University of Manchester



EULAR recommendations for cardiovascular disease risk management in patients with rheumatoid arthritis and other forms of inflammatory joint disorders: 2015/2016 Update Version July 15, 2016Authors R. Agca,* S.C. Heslinga,* S. Rollefstad,* M. Heslinga,* I.B. McInnes, M.J.L. Peters, T.K. Kvien, M. Dougados, H. Radner, F. Atzeni, J. Primdahl, A. S?dergren, S. Wallberg Jonsson, J. van Rompay, C. Zabalan, T.R. Pedersen, L. Jacobsson, K. de Vlam M.A. Gonzalez-Gay, A.G. Semb, G.D. Kitas, Y.M. Smulders, Z. Szekanecz, N. Sattar, D.P.M. Symmons,** M.T. Nurmohamed***shared first authorship**shared senior authorshipCorresponding author: Prof. Dr. Michael T. Nurmohamed, rheumatologistAmsterdam Rheumatology and immunology Center | VU University Medical Center & Reade P.O. Box 7057, 1007 MB AmsterdamTelephone: +31-20-4444824E-mail address: mt.nurmohamed@vumc.nlAbstractBackground: Patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD) have increased cardiovascular disease (CVD) risk compared to the general population. In 2009 a EULAR taskforce recommended screening, identification of CVD risk factors and CVD risk management largely based on expert opinion. In view of substantial new evidence, an update was conducted with the aim of producing CVD risk management recommendations for patients with IJD that now incorporates an increasing evidence base. Objectives: To update the 2009 EULAR recommendations concerning the assessment and management of CVD risk in persons with IJD.Methods: A multidisciplinary steering committee (representing 13 European countries) comprised 26 members including patient representatives, rheumatologists, cardiologists, internists, epidemiologists, a health professional and fellows. Systematic literature searches were performed and evidence was categorized according to standard guidelines. The evidence was discussed and summarised by the experts in the course of a consensus finding and voting process. Results: Three overarching principles were defined. First, there is a higher risk for CVD in RA, and this may also apply to AS and PsA. Second, the rheumatologist is responsible for CVD risk management in patients with IJD. Third, the use of NSAIDs and corticosteroids should be in accordance with treatment specific recommendations from EULAR and ASAS. Ten recommendations were defined, of which one is new, and six were changed compared to the 2009 recommendations. Each designated an appropriate evidence support level.Conclusion: The present update extends on the evidence that CVD risk in the whole spectrum of IJD is increased. This underscores the need for CVD risk management in these patients. These recommendations are defined to provide assistance in CVD risk management in IJD, based on expert opinion and scientific evidence. IntroductionCardiovascular disease (CVD) risk in patients with rheumatoid arthritis (RA) and other inflammatory joint disorders (IJD), in particular ankylosing spondylitis (AS) and psoriatic arthritis (PsA), is substantially elevated compared to the general population. For RA, the magnitude of this excess risk appears comparable to that reported for patients with diabetes mellitus PFJlZm1hbj48Q2l0ZT48QXV0aG9yPnZhbiBIYWxtPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48

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ADDIN EN.CITE.DATA 1-3, necessitating aggressive and targeted CVD risk management. In 2009, a European League Against Rheumatism (EULAR) task force was convened to critically appraise existing evidence on CVD risk in patients with IJD. This EULAR task force formulated ten recommendations for the screening and identification of CVD risk factors and the implementation of CVD risk management in IJD (see Supplementary file 1).PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBldGVyczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 4 In view of substantial new evidence, an update of the CVD risk management recommendations was performed.In general, CVD risk management involves the determination of a cardiovascular risk profile of an individual patient by using values including gender, age, smoking status, blood pressure, lipid values and diabetes mellitus status. These variables are used in risk prediction algorithms such as Framingham ADDIN REFMGR.CITE <Refman><Cite><Author>D&apos;Agostino</Author><Year>2008</Year><RecNum>3</RecNum><IDText>General cardiovascular risk profile for use in primary care: the Framingham Heart Study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>3</Ref_ID><Title_Primary>General cardiovascular risk profile for use in primary care: the Framingham Heart Study</Title_Primary><Authors_Primary>D&apos;Agostino,R.B.,Sr.</Authors_Primary><Authors_Primary>Vasan,R.S.</Authors_Primary><Authors_Primary>Pencina,M.J.</Authors_Primary><Authors_Primary>Wolf,P.A.</Authors_Primary><Authors_Primary>Cobain,M.</Authors_Primary><Authors_Primary>Massaro,J.M.</Authors_Primary><Authors_Primary>Kannel,W.B.</Authors_Primary><Date_Primary>2008/2/12</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Algorithms</Keywords><Keywords>blood</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Longitudinal Studies</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>Multivariate Analysis</Keywords><Keywords>Primary Health Care</Keywords><Keywords>Proportional Hazards Models</Keywords><Keywords>Risk Assessment</Keywords><Keywords>Risk Factors</Keywords><Keywords>Sex Factors</Keywords><Reprint>Not in File</Reprint><Start_Page>743</Start_Page><End_Page>753</End_Page><Periodical>Circulation</Periodical><Volume>117</Volume><Issue>6</Issue><Misc_3>CIRCULATIONAHA.107.699579 [pii];10.1161/CIRCULATIONAHA.107.699579 [doi]</Misc_3><Address>Boston University, Department of Mathematics and Statistics, 111 Cummington St, Boston, MA 02215, USA</Address><Web_URL>PM:18212285</Web_URL><ZZ_JournalStdAbbrev><f name="System">Circulation</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>5 and the Systematic Coronary Risk Evaluation (SCORE)PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNvbnJveTwvQXV0aG9yPjxZZWFyPjIwMDM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 6 to calculate a 10-year risk of CVD events. When this CVD risk exceeds a certain value, i.e. a 10-year risk of 10% for a fatal or non-fatal CVD event (Framingham) or a 10-year risk of 5% for fatal CVD events (SCORE), lifestyle changes and treatment with lipid lowering agents is recommended. The importance of a healthy lifestyle is emphasized for all persons, including patients at low- and intermediate cardiovascular risk. Additionally, the ESC guideline on cardiovascular disease prevention in clinical practice also recommends CVD risk stratification for patients with hypertension.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 7 The initiation of antihypertensives depends on the grade of hypertension and total cardiovascular risk. Drug treatment is recommended for patients with grade 3 hypertension, but also grade 2 and grade 1 hypertension with a high CVD risk.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 7 Validated RA-specific CVD risk prediction models with a proven superiority over general population CVD risk prediction algorithms are currently lacking.7 Furthermore, the existing general population risk prediction models that aid the identification of patients who would benefit from primary prevention of CVD have been shown to inaccurately estimate the CVD risk in RA.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFydHM8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 8;9 Therefore, in 2009 the EULAR task force advocated the use of a 1.5 multiplication factor for these risk prediction models when certain RA disease characteristics were present.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBldGVyczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 10 In addition, certain commonly used variables in existing CVD risk prediction algorithms are influenced by inflammation and anti-inflammatory therapy. These risk factors behave differently in patients with IJD than in the general population, necessitating clarification and practical guidelines for rheumatologists in daily clinical practice. For this update a new EULAR task force reviewed all the previous recommendations from 2009 on CVD risk management in IJD. New areas were addressed, including the value of imaging in the routine assessment of CVD risk. Methods Task forceWith the approval of the EULAR Executive Committee, the convenor (MN) and methodologist (DS) who guided the task force in 2009 formed a new task force with the aim of reviewing and updating the 2009 EULAR recommendations for CVD risk management in RA and other IJD (supplementary file 1).PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBldGVyczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 4 The task force comprised 26 members from 13 European countries, including two patient representatives, 14 rheumatologists, two cardiologists, three internists, one health care professional and four fellows. The entire process was conducted in accordance with the 2014 EULAR standardised operating procedures.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPnZhbiBkZXIgSGVpamRlPC9BdXRob3I+PFllYXI+MjAxNTwv

