Ep 46: The Immunology of Lupus

Join Dr Mariele Gatto in conversation with Dr Chris Wincup as they discuss all things related to lupus immunology, from pathogenesis to treatment decisions.

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Transcript

CW - My name is Chris Wincup, and I'm a consultant rheumatologist based at King's College Hospital in London. And today, I'm delighted to be joined by professor Mariel Gatto, who is a rheumatologist based in Turin, Italy. Today, we will be talking about the complex subject of immunology relating to lupus. So I guess the first question that I'd like to ask is, what is lupus? And can you perhaps try and elaborate on that when you think about immunologically what is going on when we see patients with lupus? 

MG - Sure. Thank you, Chris, for kind invitation, and it's a pleasure to be here as well. So, I mean, that's a real difficult question. That's the mother of all questions. And it's mesmerizing because we talk about this and patients even ask the same questions. Of course, you have to use double language and different ways to kind of metabolize the content in order for it to be delivered to scientists and to patients. So that's, yeah, that's, the first challenge. And, I mean, what do I do when I try to explain lupus to, non lupologist at least that that could be patients that could be colleagues, maybe from other specialties. And so I started always with the same statement. Lupus is a complex disease where the immune system attacks the body's own organs and systems. So, and this is like the first picture of the get in their mind that looks like, a terrible fight. And then I try to motivate it. So why does it do that? Because it does not recognize anymore what is going on in the body itself. And disease is, the, immune system is unleashed in its responses that are elicited by, small changes, tiny changes into self molecules that then spread and give the immune system the idea that every molecule in body is indeed a foreigner and then gets attacked. This is very true when it comes to, surfaces or organs that are surfaces in contact with the environment. So this is why UV light, for example, it's so dangerous because it gets into your skin, changes and transforms the superficial antigens of keratinocytes and also nucleic acid DNAs and it spreads a damage that is not, restrained anymore by the normal, defense, first line defense of your, of our, normal clearing immune system. So a lot of damage antigens just persists in the extracellular environment, and they get, they become sort of fire alarm for the immune system itself. So you get, like, a paraphysiological response that then is not stopped anymore. It's just unchained and spreads throughout, the body and the organs. So this is like my first, statement when I try to explain that to people who are not, maybe so much into lupus. But, of course, we can go into details and just mention all the stimuli and cell populations that, come into play for that. So feel free to, take the lead on this and we can.

CW - Great. Thanks very much. It's really nice to hear the way that you very eloquently describe what happens there, and I think one of the things that comes through whenever talking to anyone about lupus immunology is that it's complex, and I think you touched on a number of different points there in terms of key areas of immunology. So, for example, you mentioned the loss of immune tolerance, which we think of in many, many autoimmune diseases, but seems to be particularly marked in in lupus with the systemic fashion in which the the disease presents. And you also touched on on the role of UV and ultraviolet, and we do know that there are other types of risks associated with the immune response in lupus. Talking a little bit about those risks, I guess we have genetic risks and one of the things that we find in in practice is many of our patients are women, particularly young women, and so I think another thing to really highlight is the role of hormones on the immune system, which I think overall we know very little about, but particularly in lupus where you do see this very marked prevalence of the disease in females, particularly in in those females of childbearing age, it is really one of the mysteries in lupus as to as to what is going on immunologically interacting with hormones to drive the disease. I was also really pleased to hear you describe the kind of loss of immune tolerance and the damage that gets brought about, and this failure of clearance of immune cells or failure of clearance of of DNA and other such, cellular components in the disease. So that, I guess, kind of brings us on quite nicely to think about, well, if you've got failure of your innate immune response and failure of apoptosis, you're not clearing all of this dead cellular debris, and then you generate this adaptive immune response to it in many cases. And for perhaps the non expert listeners, when we're thinking of an adaptive immune response, we're thinking about predominantly, cells relating to t cells and b cells. So what would you say is the evidence for b cells being involved in the pathogenesis of lupus? Again, thinking very clinically about antibodies, and then perhaps a bit more about what these antibodies are doing in in the disease in general. 

