CVD ved reumatoid artritis. Hvor stort er problemet og hvad kan/skal vi gøre?

Hvad er problemet? RA-populationen udgør 1% af befolkningen Livslængde afkortes betydeligt 1,2,3,4 Risiko for cardiovaskulær sygdom (CVD) øget ved artritis 5,6,7,8,11,12 Traditionelle risikofaktorer for CVD forklarer det ikke8 Fokus på inflammatoriske proces i plaquen9, 10 Wolfe F, 1994, 2. Pincus T, 1984, 3. Cobb S, 1953, 4. Allebeck P, 1982, 5. Myllykangas-Luosujaarvi R, 1995, 6. Monson RR, 1976, 7. Wallberg J, 1997, 8. Rincon ID, 2001. 9. Ross R,1999, 10. Lee D, 2001., 11. Avina-Zubieta J, 2008 12. Lems 2009

Risk of Cardiovascular Mortality in Patients With Rheumatoid Arthritis: A 50 % increase A Meta-Analysis of Observational Studies A-Zubieta J, Arthritis & Rheumatism vol 59, No. 12, December 15, 2008, pp 1690–1697

RA: Dødsårsager 1986 og 2004 Dødsårsag RA (%) Kontrol (%) 42 41 14 20 CVD 42 41 Cancer 14 20 Infektion 10 1 Nyresygdom 8 Lungesygdom 7 4 GI-sygdom 2 Pincus & Callahan, J Rheumatol 1986 Dødsårsag Mænd (n=179) Kvinder (n=327) Alle (n=506) Alle dødsfald 54 (30.2 %) 50 (15.3 %) 104 (20.6 %) CVD 20 (11.2 %) 20 (6.1 %) 40 (7.9 %) Lungesygdomme 9 (5.0 %) 5 (1.5%) 14 (2.8 %) Cancer 17 (9.5 %) 14 (4.2 %) 31 (6.1 %) Goodson Goodson NJ, Arthritis Rheum 2005;vol 52(8):2293-99

bedre lipidprofil med visse DMARDS Declines in Mortality From Acute Myocardial Infarction in Successive Incidence and Birth Cohorts of Patients With Rheumatoid Arthritis. Krishnan, 2004. ARAMIS , N=3862 med RA. mere DMARD (MTX) mindre NSAID bedre lipidprofil med visse DMARDS større fysisk aktivitet med bedre behandling Figure 2. Comparing risk of fatal AMI after disease onset in successive incidence cohorts of rheumatoid arthritis (157 deaths in 22 209 person-years). © 2004 American Heart Association, Inc. Published by American Heart Association. 5

MTX og død ved RA. Mean follow-up 6 år (eller til død). Prospektivt cohorte-studie. N = 1240 Af disse 588 ptt. i MTX behandling (mean 13 mg/uge) I alt 191 døde 84 af CV død 107 non-vaskulær død 72 af de døde havde fået MTX Choi et al The Lancet april 2002

RISIKO FOR DØD UNDER MTX BEHANDLING Choi et al The Lancet april 2002

Risiko for død under DMARD behandling Hazard ratio ikke dosisafhængig ved MTX og ikke afhængig af folatsubstitution Choi et al The Lancet april 2002

Konklusioner MTX behandling reducerer risiko for død med 60 % MTX behandling reducerer risiko for HJERTE-KAR-død med 70 % Øvrige DMARD’s synes ikke at have effekt på mortalitet. Choi et al The Lancet april 2002

IHD og inflammationsmarkører. Accumulation af T-celleabnomiteter er relateret til plaqueinstabilitet, ruptur, thrombose ved ustabil angina11 Cytokiner og CRP er forhøjet ifm det iskæmiske event12,13 11. Liuzzo G, Circulation, 2001;101:2883-88, 12. Liuzzo G, NEJM 1994;331:417-24 13. Ridker P, NEJM, 1997;336:336:973-79,

