Management of Neurosarcoidosis – SarcoidosisUK Neurosarcoidosis Patient Day 2023

Transcript 

Dr. Tarunya Arun: I hope you can all see my screen. So Leo and SarcoidosisUK, thank you very much for this opportunity. I feel really honoured, actually, to be in the midst of so many patients who’ve taken the time to join this afternoon. 

So the brief for my talk this afternoon was really to speak about the management of neurological Sarcoidosis. Now I can’t really start talking about this without paying real kind of tribute to the amount of changes happen within the pathophysiology, understanding the pathophysiology of Neurosarcoidosis within the last ten years or so. And this has certainly improved the way we manage patients with neurological Sarcoidosis because we understand the condition better. 

And a lot of my talk is designed today to provide you practical views on management of Neurosarcoidosis from my personal perspective, but also drawing on the small studies we’ve got within neurological Sarcoidosis. There is obviously a dearth of the study scenario within neurological Sarcoidosis. There are no randomized control trials to date. And there’s, of course, an urgent need for us to understand what we’ve got to do with patients with neurological Sarcoidosis, particularly people who are refractory to the current treatment scenarios we’ve got. 

So the goal of therapy, so in any patient with Sarcoidosis as an entity, but more often in neurological Sarcoidosis, it’s very important then to define what the goal of therapy is. First of all, I think when we look after people with Sarcoidosis, from my perspective, and of course, from perspective of patients who attend clinic, it is to identify patients who are in danger of poor outcome, i.e. so people whose organ function is threatened versus people we can actually wait to treat or perhaps monitor closely. There needs to be a distinction. 

The other goal of therapy is to improve quality of life. So we need to worry about how we are impacting the wider patient in terms of not only their sort of themselves, but also their families, their carers and a number of other things which play a significant role in their life as an entity. Then, of course, the treatment scenario, as I said, the pathophysiology of Neurosarcoidosis has now resulted in us understanding the condition better. But there’s also a number of more patients who are being treated with potentially toxic treatments. So we’ve got to identify how we minimize those drug-induced toxicities within patient groups. 

And then, of course, very importantly, it needs to be very much a mutually acceptable situation, which is clearly defined to both the physician and the patient. So what I really think is that a lot of our treatments have to be really based on not only based on patients’ needs, but also on the preferences of patients and their treatments. The goal of therapy is much more complicated than just pharmacological treatment. 

It is also very important for us to define, before we talk about management of Sarcoidosis, what the challenges to those management might be. This can be diagnosing. Neurosarcoidosis, I think, is a challenge. So a number of patients in this meeting would probably agree in that diagnosing their condition has been a significant challenge. 

That by itself places an important question as to what the clinical cause of that patient might be. So the clinical course might be very uncertain. Sometimes Neurosarcoidosis is found as an incidental finding. So in patients like this, what do we actually do? There isn’t a defined treatment pathway and it tends to be more art than algorithm in managing patients such as that. And certainly, as I said, again, no randomized control trials, so very much treatment is based on what an expert thinks, based on clinical experience and a number of case reports. So the challenges are there are a number, but obviously we’ll talk about each one of those aspects just as we go along. 

Now, I like defining Neurosarcoidosis Care as ABCD, so it makes it very easy to understand this. And a lot of you can probably relate to this as well. First of all, it’s assessment, so the A stands for assessment. So what is the symptom burden in a patient with Sarcoidosis? What are the organs involved?

So this is a very unusual entity. So particularly as a neurologist, I think it’s a very unusual condition we treat because almost any organ within the body can be involved in patients with Sarcoidosis. So it’s very important not only to assess whether that patient has got neurological involvement with sarcoid, but essentially, is their liver involved, is their kidney involved, you know, skin and bones? So they can be sort of the assessment has to be holistic, very important to then think about side effects, as I said, patient needs and preferences and carer support. 

Now, B stands for education. It’s backing within the base of education and also self-management, psychological support and patient groups. We’ll talk about that as we sort of come along in the stock. So really important to educate patients on what their disease condition is. So you’ve got to understand what you have and then it makes it sort of much more easy to have almost a holistic approach to management. Psychological support, I think, is incredibly important. 

