Q&A with Graham Hughes – 14 September
This video was recorded on 14th September 2020 and answers some questions put to us from the GHIC community about APS. You can read a transcript of the video below.
Henry: Hi everyone and thank you very much for joining us. So we’re very excited to bring to you Professor Graham Hughes again for a live Q&A for the benefit of GHIC, the Graham Hughes International Charity. We’re thrilled to have the man himself and he hardly needs any introduction but obviously he discovered the syndrome, then called APS and then given the honorary name of the Graham Hughes syndrome as a large symposium which shows you the regard in which he is held. He founded GHIC really to provide more information for people and for clinicians and to further the understanding of the disease, to look to to fund research and provide support. Any donations are very much welcomed and could be done on the website. All right, without further ado I’m going to introduce Graham and say hello. Hello Graham!
Henry: Wonderful to to be joining you, last time we were socially distanced in our office now this time we’re socially distanced with 75 miles between us
Henry: Well it’s wonderful to be able to join you and wonderful to have you here. So without further ado we’ve had a lot of questions sent in as you know there’s a lot of interesting excitement whenever you come on from a global audience and I look forward to it. If anyone has any further questions do comment them either in the Facebook thread or in the Twitter thread, we will try to get to them. We’ve had a lot of questions sent in before which we’re going to start with, we’ve split them into four main groups; Medication, Living with APS, Symptoms and Other. We’ll try and intercede any questions people upload as we go along. So the first question from Sam on Facebook was: ‘Are there any alternatives to warfarin for APS patients?
Graham: Yes is the answer, thank you for the question which is always being asked, but the treatment at the moment basically is anti-coagulation stopping clotting, and there are three drugs being used around for donkey’s years which are aspirin, heparin and warfarin. And for mild cases aspirin is the main drug. Heparin we’ll come back to that because it’s more quick acting and so on but it is an injection so therefore it’s not popular and warfarin which is hated by the media but is an extremely useful drug and especially if it’s monitored by patients as well as their clinics. There are all the time new drugs being tried, old drugs such as hydroxychloroquine which has been touted for the COVID virus, steroids but not very successfully and immunosuppressive because they’ve been used in other what we call autoimmune disease. And I can come back to those individually, for most people at the moment we’re still limited with the three drugs that we know and trust
Henry: You mentioned a link with a drug being used for COVID. Can I ask a bit more about that?
Graham: Yes the drug which is called chloroquine or it’s derivative of chloroquine called hydroxychloroquine or plaquenil has been claimed, but I gather that the results haven’t borne out the great hope that was there. But it is a used drug, it’s well used in a disease called Lupus which is like a cousin of Hughes Syndrome if you like, an autoimmune disease, very useful for the fatigue and aches and pains. The other drug that’s been used and claimed to be useful is of course steroids, but you’d expect that because high-dose steroids are amazingly strong when it comes to inflammation. So for a short period of time the intensive care doctors have been using that. The third one is quite interesting it’s that many people with COVID get thrombosis and there have been suggestions that it’s like Hughes Syndrome in some ways and in fact, talking to my colleagues at London Bridge, they certainly use anticoagulants for the very acute sick patients on COVID ward, but that’s temporary not a long-term treatment.
Henry: Yes I just realized that chloroquine is the one that Trump was talking about
Graham, It was, and I don’t know if it pushed up the sales in the States but it was tried early on but has not proved the great success I understand.
Henry: And do we know anything about people with Graham Hughes Syndrome and getting COVID, do they have more issues, less issues, do we have any information?
Graham: Luckily there’s very little negative data that we don’t know that there’s been a specific risk. The same applies for other autoimmune diseases like Lupus. Our Lupus unit and our colleagues who work in the NHS in the places in London and Southampton and so on don’t feel that patients with autoimmune disease have a bigger risk from COVID than those without which is reassuring.
Henry: It is, it’s very important I think we all remain very worried, particularly as we’re seeing numbers start to tick up again. Numbers ticking up in the previous take up has been in a younger age group and now we’re seeing it tick up in the wider population. And as we speak today there’s just been a new rule with only six people can be together so we’ve had a tightening of rules today.
Graham: Yes yes it’s very depressing isn’t it, actually everyone thought we were coming out of the tunnel but we’ll see
Henry: And now how are you treating the COVID risk, how have you changed what you’re doing?
Graham: Well my wife is under the care of the asthmatic clinic and she’s at high risk from the lungs. We’ve been self isolating, we’re lucky in that we have family and friends and so on down here in the village near the coast where I am and we don’t have a sort of ‘one flat and three kids scenario’ which must be awful for those people. So we’ve been protecting us, protecting our family from any contacts and obeying all the rules but it has meant a break in my normal practice.
Henry: Yeah, so you had started coming up to London again, do you think you’ll still do that or do you think you’ll be reviewing how things are going?
Graham: We’ll review I think we just don’t know. We’ve listened to the rate you know on the radio and the telly every evening for the latest figures but there’s undoubtedly been an increase and not just people have been to nightclubs and things but more generally I think.
Henry: Yes I think that’s what we’re seeing as well. Now the reason I thought it’d be interesting for people to hear is to know that you and everyone really are changing what they’re doing and how they’re not alone in doing that and sort of communicate to the wider population how we’re all being careful. Right Carolyn on Facebook, thank you for your question we will get to it, I just wanted to acknowledge it and let you know that we’ve got it. Right Di on Facebook sent in a question before and you touched blood clots or thrombosis around COVID. She wanted to know ‘do people with diagnosed APS on warfarin have more risk of clots with COVID than people without APS?’ So you touched on that people are treating COVID with thrombosis, that’s where she wants to know if she’s more at risk.
Graham: Theoretically you might be less at risk because your own anticoagulant is stopping the sticky blood situation. As far as I know at the moment there is no increase or for that matter decrease risk of COVID in patients who are antiphospholipid positive, but you know my feeling in a practical term is that if you have this, that you are anyway at double risk if you get lung clots and then COVID affecting the lungs. So in that respect I think you have a potential illness that you could cover by being even more safe about distancing and all the rest of it, does that make sense? Henry: It does I think that’s the conundrum isn’t it that you’ve got an increased risk because we don’t know right now but there’s obviously a concern of the having the two at the same time, but at the same time you’re already on one of the treatments that’s supposed to help and if you’re on the steroids they might balance things out, but overall we still don’t know, it’s a new disease and then this is a new disease interacting with another disease and right now the data we just don’t have enough and playing safe is the the right thing to do. Is that summary about right?
