Inflammation, rheumatoid arthritis and cardiovascular disease

Transcription

1 Inflammation, rheumatoid arthritis and cardiovascular disease Yvette Meißner, Pharmacoepidemiology, German Rheumatism Research Centre www. chronische-entzuendung.org

2 Outline I. Cardiovascular disease II. Rheumatoid arthritis III. Inflammation IV. Medication

3 Cardiovascular diseases (CVDs) Disorders of the heart and blood vessels: Coronary heart disease (myocardial infarction) Cerebrovascular disease (stroke) Peripheral arterial disease Congenital heart disease Deep vein thrombosis and pulmonary embolism Rheumatic heart disease WHO: The Atlas of Heart Disease and Stroke

4 Risk factors for CVDs Major modifiable risk factors Other modifiable risk factors Non-modifiable risk factors Novel risk factors High blood pressure Abnormal blood lipids Obesity Diabetes mellitus Tobacco use Physical inactivity Unhealthy diet Low socioeconomic status Depression Psychosocial stress Alcohol use Use of certain medication Left ventricular hypertrophy Advancing age Family history Gender Ethnicity / race High homocysteine levels Abnormal blood coagulation Inflammation WHO: The Atlas of Heart Disease and Stroke

5 CVDs Key facts of the World Health Organization Number 1 cause of death globally An estimated 17.9 million people died from CVDs in 2016 (= 31% of all deaths) Main causes: heart attack and stroke (85%) Most CVDs can be prevented by addressing behavioural risk factors such as tobacco use, unhealthy diet, obesity, physical inactivity and harmful alcohol use People with CVD or who are at high CV risk (= presence of 1 factor such as hypertension, diabetes, hyperlipidemia or already established disease) need early detection and management using counselling and medicines, as appropriate.

6 Rheumatoid arthritis (RA) Chronic, systemic autoimmune disease that predominantly affects the joints Symmetrical Symptoms Swelling and pain Morning stiffness Fatigue Affects ~1% of the population Almost three times as many women have rheumatoid arthritis as men Manifestation: between the ages of 55 and 64

7 RA is a systemic disease Malignancies Chronic lung diseases Cartilage damage, bone erosion, joint destruction Fatigue and depression Bone density Cardiovascular diseases

8 Cardiovascular risk in rheumatoid arthritis Morbidity: 48% higher risk for incident CVD compared to the general population Myocardial infarction: pooled RR 1.7 [95%CI ] Heart failure: RR 1.9 [95% CI ] (only one study) Cerebrovascular event: pooled RR 1.4 [95%CI ] Mortality: 50% higher risk to die from CVD compared to the general population Ischemic heart disease: meta-smr 1.6 [95%CI ] Cerebrovascular event: meta-smr 1.5 [95%CI ] Avina-Zubieta et al., Ann Rheum Dis, 2012; 70: 990-5; Avina-Zubieta et al., Arthritis Rheumatol, 2008; 59:

9 Mortality in rheumatoid arthritis Premature mortality in patients with RA compared to general population Leading causes of death: Cardiovascular diseases Infections Gabriel et al., Arthritis Rheum. 2003;48(1):54-8.

10 Risk factors for CVDs in RA Comparison of CVD incidence in RA cohort vs. non-ra cohort: Crude incidence rate: 3.4/100 PY vs. 0.6/100 PY Crude incidence rate ratio: 5.8 [95%CI ] Adjusted incidence rate ratio (age, gender): 4.0 [95%CI 1.9; 8.4] Comparison of risk factors: Risk factors IRR [95% CI] Age per 10 years 2.2 [ ] Male gender (vs. Female) 2.0 [ ] Diabetes mellitus 2.3 [1.7; 3.1] Systolic blood pressure per 15 mm Hg 1.2 [ ] BMI per 5 kg/m [ ] Smoking 1.4 [ ] Hypercholesterolemia 1.4 [ ] Cohort membership (RA vs. Non-RA) 3.2 [ ] The increased incidence of CV events in RA patients is independent of traditional CV risk factors. del Rincón, Arthritis Rheum. 2001;44(12):

