Inflammation, rheumatoid arthritis and cardiovascular disease
Yvette Meißner, Pharmacoepidemiology, German Rheumatism Research Centre
www. chronische-entzuendung.org
Outline
I. Cardiovascular disease
II. Rheumatoid arthritis
III. Inflammation
IV. Medication
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
Risk factors for CVDs
Major modifiable risk factors
• High blood pressure • Abnormal blood lipids • Obesity • Diabetes mellitus • Tobacco use • Physical inactivity • Unhealthy diet
Non-modifiable risk factors
• Advancing age • Family history • Gender • Ethnicity / race
“Novel” risk factors
• High homocysteine levels • Abnormal blood
coagulation • Inflammation
Other modifiable risk factors
• Low socioeconomic status • Depression • Psychosocial stress • Alcohol use • Use of certain medication • Left ventricular hypertrophy
WHO: The Atlas of Heart Disease and Stroke
• 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.
CVDs – Key facts of the World Health Organization
Rheumatoid arthritis (RA)
• 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
Chronic, systemic autoimmune disease that predominantly affects the joints
RA is a systemic disease
Cartilage damage, bone erosion, joint destruction
Chronic lung diseases
Cardiovascular diseases Fatigue and depression
Malignancies
Bone density
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 1.4 – 2.0]
• Heart failure: RR 1.9 [95% CI 1.5 – 2.4] (only one study)
• Cerebrovascular event: pooled RR 1.4 [95%CI 1.1 – 1.7]
Mortality: 50% higher risk to die from CVD compared to the general population
• Ischemic heart disease: meta-SMR 1.6 [95%CI 1.5 – 1.7]
• Cerebrovascular event: meta-SMR 1.5 [95%CI 1.4 – 1.7]
Avina-Zubieta et al., Ann Rheum Dis, 2012; 70: 990-5; Avina-Zubieta et al., Arthritis Rheumatol, 2008; 59: 1690-7
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.
Risk factors for CVDs in RA
del Rincón, Arthritis Rheum. 2001;44(12):2737-45.
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 2.3 – 12.2]
• Adjusted incidence rate ratio (age, gender): 4.0 [95%CI 1.9; 8.4]
The increased incidence of CV events in RA patients is independent of traditional CV risk factors.
Risk factors IRR [95% CI]
Age per 10 years 2.2 [1.5-2.6]
Male gender (vs. Female) 2.0 [1.5-2.7]
Diabetes mellitus 2.3 [1.7; 3.1]
Systolic blood pressure per 15 mm Hg 1.2 [1.0-1.3]
BMI per 5 kg/m2 1.1 [0.99-1.3]
Smoking 1.4 [1.0-1.8]
Hypercholesterolemia 1.4 [1.0-1.8]
Cohort membership (RA vs. Non-RA) 3.2 [1.3-6.4]
Comparison of risk factors:
Risk factors for CVDs in RA
Symmons and Gabriel, Nat Rev Rheumatol, 2011 May 31;7(7):399-408.
Major modifiable risk factors
Non-modifiable risk factors
“Novel” risk factors
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
2001 2003 2007 2009 2015 2016 1.5.2017 1.1.2018 Enbrel Humira MabThera Cimzia Inflectra Benepali Olumiant Kevzara Remicade Kineret Orencia RoActemra Remsima Xeljanz Simponi Rixathon Erelzi
Control group: conventional synthetic DMARDs (csDMARD)
Other biologics
• Inhibition of T-cell activation
• Depletion of B-cells via CD20-receptor
• Inhibitors of the cytokine or IL-6
Adapted to van Vollenhoven, Nat Rev Rheumatol 2011, 7: 205-15
bDMARD – biologic disease modifying anti-rheumatic drug | Biologics • Proteins, biotechnologically produced
csDMARD – conventional synthetic disease modifying anti-rheumatic drug • Synthetically produced, chemical structure • Different targets Methotrexat (MTX)
TNF inhibitors (TNFi)
• Antibodies or receptor that inhibit the cytokine tumor necrosis factor (TNF)
Comedikation – Glucocorticoids and non-steroidal anti-rheumatic drugs (NSAID)
tsDMARD – targeted synthetic disease modifying anti-rheumatic drug | JAK inhibitors
Treatment of rheumatoid arthritis
Patients enrolled in RABBIT
1067
730
1274
1460
432
762
851
2858
2893
0 1000 2000 3000 4000
Biosimilars | JAKi
Orencia® (Abatacept)
RoActemra® (Tocilizumab)
MabThera® (Rituximab)
Simponi® (Golimumab)
Remicade® (Infliximab)
Cimzia® (Certolizumab)
Enbrel® (Etanercept)
Humira® (Adalimumab)
TNF inhibitors 7,796
Other biologics 3,467
Control group (csDMARD) 5,462
New therapies (since 2015) 1,067
17,789 patients enrolled (1st November 2018)
RABBIT: Data reporting
• Patient follow up: 5 (-10) years
• Data reporting:
• Disease activity (e.g. DAS28, ESR, CRP)
• Therapies (DMARDs, Co-medication)
• (Serious) Adverse events