MG - Well, we have been learning over the the decades to how important b cells are in lupus and proof of concept is that, nowadays, we have plenty of drugs targeting b cells or maybe not plenty, but at least they are on pipeline. But, in the clinic, we still do use, B cell depleting therapies as you know very well and they work. And that is because B cells are the main actors or one of the main actors in lupus. For a long time, it was not clear how pathogenic antibodies were. So we knew there were plenty, but we didn't know which one could really cause the damage. Now there is a good evidence, good level evidence about, anti DS DNA and anti DNAs one like three antibodies, especially, which are very much involved in, but not only because they can pave the way to a very complex inflammation by, by, dampening the, the, the proper degradation of nucleic acid disease when it comes to anti DNA antibodies. And they just, promoted the local and systemic inflammation but the role of B cells starts much earlier than antibody production because we have failure of several checkpoint of several, gates of tolerance, both at the central and at the peripheral levels. So there are, there are stat nine studies showing a lot of bone marrow failures, checkpoint failures, before the B cells are even released. So we do have a very, very, let's say, weak, negative depletion, negative selection most B cells can be released in the periphery and that is even due to a higher rate of apoptosis in the bone marrow, which provides a lot of foreign antigens or inner antigens modified apoptotic antigens to the b cells, which are challenged in the bone marrow and some of them escape the central tolerance gates like that. And they have maybe, mutations, in their in the small, transaction system from their provisional BCR down, which makes them, quite invisible to the  depleting mechanisms. So it comes to that a lot of, immature B cells that are released in the periphery are do they carry, an autorected BCR? And the transitional vessel pool, which is very important in early lupus, is, enriched with the autoreactive species that are not effectively depleted in the periphery. And instead, they can be kept alive by a pro inflammatory environment where, for example, Bliss billing process simulator, plays a great role. So it keeps, b cells alive and allows transformation for from immature to more mature, more mature subset so from transitionals to naive and to the follicular and extra follicular roots. So that there is a lot happening before autoantibodies are even produced. And it is the last step of a very long course that is invisible to us, but then we get a small, small flags which are the antibodies and we know that in a way it is already late, so we have not been able to prevent it. So when we see them, it means that, a very adaptive process is already established. 

CW - I mean, that's a really comprehensive and very nice overview of b cells, and I think that many people will think of b cells in very superficial terms, not just with lupus, but in in many conditions you think about infection as well, and I think many people feel that b cells are just, producers of antibodies, and in the case of autoimmunity, there's a producer of autoantibodies. But as you mentioned it takes a lot to get to that point. There are a number of factors that are needed before these cells start producing these autoantibodies, and I think it's also really interesting because there's probably a lot more to b cells in the pathogenesis of lupus and other autoimmune diseases than simply just being a factory for auto antibodies and you touched on a number of those points, very nicely there. This kind of perhaps brings us on a bit to therapeutics, and you mentioned b cell depletion, and I know that you and I have both had conversations about this with the very checkered history of b cell depletion in lupus with, rituximab, which we obviously do use in occasions, you know, fairly liberally in The UK, but perhaps not elsewhere, and that was on the basis of open label data having seen two large randomized controlled trials, produce negative results but perhaps more recently with not just the cellular therapies like CAR T cell therapies, but obonatuzumab showing efficacy, this speaks to this being a good target for the disease, and you mentioned BLIS as well. I think one of the things many clinicians who perhaps don't use the drug, so much, don't really understand is belimumab and what belimumab does. So if you could perhaps just very briefly tell us a bit about targeting b cells with, you know, conventional monoclonal antibodies, and if you wanted perhaps to dream more of the future and talk about other ways that b cells we target both in terms of b cell depletion and in in the inhibition of bliss or BAFF. Where would you kind of say that is at the moment for the treatment of lupus when you think about the immunology of the disease? 

