Severity Of Rheumatoid Arthritis Research Articles

Bone mass density in patients with rheumatoid qrthritis: Influence of disease activity

Rheumatoid arthritis (RA) can affect bone density. Given the significant risk of low bone mass density (BMD) in RA patients, the present study aims to investigate the BMD in these patients. The present cross-sectional study included 415 RA patients from the Rafsanjan Rheumatology Clinic. The patients were included in the study by census based on the inclusion criteria, which included a physician's diagnosis of RA according to the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) criteria, at least three months of disease history, and age between of 35 and 70 years. The BMD was measured using the dual-energy x-ray absorptiometry method in both the hip and the spine, and the RA severity was determined using the disease activity score-28 (DAS-28) index. The mean age of RA patients was 56.49 ± 11.73 years, with females accounting for 86.7% (300 people). The frequency of osteoporosis was 7.5% (26 people), and osteopenia was 43.6% (151 people) based on hip bone density, and 33% (137 people) and 38.1% (158 people) based on spine density, respectively. Age, fracture history, and DAS-28 score increased the probability of developing osteopenia or osteoporosis based on hip and spine bone density. According to the findings of a study in RA patients, increasing age, history of bone fracture, and DAS-28 score increase the probability of osteopenia or osteoporosis. Therefore, it is advised to pay close attention to the mentioned factors to prevent complications in these patients.

Eggerthella lenta augments preclinical autoantibody production and metabolic shift mimicking senescence in arthritis.

Although the etiology of rheumatoid arthritis (RA) is unknown, a strong genetic predisposition and the presence of preclinical antibodies before the onset of symptoms is documented. An expansion of Eggerthella lenta is associated with severe disease in RA. Here, using a humanized mouse model of collagen-induced arthritis, we determined the impact of E. lenta abundance on RA severity. Naïve mice gavaged with E. lenta produce preclinical rheumatoid factor and, when induced for arthritis, develop severe disease. The augmented antibody response was much higher in female mice, and among patients with RA, women had higher average load of E. lenta. Expansion of E. lenta increased CXCL5 and CD4 T cells, and both interleukin-17- and interferon-γ-producing B cells. Further, E. lenta gavage caused gut dysbiosis and decline in amino acids and nicotinamide adenine dinucleotide with an increase in microbe-dependent bile acids and succinyl carnitine causing systemic senescent-like inflammation.

Correlation of Rheumatoid arthritis disease severity with serum vitamin D levels

Rheumatoid arthritis (RA) is an autoimmune disorder marked by characteristic inflammation of the small joints in addition to diverse systemic manifestations. Vitamin D has immunomodulatory properties, and its deficiency has a significant role in the clinical course of RA. The present research was conducted to study the correlation between serum vitamin D levels and disease activity scores in RA patients. A cross sectional study was carried out on a sample of 50 patients presenting with RA. Disease activity was measured using Modified Disease Activity Score (DAS) criteria. Estimation of serum Vitamin D levels were done using the electrochemiluminescence method and values less than 20ng/ml were considered as deficiency. Vitamin D levels were then correlated with disease activity scores. The Vitamin D deficiency was observed in 50% of the study population. Rheumatoid arthritis showed female preponderance in this study. Inflammatory markers such as C - reactive protein (CRP) levels and Erythrocyte Sedimentation Rate (ESR) did not differ with RA disease activity. More the number of large joints involved lesser were the vitamin D levels. There was an inverse correlation between Vitamin D levels and RA disease activity. Vitamin D deficiency is significantly correlated with disease severity of RA. This study points to the importance of screening for deficit of vitamin D among RA patients and treat it as early as possible.

The interplay between Epstein-Barr virus DNA and gut microbiota in the development of arthritis in a mouse model.

