Inflammation
Inflammation is the body's response to damage in a tissue, and it is closely linked to the immune system. It shows through five classical signs or through subtler symptoms, it is acute or chronic, and it runs as a spectrum through chronic disease and through normal processes such as ageing, digestion and exercise. Two drug classes are called the anti-inflammatories, although other drugs also have anti-inflammatory effects.
Aggression and response
Inflammation is the body's response to an aggression. An aggression is anything that disturbs a tissue or its cells, such as a viral, bacterial or fungal infection, trauma, a foreign body, chemicals or allergens. Ideally the response allows the injury to be removed: the cells ask for help, the immune system comes to the rescue, and the disturbance is sorted out. So the immune system is closely linked with the inflammatory response.
Some things can go wrong with the response. The immune system can overreact and mount a very strong inflammatory response to minor damage. It may not be possible to remove whatever caused the inflammation. And the inflammatory cascade, in which one element triggers another, which triggers another in turn, may be difficult to stop, and sometimes very hard.
Classical signs and the inflammatory process
Inflammation has five classical signs: warmth or heat in the affected area, pain, redness, swelling and loss of function.
The process itself can be described mechanically or biochemically. Mechanically, there is transient local vasodilation and increased capillary permeability, and leucocytes, monocytes and phagocytic cells leave the vessels for the surrounding tissue, which can suffer some damage, fibrosis or scar tissue. Biochemically, many molecules take part: prostaglandins, cytokines and interferons are among the more familiar ones, and histamine, bradykinin and serotonin, less often named in connection with inflammation, may also be present. The mechanical and biochemical changes serve to keep an open road for the cells of the immune system and to signal that the damage is still present, and together they keep the inflammation going. Ideally, as the threat is removed, the molecules disappear, the cells return to their places and the inflammation goes away. This happens most of the time, but not every time.
Acute and chronic inflammation
Acute and chronic inflammation differ mainly in persistence. Acute inflammation usually follows the classic steps: aggression to the tissue, an inflammatory response showing the five signs, removal of the aggression, and resolution. It usually lasts one to two weeks, as in a sore throat, a toe bumped on a table leg, an insect bite, a muscle sprain or a minor cut. Chronic inflammation lingers for some time, sometimes months or even years. It either persists after the initial cause has been removed, leaving the immune system in a permanent state of alert, or it starts with no apparent cause and persists over time.
The five classical signs are mostly linked to acute inflammation, although they may also be present in chronic inflammation. Chronic inflammation may not show the five signs and can have subtler symptoms instead, such as fatigue, gastrointestinal symptoms, skin rashes and diffuse pain. Because these symptoms are diffuse, patients very often have to struggle to have their complaints validated, and, with nothing specific to report, it is very hard for the doctor to diagnose what is wrong. In some diseases a chronic inflammatory aspect is apparent only after the other disease has been diagnosed.
Inflammation as a spectrum
Inflammation moves along a continuous spectrum: it is not a yes-or-no response, and it can have multiple aspects and facets. Between a basal state, in which all goes smoothly with the cell and the tissue, and a tissue damaged by or undergoing inflammation, there is a middle state, sometimes described as para-inflammation or as chronic inflammation.
Inflammation in chronic disease
Inflammation is an underlying process in many diseases. Rheumatoid arthritis, asthma, obesity and even cancer are examples of diseases with an underlying chronic inflammatory process. That does not mean they were caused by inflammation. Rheumatoid arthritis is an autoimmune disease, but some of its signs and symptoms can be and are explained by the presence of inflammation. Cancer, or certain types of cancer, can take advantage of the open road that inflammation creates to continue growing. Much research goes into deciphering the inflammatory processes in certain chronic diseases.
Inflammation in normal processes
The role of inflammation in several physiological processes intrigues many scientists. Ageing is associated with more disease towards the end of life, and that disease can sometimes be explained by inflammation. Some research has found that high levels of pro-inflammatory markers can predict the risk of certain age-associated diseases, and the relationship between ageing and inflammation is a big research topic. Digestion is another such process: in irritable bowel syndrome, eating certain foods, usually unhealthy ones such as sugars or trans fats, is associated with an inflammatory response, and the abdominal cramps, gas and bloating that follow are clearly triggered by it. Physical exercise can increase production of IL-6, an inflammation marker, but it also induces IL-10, a cytokine with anti-inflammatory properties. Moderate exercise is clearly good for health, but sports medicine looks into the role inflammation plays in injury prevention in elite athletes and in injury management.
