Inflammatory and prothrombotic biomarkers in patients with rheumatoid arthritis: Effects of tumor necrosis factor-α blockade

doi:10.1016/j.jaut.2008.07.002

Journal of Autoimmunity

Volume 31, Issue 2, September 2008, Pages 175-179

https://doi.org/10.1016/j.jaut.2008.07.002 Get rights and content

Abstract

Objective

Increased cardiovascular (CV) risk is a rheumatoid arthritis (RA) hallmark and it has been mainly related to chronic systemic inflammation. Since inflammation is linked to coagulation perturbation, both may play a role in increasing CV risk. Treatment with tumor necrosis factor (TNF)-α blocking agents is effective in RA and reduces local and systemic inflammation but there is little information on its effect on coagulation. We therefore investigated inflammation and coagulation plasma biomarkers before and after infliximab treatment in RA patients.

Methods

We studied 20 patients with active RA and 40 healthy controls. Patients were treated with: a stable dose of methotrexate (10 mg/week), and infliximab (3 mg/kg) at weeks 0, 2, 6 and 14. At baseline and week 14, we determined: disease activity score (DAS-28), visual analogue scale pain, erythrocyte sedimentation rate (ESR), and plasma levels of C-reactive protein (CRP), TNF-α, interleukin (IL)-6, prothrombin fragment 1 + 2 (F1 + 2) and D-dimer. The same inflammation and coagulation parameters were evaluated 1 h after infliximab infusion in 10 patients.

Results

At baseline, ESR, CRP, TNF-α, IL-6, F1 + 2 and D-dimer levels were significantly higher in RA patients than in controls (P = 0.0001). After 14 weeks of infliximab treatment, there was a significant clinical improvement and ESR and CRP, IL-6, F1 + 2 and D-dimer level decrease (P = 0.001–P = 0.008). The levels of TNF-α, IL-6, F1 + 2 and D-dimer significantly decreased 1 h after infliximab infusion (P = 0.005).

Conclusions

Infliximab decreases inflammation and coagulation biomarkers in RA patients. Such a combined effect may be pivotal in reducing the whole thrombotic risk in these patients.

Introduction

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease of unknown etiology that affects about 1% of the adult population [1]. Patients with RA not only have a higher chronic disease burden, but may also experience greater cardiovascular disease (CVD) morbidity and mortality than people without RA [2], [3].

Furthermore, there is ample evidence showing that coagulation processes are active in RA [4]. Synovial rice bodies composed of fibrin and collagen fragments are pathognomonic of chronic synovial inflammation. Increased accumulation of fibrin in the RA synovium represents one of the most striking pathologic features of rheumatoid synovitis. Furthermore, anti-citrullinated protein antibodies (ACPA) may cross-react with epitopes exposed on citrullinated fibrin/fibrinogen molecules. ACPA binding to citrullinated fibrin could impair fibrin degradation by plasmin therefore sustaining synovial damage not only via proinflammatory effector mechanisms but also via impairment of fibrinolysis [5].

Inflammation, atherosclerosis and fibrinolytic systems share many characteristics in common, including the involvement of proinflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin 6 (IL-6). Proinflammatory cytokines play a pivotal role in the initiation and amplification of the inflammatory cascade in RA, but at the same time are widely accepted both as major predictors and as pathogenic mediators of CVD events in the general population [6], [7].

It has long been recognized that extensive cross-talk takes place between the coagulation pathway and the inflammatory process at various levels, and there is growing evidence that this interaction may be relevant to arthritis [4]. Large-scale, long-term studies have shown that treatment with infliximab improves clinical and laboratory measures of disease activity and reduces local and systemic inflammation [8], [9]. However, the possible relationship between coagulation and inflammation during such kind of treatment has not been addressed in detail.

With this as background, we investigated the infliximab-induced short- and long-term changes in circulating biomarkers of thrombin generation (prothrombin fragment F1 + 2), fibrin degradation (D-dimer) [10] and inflammation (TNF-α, IL-6 and C-reactive protein – CRP) in RA patients.

