Search for: rheumatoid arthritis methotrexate autoimmune disease biomarker gene expression GWAS HLA genes non-HLA genes
| ID | PMID | Title | PublicationDate | abstract |
|---|---|---|---|---|
| 35371044 | Role of Interleukin-17A in the Pathomechanisms of Periodontitis and Related Systemic Chron | 2022 | Periodontitis is a chronic inflammatory and destructive disease caused by periodontal microbial infection and mediated by host immune response. As the main cause of loosening and loss of teeth in adults, it is considered to be one of the most common and serious oral diseases in the world. The co-existence of periodontitis and systemic chronic inflammatory diseases such as rheumatoid arthritis, psoriasis, inflammatory bowel disease, diabetes and so on is very common. It has been found that interleukin-17A (IL-17A) secreted by various innate and adaptive immune cells can activate a series of inflammatory cascade reactions, which mediates the occurrence and development of periodontitis and related systemic chronic inflammatory diseases. In this work, we review the role of IL-17A in the pathomechanisms of periodontitis and related systemic chronic inflammatory diseases, and briefly discuss the therapeutic potential of cytokine targeted agents that modulate the IL-17A signaling. A deep understanding of the possible molecular mechanisms in the relationship between periodontitis and systemic diseases will help dentists and physicians update their clinical diagnosis and treatment ideas. | |
| 34334364 | Autoantibodies Against Unmodified and Citrullinated Human Endogenous Retrovirus K Envelope | 2022 Jan | OBJECTIVE: Autoantibodies against proteins encoded by human endogenous retrovirus K (HERV-K) have been reported in patients with rheumatoid arthritis (RA), but their relevance, if any, has remained unresolved. We revisited this question and tested if such autoantibodies may react with citrullinated epitopes on the envelope (Env) protein of HERV-K. METHODS: Immunoblotting and ELISAs were conducted with unmodified Env protein and with Env citrullinated by protein arginine deiminase 4 (PAD4). Sera from 100 patients with RA, plasma from 32 patients with juvenile idiopathic arthritis (JIA), and healthy adult and pediatric controls were included. Antibody reactivity was evaluated for correlations with clinical and laboratory variables of the patients. RESULTS: We replicated and expanded upon published data suggesting that patients with RA or JIA have autoantibodies against HERV-K Env, some with high titers. Anti-HERV-K antibodies correlated with cigarette smoking and with circulating myeloperoxidase-DNA complexes indicative of nonapoptotic neutrophil cell death. Further, most of the patients with RA, but not those with JIA, had autoantibodies that reacted more strongly with Env that was citrullinated by PAD4. These anticitrullinated Env autoantibodies correlated with seropositivity and tended to be higher in patients with erosive disease. CONCLUSION: Our data suggest that anti-HERV-K immunity is elevated in RA and JIA and may have a connection with pathogenic protein citrullination in RA. | |
| 35178811 | Effects of curcumin supplementation on metabolic parameters, inflammatory factors and obes | 2022 Apr | Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to cartilage damage with mostly accompanied by metabolic disorders. This study aimed to investigate the effects of curcumin supplementation on metabolic parameters (lipid profile and glycemic indices), inflammatory factors, visfatin levels, and obesity values in women with RA. This randomized, double-blind, placebo-controlled clinical trial was conducted on 48 women with RA. The patients were treated with curcumin (500 mg once a day) or placebo for 8 weeks. Fasting blood samples, anthropometric measurements, dietary intakes, and physical activity levels of subjects were collected at baseline and the end of the study. Curcumin supplementation significantly decreased homeostatic model assessment for insulin resistance (HOMA-IR), erythrocyte sedimentation rate, serum levels of high-sensitivity C-reactive protein and triglycerides, weight, body mass index, and waist circumference of patients compared with the placebo at the end of the study (p < .05 for all). HOMA-IR and triglyceride levels significantly increased within the placebo group. Changes in fasting blood sugar, insulin, other lipids profile, and visfatin levels were not significant in any of the groups (p > .05). These results support the consumption of curcumin, as a part of an integrated approach to modulate metabolic factors, inflammation, and adiposity in women with RA. | |
