Ep 56: A spotlight on Juvenile dermatomyositis - from the bench to the bedside

Dr Lilase Hakoun, paediatric rheumatology trainee, talks with Dr Charalampia Papadopoulou about JDM. They explore together a rare but important condition. Approaches to diagnosis and evidence based  management are discussed including the hot topics of research in the field.  Not just for the paediatric audience, a great listen for all those working with adults too!

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Transcript

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Hello everyone and welcome to this Talking Rheumatology Spotlight Podcast. I'm your host, Dr. Lilase Hakoun, Paediatric Rheumatology resident in Great Ormond Street Hospital, London. Today we are discussing juvenile dermatomyositis, also known as JDM. My guest today is someone I'm genuinely delighted to introduce, Dr. Charalampia Papadopoulou or Dr. Harris, as she's known to those of us lucky enough to work with her. Dr. Harris is a paediatric rheumatologist and researcher at UCL's Great Ormond Street Institute of Child Health, working in rheumatology at Great Ormond Street Hospital, and she's one of the leading voices in juvenile dermatomyositis today. Her research spans from the bench to the bedside. She's done pioneering work on the vasculopathy of JDM, looking at how blood vessel injury and hypercoagulability derive some of the most severe complications of the disease and trying to find better tests to catch that vasculitis before it causes lasting damage. She's also turned her attention to something that's often overlooked in JDM care, sleep disturbance and fatigue. This work has been recognised with a Fair Research Award in 2023. She's currently leading on the BarJDM randomised control trial, comparing standard of care treatment to baricitinib in JDM. She isn't just a brilliant researcher with local and international collaborations. She's also the department's educational lead and rota lead. And anyone who's trained alongside her knows how deeply she cares about the well-being and education of trainees. So it's a real joy to welcome her to Spotlights and Talking Rheumatology to talk all things JDM. Dr. Harris, thank you so much for joining me today.

Thank you so much, Lily, for your very nice words and for the invitation. I'm delighted to speak, you know, about JDM. You know my passion about JDM.

Perfect. So let's start at the beginning. For listeners who don't see much JDM, how do you introduce it?

So Lily, I think we need to say that JDM is the commonest inflammatory myopathy of childhood, but I think the most important thing to highlight is that JDM is not only about muscle disease and skin disease, but it is a systemic autoimmune inflammatory disease in which of course the skin and the muscles are the most prominent, but the pathology extends beyond that. The main thing we need to consider that it involves the blood vessels, the gastrointestinal tract, the swallowing, the lungs, the physical function, and it can also affect the long-term quality of life. So it is really, really important to think it as a multi-system disease. What has also become very clear over the time is that JDM is not one single uniform disease. So some children do relatively well with fairly standard treatment pathways, while others have severe vasculopathic skin disease, calcinosis, dysphagia, interstitial lung disease, or significant long-term disability. So one of the first messages I always give to the trainees is that JDM is a disease of phenotypes. And if you recognise the phenotype early, you are much more likely to manage the child well. It also matters because although the outcomes have significantly improved over the recent years, there is still, it is still a disease that can leave children with a major burden. And that burden may be physical, may be psychological, developmental, educational, or social. And because it is rare, it forces us to think carefully about how we generate evidence and how we share expertise and how we build genuine partnerships with patients and families.

Wonderful. One of the themes strongly associated with your work is vasculopathy. Why is vasculopathy such a useful lens for understanding JDM?

Because what vasculopathy does, it helps us connect what we see clinically with what is happening biologically. Since the very early descriptions of JDM, how vasculopathy has been recognised as central, you know, to the pathophysiology of JDM. And when you look carefully at the disease, especially the most severe phenotypes, vascular injury is everywhere in the story. It helps explain ulcerative skin disease, nailfold capillary abnormalities, gastrointestinal involvement, and interstitial lung disease, and some of the other more dramatic systemic complication of the disease. So what I'm always trying to emphasise to the trainees is that vasculopathy is not an optional extra in the story. It is one of the most central plot lines. If you ignore it, you missed why some children behave so differently from others. A child with significant vasculopathic skin disease, worrying constitutional symptoms, gut symptoms, or other red flags in telling you something important about the disease biology, the possible complications and the treatment that you actually need to give. It is also one of the reasons why phenotype matters so much. So you may have two children and they are both diagnosed with JDM but one may have a fairly classical pattern, while another one has a much more vasculopathic, high risk picture. Those are not patients you think the same way, and definitely those are not patients you monitor or treat the same way. So, you know, it is important to recognise the vasculopathy and to know, to recognise the possible complications of vasculopathy and take that into account when you consider treatment. Unfortunately, we do not know much and we do not understand much about the nature of vasculopathy, but what it is well recognised is that also the vasculopathy of JDM changes within the disease scores.
 So there is evidence of a true small vessel inflammatory vasculitis earlier in the disease course, while there is evidence of a non-inflammatory occlusive vasculopathy later in the disease course.

