Clinical Phenotypes, Serological Biomarkers, and Synovial Features Defining Seropositive and Seronegative Rheumatoid Arthritis: A Literature Review.

Rheumatoid arthritis (RA) is a chronic autoimmune disorder which can lead to long-term joint damage and significantly reduced quality of life if not promptly diagnosed and adequately treated. Despite significant advances in treatment, about 40% of patients with RA do not respond to individual pharmacological agents and up to 20% do not respond to any of the available medications. To address this large unmet clinical need, several recent studies have focussed on an in-depth histological and molecular characterisation of the synovial tissue to drive the application of precision medicine to RA. Currently, RA patients are clinically divided into "seropositive" or "seronegative" RA, depending on the presence of routinely checked antibodies. Recent work has suggested that over the last two decades, long-term outcomes have improved significantly in seropositive RA but not in seronegative RA. Here, we present up-to-date differences in epidemiology, clinical features, and serological biomarkers in seronegative versus seropositive RA and discuss how histological and molecular synovial signatures, revealed by recent large synovial biopsy-based clinical trials, may be exploited to refine the classification of RA patients, especially in the seronegative group.

The role of platelets in central hubs of inflammation: A literature review.

Platelets are increasingly recognized for their multifaceted roles in inflammation beyond their traditional involvement in haemostasis. This review consolidates knowledge on platelets as critical players in inflammatory responses. This study did an extensive search of electronic databases and identified studies on platelets in inflammation, focusing on molecular mechanisms, cell interactions, and clinical implications, emphasizing recent publications. Platelets contribute to inflammation via surface receptors, release of mediators, and participation in neutrophil extracellular trap formation. They are implicated in diseases like atherosclerosis, rheumatoid arthritis, and sepsis, highlighting their interaction with immune cells as pivotal in the onset and resolution of inflammation. Platelets are central to regulating inflammation, offering new therapeutic targets for inflammatory diseases. Future research should explore specific molecular pathways of platelets in inflammation for therapeutic intervention.

Gene Expression Profiling to Unfolded Proteins Response as a Risk Modulator of Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease. Despite new methods of diagnostics and treatment as well as extensive biological and immunosuppressive treatment, the etiology of RA is not fully understood. Moreover, the problem of diagnosis and treatment of RA patients is still current and affects a large group of patients. It is suggested that endoplasmic reticulum (ER)-related features may impair adaptation to chronic stress, inferring the risk of rheumatoid arthritis. The main goal in this study was evaluation of changes in mRNA translation to determine chronic ER stress conditions in rheumatoid arthritis patients. The study group consist of 86 individuals including a total of 56 rheumatoid arthritis patients and 30 healthy controls. The expression level of mRNA form blood samples of RA patients as well as controls of the unfolded protein response (UPR)-associated genes (p-eIF2, BCL-2, PERK, ATF4, and BAX) were investigated using real-time qPCR. GAPDH expression was used as a standard control. Considering the median, the expression levels of PERK, BCL-2, p-eIF2, ATF4, and BAX were found to be significantly increased in the blood of RA patients compared with the control group. The p-value for the PERK gene was 0.0000000036, the p-value for the BCL-2 gene was 0.000000014, the p-value for the p-eIF2 gene was 0.006948, the p-value for the ATF4 gene was 0.0000056, and the p-value for the BAX gene was 0.00019, respectively. Thus, it can be concluded that the targeting of the components of the PERK-dependent UPR signaling pathway via small-molecule PERK inhibitors may contribute to the development of novel, innovative treatment strategies against rheumatoid arthritis.

Association between secondhand smoke exposure and rheumatoid arthritis in US never-smoking adults: a cross-sectional study from NHANES.

