Diagnosis Of RA Research Articles

Identification of clinical characteristics biomarkers for rheumatoid arthritis through targeted DNA methylation sequencing

ObjectivesRheumatoid arthritis (RA) is a complex disease with a challenging diagnosis, especially in seronegative patients. The aim of this study is to investigate whether the methylation sites associated with the overall immune response in RA can assist in clinical diagnosis, using targeted methylation sequencing technology on peripheral venous blood samples. MethodsThe study enrolled 241 RA patients, 30 osteoarthritis patients (OA), and 30 healthy volunteers control (HC). Fifty significant cytosine guanine (CG) sites between undifferentiated arthritis and RA were selected and analyzed using targeted DNA methylation sequencing. Logistic regression models were used to establish diagnostic models for different clinical features of RA, and six machine learning methods (logit model, random forest, support vector machine, adaboost, naive bayes, and learning vector quantization) were used to construct clinical diagnostic models for different subtypes of RA. Least absolute shrinkage and selection operator regression and detrended correspondence analysis were utilized to screen for important CGs. Spearman correlation was used to calculate the correlation coefficient. ResultsThe study identified 16 important CG sites, including tumor necrosis factort receptor associated factor 5 (TRAF5) (chr1:211500151), mothers against decapentaplegic homolog 3 (SMAD3) (chr15:67357339), tumor endothelial marker 1 (CD248) (chr11:66083766), lysosomal trafficking regulator (LYST) (chr1:235998714), PR domain zinc finger protein 16 (PRDM16) (chr1:3307069), A-kinase anchoring protein 10 (AKAP10) (chr17:19850460), G protein subunit gamma 7 (GNG7) (chr19:2546620), yes1 associated transcriptional regulator (YAP1) (chr11:101980632), PRDM16 (chr1:3163969), histone deacetylase complex subunit sin3a (SIN3A) (chr15:75747445), prenylated rab acceptor protein 2 (ARL6IP5) (chr3:69134502), mitogen-activated protein kinase kinase kinase 4 (MAP3K4) (chr6:161412392), wnt family member 7A (WNT7A) (chr3:13895991), inhibin subunit beta B (INHBB) (chr2:121107018), deoxyribonucleic acid replication helicase/nuclease 2 (DNA2) (chr10:70231628) and chromosome 14 open reading frame 180 (C14orf180) (chr14:105055171). Seven CG sites showed abnormal changes between the three groups (P < 0.05), and 16 CG sites were significantly correlated with common clinical indicators (P < 0.05). Diagnostic models constructed using different CG sites had an area under the receiver operating characteristic curve (AUC) range of 0.64–0.78 for high-level clinical indicators of high clinical value, with specificity ranging from 0.42 to 0.77 and sensitivity ranging from 0.57 to 0.88. The AUC range for low-level clinical indicators of high clinical value was 0.63–0.72, with specificity ranging from 0.48 to 0.74 and sensitivity ranging from 0.72 to 0.88. Diagnostic models constructed using different CG sites showed good overall diagnostic accuracy for the four subtypes of RA, with an accuracy range of 0.61–0.96, a balanced accuracy range of 0.46–0.94, and an AUC range of 0.46–0.94. ConclusionsThis study identified potential clinical diagnostic biomarkers for RA and provided novel insights into the diagnosis and subtyping of RA. The use of targeted deoxyribonucleic acid (DNA) methylation sequencing and machine learning methods for establishing diagnostic models for different clinical features and subtypes of RA is innovative and can improve the accuracy and efficiency of RA diagnosis.

Rheumatoid Arthritis Is Not a Contraindication to Unicompartmental Knee Arthroplasty

BackgroundRheumatoid arthritis (RA) has historically been considered a contraindication for unicompartmental knee arthroplasty (UKA). However, the widespread use of disease-modifying antirheumatic drugs has substantially improved the management of RA and prevented disease progression. The objective of this study was to ascertain whether RA impacts UKA revision-free survivorship. MethodsPatients undergoing UKA from 2010 to 2021 were identified in an administrative claims database (n = 105,937) using Current Procedural Terminology code 27446. All patients who underwent UKA who had a diagnosis of RA with a minimum of 2-year follow-up (n = 1,422) were propensity score matched based on age, sex, and Elixhauser Comorbidity Index to those who did not have RA (n = 1,422). Laterality was identified using the 10th Revision of International Classification of Diseases codes. The primary outcome was ipsilateral revision to total knee arthroplasty (TKA) within 2 years, and the secondary outcome was ipsilateral revision at any time. ResultsAmong the 1,422 patients who had a UKA and a diagnosis of RA, 37 patients (2.6%) underwent conversion to TKA within 2 years, and 48 patients (3.4%) underwent conversion to TKA at any point. In comparison, 28 patients (2.0%) in the propensity-matched control group underwent conversion to TKA within 2 years, and 40 patients (2.8%) underwent conversion to TKA at any point. Statistical analysis revealed no significant difference in conversion to TKA between patients who had and did not have RA, either within 2 years (P = .31) or anytime (P = .45). ConclusionsPatients who had RA and underwent UKA did not have an increased risk of revision to TKA compared to those who did not have RA. This may indicate that modern management of RA could allow for expanded UKA indications for RA patients.