• Patient reported Outcomes (e.g. physical function)
Months 0 3 6 12 18 60 120
T0 T1 T2 T3 T4 T11 T21
Enrolment Baseline
Myocardial infarction
Stroke
Heart failure
Baseline characteristics of patients
Cohort Myocardial infarction
Male gender 23% 43%
Age in years 56 ± 13 64 ± 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. 2016 Aug 5;18(1):183
Myocardial infarction: study design
Matching criteria at baseline
• Gender
• Age (± 3 years)
• Comorbidities
• Hypertension
• Coronary artery disease
• Heart failure
• Hyperlipoproteinemia
• Year of enrolment (± 2 years)
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 of 112 cases with a myocardial infarction during follow-up to 112 controls
Meissner et al., Arthritis Res Ther. 2016 Aug 5;18(1):183
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 ± 13 64 ± 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. 2016 Aug 5;18(1):183
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 ± 11 11 ± 9
DAS28 5.2 ± 1.3 5.6 ± 1.3 5.5 ± 1.3
C-reactive protein (mg/l) 18 ± 27 24 ± 27 17 ± 22
Erythrocyte sedimentation rate (mm/h) 31 ± 23 39 ± 29 31 ± 21
% of physical function 63 ± 23 53 ± 25 58 ± 23
Smoking, ever 45% 54% 38%
BMI ≥ 30 kg/m2 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. 2016 Aug 5;18(1):183
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. 2016 Aug 5;18(1):183
Development of disease activity / inflammation
Cases Controls Cohort
ESR
Myocardial infarction/ Index date
Cases Controls Cohort
Enrolment
Mean time until myocardial infarction: 2.6 years
Risk factors for myocardial infarction
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]
Adjusted conditional logistic regression
Results are presented as Odds ratios [95% confi-dence intervals]
Risk factors for myocardial infarction
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]
Adjusted conditional logistic regression
Results are presented as Odds ratios [95% confidence intervals]
Myocardial infarctions
Stroke
Heart failure
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.”
Behrouz, J Neuroimmunol. 2014; 277(1-2):1-5. Ovbiagele, Neurotherapeutics. 2011; 8:319-329. Navi, Ann Neurol. 2015; 77(2): 291-300.
“Novel” risk factors
• Cytokines, • hsCRP • Infections • Malignancies • Hospitalizations
Major modifiable risk factors
• Comorbidities • Tobacco use
Non-modifiable risk factors
• Age • Gender
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. 2017 Sep;76(9):1583-1590
Stroke: study design
Matching criteria at baseline
• Gender
• Age (± 5 years)
• Comorbidities
• Hypertension
• Coronary artery disease
• Heart failure
• Diabetes
• Smoking (never vs. current/former)
• Enrolment period(2001-2006, 2007-2015)
Nested case control study (1:2)
Cases: Patients with an incident
non-haemorrhagic stroke in RABBIT
Controls: Patients with a
similar risk for stroke
Matching of 163 cases with an incident non-haemorrhagic stroke during follow-up to 326 controls
Cohort study
+
Meissner et al., Ann Rheum Dis. 2017 Sep;76(9):1583-1590
Baseline characteristics of patients
Matching Criteria
Cases n=163
Controls n=326
Male gender 25% 25%
Age in years 63 ± 11 63 ± 10
Hypertension 56% 56%
Coronary artery disease 9% 9%
Heart failure 2% 2%
Diabetes 17% 17%
Smoking ever + current 41% 41%
Enrolment before 2007 53% 53%
Numbers are either percentages or mean ± standard deviation
Meissner et al., Ann Rheum Dis. 2017 Sep;76(9):1583-1590
Baseline characteristics of patients
Matching Criteria
Cohort n=11.865
Cases n=163
Controls n=326
Male gender 23% 25% 25%
Age in years 56 ± 13 63 ± 11 63 ± 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 2007 40% 53% 53%
Numbers are either percentages or mean ± standard deviation
Meissner et al., Ann Rheum Dis. 2017 Sep;76(9):1583-1590
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
DAS28 5.1 ± 1.3 5.4 ± 1.3 5.4 ± 1.4
CRP in mg/l 18 ± 26 24 ± 31 21 ± 40
ESR in mm/h 36 ± 26 33 ± 23 31 ± 23
% of physical function 64 ± 23 54 ± 24 60 ± 23
≥ 2 comorbidities 39% 63% 56%
BMI ≥ 30 kg/m2 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. 2017 Sep;76(9):1583-1590
Comorbidities and their therapy
Cohort n=11,865
Cases n=163
Controls n=326
No treatment of
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. 2017 Sep;76(9):1583-1590
Disease activity and inflammation markers
Cohort
Cases
Controls
Averages during the first year of follow-up after enrolment
