BONUS CASE: Myalgia, muscle weakness and statins

In this pod Consultant Rheumatologist, Dr Judith Jade, chats with Dr Fergus To, Rheumatologist from British Columbia, about the case of a woman who presented with subacute muscle weakness. They discuss how to approach these types of  cases systemically with some handy tips along the way. Listen in and see if you can work out what the diagnosis is!

References:

1. Blazing M, et al. Effect of statin therapy on muscle symptoms: an individual participant data meta-analysis of large-scale, randomised, double-blind trials. Lancet. 2022;400(10355):832–45

2. Kim EJ, Wierzbicki AS. Investigating raised creatine kinase. BMJ. 2021;373:1–5.

3. Sharf K, Do T, Ghetie D, Choi D, Chahin N. Benefits of Early vs Late Initiation of IVIG in the Treatment of Anti‐HMGCR Immune‐Mediated Necrotizing Myopathy. Arthritis Care Res (Hoboken) 2024;76:1584–92. https://doi.org/10.1002/acr.25406.

4. Allenbach et al, 224th ENMC International Workshop, Neuromuscular Disorders, Volume 28, Issue 1, 87 - 99

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Transcript

JJ - You're listening to the Talking Rheumatology podcast brought to you by the British Society for Rheumatology. This is a Talking Rheumatology podcast for the British Society for Rheumatology, and we're recording a case-based podcast today on the topic of myositis. I'm going to keep it slightly vague because, hopefully, the answers will become clear later in the podcast. I'm hosting today. My name's Judith Jade, and I'm a rheumatologist. I just finished training last summer in 2024, and since then I've been doing a myositis fellowship in Vancouver under the supervision of Dr. To, who I'm going to introduce now. Fergus To is here with us. He is a rheumatologist from British Columbia. He works in Vancouver and he set up the myositis clinic, along with Dr. Kun Huang, in Vancouver. It's a quaternary myositis clinic, so they see lots of very interesting and specialist cases there. They run a great service, have won an innovation award for it, and Dr. To also did a fellowship with Professor Hector Chenoy in Manchester a few years ago. That's how we linked up so that I could do a fellowship with him. I've been learning a huge amount from all of his expertise over the last six to eight months so far. So, yes, welcome. Thank you so much for agreeing to do this, and we’ll kick off if that’s okay.

 FT - Absolutely. Thank you for having me.

JJ -So I'm gonna do a little synopsis of the case who this is a real case, but obviously anonymized that I have seen in the myositis clinic recently and, Fergus has been looking after for the last few years. So, the patient is a, a female in her fifties, and she's got a history of type two diabetes, dyslipidemia, diverticulosis, previous renal cyst, right lung nodule, her hepatic steatosis, so various comorbidities. And she developed analgia and some progressive proximal weakness over about a month-long period, and she was unable to actually get up the stairs, get out of bed. She had difficulty raising up her arms, and she was admitted at that point for investigations to hospital because she was so weak and then on further questioning by the doctors that saw her initially, it turns out she had some more subtle weakness that had probably been going on about ten months or so. They did a whole systems review and didn't find any dysphagia, shortness of breath, ulcers, Raynaud’s, fever, weight loss. She did have a dry sort of eczematous rash and dry dryness on her scalp. They also listed on atorvastatin for the last three to four years, and her dose had actually recently been decreased as her family physician was worried that that was the cause of her myalgia, but it hadn't improved her symptoms. She didn't she wasn't taking any other new medicines, and she doesn't drink any alcohol. On examination, she did have quite marked proximal weakness of about three minus out of five. So that's the sort of potted case history, I think, of the points, that were listed when she was first seen in the history and examination. And I was just wondering whether you could touch on us, maybe in a bit more detail if you were seeing this patient or maybe your approach in general to any new myositis patient you see focusing on the history and examination. What aspects do you really look at to try and make a diagnosis?