While smoking is widely acknowledged as a risk factor for rheumatoid arthritis (RA), the connection between secondhand smoke (SHS) exposure and RA in never-smoking adults remains limited and inconsistent. This study aims to explore and quantify this association using serum cotinine levels. We conducted a cross-sectional study with 14,940 adults who self-report as never smokers, using National Health and Nutrition Examination Survey data from 1999 to 2018. Based on previous literature, SHS exposure was categorized into four groups according to serum cotinine levels. Compared to individuals in the unexposed group (serum cotinine < 0.05 ng/mL), the adjusted odds ratio (OR) for RA was 1.37 (95% CI 1.14-1.64, p = 0.001) in the low exposure group (serum cotinine at 0.05 to 0.99 ng/mL) after adjusting for covariates. However, no significant association was found in the moderate exposure group (serum cotinine at 1 to 10 ng/mL) or the heavy exposure group (serum cotinine ≥ 10 ng/mL). Furthermore, we detected a non-linear, positively saturated correlation between the cotinine levels after log2 transformation and RA, with a turning point at approximately - 2.756 ng/mL (OR = 1.163, 95% CI 1.073-1.261, p = 0.0002). The stability of the results was confirmed by subgroup analysis.

Plasma mtDNA as a possible contributor to and biomarker of inflammation in rheumatoid arthritis.

OBJECTIVES: Neutrophil extracellular trap formation and cell-free DNA (cfDNA) contribute to the inflammation in rheumatoid arthritis (RA), but it is unknown if mitochondrial DNA (mtDNA) or nuclear DNA (nDNA) is more abundant in the circulation. It is unclear if DNA concentration measurements may assist in clinical decision-making. METHODS: This single-center prospective observational study collected plasma from consecutive RA patients and healthy blood donors. Platelets were removed, and mtDNA and nDNA copy numbers were quantified by polymerase chain reaction (PCR). RESULTS: One hundred six RA patients and 85 healthy controls (HC) were recruited. Circulating median mtDNA copy numbers were increased 19.4-fold in the plasma of patients with RA (median 1.1 x108 copies/mL) compared to HC (median 5.4 x106 copies/mL, p<0.0001). Receiver operating characteristics (ROC) curve analysis of mtDNA copy numbers identified RA patients with high sensitivity (92.5%) and specificity (89.4%) with an area under the curve (AUC) of 0.97, p <0.0001 and a positive likelihood ratio of 8.7. Demographic, serological (rheumatoid factor (RF) positivity, anti-citrullinated protein antibodies (ACPA) positivity) and treatment factors were not associated with DNA concentrations. mtDNA plasma concentrations, however, correlated significantly with disease activity score-28- erythrocyte sedimentation rate (DAS28-ESR) and increased numerically with increasing DAS28-ESR and clinical disease activity index (CDAI) activity. MtDNA copy numbers also discriminated RA in remission (DAS28 <2.6) from HC (p<0.0001). Also, a correlation was observed between mtDNA and the ESR (p = 0.006, R= 0.29). Similar analyses showed no significance for nDNA. CONCLUSION: In contrast to nDNA, mtDNA is significantly elevated in the plasma of RA patients compared with HC. Regardless of RA activity, the abundance of circulating mtDNA is a sensitive discriminator between RA patients and HC. Further validation of the diagnostic value of mtDNA testing is required.

External validation of a multi-biomarker-based score for predicting risk of cardiovascular disease in patients with rheumatoid arthritis.

