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ID PMID Title PublicationDate abstract
34380700 Preclinical models of arthritis for studying immunotherapy and immune tolerance. 2021 Oct Increasingly earlier identification of individuals at high risk of rheumatoid arthritis (RA) (eg, with autoantibodies and mild symptoms) improves the feasibility of preventing or curing disease. The use of antigen-specific immunotherapies to reinstate immunological self-tolerance represent a highly attractive strategy due to their potential to induce disease resolution, in contrast to existing approaches that require long-term treatment of underlying symptoms.Preclinical animal models have been used to understand disease mechanisms and to evaluate novel immunotherapeutic approaches. However, models are required to understand critical processes supporting disease development such as the breach of self-tolerance that triggers autoimmunity and the progression from asymptomatic autoimmunity to joint pain and bone loss. These models would also be useful in evaluating the response to treatment in the pre-RA period.This review proposes that focusing on immune processes contributing to initial disease induction rather than end-stage pathological consequences is essential to allow development and evaluation of novel immunotherapies for early intervention. We will describe and critique existing models in arthritis and the broader field of autoimmunity that may fulfil these criteria. We will also identify key gaps in our ability to study these processes in animal models, to highlight where further research should be targeted.
33611834 Periodontal inflammation and distinct inflammatory profiles in saliva and gingival crevicu 2021 Oct BACKGROUND: The association of periodontitis and Porphyromonas gingivalis (Pg) with rheumatoid arthritis (RA) is incompletely understood. To gain further insights, we evaluated periodontal status, oral, serum and joint inflammatory profiles, and Pg biomarkers in RA patients. METHODS: In this cross-sectional study, we evaluated 33 patients with predominantly untreated new-onset RA, 20 healthy individuals (HIs), and 20 non-RA chronic periodontitis patients. Thirteen mediators (IFN-γ, IL-10, IL-17A, IL-6, IL-8, CXCL10, TNF-α, CXCL13, IL-23, MMP-1, MMP-3, MMP-8, MMP-9) were measured in serum, synovial fluid, saliva and gingival crevicular fluid (GCF) by multiplex immunoassay. Serum Pg IgG antibodies and subgingival Pg DNA were determined. RESULTS: Most RA patients (91%) received routine dental care; only one currently smoked. Ten (30.3%) had periodontal health, 13 (39.4%) had gingivitis, and 10 (30.3%) had periodontitis. Th1 and innate immune responses predominated in serum. Many mediators were concentrated in joints, particularly IL-6, IL-8, and CXCL10. However, salivary and GCF profiles were more restricted, emphasizing neutrophilic inflammation (IL-8, MMP-8) and MMP-9. Compared with HI, most RA patients, regardless of periodontal status, had significantly elevated oral fluid levels of these mediators, with suppression of GCF IL-10, a pattern similar to non-RA periodontitis patients. Pg antibodies or DNA however were primarily associated with clinical periodontitis. CONCLUSIONS: Despite routine dental care, RA patients often had inflammation in oral fluids, but inflammatory profiles differed from serum and joints. Neutrophilic inflammatory profiles in oral fluids, regardless of periodontal status, suggests that gingival tissues are a common, and often unrecognized, site of extra-articular inflammation in RA.
34051386 Reproducibility and diagnostic value of a new method using ratios to diagnose anterior atl 2021 Oct OBJECTIVES: Measures on conventional radiography are used to detect, especially in rheumatoid arthritis, upper cervical spine instabilities (CSIs) with the anterior and posterior atlanto-dental intervals (AADI and PADI) measurements. Our objective was to evaluate the diagnostic performance and reliability of AADIs and PADIs extrapolated based on ratios in assessing anterior atlanto-axial subluxation (aAAS) when plain radiographs do not allow the measures. METHODS: Radiographies of 119 patients were randomly selected. Two blinded observers performed two measurements of the odontoid sagittal diameter (O), axis body base sagittal diameter (C2), AADI, PADI, Clark station and Ranawat index, and the AADI/O, AADI/C2, PADI/O and PADI/C2 ratios were calculated. The diagnostic value of AADI and PADI extrapolated from the AADI/O, AADI/C2, PADI/O and PADI/C2 ratios was evaluated using ROC curves, with AADI>2.9mm used as the gold standard. RESULTS: Among the 119 patients, 12 patients had aAAS (AADI>2.9mm), 6 of them had severe aAAS (AADI>8.9mm and/or a PADI<14mm), and 6 patients had vertical AAS (Clarks station=2 or 3 and/or Ranawat index<13mm). The AADI extrapolated from the AADI/O and AADI/C2 ratios has excellent intra- and inter-observer reproducibility. The diagnostic value of the extrapolated AADI was high for aAAS (sensitivity 92%; specificity of 100%) and severe aAAS (sensitivity75%; specificity 100%). The diagnostic value of the extrapolated PADI was good but lower than the diagnostic value of the extrapolated AADI. CONCLUSION: Extrapolated AADI can be used instead AADI to detect aAAS and severe aAAS.