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ADDIN EN.CITE.DATA 11 Literature searchThe convenor (MN) started by formulating a list of potential research questions. These were discussed and refined during a teleconference with other members of the task force. Thereafter, the fellows (RA, SH, SR, MH) under guidance of the convenor (MN) and the methodologist (DS), compiled the search terms for a comprehensive systematic literature review to cover all the research questions. The protocol for the literature search was based on the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA)-statement (prisma-). The Wiley/Cochrane Library, PubMed and were searched from inception (by RA, SH, MH and librarians LJS and JCFK). Wiley/Cochrane Library was searched up to 9 February 2015, PubMed up to 10 February 2015 and up to 13 February 2015. A single search was conducted embracing all aspects of the different research questions. The following search terms were used (including synonyms and closely related words) as index terms or free-text words: ‘rheumatoid arthritis’ or ‘spondyloarthritis’ and ‘cardiovascular disease’ and ‘cholesterol’ or ‘blood pressure’ or ‘smoking’ or ‘diabetes’ or ‘chronic kidney insufficiency’ or ‘sex factors’ or ‘vitamin D’ or ‘adrenal cortex hormones’ or ‘tumor necrosis factor’ or ‘anti-inflammatory agents’ or ‘inflammation’ or ‘carotid intima media’. The full search strategies for Wiley/Cochrane Library, PubMed and are shown in Supplementary file 2. All duplicates were removed from the results of the first search (Figure 1). The remaining studies were screened by title and abstract by six investigators (RA, SH, SR, MH, DS and MN) for suitability. Titles and abstracts were eligible if the abstract contained clear information about the aims and objectives of the study. From this selection of abstracts, full text articles were assessed for eligibility by the fellows (RA, SH, SR, MH). References of included articles were manually scanned for other relevant studies. The included articles were evenly divided among the four fellows, based on their area of expertise. Each fellow read the full texts and distilled and summarized the most important results. From these results, also taking into account the ten 2009 recommendations, ten concept recommendations were derived. Consensus findingThe EULAR task force held a one-day meeting with all members on March 31st, 2015. During this meeting the ten concept recommendations were presented by the four fellows. All ten concept recommendations were discussed and subsequently adapted or dropped, and new recommendations were formulated. The principles guiding the consensus meeting were: 1) all of the 2009 recommendations were reconsidered on the basis of new evidence 2) any of the 2009 recommendations could be kept unchanged, be modified or be totally abandoned 3) new recommendations could be added. After the meeting, the updated and new recommendations were graded based on the methodological strength of the underlying literature and were categorised according to the GRADE system. ADDIN REFMGR.CITE <Refman><Cite><Author>Guyatt</Author><Year>2008</Year><RecNum>40</RecNum><IDText>GRADE: an emerging consensus on rating quality of evidence and strength of recommendations</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>40</Ref_ID><Title_Primary>GRADE: an emerging consensus on rating quality of evidence and strength of recommendations</Title_Primary><Authors_Primary>Guyatt,G.H.</Authors_Primary><Authors_Primary>Oxman,A.D.</Authors_Primary><Authors_Primary>Vist,G.E.</Authors_Primary><Authors_Primary>Kunz,R.</Authors_Primary><Authors_Primary>Falck-Ytter,Y.</Authors_Primary><Authors_Primary>Alonso-Coello,P.</Authors_Primary><Authors_Primary>Schunemann,H.J.</Authors_Primary><Date_Primary>2008/4/26</Date_Primary><Keywords>article</Keywords><Keywords>Canada</Keywords><Keywords>Consensus</Keywords><Keywords>Decision Making</Keywords><Keywords>epidemiology</Keywords><Keywords>Evidence-Based Medicine</Keywords><Keywords>IM</Keywords><Keywords>Journal Article</Keywords><Keywords>Practice Guidelines as Topic</Keywords><Keywords>Quality Indicators,Health Care</Keywords><Keywords>standards</Keywords><Keywords>university</Keywords><Reprint>Not in File</Reprint><Start_Page>924</Start_Page><End_Page>926</End_Page><Periodical>BMJ</Periodical><Volume>336</Volume><Issue>7650</Issue><User_Def_5>PMC2335261</User_Def_5><Misc_3>336/7650/924 [pii];10.1136/bmj.39489.470347.AD [doi]</Misc_3><Address>Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada L8N 3Z5. guyatt@mcmaster.ca</Address><Web_URL>PM:18436948</Web_URL><ZZ_JournalFull><f name="System">BMJ</f></ZZ_JournalFull><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>12 Thereafter, the ten concept recommendations were sent out by e-mail for anonymous voting. All members of the task force were asked to indicate their level of agreement for each recommendation on a 0–10 scale (0, no agreement at all; 10, full agreement). The results on agreement were averaged and are hence presented as mean (standard deviation). Results Literature searchIn total, 9,328 articles were identified. After removal of duplicates, 6,783 articles were screened by title and abstract. In total, 961 full text articles were assessed for eligibility by the fellows (RA, SH, SR, MH). Ultimately, 264 articles were included (Figure 1). Overarching principlesThe task force defined three overarching principles of CVD risk management in RA and other IJD (Table 1).A. Clinicians should be aware of the higher risk for CVD in RA compared to the general population. This may also apply to AS and PsA. Acknowledging the increased CVD risk in IJD was included as a recommendation in our previous guideline of 2009. However, in view of its generic nature, this ‘recommendation’ was moved to the overarching principles section of this paper. Since the publication of the 2009 EULAR recommendations, the evidence for an enhanced CVD risk in IJD has increased. For example, it was shown in a large Danish cohort study that the risk of myocardial infarction (MI) in RA patients is comparable to that in diabetes mellitus patients. ADDIN REFMGR.CITE <Refman><Cite><Author>Lindhardsen</Author><Year>2011</Year><RecNum>2</RecNum><IDText>The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2</Ref_ID><Title_Primary>The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study</Title_Primary><Authors_Primary>Lindhardsen,J.</Authors_Primary><Authors_Primary>Ahlehoff,O.</Authors_Primary><Authors_Primary>Gislason,G.H.</Authors_Primary><Authors_Primary>Madsen,O.R.</Authors_Primary><Authors_Primary>Olesen,J.B.</Authors_Primary><Authors_Primary>Torp-Pedersen,C.</Authors_Primary><Authors_Primary>Hansen,P.R.</Authors_Primary><Date_Primary>2011/6</Date_Primary><Keywords>Adolescent</Keywords><Keywords>Adult</Keywords><Keywords>Age Distribution</Keywords><Keywords>Age Factors</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>Arthritis,Rheumatoid</Keywords><Keywords>complications</Keywords><Keywords>Denmark</Keywords><Keywords>Diabetic Angiopathies</Keywords><Keywords>Epidemiologic Methods</Keywords><Keywords>epidemiology</Keywords><Keywords>etiology</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Myocardial Infarction</Keywords><Keywords>Sex Factors</Keywords><Keywords>Young Adult</Keywords><Reprint>Not in File</Reprint><Start_Page>929</Start_Page><End_Page>934</End_Page><Periodical>Ann Rheum Dis</Periodical><Volume>70</Volume><Issue>6</Issue><Misc_3>ard.2010.143396 [pii];10.1136/ard.2010.143396 [doi]</Misc_3><Address>Correspondence to Jesper Lindhardsen, Department of Cardiology, section PA (Post 67), Gentofte Hospital, Niels Andersensvej 65, DK-2900 Hellerup, Denmark. jeslin01@geh.regionh.dk</Address><Web_URL>PM:21389043</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann Rheum Dis</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>2 Furthermore, in the same study the risk of MI in RA was found to be approximately 70% higher than in the general population, which corresponds with the risk in 10-year older non-RA subjects. ADDIN REFMGR.CITE <Refman><Cite><Author>Lindhardsen</Author><Year>2011</Year><RecNum>2</RecNum><IDText>The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>2</Ref_ID><Title_Primary>The risk of myocardial infarction in rheumatoid arthritis and diabetes mellitus: a Danish nationwide cohort study</Title_Primary><Authors_Primary>Lindhardsen,J.</Authors_Primary><Authors_Primary>Ahlehoff,O.</Authors_Primary><Authors_Primary>Gislason,G.H.</Authors_Primary><Authors_Primary>Madsen,O.R.</Authors_Primary><Authors_Primary>Olesen,J.B.</Authors_Primary><Authors_Primary>Torp-Pedersen,C.</Authors_Primary><Authors_Primary>Hansen,P.R.</Authors_Primary><Date_Primary>2011/6</Date_Primary><Keywords>Adolescent</Keywords><Keywords>Adult</Keywords><Keywords>Age Distribution</Keywords><Keywords>Age Factors</Keywords><Keywords>Aged</Keywords><Keywords>Aged,80 and over</Keywords><Keywords>Arthritis,Rheumatoid</Keywords><Keywords>complications</Keywords><Keywords>Denmark</Keywords><Keywords>Diabetic Angiopathies</Keywords><Keywords>Epidemiologic Methods</Keywords><Keywords>epidemiology</Keywords><Keywords>etiology</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Myocardial Infarction</Keywords><Keywords>Sex Factors</Keywords><Keywords>Young Adult</Keywords><Reprint>Not in File</Reprint><Start_Page>929</Start_Page><End_Page>934</End_Page><Periodical>Ann Rheum Dis</Periodical><Volume>70</Volume><Issue>6</Issue><Misc_3>ard.2010.143396 [pii];10.1136/ard.2010.143396 [doi]</Misc_3><Address>Correspondence to Jesper Lindhardsen, Department of Cardiology, section PA (Post 67), Gentofte Hospital, Niels Andersensvej 65, DK-2900 Hellerup, Denmark. jeslin01@geh.regionh.dk</Address><Web_URL>PM:21389043</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann Rheum Dis</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>2 Regarding mortality in RA, a meta-analysis including 8 studies with follow-up ranging from the year 1955 to 1995 concluded that the standardized mortality rates (SMRs) in RA were elevated compared with the general population (i.e. pooled SMR 1.47, 95% CI 1.19 – 1.83) and that these SMRs did not change over time.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkRhZG91bjwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 13 Data from the Norfolk Arthritis Register with follow-up until 2012 revealed comparable results with increased all-cause mortality in patients with RA compared to the general population along with stable SMRs over the past 20 years.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkh1bXBocmV5czwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

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Zm1hbj4A

ADDIN EN.CITE.DATA 15;16Recent studies reveal increased SMRs in AS, ranging from 1.6-1.9.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJha2xhbmQ8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 17-19 Compared to controls, AS patients have an increased risk of vascular death and CVD events. PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJyZW1hbmRlcjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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AG==

ADDIN EN.CITE.DATA 28 increased prevalence of hypertension, PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJyZW1hbmRlcjwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+

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ADDIN EN.CITE.DATA 33;34 In PsA, reported SMRs range from 0.8 to 1.6.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1vazwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA 18;35;36 Overall, patients with PsA are at an increased risk of CVD events, however data on stroke are more conflicting.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkhvcnJlYXU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 35;37-39 Likewise, in PsA CVD risk seems to be influenced by an increased prevalence of CVD risk factors such as hypertension,PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkd1bGF0aTwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 38-41 and increased arterial stiffness.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNoYW5nPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

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Zm1hbj4A

ADDIN EN.CITE.DATA 42-44 B.The rheumatologist should ensure that CVD risk management is performed in patients with RA and other IJD.The responsibility for CVD risk management should be defined locally due to different health care systems and economic priorities in each country. Therefore, CVD risk management may include healthcare professionals other than rheumatologists. In clinical practice it is not always clear who is taking responsibility for CVD risk assessment and management in patients with IJD and the task force therefore recommends that the treating rheumatologist should ensure that CVD risk assessment and management is being performed regularly, should record who is performing it and should make sure that the patient is aware of the need for regular risk assessment. C.The use of NSAIDs and corticosteroids should be in accordance with treatment specific recommendations from EULAR and the Assessment of Spondyloarthritis international society (ASAS).PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkR1cnU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 45;46Nonsteroidal anti-inflammatory drugs (NSAIDs) and corticosteroids are commonly used for the treatment of IJD and these agents effectively lower disease activity and inflammation. However, both treatment options have been associated with an increased CVD risk.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlJvdWJpbGxlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA 47-49 As these medications are often indispensable in tackling disease activity in patients with IJD, the task force feels that their use should be evaluated on an individual patient level. Furthermore, lowering disease activity may have beneficial effects on the CVD risk. Therefore, the task force recommends to use NSAIDs and corticosteroids according to treatment specific guidelines. RecommendationsIn line with the 2009 guideline we opted to give again ten recommendations for CVD risk management. In total, 3 recommendations remained unchanged, 6 recommendations were altered and there is 1 new recommendation. One of the 2009 recommendation (#1) was moved to the overarching principles as described previously. A list of the updated recommendations, including the levels of evidence with the strength of recommendation and the level of agreement based on voting by the task force, is shown in Table 1. The recommendations follow a logical sequence, and they are not listed in sequence of importance. All recommendations are discussed in detail below.Disease activity should be controlled optimally in order to lower CVD risk in all patients with RA, AS or PsA (Unchanged, LOA 9.1 (1.3))In the previous recommendations from 2009 the importance of control of disease activity to lower CVD risk was emphasized. New evidence still portrays an association between higher cumulative inflammatory burden and increased CVD risk in RA.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFqZWdhbm92YTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+