BACKGROUND: A multi-biomarker disease activity (MBDA)-based cardiovascular disease (CVD) risk score was developed and internally validated in a Medicare cohort to predict 3-year risk for myocardial infarction (MI), stroke or CVD death in patients with rheumatoid arthritis (RA). It combines the MBDA score, leptin, MMP-3, TNF-R1, age and four clinical variables. We are now externally validating it in a younger RA cohort. METHODS: Claims data from a private aggregator were linked to MBDA test data to create a cohort of RA patients ≥18 years old. A univariable Cox proportional hazards regression model was fit using the MBDA-based CVD risk score as sole predictor of time-to-a-CVD event (hospitalized MI or stroke). Hazard ratio (HR) estimate was determined for all patients and for clinically relevant subgroups. A multivariable Cox model evaluated whether the MBDA-based CVD risk score adds predictive information to clinical data. RESULTS: 49,028 RA patients (340 CVD events) were studied. Mean age was 52.3 years; 18.3% were male. HR for predicting 3-year risk of a CVD event by the MBDA-based CVD risk score in the full cohort was 3.99 (95% CI: 3.51-4.49, p = 5.0×10-95). HR were also significant for subgroups based on age, comorbidities, disease activity, and drug use. In a multivariable model, the MBDA-based CVD risk score added significant information to hypertension, diabetes, tobacco use, history of CVD, age, sex and CRP (HR = 2.27, p = 1.7×10-7). CONCLUSION: The MBDA-based CVD risk score has been externally validated in an RA cohort that is younger than and independent of the Medicare cohort that was used for development and internal validation.

Association between serum antinuclear antibody and rheumatoid arthritis.

Background: The relationship between serum antinuclear antibody (ANA) and rheumatoid arthritis (RA) remains unknown. Therefore, we aimed to evaluate whether serum ANA was associated with an increased risk of RA in a case-control study. Methods: Patients with rheumatoid arthritis hospitalized at Shandong Provincial Hospital from January 2018 to December 2022 were recruited as the case group, and patients with other types of arthritis and healthy people at the same time were taken as the control group. Antinuclear antibody (ANA) was detected by indirect immunofluorescence assays. Propensity score matching was employed to construct a cohort of patients exhibiting comparable baseline characteristics. The relationship between serum ANA and the risk of rheumatoid arthritis was analyzed by logistic regression analysis. Results: A total of 1,175 patients with RA and 1,662 control subjects were included in this study. After adjusting for potential confounding factors in the propensity-score matched cohort, the risk of RA gradually increased with rising of ANA titers. When ANA titers were divided into three groups (1:100, 1:320, and 1:1,000), the OR (95% CI) for ANA titers from low to high was 3.95 (3.01, 5.18), 16.63 (9.44, 29.30), and 17.34 (9.53, 31.54), respectively, compared to those when ANA was negative. The ANA patterns closely related to the occurrence of RA include nuclear homogeneous, nuclear speckled, and cytoplasmic speckled. Among them, the positive rate of nuclear homogeneous was the highest, which accounted for 42.64%. The OR (95% CI) of ANA patterns including nuclear homogeneous, nuclear speckled, and cytoplasmic speckled was 16.81 (11.46, 24.65), 3.40 (2.49, 4.63), and 3.09 (1.77, 5.40), respectively. Conclusion: There was a curve relation between ANA titer and RA, and the higher the ANA titer, the higher the probability of RA. However, there was no statistical difference in probability of RA for 1:320 versus 1:1,000 ANA titers. The most important kind of ANA pattern in the blood of RA patients was nuclear homogeneous. These findings suggest that ANA may be a novel risk marker for RA.

Increased serum adipokines are associated with sarcopenia in non-obese women with rheumatoid arthritis.

Large cohort studies have disclosed the association between obesity and rheumatoid arthritis (RA) risk. The sarcopenia prevalence in RA patients can be up to 31%. However, there is little information linking adipokines to sarcopenia in RA, so this study aimed to investigate whether adipokines were indeed involved in secondary sarcopenia in RA with a focus on non-obese females. Sixty-four female patients and 36 controls were included in this study. The serum adipokine levels (leptin and adiponectin) were determined by ELISA kits. The impacts of adipokines on muscle atrophy and potential autophagy were examined in mouse myoblasts, C2C12, upon treatment with recombinant leptin and adiponectin agonist (AdipoRan). Interestingly, serum adiponectin was significantly increased but the ratio of leptin/adiponectin was dramatically decreased in the RA patients with sarcopenia. After normalization by body mass, serum leptin was positively associated but adiponectin was negatively associated with muscle mass respectively, even after adjustment for fat mass. Treating C2C12 cells with leptin and AdipoRan inhibited proliferation of mature myotube respectively, as did treatment with the serum from RA patients. A combination of low leptin and high AdipoRan greatly decreased myogenin, but instead increased MAFbx and MuRF-1 as well as increased Beclin 1, Atg5, and LC3ß. Taken together, our study reveals that secondary sarcopenia of RA females may be an imbalance of RA-related, but not obesity-related, increase in adipokine production; additionally, the reduced leptin/adiponectin ratio could be a better indicator in monitoring sarcopenia in non-obese RA females. Moreover, adipokine imbalance may promote muscle atrophy through inducing autophagy.

