Ep. 188: Red flags of treatable rare myopathies

00:00:00: Welcome to EANcast, your weekly source for education research and updates from the European Academy of Neurology.

00:00:15: Hello!

00:00:15: And welcome to the EAN Cast Weekly in Neurology.

00:00:20: My name is Olimpia Musumeci.

00:00:21: I am professor of neurologic at University of Messina In Italy.

00:00:32: My main scientific interest is neurogenetics in muscle disease, in particular metabolic myopathies and mitochondrial diseases.

00:00:42: This month's topic is about neuromuscle disorders.

00:00:47: In today episode we will talk about red flags in treatable rare myopathes.

00:00:55: It is a pleasure to introduce today my guests.

00:00:58: They are two leading experts in the neuromustle field Professor Antonio Toscano, and Professor Marianne de Visser.

00:01:08: Professor Antonio is a full professor of neurology at the University of Messina in Italy.

00:01:15: He's currently Secretary of EAN and has previously served as treasurer.

00:01:22: he particularly dedicated to diagnosis management treatment metabolic myopathies as muscle glycogenosis lipid storage myopathy, mitochondrial disorders and genetic myopathies.

00:01:40: Professor Mariane de Visser is a meritus professor of neuromuscle diseases at the University of Amsterdam.

00:01:49: She led the neuromausal group at the academic medical centers in Amsterdam for several years with expertise on muscle dystrophies, myositis post polio syndrome, motor neuron diseases and hereditary neuropathies.

00:02:07: She has held leadership roles in the European level serving as governing board on EAN first as treasurer then as secretary general.

00:02:19: Welcome Marianne and welcome Antonio.

00:02:22: Thank you for joining us today.

00:02:27: We can start with First question, and I would like to ask to Antonio.

00:02:34: What

00:02:34: about do you think over the last decade what we have the advances on improving the diagnosis of rare genetic myopathies as muscle dystrophy or metabolic myopathy?

00:02:50: How does it change the diagnostic approach in this disease

00:02:56: nowadays?

00:02:58: Yes, thanks very much Olimpia for this question and I would like to also welcome Professor Dresel who is a very nice friend of us.

00:03:08: And about these questions it's really relevant.

00:03:14: in the neuromuscular field definitely in last ten years there was different approach towards diagnostic phases for neuromuscular and more specifically for muscle disorders.

00:03:31: As a brain is I would outline that still it's very important to have correct work frame of the clinical aspects, And its important guide all diagnostic processes starting from the clinical aspect every single patient.

00:03:53: And after that, we still need some generic laboratory studies.

00:03:58: For example from blood samples to have a dosage of the CK creating carinase because it's very relevant for several kinds of bisons but this is already well known.

00:04:13: what has changed in my opinion and last ten years?

00:04:17: especially the use of muscle MRI which is very relevant, especially to help us establish the real condition of muscles in the patient and try to indicate what are most affected muscle groups.

00:04:38: And this also important if you still need to perform a muscle biopsy so that you have good drive from the muscle and arrive.

00:04:50: even more relevant is the molecular genetic era.

00:04:56: So today we have opportunity to use molecular genetic pathways, try to recognize different sub-specialty of muscle disorders and this a very relevant but still not not always able to give us a complete information about the genetic disorder because we usually have something like sixty, seventy percent of detection rate of disorders but still there is an number that remain unknown or not recognized.

00:05:41: In any case today using all the somic studies, the improvement of muscle disorders diagnosis is very relevant.

00:05:55: We can also still use some targeted panels when we know already what are the genetic alterations in a family.

00:06:05: but and very helpful.

00:06:18: Last note for the muscle biopsy, because we still say ten-fifteen years ago muscle biopsy was a gold standard for muscle diagnosis but now with the advent of genetic molecular studies is less used.

00:06:37: But it's still very useful especially in cases when sure about the genetic destination of studies, but also when you have not exhausted responses from molecular genetics studies.

00:06:52: In this case muscle biopsy could be fundamental.

00:06:58: Yes thanks Antonio for your talk and of course genetic analysis changed approach of a patient with suspicious of hereditary myopathy, but still muscle biopsy has a role either in the diagnostic approach when genetic goes first.

00:07:22: And now going to another field about muscle disorders and talking about inflammatory myopathies.

00:07:30: Also in this field, the recent year we have several advances on pathophysiology diagnostic recognition that can modify also their diagnostic approach.

00:07:43: Marianne Can you give us some clues of these topics?

00:07:47: Thanks!

00:07:50: Thank You very much Olympia.

00:07:52: it's really a great honor to join you and Professor Antonio Toscano in this podcast.

00:08:00: And before responding to your question, I would like take the opportunity first briefly discuss the classification of idiopathic inflammatory myopasies.

