Rheumatoid Arthritis Phenotype Research Articles

Fibrotic remodeling in joint diseases: induction and inhibition of fibrosis in fibroblast-like synoviocytes

BackgroundWe aimed to investigate the development of synovial fibrosis in vitro and how the fibrosis can be halted. Synovial fibrosis causes joint stiffness in arthritic diseases. The pathway of the fibrotic growth factor, transforming growth factor-beta (TGF-β), has been associated with joint pain in osteoarthritis (OA) and with the fibroid phenotype of rheumatoid arthritis (RA). This suggests that synovial fibrosis, thus accumulation of extracellular matrix (ECM) proteins, plays a role in the clinical manifestations of the diseases. Improving our understanding of fibrotic development may aid in selecting appropriate treatments and development of drugs that can target synovial fibrosis.MethodsWe isolated primary fibroblast-like synoviocytes (FLS) from the synovial membrane of patients undergoing total knee replacement surgery. To investigate the development of synovial fibrosis, the FLS were cultured in a crowded in vitro model mimicking the ECM. TGF-β1 was used as the fibrotic initiator, the activin receptor-like kinase 5 inhibitor (ALK5i), the anti-fibrotic drug nintedanib, and the anti-inflammatory drug tofacitinib were used as fibrotic inhibitors. The ECM protein formation was quantified in the conditioned media using specific biomarkers of type I, III, and VI collagen formation and fibronectin turnover.ResultsThe TGF-β stimulation inducted fibrogenesis by increasing the biomarkers of fibronectin turnover, type I, III, and VI collagen formation. ALK5i and nintedanib inhibited the TGF-β response across all biomarkers. Tofacitinib trended towards inhibiting TGF-β response with up to 78% inhibition. All the treatments preserved cell viability.ConclusionWe have established an in vitro model for assessing fibrogenesis in primary FLS, which can be used to assess the anti-fibrotic effect of multiple drug types. Our study implies that synovial fibrosis can be induced by TGF-β, which additionally can be halted by both direct and indirect inhibition with anti-fibrotic substances. The anti-inflammatory drug tofacitinib also halted the fibrogenesis to some extent; thus, it may exert an anti-fibrotic effect.

Exploring the causal relationships between rheumatoid arthritis and oral phenotypes: a genetic correlation and Mendelian randomization study.

Rheumatoid arthritis (RA) frequently presents with oral manifestations, including gingival inflammation, loose teeth, and mouth ulcers; however, the causal connections between these conditions remain unclear. This study aims to explore the genetic correlations and causal relationships between RA and prevalent oral phenotypes. Using summary data from genome-wide association studies of European populations, a cross-trait linkage disequilibrium score regression was conducted to estimate the genetic correlations between RA and six oral phenotypes. Subsequently, a two-sample Mendelian randomization (MR) approach was employed to assess the causal relationships, corroborated by various sensitivity analyses. Heterogeneity was addressed through the RadialMR method, while potential covariates were corrected using the multivariable MR approach. A significant negative genetic correlation was detected between RA and denture usage (rg = -0.192, p = 4.88 × 10-8). Meanwhile, a heterogenous causal relationship between RA and mouth ulcers was observed (OR = 1.027 [1.005-1.05], p = 0.016, P heterogeneity = 4.69 × 10-8), which remained robust across sensitivity analyses. After excluding outlier variants, the results demonstrated robustly consistent (OR = 1.021 [1.008-1.035], p = 1.99 × 10-3, P heterogeneity = 0.044). However, upon adjusting for covariates such as smoking, alcohol consumption, body mass index, and obesity, the significance diminished, revealing no evidence to support independent genetic associations. Genetically predicted RA increases the risk of mouth ulcers, and a negative genetic correlation is identified between RA and denture use. The observed heterogeneity suggests that shared immunological mechanisms and environmental factors may play significant roles. These findings highlight the importance of targeted dental management strategies for RA patients. Further clinical guidelines are required to improve oral health among vulnerable RA patients.

