids, proteins, and nucleic acids targeting immune cells, especially macrophages and neutrophils. Moreover, the inherent surface of the lipid phase and physical structure of OMVs protect these effectors from exposure to the clearance mechanisms, suggesting OMV is one of the key players of interkingdom crosstalk between the host and microbes in pathogenic contexts. Therefore, we hypothesize that the gut microbiota associated OMVs may play a role in mediating the contribution of gut microbiota to the development of RA.” remarks Juan Li, one of the responding authors of the study. Through a combination of 16S rRNA-sequencing, clinical studies, and in vivo models, the researchers demonstrate that F. nucleatum is enriched in RA patients and positively correlated with disease activity. Importantly, transplanting F. nucleatum could aggravate inflammation in RA, while depleting F. nucleatum by Metronidazole could alleviate arthritis. “Previous studies mainly suggested F. nucleatum participates in various oral and gastrointestinal diseases, especially colorectal cancer. In this study, we found that F. nucleatum could affects distant joints and plays a role in mediating the aggravation of arthritis.” remarks Li. “OMV secretion is one of the most critical pathways of gram-negative bacteria interacting with the host. As one of common gram-negative bacteria, previous studies suggested that F. nucleatum derived OMV (F.n OMVs) could induce intestinal inflammation. All these studies inspired us to explore whether the effects of F. nucleatum on arthritis depend on OMVs.” explains Mukeng Hong, one of the authors of the study. To test whether F.n OMVs could translocate from the gut to the joints, authors labeled OMV with lipophilicity carbocyanine dyes DIL and observed that F.n OMVs translocated throughout the body and finally accumulated in the limbs. Also, the accumulated F.n OMVs in the joints aggravate arthritis, indicating that F. nucleatum promotes arthritis by secreting OMVs. Subsequently, considering that macrophages and neu
{"title":"Outer membrane vesicles from <i>Fusobacterium nucleatum</i> aggravate rheumatoid arthritis","authors":"Ru Li","doi":"10.1002/rai2.12093","DOIUrl":"https://doi.org/10.1002/rai2.12093","url":null,"abstract":"Researchers have identified a new interaction mode between gut microbiota and immune homeostasis of the synovium in modulating autoimmune responses in rheumatoid arthritis (RA), according to a new study published in Cell Host & Microbe.1 The study findings provide valuable information and insights into the causes of inflammation of RA and suggest Fusobacterium nucleatum (F. nucleatum) and its outer membrane vesicles (OMVs) as promising therapeutic targets for clinically ameliorating RA. The gut microbiota is gaining increasing attention as it plays essential but complex roles in maintaining host immune homeostasis of RA. However, due to physical and chemical restrictions, the gut microbiota can hardly translocate into distant organs intercellularly but primarily by secreting metabolites, proteins, and OMVs. “Accumulating evidence shows that microbiota-derived OMVs induce immune responses by carrying molecules including peptidoglycans, lipids, proteins, and nucleic acids targeting immune cells, especially macrophages and neutrophils. Moreover, the inherent surface of the lipid phase and physical structure of OMVs protect these effectors from exposure to the clearance mechanisms, suggesting OMV is one of the key players of interkingdom crosstalk between the host and microbes in pathogenic contexts. Therefore, we hypothesize that the gut microbiota associated OMVs may play a role in mediating the contribution of gut microbiota to the development of RA.” remarks Juan Li, one of the responding authors of the study. Through a combination of 16S rRNA-sequencing, clinical studies, and in vivo models, the researchers demonstrate that F. nucleatum is enriched in RA patients and positively correlated with disease activity. Importantly, transplanting F. nucleatum could aggravate inflammation in RA, while depleting F. nucleatum by Metronidazole could alleviate arthritis. “Previous studies mainly suggested F. nucleatum participates in various oral and gastrointestinal diseases, especially colorectal cancer. In this study, we found that F. nucleatum could affects distant joints and plays a role in mediating the aggravation of arthritis.” remarks Li. “OMV secretion is one of the most critical pathways of gram-negative bacteria interacting with the host. As one of common gram-negative bacteria, previous studies suggested that F. nucleatum derived OMV (F.n OMVs) could induce intestinal inflammation. All these studies inspired us to explore whether the effects of F. nucleatum on arthritis depend on OMVs.” explains Mukeng Hong, one of