Relationship between mixed exposure to phenyl hydroxides, polycyclic aromatic hydrocarbons, and phthalates and the risk of arthritis.

BACKGROUND: To determine the relationship between mixed exposure to three types of endocrine-disrupting chemicals (EDCs), namely phenyl hydroxides, polycyclic aromatic hydrocarbons (PAHs), and phthalates (PAEs), and risk of arthritis. METHODS: Participants were selected from National Health and Nutrition Examination Survey (NHANES). The relationships between the urinary concentrations of phenyl hydroxides, PAHs, and PAEs and the risk of arthritis were analyzed by generalized linear regression model. The mixed exposure to these EDCs and the risk of arthritis was analyzed by weighted quantile sums (WQSs) and Bayesian kernel machine regression (BKMR) model. RESULTS: Our analysis showed that participants with urinary benzophenone-3 and methylparaben concentrations in the highest quartile (Q4) had an increased risk of arthritis compared with those in Q1. For each one-unit increase in the natural logarithm-converted urinary concentrations of 1-hydroxynapthalene and 2-hydroxynapthalene, the risk of arthritis increased by 5% and 8%, respectively. Chemical mixing index coefficients were significantly associated with risk of arthritis in both WQS positive- and negative-constraint models. In the BKMR model, there was a significant positive correlation between mixed exposure and the risk of arthritis. CONCLUSION: Mixed exposure to phenyl hydroxides, PAHs, and PAEs increased the risk of arthritis, with exposure to PAHs being the key factor.

GLIM criteria-based identification of severe malnutrition and its relationship with the risk of mortality among older Chinese adults with arthritis or rheumatism.

BACKGROUND: Malnutrition is a well-known risk factor for mortality among older adults. Arthritis and rheumatism are characterized by chronic inflammation and are also related to malnutrition as diagnosed using the Global Leadership Initiative on Malnutrition (GLIM) criteria. This study was thus developed to examine the associations linking malnutrition and all-cause death among older adults in China, employing the GLIM criteria to assess malnutrition. METHODS: Two waves of the China Health and Retirement Longitudinal Study from 2013 and 2018 were used to conduct this study. Moderate malnutrition was defined as low BMI (< 18.5 and < 20 for individuals < 70 and 70 + years of age, respectively), an unintended 10-20% decrease in weight, or low muscle mass based on the sex-specific lowest 20% of the height-adjusted muscle mass as < 5.039 kg/m2 in women and < 6.866 kg/m2 in men. Severe malnutrition was defined as a > 20% unintended decrease in weight only or the combination of both low muscle mass and an unintended reduction of over 10% in weight. Associations between malnutrition and the risk of all-cause death were assessed through Cox regression analyses. RESULTS: Overall, this study enrolled 1766 subjects 60 + years of age, of whom 57.36% (1033/1766) were female. Malnutrition was estimated to affect 418 (23.67%) of these individuals at baseline, with 21.06% and 2.60% affected by moderate and severe malnutrition, respectively. Over the 5-year follow-up, 189 of these individuals died. Covariate-adjusted Cox regression analyses confirmed a significant association between severe malnutrition and the risk of death in this cohort (HR = 2.196, 95%CI 1.125-4.286, P = 0.021). CONCLUSIONS: Severe malnutrition, identified through screening based on the GLIM criteria, was associated with an increased risk of all-cause death among older Chinese adults with arthritis or rheumatism.

Gabapentin alleviates peripheral nerve sensitization induced by inflammatory arthritis via ionotropic glutamate receptor NR2B subunit.

