Isotypes of autoantibodies against novel differential 4-hydroxy-2-nonenal-modified peptide adducts in serum is associated with rheumatoid arthritis in Taiwanese women

Abstract Background Rheumatoid arthritis (RA) is an autoimmune disorder with systemic inflammation and may be induced by oxidative stress that affects an inflamed joint. Our objectives were to examine isotypes of autoantibodies against 4-hydroxy-2-nonenal (HNE) modifications in RA and associate them with increased levels of autoantibodies in RA patients. Methods Serum samples from 155 female patients [60 with RA, 35 with osteoarthritis (OA), and 60 healthy controls (HCs)] were obtained. Four novel differential HNE-modified peptide adducts, complement factor H (CFAH)1211–1230, haptoglobin (HPT)78–108, immunoglobulin (Ig) kappa chain C region (IGKC)2–19, and prothrombin (THRB)328–345, were re-analyzed using tandem mass spectrometric (MS/MS) spectra (ProteomeXchange: PXD004546) from RA patients vs. HCs. Further, we determined serum protein levels of CFAH, HPT, IGKC and THRB, HNE-protein adducts, and autoantibodies against unmodified and HNE-modified peptides. Significant correlations and odds ratios (ORs) were calculated. Results Levels of HPT in RA patients were greatly higher than the levels in HCs. Levels of HNE-protein adducts and autoantibodies in RA patients were significantly greater than those of HCs. IgM anti-HPT78−108 HNE, IgM anti-IGKC2−19, and IgM anti-IGKC2−19 HNE may be considered as diagnostic biomarkers for RA. Importantly, elevated levels of IgM anti-HPT78−108 HNE, IgM anti-IGKC2−19, and IgG anti-THRB328−345 were positively correlated with the disease activity score in 28 joints for C-reactive protein (DAS28-CRP). Further, the ORs of RA development through IgM anti-HPT78−108 HNE (OR 5.235, p < 0.001), IgM anti-IGKC2−19 (OR 12.655, p < 0.001), and IgG anti-THRB328−345 (OR 5.761, p < 0.001) showed an increased risk. Lastly, we incorporated three machine learning models to differentiate RA from HC and OA, and performed feature selection to determine discriminative features. Experimental results showed that our proposed method achieved an area under the receiver operating characteristic curve of 0.92, which demonstrated that our selected autoantibodies combined with machine learning can efficiently detect RA. Conclusions This study discovered that some IgG- and IgM-NAAs and anti-HNE M-NAAs may be correlated with inflammation and disease activity in RA. Moreover, our findings suggested that IgM anti-HPT78−108 HNE, IgM anti-IGKC2−19, and IgG anti-THRB328−345 may play heavy roles in RA development.

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OP0034 DOES THE RISK OF VENOUS THROMBOEMBOLISM VARY WITH DISEASE ACTIVITY IN RHEUMATOID ARTHRITIS?

Annals of the Rheumatic Diseases ◽

10.1136/annrheumdis-2020-eular.353 ◽

2020 ◽

Vol 79 (Suppl 1) ◽

pp. 23.2-24

Author(s):

V. Molander ◽

H. Bower ◽

J. Askling

Keyword(s):

