TY  - JOUR
AU  - Radovits, B.J.
AU  - Popa-Diaconu, D.A.
AU  - Popa, C.
AU  - Eijsbouts, A.M.M.
AU  - Laan, R.F.J.M.
AU  - Riel, P.L.C.M. van
AU  - Fransen, J.
PY  - 2009
UR  - https://hdl.handle.net/2066/80638
AB  - OBJECTIVE: Patients with rheumatoid arthritis (RA) are at greater risk of developing coronary heart disease than the general population. Systemic inflammation may contribute to this risk. This study investigated whether the level of disease activity is associated with the risk of developing myocardial infarction (MI) in patients with RA. METHODS: A case-control study was performed within a large prospective cohort of patients with RA. Cases were patients who developed their first MI after the diagnosis of RA, controls were patients with RA without MI. Cases and controls had similar RA disease duration. Traditional and disease-specific risk factors for MI were collected and a time-averaged disease activity score (DAS28) was calculated. The data were analysed using conditional logistic regression analysis. RESULTS: Cases of MI were significantly older, were more often male, with higher body mass index (BMI) and total cholesterol and lower high-density lipoprotein (HDL) serum levels than controls. Time-averaged disease activity was similar for cases and controls. The raw odds ratio for MI in patients with a "high" (>4.0) versus a "low" (<or=4.0) average DAS28 was 1.2 (95% CI 0.61 to 2.36). The odds ratio corrected for age, gender, BMI, baseline Health Assessment Questionnaire and baseline HDL was 0.91 (95% CI 0.39 to 2.12). CONCLUSION: Patients with RA who developed MI had more classical risk factors but not higher disease activity over time than control patients with RA. Low levels of inflammation may be sufficient for accelerated atherogenesis and an excess risk of cardiovascular disease in RA.
TI  - Disease activity as a risk factor for myocardial infarction in rheumatoid arthritis.
EP  - 1276
SN  - 0003-4967
IS  - iss. 8
SP  - 1271
JF  - Annals of the Rheumatic Diseases
VL  - vol. 68
DO  - http://dx.doi.org/10.1136/ard.2008.089862
ER  - 
TY  - JOUR
AU  - Roelofs, M.F.
AU  - Wenink, M.H.
AU  - Brentano, F.
AU  - Abdollahi-Roodsaz, S.
AU  - Oppers-Walgreen, B.
AU  - Barrera, P.
AU  - Riel, P.L.C.M. van
AU  - Joosten, L.A.B.
AU  - Kyburz, D.
AU  - Berg, W.B. van den
AU  - Radstake, T.R.D.J.
PY  - 2009
UR  - https://hdl.handle.net/2066/81045
AB  - BACKGROUND: Rheumatoid arthritis (RA) has been associated with an increased risk of infections, but the underlying pathways have not yet been identified. Toll-like receptors (TLR) probably play a role in synovial inflammation and may also contribute to the understanding of the role of infections in RA. OBJECTIVES: To investigate if the synovial expression of TLR3 and TLR7 in RA correlates with that of inflammatory cytokines, and to assess whether this has functional consequences for local cytokine production and to study potential links between the TLR3/7 axis and TLR4 in RA synovium. METHODS: Immunohistochemistry was used to study the expression of TLR3, TLR7, interferon alpha (IFNalpha), tumour necrosis factor alpha (TNFalpha) and interleukins IL1beta, IL12, IL17 and IL18 in RA synovium obtained by arthroscopy from 34 patients with RA. Monocytes, monocyte-derived dendritic cells (MoDCs) and RA synovial fibroblasts were stimulated via TLR3 (poly-IC) and TLR7 (loxorubin), after which IL1beta, IL6 and TNFalpha were measured by Luminex bead array technology. Following preincubation with IFNalpha, IL1beta and IL18, TLR3 and TLR7 mRNA expression was assessed using real-time PCR. Cytokine production after preincubation with IFNalpha and subsequent TLR stimulation was measured. RESULTS: Synovial TLR3/7 expression was co-expressed with IFNalpha, IL1beta and IL18, but not with TNFalpha, IL12 and IL17. Stimulation of TLR3/TLR7 on monocytes, MoDCs or synovial fibroblasts led to secretion of type I IFN but no biologically active IL1beta or IL18 could be detected. Type I IFNalpha increased TLR3/7 mRNA expression whereas IL1beta and IL18 did not. In spite of the fact that the mRNA level of TLR4 remained unchanged, IFNalpha enhanced the response to TLR4 agonists, a phenomenon that was clearly more marked in patients with RA. CONCLUSION: Type I interferons are highly co-expressed with TLR3/TLR7 in RA synovium. They enhance TLR3/TLR7-mediated cytokine production and also TLR4-mediated responses.