Section snippets

Patients

The study involved 20 consecutive RA patients (15 women and five men) attending the Department of Rheumatology at Istituto Gaetano Pini, Milano, Italy, who fulfilled the revised American College of Rheumatology (formerly the American Rheumatism Association) criteria for the classification of RA [11]. Their median age was 54.8 years (range 24–63 years) and the median disease duration was 6.1 years (range 5 months to 27 years). All had active disease as defined by a 28-joint disease activity score

Results

After 14 weeks of infliximab treatment, a significant clinical improvement was shown by the decrease in the DAS-28 from a median of 5.4 (interquartile range 5.2–6.0) to 4.0 (3.4–5.1) (P = 0.0001), VAS pain from 70 (70–80) to 23 (11–50) (P = 0.0001), and the number of swollen joints from 7 (4–12) to 3 (2–5) (P = 0.0001) and tender joints from 9 (6–12) to 3 (2–6) (P = 0.0001).

At baseline, TNF-α and IL-6 levels were significantly higher in RA patients, 16.00 pg/ml (11.00–20.50 pg/ml) and 29.00 pg/ml

Discussion

The results of this study show for the first time that prothrombotic biomarkers may be reduced by both short- and long-term TNF-α blockade in RA patients. We also confirm the fast and beneficial effects of infliximab in the control of symptoms and improvement of disease process.

Moreover, we provide further evidence that the long-term clinical improvement induced by intravenously administered anti-TNF-α is associated with a reduction of proinflammatory cytokines and mediators downstream the

