[ed. note: Michael Jorrin, who I like to call Doc Gumshoe, is a longtime medical writer (not a doctor) who writes about non-financial health and medical issues for us a couple times a month (past submissions can be found on his author page here). Like all of our authors, he chooses his own topics and his words and opinions are his alone. Enjoy!]
Okay, I needed a catchy title for this piece, but you already know the answer to that pretend-question. There are no archvillains, except maybe in grade D horror movies, and certainly not in disease management. But the temptation to pin that label on something such as inflammation, and then pick a “cure” that deals with that dire threat, is very substantial. It’s reassuring to fix in our minds that the chief cause of lung cancer is cigarette smoking, and if we avoid that particular archvillain, we won’t get lung cancer. Or that the chief cause of diabetes is drinking sugary soda pop. Or, as was doctrine for quite some time, that the chief cause of heart disease is feasting on red meat, eggs, and butter. Targeting an archvillain leads to an easy and quick solution, and minimizes the tedious and often confusing investigation into complex mechanisms and interrelations between external causes and internal physiologic processes.
Ascribing unitary causes to physical phenomena works quite well in the physical sciences, even when a secondary cause might also participate in the effect. In particular, it makes the investigation more transparent. Here’s an observed phenomenon. We postulate one specific direct cause. We then test it – does the phenomenon occur every single time when we apply that one specific direct cause? If it does, we’ve nailed it. If it only happens some of the time, or if it happens in the absence of that specific cause, then something else must be the cause. Our hypothesis has been proved false. Then we have to keep going until we find the precise action that always produces that effect. And then we dig until we figure out exactly why that action produces that effect. That works in the physical sciences, but not so well in the biological sciences.
In living organisms, a single cause can have multiple effects, and in some cases, can have effects that tend in contrary directions. For example, we know that diabetes can lead to high levels of glucose in the bloodstream, and those high levels of glucose can lead to serious consequences, including blindness, limb amputations, and heart disease. But we absolutely and unquestionably require glucose for life, and it has to be transported throughout the body in the bloodstream. So the issue is not whether glucose in the bloodstream is the archvillain. The question is how much is too much, and what can be done to avoid getting to that “too much” marker.
We also know that cancer occurs as a result of errors in the transcription of genetic material in stem cell division. Every time a stem cell divides, there is a chance that it will make a mistake, such that the “offspring” cells are not exact copies of the “parent” cell. These inaccurate cell divisions are essentially random mutations, and the great majority of these mutations will be meaningless – the new cells will simply die or fail to replicate. In a few cases, the mutations will be beneficial, conferring some evolutionary advantage, and these mutations may become part of the species genome. And in some cases, the mutation will lead to cancerous cells, which continue to replicate and increase in number. So, we cannot say that mutations in stem cell division are the archvillains that cause cancer, and that if we could prevent those mutations, cancer would be prevented. It is also those mutations that drive evolution, and without them we – and most of the rest of living beings – would not have come into existence.
The same principle applies to inflammation. Although we are increasingly aware of the role of inflammation in a number of different pathologies, we also know that inflammation is an essential and integral part of the healing process. This knowledge is far from new. Hippocrates, in the 5th century BC, used the term edema in his description of the healing process, and Aulus Celsus, who lived just around the beginning of the first century AD, described the four signs of inflammation as rubor (redness), tumor (swelling), calor (heat), and dolor (pain). Inflammatio means “setting on fire,” and everyone one who has sustained just about any kind of injury knows what that feels like.
Here’s a look at the inflammatory process. You sustain an injury, not severe enough to send you to the emergency room, but definitely painful – let’s say you scraped your leg while climbing over a stone wall. The scrape only slightly broke the skin, and there was just a bit of bleeding, but the impact was painful. This event triggers a sequence of events, beginning with a considerable increase in local blood flow. The capillaries become more permeable, resulting in the build-up of fluid in the space in and around muscle and nerve fibers. A large number of cells of many different types are summoned to the area, and these immediately go to work to clean up the mess. Damaged tissue is devoured and carried off by macrophages and neutrophils, and the process of replacing dead cells with new cells begins. The entire area of the injury is walled off, so as to prevent the spread of any invading pathogens. And, yes, even though your skin was only slightly broken, pathogens certainly did enter. That’s because your skin (no matter how scrupulous you are about personal hygiene) is colonized by immense numbers of microbes of various kinds, especially staphylococci, which are primed to attack your cells. The inflammatory process is highly efficient at preventing the spread of staph infections that invade in that way. Once the infection has been contained by this walling-off process, your own immune system will wage war on the invading pathogens, and in most cases, your immune system will achieve victory in this war.