FT - Yeah. So it's a great question. I know you've given me a bit of the background on the past medical history as well as her medications, but assuming I didn't have that information in to any case like this in the emergency room or in hospital, I think I'd approach it with a framework of, you know, the salient points we'd be looking for for myositis and then any mimickers, making sure we're not missing the obvious things that often we forget about.
 We're often very eager to diagnose myositis, but rhabdomyolysis, for example, making sure we're not missing that. So I do it in a systematic way, making sure I'm digging into the past medical history, asking about key things for myositis. So first of all, if they've had any muscular issue or muscle problems in general. So looking at some of the main procures like any issues growing up with congenital or I should say like exercise intolerance for example, making sure we're not forgetting about some of the inherited metabolic myopathies. And then in an adult patient, the ones that I usually work with, I'm thinking about okay do they have any coronary artery disease, do they have dyslipidemia, and sometimes patients don't even realize they've been on a statin. Of course that would be very relevant for us, so I dig down deep. Have they ever been treated with anything for cholesterol at all? And then I just name some of the common statins for them. And then any history of any sort of muscle condition would be helpful because those patients may be predisposed to, various kinds of rhabdo. And then going through the medication list, so you mentioned earlier they're not on any new meds, but I go through again, I check their medications really carefully, make sure they're not on any colchicine for example, statins, go through what they're on and then sometimes you want to think about inhibitors as well, right? Like some of the CYP, inhibitors like antimicrobials and antifungals for example, that can increase the risk of just pure stent myopathy for example. And then asking about family history, so for myositis itself, so probably a little bit less important. It's often not directly inheritable like you know our lupus patients or rheumatoid arthritis patients for example. But there is certainly a genetic background that might play a predisposition. And then on the history, this is where it's helpful to know, you know, I asked them for a full chronology. Under this start, really, when did this weakness first begin? And you told me ten months ago, but sometimes I find patients just develop weakness over the last few days and that can be very, very helpful in determining is this an insidious type of myocytes or is this something very, very quick onset, which would be more suggestive of rhabdom, for example. What else would I ask in them? I think in the acute setting, it's hard. They're just gonna tell you they're weak. They might actually be simply in pain and characterize it as weak but I really clarify, is this weakness or is this pain? And if it's weakness, where is the weakness? Are they even able to tell me? I think in the emergency setting, we would be relying heavily more on our whatever we can get from a physical examination to look for that proximal muscle weakness. I think it's pretty tough for patients to sometimes verbalize that, even mixing up myalgias with actual weakness for patients. So try try and get that off the bat and then looking for extra muscular activity as well. So in I'm thinking dermatomyocytes. You mentioned they had a rash on the scalp, I think. So really characterize, you know, could this look like a rash, for example? Could there be a rash anywhere else? Is it photosensitive? Look for some of the key things that only you as, you know, a myositis person would be looking for. So are there little rashes elsewhere that are hidden, you know, knowing your, like, your holster sign, your hiker's feet, your your, your palmar papules, ulcerations, asking for all of those on a very full review of systems that someone else who had assessed this patient may have asked otherwise. Because otherwise you're missing very very important salient information while you're waiting for a myositis panel to come back, and those can sometimes take days or weeks depending on your institution. Yeah. And I don't know if I said myologist, but definitely ask about sorry, dysphagia. Definitely ask about dysphagia. You're gonna get dysphagia in rhabdo, for example, but you're if you hear, yeah, you have like some swallowing issues. And the way I might ask is, you know, are you I mean the obvious one is choking. I think that one's an easy thing to ask, but I might ask when you're drinking water, for example, are you noticing you're having difficulty getting it down, or does your voice sound wet after if there's any retention and the bulbar muscles aren't quite working quite as well? Mhmm. So asking all of those upfront. Because if they do say they have those, then you're thinking, oh my goodness, this could be myositis, my treatment. Even how aggressively I treat this could be very different. Is that all the all the questions? Were there more about was I supposed to do examination as well? We yes. If do you wanna touch on examination now or what you would specifically be looking for in exam? That'd be great. Yeah. Thanks. Yeah. So I think actually, one of the things why I love this is  I think at this point, we're one of the rheumatologic conditions where we rely still so heavily on the physical exam to make the diagnosis because we're waiting on all these other tests that could take quite a while. Right? EMGs to organize MRIs, the mastitis panel. So Okay. I referenced some of the things I would be looking for earlier already. So a very thorough skin exam, looking for all the potential dermatomyositis rashes. I'm very curious what this patient's rash looks like because I actually don't remember. I think I saw them so actually, I don't think I met them anymore by the time I saw them, they probably didn't have rash. Making sure you do a good, examination of the cardiac system as well as the lungs. Right.
 We're looking for any sort of cardiomyopathy, any form of ILD that could be an early sign of some of our more aggressive rapidly progressive ILD cases, and then finally coming down to the the manual muscle testing, the MMT, to see if you can get any form of at least a preliminary picture of where is the gradient. Is it more proximal, is still is it widespread? Check your neck flexors, check your neck extensors, and if the if you're having trouble doing it in in bed then at least, you know, see if you can do it in anti-gravity position. I think the initial muscle exam for a lot of very, very weak patients just paints like a preliminary picture. It's just so hard to get them motivated in that, you know, noisy, emergency room setting. But at least I can say, okay how weak are they really and which muscles are.