11 Risk factors for CVDs in RA Major modifiable risk factors Non-modifiable risk factors Novel risk factors Symmons and Gabriel, Nat Rev Rheumatol, 2011 May 31;7(7):

12 Estimation of CV risk factors with real world data Rheumatoide Arthritis: Beobachtung der Biologika-Therapie Prospective longitudinal cohort study (Start: 05/2001) Enrolment of patients with rheumatoid arthritis with a new start of: A treatment with a licensed biologic / biosimilar / JAK inhibitor A treatment with conventional DMARD after one treatment failure Enbrel Humira MabThera Cimzia Inflectra Benepali Olumiant Kevzara Remicade Kineret Orencia RoActemra Remsima Xeljanz Simponi Rixathon Erelzi Control group: conventional synthetic DMARDs (csdmard)

13 Treatment of rheumatoid arthritis csdmard conventional synthetic disease modifying anti-rheumatic drug Synthetically produced, chemical structure Different targets Methotrexat (MTX) bdmard biologic disease modifying anti-rheumatic drug Biologics Proteins, biotechnologically produced TNF inhibitors (TNFi) Antibodies or receptor that inhibit the cytokine tumor necrosis factor (TNF) Other biologics Inhibition of T-cell activation Depletion of B-cells via CD20-receptor Inhibitors of the cytokine or IL-6 tsdmard targeted synthetic disease modifying anti-rheumatic drug JAK inhibitors Comedikation Glucocorticoids and non-steroidal anti-rheumatic drugs (NSAID) Adapted to van Vollenhoven, Nat Rev Rheumatol 2011, 7:

14 Patients enrolled in RABBIT Humira (Adalimumab) Enbrel (Etanercept) Cimzia (Certolizumab) Remicade (Infliximab) Simponi (Golimumab) MabThera (Rituximab) RoActemra (Tocilizumab) Orencia (Abatacept) Biosimilars JAKi ,789 patients enrolled (1st November 2018) Control group (csdmard) 5,462 TNF inhibitors 7,796 Other biologics 3,467 New therapies (since 2015) 1,067

15 RABBIT: Data reporting Patient follow up: 5 (-10) years Data reporting: Enrolment Baseline T0 T1 T2 T3 T4 T11 T21 Months Disease activity (e.g. DAS28, ESR, CRP) Therapies (DMARDs, Co-medication) (Serious) Adverse events Patient reported Outcomes (e.g. physical function)

16 Myocardial infarction Stroke Heart failure

17 Baseline characteristics of patients Cohort Myocardial infarction Male gender 23% 43% Age in years 56 ± ± 9 Hypertension 37% 60% Coronary artery disease 6% 25% Heart failure 2% 6% Hyperlipoproteinemia 8% 17% Numbers are either percentages or mean (standard deviation) Meissner et al., Arthritis Res Ther Aug 5;18(1):183

18 Myocardial infarction: study design Nested case control study (1:1) Cases: Patients with a first myocardial infarction in RABBIT Controls: Patients with a similar risk for myocardial infarction Matching criteria at baseline Gender Age (± 3 years) Comorbidities Hypertension Coronary artery disease Heart failure Hyperlipoproteinemia Year of enrolment (± 2 years) Matching of 112 cases with a myocardial infarction during follow-up to 112 controls Meissner et al., Arthritis Res Ther Aug 5;18(1):183

19 Baseline characteristics of patients Matching criteria Cohort n=11,059 Cases n=112 Controls n=112 Male gender 23% 43% 43% Age in years 56 ± ± 9 64 ± 9 Hypertension 37% 60% 61% Coronary artery disease 6% 25% 23% Heart failure 2% 6% 6% Hyperlipoproteinemia 8% 17% 16% Numbers are either percentages or mean ± standard deviation Meissner et al., Arthritis Res Ther Aug 5;18(1):183