Baseline Levels of C-Reactive Protein and Prediction of Death From Cardiovascular Disease in Patients With Inflammatory Polyarthritis. A Ten-Year Followup Study of a Primary Care–Based Inception Cohort Tendens (NS) for øget mortalitet med stigende CRP. CV død stærkest. Cohortestudie: 506 ptt med inflammatorisk artrit 10 års follow-up eller til død Goodson NJ, Arthritis & Rheumatism, Vol. 52, No. 8, August 2005, pp 2293–2299

CRP koncentration som prediktor for død CRP koncentration som prediktor for død. (CRP kun målt ved indgang i studiet). Alle dødsårsager CV død mænd kvinder CRP mg/ml n MR HR (95% CI) ≤ 4 69 24.9 1 (ref) 165 8.5 4.7 2.4 5-15 62 32.9 1.5 (0.7-2.9) 84 19.9 (0.7-3.1) 16.5 3.7 (1.0-13.9) 8.7 2.2 (0.6-7.6) ≥ 16 48 52.5 2.3 (1.0-3.7) 78 27.5 2.0 (1.0-4.0) 21.0 4.0 (1.1-15.2) 12.4 3.0 (0.9-9.8) MR = mortality rate sv.t antal individer/1000 personår i followup HR = hazard ratio korrigeret for alder CI = konfidensinterval fra Goodson NJ, ARTHRITIS & RHEUMATISM, Vol. 52, No. 8, August 2005, pp 2293–2299

RF-pos RA har særlig øget risiko for CVD. RF positiv RF negativ RA kriterier opfyldt CRP mg/ml n HR (95% CI) ≤ 4 58 1.0 (ref.) 176 1.0 (ref) 96 5-15 8.0 (1.8-36.2) 88 0.9 (0.2-3.8) 79 13.6 (1.7-107.1) ≥ 16 57 6.4 (1.2-30.8) 69 2.2 (0.7-7.0) 78 15.6 (2.0-120.7) ≥ 5 (poolet) 115 7.4 (1.7-32.2) 157 1.5 (0.5-4.5) 14.7 (2.0-109.2) HR = hazard ratio korrigeret for alder CI = konfidensinterval fra Goodson NJ, Arthritis & Rheum Vol. 52, No. 8, August 2005, pp 2293–2299

Liuzzo, Giovanna; Circulation. 94(10):2373-2380, November 15, 1996. Myocardial Ischemia/Infarction/Arteritis: Plasma Protein Acute-Phase Response in Unstable Angina Is Not Induced by Ischemic Injury. Liuzzo, Giovanna; Circulation. 94(10):2373-2380, November 15, 1996. Figure 1 . C-reactive protein (CRP) concentration in individual patients. Left, unstable angina (closed circle); right, variant angina (open circle). CRP is < 0.3 mg/dL in 90% of healthy subjects, shown by broken line. © 1996 American Heart Association, Inc. Published by American Heart Association. 2

Liuzzo, Giovanna; Circulation. 94(10):2373-2380, November 15, 1996. Myocardial Ischemia/Infarction/Arteritis: Plasma Protein Acute-Phase Response in Unstable Angina Is Not Induced by Ischemic Injury. Liuzzo, Giovanna; Circulation. 94(10):2373-2380, November 15, 1996. Figure 2 . Changes in median levels of C-reactive protein (CRP) after admission in unstable angina (closed circle) and variant angina (open circle) patients. During the 96 hours of study, the plasma concentration of CRP did not increase in either group of patients (Friedman test: P = .37 and P = .062, respectively). © 1996 American Heart Association, Inc. Published by American Heart Association. 2