Comprehensive analysis revealed the immunoinflammatory targets of rheumatoid arthritis based on intestinal flora, miRNA, transcription factors, and RNA-binding proteins databases, GSEA and GSVA pathway observations, and immunoinfiltration typing

ObjectiveRheumatoid arthritis (RA) is a chronic inflammatory arthritis. This study aimed to identify potential biomarkers and possible pathogenesis of RA using various bioinformatics analysis tools.MethodsThe GMrepo database provided a visual representation of the analysis of intestinal flora. We selected the GSE55235 and GSE55457 datasets from the Gene Expression Omnibus database to identify differentially expressed genes (DEGs) separately. With the intersection of these DEGs with the target genes associated with RA found in the GeneCards database, we obtained the DEGs targeted by RA (DERATGs). Subsequently, Disease Ontology, Gene Ontology, and the Kyoto Encyclopedia of Genes and Genomes were used to analyze DERATGs functionally. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were performed on the data from the gene expression matrix. Additionally, the protein-protein interaction network, transcription factor (TF)-targets, target-drug, microRNA (miRNA)-mRNA networks, and RNA-binding proteins (RBPs)-DERATGs correlation analyses were built. The CIBERSORT was used to evaluate the inflammatory immune state. The single-sample GSEA (ssGSEA) algorithm and differential analysis of DERATGs were used among the infiltration degree subtypes.ResultsThere were some correlations between the abundance of gut flora and the prevalence of RA. A total of 54 DERATGs were identified, mainly related to immune and inflammatory responses and immunodeficiency diseases. Through GSEA and GSVA analysis, we found pathway alterations related to metabolic regulations, autoimmune diseases, and immunodeficiency-related disorders. We obtained 20 hub genes and 2 subnetworks. Additionally, we found that 39 TFs, 174 drugs, 2310 miRNAs, and several RBPs were related to DERATGs. Mast, plasma, and naive B cells differed during immune infiltration. We discovered DERATGs’ differences among subtypes using the ssGSEA algorithm and subtype grouping.ConclusionsThe findings of this study could help with RA diagnosis, prognosis, and targeted molecular treatment.

Patient burden and joint inflammation during development of RA from arthralgia: is it similar in ACPA-positive and ACPA-negative disease?

ACPA-positive and ACPA-negative RA differ in underlying risk factors but have a similar clinical presentation at RA diagnosis. It is unknown what the ACPA-associated differences or similarities are during the symptomatic at-risk stage of RA, i.e. clinically suspect arthralgia (CSA). To deepen insights into these differences/similarities, we compared the course of symptoms/impairments and subclinical joint inflammation in the CSA phase during progression to inflammatory arthritis (IA) or to CSA resolution. A total of 845 CSA patients were followed for a median of 24 months; 136 patients developed IA and an additional 355/505 patients had resolution of CSA according to rheumatologists. Patient burden (pain, morning stiffness, fatigue, functional disabilities, presenteeism) was assessed at baseline and 4, 12 and 24 months and at IA development. Subclinical joint inflammation in the hands and feet was assessed over time with 1.5T MRI. Linear and Poisson mixed models were used. In both ACPA-positive and ACPA-negative patients, patient burden increased towards IA development and decreased towards CSA resolution. However, patient burden was lower in ACPA-positive vs ACPA-negative disease at all timepoints. Conversely, subclinical joint inflammation tended to increase more rapidly during development of ACPA-positive IA [incidence rate ratio (IRR) 1.52 (95% CI 0.94, 2.47), P = 0.089] and remained higher over time in ACPA-positive CSA patients achieving resolution compared with ACPA-negative patients [IRR 1.52 (95% CI 1.07, 2.15), P = 0.018]. Although correlation coefficients between changes in patient burden and subclinical joint inflammation during progression to IA were weak, they were consistently higher in ACPA-positive than ACPA-negative disease, e.g. ρ = 0.29 vs 0.12 for functional disabilities. During RA development and CSA resolution, ACPA-positive CSA patients have lower patient burden but more subclinical joint inflammation than ACPA-negative CSA patients. These data strengthen the notion that the development of ACPA-positive and ACPA-negative RA is pathophysiologically different and encourage further research on these differences.