the authors of the study. To test whether F.n OMVs could translocate from the gut to the joints, authors labeled OMV with lipophilicity carbocyanine dyes DIL and observed that F.n OMVs translocated throughout the body and finally accumulated in the limbs. Also, the accumulated F.n OMVs in the joints aggravate arthritis, indicating that F. nucleatum promotes arthritis by secreting OMVs. Subsequently, considering that macrophages and neu","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-10-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134976370","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Sameen Zafar, Daniel Gonzalez, Leonard Kuan‐Pei Wang, Alexandria Soybel, Emilio B. Gonzalez, Vijaya Murthy
Herein, we report a case of a 49-year-old Caucasian man with a medical history of gastroesophageal reflux disease, occasional premature ventricular contractions, and unvaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented with myalgias, fevers, and right-sided neck swelling approximately 26 days after he had tested positive for SARS-CoV-2 and 21 days after receiving the casirivimab–imdevimab (REGEN-COV) infusion. His initial workup showed leukocytosis and thrombocytopenia (platelets: 108 × 109/L, reference range [RR]: 150−328 × 109/L). The SARS-CoV-2 rapid antigen-detection test was negative. The patient was started on intravenous antibiotics for presumed lymphadenitis; however, his fevers persisted, with subsequent development of worsening thrombocytopenia at 91 × 109/L and increasing C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), with peak values at 13.4 mg/dL (RR: < 0.8 mg/dL) and 35 mm/1 h (RR: 0−10 mm/1 h), respectively. A few days later, he developed polymorphic ventricular tachycardia causing cardiac arrest. Return of spontaneous circulation was achieved after 5 min. The patient was subsequently admitted to the critical care unit for acute respiratory failure requiring mechanical ventilation, shock requiring multiple pressors, and acute renal failure requiring continuous renal replacement therapy (CRRT). Transthoracic echocardiogram showed severely reduced left ventricular ejection fraction (LVEF) of 20%–25% with multiple regional wall abnormalities. Coronary angiography of the left and right heart showed patent coronaries, increased left ventricular filling pressures, and moderate pulmonary hypertension. A physical exam showed a new erythematous, punctate rash on the right medial thigh (Figure 1A). An extensive infectious workup—including human immunodeficiency virus, syphilis, cytomegalovirus, toxoplasma, respiratory syncytial virus, influenza, hepatitis B virus, hepatitis C virus, typhus, Bartonella serologies, and Histoplasma—was negative. Given the high suspicion for multisystem inflammatory syndrome in adults (MIS-A), as the patient fulfilled the Centers for Disease Control and Prevention (CDC) case definition (unexplained fever unresponsive to antibiotics, neck lymphadenopathy, cardiac dysfunction, lymphopenia, worsening rash, high inflammatory markers 2–6 weeks after initial coronavirus disease 2019 (COVID-19), the patient was started on a 4-day course of intravenous immunoglobulin (IVIG) infusion and methylprednisone. After completion of the first round of IVIG, the patient improved clinically and his fractional inspired oxygen (FiO2) requirement decreased from 100% to 50%, pressors were weaned off, repeat echo showed recovered ejection fraction (EF) > 65%, urine output improved off CRRT, the rash started clearing up (Figure 1B), fever resolved, and inflammatory biomarkers including white blood cell count, CRP, procalcitonin, and interleukin (IL)-6 improved. However, he r
{"title":"Multisystem inflammatory syndrome in adults associated with COVID‐19: A rare life‐threatening complication","authors":"Sameen Zafar, Daniel Gonzalez, Leonard Kuan‐Pei Wang, Alexandria Soybel, Emilio B. Gonzalez, Vijaya Murthy","doi":"10.1002/rai2.12094","DOIUrl":"https://doi.org/10.1002/rai2.12094","url":null,"abstract":"Herein, we report a case of a 49-year-old Caucasian man with a medical history of gastroesophageal reflux disease, occasional premature ventricular contractions, and unvaccinated against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented with myalgias, fevers, and right-sided neck swelling approximately 26 days after he had tested positive for SARS-CoV-2 and 21 days after receiving the casirivimab–imdevimab (REGEN-COV) infusion. His initial workup showed leukocytosis and thrombocytopenia (platelets: 108 × 109/L, reference range [RR]: 150−328 × 109/L). The SARS-CoV-2 rapid antigen-detection test was negative. The patient was started on intravenous antibiotics for presumed lymphadenitis; however, his fevers persisted, with subsequent development of worsening thrombocytopenia at 91 × 109/L and