Welcome back for week four of the APP webinar series. Our first session today is Inflammatory Myopathies from A to Z, presented by Dr. Justin Kwan. Dr. Kwan is a staff physician and associate research physician at NINDS at the National Institutes of Health. He is director of the Neurodegenerative Disorders Clinic. Please enjoy this excellent talk. Welcome to the Inflammatory Myopathy from A to Z. Today, we have joining us for this talk, Dr. Shor-Bilagelar. She's associate professor of neurology and the co-director of the Neuromuscular Pathology Lab at University of Texas in Houston, McGovern Medical School. And my name's Dr. Justin Kwan. I'm a staff clinician at the National Institute of Health. And finally, we have Dr. Tasim Musafar, who is a professor of neurology and the interim chair of neurology. He's also the professor of orthopedic surgery, pathology, and laboratory medicine at University of California, Irvine School of Medicine. These are our financial disclosures. So today, we will start with three very interesting cases. And we will discuss all different aspects of inflammatory myopathies. And we'll start with Dr. Shor-Bilagelar. Thank you, Justin. I'm going to today present a case on a 24-year-old female patient. So this patient presented to our clinic with new onset of weakness. She developed a weakness within the last nine months. Major complaints were her difficulty with raising from a seated position. She had difficulty also blow-drying her hair and playing with our six-year-old child. And especially when she was on the floor playing with our son, she could not really switch to a standing position very smoothly. She denied any problems with breathing, swallowing. She denied any double vision or droopy eyelids. Family history was non-contributory. She had no significant medical history, no surgical history. She was not on any medications. Her examination did not show much on the systemic evaluation, such as her skin evaluation did not reveal any skin lesions, any rashes, any nail bed changes. Her respiratory status was normal, so was her cardiovascular exam. She had a normal speech. She did not have any cranial nerve deficits. Her sensation was normal. Her motor strength examination, though, revealed proximal weakness in both upper and lower extremities in a symmetrical fashion. Her muscle stretch reflexes were also symmetrical and 2+, and her plantar responses were flexor bilaterally. So based on the presentation and the symmetrical proximal weakness, we proceeded with a workup more geared towards muscle disorder. And as you can see here, her CK was normal. We also obtained some inflammatory markers. Her ESR was elevated. The other vasculitic-related workups, such as ANA, sugar and antibodies, and rheumatoid factor were negative. As you guys can also see, her aldolase was somewhat slightly elevated. So, sure, is it unusual for a patient to have a normal CK? Is it unusual for a patient to have a normal CK and you suspect who has a myopathy? Not really, Justin. This is something we see usually, both in hereditary myopathies, as well as acquired inflammatory myopathies, you can actually see normal CK in some of the patients. I would not have expected that. Thank you. We proceeded with electrodiagnostic studies. On the left-hand side, you're seeing the sensory nerve conduction studies, as well as the motor nerve conduction studies, and there are really no significant abnormalities. On the right-hand side, when you look at the EMG table, you can see that in the proximal muscles, both in upper and lower extremities, there is increased insertion activity, as well as abnormal spontaneous activity in the form of fibrillation and positive sharp waves. And the recruitment pattern is also early, as you can see in the right biceps brachii. Doctor, do you think that because you see the irritability, I should automatically think that this is an inflammatory myopathy now? That's a great question, Namita, but not really. My answer will be not really. Yes, there is probably some inflammation, degeneration, which is consistent with what we're seeing here, but that doesn't mean that the problem is an acquired inflammatory problem. You can see increased insertion activity and abnormal spontaneous activity also in hereditary myopathies. For example, myofibrillary myopathy is one of those. Nebulin road myopathies, you can see increased insertion activity, abnormal spontaneous activity. And also, in Asimaltes disease or adult-onset Asimaltes-Pompeys disease, you can see myotonic discharges. You can see myotonic discharges also in immediate necrotizing myopathies. So it is not really telling us exactly what this patient has. It tells us that the problem is in the muscles, though. Thank you. So to be able to determine what this patient had, we proceeded with a left biceps biopsy. So we biopsied the muscle that was not needled to make sure that we did not evaluate any false positive changes due to the needling of the muscle. So as you can see here, this is an H&E stain. As you can see here on the left-hand side, it's a lower magnification. You can see the small, really atrophic fibers within the