Ep 50: A spotlight on inclusion body myositis

Dr Hirushi Jayasekera speaks with Dr Latika Gupta, UK based rheumatologist and Professor Teerin Liewluck, US based professor of neurology at Mayo Clinic about inclusion body myositis. Their conversation covers key clinical features of IBM, the differential diagnosis and the role of the muscle biopsy in making a diagnosis.

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Transcript

00:00:01 [Speaker 1]

You're listening to the talking rheumatology spotlight podcast brought to you by the British Society for Rheumatology.

00:00:13 [Speaker 2]

Hello and welcome to the Talking Rheumatology Spotlight podcast, the podcast from the British Society for Rheumatology. I'm Hirushi Jayasekera, a rheumatology speciality trainee.And today we are focusing on a particularly challenging and often overlooked condition, inclusion body myositis or IBM for short. It is a condition that presents diagnostic uncertainty, therapeutic limitations and yet has significant implications on our I'm joined today by two colleagues whose interdisciplinary perspectives have greatly enriched how we approach complex muscle disease. Doctor Latika Gupta is a consultant rheumatologist at the Royal Wolverhampton Hospital NHS Trust, an associate professor at the University of Birmingham where she leads the myositis service and digital health pathways at Newcross and Cannock Chase hospitals. She has described unique myositis profiles and phenotypes in the Indian demographic and set up a biorepository of adult and juvenile samples for this rare disease. And joining us from the United States is Dr Liewluck, a consultant neurologist and professor of neuro the Mayo Clinic and a globally recognized expert in neuromuscular disorders. His work focuses particularly on the diagnostic evaluation and management of genetic and acquired myopathies as well as muscle pathology. Doctor Liewluck recently described a novel form of myositis known as immune mediated megaconial myopathy, IMM, for short. This condition clinically resembles seronegative immune mediated necrotizing myopathy, but is distinguished by the presence of markedly enlarged giant mitochondria known as megaconia for short. Thank you both.

 Thank you, Hirushi It's a pleasure to be part of this conversation.

00:02:05 [Speaker 5]

Delighted to join you both and thank you very much for shining the spotlight on this very important topic.

00:02:12 [Speaker 2]

Thank you both. I thought we could start with a brief reflection. A few years ago while working in one of the NHS trusts, I had the opportunity to work closely with Doctor Gupta. Doctor Gupta would say I had a tendency to attract the entire spectrum of connective tissues diseases on every on call.  Indeed, she was right. We came across a flurry of on call referrals together, each presenting differently, but all eventually linked to the common threat of suspected myositis. So who better to invite for our BSR podcast, I thought. Doctor Gupta, could you share please a bit about inclusion, sorry, about immune IIM first onto your radar, and what led to your growing interest in this area?

00:02:56 [Speaker 4]

Certainly, Hirushi My initial interest was, actually in vertebral fractures and obstetric outcomes. Both were part of my projects during rheumatology training. And when I moved into clinical myositis, I quickly realized there was a considerable service gap, especially in England in the West Midlands. Patients with myositis are often diagnosed across the board in different parts of the world or they can be referred late as well. Part of this could be related to the heterogeneity of the presentation and they can be seen by so many different specialties often without a clear diagnosis. Their presentation can be subtle, progressive, and missed in the early stages. So, we began seeing increasing numbers of these cases where patients had been treated for polymyositis without effect. And, as we know now, with recent discoveries, polymyositis, may may even cease to exist in a few years. We are describing newer forms of myositis and with newer antibodies, we can have better detection and better classification of this condition. So that's when I realized we need a more structured and interdisciplinary approach and better communication, particularly logistics, and it's really wonderful to have Dr Liewluck with us.

00:04:18 [Speaker 2]

Thank you, Doctor Gupta. The theme of diagnostic delay and the need for collaborative working is echoed internationally. We're very fortunate to be joined by Doctor Liewluck speaking to us today from the Mayo Clinic in The United States. Doctor Liewluck, could you tell us a little bit about your clinical practice at Mayo Clinic and what interested you in myositis and what's the practice largely from, shared approaches with rheumatology?

