We analyzed NAD
metabolism in patients with rheumatoid arthritis (RA), its association with disease activity and clinical outcomes of RA, and the therapeutic potential of pharmacologic NAD
boosting.
...Our study included 253 participants. In the first cohort, comprising 153 RA patients and 56 healthy donors, we assessed NAD
levels and NAD
-related gene pathways. We analyzed 92 inflammatory molecules by proximity extension assay. In the second cohort, comprising 44 RA patients starting anti-tumor necrosis factor (anti-TNF) drugs, we evaluated changes in NAD
levels and their association with clinical response after 3 months. Mechanistic studies were performed ex vivo on peripheral blood mononuclear cells (PBMCs) from patients with RA to test the beneficial effects of NAD
boosters, such as nicotinamide and nicotinamide riboside.
Reduced NAD
levels were found in RA samples, in line with altered activity and expression of genes involved in NAD
consumption (sirtuins, polyADP-ribose polymerase, CD38), transport (connexin 43), and biosynthesis (NAMPT, NMNATs). Unsupervised clustering analysis identified a group of RA patients with the highest inflammatory profile, the lowest NAD
levels, and the highest disease activity (as shown by the Disease Activity Score in 28 joints). NAD
levels were modulated by anti-TNF therapy in parallel with the clinical response. In vitro studies using PBMCs from RA patients showed that nicotinamide riboside and nicotinamide increased NAD
levels via NAMPT and NMNAT and reduced their prooxidative, proapoptotic, and proinflammatory status.
RA patients display altered NAD
metabolism, directly linked to their inflammatory and disease activity status, which was reverted by anti-TNF therapy. The preclinical beneficial effects of NAD
boosters, as shown in leukocytes from RA patients, along with their proven clinical safety, might pave the way for the development of clinical trials using these compounds.
Objective: To describe the frequency of malnutrition in older patients with rheumatoid arthritis (RA) and investigate associated risk factors. Methods: This multicenter, cross-sectional study ...included participants aged ≥65 years who met the 2010 ACR/EULAR criteria for RA. Nutritional status was assessed using the Mini Nutritional Assessment Short Form (MNA-SF) and based on variables, such as albumin level, the Geriatric Nutritional Risk Index (GNRI), and vitamin D. Data were also collected on epidemiological variables, inflammatory disease activity, quality of life, physical function, and frailty. Multivariate models were used to study factors associated with nutritional status. Results: The study population comprised 76 RA patients aged ≥65 years, of whom 68.4% had a normal nutritional status, and 31.5% had an impaired nutritional status: 28.9% were at risk of malnutrition, and 2.6% were malnourished. Additionally, 10% had albumin levels <3.8 g/L. Patients with impaired nutritional status had poorer quality of life and physical function. The factors associated with compromised nutritional status (OR 95% CI) were age (1.0 1.0–1.1; p = 0.035), DAS28-ESR (1.8 1.0–3.2; p = 0.024), and EuroQoL-5D-5L (0.9 0.9–0.9; p = 0.040). Furthermore, the GNRI was associated with the MNA score (0.06 0.0–0.1; p = 0.014). Conclusions: Approximately one-third of older patients with RA have impaired nutritional status. Older age, higher inflammatory disease activity, and decreased quality of life are associated with impaired nutritional status. The MNA and GNRI are valuable tools for assessing the nutritional status of patients with RA.
Purpose
The influence of a cheerful mood on disease activity levels in rheumatoid arthritis is investigated in this cross-sectional study.
Method
State cheerfulness (i.e., how individuals feel at the ...time of the assessment) and trait cheerfulness (i.e., how individuals usually feel) were assessed at the same time as the clinical indicators of disease activity and just before measuring patient-reported disease activity with the Disease Activity Score-28 (DAS-28).
Results
State cheerfulness contributed significantly to the variance in the DAS-28 scores that was not accounted for by trait cheerfulness or demographic or clinical variables. Higher state cheerfulness was associated with lower values of self-reported disease activity and C-reactive protein. The patient-reported disease activity was not uniquely caused by the clinical indicators of disease, but it also depended on patients’ cheerful mood at the moment of assessment.
Conclusion
The findings suggest interesting possibilities for the diagnosis and monitoring of disease activity in rheumatoid arthritis.
Enthesitis represents one of the most important peripheral musculoskeletal manifestations in patients with axial spondyloarthritis (axSpA). However, studies specifically evaluating Achilles tendon ...enthesitis and its impact over time are scarce. The objectives of this study were to evaluate the impact of Achilles' tendon enthesitis found at baseline during physical examination on the outcome measures after 2 years of follow-up in patients with ankylosing spondylitis (AS).
This was an observational and prospective study conducted during 2 years of follow-up in the REGISPONSER-AS registry. Linear regression models adjusted for age, body mass index (BMI), and anti-TNF intake were conducted to evaluate the association between the presence of Achilles enthesitis at baseline and the patient-reported outcome (PRO) scores at baseline. The impact of this feature on PROs over 2 years of follow-up was evaluated using mixed models for repeated measures adjusted for age, BMI, and anti-TNF intake.
