Objective
The persistence of biologic (b) and targeted synthetic (ts) disease‐modifying antirheumatic drugs(DMARDs) in monotherapy versus in combination with conventional synthetic (cs) DMARDs is ...still a controversial topic in rheumatic diseases. To clarify this issue, the retention of the initial treatment strategy of b/tsDMARD in combination with csDMARD versus monotherapy in rheumatoid arthritis (RA), psoriatic arthritis (PsA) and ankylosing spondylitis (AS) patients under real‐life conditions was evaluated. Factors associated with maintenance of the initial strategy were analysed.
Methods
Nested cohort study within the Spanish BIOBADASER III registry. Bivariate comparisons and multivariate Cox proportional hazards models were used for the analyses.
Results
A total of 2521 patients were included in the study. In the multivariate model, the initial strategy of combination therapy was associated with shorter persistence in patients with RA (hazard ratio HR 1.58;95% confidence interval CI 1.00–2.50; p = .049), PsA (HR 2.48; 95% CI 1.65–3.72) and AS (HR 16.77; 95% CI 7.37–38.16; p < .001), regardless of sex, time of disease progression, baseline disease activity, glucocorticoid use or type of b/tsDMARD. Overall, the combination strategy was associated with an increased incidence of adverse events (incidence rate ratio IRR 1.13; 95% CI 1.05–1.21).
Conclusions
In this real‐life study, the strategy of combining a b/tsDMARD with a csDMARD is associated with lower persistence and worse safety profile compared to monotherapy in RA and especially in PsA and AS, suggesting that combination therapy should be rethought as first choice in RA patients, but especially in PsA and AS patients.
Patients with Rheumatoid Arthritis (RA) have a higher prevalence of comorbidities compared to the general population. However, the implications of multimorbidity on therapeutic response and treatment ...retention remain unexplored.
(a) To evaluate the impact of multimorbidity on the effectiveness of the first targeted synthetic or biologic disease-modifying antirheumatic drug (ts/bDMARD), in patients with RA after 2-year follow-up; (b) to investigate the influence of multimorbidity on treatment retention rate.
Patients with RA from the BIOBADASER registry exposed to a first ts/bDMARDs were included. Patients were categorized based on multimorbidity status at baseline, defined as a Charlson Comorbidity index (CCI) score ≥ 3. A linear regression model, adjusted for sex and age, was employed to compare the absolute DAS28 score over time after ts/bDMARD initiation between the two groups. The Log-Rank test and Kaplan-Meier curve were used to compare the retention rates of the first ts/bDMARD between the groups.
A total of 1128 patients initiating ts/bDMARD were included, with 107 (9.3%) exhibiting multimorbidity. The linear regression model showed significantly higher DAS28 (beta coefficient 0.33, 95%CI:0.07-0.58) over a two-year period in patients with multimorbidity, even after adjusting for age and sex. Finally, no differences in the ts/bDMARD retention rate were found between groups (median 6.94-6.96 years in CCI < 3 vs. 5.68-5.62 in CCI ≥ 3; p = 0.610).
Multimorbidity in patients with RA was associated with greater DAS28 scores within the first two years after ts/bDMARD initiation, in comparison with patients without multimorbidity. A slightly shorter retention rate was found in patients with multimorbidity, although the difference was non-significant.
RA patients are at higher risk of cardiovascular disease, influenced by therapies. Studying their cardiovascular and cardiometabolic proteome can unveil biomarkers and insights into related ...biological pathways.
This study included two cohorts of RA patients: newly diagnosed individuals (n=25) and those with established RA (disease duration >25 years, n=25). Both cohorts were age and sex-matched with a control group (n=25). Additionally, a longitudinal investigation was conducted on a cohort of 25 RA patients treated with methotrexate and another cohort of 25 RA patients treated with tofacitinib for 6 months. Clinical and analytical variables were recorded, and serum profiling of 184 proteins was performed using the Olink technology platform.
RA patients exhibited elevated levels of 75 proteins that might be associated with cardiovascular disease. In addition, 24 proteins were increased in RA patients with established disease. Twenty proteins were commonly altered in both cohorts of RA patients. Among these, elevated levels of CTSL1, SORT1, SAA4, TNFRSF10A, ST6GAL1 and CCL18 discriminated RA patients and HDs with high specificity and sensitivity. Methotrexate treatment significantly reduced the levels of 13 proteins, while tofacitinib therapy modulated the expression of 10 proteins. These reductions were associated with a decrease in DAS28. Baseline levels of SAA4 and high levels of BNP were associated to the non-response to methotrexate. Changes in IL6 levels were specifically linked to the response to methotrexate. Regarding tofacitinib, differences in baseline levels of LOX1 and CNDP1 were noted between non-responder and responder RA patients. In addition, response to tofacitinib correlated with changes in SAA4 and TIMD4 levels.
