Session 5 – Sarcoidosis with prominent systemic disease features – The Royal Brompton & Harefield Hospitals and SarcoidosisUK 2022 Sarcoidosis Patient Day

Transcript 

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Dr. Kouranos: Yeah, I just want to say a few words about you, Elizabeth, just before you kick off for the last session of the specific forms of sarcoidosis. And I actually think that you don’t need any specific introduction. You are well-known to the sarcoidosis community you are, I think, the clinician that has been mostly involved with patients on a day to day basis, very reflective in all their symptoms and everything that is actually happening more than any other clinician that I have seen, and it’s an absolute privilege to work with you. I’ve learned a lot from you. Over to you.

Dr Elizabeth Renzoni: Thank you so much, Vasilis, that’s very, very kind introduction. And without further ado, I will move on to presenting the fifth session which is on systemic disease features. It has two speakers. One, Mr. Harry Petrushkin who will be talking about ocular involvement. He has expertise in a number of inflammatory ocular conditions, including sarcoidosis from Moorfields with whom we have a long-standing collaboration for our patients with sarcoid. And the second will be Dr. Christopher Atkins, our respiratory physician consultant who works at Norfolk and Norwich University Hospital and has a particular interest in fatigue, was also co-author of the BTS recent statement on sarcoidosis. And I would also like of course, to introduce Joanne Daly, who is our patient with whom I co-chair. And I think we’re going to be seeing the video, first of all, of Joanne.

Joanne: Thank you for inviting me today to the patient day. I just wanted to talk to you a little bit about my sarcoidosis journey. I was 28 years old, so 23 years now, since I started my journey. And I kind of, like a lot of diagnoses, took a while and things were never straightforward. But I’d just like to talk a little bit about fatigue associated with the disease, and also with the medication that we many of us take. And for me personally, it’s probably the most underestimated symptom. All the other symptoms can either be seen, or people can relate to them.

But with fatigue, it’s so misunderstood, it’s underestimated, it’s not quantifiable, people think that it’s tiredness. And actually it impacts on every aspect of your life; from friendships, relationships. I’m so many different things to different people. You know, I’m a mom, I’m a work colleague, I’m a daughter, I’m a sister, I’m a friend, and it impacts on all those relationships. And also it impacts on your mental health. You kind of have to reevaluate your whole life and look at things and work out what’s a priority. And always, sarcoidosis doesn’t define me, I’ve definitely had to readjust, I’ve had to kind of take a step back. And think what’s important, because fatigue, it kind of, it hits you like a brick, you don’t really see it coming, no amount of sleep can make it go away. But for me, personally, stress has a massive impact on the way I deal with fatigue and kind of how often I suffer, really. I can be in a meeting and suddenly I just go blank, and I lose the ability to make decisions. I can’t function.

So, for me, I’ve had to completely readapt my life. So, I have stepped off for a little while. So, I’ve moved to the beach with my dogs and my son, and I’ve changed my job. And I’ve reduced my outgoings so I have a lot more time off now and a much nicer life. I keep my friends and my family really close. And yeah, that’s the only way I can kind of manage it on a day-to-day basis. I have a really good working relationship with my boss and also occupational health are a huge form of support. There’s many, many people over and throughout my journey that I’ve kind of had to leave behind and pick up new people on the way. And I’ve had to learn to say no more, which is really uncomfortable for me. But overall, it is certainly the single most symptom that has had the biggest impact on me as a person and everything that I do. So, yes, thank you for letting me share that with you.

Dr. Renzoni: Thank you so much, Jo for this wonderful detail. So, I think we’ll leave now Mr. Petrushkin for his presentation on the ocular sarcoid and then we’ll have the sarcoid associated fatigue with Dr. Atkins.

Dr. Harry Petrushkin: All right. Hi. Thank you for inviting me. Can you all hear me okay? Yeah.

Dr. Renzoni: Yeah, we can.

Dr. Petrushkin: And you can see the right slides? I had a slight IT meltdown earlier.

Dr. Renzoni: Yeah, you’re good.