33820460 Ibuprofen-based advanced therapeutics: breaking the inflammatory link in cancer, neurodege 2021 Feb Ibuprofen is a classical nonsteroidal anti-inflammatory drug (NSAID) highly prescribed to reduce acute pain and inflammation under an array of conditions, including rheumatoid arthritis, osteoarthritis, dysmenorrhea, and gout. Ibuprofen acts as a potential inhibitor for cyclooxygenase enzymes (COX-1 and COX-2). In the past few decades, research on this small molecule has led to identifying other possible therapeutic benefits. Anti-tumorigenic and neuroprotective functions of Ibuprofen are majorly recognized in recent literature and need further consideration. Additionally, several other roles of this anti-inflammatory molecule have been discovered and subjected to experimental assessment in various diseases. However, the major challenge faced by Ibuprofen and other drugs of similar classes is their side effects, and tendency to cause gastrointestinal injury, generate cardiovascular risks, modulate hepatic and acute kidney diseases. Future research should also be conducted to deduce new methods and approaches of suppressing the unwanted toxic changes mediated by these drugs and develop new therapeutic avenues so that these small molecules continue to serve the purposes. This article primarily aims to develop a comprehensive and better understanding of Ibuprofen, its pharmacological features, therapeutic benefits, and possible but less understood medicinal properties apart from major challenges in its future application.KEY POINTSIbuprofen, an NSAID, is a classical anti-inflammatory therapeutic agent.Pro-apoptotic roles of NSAIDs have been explored in detail in the past, holding the key in anti-cancer therapies.Excessive and continuous use of NSAIDs may have several side effects and multiple organ damage.Hyperactivated Inflammation initiates multifold detrimental changes in multiple pathological conditions.Targeting inflammatory pathways hold the key to several therapeutic strategies against many diseases, including cancer, microbial infections, multiple sclerosis, and many other brain diseases.
33470401 Association between environmental air pollution and rheumatoid arthritis flares. 2021 Oct 2 OBJECTIVES: Environmental air pollution has been linked to the pathogenesis of RA. Nevertheless, evidence linking higher concentrations of air pollutants with the risk of RA reactivations is missing. The objective of the present study was to determine the association between RA flares and air pollution. METHODS: We collected longitudinal data of patients affected by RA and of the daily concentration of air pollutants in the Verona area. We designed a case-crossover study. We compared the exposure to pollutants in the 30-day and 60-day periods preceding an arthritic flare referent to the 30-day and 60-day preceding a low-disease activity visit. RESULTS: The study included 888 patients with RA with 3396 follow-up visits; 13 636 daily air pollution records were retrieved. We found an exposure-response relationship between the concentration of air pollutants and the risk of having abnormal CRP levels. Patients exposed to greater concentrations of air pollutants were at higher risk of having CRP levels ≥5 mg/l. Concentrations of CO, NO, NO2, NOx, PM10, PM2.5 and O3 were higher in the 60-day period preceding a flare. CONCLUSIONS: We found a striking association between air pollution and RA disease severity and reactivations in a cohort of patients followed over a 5-year period. The exposure to high levels of air pollutants was associated with increased CRP levels and a higher risk of experiencing a flare of arthritis. This excessive risk was evident at very low levels of exposure.