Epstein-Barr virus (EBV) DNA may influence the development of autoimmune diseases by increasing the production of proinflammatory cytokines. Such cytokines have been associated with inducing the dysbiosis of colonic microbiota, which, in turn, is a risk factor for autoimmune diseases such as rheumatoid arthritis (RA). Therefore, we investigated the role that EBV DNA may play in modulating the intestinal microbiota and consequent exacerbation of arthritis in a mouse model. Mice were treated with collagen (arthritis-inducing agent), EBV DNA and collagen, EBV DNA, or water. Fecal samples were collected from arthritic and control mice, and 16S rRNA sequencing was performed to determine the effect of EBV DNA on the composition of colonic microbiota. EBV DNA causes a change in the alpha diversity of the microbiota resulting in an increased Chao1 microbial richness and decreased Shannon diversity index in the RA mouse model. In addition, the abundance of particular genera/genus clusters was significantly altered among the various groups, with the EBV DNA-exacerbated arthritic group having the highest number of altered genera/genus cluster abundances. This group also had the highest number of cells co-expressing IL-17A, FOXP3, and IFNγ in the colons. Antimicrobial-cleared mice transplanted with fecal samples from EBV DNA-exacerbated arthritic mice showed a higher incidence and enhanced severity of RA compared to those transplanted with fecal samples from water or collagen-treated mice. IMPORTANCE Epstein-Barr virus (EBV) DNA alters the composition and diversity of the gut microbiota in a rheumatoid arthritis (RA) mouse model. These induced changes are associated with enhanced severity of symptoms. This better understanding of the various factors involved in the development of RA will possibly help in creating individualized treatments for RA patients including target mediators triggered by viral DNA. Given that a large swathe of the population harbors EBV, a significant proportion of subjects with arthritis may benefit from possible approaches that target EBV or mediators triggered by this virus.

Multiple-Factors-Induced Rheumatoid Arthritis Synoviocyte Activation Is Attenuated by the α2-Adrenergic Receptor Agonist Dexmedetomidine.

Dexmedetomidine (Dex) has analgesic and sedative properties and anti-inflammatory functions. Although the effects of Dex on arthritis have been revealed, the physiological mechanism underlying the interaction between Dex and rheumatoid arthritis (RA)-mediated inflammatory cytokines has not been fully studied. Inflamed and migrated fibroblast-like synoviocytes (FLSs) are involved in RA severity. Thus, we aimed to determine the effects of Dex on RA-FLSs treated with inflammatory cytokines and a growth factor as multiple stimulating inputs. TNF-α, IL-6, and EGF as multiple stimulating inputs increased the cAMP concentration of RA-FLSs, while Dex treatment reduced cAMP concentration. Dex reduced electroneutral sodium-bicarbonate cotransporter 1 (NBCn1) expression, NBC activity, and subsequent RA-FLS migration. The mRNA expression levels of RA-related factors, such as inflammatory cytokines and osteoclastogenesis factors, were enhanced by multiple-input treatment. Notably, Dex effectively reduced these expression levels in RA-FLSs. These results indicate that multiple inflammatory or stimulating inputs enhance RA-FLS migration, and treatment with Dex relieves activated RA-FLSs, suggesting that Dex is a potential therapeutic drug for RA.

Sinomenine ameliorates rheumatoid arthritis by modulating tryptophan metabolism and activating aryl hydrocarbon receptor via gut microbiota regulation

Gut microbiota dysbiosis is associated with the development of rheumatoid arthritis (RA). Sinomenine (SIN) is an effective immunosuppressive and anti-inflammatory drug used for treating RA, but how SIN regulates gut microbiota to alleviate RA remains underexplored. To identify the critical gut microbial species and microbial metabolites associated with the RA-protective effects of SIN, the microbiota-dependent anti-RA effects of SIN were assessed by 16S rRNA gene sequencing, antibiotic treatment, and fecal microbiota transplantation. Metabolomics analysis, transcriptional analysis, and targeted bacteria/metabolites gavage were conducted to explore how SIN regulates gut microbiota to reduce the severity of RA. SIN could restore intestinal microbial balance by mainly modulating the abundance of Lactobacillus, and significantly relieve collagen-induced arthritis (CIA) symptoms in a gut microbiota-dependent manner. SIN significantly elevated microbial tryptophan metabolites indole-3-acrylic acid (IA), indole-3-propionic acid (IPA), and indole-3-acetic acid (IAA). Tryptophan metabolites supplementation could activate aryl hydrocarbon receptor (AhR) and regulate Th17/Treg balance in CIA rats. Intriguingly, SIN relieved the arthritis symptoms involving the enrichment of two beneficial anti-CIA Lactobacillus species, L. paracasei and L. casei by mono-colonization. The promising therapeutic function of SIN was mostly attributed to the activation of AhR by explicitly targeting the Lactobacillus and microbial tryptophan metabolites. The intestinal bacterium L. paracasei and L. casei may be used to reduce the severity of CIA.