Macrophage polarization in rheumatoid arthritis: signaling pathways, metabolic reprogramming, and crosstalk with synovial fibroblasts.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Macrophages are key effector cells that play a central role in RA pathogenesis through their ability to polarize into distinct functional phenotypes. An imbalance favoring pro-inflammatory M1 macrophages over anti-inflammatory M2 macrophages disrupts immune homeostasis and exacerbates joint inflammation. Multiple signaling pathways, including Notch, JAK/STAT, NF-κb, and MAPK, regulate macrophage polarization towards the M1 phenotype in RA. Metabolic reprogramming also contributes to this process, with M1 macrophages prioritizing glycolysis while M2 macrophages utilize oxidative phosphorylation. Redressing this imbalance by modulating macrophage polarization and metabolic state represents a promising therapeutic strategy. Furthermore, complex bidirectional interactions exist between synovial macrophages and fibroblast-like synoviocytes (FLS), forming a self-perpetuating inflammatory loop. Macrophage-derived factors promote aggressive phenotypes in FLS, while FLS-secreted mediators contribute to aberrant macrophage activation. Elucidating the signaling networks governing macrophage polarization, metabolic adaptations, and crosstalk with FLS is crucial to developing targeted therapies that can restore immune homeostasis and mitigate joint pathology in RA.

Concomitant Sjögren’s disease as a biomarker for treatment effectiveness in rheumatoid arthritis - results from the Swiss clinical quality management cohort

ObjectiveTo investigate the clinical phenotype and treatment response in patients with rheumatoid arthritis (RA) with and without concomitant Sjögren’s disease (SjD).MethodsIn this observational cohort study, patients with RA from the Swiss Clinical Quality Management in Rheumatic Diseases registry were categorised according to the presence or absence of SjD. To assess treatment effectiveness, drug retention of tumor necrosis factor-α-inhibitors (TNFi) was compared to other mode of action (OMA) biologics and Janus kinase-inhibitors (JAKi) in RA patients with and without SjD. Adjusted hazard ratios (HR) for time to drug discontinuation were compared in crude and adjusted Cox proportional regression models for potential confounders.ResultsWe identified 5974 patients without and 337 patients with concomitant SjD. Patients with SjD were more likely to be female, to have a positive rheumatoid factor, higher disease activity scores, and erosive bone damage. For treatment response, a total of 6781 treatment courses were analysed. After one year, patients with concomitant SjD were less likely to reach DAS28 remission with all three treatment modalities. Patients with concomitant SjD had a higher hazard for stopping TNFi treatment (adjusted HR 1.3 [95% CI 1.07–1.6]; OMA HR 1.12 [0.91–1.37]; JAKi HR 0.97 [0.62–1.53]). When compared to TNFi, patients with concomitant SjD had a significantly lower hazard for stopping treatment with OMA (adjusted HR 0.62 [95% CI 0.46–0.84]) and JAKi (HR 0.52 [0.28–0.96]).ConclusionRA patients with concomitant SjD reveal a severe RA phenotype, are less responsive to treatment, and more likely to fail TNFi.

Metabolic changes in fibroblast-like synoviocytes in rheumatoid arthritis: state of the art review.

Fibroblast-like synoviocytes (FLS) are important components of the synovial membrane. They can contribute to joint damage through crosstalk with inflammatory cells and direct actions on tissue damage pathways in rheumatoid arthritis (RA). Recent evidence suggests that, compared with FLS in normal synovial tissue, FLS in RA synovial tissue exhibits significant differences in metabolism. Recent metabolomic studies have demonstrated that metabolic changes, including those in glucose, lipid, and amino acid metabolism, exist before synovitis onset. These changes may be a result of increased biosynthesis and energy requirements during the early phases of the disease. Activated T cells and some cytokines contribute to the conversion of FLS into cells with metabolic abnormalities and pro-inflammatory phenotypes. This conversion may be one of the potential mechanisms behind altered FLS metabolism. Targeting metabolism can inhibit FLS proliferation, providing relief to patients with RA. In this review, we aimed to summarize the evidence of metabolic changes in FLS in RA, analyze the mechanisms of these metabolic alterations, and assess their effect on RA phenotype. Finally, we aimed to summarize the advances and challenges faced in targeting FLS metabolism as a promising therapeutic strategy for RA in the future.

Identification of circulating autoantibodies to non-modified proteins associated with ACPA status in early rheumatoid arthritis.

