Inflammation, rheumatoid arthritis and cardiovascular disease · Cardiovascular diseases (CVDs)...

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.




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



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



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


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


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.


• Cytokines, • hsCRP • Infections • Malignancies • Hospitalizations


• Comorbidities • Tobacco use


• 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

+



Matching Criteria

Cases n=163

Controls n=326

Male gender 25% 25%

Age in years 63 ± 11 63 ± 10


Coronary artery disease 9% 9%

Heart failure 2% 2%

Diabetes 17% 17%

Smoking ever + current 41% 41%

Enrolment before 2007 53% 53%




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%




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


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


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)


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


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


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%




Patients without outcome

Patients with outcome

Sum of comorbidities 6 ± 3 7 ± 3


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%



Incidence rates for heart failure


Rat

e p

er 1

00

pat

ien

t ye

ars

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]



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


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?

Inflammation, rheumatoid arthritis and cardiovascular disease · Cardiovascular diseases (CVDs)...

Documents

Transcript of Inflammation, rheumatoid arthritis and cardiovascular disease · Cardiovascular diseases (CVDs)...