Rheumatoid Arthritis ◽

Logistic Regression ◽

Venous Thromboembolism ◽

Disease Activity ◽

Das28 Score ◽

Logistic Regression Models ◽

Highly Active ◽

Increased Risk ◽

Das28 Remission ◽

One Year

Background:Patients with rheumatoid arthritis (RA) are at increased risk for venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE) (1). Several established risk factors of VTE, such as age, immobilization and comorbid conditions, occur more often patients with RA (2). In addition, inflammation may in itself also increase VTE risk by upregulating procoagolatory factors and causing endothelial damage (3). Recent reports indicate an increased risk of VTE in RA patients treated with JAK-inhibitors (4), pointing to the need to better understand how inflammation measured as clinical RA disease activity influences VTE risk.Objectives:To investigate the relationship between clinical RA disease activity and incidence of VTE.Methods:Patients with RA were identified from the Swedish Rheumatology Quality Register (SRQ) between July 1st2006 and December 31st2017. Clinical rheumatology data for these patients were obtained from the visits recorded in SRQ, and linked to national registers capturing data on VTE events and comorbid conditions. For each such rheumatologist visit, we defined a one-year period after the visit and determined whether a VTE event had occurred within this period or not. A visit followed by a VTE event was categorized as a case, all other visits were used as controls. Each patient could contribute to several visits. The DAS28 score registered at the visit was stratified into remission (0-2.5) vs. low (2.6-3.1), moderate (3.2-5.1) and high (>5.1) disease activity. Logistic regression with robust cluster standard errors was used to estimate the association between the DAS28 score and VTE.Results:We identified 46,311 patients with RA who contributed data from 320,094 visits. Among these, 2,257 visits (0.7% of all visits) in 1345 unique individuals were followed by a VTE within the one-year window. Of these, 1391 were DVT events and 866 were PE events. Figure 1 displays the absolute probabilities of a VTE in this one-year window, and odds ratios for VTE by each DAS28 category, using DAS28 remission as reference. The one-year risk of a VTE increased from 0.5% in patients in DAS28 remission, to 1.1% in patients with DAS28 high disease activity (DAS28 above 5.1). The age- and sex-adjusted odds ratio for a VTE event in highly active RA compared to RA in remission was 2.12 (95% CI 1.80-2.47). A different analysis, in which each patient could only contribute to one visit, yielded similar results.Figure 1.Odds ratios (OR) comparing the odds of VTE for DAS28 activity categories versus remission. Grey estimates are from unadjusted logistic regression models, black estimates are from logistic regression models adjusted for age and sex. Absolute one-year risk of VTE are estimated from unadjusted models.Conclusion:This study demonstrates a strong association between clinical RA inflammatory activity as measured through DAS28 and risk of VTE. Among patients with high disease activity one in a hundred will develop a VTE within the coming year. These findings highlight the need for proper VTE risk assessment in patients with active RA, and confirm that patients with highly active RA, such as those recruited to trials for treatment with new drugs, are already at particularly elevated risk of VTE.References:[1]Holmqvist et al. Risk of venous thromboembolism in patients with rheumatoid arthritis and association with disease duration and hospitalization. JAMA. 2012;308(13):1350-6.[2]Cushman M. Epidemiology and risk factors for venous thrombosis. Semin Hematol. 2007;44(2):62-9.[3]Xu J et al. Inflammation, innate immunity and blood coagulation. Hamostaseologie. 2010;30(1):5-6, 8-9.[4]FDA. Safety trial finds risk of blood clots in the lungs and death with higher dose of tofacitinib (Xeljanz, Xeljanz XR) in rheumatoid arthritis patients; FDA to investigate. 2019.Acknowledgments:Many thanks to all patients and rheumatologists persistently filling out the SRQ.Disclosure of Interests:Viktor Molander: None declared, Hannah Bower: None declared, Johan Askling Grant/research support from: JA acts or has acted as PI for agreements between Karolinska Institutet and the following entities, mainly in the context of the ARTIS national safety monitoring programme of immunomodulators in rheumatology: Abbvie, BMS, Eli Lilly, Merck, MSD, Pfizer, Roche, Samsung Bioepis, Sanofi, and UCB Pharma

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The Latent Tuberculin Test after 1-year Therapy with Anti-TNF in Babylon, Iraq

Journal of University of Babylon for Pure and Applied Sciences ◽

10.29196/jubpas.v26i8.1680 ◽

2018 ◽

Vol 26 (8) ◽

pp. 144-150

Author(s):