increasing C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), with peak values at 13.4 mg/dL (RR: < 0.8 mg/dL) and 35 mm/1 h (RR: 0−10 mm/1 h), respectively. A few days later, he developed polymorphic ventricular tachycardia causing cardiac arrest. Return of spontaneous circulation was achieved after 5 min. The patient was subsequently admitted to the critical care unit for acute respiratory failure requiring mechanical ventilation, shock requiring multiple pressors, and acute renal failure requiring continuous renal replacement therapy (CRRT). Transthoracic echocardiogram showed severely reduced left ventricular ejection fraction (LVEF) of 20%–25% with multiple regional wall abnormalities. Coronary angiography of the left and right heart showed patent coronaries, increased left ventricular filling pressures, and moderate pulmonary hypertension. A physical exam showed a new erythematous, punctate rash on the right medial thigh (Figure 1A). An extensive infectious workup—including human immunodeficiency virus, syphilis, cytomegalovirus, toxoplasma, respiratory syncytial virus, influenza, hepatitis B virus, hepatitis C virus, typhus, Bartonella serologies, and Histoplasma—was negative. Given the high suspicion for multisystem inflammatory syndrome in adults (MIS-A), as the patient fulfilled the Centers for Disease Control and Prevention (CDC) case definition (unexplained fever unresponsive to antibiotics, neck lymphadenopathy, cardiac dysfunction, lymphopenia, worsening rash, high inflammatory markers 2–6 weeks after initial coronavirus disease 2019 (COVID-19), the patient was started on a 4-day course of intravenous immunoglobulin (IVIG) infusion and methylprednisone. After completion of the first round of IVIG, the patient improved clinically and his fractional inspired oxygen (FiO2) requirement decreased from 100% to 50%, pressors were weaned off, repeat echo showed recovered ejection fraction (EF) > 65%, urine output improved off CRRT, the rash started clearing up (Figure 1B), fever resolved, and inflammatory biomarkers including white blood cell count, CRP, procalcitonin, and interleukin (IL)-6 improved. However, he r","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135864220","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A 66-year-old man with a history of microscopic polyangiitis, type 2 diabetes mellitus, bronchiectasis, and emphysema presented to Jiangxi Provincial People's Hospital on September 28, 2021. The patient's major symptoms were fever, diarrhea, cough with sputum for the past month, and gangrene of the lip for the past 6 days. The patient was a farmer residing in Jiangxi Province, who was a nonsmoker with no travel history. In June 2020, his serologies were positive for perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) at 1:1280 and myeloperoxidase (MPO) at 209.9 (0–20) U/mL. His creatinine level was 411 (57–111) μmol/L. Renal ultrasound suggested renal atrophy, and computed tomography (CT) of the lungs revealed interstitial lesions. The diagnosis was microscopic polyangiitis, antineutrophil cytoplasmic antibodies (ANCA)-associated nephritis, and interstitial pneumonia. The administered treatments were glucocorticoids (starting dose of methylprednisolone at 40 mg/day, followed by a gradual reduction to a maintenance dose of prednisone at 10 mg/day), cyclophosphamide (intermittent use from June 2020 to August 2021, totaling 5.0 g), and compound sulfamethoxazole (two tablets every 12 h) for the prevention of Pneumocystis jirovecii (P. jirovecii). The patient developed fever, diarrhea with chills, nausea, vomiting, and a cough with sputum after exertion in August 2021. He consulted another hospital on September 3, 2021, and blood cultures showed a multidrug-resistant Escherichia coli infection. After discontinuing hormone treatment and using cefoperazone/sulbactam sodium and moxifloxacin to fight the infection, the patient's condition did not improve. On September 22, the patient developed oral ulcers, gangrene of the lip, aggravated diarrhea, nausea, vomiting, and a cough. Physical examination revealed an oral mucosal ulcer, gangrene of the lip (Figure 1A), weak breath sounds in both lungs, and wet rales. Laboratory tests (September 28, 2021) included a blood count with the following findings: white blood cells: 8.9 (3.5–9.5) × 109/L, neutrophils: 92.7% (40%–75%), lymphocytes: 5.8% (20%–50%), eosinophils: 0.3% (0.4%–8.0%), hemoglobin: 83 (130–175) g/L, and platelets: 61 (125–350) × 109/L. Biochemical tests revealed: creatinine 178 (57–111) µmol/L. Immunological examinations revealed: C3: 0.51 (0.79–1.52) g/L, C4: 0.15 (0.16–0.38) g/L, and negative results for p-ANCA and classic antineutrophil cytoplasmic antibody (c-ANCA). Infection indicators were as follows: erythrocyte sedimentation rate: 87 (0–15) mm/1 h, CRP: 111 (0–8) mg/L, 1–3-β-d glucan: 203.67 (60–100) pg/mL, and all other pathogen-related tests were negative. Chest CT demonstrated interstitial fibrosis of the lungs (Figure 1B). The patient received meropenem (0.5 g every 12 h). On September 30, bronchoalveolar lavage fluid microscopy revealed a small number of Strongyloides stercoralis(S. stercoralis) and P. jirovecii (Figure 1C). The patient was administered albendazole (400 mg once
