Panel discussion and Q&A session X: Rheumatology

Prof. Bhaskar Dasgupta, Prof. Kim Legault, Prof. Daniel Aletaha, Prof. Robert BM Landewé

Recorded at the 6th McMaster International Review Course in Internal Medicine.
All lectures available at the MIRCIM virtual platform, click here to buy access.

Professor Bhaskar Dasgupta: Welcome to the Q&A session related to the talks that you would have heard in the MIRCIM 2021. And we really have had 4 exciting topics that have been covered. So I am Bhaskar Dasgupta; I am a rheumatologist in England, at Southend-on-Sea, and I have also given the talk on muscle pain, muscle weakness, from symptoms to diagnosis. And I am actually chairing the session, moderating today's Q&A session. And really, it gives me great, great pleasure to welcome my co-panelists: Prof. Legault, I think Prof. Aletaha is going to join us very shortly. And we have Prof. Landewé as well. So, I think without further ado, we are going to start with the questions that were collected through the MIRCIM app. The first set of questions are for Prof. Legault, who actually gave this wonderful talk on the management of antiphospholipid syndrome according to the latest practice guidelines. So the first question to Dr. Legault is a very burning question; you see, I mean, the antiphospholipid syndrome was built up in many ways from the sphere of connective tissue disease – lupus – and now it's being extrapolated to different conditions without any inflammatory disease activity. So the first question to you, Prof. Legault is, “should we check antiphospholipid antibodies in every patient with DVT [deep vein thrombosis]? Even if there is a precipitating factor to exclude antiphospholipid syndrome?” Professor Legault?

Professor Kim Legault: Thank you, Dr. Dasgupta. I think that is a great question and I don't think that there is consensus on that question to date. What I would say is that many people are checking it under certain circumstances. So I would say that relatively commonly, the situations in which we're testing it are few-fold. So certainly, [in] those where you are seeing that immune phenomena or the other non-criteria or criteria manifestations of antiphospholipid syndrome, you know, frequent miscarriages in somebody who then had a DVT, for example, would be one of those. And if we're seeing atypical locations for thrombosis; for example, an IVC thrombus would be quite unusual as a sort of a garden-variety thrombosis. A lot of times we're looking in that population. Populations who have had both arterial and venous thrombosis would be another. And then I would say that especially young people with arterial thromboses, like having had an MI or a stroke – particularly with no cardiovascular risk factors in terms of a standard presentation – would be where we're commonly testing those patients; recurrent unprovoked thrombosis would be another area. It's interesting because, you know, from the rheumatology side, we probably have a lower threshold to test them because that population is somewhat selected. And I think that a hematologist might have a little bit of a different perspective on this, but my hematology colleagues do say that they often are testing it now in patients who have venous thromboembolism in general, though if they have a very clear predisposing factor – like it's post-operative or something like that – then frequently they would not. But, for example, a young patient on the oral contraceptive pill or something like that, which should be seen as a provoking factor, but [there might also be] that underlying suspicion for antiphospholipid syndrome, given their young age: they are frequently testing it in that population. So, this is really evolving with the recent data of the triple positive patients being better suited for warfarin rather than a direct oral anticoagulant. And I think we're actually going to see changes in the recommendations over time, as we get more data like this. So those are the circumstances where I would say it should be tested and I think we'll see more in terms of that question in the future.

Bhaskar Dasgupta: That's lovely. Thank you very much. I mean, that was a very, very comprehensive answer, really. And the next question that is in fact on everyone's lips is actually, “what do we do when the lab sort of lets us down?” I mean, do you believe in the seronegative antiphospholipid syndrome? And if so, what is your approach? I mean, if you have really all the clinical aspects of diagnosis, and yet, you know, you don't get the easy answers. Do we keep looking for this or do we start looking for other conditions that might be causing thrombosis?

Kim Legault: I think it would be reasonable under those circumstances to look for other conditions that are predisposing to thrombosis. We have had some patients who we thought had catastrophic antiphospholipid syndrome who ended up having a PNH, for example, paroxysmal nocturnal hemoglobinuria. So a few circumstances like that of making sure that you are keeping that broad differential if you do have negative antibodies, is always really important. There are commercially available assays for phosphatidylserine/prothrombin, but they are not well validated – particularly not in the clinical setting. So, I think most people who are interested in antiphospholipid syndrome would still say that they are not using them in this context. I think that what ends up happening is just… is like all disorders where there can be, for example, seronegative ANCA vasculitis, where you have a very high clinical suspicion [and] you've ruled out all other conditions, then you would potentially treat accordingly. In antiphospholipid syndrome, it would really depend on what that manifestation was. If that meant that you would consider warfarin, potentially over a direct oral anticoagulant, then maybe that is all the change, the difference, and maybe that would be something that could be negotiated with the patient. If you are looking at it from a catastrophic antiphospholipid syndrome and you are looking at more of the immune phenomenon, well, if you have an immune phenomenon that needs to be treated, then it wouldn't be unreasonable to treat with the same treatment regimen you might use for an antiphospholipid syndrome, because if it was another undefined inflammatory condition, maybe that would be appropriate. But I think that at this point we're still not using those other assays and everything else just boils down to clinical judgement and really cycling back to making sure that you know – as much as possible – that there isn't another diagnosis that's being missed.