Ali Alkazzaz ◽

Murtadha Najah Jawad ◽

Zeyad Tareq Kareem

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Medical History ◽

Demographic Data ◽

Latent Tuberculosis ◽

Tuberculin Test ◽

P Value ◽

Cross Sectional ◽

Increased Risk ◽

Significant Difference

Background: Rheumatoid arthritis (RA) patients receiving receive anti-TNF agents are at increased risk of reactivation of latent tuberculosis infection (LTBI). The tuberculin skin test (TST) is widely used to screen LTBI and providing preventive treatment, in an effort to meet the WHO target of a 90% reduction in TB by 2035. Objectives: To determine the proportion of TST conversion among RA patients after 1 year of anti-TNF treatment and association of positive TST result with patients’ socio-demographic characteristics and medical history. Methods: This community-based cross-sectional study was conducted at the Department of Rheumatology of Marjan Teaching Hospital in Iraq, for a period of 1 year. Patients with RA/and spondyloarthropathy, and who received anti-TNF therapy for >1 year, underwent TST. Their demographic data and medical history were also obtained. All statistical analysis was performed using SPSS (Version 20) and, p < 0.05 was considered as a sign. Data from the baseline and 1 year follow-up was subjected to the Kolmogorov-Smirnov test to determine whether they were normally distributed. Chi-Square test used to test significance of TST among etanrecept and infliximab at the end of the study. Results: A total of 96 patients were enrolled, including 55 (57.3%) males and 41 (42.3%) females with an average age of 41.1, and mostly 68 (70.8%) from Babylon Governorate of Iraq. A total of 40 (41.7%) patients had rheumatoid arthritis alone, and the remaining 56 (58.3%) had a comorbidity of spondyloarthropathy. Majority of the patients 65 (67.7%) received the biological agent infliximab, while 31 (32.3%) patients received Etanercept for RA for a period of 1 year. There was a statistically significant decreasing in the median ESR and disease activity from the baseline to the end of the study (p-value <0.01). There was no significant difference in TST results based on gender or age. Both infliximab and etanercept were significantly associated with a decreasing in ESR and disease activity Conclusion: This study has shown that there was very low TST conversion among RA patients after 1 year of anti-TNF treatment and, age and gender were not associated with TST.

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Levels of Urinary Complement Factor H in Patients with IgA Nephropathy are Closely Associated with Disease Activity

Scandinavian Journal of Immunology ◽

10.1111/j.1365-3083.2009.02234.x ◽

2009 ◽

Vol 69 (5) ◽

pp. 457-464 ◽

Cited By ~ 30

Author(s):

J.-J. Zhang ◽

L. Jiang ◽

G. Liu ◽

S.-X. Wang ◽

W.-Z. Zou ◽

...

Keyword(s):

Disease Activity ◽

Iga Nephropathy ◽

Factor H ◽

Complement Factor H ◽

Complement Factor

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Plasma complement factor H is associated with disease activity of patients with ANCA-associated vasculitis

Arthritis Research & Therapy ◽

10.1186/s13075-015-0656-8 ◽

2015 ◽

Vol 17 (1) ◽

Cited By ~ 23

Author(s):

Su-Fang Chen ◽

Feng-Mei Wang ◽

Zhi-Ying Li ◽

Feng Yu ◽

Ming-Hui Zhao ◽

...

Keyword(s):

Disease Activity ◽

Factor H ◽

Complement Factor H ◽

Complement Factor ◽

Anca Associated Vasculitis

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Risk of venous thromboembolism associated with Janus kinase inhibitors for rheumatoid arthritis: case presentation and literature review

Clinical Rheumatology ◽

10.1007/s10067-021-05911-4 ◽

2021 ◽

Author(s):

Shunsuke Mori ◽

Fumihiko Ogata ◽

Ryusuke Tsunoda

Keyword(s):