Efficacy and safety of the modified Zhiwang decoction combined with methotrexate in early rheumatoid arthritis: study protocol for a randomised controlled trial

IntroductionRheumatoid arthritis (RA) is a progressive inflammatory autoimmune disease characterised by chronic systemic inflammation, which can cause swelling, stiffening and destruction of articular cartilage and bone. Early diagnosis and treatment...

Identification of diagnostic genes and drug prediction in metabolic syndrome-associated rheumatoid arthritis by integrated bioinformatics analysis, machine learning, and molecular docking.

Interactions between the immune and metabolic systems may play a crucial role in the pathogenesis of metabolic syndrome-associated rheumatoid arthritis (MetS-RA). The purpose of this study was to discover candidate biomarkers for the diagnosis of RA patients who also had MetS. Three RA datasets and one MetS dataset were obtained from the Gene Expression Omnibus (GEO) database. Differential expression analysis, weighted gene co-expression network analysis (WGCNA), and machine learning algorithms including Least Absolute Shrinkage and Selection Operator (LASSO) regression and Random Forest (RF) were employed to identify hub genes in MetS-RA. Enrichment analysis was used to explore underlying common pathways between MetS and RA. Receiver operating characteristic curves were applied to assess the diagnostic performance of nomogram constructed based on hub genes. Protein-protein interaction, Connectivity Map (CMap) analyses, and molecular docking were utilized to predict the potential small molecule compounds for MetS-RA treatment. qRT-PCR was used to verify the expression of hub genes in fibroblast-like synoviocytes (FLS) of MetS-RA. The effects of small molecule compounds on the function of RA-FLS were evaluated by wound-healing assays and angiogenesis experiments. The CIBERSORT algorithm was used to explore immune cell infiltration in MetS and RA. MetS-RA key genes were mainly enriched in immune cell-related signaling pathways and immune-related processes. Two hub genes (TYK2 and TRAF2) were selected as candidate biomarkers for developing nomogram with ideal diagnostic performance through machine learning and proved to have a high diagnostic value (area under the curve, TYK2, 0.92; TRAF2, 0.90). qRT-PCR results showed that the expression of TYK2 and TRAF2 in MetS-RA-FLS was significantly higher than that in non-MetS-RA-FLS (nMetS-RA-FLS). The combination of CMap analysis and molecular docking predicted camptothecin (CPT) as a potential drug for MetS-RA treatment. In vitro validation, CPT was observed to suppress the cell migration capacity and angiogenesis capacity of MetS-RA-FLS. Immune cell infiltration results revealed immune dysregulation in MetS and RA. Two hub genes were identified in MetS-RA, a nomogram for the diagnosis of RA and MetS was established based on them, and a potential therapeutic small molecule compound for MetS-RA was predicted, which offered a novel research perspective for future serum-based diagnosis and therapeutic intervention of MetS-RA.

Immunomodulatory effect of Tityus sp. in mononuclear cells extracted from the blood of rheumatoid arthritis patients.

Pathophysiological mechanisms of rheumatoid arthritis arise because of a proinflammatory environment, generated by the interaction of autoreactive lymphocytes and proinflammatory mediators. Current strategies to mitigate the progression of the disease produce adverse effects, so there is a need for new therapeutic strategies and molecular targets to treat this disease. In this context, evidence suggests that scorpion venoms could modulate the immune response and some important cellular mechanisms of pharmacological interest. To evaluate the immunomodulatory effect of the venom of Tityus sp. (a possible new species close to Tityus metuendus) peripheral blood mononuclear cells of women diagnosed with RA were compared to cells of a control group. A case-control study was conducted with a sample of 10 women with a confirmed diagnosis of RA and controls matched by sex and age. The cytotoxicity of the venom was evaluated to find sublethal concentrations of the venom, and subsequently, their immunomodulatory capacity in terms of percentage of proliferation, cell activation, and cytokines production. the venom of Tityus sp. produced a decrease in the percentage of proliferation in the CD3+, CD3+CD4+, and CD3+CD8+ cell subpopulations of RA patients and healthy controls, at concentrations of 252 and 126 µg/mL. However, the venom did not induce significant differences in the percentage of cell activation markers. The venom caused a decrease in IL-10 at a concentration of 252 µg/mL compared to untreated cells from patients and controls. The remaining cytokines did not show significant differences. the venom of Tityus sp. is a potential source of molecules with immunomodulatory ability in CD4 and CD8 T lymphocytes. This result directs venom characterization studies to identify pharmacological targets with immunomodulatory capacity in T lymphocytes to enhance research in the treatment of autoimmune disorders such as RA.