Dr. Petrushkin: It’s very nice to see everybody’s face. I’ve seen everybody’s names last, but it’s unusual that we all get to actually see each other. So, my name is Harry Petrushkin. I’m a consultant at Moorfields Eye Hospital. And I also work at Great Ormond Street. So, I look after the kids with sarcoid at Great Ormond Street as well. And I’m going to be talking about ocular involvement. But before I talk about ocular involvement, I’m going to talk about what uveitis is because nobody really understands it, including lots of ophthalmologists. And I’m just going to go over the anatomy of the eye a little bit and talk about the difference between anterior uveitis and intermediate and posterior uveitis.

So, I apologize, this is overly basic, but I think it’s probably just useful to get a sense as to where stuff is. So, this is half an eyeball. And at the front of the eye, you’ve got your cornea, this is the clear bit, front of the eye. And then you’ve got your iris, which is either blue or brown or green. And then you’ve got your lens. So, that’s the front bit of the eye. The middle bit is filled with jelly, and that’s called your vitreous. And then the inner lining is your retina, which is strictly speaking part of your brain, not your uvea, but it all gets inflamed, so it sort of gets lumped in with uveitis. Then you’ve got your choroid, which is a sack of blood vessels that feeds the retina from the outside. And then you’ve got the white hard bit of the eye like the shell of the eyeball called the sclera. And then this is your optic nerve.

And uveitis is basically itis, inflammation of the uvea. And we can split it up into different bits of the eye. So, if it’s in front of the lens, so over here, where my mouse is, this is anterior uveitis, which is by far and away the most common type of uveitis. If it’s behind the lens and in front of the retina, it’s intermediate. And if it’s mainly in the retina, or choroid, then it’s posterior uveitis. And again, we tend to use those definitions as where the bulk of the inflammation is because your eyes a bit like a snow globe. And so it will, you know, the inflammation splashes around a bit if you move your eye. So, we’re talking about where the bulk of inflammation is most of the time. And sometimes some people have pan uveitis, which means there’s inflammation everywhere. But the location of your inflammation doesn’t really have any impact on the severity of it.

So, uveitis can be caused by infections, but that’s obviously not what we’re here to talk about, but we’re here to talk about. And it can be caused by some non-infectious inflammatory disease. So, sarcoidosis is one of the conditions we look after, one of the more common ones. 70 to 80% of patients with uveitis don’t have a concrete diagnosis. And lots of patients we look after have something we call presumed sarcoidosis. And that’s because it’s very difficult if all of your disease is isolated to your eye to get a biopsy of something to give you a concrete diagnosis of sarcoidosis. So, many patients also have lung disease or disease elsewhere, which is easier to biopsy. But particularly in the children actually, I would say it’s really problematic because children tend not to have lung involvement. And so unless they’ve got a rash or a big lymph node that we can biopsy, it can be a real challenge to get a concrete diagnosis.

So, some of you may hear us talk about, you’ve got one [inaudible 00:08:37] cells or half [inaudible 00:08:38] cells in your eye. And that’s, what we’re doing there is we’re using something called the Standardization of Uveitis Nomenclature, which is a bit of a mouthful, so we call it the SUN criteria, which is just a way of quantifying how much inflammation is in your eye. So, we look inside your eye with a millimeter beam of light, and we shine it across the front of your eye. And we literally count the number of lymphocytes, the white blood cells that have leaked out of your blood vessels because of the inflammation that are floating around the eye.

And because the eye is clear, and you can see through it, which sounds like a ridiculous thing to say, but it makes it unique in the body. We can literally see what’s going on, we can see the pathology in a way that you can’t really unless you have skin disease. And we also have ways of quantifying the inflammation at the back of the eye. And we have this neat scan called and OCT scanner. So, an optical coherence tomography which is basically like a CT scan that uses lasers and light to reconstruct images rather than radiation. So, almost all of you who come to our clinics will have an OCT scan every visit.

And it leads to about 10% of patients with visual impairment registrations in working age groups. And given that it’s a rare disease, that’s a sizable chunk of visual impairment registrations. And the reason you’d lose vision in uveitis says either because your retina’s swollen, so that’s macular oedema. That’s a reversible problem. Because you’ve got vitritis, inflammation in the jelly in the eye, that’s a reversible problem. Or you’ve got a cataract, and that’s also reversible problem. So, all of those main reasons why people lose vision are reversible. And if you’re under the care of an ophthalmologist and a uveitis team, then you are spectacularly unlikely to lose vision. Yes, you’ll have to keep coming and seeing people. But you should really feel reassured that just the fact that you’re there, all of the things that might make you lose vision are treatable and reversible.