To discover autoantibodies to non-modified proteins associated with the presence/absence of anticitrullinated protein antibodies (ACPA) in rheumatoid arthritis (RA). The autoantibody repertoire of 80 ACPA negative and 80 ACPA positive RA subjects from the Swedish population-based Epidemiological Investigation of RA (EIRA) cohort was screened using a suspension bead array built on protein fragments earlier described as autoimmunity targets. Four autoantibodies positive in the initial screening were validated in another set of EIRA samples containing 317 ACPA-positive, 302 ACPA-negative and 372 age- and sex-matched controls. The relationship between the four autoantibodies and lung abnormalities on high-resolution computed tomography (HRTC) was examined in 93 early RA patients from LURA cohort. Association between the autoantibodies, smoking and MHC class II alleles was assessed by logistic regression analysis. : Anti-ANOS1 and anti-MURC IgG levels were associated with ACPA-positive status (OR = 3.02; 95% CI 1.87-4.89; and OR = 1.86; 95% CI 1.16-2.97, respectively) and increased in ACPA-positive patients compared with controls. Anti-ANOS1 IgG was associated with smoking habit (OR = 2.11; 95% CI 1.22-3.69) and anti-MURC IgG with the presence of the MHC class II "shared-epitope" genes (OR = 1.95; 95% CI 1.11-3.46). Anti-TSPYL4 IgG was associated with ACPA-negative (OR = 0.41; 95% CI 0.19-0.89). Anti-TSPYL4 IgG and anti-MAP2K6 IgG levels were increased in the ACPA-negative patients compared with controls. Presence of anti-MAP2K6 IgG and anti-TSPYL4 IgG correlated negatively with HRCT-defined lung abnormalities. These four autoantibodies may be useful in diagnostics and in predicting clinical phenotypes of RA.

MANAGEMENT OF RHEUMATOID ARTHRITIS IN ELDERLY PATIENTS

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by polyarthritis, progresses with joint damage, and may involve extra-articular tissue. Although RA can develop at any age, its prevalence increases with age. The number of elderly RA patients is gradually increasing due to both the increase in the frequency of late-onset (age 65 and over) RA (LORA) patients and the increased life expectancy. RA is characterized by inappropriately accelerated immune aging that occurs in the early period and is independent of disease duration. Aging can affect both the onset and the clinical phenotype of RA. Moreover, one of the most challenging issues for specialists is the treatment of RA in elderly patients. Targeted treatment of RA in elderly patients is inadequate or not optimally administered due to patients’ pre-existing comorbidities, polypharmacy, physicians’ concerns about possible drug side effects, and the lack of specific treatment guidelines for elderly RA patients. Elderly RA patients have been rarely and sometimes not even included in randomized controlled trials due to both age and comorbidities. Nevertheless, evidence for the safety and efficacy of specific RA treatments in the elderly population is gradually increasing. In elderly patients with RA, disease activity, all the comorbidities of the patient, and possible side effects of the drugs should be taken into consideration when making treatment decisions, and the treatment target should be individualized. In this review, the epidemiology of elderly RA patients, their comorbidities, briefly immune aging in RA, and the medical treatment approach in elderly RA will be discussed in light of studies.

Myricetin ameliorates the IL-21-induced tumorigenic phenotype of adjuvant-induced arthritis FLS by modulating the choline kinase signaling cascade.

The synovial intimal lining is mainly governed by fibroblast-like synoviocytes (FLS), which portray a transformed tumor-like phenotype in rheumatoid arthritis (RA). Among the diverse cytokines that engender FLS, interleukin-21 (IL-21) was reported to stimulate hyperproliferation and perpetuate inflammation. Recently, choline kinase (ChoKα) has been reported to be an essential enzyme aiding RA-FLS hyperproliferation by altering phosphatidylcholine biosynthesis. The current study aimed to elucidate the therapeutic efficacy of myricetin, a flavonoid, in abating the IL-21-induced tumor-like phenotype of adjuvant-induced arthritis (AIA)-FLS via the ChoKα signaling cascade. Our results showed that myricetin suppressed IL-21 receptor expression and activation of the ChoKα signaling cascade (N-Ras, Ral-GDS, and PI3K) in IL-21-induced AIA-FLS. Consequently, myricetin treatment decreased ChoKα and PLD2 enzymatic activity and inhibited the proliferative, migratory, and invasive properties of AIA-FLSs. Our results demonstrated that myricetin could be a promising anti-arthritic compound by abating IL-21-induced hyperproliferation, migration, and invasive behavior of AIA-FLS by downregulating the ChoKα signaling cascade.