periphery of the fascicles. So this is your classical periphysicular atrophy. And on the right-hand side, we can see it a little bit better because it's higher magnification. And again, you can see the atrophic fibers, again, located within the periphery of the muscles. So does this say anything, Dr. Muzaffar? So again, the periphysicular pattern is quite specific and suggests either dermatomyositis or antisynthetase syndrome. But the fact that they are predominantly atrophic and not necrotic would suggest more of a dermatopattern. Yeah, that's a great, great answer. So basically, just based on this, yes, we're leaning more towards dermatomyositis, but we can't exclude antisynthetase syndrome either. We can move on to the next slide. So to be able to determine the exact diagnosis, we proceeded with the myositis panel. And as you can see on the right-hand side, there is a positive antibody, which is the MJ antibody. This is actually NXP2. The former name is MJ. So this is a myositis-specific antibody, and it is associated with dermatomyositis. So you are correct. Great, great answer. Correct answer, Dr. Muzaffar. So this patient has dermatomyositis. Just a quick question. In general, when you think about ordering these antibodies, are you really selective in ordering a specific type of antibody, or do you go towards the approach of ordering a can of antibodies? I order the myositis panel. Basically, I order all the antibodies. Again, we just discussed how the periphasecular atrophy does not solidify the diagnosis of dermatomyositis. This could very well be maybe antisynthetase syndrome. The panel includes all of these antibodies. So I proceed with a myositis panel. One thing you have to order separately, though, is the HMCGR antibodies. Usually, HMCGR antibodies are not included in the myositis panel. So if you have a suspicion of the presence of this antibody, you have to order this separately. Thank you. Sure. Could you comment on the necessity of doing a muscle biopsy in dermato, especially if you have somebody with a skin rash and maybe positive antibodies? So first of all, this patient did not have a skin biopsy. So that was the main reason that I proceeded with a muscle biopsy. So the muscle biopsy will help you, especially in the absence of your more typical findings, such as the rash. But having said that, the rash can also be seen in other inflammatory myopathies, such as antisynthetase syndrome. So each patient is different, I should say. So in the context of each patient, what that patient has, what type of symptoms, and how they present, muscle biopsy is going to be helpful, very helpful in your diagnosis. And the other thing is also the availability of the procedure and how fast you can get the results of the antibodies and how fast you need to proceed or start your treatment. Thank you. So this is another patient, not our patient. Our patient did not have the rash. So dermatomyositis actually is an acquired autoimmune disease. It's a heterogeneous disorder, and it involves multiple systems, such as the skin, the lungs, the heart, the vessels, the joints. And in this slide, you're seeing the very typical skin findings. On the left-hand side, you're seeing the heliotrope rash, which is an edematous erythema within the periorbital regions. And in the middle picture, you're seeing the gotron papules, and these are papules located in the metacarpophalangeal and proximal interphalangeal joints. And when they're healing, they can leave a scar or they can be scaly. And on the right-hand side, very right-hand side, you're seeing the periangle erythema, as well as, again, the gotron papules. But you're seeing that periangle erythema as well, which you can see in dermatomyositis. But again, these findings, yes, when we see them, we suspect dermatomyositis, but these findings should not conclude that the patients have dermatomyositis, because as I said, antisynthetase syndrome can also present, these patients can present with skin changes. Heliotrope rash and gotron papules are more frequently seen in dermatomyositis, but there are some cases, rare cases, that you can even see this type of rash. And dermatomyositis patients, they display an upregulation of type 1 interferon-inducible genes in muscle fibers, endothelial cells, skin, and peripheral blood. So this is also, we're thinking that this is also an interferonopathy as well. And why that matters, we're going to see in a bit. And these patients, usually they present with, like in our patients, they present with subacute weakness, proximal weakness in a symmetrical fashion, and then some might have these other systemic findings. We can move on to the next slide. So here on the left-hand side corner, that's my corner, the dermatomyositis corner, you are seeing some antibodies. So these are muscle-specific, myositis-specific antibodies, and also dermatomyositis-associated antibodies. And 50% of the time, the dermatomyositis patients can be seronegative, but 50% of the time, they will harbor an antibody. And these can be SAE, Mu2, MBA5, Tifangama, and NXP2, or as formerly known as MJ, which is the antibody that was present in our patients. We're