MG - Well, I think it's, sort of a great moment to be rheumatologist taking care of lupus nowadays, just in this very moment because when you mentioned we have plenty of bisalipidin drugs, I mean, I had in mind drugs that are about to be available besides the, the ones that we have that basically are for lupus, belimumab and rituximab, which as you mentioned is off label. But now, I mean, there is a lot, going on about B cell depletion, either very profound as the as the CAR T side and either more targeted, or let's say more traditional with the monoclonal that we know. So obinutuzumab on top of probably of other drugs. So, bisal depletion with, for me is really performed with those drugs because you cannot really rely on traditional DMARDs to efficiently deplete B cells. We do have proofs of that. I mean, these drugs that we have to be probably thankful to also for all the time they cover, but they are not so, targeted to B cells. So there may be some effects on T cells, which they do have, but this does not result into an efficient B cell depletion. So Belimo was the first licensed drug, for, B cell depletion and modulation, which I think is as important as, getting rid of the of the pathogenic ones and as you know, it is available now since 2011, and we do use it, more and more at least in my country, which but also in Europe because I went through the literature for recent research and I was pleased to see that, even before the last recommendations were released, people started to use belimumab earlier and earlier, so in a very timely fashion, just after hydroxychloroquine and corticosteroids, for example. And that makes a lot of sense, in my view, because as I mentioned, belimo was targeting bliss. So belimumocyte stimulator and, it does lower the serum, the serum levels of the cytokine, which as you very well know, is that really the engine, the fuel of, of B cell maturation from the transitional stages to the more mature phases. So breaking down the process of maturation of autoreactive B cells is a key, is a key moment in, dense queuing and shifting the disease course afterwards. So it makes a lot of sense to use this kind of, treatment quite early in time during this course. There are data now from post hoc analysis on the BLISS trials showing that the earlier use is associated with, greater, higher response rates in terms of the scores that we use to measure the lupus response. So the SRI four, for example, associated with very, with a great safety profile and this is true also for the other biological drug. So you would gain into, in terms of response, and especially in terms of safety, which is a great, a great point to make and we do have data not only on response, but also on how diseases then develops after, an early use of belimumab. I'm collecting this data with other colleagues and we are, I mean, we're showing that early lupus patients treated with belimumab versus early lupus patients treated with a traditional DMARDs disease retrospective analysis, they had very different routes after that. So the ones on belimumab did not accrue, EULAR criteria for lupus in a year time while the others did so that was a real, separation between the curves. And of course, now we have molecular also insights on belimumab effect that makes it evident that it targets not only, as you mentioned, the B sub pathway, which is of course the more intuitive, but it responders do also show a very, prominent, downregulation of the interferon pathways of STAT1, STAT3, signaling pathways of inflammatory cytokines so responders do have their whole immune response modulated. So we do have, controlling of this activity and also, let's say, a plastic modulation of the further response, in in the face of a very nice safety profile, which, I think it's great for a drug that you have to use for years. So that's amazing. And then you are the expert of, anti-CD twenty, targeting, so please, take the lead on this. Yeah.

CW - I mean, it's a very tough act to follow after you so elegantly described the role of bliss and belimumab targeting, therapies in in lupus. I think one of the, one of the things that I find really interesting about the CD20 targeting therapies is until very recently we've not had any strong amounts of evidence to base this on in terms of when you're looking at those phase three trials. I know that, we've recently discussed this at conferences and it is almost a case that we're almost completely metaphorically and literally an island in The UK given our, rituximab use and targeting of CD20. But I think just to follow on from what you very nicely talked about is this interesting collaboration between b cell depletion with a drug like rituximab and using belimumab, and I think the thing that comes to mind is these recent trials of combined biologic therapy, which is not something that many people do in rheumatology, not it's not really been tried. You think of rheumatoid arthritis where you've got so many different biologic drugs available in so many different pathways, and yet it was really in lupus where we've been looking at this combined approach of biologics and when you look at the data of that, that is really quite fascinating. We know that patients treated with rituximab, their BAFF levels tend to spike afterwards. So what's going on there? You're deleting a cell population, but what you're actually doing is almost having an evolutionary survival, as levels of bliss or BAFF then spike up afterwards, and that's led to a number of these studies in which combination of rituximab and belimumab have been used together. And the thing that I find fascinating about that is an observation was made about one compartment of b cell simulating cytokines following b cell depletion, and we already have a drug that can block that with belimumab. And so you going from the lab, from the bench to the bedside into a clinical trial, when you think of studies like the beat lupus trial, that did show prolonged efficacy and no increased risk with safety, that the there is really a lot to be said here for this combined use of therapies when you think not just of b cells as being a cell that floats around and makes antibodies, but also blocking other important, cytokines that drive the disease does really translate through to different outcomes for patients. And I think this is an exciting time. We as lupus clinicians we can't seem to go a talk without mentioning CAR T cell therapy, but the data for Obinutuzumab is looking fantastic and is, probably a lot closer to current clinical practice showing what perhaps rituximab couldn't, which was, the ability to make it through a phase three randomized controlled trial. And so I guess many people will ask the question, well, what is it about Obinutuzumab that's better than rituximab? And again, I think if you think biologically, rituximab is a very old drug. It's now these days. It's thankfully a very cheap drug, but it's a chimeric drug, so there is a mouse component to it. This increases the risk of allergy and immunogenicity to it, so there is a risk of reactions to the therapy, which we tend to see relatively frequently in in lupus compared with rheumatoid, as an example. But also that there is a potential for the drug to be more neutralized with this with this animal protein. So is it that Obinutuzumab is a better drug because it's just fully humanized and you've taken out that that kind of animal protein? Or is it that actually it's a better drug at getting rid of b cells? And I think there is some good data to suggest that they actually the b lymphocyte toxicity from the drug is also superior to rituximab. So again, you know, an example of a drug that didn't work in one trial, perhaps being looked at in a slightly different way, perhaps doing a slightly different trial and getting a positive result, and that's before we even think about things like cellular therapy, such as CAR t cell therapy, which I'm sure will be a conversation, for itself one day. 