Clonal Hematopoiesis Associated with Rheumatoid Arthritis

Introduction: Clonal hematopoiesis (CH) becomes common with age and can play a role in the pathophysiology of inflammatory diseases by modifying immune cell function. CH is characterized by the presence of somatic mutations in genes such as DNMT3A and TET2 (CH of indeterminate potential, CHIP), and as mosaic chromosomal alterations (mCAs). While CHIP, particularly in the context of TET2 mutations, can promote inflammation in cardiovascular diseases, the association between clonal hematopoiesis and autoimmunity has not been comprehensively studied to date. Rheumatoid arthritis (RA) is one of the most common autoimmune diseases primarily affecting joints. Seropositive RA is defined by the presence of anti-cyclic citrullinated peptide antibodies (ACPA) and/or rheumatoid factor (RF), whereas seronegative RA is a more heterogeneous inflammatory disease entity involving patients with clinical RA manifestations in the absence of ACPA and RF. Understanding of the association between CH and inflammatory processes may yield novel insights into prevention and management of autoimmune diseases. Methods: To comprehensively evaluate the association between CH and autoimmune diseases, we identified CHIP variants in whole exome sequencing (WES) data from the FINRISK study (N=10 129). We also detected mCAs and CHIP in the nationwide FinnGen study (N=340 173), where we manually identified CHIP carriers as outliers in SNP intensity plots at known CHIP loci in DNA microarray data. Only known CHIP loci with variant prevalence comparable to UK Biobank WES data and significant positive associations with age and hematological malignancies were included for downstream analyses. To further characterize the link between CHIP and RA phenotypes, we performed targeted panel sequencing of 69 myeloid driver genes in 675 RA patient blood samples (91% collected at diagnosis) and 60 healthy controls. We studied the association between CH and RA in multivariable models excluding participants with prevalent hematologic malignancies and adjusting for sex, age, smoking, and principal components of ancestry. We performed uni- and multivariable analyses to evaluate the link between CHIP and RA patient phenotypes. Results: We identified CHIP in 381 (3.8%) FINRISK participants. As expected, the prevalence of CHIP increased with age, and CHIP variants were associated with prevalent and incident hematologic malignancies. C-reactive protein values were higher in participants with CHIP (P<0.001). In multivariable models, CHIP status (OR 1.98, 1.13-3.45, P=0.017) was more common in participants with questionnaire-based history of RA (N=151) (Fig 1A). In the FinnGen study, CHIP carrier status was associated with prevalent autoimmune diseases (OR 1.26, 1.05-1.53, P=0.015). We validated the association between prevalent RA (N=10 990) and CHIP carrier status (N=2 393) in the FinnGen study (OR 1.58, 1.18-2.13, P=0.002) (Fig 1A). In particular, CHIP (OR 2.17, 1.40-3.36, P<0.001), and GNB1 variants (OR 4.71, 1.87-11.82, P=0.001) were associated with the seronegative RA, whereas DNMT3A was associated with seropositive RA (OR 1.83, 1.08-3.09, P=0.024). We observed no association between autosomal mCAs and RA. Using targeted panel sequencing, we found CHIP in 22% (146/675) of RA patients. RA patients with CHIP variants were older than those without a CHIP variant (median, 69 vs 63 years, P<0.001). Erythrocyte sedimentation rate (ESR) was higher in those with CHIP (median, 42.5 vs 26.0 mm/h, P=0.043). RA patients with TET2 variants were more likely to have seronegative disease compared with TET2 wild-type patients (proportion of seronegative patients, 56% vs 33%, OR 2.62; P=0.008) (Fig 1B). The association remained significant (OR 2.38, 1.14-4.96, P=0.02) when adjusting for age, sex, and smoking. Evaluation of longitudinal disease outcomes by CHIP status are currently ongoing. Conclusion: CHIP variants were more common in participants with prevalent RA in two population-level cohorts, and the association was specific to seronegative RA in the large FinnGen cohort. In newly diagnosed RA patients, TET2 mutations were more common in seronegative than in seropositive RA. While the causality and the functional basis of these observations remain to be explored in future studies, our results provide additional evidence for the association between CHIP and inflammation in various disease contexts, including autoimmune diseases.

A Review of Difficult-to-Treat Rheumatoid Arthritis: Definition, Clinical Presentation, and Management.