Inflammation has a bad side, such as allergic reactions and the cytokine storms that by July 2020 were associated with a poor prognosis in COVID-19. It also has an important and useful side: it is very important for resolving damage, for growing muscle and even for forming the calluses that protect tissue from further damage.
Glucocorticoids and NSAIDs
The two main categories of anti-inflammatory drug are glucocorticoids and non-steroidal anti-inflammatory drugs (NSAIDs), and both are used to treat acute and chronic inflammation. Glucocorticoids are steroid hormones with potent anti-inflammatory and immunosuppressant actions, and they are an essential part of the body's natural stress response. They affect almost every organ and system, so their systemic use produces a widespread therapeutic effect but also numerous side effects. Their anti-inflammatory effect comes from stopping several types of cell, especially immune cells such as macrophages, monocytes, basophils and lymphocytes, from producing the pro-inflammatory molecules, such as cytokines and interferons, that they produce in response to a damaging stimulus.
NSAIDs are a diverse group of drugs with anti-inflammatory properties that inhibit the enzyme cyclooxygenase and so suppress the formation of prostaglandins, which are pro-inflammatory molecules. The enzyme has two isoforms, COX-1 and COX-2. Acetylsalicylic acid (aspirin) and naproxen show more selectivity for COX-1, diclofenac and celecoxib show more selectivity for COX-2, and ibuprofen shows no clear preference and can inhibit both.
COX selectivity matters for understanding NSAID side effects. COX-1 is constitutive: it is always present and catalyses reactions that produce molecules essential to homeostasis, such as the mucus that protects the stomach wall from acid. COX-2 is induced by disease and by pro-inflammatory stimuli, so it is present where there is inflammation. So it made sense to try to develop selective COX-2 drugs, and that has been done, but an exclusive COX-2 inhibitor is very hard to achieve because the two isoenzymes are quite similar at molecular level.
As a general rule of thumb, glucocorticoids have much more severe side effects, because they are hormones and affect the whole body through receptors in most organs. NSAIDs have somewhat milder effects, which is why an NSAID can be bought over the counter, but larger doses and especially continued use are associated with potentially fatal outcomes such as kidney failure and liver failure, and NSAIDs have known interactions with common medications. So NSAIDs are somewhat safer, but not completely safe.
Other drugs with anti-inflammatory effects
A drug that has an anti-inflammatory effect is not thereby placed in the anti-inflammatory category. Omalizumab is one example. It is a monoclonal antibody that binds specifically to IgE, which plays a critical role in the inflammatory process of diseases such as allergic rhinitis and asthma. So it acts as an anti-inflammatory only in specific instances, respiratory tract diseases with IgE involvement, and where these are not present it does not act. Because it is a monoclonal antibody, it cannot be called an anti-inflammatory drug, and it goes into the biological category.
Chloroquine is another example. It is an antimalarial, and by 2020 a bad one, because resistance to it had become widespread. A study from before COVID-19 found that chloroquine can significantly inhibit the systemic release of cytokines known to mediate the lethality of sepsis and systemic inflammation in humans. The study was in animals, so its result cannot be translated into treatment, but it shows that chloroquine can have an anti-inflammatory effect under certain circumstances. Chloroquine is still not an anti-inflammatory drug, because its anti-inflammatory effect is secondary to its antimalarial effect.
An anti-inflammatory effect and the anti-inflammatory category are confused because drugs are organised by classification systems. A classification system sorts drugs into buckets, by the organ a drug affects or by the type of effect it has, and the sorting gets complicated when a drug has more than one effect or acts differently in different organs of the body. Classification systems also vary across countries. There is an attempt to unify them, but as of 2020 even the WHO ATC system was not used as the primary classification system all over the globe, and it has drawbacks of its own. An anti-inflammatory drug refers to the two main categories, glucocorticoids and NSAIDs, while other drugs can have anti-inflammatory effects.