Liuzzo, Giovanna, Circulation. 94(10):2373-2380, November 15, 1996. Myocardial Ischemia/Infarction/Arteritis: Plasma Protein Acute-Phase Response in Unstable Angina Is Not Induced by Ischemic Injury. Liuzzo, Giovanna, Circulation. 94(10):2373-2380, November 15, 1996. Figure 8 . Changes in median levels of C-reactive protein (CRP) after admission in patients of both groups subgrouped according to the duration of their ischemic episodes. Patients with Holter-recorded ischemic episodes lasting 10 minutes (18 patients with unstable angina, closed square; 10 patients with variant angina, open square). During the 96 hours of study, the plasma concentration of CRP did not change even in patients with long-lasting ischemic episodes (Friedman test: unstable angina, P = .89; variant angina, P = .06). © 1996 American Heart Association, Inc. Published by American Heart Association. 2

Unge RA-ptt. Uden CVD risikofaktorer. Figure 1 Univariate correlation between brachial artery flow mediated vasodilatation and CRP duration, expressed as average CRP in the past year multiplied by the disease duration in years. Endotheldysfunktion ved RA. Jo bedre FMV-respons på NTG jo bedre endothelcellefunktion. Unge RA-ptt. Uden CVD risikofaktorer. Vaudo, G et al. Ann Rheum Dis 2004;63:31-35 Copyright ©2004 BMJ Publishing Group Ltd.

Rheumatoid Arthritis Is Associated With Increased Aortic Pulse-Wave Velocity, Which Is Reduced by Anti-Tumor Necrosis Factor-[alpha] Therapy. Maki-Petaja, Kaisa 2006. FMD = flow-mediated-dilatation. Endothelfunktion. PWV = pulse-wave-velocity Figure 2. The effect of etanercept on FMD in patients with RA. Measurement were made in 9 subjects at baseline and 4 and 12 weeks after initiation of anti-TNF-[alpha] therapy and in a matched control group (n=24). Bars represent means and SEMs. Significance was determined by 1-way ANOVA with repeated measures within the RA group and by unpaired 2-tailed Student t test between RA patients (after 12 weeks of treatment with etanercept) and controls. © 2006 American Heart Association, Inc. Published by American Heart Association. 2

Rheumatoid Arthritis Is Associated With Increased Aortic Pulse-Wave Velocity, Which Is Reduced by Anti-Tumor Necrosis Factor-[alpha] Therapy. Maki-Petaja, Kaisa; 2006. Pulse-wave-velocity falder sv.t. nedsat BP. Figure 1. The effect of etanercept on aortic PWV in patients with RA. Measurements were made in 9 subjects at baseline and 4 and 12 weeks after initiation of anti-TNF-[alpha] therapy and in a matched control group (n=24). Bars represent means and SEMs. Significance was determined by 1-way ANOVA with repeated measures within the RA group and by unpaired 2-tailed Student t test between RA patients (after 12 weeks of treatment with etanercept) and controls. © 2006 American Heart Association, Inc. Published by American Heart Association. 2

Gamle dyder….. Magnyl Figure 2. Relative Risk of a First Myocardial Infarction Associated with Base-Line Plasma Concentrations of C-Reactive Protein, Stratified According to Randomized Assignment to Aspirin or Placebo Therapy. Analyses are limited to events occurring before the unblinding of the aspirin component of the Physicians' Health Study. The reduction in the risk of myocardial infarction associated with the use of aspirin was 13.9 percent in the first (lowest) quartile of C-reactive protein values, 33.4 percent in the second quartile, 46.3 percent in the third quartile, and 55.7 percent in the fourth (highest) quartile. N=543 CRPq1= < 0.55 mg/l CRPq2= 0.56-1.14 mg/l Ingen effekt på venøse thromber !! CRPq3= 1.15-2.10 mg/l CRPq4 = > 2.11 mg/l Ridker, NEJM 1997, vol 336(14);973-79