The thing that we can’t reverse is glaucoma, which is when the pressure in the eye goes high, and you get damage to your optic nerve. And when the pressure goes very low as well, that’s also much harder to reverse, but is rarer in sarcoid. So, there are a large proportion of patients that we treat with steroids, topical steroids or steroid injections inside the eye and that pushes up the pressure and about 30% of patients. So, there’s this trade off between treating the inflammation so you can see and putting you at risk of having glaucoma which may then need further treatment to prevent it progressing.

So, we use lots of steroid eye drops, we sometimes use non-steroidal eye drops, but they work less well. We use lots of steroid tablets. And we use steroid tablets at a dose, as sort of an eye watering dose really compared to lots of other doctors, because only a little bit of the medicine that you take by mouth gets to your eyeballs. So, you need, therefore, a big dose of steroid. And so if we were just using steroids to control sarcoidosis, bad sarcoid, in the eye, we’d be keeping people on a maintenance dose of 30 or 40 milligrams of prednisone, which is unacceptable in terms of the side effect profile.

So, therefore, we’re very proactive at starting patients on steroid sparing agents. So, drugs like methotrexate, mycophenolate, azatyphrine. And again, if you’re not stable on one of those first line treatments, were quite proactive about moving people on to an anti-TNF alongside. So, I think that is perhaps slightly different from some of the other talks you’ve had in terms of our eagerness to get away from steroids because we know how much steroid we need. And we know that if we keep you on steroid eye drops, or steroid injections, then we’re going to have to deal with the cataract and pressure complications of that, which is fine, if we know it’s happening, and we’ve planned for it, but we’d usually try and avoid it.

So, we also inject steroids inside the eye. And so some of you may have had steroid injections or steroid implants, and they work amazingly for sarcoid uveitis, because they completely dry out all the inflammation inside your eye. And work for three or four months for the short-acting implants and up to three years for the long-acting implants. But again, they have that trade off whereby they cause cataracts and high pressure.

So, most patients with sarcoidosis will get anterior uveitis. That’s inflammation at the front bit of the eye. It’s rarely sight threatening, it usually uncomfortable and usually get sensitivity to light with a red eye. But sometimes it’s painless, and patients will turn up to A&E and they’ll usually get steroid eye drops. And sometimes we see these little white dots at the front of the eye, which can be quite specific in sarcoid. They tend to be a bit bigger and fatter like these ones, and we call them granulomatous carotid precipitates, or you may hear the doctors say KPs for short. But what they’re talking about is those white blood cells, those lymphocytes that I was talking about sticking to the back of the cornea. And the different way they look really gives us information as to what the cause of the uveitis is. So, there are certain types of anterior uveitis that I would look at once and say, Well, that looks an awful lot like sarcoidosis.

Some patients get intermediate uveitis, which is inflammation in the middle of the eye, and so they wouldn’t get any pain, but their main symptom would be floaters and reduced vision. And you can see this is a photo of bouncing light back off the retina and the red glow is just the glow from the blood vessels at the back of the eye. And it’s highlighting all of that white kind of rubbish that’s floating around in the middle of the eye, a bit like a snow globe that’s been shaken up. And some of that is active inflammation that will be treatable with steroids and some of it is old inflammation, which will just remain as floaters.

And so those of you who have had inflammation inside your eye will know you have more floaters now than you had before you had that inflammation, even if your doctors are saying you’re fine and that’s because there’s nowhere for that to go. So, once you’ve got inflammation and sort of debris floating around inside the eye, and as you surgically remove it, which is possible but has risks and we usually try to avoid doing that. You just notice these floaters that you didn’t have before. And you can have these snowballs that appear at the bottom of your retina and your vitreous, as you can see on the other picture, that are just little aggregates of white blood cells that stuck together.