 JJ - I'm gonna ask a follow-up question if that's okay based on, like, the pattern of weakness because, it's definitely something I've learned a bit more this year with you. So is there particular types of myositis that you see particular patterns of weakness? For example, like, neck flexor weakness, neck extensor weakness, or or distal involvement.
 If you could just go into a bit more detail about that, that would be really useful.

FT - Absolutely. So the and these are all more you would expect on a textbook. I think the more cases I've seen, the more I've been humbled by how often people deviate from these patterns. In our myositis, usually, we're extent expecting more of a neck flexion weakness compared to extensor, so that's why it's important to compare side to side. And then our inflammatory myopathies, we're usually expecting proximal versus distal. That's more of a gradient. Yes, I've seen some where you can get the occasional, no actually not that, can get occasional distal, more distal weakness anyway, that's rare. The IBM cases are usually where you'll expect the more distal involvement, so inclusion body myositis where you might start off with simply the finger flexors being one of your earlier signs or you might get a earlier issues with lifting your foot for example, that's the classic textbook definition and I think any rheumatology trainee I think you guys call them registraries there. I think any registrar will be able to say that. But I have seen some, overlap in that. So I I think most patients will fall into that, that framework, but don't be, fooled. For so for example, like, even patients with rhabdo, for example, they're usually more focal. They can they can be more widespread, but it just depends on where the focus is. So you can still get it in more proximal muscles. So I wouldn't use this as the end all and be all. This is just one of the puzzle pieces we'd be relying on.

JJ - Yeah. And I've really learned from, from you about flexi digitorum profundus for that weakness in finger flexion, in IBM, which I think is a great clinical sign, to help you differentiate when sometimes it's not otherwise clear. I think that's a really helpful sign to just specifically look for. I found that useful this year.

FT - Good. My job is done.

JJ - Well, I've learned that and among many other things. Don't worry. So we thought, quite a bit about history and examination. I’m gonna ask a little bit more about the timeline because you definitely mentioned it, the timeline of symptom onset. And I think this is, if we're putting, sort of categorizing this patient as having a she's got a proximal weakness and there's a statin history. In that with that history, you know, in my mind, it always goes to, is this a statin side effect? Is it a statin myopathy? Is it rhabdomyolysis, or is it autoimmune?

FT - So with those and, could you go into a bit more detail about maybe the timeline or how to differentiate those different aspects of statin related muscle disease. So I think you actually did a really good job already whether you you knew it or not in the asking that question, just going through the different types of side effects that could come from statins. So we're thinking about big categories, right? On one end, we're well actually in my head the way I think of it is this immune driven, so we're thinking about the immune mediated necrotizing myopathies, And then on the other complete different category is just a pure myotoxicity, and then there's a whole spectrum for that. So this is just direct talk from the statin itself. So on one end, we've just got a blip in a c k. I think probably family doctors see this a lot. They probably, you know, a seasoned family doctor probably doesn't bat an eye out, just a small blip in the CK Patient's asymptomatic, you're fine to continue. And then sometimes you get a bit of myalgia, no real weakness, a little bit of higher CK. I think for the most for most cases, you're able to continue, as long as it's not too symptomatic for the patient. And then we start getting to the the further end of the spectrum from the toxicity where when you might get weakness. Now you're really thinking you probably need to switch or or an actual rhabdo as well.
 