Certainly, Hirushi. Yes.

00:04:50 [Speaker 5]

My interest in myositis began right after my graduation from medical school in Thailand that I had the opportunity to, join the National Center of Neurology and Psychiatry in Japan as a research fellow and work under the mentorship of professor Ichizo Nishino who is regarded at the Hillsborough on myositis pathology. After that, I came to the space to completed my residency and had the opportunity to, do my fellowship under professor Andy Engel, who regarded as the father of myology for the study of muscle diseases. So at Mayo Clinic, we, am a part of small group of neurologists with special interest in muscle diseases and we work very close our rheumatology colleagues who have special interest in myositis. So each week we have our dedicated, new patient slots that only are mostly reserved when rheumatoid patient require neuromuscular evaluations. And, most typical cases are when our Rheumatology colleagues got a referral, from outside Institute mostly for a patient with refractory myositis. And as you know, refractory myositis could be include some body myositis, It could also be a various form of genetic myopathies. So upon that evaluation, if our rheumatology colleague thought it could be genetic disease with the muscles, then they refer to us and make sure to, reserve the slots for them. And this important part to bring up is that the information on the biopsy is considered as class of myositis. However, certain form of genetic myopathy like some muscular dystrophies, for example, like, facial scapular humeral dystrophy or FFHD and some of the Limb girdle muscular dystrophy, for example, like those due to these further mutations, they can have information on the biopsies. Look very much like myositis, which sometimes we they can present as a refractory myocyte. And on the contrary, sometimes as a neurologist, we saw the patient who referred to us for Limb girdle mass But now we learned that the immune mediated necrotizing myopathy sometimes may present in the chronic, slowly progressive form and very difficult to distinguish from lymphoid arthritis. When we have, encountered these scenarios, sometimes we share the patient with rheumatology. And recently, my colleagues and I, we wrote the review article on atypical features of immune mediated necrotizing myopathy and try to encourage the clinicians to check for both of hMCGR and SRP antibodies in patients who suspect to havelymphocytic mastopathy, but genetic testing came back unrevealing.

Thanks, professor Liewluck. That really resonates. For the audience listening what it might help to frame this with a relatable case example just to ground the discussion in a presentation that rheumatologists are likely to come across on the wards let's consider a fictionalized case that reflects common features clinicians often encounter. So typically, an older patient referred with progressive falls, perhaps difficulty rising from a chair, and increasing hand weakness. Initial blood tests may have shown a mildly raised CK level and the clinicians may have already started them on steroids for presumed polymyositis. Several weeks in however, classically there may be little to no improvement and in fact, they may be to get worse, if anything. Doctor Gupta, when you hear of such a case example, what features raise your suspicion for inclusion body myositis?

00:09:18 [Speaker 4]

So in this case Hirushi, I'd say it's rather classic. The red flags would mean would be the age, over the age of 45. The patient has asymmetry of weakness, which is again classic, especially involving the finger flexors, and then there's poor steroid response. Another point to note that ck was only elevated, but it is not always elevated in patients with myositis. Up to twenty percent can have normal ck, and then under the influence of steroids, CK may decline, irrespective of the pathology. So, IBM doesn't fit the classic proximal weakness and high CK pattern, and this patient has some oddities, which should make me lead towards IBM.

Mhmm.

And and, if anything, if there's a modest CK and distal pattern, then it should steer us away from polymyositis.

Yes. Thank you, doctor Gupta. In practice, it's easy to assume that a raised CK equals inflammatory myopathy and to treat empirically with steroids. But IBM does not seem to present with normal or slightly raised CK and does not respond well to immunosuppression. Professor Liewluck, would you please outline the key features on neurological examination that could perhaps alert us clinicians to consider IBM and what rheumatologists may likely miss?