And finally, I’m going to talk about this thing called sarcoid choroiditis, which are these deep white things. So, you can see in this picture, these white areas underneath the retina. So, you’ve got your retina, you’ve got the blood vessels in the retina, and you remember, underneath the retina, in that first picture, you’ve got a big sack of blood vessels called your choroid, which supply the retina with oxygen. And the choroid is a really key place for granulomas to occur. And, interestingly, we see that much more commonly in older patients who are Caucasian, this particular variant, and we’re looking into why that may be but it tends to be quite insidious. So, if you have this sort of picture in the back of your eye, you may have perfectly normal vision. And your OCT scan would be normal. And we only see after many, many, many years of having this, that you then get the secondary consequences of untreated inflammation. And so this is just an example of that.

So, this is an OCT scan, so an optical coherence tomography scan. It’s a cross section of the back of your eye. And this is a normal retina. So, the top bit above the kind of bright white lines looks normal. But what you can see behind the retina is it’s all thickened. And that’s delineated by these white lines underneath it here. And that happens in tuberculosis as well. Sarcoid and tuberculosis are actually very similar in how they present at the back of the eye. And you can see once you’ve treated it that these white lines get much closer together, and the big stack of blood vessels just sort of shrinks up.

So, I’m going to do one case. This is a 19-year-old Somali girl who presented with poor vision and she had — optic nerve had lesions, granulomas at the back of her eye, and all of these punched out peripheral scars. And we didn’t know what was wrong with her. She had never had any TB contact, and I said TB and sarcoid in the eye look very similar. And you can see these dark spots at the back of the eye, which are old granulomatous lesions which have scarred up. And you can’t see very well in the middle here because this patient’s got a cataract. And just behind you can see the optic nerve, which is shining a bit pink, because it’s inflamed. And this type of picture is really classical, actually of young children, when they sarcoid, they get this white subretinal, fibrous tissue that forms around the disc, which we rarely, rarely, in fact, almost never see in adult. But often in the young adult population, it’s been undiagnosed, and so we picked up on that. So, she actually did very well, just with cataract surgery and some steroid injections inside her eye and has done well.

So, I’ve tried to keep it relatively punchy, because I’m sure that it’s quite — I would find it very difficult to listen to a full day of doctors talking, but I hope it’s been useful. And I just want to highlight the point that sarcoid is very variable. And that very, very, very, very few patients go blind, or lose their vision permanently from sarcoidosis. Children present differently from adults. And it’s difficult to get a diagnosis in children. Because once you start your treatment, then it becomes increasingly tricky to ever find a site to biopsy to then get a diagnosis. And so lots of young people I look after end up with this presumed sarcoid label long-term. But we usually have to make a risk assessment. Is it okay to hang around not treating you while we try and get a diagnosis? Or do we need to get one and treat you to save your vision.

And as everybody I’m sure said, communication is essential, particularly in big cities, where you’ve got multiple teams working across multiple hospitals. Doctors should always copy in their other doctors and I would have no problem with reminding the doctors that you see, to copy them in. Because we are bad at that, as doctors, we are always bad at that. And even when we copy them in, sometimes they don’t get posted from the hospital. And sometimes you end up needing to be the custodian of your own care, which is not great. And we all recognize that. But until it gets better, I just really want to, I guess, my final message would be to empower you all to make sure that the doctors are doing what they’re supposed to be doing in regard to communication, because we all kind of know what we’re doing in terms of the body we’re treating. But sometimes a helpful nudge is useful. Thank you very much. Happy to take any questions if we’ve got time.

Dr. Renzoni: Thank you, Harry, thank you so much for such a brilliant lecture. I think we’re going to take the questions together at the end of Chris Atkins talk. So, Chris, are you there?

Dr. Christopher Atkins: I’m here Elizabeth, yes.

Dr. Renzoni: Actually, I can’t see you on the video.

Dr. Atkins: Hang on. Let me turn that on. There we go. Hello.

Dr. Renzoni: Hello, hello. So, great to have you here and to speak about sarcoid associated fatigue. Please go ahead.

Dr. Atkins: All right, let’s see if I can share my screen. One second. Let’s find the right one, share screen. Okay, hopefully you can see the talk now. So, my talk today is about sarcoid, where there’s a significant burden of fatigue. And that in itself could fill many hours of talk. I think that the first thing that’s important to do is to define to an extent what fatigue means. And whereas there’s quite a clear demarcation between what is fatigue and what is tiredness, it can often be that the two are lumped together. Tiredness is where you want to sleep. I’ve got a two year old and a four year old at home and I feel tired 90% of the time, that’s usually relieved by sleep. However, fatigue is a daily lack of energy. It’s a constant exhaustion, and it’s not relieved by sleep. And for some people, it will vary, but it can be quite ongoing and therefore debilitating.