MG - I would like to know your perspective on how to locate it in the treatment process because I don't think it just takes the spot of rituximab. I think it has much more potential. So, I'm sure that, as an author in in the recommendations, you can give some yeah. Yeah. It's how it should be used.

CW - It's a very nice question and it kind of follows on from the debate that you and I were doing in Venice on on when we should be using biologic therapy, and I think as you mentioned already, you know, with belimumab, earlier treatment is of benefit there. Now are we going to be using early Obinutuzumab? I'm not so sure. I think if you were to say we could use it early, we probably would use it fairly early, but as you're saying, where is its position? Now I think that's going to vary drastically depending on where you work, in the world and the availability of rituximab. So rituximab, for example, in The UK, as I mentioned, we we use lots of it. It's relatively cheap these days Obinutuzumab, we anticipate, will probably be considerably more expensive, but we wait to hear exactly what the difference will be. I think there is a proportion of patients who respond to rituximab, and I imagine that that when we think about economics, rituximab will probably still be the one that that gets chosen first in the very early days of Obinutuzumab being licensed. But I do think that there are huge benefits, for Obinutuzumab, this kind of secondary nonrespondent to rituximab group. So for example, patients who have had rituximab and either it's worked well on a few occasions and then stops working. So for example, your peripheral b cell CD19 count doesn't quite reduce, you don't get full peripheral b cell depletion after several doses, or in those patients that that I alluded to earlier who have had reactions to their therapy. And we know from our previous data that, if you if you have a reaction to rituximab, the next one is likely to be more severe. So if you have a patient who has an anti-drug antibody mediated reaction to the therapy, you probably, on safety grounds, wouldn't want to go back to retreat with rituximab, but we have shown in the past that that reaction can be bypassed by giving a humanized anti CDtwenty, such as Obinutuzumab. So in the early days, I suspect, from a UK perspective, we may be looking at it slotting in where rituximab has either worked and then failed or where the you can't retreat with rituximab due to this reaction. But I guess then there is going to be more of a question as to where it sits, and I know it's something we'll perhaps discuss later on in terms of we are not used to this as lupus clinicians. We are not used to having two or three drugs that target different pathways. We have just had to take the one that we've got off the shelf, and we are going to have to move more towards, more personalized and precision medicine, and that's going to take a lot of upskilling, and I'm sure that's something that we'll touch on in a bit, and I think it's nice as we talk about Obinutuzumab that we consider there are other therapies that that are available already that target different immune pathways, and we've now covered b cells quite a lot, and you mentioned BLIS or BAFF is a cytokine relating to b cells, but perhaps we change direction slightly now and talk a little bit about other important pro inflammatory mediators in the pathogenesis of lupus that are now leading to newer therapies, and in particular I'd be keen to get your thoughts on interferon in terms of what is interferon doing in lupus and why are we now getting success with targeting this, so I'd be keen for your take on that.