00:10:41 [Speaker 5]

Certainly, Hirushi. So as doctor Gupta mentioned, we need to think about IBM when we encounter patient with muscle diseases after age 45 because IBM is the most common muscle diseases after age 45. Now, we've been talking about this few years ago, we would say the most common diseases of muscle after age 50, but I think we have been, increasingly recognize this condition. So now, we move the age earlier to 45 and the weakness pattern as Doctor Gupta mentioned, it unlike other myositis, the weakness in IBM typically asymmetric. So we really need to pay attention whether the weakness on the right side and left side asymmetric or asymmetric. And after myositis typically affect proximal muscles, the shoulder girdle muscles, the hip girdle muscles. But IBM has very unique pattern. It selectively, for whatever reason, involve parabola muscles, particularly quadriceps. And in the upper limb, it involve mostly distal muscles, particularly deep finger flexors and sometime thumb flexor muscles. So this unique combination of deep finger flexor and quadricep involvement in patient at or after age 45 should be the key feature to think about IBM. And as both of you pointed out, the CK and IVM are just mildly elevated or even normal, particularly in the advanced stage of the diseases. And typically, if the CK go up above 15 times upper limit of normal, this is beyond what we typically see in IBM. So CK should not be elevated more than that. And, the other thing is that the gold standard for diagnosis is still muscle biopsies. And the most important thing is we need to make sure that the muscle biopsy flows in tissue correctly because the paraffin embedded tissue only provide very limited information. More importantly, muscle pathology should be, interpreted by neurologists or neuropathologists who have special expertise in muscle pathology. Otherwise, those classic features of IBM may be overlooked. The other thing that we have been increasing use in the clinical practice is the anti cn1a antibody that had reported in thirty to seventy percent of IgM patients. But we need to keep in mind that it's not entirely specific. It can guide us to diagnosis but eventually patients still require the muscle biopsy. And this antibody, the CN1 antibody, sometimes can occur in other autoimmune diseases like stroke and disease or lupus patient without having any, myositis.

Yes. Absolutely. And because of this, it is extremely important to have collaborative care. There is emerging evidence of, an increasing link with Sjogren's.  So rheumatologists may pick up the early symptoms, but they may not always be a 100% sure of the diagnosis. And collaborative input from neurology and histopathology is extremely important. So at my center, we are very lucky to have a dedicated myopathologist and myoneurologist. We sent us biopsies to QE and also organized weekly MDTs. However, the input can be sometimes, challenging with long wait times in the NHS. And thankfully, we have a one stop clinic with neurology and a neurophysiologist so this has substantially reduced wait times from around three months to under five days. And I feel that having these dedicated multidisciplinary clinics and shared pathways, they go a really long way in ensuring that patients don't fall through the cracks.

Exactly. And, one of the things that I always emphasize during my, teaching is that if you suspect that polymyositis but the patient is not responding to treatment, one thing you need to consider is IBM. I always encourage performing and if needed repeating, through neurologic examination, particularly focusing on deep finger flexion quadriceps, involvement. And as is in this case the steroids typically lead to no effect in IBM patients.

It's extremely useful. Thank you, Professor Liewluck. And that leads to one of the trickiest questions. How long do we persist with steroids before we say this isn't working?

So in a typical inflammatory myopathy, we do expect some clinical improvement in four to six weeks. And if there's no objective gain, that is no improvement in function or strength and no decline in ck. Although ck sometimes be more independent of the disease course, we do need to pause and reconsider. And and imaging can help, of course, multidisciplinary input is very important. But continuing steroids in IBM can do more harm than good, especially with falls and frailty risk and just the general phenotype where, the glucocorticoid related risks are much higher.

Absolutely. We typically discontinue immunosuppressive therapy, two to three month trial if there is really no meaningful clinical improvement. As Doctor Gupta mentioned, it is important to remember that while the CK levels may decline in some patients, the more critical measure of the treatment response is the muscle strength on the physical examination. And this is where multidisciplinary team approach becomes very important bringing together neurologists, rheumatologists and physiotherapy from the outset to ensure comprehensive and accurate assessment for the patients. So in this exemplar case the patient had stopped steroids and referred for EMG and biopsy and the EMG showed mixed findings and the biopsy, thankfully processed correctly, revealed rimmed vacuoles and endomysial inflammation, which would be classic IBM. That's a really good save, but I've seen so many cases where biopsy doesn't always give the clear diagnosis. It may not be rimmed vacuoles. The diagnosis could be missed because these could be a sampling error or the disease may not be diffuse. Getting to the right pathologist and the right kind of sample can be critical. And then, of course, there's scenarios where we get odd features on a mixed phenotype. Recently, I came across a case of IBM toe and that'll be something interesting to talk about as well, with our expert.