00:08:10: About twenty years ago we distinguished three subtypes Dermatomyositis Polymyositis and inclusion body myositis.

00:08:19: However, over the years thanks to new insights based on serological findings of myositus-specific autoantibodies and muscle pathology but also muscle imaging we now distinguish five subtypes Dermatomyositis Immune mediated necrotizing myopathy Anti-synthetic syndrome overlap myositis and inclusion body myositise.

00:08:44: And you may have noticed that I do not mention polymyositis anymore because it has become clear, That probably this disease entity does not exist any more or is at least extremely rare.

00:08:57: In the past patients with anti-synthetic syndrome Overlap Myositis Immune mediated necrotizing myopathy Or IBM had been misdiagnosed as PolyMyositis.

00:09:10: To come back to your question about advances on pathophysiology and diagnosis.

00:09:15: Indeed, there are major advances as regards pathomeganisms in dermatomyositis immune-mediated necrotizing myopathies... ...and inclusion body myositis which is not only relevant for diagnosis but also a therapeutic approach and monitoring disease activity.

00:09:35: Recent studies have highlighted the pathogenic roles of myositis-specific autoantibodies.

00:09:41: First, there is a positive correlation between levels of specific myositise associated autoantipodies MSAs in serum and disease activity which supports role of MSA's in pathogenesis.

00:09:58: Second Autoantibodies may accumulate inside myofibrous, disrupting the function of their target proteins.

00:10:06: And this has been shown for the anti-Me-II autoantibody and MSA for dermatomyositis or JO-I an MSA for antisynthetic syndrome.

00:10:18: Pathogenicity of the MSAs have also being established HMGCR-Autoantibodies, which are associated with immune mediated necrotizing myopathy.

00:10:33: All these observations have relevance for the clinical practice.

00:10:38: MSAs can be used to define specific phenotypes.

00:10:42: Let me give you a few examples.

00:10:45: The anti-MDAV antibody endermatomyositis is associated with high prevalence of interstitial lung disease and skin ulcers And relatively little muscle weakness.

00:10:57: Another example is the anti-TIV-I gamma autoantibody in dermatomyositis, which indicates a risk factor for cancer.

00:11:06: These are few examples of the utility of MSAs for diagnosis.

00:11:13: Another important finding is the identification Interference.

00:11:23: are cytokines that predominantly activate the jack-stat signaling pathway, leading to expression of interferon inducible genes.

00:11:33: There are various types of interference but the induction of type I interferon in dermatomyositis is reflected by increased expression of interfering inducible gene in muscle and blood and skin the type I interferon-indusable protein MXA, mixoviroresistant protein A which can be found in perifascicular myofibers in muscle biopsies of patients with dermatomyositis and not other myositis subtypes.

00:12:10: The developments as regards pathomeganism are also very relevant for advancement of therapies Based on the overexpression of interference that, as I mentioned activated Jack's stat signaling pathway, Jack inhibitors are administered to patients with dermatomyositis and seem-to hold promise.

00:12:30: And there is emerging evidence supporting And these biomarkers can be used in patient stratification for targeted treatment, particularly with Jack inhibitors.

00:12:48: Finally the identification of highly differentiated cytotoxic T cells and their role in IBM has led to development of promising targetless therapies which are currently undergoing clinical trials.

00:13:04: Thanks Marianne Of course definitely there.

00:13:07: field of inflammatory myopathies over the last year changed completely in terms of classification, also in term diagnosis.

00:13:16: All this new antibodies is important not just for the diagnosis but also treatment and management of these patients.

00:13:26: so it's fundamental to be updated on all those things.

00:13:33: A new question for Antonio and going back to the genetic form, what do you think we can identify as clinical red flags in your opinion?

00:13:45: To shorten the diagnostic delay that is still over the years present in diagnosis of this patient.

00:13:56: Yes Olympia!

00:13:57: This a very important question.

00:14:02: a little bit larger response because there are several aspects that have to be outlined in terms of red flags, in my office.

00:14:13: So we first need you know what kind of negation on the disease?

00:14:20: We're trying to identify so we can have acute disorders but we also have The majority of cases chronic disorders or Marianna's already discussed about the acute situation, especially in inflammatory myopathy.

00:14:37: But we have a large number of other kinds of disorders that are chronic disorders and they're quite slow but still disabling for the patients.

00:14:49: so We have to consider several aspects when we Have to pay attention to these suspects Myopathies.

00:14:59: first of all muscle weakness, so we have to identify the area of the muscle weakness and also understand how rapid is involvement in different kinds of muscle groups.

00:15:15: And if this muscle weakness is present at respiratory level because the respiratory involvement present, progressive and sometimes is the cause of death for patients.