Galectin-3 and its correlation with carotid ultrasound in rheumatoid arthritis patients

BackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease resulting in disability as well as joint damage. Early diagnosis and treatment are crucial for improving outcomes. RA patients have a twofold elevated risk of cardiovascular disease (CVD) development compared to the general population. Carotid ultrasound is a noninvasive imaging modality that can detect early signs of atherosclerosis and plaque buildup in the carotid arteries, which are strongly associated with CVD risk. Galectin-3 (Gal-3), a protein involved in inflammation and fibrosis, is suggested as one of the potential RA markers. Despite the growing interest in galectin-3 as a biomarker for CVD, few studies have investigated its role in RA patients. To our knowledge, only two studies have examined the correlation between galectin-3 and CVD in RA patients, and they have yielded conflicting results. This study aimed to determine the serum level of Gal-3 as well as its correlation with carotid ultrasound assessment for cardiovascular involvement in RA patients.ResultsRA cases demonstrated substantially elevated Gal-3 levels than controls (P < 0.001), and a 3.38 pg/mL cut-off value was proven to be an excellent predictor of RA diagnosis (AUC, 0.98). Gal-3 levels were proven to be positively associated with DAS-28, Larsen score, and carotid intima-media thickness (CIMT) (P-value 0.006, 0.026, < 0.001, respectively). A positive association was also detected between right (RT) and left (LT) CIMT and disease duration (P-values of 0.040 and 0.042, respectively).ConclusionsGal-3 is a biomarker for RA that is not only associated with activity and severity of the disease but it is also related to the chronicity of the disease and is a predictor of cardiovascular comorbidity.

Screening of Cognitive Impairment in patients with Rheumatoid arthritis

AbstractBackgroundRheumatoid arthritis (RA) is a chronic inflammatory disease that affects 0.5‐1% of the population, mainly women and older adults. There is increasing evidence of the presence of cognitive impairment in patients with RA, with a prevalence of around 30%. Some underlying mechanisms involved could be inflammation within the brain, high cardiovascular comorbidity, and the use of immunosuppressive agents that can be neurotoxic with prolonged use, among others. The Montreal Cognitive Assessment (MoCA) is a validated tool for detecting cognitive impairment in our country. The objective of this study is to determine the frequency of cognitive impairment in patients with RA compared to a group of patients with osteoarthritis.MethodWe assessed adult patients diagnosed with RA (2010 ACR/EULAR criteria) and osteoarthritis (ACR criteria) according to selection criteria. Demographic and clinical data were collected. The MoCA test was administered to all patients considering the cut‐off value &lt;26 points to define the presence of cognitive impairment. The study was approved by the institutional ethics and research committee.ResultA total of 60 patients were included: 40 with RA (G1) and 20 with osteoarthritis (G2), the majority being women in both groups, mean age was 66.9 (SD 11.7) years and 71.4 (SD 10.6) years, respectively. There were no statistically significant differences in education, socioeconomic status, or vascular risk factors among groups. The frequency of cognitive impairment was significantly higher in G1 compared to G2: 42.5% (95% CI 28‐58.5) versus 15% (95% CI 4‐40)(p 0.026). Regarding MoCA domains, attention and memory were more affected in G1 compared to G2. In the multivariate analysis, the diagnosis of RA and older age were factors significantly associated with cognitive impairment.ConclusionIn our RA population, the frequency of cognitive impairment was 42.5%. RA diagnosis and older age were factors related to cognitive impairment. A substantial number of patients and the administration of a standard neuropsychological test will help us to validate these results.

Effectiveness and tolerability of antifibrotics in rheumatoid arthritis-associated interstitial lung disease