 Right

So now we're thinking actual weakness, probably muscle aches, and then we're worried about an AKI. And the way I would differentiate and again, this is not a hard and fast rule. This is but this is helpful in taking a history as well. When did you start your statin? Often there's a timeline correlation if it's a toxic effect, right? You you give the patient the the toxic insult, they develop the insult. For a myositis, it's just repeated exposure to this antigen.
 Possibly the statin is what we're thinking, right? And at some point, you turn on your autoimmune switch. And even if you remove the statin, it's gonna keep rolling along. So that's a long answer to a easy questions. I think usually there's it's usually more of a temporal relationship to the stent if it's a toxic effect versus in a myositis case, you really have to dig back, like have you ever been on a stent at all? It could come on months later, it could come on years later, and then you ask about the symptoms. Well, since you've had the symptoms, how long has it been going on for? So if if if it, you know, it just occurred over a few days, that would be very, very atypical for immune mediated necrotizing myopathy.
 Usually these ones are more insidious, they happen over months is usually what I'll see. I've seen a few cases where, it actually took years, right? They were they probably just had such mild, myositis that nobody ever detected, their CK was just kind of grumbling, and then finally, somebody figured this out. And I can give you an anecdotal story It's about my wife who's an endocrinologist. So she was running a lipid clinic and I don't actually know how she ordered the c k. She's obviously much smarter than I am, or maybe she just detected there's a c k, and she's like, why is this person's c k been high for so long? They've been on a statin.  And then she I think I had just finished doing some training in myocytes, and she was like, do you think this is a case of, you know, necrotizing myocytes? I'm like, oh, you're overthinking it. I don't know. Like, somebody would have detected it by now. They've been doing it for years or they they've had it for years, but, I eventually evaluated them. And, yeah, this woman was not too weak. But, yeah, we did the work trip and had ClearCut HMG myositis I always can't help but wonder how many of these patients are floating in our population just slightly dwindling, but not too badly.
 
 

JJ - I definitely think there's quite a lot there with milder and disease that probably don't get picked up.
 
 Yeah. For sure.
 
 Okay. That was really, really helpful. And it brings to mind another anecdote of a patient we saw not that long ago in clinic who had been treated for, she'd been started on IVIG and high dose steroids, in hospital, for, weakness severe muscle weakness, and she'd recently had a bump up in her, starting dose. And she had risk factors of a very low weight. And, actually, on the history, I remember it was over her weakness had developed over days, not weeks or months. And her husband described her urine as being rust colored, and she had a very severe AKI which had got better with fluids. So it all really pointed to rhabdomyolysis. And I think in in that case, the history was so key in differentiating. She did go on to have a muscle biopsy make sure because she'd already had IVIG by the time we saw her. 

FT - But, I think it was for the listeners. I wasn't asked to put her in IVIG.

JJ - Yeah. We should clarify that. That that those steps had already been taken. But I think from the history, for us at least, it's, it was quite clear that she had a lot of features much more in keeping with rhabdomyelitis.
 
 Absolutely.

FT -  I saw her last week. Actually doing great. She's just hanging out and living life.

So we were right?

We were right.
 
 

Great. That's reassuring. So, if we, circle back to our current case then. So, for listeners, I'm just gonna recap that we've got a fifty ish year old, female who, has been on a statin and has proximal weakness over the last ten months, which has got worse recently. So, in terms of investigation so she's had some investigations. So, an EMG and a muscle biopsy arranged.
 She'd also, had some blood tests, with a CK, which was done, which, was high at about the above 10,000 between sort of ten and fifteen thousand range. She'd had muscle antibodies sent off, which can take, quite a long time. So, they weren't back initially, but she did have, an EMG, of the left deltoid, which was on admission when she was particularly weak, and it showed fibrillations, positive sharp waves, a few myotonic discharges, very small amplitude motor action potentials with early recruitment. And then, after that, she went on to have a muscle biopsy, and, the antibodies, were still in progress. So the muscle biopsy was reported as showing, regenerating and degenerating fibres, fibres undergoing phagocytosis, by macrophages, increased macrophages, but no, lymphocytic infiltrate, and mild perimusal fatty infiltration and endomusial fibrosis. And I'm going to pause before we say what her antibody showed because it will completely give the game away. But, but maybe our listeners can guess anyway. But based on, on her EMG and a muscle biopsy findings, could you just go into a bit about what how you interpret then if if you just got those results back with with, without having the antibodies back at this stage?
 