Cognitive dysfunction, depression and serum level of brain-derived neurotrophic factor (BDNF) in Egyptian patients with rheumatoid arthritis.

AIM OF THE WORK: To evaluate serum brain-derived neurotrophic factor (BDNF) in Egyptian patients with rheumatoid arthritis (RA) and its relation with cognitive dysfunction. PATIENTS AND METHODS: The study was carried out on 60 RA patients; 30 were active (group A) and 30 were non active (group B); and 30 controls (group C). RA disease activity was assessed via DAS28 tool, cognitive function via The Montreal Cognitive Assessment and depression via the PHQ depression scale. Serum BDNF levels were measured. RESULTS: The mean age in group A was 37.8 (±9.37) years with 83.3% females, in group B was 39.97 (±8.04) years with 86.7% females and in group C was 33.17 (±3.6) years with 93.3% females. Abnormal cognitive functions test was detected in 66.7% of group A, 66.7% of group B, and in 23.3% of group C. There was a statistically significant difference in BDNF serum level between both groups of patients (1.58±0.9ng/ml for group A, 1.81±1.17ng/ml for group B) compared with the control group (3.01±1.25ng/ml, p<0.001). There was no statistically significant difference between BDNF and both disease duration and cognitive function, also no statistically significant difference regarding cognitive function, depression, and BNDF levels in patients with and without fibromyalgia. At a cut-off value of <2ng/ml, BDNF detected RA patients with cognitive dysfunction with a sensitivity of 80%, specificity of 96.67%. CONCLUSION: BDNF can be a potential biomarker of cognitive dysfunction in RA patients.

Interplay Between Systemic Inflammation, Myocardial Injury, and Coronary Microvascular Dysfunction in Rheumatoid Arthritis: Results From the LiiRA Study.

BACKGROUND: Coronary microvascular dysfunction as measured by myocardial flow reserve (MFR) is associated with increased cardiovascular risk in rheumatoid arthritis (RA). The objective of this study was to determine the association between reducing inflammation with MFR and other measures of cardiovascular risk. METHODS AND RESULTS: Patients with RA with active disease about to initiate a tumor necrosis factor inhibitor were enrolled (NCT02714881). All subjects underwent a cardiac perfusion positron emission tomography scan to quantify MFR at baseline before tumor necrosis factor inhibitor initiation, and after tumor necrosis factor inhibitor initiation at 24 weeks. MFR <2.5 in the absence of obstructive coronary artery disease was defined as coronary microvascular dysfunction. Blood samples at baseline and 24 weeks were measured for inflammatory markers (eg, high-sensitivity C-reactive protein [hsCRP], interleukin-1b, and high-sensitivity cardiac troponin T [hs-cTnT]). The primary outcome was mean MFR before and after tumor necrosis factor inhibitor initiation, with Δhs-cTnT as the secondary outcome. Secondary and exploratory analyses included the correlation between ΔhsCRP and other inflammatory markers with MFR and hs-cTnT. We studied 66 subjects, 82% of which were women, mean RA duration 7.4 years. The median atherosclerotic cardiovascular disease risk was 2.5%; 47% had coronary microvascular dysfunction and 23% had detectable hs-cTnT. We observed no change in mean MFR before (2.65) and after treatment (2.64, P=0.6) or hs-cTnT. A correlation was observed between a reduction in hsCRP and interleukin-1b with a reduction in hs-cTnT. CONCLUSIONS: In this RA cohort with low prevalence of cardiovascular risk factors, nearly 50% of subjects had coronary microvascular dysfunction at baseline. A reduction in inflammation was not associated with improved MFR. However, a modest reduction in interleukin-1b and no other inflammatory pathways was correlated with a reduction in subclinical myocardial injury. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02714881.