Thank you, doctor Gupta. Yeah. Ideally, the muscle biopsy performed before initiating treatment in patients who has no myositis specific antibodies or in those that the clinical phenotype and the myositis antibodies have some discrepancy. In clinical practice here, we often encounter patients where immunosuppressive therapy was started first. And biopsy was only performed after treatment failure and these approach can be problematic. Thyroid therapy may suppress information and obscure key findings on the muscle biopsies. As for the EMG, why it can review myopathic changes or mixed myopathic changes, these findings are not specific for IBM. It would be more important to ensure that the deep finger flexor is examined with the needle of EMG because this is not the muscle that routinely performed during the needle of EMG. So the involvement of deep finger flexor with myopathic changes on the EMG can be very helpful to support the diagnosis of IBM. As previously, emphasized, muscle biopsy remained the gold standard for diagnosis. The specimen must be properly handled, processed at the frozen tissue, in a specialized laboratory, and interpreted by neurology or neuropathology with special expertise in muscle pathology. And, it's also important to note that in up to twenty five percent of IVM patients, all these three features may not be all present. They may have only one or two of the three features. And these often, sometimes, patient drug misdiagnosed as polymyositis. So using the key clinical feature together with muscle biopsy findings are very important. And as for the polymyositis with Mitochondrial Pathology that Doctor Gupta mentioned, it long been, a debate whether this distinct entity or not. Basically, it's a group of patients that muscle biopsy show information that gave the name of polymyositis but in addition to that also show some mitochondrial pathology while racquet red fibres or cyclone c oxidase negative fibres. Mitochondrial features are common in IBM although it's not needed for diagnosis of IBM.It's not until recently that the detailed pathological studies and transcriptomic study have shown that in fact these PM mito is the early stage of IBM or include somebody else like this.

Alright. That's some crucial information there. Thank you, professor. Along those lines, from a practical standpoint, Doctor Gupta what advice would you give to rheumatologists who suspect IBM?

Well I would say it's a diagnosis of exclusion but that is more so for polymyositis And for IBM, always keep a keen eye for asymmetric distal involvement. Don't always assume that a raised c k implies polymyositis, particularly as this is now more of, a rule out as a wastebasket category once nothing else can be proven, especially if the treatment to response the response to treatment is poor. Use antibody panels judiciously. They always are not surrogate for particular conditions and refer early for EMG and muscle biopsy. And crucially involve us, a neuromuscular team, where, possible? Is it not just, for diagnosis but also for, supporting long term management? It is orthotherapy, swallowing evaluations, and, patient education.

Thank you both. That's a wonderful summary. Let's please now pivot to management if we may. Once you've diagnosed IBM, what's the strategy? Professor Liewluck, what does supportive care look like in your setting?

The cornerstone is function preserving support. We focus on physical therapy, occupational therapy, and speech or swallowing. It's important to note that about forty percent of IBM patients may eventually develop swallowing difficulty and this may lead to, aspiration pneumonia with a very high, morbidity and important factor for mortality in this patient. Nutritional support is often also overlooked but very important. And we monitor, respiratory function if this swallowing difficulty or with any involvement of diaphragm. And regular assessment and monitoring, so we need objective assessments for that. The IBM functional rating scale can be quite useful. It's easy to administer, adapted from ALS tools, can track progression very well. There are studies on other devices for measuring this, but these have not been entirely validated. But any kind of, measurement to guide changes over time be very useful. MRI scans are being evaluated to, assess, involvement and particularly because these can detect slower decline to inflammation and and placebo effect has been seen in IBM trials. The biggest challenge is this condition progresses very slowly, therefore, treatments as well have very slow effects, and perhaps the time shorter time for trials may not always, show any significant changes. So now there is a wish for embracing EMR scans for monitoring disease activity.

