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Artificial intelligence (AI) has emerged as a transformative force in precision medicine, revolutionizing the integration and analysis of health records, genetics, and immunology data. This comprehensive review explores the clinical applications of AI-driven analytics in unlocking personalized insights for patients with autoimmune rheumatic diseases. Through the synergistic approach of integrating AI across diverse data sets, clinicians gain a holistic view of patient health and potential risks. Machine learning models excel at identifying high-risk patients, predicting disease activity, and optimizing therapeutic strategies based on clinical, genomic, and immunological profiles. Deep learning techniques have significantly advanced variant calling, pathogenicity prediction, splicing analysis, and MHC-peptide binding predictions in genetics. AI-enabled immunology data analysis, including dimensionality reduction, cell population identification, and sample classification, provides unprecedented insights into complex immune responses. The review highlights real-world examples of AI-driven precision medicine platforms and clinical decision support tools in rheumatology. Evaluation of outcomes demonstrates the clinical benefits and impact of these approaches in revolutionizing patient care. However, challenges such as data quality, privacy, and clinician trust must be navigated for successful implementation. The future of precision medicine lies in the continued research, development, and clinical integration of AI-driven strategies to unlock personalized patient care and drive innovation in rheumatology., Competing Interests: Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests., (© 2025. This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.)

Background: Interleukin-1 receptor-associated kinase1 (IRAK1) plays a considerable role in the inflammatory signaling pathway. The current study aimed to identify any association between (rs1059703) single nucleotide polymorphism (SNP) and vulnerability to rheumatological diseases in the pediatric and adult Egyptian population., Patients and Methods: The current study included four patient groups: adult Systemic lupus erythematosus (SLE), Rheumatoid arthritis (RA), juvenile systemic lupus erythematosus (JSLE), and juvenile idiopathic arthritis (JIA). Two healthy matched age and sex groups were included as controls. Genotypes of IRAK1 (rs1059703) SNP in patients and controls were determined using the TaqMan allelic discrimination method., Results: The frequency of AA homozygous genotype and allele A of IRAK1 (rs1059703) SNP is higher in adult SLE patients compared to adult healthy controls (p-value < 0.005). No similar association was detected regarding RA, JSLE, or JIA. However, JSLE patients carrying the A allele have a higher SLE International Collaborating Clinics (SLICC) damage index (SDI) SDI score and a higher stage of renal biopsy than those carrying the G allele (p-value < 0.005)., Conclusions: Carriers of the A allele and its homozygous genotype of rs1059703 SNP are more prone to develop SLE in adult life and to have a more severe form of the disease in children in Egypt. No significant association was detected between this SNP and RA or JIA., Competing Interests: Declarations. Ethics approval and consent to participate: All patients or guardians provided an informed consent form to. Consent for publication: All authors have seen and approved the final version of the manuscript. Competing interests: The authors declare that they have no known competing financialinterests or personal relationships that could have appeared to influencethe work reported in this paper., (© 2025. The Author(s), under exclusive licence to Springer Nature B.V.)

Background/historical Perspective: The advent of genome-wide sequencing and large-scale genetic epidemiological studies has led to numerous opportunities for the application of genetics in clinical medicine. Leveraging this information toward the formation of clinically useful tools has been an ongoing research goal in this area. A genetic risk score (GRS) is a measure that attempts to estimate the cumulative contribution of established genetic risk factors toward an outcome of interest, taking into account the cumulative risk that each of these individual genetic risk factors conveys. The purpose of this perspective is to provide a systematic framework to evaluate a GRS for clinical application., Summary of Current Literature: Since the initial polygenic risk score methodology in 2007, there has been increasing GRS application across the medical literature. In rheumatology, this has included application to rheumatoid arthritis, gout, spondyloarthritis, lupus, and inflammatory arthritis., Major Conclusions: GRSs are particularly relevant to rheumatology, where common diseases have many complex genetic factors contributing to risk. Despite this, there is no widely accepted method for the critical application of a GRS, which can be a particular challenge for the clinical rheumatologist seeking to clinically apply GRSs. This review provides a framework by which the clinician may systematically evaluate a GRS., Future Research Directions: As genotyping becomes more accessible and cost-effective, it will become increasingly important to recognize the clinical applicability of GRSs and identify those of the highest utility for patient care. This framework for the evaluation of a GRS will also help ensure reliability among GRS research in rheumatology, thereby helping to advance the field., Competing Interests: The authors declare no conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Objectives: This study aimed to explore the potential of HIPK3 DNA methylation as a biomarker for rheumatoid arthritis (RA) by examining its methylation levels in various rheumatic immune diseases and analyzing its correlation with clinical indicators., Methods: We recruited 368 participants, including patients with RA, ankylosing spondylitis (AS), GOUT, psoriatic arthritis (PSA), sjogren's syndrome (SS), systemic lupus erythematosus (SLE), dermatomyositis (DM), and healthy controls (HC), and MethylTargetTM targeted region methylation sequencing technology was employed to analyze the DNA methylation levels of HIPK3 (cg15692052). We analyzed the HIPK3 methylation levels and correlated them with common clinical indicators. Transcriptome data from the GEO dataset (GSE93272) were also analyzed to assess HIPK3 mRNA expression levels in RA patients. Statistical analyses included Spearman correlation, One-Way ANOVA, Kruskal-Wallis tests, and ROC curve analysis., Results: HIPK3 methylation levels were significantly lower in the RA, SLE, and DM groups compared to the HC group (P < 0.05). RA subgroups based on RF and CCP statuses also showed lower HIPK3 methylation levels compared to the HC group (P < 0.05). Analysis of the GEO dataset revealed significantly elevated HIPK3 mRNA expression in RA patients (P < 0.05). A negative correlation was found between HIPK3 methylation levels and ESR (r = -0.14, P = 7.1e-3), CRP (r = -0.25, P = 4.1e-7), RF (r = -0.18, P = 5.2e-4), and DAS28-CRP (r = -0.12, P = 0.04) in the RA group. ROC analysis indicated that HIPK3 methylation levels had high diagnostic value for RA (AUC = 0.742), SLE (AUC = 0.701), and DM (AUC = 0.948), especially in distinguishing seronegative RA (AUC = 0.612, 0.747, 0.836) and differentiating RA from AS (AUC = 0.788)., Conclusions: The study suggests that HIPK3 hypomethylation in peripheral blood is associated with RA and correlated with inflammatory markers, such as CRP. HIPK3 methylation levels have potential as a novel biomarker for RA diagnosis and predicting inflammation trends, showing particular promise in differentiating RA from other types of arthritis. Key Points • MethylTargetTM targeted region methylation sequencing technology was employed to analyze the DNA methylation levels of HIPK3 (cg15692052). • HIPK3 methylation levels have potential as a novel biomarker for RA diagnosis and predicting inflammation trends., Competing Interests: Declarations. Consent to participate: All the authors listed in this manuscript have participated in the whole writing process of the manuscript and have informed consent to the publication of the manuscript. Consent for publication: The author claim that none of the material in the paper has been published or is under consideration for publication elsewhere. Competing interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