Bhaskar Dasgupta: I mean, can I just… Thank you very much for a very comprehensive answer. Can I just ask a follow-on question on that? I mean, how common is this predicament? You know…

Kim Legault: Yes, that's a great question and that's another, I think, consideration that will come up and we'll have more information about that. There are criteria, I think, that are being worked on currently for potentially, you know, a re-look at the classification for antiphospholipid syndrome. I think that the need for the criteria and the exact antibodies will hopefully form part of that. I have to say that I feel like I have seen a decent amount of antiphospholipid syndrome – though there are certainly people who are well more expert than I – and I have yet to see one where you didn't have antiphospholipid antibodies positive, though of course [it] might be [because], you know, those patients might not necessarily come down my pathway, because as a rheumatologist I'm probably only going to see the more severe ones who have clear inflammatory manifestations. So I have to say that in my experience we have found one of those antibodies positive, at least in moderate titer, for the patients where we had a high clinical suspicion. And I haven't seen a patient where I was quite convinced that they had fully seronegative antiphospholipid syndrome, though I certainly have seen patients where the titers were low at first and then they had a more severe event and the titers went a bit higher – but I haven't seen a negative to date. So I don't know that I can answer that question entirely. And again, I am hoping that some of the future work in this area will elucidate that a little bit more.

Bhaskar Dasgupta: Thank you very much. I mean, my own personal sort of clinical approach in such a situation has been to look for cancer, to look for cancer, to look for cancer. You know, with that approach, in unexplained thrombosis.

Kim Legault: Agreed. And look for endocarditis, which has been another one that has occasionally snuck by us in terms of very indolent presentations. But typically, you've done that with your initial look. But for sure, malignancies have… we have also had that experience where we were going down one pathway and then went to the other.

Bhaskar Dasgupta: Thank you very much. So, now we're coming to the question about antiphospholipid syndrome with lupus. And what is your approach to APS [antiphospholipid syndrome] in the setting of lupus? The question directly says “anticoagulation with hydroxychloroquine.” So, your views on that?

Kim Legault: Yes. I agree with that entirely. So we try to have all of our patients who have lupus on hydroxychloroquine regardless, as sort of their baseline medication from a flare prevention standpoint, as well as all the other benefits that have been shown in studies to help in lupus patients. So, with the additional data there does seem to be some reduced risk of thrombosis in patients with both conditions. I tend to encourage them to be on it – they have too good reasons to be on it in that context. But you know, the hydroxychloroquine, unfortunately, can trump the anticoagulation. Still, if they need that anticoagulation, if they've had an event, if they've had a thrombosis, then they are on anticoagulation with that. And then of course, if they have not, if they have the positive antibodies but have not had a clinical event, then we do tend to encourage the low-dose aspirin as well.

Bhaskar Dasgupta: Thank you very much. And there is a question on the chat, it's about the role of NOACs [novel oral anticoagulants]. Do you think they are indicated where you have a low-risk antiphospholipid profile, small recurring stroke, etc.?

Kim Legault: It's a great question. This is, I think, the biggest question in antiphospholipid syndrome right now: Can those people with the low-risk profile be on a direct oral anticoagulant. And it's difficult because you don't want to say “oh, yes, they are probably OK” and then be wrong about that down the line and have people be potentially deprived of what may be a better anticoagulant for that group, in warfarin. And at this point I would say that unless there are significant issues with the patient being on warfarin, I really encourage them to do that as the first line in my patients. But I would be certainly more comfortable about using a direct oral anticoagulant with low titer and a low-risk antibody profile compared to if they had the triple positive. But I think… and you know, people are currently meta-analyzing that data for the low-risk people. So I am hoping we have a little bit more of an answer for that in future. You know, it would be nice if they were, but there probably are some patients within that group who will be undertreated by it. And I think that at this point, we still don't know exactly who that group is who are going to be undertreated. And some of the failures have been stroke. I mean, in fact, stroke seems to be the issue with failure of DOAC [direct oral anticoagulants], for the most part. And that can be devastating. So from my perspective, I still like warfarin in those patients who truly fulfil criteria for antiphospholipid syndrome, but you know, again, I have the patients make an informed decision if there are low titer antibodies and things like that.