Inflammatory arthritis leads to peripheral nerve sensitization, but the therapeutic effect is often unsatisfactory. Our preliminary studies have found that in mice with inflammatory arthritis, the use of ionotropic glutamate receptor antagonists can produce a good analgesic effect without altering foot swelling, suggesting that pain relief may be related to the improvement of neuropathic pain. However, the underlying mechanisms remain unclear. To further investigate the effects of neuropathic pain medications on inflammatory arthritis and the impact of the ionotropic glutamate receptor NR2B subunit (NR2B) on inflammatory arthritis, this study employed gabapentin (GBP) treatment on the inflammatory arthritis mouse model (the adjuvant induced arthritis, AIA), and we found a significant reduction in pain. Further studies revealed that in AIA, the expression levels of NR2B, TRPV1, pain-related molecules (substance P, PGE2), inflammatory cytokines (IL-1, IL-6, TNF-α, and GM-CSF) and Ca2+ were elevated in the foot and dorsal root ganglia (DRG). GBP treatment was able to influence the downregulation of the expression levels of NR2B, TRPV1, pain-related molecules, inflammatory cytokines and Ca2+. Mechanistic studies have shown that GBP treatment affects the downregulation of NR2B, and the downregulation of NR2B expression leads to the downregulation of TRPV1, pain-related molecules and inflammatory cytokines, thereby alleviating pain. These results suggest that in peripheral sensitization caused by AIA, GBP can play a role in improving pain, and NR2B may be a key target of peripheral nerve sensitization induced by inflammatory arthritis. GBP provides a theoretical basis for the clinical treatment of inflammatory arthritis.

Get Spliced: Uniting Alternative Splicing and Arthritis.

Immune responses demand the rapid and precise regulation of gene protein expression. Splicing is a crucial step in this process; ~95% of protein-coding gene transcripts are spliced during mRNA maturation. Alternative splicing allows for distinct functional regulation, as it can affect transcript degradation and can lead to alternative functional protein isoforms. There is increasing evidence that splicing can directly regulate immune responses. For several genes, immune cells display dramatic changes in isoform-level transcript expression patterns upon activation. Recent advances in long-read RNA sequencing assays have enabled an unbiased and complete description of transcript isoform expression patterns. With an increasing amount of cell types and conditions that have been analyzed with such assays, thousands of novel transcript isoforms have been identified. Alternative splicing has been associated with autoimmune diseases, including arthritis. Here, GWASs revealed that SNPs associated with arthritis are enriched in splice sites. In this review, we will discuss how alternative splicing is involved in immune responses and how the dysregulation of alternative splicing can contribute to arthritis pathogenesis. In addition, we will discuss the therapeutic potential of modulating alternative splicing, which includes examples of spliceform-based biomarkers for disease severity or disease subtype, splicing manipulation using antisense oligonucleotides, and the targeting of specific immune-related spliceforms using antibodies.

Ferroptosis in Arthritis: Driver of the Disease or Therapeutic Option?

Ferroptosis is a form of iron-dependent regulated cell death caused by the accumulation of lipid peroxides. In this review, we summarize research on the impact of ferroptosis on disease models and isolated cells in various types of arthritis. While most studies have focused on rheumatoid arthritis (RA) and osteoarthritis (OA), there is limited research on spondylarthritis and crystal arthropathies. The effects of inducing or inhibiting ferroptosis on the disease strongly depend on the studied cell type. In the search for new therapeutic targets, inhibiting ferroptosis in chondrocytes might have promising effects for any type of arthritis. On the other hand, ferroptosis induction may also lead to a desired decrease of synovial fibroblasts in RA. Thus, ferroptosis research must consider the cell-type-specific effects on arthritis. Further investigation is needed to clarify these complexities.

Proteomic Profiling of Tears in Blau Syndrome Patients in Identification of Potential Disease Biomarkers.

Blau syndrome (BS) is a rare autoinflammatory granulomatosis characterized by granulomatous arthritis, uveitis, and dermatitis. Ocular complications are particularly severe in BS, significantly contributing to morbidity. This study aims to identify potential biomarkers for BS ocular degeneration through proteomic profiling of tear samples from affected patients. Seven subjects from the same family, including four carriers of the BS-associated NOD2 mutation (p.E383K), were recruited alongside healthy controls. Tear samples were collected using Schirmer strips and analyzed via mass spectrometry. A total of 387 proteins were identified, with significant differences in protein expression between BS patients, healthy familial subjects, and healthy controls. Key findings include the overexpression of alpha-2-macroglobulin (A2M) and immunoglobulin heavy constant gamma 4 (IGHG4) in BS patients. Bioinformatic analysis revealed that differentially expressed proteins are involved in acute-phase response, extracellular exosome formation, and protein binding. Notably, neutrophils' azurophilic granule components, as azurocidin (AZU1), myeloperoxidases (MPO), and defensins (DEFA3), were highly expressed in the most severely affected subject, suggesting a potential role of neutrophils in BS ocular severity. These proteins might be promising biomarkers for ocular involvement in BS, facilitating early detection and tailored treatment strategies.