This study aims to elucidate the potential genetic commonalities between metabolic syndrome (MetS) and rheumatic diseases through a disease interactome network, according to publicly available large-scale genome-wide association studies (GWAS). The analysis included linkage disequilibrium score regression analysis, cross trait meta-analysis and colocalisation analysis to identify common genetic overlap. Using modular partitioning, the network-based association between the two disease proteins in the protein-protein interaction set was divided and quantified. Clinical samples from public databases were used to confirm the mapped genes. Mendelian randomisation analyses were conducted using genetic instrumental variables for causal inference. MetS and rheumatoid arthritis (RA), ankylosing spondylitis (AS), systemic lupus erythematosus (SLE), Sjogren's syndrome (SS) and their primary module networks shared topological overlap and genetic correlation. Functional analysis highlighted the significance of these shared targets in processes such as a diverse array of metabolic pathways involving glucose, lipids, energy, protein transport, inflammatory response, autophagy and cytokine regulation, elucidating the pathways through which MetS intersects with rheumatic diseases. Causal associations were determined between MetS phenotypes and rheumatic diseases. The persistence of MetS effects on rheumatic diseases remained evident even after adjusting for alcohol consumption and smoking. We have highlighted specific genetic associations between MetS and rheumatic diseases. Several genes (e.g., PRRC2A, PSMB8, BAG6, GPSM3, PBX2, etc.) have been identified with molecular commonalities in MetS and RA, AS, SLE and SS, which may serve as potential targets for shared treatments., (© 2025 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Objective: To assess CXC chemokine receptor 5 (CXCR5) circulating DNA methylation differences in autoimmune rheumatic diseases and their relation with clinical features., Methods: Targeted methylation sequencing was performed using peripheral blood from 164 rheumatoid arthritis (RA), 30 systemic lupus erythematosus (SLE), 30 ankylosing spondylitis (AS), 30 psoriatic arthritis (PsA), 24 Sjögren's syndrome (SS) patients, and 30 healthy controls (HC)., Results: Significant differences in CXCR5 cg19599951 methylation were found between RA and HC, as well as AS and SLE. RA patients exhibited higher methylation than HC and AS (p < 0.01) but lower than SLE (p < 0.05). SLE patients showed higher methylation compared to HC, AS, and PsA (p < 0.001, 0.01, and 0.05, respectively). No significant differences were found in patients with SS compared to other autoimmune diseases and HC. Methylation at cg19599951&#95;103 (r = 0.17, p < 0.05) and cg19599951&#95;209 (r = 0.22, p < 0.01), along with the CC haplotype (r = 0.21, p < 0.01), showed significant positive correlations with erythrocyte sedimentation rate (ESR), while the CT (r = -0.27, p < 0.001) and TT haplotypes (r = -0.19, p < 0.05) were negatively correlated. For C-reactive protein (CRP), methylation at cg19599951&#95;103 (r = 0.29, p < 0.001) and cg19599951&#95;209 (r = 0.33, p < 0.0001), and the CC haplotype (r = 0.34, p < 0.0001) was positively correlated, whereas the CT (r = -0.36, p < 0.0001) and TT (r = -0.30, p < 0.0001) haplotypes were negatively correlated. Significant negative correlations were observed between the CT haplotype and rheumatoid factor (r = -0.25, p < 0.01), and anti-citrullinated protein antibody (r = -0.20, p < 0.05). No significant correlations were found in patients with SLE, AS, and SS. Receiver operating characteristic analysis showed CXCR5 methylation could classify patients with RA versus those with AS (AUC: 0.624-0.967)., Conclusion: Differential circulating CXCR5 methylation levels were observed in autoimmune rheumatic diseases, which correlated with inflammatory mediators in RA and may serve as potential biomarkers for RA diagnosis., (© 2025 The Author(s). Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Importance: Patients with juvenile idiopathic arthritis (JIA) may develop adult rheumatic diseases later in life, and prolonged or recurrent disease activity is often associated with substantial disability; therefore, it is important to identify patients with JIA at high risk of developing adult rheumatic diseases and provide specialized attention and preventive care to them., Objective: To elucidate the full extent of the genetic association of JIA with adult rheumatic diseases, to improve treatment strategies and patient outcomes for patients at high risk of developing long-term rheumatic diseases., Design, Setting, and Participants: In this genetic association study of 4 disease genome-wide association study (GWAS) cohorts from 2013 to 2024 (JIA, rheumatoid arthritis [RA], systemic lupus erythematosus [SLE], and systemic sclerosis [SSc]), patients in the JIA cohort were recruited from the US, Australia, and Norway (with a UK cohort included in the meta-analyzed cohort), while patients in the other 3 cohorts were recruited from US and Western European countries. All analyses were conducted between September 2023 and April 2024., Exposures: Genetic associations., Main Outcomes and Measures: Genetic correlations and shared genomic loci between JIA and adult rheumatic diseases. Genetic correlation analyses and cross-trait meta-analysis were conducted on the JIA cohort and the summary statistics of the GWASs from adult rheumatic diseases (RA, SLE, and SSc). Mendelian randomization analyses were also conducted., Results: This study included 33 207 patients across the 4 cohorts, with 4550 patients in the meta-analyzed JIA cohort (JIA cohort: 1485 patients with arthritis onset before 16 years; 1017 female [68.5%]; 10 352 controls; UK cohort: 3305 patients with JIA; 9196 controls), 143 61 patients in the RA cohort, 5201 patients in the SLE cohort; and 9095 patients in the SSc cohort. After the GWAS result of the JIA cohort was meta-analyzed with the UK JIA cohort, there was a total of 4550 JIA cases and 18 446 controls. The analysis revealed a significant global correlation between JIA and adult rheumatic diseases, with 84 regions harboring signals associated with multiple diseases. Cross-trait analyses uncovered novel disease loci and 20 loci associated with JIA and adult diseases. Mendelian randomization analysis revealed the significant association of 11 proteins with rheumatic disorders. Both shared, organ-specific, and disease-specific critical cell types were highlighted., Conclusions and Relevance: In this genetic association study, there was significant genetic overlap between JIA and adult rheumatic diseases. These findings may help to refine JIA classification, risk stratification, and therapeutic strategy of repurposing adult disease drugs for pediatric patients with similar mechanisms.