going to talk a little bit more about these antibodies, because each antibody can actually cause a unique presentation in the dermatomyositis patient, and can also have different implications. Let's first talk about the pathology, cover the pathology, and then we'll go into also some of the clinical findings. So again, paraphysical atrophy, we talked about this, and in most of the dermatomyositis subgroups, this is what you can see, paraphysical atrophy. And the subtype that might not show this finding is the MDA5 antibody patient. So those patients might have less conspicuous pathological findings. And also remember that the findings in inflammatory myopathies, as well as dermatomyositis, can be very patchy. So just because the muscle you obtained does not show paraphysical atrophy, does not mean that the atrophy is not present in the other parts of the muscle. So paraphysical atrophy, therefore, yes, it is very suggestible of dermatomyositis, but the sensitivity is somewhere around 50 to 60%. We can move on to the next slide. And on the right-hand side, we're seeing the CD3-reacted cells. They're located within the perimedium, mostly, which is also a pattern we see in dermatomyositis, but again, not pathognomonic. And on the left-hand side, you're seeing an alkaline phosphatase stain. And you don't have much alkaline phosphatase within the perimedium where you're seeing the paraphysical atrophy, but within or next to the small fibers, you're seeing some increased uptake, or I should say, you're seeing it a little bit better, the alkaline phosphatase staining, and that's due to the dilated vessels. We can move on to the next slide. And this is a stain, again, in the same patient that shows membrane attack complex deposits within the microcapillaries. This is also not a photognomonic. Again, the sensitivity around like 50%, somewhere along that line. And you can see these type of microangiopathic changes in sometimes immediate necrotizing myopathies as well, and in some other subtypes of inflammatory myopathies. We can move on to the next slide. So, so far, the findings that we see in dermatomyositis do not, yes, they are helpful, but again, do not solidify the diagnosis. So, one stain that we started using recently, and again, that has some, this is why we're also thinking that the type one interference might be relevant in the dermatomyositis, or interference might be relevant in dermatomyositis pathology, is that the myxovirus resistance protein A expression is very, very, very photognomonic in dermatomyositis. So, as you can see, the MXA staining within the periphery, within the sarcoplasm, where you see also the periphysical atrophy. So, the sensitivity is somewhere around like 77, 80%, and the specificity is almost close to 100%. So, if you see MXA staining, then your diagnosis is dermatomyositis. So, let's talk a little bit about, again, NXP2. This is what our patient had. The importance of this antibody is that the associational cancer is much higher in these patients. And as you can see here, there's an odds ratio of 2.5. And on the left-hand side, also, if you look at the age groups, as the age increases around like late 40s, then the risk of cancer even goes higher. So, one thing you need to remember and you need to know about the NXP2 antibody is that it has a very high association with cancer. Next slide, please. And one other finding is the associational calcinosis. So, calcinosis will be present in both juvenile patients, juvenile dermatomyositis patients, as well as adult patients. And as you should think about increased cancer risk, you should also think about calcinosis in these NXP2 positive patients. And they can be very resistant to treatment. So, now let's move on to another antibody, which is the Tifongama. Again, Tifongama patients, they can have very increased risk of cancer, even higher than NXP2. In some case series, it is reported to be almost like around 90%. So, when you see this antibody, you should think about cancer. You should be nervous about cancer in that patient. And again, in these patients, the higher the age, the higher the risk of cancer. When you see these antibodies in juvenile dermatomyositis patients, you don't see any cancer. So again, the cancer risk increases as age increases. This is a patient with Tifongama antibody. These patients, they will have lower CK levels, and the weakness is not going to be that significant, but their skin findings, their skin changes might be very profound as you're seeing here. Another antibody is Me2 antibody. And I also put some slides here. This is a patient with Me2 positive dermatomyositis. And as you can see on the right-hand side, this is a COX SDH stain, oxidative stain. And when you don't have any COX activity, you're going to see those fibers as blue, and you're seeing those fibers within the periphery where you see the peripherocular atrophy and the pathology. So, the mitochondrial changes can also be seen within the peripherocular area. So, that's also very suggestive of dermatomyositis as well. So, we can move on to the next slide. One other antibody that we need to talk about is the MDA5 