20 Baseline characteristics of patients Non-matching criteria Cohort n=11,059 Cases n=112 Controls n=112 RA disease duration in years 10 ± 9 11 ± ± 9 DAS ± ± ± 1.3 C-reactive protein (mg/l) 18 ± ± ± 22 Erythrocyte sedimentation rate (mm/h) 31 ± ± ± 21 % of physical function 63 ± ± ± 23 Smoking, ever 45% 54% 38% BMI 30 kg/m 2 23% 30% 17% Glucocorticoid use 80% 94% 78% NSAID use 53% 55% 55% Numbers are either percentages or mean ± standard deviation Meissner et al., Arthritis Res Ther Aug 5;18(1):183

21 Cardiovascular comorbidities and their therapy Cohort n=11,059 Cases n=112 Controls n=112 Non-treated CVD* 21% 36% 17% *Refers to hypertension, coronary artery disease, heart failure, hyperlipoproteinemia Meissner et al., Arthritis Res Ther Aug 5;18(1):183

22 ESR Development of disease activity / inflammation Myocardial infarction/ Enrolment Index date Mean time until myocardial infarction: 2.6 years Cases Controls Cohort Cases Controls Cohort

23 Risk factors for myocardial infarction Adjusted conditional logistic regression Results are presented as Odds ratios [95% confidence intervals] Model I Log CRP, before event/index date 1.6 [1.1; 2.3] DMARD (Reference: csdmard) TNFi 1.0 [0.4; 2.2] other bdmards 1.1 [0.3; 3.7] Glucocorticoids (Reference: < 5 mg/d) 5 10 mg/d 1.3 [0.6; 2.9] > 10 mg/d 2.2 [0.7; 6.8] Non-treated CVD 2.8 [0.9; 8.3] Smoking (Reference: never) Ever 3.3 [1.5; 7.6] Unknown 2.2 [0.8; 5.7] Diabetes mellitus 2.1 [0.8; 5.2]

24 Risk factors for myocardial infarction Adjusted conditional logistic regression Results are presented as Odds ratios [95% confidence intervals] Model I Model II Log CRP, before event/index date 1.6 [1.1; 2.3] Log CRP, total observation 1,5 [1.0; 2.2] DMARD (Reference: csdmard) TNFi 1.0 [0.4; 2.2] 0.9 [0.4; 2.1] other bdmards 1.1 [0.3; 3.7] 0.9 [0.3; 2.7] Glucocorticoids (Reference: < 5 mg/d) 5 10 mg/d 1.3 [0.6; 2.9] 1.2 [0.6; 2.7] > 10 mg/d 2.2 [0.7; 6.8] 1.8 [0.6; 5.9] Non-treated CVD 2.8 [0.9; 8.3] 2.7 [0.9; 8.0] Smoking (Reference: never) Ever 3.3 [1.5; 7.6] 2.9 [1.3; 6.7] Unknown 2.2 [0.8; 5.7] 2.1 [0.8; 5.7] Diabetes mellitus 2.1 [0.8; 5.2] 2.3 [0.9; 5.7]

25 Myocardial infarctions Stroke Heart failure

26 Background The pathogenic mechanism involved in augmentation of ischaemic stroke risk in RA is complex, and not fully understood. Overall it appears that a combination of traditional and non-traditional risk factors contributes to the increased risk. Major modifiable risk factors Comorbidities Tobacco use Non-modifiable risk factors Age Gender Novel risk factors Cytokines, hscrp Infections Malignancies Hospitalizations Behrouz, J Neuroimmunol. 2014; 277(1-2):1-5. Ovbiagele, Neurotherapeutics. 2011; 8: Navi, Ann Neurol. 2015; 77(2):

27 Outcome definition 199 incident cerebrovascular events (no cerebrovascular disease reported at baseline)? 22 haemorrhagic strokes 11 subarachnoid haemorrhages 101 ischaemic strokes 45 transient ischaemic attacks 20 unclassifiable strokes 166 non-haemorrhagic events Meissner et al., Ann Rheum Dis Sep;76(9):