Hvad er farligst, RA eller DM? Cardiovascular event–free probability to 3 years among nondiabetic controls (black line), patients with type 2 diabetes mellitus (DM) (light grey line), and nondiabetic patients with rheumatoid arthritis (RA) (dark grey line). The hazard ratios for the nondiabetic controls and patients with RA as compared with nondiabetic controls were as follows: for patients with type 2 DM, 2.0 (95% confidence interval [95% CI] 1.1–3.7); for nondiabetic patients with RA, 2.2 (95% CI 1.3–3.6). Differences were estimated from age- and sex-adjusted Cox proportional hazards models PETERS M, Arthritis & Rheumatism (Arthritis Care & Research) Vol. 61, No. 11, November 15, 2009, pp 1571–1579

Glukokortikoid og CVD ved RA. GK forstærker dyslipidæmi, øger BS og syst. BT1 CV events øget ved prednisone > 7.5 mg/dg2 Høj dosis relateret til flere plaques og vægstivhed i arterier.3 Antiinflammatoriske effekt betydelig både ved ra 4 og i det ateromatøse plaque5 Wei: Observationelt corhorte studie. 1 Ng M, Heart, 2004, 2. Wei L, 2004, 3.Del Rincon I,2004, 4. Hench PS, Kendall EC, 1949, 5. Libby P. Nature 2002

Nyeste viden - summary DMARD’s + prednisolon øger serum-adiponectin og HDL-cholesterol (Cansu, EULAR 2009) N=27, kontrolgruppe =OA Aterogene index ved ERA bedres ved behandling med GK (den Uyl EULAR 2009) N=21, Totalchol., HDL og LDL , Statiner sænker lipidniveauet hos RA ptt. med CHD sv.t. non-RA CHD-ptt. (Semb EULAR 2009)

Nyeste viden fortsat…. Vi er blevet bedre til at behandle RA-ptt. med magnyl: 3% (1995)  14-15 % (2005)…..!! (Mannalithara EULAR 2009) Mikrovasculære endothelfunktion bedres ved behandlingsrespons på MTX eller Enbrel (Galarraga EULAR 2009)

Hvad skal vi gøre ? Registrere CVD-markører (flere) og interventioner i DANBIO? Risikostratificere vore patienter? Lipidprofil IgMRF Måle highsensitivity CRP? Måle stivhed og reaktivitet i karvæggen? Standardisere behandling? Magnyl + simvastatin + antihypertensiva + motion på recept + aktivt rygestop…

Hvad skal vi gøre ?... forsat Intensivere antiinflammatoriske behandlingsniveau? Være hurtigere til at sætte i behandling DMARD/biobehandling? Alle patienter, risikogrupper… Øge informationsniveauet? Ingen af ovennævnte?

EULAR rekommendationer for CVD ved inflammatorisk artritis. RA should be considered as a disease in which cardiovascular risk is elevated, because of both an increased prevalence of traditional cardiovascular risk factors and the inflammatory burden. Although the evidence base is less, this may also apply to ankylosing spondylitis and psoriatic arthritis. To lower cardiovascular risk, adequate control of arthritis disease activity is necessary. All patients with RA should undergo annual cardiovascular risk evaluation with use of national guidelines. This should also be considered for all patients with ankylosing spondylitis and psoriatic arthritis. When antirheumatic treatment has been changed, risk assessments should be repeated. For patients with RA, risk-score models should be adapted by introducing a 1.5 multiplication factor when the patient meets two of the following three criteria: disease duration of more than 10 years, rheumatoid factor or anticyclic citrullinated peptide positivity, and the presence of certain extra-articular manifestations. Online Annals of Rheumatic Diseases sept 2009

Fortsat….. When using the Systematic Coronary Risk Evaluation model for determination of cardiovascular risk, triglyceride/HDL-cholesterol ratio should be used. Intervention for cardiovascular risk-factor management should be performed according to national guidelines. Preferred treatment options are statins, ACE inhibitors, and/or angiotensin-receptor blockers. The effect of cyclooxygenase-2 inhibitors and most nonsteroidal anti-inflammatory drugs (NSAIDs) on cardiovascular risk is not completely determined and should be studied further. Clinicians should therefore be very cautious in prescribing these drugs, especially to patients with cardiovascular risk factors or with documented cardiovascular disease. When corticosteroids are prescribed, this should be at the lowest possible dose. Patients should be actively encouraged to stop smoking.