In summary, this study pinpoints molecular changes linked to cardiovascular disease in RA and proposes candidate protein biomarkers for distinguishing RA patients from healthy individuals. It also highlights how methotrexate and tofacitinib impact these proteins, with distinct alterations corresponding to each drug's response, identifying potential candidates, as SAA4, for the response to these therapies.
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.
Disease severity, progression and response to therapy might be worse in obese rheumatoid arthritis (RA) patients, but paradoxically, obesity also might protect from radiographic joint damage. Thus, ...the intricate relationship between obesity and RA needs urgent clarification. The aim of this study was to assess the influence of obesity on the onset and development of RA and to determine whether arthritis could modify the adipose tissue biology and whether conventional Disease Modifying Anti-Rheumatic Drugs (cDMARDs) can modulate these alterations. Two strategies were followed: (1) clinical profiling of two cohorts of RA: non-obese and obese patients; and (2) mechanistic studies carried out in both a collagen-induced arthritis (CIA) in an obese mouse model and 3T3-L1 adipocytes treated with cDMARDs (leflunomide, methotrexate, and hydroxychloroquine). In our cohort of RA patients with low-moderate disease activity, the presence of obesity was not related to a higher activity of the disease; actually, disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) was reduced in the obese RA patients. However, the induction of arthritis promoted transcriptomic changes in the adipose tissue under obesity condition in the obese CIA model. Treatment with hydroxychloroquine reduced weight and insulin resistance, accompanied by beneficial metabolic effects in the adipose tissue. These molecular changes in adipose tissue were also observed after methotrexate administration. In sum, arthritis might affect directly the inflammatory burden and metabolic alterations associated with obesity in adipose tissue. Clinicians should be cautious measuring the activity of the disease in obesity and managing the best therapeutic options for the metabolic comorbidities of these patients, where the combination of hydroxychloroquine and methotrexate should be considered to improve adipose tissue dysfunction in obese RA.
: The objectives were as follows: (a) to identify, among patients with axial spondyloarthritis (axSpA), "clusters" of patients based on the presence of peripheral and extra-musculoskeletal ...manifestations (EMMs) and (b) to compare the effectiveness of the first anti-TNF drugs across the different clusters after 6 months of follow-up.
An observational and retrospective study of 90 axSpA patients naïve to bDMARDs was conducted. An unsupervised cluster analysis using the "k-means" technique was performed using variables of peripheral and EMMs. Baseline clinical and sociodemographic characteristics were evaluated, and the response to anti-TNF treatment (considering responders as those with an improvement ≥1.1 for the Ankylosing Spondylitis Disease Activity Score (ASDAS) or ≥2.0 for the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)) was compared across the clusters after 6 months of follow-up.
Two clusters were identified: cluster 1 (
= 14), with a higher prevalence of peripheral manifestations, inflammatory bowel disease (IBD), and HLA-B27-positive status, and a lower prevalence of uveitis in comparison with cluster 2 (
= 76). Patients from cluster 1 experienced a more pronounced absolute improvement in ASDAS and BASDAI indices after 6 months. The percentage of responders after 6 months of follow-up was superior in cluster 1 compared to cluster 2 (85.7% vs. 48.7%,
= 0.011).
This study suggests the existence of two clinical profiles in axSpA patients according to the peripheral and EMMs, with higher rates of anti-TNF effectiveness after 6 months in those with a greater presence of peripheral features.
ObjectiveTo assess whether the retention rate of certolizumab pegol (CZP) was longer than that of other tumour necrosis factor inhibitors (TNFi) based on baseline rheumatoid factor (RF) ...levels.MethodsLongitudinal, retrospective and multicentre study including patients with RA who were treated with any TNFi (monoclonal antibodies (mAB), etanercept (ETA) or CZP). Log-rank test and Cox regressions were conducted to evaluate the retention rate in the three groups according to the level of RF, with the third quartile of the baseline levels used as cut-off: <200 (<Q3) and ≥200 (≥Q3) IU/mL. A sensitivity analysis matching patients using a propensity score technique based on age, concomitant use of methotrexate and previous targeted synthetic/biological disease-modifying antirheumatic drugs was performed to address the imbalance across groups.ResultsA total of 638 individuals and 752 treatments (132 CZP, 439 mAB and 181 ETA) were included. In non-naïve patients with ≥200 IU/mL of RF, those treated with CZP showed a significantly longer retention rate in comparison with mAB and ETA. After matching using the propensity score, patients with ≥200 IU/mL RF levels exhibited longer retention rates with CZP than with mAB (HR 2.3 (95% CI 1.2 to 4.3), or ETA (HR 2.8 (95% CI 1.5 to 5.2). No differences were found between groups in patients with <200 UI/mL.ConclusionsCZP showed a longer retention rate than mAB and ETA in patients with very high RF levels (≥200 IU/mL), while these differences were absent in patients with <200 IU/mL levels. The results suggest the potential effect of RF on binding the fragment crystallisable portion of certain TNFi.