Among the 749 patients included, 46 patients (6.1%) showed Achilles' tendon enthesitis during physical examination at the baseline study visit. Patients with Achilles enthesitis had an increase in the global VAS score, BASDAI, mBASDAI, ASDAS-CRP, and BASFI scores in comparison with patients without this feature. In addition, the mean global VAS, BASDAI, and ASDAS-CRP scores were significantly higher among patients with Achilles enthesitis over the 2 years of follow-up after adjusting for age, BMI, and current anti-TNF intake. The percentage of patients achieving ASDAS low disease activity (ASDAS < 2.1) after 2 years of follow-up was 15.9% and 31.5% for patients with and without Achilles enthesitis, respectively (p = 0.030).
In patients with AS, the presence of Achilles' tendon enthesitis was associated with worse scores on the outcome measures after 2 years of follow-up, leading to a lower probability of achieving low disease activity.
To compare the effect of inflammation on subclinical atherosclerosis using carotid ultrasound in patients with rheumatoid arthritis (RA) and spondyloarthritis (SpA).
Cross-sectional study including ...347 participants (148 RA, 159 SpA, and 40 controls). We measured the carotid intima media thickness (cIMT) and detection of atheromatous plaques using carotid ultrasound. We recorded disease activity (DAS28-CRP/ASDAS-CRP) and traditional cardiovascular risk factors. We performed descriptive, bivariate, and linear multivariate analyses (dependent variable: cIMT) to evaluate the influence of diagnosis on cIMT in all patients. Two additional multivariate analyses were performed by stratifying patients according to their inflammatory activity.
cIMT correlated with the mean CRP during the previous 5 years in RA, but not with CRP at the cut-off date. We did not find such differences in patients with SpA. The first multivariate model revealed that increased cIMT was more common in patients with RA than in those with SpA (β coefficient, 0.045; 95% confidence interval (95% CI), 0.0002-0.09;
= 0.048) after adjusting for age, sex, disease course, and differential cardiovascular risk factors (arterial hypertension, smoking, statins, and corticosteroids). The second model revealed no differences in cIMT between the 2 groups of patients classified as remission-low activity (β coefficient, 0.020; 95% CI, -0.03 to 0.080;
= 0.500). However, when only patients with moderate-high disease activity were analysed, the cIMT was 0.112 mm greater in those with RA (95% CI, 0.013-0.212;
= 0.026) than in those with SpA after adjusting for the same variables.
Subclinical atherosclerosis measured by carotid ultrasound in patients with RA and SpA is comparable when the disease is well controlled. However, when patients have moderate-high disease activity, cIMT is greater in patients with RA than in those with SpA after adjusting for age, sex, disease course, and cardiovascular risk factors. Our results point to greater involvement of disease activity in subclinical atherosclerosis in patients with RA than in those with SpA.
Studies on osteoporosis in axial spondyloarthritis (axSpA) have focused on the lumbar segment, and few studies have assessed bone mineral density (BMD) in the hip and femoral neck in these patients. ...The aim of this study was to evaluate the prevalence of low BMD and osteopenia in the total hip or femoral neck and the factors associated with these conditions in axSpA patients. This was a single-centre, observational, cross-sectional study among consecutive patients with axSpA according to the ASAS criteria from the CASTRO registry. All patients underwent total hip and femoral neck DXA BMD measurements. Low BMD was defined as a Z-score less than −1, and osteopenia was defined as a T-score less than −1. Multivariate logistic and generalised linear regressions were used to evaluate factors independently associated with low BMD and osteopenia in the hip or femoral neck and those associated with variability in BMD, respectively. A total of 117 patients were included, among which 30.8% were female and the mean age was 45 years. A total of 36.0% of patients had low BMD (28.1% in the total hip and 27.4% in the femoral neck), and 56.0% of patients had osteopenia (44.7% in the total hip and 53.8% in the femoral neck). A multivariate logistic regression showed that age, radiographic sacroiliitis and ASAS-HI were independently associated with low BMD in the total hip or femoral neck. Factors that were independently associated with osteopenia were Body Mass Index, disease duration, radiographic sacroiliitis and ASAS-HI. In conclusion, 36% of the patients with axSpA had low BMD in the total hip or femoral neck. A younger age and radiographic sacroiliitis were the most important factors associated with decreased BMD.
The aim of the study was to explore the influence of psychological affective states such as cheerfulness and bad mood on self-reported disease activity in patients with ankylosing spondylitis (AS) ...while controlling for demographic and clinical variables. Patients attending a biological therapy unit were selected for a cross-sectional study if they met the criteria for AS and were already receiving treatment. Their psychological affective state was assessed with the state version of the State-Trait Cheerfulness Inventory. Clinical variables included were patient-reported disease activity using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and acute-phase reactants. We performed univariate and multivariate analyses to verify the robustness of the relationship between psychological affective states and disease activity. We also explored whether disease activity, measured either by self-report or by acute-phase reactants, was influenced by patient’s overall affective state. In the recruited 31 patients with AS, overall affective state contributed significantly to the variance in BASDAI scores, adding 21.8 % to the overall R-square of the predictive power of clinical and demographic variables (combined R-square = 17 %). A higher positive affective state was associated with lower values of C-reactive protein (
p
< 0.05). Results of a bootstrapping procedure showed that the relationship between C-reactive protein levels and BASDAI scores was mediated by overall affective state. In patients with AS, affective state can induce variability in self-reported disease activity. Patients’ overall affective state can explain the relationship between acute-phase reactants and self-reported scores. These findings suggest interesting possibilities for the monitoring of disease activity in AS.