Bhaskar Dasgupta: I mean, one of the things that some people would say [is] that, particularly when there is difficulty in monitoring, people go for NOACs. And would you agree with that?

Kim Legault: Yes. I mean, this just becomes one of those, you know, individual risk benefit balances. If you have somebody who has very labile INRs [international normalized ratio test] or who just, you know, does not seem to be able to get to the lab, you know, they've got not great access to healthcare, depending on their situation. You know, with the low antibody profile, [if] your risk of a warfarin-related bleeding event or something like that, or anticoagulation on it, seems to be higher in this patient, then this potential increased risk of it being a failure because of antiphospholipid [syndrome], then you know, you would go with the direct oral anticoagulant. I would think in that scenario. Or, you know, I suppose you could consider a low-molecular-weight heparin, though it doesn't have a lot of evidence in any way, and there are obviously issues with using low-molecular-weight heparin as well. So, from my perspective, again, it all boils down to the risk benefit of your particular situation. I don't think we would say “oh, you should never use it in a low-risk patient.” I think we just don't have a huge amount of data to say that for sure it would be safe in that group.

Bhaskar Dasgupta: Thank you very, very much. That was a very comprehensive set of answers to very pertinent questions. So thank you very much.

Kim Legault: Thank you.

Bhaskar Dasgupta: And thank you for your lecture as well. So now I move on to some of the questions that have arisen from my own talk. And so, again, 3 questions that have been sent to us from the mobile app. Number one is, “what are the indications for a muscle biopsy?” Well, the answer to that is fairly straightforward. I think if you suspect a muscle disease, that the weakness is arising from muscle, I think that's an indication for muscle biopsy. Having said all that, you know, as I portrayed in my talk, there are myriad different causes for muscle weakness, so you need to make sure that all those other causes are excluded, which include metabolic causes, electrolyte disturbance, toxicological causes, even infections – they themselves can cause muscle problems, etc. So… and neurological causes, you know, neuropathies, etc., and cerebrovascular causes. But once you have actually excluded those causes and you are faced with a person who is presenting to you with muscle weakness and, you know, especially if that person has proximal muscle weakness, then that certainly would be an indication for a muscle biopsy. Now, of course an important factor is looking at the labs. And you want to really try particularly to investigate people who have got raised muscle enzymes, such as the CK – the creatine kinase – or aldolase, etc. So, if you are faced with someone with inflammatory muscle disease type of symptoms, with muscle weakness and raised CK, certainly that would be an indication for a muscle biopsy. Now, the question is, “if the CK is entirely normal, would you still do a muscle biopsy?” And the answer to that is yes. I mean, if you have excluded all the other non-muscle causes for muscle weakness and you have normalized CK or slightly elevated CK, then certainly a muscle biopsy is very, very useful. And certainly, with proximal muscle weakness, a muscle biopsy is very important. Now, you know, you need to refine the question a little bit. It's actually, “what are you going to do when you decide for a muscle biopsy?” At this stage, I think you would probably want to get some imaging first. Certainly do an MR [magnetic resonance] of the involved muscle groups, such as the arms or the thighs, so that, you know, you can choose the site for the muscle biopsy. And we certainly do that on a regular basis – particularly if it's a surgical muscle biopsy; then we actually tell the surgeons, “look, we've done the MR and this is the muscle group involved” or “this is the muscle group that's most involved.” And that's where we do the muscle biopsy. We do muscle biopsies also in the setting of connective tissue diseases. Certainly, in patients with lupus, patients with scleroderma, and [those] who have raised muscle enzymes, we would consider doing a muscle biopsy. Some people would also say an unexplained rise in the CK, with or without symptoms, would be another indication for doing muscle biopsy, but then, in those sort of situations, you need to make sure that indeed it's related to inflammatory muscle disease. So, muscle biopsies are helpful whether you are looking at inflammatory muscle disease or dystrophies or other forms of muscle weakness. For example, I mean, you may well get histological confirmation of a steroid biopsy. I am not saying that you need to biopsy the muscle in someone who is weak and has been on steroids, but certainly, if you think that the weakness is out of proportion to the cumulative dose of steroid, certainly you may wish to do a muscle biopsy. And you know, those are sort of the indications before a muscle biopsy. And then, we have the next question. And this is a very, very comprehensive question. It's almost the talk in itself: “What scores or scales are the best tools for the classification and monitoring of muscle pain, muscle function, stiffness, and inflammation?” Well, I mean, you know, I think one needs to be certainly quite detailed in one's answer to this. So, there is no classification of muscle pain, as such. I mean, as I [said] in my talk, muscle pain is really a ubiquitous symptom which can come from different factors and you need to make sure that it is indeed muscle pain, it's not articular pain, periarticular pain, referred pain, bone pain or polymyalgic pain. So, you know, if you are faced with muscle pain, really you need to make sure that you've excluded polymyalgia from things like fibromyalgia, which can mimic muscle pain, or osteoarthritis, which can mimic muscle pain. And of course, most important[ly] make sure that the red flags are not mimicking muscle pain. So in terms of muscle function, I think that's very, very important to… in fact, in my clinic when I treat people with inflammatory muscle disease, I monitor them mainly based on function rather than just look[ing] at the CK. Muscle function can be basically boiled down to looking at function related to proximal muscles, so we find out whether the patient has difficulty with rising, lifting the head from the bed, sitting up in bed, you know, standing up, etc. And absolutely one exercise that I do at the clinic, at the bedside, or on a video consultation is actually to get the patient to put their arms across their chest and then see whether they are able to get up out of a chair. And that's very, very important, whether they can climb stairs, whether they can walk up hill, you know, all these factors you certainly need to put in your monitoring of patients with muscle