A subset of patients with rheumatoid arthritis (RA) who fail multiple biologic therapies are deemed to have "difficult-to-treat" (D2T) RA. In 2021, a European Alliance of Associations for Rheumatology (EULAR) task force proposed a clinical definition of D2T RA. Here we review RA phenotypes and clinical assessment of RA, propose a different definition of D2T RA, discuss possible D2T RA risk factors, and summarize existing literature on the management of D2T RA. High disease activity at the time of diagnosis or prior to treatment with a biologic is associated with the development of D2T RA. Prolonged time from diagnosis to beginning treatment has been consistently associated with the development of D2T RA. Other clinical factors such as burden of disease, extraarticular disease, obesity, smoking, pain, fatigue, and psychological conditions have inconsistent associations with D2T RA according to current literature. D2T RA is a relatively new concept that represents an area of great need for research regarding the characterization of those with the disease as well as how best to treat the disease. With this gained knowledge, rheumatologists will be able to better identify patients at the time of diagnosis that are likely to develop D2T RA to help guide management.

IFABP2 as a new prognostic biomarker for secondary non-response in rheumatoid arthritis

Increased intestinal permeability promotes the translocation of bacterial products from the local microbiome to the circulation, inducing inflammation and increasing clinical activity in rheumatoid arthritis (RA). This study evaluates whether intestinal fatty acid binding protein 2 (IFABP2) serum levels are prognostic biomarkers of non-response to conventional synthetic disease-modifying antirheumatic drug therapy (csDMARDs) in RA. The therapeutic schemes administered to 60 women with RA for at least 18months were assessed retrospectively, and the treatment response was classified according to the change in DAS28-ESR over time. Serum levels of IFABP2 and TNF-α were determined by ELISA. Receiver operating characteristics (ROC) curve analysis and logistic regression models were used to assess the predictive value and the association of IFABP2 with the non-responder phenotype in RA patients. Eleven women had a responder phenotype, 23 had a primary non-responder phenotype, and 26 had a secondary non-responder phenotype. Secondary non-responders showed higher DAS28-ESR (P=0.009) and higher IFABP2 serum levels compared to the responder group (P=0.023) and the primary non-responder group (P=0.018). IFABP2 serum levels were positively correlated with chloroquine dose (r=0.581, P=0.007) and negatively correlated with total cholesterol (r=-0.456, P=0.019) in secondary non-responders. The area under the curve (AUC) value of IFABP2 for predicting secondary non-response was 0.736, and IFABP2 serum levels>9.311ng/mL were associated with secondary non-response to csDMARDs (OR=6.00, P=0.003). IFABP2 serum levels are potentially a new biomarker predictive of secondary non-response to csDMARDs in RA, although our findings should be validated externally and in a larger cohort.

Vitamin D Status in Palindromic Rheumatism: A Propensity Score Matching Analysis.

To determine whether there is a correlation between vitamin D levels and palindromic rheumatism (PR) as an at-risk phenotype of rheumatoid arthritis (RA). A total of 308 participants were enrolled in this cross-sectional study. We recorded their clinical characteristics and performed propensity-score matching (PSM). Serum 25(OH)D3 levels were determined via enzyme-linked immunosorbent assay. Our PSM resulted in 48 patients with PR and 96 matched control individuals. The multivariate regression analysis we performed after the PSM did not show a significant increase in PR risk in patients with vitamin D deficiency/insufficiency. There was no significant correlation between levels of 25(OH)D3 and frequency/duration of attacks, number of joints affected, and duration of symptoms before diagnosis (P ≥ .05). Mean (SD) serum levels of 25(OH)D3 in patients with and without progression to RA were 28.7 (15.9) ng/mL and 25.1 (11.4) ng/mL, respectively. Based on the results, we found no clear association between vitamin D serum levels and the risk, severity, and rate of PR progressing into RA.

The role of inflammatory biomarkers in the association between rheumatoid arthritis and depression: a Mendelian randomization study.