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ADDIN EN.CITE.DATA 50-55 Disease duration does not seem to affect CVD risk independently. ADDIN REFMGR.CITE <Refman><Cite><Author>Arts</Author><Year>2014</Year><RecNum>242</RecNum><IDText>The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>242</Ref_ID><Title_Primary>The effect of disease duration and disease activity on the risk of cardiovascular disease in rheumatoid arthritis patients</Title_Primary><Authors_Primary>Arts,E.E.</Authors_Primary><Authors_Primary>Fransen,J.</Authors_Primary><Authors_Primary>den Broeder,A.A.</Authors_Primary><Authors_Primary>Popa,C.D.</Authors_Primary><Authors_Primary>van Riel,P.L.</Authors_Primary><Date_Primary>2014/1/23</Date_Primary><Keywords>analysis</Keywords><Keywords>Arthritis</Keywords><Keywords>article</Keywords><Keywords>Disease</Keywords><Keywords>disease activity</Keywords><Keywords>Inflammation</Keywords><Keywords>Journal Article</Keywords><Keywords>methods</Keywords><Keywords>Netherlands</Keywords><Keywords>patient</Keywords><Keywords>Patients</Keywords><Keywords>Rheumatic Diseases</Keywords><Keywords>Rheumatology</Keywords><Keywords>Risk</Keywords><Keywords>Time</Keywords><Keywords>university</Keywords><Reprint>Not in File</Reprint><Periodical>Ann Rheum Dis</Periodical><ISSN_ISBN>1468-2060</ISSN_ISBN><Address>Department of Rheumatology, Radboud University Medical Centre, Nijmegen, The Netherlands</Address><Web_URL>PM:24458537</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann Rheum Dis</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>51 However, disease activity as well as the number and duration of flares over time do contribute to the risk of CVD.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFqZWdhbm92YTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+

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ADDIN EN.CITE.DATA 50-53 There is now additional evidence showing a reduction of CVD risk in patients treated with disease modifying antirheumatic drugs (DMARDs). Reducing inflammation is important in RA for CVD risk management, but the type of treatment may be less important. Conventional synthetic DMARDs (csDMARDs), in particular methotrexate (MTX), as well as biological DMARDs (bDMARDs), such as the TNF-inhibitors (TNFi), are often associated with a significant reduction in CVD risk in RA patients.cmRzPkFkcmVuYWwgQ29ydGV4IEhvcm1vbmVzPC9LZXl3b3Jkcz48S2V5d29yZHM+YW50YWdvbmlz

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L1JlZm1hbj4A

ADDIN EN.CITE.DATA 54;57 Reduction of disease activity after treatment with tocilizumab or rituximab shows a beneficial effect on carotid intima media thickness (cIMT), a surrogate marker for CVD, and CVD risk in a limited number of studies.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJlbnVjY2k8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 55;64-66 Beneficial effects of TNFi and MTX on arterial stiffness have also been described.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFqZWdhbm92YTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

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ADDIN EN.CITE.DATA 44;67-72 One study described a reduction in aortic inflammation and stiffness measured by 18 F FDG PET-CT after TNFi treatment in patients with RA.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1ha2ktUGV0YWphPC9BdXRob3I+PFllYXI+MjAxMjwvWWVh

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ADDIN EN.CITE.DATA 73 For both AS and PsA, evidence for the association between inflammation and an enhanced CVD risk is less abundant compared to RA. In view of shared pathogenic mechanisms, it is plausible that decreasing the inflammatory burden in AS and PsA will also have favourable effects on the CVD risk in these patients. Therefore, control of disease activity, as is routinely recommended, is expected to lower CVD risk for both AS and PsA.2. CVD risk assessment is recommended for all patients with RA, AS or PsA at least once every five years and should be reconsidered following major changes in anti-rheumatic therapy (Changed, LOA 8.8 (1.1))CVD risk assessment is recommended for all patients with RA, AS or PsA at least once every five years, so that lifestyle advice and CVD preventive treatment can be initiated when indicated. The advice to screen IJD patients for CVD risk on a yearly basis has been changed to screening every five years, which is in line with the latest European Society of Cardiology (ESC) guidelines.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 7 Currently, there is no evidence that annual CVD risk assessment compared to five year risk assessment leads to a more significant reduction in CVD mortality or morbidity in IJD patients. Depending on the CVD risk algorithm that is used for screening, patients can be categorised as having low- to moderate risk (e.g. SCORE < 5%), high risk (e.g. SCORE ≥ 5% and < 10%) and very high risk (e.g. SCORE ≥10%).PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 7 Once screened, patients with a low risk can be routinely screened again after five years. However, if the risk is intermediate rescreening may be done sooner, especially if disease progression is more rapid. Patients with a high risk or established CVD should be treated for all present CVD risk factors according to existing guidelines. A healthy lifestyle should be recommended to all persons, including patients with low- and intermediate cardiovascular risk.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN REFMGR.CITE PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 7 CVD risk evaluation should be reconsidered after major changes in anti-rheumatic therapy, i.e. the initiation of bDMARDs or other drugs that may cause pronounced increases in low density lipoprotein cholesterol (LDLc) or alter other CVD risk factors, so that doctors can act accordingly.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk15YXNvZWRvdmE8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFy

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ADDIN EN.CITE.DATA 74;75 3. CVD risk assessment for patients with RA, AS or PsA should be performed according to national guidelines and the SCORE CVD risk prediction model should be used if no national guideline is available (Unchanged, LOA 8.7 (2.1))Evidence is scarce with regards to the validity of disease-specific CVD risk prediction models to accurately predict risk in individual patients with RA, and it is therefore currently recommended to perform risk evaluation according to general population guidelines. Several novel and RA disease specific factors have been associated with an increased risk of CVD, but at present it is uncertain if these factors will meaningfully and cost-effectively improve CVD risk prediction in RA patients.4. Total cholesterol (TC) and high density lipoprotein cholesterol (HDLc) should be used in CVD risk assessment in RA, AS and PsA and lipids should ideally be measured when disease activity is stable or in remission. Non-fasting lipids are perfectly acceptable. (Changed, LOA 8.8 (1.2))The relationship between serum lipid levels and CVD risk is non-linear and potentially paradoxical in RA. Patients with RA with highly active disease generally have lower serum TC and LDLc levels compared to the general population, while their CVD risk is elevated.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJveWVyPC9BdXRob3I+PFllYXI+MjAxMjwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 74;76-79 As described in the 2009 recommendations, these patients also have reduced serum levels of HDLc and higher levels of triglycerides (TG) as compared to healthy controls.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPmRlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVjTnVt

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ADDIN EN.CITE.DATA 79-82 In general, controlling disease activity has widespread effects on the lipid profile. Treatment with TNFi and/or csDMARDs (mainly MTX) results in an overall increase of lipid components, but mostly HDLc, which improves the TC/HDLc-ratio.eXdvcmRzPlRyaWdseWNlcmlkZXM8L0tleXdvcmRzPjxLZXl3b3Jkcz5UdW1vciBOZWNyb3NpcyBG

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Pm==

ADDIN EN.CITE.DATA 80-94 A limited number of studies have reported beneficial effects of rituximab (RTX) and tocilizumab on individual lipid components.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPktlcmVrZXM8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 65;95;96 However, the net effect of treatment with these agents is an overall increase of individual lipid components without changes in TC/HDLc-ratio.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkhzdWU8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 101 Still, statins are effective at reducing lipid levels in tocilizumab or tofacitinib treated patients with sustained elevations of TC and LDLc.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk5hdmFycm88L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 100;101 As described in the 2009 recommendations, the TC and HDLc independently predict CVD risk inRA and both should be measured.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBldGVyczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 79;103 From a practical point of view both TC and HDLc can be used when using online calculators. As lipid components appear to be modifiable by disease activity and anti-inflammatory therapy, assessment of the lipid profile should preferably be done when a patient has stable disease or is in remission. Finally, measurement of TC and HDL-c are perfectly acceptable in non-fasting state, as noted in the recent 2016 European Guidelines on cardiovascular disease prevention in clinical practice: prevention guidelines. 5. CVD risk prediction models should be adapted for patients with RA by a 1.5 multiplication factor, if this is not already included in the risk algorithm (Changed, LOA 7.5 (2.2))The SCORE risk calculator is recommended for CVD risk prediction in the general population by the ESC guidelines.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBlcms8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 104 However, CVD risk prediction models developed for the general population do not include non-traditional CVD risk factors and hence there is a possibility of underestimation of future CVD if these models are applied in patients with RA. It is indeed reported that several CVD prediction models inaccurately predict the risk of CVD in RA patients.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNyb3dzb248L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 8;105;106 The 2009 EULAR recommendations for CVD risk management suggested a multiplication factor of 1.5 to the calculated total CVD risk if the patient fulfilled certain disease-specific criteria (i.e. disease duration of more than 10 years, rheumatoid factor (RF) or anti-citrullinated protein antibody (ACPA) positivity and the presence of certain extra-articular manifestations).PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBldGVyczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 4 It has been argued that the application of this multiplication factor does not reclassify as many patients as was expected into a more appropriate risk category.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkdvbWV6LVZhcXVlcm88L0F1dGhvcj48WWVhcj4yMDEzPC9Z

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ADDIN EN.CITE.DATA 9;107 In addition, QRISK 2, a CVD risk prediction model that includes RA as a risk factor with a multiplication factor of 1.4 for all RA patients,PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkhpcHBpc2xleS1Db3g8L0F1dGhvcj48WWVhcj4yMDEwPC9Z

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ADDIN EN.CITE.DATA 8 Currently, there are no alternative CVD risk prediction models with a proven accuracy and superiority for IJD patients. Based on all recent epidemiology, this multiplication factor is still the most evidence-based way of estimating CVD risk in patients with RA. Therefore, the use of an RA adapted risk prediction model is recommended over the use of an unadapted general population model, since there is a higher level of evidence on their predictive value. Based on this, the EULAR task force still recommends to adapt general population CVD risk algorithms (except for QRISK 2 in which the multiplication factor is intrinsic to the algorithm) with a 1.5 multiplication factor for all patients with RA. In contrast to the 2009 recommendations, the presence of certain RA-specific criteria is not mandatory anymore for the application of this multiplication factor, as evidence on the increased CVD risk in early RA and RA patients without extra-articular manifestations has emerged.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkdvb2Rzb248L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 109;1106. Screening for asymptomatic atherosclerotic plaques by use of carotid ultrasound may be considered as part of the CVD risk evaluation in patients with RA. (New, LOA 5.7 (3.9))The presence of carotid plaques is associated with poor CVD-free survival and is strongly linked to future acute coronary syndrome (ACS) in patients with RA, with a rate of ACS of 1.1 (95% CI 0.6, 1.7) per 100 person years (pyrs) for RA patients with no carotid plaques and 4.3 (95% CI 2.9, 6.3) per 100 pyrs for those with bilateral plaques.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFqZWdhbm92YTwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+

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Zm1hbj4A

ADDIN EN.CITE.DATA 67;111 RA specific factors contribute to the presence of carotid atherosclerosis in addition to traditional CVD risk factors.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkRlbDwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA 112 Disease duration and disease activity have been shown to be associated with plaque size and vulnerability in patients with RA.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNlbWI8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 113;114 The most recent ESC Guidelines on CVD prevention in clinical practice recommend considering screening for carotid artery atherosclerosis in patients with moderate CVD risk (Class: IIa, Level of evidence: B, GRADE: strong).PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 7 Autoimmune diseases like RA, systemic lupus erythematosus and psoriasis were acknowledged as diseases with increased CVD risk.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBpZXBvbGk8L0F1dGhvcj48WWVhcj4yMDE2PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 7 Due to the high pre-test probability for detection of carotid artery plaques by use of ultrasound in RA patients, and the clinical consequence of indication for statin treatment if a carotid plaque is present, this procedure could be of additional value for CVD risk evaluation. Ultrasound of the carotid arteries to identify atherosclerosis has been shown to reclassify a considerable proportion of RA patients into a more appropriate CVD risk group in accordance with current guidelines.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNvcnJhbGVzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48