Immunomodulatory Effects of Combined Nicotinic Acid and Prednisolone in Adjuvant-induced Arthritis.

The combination of two drugs may lead to better results while reducing the need for each medication. This study aimed to explore the synergistic benefits of combination therapy by suboptimal dose of niacin (Nic.) and prednisolone (Pred.) in an experimental model of Rheumatoid arthritis (RA). About 50 male Wistar rats (weighing 150 - 160 grams) were randomly divided into five groups of ten, including healthy and RA groups treated with Nic. (80 mg/kg-orally), or Pred. (2 mg/kg-orally), and/or co-administration of Nic. and Pred. (half doses with each one-orally). RA was induced by the injection of complete Freund's adjuvant into the hind paw of each rat. All treatments were initiated on the fifth day following the induction and continued until day 30 post-induction. The combined Nic. and Pred. at half doses promoted a significant regression in the severity of the established RA, which is more pronounced than full doses of either drug alone. Combination therapy promoted a reduction in some hematological and biochemical RA parameters, like neutral red uptake by phagocytic cells, myeloperoxidase, nitric oxide, and C-reactive protein, more profound than each drug alone. Combined treatment caused a greater decrease in IFN-γ expression than other treatments in the area of plantar joints. All treatments were effective in increasing the expression of the IL-10 in the area of plantar joints. Prednisolone was less effective in reducing the expression of the TNF-α in the area of plantar joints than the other group. This combination may be a useful approach to controlling RA.

Association of Sex Hormones and Androgens with Disease Activity in Premenopausal Females with Rheumatoid Arthritis.

Gonadal sex hormone dysfunction is frequently reported in patients with Rheumatoid arthritis (RA). The relationship of these hormones with disease activity is still not clear and whether the hormone imbalance leads to increased severity of RA is not well studied in this part of the world. The present study aimed to elucidate this fact. It was a cross-sectional observational study performed in 80 premenopausal females with definite RA at a tertiary care hospital in New Delhi, India over one year. Patients were subjected to investigations as per the protocol and a fasting venous blood sample for hormone levels was collected in the follicular phase of their menstrual cycle. A statistically significant correlation by linear logistic regression analysis was found between disease activity (as measured by DAS28) and serum progesterone, FSH, and prolactin, while serum testosterone and DHEAS showed an inverse relationship with disease activity. Low s. prolactin, and s. FSH as well as high s. testosterone and s. DHEAS were found to be associated with target clinical goals in RA (ie, remission and low disease activity). On multivariate logistic regression analysis, serum prolactin showed a direct association. (p=0.016, OR= 1.009. C.I.= 1.0021.017) and serum testosterone were found to have an inverse relationship (p=0.002, OR= 0.017, C.I.=0.001-0.237) with disease activity in this group of individuals. Serum levels of sex hormones may be helpful in predicting disease activity among patients with RA, and in future, may be used to guide treatment of severe refractory disease, unresponsive to conventional treatment with DMARDs, especially in resource-poor settings.

