EDNF 2012 Conference
August 2012
Thank yous… In preparing for this mee5ng, I hoped to present informa5on that not only offers a 5mely update on vascular EDS, but that also provides something generally educa5onal. With rare disorders, we oCen5mes keep our eyes peeled on relevant research – always with the hope and expecta5on that the informa5on we need to make health related decisions will become available. However, rarely do we step back to survey the overall research landscape.
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EDNF 2012 Conference
August 2012
In my opinion, understanding the context surrounding new informa5on is important for understanding the significance of that informa5on. I don’t know that we can understand everything simply from understanding the context, as suggested by this quote; however, context is cri5cal. Take for example this piece of art – I actually chose it to represent Noland’s work to accompany his quote...for me, it was simply aesthe5c, I liked it. However, as I was prac5cing this talk with members of our lab, it became a topic of conversa5on. In the context of talking about vEDS, Dr. Byers interpreted it to represent an artery cut in cross-‐sec5on while one of our gene5c counselors, Dru, interpreted it to represent crea5ng order out of chaos. The 5tle, ‘Heat’, doesn’t seem to suggest either of these interpreta5ons. Long story short, the point is that context maVers.
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EDNF 2012 Conference
August 2012
So, what are we going to talk about today? I want to start with a framework – a tool for seeing how single research study fits in the overall research picture. We’ll then review 2 different studies – one published about a year ago on haploinsufficiency in vEDS and the other from 2010 on use of a medica5on called celiprolol in vEDS. And we’ll conclude looking ahead to what the future will hopefully hold.
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EDNF 2012 Conference
August 2012
But my real hope is that you all will walk away with a sense of the context in which research studies are performed to have a beVer understanding of where a par5cular study fits in the overall picture.
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EDNF 2012 Conference
August 2012
As means of a brief background, we’re all in this room today because vascular EDS has touched our lives in some way – whether you or a loved has been diagnosed or maybe you’re worried that you could have this condi5on…or maybe you’re a healthcare provider trying to provide the best possible care for someone with vascular EDS. In general, we know that those affected with this disorder are at risk for serious complica5ons – but we also know that every single person with vascular EDS is unique and follows their own path. If we look around the room today, you may recognize some features sugges5ve of vascular EDS, but my guess is that if we could all see each other’s gene5c test results, we would all have some surprises, too. At this point in 5me, there are essen5ally 3 ways to diagnose vascular EDS – clinically based on medical history and physical exam, biochemically by looking at the type III collagen protein and molecularly by studying the gene COL3A1. At this point in 5me, establishing the diagnosis is certainly important – oCen offering an explana5on and raising awareness of possible future risks, but we s5ll have many ques5ons about how to best care for families living with vEDS.
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EDNF 2012 Conference
August 2012
The type of ques5ons that remain unanswered are highly variable and this is just a short list of some examples. We oCen5mes turn to research to help answer the ques5ons that arise in the clinic.
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EDNF 2012 Conference
August 2012
If we went around the room and each defined what we think of as medical research, I think we would quickly see that there are many different percep5ons. I’m going to try to provide an organized overview of what I think of as medical research, but it’s likely that others may have their own way of thinking about it. My inten5on in going through this is so that when you learn about a new study, you have a way of seeing where it fits in the big picture, as well as a way of thinking about whether and what addi5onal studies need to be done before the result can be used for clinical purposes.
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EDNF 2012 Conference
August 2012
If we start looking at medical research altogether, we can divide it into primary and secondary research. Secondary research is essen5ally research studies using other research studies – this can be important for common diseases, but is less oCen a tool we can use in understanding rare disorders, so I’m not going to go into it further today. Primary research is actually collec5ng new data in hopes of learning something new that can be used more generally. We can think of it as having three different levels. If we want to look at things smaller than a whole human – such as DNA, cells, non-‐ human organisms -‐ we are talking about basic research. If we want to study one or more humans, we are interested in clinical research. And if we want to step back and look at whole popula5ons, we would be performing epidemiological research.