antibody. The MDA5 antibody positive patients can present with ulcerative skin, lesions, interstitial lung disease, arthritis, and myopathy. This is almost like an overlap syndrome because you're seeing interstitial lung disease, you're seeing vasculopathy. The muscle changes or the muscle findings might not be very prominent, and you might not see your typical peripherocular atrophy or other findings. And the MXA staining might be very scattered within the whole fascicle, not really around the periphery as we saw or we see in the other subtypes. And the interstitial lung disease is very, very important to know in these patients. So, whenever you see these antibody in a dermatomyositis patient, think about interstitial lung disease. It can be very fast progressive and we might lose these patients very fast. And the treatment should be very aggressive in these patients because of this. So, this is basically a summary of all the antibodies that we talked about. One that we didn't really mention is the SAE. That's another antibody that we can see in dermatomyositis patients. These patients, they can have dysphagia. They can have also the typical skin changes. And one thing that's also seen more frequently in the subtype is that when these patients are started on hydroxychloroquine, they can have skin eruptions. So, that might be a clue in your diagnosis. And on time E2, patients can have very elevated CK, but they're going to be very responsive to treatment. And the cancer association is still there, but not as high as NXP2 or typho-ongama patients, somewhere around zero to 20. MDA5, don't forget about interstitial lung disease. That's very important and we should not miss. Typho-ongama, NXP2, the cancer association. And again, in different variations, you can see the skin findings in any of these. So, if we need to basically apply what we learned to our workup for your typho-ongama positive or NXP2 antibody positive patients, we have to be very aggressive in our malignancy workup. So, we should do a pan-CT and then we might have to proceed with a whole pan-CT. And the other subgroup that we need to be aggressive is the seronegative dermatomyositis patients as well. So, they have a higher risk of malignancy. So, SAE, ME2 antibodies, you need to do your age and symptom appropriate cancer screening. Having said that, these patients, they can have also cancer up to 20% all the time. So, keep that in mind. So, with each patient, again, do your due diligence and then work these patients up. And MDA5 patients, they don't really have much cancer risk, but they can have interstitial lung disease. Very malignant interstitial lung disease. So, when you see this antibody, do a high resolution chest CT and make sure you obtain your pulmonary function testing and also collaborate with a pulmonologist. Okay, we can move on. So, I'll talk a little bit about the treatment. So, the first line of treatment is steroids. We start with steroids. You can start with one milligram per kilogram. And once you stabilize the patients, you can start tapering it off slowly. Methotrexate is a steroid sparing agent that we can use. But if somebody has interstitial lung disease, you might wanna prefer azathiopurine. In, again, resistant patients, you can try calcineurin inhibitors. We've been using also IVIG more and more. You can use your 0.4 milligram per kilogram over five days for induction, or you can start with basically like two grams over two days. And you can continue with like every three weeks if needed. You can also use this as subcutaneous forms as well. One other agent that we can use is rituximab. And in MDA-5 patients, JAK1 inhibitors should also come to mind. What have we learned so far? Risk of cancer increases with age, anti-typhoengamma, anti-NXP2, anti-Me2, not that much. We have limited data on that. Severe interstitial lung disease is highly associated with the presence of anti-MDA-5. Not every rash associated with myopathy myositis is dermatomyositis. Elevated CK is not a prerequisite for dermatomyositis as we saw in our patient. And MX1 or MXA is very useful in pathological diagnosis of dermatomyositis. So I am going to stop here, Justin. Sure, if I can make a comment. Yeah, sure. Not a requirement for diagnosis of dermatitis is a skin rash. And I think you alluded to it as well, but about 6% may not have a skin lesion, but may only have weakness. And for some reason, they seem to be much more associated with NXP2 antibodies as was the case in your case history that you showed. Yes, exactly. That's a great point, yeah. All right, so now we will move on to case two. So this is a patient who I saw in clinic who complained of muscle weakness. She's 51-year-old, right-handed, and she had a previous diagnosis of Lyme disease in 1999. She complained of symptoms such as flu-like illness, and she did have at that time, expanding skin lesion typical of Lyme disease, the erythema migrans, and she also had generalized weakness and diffused myalgia. At that time, she was treated with two consecutive courses of doxycycline and her diffused pain and generalized weakness did gradually improve over the following two