Within that there’s a physical component, and there’s a mental component as well. Some of those physical components will be things such as muscle aches, or weakness, muscle pains, the inability to do prolonged physical activity, probably being able to do the level activity that psychologically you feel you should be able to do. But from the patients that I’ve spoken to, the mental fatigue is probably the biggest problem. And the term that I hear the most is that brain fog, patients describing feeling like they’re wading through treacle when it comes to their brain processes. They can’t remember things, they struggle to finish tasks that they’ve started, and any kind of mental exertion leaves them feeling even more exhausted.

So, why does it occur? One of the difficult things in sarcoidosis is that there are many reasons why this occurs. The one which is perhaps more obviously associated with it is where the disease itself is active. And so there’s systemic inflammation. And we know that systemic inflammation will lead people to feeling exhausted as part of that. Patients who present acutely with sarcoidosis will frequently have fatigue as part of the problem. And that certainly came out from the British Thoracic Society’s sarcoidosis database, where fatigue was a commonly reported presenting symptom. But it can occur later on in the disease journey and there are other things that can cause that.

One of them is where the nervous system and its function, specifically the autonomic nervous system, which is the part of your nervous system that does tasks that don’t require conscious thought, that can show signs of dysregulation; certain small nerves around the body can show signs of damage. And that can commonly be associated with things such as tingling or pain in the extremities, sensation of burning upon anything touching your skin, and that can, the two often go hand in hand. These problems can also be exacerbated by issues with mood. So, we use the term depression but equally, if you will have ongoing symptoms from a condition then it’s not really depression to feel low in mood about it. It’s a completely understandable and normal reaction to that. So, when I say depression, what I really mean is low mood. And then alongside that is anxiety, and that also affects how an individual perceives their symptoms including fatigue.

There are also studies which have shown that sleep disturbance, things such as sleep apnea, restless leg syndrome and periodic limb movements are more common in patients with sarcoidosis, whether this is directly attributable to the disease, to the autonomic dysfunction that I mentioned, to the side effects of medications such as weight gain with prednisone, again, that in itself is probably multifactorial, but the presence of it is reasonably common, and can contribute to fatigue due to a lack of refreshing sleep. And then of course, finally there are medications and on the previous talk that was mentioned about leaving people on high dose of steroids not really being tolerable and there’s good reason for that. And certainly, long term high dose of steroids can cause problems. And indeed, whilst you’re on steroids, fatigue can be a big problem because of that because the steroids do impact upon sleep quality because they do cause weight gain.

But fatigue itself is a small part of a large, overarching picture. We can see that the sarcoidosis itself causes issues with direct organ damage and dysfunction. And that can lead to symptoms that leads to reduced function and performance status, which then leads to the psychological effects that go hand in hand with that. From both the sarcoid and from those psychological effects, we can see the systemic symptoms coming in, such as fatigue. And then furthermore, treatment can exacerbate that. But then that all has a knock-on effect in causing isolation and loss of social contact. And indeed, disability from sarcoidosis and from the symptom burden. But the symptom burden and the psychological burden go hand in hand. And that’s why it can be very difficult to tease out exactly where the fatigue is coming from, and which things can be modified, and which are less easy to modify. And that’s one of the challenges when faced with someone with significant fatigue in clinic.

When it comes to measuring fatigue, there are scales that have been validated for this. And the most well-known one is I think Fatigue Assessment Scale, which is scored out of 50 and can quantify fatigue, and has a well-defined, minimal clinically important difference. So, change of four points, in terms of reduction in score, is a sign of a significant improvement. But again, the honest truth is that actually your fatigue is whatever you tell me it is and a score, like the Fatigue Assessment Scale is useful in research where we’re trying to measure what’s going on in a population. But for an individual, it’s less useful. And so I don’t tend to use scores like that in clinic and instead, try to get an understanding of an individual’s story and narrative and how their fatigue has affected them and trying to get to the bottom of why it’s come through.