So this is a condition which is life-changing for a number of patients across this call treatments, and the interactions with a number of different specialities which you might see during the course of your illness, and hence that psychological support to manage this is, I think, vitally important. I think it’s empowering for patients to know how to self-manage their conditions. So, for example, being able to understand what a flare of Sarcoidosis is, for example, or what a relapse is, and sometimes what an exacerbation in symptoms is and how they can self-manage these symptoms, sometimes it’s extremely important. And of course, patient groups such as what we’ve got at the moment, where we are currently, I think is perhaps very vital to the management as well. 

Now, C stands for complaints and comorbidities. So when we manage people with Sarcoidosis, I think one of the most important things we’ve got to think about is what are the comorbidities that patient suffers from? So that could be diabetes, for example, or heart disease or concomitant liver disease. So particularly when you’re treating patients with both disease modifying treatments and symptom based treatments, it’s very important not only to understand what the complaints are, which is what are the symptoms, but also what are the other conditions that patient actually struggles with. 

D is disease modifying treatment. So this is almost synonymous with management of Sarcoidosis. So with this slide, what I want to do is to almost talk about other things which might be important apart from the disease modifying treatment, which could be people having corticosteroids or steroids, sparing, immunosuppressants or biologics and newer drugs. And I think it’s only one, as you can see on my slide, it’s just one segment of the conversation. It’s not the entity. And of course, the centre part of the slide is the multidisciplinary teams which look after you. 

So as a neurologist, I’m one spoke in the wheel, but not all of it. So really I think it’s important for that conversation to happen between the patient and multidisciplinary teams, whether that is your pulmonary consultant or your cardiologist or your neurologist, or indeed your physiotherapist, your psychologist, you’re an occupational therapist. So all these people play a very, very important role in making your disease not only well controlled, but also you reach a point when you can actually live with it and manage it really well. 

Now, the first bit is the pharmacological management of Sarcoidosis. Now, again, I can’t start describing the pharmacological management to you without actually telling you what the assessment of that decision to treat is, for example. So this is something which we run through in our heads with pretty much any patient who walks into clinic. So very important, as you know, the centre of that is the patient preference. So what do you want to do with your condition? We will endeavour to obviously manage it that way. 

First of all, I think treatment who do I think I would want to treat versus who do I think I want to watch with regards to treatment, obviously completely in conversation with you. So the first thing is, if you’re symptomatic, for example, if you’ve had Sarcoidosis for a number of years, undiagnosed, for example, and you’ve been really struggling with those symptoms, whether it’s multisystem or whether it is neurological, it’s very important to assess what impairment that organ function impairment is causing. 

You’ve obviously sort of heard from the previous speakers about the multiple different parts of the neurological system which can be involved with patients with Sarcoidosis. What I can say is that not every organ or every part of neurological involvement needs to be treated the same way. So people with cranial nerve problems are treated very differently, as you saw from previous sort of talks about people presenting with hydrocephalus or spinal cord involvement. So the treatment differs depending on which part of your not only organ in the body, but which part of your neurological system is involved. 

Is the condition progressive? So this is very important. I think, for example, somebody who’s had an MRI scan which looks the same, but it looks active over the last over four to five years is not certainly somebody with stable disease. So that is something which is very important to recognize. So if you’ve got a scan which looks like it’s not under treated and that goes on for years and years and years, it’s still an undertreated condition, it’s very important then to pick it up and treat it because that could lead to progressive disease. 

And then, of course, there are also a number of entities within neurological Sarcoidosis which I recognize as a specialist, but also you as a patient that has got a low likelihood of remission. So very often we can almost phenotype patients with Sarcoidosis and talk about what types of Sarcoid are likely to respond less to perhaps my observation of patients in clinic when compared to people who are likely to be treated. 

Now, the other side of the story is also, I think, extremely important. So who are the people who we can just observe? It might be unnecessary for people to take potentially toxic, disease modifying treatments and there is a possibility that these can actually be watched and we can monitor them. So the symptoms can essentially be minimal symptoms. 

So the symptoms can be sort of minimal, which can be sort of very much in terms of low risk of danger, for example. There’s no progression. Or people with a higher likelihood of remission, for example, as I said, with cranial nerve functions. So these are patients who can essentially be watched within a clinical scenario. 

