“Million Man Study” Finds Blocking Inflammation Long-Term Can Cause Collateral Damage

“Million Man Study” Finds Blocking Inflammation Long-Term Can Cause Collateral Damage

InflammationInflammation, one of the human body’s responses to trauma or other damaging stimuli, is a symptom largely regarded as something we would rather do without. Although inflammation one of the body’s protective mechanisms, a disproportionate inflammatory response can cause collateral damage, even in some instances causing potentially life-threatening symptoms such as in severe cases of influenza infections. Inflammation also plays a major role in a number of autoimmune diseases such as rheumatoid arthritis.

However, a massive new international Open Source study led by scientists at the University of Cambridge and published this week in the journal Lancet Diabetes and Endocrinology finds that inflammation may have a protective effect against cardiovascular disease.

This finding is an outcome of research enabled by a powerful new genetic tool that mimics certain anti-inflammatory drugs’ behavior — a technique that allows researchers to study effects of inhibiting the inflammation regulator interleukin-1 on an array of outcomes not yet investigated in clinical trials. Interleukin-1’s role in regulating the body’s inflammatory response is to set off a cascade of signals throughout the body against infection and other damage.

The Lancet Diabetes paper, entitled Cardiometabolic effects of genetic upregulation of the interleukin 1 receptor antagonist: a Mendelian randomization analysis is coauthored by the Interleukin 1 Genetics Consortium, which is composed of several dozen members representing many research and treatment institutions worldwide (the lengthy listing of contributors appears at the end of the research paper.

In order to investigate potential cardiovascular and other effects of long-term pharmacological interleukin 1 (IL-1) inhibition, the researchers studied genetic variants that produce inhibition of IL-1, one of the body’s master inflammation regulators.

To examine long-term implications of blocking this pathway, researchers from the Interleukin-1 Genetics Consortium developed a genetic score that combined the effects of two of these natural genetic variants, observing the effect of this score on key biological indicators of inflammation, and comparing it to the effect of anakinra. They investigated this score in relation to several medical conditions including rheumatoid arthritis and coronary heart disease by analyzing data from over a million individuals.

The investigators found that in individuals who carried the genetic variants giving them essentially naturally-occurring interleukin-1 inhibition, showed decreased risk of developing rheumatoid arthritis, an effect that was anticipated since anakinra is one of the drugs used to treat that disorder. However these variants were found to have no impact on risk of developing type 2 diabetes or ischaemic stroke. A surprise, however, was that they found interleukin-1-blocking increased a person’s risk of developing coronary heart disease, with a 15% greater risk of a heart attack in individuals who inherited a greater inherent tendency to block interleukin-1. Also-observed elevated levels of LDL-cholesterol (bad cholesterol) in these individuals may account for some of the increased heart attack risk — findings that provide new insights into clinical and biological effects associated with IL-1/ signaling, and that and could have implications for patients taking anakinra and related drugs.

The researchers also note that their genetic score was associated with increased abdominal aortic aneurysm risk; their findings showing that IL-1/ signaling inhibition could increase risk of both coronary heart disease and abdominal aortic aneurysm, and that findings from previous human genetic studies (including their own) have shown that inhibition of IL-6 signaling could actually reduce risk of these disorders. The scientists observe that taken together, these findings highlight the complexity of inflammatory factors that underly cardiovascular diseases, and that more studies are needed in order to better understand mechanisms that account for the divergent effects of these two interrelated inflammation pathways.

The investigators noted no evidence of associations between their genetic score and type 2 diabetes risk of, insulin sensitivity and other glycaemic traits, blood pressure, or adiposity, although they caution that their genetic study had substantially less power to assess type 2 diabetes and measures of glycaemia than it did to assess coronary heart disease and proatherogenic lipids, and that further studies may be necessary to assess any moderate effects, with similar considerations applying to the apparent null association between their genetic score and ischaemic stroke risk.

This study was huge, assessing accessed results from roughly 1 million subjects in a context of relevant diseases and traits worldwide, further supplemented with data from de-novo genotyping of a further nearly 100,000 participants. However, they did not have access to data for other potentially relevant tissues (eg, primary leucocytes or hepatocytes).

The researchers also observe that another limitation of their study “is that its findings can suggest only qualitative concordance of the effects on inflammation biomarkers of our genetic score and anakinra. Genetic and pharmacological IL-1 inhibition differ with respect to the magnitude and duration of inhibition, shown by the 510-times weaker effects that we observed of our genetic score on inflammation biomarkers compared with those of anakinra. Few people in randomized trials of anakinra have had IL-1Ra concentrations measured. In addition, whereas anakinra has mainly been studied in trials of people with pre-existing inflammatory disorders, we related our genetic score to inflammation biomarkers mainly in healthy people.”

Consequently, for reasons aforementioned, the data in this report are difficult to use as a benchmark for estimating the magnitude of potential cardiovascular hazard associated with dual IL-1/ inhibition, although, the robust but moderate associations that they identified in the study between genetic IL-1/ inhibition and cardiovascular risk don’t preclude a substantial clinical effect.

JohnDaneshProfessor John Danesh Professor of Epidemiology and Medicine, and Head of the 330-person Department of Public Health and Primary Care, at the University of Cambridge who leads the interleukin-1 consortium, comments: “Drugs such as anakinra are licensed for the treatment of inflammatory conditions including rheumatoid arthritis, but we know little about the long-term health consequences of blocking interleukin-1.Our approach was to use nature’s randomized trial to get answers currently beyond the resolution of drug trials. Our genetic analysis suggests, surprisingly, that blocking interleukin-1 over the long-term could increase the risk of cardiovascular diseases.”

FreitagDDr. Daniel Freitag, lead author of the study, also at the University of Cambridge, observes that “The common view is that inflammation promotes the development of heart disease; we’ve shown that the truth is clearly more complicated. We need to be careful that drugs like anakinra that aim to tackle rheumatoid arthritis by inhibiting interleukin-1 do not have unintended consequences on an individuals risk of heart disease.”

Dr. Freitag’s research focuses on understanding the role of inflammation in the aetiology of coronary heart disease, noting that there is substantial evidence that inflammation plays an important role in coronary heart disease development. Consequently, identification of culprit factors driving misguided inflammation in coronary heart disease is key to developing novel therapeutic strategies, in order to extend the current standard of care beyond that of cholesterol and blood pressure lowering medications.

Genome-wide association studies of coronary heart disease have identified several genetic loci with suspected role in inflammation, and Dr. Freitag uses large-scale genetic studies with information on inflammatory biomarkers (e.g. the INTERVAL study) and cellular phenotyping in order to elucidate the biological mechanism of genetic variants associated with coronary heart disease, as exemplified by his work on the interleukin-6 receptor.

WeissbergPProfessor Peter Weissberg , Medical Director at the British Heart Foundation, which helped fund the study, says: “It is important to remember that this is not a study of an anti-arthritis drug but a gene that can mimic its effects. The effects of a gene are lifelong, whereas a drug only affects a person while it is being taken. Nevertheless the study suggests that patients who are prescribed anakinra should have their cardiovascular risk factors carefully managed by their doctor.”

The research was funded by the Medical Research Council, the British Heart Foundation, the National Institute of Health Research (NIHR), the NIHR Cambridge Biomedical Research Centre, the European Research Council and the European Commission Framework Programme.

The University of Cambridge
The Lancet Diabetes
British Heart Foundation

Image Credits:
The University of Cambridge
British Heart Foundation

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