And I guess that also takes us to the myositis specific antibodies, as it is an autoimmune process, or MSA. They've changed the field enormously. How do you explain their importance to trainees?

Okay, I think the importance of myositis specific antibodies is that they have taken us from a genetic diagnosis, for example, the child has JDM, to a much more precise phenotype. They do not replace clinical judgement. And what I have learned from my mentors and I would like to highlight is that you never treat the antibody, but you actually treat, you know, the patient but certainly don't remove all the uncertainty. But what they have done, they have certainly changed our practise, and they tell us something about how the disease is likely to behave, what are the risks and what are the complications and sometimes how you can treat more effectively. So what I would say, myositis specific antibodies are very important as clinical signpost. They help you ask better question, worry about the right organs and understand why one child, for example, has prominent calcinosis. Another child has severe refractory skin disease, while, for example, a third one has unexpectedly significant lung disease, despite the fact, you know, that the muscle inflammation is relatively modest. So I hope that highlights the significant of myositis specific antibodies. Another significant aspect is that they have changed the way that we discuss with the families. So we no longer say to the families that your child has JDM, and we will see what is going to happen in the future. We tend, we now are able to give them more, you know, and to discuss more about the phenotype of their child. And also, we can tell them how we are going to monitor them more carefully, what are the possible complications that they need to be aware of, and why and how that all supports, you know, the treatment that we are giving them.

Amazing. And the interplay between vasculopathy and the myositis-specific antibodies and highlighting, you know, the risks on organs. I myself learned that it can be very high risk, for example, on even the gastrointestinal system because it can cause perforation. And that, you know, a patient who presents with abdominal pain who has JDM, should be assessed thoroughly to make sure that they have not developed the complication of perforation. So that's very interesting, Dr. Harris. Can we go through the most clinically relevant myositis-specific antibodies?

Of course, and I think the best thing is to keep it practical and some, you know, very helpful tips for the trainees. So you can start with, yes.

We can start, yeah, we can start with the anti-NXP too.

Okay, so NXP2 is a very important antibody in JDM. Clinically, it is often associated with younger children, a very severe muscle weakness, sometimes striking functional regression, because as I said, we usually see younger children having NXP2 and a higher risk of calcinosis. So it is one of the phenotypes in which vasculopathic gastrointestinal involvement can become particularly concerning. And as you said, if you have a child with a NXP2 positive antibodies and significant abdominal pain, you should not disregard that and look, you know, quite intensively for gastrointestinal involvement. Moreover, if you have a child with an anti-NXP2 disease, you need to think carefully not only about, you know, the muscle severity, but also are you controlling the disease well? What you can do to minimise the risk of the child developing carcinosis or other long-term damage? So what you need to ask yourself, are you controlling the inflammation strongly enough and are you controlling the inflammation early enough to minimise the risks of the complications that we have discussed?

Perfect. And what about anti-TIF1 gamma antibody?

So in children with T1 gamma positive antibodies, one of the most prominent features is that they have quite significant skin disease. And what we know is that this skin disease can often be very treatment resistant. So it is very difficult to treat skin disease in that group of patients. So what does that remind us that the skin disease in JDM is not only cosmetic, but the skin is actually an organ. And if it is severely affected, it can be painful, it can be functionally limiting, psychologically distressing, and biologically significant. We can also see calcinosis in patients with T1 gamma positive antibodies. So again, the antibody helps you anticipate that this may not be a patient whose entire story is captured by muscle enzymes and strength score, but you also need to take seriously the skin involvement. A significant difference between the adults and children is that T1 gamma positive, JDM, so dermatomyositis in adults, is often associated with the risk of cancer, which is not the case in children and I would really like to highlight that.