Now, treatment is stepwise within Neurosarcoidosis. So treatment essentially goes step by step. So certainly very much in terms of how we look after people. Steroids, which you’re all very familiar with, is usually the first line treatment for Sarcoidosis. So the first time somebody is diagnosed with Sarcoidosis, it almost becomes synonymous with the way we actually treat people. We would either give people oral steroids or people could be potentially treated with Methyl prednisone, either in an oral or an intravenous form. So that’s something several of you might be actually very familiar with.

Sometimes rarely, so within Neurosarcoidosis, people would remit or that might be sufficient to treat someone with Sarcoidosis. Cranial neuropathy involving the facial nerve, for example, is an example of a situation where we would manage people simply with prednisone and you may not hear about any other treatment provided you actually remain under observation and you don’t need it. 

Now very often Neurosarcoidosis, as you all recognize, perhaps is associated with a slightly different outcome to patients, say with pulmonary Sarcoidosis or other forms of Sarcoidosis, where the policy might be that we just keep an eye. Whereas in Neurosarcoidosis, we tend to keep an eye less on patients, but actually actively treat people because we know that the outcomes tend to be in a vast majority of patients poor Gestone Steroids. So the up the tree goes, other treatments such as Methotrexate, Mycophenolate, Azathioprine, so these are all treatments which again very familiar to a lot of people in this meeting. But again, that is something sometimes used because we need to escalate treatment onto something more severe or more kind of potent. 

But equally it might also be because some people have got side effects to steroids. It might be that we don’t want to carry on with high dose steroids for a very long time. And that might mean that we actually move people up that treatment tree. 

Again, things which are becoming more familiar are TNF treatments, which is tumour necrosis factor alpha blockers, which are essentially what we move on to when people tend to be what we call refractory to the current treatment. So that can essentially be Infliximab, for example, or other monoclonal antibodies such as Rituximab, Adalimumab, which is or humira as you might recognize that Cyclophosamide as a treatment. 

So really what I wanted to sort of highlight is there’s a stepwise sort of plan to treating Sarcoidosis of Sarcoidosis. Some people, as I say, require very little treatment. Majority of people with Sarcoidosis need to go up the tree. But where up the tree very much depends the phenotype or what type of Sarcoidosis that patient Neurosarcoidosis that patient actually has. 

Now, what I’ll do in the next few slides is to just show you some of the pharmacological treatments with patients with Sarcoidosis. So this can essentially be corticosteroids, for example, which can be prednisone and methylprednisolone, which are the mainstay first-line treatments which has been used for over 60 years. So people with Sarcoidosis have been have heart prednisolone and steroids for over 60 years.

There are a number of pros and cons associated with that particular treatment. For example, it’s very familiar to a clinician, so patients recognize it, clinicians are very familiar using it, including general practitioners. It’s broadly effective. So anyone with any form of Sarcoidosis would find that steroids is effective to some extent in those patients, not to specific problems, but broadly it’s an effective drug. It can be very easily titrated. 

So very often we give people treatment plans in clinic which say you need to go up to a dose of steroids and gradually reduce it over the next few months. And most people can usually understand that very easily titratable regime to it. It’s widely available. So anywhere we treat people sort of locally, elsewhere, it’s widely available. So really there’s not going to be a dearth of people being able to prescribe that medication. It is quick acting, so very often it’s life-saving in the initial few weeks of treatment and it’s quite a vital part of that particular cog in treating patients with tuberculosis. And of course, it’s very cheap, so it’s one of those things used worldwide if people are very familiar with it. 

Now, the other side of the story is that there are a number of consociated with our treatment as well. For example, as I just said, monotherapy is seldom sufficient to treat Sarcoidosis of neurological origin. So you generally find that treating people for a long period of time is associated with steroid-induced side effects, which again, very recognizable in terms of weight gain or hypertension or diabetes, bony side effects, gastritis, psychological symptoms, all very, very familiar to a lot of you. 