Rheumatoid Arthritis ◽

Diabetes Mellitus ◽

Risk Factors ◽

Pulmonary Embolism ◽

Venous Thromboembolism ◽

Disease Activity ◽

Janus Kinase ◽

Advanced Age ◽

Jak Inhibitors ◽

Increased Risk

AbstractJanus kinase (JAK) inhibitors have been developed as disease-modifying antirheumatic drugs. Despite the positive therapeutic impacts of JAK inhibitors, concerns have been raised regarding the risk of venous thromboembolism (VTE), such as deep vein thrombosis (DVT) and pulmonary embolism (PE). A recent post hoc safety analysis of placebo-controlled trials of JAK inhibitors in rheumatoid arthritis (RA) reported an imbalance in the incidence of VTE for a 4-mg daily dose of baricitinib versus placebo. In a recent postmarketing surveillance trial for RA, a significantly higher incidence of PE was reported in treatment with tofacitinib (10 mg twice daily) compared with tofacitinib 5 mg or tumor necrosis factor inhibitors. We also experienced a case of massive PE occurring 3 months after starting baricitinib (4 mg once daily) for multiple biologic-resistant RA. Nevertheless, the evidence to support the role of JAK inhibitors in VTE risk remains insufficient. There are a number of predisposing conditions and risk factors for VTE. In addition to the known risk factors that can provoke VTE, advanced age, obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking can also contribute to its development. Greater VTE risk is noted in patients with chronic inflammatory conditions, particularly RA patients with uncontrolled disease activity and any comorbidity. Prior to the initiation of JAK inhibitors, clinicians should consider both the number and strength of VTE risk factors for each patient. In addition, clinicians should advise patients to seek prompt medical help if they develop clinical signs and symptoms that suggest VTE/PE. Key Points• Patients with rheumatoid arthritis (RA) are at increased risk of venous thromboembolism (VTE), especially those with uncontrolled, high disease activity and those with comorbidities.• In addition to the well-known risk factors that provoke VTE events, advanced age and cardiovascular risk factors, such as obesity, diabetes mellitus, hypertension, hyperlipidemia, and smoking, should be considered risk factors for VTE.• Although a signal of VTE/pulmonary embolism (PE) risk with JAK inhibitors has been noted in RA patients who are already at high risk, the evidence is currently insufficient to support the increased risk of VTE during RA treatment with JAK inhibitors.• If there are no suitable alternatives, clinicians should prescribe JAK inhibitors with caution, considering both the strength of individual risk factors and the cumulative weight of all risk factors for each patient.

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Cardiovascular Autonomic Function Changes and Predictors During a 2-Year Physical Activity Program in Rheumatoid Arthritis: A PARA 2010 Substudy

Frontiers in Medicine ◽

10.3389/fmed.2021.788243 ◽

2021 ◽

Vol 8 ◽

Author(s):

David Hupin ◽

Philip Sarajlic ◽

Ashwin Venkateshvaran ◽

Cecilia Fridén ◽

Birgitta Nordgren ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Physical Activity ◽

Machine Learning ◽

Heart Rate ◽

Autonomic Function ◽

Maximal Exercise ◽

Machine Learning Algorithms ◽

Physical Activity Program ◽

Activity Program ◽

Increased Risk

Background: Chronic inflammation leads to autonomic dysfunction, which may contribute to the increased risk of cardiovascular diseases (CVD) in patients with rheumatoid arthritis (RA). Exercise is known to restore autonomic nervous system (ANS) activity and particularly its parasympathetic component. A practical clinical tool to assess autonomic function, and in particular parasympathetic tone, is heart rate recovery (HRR). The aim of this substudy from the prospective PARA 2010 study was to determine changes in HRR post-maximal exercise electrocardiogram (ECG) after a 2-year physical activity program and to determine the main predictive factors associated with effects on HRR in RA.Methods: Twenty-five participants performed physiotherapist-guided aerobic and muscle-strengthening exercises for 1 year and were instructed to continue the unsupervised physical activity program autonomously in the next year. All participants were examined at baseline and at years 1 and 2 with a maximal exercise ECG on a cycle ergometer. HRR was measured at 1, 2, 3, 4, and 5 min following peak heart rate during exercise. Machine-learning algorithms with the elastic net linear regression models were performed to predict changes in HRR1 and HRR2 at 1 year and 2 years of the PARA program.Results: Mean age was 60 years, range of 41–73 years (88% women). Both HRR1 and HRR2 increased significantly from baseline to year 1 with guided physical activity and decreased significantly from year 1 to year 2 with unsupervised physical activity. Blood pressure response to exercise, low BMI, and muscular strength were the best predictors of HRR1/HRR2 increase during the first year and HRR1/HRR2 decrease during the second year of the PARA program.Conclusion: ANS activity in RA assessed by HRR was improved by guided physical activity, and machine learning allowed to identify predictors of the HRR response at the different time points. HRR could be a relevant marker of the effectiveness of physical activity recommended in patients with RA at high risk of CVD. Very inactive and/or high CVD risk RA patients may get substantial benefits from a physical activity program.