One could say that the reason the inflammatory process results in redness, swelling, heat, and pain, is that inflammation confines and concentrates the injury to a relatively small area, like waging an all-out war on a single small battlefield.
And, naturally, as in any war, there is collateral damage. If the inflammation occurs as a result of a bruise or a minor skin infection, the collateral damage will be minor. But if, on the other hand, inflammation occurs as a response to some type of internal disruption or as a reaction to certain types of stimuli, the collateral damage can be considerable. And, in some cases, inflammation seems to occur spontaneously, not in response to injury or a specific stimulus. In those cases, the inflammatory process in itself constitutes the disease.
Mediators of inflammation
The very word “mediators” in that context is a bit confusing, at least to the non-medical reader. Most people think of mediators as the folks who try to resolve differences between two warring parties, like the opposite sides of a lawsuit or labor unions versus management. In medical terms, the mediators are the agents that trigger the response, period. There is no give-and-take.
The numbers of inflammatory mediators are legion. They can be relatively simple molecules or living cells. Some of the ones whose names most people will recognize include histamines, serotonin, prostaglandins, bradykinins, a number of cells carried in the bloodstream such as macrophages and neutrophils, B-cells, T-cells, lymphokines, caspases, and many, many others. A number of factors also stimulate generation of granulocytes and monocytes by the bone marrow; these include tumor necrosis factor (TNF), which is one of the drivers of rheumatoid arthritis (RA).
A large category of inflammatory mediators are classified as cytokines, although by no means are all cytokines pro-inflammatory. I attended a meeting of the American College of Rheumatology where a scientist attempted to present an overview of the cytokines. Rheumatology, by the way, is the branch of medicine that studies inflammatory diseases; “rheum” being the old-timey word for the wet discharge from the eyes or nose, and also for the substance that accumulates in areas affected by inflammation. Thus “rheumatism” was the word for what is now called arthritis. Rheumatologists are the medical specialists that also treat other diseases of the immune system, such as inflammatory bowel disease (IBD), Crohn’s disease, psoriasis, and ankylosing spondylitis.
The presenter began with a simple slide that mostly showed the interleukins, a well-studied group of cytokines, some of which are clearly pro-inflammatory and some, quite the contrary, are anti-inflammatory. There were about twenty on that slide. He then went on to show a slide with about one hundred cytokines on it, in different groups, in boxes connected by arrows. Then he put a slide on the screen that had so many cytokines on it that no one could possibly read one single name. He admitted that it was possible and even likely that many of the cytokines listed on the slide were identical. For example, a scientist in a lab in Cambridge might have identified this one, and a scientist in Palo Alto might have identified that one, and they were the same cytokine, but no one had spotted it. The audience erupted in laughter.
I put in that little story not to make the Gumshoe Tribe erupt in laughter, but to illustrate how the research goes. Scientists see something going on, and they investigate all the different particles – individual molecules or cells – and try to determine what roles they are playing in what’s going on. It’s easy to see what macrophages are doing. They are huge (comparatively) and one can actually watch them in action. Besides cleaning up the mess that occurs when pathogens invade and create an infection, macrophages are capable of pumping out many different small molecules that also contribute to the inflammatory process.
The small molecules such as cytokines are a different matter. Scientists detect the presence of such a molecule in association with an inflammatory process, and then they try to figure out what its role might be, if any. Cytokines do not engulf and gobble up bacteria or cells. Instead, they may interact chemically with receptors on the surface of these bodies, or they may pass through openings in their coating. These actions depend on the precise shape of the molecules and on their binding properties. Sometimes a molecule fits neatly into receptors on the surface of a cell, thereby inactivating the receptor. The activity of some of these molecules may be conceptually simple, but detecting and understanding that activity is far from simple.
Consequences of inflammation beyond the known autoimmune diseases
The evidence for this has been around for about 30 years. Before that, arthritis, at least, was thought to be a relatively benign disease. Old people with arthritis could hobble around with canes, or in the most severe cases, could get around on wheelchairs, but arthritis, whether osteoarthritis or autoimmune rheumatoid arthritis, didn’t kill people.