Rheumatic diseases, those that affect the musculoskeletal system, cause significant morbidity. Among risk factors of these diseases is a significant genetic component. Recent advances in high-throughput omics techniques now allow a comprehensive profiling of patients at a genetic level through genome-wide association studies. Without functional interpretation of variants identified through these studies, clinical insight remains limited. Strategies include statistical fine-mapping that refine the list of variants in loci associated with disease, whilst colocalization techniques attempt to attribute function to variants that overlap a genetically active chromatin annotation. Functional validation using genome editing techniques can be used to further refine genetic signals and identify key pathways in cell types relevant to rheumatic disease biology. Insight gained from the combination of genetic studies and functional validation can be used to improve precision medicine in rheumatic diseases by allowing risk prediction and drug repositioning., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The explosion in Mendelian randomization (MR) publications is hard to ignore and shows no signs of slowing. Clinician readers, who may not be familiar with jargon-ridden methods, are expected to discern the good from the many low-quality studies that make overconfident claims of causality or stretch the plausibility of what MR can investigate. We aim to equip readers with foundational concepts, contextualized using examples in rheumatology, to appraise the many MR papers that are or will appear in their journals. We highlight the importance of assessing whether exposures are under plausibly specific genetic influence, whether the hypothesized causal pathways make biological sense, and whether results stand up to replication and use of control outcomes. Quality of research can vary substantially using MR as with any design, and all methods have inherent limitations. MR studies have provided and can still contribute valuable insights in the context of evidence triangulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Rheumatic diseases (RDs) are characterized by autoimmunity and autoinflammation and are recognized as complex due to the interplay of multiple genetic, environmental, and lifestyle factors in their pathogenesis. The rapid advancement of genome-wide association studies (GWASs) has enabled the identification of numerous single nucleotide polymorphisms (SNPs) associated with RD susceptibility. Based on these SNPs, polygenic risk scores (PRSs) have emerged as promising tools for quantifying genetic risk in this disease group. This chapter reviews the current status of PRSs in assessing the risk of RDs and discusses their potential to improve the accuracy of the diagnosis of these complex diseases through their ability to discriminate among different RDs. PRSs demonstrate a high discriminatory capacity for various RDs and show potential clinical utility. As GWASs continue to evolve, PRSs are expected to enable more precise risk stratification by integrating genetic, environmental, and lifestyle factors, thereby refining individual risk predictions and advancing disease management strategies., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Aims/Background The association between rheumatic immune diseases and polycystic ovary syndrome (PCOS) remains elusive. The purpose of this study was to investigate the causal relationship between rheumatic immune diseases and the risk of PCOS through a two-sample Mendelian randomization (MR) analysis. Methods In the assessment of exposure variables, we chose systemic lupus erythematosus (SLE), polymyositis (PM), and rheumatoid arthritis (RA) as representative rheumatic immune diseases, while PCOS was designated as the outcome of interest. All data utilized in this investigation were obtained from the Medical Research Council Integrative Epidemiology Unit (MRC-IEU) database. A two-sample MR analysis was conducted using summary statistics for both the exposure and outcome variables, which were gathered from the genome-wide association study (GWAS) datasets. Single nucleotide polymorphisms (SNPs) significantly associated with rheumatic diseases were selected as instrumental variables (IVs) to estimate the causal effects on PCOS. The final results were analyzed using five MR analysis methods, namely MR-Egger, inverse variance weighted (IVW), weighted median (WM), simple mode, and weighted mode. Causal estimation of MR was primarily obtained using the IVW method. Sensitivity analyses were also conducted to evaluate pleiotropy and heterogeneity. Results In this two-sample MR analysis, a total of 1,000,246 participants were included. Among them, there were 647 cases of SLE, 44 cases of PM, 5539 cases of RA, and 797 cases of PCOS. The IVW approach indicated a causal relationship between RA and an increased risk of PCOS (odds ratio [OR] = 1.069, 95% confidence interval [CI] = 1.007-1.134, p = 0.041). The MR-Egger intercept and Cochran's Q test ( p > 0.005) further verified the stability of the MR results. However, no significant correlation was observed between the other two rheumatic immune diseases (PM and SLE) and the risk of developing PCOS (both p > 0.05). Conclusion This study suggests a potential causal association between RA and PCOS, while SLE and PM do not exhibit a causal association with PCOS, enhancing our comprehension of the etiological factors of PCOS and shedding light on prevention strategies for the disease. Additional research is required to elucidate the underlying biological mechanisms by which RA contributes to the progression of PCOS.

For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis., Competing Interests: Competing interests: JPT is scientific cofounder of MetaImmune., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ on behalf of EULAR.)

Somatic mutations (also known as acquired mutations) are emerging as common, age-related processes that occur in all cells throughout the body. Somatic mutations are canonically linked to malignant processes but over the past decade have been increasingly causally connected to benign diseases including rheumatic conditions. Here we outline the contribution of somatic mutations to complex and monogenic immunological diseases with a detailed review of unique aspects associated with such causes. Somatic mutations can cause early- or late-onset rheumatic monogenic diseases but also contribute to the pathogenesis of complex inflammatory and immune-mediated diseases, affect disease progression and define new clinical subtypes. Although even variants with a low variant allele fraction can be pathogenic, clonal dynamics could lead to changes over time in the proportion of mutant cells, with possible phenotypic consequences for the individual. Thus, somatic mutagenesis and clonal expansion have relevant implications in genetic testing and counselling. On the basis of both increased recognition of somatic diseases in clinical practice and improved technical and bioinformatic processes, we hypothesize that there will be an ever-expanding list of somatic mutations in various genes leading to inflammatory conditions, particularly in late-onset disease., (© 2024. Flore S. Castellan and David B. Beck. Parts of this work were authored by US Federal Government authors and are not under copyright protection in the US; foreign copyright protection may apply.)

Chronic rheumatological diseases are multifactorial conditions in which both the neuroendocrine hormone pathway, including cortisol, sex hormones and active vitamin D3 (calcitriol), all deriving from cholesterol, and the epigenetic modifications that they cause play an important role. In fact, epigenetics modulates the function of the DNA of immune cells, through three main mechanisms: DNA methylation, modifications to the histones that make up chromatin and production of non-coding RNAs (microRNA - miRNA). In this narrative review, the main data regarding the epigenetic modifications induced by cortisol, 17β-oestradiol, progesterone, testosterone and calcitriol on immune cells were collected, discussing how these can interfere in the predisposition and course of chronic rheumatological diseases (i.e. rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis). An ever-increasing number of miRNAs have been identified, which are produced by neuroendocrine hormones and can influence the inflammatory-fibrotic response at various levels. Concerning the involvements of the neuro-endocrine-immunology within the pathophysiology of rheumatic diseases, the epigenetic effects induced by steroid hormones must be taken into consideration to evaluate their impact on the progression of the single condition and even inside the single patient.

Telomeres, repetitive sequences located at the extremities of chromosomes, play a pivotal role in sustaining chromosomal stability. Telomerase is a complex enzyme that can elongate telomeres by appending telomeric repeats to chromosome ends and acts as a critical factor in telomere dynamics. The gradual shortening of telomeres over time is a hallmark of cellular senescence and cellular death. Notably, telomere shortening appears to result from the complex interplay of two primary mechanisms: telomere shelterin complexes and telomerase activity. The intricate interplay of genetic, environmental, and lifestyle influences can perturb telomere replication, incite oxidative stress damage, and modulate telomerase activity, collectively resulting in shifts in telomere length. This age-related process of telomere shortening plays a considerable role in various chronic inflammatory and oxidative stress conditions, including cancer, cardiovascular disease, and rheumatic disease. Existing evidence has shown that abnormal telomere shortening or telomerase activity abnormalities are present in the pathophysiological processes of most rheumatic diseases, including different disease stages and cell types. The impact of telomere shortening on rheumatic diseases is multifaceted. This review summarizes the current understanding of the link between telomere length and rheumatic diseases in clinical patients and examines probable telomere shortening in peripheral blood mononuclear cells and histiocytes. Therefore, understanding the intricate interaction between telomere shortening and various rheumatic diseases will help in designing personalized treatment and control measures for rheumatic disease.