CX-4945 inhibits fibroblast-like synoviocytes functions through the CK2-p53 axis to reduce rheumatoid arthritis disease severity

Fibroblast-like synoviocytes (FLS) mediate many pathological processes in rheumatoid arthritis (RA), including pannus formation, bone erosion, and inflammation. RA FLS have unique aggressive phenotypes and exhibit several tumor cell-like characteristics, including hyperproliferation, excessive migration and invasion. Casein kinase 2 (CK2) is reportedly overexpressed in numerous tumor types, and targeted inhibition of CK2 has therapeutic benefits for tumors. However, the expression level of CK2 and its functions in RA FLS remain unclear. Herein, we aimed to elucidate whether CK2 is responsible for the aggressive phenotypes of RA FLS and whether targeted therapy can alleviate the severity of RA. We found that CK2 subunits were elevated in RA FLS compared with osteoarthritis FLS, and the activity of CK2 also markedly increased in RA FLS. Targeted inhibition of CK2 using CX-4945 suppressed RA FLS proliferation through cell cycle arrest. Cell migration and invasion were also inhibited by CX-4945 treatment. Moreover, CX-4945 reduced Interleukin-6 (IL-6), CC motif chemokine ligand 2 (CCL2) and Matrix metalloproteinase-3 (MMP-3) secretion in RA FLS. Further proteomic investigation revealed that p53 signaling pathway significantly changes after CX-4945 treatment in RA FLS. The siRNA-mediated p53 knockdown partly abolished the anti-proliferation and reduced IL-6, MMP-3 secretion effects of CX-4945. Furthermore, CX-4945 administration alleviates arthritis severity in CIA mice. Collectively, our results demonstrated the abnormal elevation of CK2 and its positive association with abnormal phenotypes in RA FLS. Our novel findings suggest the possible therapeutic potential of CX-4945 for RA.

Plasma Wnt7b protein in rheumatoid arthritis: Detection of interstitial lung disease

ObjectiveTo determine the plasma level of Wingless-related integration site 7b (Wnt7b) protein in rheumatoid arthritis (RA) patients (with and without interstitial lung disease (ILD)) and in idiopathic pulmonary fibrosis (IPF) patients and its relationship with RA disease activity and/or severity of pulmonary fibrosis. To assess the validity of plasma Wnt7b for the detection of ILD among RA patients. MethodThis case-control study included 128 subjects (32 RA-ILD, 32 RA, 32 IPF, and 32 healthy controls). RA and RA-ILD Patients were evaluated for disease activity by DAS28 and disease activity grades were recorded according to DAS28 grades. Laboratory parameters as Erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), Rheumatoid Factor (RF), Anti-citrullinated peptide (Anti-CCP) were recorded. Plasma Wnt7b levels were measured by ELISA. Diagnosis of pulmonary fibrosis (for RA-ILD and IPF patients) was done by high resolution computed tomography (HRCT) and its severity was assessed mainly by pulmonary function test using forced vital capacity (FVC) grading. ResultsComparison of Wnt7b plasma levels showed a significant difference between the studied groups with the P-value < 0.018 (RA-ILD had the highest levels). Post hoc analysis revealed a significant difference in Wnt7b plasma levels between RA-ILD and IPF groups (P = 0.008). Also, RA-ILD and control groups had a significant difference (P = 0.039). However, there was a non-significant relationship between Wnt7b plasma levels and RA disease activity as well as the severity of pulmonary fibrosis. ROC curve analysis for the plasma Wnt7b levels revealed that a level ≥285.1 pg/ml had a sensitivity of 87.5% and a specificity of 43.8% for the detection of ILD in RA patients with positive likelihood ratio of 1.56 and negative likelihood ratio of 0.29. ConclusionRA-ILD patients had significantly higher plasma Wnt7b levels than the controls and IPF patients. These data suggest that the Wnt7b secretion is augmented by the concomitant presence of RA with pulmonary fibrosis. In addition, plasma Wnt7b may be used as a highly sensitive test for the detection of immunologically induced fibrotic changes in lung tissue among RA patients.

