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Treatment with tumour necrosis factor inhibitors and the risk of acute coronary syndromes in early rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
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2012 (English)In: Arthritis and Rheumatism, ISSN 0004-3591, E-ISSN 1529-0131, Vol. 64, no 1, 42-52 p.Article in journal (Refereed) Published
Abstract [en]

Rheumatoid arthritis (RA) is associated with an increased risk of ischemic heart disease, both in early and established disease. Data on the risk of ischemic heart disease in relation to therapy with TNF antagonists in established RA are conflicting, and are essentially lacking in early RA. In established RA, the risk of a myocardial infarction has been linked with the response to anti-TNF-alpha therapies (anti-TNF).

Objectives: To study the risk of acute coronary syndromes (ACS) in patients with early RA in relation to treatment with, and response to, anti-TNF.

Methods: A cohort consisting of patients with RA diagnosed 1999-2007 was identified from the Swedish RA Register (n=6,000) from which information on disease activity, and pharmacological treatment was extracted. The risk of first ACS among patients treated with anti-TNF or not was compared using hazard ratios (HR). In a nested case-control study, the relationship between response to anti-TNF and the risk for an ACS was investigated.

Results: In the cohort study, anti-TNF was not related to any statistically significantly altered risk of ACS, HR 0.80 (0.52-1.24). In the nested case-control study, a good or moderate EULAR response at 3 or 6 months was not associated with a risk of ACS, OR 1.7 (0.5-5.1) and 1.5 (0.3-6.9), respectively, when adjusted for disease activity before treatment start.

Conclusion: In this study of patients treated with anti-TNF therapy within the first years of RA disease, neither treatment with, nor response to, anti-TNF therapy could be linked to any statistically significant decrease in ACS risk.

Place, publisher, year, edition, pages
2012. Vol. 64, no 1, 42-52 p.
National Category
Rheumatology and Autoimmunity
URN: urn:nbn:se:umu:diva-49010DOI: 10.1002/art.30654ISI: 000298598100007PubMedID: 21898355OAI: diva2:452589
Available from: 2011-10-31 Created: 2011-10-31 Last updated: 2012-08-17Bibliographically approved
In thesis
1. Aspects on inflammation and cardiovascular comorbidity in rheumatoid arthritis
Open this publication in new window or tab >>Aspects on inflammation and cardiovascular comorbidity in rheumatoid arthritis
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is an increased risk for cardiovascular (CV) comorbidity among patients with rheumatoid arthritis (RA), with premature atherosclerosis, and a higher incidence of CV events, compared with the general population. Disease related factors add to the CV risk, and interact with the traditional CV risk factors. The underlying mechanism for this is not completely understood. In active RA there is a loss of muscle mass and an increase in body fat content. Production of cytokines, i.e., adipokines, in the adipose tissue could link the inflammation with the CV system. Control of the inflammation has been suggested to modify the CV risk in RA, and the recently introduced biological drugs, such as the tumor necrosis factor inhibitors (TNFi), have opened up new treatment opportunities. The aim of this thesis was to evaluate aspects of the interaction between inflammation and CV comorbidity in RA using biochemical and epidemiological methods.


In the first two studies, patients with established RA were examined for clinical disease activity, and blood samples were analysed for cytokines and adipokines using ELISAs and multiplex technology. In Study I (n RA=23) anthropometric measurements were assessed and in Study II (n RA=51) measurements of intima-media thickness (IMT), and endothelial function (FMD). From a subgroup of patients (Study II, n RA=13) samples of abdominal subcutaneous adipose tissue (SAT) were analysed for content of adipokines. In study III and IV associations between treatment with TNFi and acute coronary syndromes (ACS) were analysed using data from the Swedish Rheumatology Register; in Study III regarding early RA (n TNFi exposed=1,271, n bionaïve RA=4,729), and in Study IV comprising patients with RA of all stages (n TNFi exposed=7,213, n bionaïve RA=17,769) and with a matched general population comparator cohort (n=32,161). Associations between response to TNFi therapy and risk for ACS in the early RA cohort were evaluated in a nested case-control design (cases n=24, controls n=81).


Serum levels of the cytokines/adipokines interleukin-1 receptor antagonist (IL-1Ra), IL-6, osteopontin, visfatin and TNF were increased in patients compared with controls (p≤0.001-0.036). The amount of TNF receptor II extracted from SAT was greater in patients (p=0.006). The serum (s-) levels of IL-1Ra correlated with s-leptin (r=0.71, p≤0.001) and s-haptoglobin in RA patients (r=0.56, p≤0.01). The result from a factor analysis indicated IL-1Ra to be associated with both adipose tissue and inflammation. Levels of s-visfatin (p=0.019) and s-IL-1Ra (p=0.023), respectively, were positively associated with IMT independently of inflammatory activity and CV risk factors. PAI-1 and MCP-1 extracted from SAT showed inverse associations with IMT.

Patients with RA, whether exposed to TNFi or bio-naïve, had a doubled risk for ACS compared with the general population; HR 2.09 (95%CI 1.58-2.76) and 1.80 (1.49-2.17), respectively. No significant associations between risk for ACS and TNFi exposure were detected after adjustments; HR 0.80 (0.52-1.24) in early RA and HR 1.08 (0.82-1.41) in RA of any duration. Furthermore, no association between the risk for ACS and response to TNFi treatment in patients with early RA was observed, OR 1.5 (0.3-6.9).


The results indicate that cytokines/adipokines may have a role in the development of atherosclerosis in RA patients. A continuing increase in the risk of ACS in RA compared with the general population, despite modern therapeutic strategies, was noted. Neither exposure nor response to treatment with TNFi was associated with any modification of the risk for ACS.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2012. 102 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 1514
rheumatoid arthritis, co-morbidity, cardiovascular disease, atherosclerosis, acute coronary syndromes, adipokines, adipose tissue, tumor necrosis factor inhibition
National Category
Rheumatology and Autoimmunity
urn:nbn:se:umu:diva-57702 (URN)978-91-7459-461-4 (ISBN)
Public defence
2012-09-07, sal E04, Biomedicinhuset, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Available from: 2012-08-17 Created: 2012-08-09 Last updated: 2012-08-17Bibliographically approved

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