And then we come to anti-MDA 5.

Yes, and the MDA5 has really sharpened our awareness of interstitial lung disease in JDM. These patients have a very specific phenotype and it is very different to the classical phenotype that you expect to see in a patient with severe myositis so the muscle involvement is relatively mild in that group of patients, while they do have quite significant skin vasculopathy with ulcerative skin disease, constitutional symptoms, quite a significant amount of arthritis, mainly affecting the small joints of the hands and the feet. And they are also the ones that they have the higher risk of developing interstitial lung disease. So at the MPFT 5 tells you very clearly that this is a patient to whom you need to look carefully and to think carefully about ILD and potentially a very rare complication fold rapidly progressive ILD.

That seems very dangerous and we definitely should keep an eye out for that. What about anti-Ro52 which often comes up in the same conversation?

You are absolutely right, Lily. So under RO52 is not itself an MSA, but when you see it in combination, for example, with MDA5, it is an extra risk for significant ILD, for more severe disease. And these are the patients that they have the higher risk of developing rapidly progressive ILD. So it tells you the combination of MDA5 with Ro52. It tells you that you are more at risk of your child developing severe pulmonary phenotype and this is the group that you may have a very low threshold, for frequent monitoring, but also for very early escalation of your treatment.

And what about the really interesting conceptual shifts recently in that the antibodies may be doing more than just classifying patients?

And you are absolutely right. This is one of the most exciting development, I would say, nowadays. For a year, we used to use MSA mainly as markers, very useful markers, but still markers. So for example, we were using them to help us with a diagnosis and we were using them to phenotype the patients. But emerging work now in inflammatory myopathy suggests that some of these antibodies may actually have a pathogenic role. And there is evidence that some of these autoantibodies can be internalised into skeletal muscle fibres,
 and interfere with the normal function of their intracellular target artigens. So the concept is shifting from these antibodies tell us just what subtype the patient has to these antibodies may also be participating in the disease process itself. And this is very important conceptual step because it strengthens the biological relevance of the auto antibody defined phenotypes we see at the bedside. It also gives us a more mechanistic bridge between serology and tissue pathology. So in that work, what it has been shown is that internalised auto antibodies are disrupting intracellular complexes and they are altering gene expression. And that raises the possibility that at least some of them are not just epiphenomena but are active contributors to disease biology. There is also a lot of work nowadays trying to measure the levels of myocyte-specific antibodies
 and see if the levels can help us also monitor disease activity over time.

Very interesting indeed. So the modern view of MSA is richer than it used to be.

Yes, that is actually the case. So MSA help us phenotype the disease, anticipate complication, and now it is increasingly helping us understanding the pathogenesis of the disease as well. Let's stay with lung disease because that's one area you wanted to emphasise more. Why does interstitial lung disease deserve such a prominent place in the JDM conversation?

Thank you so much, Lily, for that. So ILD is one of the complications that can dramatically alter the outcome. And actually, in some children, it is the feature that dictates the prognosis. JDM is often thought that, okay, it is dominated by the muscle weakness.
 and the skin rashes. And a lot of times, you know, we are forgetting to cheque about the lungs because the lung disease is less visible, but it can be far more dangerous. It may be subtle at presentation and to be fair in the majority of the children, they may be even asymptomatic at the beginning but it can be, you know, a significant complication and in extremely rare cases, it can progress very rapidly with even fatal outcomes. What I would like to say from my experience, ILD is not again uniform in JDM. So they do not have any symptoms and ILD is only diagnosed because of the lung function test or because of the high-resolution CT, while others develop rapidly progressive ILD, which can deteriorate over days to weeks and that carries very significant mortality. Again, my experience at Greater Mall Street Hospital is that over the last 15 years, the main cause of mortality in children with JDM was ILD and that's the reason why I have developed a special interest in ILD. And, you know, I'm trying to understand more the pathophysiology of the disease. I'm trying to understand more who is the child that is more at risk of ILD and how we can more effectively treat ILD. And this is also where serology becomes especially helpful. So MDA5 positivity is probably the strongest risk factor for ILD, and especially rapidly progressive ILD, especially when you know it is in combination with Ro52. And the synthetase antibodies also matters, but they are less common in children. So one of the biggest shifts in modern JDM practise, I would say, is that the conversation about lung disease starts early and not after the child becomes, you know, breathless. So I think this is what has changed more in our practise over the last 15 years.