disease. So, stiffness – when you come to monitoring stiffness, stiffness is actually fairly straightforward. Now, I don't monitor stiffness by the duration of stiffness, because patients do not really understand what muscle stiffness means. So, you know, you can ask them whether it's half an hour, 1 hour, [or] 2 hours and they will tell you, they will give you particular duration for the stiffness, but it may not actually mean anything. What we really want in the monitoring is to try and find out about the intensity of the stiffness, how stiff the patient is, and the best way to find out about the stiffness – and this is something that I do regularly when I am monitoring my patients with polymyalgia rheumatica, where they have early morning stiffness – is I ask about disability. And I ask about disability related to primarily the functions of early morning activity. So I ask the patient, “are you able to get out of bed without any help? Are you able to reach first thing in the morning? Are you able to dress or undress first thing in the morning? Are you able to go to the toilet, get on and off the toilet first thing in the morning? Are you able to walk?” Those are my cardinal 5 questions of early morning activity. So, that's rising, reaching, dressing/undressing, hygiene, and walking. That actually is a much better surrogate for stiffness than asking for the duration of the stiffness. And then we come to the question on how we monitor muscle inflammation. Well, that has been picked up by several groups, and there is an International Myositis Assessment In Clinical Studies group, IMACS, the core set of outcomes measures that have been looked at. And certainly, there is some consensus in using the instruments for monitoring muscle weakness, but it is a multi-faceted assessment. And so you need to take into account the laboratory measures of muscle enzyme levels, usually the CK. You need to look at manual muscle testing as well as – we talked already about function – the HAQ, the Health Assessment Questionnaire. So that's very important. And a Global Visual Analogue Scale is also very useful, you know, from 0 to 100 or 0 to 10. And of course, something that we use in the UK regularly, particularly when we are using high-tariff drugs, like you know, rituximab or other drugs, is we use the myositis disease activity assessment tool. And that certainly is very useful in the monitoring of disease activity in patients with inflammatory muscle disease. So, I mean, you know, that is a slightly involved answer to the question, but there are many facets to muscle pain, many facets to muscle function, many facets to stiffness, inflammation. And your instruments have to pick up all the multi-faceted nature of the disease. So, the next question, again, that was asked of me, is “when do we suspect GCA [giant cell arteritis] in patients with polymyalgia rheumatica?” Now, that is a very, very important question, because polymyalgia can often be mistreated. And there is a problem in terms of the diagnosis of PMR [polymyalgia rheumatica] but also there is a problem in the diagnosis of GCA that can mimic PMR. As we know now, polymyalgia is now integrated into the symptoms of GCA, and certainly, you know, if you look at the modified [] criteria that we traditionally use in the diagnosis, not only do we have the typical cranial GCA features, but polymyalgia – particularly if it occurs in the presence of constitutional symptoms, so polymyalgia occurring in a patient who has got low-grade fever, a patient who is losing weight, but most importantly, a patient who is getting drenching sweats, and these drenching sweats can be night sweats [or] day sweats… So, in a patient with polymyalgia who has got constitutional symptoms and the patient is really not responding fully to low-dose steroid therapy and that patient also continues to have certain elevation of the inflammatory markers – it doesn't have to be very high, I mean, the CRP can be just slightly elevated – now, in that group of patients, you definitely want to exclude GCA. You want to also exclude GCA in a patient who has got relapsing polymyalgia. So, a patient who you've started on 15 mg [of] prednisolone, but as you drop the steroids down after the initial good response, the PMR comes back. You definitely don't want to just increase the dose of steroids; you need to make sure that you are not missing giant cell arteritis. And when I say giant cell arteritis, particularly in the context of polymyalgia, [we are] talking about large-vessel GCA. And so, now we know that there are 2 types of GCA: there is a cranial version – which typically presents with headache, jaw pain, visual symptoms, and ischemia – but there is this large-vessel GCA, which involves the aorta and its branches, such as the subclavian, the carotids, the auxiliary arteries, or even the vertebral arteries. And this group of diseases, this large-vessel GCA, typically manifests itself as polymyalgia with constitutional symptoms. And this is the sort of situation where you want to do an ultrasound scan of the arteries, in particular an ultrasound scan of the auxiliary arteries or the subclavian or the carotids, to show that actually you've got [an] increase in the intimal-medial thickness – it is actually almost diagnostic. And you can follow that, confirm that with the PET/CT, [which] will then tell you not only about the diagnosis of LV-GCA, but also about the extent of the disease and which vessels are involved. And of course, the advantage of PET/CT is that it certainly excludes other serious investigations. So, to summarize, in a patient with relapsing PMR or a patient with PMR with constitutional symptoms, or in a patient with PMR who has a persistent slight increase in the inflammatory markers, you must look very, very carefully for large-vessel GCA. So… I will just check whether there are any other questions in the chat. There is 1 question and comment. “At what level of CK do you stop statins?” So I am careful in terms of monitoring statins and certainly I would, if the CK increases once I've started a statin with or without symptoms, certainly more than 2-fold. First of all, I would certainly chop and change because, as we know, there are different statins and some statins have greater potential toxicity, you know, like the lipophilic ones. So the first thing that I would do is actually change the nature of the statin to a different one, but certainly, any [time the] CK goes more than twice the reference range, I would stop the statin. Before I stop it, I would often reduce the dose of the statin to see whether that makes a difference. But that's a very interesting question. So, there you are. Then we go on to our third speaker. So we have had a fantastic talk from Prof. Daniel Aletaha on the topic of early arthritis and how to manage it in general practice. So, the first question that arises from the talk, Prof. Aletaha, is “when are NSAIDs indicated in early arthritis?” Thank you.