years. However, she then noted that she had persistent and progressive proximal weakness, most severely affecting her lower extremities. And she noted that she had more trouble getting up from a chair, climbing the stairs, and she subsequently had falls because she had poor balance of leg weakness. At that time, she underwent another workup and was noted to have an abnormal thyroid function and was diagnosed with Graves' disease and treated with tapasol, but this also only resulted in some mild improvement in her weakness. In spite of all these diagnoses and therapies, more recently, she continued to complain of increasing weakness in her proximal leg muscles. Her past medical history is only notable for what I described and as well as recurring sinusitis and asthma. She had a partial hysterectomy and a previous nerve biopsy because of her sensory symptoms. She worked as a social worker and she didn't really have any bad habits. There's no contributory family history and her medication is as listed here. What was interesting on her general examination was that she did have the erythema of her peri-ungo region and then there were most, as well as the PIPMP joints. She did not otherwise have any skin rash on her face or her chest or trunk. On her neurological examination, she had a normal mental status and cranial nerves. Her motor examination showed decreased muscle bulk, mostly in her proximal shoulder girdle and hip girdle muscles, and she did have proximal muscle weakness. The sensory examination showed a very mild decrease of vibration in her toes. She is areflexic and her coordination was otherwise normal. Because of these findings, we went on to do electrophysiology studies, which did confirm the presence of a generalized motor greater than sensory polyneuropathy and the findings were more consistent with an axonal process. Her electromyography showed membrane irritability and short duration polyphase in motor units, mostly in the proximal muscle and mixed normal duration, short duration motor units in the distal muscle without increased membrane irritability. At this point, she underwent a number of different studies. As you can see here, extensive laboratory studies were obtained and similar to Shor's patient, because of the diagnosis of myopathic process was suspected based on her proximal muscle weakness, a CK was obtained and was normal. Her other laboratory studies and inflammatory markers were essentially normal. She had extensive workup for autoimmune conditions that were all negative. She did have a mildly elevated, borderline elevated upstranded antibody and mildly elevated ANA and mildly elevated anti-SSA and her SSB was normal. Because of her symptoms of large proximal muscle weakness, an MRI was obtained, but that was really not very helpful in her case. Finally, a muscle biopsy was pursued and a muscle biopsy was performed on the vascular lateralis. And you can see here on the H&E upper two panels, there's inflammatory infotrace that's somewhat perivascular in nature. She did have some atrophic fibers with increased non-specific esterase. But really, this findings was relatively minimal and non-specific in nature. So I think that we've talked about quite a few diagnostic testing that will be helpful for autoimmune myopathies. I don't know what our panel of experts, what else would you suggest for this patient? So obviously the myositis antibodies would be a very helpful testing. And before we do that, a couple of comments. So SSA antibodies are very common in myositis. If anything, SSA antibody is the commonest myositis associated antibody that you see with very high frequency on that. And I think Shur has already mentioned that CK can be normal in rheumatoid. But CK can also be normal in other inflammatory myopathies, especially depending on the antibodies as well. Great, I think that's extremely helpful clinical pearls. I think that we should all tucked away. Thank you. So the myositis autoantibody panel, well, I wish to say the antisystate panel was obtained, and she did have a positive PL12 antibody. So her diagnosis was consistent with an antisystate syndrome with PL12 antibody. So she did have additional diagnostic testing, including spirometry and pulmonary function testing. And there were minor abnormalities, and she did not have any O2 desaturation during a six minute walk test. She did have a CT of chest without contrast because as we have come to learn that antisystate syndrome can be associated with idiopathic pulmonary fibrosis. So she did have some mild bibasal and fibrotic changes in regular ground grass opacities. And as I said earlier, her diagnosis is consistent with antisystate syndrome with anti-PL12 antibody. Now, let's turn this time over to Dr. Muzaffar, who will provide us with a discussion about antisystate syndrome. Thank you, Justin. And I think just to reemphasize, antisystate syndrome is now considered as a primary inflammatory myopathy, and it is one of the five primary inflammatory myopathies now in the classification system for myopathies. The first antisynthetase antibody was JO1 that was described in 1980. But since then, there has been