That notion began to be exploded in 1984 when a rheumatologist named Theodore Pincus caused a considerable stir at an ACR meeting when he reported that in a group of 75 patients with RA who had been tracked for 9 years, the mortality rate was about the same as in patients with heart disease blocking three coronary arteries – i.e., really severe disease. By the mid 1990s, there were lots of data showing that, in fact, rheumatoid arthritis did kill people – or, at least, that patients with rheumatoid arthritis were more than twice as likely to die as people of the same age in the general population.
But how on earth did this disease, which apparently affected only the joints, result in fatalities? It had been observed that persons with RA tended to have higher incidences of cardiovascular disease than those without RA, and it was conjectured that a possible reason for this was that RA patients were much more limited in terms of physical activity. In the view of some, lack of exercise was the culprit that was consigning RA patients to a premature death.
That line of reasoning appears to be sound, up to a point, in that physical activity certainly does contribute to cardiovascular health, and inactivity does the opposite. But several kinds of data began to appear about 20 years ago that suggested a different mechanism. Some of the data was statistical and some was the result of close scientific observation.
The mid-1990s, you will perhaps remember, were an era in which elevated cholesterol had been confirmed, in the view of most cardiologists, as the essential cause of coronary artery disease. It had been established that atherosclerosis consisted of cholesterol deposits in the arteries, and the recent 4S trial had conclusively shown that in patients with heart disease, statin treatment greatly reduced the incidence of significant cardiac events such as heart attacks and obstruction of coronary arteries requiring revascularization. In other words, problem solved: cholesterol is the culprit.
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Some data got in the way of this unitary explanation. One was that a certain number of individuals who had “normal” cholesterol levels nonetheless experienced the same kind of cardiac events. Paul Ridker, a cardiologist at Brigham and Women’s hospital and Harvard Medical School, found that these persons, who did not have cholesterol at levels that had been associated with heart disease, did have elevated levels of C-reactive protein (CRP), which for more than 80 years has been known to be associated with generalized inflammation.
At about the same time, another Brigham and Women’s/ Harvard cardiologist, Peter Libby, learned that cholesterol didn’t just swim around in the bloodstream. It actually worked its way into the arterial wall. This appeared to constitute a kind of insult to the arterial wall and provoked an inflammatory response, which in turn resulted in the formation of blood clots. It was these blood clots that, at least in some cases, blocked coronary arteries, causing heart attacks, and also blocked cerebral arteries, causing strokes. Peter Libby coined the term “vulnerable plaque” for plaque affected by inflammation that was prone to clot formation.
(Now, lest the above information confirm the views of those who claim that it’s not cholesterol but inflammation that is the archvillain, let me insert a modest demurral, viz, lots of factors besides inflammation can cause the formation of blood clots. Blood tends to clot all on its own, and conditions such as atrial fibrillation, in which blood pools in the heart antechambers, or venous thrombosis, favor the formation of blood clots.)
Paul Ridker followed up his discovery about CRP with a study in which it was shown that treatment with statins not only lowered cholesterol levels, but also lowered levels of this inflammation marker. And in 2008, Ridker presented the results of the JUPITER trial at the New Orleans meeting of the American Heart Association. (Ridker P et al. New Engl J Med 2008;359:2195-2207) This large trial (17,802 subjects) compared two cohorts of persons, all of whom had normal cholesterol levels. One group of 8,901 subjects received 20 mg. of rosuvastatin daily, and the other, also 8,901, got the placebo. The primary endpoint, was incidence of signal cardiac events consisting of nonfatal myocardial infarction, nonfatal stroke, unstable angina, or death from cardiovascular causes. Subjects receiving rosuvastatin experienced 142 such events, while those on placebo experienced 251 events. Although the reduction was small in terms of absolute risk – about 1.2% – it was considered highly significant, both statistically and in terms of implications for treatment. As a result of these results, the trial was stopped after a bit less than two years because the sponsors considered it unethical to continue a large cohort of patients on placebo when significant benefit had been demonstrated in the treatment arm.
The subjects in the JUPITER trial had baseline LDL-cholesterol levels of 108 mg/dL and CRP levels of 4.2/4.3 mg/L. Those LDL-C levels are considered desirable in patients with no established cardiac risk factors. CRP levels > 4.0 mg/L are now considered elevated and associated with significant risk.
