“Inflammaging” – Inflammation in chronic disease Dr Paul Kubler Rheumatologist Royal Brisbane & Women’s Hospital
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2 Learning Objectives
1) Describe the biologic processes involved with ageing and chronic disease.
2) Identify the markers associated with inflammation in chronic disease.
3) List the features of frailty and how they may impact management approach.
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What is Inflammaging and its clinical significance
“Inflammaging” refers to tipping of physiological haemostasis towards a chronic pro-inflammatory status with increasing age Many chronic diseases (& unhealthy lifestyle) share common pathology and immune features with ageing “Premature ageing” with chronic kidney disease, COPD, chronic heart failure Auto-inflammatory processes are evident in many diseases not classically considered to be autoimmune – atherosclerosis, type II diabetes mellitus and insulin resistance, osteoporosis, macular degeneration, Alzheimer’s disease Inflammaging is associated with significant increase in mortality & functional decline (muscle wasting); progressive pro-inflammatory changes linked to frailty Frailty refers to increased vulnerability to adverse health outcomes due to decline in physiological reserve & functional capacity; results in loss of independence; strongly associated with polypharmacy
4 Pathophysiology of Inflammaging
Similar cytokines expressed as seen with active rheumatoid arthritis – increased levels and action of pro-inflammatory cytokines such as Interleukin (IL) 1 and 6 + Tumour necrosis factor
C-reactive protein (CRP) is most readily available clinical measure of IL-6 – for non-autoimmune conditions, typically measured using high sensitivity assays (hsCRP) to capture small elevations between 2-5 mg/L
Frailty associated with reduced levels of anti-inflammatory cytokines – notably IL-10
Other immune changes with frailty – various T- and B-lymphocyte changes favouring pro-inflammatory status; increased apoptosis; increased endothelial permeability
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Secondary Prevention of Major Adverse Cardiovascular Events in high risk patients
Best studied example of role of inflammation in chronic disease Survivors of first acute MI have 18% incidence at 1 year of MACE (death, recurrent MI, angina, stroke, heart failure) – NHF Australia; 3 year recurrence rate of 40% 2 key concepts thought to explain recurrent risk – lipid hypothesis (well known to all) & inflammatory hypothesis of atherothrombosis Data from >20 studies indicate that hsCRP >2 mg/L is independent risk factor for first & recurrent MI and every 1 SD increase in hsCRP (as a measure of subclinical vascular inflammation) carries risk equal to 1 SD increase in BP and LDL cholesterol JUPITER Study (NEJM 2008) randomised 17,802 healthy patients with CRP>2 & normal LDL cholesterol (<3.4 mmol/L) to rosuvastatin or placebo (1:1) – stopped at median of 1.9 years because statin reduced MACE by 50% (50% decrease in lipids and also mean hsCRP reduced by 37%) – statins have anti-inflammatory action to explain part of their overall efficacy. However, does direct inhibition of inflammation reduce occurrence of MACE?
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8 CANTOS Study Design
Event driven RCT comparing canakinumab (CAN) with placebo in patients with previous MI (>30 days) & hsCRP >2 mg/L receiving standard of care treatment
>90% on lipid lowering drugs & anti-thrombotics; >80% on beta-blockers & ACE-I
CAN inhibits IL-1 beta, which is key cytokine for atherosclerosis
CAN (3 dose arms) or placebo given by SC injection every 3 months
Primary outcome = time to first MACE
Secondary endpoints = time to first MACE or hospitalisation & time to all cause mortality (including each type of MACE)
Dose dependent reductions in hsCRP (and IL-6) & no change in lipid profile
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CANTOS Study Results
At median follow-up of 3.7 years, 15% reduction in MACE – about 320/2200 in each CAN dose arm versus 535/3344 MACE episodes in placebo Result mainly due to 24% reduction in MI and 10% decrease in CVS death with divergent result evident by 6 months (no change in stroke and all cause death) Pre-specified subgroup of patients with hsCRP <1.8 mg/L after 1st dose (3 months) had 27% decrease in MACE (NNT of 50 at 2 years, 30 at 3.7 years) Effect came at expense of increased risk of serious & fatal infection Off target benefits – marked reduction in incident cancers (halved), especially lung cancer in current/past smokers (77% reduction) Link between low grade systemic inflammation and malignancy development (biologically, angiogenesis, invasion & metastases linked to inflammation)
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Cardiovascular Inflammation Reduction Trial (CIRT) – low dose methotrexate
Highly similar design to CANTOS except active treatment arm was 15-20 mg weekly of oral methotrexate (about 1700 patients in each group)
Main difference = didn’t mandate hsCRP>2 at baseline (median level of 1.5)
Stopped early at median of 2.3 years because no benefit with MTX added to standard of care treatment (MACE 3.4 per 100 PY)
MTX did not alter hsCRP, IL-6, IL-1 or lipid profiles
MTX resulted in greater proportion of liver function test abnormalities, reduced WCC, anaemia & non-melanoma skin cancers
Conclusion from both studies – inflammatory pathways are very important in atherosclerosis & need to explore approaches at inhibiting inflammation
12 Increased age & many chronic diseases are associated with chronic low-grade systemic inflammation
Frailty is the clinical picture based upon pro-inflammatory changes
Future strategies targeting restoration Conclusion – of physiologic haemostasis (dampening pro-inflammatory status) may unlock Inflammaging significant treatment advancement
As an example, CANTOS trial provides insight into how control of chronic low- grade systemic inflammation may improve major cardiovascular outcomes
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