Application of Salivary Alpha-1 Antitrypsin in the Diagnosis of Rheumatoid Arthritis: A Pilot Study.

Background and Objective: Rheumatoid arthritis (RA) is an autoimmune disease in which joints are gradually destroyed. Early diagnosis and treatment before joint deformation or destruction is important. The detection of novel RA biomarkers in saliva may facilitate early detection of RA before disease onset. This study aimed to evaluate salivary concentration of α1-antitrypsin (A1AT) in healthy patients and those with RA, and to assess the diagnostic value of salivary A1AT. Materials and Methods: In total, 80 participants were included: 20 healthy participants, and 60 patients with RA. Saliva and serum samples were obtained from all the patients. Levels of A1AT and cytokines, including interleukin-1 beta (IL-1ß), IL-6, and IL-10 in saliva and serum, were evaluated using an enzyme-linked immunosorbent assay kit and Luminex assay. Data were analyzed using SPSS for Windows. Results: There was a higher level of A1AT in the saliva of patients with RA (median: 2388.66 ng/mL) than that in healthy controls (1579.06 ng/mL). There was a positive mild-to-moderate accuracy (area under the curve: 0.57-0.85) of A1AT in saliva to diagnose RA. The cut-off level (ng/mL) of A1AT in saliva for detecting RA was 1689.0. Conclusions: The obtained data can promote the application of the measurements of A1AT in saliva to diagnose RA.

C-reactive protein lowers the serum level of IL-17, but not TNF-α, and decreases the incidence of collagen-induced arthritis in mice.

The biosynthesis of C-reactive protein (CRP) in the liver is increased in inflammatory diseases including rheumatoid arthritis. Previously published data suggest a protective function of CRP in arthritis; however, the mechanism of action of CRP remains undefined. The aim of this study was to evaluate the effects of human CRP on the development of collagen-induced arthritis (CIA) in mice which is an animal model of autoimmune inflammatory arthritis. Two CRP species were employed: wild-type CRP which binds to aggregated IgG at acidic pH and a CRP mutant which binds to aggregated IgG at physiological pH. Ten CRP injections were given on alternate days during the development of CIA. Both wild-type and mutant CRP reduced the incidence of CIA, that is, reduced the number of mice developing CIA; however, CRP did not affect the severity of the disease in arthritic mice. The serum levels of IL-17, IL-6, TNF-α, IL-10, IL-2 and IL-1ß were measured: both wild-type and mutant CRP decreased the level of IL-17 and IL-6 but not of TNF-α, IL-10, IL-2 and IL-1ß. These data suggest that CRP recognizes and binds to immune complexes, although it was not clear whether CRP functioned in its native pentameric or in its structurally altered pentameric form in the CIA model. Consequently, ligand-complexed CRP, through an as-yet undefined mechanism, directly or indirectly, inhibits the production of IL-17 and eventually protects against the initiation of the development of arthritis. The data also suggest that IL-17, not TNF-α, is critical for the development of autoimmune inflammatory arthritis.

A novel diagnostic model based on lncRNA PTPRE expression, neutrophil count and red blood cell distribution width for diagnosis of seronegative rheumatoid arthritis.