And I definitely can see that we often do lung function testing on children at the point of diagnosis as a workup. So that's definitely something we do in Great Ormond Street Hospital. What should trainees do in practise when they are worried about interstitial lung disease?

I think you said the right thing. They need to, first of all, is to identify who is at higher risk of ILD. And this again is where the antibody profile plays a significant role, but also the phenotype of the disease overall. Do you have significant evidence of a vasculopathy? Do you have constitutional symptoms? What is the arthritis pattern? Does your child have weight loss? And does your child have any, even subtle respiratory symptoms? A lot of times, I think the important thing is to take a very good history and ask the right questions. A lot of times the family and the patient is reporting that the child is not having any respiratory symptoms. But if you ask carefully and you ask them, has their exercise tolerance reduced? Do they become breathless in exercise? Then are they coughing at all? Then they start giving you more information about possible symptoms associated with ILD.
 And then the most important thing, as you said, Lily, is to screen patients appropriately. Our practise has changed over the most recent year, and we are actively screening all of our newly diagnosed patients with JDM for ILD. Depending on the age, if they can do pulmonary function tests, we're requesting pulmonary function tests to all the patients with newly
 diagnose JDM. And to the younger ones that they cannot do pulmonary function test, we are requesting if they are at risk of higher D, a high resolution CT at screening. So, you know, the important thing is to understand that especially in high risk disease, you cannot afford to be slow or you cannot afford to be falsely reassured because your child does not have symptoms. The problem is that even among the specialists, even in the same country and even more internationally, there is a huge variation in how ILDs screened, diagnosed, monitored, and escalated in JDM. And this is a big problem, but this is exactly why collaborative work is so important. We need to harmonise approaches to screening, management, and monitoring in patients with JDM. That is also why we are putting a lot of effort in collaborative work, such as a project that we are now leading called Harmonise ILD, with the main aim of the project is to develop clearer recommendation for how we screen, manage and follow ILD and JDM in a more consistent way.

And how aggressive should treatment be in high-risk interstitial lung disease?

What I would like to highlight before I go to the treatment is that rapidly progressive ILD is not common. And as I said, at Great Ormond Street Hospital during the last 15 years, we have seen three children with rapidly progressive ILD all of them, unfortunately, with a poor outcome. So how do we treat those patients is that we have moved from slowly introducing, you know, more immunosuppressive agents if the response is suboptimal.
 So we have moved away from a step-wide escalation. And the way of thinking nowadays is that we are giving up front a combination of immunosuppressive agents. The combination, as I said, varies between the different centres, even, you know, in the same country. And the main agent used are rituximab, they can be cyclophosphamide, MMF calcineurin inhibitors, and more recently, JAK inhibitors. So in the high-risk phenotypes, especially the MDA5 positive ILDs, the lesson from both paediatric and adult experience is that you need to be aggressive at the beginning with combination of immunosuppressive agents to have the better outcome, you know, at the end.

That sounds very logical, to be honest, because corticosteroids alone are often not enough. If you are a trainee seeing a possible case for the first time, what absolutely must not be missed?