The JUPITER trial cannot be said definitely to demonstrate that lowering CRP was the determining factor in reducing the numbers of signal cardiac events. Treatment with rosuvastatin not only reduced CRP from the baseline level to about 1.8 mg/L, but also lowered the LDL-C levels from a pretreatment 108 mg/dL to 55 mg/dL, so the benefit may have in part been due to the LDL-C reduction. But the reduction in that marker of inflammation was certainly an eye-opener. At the AHA meeting, Steven Nissen of the Cleveland Clinic was quoted as follows: “…if a patient comes to me with normal LDL-cholesterol levels, I tell him to keep doing what he’s doing and to go about his business. Now, what happens when that same patient arrives in my office and I know his CRP is elevated? I know that treating him with intensive statins therapy, despite what the guidelines state, is going to cut his risk of cardiovascular morbidity and mortality in half.”
In further analysis of the JUPITER trial results, Ridker came to the conclusion that elevated CRP levels signal more heart disease risk than do elevated LDL-C levels, although the highest risk is in patients in whom both of those are elevated. CRP levels below 1 mg/L are related to low risk, between 1 and 3 mg/L to medium risk, and higher than 3 mg/L to higher risk. The chart below traces the relationship between LDL-C and CRP levels and cardiac risk over an 8-year period.
Another graphic presents a similar conclusion, that the highest level of risk is in those persons with elevated levels both of LDL-C and CRP.
The LDL-C levels considered as low in these graphics are based on the guidelines promulgated by the National Cholesterol Educational Program (NCEP) Adult Treatment Panel III in 2001, which used 130 mg/dL as the cutpoint for borderline high LDL-C. More recently, many clinicians have argued for a target LDL-C reading of about 100 mg/dL in individuals with no specific cardiac risk factors, and below 70 mg/dL in persons with one or more risk factors. Thus, the data above could be criticized as minimizing the risk presented by elevated levels of LDL-C.
Although the data as presented strongly suggests that inflammation is a greater risk factor for heart disease than elevated cholesterol, it is far from presenting satisfactory vindication for the supporters of the view that inflammation is the whole story and cholesterol is a mere ruse cooked up by the pharmaceutical industry as a way to push their products. After all, the JUPITER trial demonstrated that a statin lowered both CRP and LDL-C, and in so doing conferred significant reductions in heart disease risk in a cohort of persons who, according to the standards at the time, were not considered to have any heart disease risk at all.
Managing heart disease risk in patients with RA and other inflammatory diseases
The JUPITER trial, and several others, offered strong evidence that treating RA patients with statins, even when their LDL-C levels would not have – at least according to guidelines – led to such treatment, significantly reduced their risk of cardiovascular events. The benefits of other forms of treatment are somewhat more questionable.
The usual progression of treatment for persons affected by arthritis is from NSAIDs (non-steroidal anti-inflammatory drugs) such as ibuprofen, naproxen and others, through DMARDs (disease-modifying anti-rheumatic drugs) such as methotrexate (MTX), and ultimately biologics, such as tumor-necrosis factor inhibitors (TNFi’s) and agents that affect one of the pro-inflammatory cytokines. These individuals are also sometimes treated with glucocorticoids, although not usually on a long-term basis.
It is in evaluating the effects of these forms of treatment that the vista gets murky. For many individuals affected by arthritic joint pain, the priority is pain management. Quite reasonably, they want to be able to do whatever it is they need to do, or enjoy doing, without the pain that accompanies movement. It is common for persons with arthritic pain to go for a considerable time without consulting a physician. Joints hurt? Pick up a bottle of some kind of pain killer from the drugstore.
The NSAIDs do mitigate inflammation, and to the degree to which they make it easier for the individual to remain reasonably active, they may slow the progression of factors that contribute to cardiovascular disease. But some NSAIDs do increase the risk for both MIs and strokes. In June of 2015 the FDA beefed up the warning label on prescription NSAIDs, and various professional groups have urged physicians to prescribe NSAIDs at the lowest possible dose and for the shortest possible time. This does not mean that if you wrench your shoulder or sprain your ankle you should stay away from taking an NSAID; what it means is that regular high doses of NSAIDs for patients with chronic pain is not a good idea.
Similarly, there is evidence that prednisone is linked with higher cardiovascular risk. Again, that does not translate into “never prednisone,” just that a steroid as regular treatment for a chronic inflammatory ailment is bad medicine.