a number of antisynthetase and antibodies that have been described, most recently the anti-ZO antibodies, and the number keeps growing on that. Anti-JO1 and anti-PL7 and anti-PL12 are probably the three commonest, but the difference being that JO1 is muscle tropic. So when you get JO1, you get much more muscle inflammatory disease, and a normal CK would have been unusual for JO1 because it's a very aggressive myopathy, whereas PL7 and PL12 are much more lung tropic disease or pulmonary tropic disease. And so your muscle disease may be minimal or mild, and that's why your CK can be normal in PL7 and PL12 disease as well. If I can have the next slide, please. So the antisynthetase syndrome is now defined based on a clinical pattern. So the clinical pattern is usually an inflammatory myopathy, much more in JO1 than PL7 and PL12, but you still have muscle involvement. Interstitial pneumonitis or pneumonia, as this woman exhibited by basilar atelectasis. Reynolds phenomena, which is very common. A mechanic hand is usually the most prominent skin lesion, although they can have gautrons, papules, they can have periangle telangiectasias, especially the skin features. And then a non, a seronegative erosive arthritis. So they have a very severe arthritis that can be quite damaging. As I mentioned, JO1 is muscle tropic, whereas PL7 and PL12 are more pulmonary tropic, and that's why the mortality is actually worse in PL7 and PL12 because of early and quite severe interstitial lung disease. Next slide, please. So these are some of the clinical features. As I said, this is a chest CT that shows by basilar disease and very severe interstitial pneumonitis. You can see mechanic's hand on the upper right-hand panel, Reynolds phenomena in the right lower panel, and then a very severe and erosive arthritis that is a feature of this disease. Next. So back in 2000, Alan Pastranken and I described for the first time the pathological features of JO1 myositis. And at that time, JO1 was considered to be part of polymyositis and dermatomyositis. And what we saw on the pathology evaluation of these patients is that they had a very distinct disease where there were very prominent connective tissue abnormalities with fragmentation of the interstitial connective tissue. There were large plumb histiocytic cells in the connective tissue, which you could see on morphological stains, but if you stained for macrophages or if you stained for histiocytes using CD68 or alkaline, acid phosphatase, you could see them. The alkaline phosphatase in the perimysium was very prominently present, and it's a very striking feature of the disease. And the muscle pathology, we weren't as impressed with the muscle pathology, although there was atrophy, and the paper actually mentions atrophy. And one of the things that we looked at at the request of the journal reviewers was to distinguish it from dermatomyositis. We were asked to look at capillary counts. So we went back and stained the muscles with lectin, which is a capillary stain, and we showed that unlike dermatomyositis where there is clearly a dropout of muscle capillaries, in JO1 myositis, the muscle capillaries were normal, setting it apart from dermatomyositis. If I can have the next slide. And so that was in 2000. For about the next 12 years, that pathological description was pretty much ignored, I would say. But in 2013, the group from Paris and Berlin revisited that syndrome, and not only confirmed pretty much all the findings that we had reported, but also found a very specific abnormality of actin aggregation in the nuclei of the muscles that happened on over 50% of the patients and turned out to be the pathological hallmarks. So I'm gonna take you through some of the findings from that paper. On the top left, which is a trichrome stain, you can see the necrotic fibers. And one of the features of antisynthetase is unlike dermatome, where you have atrophy of the periphysicular muscle fibers, in antisynthetase, it's predominantly necrosis of the periphysicular fibers. So you can see a lot more of those ghost-looking pale fibers on that, and some of them may be regenerating. The next stain, D, is the HNE, and you can see the fragmentation of the connective tissue. So the connective tissue has large holes in them. They're what some people consider as muscle edema, edema of the interstitial connective tissue. Panel C is a oxidative stain, and you can see that because of the necrosis, a number of those periphysicular fibers are missing oxidative stain. And then the next stain is the histiocytic stain, and you can see most of the inflammatory cells in the interstitial connective tissue are histiocytic cells. And then you can also see that on HNE as well as on esters and acid phosphatase stain. If I can go to the next slide, Justin. And then there is very prominent HLA staining. There is evidence for the regeneration of the fibers and necrosis defined by deposition of C5 through 9B, which is a complement cascade. So panel E and F really show the deposition of complement on the periphysicular fibers, confirming the necrosis of the muscle fiber in the periphysicular region, whereas