Now, we were in a situation where we had no guidelines for sarcoidosis, really, apart from part of the BTS work from 2008 on sarcoidosis. And then all of a sudden, we’ve had several in the last couple of years. And two of these do specifically mention fatigue. The first is the British Thoracic Society guidance, and that’s looking at fatigue that’s directly attributable to sarcoidosis, as well as those which are caused by alternative things. And so the treatment is essentially where either the management is to identify that fatigue is present. And that’s not always something which is done in a standard clinic. And so we’re trying to rule out other things. So, is there another, is there an active disease which needs treating first? If so, yes, then we treat that and treat with the appropriate medications that determine how the fatigue responds to treatment there.

If we don’t believe the sarcoidosis is active, then we need to identify alternative things that might be attributing to — we can attribute the symptoms to things like anemia and iron deficiency, thyroid dysfunction, hypercalcemia, which would fit in with the disease activity, and sleep disorders, as mentioned. So, it’s very important to take a very good sleep history in terms of looking for signs of sleep disorders, and then going through necessary sleep studies to see what’s going on there. And if we find an alternative course, then we treat that and we go back to the start. But if we don’t, and we strongly believe that this is directly attributed to sarcoidosis, then we treat the fatigue accordingly.

And there was some discussion about whether the first step would be to try low dose prednisone with or without hydroxychloroquine which is a drug which is an anti-malarial and is sometimes used in sarcoidosis. It was a consensus decision that low dose steroids might have a role here. But there was equally concern held that patients might then end up on long-term steroids with the consequent problems. And so it’s a very real issue. But one which is a reasonable treatment strategy.

For those where steroids are ineffective, hydroxychloroquine is ineffective or indeed after discussion of the risks and potential benefits, there’s a joint decision that treatment isn’t indicated in that way. We can look at alternative strategies. In some cases, that will be things such as looking at a fatigue diary, what exhausts you, what doesn’t exhaust you, how we can pace activities to fit in with the energy level that you have, looking at exercise. This was created at a time when the guidance nationwide for things like chronic fatigue syndrome still included graded exercise, but you may be aware that chronic fatigue syndrome that’s now fallen out of favor, but there’s still, I think, a role here for gradually increasing exercises. There is evidence suggesting that exercise classes or rather probably rehabilitation type classes geared towards sarcoid patients can have a benefit.

And then some patients find benefit from taking certain over the counter medication. So, there’s a medication called ginkgo biloba, which has some properties which probably not unlike caffeine in many ways, but which can improve fatigue, although the evidence for that is poor. It’s always important to check with your doctors in terms of where there’s an interaction with medications, because even over the counter supplements can cause impacts on medications, like warfarin, for example. But it’s definitely something that can be tried. And if all that is ineffective, then guidance is to consider neurostimulant medications with either methylphenidate or Modafinil. And if we get down here, then it’s something which needs to be constantly monitored. So, that’s directly treating fatigue.

I’ll go quickly through the ERS guidance, which has come out since the BTS guidance and perhaps looks at things slightly the other way around. If they found that there is no — If the European guidance have found that there’s no response to treating the sarcoidosis, then exercise training becomes again, the first standpoint and should that be ineffective then they talk about stimulant medications, and only at the end, if that’s ineffective do they introduce treatment.

So, you can see there’s a mention of neurostimulants and there is some degree of evidence for that in that there is a study for methylphenidate, rather dexmethylphenidate, which you can’t get in this country easily. But that was looking at five patients in a single letter, which describe those patients as tolerating it well and having marked objective improvement in their fatigue. And then a subsequent crossover study in 2008, which is where patients act as their own controls. They receive both the active drug and a matched placebo, but they don’t know in which order they get it. And that showed that they improved their Fatigue Assessment Scale score by an average of five points. So, that’s a significant improvement.

And likewise, Modafinil was also trialed. And that also showed a similar response. So, these are called neurostimulants, they improve wakefulness, they are used in other conditions, such as attention deficit hyperactivity disorder. And they have a reasonable rationale for why it works. But one of the problems with these crossover trials is that if you’re receiving the active drug, and then you’re receiving placebo, but you’re using a drug, where it’s quite clear from its effects, and side effects, when you’re receiving it, you can’t truly be blinded and so there can be a strong placebo effect.