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ADDIN EN.CITE.DATA 1157. Life style recommendations should emphasise the benefits of a healthy diet, regular exercise and smoking cessation. (Changed, LOA 9.8 (0.3))Since the 2009 recommendations no new strong evidence has emerged on the role of smoking on CVD risk in IJD and hence this recommendation remains unchanged. Thus, patients should be advised to stop smoking and directed towards the locally defined evidence-based smoking cessation programs, even if they have failed previously. The 2009 recommendations did not discuss diet or exercise, but it was mentioned in the research agenda.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBldGVyczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 10 Research on the role of exercise in RA management has advanced considerably since 2009. Physical inactivity is common in RA patients, and has been associated with an adverse CVD risk profile.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPnZhbiBkZW4gQmVyZzwvQXV0aG9yPjxZZWFyPjIwMDc8L1ll

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ADDIN EN.CITE.DATA 116-118 There is accumulating data that structured exercise therapy has beneficial CVD effects in RA patients, at least in the short and medium term.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1ldHNpb3M8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 119-121 Exercise has been shown to reduce long-term inflammation in epidemiological studies conducted in the general population and increased physical activity was associated with lower levels of CRP. ADDIN REFMGR.CITE <Refman><Cite><Author>Ford</Author><Year>2002</Year><RecNum>8</RecNum><IDText>Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>8</Ref_ID><Title_Primary>Does exercise reduce inflammation? Physical activity and C-reactive protein among U.S. adults</Title_Primary><Authors_Primary>Ford,E.S.</Authors_Primary><Date_Primary>2002/9</Date_Primary><Keywords>Adult</Keywords><Keywords>analysis</Keywords><Keywords>Atherosclerosis</Keywords><Keywords>blood</Keywords><Keywords>C-Reactive Protein</Keywords><Keywords>Coronary Artery Disease</Keywords><Keywords>Coronary Vessels</Keywords><Keywords>etiology</Keywords><Keywords>Exercise</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Inflammation</Keywords><Keywords>Logistic Models</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>Nutrition Surveys</Keywords><Keywords>Odds Ratio</Keywords><Keywords>pathology</Keywords><Keywords>Risk Factors</Keywords><Keywords>United States</Keywords><Reprint>Not in File</Reprint><Start_Page>561</Start_Page><End_Page>568</End_Page><Periodical>Epidemiology</Periodical><Volume>13</Volume><Issue>5</Issue><Misc_3>10.1097/01.EDE.0000023965.92535.C0 [doi];00001648-200209000-00012 [pii]</Misc_3><Address>Division of Nutrition and Physical Activity, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, GA 30333, USA. esf2@</Address><Web_URL>PM:12192226</Web_URL><ZZ_JournalStdAbbrev><f name="System">Epidemiology</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>122 This has also been demonstrated in a study with RA patients in which a 6-month exercise program lowered CRP levels, probably related to a reduction in body fat.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1ldHNpb3M8L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 124 To date, no studies have shown any adverse effects as a result of exercise. ADDIN REFMGR.CITE <Refman><Cite><Author>Lemmey</Author><Year>2009</Year><RecNum>9</RecNum><IDText>Effects of high-intensity resistance training in patients with rheumatoid arthritis: a randomized controlled trial</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>9</Ref_ID><Title_Primary>Effects of high-intensity resistance training in patients with rheumatoid arthritis: a randomized controlled trial</Title_Primary><Authors_Primary>Lemmey,A.B.</Authors_Primary><Authors_Primary>Marcora,S.M.</Authors_Primary><Authors_Primary>Chester,K.</Authors_Primary><Authors_Primary>Wilson,S.</Authors_Primary><Authors_Primary>Casanova,F.</Authors_Primary><Authors_Primary>Maddison,P.J.</Authors_Primary><Date_Primary>2009/12/15</Date_Primary><Keywords>Arthritis,Rheumatoid</Keywords><Keywords>Body Composition</Keywords><Keywords>Cachexia</Keywords><Keywords>Exercise</Keywords><Keywords>Exercise Therapy</Keywords><Keywords>Female</Keywords><Keywords>growth &amp; development</Keywords><Keywords>Health Status</Keywords><Keywords>Humans</Keywords><Keywords>Insulin-Like Growth Factor Binding Protein 3</Keywords><Keywords>Insulin-Like Growth Factor I</Keywords><Keywords>Male</Keywords><Keywords>metabolism</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>Muscle Strength</Keywords><Keywords>Muscle,Skeletal</Keywords><Keywords>physiopathology</Keywords><Keywords>Range of Motion,Articular</Keywords><Keywords>Resistance Training</Keywords><Keywords>Severity of Illness Index</Keywords><Keywords>therapy</Keywords><Keywords>Treatment Outcome</Keywords><Reprint>Not in File</Reprint><Start_Page>1726</Start_Page><End_Page>1734</End_Page><Periodical>Arthritis Rheum</Periodical><Volume>61</Volume><Issue>12</Issue><Misc_3>10.1002/art.24891 [doi]</Misc_3><Address>Bangor University, Bangor, UK. a.b.lemmey@bangor.ac.uk</Address><Web_URL>PM:19950325</Web_URL><ZZ_JournalStdAbbrev><f name="System">Arthritis Rheum</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>125 Hence, in RA, high-intensity exercise is not contraindicated and should be encouraged in those already accustomed to activity. Physical activity that is enjoyable is more likely to be sustained. A Mediterranean diet is characterized by a high consumption of fruit, vegetables, legumes and cereals, and contains less red meat and more fish compared to common Western diets. Olive oil or vegetable oil is the primary source of fat intake. This diet has been shown to be associated with a reduced incidence of major CVD events in the general population.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkVzdHJ1Y2g8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 126 In RA, the positive effect of a Mediterranean diet may be mediated by the effect of this diet on disease activity. ADDIN REFMGR.CITE <Refman><Cite><Author>Skoldstam</Author><Year>2003</Year><RecNum>7</RecNum><IDText>An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>7</Ref_ID><Title_Primary>An experimental study of a Mediterranean diet intervention for patients with rheumatoid arthritis</Title_Primary><Authors_Primary>Skoldstam,L.</Authors_Primary><Authors_Primary>Hagfors,L.</Authors_Primary><Authors_Primary>Johansson,G.</Authors_Primary><Date_Primary>2003/3</Date_Primary><Keywords>Adult</Keywords><Keywords>Aged</Keywords><Keywords>Anti-Inflammatory Agents,Non-Steroidal</Keywords><Keywords>Arthritis,Rheumatoid</Keywords><Keywords>blood</Keywords><Keywords>Body Weight</Keywords><Keywords>diet therapy</Keywords><Keywords>Diet,Mediterranean</Keywords><Keywords>drug therapy</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Lipids</Keywords><Keywords>Male</Keywords><Keywords>Middle Aged</Keywords><Keywords>Quality of Life</Keywords><Keywords>therapeutic use</Keywords><Reprint>Not in File</Reprint><Start_Page>208</Start_Page><End_Page>214</End_Page><Periodical>Ann Rheum Dis</Periodical><Volume>62</Volume><Issue>3</Issue><User_Def_5>PMC1754463</User_Def_5><Address>Department of Medicine, Kalmar County Hospital, S-391 85 Kalmar, Sweden</Address><Web_URL>PM:12594104</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann Rheum Dis</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>127 However, there is no specific evidence available on the effect of dietary modifications on CVD risk in patients with IJD. Therefore, we recommend following national guidelines regarding a healthy diet as part of a healthy lifestyle. An important issue remaining is how lifestyle interventions should be advocated to IJD patients. Studies in this field demonstrate that if information is provided, this should be linked to behavioural education. ADDIN REFMGR.CITE <Refman><Cite><Author>Iversen</Author><Year>2010</Year><RecNum>18</RecNum><IDText>Self-management of rheumatic diseases: state of the art and future perspectives</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>18</Ref_ID><Title_Primary>Self-management of rheumatic diseases: state of the art and future perspectives</Title_Primary><Authors_Primary>Iversen,M.D.</Authors_Primary><Authors_Primary>Hammond,A.</Authors_Primary><Authors_Primary>Betteridge,N.</Authors_Primary><Date_Primary>2010/6</Date_Primary><Keywords>Arthritis,Rheumatoid</Keywords><Keywords>Chronic Disease</Keywords><Keywords>Fibromyalgia</Keywords><Keywords>Humans</Keywords><Keywords>methods</Keywords><Keywords>Osteoarthritis</Keywords><Keywords>Patient Participation</Keywords><Keywords>Randomized Controlled Trials as Topic</Keywords><Keywords>Research Design</Keywords><Keywords>Rheumatic Diseases</Keywords><Keywords>Self Care</Keywords><Keywords>therapy</Keywords><Keywords>Treatment Outcome</Keywords><Keywords>trends</Keywords><Reprint>Not in File</Reprint><Start_Page>955</Start_Page><End_Page>963</End_Page><Periodical>Ann Rheum Dis</Periodical><Volume>69</Volume><Issue>6</Issue><Misc_3>ard.2010.129270 [pii];10.1136/ard.2010.129270 [doi]</Misc_3><Address>Correspondence to Professor Maura Daly Iversen, Department of Physical Therapy, Bouve College of Health Sciences, Northeastern University, 301 C Robinson Hall, 360 Huntington Avenue, Boston, MA 02115, USA. m.iversen@neu.edu</Address><Web_URL>PM:20448289</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann Rheum Dis</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>128 A randomized controlled trial in RA patients evaluated the effect of cognitive behavioral patient education with regard to modifiable CVD risk factors in people with RA: patients receiving this intervention had more knowledge, and improved behavioral intentions, however, actual behavior did not differ between groups. ADDIN REFMGR.CITE <Refman><Cite><Author>John</Author><Year>2013</Year><RecNum>19</RecNum><IDText>A randomized controlled trial of a cognitive behavioural patient education intervention vs a traditional information leaflet to address the cardiovascular aspects of rheumatoid disease</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>19</Ref_ID><Title_Primary>A randomized controlled trial of a cognitive behavioural patient education intervention vs a traditional information leaflet to address the cardiovascular aspects of rheumatoid disease</Title_Primary><Authors_Primary>John,H.</Authors_Primary><Authors_Primary>Hale,E.D.</Authors_Primary><Authors_Primary>Treharne,G.J.</Authors_Primary><Authors_Primary>Kitas,G.D.</Authors_Primary><Authors_Primary>Carroll,D.</Authors_Primary><Date_Primary>2013/1</Date_Primary><Keywords>Aged</Keywords><Keywords>Arthritis,Rheumatoid</Keywords><Keywords>blood</Keywords><Keywords>Blood Pressure</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>Cognitive Therapy</Keywords><Keywords>complications</Keywords><Keywords>Diet,Fat-Restricted</Keywords><Keywords>Exercise</Keywords><Keywords>Female</Keywords><Keywords>Humans</Keywords><Keywords>Male</Keywords><Keywords>methods</Keywords><Keywords>Middle Aged</Keywords><Keywords>mortality</Keywords><Keywords>Pamphlets</Keywords><Keywords>Patient Education as Topic</Keywords><Keywords>psychology</Keywords><Keywords>Risk Factors</Keywords><Keywords>Treatment Outcome</Keywords><Reprint>Not in File</Reprint><Start_Page>81</Start_Page><End_Page>90</End_Page><Periodical>Rheumatology (Oxford)</Periodical><Volume>52</Volume><Issue>1</Issue><Misc_3>kes237 [pii];10.1093/rheumatology/kes237 [doi]</Misc_3><Address>Department of Rheumatology, Dudley Group of Hospitals NHS Foundation Trust, Russells Hall Hospital, Pensnett Road, Dudley DY1 2HQ, UK. hollypiper@</Address><Web_URL>PM:22942402</Web_URL><ZZ_JournalStdAbbrev><f name="System">Rheumatology (Oxford)</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>129 Obviously, this area is in need of more research.8. 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ADDIN EN.CITE.DATA 130-132 Several mechanisms may lead to the development of hypertension, including the use of certain anti-rheumatic drugs such as corticosteroids, NSAIDs, ciclosporin and leflunomide.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBhbm91bGFzPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48

