C. Popa

Modulation of lipoprotein plasma concentrations during long-term anti-TNF therapy in patients with active rheumatoid arthritis

Objective: Durable blockade of tumour necrosis factor-alpha (TNF-α) in patients with rheumatoid arthritis (RA) suppresses disease activity and its progression. Cardiovascular diseases are 1.5–2-fold more frequent in RA patients than in the general population. Although TNF-α has well-established effects on lipid metabolism, the long-term effects of TNF-α blockade on lipid pattern are still unclear. In the present study, we investigated the effects of 1-year therapy with anti-TNF on the lipid profile of RA patients. Methods: Disease activity (DAS28) and plasma lipoproteins concentrations (total, HDL and LDL-cholesterol, triglycerides, ApoA, ApoB) were assessed in 55 RA patients and 55 controls. The whole RA group was followed up for 6 months, and 31 of the patients were followed up for 1 year. Results: In RA patients, DAS28 decreased after 2 weeks from the start of therapy (p<0.001) and remained low during the entire study duration. Short-term effects of anti-TNF on plasma lipid concentrations seemed beneficial and anti-atherogenic. However, these changes did not persist: plasma concentrations of total and LDL-cholesterol and the atherogenic index increased after 6 months and 1 year from the start of therapy. During therapy, the changes in disease activity and inflammatory status were inversely correlated with changes in plasma total and HDL cholesterol levels and positively correlated with the variation of atherogenic index. Conclusion: We conclude that one-year therapy with infliximab is likely to lead to a more pro-atherogenic pattern of the plasma lipids concentrations. However, the overall impact of these changes on the cardiovascular risk is more complex, considering the strong anti-inflammatory effects of anti-TNF drugs.

Performance of four current risk algorithms in predicting cardiovascular events in patients with early rheumatoid arthritis

Objective This study was undertaken to assess the predictive ability of 4 established cardiovascular (CV) risk models for the 10-year risk of fatal and non-fatal CV diseases in European patients with rheumatoid arthritis. Methods Prospectively collected data from the Nijmegen early rheumatoid arthritis (RA) inception cohort was used. Discriminatory ability for CV risk prediction was estimated by the area under the receiver operating characteristic curve. Calibration was assessed by comparing the observed versus expected number of events using Hosmer-Lemeshov tests and calibration plots. Sensitivity and specificity were calculated for the cut-off values of 10% and 20% predicted risk. Results Areas under the receiver operating characteristic curve were 0.78–0.80, indicating moderate to good discrimination between patients with and without a CV event. The CV risk models Systematic Coronary Risk Evaluation (SCORE), Framingham risk score (FRS) and Reynolds risk score (RRS) primarily underestimated CV risk at low and middle observed risk levels, and mostly overestimated CV risk at higher observed risk levels. The QRisk II primarily overestimated observed CV risk. For the 10% and 20% cut-off values used as indicators for CV preventive treatment, sensitivity ranged from 68–87% and 40–65%, respectively and specificity ranged from 55–76% and 77–88%, respectively. Depending on the model, up to 32% of observed CV events occurred in patients with RA who were classified as low risk (<10%) for CV disease. Conclusions Established risk models generally underestimate (Systematic Coronary Risk Evaluation score, Framingham Risk Score, Reynolds risk score) or overestimate (QRisk II) CV risk in patients with RA.

Anti-inflammatory therapy with tumour necrosis factor alpha inhibitors improves high-density lipoprotein cholesterol antioxidative capacity in rheumatoid arthritis patients

Objective: High-density lipoprotein (HDL) antiatherogenic functions seem to be diminished during inflammatory conditions such as rheumatoid arthritis (RA). The aim of this study was to investigate the effects of tumour necrosis factor (TNF) inhibition on the antioxidative capacity of HDL in RA. Methods: Plasma lipids and paraoxonase (PON-1) activity were investigated in 45 RA patients, before and during 6 months of anti-TNF therapy. In addition, HDL was isolated and tested for its ability to inhibit copper-induced oxidation of low-density lipoprotein in vitro. Results: Plasma HDL concentrations did not change considerably after 6 months of therapy. However, stable increases of PON-1 activities were observed throughout the same period (p<0.03). The increases were more obvious when related to HDL or apolipoprotein AI concentrations. HDL total antioxidative capacity significantly improved 6 months after the initiation of anti-TNF therapy (p = 0.015). The initial improvement of PON-1 activity paralleled a decrease in the inflammatory status, whereas specific TNF blockade was likely to be responsible for the long-term effects. Conclusions: Anti-TNF therapy with infliximab has beneficial effects on lipids through changes in HDL antioxidative capacity, which might be clinically relevant and contribute to the reported protective effect of anti-TNF on cardiovascular morbidity in RA. This emphasises the importance of HDL antiatherogenic capacity for cardiovascular risk in chronic inflammatory conditions.