28 Stroke: study design Cases: Patients with an incident non-haemorrhagic stroke in RABBIT Controls: Patients with a similar risk for stroke Meissner et al., Ann Rheum Dis Sep;76(9): Cohort study + Nested case control study (1:2) Matching criteria at baseline Gender Age (± 5 years) Comorbidities Hypertension Coronary artery disease Heart failure Diabetes Smoking (never vs. current/former) Enrolment period( , ) Matching of 163 cases with an incident non-haemorrhagic stroke during follow-up to 326 controls

29 Baseline characteristics of patients Matching Criteria Cases n=163 Controls n=326 Male gender 25% 25% Age in years 63 ± ± 10 Hypertension 56% 56% Coronary artery disease 9% 9% Heart failure 2% 2% Diabetes 17% 17% Smoking ever + current 41% 41% Enrolment before % 53% Numbers are either percentages or mean ± standard deviation Meissner et al., Ann Rheum Dis Sep;76(9):

30 Baseline characteristics of patients Matching Criteria Cohort n= Cases n=163 Controls n=326 Male gender 23% 25% 25% Age in years 56 ± ± ± 10 Hypertension 37% 56% 56% Coronary artery disease 6% 9% 9% Heart failure 2% 2% 2% Diabetes 10% 17% 17% Smoking never 43% 41% 41% Enrolment before % 53% 53% Numbers are either percentages or mean ± standard deviation Meissner et al., Ann Rheum Dis Sep;76(9):

31 Baseline characteristics of patients Non-matching Criteria Cohort n=11,865 Cases n=163 Controls n=326 RA disease duration in years 10 ± 9 11 ± 9 11 ± 10 DAS ± ± ± 1.4 CRP in mg/l 18 ± ± ± 40 ESR in mm/h 36 ± ± ± 23 % of physical function 64 ± ± ± 23 2 comorbidities 39% 63% 56% BMI 30 kg/m 2 24% 25% 23% Glucocorticoid > 10mg/d 20% 20% 17% NSAID use 52% 55% 58% Numbers are either percentages or mean ± standard deviation Meissner et al., Ann Rheum Dis Sep;76(9):

32 Comorbidities and their therapy No treatment of Cohort n=11,865 Cases n=163 Controls n=326 CVDs* 21% 34% 21% Diabetes 20% 15% 30% Osteoporosis 16% 12% 17% *Refers to hypertension, coronary artery disease, heart failure, hyperlipoproteinemia Meissner et al., Ann Rheum Dis Sep;76(9):

33 Disease activity and inflammation markers Cohort Cases Controls Averages during the first year of follow-up after enrolment DAS ( ) 4.6 ( ) 4.4 ( ) C-reactive protein(mg/l) 13.4 ( ) 18.5 ( ) 14.3 ( ) Erythrocyte sedimentation rate (mm/h) 25.7 ( ) 30.8 ( ) 27.0 ( ) Values within a 6 months risk window before the event/index date DAS ( ) 3.5 ( ) C-reactive protein(mg/l) 16.2 ( ) 8.0 ( ) Erythrocyte sedimentation rate (mm/h) 28.0 ( ) 21.5 ( ) Numbers are presented as mean (95% confidence interval) Mean time until stroke: 3.9 years Meissner et al., Ann Rheum Dis Sep;76(9):

34 Risk factors for stroke in the complete cohort Adjusted Cox proportional hazard model Matching criteria Hazard ratio [95% CI] Age per 5 years 1.4 [1.3; 1.5] Gender, males 1.0 [0.7; 1.5] Smoking, never (Reference) Smoking, ever Smoking, unknown Comorbidities Hypertension Hyperlipoproteinemia Chronic renal disease Diabetes mellitus 1.9 [1.3; 2.6] 1.2 [0.6; 2.3] 1.3 [0.95; 1.9] 1.6 [1.0; 2.5] 1.3 [0.8; 1.9] 1.3 [0.7; 2.4] Better physical function, per 10 points 0.9 [0.8; 0.96] Log C-reactive protein 1.2 [0.99; 1.4] csdmard (Reference) TNFi Other bdmards 0.9 [0.6; 1.2] 0.9 [0.6; 1.4] Glucocorticoids, cumul. (>10mg/d) 1.2 [0.6; 2.5] Cox-2 inhibitors 1.3 [0.8; 2.1]