Graham: Yes very much so
Henry: Because obviously it’s something people are understandably very very worried about. Ali on Facebook: ‘I’m on fondaparinux and I’ve been on blood thinners since 2006 when diagnosed by a doctor now, a professor in the Lupus unit at Tommy’s and Guys’ – and a side note to everyone watching, listing all Graham’s achievements takes too long and we know how much he’s done but one of the things he did was actually he is the founder of the Lupus clinic at St Thomas’ which was the second Lupus clinic he founded after founding the first one in the country and in Europe was it was?
Graham: Yes it was
Henry: So he founded this clinic! – ‘Recently I’ve been told I may have to come off all blood thinners. I’ve gone from warfarin to clexane’ – Ali this is a very difficult question in terms of enunciation, have I said this right ‘clopidogrel’?
Henry: Oh one of my patients calls it cloppy dog roll
Graham: Okay I’m going with cloppy dog roll – ‘I’ve gone to warfarin to clexane, fondaparinux to nothing. Is this a new protocol please?
Graham: No it’s not a new protocol it’s something that’s tried. Obviously there are patients who were very ill to start with severe clots, and they usually end up going quickly through the list until they reach warfarin and many stay on that for the fullness of time. But the difficulty for us is that in some patients the tests for sticky blood do become negative, the patient remains well, can I please come off this dreadful warfarin because it stops me taking fruits or eating different foods and things. What we do then is retest, if the tests remain negative it’s a slightly unknown quantity for us and for the patients, but we would tail down as slowly as we conveniently can the medicine, and ultimately we have quite a few patients who are off everything. I think it’s just risking things too much to stop, if for instance warfarin bang like that, and that applies to most drugs I think. If that doesn’t answer the question come back to me on it please because you’re asking a very difficult question. Patient who’s doing well on a drug which is very difficult to handle for some patients and you’ll walk a very fine balancing act between reducing and stopping the drug. Now the fondaparinux and other things, clopidogrel, are alternatives. Clopidogrel is, I call it expensive aspirin, very similar. It affects platelets and makes them less sticky, it’s a very useful drug if a patient has not tolerated aspirin or is in some way against using it. So that’s one of the reasons that drugs are in our basket of drugs. The next one is heparin which is a brilliant medicine, it stops clotting but the major disadvantage is it’s an injection and we use that as a holding drug in many patients before deciding whether to move complicated drugs such as warfarin or even one of the newer ones which I’m sure you’ll be asking about in a minute.
Henry: You said that the reason for coming off the drugs is that someone might now be negative for the syndrome, are there other reasons people would be coming off?
Graham: Small numbers I think is the correct answer at the moment. You know of course we are a hospital clinic so we by definition see the most complicated cases patients, with more mild disease many of them are aspirin alone and of course some patients refuse everything. As far as warfarin is concerned it’s a very useful drug, I keep telling patients it’s the one drug that the patient can control herself, control the dosage on, which gives it a huge advantage over many of the newer oral anticoagulants for instance. The trouble is it’s a pain in the neck because the dose is different for every individual, some patients only need a tiny dose, three milligrams, others it’s 12. And many of our patients buy their own self-testing thing for stickiness of the blood. Many of our patients swear by that even though they’re still under the anticoagulant clinics and I believe in it, I think it’s if you start getting headaches or symptoms of Hughes Syndrome again you check your blood stickiness with this machine.
Henry: We’re going to bring in a question that’s been posted online so Wendy who says ‘Good Morning from South Africa’ so wonderful to have her join us and from so far. ‘My mom has been on warfarin for her ABS for around two years now and her INR has never been stable, it ranges between 1 – 8 and its worst ever was over 9.Why does she still clot at an INR of between 3 and 3.5? What should the INR be in an APS patient and how do you recommend it be stabilized?
Graham: It’s a very important question, it’s common. Warfarin is affected by, as you probably know, everything. I mean if you drink alcohol at the weekend your INR goes funny, if you take certain fruits it affects it, certain berries, green foods. Some patients diet just to keep the INR more stable but I think that’s almost impractical, so what do you do? I am a strong believer in getting your anticoagulant clinic to blend you or to buy yourself an anticoagulant. You mentioned INR – INR is the fingerprint test for stickiness of the blood, it should be 1, if your blood is thin it comes up to three, five, seven as you say. For patients in the ordinary anticoagulant clinic the ratio is about two but this is usually for little old ladies with it atrial fibrillation it’s not for patients with Hughes Syndrome who are more at risk. Now most of my patients who’ve had a major clot need an INR up around three, in some cases 3.5 or even four. Now your anticoagulant nurse may throw his or her hands up in horror at that because over 4 the risk of a bleed increases, but it does give you the individual way of monitoring your INR and very very gently nudging the dose up and down. I think for a patient sticking with their anticoagulant clinic of course, this is one way forward. Whenever I see a patient especially with a history like this I ask if I can see their little booklets. In this country and South Africa I don’t know if it’s the same, but your little book with your INR recorded and what you see are the patients still getting symptoms, INR 2, 2.5, 2.7, 2.3, patients not being treated, it’s like giving too little digoxin for a heart condition you’ve got to get the dose right and the patient knows that dose normally if they keep their eye out. And I will need to bet that her INR has fluctuated wildly. There are alternatives – if it is truly a total failure then there are new anticoagulants and there’s great interest in them but the evidence is not yet strong that they’re effective and there are slightly worrying case reports of people who’ve shared in one way or another on one of the new oral anticoagulants. So slightly watch this space, our teenagers don’t like being on warfarin because it affects your social life, some of them are advocating the new anticoagulants but we’re in the middle of looking and there’s a number of trials going on to see how they come out.
Henry: Great, we’ve had a question come in as you just started talking about other drugs, we’ve had two come in on Facebook: Christelle asking if non k anticoagulants are as effective as warfarin and Anna from Barcelona, hello Anna, she’s on acenocoumarol instead of warfarin and is that okay, and she’s been on it for 11 years since being diagnosed with APS after a double embolism.
Graham: The answer to that is it depends on the individual. We did a lot of our research work with the group in Barcelona actually and they are really outstanding in their contribution to the history of this disease. It’s one of the things that is tried and what applies is what I said in the last answer that if it works for the patient that’s great and we have a number of patients on it very happy, but the overall data has been worrying, that there have been some new clots in patients who swap from warfarin to acenocoumarol, but if you’re well, if you’re asymptomatic, you’re not getting headaches and so on probably stick with that.