Rituximab exerts its anti-arthritic effects via inhibiting NF-κB/GM-CSF/iNOS signaling in B cells in a mouse model of collagen-induced arthritis

Rheumatoidarthritis (RA) is an autoimmune disease characterized by uncontrolled joint inflammation and damage to bone and cartilage. B cells are known to play a crucial role in the pathogenesis and development of arthritis. Previous studies have found that B cells may be a potential target for treating RA. Rituximab, a monoclonal antibody targeting B cells, has induced long-term clinical responses in RA. Collagen-induced arthritis (CIA) mouse model is a widely studied autoimmune model of RA. CIA mouse model was used to investigate the effect of rituximab on the RA severity in the mice. Following induction of CIA, animals were treated with rituximab (250 mg/kg/week) intraperitoneally on the days 28, 35, 42, 49, 56, and 63 after collagen induction. We investigated the effect of rituximab on NF-κB p65, IκBα, GM-CSF, MCP-1, iNOS, TNF-α, and IL-6 cells in splenic CD19+ and CD45R+ B cells using flow cytometry. We also assessed the effect of rituximab on NF-κB p65, GM-CSF, IκBα, MCP-1, iNOS, TNF-α, and IL-6 at mRNA levels using RT-PCR analyses of knee tissues. Rituximab treatment significantly decreased CD19+NF-κB p65+, CD45R+NF-κB p65+, CD19+GM-CSF+, CD45R+GM-CSF+, CD19+MCP-1+, CD45R+MCP-1+, CD19+TNF-α+, CD45R+TNF-α+, CD19+iNOS+, CD45R+iNOS+, CD19+IL-6+, and CD45R+IL-6+, and increased CD45R+IκBα+ in spleen cells of CIA mice. We further observed that rituximab treatment downregulated NF-κB p65, GM-CSF, MCP-1, iNOS, TNF-α, and IL-6, whereas it upregulated IκBα, mRNA level. All these findings suggest that rituximab may be a novel therapeutic target for the treatment of RA.

An update on thermal imaging in rheumatoid arthritis.

This review aims to summarise the recent literature concerning the usage of thermal imaging in the study of rheumatoid arthritis (RA). Most RA studies have applied thermal imaging as a static process alone although thermal imaging has been conducted with an additional dynamic/functional component. Algorithms to automate the analysis of thermal imaging in RA have also been described. Several RA thermal imaging studies have demonstrated differences in thermographic findings between RA patients and healthy controls and/or compared thermographic parameters with other clinical/functional/imaging parameters; while fewer studies have assessed the role of thermal imaging in discriminating disease severity in RA. Thermal imaging is a relatively low cost, non-invasive imaging technique offering an objective measurement of joint surface temperature in RA joint inflammation assessment. Although there has been an increasing literature build up on the use of thermography in RA, more validation work is still necessary to delineate the potential role(s) of its use among patients with RA. This timely review focusses on the recent literature concerning thermal imaging, and provides clinicians with an update on its recent development in RA.

Fusobacterium nucleatum aggravates rheumatoid arthritis through FadA-containing outer membrane vesicles

Rheumatoid arthritis (RA) is an autoimmune disorder that has been associated with the gut microbiota. However, whether and how the gut microbiota plays a pathogenic role in RA remains unexplored. Here, we observed that Fusobacterium nucleatum is enriched in RA patients and positively associated with RA severity. F.nucleatum similarly aggravates arthritis in a mouse model of collagen-induced arthritis (CIA). F.nucleatum outer membrane vesicles (OMVs) containing the virulence determinant FadA translocate into the joints, triggering local inflammatory responses. Specifically, FadA acts on synovial macrophages, resulting in the activation of the Rab5a GTPase involved in vesicle trafficking and inflammatory pathways and YB-1, a key regulator of inflammatory mediators. OMVs containing FadA and heightened Rab5a-YB-1 expression were observed in RA patients compared with controls. These findings suggest a causal role of F.nucleatum in aggravating RA and provide promising therapeutic targets for clinically ameliorating RA.