 Absolutely.
 
 So preface out there, I am absolutely not an expert in EMJ. I don't do I don't do pathology, so I I do always rely on my neurology colleagues as well as my pathology colleagues if I have any questions. But I think you actually gave me a lot of buzzwords in it. Was that the actual report?

Yeah.
 
 Okay.
 
 Alright.
 
 Okay.
 
 Well okay.

The summary. The conclusion.

Okay. That's helpful. So ENGs are helpful. They won't tell me if it's myocytes. They'll just tell me if there's a myopathy.
 
 Right?
 
 So you you used a lot of buzzwords in there is what I'm often looking for like fibrillation, positive sharp waves, both of those can if there's potential myositis involved, there's that indicates myo like I think it's a membrane instability. And then what else did you say there was like early recruitment as well? We often see that

JJ - So we've got, yeah, early recruitment and very small amplitude.
 
 Oh, yeah.
 
 Yeah.

So if it's a small amplitude, that's often suggestive of a myopathic process as well. We're essentially measuring the size and density of the muscle fibers and normally would vary right within and now now you've just got damaged muscles as well. You're gonna get a myopathic feature with a smaller amplitude. I'm sure the neurologists are rolling their eyes at my explanation, but that's my interpretation. Those would usually be the buzzwords I'm looking for in the report there. And I think that can really help us differentiate broadly from a neurogenic type EMG, can't it? Which is the opposite. You get, like, a these large, motor action potentials instead of polyphasic.

Yes.

Yep and then, great.
 
 So we think on the based on the EMG, that sounds like it could be a myopathic process, but I guess that doesn't really differentiate at all for us, whether it's an inflammatory myositis versus a toxic myopathy, or or even an inherited myopathy Mhmm.
 
 

So I mean, toxic ones are fairly nonspecific. They might sometimes even be a bit normal, but there's but you can also see this pattern.

Right?
 
 

So you're you're correct in that as well.

And then you mentioned to talk about that?

And then yeah. So then you've you've got the biopsy, which gives us a bit more information. So what what do you think about that result?

So you, again, you know, fed me some key buzzwords there. So it, you I think you said regenerating, degenerating, so I see some variability, in necrosis and regeneration. That in my head, right, I'm I'm, of course, I'm always wearing the mastitis hat, makes me think of a very specific type of inflammatory myopathy, the immune mediated necrotizing myopathies and then there are a couple of other things you said so no definitive foci of lymphocytic infiltrates. So we usually would expect that more in, like, dermatomycotic, for example. For whatever reason, in the patients with IMNM, so that I'll use that short for immune mediated necrotizing myopathy. We don't see that same degree. So that's another What else did you say? And then you said macrophage increase. So usually we're more likely to see this macrophage in this. It's a bit more predominant without without the same lymphocytic in this invasion.

Yeah.
 
 

I'll see all these stains, and then I'll pretend I know when I'm reading it, and then I'll have to pull up the chart to say, okay. What is the stain actually stained for but you actually, fed me all the key things that I'm thinking about. So based on what you're saying, right now, I'm thinking, okay. Well, there's a myopathy based on EMG and a biopsy that's suggestive of an IMNM.

 JJ - So I think, this definitely learned that this year as well that that that particular description is quite specific for IMNM, in terms of so we've got the degenerating and regenerating fibers, and we've got the, phagocytosis by by macrophages, with very little lymphocytic infiltrate. And then she also had some fatty infiltration and endomysial fibrosis, maybe suggesting that the process had been going on quite a while.

Right. Yeah.

Like we've been discussing and then so, her antibodies finally come back stronger.
 
 Right.