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.
The objective of this study was to assess the association of carotid intima-media thickness (CIMT), and also the presence of atheromatous plaque, with biological and targeted synthetic ...disease-modifying antirheumatic drugs, in an established cohort of patients with rheumatoid arthritis (RA).
We conducted a cross-sectional observational study based on a cohort of patients with RA and a registry of healthy controls, in whom the CIMT and presence of atheromatous plaque were assessed by ultrasound. Data were collected on disease activity, lab results and treatments. Descriptive and bivariate analyses were performed and two multivariate linear regression models (with CIMT as the dependent variable) were constructed to identify variables independently associated with CIMT in our sample of patients with RA.
A total of 176 individuals (146 patients with RA and 30 controls) were included. A higher percentage of patients than controls had atheromatous plaque (33.8% vs. 12.5%,
= 0.036), but no differences were found in terms of CIMT (0.64 vs. 0.61,
= 0.444). Compared to values in patients on other therapies, the CIMT was smaller among patients on tumour necrosis factor alpha (TNFα) inhibitors (mean SD: 0.58 0.10 vs. 0.65 0.19;
= 0.013) and among those on Janus kinase inhibitors (mean SD: 0.52 0.02 vs. 0.64 0.18;
< 0.001), while no differences were found as a function of the use of the other therapies considered. The multivariate linear regression analysis to identify factors associated with CIMT in our patients, adjusting for traditional cardiovascular risk factors such as hypertension, high levels of low-density lipoproteins, diabetes mellitus and smoking, showed that male sex, older age and having a greater cumulative erythrocyte sedimentation rate were independently associated with a larger CIMT, while patients on TNFα inhibitors had a CIMT 0.075 mm smaller than those on other treatments.
The use of TNFα inhibitors may protect against subclinical atherosclerosis in patients with RA, patients on this biologic having smaller CIMTs than patients on other disease-modifying antirheumatic drugs. Nonetheless, these results should be confirmed in prospective studies with larger sample sizes.
The aim of this study was to investigate the microRNA expression pattern in neutrophils from rheumatoid arthritis patients and its contribution to their pathogenic profile and to analyze the effect ...of specific autoantibodies or inflammatory components in the regulation of microRNAs in rheumatoid arthritis neutrophils and its modulation by biological therapies. Neutrophils were isolated from paired peripheral blood and synovial fluid samples of 40 patients with rheumatoid arthritis and from peripheral blood of 40 healthy donors. A microRNA array was performed using nCounter technology. Neutrophils from healthy donors were treated in vitro with antibodies to citrullinated protein antigens isolated from rheumatoid arthritis patients and tumor necrosis factor-α or interleukin-6. A number of cytokines and chemokines were analyzed. In vitro treatments of rheumatoid arthritis-neutrophils with tocilizumab or infliximab were carried out. Transfections with pre-microRNAs and DICER downregulation were further performed. Rheumatoid arthritis-neutrophils showed a global downregulation of microRNAs and genes involved their biogenesis, alongside with an upregulation of various potential mRNA targets related to migration and inflammation. Decreased levels of microRNAs and DICER correlated with autoimmunity, inflammation and disease activity. Citrullinated protein antigens and tumor necrosis factor-α decreased the expression of numerous microRNAs and their biogenesis-related genes, increasing their potential mRNA targets. Infliximab reversed those effects. Transfections with pre-miRNAs-223, -126 and -148a specifically modulated genes regulating inflammation, survival and migration. DICER depletion influenced the neutrophils inflammatory profile. Taking together rheumatoid arthritis neutrophils exhibit a global low abundance of microRNAs induced by autoantibodies and inflammatory markers, which might contribute to their pathogenic activation. microRNA biogenesis is significantly impaired in rheumatoid arthritis-neutrophils and further associated with a greater downregulation of microRNAs mainly related to migration and inflammation in synovial neutrophils. Finally, anti-tumor necrosis factor-α and anti-interleukin-6 receptor treatments can modulate microRNA levels in the neutrophils, minimizing their inflammatory profile.
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