MG - Yeah. Well, I guess all of us know what interferon do in general, but maybe it's worth, just a little bit a reminder on that. That is it is a very, preserved system from some from the very first organisms, and it plays a very prominent role, the interferon system in the first line defense against viruses and invaders in general. So we do have three classes of interferon. So new one type one, two, three, they are slightly different and cover different areas. But, for the keen and, for the sake of lupus, so we, of course, focus more on the first two types. So one and two. And what they do is basically that they activate cells, in being aware and ready to react to any kind of invaders, even though those are, inner antigens and was mentioned before. And their production can be triggered by a number of signals, mostly, danger particles, so dumps, pumps that, alerted the innate receptor systems. So that means, for example, toll like receptors are key players in the interferon cascade. So they get activated, they migrate, or they are already in the intracellular organs. And, especially for for the lupus pathway, the most important ones are TLR seven and TLR, TLR nine. We know that they receive nucleic acids from the outside of the of the cell, and they're basically protein side, efficiently by immune complexes. So the cells internalizes the immune complex, binding the nucleic acid that migrates, to the intracellular or organ where the TLR is and that incites an interferon response. When this system is unchained, because we do have a lot of nuclear cases freed in the extracellular space, the system becomes uncontrolled and you mentioned the, the influence of gender. It's interesting to know that TLR seven, which is a prominent inductor of interferon, is sitting on chromosome x. So, the one of the hypothesis for the, the women, susceptibility to SLE is that we do have a higher production of TLR seven. Then there are also some gain of function mutations that have been, have been describing this, delivery system of nuclear cases to the TLR, which, we don't go into detail now, but they look more pronounced into people susceptible to lupus and in women susceptible to lupus. So that could be one one part of the explanation. And then after that, when interferon made, then it activates not only, the neighbor cells, but it can have a very, wide effect on a lot of cellular species, not only immune competent, but also resident cells become activated, to, under the influence of interferon. And it just gets its own production, more and more efficient because it also induces, toll like receptors themselves. So then you get like a non-unlimited, let's say, nonstop, self-maintaining interferon productive loop that gets increasingly dangerous in people with lupus. And this is like the core of the response. As in normal antiviral responses, you also have a certain rate of apoptosis of infected cells which are not infected in lupus but they are damaged and this increases also the rate of, interferon production. And, what happens is that in target organs, then, you kind of find, some sort of, very local specific interferon sources, which are the target organs themselves. So it has been shown in lupus that, the main producers are not only on not just the plasmacytoid dendritic cells, which we are known and are meant to be like the main producer self interferons, but the inflamed organs start to be activated, and they kind of produce their own interferon. So you have a lot of interferon in the skin, because keratinocytes can make interferon and they promote their own destruction by themselves. So they become sort of victim, but also, the murderers of sorry, of the keratin of the keratinocytes themselves. And this is also true for mesenchymal cells in the kidney, where you can have a balance between type one and type two, which is under investigation, and in other target organ. So it is really a key cytokine in activation, promotion, and sustainment of lupus development.

CW - Great, and so you've kind of very nicely highlighted interferon for the non expert, and that was a really great deep dive into where the interferon is coming from and how it's involved in the pathogenesis of the disease, and perhaps most excitingly of all we have another therapeutic target and obviously Anifrolumab, another drug making it through a phase three clinical trial. So I think you know we're now talking about several different drugs, this one really unique because it is targeting a pathway that not many other diseases have targeted. So can you perhaps tell us a little bit about your experience with Anifrolumab? What kind of patients do you think would benefit from it? How can you tell whether someone should get, Anifrolumab and actually how do you know whether someone's lupus is being driven by interferon? I know that's a tricky question, are we at a position to know who should be getting an interferon targeting drug versus a b cell targeting drug, or is there work still to do in that area? 

