“Inflammaging” – 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 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 – , 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 reduced MACE by 50% (50% decrease in lipids and also mean hsCRP reduced by 37%) – 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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