00:15:36: So we also have to consider other kind of disorders that can be also the onset of disorder like Diplopia, dysphagia or Disaster and all these aspects are to be taken in a great consideration especially the involvement of the eyes is relevant in several kinds of myobodies.

00:16:02: For example, high disorder like ptosis or oftalmopregia are very prominent in mitochondrial disorders as others.

00:16:13: but also we have to take into consideration some specific muscle weeks.

00:16:19: for example there's a sort recurrent situation, which is the drop in head syndrome.

00:16:28: Which means that muscle necks are quite weak and this could be present at different kind of disorders.

00:16:37: but we need to identify these specific synics because you know some myopathic disorder like for example several let me give the majorities, or also in inflammatory majorities.

00:16:58: But also some metabolic majorities like for example Pompe disease.

00:17:05: and apart from this specific muscle weakness in different ass groups we are also considered to try better identify these kinds of a Majority The extra muscular involvement.

00:17:22: Marianna has alluded to the inclusion of skin rashes, for example... ...to identify them at myocytes.

00:17:33: but we know that also apart from the sphere of involvement... Also cardiac involvement is often accompanied by a specific muscle disorder.

00:17:47: Apart from these specific clinical aspects that we definitely have to take in great consideration, I remind you the elevation of CK or a sort of rambdomyolysis with the presence of dark urines and so-called coca cola like urine is very relevant especially to identify as different kinds of metabolic metabolism.

00:18:19: So I think that these are the major aspects we have to take in consideration, as a starting point.

00:18:37: So, Marianne going back to the inflammatory myopathies.

00:18:40: Do you think that diagnostic delay is still an issue in the diagnosis of myositis?

00:18:46: Well actually it's a rhetorical question Olympia.

00:18:50: It's extremely difficult To diagnose patients if they are first seen by someone who is unknown with myositis.

00:19:04: And in the Netherlands, I don't know about Italy and other European countries... ...the patient first has to go to their general practitioner, GP,... ..and the GP has to refer a specialist.

00:19:17: So if the GP is unaware of the presentations of myositise it can cause a diagnostic delay.

00:19:24: In particular holds true for inclusion by the myositis, where diagnostic delay is between five to seven years usually.

00:19:33: And that's because weakness is slowly progressive but also because weakness can manifest with a very atypical presentation... ...for instance unilateral food drop or dysphagia.

00:19:46: We have realized that myosititis has multi-system disorder which not always presents clinically with muscle weakness.

00:19:54: For instance, in anti-synthetic syndrome interstitial lung disease or arthritis can be the presenting symptoms and in dermatomyositis there can only skin features and no muscle weakness at which may delay the diagnosis.

00:20:11: Treations with connective tissue disorders such as rheumatoid arthritis or shogun syndrome May develop myositis in due course which is called overlap myositis and the muscle weakness, it's not always recognized.

00:20:26: And finally we have to realize that myospecific auto-antipodies are very helpful for diagnosis but only positive in sixty percent of cases.

00:20:36: so delay of the diagnosis certainly an issue because sooner therapy started better outcome.

00:20:44: So thanks Mariana.

00:20:46: going back to genetic disorders Talking about red flags, I think we have to say something about advances in terms of treatment of these disorders.

00:20:59: and i'm going back to Antonio if he can give you has some clues on advances on treatment of genetic disorders as LGMD or mainly metabolic myopathy Pompidysis.

00:21:12: Thanks!

00:21:14: Yes thanks this is very updated.

00:21:18: that would take question because In the last five, six years we had some innovative treatment for some of the myopathic disorders.

00:21:33: So our wishes go to gene therapy but still we have not so many defined gene therapies although we know that there are several different kinds of disorders, they have ongoing several trials like for example myotonic dystrophy or fascia scuffle disorders but still do not have the complete results.

00:22:12: and I would say in the next one, two or three years result of this very ample trials that are ongoing.

00:22:28: What we can say is on some other kind of disorders... We have some solid results for example metabolic myobodies take glycogenosis type II or pulpy disease.

00:22:46: We have new therapies that I've been matured in the last three years.

00:22:54: You know, that Pompey disease has been treated in the past with an enzyme replacement therapy and The enzyme replacement therapist as being largely updated to two new molecules That now are available for the treatment plus the old one our glucosidase, and now we have the avalucotase in the C-pagluposidases plus milustrates to treat the patients.

00:23:23: And this is very important because We know that these kind of therapies are not fully efficient.

00:23:34: but also we have taken consideration.

00:23:37: after first two or three years there's a sort of decline on efficiency treatments.

00:23:46: So to have the opportunity, change in case of decline from one kind of enzyme replacement therapy for another is a very good opportunity because patient could be treated longer and with more efficient results.

00:24:05: Of course also this area.

00:24:08: we know that there's promising gene therapy and we are really waiting for the results of the trial which is very close to be finished.