34019595 Associations of ultrasound-based inflammation patterns with peripheral innate lymphoid cel 2021 OBJECTIVES: We aimed to explore the associations of musculoskeletal inflammation patterns with peripheral blood innate lymphoid cell (ILC) populations, serum cytokines/chemokines, and treatment response to methotrexate in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA). METHODS: We enrolled 100 patients with either RA or SpA and performed ultrasound to evaluate power Doppler signals for synovitis (52 joint regions), tenosynovitis (20 tendons), and enthesitis (44 sites). We performed clustering analysis using unsupervised random forest based on the multi-axis ultrasound information and classified the patients into groups. We identified and counted ILC1-3 populations in the peripheral blood by flow cytometry and also measured the serum levels of 20 cytokines/chemokines. We also determined ACR20 response at 3 months in 38 patients who began treatment with methotrexate after study assessment. RESULTS: Synovitis was more prevalent and severe in RA than in SpA, whereas tenosynovitis and enthesitis were comparable between RA and SpA. Patients were classified into two groups which represented synovitis-dominant and synovitis-nondominant inflammation patterns. While peripheral ILC counts were not significantly different between RA and SpA, they were significantly higher in the synovitis-nondominant group than in the synovitis-dominant group (ILC1-3: p = 0.0007, p = 0.0061, and p = 0.0002, respectively). On the other hand, clustering of patients based on serum cytokines/chemokines did not clearly correspond either to clinical diagnoses or to synovitis-dominant/nondominant patterns. The synovitis-dominant pattern was the most significant factor that predicted clinical response to methotrexate (p = 0.0065). CONCLUSIONS: Musculoskeletal inflammation patterns determined by ultrasound are associated with peripheral ILC counts and could predict treatment response to methotrexate.
34656753 Cognitive impairment in patients with rheumatoid arthritis: A systematic review and meta-a 2022 May OBJECTIVE: An increasing number of studies have demonstrated cognitive impairment in patients with rheumatoid arthritis (RA). The literature indicates many factors play an important role in this clinical problem, such as the severity of depressive symptoms and the treatment used. The aim of this study was to systematically review studies comparing cognitive functioning between healthy participants and RA patients and to determine both the severity and potential moderators of cognitive impairment. METHODS: For this purpose, 16 studies that fulfilled all selection criteria were carefully selected. Altogether, 921 patients with RA (812 women and 109 men) and 700 controls participated in these studies. Due to the inability to perform a network meta-analysis, it was decided to determine the effect sizes for studies which used the same measurement methods. RESULTS: The analysis demonstrated greater impairment of cognitive functioning in patients with RA than in healthy controls, with effect sizes ranging from small to large, depending on the assessment method used in the study. CONCLUSIONS: The study pinpoints potential biases, lack of replication, and inconsistencies in reporting data as possible confounding factors and suggests further recommendations for assessment methods, research directions and clinical implications. CLINICAL TRIAL REGISTRATION: Not applicable.
33640011 Comprehensive assessment of alterations in hand deformities over 11 years in patients wit 2021 Feb 27 BACKGROUND: Although drug therapy for rheumatoid arthritis (RA) has recently improved, treating patients with established disease, whose hands have three major deformities (thumb deformity, finger deformities, and ulnar drift), remains a challenge. The underlying complex pathophysiology makes understanding these deformities difficult, and comprehensive assessment methods require accumulated skill with long learning curves. We aimed to establish a simpler composite method to understand the pathophysiology of and alterations in the hand deformities of patients with RA. METHODS: We established a rheumatoid hand cohort in 2004 and clinically evaluated 134 hands (67 patients). We repeated the evaluations in 2009 (100 hands of 52 patients) and 2015 (63 hands of 37 patients) after case exclusion. Thumb deformities, finger deformities (swan-neck and boutonnière deformity), and ulnar drift were semi-quantitated and entered as parameters into a two-step cross-sectional cluster analysis for the data in 2004. The parameters in each cluster were plotted at each evaluation point. Two-way analysis of covariance was used to examine whether differences existed between evaluation points and clusters of deformity parameters. RESULTS: Five clusters most appropriately described hand deformity: (i) cluster 1, minimal deformity; (ii) cluster 2, type 1 thumb deformity; (iii) cluster 3, thumb deformity and severe boutonnière deformity; (iv) cluster 4, type 2 or 3 thumb deformity and severe ulnar drift; and (v) cluster 5, thumb deformity and severe swan-neck deformity. Clusters 1 and 2 had higher function than cluster 5, and cluster 3 had moderate function. Clusters 1-4 had similar disease duration but showed different paths of deformity progression from disease onset. Clusters 1 and 2 represented conservative deformity parameters and clusters 3, 4, and 5 represented progressive deformity parameters. Over time, thumb deformity evolved into other types of deformities and swan-neck deformity worsened significantly. CONCLUSIONS: Our comprehensive analysis identified five deformity patterns and a progressive course in the rheumatoid hand. Knowledge of the characteristics of progressive deformity parameters may allow rheumatologists to more easily implement practical interventions and determine functional prognosis.
