Pathophysiology (how the disease develops) – SarcoidosisUK Neurosarcoidosis Patient Day 2023

Transcript 

Peter Fernandes: My name is Peter Fernandes. Thank you very much for the very kind introduction from Leo and the invitation to speak today. Desmond asked me to talk on what causes Sarcoidosis, and since he’s not here, I can slightly confess to this being probably a very difficult topic to answer, but I’ll try my best.  

So just so to start with, so it’s traditional to put in whether you’re paid by anyone else apart from the NHS, and I am not, so I don’t have any commercial disclosures to mention. I’ll crack straight on. So I’m going to talk about Sarcoidosis itself rather than Neurosarcoidosis. We don’t really know what causes either, so in some ways they’re interchangeable in terms of the answer to that question. But I’m going to restrict myself to Sarcoidosis as a whole, rather than just talk about Neurosarcoidosis, if that’s okay. 

And the short answer is very quick, which is we don’t know. And I think most of you will understand that already because there’s a lot of questions about Sarcoidosis and a lot of answers still to be found, and we’re working on that. But I think it’s fair to say that at the moment, if you had a truthful answer to the question, what causes Sarcoidosis? The answer we don’t know would be pretty accurate. But that would be quite a short talk. 

So I’m going to keep going and I’ll give you a longer answer. So the longer answer, that’s a picture of a long jump. Sorry, I couldn’t find a good picture for longer is we really don’t know. But we do have some ideas. So I’m going to talk about the ideas we have in terms of what we think the causes are. 

So when you have this problem, when you have a disease, a disorder that you don’t know the cause of, you have to try and look for clues. And there’s quite a few ways you do this. But I think in the main, there’s three main ways, which is, firstly, are there any similar diseases? Diseases look very, very almost identical and you could say, well, it’s probably likely to be related to that disease in some way. 

The second way you could think of it is, well, perhaps we can get a clue from the way we treat the disease. So if we know what drugs work for Sarcoidosis, and we know how those drugs work, then that gives us a clue into what sort of disorder Sarcoidosis is. 

And the third method, which is a little bit more content, more contentious, really, is epidemiology. So who gets Sarcoid and does that give us any clues? And that’s more tricky in terms of a technique, but I’ll go on to that. So I’ll start with the first one. 

So, are there any similar diseases? So, just a recap. I suspect many of you will be familiar with this, but Sarcoidosis is characterized by granulomas. What granulomas are, are collections, essentially, of immune cells that wall off the inside of that collection. It’s very small. You have to use a microscope to see it. 

And you can divide them into two types. And the first type is the one on the top left, which has a centre that is alive. And the bottom type is a centre where what’s in the middle is essentially dead. There’s nothing alive there in terms of cells. Okay, so there’s two types of granulomas and in Sarcoid we see the first type where the inside is alive, as opposed to the second type where the inside is dead. 

And rather charmingly the way the pathologists, the doctors who look at tissues have named these as caseating for dead and non caseating for alive. And caseating means cheesy. So if you have, luckily, in cycloid group with a non-cheesy type of granulomas, which is a better way of naming it, I think, and the picture on the right is just to illustrate that really Sarcoid can affect any part of the body almost completely. I think it was John Zeich told me once that he didn’t think the adrenals were affected, but having looked it up, you can certainly get adrenal Sarcoid. So I have to say, I can’t think of a single part of the body that isn’t affected. 

So what we’re looking for really is a disease that causes granulomas that can affect any part of the body. So what diseases do we know that are like that? Well, in terms of the we’ll start with the cheesy forms, I know they’re different, but cheesy forms are generally infections, so things like TB or fungus or parasites. 

Now, we don’t get much parasites in this country that’s more elsewhere. We don’t get much fungal disease actually in this country either, but we do see a bit of TB more in other countries, but a bit of TB here. There’s always been that question mark about whether Sarcoid is related to TB in some way, but the granulomas are actually different in TB. So what about the non-cheesy granulomas, the ones that we’re interested in in Sarcoid? 

Well, the causes of that are, number one, are autoimmune diseases, and those include what we call vasculitis, so inflammation of blood vessels. Crohn’s disease, which typically is just the GI tract, so the stomach and the intestines, and sometimes the mouth as well. And then you get a second type, which is really foreign body reaction. So you have something in your body that’s not supposed to be there, that isn’t alive, but your body has a particular reaction to that. 

And buriosis, which is a very pretty mineral, actually used as a gemstone. So we know that people who mine gemstones who have exposure to buriosis dust get this disease, particularly in the lungs, but it can be elsewhere in the body, which looks relatively similar to Sarcoid under the microscope. Although often if you look really carefully, you can see the mineral inside the granuloma and you can also get foreign body reactions. So if someone cuts you open and leaves a suture inside you that doesn’t dissolve, then sometimes you can get a granuloma around that. Okay, but that’s usually in one place only. Of course, it’s not spread throughout the body. 