00:24:19: And, uh...the result seems to be promising as well.

00:24:23: but we also have other kind of metabolic disorders that are treated now For example, mitochondrial myopadias.

00:24:35: It's a very large field over different kinds of disorders because the multi-system nature of this kind would be better.

00:24:47: And in this field, for example, lead per disease could be treated by Pidepano.

00:24:55: but we know that now there are some drugs very close to being recognized by the Tvarnako institutions and we are still waiting for the definition of the treatment of decay to deficiency, which is a very relevant mitochondrial disorder as well as others.

00:25:18: For example you know that Friedreich at AXIA is somehow a mitochondrial disorders considered because the protein involved in this included it.

00:25:27: on the mitochondrial area also In this case We have some news.

00:25:35: So, I would say that the future is very promising because a big group of patients with myodontic dystrophy or fascial scapulaeumeral dystrophies could be treated for even more large retreators in the next few years especially waiting.

00:26:04: Okay, so going back to myositis.

00:26:09: talking about autoimmune disorders We know that in the last year we have the introduction of several new drugs That involved also the treatment of myositise.

00:26:21: So Marianne can you give me some advice on this?

00:26:26: Yes, Olympia I will try to give examples promising developments in myositis.

00:26:36: And that holds both for pharmacological and non-pharmacological approaches.

00:26:43: As I mentioned before, we need to realize that Myositis is a multi system disorder.

00:26:49: Antonio also mentioned that For hereditary myopathys That offer the respiratory muscles The heart are involved as i explained is anti-synthetic syndrome in which the lungs, not the respiratory muscle but the lungs as interstitial lung disease.

00:27:10: The heart is often involved with a number of subtypes and the myositis specific autoantibodies might be very helpful for this regard.

00:27:22: I mentioned the presence of ILD interstital lung diseases in dermatomyositis with MDA-V autoantibodies and cancer in patients with dermatomyositis TIF-I gamma-autoantibody as a risk factor.

00:27:38: If that risk factor is present, in a dermatomyositis patient screening for cancer is required not only at diagnosis but three years after diagnosis.

00:27:51: recently very nice guideline has been developed.

00:28:00: Myositis is a very disabling disease and only in one-third of the cases there's complete remission after therapy with corticosteroids, other immunosuppressants like azathioprine or metotrexate.

00:28:14: There are others second or even third line therapies such as intravenous immunoglobulins IVG.

00:28:22: recently an RCT showed efficacy of IVIG in refractory dermatomyositis patients.

00:28:29: However, there is still an urgent need for better therapies.

00:28:35: Since the B-cell plays a important role in the pathomeganism of dermatomyositis immune mediated necrotizing myopathy and anti-synthesis syndrome, RETOXYMAP classic CD-II targeting antibody drug is widely used to deplete B cells in various myositis subtypes which are associated with myositis-specific autoantibody, albeit a previously conducted randomized control trial was negative.

00:29:06: That's very interesting!

00:29:08: Recently some spectacular improvements and maybe you're alluding to that olympia have proven of cases of anti-synthetic syndrome an immune mediated necrotizing myopathy with anti-CD-IX CAR T cell therapy have been reported.

00:29:24: The CAR T Cell Therapy has demonstrated strong tissue penetrating capabilities, leading to stronger and long lasting B cell wipeout than RETUXIMAP.

00:29:37: There are currently numerous trials underway that further investigate not only its efficacy but also the duration of remission.

00:29:48: There are drugs available or they're currently investigated in clinical trials based on the pathovaginistic findings of the interferon pathway in dermatomyositis.

00:30:00: And TOVA CTNIP, Jack one specific inhibitor has shown great promise in treating Dermatomyositus particularly in patients with the entire MDA auto antibodies.

00:30:13: Dempting the humoral response might also be a therapeutic approach.

00:30:18: In miastinographis, IgG lowering strategies for instance with F-car GT mod has shown to improve outcome and trials with this medication are currently also under way from myositis.

00:30:33: And finally if there is still some time Olympia I would like stress the importance of exercise as an additional therapeutic approach in patients with myositise.

00:30:47: positive care.

00:30:49: In the severe cases of interstitial lung disease, for example in the MDA-V associated dermatomyositis and also for patients with IBM inclusion by myositis which is associated with a severe disabling weakness as yet not amenable to treatment.

00:31:10: Yes, thanks Marianne for this overview about the new treatment of myositis.

00:31:16: and now we are at.

00:31:19: I think we gave an updated overview in terms of diagnosis, clue but also in terms treatment management.

00:31:29: Of most the more common also rare metabolic and not genetic acquired myopathies.

00:31:38: so i want to thanks a lot our two guests professor Antonio Toscano and Professor Marianne de Visser.

00:31:46: And now I can conclude this too.

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