[Case Report] 35yo male with proximal weakness and skin changes

[Case Report] 35yo male with proximal weakness and skin changes
Date:
19 December 2024
Category:

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This case report describes a 35-year-old Caucasian male presenting with 5 weeks of progressive weakness in the proximal limbs and trunk and associated changes to the skin. The man was previously well and not taking any regular medications. There are many pathways this undifferentiated patient could go down. Consultant physician, Professor Josephine Thomas demonstrates a systematic way to work through the differential diagnoses as would be expected in a long-case presentation for basic physician training exams. She's the Clinical Dean for the Adelaide Medical School at the Northern Adelaide Local Health Network.

Credits

Guest
Prof Josephine Thomas
FRACP FRACGP FANZAPHE PhD (Northern Adelaide Local Health Network; University of Adelaide)

Hosts
Associate Professor Stephen Bacchi (Massachusetts General Hospital; University of Adelaide)
Dr Caleb Chong (Northern Adelaide Local Health Network)

Production
Produced by Stephen Bacchi and Mic Cavazzini. Music licenced from Epidemic Sound includes ‘Rockin’ for Decades’ by Blue Texas and ‘Brighton Breakdown’ by BDBs. Image created and copyrighted by RACP.

Editorial feedback kindly provided by Dr Brandon Stretton and Ben Cook.

Key Reference (Spoiler Alert)

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A case of haemorrhagic myositis with concurrent anti-Ro52 and anti-NXP-2 antibodies treated with plasmapheresis [Rheumatology. 2020]

 


Transcript

PLEASE NOTE: While an effort has been made to correct errors in this AI-generated transcript, some mistakes may have been missed by the non-clinician moderator. This transcript should be taken merely as supporting material to the podcast discussion and neither is as an authoritative last word on the subject matter.

MIC CAVAZZINI:         Welcome to Pomegranate Case Report, and the last podcast of 2024. I’m Mic Cavazzini, but these case report episodes are all developed by Associate Professor Stephen Bacchi. He’s a registrar from Adelaide, now on fellowship in the USA with the Fulbright program.

Today’s case report was published in a letter to the editor of the journal Rheumatology which I’ll link in the show notes. Stephen and his co-host Caleb Chong will walk you through the presentation and investigation results as if this were a long case in the basic training clinical exam. It starts with a 35-year-old Caucasian male who has experienced 5 weeks of progressing weakness in the proximal lower limbs and trunk. Associated with this is a generalized non-pruritic rash. There are many many pathways this undifferentiated patient could go down. Today’s guest demonstrates a systematic way to work through the differential diagnoses.

STEPHEN BACCHI:      Hi, I'm Stephen. I'm a neurology fellow at the Massachusetts General Hospital and today with me, I've got Professor Josephine. Joe Thomas, who's a specialist general physician, clinical pharmacologist and educator. She's the Clinical Dean for the Adelaide Medical School at the Northern Adelaide Local Health Network, which includes the Lyell McEwin Hospital. She has a long-term involvement in education and training. We are fortunate to be able to learn from her today. And Caleb Chong is a basic physician trainee also in the Northern Adelaide Local Health Network, and he has recently passed his clinical examinations. Thank you for joining us.

JOSEPHINE THOMAS:
Thanks very much, Stephen. It's a pleasure to be here. I'm on Kaurna land, so I'd like to pay my respects to elders, past, present and emerging and acknowledge the strong relationship of traditional owners to the country here.

CALEB CHONG:           And thank you, Steven, for having me as well.

STEPHEN BACCHI:      Great. Do you want to take it away with the case, Caleb?

CALEB CHONG:           Yep, sure. So as previously, we'll be discussing a published case in a step-by-step manner. There will be focus on content revenue to trainees and a generalist audience. So, in this case, we have a 35 year old male who has presented with a proximate muscle weakness and skin changes over the course of five weeks. Now, as if this is a short case without knowledge of past medical history of medications. What sort of differentials would you consider in this particular case?

JOSEPHINE THOMAS: Yeah, that's a good way to approach it when someone presents like this and I guess we need to think about it broadly, from a proximal weakness perspective. So, I guess I would be certainly thinking about the classic medication related cases, because we do see cases like statin mypoathy presenting to hospital. Also, steroid therapy. And so, I'd be looking for some of those typical changes. We've got that clue that there's some skin changes, so you could look for those typical skin changes that you'd steal with steroid therapy, particularly easy bruisability. And perhaps you'd even consider things like endogenous Cushing's—about 60 percent of those will have a proximal weakness, so that would be important.

