Inflammation has long been recognised as the hallmark of injured tissues, such as a splinter in the finger, or invading pathogens like bacteria or viruses, where our immune system mounts its defense mechanism with white blood cells and related chemicals to defend our body.

Nonetheless, biomedical and clinical studies in the past decades discovered that, in addition to being our natural defence mechanism, inflammation plays a crucial role in the pathophysiology of many non-infectious diseases. Specifically, the inappropriate activation of the inflammatory mechanism may be the underlying factors which induce the development of numerous pathological conditions.

In addition, inflammation has been strongly implicated in cancers as cytokines produced by chronic inflammation may contribute to the creation of a microenvironment that is conducive to tumorigenesis or metastasis.

The culprit of diseases

The idea where inflammation is the source — or at least one of the culprits, of many diseases — has stirred tremendous interest in the scientific world. One of the latest evidence indicative of inflammation’s central role in diseases was the CANTOS study by Novartis.

The trial looked into the effect of canakinumab in the prevention of recurrent cardiovascular events among patients who suffered from a prior heart attack and inflammatory atherosclerosis. According to Novartis, about 40% of heart attack patients are still at a higher risk to develop a second attack, stroke, or death due to high-risk inflammatory atherosclerosis.

Canakinumab acts mainly through the inhibition of interleukin 1 beta (IL-1β), which is a key inflammatory cytokine that underpins the progression of inflammatory atherosclerosis.

The drug was hailed as “the first and only agent which has shown that selectively targeting inflammation significantly reduces cardiovascular risk in patients who have had a prior heart attack and have an increased cardiovascular inflammatory burden”.

Inflammation and lung cancers

The CANTOS study also reported a significant reduction in lung cancer rates among those who were randomised to receive canakinumab.

Lead investigator of the study, Dr Paul Ridker, explained. "[The] NLRP3 pathway that we study, increases your risk of other kinds of cancers, including non-small cell lung cancer… It's also been hypothesised that inflammation of the tumour microenvironment plays a role in the growth and metastases of tumor — though, not necessarily triggering the tumour to grow in the first place."

Although this finding excites medical researchers and oncologists alike, Dr Ridker cautioned that they have yet to find out how to translate the study results into the actual treatment algorithm.

If anti-inflammatory is the answer — then?

The collective evidence available in the literature points towards anti-inflammatory medication as the answer to many diseases, whereby uncontrolled or inappropriate inflammation may be the underlying contributing factor. Nonetheless, the biology of inflammation is exceptionally complex and intertwined with many other vital physiological processes. It will be naive of us to solve the issue with a brute force – the “sledgehammer”-style approach.

The inflammatory cascade consists of numerous cytokines and chemokines that interact with, and subsequently affect each other in an intricate network whereby the balance between pro- and anti-inflammatory mediators is critical. Many of these cytokines and chemokines are themselves crucial to our normal physiological functions. A blanket approach that indiscriminately dampens the inflammatory responses is bound to trigger more problems than it can solve.

As stated by Dr Clay Semenkovich, chief of endocrinology, metabolism and lipid research at Washington University, “The problem is if you block inflammation, you’re blocking a primordial mechanism by which we are protected from the organisms that share the planet with us.”

Not all anti-inflammatory drugs are equal

Moreover, anti-inflammatory drugs may not function in an identical manner. Individual genetic makeups of each patient will affect the rate and extent of absorption, metabolism and removal of anti-inflammatory drugs from the body; thus introducing substantial variations in drug effects among different populations.

Side-effects are another aspect worth taken into consideration. In the CANTOS study, it was noted that there were several fatal infections, which could be attributed to the suppression of patients’ immune system. As such, the researchers did not observe a significant difference in overall mortality — probably due to the increase deaths from infection had cancelled out the number of lives saved by the drug.

Additionally, some researchers argued that the long treatment period required for an anti-inflammatory drug to work its wonder may not be favourable, given the side-effects.

As a conclusion, the inhibition of any critical component of the inflammation cascade, the "master switch" that turns inflammation "on" or "off", will almost always trigger a compensatory signaling. As discussed earlier, inflammation is a complex biological process consisting of different pathways that is capable of counterbalancing each other. Therefore, the effect of an anti-inflammatory drug may subsequently trigger another pro-inflammatory process which nullifies the drug's effect in the end.

The bottom line

Although there are considerable challenges in our effort to elucidate the complete picture of inflammation and its effect on disease progression, the progress we’ve achieved in this field opens up exciting avenues for drug discovery and development. Only time will tell what our future holds — when we have unravelled the mystery of inflammation. MIMS

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