| 34424334 | Ultrasound assessment of hands and feet for synovitis at time of first clinical visit mark | 2022 May 5 | OBJECTIVES: The role of musculoskeletal US (MSUS) in routine care for diagnosing arthritis is not fully elucidated, but US is more sensitive than clinical joint examination for detecting synovitis. Therefore, the use of US may facilitate diagnosis of arthritis. The aim of the study was to assess whether MSUS examination of hands and feet in relation to the first clinical visit had an impact on the time to reach a final diagnosis and the number of clinical follow-up visits needed after first consultation. METHODS: Two cohorts referred to the outpatient arthritis clinic with suspected arthritis were compared with each other, (i) MSUS (October 2017 to June 2018) of hands and feet performed prior to the first clinical visit and (ii) MSUS (November 2016 to June 2017) was performed ad hoc, for the following aspects: time to clinical diagnosis, number of clinical visits needed, and number of US examinations. RESULTS: In total, 163 and 109 patients were included in the MSUS and comparative cohorts, respectively. Adding MSUS to the first clinical visit reduced the time to diagnosis from mean 31 (32.2) days to 12 (17.3) days (P < 0.01). The number of clinical visits needed was reduced from mean 2.8 (1.1) to 2.1 (1.3) (P < 0.01), corresponding to a reduction of 114 visits in the MSUS cohort. A final diagnosis with inflammatory arthritis was found in 76 (47%) of patients in the MSUS cohort vs 29 (27%) in the comparative cohort (P < 0.01). CONCLUSION: In patients referred for suspected arthritis, routine MSUS in relation to the first clinical visit significantly reduces time to diagnosis and number of clinical visits needed to reach a final diagnosis. | |
| 35514972 | Serum Antigenome Profiling Reveals Diagnostic Models for Rheumatoid Arthritis. | 2022 | OBJECTIVE: The study aimed to investigate the serum antigenomic profiling in rheumatoid arthritis (RA) and determine potential diagnostic biomarkers using label-free proteomic technology implemented with machine-learning algorithm. METHOD: Serum antigens were captured from a cohort consisting of 60 RA patients (45 ACPA-positive RA patients and 15 ACPA-negative RA patients), together with sex- and age-matched 30 osteoarthritis (OA) patients and 30 healthy controls. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was then performed. The significantly upregulated and downregulated proteins with fold change > 1.5 (p < 0.05) were selected. Based on these differentially expressed proteins (DEPs), a machine learning model was trained and validated to classify RA, ACPA-positive RA, and ACPA-negative RA. RESULTS: We identified 62, 71, and 49 DEPs in RA, ACPA-positive RA, and ACPA-negative RA, respectively, as compared to OA and healthy controls. Typical pathway enrichment and protein-protein interaction networks were shown among these DEPs. Three panels were constructed to classify RA, ACPA-positive RA, and ACPA-negative RA using random forest models algorithm based on the molecular signature of DEPs, whose area under curve (AUC) were calculated as 0.9949 (95% CI = 0.9792-1), 0.9913 (95% CI = 0.9653-1), and 1.0 (95% CI = 1-1). CONCLUSION: This study illustrated the serum auto-antigen profiling of RA. Among them, three panels of antigens were identified as diagnostic biomarkers to classify RA, ACPA-positive, and ACPA-negative RA patients. | |