Okay, that's a very good question, Lily. So first of all, I think you need to either confirm or refute the diagnosis, yes? Secondly, you need to phenotype the disease. And then, and very importantly, you need to screen for the complications because that might change your management early in the disease course. So from a diagnostic point of view, you need to look thoroughly for any signs and symptoms that could support the diagnosis of JDM. You need to examine your child from head to toe. I had a lot of cases when, for example, nobody had looked for a rash in the armpits and the child had significant ulcerative skin rashes in the armpits. So you need to do a very thorough examination, look for rashes, look for proximal muscle weakness. You need to do blood tests, looking what is happening to the muscle enzymes and more recently, we are using modalities like the MRIs to look for any muscle inflammation and muscle biopsies, depending, you know, of course, on the setting. So we use MRI more and more to support the diagnosis. And as I said, to assess muscle inflammation. We use the antibody testing in a way to confirm the diagnosis, but also to refine the phenotype. And what someone should not forget is to also look for extra muscular disease. So it's not only about muscles and skin. You should actively look for arthritis, for lung involvement, for GI involvement, dysphagia, you know, look for any other organ involvement apart from the muscles. From a respiratory point of view, you need to ask the right questions, as we said. So you need to ask about exceptional breathlessness, any cough, any chest discomfort. You need to take more information about the exercise tolerance. And of course, you should never forget that the absence of symptoms does not exclude ILD. Actually, the majority of children with ILD, they are asymptomatic. And then you should screen, you know, to, especially in the high risk populations you should screen for specific complications of the disease and you should forget that one-size-fits-all JDM management. So according to your phenotype, according to your serology, you need to decide then what is the best management for your patient. Regarding now other features that someone should actively look, you should not forget about dysphagia, which is another feature that can be a marker of significant disease activity. It can affect nutrition, but also it can affect safety. So for example, you need to look for silent aspiration. A lot of time this is something that it is missed. And what we are trying now to do in all the patients is to request a salt assessment for all the newly diagnosed patients regarding of the degree of muscle weakness, because we have seen children aspirating, even if they're not profoundly weak. So again, speak with your SALT team and discuss the need of video fluoroscopy. This is what I would suggest, you know, that they are the main points that you should not forget.

Perfect. And are muscle enzymes always elevated in JDM?

That's a very good question. No, and someone should not say that a child does not have JDM because the muscle enzymes are normal. There are cases, especially if there is a delay, you know, in the diagnosis, that the muscle enzymes have normalised, despite the fact
 that, for example, your patient has still ongoing significant proximal muscle weakness. There are also patients that they do not have severe muscle involvement, and in that case, again, the muscle enzymes may be normal. So a normal muscle enzyme should not be considered as exclusive, you know, for the diagnosis of JDM. What I would also rather like to point, you should not only look on CK or Aldolase, but for example, if your LDH is mildly elevated, if your ASD is mildly elevated this again can be an indicator of mass involvement in JDM.

Perfect. And I guess one of the points that trainees have been discussing is that we now have MRI, thigh MRI to look for myositis. And that kind of, there is a way for, you know, it takes us away from more invasive procedures such as EMGs and muscle biopsies.
 Can one test replace the other?

Okay, so it is absolutely true that we are using more and more MRI and especially T to still fat suppress, you know, images to look for edoema in the muscles and the fascia, because that can help us with a diagnosis of JDM, but that can also give us an idea of the severity of the disease. What I would like to say, Lily, is that, for example, we are doing a great or most trick, a thigh MRI, but there are other centres that they are doing whole body MRI or they are doing MRI of the shoulders. These are all, you know, good modalities and it can tell you if there is inflammation in the muscles in your patient. The good thing is that this is a non-invasive test. Sometimes it still requires you give general anaesthesia to a very young patient. We do not use EMG anymore because it is painful, it is more invasive and regarding now the muscle biopsy, this is a very big discussion. There is some evidence that apart from the diagnostic role of muscle biopsy, there is also a prognostic role in muscle biopsy. So the muscle biopsies can give us a lot of information, not only about the child having or not, JDM, but also to help us predict, you know, if the child is going to be on treatment in the next five years. So I cannot say one can be used instead of the other because they can give us different information. And there are also cases, for example, that there is no inflammation in the MRI.
 But when you actually perform a muscle biopsy, there is quite a lot of inflammation. So, you know, ideally, if we could find a way to do less invasive muscle biopsies, I would strongly favour to do a muscle biopsy to each one of the newly diagnosed patients with JDM. I know this is not possible at the moment. And I know that there are a lot of centres that they do not have the possibility of performing a muscle biopsy and they're only doing, you know, muscle biopsies in the cases where it is not, they do not have a definite diagnosis. Yes.

Perfect. Let's move to management. One of the major shifts in recent years has been the treat to targets. What does that mean in JDM?

