Change search
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf
Aspects on inflammation and cardiovascular comorbidity in rheumatoid arthritis
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Reumatology.
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.

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).

Results

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).

Conclusions

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.
Series
Umeå University medical dissertations, ISSN 0346-6612 ; 1514
Keyword [en]
rheumatoid arthritis, co-morbidity, cardiovascular disease, atherosclerosis, acute coronary syndromes, adipokines, adipose tissue, tumor necrosis factor inhibition
National Category
Rheumatology and Autoimmunity
Identifiers
URN: urn:nbn:se:umu:diva-57702ISBN: 978-91-7459-461-4 (print)OAI: oai:DiVA.org:umu-57702DiVA: diva2:543797
Public defence
2012-09-07, sal E04, Biomedicinhuset, byggnad 6E, Norrlands Universitetssjukhus, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2012-08-17 Created: 2012-08-09 Last updated: 2012-08-17Bibliographically approved
List of papers
1. Interleukin-1 receptor antagonist is associated with both lipid metabolism and inflammation in rheumatoid arthritis
Open this publication in new window or tab >>Interleukin-1 receptor antagonist is associated with both lipid metabolism and inflammation in rheumatoid arthritis
Show others...
2007 (English)In: Clinical and Experimental Rheumatology, ISSN 0392-856X, E-ISSN 1593-098X, Vol. 25, no 4, 617-620 p.Article in journal (Refereed) Published
Abstract [en]

BACKGROUND: There is a relationship between cardiovascular morbidity, inflammatory activity, and changes in the lipid profile in rheumatoid arthritis (RA), although the mechanisms are not fully elaborated. Recent know-ledge that white adipose tissue (WAT) is a producer of immunologically and metabolically active substances gives another perspective to study.

OBJECTIVE: To evaluate the relationship between interleukin-1 receptor antagonist (IL-1Ra) and variables associated with WAT and inflammation in RA.

METHODS: Anthropometric, inflammatory and metabolic variables were assessed in 23 women with RA and 23 matched controls. Spearman, partial correlation and factor analyses were performed.

RESULTS: Inflammatory markers were increased in patients. In both groups, IL-1Ra correlated with leptin independent of age and BMI. IL-1Ra also correlated with haptoglobin and apolipoprotein (Apo) B in patients and with soluble TNF receptor (sTNFR) 1 in controls. In factor analysis, three latent factors were identified among patients. The first loaded on IL-1Ra, leptin, BMI, ApoB and body fat content (BF%), the second loaded on IL1-Ra and sTNF-receptors and the third showed inverse loadings on ApoA-I together with loadings on ESR, haptoglobin, orosomucoid, BF% and BMI.

CONCLUSION: IL-1Ra was associated with markers of inflammation and with fat-related factors in RA patients, suggesting a dualistic relationship of IL-1Ra in RA. IL-1Ra correlated independently with leptin in both patients and controls, indicating a relationship between inflammation and leptin.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-16984 (URN)17888220 (PubMedID)
Available from: 2007-10-25 Created: 2007-10-25 Last updated: 2017-12-14Bibliographically approved
2. Inflammatory markers in serum and adipose tissue in relation to markers of sub-clinical atherosclerosis in rheumatoid arthritis patients
Open this publication in new window or tab >>Inflammatory markers in serum and adipose tissue in relation to markers of sub-clinical atherosclerosis in rheumatoid arthritis patients
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-57700 (URN)
Available from: 2012-08-09 Created: 2012-08-09 Last updated: 2012-08-17Bibliographically approved
3. Treatment with tumour necrosis factor inhibitors and the risk of acute coronary syndromes in early rheumatoid arthritis
Open this publication in new window or tab >>Treatment with tumour necrosis factor inhibitors and the risk of acute coronary syndromes in early rheumatoid arthritis
Show others...
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.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-49010 (URN)10.1002/art.30654 (DOI)000298598100007 ()21898355 (PubMedID)
Available from: 2011-10-31 Created: 2011-10-31 Last updated: 2017-12-08Bibliographically approved
4. The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study
Open this publication in new window or tab >>The risk of acute coronary syndrome in rheumatoid arthritis in relation to tumour necrosis factor inhibitors and the risk in the general population: a national cohort study
2014 (English)In: Arthritis Research & Therapy, ISSN 1478-6354, E-ISSN 1478-6362, Vol. 16, no 3, R127Article in journal (Other academic) Published
Abstract [en]