Bartonella quintana Lipopolysaccharide Is a Natural Antagonist of Toll-Like Receptor 4

ABSTRACT Bartonella quintana is a gram-negative microorganism that causes trench fever and chronic bacteremia. B. quintana lipopolysaccharide (LPS) was unable to induce the production of proinflammatory cytokines in human monocytes. Interestingly, B. quintana LPS is a potent antagonist of Toll-like receptor 4 (TLR4), as it inhibited both mRNA transcription and the release of tumor necrosis factor alpha, interleukin 1β (IL-1β), and IL-6 by Escherichia coli LPS in human monocytes, at ratios ranging from 1,000:1 to 10:1 (B. quintana LPS to E. coli LPS). Likewise, B. quintana LPS blocked the interaction of E. coli LPS with TLR4 in transfected cell lines. The extent of the inhibitory effect of B. quintana LPS was demonstrated in microarray studies, which showed downregulation of practically all genes induced by LPS in monocytes. Because of the role of TLR4 in inflammation, B. quintana LPS may prove useful as a potent anti-TLR4 agent with therapeutic potential in both infections and autoimmune inflammation.

Circulating leptin and adiponectin concentrations during tumor necrosis factor blockade in patients with active rheumatoid arthritis.

Objective. Adipocytokines, including leptin and adiponectin, may play an important role in the pathogenesis of rheumatoid arthritis (RA). We investigated the effects of longterm therapeutic tumor necrosis factor (TNF) blockade on adipocytokine concentrations in patients with RA. Methods. We studied 58 RA patients starting anti-TNF therapy and 58 healthy controls matched for age, sex, and body mass index (BMI). Fasting blood samples were drawn at baseline, 2 weeks, and 6 months after the start of anti-TNF therapy and serum levels of leptin and adiponectin were measured. Results. Patients with RA had increased adiponectin (p < 0.001) and similar leptin concentrations compared with the controls. Leptin concentrations were significantly higher in patients with high BMI (p < 0.001) and correlated positively with BMI at all timepoints (r > 0.75). In contrast, serum adiponectin tended to be higher in lean RA patients and did not correlate with BMI at any timepoint. There were no clear correlations between serum concentrations of adipocytokines and disease activity (Disease Activity Score 28). Short or longterm TNF blockade alone had no influence on circulating leptin and adiponectin concentrations. Patients treated with anti-TNF and concomitant corticosteroids on a stable basis showed a significant decrease in adiponectin levels after 6 months of therapy (p < 0.025). Conclusion. In patients with RA, chronic inflammation and its suppression during anti-TNF therapy have limited influence on plasma leptin concentrations, while significantly decreasing circulating adiponectin levels. Our findings question the suggested key role of inflammatory markers in regulating adipocytokine patterns in RA.

Improved insulin sensitivity by anti‐TNFα antibody treatment in patients with rheumatic diseases

Insulin resistance is a key factor in the pathogenesis of the metabolic syndrome and type 2 diabetes, but the underlying mechanisms remain poorly understood. Adipocytokines, including tumour necrosis factor α (TNFα), interleukin 6, leptin and adiponectin,1,2 are increasingly recognised as important regulators of both insulin sensitivity, as well as inflammation, and a dysregulation of their levels and/or functions has been shown in both obesity and rheumatoid arthritis.3 Further investigations have substantiated the important negative effects of TNFα on insulin-mediated glucose uptake and the development of insulin resistance.4 In this study, the influence of therapeutic TNFα blockade on insulin sensitivity was investigated in regularly treated patients with rheumatic diseases. A group of eight patients who were non-diabetic and having various chronic inflammatory disorders (table 1) were investigated in an open prospective …

TLR2 promotes Th2/Th17 responses via TLR4 and TLR7/8 by abrogating the Type I IFN amplification loop

TLR2 plays an important role in the removal of Gram-positive bacteria; contrastingly, it also appears to have important protective effects against unrestrained inflammation and subsequent organ injury during infection and autoimmunity. We hypothesized that TLR2 tunes the phenotype of dendritic cells (DCs) activated through other TLRs, thereby fulfilling a crucial role in the modulation of the immune response. TLR2 potently inhibited TLR4- and TLR7/8-induced cytokine production by human DCs. The inhibitory effect of TLR2 on the release of TNF-α but not of IL-12p70 was mediated by PI3K. TLR2 inhibits the production of IL-12p70 by dampening the type 1 IFN amplification loop. When DCs were triggered with the potent synergistic combination of LPS (TLR4) and R848 (TLR7/8) in conjunction with a TLR2 ligand, a clear shift to more Th2- and Th17-prone responses in the naive and memory T cell subpopulations was observed. This shift in T cell responses was inherent to the inability of TLR2-stimulated DCs to produce IL-12p70 and was dependent on the production of IL-1 and IL-6.

