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The new hypothesis that is revolutionising medicine

 

Inflammation has lately become one of the hottest topics in current medical research. Last month, a breakthrough trial presented at the congress of the European Society of Cardiology looks like putting the so-called ‘inflammation hypothesis’ in chronic disease firmly on the map.

The US-based CANTOS trial randomised 10,000 patients who had already survived a myocardial infarction to a drug called canakinumab, which targets the inflammatory pathway interleukin-1 beta but does not affect cholesterol levels. The researchers found a 15% reduction in the risk of myocardial infarction or stroke, and a 30% reduction in the need for a major intervention such as angioplasty or bypass surgery, compared with usual treatment.

The trial won’t be changing clinical practice in heart disease any time soon, not least because canakinumab is a phenomenally expensive drug, and one that also has complex side effects. But the results are nonetheless hugely important, because for the first time researchers have found hard evidence for the role of inflammation in chronic heart disease, independent of lipid levels.

The principal investigator Dr Paul Ridker, a cardiologist at the Brigham and Women’s Hospital in Boston, said the findings have far-reaching implications.

“It tells us that by leveraging an entirely new way to treat patients – targeting inflammation – we may be able to significantly improve outcomes for certain very high-risk populations”.

Another fascinating finding from the study was a substantial reduction in the incidence of lung disease in patients randomised to canakinumab, suggesting that inflammation may play a role in cancer growth as well.

This finding, Dr Ridker said, will “turn the way people look at oncology upside down”.

Heart disease and cancer are hardly the only areas where researchers are looking at how reducing inflammation might reduce risk. Diabetes, HIV, neurodegenerative diseases such as Alzheimer’s or multiple sclerosis, and even depression have been the subject of research.

A study published just this month looks at how inflammation may be implicated in the pathogenesis of Alzheimer’s disease. The brains of people with Alzheimer’s typically have abnormal deposits of two proteins, amyloid beta and tau. US researchers from the University of North Carolina have shown in cell cultures how accumulation of amyloid beta can trigger an inflammatory response, which in turn damages neurons. The type of neuronal damage leads to the formation of bead-like structures containing abnormal tau protein; similar structures as these are found in the brains of people with Alzheimer’s.

Another study has shown that people with fattier, more pro-inflammatory diets tend to have smaller brain volumes and worse cognition.

Brain inflammation may also play a role in depression, according to several recent studies which found high levels of inflammatory markers in the brains of people suffering from the condition. A trial is currently enrolling to trial a biologic called sirukumab for people with major depressive disorder. This drug was initially developed to treat people with rheumatoid arthritis, but when it was trialled in that area, researchers found an interesting side-effect: patients randomised to sirukumab reported having improved moods and less depression.

Targeting inflammatory pathways in the immune system is clearly a promising avenue for drug development, but it’s far from straightforward: dampening the immune response can have dangerous consequences and can promote infection.

For example, sirukumab, the drug being trialled for depression, was recently knocked back by the FDA as a treatment for rheumatoid arthritis, as it had been implicated in several deaths from serious infection and heart disease. Similarly, in the CANTOS trial for heart disease, several deaths from serious infection were reported with canakinumab.

Dr Ridker, the lead researcher on the CANTOS trial, is now enrolling for a second trial, this time testing the anti-inflammatory effects of the immunosupressive drug methotrexate, which has long been used in the treatment of rheumatoid arthritis and whose safety profile is well understood.

Patients will be tracked not only to see if methotrexate lowers risk of cardiovascular events, but also if it reduces cancers. Time will tell, but one thing is certain: the “inflammation hypothesis” is now very much a fixture in the medical research firmament.