35 Risk factors for stroke in the matched cohort Adjusted Cox proportional hazard frailty model Hazard ratio [95% CI] Better physical function, per 10 points 0.9 [0.8; 0.9] Log C-reactive protein 1.2 [0.98; 1.4] csdmard (Reference) TNFi Other bdmards 0.8 [0.5; 1.3] 0.6 [0.4; 1.1] Glucocorticoids, current by 5mg/d 0.9 [0.7; 1.1] Number of previous bdmards 1.3 [1.0; 1.8] No CV disease (Reference) CV disease with therapy CV disease and no therapy Serious adverse events, 6 months prior Serious infections Cardiovascular diseases Surgeries Other events 1.8 [0.9; 3.8] 3.3 [1.5; 7.2] 4.4 [1.6; 12.5] 2.9 [0.9; 8.7] 0.9 [0.3; 2.3] 2.6 [1.4; 4.8] Meissner et al., Ann Rheum Dis Sep;76(9):

36 Myocardial infarctions Stroke Heart failure

37 Background Incidence of congestive heart failure Survival Nicola et al., Arthritis Rheum. 2005;52(2): ; Nicola et al., Arthritis Rheum. 2006; 54(1): 60-67

38 Heart failure: study design and outcome defintion Selection of 393 patients with prevalent HF Analysis of a combined outcome 19 deteriorations of heart failure defined as hospitalisation Mean time until deterioration: 30 months 123 deaths Main causes of death: infections (34%) CV events (31%, thereof 58% heart failure) Mean time until deterioration: 30 months Meissner et al., EULAR 2018, Poster THU0142

39 Baseline characteristics of patients Patients without outcome Patients with outcome Male gender 32% 43% Age in years 67 ± 9 69 ± 8 DAS ± ± 1.5 C-reactive protein (mg/l) 23 ± ± 57 % of physical function 50 ± ± 24 Dosage of glucocorticoids (mg/d) 5.5 ± ± 6.1 Actual therapy with csdmard TNF inhibitor Other bdmard 14% 55% 32% Numbers are either percentages or mean (standard deviation) Meissner et al., EULAR 2018, Poster THU % 50% 28%

40 Baseline characteristics of patients Patients without outcome Sum of comorbidities 6 ± 3 7 ± 3 Hypertension 79% 80% Coronaray artery disease 42% 47% Diabetes mellitus 28% 34% Chronic renal disease 24% 34% Osteoporosis 40% 53% Smoking Never Ever Unknown 45% 45% 10% Numbers are either percentages or mean (standard deviation) Meissner et al., EULAR 2018, Poster THU0142 Patients with outcome 24% 40% 26%

41 Rate per 100 patient years Incidence rates for heart failure Meissner et al., EULAR 2018, Poster THU0142

42 Risk factors for heart failure Generalized estimation equations model (GEE) Restricted to 335 patients who had at least one treatment episode >6 months. Results are presented as Relative risk [95% confidence intervals] csdmard TNF inhibitor Abatacept Rituximab Tocilizumab Relative risk Ref [0.4; 1.3] [0.3; 2.3] [0.2; 1.1] [0.3; 2.6] Baseline age per 5 years 1.3 [1.1; 1.5] Male vs. female 2.4 [1.4; 3.9] C-reactive protein per 5 mg/l 1.03 [1.004; 1.1] % of physical function per 10 points 0.9 [0.4; 0.999] Sum of comorbidities 1.1 [0.96; 1.3] Oral glucocorticoids per 5 mg/d 1.4 [1.03; 1.8] Smokers vs. non-smokers 1.7 [1.02; 3.0] Meissner et al., EULAR 2018, Poster THU0142