Galectin-1 in Psoriatic arthritis, Psoriasis, Rheumatoid arthritis and its relation with disease activity and skin lesion

Immune mediated inflammatory diseases (IMIDs) are a diverse range of diseases that affect joints with early overlapping symptoms. Rheumatoid arthritis (RA) and psoriatic arthritis (PsA) are the most common disorders sharing immune-pathogenic mechanisms that cause peripheral arthritis. Psoriasis (Ps) is a chronic inflammatory autoimmune skin disease characterized by epidermal hyperplasia with significant invasion by inflammatory cells. New biomarkers are required to enable an early diagnosis and differentiation between different types of IMIDs. In autoimmune disorders, galectin 1 (Gal-1) is a recognized as negative immune system regulator. This study aimed to determine the possibility of using gal-1 as a diagnostic marker to differentiate between RA and PsA with polyarthritis pattern, and between PsA and Ps, and to assess its relationship with disease activity and with skin lesion. In this case-control study included 40 PsA patients with polyarthritis pattern, 40 psoriatic patients, 40 RA patients and 20 normal controls. Gal-1 levels were measured in serum and skin biopsy and disease Activity Score (DAS-ESR) was assessed. Serum gal-1 level was significantly higher in RA group in comparison to PsA, psoriatic and control. In addition, compared to the normal group, psoriatic skin lesions from PsA and Ps patients had lower levels of gal-1. Serum gal-1 levels in the RA group did not correlate with other factors such as age, disease duration, deformity, extra-articular symptoms, or DAS-ESR. Furthermore, there was no correlation between the skin's level of gal-1 and psoriatic area and severity index (PASI) score, body surface area (BSA). In conclusion, serum Gal-1 concentration may serve as a diagnostic biomarker to distinguish between RA and PsA. However, it cannot assess activity or severity of RA, and cannot differentiate psoriatic lesion either from only Ps or PsA.

Use of some bone-related cytokines as predictors for rheumatoid arthritis severity by neural network analysis

Background. Rheumatoid arthritis (RA) is characterized by synovial membrane inflammation that results in joint damage. Many earlier studies have measured cytokines for a better diagnosis of RA. In the present study, three bone biomarkers [osteopontin, stromelysin-1 (MMP3), and vascular endothelial growth factor-A (VEGF)] are examined for their ability to estimate the severity of disease by using artificial neural network (NN) analysis and binary logistic regression analysis. Methods. The study enrolled 87 RA patients and 44 healthy control subjects. The biomarkers were measured by the enzyme-linked immunosorbent assay technique. Disease Activity Score (28 joints) and C-reactive protein (CRP) (DAS28-CRP) was calculated by using DAS28-CRP calculator. The patients with DAS28-CRP 5.1 are considered as having high disease activity (HDA). While patients group with DAS28-CRP 5.1 are considered as moderate disease activity (MDA). The neural network (NN) analysis was used for the differentiation between groups. Results. Results showed that the most sensitive predictor for high disease activity (HDA) of RA is MMP3, followed by osteopontin and VEGF. These three biomarkers can differentiate significantly between HDA and MDA with a relatively high size effect (Partial 2 = 0.323, p 0.001). The HDA group has a significantly higher MMP3, CRP, RF, and anti-citrullinated protein antibodies (ACPA) than the MDA group. MMP3 is strongly associated with two inflammatory indicators; CRP and ESR. Conclusion. There was a significant elevation in the serum level of MMP3 in RA patients with HDA compared to the MDA and control groups. High DAS28, RF, CRP, and ACPA were found in HDA patients compared with the MDA group. The use of the NN analysis indicated that the measured biomarkers help predict the HDA state in RA patients. MMP3 and osteopontin are diagnostic biomarkers for the severity of RA and are related to many disease-related characteristics with a sensitivity of 88.9% and specificity of 68.4%.

The Involvement of Glucose and Lipid Metabolism Alteration in Rheumatoid Arthritis and Its Clinical Implication.