{"title":"Hyperinfection syndrome in a microscopic polyangiitis patient after treatment with immunosuppressive drugs","authors":"Jiao Luo, Haotong Zhou, Chunhua Shi, Lihua Duan","doi":"10.1002/rai2.12090","DOIUrl":"https://doi.org/10.1002/rai2.12090","url":null,"abstract":"A 66-year-old man with a history of microscopic polyangiitis, type 2 diabetes mellitus, bronchiectasis, and emphysema presented to Jiangxi Provincial People's Hospital on September 28, 2021. The patient's major symptoms were fever, diarrhea, cough with sputum for the past month, and gangrene of the lip for the past 6 days. The patient was a farmer residing in Jiangxi Province, who was a nonsmoker with no travel history. In June 2020, his serologies were positive for perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) at 1:1280 and myeloperoxidase (MPO) at 209.9 (0–20) U/mL. His creatinine level was 411 (57–111) μmol/L. Renal ultrasound suggested renal atrophy, and computed tomography (CT) of the lungs revealed interstitial lesions. The diagnosis was microscopic polyangiitis, antineutrophil cytoplasmic antibodies (ANCA)-associated nephritis, and interstitial pneumonia. The administered treatments were glucocorticoids (starting dose of methylprednisolone at 40 mg/day, followed by a gradual reduction to a maintenance dose of prednisone at 10 mg/day), cyclophosphamide (intermittent use from June 2020 to August 2021, totaling 5.0 g), and compound sulfamethoxazole (two tablets every 12 h) for the prevention of Pneumocystis jirovecii (P. jirovecii). The patient developed fever, diarrhea with chills, nausea, vomiting, and a cough with sputum after exertion in August 2021. He consulted another hospital on September 3, 2021, and blood cultures showed a multidrug-resistant Escherichia coli infection. After discontinuing hormone treatment and using cefoperazone/sulbactam sodium and moxifloxacin to fight the infection, the patient's condition did not improve. On September 22, the patient developed oral ulcers, gangrene of the lip, aggravated diarrhea, nausea, vomiting, and a cough. Physical examination revealed an oral mucosal ulcer, gangrene of the lip (Figure 1A), weak breath sounds in both lungs, and wet rales. Laboratory tests (September 28, 2021) included a blood count with the following findings: white blood cells: 8.9 (3.5–9.5) × 109/L, neutrophils: 92.7% (40%–75%), lymphocytes: 5.8% (20%–50%), eosinophils: 0.3% (0.4%–8.0%), hemoglobin: 83 (130–175) g/L, and platelets: 61 (125–350) × 109/L. Biochemical tests revealed: creatinine 178 (57–111) µmol/L. Immunological examinations revealed: C3: 0.51 (0.79–1.52) g/L, C4: 0.15 (0.16–0.38) g/L, and negative results for p-ANCA and classic antineutrophil cytoplasmic antibody (c-ANCA). Infection indicators were as follows: erythrocyte sedimentation rate: 87 (0–15) mm/1 h, CRP: 111 (0–8) mg/L, 1–3-β-d glucan: 203.67 (60–100) pg/mL, and all other pathogen-related tests were negative. Chest CT demonstrated interstitial fibrosis of the lungs (Figure 1B). The patient received meropenem (0.5 g every 12 h). On September 30, bronchoalveolar lavage fluid microscopy revealed a small number of Strongyloides stercoralis(S. stercoralis) and P. jirovecii (Figure 1C). The patient was administered albendazole (400 mg once","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"135300065","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Researchers have developed a novel nanogel that effectively traps and degrades cell-free DNA (cfDNA), a potential cause of rheumatoid arthritis (RA), according to a new study published in Proceedings of the National Academy of Sciences (PNAS).1 This breakthrough offers insights into the potential of nanomedicine for treating RA and various autoimmune diseases. Excessive levels of cfDNA in the serum and synovium have been identified as a causative factor of RA, participating in its pathogenesis. Scavenging cfDNA has been recognized as an effective therapeutic approach for RA. Cationic polymers, driven by static charge interactions, can neutralize anionic cfDNA and hinder the progression of joint inflammation in RA models. However, the development of biocompatible cationic materials for RA treatment is still in its early stages. “Innovative and effective strategies to locally and thoroughly scavenge cfDNA are urgently needed,” remarks Lingyun Sun, one of the