Introduction: The elevated risk of ischaemic heart disease in patients with rheumatoid arthritis (RA) has been linked to inflammation and disease severity. Treatment with tumour necrosis factor inhibitors (TNFis) is often effective in reducing disease activity and could possibly modify cardiovascular risk. Our objective in the study was to evaluate the risk of acute coronary syndrome (ACS) in patients with RA treated with TNFis compared with the risk among biologic-naive RA patients and the general population.

Methods: By linkage of the Swedish National Patient Register and the Swedish Biologics Register, we identified a cohort of patients who were started on their first biologic, a TNFi, between 2001 and 2010 (N = 7,704), and a cohort comprising matched biologic-naive RA patient referents at a 3:1 ratio. Furthermore, a matched comparator cohort (5:1 ratio) was extracted from the Swedish population register. The incidence rates of a first ACS event were calculated and compared between cohorts using Cox proportional hazards regression in three different risk windows: 'ever-exposed', 'actively on TNFi' and 'short-term exposure' (active treatment maximized to 2 years). The models were adjusted for disease duration, joint surgery, comorbidity and socioeconomic factors, and, in a sensitivity analysis including a subpopulation started on therapy beginning 1 January 2006 or later, for dispensed drugs.

Results: Based on 221 events in 7,704 patients (comprising 32,621 person-years) treated with TNFi biologics, the hazard ratio ((HR); ever-exposed) for ACS among the TNFi-exposed RA patients compared with biologic-naive RA patients was 0.8 (95% confidence interval (CI) = 0.7 to 0.95). In comparison with the general population referents, statistical analysis using fully adjusted models resulted in a HR of 2.0 (95% CI = 1.8 to 2.3) for biologic-naive RA patients and a HR of 1.6 (95% CI = 1.4 to 1.9) for the TNFi-exposed group. Similar risk estimates were obtained using the other two risk windows. A sensitivity analysis in which we compared the TNFi-exposed patients included from 1 January 2006 onward with biologic-naive patients resulted in a HR (ever-exposed) of 0.7 (95% CI = 0.5 to 1.0).

Conclusions: RA patients treated with TNFi had a lower risk of ACS compared with biologic-naive RA patients. Compared with the general population, the risk among patients with RA was elevated, although the difference was less pronounced among the TNFi-exposed patients. This finding could be attributable to the TNFi as such, or it could correspond to a lower degree of inflammation in the TNFi-treated group.

National Category
Rheumatology and Autoimmunity
Identifiers
urn:nbn:se:umu:diva-57701 (URN)10.1186/ar4584 (DOI)000347078700022 ()
Note

Originally published in manuscript form with title The risk of acute coronary syndrome in rheumatoid arthritis in relation to TNF inhibitors and the risk in the general population: a national cohort study.

Available from: 2012-08-09 Created: 2012-08-09 Last updated: 2017-12-07Bibliographically approved

Open Access in DiVA

fulltext(1175 kB)632 downloads
File information
File name FULLTEXT01.pdfFile size 1175 kBChecksum SHA-512
e16208b112c15de78ed39dd704c312b9d470a88998837df827c7fbe4739fa491a407a2e27c980b04e24575cccb1b85411760ecbefad3e5692e29a2fb01848999
Type fulltextMimetype application/pdf

Search in DiVA

By author/editor
Ljung, Lotta
By organisation
Reumatology
Rheumatology and Autoimmunity

Search outside of DiVA

GoogleGoogle Scholar
Total: 632 downloads
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

isbn
urn-nbn

Altmetric score

isbn
urn-nbn
Total: 1093 hits
CiteExportLink to record
Permanent link

Direct link
Cite
Citation style
  • apa
  • ieee
  • modern-language-association-8th-edition
  • vancouver
  • Other style
More styles
Language
  • de-DE
  • en-GB
  • en-US
  • fi-FI
  • nn-NO
  • nn-NB
  • sv-SE
  • Other locale
More languages
Output format
  • html
  • text
  • asciidoc
  • rtf