Other types of conditions you might want to consider would be thyroid disease, both hyper and hypothyroid cases can have proximal weakness, which is confusing. And they will both, possibly, have a rash associated with them as well. So you might be looking at the changes of acute or chronic urticaria that you can see with hyperthyroidism or those changes that you see with pretibial myxedema. Or even in thyroid disease, if you had hyperthyroidism, you might have more sweating, flushing, heat rash type changes.

So, you have to think quite widely. I guess you definitely would think about the rash of dermatomyositis. You might think about polymyositis. So you'd be looking for those changes associated with rheumatoid disease, SLE, scleroderma, other autoimmune conditions. And so, there's a lot to consider, actually, so your differentials are quite broad. Then I’d think of some other kinds of causes of proximal weakness like sarcoid, where you might have a granulomatous inflammation and muscle injury. Not all that common, but you'd be looking for those other changes that you would see with sarcoid and then amyloid. An uncommon manifestation, is the myopathy or myositis but you would also be looking for the other changes that you see with that such as peripheral neuropathy.

And I guess, although we're thinking about, myopathy or with this proximal weakness, you'd be looking for any—we haven't been given the clue of neuropathy, but some myopathic processes can have proof of neuropathy with them, such as the thyroid disease such as amyloid. So those are all important things to think about. Is that making sense?

STEPHEN BACCHI:      Yeah, that makes a lot of sense. I think the proximal weakness short case is always a favourite of mine but that's, again, with my neurological inclinations. But there's certainly a lot to unpack in the discussion and a lot of systemic metabolic disorders to consider in addition to neuromuscular junction and myopathic processes.

So now we get some more information. He's had no past medical history and medications, so that would exclude a few of the differentials. He has three out of five upper lower limb proximal weakness, without bulbar or cardiorespiratory involvement, which is good. He has an erythematous rash in the region of skin that would be exposed to sunlight. And red purple discoloration over the dorsal surface of his metacarpophalangeal joints. And the serum creatinine kinase or CK turns over 17,000. So, this is now sounding almost a bit like a multiple choice question and a few buzzwords come to mind that could be used to describe those signs. What sorts of diagnosis do you think might be in play here, and how would you investigate further?

JOSEPHINE THOMAS: Well, we've got some pretty good exclusions now when you say he hasn't had steroids or any medications. So, we start focusing on some other issues. Right, so, that's a very high CK, and I mean, it's really indicates that he's got clear muscle damage. And so, I really start to wonder about dermatomyositis, now. I guess, earlier on I didn't mention things like inclusion body myositis, which I don't feel he’s in that sort of age group for, and I'm assuming this is an acute process not a congenital type process or a childhood type process. So, I really want to get in there and investigate more but I do think the rash is a big clue here.

CALEB CHONG:           Yeah, and the rash points to a typical inflammatory process as well, and it will either be some form of myositis given, the markedly elevated creatine kinase, either the dermato or polymyositis. And given the typical skin changes, this would be more fitting with dermatomyositis.

JOSEPHINE THOMAS: Definitely. I mean, earlier on, I didn't mention something like rhabdomyolysis because you should be able to really exclude that pretty quickly by looking at the urine. But you do will sometimes see really high CO like this in a rhabdomyolysis, and I always think back to cases I've had where they had a malignant hyperthermia phenotype and didn't really require massive heat stress or any particular anaesthetic trigger to actually set off a really severe case of rabdo.

CALEB CHONG:           Ah right. And those would be cases where they are on antipsychotics?

JOSEPHINE THOMAS:            That is definitely more common because the antipsychotic sort of do change the way you deal with heat stress, but not always. One case I found definitely just ended up having a malignant hypothermia phenotype and genotype. But unusual, you know. I think those unusual cases sometimes stick in your mind. And that was very much a proximal myopathy bit. So he actually suffered quite profound proximal muscle loss after that severe rabdomyolysis.

CALEB CHONG: And also I'd like to add that the fact that the distribution of the discoloration over the dorsal surface of his metacarpophalangeal joints, it could also point to other differentials for rash like psoriasis or dermatitis. But they wouldn't explain the extent of his proximal weakness or it could be a concurrent pathology. But the most likely thing would be some are on the lines of a dermatomyositis in this case.

STEPHEN BACCHI: Yeah, I agree. I think it sounds like Gottron’s papules to me. You're looking for that heliotrope rash as well. Do you want to take it away with some more investigations, Caleb?