34096679 Survivin promotes rheumatoid arthritis fibroblast-like synoviocyte cell proliferation, and 2021 Jul BACKGROUND: Survivin have been shown to play a crucial role in rheumatoid arthritis (RA); however, the regulatory mechanism of survivin in RA has not been fully elucidated. This study aims to investigate the effect of survivin on the proliferation and apoptosis of human RA fibroblast-like synoviocyte (RA-HFLS) cells in RA and its underlying mechanism through the NOTCH pathway. METHODS: The RA synovial tissues of 65 RA patients with partial resection of synovium of knee joint by arthroscopy were collected. The expression of survivin in synovial tissue was detected by immunohistochemistry, and the correlation of survivin expression and clinical-pathological parameters of patients was analyzed. In vitro, the proliferation of HFLS and RA-HFLS were detected by MTT; the apoptosis of HFLS and RA-HFLS were detected by flow cytometry; the expression of survivin proteins, key protein factors (Notch1, Jagged1, Hes1) in the Notch pathway, and angiogenesis-related proteins (vascular endothelial growth factor receptor 1 [VEGFR1], Ang1, Ang2) were determined by western blot. RESULTS: We found that survivin was highly expressed in RA synovial tissues and RA-HFLS cells, and was positively correlated with erythrocyte sedimentation rate, cyclic citrullinated peptide, C-reactive protein, Disease Activity Score of 28 joints and other pathological indexes. Knockdown survivin induces RA-HFLS cell apoptosis, suppresses proliferation and the expression of VEGFR1, Ang1, Ang2. In addition, blocking Notch pathway using FLI-06 significantly down-regulated survivin expression. When survivin is up-regulated, it promotes RA-HFLS cell proliferation, the expression of VEGFR1, Ang1, Ang2 and suppresses apoptosis by activating the NOTCH. CONCLUSION: This study confirmed that survivin promotes RA-HFLS cell proliferation, the expression of angiogenesis-related proteins and suppresses apoptosis by activating the NOTCH pathway.
34242749 Recent advances on signaling pathways and their inhibitors in rheumatoid arthritis. 2021 Sep Rheumatoid arthritis (RA) is characterized by systemic synovitis leading to joint destruction in which imbalances in pro-inflammatory and anti-inflammatory cytokines promote the induction of autoimmunity. Some pro-inflammatory cytokines can trigger the signaling pathways which responsible for immune-mediated inflammation in RA, and the activated signaling pathways produce pro-inflammatory cytokines, resulting in aggravation of RA. Hence, understanding of the signaling pathways and their inhibitors might be advantageous in the development of therapeutic targets and new drugs for RA. In the current review, we summarize the signaling pathways involved in the pathogenesis of RA as well as the potential role of specific inhibitors in its management. We hope this paper may serve a reference for future studies on signaling pathways implicated in the pathogenesis of RA and benefit the treatment of RA.
33026178 Disease severity affects myocardial functions in patients with treatment-naive early rheum 2021 Apr OBJECTIVES: The cross-sectional study aimed to assess myocardial functions using global longitudinal strain (GLS) echocardiography and arrhythmia parameters with treatment naive newly diagnosed rheumatoid arthritis (RA) and no clinical evidence of cardiovascular disease (CVD). METHODS: Seventy seven newly diagnosed treatment-naive RA patients were enrolled. Disease severity was evaluated according to rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) positivity, and Disease Activity Score 28 C-reactive protein (DAS28 CRP). Myocardial functions were assessed using conventional echocardiography and GLS technique and electrocardiogram parameters cQT and Tp-e/cQT. RESULTS: Twenty three patients had severe disease while 54 patients were non-severe. The Left Ventricle GLS (17.98 ± 1.24 vs 21.29 ± 1.03, P < .001), cQT (428.71 ± 9.05 vs 394.61 ± 17.83, P < .001), Tp-e/cQT (0.19 ± 0.02 vs 0.16 ± 0.01, P < .001) for severe RA patients was reduced compared to RA non-severe patients. Penalized maximum likelihood estimation logistic regression analysis revealed LVGLS as the only significantly independent predictor of severe RA disease (OR 0.70, CI 95% 0.52-0.92, P = .001). Receiver operating characteristic (ROC) curves of the LVGLS was revealed 19.9 as GLS discriminative value with 88.8% positive predictive value for predicting severity. Severe RA risk increases when log-odds value was over 0, corresponds to LVGLS value less than 18 by partial effect plots. CONCLUSION: RA severity was associated with lower LV systolic myocardial function and increased arrhythmia parameters. Only LVGLS was significantly independent predictor of RA disease severity.