Professor Daniel Aletaha: Thank you very much. I think it's a fair question. I think we usually ask the question the other way around: “When should we not only use NSAIDs?” We've come, I think, a long way from this question. I think NSAIDs are symptomatic drugs, as we all know, and they're useful drugs – also in early arthritis. I guess the question probably needs to be rephrased [to] “when do we add something on top of NSAIDs,” because there is obviously no reason in early arthritis not to treat symptoms, but there is a good reason to look out for treating the underlying cause of symptoms. So in very early arthritis, obviously, we have lots of reasons for self-limiting disease, as we all know, some of which we can determine and investigate on, most of which I would say we don't ever discover. So [in] short-onset arthralgia, certainly the NSAIDs are the drugs of choice, but we always have to keep an eye on persistence of symptoms, on recurrence of symptoms, on the full extent of how NSAIDs really treat the symptoms. I think these are all indications that should guide us in making a not too prolonged use of NSAIDs waiting for self-limiting disease, while we do investigations that may help us to determine inflammatory disease, a truly inflammatory disease.

Bhaskar Dasgupta: Thank you. I mean, that's a very comprehensive answer. My question to you – perhaps I have a different view on NSAIDs, you know – should we be really cautious about using NSAIDs in anything? On a chronic basis, particularly in the standard age group [of] patients that we see, older patients with slightly impaired renal function and having other, you know, relative contraindications. I tend to not use NSAIDs very much at all. Your views?

Daniel Aletaha: I think we've also come a long way in the types of NSAIDs that we've used over time. And I think there is… NSAIDs today do not lead to interstitial nephritis as frequently as the old drugs did, when there were only NSAIDs and glucocorticoids, before DMARDs were actually put in place for treatment of arthritis. I fully agree [with] that – and you've [added a] very important word there, I think, that was “chronic” use, and I am totally in agreement [about] the chronic use. And this is something I often discover in the community and talking to people: that the prolonged use of NSAIDs seems to be for many the less harmful choice, as opposed to starting, for example, methotrexate. And I think the reason for that is… and we all know, and if you ask any of us, probably we all would rather take half a year of methotrexate than half a year of NSAIDs, even though both drugs have side effects. And I think the reason why we are still facing lots of people prescribing chronic NSAIDs, or prescribing it long-term to patients, is because with NSAIDs I guess people feel that you can always stop, you have a quicker onset of action. [With] methotrexate or any other type of DMARD, the prescription of these drugs is a commitment, also from the doctor; you need to commit to a prolonged use, probably over years, likely over years, if people tolerate it and it works. So I think there is still the reluctance or maybe this is disfavoring the use of methotrexate still in early arthritis as opposed to NSAIDs. But really, I was referring more to early-onset arthralgia, recent onset of arthralgia, with people who need symptomatic control. And maybe this group of patients where you are not ready to start glucocorticoids because the reason being inflammatory is not clearly… you haven't yet made the diagnosis of subclinical arthritis, for example, so you want to control symptoms. I think that's the niche for NSAIDs, certainly not for prolonged use, I'd agree.