Kardiovaskulær risiko og RA. Klinisk praktisk guideline baseret på best evidens og expert opinion. Pham T, Joint Bone Spine, 2006;73:379-87

5 spørgsmål Giver RA øget risiko for arteriel og/eller venøs thromboemboliske episoder? Event-rater? Hvilke faktorer er betydende for ovenstående? Skal RA-ptt. Undersøges og følges specielt ift thrombomboliske sygdomme? Påvirker DMARD’s/GK forekomsten af CVD ved RA? Hvad er den bedste strategi til forebyggelse af thrombemboli ved RA?

9 rekommendationer: RA og CVD Øget opmærksomhed ved RA Acceptere RA som isoleret risikofaktor CVD risiko skal evalueres på personniveau og reversible faktorer korrigeres Systemisk steroidbehandling i mindst mulige dosis Acceptere MTX som protektiv ift CVD TNFα-blokker stadig ikke til svært incomp cordis, men OK i øvrigt og mulig protektiv ift CVD S-LDL-kolesterol skal være < 4.1 mmol/l ved aktiv RA Statiner bør anvendes ved utilstrækkelig effekt af diæt Magnyl skal ikke anvendes som primær profylakse p.g.a. RA. Samtidig brug af NSAID kan modvirke effekten af Magnyl. Pham T, Joint Bone Spine, 2006;73:379-87

Referenceliste. Wolfe F, Arthritis Rheumatism, 1994;37:481-94 Pincus T, Arthritis Rheuamtism, 1984;27:864-72 Cobb S, NEJM, 1953;249:553-56 Allebeck P, Scan J Rheumatol 1982;11:81-86 Myllykangas-Luosujaarvi R, J Rheumatol, 1995;22:1065-67 Monson RR, J Chron Dis 1976;29:459-67 Wallberg J, J Rheumatol, 1997;24:445-45 Rincon ID, Arthritis Rheum 2001;44:2737-48 Ross R, NEJM, 1999;340:115-126, Lee D, Lancet 2001;358:903-911 1 Avina-Zubieta J, Arthritis Rheum 2008;vol 59(12):1690–1697 Pincus & Callahan, J Rheumatology 1986; Oct;13(5):841-5

Referenceliste fortsat…….. Ng M, Heart, 2004;90;829-830 Wei L, Ann Intern Med 2004, 141:764-70 Del Rincon I, Artrihritis & Rheum, 2004;50:3813-22 Hench PS, Kendall EC, Proc Staff Meet Mayo Clin 1949;24:181–97. Libby P. Nature 2002;420:868–74. Pham T, Joint Bone Spine, 2006;73:379-87 Peters M, Arthritis & Rheumatism 2009;61(11):1571–1579 Ridker, NEJM 1997, vol 336(14);973-79 Maki-Petaja K, Circulation. 114(11):1185-1192, September 12, 2006. Vaudo, G et al. Ann Rheum Dis 2004;63:31-35 Krishnan, Circulation. 110(13):1774-1779, September 28, 2004. Annals of the Rheumatic Diseases, The EULAR Journal, 2009

Referenceliste igen-igen… Liuzzo G, Circulation, 2001;101:2883-88, Liuzzo G, NEJM 1994;331:417-24 Liuzzo, Giovanna, Circulation. 94(10):2373-2380, November 15, 1996. Choi HK, Lancet 2002;359:1173-77. Goodson NJ, Arthritis Rheum 2005;vol 52(8):2293-99 Lems K, Ann Rheum Dis 2009;68;1509-10 Peters M, Ann Reum Dis online sept 2009.