CALEB CHONG: Yeah sure. So, as I pointed out earlier, his creatine kinase is markedly elevated. The next step to investigate a likely myositis will include an autoimmune screen and that would entail antinuclear antigen panel along with double-stranded DNA. But the clincher would be a myositis immunoplot and this would be useful in isolating specific antibodies that are related to the dermato or polymyositis.

JOSEPHINE THOMAS: Yep, absolutely. I think when we see cases like this, there's value in doing several things, and the myositis immunoblot is definitely something that has gained more traction. But a skin biopsy can be useful for looking at a number of the conditions that we've already mentioned. Obviously, if he's got that classic skin pattern of the Gottron’s papules, the heliotrope rash, you think of dermatomyositis. And in this actual case it was a pre-exam trainee that picked that up. So he was he was lucky to present at that time. The pre-exam trainee nailed this one.

I always want to have a look at the muscles. You really feel quite strongly when you see a case like this with this degree of weakness that a biopsy is going to be helpful. And I guess if he'd been on a statin, I would have rushed straight to biopsy. But this wasn't the case. It's still worth sending off those HMG CoA reductase antibodies and it is worth setting up the biopsy. Because there are some rare cases where you can get [myositis?] without actual statin use now the common profile is that you've got statin use, but the biopsy can also be quite helpful in ensuring that you know exactly what you're facing. But prior to that we often, these days, have the benefit of getting an MRI. And the MRI, much like the myositis immunoblot has the benefit of showing you that sort of baseline, particularly when you're looking at getting into your therapy later and monitoring that as you go along.

STEPHEN BACCHI: Brilliant. Well, let's get some test results then. So, the anti-nuclear antigen returned with a 1 to 640 titer and a speckled pattern. Myositis immunoblot reveals positive anti-Ro52 antibodies and antinuclear matrix protein 2, abbreviated to NXP2, antibodies. There was evidence of previous hepatitis B exposure. An MRI demonstrated diffuse high T2 signal in the lower limb musculature. Skin punch biopsy showed an inflammatory infiltrate at the dermo-epidermal junction, which was consistent with the dermatomyositis. Vastus lateralus muscle biopsy showed necrotizing myopathy. However, perifasicular atrophy was not seen. So, Prof Thomas, how do you name or characterise the diagnosis now? And does it have any paraneoplastic associations or considerations?

JOSEPHINE THOMAS: Well, I guess necrotizing myopahty is something that we see in a number of conditions. So that's not particularly specific and you can see that with some of the statin type reactions. I found this a confusing result because it didn't quite fit with what we expected. it wasn't necessarily typical. The anti-ro antibodies are not that specific, they're seen in a wide variety of autoimmune disease. And they’re often associated with interstitial lung disease. Now this man had had no history of lung disease, didn't appear to be exhibiting signs of that, but we did, of course, scan to look for that. And there was no sign of that either.

Certainly that, it confirms that he's got a myopathic process, but we don't really expect exactly what we saw on the biopsy as we did with him. The NXP2 antibodies were not something I was familiar until this case and someone said to me that they sounded like a new racing car. However, this was really important in this case. So they are definitely a marker for dermatomyositis and usually a marker for more severe myositis, which this man appeared to be exhibiting. In fact, with each day he did seem to be getting a little worse, and so it felt quite time pressured. There is a slightly unclear association in within NXP2 and with cancer. And so that became another focus about whether we needed to actually investigate for a malignancy in this case.

STEPHEN BACCHI:      Alright, so, malignancy screening was conducted and was non-contributory. And then the patient was treated with one gramme of IV methyl prednisolone daily for five days and intravenous immunoglobulin, Ivig. However, as you were mentioning, he was declining and he did rapidly deteriorate over three days with worsening weakness including respiratory decline, concerningly. And a repeat MRI was performed which demonstrated haemorrhagic myositis. Haemorrhagic myositis is not something I've encountered terribly often. How serious is haemorrhagic myositis and what does that mean for further treatment in this patient?

JOSEPHINE THOMAS: Well, I'm just going to go back to your first point about he we were we screened him for malignancy and found nothing. It's pretty hard to do in a case where you're mixing steroids with critical and declining health status and instability. It was really quite concerning that we weren't sure in this very young gentleman whether we actually were facing something that was linked to perhaps a paraneoplastic process. So we couldn't really be sure, but we did make a plan to look at what we could and then defer further investigations for malignancy.