Exploring the causal association between frailty index with the common types of arthritis: a Mendelian randomization analysis.

BACKGROUND: Previous observational studies indicated a complex association between frailty and arthritis. AIMS: To investigate the genetic causal relationship between the frailty index and the risk of common arthritis. METHODS: We performed a large-scale Mendelian randomization (MR) analysis to assess frailty index associations with the risk of common arthritis in the UK Biobank (UKB), and the FinnGen Biobank. Summary genome-wide association statistics for frailty, as defined by the frailty index, and common arthritis including rheumatoid arthritis (RA), osteoarthritis (OA), psoriatic arthritis (PSA), and ankylosing spondylitis (AS). The inverse-variance weight (IVW) method served as the primary MR analysis. Heterogeneity testing and sensitivity analysis were also conducted. RESULTS: Our results denoted a genetic association between the frailty index with an increased risk of OA, the odds ratio (OR)IVW in the UKB was 1.03 (95% confidence interval [CI]: 1.01-1.05; P = 0.007), and ORIVW was 1.55 (95% CI: 1.16-2.07; P = 0.003) in the FinnGen. For RA, the ORIVW from UKB and FinnGen were 1.03 (1.01-1.05, P = 0.006) and 4.57 (1.35-96.49; P = 0.025) respectively. For PSA, the frailty index was associated with PSA (ORIVW = 4.22 (1.21-14.67), P = 0.023) in FinnGen, not in UKB (P > 0.05). However, no association was found between frailty index and AS (P > 0.05). These results remained consistent across sensitivity assessments. CONCLUSION: This study demonstrated a potential causal relationship that genetic predisposition to frailty index was associated with the risk of arthritis, especially RA, OA, and PSA, not but AS. Our findings enrich the existing body of knowledge on the subject matter.

Posttraumatic Arthritis After Acetabular Fractures.

This article highlights patient, radiographic, and surgical risk factors for the development of posttraumatic arthritis after acetabular fractures. Surgical treatment options including acute and staged total hip arthroplasty as well as outcomes after arthroplasty for fracture management are addressed.

Total Joint Arthroplasty in the Patient with Inflammatory Arthritis: A Review.

Inflammatory arthritis is a family of conditions including rheumatoid arthritis, juvenile inflammatory arthritis, and spondyloarthropathies affecting both the large and small joints. Total joint arthroplasty is commonly used for surgical management of end-stage disease. Preoperative and postoperative considerations as well as perioperative medical management and intraoperative treatment of patients with inflammatory arthritis undergoing total joint arthroplasty are reviewed. Although individualized, multidisciplinary approaches to treatment are necessary due to the complex nature of the disease and the varying levels of severity, patients generally have favorable outcomes with respect to pain scores and functional outcomes.

Management of Index Finger Metacarpophalangeal Joint Arthritis.

Metacarpophalangeal joint arthritis of the index finger is a debilitating disease often caused by osteoarthritis or inflammatory arthritides such as rheumatoid arthritis. Treatment options include nonsurgical management with nonsteroidal anti-inflammatory drugs, splinting, occupational therapy, corticosteroid injections, and disease-modifying antirheumatic drugs. Operative management options include arthrodesis and arthroplasty, which can be further broken down into silicone implants and 2 component resurfacing implants. The article summarizes the current literature for each of the treatment options for metacarpophalangeal joint arthritis of the index finger.

Construction of a highly specific fluorescence "turn-on" probe for H2S detection and imaging in drug-induced live cells, zebrafish and mice arthritis models.