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Effects of Tocilizumab, an Anti-Interleukin-6 Receptor Antibody, on Serum Lipid and Adipokine Levels in Patients with Rheumatoid Arthritis

International Journal of Molecular Sciences ◽

10.3390/ijms20184633 ◽

2019 ◽

Vol 20 (18) ◽

pp. 4633 ◽

Cited By ~ 10

Author(s):

Elinoar Hoffman ◽

Michal A. Rahat ◽

Joy Feld ◽

Muna Elias ◽

Itzhak Rosner ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Disease Activity ◽

Lipid Profile ◽

Interleukin 6 ◽

Density Lipoprotein ◽

High Sensitivity ◽

Mechanistic Explanation ◽

Receptor Antibody ◽

Increased Risk ◽

Interleukin 6 Receptor

Patients with rheumatoid arthritis (RA) are at increased risk of cardiovascular disease. Dyslipidemia is a known adverse effect of tocilizumab (TCZ), an anti-interleukin-6 receptor antibody used in RA treatment. We aimed to assess the effect of TCZ on lipid profile and adipokine levels in RA patients. Height, weight, disease activity scores, lipid profile and atherogenic indices (AI), leptin, adiponectin, resistin, interleukin-6, and high-sensitivity C-reactive protein (CRP) were measured before and four months after initiation of TCZ in 40 RA patients and 40 healthy controls. Following TCZ treatment, total cholesterol, high density lipoprotein (HDL), and triglycerides were significantly elevated, but no significant changes in weight, body mass index (BMI), low density lipoprotein (LDL), and AI were observed. Compared with controls, significantly higher adiponectin levels were measured in the RA group at baseline. Following TCZ treatment, resistin levels and the leptin-to-adiponectin ratio increased, adiponectin levels decreased, and leptin levels remained unchanged. No correlation was found between the change in adipokine serum levels and changes in the disease activity indices, nor the lipid profile. In conclusion, the changes observed suggest a protective role for TCZ on the metabolic and cardiovascular burden associated with RA, but does not provide a mechanistic explanation for this phenomenon.

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Serum Metabolomic And Lipidomic Profiling Identifies Diagnostic Biomarkers For Seropositive And Seronegative Rheumatoid Arthritis Patients

10.21203/rs.3.rs-816146/v1 ◽

2021 ◽

Author(s):

Hemi Luan ◽

Wanjian Gu ◽

Hua Li ◽

Zi Wang ◽

Lu Lu ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Machine Learning ◽

Disease Activity ◽

Acid Metabolism ◽

Serum Markers ◽

Classification Model ◽

Diagnostic Biomarkers ◽

Validation Set ◽

Lipids Metabolism ◽

Normal Controls

Abstract Background: Diagnosing seronegative rheumatoid arthritis (RA) can be challenging due to complex diagnostic criteria. We sought to discover diagnostic biomarkers for seronegative RA cases by studying metabolomic and lipidomic changes in RA patient serum. Methods: We carried out metabolomic and lipidomic profiling of metabolites and lipids in serum of 225 RA patients and 100 normal controls. These samples were divided into a discovery set (n = 243) and a validation set (n = 82). A machine-learning-based multivariate classification model was constructed using distinctive metabolites and lipids signals. Results: Twenty-six metabolites and lipids were identified from the discovery cohort to construct a RA diagnosis model. The model was subsequently tested on a validation set and achieved accuracy of 90.2%, with sensitivity of 89.7% and specificity of 90.6%. Both seropositive and seronegative patients were identified using this model. A co-occurrence network using serum omics profiles was built and parsed into six modules, showing significant association between the inflammation and immune activity markers and aberrant metabolism of energy metabolism, lipids metabolism and amino acid metabolism. Acyl carnitines (20:3), aspartyl-phenylalanine, pipecolic acid, phosphatidylethanolamine PE (18:1) and lysophosphatidylethanolamine LPE (20:3) were positively correlated with the RA disease activity, while histidine and phosphatidic acid PA (28:0) were negatively correlated with the RA disease activity. Conclusions: A panel of 26 serum markers were selected from omics profiles to build a machine-learning-based prediction model that could aid in diagnosing seronegative RA patients. Potential markers were also identified in stratifying RA cases based on disease activity.

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