Patients with primary biliary cholangitis (PBC) commonly experience extrahepatic rheumatic diseases. However, the epidemiologic and genetic associations as well as causal relationship between PBC and these extrahepatic conditions remain undetermined. In this study, we first conducted systematic review and meta-analyses by analyzing 73 studies comprising 334,963 participants across 17 countries and found strong phenotypic associations between PBC and rheumatic diseases. Next, we utilized large-scale genome-wide association study summary data to define the shared genetic architecture between PBC and rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc) and Sjögren's syndrome (SS). We observed significant genetic correlations between PBC and each of the four rheumatic diseases. Pleiotropy and heritability enrichment analysis suggested the involvement of humoral immunity and interferon-associated processes for the comorbidity. Of note, we identified four variants shared between PBC and RA (rs80200208), SLE (rs9843053), and SSc (rs27524, rs3873182) using cross-trait meta-analysis. Additionally, several pleotropic loci for PBC and rheumatic diseases were found to share causal variants with gut microbes possessing immunoregulatory functions. Finally, Mendelian randomization revealed consistent evidence for a causal effect of PBC on RA, SLE, SSc, and SS, but no or inconsistent evidence for a causal effect of extrahepatic rheumatic diseases on PBC. Our study reveals a profound genetic overlap and causal relationships between PBC and extrahepatic rheumatic diseases, thus providing insights into shared biological mechanisms and novel therapeutic interventions., (Copyright © 2024. Published by Elsevier Ltd.)

The past 25 years have seen major novel developments in the field of paediatric rheumatology. The concept of autoinflammation was introduced to this field, and medicine more broadly, with studies of familial Mediterranean fever, the most common autoinflammatory disease globally. New data on the positive evolutionary selection of familial Mediterranean fever-associated genetic variants might be pertinent to mild gain-of-function variants reported in other disease-associated genes. Genetic studies have unveiled the complexity of human heritability to inflammation and flourishing data from rare monogenic disorders have contributed to a better understanding of general disease mechanisms in paediatric rheumatic conditions. Beyond genomics, the application of other 'omics' technologies, including transcriptomics, proteomics and metabolomics, has generated an enormous dataset that can be applied to the development of new therapies and in the practice of precision medicine. Novel biomarkers for monitoring disease activity and progression have also emerged. A surge in the development of targeted biologic therapies has led to durable remission and improved prognosis for many diseases that in the past caused major complications. Last but not least, the COVID-19 pandemic has affected paediatric rheumatology practice and has sparked new investigations into the link between viral infections and unregulated inflammatory responses in children., (© 2024. Springer Nature Limited.)

Background: An association has been observed between primary biliary cholangitis (PBC) and systemic rheumatic diseases (SRDs) in observational studies, however the exact causal link remains unclear. We aimed to evaluate the causal effects of PBC on SRDs through Mendelian randomization (MR) analysis., Methods: The genome-wide association study (GWAS) summary data were obtained from MRC IEU OpenGWAS and FinnGen databases. Independent genetic variants for PBC were selected as instrumental variables. Inverse variance weighted was used as the main approach to evaluate the causal effects of PBC on Sjögren syndrome (SS), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), systemic sclerosis (SSc), mixed connective tissue disease (MCTD) and polymyositis (PM). Horizontal pleiotropy and heterogeneity were measured by MR‒Egger intercept test and Cochran's Q value, respectively., Results: PBC had causal effects on SS (OR = 1.177, P = 8.02e-09), RA (OR = 1.071, P = 9.80e-04), SLE (OR = 1.447, P = 1.04e-09), SSc (OR = 1.399, P = 2.52e-04), MCTD (OR = 1.306, P = 4.92e-14), and PM (OR = 1.416, P = 1.16e-04). Based on the MR‒Egger intercept tests, horizontal pleiotropy was absent (all P values > 0.05). The robustness of our results was further enhanced by the leave-one-out method., Conclusions: Our research has provided new insights into PBC and SRDs, indicating casual effects on various SRDs., (© 2024. The Author(s).)

Autoimmune rheumatic diseases comprise a group of immune-related disorders characterized by non-organ-specific inflammation. These diseases include systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), ankylosing spondylitis (AS), gout, among others. Typically involving the hematologic system, these diseases may also affect multiple organs and systems. The pathogenesis of autoimmune rheumatic immune diseases is complex, with diverse etiologies, all associated with immune dysfunction. The current treatment options for this type of disease are relatively limited and come with certain side effects. Therefore, the urgent challenge remains to identify novel therapeutic targets for these diseases. Sterol regulatory element-binding proteins (SREBPs) are basic helix-loop-helix-leucine zipper transcription factors that regulate the expression of genes involved in lipid and cholesterol biosynthesis. The expression and transcriptional activity of SREBPs can be modulated by extracellular stimuli such as polyunsaturated fatty acids, amino acids, glucose, and energy pathways including AKT-mTORC and AMP-activated protein kinase (AMPK). Studies have shown that SREBPs play roles in regulating lipid metabolism, cytokine production, inflammation, and the proliferation of germinal center B (GCB) cells. These functions are significant in the pathogenesis of rheumatic and immune diseases (Graphical abstract). Therefore, this paper reviews the potential mechanisms of SREBPs in the development of SLE, RA, and gout, based on an exploration of their functions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Jin, Chang and Ding.)

Advances in DNA sequencing technologies, especially next-generation sequencing (NGS), which is the basis for whole-exome sequencing (WES) and whole-genome sequencing (WGS), have profoundly transformed immune-mediated rheumatic disease diagnosis. Recently, substantial cost reductions have facilitated access to these diagnostic tools, expanded the capacity of molecular diagnostics and enabled the pursuit of precision medicine in rheumatology. Understanding the fundamental principles of genetics and diversity in genetic variant classification is a crucial milestone in rheumatology. However, despite the growing availability of DNA sequencing platforms, a significant number of autoinflammatory diseases (AIDs), neuromuscular disorders, hereditary collagen diseases, and monogenic bone diseases remain unsolved, and variants of uncertain significance (VUS) pose a formidable challenge to addressing these unmet needs in the coming decades. This article aims to provide an overview of the clinical indications and interpretation of comprehensive genetic testing in the medical field, addressing the related complexities and implications., (© 2024. The Author(s).)