ObjectiveOur aim was to investigate the effectiveness and tolerability of antifibrotics in a real-world cohort of patients with rheumatoid arthritis-associated interstitial lung diseases (RA-ILD). MethodsIn this retrospective cohort study, we identified RA-ILD patients initiating antifibrotics at Mass General Brigham Integrated Health Care System, a large multi-hospital healthcare system in Boston, MA, USA. We used electronic query to identify all patients with at least 2 RA diagnosis codes and a prescription for either nintedanib or pirfenidone (2014–2023). All analyzed patients met 2010 American College of Rheumatology/European Alliance of Associations for Rheumatology classification criteria for RA and had definite RA-ILD according to Bongartz criteria. Data regarding pulmonary function test (PFT) results, adverse events (AEs), tolerability, and clinical data were collected. A linear mixed model with random intercept was used to compare the within-patient trajectory of the percent predicted forced vital capacity (FVCpp) within 18-months before to 18-months after antifibrotic initiation among those with these PFT data. Lung transplant-free survival and drug retention was estimated in a Kaplan-Meier analysis and a Cox regression analysis was performed to identify independent baseline factors associated with lung transplant or mortality. ResultsWe analyzed 74 patients with RA-ILD that initiated antifibrotics (mean age 67.8 years, 53 % male); 40 patients initiated nintedanib and 34 initiated pirfenidone. Median follow-up was 89 weeks (min 4, max 387). There was a significant improvement in the estimated slope of FVCpp after antifibrotic initiation (−0.3 % per year after initiation compared to −6.2 % per year before antifibrotic initiation, p = 0.03). Nintedanib and pirfenidone had similar FVCpp trajectory. Twenty-six patients (35 %) died and 4 (5 %) had undergone lung transplantation during follow-up. Male sex and heavy smoking were each associated with the composite outcome of lung transplant or mortality. AEs were reported in 41 (55 %) patients, with gastrointestinal (GI) AEs being most common (n = 30). The initial antifibrotic was discontinued in 34 (46 %) patients mostly due to GI AEs (n = 19). The median drug retention time was 142 weeks (95 %CI 56, 262) with no difference between nintedanib and pirfenidone (p = 0.68). ConclusionIn this first real-world study of antifibrotic use dedicated to RA-ILD, antifibrotic initiation was associated with a modestly improved trajectory of FVCpp. AEs were frequently reported, particularly GI, and discontinuation was common. However, lung transplant and mortality rates were still high, emphasizing the need for further therapeutic strategies in patients with severe RA-ILD. These real-world data complement previous trial data that investigated efficacy and safety.

Exploring the differences in serum metabolite profiles after intake of red meat in women with rheumatoid arthritis and a matched control group

PurposeStudies have suggested that women with RA tend to avoid red meat more often than women without RA, based on their perception that it exacerbates their symptoms. Therefore, the aim of this study is to investigate and compare the postprandial metabolic response following the consumption of a red meat meal in patients with RA and a matched control group.MethodsParticipants were challenged with a meal with red meat and blood samples were collected before and at 0.5, 1, 2, 3 and 5 h after the meal. Serum metabolites were quantified by Nuclear Magnetic Resonance (NMR) analysis. Orthogonal Projections to Latent Structures with Discriminant Analysis (OPLS-DA) was used to evaluate separation by metabolites due to diagnosis of RA or not and to identify changes in metabolites related to RA. Incremental area under the curve was calculated for univariate comparisons for 23 metabolites.ResultsThe matched groups, including 22 women with RA and 22 women without RA, did not differ significantly in age, body mass index, diet quality or reported physical activity. OPLS-DA models had a limited quality indicating that there were no differences in metabolite patterns between the groups. However, phenylalanine was significantly higher in concentration in women with RA compared to controls in both fasting and postprandial samples.ConclusionTo conclude, this well-controlled postprandial intervention study found a significantly higher concentration of phenylalanine in both fasting and postprandial samples of women with RA compared to matched women without RA. These findings warrant further investigation in larger studies.Trial registrationThe PIRA (Postprandial Inflammation in Rheumatoid Arthritis) trial is Registered at Clinicaltrials.gov (NCT04247009).

P25 TB or not TB? An unusual case of inflammatory arthritis in an anti-CCP positive patient

P25 TB or not TB? An unusual case of inflammatory arthritis in an anti-CCP positive patient

B-103 A Single Centre Experience of Anti-carbamylated Protein Antibody Testing in the Routine Evaluation of Rheumatoid Arthritis