corresponding authors of the study. Inspired by the biological functions of organelles, the nanogel is formed by a cationic peptide dendrimer that binds to negatively charged cfDNA and a nuclease enzyme that breaks down cfDNA into harmless fragments. The nanogel modulates key molecular pathways involved in RA pathogenesis, such as the toll-like receptor 9 (TLR9) signaling pathway, which is activated by cfDNA and triggers immune responses. “The nanogels with a positive charge on their surface can bind and scavenge anionic cfDNA through electronic interaction, inhibit the intracellular trafficking of cfDNA from the plasma membrane to the endolysosomes, and prevent it from reaching TLR9. By clearing cfDNA, the ligand for TLR9 is reduced, which in turn induces the expression of inflammatory genes,” explains Sun. The nanogel is based on a third-generation polylysine dendrimer (G3K) modified with 2,2′-bipyridine-4-carboxylic acid (BPY) groups on its periphery. The BPY groups enable cross-linking of the dendrimer via aromatic stacking interactions in an aqueous solution, forming a spherical nanogel with a diameter of about 200 nm. The nanogel has a high density of positive charges on its surface, enabling interaction with the negative charges of cfDNA. To enhance the cfDNA degradation capability of the nanogel, the researchers conjugated deoxyribonuclease I (DNase I), an enzyme that cleaves DNA strands, to the surface of the nanogel using active ester chemistry. The resulting nanogel, named DG3K10, exhibits high biocompatibility and stability, and rapidly targets inflamed joints where cfDNA accumulates. In vivo testing of the nanogel was conducted using two different models of RA: one induced by injecting CpG oligodeoxynucleotides (ODNs), synthetic DNA fragments that mimic bacterial DNA and activate TLR9, and another induced by immunizing mice with bovine type II collagen (collagen-induced arthritis [CIA]), which triggers an autoimmune response against the host's own cartilage. In both models, the nan
{"title":"Novel nanogel offers potential treatment for rheumatoid arthritis by trapping and degrading cfDNA","authors":"Ru Li","doi":"10.1002/rai2.12091","DOIUrl":"https://doi.org/10.1002/rai2.12091","url":null,"abstract":"Researchers have developed a novel nanogel that effectively traps and degrades cell-free DNA (cfDNA), a potential cause of rheumatoid arthritis (RA), according to a new study published in Proceedings of the National Academy of Sciences (PNAS).1 This breakthrough offers insights into the potential of nanomedicine for treating RA and various autoimmune diseases. Excessive levels of cfDNA in the serum and synovium have been identified as a causative factor of RA, participating in its pathogenesis. Scavenging cfDNA has been recognized as an effective therapeutic approach for RA. Cationic polymers, driven by static charge interactions, can neutralize anionic cfDNA and hinder the progression of joint inflammation in RA models. However, the development of biocompatible cationic materials for RA treatment is still in its early stages. “Innovative and effective strategies to locally and thoroughly scavenge cfDNA are urgently needed,” remarks Lingyun Sun, one of the corresponding authors of the study. Inspired by the biological functions of organelles, the nanogel is formed by a cationic peptide dendrimer that binds to negatively charged cfDNA and a nuclease enzyme that breaks down cfDNA into harmless fragments. The nanogel modulates key molecular pathways involved in RA pathogenesis, such as the toll-like receptor 9 (TLR9) signaling pathway, which is activated by cfDNA and triggers immune responses. “The nanogels with a positive charge on their surface can bind and scavenge anionic cfDNA through electronic interaction, inhibit the intracellular trafficking of cfDNA from the plasma membrane to the endolysosomes, and prevent it from reaching TLR9. By clearing cfDNA, the ligand for TLR9 is reduced, which in turn induces the expression of inflammatory genes,” explains Sun. The nanogel is based on a third-generation polylysine dendrimer (G3K) modified with 2,2′-bipyridine-4-carboxylic acid (BPY) groups on its periphery. The BPY groups enable cross-linking of the dendrimer via aromatic stacking interactions in an aqueous solution, forming a spherical nanogel with a diameter of about 200 nm. The nanogel has a high density of positive charges on its surface, enabling interaction with the negative charges of cfDNA. To enhance the cfDNA degradation capability of the nanogel, the researchers conjugated deoxyribonuclease I (DNase I), an enzyme that cleaves DNA strands, to the surface of the nanogel using active ester chemistry. The resulting nanogel, named DG3K10, exhibits high biocompatibility and stability, and rapidly targets inflamed joints