Monitoring people with Sarcoidosis, I think this is something because steroids are so commonly used and they’re broadly effective. I think people become less worried about prescribing large doses of steroids. But it’s really important to clinically monitor people on steroids, not only due to infection risk, but also that regular check in glucose, for example. So anyone with high dose steroids, as with a number of other conditions treated, must have their blood glucose checked every few weeks. They must make sure that their chronic diet control of sugars are properly checked in the form of HbA1C. And of course, very often forgotten is actually checking bone density for loss in bone on people on high dose steroids. 

Again, as going up the tree to Methotrexates, which is the next agent, again, sort of becoming more and more of a familiar entity, titrated up from a low dose to up to 25 milligrams, always prescribed in conjunction with folic acid, which we give five milligrams a week but in some patients requiring a higher frequency. It’s water soluble and usually prescribed on all days excepting the day when people take Methotrexate. 

Now, the adverse effects, as again we go around the tree, does increase. So very important to clinically monitor blood cancer, anaemia, neutropenia toxicity to the liver, lung, sort of involvement with pneumonitis. It’s extremely rare, but something we must keep an eye on. And of course, very important perhaps to remember that it is not a drug which can be taken during pregnancy and breastfeeding. So really important in that counselling of people going on to Methotrexate, not only to ladies on Methotrexate, but also gentlemen who are perhaps going to have a baby with their partners. Very, very important sort of think about when we stop that Methotrexate before. And important to counsel people about the longer term side effects of Methotrexate also.

Azathioprine again started at low dose, can be titrated up to 250 milligrams. So usually we base it on two milligrams per kilogram, but up to 250 milligrams once a day. The side effects are not very dissimilar to Methotrexate, slightly higher risk frequency of infection when compared to Methotrexate in the general population, obviously increasing with age as well and the monitoring which goes with it. 

Mycophenolates, again, sort of commonly heard entity people on a wide range of doses. So somewhere between 500-1500, so generally along same lines, monitoring extremely crucial to liver and renal toxicity and infections. Again, this is a teratogenic drug, so very important to consider stopping it before conception and sort of important also to counsel from physician’s perspective, to counsel patients, but also from patients perspective, very important to be aware of that as well. 

Now, the three treatments which I just spoke about right now, in addition to steroids are pretty much what we describe the cornerstone of management of neurological Sarcoidosis. Now ever so often we get patients who do not respond to the standard treatments with neurological Sarcoidosis, either because of unresponsive or refractory disease or equally because patients might also have what we would describe as intolerance to one of those drugs. 

Now, cyclophosamide is a drug which again, those of you who are sort of familiar with some rheumatological conditions like lupus might be aware of. So Cyclophosamide is a drug which has been used in the management of lupus, for example, for decades, for neurological Sarcoidosis, particularly some types of neurological Sarcoidosis, particularly patients who’ve got vasculitis presentations or patients who’ve basically got presentations of stroke, but due to vasculitis or a number of other entities like peripheral nerve disease due to Sarcoidosis. In some patients, Cyclophosamide might be quite important to escalate too. The side effects in addition to infection would also include cystitis of the bladder, also negated by the concomitant use of other agents with cyclophosamide to reduce those effects. 

Now, very often people ask when we start people in therapy, in clinic, but also sort of a question which very often comes up from clinicians alike is what is the evidence, I’m on Methotrexate, is it a better drug than Azathioprine or is Azathioprine better than Methotrexate? Now, again, to reiterate that we need urgently, we do need randomized control trials in order to look at these things, the number of patients we have and also the diagnosis of this condition so difficult that it essentially makes it has been difficult to design these trials, but we urgently need them. 

But what information we have would suggest that there was a retrospective study which compared Methotrexate and Azathioprine as second iron treatment for Sarcoidosis. So this is bearing in mind pulmonary Sarcoidosis, not neurological Sarcoidosis. And what was found was that both Methotrexate and Azathioprine both had the same steroid sparing potency with perhaps Azathioprine group having a slightly higher risk of infections. 

Moving on to biological treatments. So biological therapies, which are becoming more commonly used among us to escalate patients too, would be Infliximab, which is a murine IgG antibody. So it’s given IB to patients used for refractive Neurosarcoidosis and often due to the fact that you can have antibodies to Infliximab which reduces how effective it is, it’s very much co-administered with Methotrexate or Mycophenolate or other immunosuppressants as well. 