Abstract Background Rheumatoid arthritis (RA) early diagnosis and treatment can slow disease progression and potentially prevent bone erosion. Anticyclic citrullinated peptide (CCP) IgG and rheumatoid factors (RF) serological testing supports the diagnosis of RA; however, these markers are not detected in about 20% of RA patients. Recently, IgG antibodies against carbamylated proteins (CarP) emerged with implications on preclinical RA diagnosis and disease severity. CarP testing is offered as part of RA panel (CarP, RF and CCP) and as a standalone test in our institution. In this study, we evaluated the contribution of CarP testing for RA diagnosis in our routine clinical practice. Our objectives were 1) to assess the clinical performance of CarP in combination with CCP and/or RF antibodies 2) to understand the association of CarP with disease severity. Methods Our cohort included 331 subjects submitted for RA panel serology. Retrospective chart-review revealed 136 clinically defined RA-positive and 195 RA-negative patients. Patients’ sera were tested for CCP, CarP (Inova Diagnostics, San Diego, US) and RF (Roche Diagnostics, Indianapolis, US) antibodies. Clinical performance characteristics were evaluated for CarP individually and in combination with CCP and RF. Disease manifestations (bone damage and synovitis), were correlated with CarP testing. Results Single antibody testing for CarP differentiated RA patients from disease-controls with a 27.2% sensitivity, 93.3% specificity, 74.0% positive predictive value and 64.8% negative predictive value. When CarP testing was combined with RF, specificity increased to 95.4%, in combination with CCP it increased to 98.5% and in a triple combination with CCP and RF, specificity increased to 99.5%. The specificity observed in CCP and RF combination (98.5%) was equivalent to CCP and CarP combination or CCP, CarP and RF triple combination. Amongst the RA patients, frequency of bone erosions was slightly greater (P = 0.76) in the presence of CarP positivity (19/37, 51.4%) compared to the presence of CCP (51/107, 47.7%) or RF (50/112, 44.6%) positivity in isolation and/or in combination. Frequency of synovitis was higher in RA patients that tested positive for CarP (20/37, 54.1%) compared to patients who tested positive for CCP (44/107, 41.1%) or RF (43/112, 38.4%). In the seronegative subgroup, 17.2% (5/29) of CCP negative and 14.3% (3/21) of RF negative patients were positive for CarP. Six out of 8 patients in this subgroup displayed bone erosions and/or synovitis. Of the early RA- diagnosed patients (&amp;lt; 6 months of symptom onset), 22.2% (2/9) were CarP positive, of which one patient (11.1%) was seronegative for CCP but positive for RF. Conclusion Despite low sensitivity, individual CarP testing offered a specificity comparable to CCP. In combination with CCP and/or RF, CarP displayed a superior specificity compared to any individual testing, however, was inferior to the CCP and RF combination. CarP positivity independently and/or in combination was associated with a severe disease course. These data support the use of CarP in combination with CCP and RF for assessing disease severity but may not be advantageous for initial diagnosis. In CCP or RF seronegative patients, CarP testing may be beneficial in establishing a diagnosis of RA.

A serum metabolic biomarker panel for early rheumatoid arthritis.

There is an urgent need for novel biomarkers to improve the early diagnosis of rheumatoid arthritis (ERA). Current serum biomarkers used in the management of ERA, including rheumatoid factor and anti-cyclic citrullinated peptide (ACPA), show limited specificity and sensitivity. Here, we used metabolomics to uncover new serum biomarkers of ERA. We applied an untargeted metabolomics approach including gas chromatography time-of-flight mass spectrometry in serum samples from an ERA cohort (n=32) and healthy controls (n=19). Metabolite set enrichment analysis was performed to explore potentially important biological pathways. Partial least squares discriminant analysis and variable importance in projection analysis were performed to construct an ERA biomarker panel. Significant differences in the content of 11/81 serum metabolites were identified in patients with ERA. Receiver operating characteristic (ROC) analysis showed that a panel of only three metabolites (glyceric acid, lactic acid, and 3-hydroxisovaleric acid) could correctly classify 96.7% of patients with ERA, with an area under the ROC curve of 0.963 and with 94.4% specificity and 93.5% sensitivity, outperforming ACPA-based diagnosis by 2.9% and, thus, improving the preclinical detection of ERA. Aminoacyl-tRNA biosynthesis and serine, glycine, and phenylalanine metabolism were the most significant dysregulated pathways in patients with ERA. A metabolomics serum-based biomarker panel composed of glyceric acid, lactic acid, and 3-hydroxisovaleric acid offers potential for the early clinical diagnosis of RA.

Neutrophil- and Platelet-to-Lymphocyte Ratios (NLR &amp; PLR) and Their Relation with Disease Activity in Rheumatoid Arthritis Patients

Abstract Background RA is the most common chronic inflammatory arthritis and is associated with progressive destruction of synovial joints and physical disability. It is a polygenic disease characterized by autoimmunity and systemic inflammation with progressive impairment of the joints, resulting in lifelong disability and increased mortality. Aim of the Work The aim of the study is to study the correlation between both of Neutrophil- and platelet-to-lymphocyte ratios (NLR&amp;PLR) and disease activity in RA patients. Patients and Methods Our cross-sectional case-control study enrolled 50 patients with RA, in addition to 30 healthy volunteers as a control group.All included patients were subjected to full history taking with special emphasis on history of RA, thorough clinical examination was done with special emphasis on musculoskeletal examination. Results When we compared RA patients with the controls, we found a highly statistically significant difference between them regarding NLR and PLR being higher in the RA group. In our study we found that both NLR and PLR has fair diagnostic value to discriminate between RA patients and controls using the ROC curve at a cut-off value of 2.58 and 151.05 respectively. In RA patients, highly statistically significant correlation was found between both NLR and PLR. In addition, statistically significant correlation was found between NLR with both VAS score and DAS28_ESR and also between PLR with ESR, VAS score and RF.PLR also correlated significantly with US7 score, PDUS synovitis and gray GSUS tenosynovitis. Conclusion NLR and PLR that can be obtained via CBC (which is convenient, inexpensive and fast), can serve as an additional useful marker for the diagnosis of RA. NLR and PLR has important value in the assessment of RA related disease activity. In contrast to traditional markers, they are less expensive and effective measure of inflammation that is not impacted by the cytokines influencing the ESR and CRP. US7 score is a simple and effective measure to detect subclinical synovitis in RA patients and to assess and follow up disease activity.