 She's she's high positive for hMG CR antibody and I guess a follow on question for that then would be, if you work in a you can get, antibodies done reasonably quickly.
  Would you would you have done her EMG? Would you have done an MRI and just waited for antibodies, or would you have still gone ahead with the muscle? I know it's it's hard to just think backwards like that but I think it would be nice to still document I I probably wouldn't do the biopsy. I think if I if I unless there if unless I change my treatment. So if I can get the HMG quickly or the the myositis panel, quickly, yeah, let's get that done because that's so helpful in figuring out what subtype this is. It's just make sure that you're you're aware there's a lot of false positives and false negatives associate with that as well. And then document, perhaps on either EMG or MRI. And in this situation, I think either one would have been okay because you know she is weak.
 
 Right?
 
 And if you can get the myositis panel back, you have a bit of an answer. If you're not sure if it's a myopathy or something else, then you know, certainly the EMG is a lot more helpful for that. But, yeah, I would not have done the biopsy in this patient. I think often even in like some of her dermatomyocytes cases, antisynthase cases, we're not gonna be pursuing a biopsy necessarily if the phenotype fits and you've got the antibody status.
 
 JJ - That's really helpful to know. Fantastic. So we've now got the diagnosis. So she's got, CR antibody positive IMNM. As you said, immune mediated necrotizing myopathy. So in that case, so so that was her diagnosis. I'll briefly talk about her treatment, and then maybe we could talk a bit more in detail about treatment in general for these patients if that's okay.

FT - Yeah.

JJ - So she was started on oral steroids at a dose of one milligram per, per kilogram, weaning course, and methotrexate but weakness improved for her. CK did improve, but it didn't get below 3,000. So, azathioprine was added in, and she also had a course of IVIG monthly for three months. And, eventually, that normalized her CK and her strength returned to normal. Methotrexate was then stopped due to abnormalities with her liver function, and she does have this background of hepatic steatosis. But she was still on azo thioprine at that stage. She'd been weaned off steroids. Unfortunately, flare, with weakness and a rise in her c k, while she was just on azathioprine. So micaphenolate was added in. So then she's, been on micaphenolate and azathioprine since then. I think oh, no. I think, actually, when we last saw her, she'd had some side effects, unfortunately, and we were thinking about changing her treatment again. So this, obviously, that's quite a complex treatment history, but I think that probably represents quite a lot of the patients in myositis clinic, that ends up being on various combinations of treatment and trialing different things until you find something that really works. So I just wonder yeah. What's for particularly this subtype of myositis, IMNM? What's your go to, like, first, second, and third line treatment? And if you if there is any evidence out there, would you mind pointing us in the right direction?

 FT - Yeah. So I think the highlights are usual go to first, second, third, but I'll go through a little bit more systematically here. So, is there any evidence out there? I think it's all very weak evidence. This is still very much evidence based more than evidence-based zone that we're dealing with. The reality is most of the algorithms come from case series, case or observational cohorts expert opinion. So the if you wanted, you know, a nice simple so if the listeners wanted a nice simple approach, so the 2016 European Neuromuscular Centre published a nice flowchart on this, and this is usually what most rheumatologists will go to for the treatment algorithm. So up front, most of these patients you will want steroids. I'll talk about there's some evidence maybe you can get away without steroids for some patients. You usually want a high dose and you want to pulse them if it's severe. And how do you even define severe? So maybe is it dysphagia? Is it very, very, very, very weak? I don't think that's, I think it depends on who you ask. I try not to pulse them, meaning IV steroids.
 You know these patients have dyslipidemia upfront already, but if it is severe enough, you can't consider if they're exceedingly weak with dysphagia, for example. But otherwise, milligram per kilogram in this patient seems reasonable. And I think the case you presented, she was very weak upfront, and it still worked. Just remember you're gonna see the CK melt away. It doesn't necessarily mean you're you're halting the whole process right away. But you start off with your steroids, and then upfront very early on, you wanna initiate something like methotrexate. I prefer that. It's I'm I think it's mostly because I have a lot of familiarity and it's well, you know, supported in in case series and observations. That doesn't work or if there's a contraindication, then you're thinking about azathioprine or Michael Fenway, sometimes even a combination, right, which is what we see here. And then think about IVIG early, and I I think IVIG practice parents differ across the world so much depending on access, it's just such an expensive product out there. When do we use it, how do we use it, how long do we use it for, so various studies have looked at that as if we're looking at evidence. You and I recently, read a paper in 2024 just comparing early and late IVIG. A lot of limitations to that study, but maybe there's some evidence for earlier initiation of IVIG, but I think that's just in reality, not practical for a lot of centers depending on what their practice or what how easy they can access the IVIG. But you can essentially put IVIG in anywhere in this algorithm if they're really sick upfront.
 