Objective: Familial aggregation of systemic autoimmune diseases is frequently reported, but little is known about how fathers and mothers differentially contribute to the development of autoimmune diseases in their offspring. This study aimed to investigate the impact of maternal and paternal autoimmunity on the risk of offspring rheumatic diseases., Methods: We constructed a nationwide population-based cohort using data from the Maternal and Child Health Database and the Taiwan National Health Insurance Research Data (NHIRD) from 2004 to 2019. The outcome was presence of an autoimmune disease in the offspring. Inverse probability of treatment-weighted Cox models were used to estimate adjusted hazard ratios (aHRs) and 95% CIs for autoimmune diseases., Results: Babies born to a father or mother with an autoimmune disease had, respectively, 1.22 times and 1.38 times the risk of developing an autoimmune disease compared with their counterparts with no parental autoimmune diseases. Maternal autoimmunity substantially contributed to the risk of SLE (aHR = 5.46, 95% CI: 5.28-5.66), and paternal autoimmunity contributed to the risk of JIA (aHR = 1.76, 95% CI: 1.71-1.81) and of type 1 diabetes mellitus (aHR = 1.59, 95% CI: 1.39-1.81) in their offspring. The contributions of mothers to the risk of development of SLE (aHR = 8.55, 95% CI: 8.10-9.02) and inflammatory myopathy (aHR = 2.08, 95% CI: 1.72-2.51) in their offspring were exacerbated in boys. Babies of two parents with an autoimmune disease showed a 1.39-fold risk of developing an autoimmune disease. The maternal contribution effect was stronger for preterm births than for full-term births., Conclusion: This study demonstrated broadly how autoimmune diseases pass from parents to infants of both genders and separately quantified the maternal and paternal contributions to disease., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Patients with rare and complex rheumatic diseases (RDs) present with immense clinical variability inherent to all immunologic diseases. In addition to systemic and organ-specific inflammation, patients may display features of immunodeficiency or allergy, which may represent major diagnostic and therapeutic challenges. The person's genetic architecture has been a well-established risk factor for patients with RDs, albeit to variable degrees. Patients with early-onset diseases and/or positive family history (FH) have a strong genetic component, whereas patients with late-onset RDs demonstrate a more complex interplay of genetic and environmental risk factors. Overall, the genetic studies in patients with RDs have been instrumental to our understanding of innate and adaptive immunity in human health and disease. The elucidation of the molecular causes underlying rare diseases has played a major role in the identification of genes that are critical in the regulation of inflammatory responses. In addition, studies of patients with rare disorders may help determine the mechanisms of more complex autoimmune diseases by identifying variants with small effect sizes in the same genes. In contrast, studies of patients with common RDs are conducted in cohorts of patients with well-established phenotypes and ancestry-matched controls, and they aim to discover disease-related pathways that can inform the development of novel targeted therapies. Knowing the genetic cause of a disease has helped patients and families understand the disease progression and outcome. Here, we discuss the current understanding of genetic heritability and challenges in the diagnosis of RDs in patients and how this field may develop in the future., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.)

Background: Previous studies have implicated rheumatoid arthritis as an independent risk factor for bone density loss. However, whether there is a causal relationship between rheumatic diseases and bone mineral density (BMD) and fractures is still controversial. We employed a bidirectional Mendelian analysis to explore the causal relationship between rheumatic diseases and BMD or fractures., Methods: The rheumatic diseases instrumental variables (IVs) were obtained from a large Genome-wide association study (GWAS) meta-analysis dataset of European descent. Analyses were performed for the three rheumatic diseases: ankylosing spondylitis (AS) (n = 22,647 cases, 99,962 single nucleotide polymorphisms [SNPs]), rheumatoid arthritis (RA) (n = 58,284 cases, 13,108,512 SNPs), and systemic lupus erythematosus (SLE) (n = 14,267 cases, 7,071,163 SNPs). Two-sample Mendelian randomization (MR) analyses were carried out by using R language TwoSampleMR version 0.5.7. The inverse-variance weighted (IVW), MR-Egger, and weighted median methods were used to analyze the causal relationship between rheumatic diseases and BMD or fracture., Results: The MR results revealed that there was absence of evidence for causal effect of AS on BMD or fracture. However, there is a positive causal relationship of RA with fracture of femur (95% CI = 1.0001 to 1.077, p = 0.046), and RA and fracture of forearm (95% CI = 1.015 to 1.064, p = 0.001). SLE had positive causal links for fracture of forearm (95% CI = 1.004 to 1.051, p = 0.020). Additionally, increasing in heel bone mineral density (Heel-BMD) and total bone mineral density (Total-BMD) can lead to a reduced risk of AS without heterogeneity or pleiotropic effects. The results were stable and reliable. There was absence of evidence for causal effect of fracture on RA (95% CI = 0.929 to 1.106, p = 0.759), and fracture on SLE (95% CI = 0.793 to 1.589, p = 0.516)., Conclusions: RA and SLE are risk factors for fractures. On the other hand, BMD increasing can reduce risk of AS. Our results indicate that rheumatic diseases may lead to an increased risk of fractures, while increased BMD may lead to a reduced risk of rheumatic diseases. These findings provide insight into the risk of BMD and AS, identifying a potential predictor of AS risk as a reduction in BMD., (© 2024. The Author(s).)

Background: Although observational studies have suggested a correlation between vitiligo and rheumatic diseases, conclusive evidence supporting a causal relationship is still lacking. Therefore, this study aims to explore the potential causal relationship between vitiligo and rheumatic diseases., Methods: Using genome-wide association studies, we performed a two-sample Mendelian randomization (MR) analysis. In our analysis, the random-effects inverse variance weighted (IVW) method was predominantly employed, followed by several sensitivity analyses, which include heterogeneity, horizontal pleiotropy, outliers, and "leave-one-out" analyses., Results: The genetically predicted vitiligo was associated with an increased risk of rheumatoid arthritis (RA) (OR, 1.47; 95% confidence interval [CI], 1.29-1.68; p < 0.001), and systemic lupus erythematosus (SLE) (OR, 1.22; 95% CI, 1.06-1.39; p = 0.005). The causal associations were supported by sensitivity analyses. In Sjögren's syndrome and ankylosing spondylitis, no causal relationship with vitiligo was found in the study., Conclusion: Our MR results support the causal effect that vitiligo leads to a higher risk of RA and SLE. Individuals with vitiligo should be vigilant for the potential development of RA and SLE. Managing and addressing this potential requires regular monitoring., (© 2024 The Authors. Skin Research and Technology published by John Wiley & Sons Ltd.)

Competing Interests: Competing interests: None declared.

Lysosomal storage diseases are a group of rare hereditary metabolic diseases. Due to a deficiency of lysosomal enzymes, complex substrates accumulate in the lysosomes of various organs. Depending on the affected enzyme, this results in clinically variable and chronic progressive multiorgan diseases. Diagnosis is often delayed. As clinical symptoms include the musculoskeletal system, an awareness of lysosomal storage diseases is of relevance to (pediatric) rheumatologists. This article is focused on Mucopolysaccharidosis type I‑S, Mucolipidosis type III, Gaucher disease and Fabry disease. When suspecting a lysosomal storage disease, enzyme activity should be determined in dried blood spots or leukocytes. For some diseases, specific biomarkers can additionally be analyzed. Diagnosis should be confirmed by genetic testing. As causal treatment options are available for three of the presented diseases, a timely diagnosis is very important., (© 2024. The Author(s), under exclusive licence to Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

In genomic medicine, the concept of genetically transitional disease (GTD) refers to cases in which gene mutation is necessary but not sufficient to cause disease. In this Perspective, we apply this novel concept to rheumatic diseases, which have been linked to hundreds of genetic variants via association studies. These variants are in the 'grey zone' between monogenic variants with large effect sizes and common susceptibility alleles with small effect sizes. Among genes associated with rare autoinflammatory diseases, many low-frequency and/or low-penetrance variants are known to increase susceptibility to systemic inflammation. In autoimmune diseases, hundreds of HLA and non-HLA genetic variants have been revealed to be modest- to moderate-risk alleles. These diseases can be reclassified as GTDs. The same concept could apply to many other human diseases. GTD could improve the reporting of genetic testing results, diagnostic yields, genetic counselling and selection of therapy, as well as facilitating research using a novel approach to human genetic diseases., (© 2024. Springer Nature Limited.)