Rheumatoid arthritis specific autoimmunity in the lung before and at the onset of disease.

The lung is implicated as a site for breaching tolerance prior to onset of seropositive RA. To substantiate this, we have investigated lung-resident B cells in bronchoalveolar lavage (BAL) samples from early untreated RA patients (n=9) and anti-citrullinated protein antibody (ACPA)-positive individuals at risk of developing RA (n=3). Single B cells (n=7680) were phenotyped and isolated from BAL of individuals during the risk-RA phase and at RA diagnosis. The Immunoglobulin variable region transcripts were sequenced and selected for expression as monoclonal antibodies (n=141). Monoclonal ACPAs were tested for reactivity patterns and binding to neutrophils. By our single cell approach, we found significantly increased proportions of B lymphocytes in autoantibody-positive as compared to negative individuals. Memory and double negative (DN) B cells were prominent in all subgroups. Upon antibody re-expression, seven highly mutated citrulline autoreactive clones originating from different memory B cell subsets where identified, both in at-risk and early RA patients. Lung IgG variable gene transcripts from ACPA-positive individuals carry frequent mutation-induced N-linked Fab glycosylation sites (p<0.001), often in the framework-3 of the variable region. Two of the lungs ACPAs bound to activated neutrophils, one from an at-risk individual and one from early RA. We conclude that T cell driven B cell differentiation, resulting in local class switching and somatic hypermutation are evident in lungs before, as well as in, early stages of ACPA-positive RA. Our findings add to the notion of lung mucosa being a site for initiation of the citrulline autoimmunity preceding seropositive RA. This article is protected by copyright. All rights reserved.

A new serum biochemical marker of synovium turnover predicts radiographic progression in patients with early arthritis.

To investigate whether serum Col 3-4, a new biochemical marker of synovial tissue turnover, was associated with progression of joint damage in patients with early arthritis. A total of 788 early arthritis patients (<6 months of symptoms, 82% diagnosis of RA, 18% undifferentiated arthritis) from the prospective ESPOIR study were investigated. Progression was defined as an increase of 1 or 5 unit(s) in radiographic van der Heijde modified Sharp score between baseline and 1 or 5 years, respectively. Associations between baseline Col 3-4 and progression were assessed by logistic regression. Each standard deviation increase of baseline Col 3-4 levels was associated with an increased 5-yr total damage progression with an odds ratio (OR, 95% CI) of 1.51 (1.21, 1.88), which remained significant when DAS28, C-reactive protein and anti-citrullinated protein antibodies positivity were included in the model [OR (95% CI): 1.34 (1.01, 1.76)]. Further adjustment for bone erosion did not modify the association. Patients with both Col 3-4 in the highest quintile and bone erosion had a >2-fold higher risk of progression [OR (95% CI): 7.16 (2.31, 22)] than patients with either high Col 3-4 [2.91 (1.79, 4.73)] or bone erosion [2.36 (2.38, 3.70)] alone. Similar associations were observed for prediction of 12 months progression. Increased serum Col 3-4 is associated with a higher risk of structural progression, independently of major risk factors. Col 3-4 may be useful in association with bone erosion to identify patients with early arthritis at higher risk.