TI  - Type I interferons might form the link between Toll-like receptor (TLR) 3/7 and TLR4-mediated synovial inflammation in rheumatoid arthritis (RA).
EP  - 1493
SN  - 0003-4967
IS  - iss. 9
SP  - 1486
JF  - Annals of the Rheumatic Diseases
VL  - vol. 68
DO  - http://dx.doi.org/10.1136/ard.2007.086421
ER  - 
TY  - JOUR
AU  - Plater-Zyberk, C.
AU  - Joosten, L.A.B.
AU  - Helsen, M.M.A.
AU  - Koenders, M.I.
AU  - Baeuerle, P.A.
AU  - Berg, W.B. van den
PY  - 2009
UR  - https://hdl.handle.net/2066/81263
AB  - OBJECTIVE: A pathogenic role for granulocyte-macrophage colony stimulating factor (GM-CSF) and interleukin (IL)17 in rheumatoid arthritis (RA) has been suggested. In previously published work, the therapeutic potentials of GM-CSF and IL17 blockade in arthritis have been described. In the present study, the simultaneous blockade of both pathways in a mouse model for chronic arthritis was investigated to identify whether this double blockade provides a superior therapeutic efficacy. METHODS: A chronic relapsing arthritis was induced in C57Bl/6 wild type (WT) and C57Bl/6 genetically deficient for IL17 receptor (IL17R knockout (KO)) mice by intra-articular injection of Streptococcal cell wall (SCW) fragments into knees on days 0, 7, 14 and 21. Treatments (intraperitoneal) were given weekly starting on day 14. Animals were analysed for inflammation, joint damage and a range of inflammatory mediators. RESULTS: Joint swelling and cartilage damage were significantly reduced in the IL17R KO mice and in WT mice receiving anti-GM-CSF neutralising mAb 22E9 compared to isotype control antibodies. The therapeutic effect was significantly more pronounced in mice where IL17 and GM-CSF pathways were inhibited (eg, IL17R KO mice treated with 22E9 mAb). Tumour necrosis factor (TNF)alpha blockade had essentially no effect. CONCLUSION: Our data further support the therapeutic potentials of GM-CSF and IL17 blockade in a RA model that is no longer responsive to an established TNFalpha antagonist, moreover, our results suggest that concomitant inhibition of both pathways may provide the basis for a highly effective treatment of chronic RA in patients that are resistant to treatment by TNFalpha inhibitors.
TI  - Combined blockade of granulocyte-macrophage colony stimulating factor and interleukin 17 pathways potently suppresses chronic destructive arthritis in a tumour necrosis factor alpha-independent mouse model.
EP  - 728
SN  - 0003-4967
IS  - iss. 5
SP  - 721
JF  - Annals of the Rheumatic Diseases
VL  - vol. 68
DO  - https://doi.org/10.1136/ard.2007.085431
ER  - 
TY  - JOUR
AU  - Popa, C.
AU  - Tits, L.J.H. van
AU  - Barrera Rico, P.
AU  - Lemmers, H.L.M.
AU  - Hoogen, F.H.J. van den
AU  - Riel, P.L.C.M. van
AU  - Radstake, T.R.D.J.
AU  - Netea, M.G.
AU  - Roest, M.
AU  - Stalenhoef, A.F.H.
PY  - 2009
UR  - https://hdl.handle.net/2066/80105
AB  - 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.
TI  - Anti-inflammatory therapy with tumour necrosis factor alpha inhibitors improves high-density lipoprotein cholesterol antioxidative capacity in rheumatoid arthritis patients.
EP  - 872
SN  - 0003-4967
IS  - iss. 6
SP  - 868
JF  - Annals of the Rheumatic Diseases
VL  - vol. 68
DO  - https://doi.org/10.1136/ard.2008.092171
ER  -