 Right?

You may actually wanna think about this early on. And then if you're still getting a subvalence after that, that's when you start reaching for other products like rituximab. And again, that may vary depending on the site you're working on, how easy it is to access rituximab. Once you've once you've got this patient in, you know, relatively okay control, then you can think about well, actually, you probably wanna start tapering them earlier than later. But usually, once they've started and I see some improvement, I start them tapering, and I keep the DMARD, on in the background. But usually, we'll taper after about two to four weeks right away because, I mean, they they have to slip a d likely have to in the in the beginning. So we or other metabolic issues, so you don't wanna keep them on a steroid for too long either. So that's usually the first, second, third line. So steroids up front, a DMARD, often methotrexate. You can consider IVIG early, if possible, and then rituximab switch thereafter. What other evidence do we have for other things? So we don't have a whole ton. There no phase three trials whatsoever, that I'm aware of. There was a phase two trial, that looked at a c five completer. They basically just looked at patients with IM and M against, placebo to or sorry. IM and M, receiving this medication against placebo to see if their c k would get better, but they didn't. So, unfortunately, that that didn't pan out quite as as we're hoping to. And then another one that oh I mentioned earlier, can we get away without steroids? I think it's a bit dicey. I mean when we think necrotizing myopathy, we're often a lot of us will think, oh this is really bad. Can we get away without steroids? There is a Canadian study rah rah right my country where we looked at patients who there may be a subset who can get away without steroids, and possibly if we capture those earlier with minimal weakness, that might be one you could trial on. But those patients that even if I put them on no steroids, let's say we're just starting methotrexate, for example, I'd watch them carefully, so for flare or lack of control. And if I'm unable to control, I I would go ahead for my traditional algorithm.

JJ - That's really helpful. It's even helpful just to know that's an option for some patients.

FT - At least there's some weak evidence or at least there's some evidence published evidence out there, right, I should say.
 
 JJ - And then if we're thinking further down the line, or, actually, no. I'm gonna ask another question first if that's okay. Either on the evidence, you mentioned the IVI trial we looked at with early versus late IVIG, in IMNM with some evidence in that trial, that the early cohort did better. Is there any other evidence that you know of or just anecdotally or in your experience with myositis, whether these patients particularly do, a lot better if you manage to treat them early, versus treating them late?

 FT - I think always treating them late because we're worried about damage. And how do you if you're giving it so late at the later on, you know, time is muscle. And the later you are treating them, the more damage they've accrued over time. So they're not gonna get back to that same functional capacity at all. And I think that goes to that applies to all of our inflammatory myopathies, whether it's dermatomyositis or this one here. So upfront aggressive therapy is very important. Certainly thinking about some cases that I think perhaps weren't treated quite aggressively previously, and these patients do have functional weakness as a result.

JJ - I've been so impressed by how well these patients do when they're treated early and aggressively, and that's really, like, left a mark. I'm really impressed by how they get so much better even though you have this impression of a necrotizing myopathy. You think, oh my gosh. How is it ever gonna improve? But, really, they do fantastically if you treat them early and and aggressively like you've seen. I'm impressed by, the outcomes there. And, in terms of then down the line, so if they do get better, at what stage or if ever do you think about weaning them off and treatment? Well, that's a million-dollar question. Kind of like for all of our rheumatologic conditions. So oftentimes these patients have trouble weaning off and we do have to keep them on for a long period of time. I will usually say, and this is purely based on anecdotal just experience and, you know, I'm not that far into practice, so I'm sure someone who's deeper into practice will have made so I I'll let the patient know upfront these patients with, IMNM, they don't, they may need immunosuppression for a long, long period of time.
 