| 35438963 | Cyclic Citrullinated Peptide Aptamer Treatment Attenuates Collagen-Induced Arthritis. | 2022 May 9 | We describe the study of a novel aptamer-based candidate for treatment of seropositive rheumatoid arthritis. The candidate is a nanoparticle-formulated cyclic citrullinated peptide aptamer, which targets autoantibodies and/or the immune reactions leading to antibody production. Due to its specificity, the peptide aptamer nanoparticles might not interfere with normal immune functions as seen with other disease-modifying antirheumatic drugs. Over a 3-week course of treatment, joint swelling and arthritis score in collagen-induced rats were significantly decreased compared with animals treated with phosphate-buffered saline, unloaded nanoparticles, or nanoparticles with a noncitrullinated control peptide. The reduction in joint swelling was associated with decreased anticitrullinated peptide autoantibody levels in the blood. Treatment with aptamer nanoparticles also increased interleukin-10 levels. The effect seen with the proposed treatment candidate could be mediated by upregulation of anti-inflammatory mediators and decreased levels of anticitrullinated peptide antibodies. | |
| 34997059 | Factors affecting drug retention of Janus kinase inhibitors in patients with rheumatoid ar | 2022 Jan 7 | This multi-center, retrospective study aimed to clarify the factors affecting drug retention of the Janus kinase inhibitors (JAKi) including baricitinib (BAR) and tofacitinib (TOF) in patients with RA. Patients were as follows; females, 80.6%; age, 60.5 years; DAS28-ESR, 4.3; treated with either BAR (n = 166) or TOF (n = 185); bDMARDs- or JAKi-switched cases (76.6%). The reasons for drug discontinuation were classified into four major categories. The drug retention was evaluated at 24 months using the Kaplan-Meier method and multivariate Cox proportional hazards modelling adjusted by confounders. Discontinuation rates for the corresponding reasons were as follows; ineffectiveness (22.3%), toxic adverse events (13.3%), non-toxic reasons (7.2%) and remission (0.0%). Prior history of anti-interleukin-6 receptor antibody (aIL-6R) ineffectiveness significantly increased the risk of treatment discontinuation due to ineffectiveness (p = 0.020). Aging (≥ 75 years) (p = 0.028), usage of PSL ≥ 5 mg/day (p = 0.017) and female sex (p = 0.041) significantly increased the risk of treatment discontinuation due to toxic adverse events. Factors not associated with treatment discontinuation were: number of prior bDMARDs or JAKi, concomitant MTX usage, difference of JAKi, and prior use of TNF inhibitor, CTLA4-Ig or other JAKi. | |
| 34187325 | Arthritis-associated osteoclastogenic macrophages (AtoMs) participate in pathological bone | 2022 Mar | Rheumatoid arthritis is a chronic form of arthritis that causes bone destruction in joints such as the knees and fingers. Over the past two decades, the clinical outcomes of rheumatoid arthritis have improved substantially with the development of biological agents and Janus kinase inhibitors. Osteoclasts are myeloid lineage cells with a unique bone-destroying ability that can lead to joint destruction. On the other hand, osteoclasts play an important role in skeletal homeostasis by supporting bone remodeling together with osteoblasts in the bone marrow under steady-state conditions. However, the same osteoclasts are considered to participate in physiological bone remodeling and joint destruction. We found that pathological osteoclasts have different differentiation pathways and regulatory transcription factors compared to physiological osteoclasts. We also identified arthritis-associated osteoclastogenic macrophages (AtoMs), which are common progenitors of pathological osteoclasts in mice and humans that develop specifically in inflamed synovial tissue. This review presents details of the newly identified AtoMs and the original intravital imaging systems that can visualize synovial tissue and pathological osteoclasts at the pannus-bone interface. | |
| 33002323 | Weight Fluctuation and the Risk of Cardiovascular Events in Patients With Rheumatoid Arthr | 2022 Feb | OBJECTIVE: Fluctuations in weight have been linked to cardiovascular (CV) outcomes in the general population. The present study was undertaken to evaluate whether weight fluctuation was independently predictive of CV events in patients with rheumatoid arthritis (RA). METHODS: We studied patients with RA from the Corrona registry. Weight change was categorized as loss of ≥10%, loss of 5-10%, stable, gain of 5-10%, and gain of ≥10%. We also categorized patients by quintile of variability in weight in prior observation periods. Cox proportional hazards models explored independent associations between time-varying weight change and weight variability and risk of CV events before and after