Objective: We aimed to compare the genetic contribution to osteoarthritis (OA) versus other rheumatic/musculoskeletal diseases (RMDs) in the same population and to explore the role for any shared genetics between OA and other RMDs., Methods: In 59,970 Swedish twins aged 35 years or older, we estimated the heritability (the variance explained by genetic factors) of OA in peripheral joints, back and neck pain, shoulder pain (adhesive capsulitis, impingement syndrome, etc), rheumatoid arthritis, spondyloarthritis (SpA) and psoriatic arthritis, myalgia, and osteoporosis diagnosed in specialist and inpatient care. We also studied how much covariance between OA and each of the RMDs could be explained by genetics by studying phenotypic correlations in bivariate classical twin models., Results: Any-site OA and hip OA (50% and 64%) were among the most heritable RMDs (as compared with 23% for fibromyalgia [lowest] and 63% for SpA [highest]). The highest phenotypic correlations were between OA (any joint site) and shoulder pain in the same individual (r = 0.33, 95% confidence interval 0.31-0.35), of which 70% (95% confidence interval 52-88) could be explained by shared genetics. The phenotypic correlation between OA and back/neck pain was r = 0.25, with 25% to 75% explained by genetics. Phenotypic correlations between OA and each of the other RMDs were lower (r ~ 0.1 to r ~ 0.2), with inconclusive sources of variation., Conclusion: OA has relatively large heritability as compared with other RMDs. The coexistence of OA and shoulder pain, as well as back pain, was common and could often be explained by genetic factors. Findings imply similar etiologies of OA and several pain conditions., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Polygenic risk scores (PRS) estimate an individual's genetic risk for a disease or trait compared to a matched population. For many rheumatic diseases PRS have been developed that have discriminatory capacity better than some widely used biomarkers, and in some cases are the most discriminatory tests available. These PRS assessments do not rely on the disease being present or its activity level, making them highly valuable for predicting disease development or enabling early diagnosis. However, most PRS to date have been developed in research settings, and in populations of European-ancestry. Further studies are required to assess their utility in clinical settings, in relation to existing tests, and in non-European populations. Such studies are underway, and it is likely in the near future these tests will become widely available, with significant benefits for the practice of medicine., Competing Interests: Declaration of Competing Interest The author has no conflict of interest to declare with regard to this manuscript., (Copyright © 2023. Published by Elsevier Inc.)

Modest effect sizes have limited the clinical applicability of genetic associations with rheumatic diseases. Genetic risk scores (GRSs) have emerged as a promising solution to translate genetics into useful tools. In this review, we provide an overview of the recent literature on GRSs in rheumatic diseases. We describe six categories for which GRSs are used: (a) disease (outcome) prediction, (b) genetic commonalities between diseases, (c) disease differentiation, (d) interplay between genetics and environmental factors, (e) heritability and transferability, and (f) detecting causal relationships between traits. In our review of the literature, we identified current lacunas and opportunities for future work. First, the shortage of non-European genetic data restricts the application of many GRSs to European populations. Next, many GRSs are tested in settings enriched for cases that limit the transferability to real life. If intended for clinical application, GRSs are ideally tested in the relevant setting. Finally, there is much to elucidate regarding the co-occurrence of clinical traits to identify shared causal paths and elucidate relationships between the diseases. GRSs are useful instruments for this. Overall, the ever-continuing research on GRSs gives a hopeful outlook into the future of GRSs and indicates significant progress in their potential applications.

Autoimmune polyglandular syndromes (APS) are a heterogeneous group of clinical conditions characterized by functional impairment of multiple endocrine glands due to loss of central or peripheral immune tolerance. These syndromes are also often accompanied by autoimmune damage to non-endocrine organs. Taking into account the wide range of components and variants of the disease, APS is usually divided into a rare juvenile type (APS 1) and a more common adult type (APS 2-4). APS type 1 is caused by a monogenic mutation, while APS types 2-4 have a polygenic mode of inheritance. One subtype of adult APS (APS 3D) is characterized by a combination of autoimmune thyroid disease and autoimmune rheumatic disease. This review considers the available literature data on combinations that meet the above criteria. Many studies have noted a significantly higher prevalence of rheumatic diseases in patients with autoimmune thyroid disease compared with the control group. Also, as in a number of rheumatic diseases, a more frequent occurrence of autoimmune thyroiditis, primary hypothyroidism and Graves' disease was noted.