Differential function of the NACHT-LRR (NLR) members Nod1 and Nod2 in arthritis

The pathogenesis of chronic joint inflammation remains unclear, although the involvement of pathogen recognition receptors has been suggested recently. In the present article, we describe the role of two members of the NACHT-LRR (NLR) family, Nod1 (nucleotide-binding oligomerization domain) and Nod2 in a model of acute joint inflammation induced by intraarticular injection of Streptococcus pyogenes cell wall fragments. Here, we show that Nod2 deficiency resulted in reduced joint inflammation and protection against early cartilage damage. In contrast, Nod1 gene-deficient mice developed enhanced joint inflammation with concomitant elevated levels of proinflammatory cytokines and cartilage damage, consistent with a model in which Nod1 controls the inflammatory reaction. To explore whether the different function of Nod1 and Nod2 occurs also in humans, we exposed peripheral blood mononuclear cells (PBMCs) carrying either Nod1ins/del or Nod2fs mutation with SCW fragments in vitro. Production of both TNFα and IL-1β was clearly impaired in PBMCs carrying the Nod2fs compared with PBMCs isolated from healthy controls. In line with results in Nod1 gene-deficient mice, PBMCs from individuals bearing a newly described Nod1 mutation produced enhanced levels of proinflammatory cytokines after 24-h stimulation with SCW fragments. These data indicate that the NLR family members Nod1 and Nod2 have different functions in controlling inflammation, and that intracellular Nod1–Nod2 interactions may determine the severity of arthritis in this experimental model. Whether a distorted balance between the function of Nod1 and/or Nod2 is involved in the pathogenesis of human autoinflammatory or autoimmune disease, such as rheumatoid arthritis, remains to be elucidated.

The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients

Objective Disease duration and disease activity may be associated with an increased risk of cardiovascular disease (CVD) in rheumatoid arthritis (RA). The objectives of this study were to investigate (1) the relationship between duration of inflammation and the development of CVD in RA patients and (2) the relationship between RA disease activity over time and CVD in patients with RA. Methods RA patients with a follow-up of ≥6 months in the Nijmegen early RA cohort without prior CVD were included. Disease activity over time was calculated using the time-averaged 28 joint disease activity score (DAS28) for each patient. Kaplan–Meier survival analysis and Cox proportional hazards regression were used for the analyses. Results During follow-up of the 855 patients that were included, 154 CV events occurred. The course of hazards over time did not indicate a change in the risk of CVD over the course of RA (disease duration), which is also reflected by the absence of a deflection in the survival curves. The survival distributions did not differ between patients with a disease duration of <10 years or >10 years (Log-rank test: p=0.82). Time-averaged DAS28 was significantly associated with CVD (p=0.002) after correction for confounders. Conclusions Disease duration does not appear to independently affect the risk of CVD. The risk of CVD in RA patients was not increased after 10 years of disease duration compared with the first 10 years. Disease activity over time may contribute to the risk of CVD.

Atherogenic Index and High-Density Lipoprotein Cholesterol as Cardiovascular Risk Determinants in Rheumatoid Arthritis: The Impact of Therapy with Biologicals

Cardiovascular (CV) diseases are a serious concern in rheumatoid arthritis (RA), accounting for approximately one-third to one-half of all RA-related deaths. Besides the attempts to identify new risk factors, the proper management of traditional CV risk factors such as dyslipidemia should become a priority in the periodic evaluation of every RA patient. Atherogenic index has been suggested to be less susceptible to disease activity variation during large periods of time, making him more attractive to be used in CV risk prediction in this group of patients as compared to individual lipids concentrations. Nevertheless, inflammation may negatively impact HDL antiatherogenic properties, suggesting that HDL function assessment is of particular importance when predicting CV risk in these patients. A tight control of inflammation becomes therefore crucial for a successful CV risk management. The present paper debates these hypotheses focusing on the effects of therapy with biologicals on the above mentioned parameters.