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Of note, data from a genome-wide association study revealed that the proportion of variation in plasma D-dimer explained by genetic variants located in hemostatic factor genes was modest [20]. Thus, a high D-dimer may particularly reflect acquired underlying conditions that predispose to VTE, such as obesity and inflammatory diseases [14,18,19]. However, whether a state of chronic low-grade inflammation explains, at least in part, the association between D-dimer and incident VTE remains unclear.
D-dimer, a global biomarker for activation of the coagulation and fibrinolysis systems, is useful in assessing individual risk of venous thromboembolism (VTE) recurrence. However, there is limited information on the association between D-dimer and risk of a first lifetime VTE event.
To investigate the association between plasma D-dimer levels and risk of future incident VTE.
A population-based nested case-control study, comprising 414 VTE patients and 843 randomly selected age- and sex-matched controls, was derived from the Tromsø Study (1994–2007). D-dimer was measured in plasma samples collected at cohort baseline (1994–95). Odds ratios (ORs) for VTE with 95% confidence intervals (CIs) were estimated according to quartile cut-offs of D-dimer levels determined in controls.
The risk of VTE increased across quartiles of D-dimer levels (P_trend = 0.014) in the age- and sex-adjusted model. Participants with plasma D-dimer levels in the highest quartile (≥152 ng/mL) had an OR for VTE of 1.65 (95% CI 1.14–2.40) compared with those in the lowest quartile (<94 ng/mL). The ORs were marginally attenuated after additional adjustment for body mass index (BMI) (OR 1.51, 95% CI 1.04–2.20) and C-reactive protein (CRP) (OR 1.34, 95% CI 0.90–1.98). Similar results were obtained for VTE subgroups, i.e. deep vein thrombosis, pulmonary embolism, and provoked/unprovoked events.
Our results indicate that elevated plasma D-dimer levels are associated with increased risk of incident VTE. However, the attenuation of risk estimates upon additional adjustment for BMI and CRP suggests that D-dimer partly reflects underlying conditions associated with obesity and an inflammatory state.
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Coronavirus disease 2019 (COVID-19) has caused significant devastation globally. Despite the development of several vaccines, with uncertainty around global uptake and vaccine efficacy, the need for effective therapeutic agents remains. Increased levels of cytokines including tumour necrosis factor are significant in the pathogenesis of COVID-19 and associated with poor outcomes including ventilator requirement and mortality. Repurposing tumour necrosis factor blocker therapy used in conditions such as rheumatoid arthritis and inflammatory bowel disease seems promising, with early feasibility data showing a reduction in circulation of pro-inflammatory cytokines and encouraging the evaluation of such interventions in preventing disease progression and clinical deterioration in patients with COVID-19. Here, we examine the biological activities of tumour necrosis factor inhibitors indicative of their potential in COVID-19 and briefly outline the randomised control trials assessing their benefit-risk profile in COVID-19 therapy.
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Coronavirus disease 2019 (COVID-19) currently has few effective treatments. Given the uncertainty surrounding the effectiveness and uptake of a vaccine, it is important that the search for treatments continue. An exaggerated inflammatory state is likely responsible for much of the morbidity and mortality in COVID-19. Elevated levels of tumor necrosis factor (TNF), a key pro-inflammatory cytokine, have been shown to be associated with increased COVID-19 mortality. In patients with rheumatoid arthritis, TNF blockade reduces not only biologically active TNF but other pro-inflammatory cytokines important in COVID-19 hyperinflammation. Observational data from patients already on anti-TNF therapy show a reduced rate of COVID-19 poor outcomes and death compared with other immune-suppressing therapies. Anti-TNF has a long history of safe use, including in special at-risk populations, and is widely available. The case to adequately assess anti-TNF as a treatment for COVID-19 is compelling.
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Indeed, TNF-α and IL-6 are critical proinflammatory cytokines in the pathogenesis of axSpA [33], which may activate the coagulation system in axSpA. In addition, anti-TNFα chimeric monoclonal antibody improved the clinical and laboratory parameters, reduced the activation of coagulation in RA [34], and restored the hemostatic and fibrinolytic balance in psoriatic arthritis (PsA) [28], suggesting that control of inflammation may help recover the coagulation function in axSpA. In turn, activated coagulation plays a role in the activation of inflammatory pathways.
Activation of the coagulation system has been related to disease activity in some inflammatory diseases. Here, we aimed to investigate the relationship between coagulation function and the disease activity of axial spondyloarthritis (axSpA).
This study retrospectively recruited 144 axSpA patients and 55 healthy controls. The patients were divided into an active group (Bath Ankylosing Spondylitis Disease Activity Index, BASDAI ≥ 4) and a remission group (BASDAI < 4). The coagulation, inflammatory and clinical parameters were detected. The correlations between these parameters were analyzed with Spearman’s correlation analysis. Receiver operating characteristic (ROC) curve analysis was performed to compare the values of these variables in discriminating disease activity. Furthermore, binary logistic regression analysis was used to assess the risk factors for axSpA disease activity.
Fibrinogen (FIB) was increased in the axSpA group compared to healthy controls (P < 0.001). Additionally, FIB and D-dimer were higher in the active group than in the remission group (P < 0.05, respectively). FIB and D-dimer were positively correlated with ESR, CRP, BASDAI, Bath Ankylosing Spondylitis Functional Index (BASFI) and Bath Ankylosing Spondylitis Metrology Index (BASMI) (P < 0.05, respectively). The area under the curve (AUC) of FIB was higher than that of ESR, CRP and D-dimer. The optimal cut-off value of FIB was 3.23 g/L, with a specificity of 62.0% and sensitivity of 75.0%. FIB (OR = 4.335, 95% CI: 1.262–14.888, P = 0.020) and BASFI score (OR = 1.878, 95% CI: 1.441–2.448, P < 0.001) were independent risk factors affecting disease activity.
Activated coagulation is closely related to the disease activity of axSpA. FIB and D-dimer might be novel indicators for monitoring the disease activity of axSpA.

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Inflammatory and prothrombotic biomarkers in patients with rheumatoid arthritis: Effects of tumor necrosis factor-α blockade

Abstract

Objective

Methods

Results

Conclusions

Introduction

Section snippets

Patients

Results

Discussion

Blood

Gastroenterology

Epidemiology of the rheumatic diseases

Increased unrecognized coronary heart disease and sudden deaths in rheumatoid arthritis. A population-based cohort study

Arthritis Rheum

Cardiovascular risk factors, including thrombotic variables, in a population with rheumatoid arthritis

Rheumatology

Extravascular coagulation and the plasminogen activator/plasmin system in rheumatoid arthritis

Arthritis Rheum

Epitopes of human fibrin recognized by the rheumatoid arthritis-specific autoantibodies to citrullinated proteins

Eur J Immunol

Activation of coagulation after administration of tumor necrosis factor to normal subjects

N Engl J Med

C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women

N Engl J Med