And so for that reason, a study was undertaken to determine at least the feasibility about whether it’d be possible to do a true parallel arm study. And that’s where half, or in this case, 60% gets the medication, the remainder get a placebo. And so that ensures or at least to an extent, improves the blinding. And full disclosure, this study was run by me. So, this is how I came to know about stimulants in this indication. And so these are the outcomes for fatigue scores. You can see that people start off very fatigued, so Fatigue Assessment Scale score above 31, which is a very high score. So, a very fatigued group. Both groups show significant improvements, both groups remain below the line, this dotted line is the minimal clinically important difference, on average, both groups go below the line, so great, and one line is slightly better than the other.

So, one arm not showing a great deal of daylight, but maybe doing slightly better, the only problem is, is the placebo arm that did better. So, these neurostimulants aren’t quite the panacea that we think they are. But that doesn’t mean that they are ineffective, and it doesn’t mean that I don’t use them in certain cases. But it does mean that we have to be very careful about where we use them, how we follow them up, and whether they are indeed the right tool for the drug.

I just briefly talked about why those slightly strange results might have occurred. So, one thing that occurred in this trial was that there was a lot of contact with me throughout. And so patients got a lot of support from me, from the respiratory department going through this study. So, a lot of contact time. And what we see is that this is their anxiety score. The placebo arm becomes a lot less anxious, and remains a lot less anxious. The methylphenidate arm doesn’t do too much different actually, to be honest. That may well be because they would have had this effect, but the symptoms of the methylphenidate used actually makes them feel a bit more anxious as it is a common side effect. Depression scores didn’t change significantly between the arms. So, there was a degree of effect of essentially having frequent contact with their treating team, and therefore reduction in anxiety, and that might have led to the observed impact in the placebo arm. But it’s important to note that even those that had methylphenidate also showed a benefit.

So, coming towards the end, I’m wrapping up now. When I approach fatigue, it’s important to take a structured approach, and that’s shown in the latest guidelines. But it can take time to work through all those things. And that can often be frustrating, but it’s important to make sure that we are taking a structured approach to that. When discussing about what’s going on, it’s important to be open about what our aims and what our treatment goals are. It may not be possible to completely reverse the fatigue but with reasonable goals it may be possible to work towards those.

For all treatments there are risks and benefits and it’s important to discuss which ones would suit an individual. And whilst there is a reasonably rigid structure in those guidelines, they are just that, they are guidelines. And so that doesn’t mean that you have to try all the ones before you get to the step that you want to trial. We can change things for the individual. And then it’s important to monitor any treatment you are giving closely.

From a patient perspective, the question is, what can you do as it’s not just a paternal medicine type process, it’s not me telling you what we should do here. And in many ways, a degree of common sense in the approach is necessary. And that’s trying to look at what works for you. And keeping things such as diaries about what works can be very helpful. Identifying what works for sleep, what works in terms of your diet, what days you’re better, why that might have been, try and identify things that make the symptoms worse, pacing yourself within the energy levels that you have.

And then also support from patients within support groups such as SarcoidosisUK, who have similar problems, and you can share tips and tricks and find out what works for you. What works for someone else might not work for you. But you may find something that you’ve not tried that might be beneficial.

So, to summarize, this can be a difficult manifestation to treat. It’s not always directly due to the sarcoidosis. And we have to keep an open mind throughout. As an individual, what works for you won’t necessarily work for someone else. And so strategies always have to be individualized. It’s important that we agree on the treatment goals and what is reasonable, and try to move towards achievable goals. And then as I said, it’s important, again, to individualize this therapy. And it may well be that multiple strategies need to be tried, and to an extent failed before we find something that works for you. And with that, that’s the end of my talk. Thank you.

Dr. Renzoni: Thank you so much, Chris. Thank you both for such wonderful presentations. I’m going to go to Jo. We only have a few moments. But Jo, do you have some questions from patients?

Joanne: Yes, I do, thank you. I’ve been told I have systemic sarcoidosis, which is potentially causing problems all over my body. If you get your ACE tested, as I did recently at a rheumatology clinic, and this is within range. The person treating you doubts whether you have active sarcoid. How do we overcome this?

