Rheumatoid Arthritis (RA) is an autoimmune disease that principally attacks joints. It causes a lot of trouble, attacking about half a percent of the population in the US.
It causes characteristic changes in the bones. Key point: it is vanishingly rare in Old World skeletons before the 17th century. Those changes, however, been seen in some pre-Columbian Amerindian skeletons [work by Bruce Rothschild].
The obvious explanation is that RA is caused by some pathogen that originated in the Americas and later spread to the rest of the world. Like the French disease.
However, someone [Jim Mobley, at Pfizer] ] came up with the idea that selection for protection against tuberculosis leads (a few generations later) to overactive immune systems that cause rheumatoid arthritis. A number of people, including Bruce Rothschild [who is a great guy] , seem to have bought into this idea.
There’s no way that idea can be right. Mobley talks about 200 year lags between TB epidemics and high frequencies of RA: that’s not nearly long enough. Selection doesn’t work that fast. There are other issues hat make this notion implausible, but that’s enough.
Genetics does of course influence susceptibility to RA. So what? Is that a useful line of inquiry? Shit no: you want to find key causes, factors in the absence of which disease never occurs. Then you can prevent the disease or even cure the sucker, rather than medicating the poor guy till his money runs out.
A pathogen is overwhelmingly likely to be the cause. If medicine researchers ate their Wheaties, they’d be hearing things:
Till a voice, as bad as Conscience, rang interminable changes On one everlasting Whisper day and night repeated -- so: "Something hidden. Go and find it. Go and look behind the Ranges -- "Something lost behind the Ranges. Lost and waiting for you. Go!"
I did see the recent note about gut bacteria maybe being the cause. But I’ve been saying this for a long time. I mentioned this in our book, and on the blog.
It’s time for someone to run and find out.
West Hunter 
So, another case of “if the disease is complicated and hard to treat, then the cause must be very complicated, and certainly not something simple like a bug”? Time for more hand washing, and certainly more boot wearing? Good post.
There’s a rising theory among Sarcoidosis experts that a mycobacterial infection, once cleared, leaves behind antigens that can keep activating some people’s immune system, leading to sarcoid granulomas. If that is true, it could apply to RA as well.
I like your line of reasoning, it seems quite possible. I’ve been told that RA runs in my wife’s family. My mother in law was in terrible pain the last twenty years of her life because of RA, I wouldn’t wish that on anybody. But of course Greg could be right, it could just be because they are genetically susceptible to (Jack’s Idea) an immune system reaction from some bacterial infection. This is a crippling disease, incredibly painful in it’s advanced stages, that attacks around 1.3 million Americans. One would think medical researchers could have and should have followed the causation trail back to it’s real source by now. But I guess that is Greg’s whole point.
“gut bacteria maybe being the cause”
Fecal transplant treatment might be used as investigation.
I take it that such a large stock of “Old World skeletons before the 17th century” have been examined that the case is very strong? Is there any chance that, say, not enough Sub-Saharan African skeletons from before the 17th century have been examined that we can rule out the Atlantic slave trade as a source, rather than the Amerindians? Still, the conclusion would be unchanged: pathogen.
On second thoughts, the Muslim slave trade became a big deal long before the Atlantic slave trade, so if SSA were the source, it might show up in North African or Middle Eastern skeletons before the 17th century. Have enough of them been examined for the period, say, 700AD-1500AD?
But they seem to have already found evidence of the disease in native american skeletons prior to colonization. This bacteria could have also been present in other parts of the world, but then it would likely be coming from both the Americas and Africa etc- I can’t think of a reason why it would not come from one place it was present and not another.
Maybe you could compare skeletons from conquistators in the Americas with skeletons of say Russian people who were nowhere near the Americas from the 16h century? Then you would have to again compare this with contemporary rates of RA in Spaniards and Russians to see if there is a difference in the 16th century and now.
Still, that wouldn’t necessarily indicate disease progression because diseases can travel extremely fast, especially if they are non lethal over a short time frame. I think the Bubonic plague swept through Eurasia in less than one generation, so even if the disease originated in the Americas, it is possible that it could get all the way through Europe so fast that you wouldn’t even observe a difference in RA rates between Spaniards and Russians by the end of the generation that first encountered the disease
Human beings seem to resist the notion that microorganisms and tiny vectors have much effect. Walter Reed apparently had little trouble getting volunteers to be human guinea pigs. The big strong men couldn’t see how little bugs could possibly hurt them.
As it happens I’m reading a biography of Belisarius right now. There is a lot of discussion and analysis of the tactical abilities of the general and the plotting and scheming of his and Justinian’s wife. But the whole attempt to reestablish the Roman Empire in Italy took place during a bubonic plague epidemic. The author mentions disease from time to time but then he gets back to the what he sees as the real issues. Issues that revolve around human beings.