adjusting for CV risk factors, RA disease features, and disability. RESULTS: Among 31,381 participants, those who lost or gained 10% of their weight had greater disease activity and worse physical function, and they were more likely to smoke, have diabetes mellitus, receive corticosteroids, and be disabled. In adjusted models, a greater risk of CV events was observed in those who experienced 10% weight loss (hazard ratio [HR] 1.18 [95% confidence interval (95% CI) 1.03-1.36], P = 0.02) or weight gain (HR 1.20 [95% CI 1.04-1.38], P = 0.01). The association between weight change and CV events was stronger among participants with body mass index <25 kg/m(2) for 10% weight loss (HR 1.34 [95% CI 1.08-1.66], P = 0.001] and 10% weight gain (HR 1.74 [95% CI 1.41-2.24], P < 0.001). Patients with greater variability in weight had a higher risk of CV events. CONCLUSION: Recent changes and high variability in weight predict CV events in RA, particularly among thin patients. Further study is necessary to determine if weight fluctuation has adverse cardiometabolic consequences that are independent of other risk factors. | |
| 34894260 | Effects of the COVID-19 pandemic on body composition among patients with rheumatoid arthri | 2022 Feb 28 | OBJECTIVES: To evaluate effects of the COVID-19 pandemic on body composition among patients with rheumatoid arthritis (RA). METHODS: A total 102 patients with RA were enrolled. We examined muscle mass, fat-free mass index (FFMI) and fat mass index (FMI) values using bioelectrical impedance analysis between November 2019 and January 2020 (for the first measurement) and September 2020 and January 2021 (for the second measurement). RESULTS: The muscle mass was significantly decreased from a median of 34.6 kg at the first measurement to a median of 33.9 kg at the second measurement (p = 0.002). The FFMI was significantly decreased from a median of 15.3 at the first measurement to a median of 14.8 at the second measurement (p = 0.011). CONCLUSIONS: The present study reveals that muscle mass and FFMI decreased among patients with RA during the COVID-19 pandemic. | |
| 35545292 | Genome-Wide Mapping of Plasma IgG N-Glycan Quantitative Trait Loci Identifies a Potentiall | 2022 Jun 1 | Observational studies highlight associations of IgG N-glycosylation with rheumatoid arthritis (RA); however, the causality between these conditions remains to be determined. Standard and multivariable two-sample Mendelian randomization (MR) analyses integrating a summary genome-wide association study for RA and IgG N-glycan quantitative trait loci (IgG N-glycan-QTL) data were performed to explore the potentially causal associations of IgG N-glycosylation with RA. After correcting for multiple testing (p < 2 × 10(-3)), the standard MR analysis based on the inverse-variance weighted method showed a significant association of genetically instrumented IgG N-glycan (GP4) with RA (odds ratio(GP4) = 0.906, 95% confidence interval = 0.857-0.958, p = 5.246 × 10(-4)). In addition, we identified seven significant associations of genetically instrumented IgG N-glycans with RA by multivariable MR analysis (p < 2 × 10(-3)). Results were broadly consistent in sensitivity analyses using MR_Lasso, MR_weighted median, MR_Egger regression, and leave-one-out analysis with different instruments (all p values <0.05). There was limited evidence of pleiotropy bias (all p values > 0.05). In conclusion, our MR analysis incorporating genome-wide association studies and IgG N-glycan-QTL data revealed that IgG N-glycans were potentially causally associated with RA. Our findings shed light on the role of IgG N-glycosylation in the development of RA. Future studies are needed to validate our findings and to explore the underlying physiological mechanisms in the etiology of RA. | |