Bhaskar Dasgupta: Thank you very much. That's very elucidating and, you know… all the problems, it's such a complex problem in using NSAIDs. You know, for example, in my own interest, you know, we see so many of these patients with PMR put on NSAIDs, older patients, you know. I am personally quite against using chronic NSAIDs in these elderly patients. The next question that has been put to you is “what should our approach be to early arthritis, even when it is not fitting into particular diagnosis criteria?” A difficult question.

Daniel Aletaha: I think the whole story again is about how can we make sure we are not starting long-term treatment in the wrong patient. I think that's always what it comes back to, because you could very well argue, “why is treatment of any type of arthritis not based on use of DMARDs immediately?” And maybe we are moving towards that situation. I think the management of very early arthritis is clearly based on imaging, detecting subclinical synovitis in whatever way. If you are experienced and you know how to hold an ultrasound probe, you would do the ultrasound. If you'd like others to do the work, you do an MRI; some people have to work on MRI [and] some people have to work on the interpretation. Most rheumatologists these days look at the MRI themselves or in radiology rounds, where you can learn from others. I think these are developments of the last 2 decades that have clearly also made rheumatologists a little bit like radiologists in that respect. So I think we also need to look at something else in early arthritis, that not every early arthritis is arthritis; it might be tenosynovitis [or] it might be related to periarticular structures. So, just examining the joints alone may not be sufficient on a clinical basis and that again brings us back to the imaging modalities that – together with the CRP, as you outlined for PMR – is clear, but here you have more subtle changes. You may even interpret some… you know, even if it's not elevated, if you have a high normal CRP, sometimes in very early diseases, this might be – now that we have higher-sensitivity CRPs, where results are often enough less than 0.3 mg/dL in our lab, and you have 0.9 on the CRP – it might be something that you consider in that early situation already [to be] a part of the puzzle. So serology, we now have all this data about the increasing proportion of individuals with serological abnormalities as they approach the clinical onset of a disease. We know immunologically there is a lot going on before the onset of disease: the antibodies spread, you get an increase in [], as I was showing in my talk. And the moment you have the onset, somehow it's really the peak of the immunological activity and then things cool a little bit off. So, I think the combination [therapy], maybe it was 10 years ago and 15 years ago, but maybe our [out]look has changed a little bit.

Bhaskar Dasgupta: Thank you very much. So the last question is something that really exercises us quite a lot. Do you think now there is room for biologics without DMARDs in patients, you know, starting biologics without considering DMARDs?

Daniel Aletaha: Bhaskar, it's really not a question [of whether] I think, if the fact is it's been done in 1/3 of the patients. So asking me the question – it really doesn't matter what the answer is; the reality is that 1/3 of biological patients are going on monotherapy, even though we know that combination [therapy] is more effective. And the reason for that, you know, we discuss that quite often, I think. I think it comes back to the resistance or reluctance of patients to continue a drug – methotrexate or DMARDs – that was not effective, and to add a drug that then makes a big difference, it's very difficult for patients to understand why they need to continue that drug that did not help them. So I think in reality… and all the registers show that pretty much 33% of patients are on monotherapy. We know that with IL-6, it might do the whole thing, although even there, combination therapy is more effective. But you know, we have so many options now in biologics and we have small molecules that are effective. So I think these JAK inhibitors again put your question on the spot because are we treating them now like biologics or as chemical compounds, more comparable to methotrexate, by the chemistry rather by the rationale for development. And I think there it is pretty much, I feel in the community the sense that monotherapy is pretty obviously the way to go with JAK inhibitors, although conceptually, the same type of data exists – or very comparable data – that show you get a little add-on effect if you have the combination therapy, as it was for biologics and recommendations often enough are that you should combine them. I think it's a difficult question, but I think that people make the choices and shared decision-making really is already in place and I would say [that] you can pretty much tell by the proportion of patients on monotherapy.

Bhaskar Dasgupta: Thank you very much. Thank you very much, Daniel. So we come to the sort of question and answer session on our final speaker, and that's Prof. Landewé, who spoke to us about COVID-19 and rheumatic diseases. The first question is a very pertinent one and it really exercised all of us, particularly in the first half of last year: “Can you elaborate on the hydroxychloroquine story, you know, progress from benefit to harm?” Over to you, Prof. Landewé.