DAS28 4.3 (4.2-4.3) 4.6 (4.5-4.8) 4.4 (4.2-4.5)
C-reactive protein(mg/L) 13.4 (13.1-13.7) 18.5 (14.3-22.7) 14.3 (12.2-16.3)
Erythrocyte sedimentation rate (mm/h) 25.7 (25.4-26.0) 30.8 (27.6-34.0) 27.0 (25.0-29.1)
Values within a 6 months risk window before the event/index date
DAS28 4.1 (3.8-4.3) 3.5 (3.3-3.7)
C-reactive protein(mg/L) 16.2 (8.1-24.3) 8.0 (6.1-9.9)
Erythrocyte sedimentation rate (mm/h) 28.0 (23.7-32.2) 21.5 (18.9-24.0)
Numbers are presented as mean (95% confidence interval)
Meissner et al., Ann Rheum Dis. 2017 Sep;76(9):1583-1590
Mean time until stroke: 3.9 years
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
1.9 [1.3; 2.6] 1.2 [0.6; 2.3]
Comorbidities Hypertension Hyperlipoproteinemia Chronic renal disease Diabetes mellitus
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]
Matching criteria
Risk factors for stroke in the complete cohort
Adjusted Cox propor-tional hazard model
Meissner et al., Ann Rheum Dis. 2017 Sep;76(9):1583-1590
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
1.8 [0.9; 3.8] 3.3 [1.5; 7.2]
Serious adverse events, 6 months prior Serious infections Cardiovascular diseases Surgeries Other events
4.4 [1.6; 12.5] 2.9 [0.9; 8.7] 0.9 [0.3; 2.3] 2.6 [1.4; 4.8]
Risk factors for stroke in the matched cohort
Adjusted Cox propor-tional hazard frailty model
Myocardial infarctions
Stroke
Heart failure
Background
Nicola et al., Arthritis Rheum. 2005;52(2):412-20.; Nicola et al., Arthritis Rheum. 2006; 54(1): 60-67
Incidence of congestive heart failure Survival
Heart failure: study design and outcome defintion
Selection of 393 patients with prevalent HF
Analysis of a combined outcome
Meissner et al., EULAR 2018, Poster THU0142
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
Baseline characteristics of patients
Patients without outcome
Patients with outcome
Male gender 32% 43%
Age in years 67 ± 9 69 ± 8
DAS28 5.4 ± 1.3 5.6 ± 1.5
C-reactive protein (mg/l) 23 ± 33 39 ± 57
% of physical function 50 ± 24 43 ± 24
Dosage of glucocorticoids (mg/d) 5.5 ± 5.5 6.8 ± 6.1
Actual therapy with csDMARD TNF inhibitor Other bDMARD
14% 55% 32%
22% 50% 28%
Numbers are either percentages or mean (standard deviation)
Meissner et al., EULAR 2018, Poster THU0142
Baseline characteristics of patients
Patients without outcome
Patients with 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%
24% 40% 26%
Numbers are either percentages or mean (standard deviation)
Meissner et al., EULAR 2018, Poster THU0142
Incidence rates for heart failure
Meissner et al., EULAR 2018, Poster THU0142
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Risk factors for heart failure
Relative risk
csDMARD TNF inhibitor Abatacept Rituximab Tocilizumab
Ref. 0.7 0.8 0.5 0.9
[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]
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]
Meissner et al., EULAR 2018, Poster THU0142
Myocardial infarction
Stroke Heart failure
Baseline: 24 mg/l
Baseline: 24 mg/l
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]
C-reactive protein (CRP)
Liao, Trends Cardiovasc Med. 2017;27(2):136-140.
CRP for cardiovascular risk estimation
Myocardial infarction
Stroke Heart failure
Baseline: 24 mg/l
Baseline: 24 mg/l
Baseline: 23 mg/l 39 mg/l
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
Contribution of inflammation to CVD
Nurmohamed et al. Nat Rev Rheumatol. 2015;11(12):693-704.
High prevalence of atherosclerosis, even in
early rheumatoid arthritis
Inflammation, RA and CVD
Adapted: Nurmohamed et al. Nat Rev Rheumatol. 2015;11(12):693-704.
Rheumatoid arthritis
Effects of DMARDs on CVD
Barnabe et al. Arthritis Care Res. 2011 Apr;63(4):522-9.; Micha et al. Am J Cardiol. 2011 Nov 1;108(9):1362-70.
Adjusted relative risk of cardiovascular events in rheumatoid arthritis patients
treated with TNF inhibitors
Risk of cardiovascular disease associated with methotrexate (MTX) use
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
Ridker et al. N Engl J Med. 2017; 377:1119-113
Canakinumab (150 mg/3 months) led to a significantly lower rate of recurrent CV events than placebo, independent of lipid-level lowering
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)
Ridker et al. N Engl J Med. 2018 Nov 10. [Epub ahead of print]
No effect of MTX on incidence rate and risk of CV endpoints
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
Questions?