The haemorrhagic myositis was a bit of a shock and adds a burden on a couple of levels. He didn't have a normal haemoglobin to start with and that was making me consider whether a GI malignancy could be a possibility. But you know this quite obvious inflammatory state could have been responsible for the haemoglobin. But the haemoglobin drop was definitely contributed to by the haemorrhage. Haemorrhagic myositis is uncommon, very uncommon. However, it does certainly denote a severity, and certainly this this dual set of markers that he had—the anti-Ro and the NXP 2—is felt to represent a marker of severity. It's a rare complication to have this haemorrhagic myositis, and it might add to both the mortality and the burden of disease from what we know in the literature.

This man had had severity sort of everywhere we turned. In fact, he seemed to manifest this tachycardia, which was a bit of a concern but couldn't quite be attributed to anything that was happening while we were doing it. It just seemed to be very persistent. And the PET later showed that he had cardiac involvement, so that worried me in that it seemed that all of the things that would spell a quite difficult course and poor prognosis were present. Even though we do matter myositis you expect the patient to come through this with support and to recover this was starting to look a bit tenuous in this case.

STEPHEN BACCHI:      And then the other thing is this patient did have evidence of previous hepatitis B exposure, which is relevant when we're immunosuppressing them for their daily formulated course of inflammatory disorder. So the patient was provided with in Entecavir and then rituximab and cyclophosphamide. They continued to deteriorate and this prompted plasma exchange, so they had a prolonged ICU admission, but was ultimately able to be discharged to rehab with a slow prednisolone taper. So that's a great relief. I'm glad to hear that the patient's outcome was good despite this fulminant presentation. So, this now transitions into a different setting of care really. This is now patient who’s on long-term immunosuppression, long term steroids and that's certainly something that comes up in long cases fairly frequently. Prof Thomas how do you approach this issue?

JOSEPHINE THOMAS: Yeah, I think there was a there's a mix of short and long term things to consider here. You know, this man had no idea he had hepatitis B. So the early screening, which had to be done quite quickly before we started treatment was important in his case. So obviously, once you start steroids, and you know you're going to be at a reasonable dose for more than a couple of months then you have to prepare for prophylaxis for PJP [pneumocystis jirovecii pneumonia]. You have to determine what his infection risk is going to be and to try and educate the patient about that. And you have to look at bone health, so we needed to do some baseline sort of work up in this in this man. There was no reason to suspect he was going to have problems with his bone health as a baseline, but ensuring he’s replete for vitamin D and things like that was important.

We ended up having him on steroids for a very long time and so the entacavir had to continue for all of that period. He didn't have any evidence of TB but it was felt important to screen for that as well. So, I guess you have to make sure that there are no conditions that are going to be aggravated by having someone on that kind of immunosuppression, and you've got to look after bone health. You've got to look after prophylaxis for PJP. That was an additional complication in this fellow because he did have an episode of Stevens-Johnson [syndrome], and we weren't sure what the agent was. And so, he ended up not being able to have standard Bactrim prophylaxis, so that was an another case where we had to determine alternative prophylaxis for him.

He had so many medications used at one time that it was quite impossible to determine which one would have been the driver, despite skin biopsies and all that sort of thing. And we weren't really happy to rechallenge this fellow at this point in time. He remained quite tachycardic at baseline when he was relatively well and he was in ICU for a long time, needed extensive support. So, infection did become a problem on and off for him, and he did suffer a number of other complications. So, he had at one point an ischiorectal abscess which had to be drained, so steroids are not without their risk.

I guess the whole approach for me with long term steroid therapy is ensuring that you're revisiting constantly whether you can reduce because it just is a dose-dependent problem to have someone on steroids and so you know the lowest effective dose is the way forward. And ensuring that you are really monitoring and that you're giving sound patient education about things to watch for. It was hard to educate this man because there were just so many things to watch for and, in fact, it was a collaborative effort taking care of all of the problems that arose. Yeah, so I think I think he's a good education in how you approach steroid therapy, but we weren't able to have him off steroids or reduce him fully in one go. It took a number of episodes.

STEPHEN BACCHI:      It’s a striking case. It's gone from a very acute presentation to, now, the management of multiple long term conditions that all interact. So, it's been a great one for my learning. So, thank you very much for taking us through it. I've certainly learned a lot. Could you please outline what you thought were a couple of key learning points or take home messages that you took from the case for physician trainees in general?

JOSEPHINE THOMAS: This was a florid case of dermatomyositis. And I think, essentially, the successful management of this case was a collaborative effort between multiple disciplines; rheumatology, infectious diseases and critical care. It was very active management for a very long time and it tested all of those physicianly skills because the new challenges were thrown up both by the medications we needed to use and the severity of the disease itself.