The hit movie ‘Gladiator’ similarly just mentions in passing the Antonine Plague(s) that were decimating Rome at the time. The focus of the drama is on the relatively inconsequential actions of Aurelius and Commodus.
Right out of grad school I got a consulting job working on Nixon’s War on Cancer. Cancer was not conceived as infectious in those days. It was thought of as vaguely environmental. There were ‘factors’ that influenced cancer in some quasi-mysterious correlative fashion. Maybe that’s why everyone on our project was hired for their math ability not for their knowledge of medicine – incredible as that now seems.
People still psychologically seem to resist the idea that little invisible critters can harm big strong people. People know about Pasteur, Koch and germ theory but they never liked that theory, and they insist that it has no relevance today for poorly understood ailments.
Yes, historians tend to mention only in passing vast epidemies like the Antonine Plague ir the Black Death that killed one third of Europe’s population. But “the actions of Aurelius and Commodus” were not inconsequential, the plague was. Humanity always lived near the Malthusian extreme, and for example the sudden disappearance of half of English parish priests (and tenured professors…) had no consequences as they were replaced in no time, and the Plague had little economic or political impact.
It had a pretty big English impact IIRC as it knocked the old feudal order on the head, people left their lords for better money elsewhere and their new lord, who they served for payment, would keep schtum because there were a lot fewer workers available.
https://www.economist.com/blogs/freeexchange/2013/10/economic-history-1
“Manorial records of the late 14th century are full of despondent reports. Some lords abandoned their holdings. Others were forced to surrender to tenants on almost any terms the peasants cared to offer. Workers were paying lower rents—and had fewer obligations to their lord. Labour services faded out, to be replaced by purely monetary arrangements between employers and employees. These arrangements became customary, and led to the dissolution of feudalism by the 16th century. Higher labour costs incentivised employers to improve economic efficiency”
Patrick Boyle,
I share your frustrations. I find the topic of the societal implications of pathogens incredibly
interesting, but from my observations it seems that very few people think deeply about the subject like they do when it comes to the impact of moral codes, religion, and to a lesser extent, innate traits such as intelligence.
I’d love to hear Prof. Cochran’s thoughts on this.
In the Steveosphere, which is famously deterministic, this disinterest is still the rule. I consider myself among the lesser deterministic denizens in this part of the internet, but everything changes when it comes to germs. I have never experienced, or read, a rollicking, give-and-take discussion with respect to pathogens. I don’t even recall another blog picking up on another blogger’s pathogen post and saying, “Hey, check this out! I agree/disagree… here are *my* thoughts…”. This isn’t to dismiss the the value of morality, religion, etc., but there is NO place for pathogen discussion.
As Patrick says, people may not like the idea of being felled by something tiny, but we have a lot of people who aren’t turned off by the randomness and determinism of genes, but even they mostly have a problem with germs… why? This goes quadruple for venereal pathogens.
Here is a typical reaction where there are a couple of comments by me and an anecdote by someone. This isn’t at all to pick on Mangan who is a more social blogger and who is great at what he does; I find this everywhere, but this was just the most recent. With regards to the anecdote, it is extremely rare to be offered such a glimpse of the real world dealings with not just STDs, but what the medical professionals are saying about their state by an articulate person, but I seemed to be the only who found it interesting.
Had the thread/blog culture been receptive, I would have loved to question that commenter all day long! Tactfully and respectfully, of course 🙂
Peter Frost is a blogger who is also interested in germs, but his regular commenters don’t seem to share his passion nearly as much. And like I mentioned earlier, another blog picking up the discussion happens almost never.
http://mangans.blogspot.com/2013/11/what-happened-in-60s.html
There is another blogger, JayMan, who has an interest in germs and possible social implications (particularly w.r.t. homosexuality); see these posts, for instance.
Personally, I think the pathogenic theories are plausible; we already have evidence of pathogens altering behavior in their hosts (see, for instance, this Nature article on Toxoplasma gondii infection). It wouldn’t surprise me in the least if research revealed venereal diseases – and other less-understood (or misunderstood) conditions or behavioral changes – were traced to one or more pathogens.
I made a little talking head movie on toxoplasma and homosexuality. See it at:
I had been making blog comments to that effect for several years now. No one seems to noticed. It is an easy hypothesis to disprove if it’s wrong. Just test the mothers of gays for the T. Gondii antigen. If I’m right they will all test positive. If not then it must be something else.
Rheumatoid arthritis is treated with Auranofin, a gold-containing compound. Gold salts were used historically to treat the disease as they were effective against pathogens and RA was thought to be an infectious disease. Now the therapeutic effects of Auranofin is attributed to its anti-inflammatory properties. It is currently being repurposed as anti-parasite treatment.