Quantitatively and selectively detecting the biomarker of hydrogen sulfide (H2S) in arthritis diseases is of great significance for the early diagnosis and treatment of arthritis. Modern medical studies show that H2S as a biomarker is involved in the development of inflammation. In this work, a new highly specific fluorescence "turn-on" probe JMD-H2S was tailored for H2S detection and imaging in drug-induced live cells, zebrafish and mice arthritis models, which utilized pyrazoline molecule as the fluorescence signal reporter group and 2,4-dinitrophenyl ether group (DNB) with strong intramolecular charge transfer (ICT) effect as the H2S recognition moiety and fluorescence quenching group. JMD-H2S showed a fast response time (<60 s), a large fluorescence response ratio (enhanced ∼20 folds) at I453/I0, excellent sensitivity toward H2S over other analytes, and an outstanding limit of detection (LOD) as low as 25.3 nM. In addition, JMD-H2S has been successfully applied for detecting and imaging H2S in drug-induced live cells, zebrafish, and mice arthritis models with satisfactory results, suggesting it can be used as a robust molecular tool for investigating the occurrence and development of H2S and arthritis.

Blau syndrome-the skin as a warning sign.

Blau syndrome is an autosomal dominant chronic inflammatory disease, which may begin with skin manifestations in the first months of life, alerting physicians to the diagnosis. This case reports a patient diagnosed jointly by pediatric dermatology and rheumatology consultants at two years of age.

Association between endometriosis and arthritis: results from NHANES 1999-2006, genetic correlation analysis, and Mendelian randomization study.

Background: Previous studies reported that endometriosis may have a higher risk of arthritis. However, it remains unclear whether the association between endometriosis and arthritis has genetic correlations, or the relationship is causal. Linkage Disequilibrium Score (LDSC) and Mendelian Randomization (MR) analyses use genetic variation as a natural experiment to explore genetic correlations and causal inferences from observational data, reducing unmeasured confounding factors. Method: Participants (aged 20-54 years, n = 2,915) for the cross-sectional study were obtained from the National Health and Nutrition Examination Survey (NHANES). Endometriosis and arthritis were diagnosed based on self-reported by reproductive health and medical condition questionnaire. Weighted multivariable logistic regression was used to explore the relationship between endometriosis and arthritis. LDSC and MR analysis were performed using the genome-wide association study (GWAS) summary statistics to identify the causal association. Result: A significant positive association between endometriosis and arthritis was found after multivariable adjustment (OR = 1.89; 95% CI: 1.33, 2.67). When exploring different types of arthritis, a positive association was revealed with rheumatoid arthritis (RA), other types of arthritis, and cases that the arthritis type were unknown, with an OR of 2.07 (95% CI: 1.03, 4.17), 2.78 (95% CI: 1.30, 5.95), and 2.06 (95% CI: 1.36, 3.11), respectively. However, genetic correlation analysis between endometriosis and RA did not reveal any significant findings (all P values > 0.05). Moreover, MR analysis also failed to identify a causal relationship between endometriosis and RA (all P values > 0.05). Conclusion: Cross-sectional study identified a significant positive association between endometriosis and arthritis among US women, especially among RA, while findings based on LDSC and MR analysis did not support a genetic correlation or causal role. These findings suggest that clinicians should pay more attention to the coexistence of RA in endometriosis patients and explore the shared pathophysiological mechanisms of these two disorders, with a particular focus on extrinsic factors rather than intrinsic genetic inheritance.

Total ankle arthroplasty improves discrete and continuous stance phase gait symmetry.