Objective: Although the association between obesity and risk of rheumatic disease is well established, the precise causal relation has not been conclusively proven. Here, we estimate the causal effect of body mass index (BMI) on the risk of developing 5 different rheumatic diseases., Methods: Linear and nonlinear mendelian randomization (MR) were used to estimate the effect of BMI on risk of rheumatic disease, and sex-specific effects were identified. Analyses were performed in 361,952 participants from the UK Biobank cohort for 5 rheumatic diseases: rheumatoid arthritis (n = 8,381 cases), osteoarthritis (n = 87,430), psoriatic arthropathy (n = 933), gout (n = 13,638), and inflammatory spondylitis (n = 4,328)., Results: Using linear MR, we found that 1 SD increase in BMI increases the incidence rate for rheumatoid arthritis (incidence rate ratio [IRR] 1.52 [95% confidence interval (95% CI) 1.36-1.69]), osteoarthritis (IRR 1.49 [95% CI 1.43-1.55]), psoriatic arthropathy (IRR 1.80 [95% CI 1.31-2.48]), gout (IRR 1.73 [95% CI 1.56-1.92]), and inflammatory spondylitis (IRR 1.34 [95% CI 1.14-1.57]) in all individuals. BMI was found to be a stronger risk factor in women compared to men for psoriatic arthropathy (P for sex interaction = 3.3 × 10 -4 ) and gout (P for sex interaction = 4.3 × 10 -3 ), and the effect on osteoarthritis was stronger in premenopausal compared to postmenopausal women (P = 1.8 × 10 -3 ). Nonlinear effects of BMI were identified for osteoarthritis and gout in men, and for gout in women. The nonlinearity for gout was also more extreme in men compared to women (P = 0.03)., Conclusion: Higher BMI causes an increased risk for rheumatic disease, an effect that is more pronounced in women for both gout and psoriatic arthropathy. The novel sex- and BMI-specific causal effects identified here provide further insight into rheumatic disease etiology and mark an important step toward personalized medicine., (© 2023 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Circular RNAs (circRNAs), a class of non-coding RNAs (ncRNAs), are highly stable and ubiquitous molecules that exhibit tissue-specific expression. Accumulating evidence has shown that aberrant expression of circRNAs can play a role in the pathogenesis of several diseases. Rheumatic diseases are a varied group of autoimmune and inflammatory disorders affecting mainly the musculoskeletal system. Notably, circRNAs, which are essential immune system gene modulators, are strongly linked to the occurrence and progression of autoimmune disorders. Here, we present and discuss the current findings concerning the roles, implications and theragnostic potentials of circRNAs in common rheumatic diseases, including ankylosing spondylitis (AS), osteoarthritis (OA), osteoporosis (OP), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Crohn's disease (CD), and gout. This review aims to provide new insights to support the development of novel diagnostic and therapeutic strategies for these disabling diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Inborn errors of immunity (IEIs) are immunological disorders characterized by variable susceptibility to infections, immune dysregulation and/or malignancies, as a consequence of damaging germline variants in single genes. Though initially identified among patients with unusual, severe or recurrent infections, non-infectious manifestations and especially immune dysregulation in the form of autoimmunity or autoinflammation can be the first or dominant phenotypic aspect of IEIs. An increasing number of IEIs causing autoimmunity or autoinflammation, including rheumatic disease have been reported over the last decade. Despite their rarity, identification of those disorders provided insight into the pathomechanisms of immune dysregulation, which may be relevant for understanding the pathogenesis of systemic rheumatic disorders. In this review, we present novel IEIs primarily causing autoimmunity or autoinflammation along with their pathogenic mechanisms. In addition, we explore the likely pathophysiological and clinical relevance of IEIs in systemic rheumatic disorders., Competing Interests: Declaration of interests The authors declare no conflict of interest., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Objective: The causalities between the coronavirus disease 2019 (COVID-19) and the risk of rheumatic diseases remain unclear. The purpose of this study was to investigate the causal effect of COVID-19 on rheumatic disease occurrence., Methods: Single nucleotide polymorphisms (SNPs), acquired from published genome-wide association studies, were used to perform 2-sample Mendelian randomization (MR) on cases diagnosed with COVID-19 (n = 13 464), rheumatic diseases (n = 444 199), juvenile idiopathic arthritis (JIA, n = 15 872), gout (n = 69  374), systemic lupus erythematosus (SLE, n = 3094), ankylosing spondylitis (n = 75 130), primary biliary cholangitis (PBC, n = 11 375) and primary Sjögren's syndrome (n = 95 046). Three MR methods were used in the analysis based on different heterogeneity and pleiotropy using the Bonferroni correction., Results: The results revealed a causality between COVID-19 and rheumatic diseases with an odds ratio (OR) of 1.010 (95% confidence interval [CI], 1.006-1.013; P = .014). In addition, we observed that COVID-19 was causally associated with an increased risk of JIA (OR 1.517; 95%CI, 1.144-2.011; P = .004), PBC (OR 1.370; 95%CI, 1.149-1.635; P = .005), but a decreased risk of SLE (OR 0.732; 95%CI, 0.590-0.908; P = .004). Using MR, 8 SNPs were identified to associate with COVID-19 and recognized as significant variables. None of them were previously reported in any other diseases., Conclusions: This is the first study to use MR to explore the impact of COVID-19 on rheumatic diseases. From a genetic perspective, we found that COVID-19 could increase the risk of rheumatic diseases, such as PBC and JIA, but decrease that of SLE, thereby suggesting a potential surge in the disease burden of PBC and JIA following the COVID-19 pandemic., (© 2023 Asia Pacific League of Associations for Rheumatology and John Wiley & Sons Australia, Ltd.)

The purpose of this review is to present the main aspects of the genetic component of autoimmune rheumatic diseases, including the characteristics of the multifactorial or polygenic inheritance model, and its monogenic forms, as well as the main associated genes in both cases. The epigenetic changes involved, and the influence of the environment and sex that confer greater risk to women suffering from any of these diseases. Finally, to make known the advances that the study of omic sciences has allowed, opening the way to a new molecular classification of these diseases, aimed at personalized medicine. A review of the literature of the last 5 years, of English-language publications, in the PubMed database was performed and 28 review articles, and 19 original articles were included. Knowledge of the genetic factors involved in the aetiology of autoimmune rheumatic diseases, thanks to the availability of molecular studies, allows a better understanding of their pathophysiology and the possibility of diagnosis and treatment based on molecular markers in the future., (Copyright © 2021 Elsevier España, S.L.U. and Sociedad Española de Reumatología y Colegio Mexicano de Reumatología. All rights reserved.)

Artemisia argyi (AA) has been proven to be effective in the adjuvant treatment of rheumatism (RA), but the mechanism of its action in RA is not clear. This study aims to clarify the molecular mechanism of AA as a potential therapy for RA by using network pharmacology. The TCM systems pharmacology (TCMSP) was used to screen the active components of AA, and identification of the potential target genes of active compounds and rheumatism was performed with PharmMapper and GeneCards, respectively. Construction of complex target networks and protein-protein interaction networks was based on the Cytoscape software. The biological functions and pathway analysis of targets and effective targets were analyzed using DAVID. Our study demonstrated that 105 target genes were associated with these active compounds and RA. ALB, AKT1, and MAPK1 were the first three hub genes, and the metabolic and signaling pathways related to these hub genes were remarkably abundant. Results showed that AA might play a role in RA by affecting multiple targets and multiple ways, reflecting that TCM was characterized by multicomponents and multitargets. AA has the potential to be a promising new candidate for the treatment of RA and has value for further research and development., (© 2022. The Author(s).)

Laetiporus sulphureus mushroom is a complementary and alternative medicine that has anticancer, antioxidation, and analgesic effects and immunomodulatory activity; it is used as a treatment for cough and rheumatism and is a functional food that can improve physical fitness. Even though L. sulphureus has garnered considerable biotechnological and pharmacological interest due to its excellent cellulose-degrading ability and diverse biological activities, its biosynthetic potential regarding polysaccharides and secondary metabolites has not been thoroughly examined. In this study, we sequenced and assembled the whole genome of a wild L. sulphureus isolate, NWAFU-1, from the Qinling Mountains in China. Comparative genomes analysis revealed genomic differences between subspecies, and phylogenomic analysis revealed evolutionary divergence as well as genome expansion and contraction of individual Polyporaceae family species. Bioinformatics investigation identified candidate genes associated with mating type, polysaccharide synthesis, carbohydrate-active enzymes, and secondary-metabolite biosynthesis, which included multiple terpenoids, nonribosomal peptides, and polyketides. The locations of biosynthetic core genes were mapped and displayed on chromosomes and contigs. Totals of 143 proteins from 126 coding genes were identified and divided into 14 cytochrome P450 families. Furthermore, the biosynthetic network of tetracyclic triterpenoid active components was postulated by genome mining of related genes combined with the molecular network of metabolites. The genome analysis of L. sulphureus in this study improves the understanding of the biosynthesis of active compounds, which will lay a theoretical foundation for subsequent research on active-compound biosynthesis and promote the application of Laetiporus in the field of drug research and functional-food creation. IMPORTANCE L. sulphureus is a parasitic basidiomycete fungus that causes brown rot. The fruiting bodies of L. sulphureus are used as ancient medicines in China and Europe to cure cancer, analgesia, cough, and rheumatism and are considered a functional food that regulates the body and improves health. L. sulphureus was inferred to be a tetrapolar system based on a high-quality genome, which will aid molecular breeding and artificial farming. Screening polysaccharide synthesis candidate genes and comparing carbohydrate-associated genes in brown-rot basidiomycetes help understand their growth. Identifying core genes for secondary-metabolite biosynthesis, gene cluster family analysis, and comparative cluster analysis will guide heterologous-biosynthesis investigations of these genes and help elucidate the biosynthetic pathways for L. sulphureus bioactive natural components. The biosynthesis network of tetracyclic triterpenes was mapped using metabolite profiling and genome scanning. This work explores the biosynthetic capacity of L. sulphureus -derived natural products and lays the foundation for biosynthetic studies of them.