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ADDIN EN.CITE.DATA 133-136 It is important to realize that hypertension seems to be both underdiagnosed and undertreated in patients with RA.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlByb3RvZ2Vyb3U8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy

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ADDIN EN.CITE.DATA 137 For the management of hypertension and hyperlipidaemia, there is no evidence that treatment thresholds should differ in patients with IJD compared to the general population. In the last years no new evidence has emerged that angiotensin converting enzyme (ACE) inhibitors and angiotensin II (ATII) receptor blockers should be the preferred treatment choice for hypertension in RA patients. Therefore, the previous treatment preferences for ACE-inhibitors and AT-II receptor blockers have been omitted. Since the 2009 recommendations several studies have assessed the efficacy of statins in patients with RA. Statins appeared to be at least as effective in reducing cholesterol levels, atherosclerotic burden and CVD morbidity and mortality, and they do not have more adverse reactions in RA patients when compared to non-RA controls.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkRlIFZlcmE8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 78;138-144 In addition, statins have anti-inflammatory properties that may result in an even greater CVD risk reduction when combined with anti-inflammatory therapy in RA, but studies on this effect are scarce.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNvam9jYXJ1PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48

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ADDIN EN.CITE.DATA 145-147 A few pre-clinical studies found unfavourable effects of statins on RTX efficacy in patients with haematological malignancies.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkNyYWdnPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 150-153 Clinical trials investigating this issue in RA are scarce. Three clinical studies in RA found no adverse effect of statins on RTX efficacy.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkRhczwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA 154-156 Only one observational study reported a significant difference in disease activity six months after first RTX treatment in statin users as compared to non-users, but this finding was borderline significant (p=0.049) in a small sample size of statin-exposed patients (n=23 exposed vs n=164 non-exposed).PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFydHM8L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 157 Obviously, further research is necessary to address this issue properly. 9. Prescription of NSAIDs in RA and PsA should be with caution, especially for patients with documented CVD disease or in the presence of CVD risk factors. (Changed, LOA 8.9 (2.1))The 2009 recommendations advocate that NSAIDs should be used with caution in this population or may even be contraindicated.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBoYXJtYWNvdmlnaWxhbmNlIFJpc2sgQXNzZXNzbWVudCBD

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ADDIN EN.CITE.DATA 4;158;159 Since the publication of the former recommendations, new evidence has emerged on the role of cyclo-oxygenase-2 inhibitors (COXIBs) and non-selective NSAIDs in CVD risk. A recent meta-analysis concluded that, overall, both non-selective NSAIDs and COXIBs have adverse effects on CVD outcomes in patients with RA and PsA.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlJvdWJpbGxlPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA 160 However, the increased CVD risk was mainly observed for rofecoxib, which was withdrawn from the market in 2004. There is evidence that NSAIDs might increase CVD risk in RA to a lesser extent in comparison to the general population than was previously thought. ADDIN REFMGR.CITE <Refman><Cite><Author>Lindhardsen</Author><Year>2013</Year><RecNum>11</RecNum><IDText>Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>11</Ref_ID><Title_Primary>Non-steroidal anti-inflammatory drugs and risk of cardiovascular disease in patients with rheumatoid arthritis: a nationwide cohort study</Title_Primary><Authors_Primary>Lindhardsen,J.</Authors_Primary><Authors_Primary>Gislason,G.H.</Authors_Primary><Authors_Primary>Jacobsen,S.</Authors_Primary><Authors_Primary>Ahlehoff,O.</Authors_Primary><Authors_Primary>Olsen,A.M.</Authors_Primary><Authors_Primary>Madsen,O.R.</Authors_Primary><Authors_Primary>Torp-Pedersen,C.</Authors_Primary><Authors_Primary>Hansen,P.R.</Authors_Primary><Date_Primary>2013/6/8</Date_Primary><Keywords>Cohort Studies</Keywords><Keywords>methods</Keywords><Keywords>mortality</Keywords><Keywords>Myocardial Infarction</Keywords><Keywords>Risk Factors</Keywords><Keywords>Stroke</Keywords><Reprint>Not in File</Reprint><Periodical>Ann Rheum Dis</Periodical><Misc_3>annrheumdis-2012-203137 [pii];10.1136/annrheumdis-2012-203137 [doi]</Misc_3><Address>Department of Cardiology, Copenhagen University Hospital Gentofte, Hellerup, Denmark</Address><Web_URL>PM:23749610</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ann Rheum Dis</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>49142 Hence, there is no evidence to be stricter with NSAID treatment in patients with RA than what is recommended in the national guidelines for non-RA patients. Safety data regarding the use of NSAIDs in patients with IJD and prevalent CVD comorbidities is lacking. Naproxen seems to have the safest CVD risk profile.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkxpbmRoYXJkc2VuPC9BdXRob3I+PFllYXI+MjAxMzwvWWVh

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ADDIN EN.CITE.DATA 47;49 In general, diclofenac is contra-indicated in patients with established congestive heart failure (NYHA class II-IV), ischaemic heart disease, peripheral arterial disease or cerebrovascular disease, and new evidence supports similar restrictions for ibuprofen use.158,159 For patients with AS, NSAIDs are recommended as first-line drug treatment by the ASAS/EULAR group in the recommendations for the management of pain and stiffness in AS patients, and an individual clinical evaluation regarding NSAIDs use in AS patients with established CVD is therefore needed.148 10. Corticosteroids: for prolonged treatment, the glucocorticoid dosage should be kept to a minimum, and a glucocorticoid taper should be attempted in case of remission or low disease activity; the reasons to continue glucocorticoid therapy should be regularly checked. (Unchanged, LOA 9.5 (0.7)Corticosteroids rapidly and effectively reduce inflammation in RA, but they have also been associated with an increased CVD risk, although the literature shows conflicting results. Since the 2009 recommendations, new studies have found a dose and duration dependent increase in CVD risk associated with corticosteroid use in RA.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPmRlbCBSaW5jb248L0F1dGhvcj48WWVhcj4yMDE0PC9ZZWFy

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ADDIN EN.CITE.DATA 48;161;162 A relatively high daily dose (i.e. already starting from 8-15 milligrams per day), a high cumulative dose and a longer exposure to corticosteroids (in years) appear to be associated with a higher CVD risk.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkF2aW5hLVp1YmlldGE8L0F1dGhvcj48WWVhcj4yMDEzPC9Z

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AG==

ADDIN EN.CITE.DATA 48;162-164 Some authors argued that this increased CVD risk was confounded by indication, as it was no longer significant after correction for disease activity.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkF2aW5hLVp1YmlldGE8L0F1dGhvcj48WWVhcj4yMDExPC9Z

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ADDIN EN.CITE.DATA 54;165-167 On the contrary, other studies that had corrected for disease activity still found a (cumulative) dose and duration dependent increase in CVD related morbidity and mortality in RA patients.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFqZWdhbm92YTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+

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ADDIN EN.CITE.DATA 48;168However, this does not mean that confounding by indication has been completely addressed and this is a major limitation of all safety studies on corticosteroids. There is no conclusive evidence about the long-term effects of corticosteroids, particularly in low daily dosage, on safety outcomes including CVD events in RA. In patients with active disease, the benefit of reducing high grade inflammation may counteract the adverse CVD effects of corticosteroid use, not only by reduction of inflammation, but also by improving mobility. In other words steroids may help to abrogate the harmful effect of inflammation on the CVD system, but they will still carry their own adverse effects on CVD risk. Altogether, from a CVD prevention point of view, the lowest effective dose of corticosteroids should be prescribed for the shortest possible duration in the treatment of active IJD. This recommendation is in line with the EULAR recommendations on management of glucocorticoid therapy.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkR1cnU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 45DiscussionThe 2015 update of the 2009 EULAR recommendations for CVD risk management in IJD comprisesthree overarching principles and ten recommendations. The first overarching principle reinforces and extends the evidence of an increased CVD risk in IJD. The second principle indicates the responsibility of the rheumatologist for coordinating CVD risk management in patients with IJD, whereas the last principle aims to put this recommendation update more in line with other (EULAR) recommendations. CVD risk assessment in IJDPresently, the enhanced CVD risk in RA, but also in AS and PsA, is widely acknowledged. Thus far, fully validated RA-specific CVD risk prediction models that both improve on general population models and are cost-effective are lacking, although multiple attempts have been made.7,147,148 Some even question the need for a disease specific CVD risk prediction model for RA, although existing models inaccurately estimate the CVD risk in these patients.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkFydHM8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxSZWNO

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ADDIN EN.CITE.DATA 8;9 In 2009, this led to the addition of a 1.5 multiplication factor for the calculated CVD risk in RA patients if certain disease characteristics were present.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlBldGVyczwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl

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ADDIN EN.CITE.DATA 10 Meanwhile, alternative approaches have also been advocated, e.g. to increase the age of an RA patient by 15 years ADDIN REFMGR.CITE <Refman><Cite><Author>Wiersma</Author><Year>2012</Year><RecNum>30</RecNum><IDText>[Summary of the multidisciplinary guideline on cardiovascular risk management (revision 2011)]</IDText><MDL Ref_Type="Journal"><Ref_Type>Journal</Ref_Type><Ref_ID>30</Ref_ID><Title_Primary>[Summary of the multidisciplinary guideline on cardiovascular risk management (revision 2011)]</Title_Primary><Authors_Primary>Wiersma,T.</Authors_Primary><Authors_Primary>Smulders,Y.M.</Authors_Primary><Authors_Primary>Stehouwer,C.D.</Authors_Primary><Authors_Primary>Konings,K.T.</Authors_Primary><Authors_Primary>Lanphen,J.</Authors_Primary><Date_Primary>2012</Date_Primary><Keywords>analysis</Keywords><Keywords>Antihypertensive Agents</Keywords><Keywords>Arthritis</Keywords><Keywords>blood</Keywords><Keywords>Blood Pressure</Keywords><Keywords>Cardiovascular Agents</Keywords><Keywords>Cardiovascular Diseases</Keywords><Keywords>complications</Keywords><Keywords>Cost-Benefit Analysis</Keywords><Keywords>Diabetes Mellitus,Type 2</Keywords><Keywords>drug therapy</Keywords><Keywords>economics</Keywords><Keywords>Humans</Keywords><Keywords>Hypertension</Keywords><Keywords>Hypolipidemic Agents</Keywords><Keywords>Netherlands</Keywords><Keywords>Practice Guidelines as Topic</Keywords><Keywords>prevention &amp; control</Keywords><Keywords>Risk</Keywords><Keywords>Risk Assessment</Keywords><Keywords>Risk Factors</Keywords><Keywords>Risk Management</Keywords><Keywords>therapeutic use</Keywords><Reprint>Not in File</Reprint><Start_Page>A5104</Start_Page><Periodical>Ned Tijdschr Geneeskd</Periodical><Volume>156</Volume><Issue>36</Issue><Address>Nederlands Huisartsen Genootschap, afd. Richtlijnontwikkeling en Wetenschap, Utrecht, the Netherlands. T.Wiersma@</Address><Web_URL>PM:22951134</Web_URL><ZZ_JournalStdAbbrev><f name="System">Ned Tijdschr Geneeskd</f></ZZ_JournalStdAbbrev><ZZ_WorkformID>1</ZZ_WorkformID></MDL></Cite></Refman>169 or adding a multiplication factor of 1.4.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPkhpcHBpc2xleS1Db3g8L0F1dGhvcj48WWVhcj4yMDA4PC9Z

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ADDIN EN.CITE.DATA 3 Currently, it is unknown what approach would be most appropriate. In the light of this, the task force opted to retain the 1.5 multiplication factor to correct for the increased CVD risk in RA compared to the general population. However, considering that the CVD risk is already increased in early disease or at disease onset and in patients without extra-articular manifestations, the three disease-specific criteria for the application of this multiplication factor were removed. This makes the estimation of CVD risk in RA patients easier and therefore more feasible for daily clinical practice. As no conclusive evidence has emerged regarding the precise CVD risk in AS and PsA, the task force opted not to include a multiplication factor for these diseases. In line with the ESC Guidelines, the recommendation to perform CVD risk assessment was extended to once every five years for patients found to be at low-to-moderate cardiovascular risk as there is no evidence that CVD risk assessment every year for IJD reduces CVD risk more than screening every five years.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlJheTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJlY051

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ADDIN EN.CITE.DATA 170 In patients with an intermediate risk for CVD, screening should be performed more often. Patients at high- to very high cardiovascular risk should promptly be treated for existing CVD risk factors. The new recommendation (#6) includes the option of screening for carotid plaques in RA patients as a tool for CVD risk assessment, because carotid plaques are associated with future ACS in patients with RA. Whether routine screening of the carotid arteries is possible in daily clinical practice will depend on local availability. The LOA of 5.7 (3.9) for recommendation #6 possibly indicates the absence of evidence for routine screening of the carotid arteries in general. CVD risk reduction in IJDJust as in the 2009 recommendations, the importance of optimal anti-inflammatory therapy for CVD risk reduction in RA is emphasised in this update. There is accumulating evidence that decreasing the inflammatory burden in RA translates into a lower CVD risk. As inflammation is related to CVD risk in all IJD, we extrapolated this recommendation to AS and PsA, although further evidence for these types of IJD would be valuable. Equally important is the treatment of traditional CVD risk factors that are present in these patients according to national guidelinesPFJlZm1hbj48Q2l0ZT48QXV0aG9yPkJhZ2hkYWRpPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48

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ADDIN EN.CITE.DATA 132. However, awareness of some issues when performing risk estimation and management in patients with IJD is important. Active disease of IJD is associated with reduced lipid levels that increase (i.e. normalize) during effective anti-inflammatory treatment. Biologics have the most pronounced lipid increasing effect, which has led to mandatory lipid assessment during treatment with tocilizumab.PFJlZm1hbj48Q2l0ZT48QXV0aG9yPlNvdXRvPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48UmVj

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ADDIN EN.CITE.DATA 101 However, it is also important to realize that the anti-atherogenic properties of HDLc cholesterol improve during biologic treatment. PFJlZm1hbj48Q2l0ZT48QXV0aG9yPk1jSW5uZXM8L0F1dGhvcj48WWVhcj4yMDE1PC9ZZWFyPjxS