I do not believe that RA has a directly infectious etiology. More likely, it is a self-destructive immune response triggered by prior infections–similar to rheumatic fever and Group A Strep infections.
I was not aware of the TB-RA theory. 1/3 of the earth’s population is infected with TB–so clearly there is not much immunity out there that has been selected for. Also the type of immune response that is protective against TB (Th1) is different from the response that mediates RA (Th17). And as you mention, the time frame is way off. So I think that’ s one theory we can safely cast aside.
Quite possibly, but it must be then be triggered by a fairly specific pathogen that did not originate in the Old World.
Well syphilis is a New World pathogen. A spirochete–a tough bugger to find in a patient. One that caused less obvious symptoms could evade detection for a long time. For example, Lyme disease is caused by a related microbe and has some RA-like symptoms and wasn’t discovered until 1980 even though reports of the disease go back to colonial times–unless you believe the conspiracy theory that it was created by the gov’t at Plum Island.
Is RA incidence pretty uniform around the world; are there any places where few people get it?
You are thinking that if it evolved with New World populations, they should get it least or least badly?
Are there any places where arthritis is buried under the other problems of old people as they shrivel up and die? Lot of that going around.
Need a Manhatten Project level of investment into (reinflating shriveled oldies) blood doping for elders. Methuselah’s Children, cave Lazarus Long.
What about the old saying about beekeepers not getting arthritis?
http://www.apitherapy.org/category/apitherapy/arthritis/
Major changes in diet are also a likely suspect and the 17th century was when sugar consumption increased tremendously.
Radical dietary changes can easily change the makeup of gut flora.
Here is a paper about RA. It discusses history and possible causes. It mentions various theories but nothing about selection or TB. People with RA tend to be more susceptible to infections, if anything. I have RA.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3119866/#!po=56.2500
Some more evidence pointing to an intestinal bacteria as a cause of RA.
http://www.sciencedaily.com/releases/2013/11/131105132031.htm
My anecdata:
My son has JRA, which he got just after having had a bout of hand, foot and mouth disease, which supports the “infection triggers immune overreaction” theory. But my wife is also Type 1 Diabetic, which is also an autoimmune disease and therefore supports a genetic predisposition theory.
Did you know about prevotella copri before writing the post?
I’d seen the recent reports mentioning it as a possible cause. The evidence for an American origin has been around for years. But nobody seems to do much about it. This has been irritating me for some time – what is probably an easy win is being vigorously ignored.
MDs are, on average, truly lousy puzzle-solvers. When they say that the cause of RA “may involve a combination of genetic, environmental, and stochastic factors”, they think they’ve accomplished something.
This obscurantism must be due to innate traits as well as training.
In the university I attended as an undergraduate the medical students knew themselves to be very fine fellows. And they were – up to a point. Almost all of them had a quick intelligence – the sort who do well at school and on IQ tests, I’m sure. But I found that often they had nothing that you might call intellectual interests or a sense of intellectual curiosity, so that these clever people tended to hoover up information rather uncritically.
The contrast between the medics and other students who would have tended to have had comparably good academic records (and who would therefore have been near the top of their classes) was striking. I remember as characteristic one stunningly good and lengthy debate in the junior common room (an argument, if you prefer, not a formal debate) which was dominated by four people – an engineer, a mathematical physicist, a lawyer, and a (I think) historian or maybe philosopher. The speed and purpose with which these four argued, and the range of evidence to which they appealed, was formidable. Their squashing of a couple of medics who tried to enter the fray was painful to behold.
From which I conclude that it takes all sorts.
After 40 years of teaching medical students……the effect of training is to make already conservative doctors avoid thinking, avoid trouble, and let someone else get struck off for innovation. In social science “multifactorial” means “I am sophisticated while you are simple-minded so keep paying my wages”. My rule of thumb is that social scientists should be confined to two variables at a time.
Perhaps “bugs” is too simple a word for pathogens, and that leads to the disparagement of the concept. “Bio-engineered, genetically modified, Big Pharma toxins” has a more powerful and conspiratorial ring to it. Here’s hoping you make good progress in driving medicine towards enlightenment.
Many times, Ph.D.s working on some project involving live human subjects need to have an M.D.in the crew. They complain a lot about this.
In a 2003 speech Michael Crichton, graduate of Harvard Medical School and author of State of fear, said,
I have been asked to talk about what I consider the most important challenge facing mankind, and I have a fundamental answer. The greatest challenge facing mankind is the challenge of distinguishing reality from fantasy, truth from propaganda. Perceiving the truth has always been a challenge to mankind, but in the information age (or as I think of it, the disinformation age) it takes on a special urgency and importance.