Professor Robert B. M. Landewé: It's an interesting question. I can talk about it for more than an hour, I think, which I will not do. The hydroxychloroquine question… early, during the pandemic last year, we were seeing many patients with a disease that we did not know. We saw patients sometimes recovering themselves, but obviously then we recognized definitely the patients that had a very severe course. There was a lot of information there. And if you are talking about a disease that you don't know, in which you detect a lot of inflammation, then a substance like hydroxychloroquine comes easy to mind always, as a good candidate to try. That is because it is an old drug; we know it very well, for many years. We know that it is actually – among all the DMARDs that we use – probably among the safest ones. And especially rheumatologists, but also many people outside rheumatology, in many different diseases, dermatological diseases and so on and so on, prescribe hydroxychloroquine. We started the discussion an hour ago with antiphospholipid syndrome and especially lupus. And a patient with lupus who is not on hydroxychloroquine, we are taught, is not well treated. So it is a very, so to say, ubiquitous drug and [the fact] that it was tried in the early days of severe COVID-19 was not a surprise to me, because we didn't know the course of the disease. We didn't realize ourselves that 80% to 90% of COVID-19 patients were actually more or less having self-limiting disease and it was the 10% of patients that overwhelmed our healthcare system. And if you decide that… a drug like hydroxychloroquine, in a condition for which you do not have other drugs, if you decide that it may work and you try it out in 10 patients, you probably will find that 9 out of these 10 will do relatively well. It takes a while before you realize that it is self-limiting disease that you are treating and not severe COVID-19. And you need the RCTs that were done later on to tell you that the drug actually is not effective at all. I must admit that it hasn't helped, how the media responded to the hydroxychloroquine story, that it hasn't helped how the transatlantic president – or at least transatlantic for me, so in the United States – responded to that. It made it extremely popular for a while; the, so to say, additional effect, however, that arose was that hydroxychloroquine actually was pretty well trialed later on. We at EURAL are doing the systematic literature research at the moment, investigating how drugs work in the context of severe COVID-19. I can tell you that the bottom line of the hydroxychloroquine story is, firstly, that it has been relatively well studied in trials, in good observational studies and, secondly, that we are now pretty sure that it doesn't work. We cannot say the same thing for many of the drugs in the realm of treatment of COVID-19. So yes, it's a story that tells you that you cannot rely on some sort of basic or translational science alone. In the end, before you apply it in many, many patients, you need the trial data or the good clinical epidemiological data that can tell you in the end truly whether a particular drug works or not.

Bhaskar Dasgupta: Thank you very much. That was a very comprehensive answer. The next question that I've got here is “what DMARDs should we withhold?” No – is it DMARDs…? “What anti-rheumatic drugs” – so it's more than DMARDs – “should we withhold after COVID-19 vaccination? Are there any?”

Robert B. M. Landewé: Well, if you can tell me. Actually, the answer is we don't know. I would put it rather upside down: at the moment, we don't have drugs which we are certain we should stop after COVID-19 vaccination, or maybe even before COVID-19 vaccination. Maybe the questioner is pointing to the data on drugs like rituximab. We talk a lot about that; studies are still scarce and these studies give conflicting results. These studies sometimes say that you have a blunted antibody response in response to vaccination for SARS-COV-2. That doesn't immediately tell us that there is no vaccination response; it only tells us that there is less or maybe absent antibodies. And we don't know exactly what it means, so that is uncertain. I think the best answer to give – with regard to drugs like rituximab, that you can time to some extent – is if you know when to vaccinate and you have the opportunity to wait a while with the next rituximab cycle, I would say wait a couple of weeks. I think in many guidelines nowadays, in many recommendations, it is postulated that it should be approximately 4 weeks at least. But I should say that is good guessing [because] we don't have really good data about this. And the same pertains to all the other drugs that we use. EURAL has issued, already in December 2020, that there is no reason to not vaccinate patients with RMDs [rheumatic and musculoskeletal diseases] who are using anti-rheumatic drugs. And we didn't explicitly [differentiate] between anti-rheumatic drugs those days; we are now 6 months further and I do not have ample reason to argue that particular [] statement.

Bhaskar Dasgupta: Thank you very much. That was again a very comprehensive answer. Just to follow-on to that, you mentioned rituximab. Certainly in the United Kingdom, because of the different problems, you know, and slight apprehensions about rituximab and the irreversibility of rituximab in the middle of the COVID-19 pandemic, giving it as intravenous infusion, you know – patients don't like coming in to the hospital to have an IV infusion. So in many ways, for different reasons, the popularity and the usage of rituximab has decreased in rheumatology patients. Your comments on that?