panel C and D are the MHC1 and MHC2 upregulation in the periphysicular region. Next. Now these were, and then this particular group of figures, and I would focus on panel A, panel B, and panel C, which are the intranuclear actin aggregates that, as I mentioned, are present in over 50% of these muscle biopsies and seem to be one of the most specific findings in antisynthetase syndrome. These findings were confirmed subsequently by the French group. If we can have the next slide. This is the group from Olivier Benveniste, and they really highlighted the very characteristic necrotizing periphysicular myositis that is prominent in anti-JO1 antibodies. Next. And these are, again, some of the pictures from that paper where the arrows will highlight the necrotic fibers, as well as the perimysial connective tissue fragmentation, the inflammation around the blood vessels in B, but also deposition of complements in some of the muscle fibers, as well as in some fibers in a concentric, very sort of sarcolembal pattern, suggesting that there is necrosis going on there. Panel C is the MSC class II upregulation in these fibers. And then panel D shows the macrophages and the histiocytes in the connective tissue, which is, again, a very prominent feature of this disease. Now, subsequent to this, the Japanese group showed that these pathological findings are also seen in the other antisynthetase antibody syndrome. So these are not only specific to JO1, but you can see them in PL7, you can see them in OJ and EJ. So again, it sort of cements the idea that there is a unique pathology that happens in patients who harbor antisynthetase antibodies, in addition to a unique clinical phenotype that also happens in these patients. Next. Now, Dr. Pestrong's group in St. Louis looked at this in a reverse way. So what they did was they looked at all of their muscle biopsies independent of the clinical finding and actually blinded to the clinical finding. And what they focused on was patients with what they like to call as immune myopathies with perimyceal pathology. So these are immune muscle disorders where the bulk of the pathology was in the perimyceal region. And they went back and looked at the clinical phenotype or the clinical correlates of these muscles. Next. So, and what they found was that if a patient has, and again, blinded to the clinical information, if a muscle pathologist finds evidence for immune myopathy with perimyceal pathology, there is a very, very high likelihood that this patient will have interstitial lung disease, will have Raynaud's phenomena, will have mechanic sense as the property dominant skill pathology, arthralgias. But the good news is that there is less frequent malignancy and there is a sustained response to immunomodulatory therapy. Next. So Dr. Mozaffar, do patients in the prior slide, do patients have to have all the clinical features in order to qualify as antisympathetic syndrome? Not all the features, but definitely most of the features. And again, just to reemphasize, and if I can go back on the slide, Justin, and that figure actually shows some of the features. So you can see the periphysicular predominance of the muscle pathology. And most of these are either regenerating fibers or necrotic fibers. You can see the very prominent histiocytic inflammation in panel C in the connective tissue. And I think one of the features that is very prominent is the connective tissue or the perimyceal staining with alkaline phosphatase, which tends to be robust. The only other disease that may actually show that is MI2 dermatomyositis, where you can have very prominent alkaline phosphatase staining. But again, if I see a pattern like this, it's probably antisynthetase. And then you can see the panel G has the complement deposition on the perimyceal, periphysicular muscle fibers, again, suggesting that unlike dermatoma, which has atrophy and no complement deposition, antisynthetase has necrosis. And that's why you see the complement deposition. And you can also do the MXA staining too, because the same group from like Paris and Berlin, when they checked the MXA staining, there was no staining in the antisynthetase group. True. So as I mentioned, one of the ways to distinguish it from dermatoma, and back in 2000, we had to do the lectin staining, but the easiest testing right now would be to do the MXA staining, which is myxoma-resistant antigen. And so unlike dermatoma, these patients have MXA. MXA is absent. This is not an interferon disorder in this one. Next. And then again, there is about a 60 to 70% risk of interstitial lung disease. And again, a very high incidence of inflammatory myopathy than patients who don't have these. And they also had very high association with SSA antibodies and with very frequent JO1 antibodies. Now, as I mentioned, the majority of these patients will have very high serum creatinine, and it's not unusual to have CK levels of 1,000 or higher in these patients because of the very frequent necrosis that happens in these patients. Next. So again, the muscle pathology just reemphasizes perimysial. There's connective tissue fragmentation and inflammation with