Dr. Atkins: That’s a common problem I think. I think we’ve all faced that with patients. Serum ACE is just part of the puzzle. There are some patients who present with very obvious sarcoidosis, who have no raise in their serum ACE. And we know those people, serum ACE is unlikely to be useful for some people, they present with a very high serum ACE, and we use it to an extent to see when disease activity is occurring. So, if you’re someone that had a high serum ACE to begin with, and it’s low later on, yes, it factored into my decision making, it isn’t the be all and end all if there is clear evidence to the contrary elsewhere. How do we overcome this? It is challenging. I think all of us try and inform our colleagues that serum ACE is not the gold standard for making a diagnosis and monitoring of sarcoidosis. And we’ll keep doing that. But I don’t know if anyone else has anything else to suggest on that. It’s something else that I have come across as well.

Dr. Kouranos: Elizabeth, what would your comment be on that?

Dr. Renzoni: It is sometimes difficult. In fact, it’s one of the most difficult issues sometimes when you have fatigue as the main symptom of sarcoid. We know fatigue can happen also, once a sarcoid is no longer active, and you’re left with dreadful fatigue regardless of that. And sometimes when it is really a very troublesome situation, you could do a PET scan, although you know, you have to be careful with PET scans because of radiation. But sometimes that can be helpful because if you see activity on a PET scan, you might want to increase treatment. If you don’t, you might want to go for the other actions that we’ve heard from Chris. So, that could be — when there are other markers that are used, such as soluble interleukin-2 receptor. We don’t use it here at the Brompton, but that might be something that we might be looking at introducing. So, it’s a difficult problem. Jo, do you have any other questions from patients?

Joanne: Yeah, there’s another one here. How can you encourage a health care professional to determine whether the problems you are experiencing are due to sarcoidosis or not when you are told well, it could be the sarcoidosis that is causing it and have no further investigations? For example, I have severe reflux causing swallowing difficulties and was referred for a fundoplication. The surgeon advised me not to have it as it could be due to inflammation due to the sarcoidosis, which wouldn’t go away regardless of the surgery. I’m now on high dose Lansoprazole for potentially the rest of my life.

Dr. Kouranos: I think that the questions are not really directed to the specific issues that we covered in the sense of ocular involvement or systemic or fatigue per se. So, I don’t know whether Jo, you want to place these questions in the Q&A session, I will reply to the patient.

Joanne: There are two others Dr. Kouranos.

Dr. Kouranos: If you can, especially since we have the ophthalmologist as well, if you have any eye questions or any fatigue specific questions.

Joanne: There’s one about bones and muscles and there’s one about spinal sarcoidosis.

Dr. Renzoni: I’ve got perhaps just one for Harry. And that is how much can a regular eye test, can you show ocular sarcoid with a regular eye test or do you always need more specialist tests?

Dr. Petrushkin: You can tell a huge amount with a regular eye test. So, if your optician or your optometrist, whoever prescribed your glasses, has seen you and examined you and told you that your vision is normal, and your pressure is normal, and taken a photograph of the back of your eye and told you that that is normal. That is very reassuring. Most optometrists also have OCT now in-house and they’ll charge you not that much money to have an OCT done if they think it’s necessary. And so actually the workup you’ll have on a high street optometry practice is really good. If you go to see an optometrist, if you think you have an eye problem and your optometrist doesn’t have the ability to take photographs, then go to another optometrist next door who does. It is not fair to ask your optometrist to tell you whether or not you’ve got ocular sarcoidosis. That’s an unfair question. But it’s a fair question to ask your optometrists, whether they think there’s any reason for you to be referred to a specialist. And actually, if they say everything looks fine, your vision is normal, everything’s normal; it would be unusual, very, very unusual for us to pick up something blindingly obvious.

Dr. Renzoni: That’s very useful. Thank you. Thank you, Harry. Vasilis, do we need to move on or do we have time for another question?

Dr. Kouranos: I would say that there are international colleagues have joined. So, just because I think that we have gone from one session to the other, I’ll just give us five minutes as a break, then we will start in five minutes, 20 past two, if that’s okay. I can see that colleagues from the Netherlands and Italy have joined.

Dr. Renzoni: And if there’s any, I know, Harry has already started doing that. But if there’s any questions on fatigue or ocular if you don’t mind just answering I think you’ve already started doing that. And thank you both so much, and the patients for all their questions.

Dr. Kouranos: Thank you very much.