| 35149192 | Anti-rheumatic activity of topical nanoemulsion containing bee venom in rats. | 2022 Mar | PURPOSE: Bee Venom (BV) has been used to treat rheumatoid arthritis (RA) for many centuries. However, its clinical use is limited by pain and fear of bee stings/injection. Nanoemulsions (NEs) are nanocarriers that are able to help their content(s) penetrate through the skin. They also act as drug reservoirs on the skin to provide an efficient, sustained-release vehicle. METHODS: In this paper, we present the development of a stable water-in-oil NE to help passing BV through the animal skin when used topically. RESULTS: Particle size of NE was 12.7 to 29.8 nm for NEs containing 0 to 150 µg/ml BV. Also, its anti-inflammatory effects were evaluated in rat models of type II collagen-induced arthritis. Topical administration of NEs containing 18.75 or 9.37 μg/ml BV were able to significantly (p < 0.05) reduce inflammation in the rat paws compared to the blank and control groups. CONCLUSION: Our findings demonstrated the efficacy of NEs containing BV to reduce inflammation caused by RA animal model. | |
| 35073310 | Endogenously produced catecholamines improve the regulatory function of TLR9-activated B c | 2022 Jan | The sympathetic nervous system (SNS) contributes to immune balance by promoting anti-inflammatory B cells. However, whether B cells possess a self-regulating mechanism by which they modulate regulatory B cell (Breg) function is not well understood. In this study, we investigated the ability of B cells to synthesize their own catecholamines upon stimulation with different B cell activators and found that expression of the enzyme tyrosine hydroxylase (TH), required to generate catecholamines, is up-regulated by Toll-like receptor (TLR)9. This TLR9-dependent expression of TH correlated with up-regulation of adrenergic receptors (ADRs), enhanced interleukin (IL)-10 production, and overexpression of the co-inhibitory ligands programmed death ligand 1 (PD-L1) and Fas ligand (FasL). Moreover, concomitant stimulation of ß1-3-ADRs together with a B cell receptor (BCR)/TLR9 stimulus clearly enhances the anti-inflammatory potential of Bregs to suppress CD4 T cells, a crucial population in the pathogenesis of autoimmune diseases, like rheumatoid arthritis (RA). Furthermore, TH up-regulation was also demonstrated in B cells during the course of collagen-induced arthritis (CIA), a mouse model for the investigation of RA. In conclusion, our data show that B cells possess an autonomous mechanism to modulate their regulatory function in an autocrine and/or paracrine manner. These findings help to better understand the function of B cells in the regulation of autoimmune diseases and the interplay of SNS. | |
| 35014010 | The Janus kinase inhibitor (baricitinib) suppresses the rheumatoid arthritis active marker | 2022 Apr | Gliostatin/thymidine phosphorylase (GLS/TP) is known to have angiogenic and arthritogenic activities in the pathogenesis of rheumatoid arthritis (RA). The novel oral Janus kinase (JAK) inhibitor baricitinib has demonstrated high efficacy in RA. However, the effect of baricitinib on fibroblast-like synoviocytes (FLSs), a key component of invasive synovitis, has not been still elucidated. This study investigated whether GLS/TP production could be regulated by JAK/signal transducers and activators of transcription (STAT) signaling in FLSs derived from patients with RA. FLSs were cultured and stimulated by interferon (IFN)γ in the presence of baricitinib. Expression levels of GLS/TP were determined using reverse transcription-polymerase chain reaction (RT-PCR), enzyme-linked immunosorbent assay (ELISA), and immunocytochemistry. Phosphorylation of STAT proteins was investigated by Western blot. In cultured FLSs, GLS/TP mRNA and protein levels were significantly induced by treatment with IFNγ and these inductions were suppressed by baricitinib treatment. Baricitinib inhibited IFNγ-induced STAT1 phosphorylation, while JAK/STAT activation played a pivotal role in IFNγ-mediated GLS/TP upregulation in RA. These results suggested that baricitinib suppressed IFNγ-induced GLS/TP expression by inhibiting JAK/STAT signaling, resulting in the attenuation of neovascularization, synovial inflammation, and cartilage destruction. | |