33901204 Understanding interactions between risk factors, and assessing the utility of the additive 2021 Understanding the genetic background of complex diseases requires the expansion of studies beyond univariate associations. Therefore, it is important to use interaction assessments of risk factors in order to discover whether, and how genetic risk variants act together on disease development. The principle of interaction analysis is to explore the magnitude of the combined effect of risk factors on disease causation. In this study, we use simulations to investigate different scenarios of causation to show how the magnitude of the effect of two risk factors interact. We mainly focus on the two most commonly used interaction models, the additive and multiplicative risk scales, since there is often confusion regarding their use and interpretation. Our results show that the combined effect is multiplicative when two risk factors are involved in the same chain of events, an interaction called synergism. Synergism is often described as a deviation from additivity, which is a broader term. Our results also confirm that it is often relevant to estimate additive effect relationships, because they correspond to independent risk factors at low disease prevalence. Importantly, we evaluate the threshold of more than two required risk factors for disease causation, called the multifactorial threshold model. We found a simple mathematical relationship (square root) between the threshold and an additive-to-multiplicative linear effect scale (AMLES), where 0 corresponds to an additive effect and 1 to a multiplicative. We propose AMLES as a metric that could be used to test different effects relationships at the same time, given that it can simultaneously reveal additive, multiplicative and intermediate risk effects relationships. Finally, the utility of our simulation study was demonstrated using real data by analyzing and interpreting gene-gene interaction odds ratios from a rheumatoid arthritis case-control cohort.
32249644 Mortality of Sepsis in Patients With Rheumatoid Arthritis: A Single-Center Retrospective A 2021 Jul INTRODUCTION/BACKGROUND: Patients with rheumatoid arthritis (RA) have a high risk of infections that may require intensive care unit (ICU) admission in case of resulting sepsis. Data regarding the mortality of these patients are very limited. This study investigated clinical characteristics and outcomes of patients with RA admitted to the ICU for sepsis and compared the results to a control cohort without RA. METHODS: All patients with RA as well as sex-, age-, and admission year-matched controls admitted to the ICU of a university hospital for sepsis between 2006 and 2019 were retrospectively analyzed. Mortality was calculated for both the groups, and multivariate logistic regression was used to determine independent risk factors for sepsis mortality. The positive predictive value of common ICU scores was also investigated. RESULTS: The study included 49 patients with RA (mean age 67.2 ± 9.0 years, 63.3% females) and 51 matched controls (mean age 67.4 ± 9.5 years, 64.7% females). Among the patients with RA, 42.9% (n = 21) were treated with conventional synthetic (cs) disease-modifying antirheumatic drugs (DMARDs) and 30.6% (n = 15) received glucocorticoids only. Seven (14.3%) patients received biologic (b) DMARDs. The hospital mortality was higher among patients with RA (42.9% vs 15.7%, P = .0016). Rheumatoid arthritis was independently associated with mortality in multivariate logistic regression (P = .001). In patients with RA, renal replacement therapy (P = .024), renal failure (P = .027), and diabetes mellitus (P = .028) were independently associated with mortality. Acute Physiology and Chronic Health Evaluation II (APACHE II), Simplified Acute Physiology Score II (SAPS II), and Sequential Organ Failure Assessment (SOFA) scores were good predictors of sepsis mortality in patients with RA (APACHE II area under the curve [AUC]: 0.78, P = .001; SAPS II AUC: 0.78, P < .001; SOFA AUC 0.78, P < .001), but their predictive power was higher among controls. CONCLUSIONS: Hospital sepsis mortality was higher in patients with RA than in controls. Rheumatoid arthritis itself is independently associated with an increased sepsis mortality. Renal replacement therapy, renal failure, and diabetes were associated with an increased mortality. Common ICU scores were less well predictors of sepsis mortality in patients with RA compared to non-RA controls.