where cfDNA accumulates. In vivo testing of the nanogel was conducted using two different models of RA: one induced by injecting CpG oligodeoxynucleotides (ODNs), synthetic DNA fragments that mimic bacterial DNA and activate TLR9, and another induced by immunizing mice with bovine type II collagen (collagen-induced arthritis [CIA]), which triggers an autoimmune response against the host's own cartilage. In both models, the nan","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2023-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"134994520","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Some of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients are facing long-term devastating effects like induction of autoimmune diseases. Here, I discuss molecular mechanisms and risk factors involved in the induction of autoimmune diseases after SARS-CoV-2 infections. Transcript editing genes were upregulated during SARS-CoV-2 infections, which might have edited host gene transcripts and paved the way for autoantigens generation and presented as nonself to generate autoantibodies followed by auto immunogenicity after SARS-CoV-2 infections. Therefore, some SARS-CoV-2 patients acquire autoimmunity. The transient and/or innocuous autoimmune response in some SARS-CoV-2 infected patients may be due to a lack of repeated production of autoantibodies to host autoantigens and/or viral antigens, which are needed to boost autoimmune response. In the future, SARS-CoV-2 mediated autoimmune disease onset will be a challenging task. Therefore, possible preventive measures and strategies to minimize and/or preclude such SARS-CoV-2 mediated autoimmune diseases have been presented in this commentary.
{"title":"Molecular insights into onset of autoimmunity in SARS-CoV-2 infected patients.","authors":"Dama Laxminarayana","doi":"10.1002/rai2.12056","DOIUrl":"https://doi.org/10.1002/rai2.12056","url":null,"abstract":"<p><p>Some of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infected patients are facing long-term devastating effects like induction of autoimmune diseases. Here, I discuss molecular mechanisms and risk factors involved in the induction of autoimmune diseases after SARS-CoV-2 infections. Transcript editing genes were upregulated during SARS-CoV-2 infections, which might have edited host gene transcripts and paved the way for autoantigens generation and presented as nonself to generate autoantibodies followed by auto immunogenicity after SARS-CoV-2 infections. Therefore, some SARS-CoV-2 patients acquire autoimmunity. The transient and/or innocuous autoimmune response in some SARS-CoV-2 infected patients may be due to a lack of repeated production of autoantibodies to host autoantigens and/or viral antigens, which are needed to boost autoimmune response. In the future, SARS-CoV-2 mediated autoimmune disease onset will be a challenging task. Therefore, possible preventive measures and strategies to minimize and/or preclude such SARS-CoV-2 mediated autoimmune diseases have been presented in this commentary.</p>","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/57/27/RAI2-2-198.PMC9874720.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9152181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2022-09-01Epub Date: 2022-06-15DOI: 10.1002/rai2.12043
V Michael Holers, Kristine A Kuhn, M Kristen Demoruelle, Jill M Norris, Gary S Firestein, Eddie A James, William H Robinson, Jane H Buckner, Kevin D Deane
In seropositive rheumatoid arthritis (RA), the onset of clinically apparent inflammatory arthritis (IA) is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF). This period prior to clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA, and an 'at-risk' status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA. With the goal of developing RA prevention strategies, studies have characterized immune phenotypes of preclinical RA/at-risk states. From these studies, a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production that should normally be transient, but instead is followed by systemic spread of the autoimmunity as manifest by serum autoantibody elevations, and ultimately drives the development of clinically identified joint inflammation. This model can be envisioned as the progression of disease development through serial 'checkpoints' that in principle should constrain or resolve autoimmunity; however, instead the checkpoints 'fail' and clinical RA develops. Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay, diminish, halt or even reverse the progression to clinical RA. Notably, these prevention strategies could utilize existing therapies approved for clinical RA, therapies approved for other diseases that target relevant pathways in the preclinical/at-risk state, or approaches that target novel pathways.