(Quoted from WattsUpWithThat.com)
When I was pregnant with my first child in 1977 the OB told me I had unusually high levels of rubella anti-bodies–something like 5000 times the average levels, as I recall. About 20 years later I was diagnosed with RA. There have been studies about rubella and RA but I don’t think any relationship has been found. These sorts of things have been studied a lot–people have been looking for some sort of RA-causing germ for years.
The chances of the general population distinguishing fantasy from reality are virtually zero. Even when they become disiilusioned with one particular fantasy they mostly just switch to another
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I thought the current theory was that improvements in sanitation, cleanliness, etc, were what was causing the big upswing in auto-immune diseases, including RA. The immune system over-reacts to itself because it hasn’t experienced enough real pathogens to ‘train’ it. It’s noteworthy that the same time frame that you say RA showed up in Europe is right about when childhood mortality in Europe took it’s first big downward dip.
A bad theory.
The recent issues with Zika virus, and now the recent claim to have found a genetic cause for schizophrenia got me thinking about this thread once again.
The Zika would seem to bolster all your thoughts on seemingly unremarkable infections leading to long term issues, perceived as genetic. The virus was thought to just cause minor problems in adults, and then suddenly not. Yet I have heard nothing about correlating this with other infections in the news.
And then now I hear someone claims to have found a genetic marker linked-to / causing Schizophrenia. That person could be 100% right about the correlation but leading everyone down the completely wrong path.
In short, I can’t believe your 2000 paper on infectious disease doesn’t get cited more often.
Suppose there is a pathogen that ultimately causes RA. Presumably it spreads among younger people, and then after many years tends to cause some kind of mistargeted immune response. (From a quick look at Wikipedia’s RA article, I guess it’s driven by an antibody response.) Further, suppose this originated in Central/South America so it could be brought back by the Spanish and eventually cause trouble for everyone. This leads to a couple places we could check for consistency with this idea:
a. If Central/South American Indians lived with the pathogen for a long time, they may have adapted somewhat to it. If so, we’d expect people of Central/South American Indian descent to have lower rates of RA or smaller problems with it (less debilitating illness). You could even imagine this explaining some of the life expectancy advantages of hispanics. (But it’s possible they didn’t adapt much, since RA mostly hits you well past your childbearing years, when your further contribution to your genes’ fitness is pretty limited.)
b. We should see a lot of cases where other isolated populations got RA in one or two generations, after the pathogen was introduced. Do we see this pattern on Polynesian islands? Among the Aboriginees in Australia? In Japan and the Philipines after they were visited by Europeans?
Quite late for the party, but I brought a paper:
https://www.ncbi.nlm.nih.gov/pubmed/23992372
Ankylosing spondylitis is caused by a pathogen. I think it is likely that other types of arthritis are also caused by pathogens.
Ankylosing spondylitis (AS) is a type of arthritis, in which there is long term inflammation of the joints of the spine.There is one theory by Alan Ebringer, Professor at the University of London, that AS is caused by the gut bacteria Klebsiella. Starch feeds Klebsiella, which multipies in the gut. Your immune system attacts Klebsiella by producing antibodys. For people with HLA-B27 these antibodys also attack your own cells.
You can get fully rid of your AS-symptoms buy stop eating starch. Taking antibiotics also works. You have multiple patent reports for this.
I was personally diagnosed with AS 2 years ago. After reading the patient reports and the theory behind ist I stopped eating starch. Klebsiella in my column starved and my symptoms are gone. I introduced starch again, the sympotms reappeared. I manage to switch my symptoms on and of depending on my diet.
Summary The discovery that HLA-B27 is linked to ankylosing spondylitis (AS) and HLA-DR1/DR4 to rheumatoid arthritis (RA) has provided new approaches to the study of the possible causation of these diseases.
Several theories have been proposed, to explain these associations but only one, namely “molecular mimicry”, has provided a specific aetiological agent for each of these diseases.
Molecular mimicry between HLA-B27 and two molecules in Klebsiella microbes: nitrogenase and pullulanase D has been reported whilst in Proteus microbes, the haemolysin molecule shows sterochemical similarity to HLA-DR1/DR4.
Elevated immune responses to Klebsiella microbes have been demonstrated in AS patients from 10 different countries and this wide geographical distribution suggests that the same aetiological agent is probably acting in producing this condition.
Furthermore RA patients show similar immune responses to Proteus microbes. Whether AS or RA are caused by these bacteria can only be resolved by tissue typing all rheumatological patients early, in the course of their disease and then assessing their response to antibiotic chemotherapy in longitudinal studies involving double-blind crossover trials.
It is possible that in the future, the course of AS or even RA could be modified by adequate antibiotic chemotherapy or even diets which affect the substrates on which these bacteria grow.