Inflammation may mediate the co-pathogenesis of rheumatoid arthritis (RA) and depression because inflammatory cytokines are associated with RA and depression. However, traditional observational research was not able to address problems with residual confusion and reverse causality. We summarized and retrieved 28 inflammatory cytokines associated with RA, depression, or RA with depression through a literature search. The summary statistics from genome-wide association studies for RA, inflammatory biomarkers, broad depression, and major depression disease phenotypes were used. Mendelian randomization was performed to assess the causal association between RA and inflammatory biomarkers, as well as the effects of inflammatory biomarkers on depression. Bonferroni correction was used to reduce the possibility of false positive results. The study found that evidence for associations of genetically predicted RA was associated with higher levels of interleukin (IL)-9 (OR = 1.035, 95%CI = 1.002-1.068, P = 0.027), IL-12 (OR = 1.045, 95%CI = 1.045-1.014, P = 0.004), IL-13 (OR = 1.060, 95%CI = 1.028-1.092, P = 0.0001), IL-20 (OR = 1.037, 95%CI = 1.001-1.074, P = 0.047), and IL-27 (OR = 1.017, 95%CI = 1.003-1.032, P = 0.021). The level of IL-7 (OR = 1.029, 95%CI = 1.018-1.436, P = 0.030) was significantly related to RA. Only the analysis results between RA and IL-13 were satisfied with the statistical significance threshold corrected by Bonferroni (P < 0.002). However, a causal effect was not found between inflammatory biomarkers and depression. In the current study the inflammatory cytokines associated with RA comorbid depression may not be the mediators that directly lead to the co-pathogenesis of RA and depression.

The role of interleukin 17 in the pathogenesis of rheumatoid arthritis. Are there any prospects for the use of IL-17 inhibitors?

Rheumatoid arthritis (RA) is an immunoinflammatory rheumatic disease (IMRI) characterized by chronic erosive arthritis and systemic damage to internal organs, leading to early disability and reduced life expectancy in patients. Thanks to the progress in the study of the mechanisms of the development of the IVRI and industrial biotechnology, new anti-inflammatory drugs have been created, the use of which has significantly increased the effectiveness of the pharmacotherapy of RA. However, the possibilities of pharmacotherapy for RA are limited, since all genetically engineered biological drugs (GEBDs), regardless of the mechanism of action, have approximately the same effectiveness in achieving remission. It is believed that the relatively unsatisfactory results of RA therapy are due to the heterogeneity of the mechanisms of inflammation. and pain. The significance of the Th17 type of immune response in the pathogenesis of RA, the results of controlled studies of IL-17 inhibitors, and the advisability of further studying the effectiveness of these drugs in patients with certain RA phenotypes are discussed.

Differentiated embryonic chondrocyte expressed gene-1 is a central signaling component in the development of collagen-induced rheumatoid arthritis

Rheumatoid arthritis (RA) is one of the most common autoimmune diseases and affects almost 1% of the population. Differentiated embryo-chondrocyte expressed gene-1 (DEC1) has been associated with both osteogenesis and osteoclastogenesis. RA condition is marked by inflammatory hyperplasia, and DEC1 is known to support inflammatory reactions and implicated in antiapoptosis and cell invasion. Here, our goal was to test the hypothesis that DEC1 enhances RA development induced by collagen-induced arthritis (CIA), a well-recognized protocol for developing RA animal models. DEC1+/+ and DEC1-/- mice were subjected to CIA protocol, and the development of RA condition was monitored. We found that CIA robustly induced RA phenotypes (e.g., synovial hyperplasia) and greatly increased the expression of proinflammatory cytokines such as TNF-α. However, these changes were detected in DEC1+/+ but not DEC1-/- mice. Interestingly, these very cytokines strongly induced DEC1, and such a dual role of DEC1, as an inducer for and being induced by proinflammatory cytokines, constitutes a DEC1-amplifying circuit for inflammation. Knockdown of DEC1 in human MH7Acells strongly decreased cell migration and invasion as well as the expression of genes related to RA phenotypes. The combination of DEC1-directed migration and invasion invitro with synovial hyperplasia invivo mechanistically establishes cellular bases on how DEC1 is involved in the development of RA phenotypes. In addition to inflammatory signaling, DEC1 functionally interacted with PI3KCA(p110α)/Akt/GSK3β, Wnt/β-catenin, and NFATc1. Such engagement in multiple signaling pathways suggests that DEC1 plays coordinated and integral roles in developing RA, one of the most common autoimmune diseases.

Role of Sirtuins in the Pathogenesis of Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is an autoimmune and inflammatory disease leading to joint destruction. The causes of RA are not fully known. Most likely, the development of the disease depends on the coexistence of many factors, such as hereditary factors, immune system defects, gender, infectious agents, nicotine, and stress. Various epigenetic changes have been identified and correlated with the aggressive phenotype of RA, including the involvement of sirtuins, which are enzymes found in all living organisms. Their high content in the human body can slow down the aging processes, reduce cell death, counteract the appearance of inflammation, and regulate metabolic processes. Sirtuins can participate in several steps of RA pathogenesis. This narrative review presents, collects, and discusses the role of all sirtuins (1-7) in the pathogenesis of rheumatoid arthritis.