And then various drugs can cause granulomas, typically immune system drugs. So some of the HIV drugs, some of the immune system drugs like immune checkpoint inhibitors, which are used for cancer treatment, we can see Sarcoid like granulomas in those too. And lastly, infections. So often you get non cheesy granulomas alongside cheesy granulomas and infections, but typically you will see the cheesy ones. 

So I’ve said talk too much about cheese. So I’m going to move on to the second point, which is, well, if we know a little bit about what Sarcoid looks like in other disease, the granulomas look like in other diseases, maybe we should move on to how we treat Sarcoid. And I think most of you will be familiar with many of these medications that we use for treating Sarcoids. 

So prednisolone, methotrexate, mycophenolate and infliximab, although they have significant side effects and they don’t work for everyone, I think it’s fair to say that there is significant benefit for many people on these treatments, which is really helpful because it tells us that these treatments are doing something against what probably the cause of Sarcoid is. 

And what are they doing? Well, they are all suppressing the immune system to some degree, and if they’re suppressing the immune system that helps Sarcoid, then the clue that gives us is that Sarcoid is a disease mediated in some way by the immune system. 

So it’s an autoimmune disease of some form. Doesn’t take us a huge amount forwards because there’s lots of causes in autoimmune diseases and in fact, for most of them, we don’t really know what the underlying cause is. But it’s helpful nonetheless that we think this is more likely to be an autoimmune disease than an infectious disease. That makes sense. It’s unlikely to be something like TB or causing Sarcoid or active TB causing Sarcoid because if it was and you gave someone immunosuppression like these treatments, then it would get a lot worse rather than a lot better. 

Okay, so I’m going to move on to the third point, which is how can this epidemiology, so who gets Sarcoid? Try and give us some clues. And this is really difficult to do well, actually, so sometimes it seems like it’s pretty obvious. So this is a graph of cigarettes versus lung cancer deaths. And you can see they match each other pretty well with a bit of lag. So you could clearly work out from that that it’s likely that cigarettes cause lung cancer, and of course you’d be right to say that. 

But the problem is, of course, is that you might get mixed up. You might say, well, unless you knew any better, that perhaps people who get lung cancer. Smoking helps them feel better when they have lung cancer. So you’d actually say that lung cancer causes smoking. Of course, you’d be wrong to say that, but you could think that’s what’s called reverse causation. So you need to make sure you’re not getting things mixed up in terms of A to B rather than B to A, if that makes sense. 

And the second thing you need to be careful about is that link between association and causation. So just because two things go together doesn’t mean that one causes another. And this graph, which I really like, just shows that. So this is a graph comparing how much cheese sorry, I’d come back to cheese. I promised I wouldn’t, but I have, how much cheese people in America eat, compared to the number of people who died by getting tangled up in their bed sheets. 

And you would think, and I think you’d be right to think that those things are not related at all. But if you look at the graph, it’s pretty close, isn’t it? And that’s just coincidence. That’s just pure coincidence that those things are going together, because there can’t be any link, at least I can’t think of any link between how much cheese people eat and how many people die in their bed sheets. 

But you can see what I mean from this. You need to be careful about saying these two things go together, therefore they must be causing each other, because it’s not always the case. So with those kind of caveats, with those warnings, let’s move on and look at what we know about Sarcoid. So we’ll start with geography. So this is a map of who gets Sarcoid. And the darker blue it is, is the more common it is. And the lighter blue, the less common it is. And grey is we really don’t know because no one’s looked at it. 

And you can see most of the world is grey. And that’s because we really don’t know how many people in, for example, Africa or South America or much of Asia get sarcoid. And even when we do know, we’re probably wrong, because Sarcoid is very difficult to diagnose. And often people say, I think it’s Sarcoid and it’s not. Or they might say, I think it’s TB and it’s actually Sarcoid, or the other way around. 

But I think what this graph shows us is it’s most common in the Americas, so the USA and Canada, and in Northern Europe, so Scandinavia, particularly Britain, and then slightly less common as you go towards the Mediterranean. 

What is interesting, I think, is that if you look at the Far East, so very rich countries like Japan and Korea, they don’t really seem to get much sarcoid. So I think that’s useful to say. Well, we think it’s mostly a Northern European and American, as far as we can tell, but Far East seems to be relatively protected. For what it’s worth, I think that ties into ethnicity as well, because obviously they’re linked to geography and ethnicity. And what we typically see is that in America it seems to be black Americans, Afro Caribbean particularly, who are more likely to get Sarcoid, whereas in Europe it tends to be more people from Northern European backgrounds, particularly Scandinavian, who seem to be a bit more likely. 

I have to be honest with you, the studies are a little bit conflicting, but I think in general, it’s from an ethnicity point of view. People of black heritage or Northern European heritage seem to be at slightly higher risk than people from other ethnic backgrounds, although, of course, everyone has a risk to some degree. 