BACKGROUND: Total ankle arthroplasty (TAA) is used to treat symptomatic end-stage ankle arthritis (AA). However, little is known about TAA's effects on gait symmetry. RESEARCH QUESTION: Determine if symmetry changes from before surgery through two years following TAA utilizing the normalized symmetry index (NSI) and statistical parametric mapping (SPM). METHODS: 141 patients with end-stage unilateral AA were evaluated from a previously collected prospective database, where each participant was tested within two weeks of surgery (Pre-Op), one year and two years following TAA. Walking speed, hip extension angle and moment, hip flexion angle, ankle plantarflexion angle and moment, ankle dorsiflexion angle, weight acceptance (GRF1), and propulsive (GRF2) vertical ground reaction forces were calculated for each limb. Gait symmetry was assessed using the NSI. A linear mixed effects model with a single response for each gait symmetry variable was used to examine the fixed effect of follow-up time (Pre-Op, Post-1 yr, Post-2 yr) and the random effect of participant with gait speed as a covariate in the model. A one-dimensional repeated measures analysis of variance (ANOVA) statistical parameter mapping (SPM) was completed to examine differences in the time-series NSI to determine regions of significant differences between follow-up times. RESULTS: Relative to Pre-Op values, GRF1, and GRF2 showed increased symmetry for discrete metrics and the time-series NSI across sessions. Hip extension moment had the largest symmetry improvement. Ankle plantarflexion angle was different between Pre-Op and Post-2 yr (p=0.010); and plantarflexion moment was different between Pre- Op and each post-operative session (p<0.001). The time-series Ankle Angle NSI was greater during the early stance phase in the Pre-Op session compared to Post-2 yr. SIGNIFICANCE: Symmetry across most of the stance phase improved following TAA indicating that TAA successfully improves gait symmetry and future work should determine if these improvements restore symmetry to levels equivalent with health age-match controls.

Integrating ADMET, enrichment analysis, and molecular docking approach to elucidate the mechanism of Artemisia herba alba for the treatment of inflammatory bowel disease-associated arthritis.

Inflammatory Bowel Disease-Associated Arthritis (IBD-associated arthritis) poses a significant challenge, intertwining the complexities of both inflammatory bowel disease (IBD) and arthritis, significantly compromising patient quality of life. While existing medications offer relief, these drugs often initiate adverse effects, necessitating the requirement for safer therapeutic alternatives. Artemisia herba-alba, a traditional medicinal plant known for its anti-inflammatory properties, emerges as a potential candidate. Our computational study focused on examining 20 bioactive compounds derived from A. herba-alba for potential treatment of IBD-associated arthritis. These compounds detected in A. herba-alba include camphor, alpha-thujone, eucalyptol, cis-chrysanthenyl acetate, vicenin-2, 4,5-di-O-caffeoylquinic acid, chlorogenic acid, hispidulin, isoschaftoside, isovitexin, patuletin-3-glucoside, vanillic acid, rutin, schaftoside, lopinavir, nelfinavir, quercetin, artemisinin, gallic acid, and cinnamic acid. Following rigorous analysis encompassing pharmacokinetics, toxicity profiles, and therapeutic targets, compounds with favorable, beneficial characteristics were identified. In addition, comparative analysis with disease-gene associations demonstrated the interconnectedness of inflammatory pathways across diseases. Molecular docking studies provided mechanistic insights indicating this natural plant components potential to modulate critical inflammatory pathways. Overall, our findings indicate that A. herba-alba-derived compounds may be considered as therapeutic agents for IBD-associated arthritis, warranting further experimental validation and clinical exploration.

Differential interplay between multimorbidity patterns and frailty and their mutual mediation effect on mortality in old age.

BACKGROUND: Multimorbidity and frailty often concurrently occur among older adults. OBJECTIVES: To assess the reciprocal association between multimorbidity (condition count and patterns) and frailty and examine the mutual mediation effect of multimorbidity and frailty in their associations with mortality among Chinese older adults. METHODS: This nationwide population-based longitudinal study included 16,563 participants aged ≥65 years in the Chinese Longitudinal Healthy Longevity Survey who were surveyed in 2008 and followed up in 2011, 2014, and 2018. Frailty phenotype was assessed by the modified Fried criteria and vital status was ascertained from family members. Cross-lagged panel model (CLPM) was used to test bidirectional associations between multimorbidity and frailty. The direct and indirect effects of multimorbidity and frailty on mortality were evaluated using the combined CLPM with survival analysis. RESULTS: Three multimorbidity patterns were identified: cardiometabolic diseases, cognitive-sensory disorder, and arthritis-digestive-respiratory diseases. The number of chronic conditions and cognitive-sensory disease pattern showed bidirectional associations with frailty across waves (range for ß: 0.046-0.109; all P < 0.001), while cardiometabolic and arthritis-digestive-respiratory patterns unidirectionally predicted frailty change. Furthermore, frailty mediated 23%-27% of the association between multimorbidity and mortality. Only the number of conditions and cognitive-sensory disease pattern were significant mediators in the association between frailty and mortality, with the proportion of mediation ranging 4%-12%. CONCLUSIONS: Multimorbidity measures including condition count and cognitive-sensory disease pattern are bi-directionally associated with frailty in older adults. These multimorbidity measures and frailty partially mediated each other's association with mortality, with frailty acting as a more prominent pathway in the association between multimorbidity and mortality.