MG - I mean, there is a lot of work to do. We do have some hints about that, we can take on as clinicians also. So we can talk about factors that are associated with a response to either track. Of course, they're not sufficient. We should have a more definite picture of the endotype of the patients, which I'm not sure how close we are at getting in the clinical practice. So at the moment, my take is that when it's a lot of, antibodies, a lot of active serology, I am still, bound to, first at least for first line, on a on a B cell approach, which I don't say it's the absolute truth. I mean, people with active serology can still get Anifrolumab and be very well. So I don't mean that you have to do that, but in my mind, that this is still a biomarker of, prominent B cell activation. So I'm happy with both approaches. Well, when I'm facing more chronic manifestation, as I mentioned, the skin is, I think, a little bit the paradigm of all this. You can really see that, subacute lesions, or chronic lesions, they look very different from the active rash that we that we know very well. So in that case, I skip, the B cell, the B cell depletion, the approach in most of the cases. Now do we have an anti-interferon, and I turned to that. But the skin is, like, quite easy. I mean, because you have a clinical, evidence at the baseline. And after a few days or weeks, you can you can, already have the proof if you were right because this drug, and pharma works so quick that, I think that's amazing for the patients and the clinician. And then it is more difficult when it comes to, other manifestations or lupus nephritis for which we do not, still do not have. We know that there is a lot of interferon there, but we do not have, of course, the chance of treating it with an anti interferon so far. And, when you get to have a choice to make a choice between the two biologics in early active lupus patients, that's my target, my preferred target to change the disease course, then it's difficult to be sure that you are making the right choice. But, yeah, I agree with you that this is a revolutionary drug, and they were smart enough to target not the cytokine, but the receptor, which I think it made a difference because there were attempts before to target interferon in lupus. But as you know, I see over well, it is a very tricky and redundant system. So targeting the cytokine probably would not do, but that was, overcome by targeting interferon type one receptor, which is the target, of course, of Anifrolumab.

And yeah. It's a I think it's a great time now to have all these, drugs in, at our disposal. What is more difficult is beside choosing is when how to to take on this treatment, but probably are not there yet, for biologics. 

Fantastic. And I think one of the questions that that I often am asked by colleagues is, well, if you got a drug that targets interferon, why don't you just measure someone's interferon And if it's high, give them some anti interferon based treatment like Anifrolumab. It's not something that we measure routinely in the labs, and, actually, there's very little data on in terms of actual circulating levels of interferon. Could you perhaps just tell us a little bit about why we don't check interferon levels in patients to decide whether they should get Anifrolumab  treatment or predict response to treatment? What are the challenges there, and how could you perhaps subtype patients into being an interferon driven group? For example, we see a lot of literature saying, patients have high interferon scores what kind of things are people talking about here? 

MG - Yeah. That's still quite far from the clinic, I know. I think even though we know that it's it's all over the literature that we're reading about it. So we talk about interferon signature, that means we talk about high serum level of interferon, but, especially higher expression of interferon driven and related genes. So, the circulating interferon can be very variable, so it's not really reliable for, to be measured as a proxy for interferon signature, and it is difficult to capture with a normal, immunosomatic assays. I don't know your experience, but I was not so successful in measuring interferon of my patients. It would give a very different answers, difficult to standardize. And that's why, most of the community turned to, measuring the expression of interferon related genes as, interferon signature. But also in that case, we didn't have a standardized collections of genes that we like to use, like the community likes to use. So we do have some sets that that can vary, across groups and the research purposes. So, at the moment, there is no standardized, say, for interferon signature measurement, which I think it's a little bit of a pitfall. And that could be, in a way, overcome in my view if we decide and pick the most significant genes for maybe different ethnicities. That's also a point. And we integrate this into the, of course, and more holistic approach. I don't think we can rely on one even very fascinating, but just one, let's say biomarkers to choose, which patient which drug is suitable for which patient. So I'm not going that way because I don't want to prevent any patients from accessing drugs, which we are not able to tell if they would be successful or not. But I don't just get it out because I don't have a lab proxy for that. No. I don't do that.