Rheumatoid arthritis study of the Egyptian College of Rheumatology (ECR): nationwide presentation and worldwide stance

To depict the spectrum of rheumatoid arthritis (RA) in Egypt in relation to other universal studies to provide broad-based characteristics to this particular population. This work included 10,364 adult RA patients from 26 specialized Egyptian rheumatology centers representing 22 major cities all over the country. The demographic and clinical features as well as therapeutic data were assessed. The mean age of the patients was 44.8 ± 11.7 years, disease duration 6.4 ± 6 years, and age at onset 38.4 ± 11.6 years; 209 (2%) were juvenile-onset. They were 8750 females and 1614 males (F:M 5.4:1). 8% were diabetic and 11.5% hypertensive. Their disease activity score (DAS28) was 4.4 ± 1.4 and health assessment questionnaire (HAQ) 0.95 ± 0.64. The rheumatoid factor (RF) and anti-cyclic citrullinated peptide (anti-CCP) were positive in 73.7% and 66.7% respectively. Methotrexate was the most used treatment (78%) followed by hydroxychloroquine (73.7%) and steroids (71.3%). Biologic therapy was received by 11.6% with a significantly higher frequency by males vs females (15.7% vs 10.9%, p = 0.001). The least age at onset, F:M, RF and anti-CCP positivity were present in Upper Egypt (p < 0.0001), while the highest DAS28 was reported in Canal cities and Sinai (p < 0.0001). The HAQ was significantly increased in Upper Egypt with the least disability in Canal cities and Sinai (p = 0.001). Biologic therapy intake was higher in Lower Egypt followed by the Capital (p < 0.0001). The spectrum of RA phenotype in Egypt is variable across the country with an increasing shift in the F:M ratio. The age at onset was lower than in other countries.

Mir204 and Mir211 suppress synovial inflammation and proliferation in rheumatoid arthritis by targeting Ssrp1.

Rheumatoid arthritis (RA) is a chronic inflammatory joint disease characterized by synovial hyperplasia. Mir204 and Mir211 are homologous miRNAs with the same gene targeting spectrum. It is known that Mir204/211 play an important role in protecting osteoarthritis development; however, the roles of Mir204/211 in RA disease have not been determined. In the present study, we investigated the effects and molecular mechanisms of Mir204/211 on synovial inflammation and hyperproliferation in RA. The effects of Mir204/211 on the inflammation and abnormal proliferation in primary fibroblast-like synoviocytes (FLSs) were examined by Mir204/211 gain-of-function and loss-of-function approaches in vitro and in vivo. We identified the structure-specific recognition protein 1 (Ssrp1) as a downstream target gene of Mir204/211 based on the bioinformatics analysis. We overexpressed Ssrp1and Mir204/211 in FLS to determine the relationship between Ssrp1 and Mir204/211 and their effects on synovial hyperplasia. We created a collagen-induced arthritis (CIA) model in wild-type as well as Mir204/211 double knockout (dKO) mice to induce RA phenotype and administered adeno-associated virus (AAV)-mediated Ssrp1-shRNA (AAV-shSsrp1) by intra-articular injection into Mir204/211 dKO mice. We found that Mir204/211 attenuated excessive cell proliferation and synovial inflammation in RA. Ssrp1 was the downstream target gene of Mir204/211. Mir204/211 affected synovial proliferation and decelerated RA progression by targeting Ssrp1. CIA mice with Mir204/211 deficiency displayed enhanced synovial hyperplasia and inflammation. RA phenotypes observed in Mir204/211 deficient mice were significantly ameliorated by intra-articular delivery of AAV-shSsrp1, confirming the involvement of Mir204/211-Ssrp1signaling during RA development. In this study, we demonstrated that Mir204/211 antagonize synovial hyperplasia and inflammation in RA by regulation of Ssrp1. Mir204/211 may serve as novel agents to treat RA disease.