Significant others in inflammatory arthritis: roles, influences, and challenges-a scoping review.

Improving self-management in individuals with inflammatory arthritis (IA) is crucial for effective disease management. However, current recommendations primarily focus on interventions for the diagnosed individuals, overlooking the potential impact of their significant others on their self-management abilities. This review aims to fill this gap by identifying and mapping relevant research employing both qualitative and quantitative design to provide a broader understanding of the potential of significant others in relation to IA management. We examined studies published from 2007 to 2024 that explore our research questions using electronic databases and grey literature searches. Two independent reviewers meticulously screened and categorized the studies based on a developed framework employing basic content analysis. Out of 20.925 studies, 43 were included: 22 quantitative studies (including 1 educational trial), 20 qualitative studies, and 1 mixed-methods study. Our analysis of the included studies revealed that significant others predominantly provided practical and emotional support and could positively or negatively influence the person with IAs self-management abilities. Additionally, significant others reported their own feelings of emotional distress and expressed the need for knowledge, skills and social support enabling them to provide better support while taking care of them self. Greater focus on the significant others of those diagnosed with IA in their provision of support to this patient group may both improve the people with IA self-management skills and address significant others' reported needs. Future studies should explore the impact of such initiatives through randomized controlled trials.

A getah virus-like-particle vaccine provides complete protection from viremia and arthritis in wild-type mice.

Getah virus (GETV) is an emerging mosquito-borne virus with economic impact on the livestock industry in East Asia. In this study, we successfully produced GETV virus-like particles (VLPs) in insect cells using the baculovirus expression vector system. We show that the GETV envelope glycoproteins were successfully expressed at the surface of the insect cell and were glycosylated. VLPs were isolated from the culture fluid as enveloped particles of 60-80 nm in diameter. Two 1 µg vaccinations with this GETV VLP vaccine, without adjuvant, generated neutralizing antibody responses and protected wild-type C57/BL6 mice against GETV viremia and arthritic disease. The GETV VLP vaccine may find application as a horse and/or pig vaccine in the future.

Sarcoidosis Presenting as Granulomatous Mastitis, Erythema Nodosum, and Arthritis Syndrome: A Case Report and Comprehensive Review of the Literature.

Granulomatous mastitis (GM) is a long-term inflammatory disease of the breast that usually occurs in women of reproductive age. Autoimmune mastitis is one of the most common pathological breast conditions necessitating tailored treatment. However, GM as a first clinical manifestation of sarcoidosis is uncommon. Simultaneous occurrence of GM, erythema nodosum (EN), and arthritis, termed "GMENA" syndrome, is a rare clinical entity associated with autoimmune rheumatic diseases. Herein, we report the case of a 31-year-old female patient with GMENA syndrome, who presented with a painful nodule of the left breast. Initial treatment entailed antibiotics under the presumption of a breast abscess, yielding negligible improvement. During this period, the patient developed polyarthritis and bilateral EN on the lower extremities. Histopathologic examination of the breast tissue exhibited noncaseating granulomas. The patient responded positively to prednisolone and methotrexate treatment. Literature review revealed a coherent pattern across GMENA cases. Our findings suggest that the "GMENA" syndrome represents a unique acute manifestation of sarcoidosis and highlight the necessity for heightened awareness, accurate diagnosis, and tailored therapeutic approaches for GMENA syndrome. Further research is warranted to elucidate its cause and optimize patient management. This case highlights the importance of identifying and effectively managing such interrelated clinical presentations.