CW - Right. I think you mentioned the challenges in measuring interferon in the serum. I think I share your pain having tried to measure them and finding these levels so low in in in peripheral blood or serum, and you very nicely outlined the challenges, in terms of making this widely available for use in clinic standard clinical practice when selecting drugs. So overall I think this is an exciting time, and I think what you've done very skillfully in the space of half an hour is cover the key immunological drivers of lupus, how they occur in the disease, and why they're important targets, and I think it's certainly much more exciting to be discussing this than perhaps ten years ago where we didn't know so much about the immunology of lupus. Now we actually have a better idea of who those key players are in the disease and actually have therapeutics against it. So we're in the very exciting position of having multiple different pathways and multiple different drugs. I often look down the corridor at my colleagues treating rheumatoid arthritis almost enviously with the multiple drugs that they have available, and I often find myself thinking, well, how do they choose which drug for which patient? And I think that's potentially somewhere we're going to be moving with within lupus in the coming years as more drugs become available and hopefully more widely used. So I think perhaps just to just to wrap up as a final point, I'd be keen to get your thoughts on what we need to do in the future so that we can make sure patients get the right treatment. We can't just trial and error medicines in the future, we would hope so what kind of things do you think we need to do to help decide who's got a b cell driven disease that needs b cell depletion or belimumab, and who's perhaps more interferon driven and therefore would benefit from drugs like Anifrolumab, but where do we need to move in perhaps the next 10 if you were to dream and say we're doing this podcast in 2035, what do we need to achieve to better stratify patients by that point? 

MG - Yeah. I mean, well, if I had the answer, I would be probably a noble prize for lupus. But, yeah, just as you mentioned, dream, we can stratify patients, We can already start doing that, so we should definitely improve this path. I think we are much more now thinking when we give drug because we do have a choice, a choice makes it makes it more difficult all the time. It's better, but more difficult. So we do we do this already with the instruments we have now at our disposal. So we should try to increase those to and to create a bridge between the real translational research and what then is coming into clinical practice because that's also the challenge. We already have a lot of data about, multi omics in patients with lupus, but, of course, they are not, and they're not at the moment suitable for using that in clinical practice. What we can do is join in the clinical stratification, which I think is always, is still it always gets to be important even when we go farther with molecular research, we have to keep an eye on that. We do have, clues on more chronic manifestations. We can see them. I mentioned before chronic, cutaneous lupus or subacute cutaneous lupus. We know that those manifestations would be more interferon driven so that would be, would be a point. We know that some autoantibody subset express, not only, B cell, driven signature but they also depend on the crosstalk between interferon B cells. We know that when a patient has higher level of anti-DNA, anti SM, anti, also to mention DNAs one like three, when they will start to be routinely measured, it means that B cells are active, but it also means that this patient has a lot of immune complexes capable of activating the entire front path. So we know that these patients can be probably, efficiently treated with both. And we do have already access on a B cell, phenotype, phenotyping. That is something that maybe we overlook a bit, but it doesn't take a lot to, to ask for immunophenotype to your lab. And that gives a lot of information. We in our groups, we have shown recently that an enrichment in the transitional B cell, subset circulating, that is associated with a better response, to belimumab in lupus patients, probably because of the effect that I mentioned before of bliss on transitional B cells. So we already have a lot of pieces we can put together to have a better understanding of which, immunological pathways drive clinical manifestations because maybe we're not so lucky that the clinical manifestation are so clearly, told apart just by looking at them. So we can do better right now. And, of course, my dream would be integrating the big data, the multi omics that we already have into probably, repeatable, schemes that we can translate to the clinic. So we know if the patient fits into, some kind of, higher expression of, sets standardized sets and we can we can arrange of genes that we can share, then it means some more susceptibility to targeting one or the other pathway. And we can then create a hierarchy between the drugs. Maybe I remember beating myself, but I don't like to just say, okay. You're getting this drug. You're getting the other drug. In no way, you will get the other because you don't look like you would respond to that. I would just go for, like, a rationale that drives a kind of hierarchy in the choice, not excluding then chances for refractory patients of course. 

CW - Fantastic, thank you. I think we could talk about this for many hours on end but I think that you very nicely summarized everything there and thank you very much for ending on such a positive note. We've got an exciting time ahead of us in lupus and there's still lots of questions to answer as we get these new therapies come through, so thank you very much for joining me today Professor Gatto. It has been an absolute pleasure to spend this time speaking with you and I'm sure we will have many more conversations like this in the future. 

MG - Absolutely, thank you so much and have a nice day thank you Chris