| 34713773 | The role of NLRP3 inflammasome in the pathogenesis of rheumatic disease. | 2022 Feb | Inflammasome is a molecular platform that is formed in the cytosolic compartment to mediate host immune responses to infection and cellular damage. Inflammasome can activate caspase-1, leading to the maturation of two inflammatory cytokines interleukin 1β (IL-1β) and IL-18 and initiation of a proinflammatory form of cell death called pyroptosis. Among various inflammasome complexes, the NLRP3 inflammasome is by far the most studied inflammasome. NLRP3 inflammasome is a key factor in regulating host immune defense against infectious microbes and cellular damage. However, the dysregulated NLRP3 inflammasome activation also participates in the pathogenesis of many human disorders. NLRP3 inflammasome plays an important role in the pathogenesis of rheumatic disease such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), Sjögren's syndrome (SS), dermatomyositis/polymyositis (DM/PM), gout, and systemic sclerosis (SSc). For example, NLRP3 inflammasome has been found highly activated in synovial tissues and peripheral blood mononuclear cells from RA patients. In this paper, we will discuss the role of NLRP3 inflammasome in the pathogenesis of rheumatic disease. | |
| 35241516 | Antidepressant Fluoxetine Does Not Appear to Interfere With Key Translational Parameters i | 2022 Mar | BACKGROUND/AIM: This study aimed to investigate the analgesic effects of fluoxetine on Lewis rats of both sexes in the adjuvant-induced arthritis (AIA) rat model. In humans, chronic pain syndromes typical of rheumatoid arthritis (RA) co-exist with depression which is often treated with fluoxetine antidepressant known to have antinociceptive effects. MATERIALS AND METHODS: The experiment was terminated on day 26, after seven days of oral treatment (days 19-25) with fluoxetine and indomethacin. The effects of treatments were assessed on the final day of the study through measuring body weight, serum concentrations of a1-acid glycoprotein, visual arthritis assessment and post mortem histopathology assessment. RESULTS: Statistically significant difference was determined in the body weight of male subjects, with indomethacin-treated animals putting on significantly more weight than the vehicle and fluoxetine-treated counterparts. No differences were found between the different treatment groups in other study assessments. CONCLUSION: The present study did not provide support for analgesic effects of fluoxetine aimed at reducing the severity of the AIA model. | |
| 34559213 | Synovial single-cell heterogeneity, zonation and interactions: a patchwork of effectors in | 2022 Mar 2 | Despite extensive research, there is still no treatment that would lead to remission in all patients with rheumatoid arthritis as our understanding of the affected site, the synovium, is still incomplete. Recently, single-cell technologies helped to decipher the cellular heterogeneity of the synovium; however, certain synovial cell populations, such as endothelial cells or peripheral neurons, remain to be profiled on a single-cell level. Furthermore, associations between certain cellular states and inflammation were found; whether these cells cause the inflammation remains to be answered. Similarly, cellular zonation and interactions between individual effectors in the synovium are yet to be fully determined. A deeper understanding of cell signalling and interactions in the synovium is crucial for a better design of therapeutics with the goal of complete remission in all patients. | |
| 35494209 | The Combination of (18)F-Fluorodeoxyglucose Positron Emission Tomography Metabolic and Cli | 2022 | OBJECTIVE: To evaluate (18)F-fluorodeoxyglucose positron emission tomography ((18)FDG PET) and clinical parameters to differentiate rheumatoid arthritis (RA) and polymyalgia rheumatic (PMR). Patients and Methods. This retrospective study evaluated 54 patients with suspected RA (n = 23) and PMR (n = 31) who underwent (18)F-FDG PET/CT before treatment. The complete diagnosis was based on each classification criterion and at least followed up for 6 months. Demographic and clinical data were also collected. Semiquantitative analysis (maximum standardized uptake value, SUVmax) of abnormal (18)F-FDG uptake was undertaken at 17 musculoskeletal sites, and two scoring systems (mean reference (liver/control) scores) were evaluated. The differential diagnostic efficacy of each independent parameter was evaluated using the receiver operating characteristic (ROC) curve. Integrated discriminatory improvement (IDI) and bootstrap tests were used to evaluate the improvement in diagnostic efficacy using a combination of multiple parameters. RESULTS: The ROC curve analysis of SUVmax indicated that the interspinous ligament showed the highest discriminative diagnostic