Treat to target is that means that we defined where we want the child to get to. We can monitor progress explicitly and adapt treatment if we are not on track. And that sounds obviously, but it is actually a major cultural shift in a rare disease where historically care could sometimes be more descriptive than target driven. So there was a recent recently published international recommendation where, you know, about treat to target in JDM.
 And these recommendations actually endorse inactive disease as the preferred treatment target in JDM. So they also suggest in 30 milestones, such as, for example, what is the minimal improvement someone would expect to see in around six weeks? What is the moderate improvement by three months and normalisation of muscle strength within six months, while the target outcome in one year is clinically inactive disease. They also emphasise the importance of tapering steroids and discontinuation of steroids where possible within 12 months to optimise by optimising the rest of the regime and to minimise
 the side effects, you know, related with the corticosteroid treatment. So I think it is the treat to target concept is extremely useful, especially for trainees, because it gives you a mental framework. You are no longer asking, does this child seem a bit better, what you are actually asking, are we where we need to be by this point? And if not, why not? And what we can do to meet the target? So that leads to more disciplined monitoring, earlier recognition of treatment failure, and hopefully less acceptance of some ongoing, you know, disease activity, so the target is not just paid partial control. Now, we are moving away from that. So the target is actually clinically inactive disease and this is what we should all be aiming for in 12 months from the diagnosis of the disease.

Perfect. Let's come to the pathogenesis and targeted therapy. Interferon has become one of the central themes in JDM. How do you explain that to a broad rheumatology audience?

Yes, so what the interferon biology has helped us is to connect the molecular immunology with the clinical phenotype in a very meaningful way. So we now know very well that type 1 interferon signalling is strongly implicated in JDM pathogenesis. And that matters because it helps explain why some forms of the disease behave the way they do and why certain targeted therapies make mechanistic sense. So to keep the message practical, the important point is that not everyone needs to become an expert in interpreting, you know, interferon-stimulated gene scores. But the important point is that JDM is increasingly understood as a disease in which interferon pathway activation is central. And that insight is helping us think more clearly about, you know, what biomarkers we can use, about risk stratification,
 and about targeted therapy. So I think the main point is to understand that type 1 interferon plays a significant role in the disease pathogenesis and that can guide our monitoring and our management for the disease. And there are other mechanistic strands beyond interferon that are becoming increasingly interesting as well, such as the topic of mitochondrial disease and mitochondrial involvement.

You're absolutely right, and this is one of the most interesting things, you know, what we understand more and more, and we appreciate that there is a growing role of the mitochondria in JDM pathogenesis. Recent work has suggested that the mitochondrial dysfunction is not just a secondary effect from the inflamed muscles, but actually they play a role, a significant role in the disease process itself. So the current model is that oxidative stress and oxidised mitochondrial DNA can amplify inflammation, including interferon-driven pathways, So mitochondria may sit right at the interface between the tissue injury and the immune activation. So I want you to think it has a vicious circle. And mitochondrial dysfunction help us connect systemic immune activation with local tissue damage. So rather than thinking only about inflammation, attacking the muscle, we're increasingly thinking about, as I said, the feed forward loop in which oxidative stress, mitochondrial injury and interferon signalling reinforce one another. For trainees, the important message is not that mitochondrial biology replaces interferon biology, but that it enriches our understanding of why disease can become self-sustaining and why new therapeutic approaches targeting oxidative stress and mitochondrial dysfunctions are of such interest nowadays.

And this is probably a good point to mention your recent work as well, because it seems to sit exactly at the interface between mechanism and clinical practise.

So, what we have done, we have only recently published in Rheumatology a paper looking at the interferon-related gene expression in JDM. And what we found was that these interferon signatures track disease activity very closely including both the muscle and the skin involvement, and in some contexts may actually give us a more sensitive picture than some of the conventional markers we often rely on. What was particularly interesting was that these signatures were not simply reflecting global inflammation and global disease activities, but they were also linked to specific organ involvement. For example, we demonstrated that CXCL9 was associated with interstitial lung disease, while IL-18 was associated with calcinosis, cutaneous alceration, and gastrointestinal involvement. We also saw that this interferon signatures fell as children improved. So the schools were getting better as disease activity was better controlled, including in those treated with baricitinib, which is exciting because it suggests a real role for biology-led monitoring and the more precise approach to treatment response in JDM. So hopefully in the future, we will be able to use the interferon related gene scores to monitor better, you know, disease response and maybe, you know, to be able to predict disease flares o that's the precision medicine in a very practical sense.