histiocytic cells. Unlike dermatoma, there's no atrophy. In fact, there is necrosis and regeneration. There's MHC class II upregulation and intranuclear agglutinant aggregates. And just to show you some more recent examples, these are pictures from our lab where you can see the very, very severe peripheral changes in a case of JO1 myositis. As I said, you can see that on trichrome as well. And a lot of those fibers are necrotic fibers with pale-looking fibers. But the panels on the right are probably the most interesting. A very striking alkaline phosphatase staining pattern that is not seen on any other disease with this degree of intensity. And a very, very striking acid phosphatase staining, which highlights the histiocytic involvement as well as the muscle myofagocytosis, which again is usually not seen on any other disease pattern. So these pathological findings are very characteristic of antisynthetase syndrome. And then one stain that I like using a lot, but again, every lab has their favorite, minus CD56, which is a very good marker of muscle fiber regeneration. So you can see that most of the fibers that are taking up CD56 are in the periphysicular region, suggesting that some of these fibers are also regenerating. So in addition to necrotic fibers, you have very striking regenerating fibers as well. So I'm gonna stop here. Do you ever do electron microscopy? Because you mentioned the... We routinely don't do electron microscopy. We only do it if there are atypical features. But so to answer your question, we have not in the habit of looking for the intranuclear aggregate molecules on that. Thank you, Dr. Mosfar, for that really wonderful discussion of antisynthetase syndrome. Great. Well, I wanna thank all of our excellent speakers today for their wonderful discussion of a variety of issues that we have to grapple with when it comes to this very complex group of disorder inflammatory myopathies. And we will take questions. Thank you for participating in this meeting and talk. And I'm happy to take any questions that you have. I think before we start taking questions, I just want to take a minute to highlight the complexity of inflammatory myopathy. And it really requires a good understanding of the different presentations of the different subtypes of inflammatory myopathy and how to use the tools that we currently have effectively to really drill down until you get to a specific diagnosis. And I think that sometimes the referrals to evaluate muscle weakness comes to us from different sub-specialists. And it's really important to keep in mind that this group of disorder is actually a multisystemic disease with involvement of the skin, the lung, the heart, and the joint. So we have to keep that in mind as we get referrals from some of our colleagues in rheumatology, dermatology, and pulmonology that sometimes we get consults and requests to see patients with mild weakness or vague symptoms or fatigue, but just understanding that the spectrum of autoimmune myopathies or inflammatory myopathies can present itself initially with involvement of another organ system outside the neuromuscular system is important because ultimately having a broad differential can lead us to the correct diagnosis in this group of patients. I guess if there are no questions, one other comment I just want to make quickly is that another important aspect about this group of disorder is always having a dialogue with your neuromuscular pathologist, because sometimes the findings may be subtle. I think that we tend to present cases that have very dramatic or typical findings or textbook findings, but sometimes the pathologists are not getting the full clinical picture, especially when they receive a piece of tissue from the surgeon. So it is important for you to communicate with a pathologist to let them know exactly what are the differential diagnoses that you have in mind, and it's important to fill them in on the clinical presentation and other clinical biomarkers you may have obtained for the patients, including creatine kinase, aldolase, and some of these myositis-specific antibodies and myositis-associated antibodies, because they may then take that information in addition to the pathological findings, and it may help you arrive at the correct diagnosis by communicating effectively with your neuromuscular pathologist. I don't know if there are any other questions. Dr. Kwan, thank you so much for your wonderful talk and all of your wonderful wisdom. Is there any way that this crowd could get ahold of you if there was a question, say, afterwards? Sure, so you can always get in touch with me through my email, it's actually fairly easy. It's Justin, J-U-S-T-I-N, the period, my last name's Kwan, K-W-A-N, at NIH.gov. Wonderful, thank you so much for everything. We truly appreciate having you here. Thank you, and thank you for having us, and really, we appreciate you joining us for this talk. Thank you, have a good day. Wonderful afternoon.

Inflammatory Myopathies

A to Z

patient cases

dermatomyositis

PL12 antibody

antisynthetase syndrome

pathology findings

neuromuscular pathologists

multisystemic involvement