Obviously, immune cells like T cells and macrophages play a major role in rheumatoid arthritis (RA). On one hand, the breakdown of immune homeostasis directly induces systemic inflammation; on the other hand, these cells initiate and perpetuate synovitis and tissue damages through the interaction with fibroblast-like synoviocytes (FLS). In recent years, the pathological link between metabolic disorders and immune imbalance has received increasing attention. High energy demand of immune cells leads to the accumulation of metabolic byproducts and inflammatory mediators. They act on various metabolism-sensitive signal pathways as well as relevant transcription factors, such as HIF-1α, and STATs. These molecular events will impact RA-related effectors like circulating immune cells and joint-resident cells in return, allowing the continuous progression of systemic inflammation, arthritic manifestations, and life-threatening complications. In other words, metabolic complications are secondary pathological factors for the progression of RA. Therefore, the status of energy metabolism may be an important indicator to evaluate RA severity, and in-depth explorations of the mechanisms underlying the mystery of how RA-related metabolic disorders develop will provide useful clues to further clarify the etiology of RA, and inspire the discovery of new anti-rheumatic targets. This article reviews the latest research progress on the interactions between immune and metabolism systems in the context of RA. Great importance is attached to the changes in certain pathways controlling both immune and metabolism functions during RA progression.

Anti-inflammatory potential of selective small compounds by targeting TNF-α & NF-kB signaling: a comprehensive molecular docking and simulation study

Tumor necrosis factor alpha (TNF-α) is the major cause of inflammation in autoimmune diseases like rheumatoid arthritis (RA). It’s mechanisms of signal transduction through nuclear factor kappa B (NF-kB) pathway via small molecules such as metabolite crosstalk are still elusive. In this study, we have targeted TNF-α and NF-kB through metabolites of RA, to inhibit TNF-α activity and deter NF-kB signaling pathways, thereby mitigating the disease severity of RA. TNF-α and NF-kB structure was obtained from PDB database and metabolites of RA were selected from literature survey. In-silico studies were carried out by molecular docking using AutoDock Vina software and further, known TNF-α and NF-kB inhibitors were compared and revealed metabolite’s capacity to targets the respective proteins. Most suitable metabolite was then validated by MD simulation to verify its efficiency against TNF-α. Total 56 known differential metabolites of RA were docked with TNF-α and NF-kB compared to their corresponding inhibitor compounds. Four metabolites such as Chenodeoxycholic acid, 2-Hydroxyestrone, 2-Hydroxyestradiol (2-OHE2), and 16-Hydroxyestradiol were identified as a common TNF-α inhibitor’s having binding energies ranging from −8.3 to −8.6 kcal/mol, followed by docking with NF-kB. Further, 2-OHE2 was selected because of having binding energy −8.5 kcal/mol, found to inhibit inflammation and the effectiveness was validated by root mean square fluctuation, radius of gyration and molecular mechanics with generalized born and surface area solvation against TNF-α. Thus 2-OHE2, an estrogen metabolite was identified as the potential inhibitor, attenuated inflammatory activation and can be utilized as a therapeutic target to disseminate severity of RA.

Genetic Polymorphism and serum levels of Insulin like Growth Factor-1 (Igf-1) in patients of rheumatoid arthritis.

Insulin like growth factor-1(IGF-1), is a modulator of immunity and inflammation, it promotes the anabolic role of growth hormone (GH) on bone and skeletal tissue. Genetic polymorphism in IGF-1 gene is reported to affect the transcriptional efficiency affecting its serum level. In this study we aim: 1) To study the presence of 192bp polymorphism of IGF-1 gene in patients of rheumatoid arthritis (RA), 2) To study the association of 192 bp polymorphism of IGF-1 gene with serum IGF-1 levels and disease severity in patients of RA. A cross-sectional study was carried out at University of Health Sciences (UHS), Lahore. Diagnosed RA cases who fulfilled the American College of Rheumatology (ACR) criteria were recruited from Fatima Memorial Hospital (FMH) and Behbud Rheumatology Clinics, Lahore during 2018-2019. Serum IGF-1 levels were determined by ELISA in blood samples of 200 RA patients and 200 healthy individuals. DNA was extracted and genetic polymorphism was determined. The serum IGF-1 level in RA group was significantly lower compared to healthy group. Our study shows presence of 192bp allele of IGF-1in 77% of the studied population. Carriers of 192bp allele of IGF-1 had a significantly higher serum level of IGF-1 as compared to non-carriers in the RA patients. Rheumatoid factor (RF) positive patients had a higher number of 192bp carriers in comparison to RF negative patients. Significant difference was also seen in severity of disease between carrier and non-carriers of 192bp allele with the disease being more severe in male carriers. There is an association of IGF-1gene polymorphism with variation in serum IGF-1 levels and severity of RA.