33592002 The anti-arthritis effect of sulforaphane, an activator of Nrf2, is associated with inhibi 2021 Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is an important transcription factor that plays a pivotal role in cellular defense against oxidative injury. Nrf2 signaling is involved in attenuating autoimmune disorders such as rheumatoid arthritis (RA). B cells play several roles in the pathogenesis of RA, such as in autoantibody production, antigen presentation, and T-cell activation. We investigated the anti-arthritic mechanisms of sulforaphane, an activator of Nrf2, in terms of its effect on B cells. To investigate the effect of sulforaphane on collagen-induced arthritis (CIA), sulforaphane was administered intraperitoneally after CIA induction. Hematoxylin and eosin-stained sections were scored for inflammation, pannus invasion, and bone and cartilage damage. We assessed the expression levels of inflammation-related factors by real-time PCR and the levels of various IgG subclasses by enzyme-linked immunosorbent assay. Sulforaphane treatment reduced the arthritis score and the severity of histologic inflammation in CIA mice. The joints from sulforaphane-treated CIA mice showed decreased expression of interleukin (IL)-6, IL-17, tumor necrosis factor (TNF)-α, receptor activator of NF-κB ligand, and tartrate-resistant acid phosphatase. Sulforaphane-treated mice showed lower circulating levels of type-II-collagen-specific IgG, IgG1, and IgG2a. In vitro, sulforaphane treatment significantly reduced the differentiation of lipopolysaccharide-stimulated murine splenocytes into plasma B cells and germinal-center B cells. Finally, sulforaphane significantly inhibited the production of IL-6, TNF-α, and IL-17 by human peripheral blood mononuclear cells stimulated with an anti-CD3 monoclonal antibody in a dose-dependent manner. Inhibition of differentiation into plasma B and Germinal Center B cells may be the mechanism underlying the anti-arthritic effect of sulforaphane.
32681975 Pop a pill or give myself a shot? Patient perspectives of disease-modifying anti-rheumatic 2021 Jan OBJECTIVE: To assess how patients with rheumatoid arthritis (RA) decide whether to add oral disease-modifying anti-rheumatic drugs (DMARDs) versus injectable biologic DMARDs when methotrexate response is inadequate. METHODS: Using nominal group technique (NGT), RA patients answered the question "What sort of things are important to you when you make a decision between adding pills versus injectable medications to treat rheumatoid arthritis when methotrexate fails to control RA disease activity?" Patients nominated, discussed, and voted for the responses. RESULTS: Forty-seven RA patients participated: Birmingham (n=6 NG; 21 patients) and New York City (n=4 NG; 26 patients). They were predominantly female (85%), 70% white, with a mean age of 64.5 years and 58% had>10-year RA duration. Present/past DMARDs included methotrexate only in 6%, other traditional DMARDs in 15%, glucocorticoids in combination with traditional DMARDs in 11%, and biologics and/or Jak-kinase inhibitors in 68% of participants. Voted domains in order were: (1) efficacy/effectiveness and the onset/mode of action (78/282 votes); (2) side effects/fear of side effects (84/282 votes); (3) cost including out of pocket, co-payments and patient responsibility (54/282 votes); (4) convenience/frequency of use (27/282 votes); (5) doctor's opinion (20/282 votes); (6) other drugs/comorbidity/other patient's experience/effects on other people (3/282 votes); (7) fear of needles (8/282 votes); and (8) newness of the medication (8/282 votes). CONCLUSIONS: We identified the patient perspective regarding the choice between adding oral versus injectable DMARD once methotrexate failed to control RA disease activity. This knowledge can help in shared decision-making for DMARD choice in RA treatment.