Henry: What is acenocoumarol, is that a non-k non k anticoagulant? I don’t know what a non-k anticoagulant is.
Graham: Vitamin k is part of the clotting, don’t ask me about clotting. I don’t understand it it’s so complicated, every time you go to a lecture on clotting your eyes close and you sit sideways. It’s complicated because there are dozens of 15 steps in clotting. The good news is that the boffins who deal with studies or clotting can isolate the various steps and hopefully provide an anecdote to each stem.
Henry: And are the non-k anticoagulants as effective as warfarin or what’s your view of that or is it more an individual case?
Graham: Well the original studies show that they are as effective. There have been studies in China of all places for people with heart clotting troubles, they’ve found that the new ones have been as good in trials, there’s only one big trial so far that I know of that’s been comparing these newer drugs with warfarin and that’s a combined study with Guys and Thomas’s and UCLH in London and sadly that’s been published showing it’s not as great an overall effect in terms of scientific lack of side effects and or stopping re-thrombosis risk.
Henry: Great well we’re going to go back to some of the questions that were sent in before. From Irene: ‘Can metformin cause a flare? It gave me a rash and other Lupus’y symptoms.’
Graham: Indeed, I don’t know that metformin is usually diabetes interferes I don’t know that I’m afraid, however if on starting that drug she developed a rash that almost certainly is an allergic reaction and you should try off the driver and see the dermatologist. Every drug can cause a rash, even our old friend plaquenil rarely can cause a rash.
Henry: And we had a question, which I do want to refer to. You said you don’t understand blood clotting. I think that was you being extremely modest. Sam asked ‘Must I come off anticoagulants to get accurate results for a blood screen?’
Graham: No you don’t, the only thing it does affect of course is the clotting mechanism and so in general it does not affect your routine bloodstream.
Henry: Right we’re going to our second set of questions, Living with APS, and we are trying to get to as many questions that are being posted as we speak as well and so I’ll try and blend those in.
Well kicking off with a pretty hard one on living with APS, so Tracy messaged in and she said: ‘What proportion of people diagnosed with APS live with a permanent impairment in their lives?’
Graham: I don’t know the figure I’m guessing but I would say five to ten percent have had a major clot and of course the most major ones are almost certainly the neurologic things. I mean I always teach that the two organs that are most sensitive to sticky blood are the brain and when you’re pregnant the placenta hence the recurrent miscarriage story, so the worst feature of APS of course would be a stroke. There’s one study which is really alarming and it came from Rome in Italy, that one in five young strokes under the age of 45 the stroke is associated with their Hughes Syndrome and antiphospholipid antibodies. So here with the government looking at causes of stroke and a lot of money being spent on diagnosis, here’s a very very important cause of stroke if you like in untreated patients.
Henry: Right and actually you reference pregnancy just then and we’ve had a question come in Gem on Facebook where she asked ‘How early on would you recommend taking baby aspirin and heparin please? I’ve been told by some people to start straight away or even when trying to conceive but others don’t start until 7 to 12 weeks’
Graham: Immense discrepancies here in the way doctors look at this. ABS is the commonest treatable cause, the commonest treatable cause of recurrent miscarriages. The problem is that when you look at the medical economics of it, testing all pregnancies apparently is prohibitive in terms of cost etc. Now I think strongly we can do better than that, better than waiting for three miscarriages which is the current talk. I think if the midwife or the doctor attending the patient on her first visit asks three simple questions; have you had a clot, are you a migraine sufferer or do you have a family history of what we call autoimmune diseases, by which I mean MS, thyroid disease, Lupus, then you should be tested and I’m sure that would limit the numbers who need the test. Now if the test is positive then of course the evidence suggests aspirin, certainly in my family it would be the rule, I mean there’s so little side effect in baby aspirin alone and it’s certainly been shown to be effective, but others have suggested that in their studies aspirin alone is not good enough in a patient who has got the diagnosis, and the present for those who’ve had a clot or have had recurrent miscarriages, there has been a move towards the combination of aspirin and heparin and that certainly has seemed to have improved the outcome. What about not being able to conceive? Yes that is a definite feature of my syndrome and we often have patients getting married, trying for pregnancy, nothing happened for two years three years and then for one reason or another they go on aspirin. Now we don’t know yet whether aspirin is the cause of the success in those patients or whether it’s a fluke, but the figures are improving year on year and it really has had a major impact in the world of pregnancy.
Henry: So I think one of the things you just said is that in general you see a positive outcome from treatment, assistance in conception and then pregnancy. So your general advice would be, and I should have said earlier but obviously the caveat is that this is a live Q&A not an individual diagnosis and you must talk to your doctor and that was obviously also particularly for people with the syndrome. So obviously people watching, you can see that we’re fluidly bringing in your questions as we can, going back to one that was sent before so Irene: ‘Doctors tell me that I don’t have APS but I’ve had TIA’s and been told that I have a brain aneurysm. How can I get doctors to take APS seriously when I don’t test positive on bloods but only on symptoms?’
Graham: That’s a problem in most aspects of medicine where the patient has many of the symptoms but the tests are negative and that’s certainly very much something we see now. If you’re sure clinically that this is the direction the patient’s going in then I would be treating her as a case of antiphospholipid syndrome. There are three reasons that that might be the case: one is that the tests were positive and they’re now negative, we see that, the other is that we’ve got the wrong diagnosis and I’ll come back to that, and the third one is trial and error, which is never the best thing. Having said that we’ve seen a large number, we’ve published on this, what we call seronegative APS will be improved dramatically once treatment has been started. Now the problem with this lady’s question is I think I’m right in saying she has an aneurysm and that opens a whole differential diagnosis. So there’s a questionnaire you can ask, I mean I’ve written one for our charity but there are 40 or so symptoms and signs that you can add up and get you know percentages that are indicative and that’s sort of a bit like self-diagnosis. But I think it’s what the doctors do and what many patients can do and having mentioned it I’ll send the team this list and some may argue with it but it includes very commonly things like migraine, balance problems, sometimes low platelets, bruising, movement disorders, shaky hands, they’re all neurological things and even seizures or an odd epilepsy type thing, they’re all features we see that are not put together by the doctor she’s seeing as one diagnosis.
Henry: Can you have Graham Hughes syndrome and test negative on the blood test?