Robert B. M. Landewé: It probably has. In my clinic, maybe in my country even, it has never been extremely popular for treating the diseases that are most common, like rheumatoid [arthritis]. Having said that, we have a full arena of systemic rheumatic diseases and vasculitides, in which we nowadays use rituximab. Whether that attitude of trying to avoid the hospital is correct or not, I don't know, I must admit. It depends a lot on the infection pressure, I would say. So, during times in which the infection pressure is very high, as we've seen over the last couple of years, quite a few months, it may be good policy to sort of avoid the hospital. On the other hand, it's always weighing… it always a balance. It's pros and cons, risks versus benefits. Sometimes we use rituximab in patients with very severe diseases and this is also not a good policy to withhold a possibly life-[saving] drug to patients, well, who need it.

Bhaskar Dasgupta: Thank you very much; I totally agree. So the next question is a very popular one. And I have my own views about it because I spend a lot of time treating people with steroids, like many other rheumatologists. But what do you think are the precautions and practices we should adopt with glucocorticoids in the middle of this COVID-19 pandemic?

Robert B. M. Landewé: Yes, glucocorticoids are among the drugs that have been studied a little bit more frequently as compared to other DMARDs. What arises in the observational studies that we have looked at is that you see some negative effect of corticosteroids. So, actually, what you see is that patients who are using corticosteroids have a higher risk of severe COVID-19, a little bit higher risk to contract it and also a higher risk of a severe course. We personally – well, I personally think – we also think within the epidemiological group in EURAL, that this to a large extent is confounding by indication, which essentially means that if you are a patient with a severe disease, you need glucocorticoids, and it is having a severe disease and maybe a compromised immune system rather than the corticosteroids themselves that give the additional risk. Having said that, you are never sure and we always say that you should use the lowest possible chronic maintenance dose of glucocorticoids that you can arrive at. But that has nothing to do with COVID-19; it's actually very common advice, and probably very appropriate advice, to every patient on long-term glucocorticoid treatment.

Bhaskar Dasgupta: Thank you. I will just give you my own slight views on this. You know, I am quite exercised by what I see as sort of almost a bit of abuse of glucocorticoids during the COVID-19 pandemic. You know, many patients with inflammatory arthritis or different other conditions. You know, rheumatologists and patients have sort of combined, I think. Certainly in the UK, we are seeing an overuse of glucocorticoids with a relative underuse of all the effective DMARDs and biologics. Certainly, this was true in the first part of the pandemic. You know, my worry is whether, after COVID-19 abates, whether we will be seeing the excess COVID-19-related morbidity in our patients because we have been frightened of using the biologics and the DMARDs. We have ultimately actually moved the specialty to such a fine art. So, you know, I wondered whether EURAL is going to be looking at the excess COVID-19 morbidity. Our patients don't die that quickly, but certainly, the accumulated damage from the overuse of glucocorticoids is going to show up 1 or 2 years after the pandemic has ended.

Robert BM Landewé: Yes. And I don't know. EURAL is taking part in and has organized several registries in which patients are followed. So the answer is probably yes, although I don't know it in detail. With regard to overuse of glucocorticoids, well, I would say not in my country; maybe in the UK, but you are the country in which the famous RECOVERY study has taken [place], in which dexamethasone was invented, so to say, to treat patients with COVID-19. Unfortunately, that study included approximately all patients who were admitted with COVID-19 and even patients who were not admitted, so also all those patients who did not have a very severe disease. I think a wiser way of treating COVID-19 with glucocorticoids, in which I strongly believe by the way, is to select only those patients with severe disease, which means signs of hyperinflammation in which the immune system gets so uncontrolled that actually the immune response is worse than the effect for which it is meant. So, you should make a proper selection for treating patients with immunosuppressants – including, by the way, biologics – if you are going to treat COVID-19 patients with these drugs.

Bhaskar Dasgupta: Thank you very much. So, we've had a very interesting session, an hour of looking at some of the finer points and the burning questions, with antiphospholipid syndrome, with muscle pain, muscle weakness, with approach to early arthritis in clinical practice, and COVID-19 and rheumatic diseases. So it really gives me great pleasure to thank all the panelists and also the questioners themselves for having posed such an interesting set of questions. So thank you very much.

Robert B. M. Landewé: Thank you too. Goodbye.

Bhaskar Dasgupta: Bye.

Daniel Aletaha: Thank you, bye, bye.

Co-financed by the Polish Ministry of Education and Science within the program „Doskonała Nauka”
(„Excellent Science”)

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