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Hi, good afternoon and welcome. My name's um Steven Marks. I'm professor pediatric nephrology and transplantation in London at Greater Mystery Hospital for Children NHS Foundation Trust and University College London. And I'm also the director of R N I H R badged Clinical Research Facility. And it gives me great pleasure and to come today and to talk to you as part of the crisis Rescue Foundation, Ukraine Medical School UK Elective program and an update on lupus nephritis. And for 2023 can I just check that you can hear me, see me and you can see the slides. Okay. Yes, but the slideshow is not full screen. Mhm. We sorted out before but it sometimes thoughts around is that better now? Hasn't changed yet? Has that changed? No. Okay. It does my screen so I will stop and I will. How about that? Yeah, that's great. So just one slight night. Yeah, excellent. And so we have a patient who joins us today and I put this slide up to show um I'm in charge of our patient public involvement, engagement and participation. And I really think for patient's living with lupus every day as a test for survival. So I got this um slide from the internet very often. You can see from a patient perspective, getting the diagnosis and then finding out that you've got lupus as a life long life threatening condition can be very, very troublesome, especially for many of the patient's that I look after were on their adolescent years. So I'll talk a little bit about the difference between Children and adults. A little bit about the background and epidemiology. A bit about kidney involvement, what we call lupus nephritis and management of the condition and then try and bring it all together. So I thought I'd start with the case history. This was about 13 year old Nigerian girl. She was on holiday in America and she'd had a three month history of occipital headaches. She was seen by medical staff without vomiting or migrainous symptoms. And the feeling was that she had premenstrual syndrome. She then developed a two month history of arthralgias, myalgias with weakness of her shoulders and thighs. She developed scabs on her forehead but no evidence of active arthritis and is treated with oral amoxicillin by her local general practitioner. She then had a two week history of swelling of her islands and lips, uh developed some viral symptoms, feeling a bit flu like and then deteriorated and went to a local emergency department where she admitted that she'd been offered food with anorexia, had intimate and fevers and have been feeling shortness of breath from exertion. There was no other past medical their family history note when she was seen in her local hospital, she was unwell. She had a temperature at 38 C and she had an estimated weight loss of about 8 kg. Over the last few months, cardiovascular examination revealed an injection, systolic murmur, the lower sternal edge, but she had normal BP and she had a rash on her fingers and toes with some splintered hemorrhages and more than 30 scamps on her forehead. The feeling like that they'd come out because of the better weather and a bit of photosensitivity. However, she had a very tender abdomen, evidence of puritanism. An investigation has shown that she was in kidney failure with an elevated plasma plan in a 300 micromoles per liter with four plus of protein, urine four plus of hematuria. And she was reviewed by a consultant dermatologist, an accident emergency and transferred to create or ministry of hospital with intravenous antibiotics includes by the time she came to Great Ormond Street, she had not passed any urine for 24 hours. Numbers in hyper vilamit shaw, she had a prolonged capillary refill time of three seconds with dry mucous membranes. She was hypertensive with a systolic BP of 100 millimeters of mercury. She had evidence of these splintered hemorrhages which I'll show you affecting the nail bed of her fingers and toes. And these vasculitic lesion's affected her finger and toe pops and she had an acute abdomen with diminished ball sounds. So here you can see the vascular sick lesion's in the top parts and you can see here in the nails and you can see evidence here of brown discoloration, the nails. And actually, historically, we biopsy distancing some evidence of hemosiderosis deposition which you get after acute inflammation. Her initial blood test showed that she had a normal hemoglobin of 149. She wasn't anemic but she had elevated neutrophils and white cell count with the neutrophilic leukocytosis of 13.2 of a total of 17.3 in evidence of thrombocytopenia locally, that's a 94 times 10 to the para nine people eater. She had evidence of inflammation with an increased erythrocyte sedimentation rate of 70 mills millimeters per hour and she had slightly abnormal floating which corrective by chemistry showed that she was in kidney failure with an elevated plasma Kratt in the 334 a urea of 39.8. She was acidotic with the bicarbonate 17 hyponatremia with the low sodium at 123 millimoles per liter and an elevated potassium level hyperkalemic at 6.1 million moles per liter. She had significant hypoglycemia down to 21 g. Benito with a calcium of 1.7 tuna correct and calcium of 2.2. An evidence of an elevated prostate should an elevated creatinine kinase and analyze as you can see here, initial uh immunology had shown again depending on your laboratories. But a low complement C three and C four here with the auto antibodies pending. She was in hyperglycemic shock delivery full time, then became more prolonged for seconds and she had evidence of trying mucous membranes and became increasingly unwell with her acute abdomen became hypertensive with systolic BP of 90 millimeters of mercury and increase splinting of the abdomen. So she was ventilated electively and required kidney replacement therapy in intensive care with continue of intravenous chemo filtration with intravenous antibiotics and antibiotics. And they're wondering whether she had a vasculitis or lupus complicated by acute pancreatitis as part of the mesentery vasculitis. Initial investigations came back showing she had an elevated double stranded DNA 131. But there was evidence of infection with a staphylococcus aureus and her blood cultures from the local hospital. And although there was no perforation in their chest X ray, there was a diffuse whiteness, potentially do two societies with fluid in there. ABD um which was seen an abdominal X ray and the ultrasound which on a society's with bright and