Graham: Yes you can and we don’t know the percentage by definition but the number of people like Laura in our unit is looking at newer tests. So the third reason for negative tests is we’re not clever enough yet, that there are tests now available that come up positive where the others are negative. They’re available in research centers but they’re not out there yet so at the moment we’re still sticking with the three blood tests. When you give a blood sample three tests are done; APL or apple test as I call it, Lupus anticoagulant which is a fussy test and those are the two most widely used, or another one for 10 years now the beta-2 test, but as far as the doctor’s ticking the box is concerned, one tick and that’s tests for APL antiphospholipid antibodies.
Henry: I think that’s very interesting and obviously shows the complexity of the disease and also just the complexity of medicine that I think when you’re a patient you always rather hope that there’s an exact answer, that it’s always very clear and unfortunately that’s not the reality.
Graham: I should say that if her family or she puts herself through this questionnaire, she’ll get good halfway up if not more towards a diagnosis. Can I tell you about one patient I had, she had all the features of Hughes Syndrome, she was falling about, she had headaches, her memory was gone, she couldn’t remember family names and so on and she was diagnosed, tested positive, she was treated ultimate heparin first then warfarin, she’s perfectly normal now, working in a shop I see her once a year. And then it turned out she has an identical twin and stupidly we didn’t realize this and mother has Lupus and hence her referral to me and so we looked at the identical twin; falling about headaches, all the features but the tests were negative. Would you treat? The answer is yes, very definitely, so we treated with aspirin first then heparin and then she’s now on warfarin completely free of symptoms and she also works in the shop 200 miles away. So negative and positive but identical disease and so it shows where we are at with some patients.
Henry: That’s extraordinary I hadn’t heard that story before with a twin one being positive and one being negative but they both clearly showed the symptoms of having the syndrome. Gene from Facebook, perhaps a simpler question; ‘Is blood type connected to APS?’
Graham: No it’s not you mean ABO, as far as I know there’s no correlation, we looked at this many years ago and didn’t find one. Short answer
Henry: From Marion; ‘What is the recommended INR for positive APS with a history of DVT 3?
Graham: I mean this is very artificial because I haven’t seen the patient but 3 – 3.5, I think the rare patients were getting new mini strokes on warfarin that’s when you go higher, 3.5 to 4. Now the statistics show that the risk of bleeding is not as high as you think. I mean it’s only over four when the linear risk rises if that makes sense.
Henry: What do you mean by linear risk?
Graham: Well if your INR is 2 you may get marked improvement but still get headaches for instance, if you go up to 2.5 you may get an improvement in the headaches but if you don’t you’re starting to get mini strokes or whatever we often go pushing it very gently up towards 4. The figures going back 100 years or however long it’s been around for shows that if it’s over four that the risk of bleeding is higher.
Henry: Gene from Facebook posted a question for us: ‘I’m diagnosed as APS anti beta2 glycoprotein IGM and weak LA and Antithrombin III’ – think people will be interested to know what those all of those things mean
Graham: It’s getting to what we were saying in the last question actually there are three current tests. I mean until 10 years ago there were two tests, anti-cardiolipin which I think is the best test and then three groups actually one in Italy one in Australia found that there was a protein called beta2 involved in clotting and the antibodies to beta2 were a risk factor for thrombosis. So most labs now do the three tests but next year you may find it’s four or even five tests for one sample of blood, so your patients would just question me that that for me would be strong evidence of a clotting disorder.
Henry: Okay I think they’re asking what causes there to be different results with the different tests?
Graham: All biological tests and this is one which is for instance counting platelets, a variable of technical reasons as well as daily life reasons. There is a 24-hour clock which has effects on drugs and on symptoms and so on and some tests are very stable – they put some people in the North Pole 20 years ago and half of them were on a 13 hour clock and half of them were on a 12 hours o’clock, I may be slightly wrong there but that’s what they did and all the tests of the body except one were unstable. And the one was potassium, it remained absolutely the same, so obviously our maker gave a great importance to potassium whereas not quite so important for all the other tests.
Henry: Do you want to just go into a bit of detail about the potassium for people watching?
Graham: Potassium is one of the things, one of the chemicals in your blood that electrolytes and it’s important to keep it stable. It affects muscle function, it affects heart function and so on, but it’s important to measure it if a patient has any kidney problems
Henry: Gene went on to say that she didn’t want her children to have the syndrome and asked if there’s anything that can be done to prevent that.
Graham: Yes there is, go back to the family history – is it strong, you know is it just one relative maybe with a mild symptom or do you have an aunt with Lupus and a mother with thyroid disease, and if there’s a strong family history you should push to check your child. Now first of all it’s commoner in women than men, I think five times more common in females than males, recently that was because they were picked up from pregnancy problems but it may be a true difference. In my patients it’s uncommon to start before the period starts and if your daughter starts getting symptoms when the periods start which are not normal which are menstrual problems, starting period problems then I would push because we’ve seen a number of cases where the illness has started in the teens and the classic is a young girl who gets glandular fever type of illness, remains unwell, misses a whole term sometimes misses the whole year of illness and that’s often the history we get prior to any autoimmune disease including MS, thyroid and Hughes Syndrome.
Henry: So I think to answer Gene’s question, there’s nothing that can be done to prevent it but what you can do is intervene because I think she talked about some family relatives who have been very affected and have had a stroke while young. So I think what you’re saying is if there is a strong family history then tests particularly around the teen years and around when menstruation is starting. But to note that you could be negative before and after so you need to test a few times and really test just to check and make sure so that you can be preemptively treating to avoid a very significant event.
Graham: That’s what I would do in my family if I came across that I really would
Henry: We’re going on to symptoms now. Rosie from Facebook asked; ‘Does APLA affect your eyesight?’
Graham: Yes APLA can affect eyesight, that can be one of the symptoms. Usually it’s from the brain that there’s a feeling of partial loss of vision in one eye, occasionally it’s more dramatic and there’s a clot in the eye with some loss of vision. Luckily that’s rare but sadly it’s a feature in some patients – a medical emergency, heparin needed, anti-clotting and then possibly warfarin later.
Henry: And what happens to the eyes or what’s the impact?
Graham: The common symptoms are visual disturbances seeing funny shapes and so on or loss of partial field vision, you can’t see the right hand side of your picture, or dramatically very rare I’ve only seen a few cases where sudden loss of the vision in one eye. Loss of vision in one eye I always think of a clot because it’s not a disease for both eyes.