Diagnosis of seronegative rheumatoid arthritis (SNRA) is difficult due to the lack of diagnostic markers. The study aims to construct a novel diagnostic model based on long noncoding RNAs (lncRNAs) expression and laboratory indicators to provide a new idea for diagnostic methods of SNRA. Differentially expressed lncRNAs in peripheral blood cells of RA patients were screened through eukaryotic long noncoding RNA sequencing and validated by quantitative real-time PCR. Meanwhile, the correlation between lncRNAs expression and laboratory indicators was analyzed. The diagnostic value was evaluated by receiver operating characteristic curve analysis. Finally, combined with laboratory indicators, a diagnostic model for SNRA was constructed based on logistic regression and visualized by nomogram. Expression of ADGRE5, FAM157A, PTPN6 and PTPRE in peripheral blood was significantly increased in RA than healthy donors. Meanwhile, we analyzed the relationship between lncRNAs and erythrocyte sedimentation rate, C-reactive protein and CD4 + T cell-related cytokines and transcription factors. Results showed that FAM157A and PTPN6 were positively related to RORγt, and negatively related to GATA3. Moreover, PTPRE has potential discrimination ability between SNRA and healthy donor (AUC = 0.6709). Finally, we constructed a diagnostic model based on PTPRE, neutrophil count and red blood cell distribution width (RDW). The AUC of the model was 0.939 and well-fitted calibration curves. Decision curve analysis indicated the model had better predict performance in SNRA diagnosis. Our study constructed a novel diagnostic model based on PTPRE, neutrophil count and RDW which may serve as a potential tool for the diagnosis of SNRA.

Three-year follow-up of rheumatoid meningitis with matrix metalloprotease-9 levels in the serum and cerebrospinal fluid as indicators of disease activity: A case report.

Rheumatoid meningitis (RM) is an extra-articular complication of rheumatoid arthritis (RA). Although reports of RM sine arthritis exist, most patients with this presentation were diagnosed with RA within one year of RM onset. There are no established biomarkers reflecting the disease activity of RM. This case report highlights the elevation of matrix metalloprotease (MMP)-9 levels during the acute phase of RM and decline during remission. Additionally, this is the first case report of RA diagnosed three years after the onset of RM. It is important to further validate the utility of MMP-9 and conduct long-term follow-up of RM sine arthritis.

Association of serum concentrations of remnant cholesterol with incident cardiovascular disease in patients with rheumatoid arthritis: A real-world data from 2001 to 2022.

BACKGROUND: Remnant cholesterol (RC) promotes cardiovascular disease (CVD) in the general population, but its role among rheumatoid arthritis (RA) patients remains unknown. We aimed to investigate circulating RC levels associated with incident CVD among Chinese patients with RA. METHODS: A total of 1018 RA patients free of baseline CVD were included and followed up in a prospective RA CVD cohort from 2001 to 2022. Fasting serum levels of triglycerides, total cholesterol (TC), low-density (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were measured, while RC and Non-HDL-C levels were calculated. The primary exposure was RC levels. A LASSO Cox model was used to select covariates. The Fine-Gray competing risk model was used to estimate hazard ratios (HRs). RESULTS: RA patients had a mean age of 53.9 years, and 802 (78.8%) were females. After a median follow-up of 5.54 years, 131 patients developed CVD with an incidence rate of 21.6 per 1000 person-years. Continuous and quartile-categorized RC levels were associated with incident CVD before and after multivariate adjustment and Bonferroni correction (all P < 0.001). There were no robust associations of other lipids with incident CVD. The fully adjusted HRs for RC were 2.30 (95% CI 1.58-3.35) per 1 mmol/L increase, and 2.40 (1.36-4.25) and 2.81 (1.60-4.94) for patients in the 3rd and 4th versus the 1st quartile, respectively. CONCLUSIONS: Circulating RC levels are positively associated with incident CVD among Chinese RA patients independent of known risk factors, implying its clinically preferable use for improving the stratification of CVD risk in RA patients.

Serum netrin-1 levels are high in Rheumatoid arthritis associated interstitial lung disease.