This study aimed to: 1) analyze the inflammatory profile of Rheumatoid Arthritis (RA) patients, identifying clinical phenotypes associated with cardiovascular (CV) risk; 2) evaluate biologic and ...targeted-synthetic disease-modifying antirheumatic drugs (b-DMARDs and ts-DMARDs’: TNFi, IL6Ri, JAKinibs) effects; and 3) characterize molecular mechanisms in immune-cell activation and endothelial dysfunction.
A total of 387 RA patients and 45 healthy donors were recruited, forming three cohorts: i) 208 RA patients with established disease but without previous CV events; ii) RA-CVD: 96 RA patients with CV events, and iii) 83 RA patients treated with b-DMARDs/ts-DMARDs for 6 months. Serum inflammatory profiles (cytokines/chemokines/growth factors) and NETosis/oxidative stress-linked biomolecules were evaluated. Mechanistic in vitro studies were performed on monocytes, neutrophils and endothelial cells (EC).
In the first RA-cohort, unsupervised clustering unveiled three distinct groups: cluster 3 (C3) displayed the highest inflammatory profile, significant CV-risk score, and greater atheroma plaques prevalence. In contrast, cluster 1 (C1) exhibited the lowest inflammatory profile and CV risk score, while cluster 2 (C2) displayed an intermediate phenotype. Notably, 2nd cohort RA-CVD patients mirrored C3's inflammation.
Treatment with b-DMARDs or ts-DMARDs effectively reduced disease-activity scores (DAS28) and restored normal biomolecules levels, controlling CV risk. In vitro, serum from C3-RA or RA-CVD patients increased neutrophils activity and CV-related protein levels in cultured monocytes and EC, which were partially prevented by pre-incubation with TNFi, IL6Ri, and JAKinibs.
Overall, analyzing circulating molecular profiles in RA patients holds potential for personalized clinical management, addressing CV risk and assisting healthcare professionals in tailoring treatment, ultimately improving outcomes.
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•Unsupervised clustering of RA profiles revealed 3 groups with diverse inflammatory, oxidative, and netotic profiles.•RA patients without CV events but highest CV-risk showed inflammatory profiles akin to those with prior CV events.•TNFi, IL6Ri, and JAKi treatment for six months restores normal inflammatory biomolecule levels, cutting-RA-related CV-risk.•High CV risk RA serum activates neutrophils, modulates monocytes, and disrupts endothelial cells, reversed by b/ts-DMARDS.•Analyzing RA patients' molecular profiles enhances personalized management, addressing their cardiovascular risk.
This prospective multicenter study developed an integrative clinical and molecular longitudinal study in Rheumatoid Arthritis (RA) patients to explore changes in serologic parameters following ...anti-TNF therapy (TNF inhibitors, TNFi) and built on machine-learning algorithms aimed at the prediction of TNFi response, based on clinical and molecular profiles of RA patients.
A total of 104 RA patients from two independent cohorts undergoing TNFi and 29 healthy donors (HD) were enrolled for the discovery and validation of prediction biomarkers. Serum samples were obtained at baseline and 6 months after treatment, and therapeutic efficacy was evaluated. Serum inflammatory profile, oxidative stress markers and NETosis-derived bioproducts were quantified and miRNomes were recognized by next-generation sequencing. Then, clinical and molecular changes induced by TNFi were delineated. Clinical and molecular signatures predictors of clinical response were assessed with supervised machine learning methods, using regularized logistic regressions.
Altered inflammatory, oxidative and NETosis-derived biomolecules were found in RA patients vs. HD, closely interconnected and associated with specific miRNA profiles. This altered molecular profile allowed the unsupervised division of three clusters of RA patients, showing distinctive clinical phenotypes, further linked to the TNFi effectiveness. Moreover, TNFi treatment reversed the molecular alterations in parallel to the clinical outcome. Machine-learning algorithms in the discovery cohort identified both, clinical and molecular signatures as potential predictors of response to TNFi treatment with high accuracy, which was further increased when both features were integrated in a mixed model (AUC: 0.91). These results were confirmed in the validation cohort.
Our overall data suggest that: 1. RA patients undergoing anti-TNF-therapy conform distinctive clusters based on altered molecular profiles, which are directly linked to their clinical status at baseline. 2. Clinical effectiveness of anti-TNF therapy was divergent among these molecular clusters and associated with a specific modulation of the inflammatory response, the reestablishment of the altered oxidative status, the reduction of NETosis, and the reversion of related altered miRNAs. 3. The integrative analysis of the clinical and molecular profiles using machine learning allows the identification of novel signatures as potential predictors of therapeutic response to TNFi therapy.
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