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EDNF 2012 Conference
August 2012
But the sub-‐classifying doesn’t stop there. There are several types of basic research. There are studies of animals and animal model of disease – which is when researchers try to re-‐create a human disease in an animal species for research studies. Some people have strong opinions as to whether this is morally correct, but from a medical perspec5ve, animal models are a very important resource for understanding human diseases. There is a mouse line that has been created with loss of COL3A1 and recent research has focused on used of a medica5on called doxycycline in those mice to see if it reduces the risk of vascular complica5ons. Use of cultured cells can also be very helpful in understanding gene5c disorders, as Dr. McDonnell discussed at last year’s conference. Many 5mes, basic gene5c studies focus on trying to iden5fy the cause of rare disorders, such as vEDS – but now we can use that knowledge to try to understand whether abnormali5es in type III collagen play a role more common types of arterial aneurysms and dissec5ons in individuals without vascular EDS.
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EDNF 2012 Conference
August 2012
There are also different types of clinical research studies. In general, we can think of clinical studies as coming in two different flavors: experimental and observa5onal “Experimental” studies are what come to mind for many people when they think of medical research – we’re doing something to try to influence natural course of the condi5on. This may be trying a medica5on, as I’ll discuss in more detail later, or it could mean performing a procedure or surgery trying to see if it is clearly beneficial. Observa5onal studies, on the other hand, focus on trying to understand the condi5on as it is when unperturbed by experimental interference. For example, many of you may be familiar with the paper in the New England Journal of Medicine from 2000 on the natural history of vEDS – this provided us with informa5on on the average age of first complica5ons, type of complica5ons and life expectancy of persons with vEDS. Not only is this informa5on important for families and healthcare providers, it is cri5cal to provide baseline informa5on for comparison to determine whether an experimental treatment makes a difference. ACer all, how can we know if a medica5on or treatment reduces the risk of a complica5on if we don’t know the likelihood of a complica5on happening in the first place? Another type of observa5onal study is called a trying to see if there is a ‘genotype-‐ phenotype correla5on’ – this is when we ask whether people with vEDS but different
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EDNF 2012 Conference
August 2012
In rare disorders, epidemiological studies can be more difficult due to the small number of affected people, but this informa5on is s5ll vitally important to diagnosing and managing rare condi5ons like vEDS.
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EDNF 2012 Conference
August 2012
Before we move on to focus on an few recent studies, there are some points that are important to highlight. The first is that a single study rarely is sufficient to answer a ques5on with enough confidence to change clinical care. We want to be sure that the findings are replicable and applicable to pa5ents in a real world sekng. The second thing to consider is that using research findings to influence healthcare decisions too quickly can result in harm – one example is the public’s response to childhood vaccina5ons aCer a study reported an associa5on between childhood vaccina5ons and au5sm. That finding has not only been disproved, it was revealed to be fraudulent. However, we con5nue to face the ramifica5ons of unvaccinated children suffering preventable illnesses and deaths.
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EDNF 2012 Conference
August 2012
Now then, turning our focus back to vascular EDS. As I men5oned earlier, this study from 2000 has been pivotal in beVer understanding the natural history of vascular EDS. That is, it offers some insight into things like life expectancy and age of first complica5ons. In essence, this is the baseline informa5on that most other studies on vEDS will use as a reference.
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EDNF 2012 Conference
August 2012
Shortly following the natural history study was the first report of haploinsufficiency in vEDS. In that paper, now published 11 years ago, the author’s commented that individual’s with null muta5ons were seen less frequently than expected. They suggested that this may be because those individuals had a different clinical course from most people with vascular EDS. The reasoning being that those will null muta5ons had complica5ons less oCen and, therefore, oCen never came to clinical aVen5on to be tested. Before moving on, I want to take a moment to explain haploinsufficiency, since it’s a term that most people have no reason to know.