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ADDIN EN.CITE.DATA 95;96 Therefore, it is important to assess the net effect of lipid modulation by biologics. Currently, the effect of these changes on CVD outcomes is not known. In addition, awareness of possible adverse effects of certain medications such as NSAIDs and corticosteroids has been emphasized. Except for smoking cessation, lifestyle recommendations were not given in our previous guideline. Since then accumulating data demonstrate that regular physical activity has beneficial CVD effects in RA patients and hence, this has been incorporated in the updated recommendations. In addition, favourable CVD effects have also been observed for a Mediterranean diet, albeit that a formal study in patient with IJD has not yet been conducted. As it is not likely that the effect of diet would be different in patients with IJD than in the general population, we also added this in our lifestyle recommendation. ConclusionIn general, the level of agreement (LOA) for the recommendations was (very) high, except for recommendations #5 (LOA 7.5) and #6 (5.7). As in 2009, the level of evidence was moderate for most of the recommendations. Several important questions which arose during the development of these recommendations remain unanswered. These questions have been put on the research agenda (Box 1). The 2015/16 update of the EULAR recommendations for CVD risk management in patients with RA and other forms of IJD confirms and further extends the evidence of an increased CVD risk in the whole spectrum of IJD and reinforces the need for proper CVD risk management in these patients. As these updated recommendations are based on a pan-European consensus, it is hoped that they will facilitate CVD risk management in daily clinical practice, ultimately leading to a decreased CVD burden in our patients.Table 1. Overarching principles and recommendationsLevel of evidence Strength of recommendationLevel of agreement (SD) Overarching principlesClinicians should be aware of the higher risk for CVD in RA compared to the general population. This may also apply to AS and PsA.The rheumatologist is responsible for CVD risk management in patients with RA and other IJD.The use of NSAIDs and corticosteroids should be in accordance with treatment specific recommendations from EULAR and ASAS.RecommendationsDisease activity should be controlled optimally in order to lower CVD risk in all patients with RA, AS or PsA.CVD risk assessment is recommended for all patients with RA, AS or PsA at least once every five years and should be reconsidered following major changes in anti-rheumatic therapy.CVD risk estimation for patients with RA, AS or PsA should be performed according to national guidelines and the SCORE CVD risk prediction model should be used if no national guideline is available.TC and HDLc should be used in CVD risk assessment in RA, AS and PsA and lipids should ideally be measured when disease activity is stable or in remission. Non-fasting lipids measurements are also perfectly acceptableCVD risk prediction models should be adapted for patients with RA by a 1.5 multiplication factor, if this is not already included in the model.Screening for asymptomatic atherosclerotic plaques by use of carotid ultrasound may be considered as part of the CVD risk evaluation in patients with RA.Lifestyle recommendations should emphasise the benefits of a healthy diet, regular exercise and smoking cessation for all patients.CVD risk management should be carried out according to national guidelines in RA, AS or PsA, antihypertensives and statins may be used as in the general population.Prescription of NSAIDs in RA and PsA should be with caution, especially for patients with documented CVD disease or in the presence of CVD risk factors. Corticosteroids: for prolonged treatment, the glucocorticoid dosage should be kept to a minimum, and a glucocorticoid taper should be attempted in case of remission or low disease activity; the reasons to continue glucocorticoid therapy should be regularly checked.2b-33-43-433-43-43 3-42a-33-4BCC-DCCC-DCC-DCC9.1 (1.3)8.8 (1.1)8.7 (2.1)8.8 (1.2)7.5 (2.2)5.7 (3.9)9.2 (1.3)9.8 (0.3)8.9 (2.1)9.5 (0.7)AS: ankylosing spondylitis, ASAS: Assessment of spondyloarthritis international society, CVD: cardiovascular disease, EULAR: European League against Rheumatism, HDLc: high density lipoprotein cholesterol, IJD: inflammatory joint disorder NSAID: non-steroidal anti-inflammatory drug, PsA: psoriatic arthritis, RA: rheumatoid arthritis, SCORE: systematic coronary risk evaluation, TC: total cholesterolFigure 1. Flow chart of the search and selection process RA= rheumatoid arthritis, AS = ankylosing spondylitis, PsA = psoriatic arthritisBox 1. Research agendaResearch agenda Can we make adjustments to the current CVD risk models to improve estimation of CVD risk in patients with IJD?How high is the CVD risk in patients with spondyloarthropathies or non-radiographic axial SpA compared to the general population?What is the benefit/risk ratio of intensive anti-inflammatory therapy on CVD risk in patients with IJD?Is the increased CVD risk in patients with spondyloarthropathies independent of traditional risk factors and what is the association between CVD risk and inflammation in spondyloarthropathies? Is there an increased prevalence of cardiac abnormalities, including aortic valve dysfunction and conduction disorders in patients with spondyloarthropathies and how does this affect overall CVD risk?How does treatment with NSAIDs affect the CVD risk in IJD patients, in particular patients with AS?Should we treat patients with AS continuously or intermittently with NSAIDs from a CVD point of view?Should treatment targets for blood pressure and lipids be different in patients with IJD from the general population?What is the effect of different modes of action of antirheumatic drugs on CVD risk?What is the relationship between residual disease activity and CVD risk in RA patients on stable DMARD therapy?Is there additional value in measuring lipid sub-particles in patients with IJD for estimation of CVD risk?What is the added value of ultrasound of the carotid arteries to measure c-IMT and reveal presence of atherosclerotic plaques in IJD patients regarding CVD risk estimation and in which (sub) population should we conduct this?What is the additional value of novel biomarkers for CVD risk prediction?What is the best technique for implementing lifestyle changes and education in IJD patients?Health economics. Are interventions cost-effective in terms of reducing the number of fatal and non-fatal CVD events? Is the prevalence of venous thrombotic events in IJD patients increased? If so, what are the underlying mechanisms?AS: ankylosing spondylitis, CVD: cardiovascular disease, DMARD: disease modifying anti rheumatoid drug IJD: inflammatory joint disorder, IMT: intima media thickness, NSAID: non-steroidal anti-inflammatory drug, PsA: psoriatic arthritis, RA: rheumatoid arthritis, SpA: spondyloarthropathyAuthor af?liationsR. Agca, Amsterdam Rheumatology and immunology Center, Departments of Rheumatology Reade & VU University Medical Center, Amsterdam, the Netherlands.F. Atzeni, IRCCS Galeazzi Orthopedic Institute, Milan, ItalyM. Dougados, Paris Descartes University, Department of Rheumatology - H?pital Cochin. Assistance Publique -? H?pitaux de Paris INSERM (U1153): Clinical epidemiology and biostatistics, PRES Sorbonne Paris-Cité. PARIS 14, France.M.A. Gonzalez-Gay, University of Cantabria, IDIVAL, Santander , Spain.M. Heslinga, Amsterdam Rheumatology and immunology Center, Departments of Rheumatology Reade & VU University Medical Center, Amsterdam, the NetherlandsS.C. Heslinga, Amsterdam Rheumatology and immunology Center, Departments of Rheumatology Reade & VU University Medical Center, Amsterdam, the NetherlandsI.B. McInnes, College of Medical, Veterinary and Life Sciences, Institute of Infection, Immunity and Inflammation, University of Glasgow, UKL. Jacobsson, Dept of Rheumatology & Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg and Section of Rheumatology, Department of Clinical Sciences Malm?, Lund University, Lund, SwedenG.D. Kitas, Head of Research and Development – Academic Affairs Dudley Group NHS Foundation Trust, Professor of Clinical Rheumatology, Arthritis Research UK Centre for Epidemiology, University of Manchester, Russells Hall Hospital, Clinical Research UnitT.K. Kvien, Dept. of Rheumatology, Diakonhjemmet Hospital, Oslo, NorwayM.T. Nurmohamed, Amsterdam Rheumatology and immunology Center, Departments of Rheumatology Reade & VU University Medical Center, Amsterdam, the NetherlandsT.R. Pedersen, Oslo University Hospital, Ullev?l , Center for Preventive Medicine and Medical Faculty, University of Oslo, Norway.M.J.L. Peters, Internal-vascular medicine VU University Medical Center, Amsterdam, The NetherlandsJ. Primdahl, Institute for Regional Health Research, University of Southern Denmark, Denmark, Sygehus S?nderjylland (Hospital of Southern Jutland), Aabenraa, Denmark and King Christian 10’s Hospital for Rheumatic Diseases, Graasten, Denmark.H. Radner, Department of Internal Medicine III, Division of Rheumatology, Medical University Vienna; AustriaS. Rollefstad, Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, NorwayJ. van Rompay, PARE (patient research partners).C. Zabalan, Romanian League against Rheumatism (vice-president) and Board Member (General Secretary) of AGORA, the Platform of S-E organisations for patients with RMDs.N. Sattar, Institute of Cardiovascular and Medical Science, University of Glasgow A.G. Semb, Preventive Cardio-Rheuma Clinic, Department of Rheumatology, Diakonhjemmet Hospital, Oslo, NorwayY. Smulders, MD, PhD, Internal-vascular medicine VU University Medical Center, Amsterdam, The NetherlandsA. S?dergren, Department of Public Health and Clinical Medicine/Rheumatology, University of Ume?, Ume?, SwedenD.P.M. Symmons, Rheumatology and Musculoskeletal Epidemiology, Arthritis Research UK Centre for Epidemiology, The University of Manchester, Manchester, UKZ. Szekanecz: University of Debrecen, Faculty of Medicine, Department of Internal Medicine, Division of Rheumatology, Debrecen, Hungary.K. de Vlam, Department of Rheumatology, University Hospitals Leuven, Leuven, Belgium.S. Wallberg Jonsson, Department of Public Health and Clinical Medicine/Rheumatology, University of Ume?, Ume?, SwedenContributors. All authors participated in the activities of the Task Force and have provided important contributions to the manuscript. Funding European League Against Rheumatism. Competing interests All the participants in this initiative have disclosed any con?icts of interest. R. Agca: No disclosures.F. Atzeni: has received personal remuneration from BMS, Phizer, MSD.M. Dougados: No conflicts of interest.M.A. Gonzalez-Gay: Nothing to disclose (no conflict of interest related to this manuscript).M. Heslinga: No conflicts of interest.S.C. Heslinga: No conflicts of interest.I.B. McInnes: I have received research funding or honoraria from Abbvie, BMS, Pfizer, Janssen, Novartis, Celgene, MSD, UCB and Roche.L. Jacobsson: consultancy fees or speaker honoraria from Abbvie, Actavis, Celgene, Novartis and Pfizer. 2016).G.D. Kitas: has received honoraria for lectures or advisory boards or hospitality by: Pfizer, Abbvie, Novartis, UCB, Genesis, Roche, BMS, GSK, Lilly, Astra-Zeneca.T.K. Kvien: has received fees for speaking and/or consulting from AbbVie, Biogen, BMS, Boehringer Ingelheim, Celgene, Celltrion, Eli Lilly, Epirus, Hospira, Merck-Serono, MSD, Novartis, Orion Pharma, Pfizer, Roche, Sandoz and UCB and received research funding to Diakonhjemmet Hospital from AbbVie, BMS, MSD, Pfizer, Roche and UCB.M.T. Nurmohamed: No relevant disclosures.T.R. Pedersen: No disclosures.M.J.L. Peters: No conflicts of interest.J. Primdahl: No conflicts of interest.H. Radner: No disclosures.S. Rollefstad: No disclosures.J. van Rompay: No diclosures.C. Zabalan: No conflicts of interest.N. Sattar: has consulted for Roche, Amgen, Sanofi, Astrazeneca and received Grant funding from Roche.A.G. Semb: no disclosures.Y.M. Smulders: No relevant conflicts of interest.A. S?dergren: I have no potential conflicts of interest or any disclosures to make.D.P.M. Symmons: No relevant conflicts of interestZ. Szekanecz: No relevant conflicts of interest.K. de Vlam: no disclosures for this article.S. Wallberg Jonsson: received speaker honoraria from MSD and Pfizer.AcknowledgementsWe thank Johannes C.F. Ket, MSc and Linda J. Schoonmade, MSc, Medical Information Specialists, Medical Library, VU University Amsterdam, for their contribution to the systematic literature searches ADDIN REFMGR.REFLIST Reference List(1) van Halm VP, Peters MJL, Voskuyl AE, Boers M, Lems WF, Visser M et al. Rheumatoid arthritis versus diabetes as a risk factor for cardiovascular disease: a cross-sectional study, the CARRE Investigation. 