Factors associated with interstitial lung disease and the progressive fibrosing phenotype in rheumatoid arthritis–related interstitial lung disease

BackgroundThe risk factors for interstitial lung disease (ILD) in rheumatoid arthritis (RA) are inconsistent among previous studies. Furthermore, the factors associated with the emergence of the recently defined progressive fibrosing (PF) phenotype are unknown. Herein, we analyze the risk factors for ILD in RA. We also analyze the factors associated with a PF phenotype. MethodsWe collected the clinical and laboratory details of subjects with RA with (cases) or without (controls) ILD. Scoring of high-resolution computed tomography (HRCT) features of ILD was performed. We identified the subgroup that developed the PF phenotype during follow-up. We analyzed the factors associated with ILD using logistic regression (primary objective). We also compared the characteristics of ILD subjects with or without the PF phenotype (secondary objective). ResultsWe included 60 subjects (30 cases, 30 controls). Subjects with ILD had higher age, lower body mass index, longer duration of RA, and poorer lung function than the controls. Age (p = 0.007) and the duration of RA (p = 0.049) were the only significant predictors of ILD on univariate and multivariate analysis, respectively. Six (20%) subjects with RA-ILD developed a PF phenotype. These subjects were older, had greater frequency of honeycombing, and higher HRCT scores for honeycombing and aggregate fibrosis than those without the PF phenotype. Among subjects with honeycombing, 41.7% developed the PF phenotype. ConclusionsRA-ILD was associated with the duration of RA and age. Subjects with the PF phenotype were older and had higher honeycombing and fibrosis scores on HRCT chest.

Risk of severe COVID-19 outcomes associated with rheumatoid arthritis and phenotypic subgroups: a retrospective, comparative, multicentre cohort study.

BackgroundRheumatoid arthritis has been associated with severe COVID-19, but few studies have investigated how phenotypes of rheumatoid arthritis affect these associations. We aimed to investigate the associations between rheumatoid arthritis and phenotypes of interstitial lung disease, serostatus, and bone erosions with COVID-19 severity.MethodsWe did a retrospective, comparative, multicentre cohort study at two large health-care systems (Mayo Clinic [19 hospitals and affiliated outpatient centres] and Mass General Brigham [14 hospitals and affiliated outpatient centres]) in the USA. Consecutive patients with rheumatoid arthritis meeting the 2010 American College of Rheumatology/European League Against Rheumatism classification criteria and who had COVID-19 between March 1, 2020, and June 6, 2021, were matched 1:5 on age, sex, and calendar date with patients without rheumatoid arthritis (comparators). Data were received from electronic health records from Mayo Clinic and Mass General Brigham. We examined subgroups of patients with rheumatoid arthritis by phenotypic features: rheumatoid arthritis-associated interstitial lung disease, seropositivity (for anti-cyclic citrullinated peptide, rheumatoid factor, or both), and bone erosions. Severe COVID-19 was a composite of hospitalisation or death. We used Cox regression to estimate hazard ratios (HR) for severe COVID-19, comparing rheumatoid arthritis and subgroups to the comparator group.FindingsWe identified 582 patients with rheumatoid arthritis and 2875 matched comparators, all of whom had COVID-19 within the study dates. The mean age of those with rheumatoid arthritis was 62 [SD 14] years, 421 (72%) of 582 were women and 161 (28%) were men, 457 (79%) were White, 65 (11%) were Hispanic or Latino, and 41 (7%) were Black. Among patients with rheumatoid arthritis, 50 (9%) of 582 had interstitial lung disease, 388 (68%) of 568 were seropositive, and 159 (27%) of 582 had bone erosions. Severe COVID-19 occurred in 126 (22%) of 582 patients with rheumatoid arthritis versus 363 (13%) 2875 in the comparator group. Patients with rheumatoid arthritis had an HR of 1·75 (95% CI 1·45–2·10) for severe COVID-19 versus the comparator group. Patients with rheumatoid arthritis-associated interstitial lung disease had an HR of 2·50 (1·66–3·77) versus the comparator group for severe COVID-19. The risk for severe COVID-19 was also higher in patients with rheumatoid arthritis who were seropositive (HR 1·97 [95% CI 1·58–2·46]) or had erosive disease (1·93 [1·41–2·63]) than for those in the comparator group.InterpretationPatients with rheumatoid arthritis have an increased risk of severe COVID-19 across phenotypic subgroups, especially among patients with interstitial lung disease. These findings suggest that rheumatoid arthritis with interstitial lung disease, or its treatment, might be a substantial contributor to severe COVID-19 outcomes for patients with rheumatoid arthritis.FundingNone.