43 C-reactive protein (CRP) Myocardial infarction Baseline: 24 mg/l Stroke Baseline: 24 mg/l Heart failure Baseline: 23 mg/l 39 mg/l OR=1.6 [95%CI 1.1; 2.3] HR=1.2 [95%CI 0.99; 1.4] RR=1.03 [95%CI 1.004; 1.1]

44 CRP for cardiovascular risk estimation Myocardial infarction Baseline: 24 mg/l Stroke Baseline: 24 mg/l Heart failure Baseline: 23 mg/l 39 mg/l Liao, Trends Cardiovasc Med. 2017;27(2):

45 C-reactive protein Acute-phase protein of the blood plasma Synthesized by the liver Binds to the surface of dead or dying cells Activates the complement system Increases interleukin-6 secretion by macrophages and T cells Marker of inflammation Wikipedia: C-reactive protein

46 Contribution of inflammation to CVD High prevalence of atherosclerosis, even in early rheumatoid arthritis Nurmohamed et al. Nat Rev Rheumatol. 2015;11(12):

47 Inflammation, RA and CVD Rheumatoid arthritis Adapted: Nurmohamed et al. Nat Rev Rheumatol. 2015;11(12):

48 Effects of DMARDs on CVD Adjusted relative risk of cardiovascular events in rheumatoid arthritis patients treated with TNF inhibitors Risk of cardiovascular disease associated with methotrexate (MTX) use Barnabe et al. Arthritis Care Res Apr;63(4):522-9.; Micha et al. Am J Cardiol Nov 1;108(9):

49 Prevention of CVD Canakinumab Antiinflammatory Thrombosis Outcomes Study (CANTOS) RCT: Canakinumab vs. Placebo Canakinumab: Inhibitor of interleukin-1β (50 mg, 150 mg, and 300 mg, s.c. every 3 months) Inclusion of 10,061 patients with previous myocardial infarction and hscrp level 2 mg/l Primary end point: composite of nonfatal myocardial infarction, nonfatal stroke or CV death Median follow-up of 3.7 years Results: Canakinumab reduced hscrp levels by 26%/37%/41% in 50/150/300 mg group vs. placebo No effect on lipid levels Incidence rates of primary end point: 4.1/3.9/3.9 per 100 PY vs. 4.5/100 PY Risk for primary endpoint: HR=0.9 (95% CI 0.8; 1.1) / 0.9 (0.7; 0.98; P = 0.021) / 0.9 (0.8; 0.99; P = 0.031) No significant difference in all-cause mortality, but higher rates of fatal infections Canakinumab (150 mg/3 months) led to a significantly lower rate of recurrent CV events than placebo, independent of lipid-level lowering Ridker et al. N Engl J Med. 2017; 377:

50 Prevention of CVD Cardiovascular Inflammation Reduction Trial (CIRT) RCT: MTX (15-20 mg/week ) vs. Placebo Inclusion of 4786 patients with previous myocardial infarction or multivessel coronary disease who additionally had either type 2 diabetes or metabolic syndrome Primary end point: composite of nonfatal myocardial infarction, nonfatal stroke or CV death + hospitalization for unstable angina that led to urgent revascularization Median follow-up of 2.3 years Results MTX did not result in lower interleukin-1β, interleukin-6, or CRP levels than placebo Incidence rates of primary end point: 4.1/100 PY vs. 4.3/100 PY Risk for primary endpoint: HR=0.96 (95% CI 0.8; 1.2) No effect of MTX on incidence rate and risk of CV endpoints Ridker et al. N Engl J Med Nov 10. [Epub ahead of print]

51 Summary Rheumatoid arthritis is characterized by high inflammation levels Inflammation is recognized as cardiovascular risk factor in the general population Effective treatment can reduce inflammation levels and prevent cardiovascular disease in patients with rheumatoid arthritis Prevention of cardiovascular diseases by DMARDs: Trilas showed fewer events in patients treated with canakinumab but no effect of methotrexate

52 Questions?