34918708 The influence of the -94 Ins/Del ATTG polymorphism of NFkB on the anti-CCP antibody levels 2021 Dec 17 Rheumatoid arthritis (RA) is an autoimmune disease characterized by an inflammatory process that affects mainly synovial tissue in joints, and by the production of cyclic citrullinated peptides (anti-CCP) antibodies. In the inflammatory process the regulation of the nuclear factor kappa B (NFkB) transcription factor activation is a key point in the production of inflammatory cytokines. On the other hand, polymorphisms in several genes could contribute to the promotion of the inflammatory process observed in RA, and the association of the rs28362491 polymorphism in the NFkB gene with RA has been studied in different population. Therefore, it could be one of the interest targets to analyze their association with RA in a Mexican population.This is a case-control study to determine the influence of rs28362491 in the NFkB gene on RA and on clinical features of this disease, such as anti-CCP antibody levels, Disease Activity Score, and Health Assessment Questionnaire-Disability Index.The genotype of rs28362491 in the NFkB gene was determined in 140 RA patients and 135 healthy controls using the polymerase chain reaction-restriction fragment length polymorphism method with the enzyme PflMI. The following clinical variables were also determined: anti-CCP levels, Disease Activity Score, and Spanish version of the Health Assessment Questionnaire Disability-Index.Although no association of the polymorphism as a risk/protection factor with RA was found, the RA patients who carried the Ins/Ins genotype showed higher anti-CCP levels, while those with the Del/Del genotype showed higher Spanish version of the Health Assessment Questionnaire-Disability Index levels, compared to the other genotypes.The NFkB -94 Ins/Del ATTG (rs28362491) polymorphism is, therefore, associated with higher levels of anti-CCP antibodies, though no significant association as a risk or protection factor in RA cases was identified.
34030529 LncRNA FOXD2-AS1 promotes cell proliferation and invasion of fibroblast-like synoviocytes 2021 Aug Rheumatoid arthritis (RA) is a chronic autoimmune disorder that leads to systemic inflammation of diarthrodial joint, synovial hyperplasia, cartilage damage, and ultimately joint destruction and deformity. As the dominant non-immune cells in the synovium, fibroblast-like synoviocytes (FLSs) significantly contribute to the deterioration of RA. Our study aimed to explore the regulatory role of long non-coding RNA FOXD2-AS1 in RA progression. Compared to patients with joint trauma, the expression of FOXD2-AS1 was elevated in serum and synovial tissue samples of RA patients. FOXD2-AS1 knockdown inhibited the proliferation and invasion of rheumatoid FLSs but restored their apoptotic ability. Furthermore, FOXD2-AS1 acted as a sponge for microRNA (miR)-331-3p. The expressions of FOXD2-AS1 and miR-331-3p in synovial tissues of RA patients were negatively correlated. Protein inhibitor of activated STAT 3 (PIAS3) was predicted as a downstream target of miR-331-3p. The expressions of FOXD2-AS1 and PIAS3 in synovial tissues of RA patients were positively correlated, whereas a negative correlation was observed between the levels of miR-331-3p and PIAS3. Moreover, increased proliferation and invasion of rheumatoid FLSs induced by FOXD2-AS1 overexpression was inhibited by the knockdown of PIAS3. In summary, this study demonstrated that FOXD2-AS1 promoted RA progression via regulating the miR-331-3p/PIAS3 pathway, suggesting that therapeutic strategies based on the FOXD2-AS1/miR-331-3p/PIAS3 axis may represent a promising treatment approach for RA patients.
34139524 Intestinal permeability in spondyloarthritis and rheumatoid arthritis: A systematic review 2021 Aug OBJECTIVES: To describe the current methods usable to assess intestinal permeability in spondyloarthritis (SpA) and rheumatoid arthritis (RA), to analyze the available data on intestinal permeability in SpA and RA patients and the effects of drugs such as non-steroidal anti-inflammatory drugs (NSAIDs) on intestinal permeability. METHODS: A systematic review was conducted. Medline, Embase, and Cochrane Library databases were searched. Studies published in the last 40 years (January 1980-September 2020) with patients with SpA and/or RA assessing the intestinal permeability were selected. RESULTS: A total of 2916 articles were collected, after discarding 1125 duplicate articles, we analyzed the titles and abstracts of 1791 studies. There were 459 articles that met the inclusion criteria and whose text was read. A total of 23 studies were included in the final analysis. Sample sizes ranged from 6 to 206 participants. In patients with spondyloarthritis, a large majority of studies reported an increase in intestinal permeability regardless of the method used. No increase in intestinal permeability was found in RA patients compared to healthy subject in half of the studies. NSAID treatment does not appear to influence intestinal permeability in SpA and seems to increase the intestinal permeability in RA patients as much as in healthy subjects. CONCLUSION: The results of our review suggest the existence of increased intestinal permeability in SpA patients even in the absence of NSAIDs use and regardless of the method assessing the intestinal permeability. Studies in RA patients are more controversial.