I think, certainly, the dual combination of the myositis antibodies that we saw in this man did herald a very severe case and I think it was probably important to be aware of that, prognostically, because we had to advocate for his ongoing support and active therapy over a very long period, and it  was successful in the end. One of the other things that's quite striking in this case was that plasma exchange was felt to be very important in this man. We think that it was responsible for his early improvement and that's really down to the fact we saw a very brisk response after plasma exchange in his CK declining and also his Ro52 antibodies becoming negative.

Now rituximab has about a 20-week median response time, which is a long time when you're watching someone deteriorate with a fulminant myositis like this. So, I think having other immediate modalities up your sleeve that can have a rapid onset of action is really important. Despite cyclophosphamide, despite rituximab, this man was declining and manifesting new symptoms; the bulbal weakness, the myocardial involvement, it was pretty hairy there, hanging in as a clinician, watching him deteriorate, and so it was really important to have that additional therapy.

For the trainees, you're at the peak of your powers when you're studying for the exam. When you see a case that looks like Gottran’s papules and a heliotrope rash and comes along with those other features, don't be shy. Get in there because it was really important for this man that he got rapidly admitted and got those investigations rolling because the multiplicity of investigations really helped us sort out his case and get his therapy started.

CALEB CHONG:           Yeah, absolutely.

STEPHEN BACCHI: And another fun fact that I always found interesting was that heliotrope refers to a purple flower. Was something I didn't know during my exams and didn't come up in too many long case discussions, but there you go. And Caleb, did you have any particular take home points that you think is important for physician trainees from this sort of case?

CALEB CHONG: Yeah, since coming off the clinical exam and having done long cases, it's good to have a broad differentials for simple complaints. It can be a proximate myopathy or even a skin rash. And to always go to basic things and that includes medications. And I'm always surprised at how simple going through medications can be to elicit a cause for their complaints and. But also having other differentials and sarcoidosis was something that stuck out to me on doing some background readings for this case. But yes, this case highlights a very classical presentation of myositis and are rather quite fulminant course during his treatment, and it's quite miraculous that he survived this and is now helping us doctors learn about this case as well.

STEPHEN BACCHI:        A striking case. So, I think for more details people can read the article. So the article was titled, “A case of haemorrhagic myositis with concurrent anti-Ro52 and anti-NXP-2 antibodies treated with plasmapheresis,” and that was published in Rheumatology in 2020. The authors were Zoe Brown, Prof Josephine Thomas and Prof Vidya Limaye. So, thankyou again for joining us, we really appreciate it.

JOSEPHINE THOMAS: Thanks, Stephen. All the best.

MIC CAVAZZINI:         And many thanks also to Stephen Bacchi and Caleb Chong for thinking of their fellow trainees in developing this resource. Please remember that this is a passion project developed in their spare time, and neither the podcast nor the transcript should be taken as the authoritative last word on the subject. There is plenty of vetted training material on rheumatology, dermatology, immunology and pharmacology in the College Learning Series.

Dr Bacchi is just one of the many kind physicians who have put their time into reviewing Pomegranate Health over 2024. I am greatly indebted also to Michael Herd, Rosalynn Pszczola, Aidan Tan, Rachel Murdoch, David Arroyo, Sasha Taylor, Rahul Barmanray, Rachel Bowden, Zac Fuller, Fionnuala Fagan, Chris Leung, Thazin Thazin, Joseph Lee, Amy Hughes, Ronaldo Piovezan, Nele Legge, Brandon Stretton, Li-Zsa Tan, Keith Ooi, Courtney Dowd, Saion Chaterjee and Duncan Austin. Jia Wen Chong and Paul Cooper are two generous contributors who aren’t even members of RACP. From the IMJ editorial board, Ian Woolley, Paul Bridgman and Christian Gericke made valuable appearances, and I don’t have time to name drop all the people who came onto the show as guests.

And thank you for being one of our many thousands of listeners. You’re always welcome to send feedback or ideas to podcast@racp.edu.au. I’d love to hear what makes a good episode and what makes you tune out, so we can keep improving the quality for you. You can even leave a review at Apple Podcasts to help others find Pomegranate Health.

This podcast was recorded on the lands of the Kaurna and Gadigal clans. I pay respect to their elders and teachers over tens of thousands of years. I’m Mic Cavazzini. Wishing you the best over the Gregorian new year!

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