 Right?

They may very well flare. I have one who's flaring right now because I tried to taper him off a bit. But if they're doing well, if I captured early, I will have a discussion with them. And say, you know, you did really well. We didn't really have to go down an algorithm where we needed IVIG or rituximab. I just put you on methotrexin. You did so exceptionally well. Why don't we just, you know, after two or three years of quiescent disease, try and reduce the methotrexate very, very carefully. And we do this over a course of every three to six months where I'll drop the dose a little bit, and then I'll check-in on them, drop the dose, check-in on them, drop the dose. I've done that for a couple of my patients or quite a few actually that did really well at the beginning, and those patients have done quite well. So I'm sure I'm certain if their early presentation was on the milder side, didn't need a lot of, aggressive therapy, those patients probably will do better on tapering. And I  usually a few years where their condition's very quiet before doing that. It's similar to my, you know, other inflammatory arthriticities, for example, just extrapolated there based on, personal choice of mine.

Okay. That's great.
 
 Thank you.

JJ - And I'll just throw in one one extra question if that's okay, which is, something I've seen a few times with these particular patients. Their CK doesn't necessarily all normalize. How what's your approach to, to that?

FT - That is a very good question. So and I this actually probably is true for a lot of our inflammatory myopathies where the CK never fully normalizes. So, and I've I've had, one of my patients that I took with IMNM, I took the most medications. They were doing really well. The GP was kept writing me saying, hey. There's there's CKs in, you know, three to four hundreds. We gotta do something. I kept explaining to them, no. This patient is not weak functionally not weak. But you're right. Let's let's not write this off. Let's not say there's nothing going on. Let's make sure there's no activity. So if I'm concerned, if there's any weakness, I, you know, will make sure that there's no disease activity, whether it's an EMG that you're getting or repeating an MRI. But really, we're looking for their strength, right Their MMT really counts a lot here. And just remember, after a patient has had myositis, their CK can stay high, they've got some membrane instability in their muscles, they might be leaking some CKO into into their blood as well. So their baseline now may simply be a bit higher ongoing, and I'm just looking for, like, a big picture, right? If they go from, like, 400 to 300 to 500, back to 300 to 400, and they're always kinda stable in that range, but they're strong and they're asymptomatic, that's reassuring to me. But if I'm seeing 300, 400, 600, a thousand, that that is a very different story. It's like it's like the stock market. We care about or maybe actually, I don't invest. Maybe that's not what people in the stock market think about.

That makes a lot of sense.
 
 Thank you.

Fantastic. Is there any questions you think I should have asked or, like, vital information you'd want people listening to this to know?

I was actually gonna, talk about this earlier is just being so careful to differentiate between rhabdo and IMNM in setting. And like that story or that patient that you and I saw where they they had started her on a dose of IVIG already, but when we went back to the history, it just really didn't fit. Right? So I think we get quite anxious. We're worried about IMNM in the acute setting. Patient's got a high CK. I think it's really important just to think, okay, are they responding at all to fluids? Are is there any reason why you truly have to give this patient a hydro steroid tonight and not tomorrow? Can you just flush them with some fluid if they can tolerate it? I think that is such an ickle pearl because I've seen numerous times where patients are treated with hydro steroids inappropriately and it was actually rhabdo.
 
 Right?
 
 You look, they've got a t color urine, they had an AKI, so look for those features and don't concurrently treat them unless, you know, it's it's gonna be a life or death situation over there. I think if they can just benefit from a bit of fluids upfront and they're doing okay, just give them a bit more. Make sure they're properly fluid replete. Look for an AKI. Look for any myoglobin in their, or or hemoglobin, for example, in their urinalysis that might have been.
 
 Right?
 
 Because you're not necessarily gonna see those in our inflammatory myopathies. Usually, you don't see that type of AKI, in an inflammatory myopathy. So if you see the AKI, I should be really telling you this is someone you need to push fluids for and not so much steroids upfront.

Mhmm.
 
 That's great. I think that's a really important takeaway point. And there are a couple of good papers on, on sort of differentiating statin side effects, which we can always put in the show notes and references, which I found helpful reading about.
 
 Thank you so so much.