Mhmm. That's really helpful. What about differentials? What else should we be thinking about before diagnosing it as IBM? Yes.

So, pulverocytes is actually the most common misdiagnosis, particularly when the key histopathological features such as rim vacuoles, conchotic deposits, or protein acupress are absent or missed on the biopsy. However, this often be avoided by carefully assessing the patient's asymmetric weakness, deep finger flexor involvement, and quadriceps. These are the key features particularly in patients age 45 or older. And ideally, as I mentioned before, the muscle biopsy should be performed prior to initiating the therapy. It's worth noting that, some genetic myopathies can also show rim vacuoles on the biopsy. And these, you'll be talking about it a few years ago, these diseases, called hereditary human body myopathy. Although this term has been largely repressed by, myopathy between vacuoles or in macular myopathy. Additionally, we're talking so much about deep finger flexural weakness. Not to surprise, deep finger flexural weakness can also occur in atherogenic myopathies, particularly, myotonic dystrophy and that's why the muscle biology remain the gold standard and not just diagnose IBM based on, the clinical osteology. Now you may encounter some cases that patients suspect to have motor neuron diseases like ALS because they can affect, causing hand weakness, hand atrophy. However, the key is that finger flexor gel is spared in motor neuron disease. They can affect finger extensors, intrinsic hand muscles, but deep finger usually is a key feature to help us distinguish from motor neuron disease.

Thank you Professor Liewluck. So for the general rheumatologist listening, what are the top tools or resources you'd recommend?

Be sure to access for weakness of the deep finger flexors and carefully evaluate the pattern of muscle involvement, specifically whether it is symmetric or asymmetric, particularly in patients who is 45 or older. In cases where IBM is suspected, a muscle biopsy performed before initiating thyroid therapy. It is essential that the biopsy specimen is processed as frozen tissue, not a paraffin embedded tissue to preserve critical heat or pathological features. And if I may, accurate interpretation requires expertise, which is not always available. So, just liaising with local experts, myopathologist, myoneurologist, it it can be more important than else because the field is continuously developing and then your discoveries. So when in doubt, refer to a neurologist with experience in these conditions or at least have the lines of communication open maybe with, a rheumatologist experienced in this who may be aware of local neurology expertise in this space. So so the patients can be referred in a timely manner and can get the right kind of treatment.

Yes. Very valid points for our everyday practice. Before any last advice to our listeners, please?

Well, I would say don't assume a diagnosis based on elevated CK, which is the most common referral in my, at my center or EMG alone. If the story doesn't fit, which it often doesn't, go back to the patient, maybe observe their gait, their grip, their quads, get clear history of the progression and the onset. If it's more insidious, it's more likely to not be polymyositis, and this is where the main clues would be. And it's not that rare, it is just under recognized because of the slow and indolent course. So if you're seeing older patients with unexplained falls, I feel falls are a very important sign. Hand weakness, particularly the grip or post steroid response, swallowing difficulties, which can be subtle as well. So one got to think of IBM.

Yeah.Certainly. The IBM is not rare as doctor Gupta mentioned. It is in fact the most common muscle diseases after five. So when you encounter patient after age 45 suspected to have muscle disease, you need to think about the IBM and don't delay the muscle biopsies. The earlier you diagnose IBM, the sooner you can stop unhelpful treatments and support your patients properly. Early referral and interdisciplinary collaboration are key. And remember, getting the biopsy right can make all the difference.

That's a great note to end on. Doctor Gupta and doctor Liewluck, thank you both for such a rich and practical discussion. It has been an absolute pleasure to host this podcast on a topic very relevant to our daily practice. And to our listeners, thank you for tuning in to Talking Rheumatology. You can find links to IBM resources and our podcast archive on the BSR website. We'll see you next time on talking rheumatology.