value (sensitivity, 64.5%; specificity, 78.3%; area under the curve (AUC), 0.764; positive predictive value, 0.800; negative predictive value, 0.621). The combined model with the rheumatoid factor (RF) and metabolic parameters of (18)F-FDG PET resulted in the highest AUC of 0.892 and showed significant reclassification by IDI (IDI, 9.51%; 95% confidence interval: 0.021-0.175; P = 0.013). According to the bootstrap test, compared with RF alone, the combination of RF and metabolic parameters showed an improvement in ROC and was statistically significant (P = 0.017). CONCLUSIONS: The combination of (18)F-FDG PET metabolic and clinical parameters can further improve the differential diagnosis of RA and PMR. | |
| 35193872 | Baricitinib further enhances disease-modifying effects by uncoupling the link between dise | 2022 May | OBJECTIVES: To evaluate if baricitinib, a Janus kinase inhibitor, further enhances disease-modifying effects by uncoupling the link between disease activity and structural damage progression in patients with rheumatoid arthritis (RA) using two phase III randomised, double-blinded trials. METHODS: In RA-BEAM, patients with established RA and inadequate response to methotrexate (MTX-IR) received placebo (PBO), baricitinib 4 mg or adalimumab 40 mg on background MTX. In RA-BEGIN, conventional synthetic disease-modifying antirheumatic drug (csDMARD)-naïve patients received MTX, baricitinib 4 mg or baricitinib 4 mg plus MTX. Using linear regression analyses, joint damage progression (assessed by change from baseline in van der Heijde modification of the Total Sharp Score) was compared between treatment groups for patients achieving certain disease activity states by the Clinical Disease Activity Index. Time-averaged postbaseline responses were used to week 24 (RA-BEAM) and week 52 (RA-BEGIN). RESULTS: For MTX-IR patients, structural damage progression was reduced regardless of disease activity states in baricitinib-treated patients (p=0.6), whereas in PBO patients there was a clear dependence on disease activity states, being significantly lower in those who achieved remission/low disease activity (REM/LDA) compared with moderate/high disease activity (MDA/HDA) (p=0.02). Furthermore, the baricitinib MDA/HDA group had less damage progression than the PBO MDA/HDA group (p<0.001). For csDMARD-naïve patients, progression was lower in REM/LDA versus MDA/HDA within the MTX group (p<0.001). However, for baricitinib+MTX (p=0.5) or baricitinib monotherapy (p=0.07), progression was similar regardless of disease activity. In MDA/HDA groups, progression was lower with baricitinib+MTX (p<0.001) and numerically lower with baricitinib monotherapy (p=0.07) versus MTX. C reactive protein (≤5 mg/L and >5 mg/L) sensitivity analyses supported the primary findings. CONCLUSIONS: Baricitinib reduces structural damage progression versus PBO with background MTX and/or MTX, even in patients with MDA/HDA, showing a disease-modifying effect across all disease activity states. | |
| 35641025 | Targeting protein-protein interaction for immunomodulation: A sunflower trypsin inhibitor | 2022 Jul | Protein-protein interactions (PPI) of co-stimulatory molecules CD2-CD58 are important in the early stage of an immune response, and increased expression of these co-stimulatory molecules is observed in the synovial region of joints in rheumatoid arthritis (RA) patients. A CD2 epitope region that binds to CD58 was grafted on to sunflower trypsin inhibitor (SFTI) template structure to inhibit CD2-CD58 PPI. The peptide was incorporated with an organic moiety dibenzofuran (DBF) in its structure. The designed peptidomimetic was studied for its ability to inhibit CD2-CD58 interactions in vitro, and its thermal and enzymatic stability was evaluated. Stability studies indicated that the grafted peptidomimetic was stable against trypsin cleavage. In vivo studies using the collagen-induced arthritis (CIA) model in mice indicated that the peptidomimetic was able to slow down the progress of arthritis, an autoimmune disease in the mice model. These studies suggest that with the grafting of organic functional groups in the stable peptide template SFTI stabilizes the peptide structure, and these peptides can be used as a template to design stable peptides for therapeutic purposes. |