Henry: Our second question on symptoms from Mavis: ‘My daughter was hospitalized with a suspected heart attack, results were not conclusive – she continues to have angina attacks, swollen joints and Lupus symptoms. She injects twice a day to thin the blood. Could her systems mean a micro vascular disease and is there anything else she should be doing?’
Graham: So how old is she?
Henry: Apparently you diagnosed her around 20 years ago so we will have to guess from that. It’s lovely you have a lot of patients who come and watch and ask questions, it shows the high regard everyone has for you.
Graham: Well there’s two parts to this question, one is angina and the heart and the other is Lupus and angina is definitely a feature. Funnily enough we concentrated over the last 30 years on the brain much more and on DVT’s but we actually didn’t publish as much on heart disease. Things are changing, our cardiologists sending us now young women under 40 with angina and that’s one presentation. I don’t know if any of you have read Kay Thackray’s book which I think is the best book on the subject, Kay Thackray is one of my patients and amongst her many symptoms and the many clinics she had to visit was the cardiology clinic angina and that improves once you start anticoagulant. Lupus is very important because it’s a cousin of Hughes Syndrome, it’s an autoimmune disease, it’s now recognized as common and it was in our Lupus clinic at Hammersmith Hospital that we first described this syndrome in detail. We noticed that amongst our Lupus patients a small number, in fact it turns out to be one in five, have the sticky blood features and they differ somewhat from Lupus they’re not so much aches and pains as Lupus, more clots obviously in Lupus and the miscarriage problem it’s not Lupus it’s the sticky blood side. So one in five, it keeps coming up, one in five Lupas’s have Hughes Syndrome and some people call it a secondary APS as opposed to the primary APS which occurs in the absence. So most of our patients with Hughes Syndrome, four out of five do not have Lupus and the good news is that they do not seem to go on to get Lupus, and I speak from 40 years experience, that’s very rare. So if you have a young teenager with aches and pains, feelings of lupus, other funny symptoms like angina, specifically test for Lupus every time. Anti-DNA, simple test, test for sticky blood of course and they have different treatments. If it’s Lupus with sticky blood you with steroids and with an anticoagulant of some sort for Hughes Syndrome.
Henry: I’m sure it’s very helpful. Now she specifically mentioned microvascular disease, what is that and what could be done about it?
Graham: Microvascular, that term has come up a lot in the last decade, and that is instead of getting a big clot in your leg and your leg getting fat or a major clot in your heart and getting a heart attack, in some patients it seems to be a more widespread small vessel disease – microvascular in other words. And if a patient dies and they do an autopsy you see small plots all over the place and that’s important. So it’s diagnostically important because the patient can have a very confusing history given and hearts brain muscles joints and nothing too much to see and that’s certainly something that modern tests are able to help much more, scanning techniques are better and yes they need treatment as much as the patient with the clot is concerned.
Henry: We had a question emailed in and we’ve had a few questions come in which have been posted, for that reason for people watching they won’t be quite as well organised but we will get to them. I think this is a good point for me to say we are a charity, the Graham Hughes International Charity and donations are incredibly important. Normally charities will be relying on events and those kinds of things to raise money and those aren’t available to us, so if you are able to donate, donations are very important and very valued and without them obviously we can’t do anything. So I had to put that plug in but it is absolutely essential. Right so we had a question and it was sent in by email so: ‘My daughter has suffered severe intermittent psychotic episodes each lasting around five months since the age of 15. She was born two months premature and suffered an introvert ventricular bleed. If she has got Hughes Syndrome from me is there a chance that it’s sticky blood that is an intermittent trigger for sudden psychotic relapses? If she is put on some form of anticoagulant might there be a chance that these repeated psychotic episodes might stop?
Graham: It’s a big question, the answer is yes, I’ve got one patient with exactly that history who has responded to anti-coagulation. Long shot obviously there are many causes, I’ve forgotten whether you say there’s a family history or not, but it’s important to go to all those questions including family history. The brain is stupid if it doesn’t get enough oxygen you get headaches or your memory goes or you get seizures, there’s a study now to say that one in five teenage epidemics they’ve got this underlying problem the stickiness of the blood. My old answer would have been to say I must see the patient and go over it with her and her family, the question is weighing up the side effects of treatment on the effect of the illness. Now there’s no question that the doctor must not do harm but here it’s a terrible situation and it’s a consideration – I would do all the blood tests including the newer ones for this patient for sticky blood, I would even test the family for it which will give you an added help towards a possible label for your daughter. Then I would consider treatment – now there’s one treatment which we use a lot in my clinic, that is the use of heparin. No good giving aspirin alone I think here because it’s probably been tried. Heparin is a daily injection, it’s used for anyone with a clot because it acts immediately and I’ve found from our pregnancy clinic that when a woman who’s had miscarriages goes on, her symptoms disappear, headaches are gone for most of the nine months. At the moment it’s the best we’ve got, two or three weeks of self-administered heparin the daily injection given by the patient herself and it may not be long enough but it often gives you a clear black and white answer and it’s something that we’ve published on and it’s out there, we certainly have experience of it.
Henry: So you’ve published on psychotic episodes and Graham Hughes Syndrome?
Graham: We have
Henry: Well look I hope David that’s helped, it’s clearly very very very important. Those are all our questions that we’ve had sent in prior and now we’re just going to go through some that have been done now. Right COVID is obviously a question here so we’ve got Christina from Malaga in Spain: ‘Could COVID be a trigger for CAPS, are we at risk?’
Graham: CAPS is for catastrophic APS and there’ve been a number of studies and people in Barcelona actually are the main collectors of all the data on this very rare disease. Patients suddenly change and get clots everywhere, they’ve been going along nicely for 10 years or whatever, I’ve only seen three or four in my life. It’s very complicated. Occasionally it’s caused when a patient suddenly stops their anticoagulant, the other time it’s been associated with a big infection that has triggered it. So you’re very wise to ask whether that could be a factor, now all I need to do is contact the group in Barcelona and say has this been reported but to my knowledge it’s not a risk factor, I think you would have heard about it. One of my hats is as the editor of the General Lupus and I have not seen papers yet suggesting this.
Henry: I’m aware from the GHIC trustee meetings obviously this is a very significant discussion point and as yet I don’t think people are aware of a significant difference for patients with Graham Hughes Syndrome and having different outcomes but obviously it’s very tough right now in terms of the amount of data being available. At the moment there isn’t thought to be a significant issue but studies are coming out at the moment so we will learn more in the next few weeks and months. We had a question from Carolyn: ‘What’s the correlation between APS and anemia?’