33033859 Pathological features of established osteoarthritis with hydrathrosis are similar to rheum 2021 May OBJECTIVES: The prevalence of rheumatoid arthritis (RA) and knee osteoarthritis (OA) is increasing with our aging society. Some reports suggest that OA with effusion synovitis develops into RA and early OA patients with effusion are pathologically similar to those with RA. The purpose of this study was to examine the relationship between histological features of established knee OA with or without effusion and RA. METHODS: Seventy-nine patients in which synovial specimens were obtained during total knee arthroplasty were included. Patients were divided into an RA group, OA with effusion (OA+) group, and OA without effusion (OA-) group. The Rooney synovitis score and serum matrix metalloproteinase (MMP)-3 levels were compared among groups. We also examined the correlation between the Rooney synovitis score and its sub-scores with MMP-3 levels. RESULTS: The total Rooney score was significantly higher in the RA group than in the OA+ and OA- groups (25.4 vs 17.1, p < 0.01; 25.4 vs 13.5, p < 0.001, respectively). This score also was significantly higher in the OA+ group than in the OA- group (p < 0.05). The proliferating blood vessels score, perivascular infiltrates of lymphocytes score, focal aggregates of lymphocytes score, and diffuse infiltrates of lymphocytes score were significantly higher in the RA group than in the OA- group (7.05 vs 3.29, 4.95 vs 3.43, 3.29 vs 1.46, and 2.26 vs 1.18, respectively; p < 0.05), but not compared with the OA+ group. The total Rooney score demonstrated a significantly positive correlation with serum MMP-3 levels in the RA group (r = 0.61; 95% CI: 0.28 to 0.81; p < 0.01) and in the OA+ group (r = 0.57; 95% CI: 0.24 to 0.78; p < 0.01). CONCLUSIONS: Previous reports showed the histological similarity between RA and early OA with effusion. We confirmed this histological similarity, in particular the distribution of lymphocytes, between RA and established OA with effusion. It is possible that cases diagnosed as OA with effusion might progress to overt RA. KEY POINTS: • Histological similarity was observed between RA and established OA with effusion.
33124564 Major vault protein/lung resistance related protein: a novel biomarker for rheumatoid arth 2021 Sep OBJECTIVES: Rheumatoid arthritis (RA) can lead to joint destruction and early institution of effective treatment can preserve joint function. Biomarkers can establish early diagnosis and predict effect of treatment. Vault particles, large cytoplasmic ribonucleoprotein particles that participate in inflammation, might serve as biomarkers. The aim of this study was to assess the diagnostic and the prognostic value of major vault protein (MVP) and their antibodies in RA. METHODS: Serum samples from 159 RA patients, 26 early RA (ERA) patients, 21 patients with osteoarthritis (OA) and 30 healthy individuals were tested for MVP, anti-cyclic citrullinated peptide (anti-CCP) and C-reactive protein (CRP) using enzyme-linked immunosorbent assays (ELISA). Rheumatoid factor (RF) was tested by nephelometry, and anti-MVP antibodies were detected by anti-MVP peptide ELISA using an in-house protocol. RESULTS: MVP levels were higher in RA and ERA, compared to OA and healthy controls (p<0.00001). A combination of MVP with RF or anti-CCP showed an improved diagnostic accuracy compared to RF or anti-CCP alone in RA and ERA. MVP exhibited similar AUC levels to anti-CCP and RF in RA whereas in ERA, MVP exhibited the same or slightly higher AUC levels, compared to anti-CCP and RF, respectively. High MVP levels were associated with lack of response to treatment. Levels of anti-MVP peptide 2 antibodies were significantly higher in RA compared to healthy controls (t= 2.73, p=0.007). CONCLUSIONS: MVP and autoantibodies against MVP may have the potential to serve as diagnostic and prognostic biomarkers in RA.