BACKGROUND: Recent data show that netrin-1 has a role in development of pulmonary fibrosis. This study was aimed to investigate serum netrin-1 level and its relation to interstitial lung disease(ILD) in patients with rheumatoid arthritis (RA). METHOD: 42 RA patients with RA-ILD, 58 RA patients without RA-ILD (RA non-ILD group), and 61 healthy volunteers were included in this study. The modified DAS28-ESR score was used to calculate disease activity in RA patients. Using the quantitative immunoassay method, Serum netrin-1 levels were measured with an ELISA kit (Catalog number: E-EL-H2328; lab science, lot number: GZWTKZ5SWK, Texas, USA). RESULTS: The median value of netrin-1 was found to be significantly higher in the RA-ILD group (82.9 [59.9-124]) compared to both the RA non-ILD group(52.9 [49.5-73.1])(B = -0.006, OR = 0.994, CI 95 %=0.989-0.999, P = 0.018) and the control group(53.5 [49.5-87.5]) (B: -0.005, OR: 0.994, CI 95 %: 0.990-0.999, p: 0.022). A cut-off value of 61.78 for netrin-1 was found to have a sensitivity of 73.8 % and a specificity of 69 % for the diagnosis of RA-ILD (AUC [95 %Cl] = 0.771 [0.679-0.862], p < 0.0001).It was found that high serum netrin-1 level was strongly associated with the RA-usual interstitial pneumonia(UIP) pattern and poorly related to the RA-nonspecific interstitial pneumonia(NSIP) pattern compared to the RA non-ILD group. CONCLUSIONS: Netrin-1 is elevated in the serum of patients with RA-ILD, especially in the UIP pattern. Netrin-1 may be a potential candidate for predicting the development of RA-ILD that should be investigated in the pathophysiological and therapeutic fields..

The effect of plasma cytokines on the expression of adiponectin and its receptors in the synovial membrane of joints and the infrapatellar fat pad in patients with rheumatoid arthritis and osteoarthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease that leads to joint destruction. Numerous pro-inflammatory mediators, including adipokines, play an important role in the pathogenesis of RA. OBJECTIVE: The aim of the study was to investigate the relationships between selected plasma cytokines and expression of adiponectin and its receptors in the synovium and the infrapatellar fat pad in patients with RA and osteoarthritis (OA). METHODS: Blood, synovium and fat pad samples from 18 patients with RA and 18 with OA were collected during joint replacement surgery. Spearman rank correlations between plasma concentrations of selected cytokines (IL-1ß, IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12 p40, IL-13, IL-17, G-CSF and GM-CSF) and the expression of adiponectin and its receptors were determined. Plasma levels of cytokines were determined using a magnetic bead-based multiplex assay, mRNA expression of adiponectin and its receptors were determined by real-time PCR. RESULTS: In OA patients, there were significant positive correlations between adiponectin expression in the synovial membrane and plasma levels of IL-1ß, IL-4, G-CSF and GM-CSF, as well as a significant positive correlation between adiponectin expression in the fat pad and plasma levels of GM-CSF. In addition, OA patients showed significant negative correlations between AdipoR1 and AdipoR2 expression in the synovial membrane and plasma IL-6 levels, as well as between AdipoR2 expression in the synovial membrane and plasma MCP-1 and TNF-α levels. In patients with RA, there were no significant correlations between adiponectin expression in the synovial membrane and infrapatellar fat pad and plasma levels of the cytokines studied. In addition, RA patients showed a statistically significant negative correlation between AdipoR1 expression in the synovial membrane and plasma levels of TNF-α, IL-7, IL-12 and IL-13, and a significant negative correlation between AdipoR1 expression in the infrapatellar fat pad and plasma levels of IL-1ß. CONCLUSIONS: Adiponectin and its receptors showed the correlations with several plasma cytokines, however, a thorough understanding of the role of adiponectin in RA and OA requires further investigation.

Laboratory features of effects of peloidotherapy and aromatherapy in patients with rheumatoid arthritis.