Graham: It’s not a major correlation in that you know all patients with APS get anemia but in some patients bleeding is a problem, of course depends if it’s in the lower bowel, a clot there can affect the bowel, cause an ulcer and cause bleeding, but it’s very rare to have a patient whose main problem is ongoing anemia as it may sound that this patient has. But it’s not a common thing that we see associated. The other thing in the blood is the platelets and they are part of the syndrome and in the old days we used to think this was the main problem that the antibodies messed up the platelets, which I would like to think of the platelets as salmon swimming in a river, they don’t touch each other but if they are affected by the antibody they get sticky and clot, and some patients run along with a low platelet. The normal is above 100 and they run along with 80. And that should be taken into account when you’re doing your tick list of features.
Henry: Right and we’ve had a couple of questions around vitamins. So Anna wrote in saying; ‘I’ve been diagnosed with APS and a protein C deficiency, I’ve been on warfarin ever since. I had a stroke when I was 19 after taking contraceptive pills and in 2018 another stroke and DVT again, a clot in a hip and changes in lungs but I’ve always had problems with painful heavy periods. Some women feel better after taking apixaban, would it be safe to change to apixaban or is it better to stay on warfarin?’
Graham: The answer is we don’t know at the moment. I wouldn’t say yes if you’re doing well on that with your bad clotting problem. Protein C is another of the clotting proteins, it’s a different condition, it’s bad luck because quite a lot of people have protein C deficiency and if they get Hughes Syndrome as well it’s a double whammy if you like, and if she’s okay on warfarin I would personally wouldn’t rock the boat but it sounds like the patient wants to try a change and I have no major objection. The worry is the symptoms she has are severe obviously.
Henry: So in terms of how well would you say someone’s doing, so she said that she’s been on warfarin since 2003 but in 2018 she had a stroke and a DVT clot in her hip and changes in lungs. Would you consider that normal?
Graham: That is very serious, obviously she’s in danger of another stroke and these are the patients where in warfarin you’ll be talking about an INR 3.5 to 4 and the patient will tell you with her diary whether she’s improving dramatically on 3.8 or 3.9. That would be my first move.
Henry: So you’d be looking at that you’d be very concerned and you would look at their medication and potentially increase the amount of warfarin. And where does apixaban sit alongside warfarin?
Graham: There have been a number of patients who have developed a new mini clot having gone across from warfarin and that’s where I was rather worried and negative about the new drugs. Well perhaps I’m too negative, a lot of people are finding them useful but this patient, she’s getting many strokes and therefore she’s not being fully treated yet. It may be that she’s on other medicines that I don’t know about that are interfering with warfarin and I don’t know that.
Henry: Actually talking of other medicines, so Fiona on Facebook has asked: ‘Is it safe to have warfarin in HRT?’
Graham: The answer is yes it will affect the warfarin dose, the INR slightly but surprisingly it does alter the level at which you run with your anticoagulant clinic but no there’s no major contraindication.
Henry: And we had Chris also on Facebook ask about levels of vitamin D – ‘Is there a recommended level of vitamin D for APS patients?’
Graham: Interestingly vitamin D has become a major drug in autoimmune diseases, it’s been found that vitamin D deficiency is very common in Lupus, very common in other autoimmune diseases and there have been studies suggesting that some patients with Hughes Syndrome have a low vitamin D. How that works or interferes with I don’t know but most of our patients are taking the vitamin D spray or tablet daily so long as whatever you’re taking I think is on a level basis then I would not be against it.
Henry: Yeah and I think it’s common for people, obviously we’ve got an international audience but in the UK it is actually quite common for people to have a deficit of vitamin D particularly in the winter and marginally too I think in Autumn and Spring.
Graham: Yeah it’s very interesting, there’s a very interesting study on Lupus and vitamin D because it’s supposed to be linked to a shortage and they looked at the slave generation going from Africa to South Carolina and the black population of South Carolina had a lot of Lupus and then they looked at the people of Sierra Leone, identical genetics but no Lupus and so why the difference? The only difference they could find was the vitamin D levels were normal in Sierra Leone and low in America and that’s where that bit of data stands for the moment.
Henry: Wow interesting! We had a couple of questions, we’ve tried to bundle them together. So Beck’s messaged in saying; ‘Hi I used to be able to run a lot of marathon distances but since I got severe DVT’s and APS diagnosis I struggled to run 5k without pain in my legs. Is there any chance I would be able to do fitness again without being in pain?’. And at the same time Carol said; ‘I was diagnosed in 2003 after DVT and given very little information’. I’m sorry Carol obviously we’re trying to change that at least for Graham Hughes Syndrome. ‘I have not seen any specialists for this since, despite going back and forth to my GP with various symptoms, fatigue, pain etc over the years. I’d never been told these symptoms had the potential to be APS related until I met another sufferer who put me in touch with the APS site and everything fell into place. Should I be pushing to see a consultant because my GP doesn’t seem to know much about APS?’.
Graham: Yes definitely, DVT may just be the tip of the iceberg. The patient who runs for instance, is there an element of angina, what’s stopping that patient going, yes DVT can affect the blood supply to your lower limbs of course but diagnosis being made therefore you should look at the rest of the body’s physiology or diagnosis and that’s one of the reasons why my colleagues have set up this charity. We have 75 international doctors on our books and we’re hoping to increase that hugely, there’s only 34 countries involved so far, obviously that’s wrong but talking about the UK it’s something that we really really are pushing that we get a list of doctors who are knowledgeable about Hughes Syndrome in a big way. They’re not from Lupus doctors, they’re often doctors who are under clinics as part of Rheumatology, they may be a place to start or hematologists but I’m sorry it can’t be more helpful I hope we’ll be able to help you with addresses and details and maps in the future.
Henry: So I think answering the question, yes you should definitely push for seeing a consultant and we as a charity are obviously trying to help you find consultants and that’s something we’re working on at the moment, there is already a list on the website that you can use and we’re looking to expand that. I think Graham was doing a good job of saying that we recognize it’s an international problem and we’re trying to build that out internationally as well and that’s one of the many things the charity is trying to do. As I say donations are very very important and please donate to the charity, you can donate on the website. But fatigue and pain, just to clarify those are symptoms of Graham Hughes Syndrome?