Exactly. And this is what brings us closer to using more molecular information, not just to understand the disease, but also to monitor the disease more intelligently in clinic. So just to give you an example, let's say that you have a child that comes to your clinic and complains for more fatigue, but you cannot find any clear clinical evidence of disease flare. A useful way to use the interferon-related genus A would be to do that. And if you see that there is a significant worsening in the interferon-related genus A, it is highly likely that actually your patient is flaring, despite the fact that you cannot see it yet clinically.

That leads naturally into JAK inhibitors. Where do you think they currently sit in JDM?

JAK inhibitors are one of the most exciting developments in the recent years in JDM, because there is a strong biological rationale behind their use. So as we previously said, interferon signature is central to disease pathogenesis. So you can imagine that therapies that interrupt that signalling make a lot of sense. In practise, they have been increasingly used, especially in refractory disease, and the literature so far has been encouraging, particularly for resistance kid disease, muscle disease, and high risk phenotypes, including MDA5 associated disease but it is very important not to overstate the evidence. So much of the data remain retrospective or based on case series and observational experience. There was a review published back in 2024 where 190 JDM patients were treated with a JAK inhibitor and they found very high reported rates of improvement across agents, with infections being the most commonly reported adverse event. But it also concluded a review that we still need properly controlled studies to define optimal use. So I think the balance message is the JAK inhibitors are very promising, increasingly important and biologically rational, but still an area where stronger prospective evidence is needed.

And one of the really interesting changes seems to be the move from JAK inhibitors as rescue therapy towards considering them much earlier. Is that fair?

Yes, I think that's absolutely fair. Historically, JAK inhibitors were mostly used in the context of refractory disease. But increasingly, the field is asking a more ambitious question. So if the biology is compelling and the signal in difficult diseases encouraging, should we be using this treatment earlier, perhaps even up front in selected patients? And that's why the current trials matter so far. Bar JDM is one of them. Bar JDM is a multi-center, open-label, randomised controlled Bayesian phase 3A trial where we compare baricitinib plus glucocorticoids with methotrexate blood plus glucocorticoids over a 52 week period in newly diagnosed patients with JDM. So conceptually, that's a hugely important because it asks whether a JAK inhibitor based first line strategy may improve outcomes or alter the early treatment trajectory. There is also the trial, a French study evaluating again baricitinib in association with corticosteroids in new onset JDM. And we have just seen very promising, you know, the very first results are very promising, but the direction of travel is very clear. So the field is no longer asking only whether JAK inhibitors can rescue refractory disease, but what we are really asking is whether they may have a role much earlier in the disease course.

And you've said several times that collaboration is essential in JDM. Can you expand on that?

Yes, because in JDM collaboration is not a luxury, but it is actually a necessity. No single clinician, really no single centre, regardless of how big it is, sees enough patient to answer the most important question. So if we want to really understand the phenotype, prognosis, biomarkers, lung disease, treatment response, pathophysiology, long-term outcomes, we really have to work together across centres and across countries. One of the major strengths in the UK has been the Juvenile Dermatomyositis Cohort and Biomarker Study, or JDCBS, which has been hugely important in building the evidence base in a rare disease.
 Cohorts like that allow us to understand to understand heterogeneity, identify its factors, study biomarkers, and track long-term outcomes in a way that routine single centre experience simply cannot. And I think what it is especially important is that
 That cohort work actually reminds us that outcome is not only about disease activity score, it is also about education, fatigue, mental health, physical independence, transition to adulthood, and participation in normal life. So a good cohort research broadens our concept of what really success means and beyond the UK, there's also major international network building.

Absolutely. 

And as you know, there is the PRES JDM Working Party, which is a very good example, what the rare disease community can do when it works together internationally. So the aim of the PRES JDM Working Party is to bring together clinicians and researchers to increase knowledge and facilitate research in JDM on a collaborative international platform looking into basic science, clinical care and education. It also explicitly works with patients and parent groups, which I think it is extremely important. What I would like to say here, for example, we are now organising the very first international webinar for patients and parents with JDM. And we are hoping that that will help, you know, increase the knowledge and the understanding of the disease, but also will help us understand better what are the difficulties that families with JDM are facing.