在血清反应阳性的类风湿性关节炎（RA）患者中，临床表现为炎症性关节炎（IA）的发病前通常会有一段较长的自身免疫期，表现为存在循环自身抗体，包括瓜氨酸化蛋白抗原（ACPA）和类风湿因子（RF）抗体。对于那些已发展到临床诊断为类风湿关节炎的人，临床IA之前的这段时间可被称为临床前类风湿关节炎，而对于那些尚未发展到临床IA但表现出未来临床类风湿关节炎的预测性生物标志物的人，则处于 "高危 "状态。为了制定RA预防策略，研究人员对临床前RA/高危状态的免疫表型进行了描述。从这些研究中，我们发现了一个模型，即粘膜炎症和菌群失调可能首先导致局部自身抗体的产生，这种产生通常是短暂的，但随后会导致自身免疫的全身扩散，表现为血清自身抗体升高，并最终导致临床上确定的关节炎症的发展。这一模型可被视为通过一系列 "检查点 "进行疾病发展的过程，这些检查点原则上应限制或解决自身免疫问题，然而，检查点却 "失效 "了，从而导致临床 RA 的发生。在此，我们回顾了每一步可能出现的免疫过程，以及可用于延缓、减轻、阻止甚至逆转临床RA进展的潜在治疗策略。值得注意的是，这些预防策略可以利用已获准用于临床RA的现有疗法、已获准用于其他疾病（针对临床前/风险状态下的相关途径）的疗法或针对新型途径的方法。
{"title":"Mechanism-driven strategies for prevention of rheumatoid arthritis.","authors":"V Michael Holers, Kristine A Kuhn, M Kristen Demoruelle, Jill M Norris, Gary S Firestein, Eddie A James, William H Robinson, Jane H Buckner, Kevin D Deane","doi":"10.1002/rai2.12043","DOIUrl":"10.1002/rai2.12043","url":null,"abstract":"<p><p>In seropositive rheumatoid arthritis (RA), the onset of clinically apparent inflammatory arthritis (IA) is typically preceded by a prolonged period of autoimmunity manifest by the presence of circulating autoantibodies that can include antibodies to citrullinated protein antigens (ACPA) and rheumatoid factor (RF). This period prior to clinical IA can be designated preclinical RA in those individuals who have progressed to a clinical diagnosis of RA, and an 'at-risk' status in those who have not developed IA but exhibit predictive biomarkers of future clinical RA. With the goal of developing RA prevention strategies, studies have characterized immune phenotypes of preclinical RA/at-risk states. From these studies, a model has emerged wherein mucosal inflammation and dysbiosis may lead first to local autoantibody production that should normally be transient, but instead is followed by systemic spread of the autoimmunity as manifest by serum autoantibody elevations, and ultimately drives the development of clinically identified joint inflammation. This model can be envisioned as the progression of disease development through serial 'checkpoints' that in principle should constrain or resolve autoimmunity; however, instead the checkpoints 'fail' and clinical RA develops. Herein we review the immune processes that are likely to be present at each step and the potential therapeutic strategies that could be envisioned to delay, diminish, halt or even reverse the progression to clinical RA. Notably, these prevention strategies could utilize existing therapies approved for clinical RA, therapies approved for other diseases that target relevant pathways in the preclinical/at-risk state, or approaches that target novel pathways.</p>","PeriodicalId":74734,"journal":{"name":"Rheumatology & autoimmunity","volume":null,"pages":null},"PeriodicalIF":1.2,"publicationDate":"2022-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9610829/pdf/nihms-1809597.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10133456","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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