Graham: The answer is yes, it can be and often is. One thing which I haven’t mentioned is memory loss. Migraine I think it’s one of the commonest features starting when you’re 15 saying ‘oh yes I used to get regular migraine headaches and I was off college and school for two terms then it went away and then it came back’ and that’s often the history we get of headaches. But the one above that in frequency I think will turn out to be memory loss. So many of my patients would go through the history and I asked almost accidentally if you have any problems with memory and it comes pouring out ‘I’m the joke of the family I can’t remember names’. I always quote one patient when I give a lecture who couldn’t remember the exit from the roundabout when she was driving her children to school and about five or ten years ago I suppose we did work at St Thomas’s where we had a registrar from the neurology department or neuropsychiatric department doing memory tests. Just to give you one example: a young woman aged 20 something, her memory was so bad on his testing, it was word finding, she was under 20% of the normal and she had a three weeks heparin trial, which I mentioned earlier on, and her memory test dramatically improved, nearly 90%. Now that’s a true figure, anecdotal, in one patient, our professor psychiatry said no psychiatric person comes anywhere near that sort of improvement. So I take memory history very very carefully as an indication perhaps to be a bit more positive about treatment.
Henry: You talked on memory just then and we had a question from Jillian who’s watching and she said: ‘Is dementia common in APS?’ Her last brain scan report two years ago had a comment that there might be signs of dementia.
Graham: So don’t sit on that, run to the doctor to get seen because the tests are clinical, first of all do you have memory problems, can you be tested or other simple rules, yes there are, is the family history, same old questions, any form of clot suspected. And then fancy tests which of the moment the fanciest test of course is the brain MRI and that shows one of two things; either nothing wrong which is common or little dots like the sky at night and that is probably a little mini clots, that is an indication which probably was the case in your brain scan, that there have been blood clotting problems and if there are still symptoms and signs then I would be on anticoagulants. Because in the early days, one of my earliest cases was sadly dementia. She was playing a piano I think in a little band that toured a country, wasn’t this country, and slowly couldn’t get the notes right, bit by bit went into full dementia, so here’s a woman not diagnosed, not treated and not getting the right treatment for what is a treatable condition.
Henry: And so is dementia linked to APS?
Graham: We’ve linked it, we’ve put this forward as a rare manifestation of untreated APS and that’s what I would say, that one of our main aims is to catch this thing before it causes brain symptoms which are irreversible. As a main cause of dementia I don’t think we yet know, I don’t know of any study of a large dementia clinic. Maybe I’m wrong there, somebody must have done this, but certainly it’s a feature of some patients in APS that if not treated goes in the direction of dementia.
Henry: That’s very important and interesting so your recommendation to Julian is to go and get that investigated very quickly.
Graham: Yes and there’s always a risk as a doctor of overstating the case for what they’ve done and I recognise that but in a patient with worrying episodes of dementia at this young age I will be chasing.
Henry: I think with both conditions more is being learnt all the time and so it’s very important to get investigated and talk to a specialist. We’ve got four more questions and I think we’ll stop taking questions from the floor now and start to finish up. If you do have further questions do still put them in the comments and we’ll log them for next time as Graham’s very kind and generous and I’m sure we’ll do this again. Carolyn from Facebook has said ‘Is a repetitive weak positive blood result over three years still a positive and clinically recognised?’
Graham: Yes is the answer I would say yes. We see a lot of that borderline positive, intermittently positive, and you should be suspicious. Taking the patience and picture rather than just the blood tests.
Henry: And that goes back to the list, you were talking of other symptoms that help you understand that the disease is present and the list obviously we will be putting up on the GHIC website for people to review for themselves as well. Ellen has sent in a question, I think it was particularly interesting because we’ve talked a lot about women and this is about boys so: ‘I’ve been tested because my son got APS, the symptoms came back with numbers just above the values. Doctors say it’s nothing to worry about but I have some problems with short-term memory and chronic migraines. I’ve got three children and one miscarriage – should I push this with my doctor?’
Graham: The answer is yes, doctors would hate me for this I know but she’s got the history of miscarriage, she’s got migraines certainly, possibly memory loss. Looking into the family, yes is the answer, very important and she will find this is one of the best things she’s ever done.
Graham: And talking to her other children and her sons, should she be asking for her sons to be tested?
Graham: Yes. In statistics terms, as I mentioned, women outnumber men five to one, figure five to one keeps coming up and so boys seem to escape more the disease than women but with her family any of the boys getting headaches or any symptom which is unusual I suppose, the boys are what mid-teens, then they’re probably okay but if they’re getting symptoms, test. Even if all they need is a baby aspirin every day it just can help that situation.
Graham: Her son has been diagnosed and I think she’s asking if she should go and be tested and your answer is very very clearly yes. You’ve talked about looking into family histories, so how genetic is Graham Hughes Syndrome?
Graham: Good question, I was going to mention that there are genetic studies going on. There are family histories which have large family trees with this so there is definitely, like all autoimmune diseases like thyroid for instance, there’s often a family history. We don’t know what the gene is yet or the genes involved are but that’s under study. Every two years there’s an international meeting on Hughes Syndrome and quite a portion of that meeting is discussed on genetics.
Henry: Which further goes to show that if her son has been diagnosed with APS that it increases the probability that she may have it, particularly if showing symptoms. Last two questions, Elaine; ‘I’ve had APS for 14 years, I take warfarin and suffer from bone pain plaquenil’. I thought she asked a really important question and we’ve already touched on dementia, what can she expect as she gets older?
Graham: Well it’s like many autoimmune diseases, if you get the diagnosis right and very precisely get the treatment right you would expect the full length of life. Now there are statistics on that of course, they don’t go up to the 80s but I’ve got many patients who have these. I’ve got one school teacher who I know personally, who 40 odd years ago had memory problems and thought she was becoming demented. Gave up her job and she’s now in her late 80s I think, perfectly well, very sharp. So if you get the treatment right, you get blood flow right to the various organs you can be so much more positive.
Henry: Are there any particular conditions that you see more in older patients with APS?
Graham: Obviously the differential form of memory loss in older people is hard, there are many causes but APS is one of them and if it’s looked for with a useful test, blood test, the apple test, then I think you’re starting to make inroads into that story.
Henry: Michelle sent in a question under the wire of questions but she has APS and two young sons. When should she get them tested? Because we talked with girls that around when they’re having their first period is a good time to get them tested, is there a particularly good time to get boys tested or when would you do that?