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EDNF 2012 Conference
August 2012
In persons without vascular EDS, the typical situa5on is that there are two copies of the COL3A1 gene, one inherited from the mother and one from the father. Each copy makes protein chains in roughly equal amounts. Three of those chains then randomly come together to form the triple helix of type III collagen. The protein chains do not discriminate in who they associate with – those produced from the maternal copy will associate with those from the paternal copy and vice versa.
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EDNF 2012 Conference
August 2012
Now, if there’s a muta5on in one copy of the gene that leads to a change in the protein, then half of the chains will be abnormal. The abnormal chains are incorporated into the triple helix of type III collagen and if even one of the three chains is abnormal, it is sufficient for the en5re triple helix to be abnormal.
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EDNF 2012 Conference
August 2012
In the case of haploinsufficiency, the muta5on is such that it does not cause an abnormal chain to be formed. Instead, it essen5ally causes one gene copy to not produce any chains at all. All the chains come from the other copy of the gene and are normal. The result is that all the type III collagen made is normal, but it’s only half the normal amount because the unaltered copy of the gene doesn’t get turned up to compensate for the other.
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EDNF 2012 Conference
August 2012
Another way to think of it is quality vs. quan5ty. For example, I think it’s safe to say the scanty materials making up the bridge on the leC would be in5ma5ng from most of us. However, the bridge on the right looks as though it was built of heavier material but it looks as though those materials were not structurally sound.
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EDNF 2012 Conference
August 2012
About a year ago, Dru and others in our lab looked at the natural history of families with vascular EDS due to haploinsufficiency in closer detail. Referring back to our medical research framework, this was a clinical observa5onal study. 19 families with haploinsufficiency were iden5fied with 54 total people. When they looked at complica5ons, most of those who were the first diagnosed in their family had complica5ons – this is expected because there had to be some reason for them to have been tested in the first place. However, when people we tested because a rela5ve was diagnosed, then major complica5ons were seen in less than a third.
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EDNF 2012 Conference
August 2012
In looking at the ages of those tested, it was observed that many more people with haploinsuffiency were alive at older ages compared to the other natural history study I men5oned previously. Here we have the ages from birth to 85 years and the bars represent the percent of individuals who were tested. The higher black bards seen outside the orange curve represent more people with null muta5ons being tested at older ages, likely because they never had a reason to be tested when younger – they are living longer and having less complica5ons to bring them to clinical aVen5on.
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EDNF 2012 Conference
August 2012
And if we step away from major complica5ons and look at minor features, we see that the majority of people with haploinsufficiency have no minor features sugges5ve of a diagnosis of vascular EDS.
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EDNF 2012 Conference
August 2012
In summary, the study found that individuals with haploinsufficiency due to null muta5ons have a different clinical course with longer life expectancy, later age of first complica5ons, less bowel and pregnancy complica5ons and less minor features. Of course, there are some limita5ons we have to keep in mind – the most important being that these are the families with haploinsufficiency who came to tes5ng because someone had a complica5on – based on what we know of the gene sequence, it’s likely that the many families are never iden5fied because there’s no complica5ons that lead to tes5ng. For this reason, the risk es5mates may be higher in this study than actuality.
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EDNF 2012 Conference
August 2012
What implica5ons does this study have? For families, it may be somewhat reassuring. Or, as I heard one father explain to his daughter – “if you have to have it, this is the one you want”. Personally, I s5ll err on the side of cau5on and make the same medical recommenda5on. From the research perspec5ve, it will be cri5cally important to take muta5on type into account in the study design – which we’ll revisit in the next study we discuss.
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EDNF 2012 Conference
August 2012
So, it seems that while having half the amount of type III collagen does represent some risk, it may be sufficient to accomplish the goal.
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EDNF 2012 Conference
August 2012
On that note, let us briefly look forward to where research may go – or where it is going, in some cases.
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EDNF 2012 Conference
August 2012
On that note, let us briefly look forward to where research may go – or where it is going, in some cases.