Peloidotherapy and aromatherapy have been used for years in the treatment of numerous inflammatory conditions, including rheumatoid arthritis (RA). The exact mechanism of their action in RA is unclear. The goal of our research is to determine the effect of peloidotherapy and aromatherapy on inflammation parameters in RA patients. Our study included 20 patients of both sexes, with confirmed diagnosis of RA, older than 18 years. Patients were treated during 28 days with combination of peloidotherapy and aromatherapy. Serum samples for detection of levels of inflammation parameters were taken at two intervals: before the start of therapy and at the end of treatment. The results of our study show that there were no significant changes in the parameters of the complete blood count. Nevertheless, a statistically significant decrease in the serum concentration of two markers of inflammation-interleukin-6 (IL-6) and nitrogen-oxide (NO)-was detected. Correlation analyses results say that there is a synchronized drop in the serum concentrations of CRP and the sedimentation rate, and the serum concentrations of fibrinogen and IL-6 are in the same relationship as well as serum levels of IL-6 and NO. Bearing in mind the importance of IL-6 and NO in the pathogenesis of inflammation in RA, we conclude that the application of our therapeutic protocol can be a significant add-on treatment to classic immunomodulators. Due to the small number of study participants, the lack of a control group, and the short follow-up time of patients, additional research is needed.

Targeting the vivid facets of apolipoproteins as a cardiovascular risk factor in rheumatoid arthritis.

Mostly, cardiovascular diseases are blamed for casualties in rheumatoid arthritis (RA) patients. Customarily, dyslipidemia is probably the most prevalent underlying cause of untimely demise in people suffering from RA as it hastens the expansion of atherosclerosis. The engagement of inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), etc., is crucial in the progression and proliferation of both RA and abnormal lipid parameters. Thus, lipid abnormalities should be monitored frequently in patients with both primary and advanced RA stages. An advanced lipid profile examination, i.e., direct role of apolipoproteins associated with various lipid molecules is a more dependable approach for better understanding of the disease and selecting suitable therapeutic targets. Therefore, studying their apolipoproteins is more relevant than assessing RA patients' altered lipid profile levels. Among the various apolipoprotein classes, Apo A1 and Apo B are primarily being focused. In addition, it also addresses how calculating Apo B:Apo A1 ratio can aid in analyzing the disease's risk. The marketed therapies available to control lipid abnormalities are associated with many other risk factors. Hence, directly targeting Apo A1 and Apo B would provide a better and safer option.

Influence of rheumatoid factor on serum drug levels of TNF inhibitors with different structures in rheumatoid arthritis.

OBJECTIVES: Certolizumab pegol (CZP), an Fc-free antibody fragment, has shown stable serum levels and steady efficacy in the treatment of RA patients, irrespective of RF levels at baseline. Here, we examine, in clinical practice, the effect of baseline RF and ACPA levels on serum drug levels of IFX, ADL and CZP an Fc-free antibody fragment. METHODS: This is a retrospective study performed in real-world patients. We assessed 170 patients with RA: 90 (53%) received IFX, 48 (28%) ADL and 32 (19%) CZP. Demographic and clinical variables, RF and ACPA levels were obtained at the baseline visit (T0), and patients were stratified based on negative, low, medium, or high levels. After 6 months (T6) serum drug levels and anti-drug antibodies (ADAb), were computed. RESULTS: While CZP serum levels did not differ across RF groups at T6, high baseline RF was linked to lower serum drug levels compared to RF negative status in treatment with complete monoclonal antibodies IFX and ADL. No differences in disease activity measured by DAS28 at baseline were observed across RF quartiles in patients treated with IFX or ADL. ADAb was observed in 26 patients with IFX, 3 with ADL and 1 with CZP, following 6 months of treatment. Patients with high baseline RF levels dropped out more frequently by secondary non-response in IFX or ADL than CZP (80% vs. 75% vs. 33%, p=0.002). CONCLUSIONS: In this real word data evaluation, CZP serum levels were independent of RF levels in patients however patients with high baseline RF levels who obtained IFX or ADL had lower serum drug levels at 6 months than baseline RF-negative patients. In addition, secondary non-response was more frequent in patients with high RF levels treated with IFX and ADL.