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Arthritis Care Res (Hoboken ) 2012; 64(6):809-816.(139) Rollefstad S, Ikdahl E, Hisdal J, Kvien TK, Pedersen TR, Holme I et al. Systemic inflammation in patients with inflammatory joint diseases does not influence statin dose needed to obtain LDL cholesterol goal in cardiovascular prevention. Ann Rheum Dis 2014.(140) Semb AG, Kvien TK, DeMicco DA, Fayyad R, Wun CC, LaRosa JC et al. Effect of intensive lipid-lowering therapy on cardiovascular outcome in patients with and those without inflammatory joint disease. Arthritis Rheum 2012; 64(9):2836-2846.(141) Sheng X, Murphy MJ, MacDonald TM, Wei L. The comparative effectiveness of statin therapy in selected chronic diseases compared with the remaining population. BMC Public Health 2012; 12:712.(142) Rollefstad S, Kvien TK, Holme I, Eirheim AS, Pedersen TR, Semb AG. Treatment to lipid targets in patients with inflammatory joint diseases in a preventive cardio-rheuma clinic. 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Ann Rheum Dis 2015; 74(3):480-489.(161) Avina-Zubieta JA, Abrahamowicz M, De Vera MA, Choi HK, Sayre EC, Rahman MM et al. Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study. Rheumatology (Oxford) 2013; 52(1):68-75.(162) Ajeganova S, Svensson B, Hafstrom I. Low-dose prednisolone treatment of early rheumatoid arthritis and late cardiovascular outcome and survival: 10-year follow-up of a 2-year randomised trial. BMJ Open 2014; 4(4):e004259.(163) Avina-Zubieta JA, Abrahamowicz M, De Vera MA, Choi HK, Sayre EC, Rahman MM et al. Immediate and past cumulative effects of oral glucocorticoids on the risk of acute myocardial infarction in rheumatoid arthritis: a population-based study. Rheumatology (Oxford) 2013; 52(1):68-75.(164) Greenberg JD, Kremer JM, Curtis JR, Hochberg MC, Reed G, Tsao P et al. Tumour necrosis factor antagonist use and associated risk reduction of cardiovascular events among patients with rheumatoid arthritis. Ann Rheum Dis 2011; 70(4):576-582.(165) Avina-Zubieta JA, Abrahamowicz M, Choi HK, Rahman MM, Sylvestre MP, Esdaile JM et al. Risk of cerebrovascular disease associated with the use of glucocorticoids in patients with incident rheumatoid arthritis: a population-based study. Ann Rheum Dis 2011; 70(6):990-995.(166) Nadareishvili Z, Michaud K, Hallenbeck JM, Wolfe F. Cardiovascular, rheumatologic, and pharmacologic predictors of stroke in patients with rheumatoid arthritis: a nested, case-control study. Arthritis Rheum 2008; 59(8):1090-1096.(167) van Sijl AM, Boers M, Voskuyl AE, Nurmohamed MT. Confounding by indication probably distorts the relationship between steroid use and cardiovascular disease in rheumatoid arthritis: results from a prospective cohort study. PLoS One 2014; 9(1):e87965.(168) Ajeganova S, Svensson B, Hafstrom I. Low-dose prednisolone treatment of early rheumatoid arthritis and late cardiovascular outcome and survival: 10-year follow-up of a 2-year randomised trial. BMJ Open 2014; 4(4):e004259.(169) Wiersma T, Smulders YM, Stehouwer CD, Konings KT, Lanphen J. [Summary of the multidisciplinary guideline on cardiovascular risk management (revision 2011)]. Ned Tijdschr Geneeskd 2012; 156(36):A5104.(170) Ray KK, Kastelein JJ, Boekholdt SM, Nicholls SJ, Khaw KT, Ballantyne CM et al. The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011. Eur Heart J 2014; 35(15):960-968.Supplementary File 1 – The 2009 RecommendationsSupplementary file 2 – Literature searchSearch strategy for Wiley/Cochrane Library (9 February 2015)SearchQueryItems found#1(rheumatoid AND arthritis) OR spondylarthritis OR bechter* OR (ankylos* AND spondylitis*) OR (arthriti* AND psoria*)7,867#2cholesterol* OR ("lipid metabolism” AND disorder*) OR dyslipidemi* OR hypercholesterolemi* OR hypertriglycerid* OR lipid* OR lipoprotein* OR triglycerid* OR atherogenic* OR ldl OR hdl OR statin* OR smoking OR smoke* OR cigar* OR tobacco OR (blood AND pressure) OR hypertensi* OR diabetes OR diabetic* OR (((chronic* OR “end stage”) OR (chronic* OR “end stages”)) AND (renal* OR kidney*) AND (insufficien* OR failur* OR disease*)) OR sex OR gender OR female* OR male OR males OR age OR ("anti-inflammatory” AND agent*) OR antirheumat* OR ("adrenal cortex” AND hormone*) OR nsaid* OR ((anti OR inhibitor*) AND (tnf OR (necrosis AND factor))) OR (anti AND rheumat*) OR methotrexa* OR mtx OR corticosteroid* OR predniso* OR rituximab* OR tocilizumab* OR "Vitamin D" OR rituxan* OR mabthera* OR atlizumab* OR actemra* OR “vitamin d2” OR “vitamin d3” OR dihydrotachysterol* OR “hydroxyvitamin d3” OR “hydroxyvitamin d2” OR ergocalciferol* OR hydroxycholecalciferol* OR cholecalciferol* OR colecalciferol* OR inflammat* OR (risk AND (assessment* OR predictor* OR model*)) OR prediction* OR framingham OR score OR scores OR “carotid intima media thickness” OR echocardiograph* OR tte OR ttes OR “coronary calcium score” OR “coronary calcium scores” OR cac OR cacs OR cimt OR cimts OR (coronary AND ct*)591,686#3cardiovascular*28,925#4#1 AND #2 AND #3160Search strategy for PubMed (10 February 2015)[Mesh] = Medical subject headings[Mesh:NoExp] = MeSH without explosion[tiab] = words in title OR abstract[ti] = words in title[ot] = words as other terms, especially author keywordsSearchQueryItems found#16#12 AND #13 AND #152,595#15#3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #145,826,773#14"Age Factors"[Mesh] OR age[tiab]1,778,227#13#1 OR #2127,025#12"Cardiovascular Diseases"[Mesh:NoExp] OR cardiovascular[tiab]328,304#11"Carotid Intima-Media Thickness”[Mesh] OR carotid intima media thickness*[tiab] OR "Echocardiography"[Mesh] OR echocardiograph*[tiab] OR tte[tiab] OR ttes[tiab] OR coronary calcium score*[tiab] OR cac[tiab] OR cacs[tiab] OR cimt[tiab] OR cimts[tiab] OR coronary ct*[tiab]152,824#10"Risk Assessment"[Mesh] OR risk assessment*[tiab] OR risk predictor*[tiab] OR prediction*[tiab] OR framingham[tiab] OR score[tiab] OR scores[tiab] OR risk model*[tiab]886,470#9"Inflammation"[Mesh:NoExp] OR inflammat*[tiab]620,803#8"Anti-Inflammatory Agents"[Mesh] OR "Anti-Inflammatory Agents"[Pharmacological Action] OR "Anti-Inflammatory Agents, Non-Steroidal"[Pharmacological Action] OR "Antirheumatic Agents"[Mesh:NoExp] OR "Antirheumatic Agents"[Pharmacological Action] OR "Adrenal Cortex Hormones"[Mesh] OR "Adrenal Cortex Hormones "[Pharmacological Action] OR nsaid*[tiab] OR ((anti[tiab] OR inhibitor*[tiab]) AND (tnf[tiab] OR (necrosis[tiab] AND factor[tiab]))) OR antirheumat*[tiab] OR (anti[tiab] AND rheumat*[tiab]) OR methotrexa*[tiab] OR mtx[tiab] OR corticosteroid*[tiab] OR predniso*[tiab] OR "rituximab" [Supplementary Concept] OR "tocilizumab" [Supplementary Concept] OR "Vitamin D"[Mesh] OR "Vitamin D Deficiency"[Mesh] OR rituximab*[tiab] OR rituxan*[tiab] OR mabthera*[tiab] OR tocilizumab*[tiab] OR atlizumab*[tiab] OR actemra*[tiab] OR vitamin d[tiab] OR vitamin d2[tiab] OR vitamin d3[tiab] OR dihydrotachysterol*[tiab] OR hydroxyvitamin d3[tiab] OR hydroxyvitamin d2[tiab] OR ergocalciferol*[tiab] OR hydroxycholecalciferol*[tiab] OR cholecalciferol*[tiab] OR colecalciferol*[tiab]891,077#7"Sex Factors"[Mesh] OR sex[tiab] OR gender[tiab] OR female*[tiab] OR male[tiab] OR males[tiab]1,561,894#6"Diabetes Mellitus"[Mesh] OR diabetes[tiab] OR diabetic*[tiab] OR "Renal Insufficiency, Chronic"[Mesh] OR ((chronic*[tiab] OR end stage*[tiab]) AND (renal*[tiab] OR kidney*[tiab]) AND (insufficien*[tiab] OR failur*[tiab] OR disease*[tiab]))599,809#5"Blood Pressure"[Mesh:NoExp] OR "Hypertension"[Mesh:NoExp] OR hypertensi*[tiab] OR (blood[tiab] AND pressure[tiab])652,221#4"Smoking"[Mesh] OR smoking*[tiab] OR smoke*[ti] OR cigar*[ti] OR tobacco[ti]227,212#3"Cholesterol"[Mesh:NoExp] OR "Cholesterol, HDL"[Mesh] OR "Cholesterol, LDL"[Mesh] OR "Lipid Metabolism Disorders"[Mesh:NoExp] OR "Dyslipidemias"[Mesh:NoExp] OR "Hypercholesterolemia"[Mesh] OR "Hypertriglyceridemia"[Mesh:NoExp] OR "Lipids"[Mesh:NoExp] OR "Lipoproteins"[Mesh] OR "Triglycerides"[Mesh:NoExp] OR "very low density lipoprotein triglyceride"[Substance Name] OR lipid*[tiab] OR hypercholesterolemi*[tiab] OR dyslipidemi*[tiab] OR atherogenic*[tiab] OR triglycerid*[tiab] OR ldl[tiab] OR hdl[tiab] OR cholesterol*[tiab] OR statin*[tiab] OR (lipid[tiab] AND lowering[tiab] AND agent*[tiab])636,969#2"Spondylarthritis"[Mesh] OR ((ankylos*[tiab] AND spondyliti*[tiab]) OR (arthriti*[tiab] AND psoria*[tiab])) OR bechter*[tiab]25,058#1"Arthritis, Rheumatoid"[Mesh:NoExp] OR (rheumatoid[tiab] AND arthritis [tiab])109,137Search strategy for (13 February 2015)/exp = EMtree keyword with explosion/de = EMtree keyword without explosion:ab,ti = words in title OR abstractNEXT/x = words in that order next to each other, x places apartSearchQueryItems found#16?#13 AND #14 AND #156,516#15?#3 OR #4 OR #5 OR #6 OR #7 OR #8 OR #9 OR #10 OR #11 OR #127,987,468#14?#1 OR #2186,396#13?'cardiovascular disease'/de OR cardiovascular:ab,ti466,884#12?'arterial wall thickness'/exp OR 'echocardiography'/exp OR (carotid:ab,ti AND intima:ab,ti AND media:ab,ti AND thickness*:ab,ti) OR echocardiograph*:ab,ti OR tte:ab,ti OR ttes:ab,ti OR (coronary:ab,ti AND (calcium NEXT/1 score*):ab,ti) OR cac:ab,ti OR cacs:ab,ti OR cimt:ab,ti OR cimts:ab,ti OR (coronary NEXT/1 ct*):ab,ti286,910#11?'risk assessment'/exp OR (risk NEXT/1 assessment*):ab,ti OR (risk NEXT/1 predictor*):ab,ti OR prediction*:ab,ti OR framingham:ab,ti OR score:ab,ti OR scores:ab,ti OR (risk NEXT/1 model*):ab,ti1,267,461#10?'inflammation'/de OR inflammat*:ab,ti846,795#9?'antiinflammatory agent'/exp OR 'antirheumatic agent'/exp OR 'corticosteroid'/exp OR nsaid*:ab,ti OR (anti:ab,ti OR inhibitor*:ab,ti AND (tnf:ab,ti OR (necrosis:ab,ti AND factor:ab,ti))) OR antirheumat*:ab,ti OR (anti:ab,ti AND rheumat*:ab,ti) OR methotrexa*:ab,ti OR mtx:ab,ti OR corticosteroid*:ab,ti OR predniso*:ab,ti OR 'rituximab'/exp OR 'tocilizumab'/exp OR 'vitamin d'/exp OR 'vitamin d deficiency'/exp OR rituximab*:ab,ti OR rituxan*:ab,ti OR mabthera*:ab,ti OR tocilizumab*:ab,ti OR atlizumab*:ab,ti OR actemra*:ab,ti OR 'vitamin d':ab,ti OR 'vitamin d2':ab,ti OR 'vitamin d3':ab,ti OR dihydrotachysterol*:ab,ti OR 'hydroxyvitamin d3':ab,ti OR 'hydroxyvitamin d2':ab,ti OR ergocalciferol*:ab,ti OR hydroxycholecalciferol*:ab,ti OR cholecalciferol*:ab,ti OR colecalciferol*:ab,ti1,682,735#8?'age'/exp OR age:ab,ti2,546,464#7?'sex difference'/exp OR sex:ab,ti OR gender:ab,ti OR female*:ab,ti OR male:ab,ti OR males:ab,ti2,081,585#6?'diabetes mellitus'/exp OR diabetes:ab,ti OR diabetic*:ab,ti OR 'chronic kidney failure'/exp OR (chronic*:ab,ti OR (end NEXT/1 stage*):ab,ti AND (renal*:ab,ti OR kidney*:ab,ti) AND (insufficien*:ab,ti OR failur*:ab,ti OR disease*:ab,ti))865,709#5?'blood pressure'/de OR 'hypertension'/de OR hypertensi*:ab,ti OR (blood:ab,ti AND pressure:ab,ti)891,020#4?'smoking'/exp OR smoking*:ab,ti OR smoke*:ti OR cigar*:ti OR tobacco:ti320,513#3?'cholesterol'/de OR 'cholesterol ester'/de OR 'high density lipoprotein cholesterol'/exp OR 'low density lipoprotein cholesterol'/exp OR 'very low density lipoprotein cholesterol'/exp OR 'disorders of lipid and lipoprotein metabolism'/de OR 'disorders of cholesterol metabolism'/exp OR 'disorders of lipid metabolism'/exp OR 'disorders of lipoprotein metabolism'/exp OR 'dyslipidemia'/exp OR 'hyperlipidemia'/exp OR 'lipid'/de OR 'lipoprotein'/exp OR 'triacylglycerol'/de OR lipid*:ab,ti OR hypercholesterolemi*:ab,ti OR dyslipidemi*:ab,ti OR atherogenic*:ab,ti OR triglycerid*:ab,ti OR ldl:ab,ti OR hdl:ab,ti OR cholesterol*:ab,ti OR statin*:ab,ti OR (lipid:ab,ti AND lowering:ab,ti AND agent*:ab,ti)869,664#2?'spondylitis'/de OR 'ankylosing spondylitis'/exp OR 'spondylarthritis'/exp OR (ankylos*:ab,ti AND spondyliti*:ab,ti) OR (arthriti*:ab,ti AND psoria*:ab,ti) OR bechter*:ab,ti37,282#1?'rheumatoid arthritis'/de OR (rheumatoid:ab,ti AND arthritis:ab,ti)161,392 ................
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