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EDNF 2012 Conference
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August 2012
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EDNF 2012 Conference
August 2012
In summary, we’re making progress but we will never know enough fast enough. It’ll be important for you, the individuals and families living with vEDS, to drive research to answer the ques5ons you have. As healthcare providers and researchers, we tend to be very limited and biased in the types of ques5ons we ask – I ask ques5ons as a doctor, not as someone living with vascular EDS. It really is up to the EDS community to point us in the right direc5ons and that can only be done through being engaged and working together with us as team. It truly is my hope that today’s talk helps you beVer understand the overall landscape of medical research and provides a tool for you to use when assessing par5cipa5ng in or using the informa5on from future studies.
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EDNF 2012 Conference
August 2012
With that, I would like to extend my most sincere gra5tude to you, EDNF and my home ins5tute and lab. In par5cular, I am deeply indebted to the Freudmann Fund, without whom I would not have the opportunity to focusing on heritable connec5ve 5ssue disorders in my clinical prac5ce or research. I’m happy to open the discussion for any ques5ons or concerns you may have.
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EDNF 2012 Conference
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August 2012
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EDNF 2012 Conference
August 2012
Now, I’d like to turn our aVen5on briefly to a second study. I believe this study was men5oned last year by Dr. Black, so I won’t go into great detail. In essence, this is the first clinical interven5onal study of reasonable scale to test a medica5on in humans with vascular EDS. The goal was to assess the preven5ve effect of celiprolol on major complica5ons. Celiprolol is a type of blood pressure medica5on called a beta-‐blocker and the theory behind using it is that it would decrease blood pressure, which decreases the mechanical stress on the vessels and, therefore, decrease the risk of arterial dissec5on or rupture.
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EDNF 2012 Conference
August 2012
It’s important to note that this study began before gene5c tes5ng was standardly available – for this reason, many people weren’t tested un5l aCer they enrolled. Those eligible for the study had either 1 major and 2 minor criteria, as listed here, or 4 minor with no major criteria.
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EDNF 2012 Conference
August 2012
53 people were enrolled, treated half with celiprolol and the other half received no study medica5on, then they observed the rate of complica5ons
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EDNF 2012 Conference
August 2012
At face value, their findings are exci5ng and lead to the study being stopped early – they observed a 69% risk reduc5on in the group that received celiprolol compared with the group that did not. Interes5ng, there was no significant difference in the blood pressure of the treated group.
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EDNF 2012 Conference
August 2012
In my opinion, this issue with the two group being different warrants cau5on in how excited we get about the results. In addi5on, if it’s true that celiprolol is beneficial, then it warrants ques5oning how it works since it wasn’t observed to lower blood pressure, which was the driving theory behind choosing this medica5on.
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EDNF 2012 Conference
August 2012
In the end, the author’s concluded that the results suggest a benefit but that the results must be carefully assessed. Is there reason to be op5mis5c – yes! Is further research needed to try to replicate this finding – absolutely! Do I think we should start prescribing everyone with vascular EDS a beta-‐blocker solely for the purpose of preven5ng complica5ons – not so much. Some of you may be wondering what we have to lose – why not just do it? My response to that would be two fold. The most important one is because no medica5on is without poten5al side effects or harms – beta blockers, included. I have a hard 5me jus5fying exposing someone to a poten5al harm unless I have good evidence that there is a poten5al benefit to balance it out. For me, this study was not sufficient to establish a true benefit. The second reason may be a liVle more difficult to understand, but I think it’s just as legi5mate. If everyone just starts having their doctor prescribe a beta blocker with the hope that it might work, then we forever lose the opportunity of knowing whether it actually does or not. If we want to know the truth, then we have to engage individuals with vascular EDS who decide to take medica5ons for the sole purpose of risk reduc5on in research studies to that we can learn what works – otherwise, we will find ourselves in exactly the same posi5on when talking to future genera5ons that we are now…no progress will have been made.
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