Perfect. And for our listeners, PRES is the Paediatric Rheumatology European Society, and they work in collaboration, and that's an international effort, which is very impressive. So when we talk about collaboration, we're really talking about the mechanism by which the field moves forward.

Exactly. In JDM collaboration is the engine of progress. Without collaboration, we wouldn't be able, you know, to achieve anything. He also wanted to highlight family collaboration and patient public involvement.

Yes, and thank you so much for that, Lily. Because the disease is lived in the real world, it's not just in the clinic. Families are the ones actually managing the medicines, the school attendance, the fatigue, the exercise programmes, the appointments, they are actually the ones that they see the side effects and they have their certainty and the emotional burden of a rare diagnosis. So if we want to improve care meaningfully, patient and families cannot be passive recipients of decisions. They have to be partners in the care and research. So one of the most positive developments in the field has been the increasing emphasis on patient public involvement and co-designed research that matters because unfortunately us researchers do not always guess correctly what are the family priorities. So family may care deeply about fatigue, as I said, school participation, appearance related distress, treatment burden and transition in ways that we are not fully capturing by traditional clinical outcome measures. So meaningful research in JDM is not just scientifically strong, it is collaborative, it is transparent, and to listen carefully to the people living with the disease.

Oh, let's finish by looking ahead. When we talk about future therapies in JDM, what is genuinely exciting and what needs to be framed more cautiously?

I think the first principle is honesty. So some things are exciting because they are close enough to clinic to change practise soon. And then there are other things that they are exciting because they expand the horizon. But we need to understand that they remain experimental and they should be presented that way. So for example, we now are able to do better phenotyping. We have clearer treat to target pathways. We are doing a smarter use of the MSA and the biomarkers, and we are having stronger evidence about JAK inhibitors.
 and hopefully in the near future, more consistent ILD pathways. So these are clinically actionable. And then in the more frontier category, we have the CAR-T therapies, which are clearly attracting an enormous interest. There are now early reports and reviews suggesting that CAR-T approaches may use profound remission in refractory juvenile autoimmune diseases, including severe JDM, by effectively resetting pathogenic B-cell driven immunity. There is also growing trial interest relevant to juvenile myositis. But having said that, at the same time, we have to be cautious. CAR-T is not the standard of care for JDM. The experience remains limited and we still need to define the long-term safety, the cost, and some of the major questions is which patients should be selected, what is the toxicity, and where these therapies will fit, I'm sorry, in paediatric autoimmune diseases. So CAR-T is a very exciting, you know, proof of concept for the most refractory end of the disease.
 
 

That's very good to know. So Dr. Harris, if you wanted listeners to take away just a handful of messages from this episode, what would they be?

There are, I would point three, you know, points that I would like them to take away. So first of all, JDM is a heterogeneous systemic disease. Please do not think just about RAS and weakness. You need to understand the phenotype before because that way you will understand the patient better. Secondly, vasculopathy is central to the disease story, especially in the most severe phenotypes. It helps explain why some children develop ulceration, gastrointestinal involvement, dysphagia, and other major complications. And the more we understand about vasculopathy, the more we will be able to treat our patients more effectively. Third, myosotis-specific antibodies have changed our practise because they help us phenotype the disease, anticipate complication, but also personalised monitoring. And emerging work suggests that may also help drive disease biology and not only reflect it. If I wanted to add something more is, you know, you should always look for ILD and you should never actually treat ILD as a side issue in JDM. Early recognition is the key, appropriate screening and then appropriate management, it is really, really important. Finally, you know, what I would like to highlight is that progress in JDM really depends on collaboration, clinicians, scientists, other specialties, international working groups, patients and families, we all need to work together to have better, you know, outcomes, whether we are talking about the JDCBS, whether we are talking about the PRES JDM working party, all our efforts to harmonise ILD or the trials of targeted therapy, the field advances because people work together, I think this is something we all need to keep in mind.

That's a perfect place to conclude our episode today. Dr. Harris, thank you so much. That was incredibly clear and thoughtful. And I hope our listeners benefit greatly from your expertise. Thank you so much.

Thank you so much, Lily. It was very pleasure always, you know, speaking to you. Thank you so much.