Graham: No don’t go down that path yet, unless the boy shows something maybe that’s wrong, maybe that’s too conservative but if the boys are doing well and have got full fitness doing normal sports, no headaches etc then I would not push at this stage but as I say we’re gaining more information all the time and hopefully more sensitive tests.
Henry: Keep an eye on our website, subscribe to our list, we’ll let everyone know when that list of symptoms goes up that you’ve talked about but I think your comment to her is keep an eye out for other symptoms, I think listening to this video has given an idea of what some of those are and if one of the sons starts to show those then think about a test, but there’s no need to just go and test regardless.
Graham: Yeah I mean a teenager, I mentioned idiopathic teenage epilepsy, there’s quite a story now that some people get their first seizure, and that includes boys of course, and that’s a severe symptom obviously. Before we end can I come back to genetics, the family study.
Henry: Yeah absolutely
Graham: Well I had a an elderly man in his 60s I think who came to our clinic at St Thomas’s accompanied by his daughter who happened to be one of my patients who herself suffered from Lupus, and this old boy came from the Old Kent Road, which is the poorest place on the game, and he had a DVT and a few other things and I asked ‘Do you have any family history?’ ‘Oh no doc nothing nothing no family history’. Anyways his daughter poked him in the stomach and said come on dad. It turned out he was one of 11 siblings, all of them except one I think had features, one had migraine, couple had strokes, one had a heart attack, a couple had DVT’s and the daughter had Lupus. So there’s a family study for you!
Henry: Say if we take women, if the mother has Graham Hughes Syndrome do we know what percentage of daughters are likely to have it?
Graham: I think there are some studies out there, I don’t know the true figure now but I’ll find it for you, it’s published, 250 rings a bell but don’t quote me on that until I get the figure.
Henry: But the main point being it’s a small fraction, it’s not guaranteed. Do you think the gender split could be due to the increased diagnosis in women due to issues around conception and pregnancy, or do you think it’s not evenly split between genders or do you think it could be?
Graham: We used to think originally that it was the first thing you mentioned which is that they were picked up because they’d seen the doctor for pregnancy. We know now that that’s not quite the truth, that women outnumber men about five to one and that’s interesting because all the autoimmune diseases are common in women and it’s believed now that female hormones increase the autoimmune response in general. Lupus for instance nine to one women to men, so you know a huge difference in sex ratio and all the diseases I mentioned like thyroid rheumatoid, MS and so on, commoner in women and I think that applies to this which is an autoimmune disease. If the immune system has gone wrong it’s producing antibodies which are bad guys, not good on the whole, and it’s a disease that we can diagnose and we can treat which is marvellous.
Henry: Our last question, Carolyn said; ‘APS is still massively unheard of across primary care and secondary care specialists, therefore how can we drive awareness and learning and ensure APS is part of the curriculum in doctor’s foundation and core medical training?’
Graham: Well I think doing more of what you’re doing here now, making videos, I’ve written lots of booklets and books for patients. The modern thing is of course the internet and I think with teams like Henry’s here that we will get through in the UK and I’ve lectured all over the world on this and it’s surprising how widespread the keenness and the interest is full house always amongst doctors. So I think that the word is getting out there, some countries like Italy, France, Spain where knowledge is jumping ahead, the very good teams working on this, and so internationally it’s becoming more recognised certainly in the Journal of Lupus which I’m involved with, more papers coming through.
Henry: And is it a part of core training for a doctor do you know?
Graham: I’m prejudiced because I think it’s important
Henry: Obviously we all agree it should be but do you know if it’s a part?
Graham: It should be part of core training because it touches on all branches of medicine.
Henry: I think one of the issues obviously is the weight that it’s given and then that doctor remembering it is an important time in the future and raising the profile of the disease in the medical community and in the patient communities and the wider population is obviously very important. The reason I had this question last is because it’s a lot of what the charity is trying to do and we need money to do that so please donate and absolutely that’s why that was at the end but it’s actually a genuine thing that we, raising awareness doing this kind of thing, increasing the profile of the disease and the charity is a core part of our work and and very very important. And more awareness actually means more diagnosis and more life saved, it is implicitly important we’re then working to provide quality information so people can understand the disease well and we’re constantly building that out as you’ve seen on the website which we renewed just a couple of months ago. Ongoing looking to fund research and as you’ve heard Graham is instrumental in the research area and runs the Journal for Lupus which is collating and publishing a lot of the papers on Graham Hughes Syndrome, so very important and is one of the many reasons he remains one of the centre’s leading experts on the disease because he’s constantly keeping up to date and being a part of moving that knowledge forward. That’s all our questions Graham, you’ve been fantastic as ever, I know it’s hugely valued, we’ve seen all the questions coming in and we obviously know from the comments, I’m sure we’ll see some later but people from all over the world, from South Africa from Spain and other places tuning in to watch. I know from comments previously that people scheduled to take days off work to be watching this and so it’s hugely valued and thank you on behalf of everyone. And obviously it’s the Graham Hughes International Charity so you’re both the founder and remain the centre of the charity. So thank you very much, do you have any final words you want to say to people, is that anything you particularly want to cover?
Graham: Well thank you to Henry and his team and thank you to the colleagues who’ve started this charity. I don’t understand clotting and I don’t understand the internet but you’re doing it for me, I hope I understand clottings more when I speak to you but many thanks to all of you, thank you.
Henry: Well thank you very very much indeed for doing this and I look forward to doing it again. For everyone watching Graham has very kindly promised to keep doing these and I think a huge advantage. So I’ll say goodbye to Graham and thank you very much, obviously my final thing I have to say is that GHIC is trying to do something very important, trying to really change what it means to have Graham Hughes Syndrome and to change the impact when you’re diagnosed, provide you with information, provide you with support and then fund research to change those outcomes and look into more about the disease. Obviously our main thing is to try and find a cure but everyone is working very hard, we can’t do anything without donations so please do consider donating, you can donate on our website and links are on social media. Thank you for watching, if you’ve got any further questions do post them in the comments we will store them and post them next time, otherwise look out for our next announcement, we will also be bringing in other people who are part of the Trustee Board and specialists in Graham Hughes Syndrome to compliment the great man himself and to provide other viewpoints and answers. So we look forward to doing that, please subscribe to the mailing list and follow us on social media to be notified of that. That’s it so goodbye again to Graham and thank you very much, we look forward to everyone hopefully joining us again!