KW2449 ameliorates collagen-induced arthritis by inhibiting RIPK1-dependent necroptosis.

Necroptosis has recently been found to be associated with the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). This study was undertaken to explore the role of RIPK1-dependent necroptosis in the pathogenesis of RA and the potential new treatment options. The plasma levels of receptor-interacting protein kinase 1 (RIPK1) and mixed lineage kinase domain-like pseudokinase (MLKL) in 23 controls and 42 RA patients were detected by ELISA. Collagen-induced arthritis (CIA) rats were treated with KW2449 by gavage for 28 days. Arthritis index score, H&E staining, and Micro-CT analysis were used to evaluate joint inflammation. The levels of RIPK1-dependent necroptosis related proteins and inflammatory cytokines were detected by qRT-PCR, ELISA and Western blot, and the cell death morphology was detected by flow cytometry analysis and high-content imaging analysis. The plasma levels of RIPK1 and MLKL in RA patients were higher than those in healthy people, and were positively correlated with the severity of RA. KW2449 could reduce joint swelling, joint bone destruction, tissue damage, and the plasma levels of inflammatory cytokines in CIA rats. Lipopolysaccharide combined with zVAD (LZ) could induce necroptosis in RAW 264.7 cells, which could be reduced by KW2449. RIPK1-dependent necroptosis related proteins and inflammatory factors increased after LZ induction and decreased after KW2449 treatment or knockdown of RIPK1. These findings suggest that the overexpression of RIPK1 is positively correlated with the severity of RA. KW2449, as a small molecule inhibitor targeting RIPK1, has the potential to be a therapeutic strategy for RA treatment by inhibiting RIPK1-dependent necroptosis.

SARS-CoV-2 spike protein promotes inflammatory cytokine activation and aggravates rheumatoid arthritis

BackgroundCoronavirus disease 2019 (COVID-19) induces inflammation, autoantibody production, and thrombosis, which are common symptoms of autoimmune diseases, including rheumatoid arthritis (RA). However, the effect of COVID-19 on autoimmune disease is not yet fully understood.MethodsThis study was performed to investigate the effects of COVID-19 on the development and progression of RA using a collagen-induced arthritis (CIA) animal model. Human fibroblast-like synoviocytes (FLS) were transduced with lentivirus carrying the SARS-CoV-2 spike protein gene in vitro, and the levels of inflammatory cytokine and chemokine expression were measured. For in vivo experiments, CIA mice were injected with the gene encoding SARS-CoV-2 spike protein, and disease severity, levels of autoantibodies, thrombotic factors, and inflammatory cytokine and chemokine expression were assessed. In the in vitro experiments, the levels of inflammatory cytokine and chemokine expression were significantly increased by overexpression of SARS-CoV-2 spike protein in human FLS.ResultsThe incidence and severity of RA in CIA mice were slightly increased by SARS-CoV-2 spike protein in vivo. In addition, the levels of autoantibodies and thrombotic factors, such as anti-CXC chemokine ligand 4 (CXCL4, also called PF4) antibodies and anti-phospholipid antibodies were significantly increased by SARS-CoV-2 spike protein. Furthermore, tissue destruction and inflammatory cytokine level in joint tissue were markedly increased in CIA mice by SARS-CoV-2 spike protein.ConclusionsThe results of the present study suggested that COVID-19 accelerates the development and progression of RA by increasing inflammation, autoantibody production, and thrombosis.59fM9u75V6mBvt9-5NRNd5Video