Background: Transcriptome profiling of blood cells is an efficient tool to study the gene expression signatures of rheumatic diseases. This study aims to improve the early diagnosis of pediatric rheumatic diseases by investigating patients' blood gene expression and applying machine learning on the transcriptome data to develop predictive models., Methods: RNA sequencing was performed on whole blood collected from children with rheumatic diseases. Random Forest classification models were developed based on the transcriptome data of 48 rheumatic patients, 46 children with viral infection, and 35 controls to classify different disease groups. The performance of these classifiers was evaluated by leave-one-out cross-validation. Analyses of differentially expressed genes (DEG), gene ontology (GO), and interferon-stimulated gene (ISG) score were also conducted., Results: Our first classifier could differentiate pediatric rheumatic patients from controls and infection cases with high area-under-the-curve (AUC) values (AUC = 0.8 ± 0.1 and 0.7 ± 0.1, respectively). Three other classifiers could distinguish chronic recurrent multifocal osteomyelitis (CRMO), juvenile idiopathic arthritis (JIA), and interferonopathies (IFN) from control and infection cases with AUC ≥ 0.8. DEG and GO analyses reveal that the pathophysiology of CRMO, IFN, and JIA involves innate immune responses including myeloid leukocyte and granulocyte activation, neutrophil activation and degranulation. IFN is specifically mediated by antibacterial and antifungal defense responses, CRMO by cellular response to cytokine, and JIA by cellular response to chemical stimulus. IFN patients particularly had the highest mean ISG score among all disease groups., Conclusion: Our data show that blood transcriptomics combined with machine learning is a promising diagnostic tool for pediatric rheumatic diseases and may assist physicians in making data-driven and patient-specific decisions in clinical practice., (© 2022. The Author(s).)

Discovery of the VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome demonstrates that somatic mutations in haematological precursor cells can cause adult-onset, complex inflammatory disease. Unlike germline mutations, somatic mutations occur throughout the lifespan, are restricted to specific tissue types, and may play a causal role in non-heritable rheumatological diseases, especially conditions that start in later life. Improvements in sequencing technology have enabled researchers and clinicians to detect somatic mutations in various tissue types, especially blood. Understanding the relationships between cell-specific acquired mutations and inflammation is likely to yield key insights into causal factors that underlie many rheumatological diseases. The objective of this review is to detail how somatic mutations are likely to be relevant to clinicians who care for patients with rheumatological diseases, with particular focus on the pathogenetic mechanisms of the VEXAS syndrome., (Published by Oxford University Press on behalf of the British Society for Rheumatology 2021. This work is written by a US Government employee and is in the public domain in the US.)

Systemic autoimmune rheumatic diseases (SARDs) exhibit extensive heterogeneity in clinical presentation, disease course, and treatment response. Therefore, precision medicine - whereby treatment is tailored according to the underlying pathogenic mechanisms of an individual patient at a specific time - represents the 'holy grail' in SARD clinical care. Current strategies include treat-to-target therapies and autoantibody testing for patient stratification; however, these are far from optimal. Recent innovations in high-throughput 'omic' technologies are now enabling comprehensive profiling at multiple levels, helping to identify subgroups of patients who may taper off potentially toxic medications or better respond to current molecular targeted therapies. Such advances may help to optimize outcomes and identify new pathways for treatment, but there are many challenges along the path towards clinical translation. In this Review, we discuss recent efforts to dissect cellular and molecular heterogeneity across multiple SARDs and future directions for implementing stratification approaches for SARD treatment in the clinic., (© 2022. Springer Nature America, Inc.)

Background: Genetic variations of neutrophil cytosolic factor 2 (NCF2), a subunit of NADPH oxidase, are usually associated with chronic granulomatous disease, and their relationship with autoimmune disorders through the defective NADPH oxidase function during phagocytosis is suggested. Our study aimed to explore whether there is an association between the non-synonymous single nucleotide polymorphism in the NCF2 gene (rs17849502, NC&#95;000001.11:g.183563445G>T) and the development of juvenile autoimmune rheumatic diseases., Methods: In order to test this hypothesis, we conducted a pilot case-control study. In total, 709 children and adolescents, all Belarusians, were involved in the study including patients with juvenile-onset systemic lupus erythematosus (JSLE), juvenile idiopathic arthritis (JIA), Kawasaki disease (KD), and subjects without autoimmune and inflammatory diseases as the clinical control, as well as health newborns as the population control. Real-time polymerase chain reaction was used for genotyping., Results: The minor T allele of NCF2 occurred most frequently in patients with JSLE (OR = 2.60, 95% CI = 1.18-5.73, p = 0.023 as compared to the clinical control). In groups with JIA and KD, its frequency did not differ from the control. The TT genotype was only observed in 5.7% of patients with JSLE (p = 0.007), but not in other groups., Conclusion: Therefore, our study suggested that NCF2 rs17849502 polymorphism is a potential genetic risk factor for JSLE, while it is probably not for such autoimmune rheumatic diseases as JIA or KD., (© 2021 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals LLC.)

The striking association of specific autoantibodies with distinct disease phenotypes and trajectories in human autoimmune rheumatic diseases provides a powerful opportunity to interrogate disease mechanism. In scleroderma, a subgroup of patients with autoantibodies to POLR3 have coincident onset of cancer and scleroderma. The majority of these patients have genetic changes (somatic mutations and loss of heterozygosity) in the POLR3A gene in their matched cancers, coupled with immune responses directed against the mutated and wild type autoantigen. In some individuals with scleroderma or dermatomyositis where specific immune responses mark a high risk of emergent cancer, cancer does not emerge. Such patients have a broader immune response that targets additional autoantigens, suggesting that the breadth and magnitude of the immune response regulates cancer, and that the rheumatic diseases provide a unique window into natural immunoediting of cancer in humans. This has implications for prediction and therapy in both autoimmunity and cancer., Competing Interests: Potential Conflicts of Interest: None disclosed., (© 2022 The American Clinical and Climatological Association.)