Incidence, risk factors, and prognosis of acute exacerbation of rheumatoid arthritis-associated interstitial lung disease: a systematic review and meta-analysis

IntroductionAcute exacerbation (AE) is a devastating complication of rheumatoid arthritis-associated interstitial lung disease (RA-ILD) and leads to high mortality. This study aimed to investigate the incidence, risk factors, and prognosis of acute exacerbation of rheumatoid arthritis-associated interstitial lung disease (AE-RA-ILD).MethodsPubMed, EMBASE, Web of Science, and Medline were searched through 8 February 2023. Two independent researchers selected eligible articles and extracted available data. The Newcastle Ottawa Scale was used to assess the methodological quality of studies used for meta-analysis. The incidence and prognosis of AE-RA-ILD were investigated. Weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) and pooled odds ratios (ORs) with 95% CIs were calculated to explore the risk factors of AE in RA-ILD.ResultsTwenty-one of 1,589 articles were eligible. A total of 385 patients with AE-RA-ILD, of whom 53.5% were male, were included. The frequency of AE in patients with RA-ILD ranged from 6.3 to 55.6%. The 1-year and 5-year AE incidences were 2.6–11.1% and 11–29.4%, respectively. The all-cause mortality rate of AE-RA-ILD was 12.6–27.9% at 30 days and 16.7–48.3% at 90 days. Age at RA diagnosis (WMD: 3.61, 95% CI: 0.22–7.01), male sex (OR: 1.60, 95% CI:1.16–2.21), smoking (OR: 1.50, 95% CI: 1.08–2.08), lower forced vital capacity predicted (FVC%; WMD: −8.63, 95% CI: −14.68 to − 2.58), and definite usual interstitial pneumonia (UIP) pattern (OR: 1.92, 95% CI: 1.15–3.22) were the risk factors of AE-RA-ILD. Moreover, the use of corticosteroids, methotrexate, and biological disease-modifying anti-rheumatic drugs, was not associated with AE-RA-ILD.ConclusionAE-RA-ILD was not rare and had a poor prognosis. Age at RA diagnosis, male sex, smoking, lower FVC%, and definite UIP pattern increased the risk of AE-RA-ILD. The use of medications, especially methotrexate and biological disease-modifying anti-rheumatic drugs, may not be related to AE-RA-ILD.RegistrationCRD42023396772.

Exploring New Therapeutic Approaches for Rheumatoid Arthritis Based on Basic Signaling Pathways

RA is an incurable systemic inflammation the main features are infiltration of pro-inflammatory factors with joint swelling and pain as the main clinical manifestation. Studies have shown that there are many causes of RA, among which immune factors are the most important pathogenesis of rheumatoid arthritis. At present, emerging studies have found that PI3K / AKT / mTOR signaling axis is abnormal in patients with RA, which opens up new ideas for the treatment of RA through the normal expression of signal transduction by targeted drugs. Janus kinase family ( JAKs ), are up-regulated in non-receptor protein tyrosine kinase cytokine signaling ( SOCS ) inhibitors, suggesting that the existence of SOCS is most possibly to constitute the main machine-made of negative adjustment of JAK / STAT signaling. In RA patients, there is a correlation between the activation of mTOR signaling and the quantity of osteoclasts. The recently discovered cytokine IL-22 has been shown to significantly increase the number of fibroblasts isolated from the skin of the patients with psoriasis. The dual inhibitor of P1-3K / mTOR, NVP-BEZ235, effectively blocks the spread. This article mainly explores and discusses new targeted drugs such as tofacitinib and Ruxolitinib by discussing new pathological mechanisms and conventional diagnosis and treatment methods of RA. Since RA is one of the most representative diseases of skeletal immune diseases, the study of ra abnormal signaling pathways to discuss related treatment methods provides valuable insights into the disease and other inflammatory and autoimmune diseases.

A Standardized Physical Examination Method for Joints to Determine Rheumatoid Arthritis Activity Using the Modified RAND/UCLA Appropriateness Method.

Rheumatoid arthritis activity is evaluated based on a physical examination of each of the joints. However, the joint examination is not standardized, and the techniques are variable and difficult to reproduce due to disagreements among examiners. To recommend standardized joint examination techniques based on the modified RAND-UCLA appropriateness method. A review of the literature was conducted to determine the items to be included in the joint examination; subsequently, a consensus of rheumatologists was achieved with the modified RAND-UCLA methodology to issue the recommendations. The diagnosis of RA and differential diagnoses were excluded. Two hundred fifteen rheumatologists were invited to participate. Five were included in the core group and 26 in the group of clinical experts. Clinical experience ranged between 2 and 25 years (mean 15.6 years; standard deviation 6.3 years). Most rheumatologists participated in all rounds (Round 1: 100%, Round 2: 61%, and Round 3: 61%). Of the 45 statements in the questionnaire assessing the examination techniques, 28 (62%) were retained. In addition, 6 other statements were included during the face-to-face meeting for a total of 34 final statements. Physical examination techniques for joints that determine RA activity are heterogeneous and differ markedly in terms of several characteristics. A list of recommendations is proposed as a guide to improve and standardize the method for the physical examination of the joints. This standardization will improve the diagnosis and results for patients with RA and help health caregivers provide better treatment.