Then Adalimumab, this is not murine, this is very much humanized monoclone antibody or Humira, which again, those of you are familiar with rheumatological conditions might have heard of, is also another treatment increasingly used in people we can’t use Infliximab due to antibody formation or due to intolerance or other factors. And rituximab, which is an anti CD 20, which is again a form of antibody treatment which essentially we do use in other conditions, also can be used in Sarcoidosis. 

Now, there are newer drugs for refractory Sarcoidosis. None of these are licensed in the UK, but certainly we do have them in our arm and term to kind of use them in people who are refractory on an individual basis by special funding measures such as Janus Kinase Inhibitors, IL6 Inhibitors. So these are all based on our knowledge of the pathophysiology of Neurosarcoidosis and the mTOR inhibitor Rapamycin. 

So these are all drugs which are sort of more and more coming into sort of use in people with refractory Sarcoidosis, although the understanding of these in a larger scale in people with not only Neurosarcoidosis, but generally in Sarcoidosis has got a little way to go. 

Now, in the interest of time, what I’ll do is I’ll just sort of summarize this for you. So this is the evidence, current evidence. So Infliximab was licensed for use for refractory Sarcoidosis in the UK a few years ago, very much based on what evidence we have. So people usually have a favourable treatment response. Over 80% of people who are refractory to all treatments respond very well to Infliximab, almost achieving complete remission in 50% and partial remission in a third. 

In terms of clinical improvement with this, there’s certainly a complete neurological recovery. As I said, majority of people are actually doing pretty well on this. But again, bearing in mind that going back to my step analogy, as you go up the step, you basically accrue toxic side effects and hence it’s very important to kind of think about how we monitor patients on treatments as such. 

Again, another study which went on to look at a very similar aspect, again went on to just say that Infliximab has a very important treatment in our and got a significant role in people with refractory Sarcoidosis in achieving that complete remission in about a third of patients who’ve been initiated were completely disease free within that particular ruling. 

Now, I just wanted to before sort of the last few slides where we finished I also wanted to kind of talk about this which is a little bit of work which we did looking at treatment outcomes of patients when, with certain phenotypes of patients with Sarcoidosis were just given corticosteroids alone as opposed to people given steroids with Azathioprine and Infliximab. And what this upper part of this particular graph actually sort of ables out is that actually there was a very significant difference between people just treated with corticosteroids alone, as opposed to people triple treatment. 

Really, to highlight that corticosteroids and lower step treatments are not sort of one sort of glove fit all type of situation, really. There are patients in whom there’s a significant superiority in treating people with higher level treatments and particularly combination of those treatments when compared to single treatments. 

So factors that influenced a choice from our perspective is really steroids are favoured in patients who plan pregnancy, kidney and liver disease, limit their use, rapid disease control is needed and symptomatic treatment for acute conditions is needed. And of course, when people become either refractory to steroids or we worried about steroid side effects, which is very important to think about, or there’s organs that are involved and we need long term treatment, then we would move towards the steroid sparing agents which such as the Methotrexate and the Azathioprine and the Mycophenolate. 

My last slide is I’m sorry, slightly over time. So in terms of the last slide really, is to talk about the known organ manifestations of Sarcoidosis. Now, in all the people with Sarcoidosis we treat in our clinics, I cannot think of the last patient who came with a scan which had sort of got significantly better, who essentially came in and said, actually, I don’t have any fatigue, I’ve never had neuropsychological involvement. And that is extremely important to recognize. 

So these are all the hidden parts of Sarcoidosis. So no scan is going to be able to pick up fatigue and neuropsychological symptoms, but it is a real situation. So it’s very important to recognize that because the impact on quality of life is essential in order to achieve that optimal treatment for patients. 

And the MDT role. Again, the centre of my ABCD, which is MDT role, which is physical therapy. Empowering you as a patient is really important and providing that psychological support in order for you to be able to fight that fatigue and mood disorders, which plays a much more significant role to your whole disease in the way you can work and function and carry on. I think it’s really important. So MDT is really vital and I cannot sort of stress the importance of that sort of enough, really. 

So I think that was all I was going to talk about today, so essentially pinning down. So thank you and happy to take any questions later.