The methotrexate story is contradictory. Some evidence supports the view that MTX reduces cardiovascular events in RA patients by around 20% (Micha R et al. Am J Cardiol 108: 1362–1370). Other evidence points in the opposite direction. An analysis of the CORRONA registry, including data on more than 10,000 patients with RA, found that treatment with MTX in those patients did nothing to reduce their risk of cardiac events. (Greenberg JD et al. Ann Rheum Dis; 2011;70:576)
However, the same analysis found a considerable benefit in patients who were given TNF inhibitors. The incidence rate for composite cardiovascular events in patients who used TNFi’s was 2.93/1,000 patient-years of exposure, compared with 6.73/1,000 patient-years for methotrexate and 7.51 for the reference group of patients who used DMARDs, a 61% reduction in relative risk. Again, part of this benefit may be due to the increased capacity for activity and movement in the patients taking TNFi’s. Some observers attribute the benefit to specific anti-inflammatory effects in the vascular system, such as stabilization of arterial plaques and improvement in vasodilation, which facilitates blood flow.
Similar effects have been observed with biologics used in treating psoriatic arthritis, inflammatory bowel disease, Crohn’s disease, and others.
The role of inflammation in other medical conditions
Inflammation occurs in other parts of the body than those in which the diseases discussed above manifest themselves, i.e., the skin, the joints, the intestines, or the heart. Inflammation in the pancreas may contribute to diabetes, and inflammation in the brain may be a factor in Alzheimer’s disease. In both cases, the inflammation appears to be purely local. There is no good evidence that the rheumatic diseases are causally linked with either diabetes or Alzheimer’s disease.
Some observers have made the case that persons with RA have a higher incidence of diabetes. The weight of the numbers does not support that conclusion. Simply put, the percentage of RA patients with type 2 diabetes (T2DM) is roughly similar to the percentage of people in the general population with T2DM. In other words, lots of people with RA and other rheumatic diseases have T2DM, but so do lots of people who do not have those diseases.
But this does not mean that inflammation is not a factor. The question is whether inflammation in the pancreas is the cause of T2DM, or whether stress on the system of insulin receptors resulting in greater demand on the pancreas is what triggers the inflammatory response. On the other hand, type 1 diabetes is recognized as an autoimmune disease; inflammation by definition is part of the pathology.
It has been suggested by some that glucose on its own is proinflammatory. This is more than a bit paradoxical. After all, we live on glucose; it is our principal source of energy. According to this doctrine, it’s okay to consume foods that do not contain sugar or simple carbohydrates, such as whole grains. We can then convert those into glucose and continue on our merry way. But sugars and refined grains are verboten.
A prominent spokesman for this point of view is Mark Hyman, MD, founder of the UltraWellness Medical Center and director of the Cleveland Clinic Center for Functional Medicine. A book he co-wrote, The Daniel Plan, was a New York Times best-seller in 2013. His formula for curbing inflammation includes strict avoidance of sugar, caffeine, beans, all dairy foods, all foods containing gluten, and all processed foods. Instead, he proposes a variety of supplements including fish oil, probiotics, and several vitamins. He strongly favors turmeric, which contains curcumin.
We’ve discussed turmeric/curcumin in these posts before. (See “Somewhere Between ‘The Next Aspirin’ and ‘An Ingredient in Curry'”) Curcumin certainly does possess anti-inflammatory properties. The problem is that we cannot absorb enough of it in its natural form – i.e., from turmeric – to have much effect.
Hyman may be an effective physician in terms of managing the treatment of individual patients one-on-one. But my skepticism index regarding his one-size-fits-all proposal for achieving health by curbing inflammation through a strict diet based on supplements is as high as could be.
Hyman, by the way, is on the record as opposing the measles-mumps-rubella vaccine on the grounds that it leads to autism. Need I say more?
My own conclusion on this subject is, how shall I put it? – inconclusive. There’s no doubt that inflammation is an important factor in many diseases. But at the same time, it’s an immune response, and we absolutely require those immune responses to survive. Immune responses are what kill newly-formed cancer cells every day of our lives. Cancer researchers are currently investigating ways to harness immune mechanisms for cancer treatment. And, of course, without inflammation, healing would not take place.
But it is certainly possible that mechanisms that carefully dial down the immune reaction leading to inflammation may be identified and employed to reduce the impact of several diseases. The biologic agents used to treat RA essentially do just that. The simple solutions – diets and supplements – are not supported by any evidence. Too bad!