Moving on to sex and gender, so, again, quite conflicting. Depends on what study you read in terms of who gets it. But I think most studies would agree that women have a slightly higher risk of getting Sarcoid than men. It’s not hugely high, so we’d say probably about 1.5 times. So women, there’s 1.5 times risk in women compared to men. Again, it depends on what study you read, and that fits in with most autoimmune diseases. So most autoimmune diseases, MS for example, are more likely to affect women than men because of the way the immune system is slightly different in men and women. So that’s added support to it being an autoimmune disease. 

Let’s go into genetics. So genetics is really interesting because it gives us really loads of clues. So we know that if you have Sarcoid, it’s not unusual to have a family member Sarcoid as well. So we think about 5 to 10% people, sarcoid will have a family member with Sarcoid as well. If you identical twin, then your risk is much, much higher. So it’s about 80 times higher than background population risk if you have identical twin, if you have a non-identical twin. So that’s Scarlett Johansson and her and her brother, who are clearly non identical twins, since they’re different sexes, and their risk is about seven times higher. If you have a non-identical twin with Sarcoid, a sibling alone is about five times, so a bit less and parent is about four times. 

Okay, so that’s a bit tricky, though, because you know that if you grow up in the same environment as someone else, then it’s likely you expose the same infections, the same environmental exposures, the same kind of mud and other environmental issues, same water supply. So it’s difficult to disentangle genetics from how you’re brought up, but I think there is a difference in identical twins and non-identical twins. And that really does show us that there is a clear contribution from genetics here. 

And just so you know, spouses. So the bottom right there, that Lego figure of the groom and his bride, you actually are protected to some degree. So we think the spousal risk is about 0.2 times the risk. So if you are a husband or wife or partner or someone with cypher, your risk actually seems to be a bit lower. I don’t know how to explain that, so don’t ask me how, but that’s an interesting fact nonetheless. 

Other possible factors, and I put possible in underlined, but should be bold, italics and underline, really, because we really don’t know. There’s always been this question about whether TB is involved, and that’s because TB looks quite similar. It’s a granulomas disease that affects all parts of the body and there is some evidence for that in that when you take granulomas and you really look carefully at them, you can see there’s some evidence of some TB proteins in that. 

What is clear is that there’s no TB there. So the TB, it may be that people have been exposed to TB and then that’s been cleared by the immune system, but there’s a little bit of immune system being kind of activated in some way that it finds it difficult to deactivate even when the TB is gone. That’s quite contentious. It’s still argued about, but I think it’s an interesting theory nonetheless, with some evidence. There’s some evidence that if people who are overweight are slightly more likely to get sarcoid. But I think that’s very debatable. 

And the third area, which I think many people are interested in, is whether parts of the environment are making it more likely for you to develop sarcoid. Is there something in the environment that triggers sarcoid in some way? And people look really carefully. It’s really difficult to study that. It’s always been this theory that exposure to certain professions, so particularly being in agriculture, and sometimes we think that water supplies, if they aren’t filtered properly, is a link, but it’s very arguable and very debatable, including for most of us in the UK. That is an issue too, because we all get our water from mains water. But it’s a theory, particularly in Canada, I think, is where this came out of.

Then, exposures to metal dust because of this buriosis, the mineral I talked about before, and it’s thought maybe that triggers it. It’s quite difficult, though, because if you’re exposed to metal dust, you tend to have lots of X-rays done because of lung disease. Not sarcasm, but lung disease. And when you get elder X-rays done, we pick up more Sarcoid than if you don’t have X-rays done. 

So it’s difficult to know whether that’s actually true or not. There does seem to be a slightly higher rate in the firefighters, 911, who are obviously exposed to loads of different chemicals. But again, we don’t really know. But some theories need more work. I’m not entirely convinced, to be honest with you, but things will become more evident over time. 

And just my last slide, then. And so this is a summary. So what causes sarcoid? So I think we’ve got evidence to suggest it’s an autoimmune disease. It’s probably triggered, possibly triggered by an infection, but we don’t know what infection we don’t think it’s an ongoing infection, but right at the start, perhaps, and it may be that people have an environmental exposure in the addition. What that is, we don’t know. And it seems to be more likely people have a high genetic risk, but we don’t know what genes are involved. 

And I’ll leave you with a quote from this is the earliest possible paper on Sarcoid I can find on the Internet, and it’s from 1938 British Medical Journal. And I won’t read out the whole paper because it’s very long, but I’ll just put one sentence I think was really helpful, which says, 

“An acrimonious dispute over the nature of Sarcoidosis has been in progress for many years”. 

I have to be honest with you; I think it’s still in progress now, nearly 100 years later. So thanks very much for listening. I’m not going to take questions now because I think we’re going to do that at the end, but I’ll hand over now. Thank you!