bulky head of the pancreas and a bright large kidneys with poor causticum gallery differentiation. Although she had a structurally normal hearts, it and the hyper dynamic circulation of no vegetations and concentric left ventricular hypertrophy. She was fully restricted lateral required TPN was given opiate analgesia treated with intravenous fluids and antibiotics and pulse with intravenous methylprednisolone. So 600 mg per meter squared. So 1 g intravenous pulse of methylprednisolone once a daily for three consecutive days in those days and gave more cycle post might which we would still give for some patient's who had multi organ failure in intensive care. Been feeling that intravenous cyclophosphamide would work quickly with 500 mg meter squared with mesna cover and limited hyper hydration. And due to multi organ involvement and significant involvement, she had two volume daily plasma exchange which were planned for 10 days. Usually we give five days and then do a further assessment. She was extubated and returned to the ward and about a week later and she developed some lip smacking. The subsequent day was spreading into mother with slightly reduced Glasgow coma scale of 13. But in fact, her mother said this was her normal behavior typical of a teenager. Um However, she did a neurological signs which is newly developed with brisk up her in absent Norland reflexes with no evidence of papilledema, meningism and she was fluid overloaded, but she did start to pass some urine. So, the differential diagnosis that we've discussed is obviously systemic lupus, erythematosus and lupus nephritis. Could this be the development of brain involvement with cerebral lupus or spinal involvement with the transverse myelitis? But sometimes in Children, you do see an overlap syndrome with juvenile dermatomyositis. Uh There was biochemical and clinical evidence of a myopathy which in association with pancreatitis is well recognized in juvenile dramatic sinusitis. But it also can happen in systemic lupus erythematosus but less classical features, we got her results back confirming her hypocomplementemia. Her low complement levels with see 3.51 C four of 0.9 without a C three nephritic factor. Her E N A was negative with this positive speckled anti nuclear antibody one in 1280 she had a positive double stranded D N A positive late 32.9 with normal anti cardio life and antibodies and negative anxious. She had electoral effusion and an abnormal E G which we'll talk about in a minute and she had a cranial MRI with lumber puncture. At the same time, we did a percutaneous renal biopsy under general anesthetic to get a sample of her kidney. Her CSF from her lumber puncture showed a negative two viruses and slightly elevated CSI protein, but there were no cells and a glucose of 4.2 with the plasma of 6.8. Here you can see the chest X ray with the evidence of a left pleural effusion. And here you can see this abnormal brain waves on her electroencephalogram which shows a low amplitude background activity with excess regular theta and slow components indicating quite a marked and careful pathic picture which was unlikely to be secretary to just renal failure. And here you can see the dip use white matter changes that were prominent on the MRI of the brain. We undertook a kidney biopsy and I'll talk about the classification. This patient had an international society and fold your renal pathology society. Class tune MS angio proliferative glomerulonephritis. 52 Amaryl I was seen and there was an increase in the MS angio hypercellularity matrix with highland drop the change in the tubules but otherwise normal institution and blood vessels. And she had what we call a full house stadium with um you know, his chemistry showing Mizan Juul deposition of the full house of immunoglobulins, T one Q and competency three. She had evidence of not only was Andrea hypercellularity but also dense deposits on electron microscopy. So here you can see the kidney biopsy. This is a pas then that I'm magnified by 200 times. And here you can see that this girl Maria, this this filtering unit of the kidney is stuck them of cells. I can sure that's immunohistochemical tree is standing with lots of immunoglobulins and you can see that they're all positive and this is standing times 400. And this is the really thinly cut electron microscopy where you can see these bends deposits. Um as that we see in your wrist arthritis, she was further pulsed with intravenous methylprednisolone, converted on two oral prednisoLONE. Um due to being unwell and spiking fevers. The staph aureus infection bled for refuge in. She was continued on broad spectrum antibiotics, antivirals and antifungals with few cloxacillin, amikacin tazobactam acyclovir, fluconazole, azithromycin, and then a further cyclophosphamide was planned in a couple of weeks. So in summary, she has sle she's got skin involvement and myositis. She's got mesenteric vasculitis, cerebral lupus, a class to lupus and writers and acute kidney injury, secondary type of Lubick shock, impossible, nephrotoxicity state. So can we have thumbs up, then can we have thumbs down or you can um mute or put in the chat if you think how she did a few years later? So if you followed her out for five years, how many of you think she's got a good outcome, you can see that she's very, very unwell, very sick. And how many think that she's got a bad outcome? So we've got good outcome. I can see here anything else? Can you put your hands up? Yeah. So I've got a bad outcome. I can see you got 50 50. Yeah, another bad outcome. That's another good outcome. It's probably about 50 50 on you. So we followed her up for five years and she did really well actually. And the reason being is because there was only mild inflammation in the kidney, which I'll talk about the class to lupus, no privatise and most of the other symptoms and signs can actually resolve with good immunosuppressive treatment. She developed insulin dependent diabetes after presentation which resolved she had a relapse a couple of years later and she was treated with riTUXimab. Uh I'd say that nowadays, she probably had the intravenous riTUXimab i that first um presentation and she wouldn't have had the cumulative doors of cyclophosphamide 4 g for me to square. And actually following her up 18 years and now transferred her on two adults. She's got normal BP, protein urea was two plus, but with minimal albumin urea with the urine albumin to creatine ratio in the early morning urine of 11.2 mg for minimal a normal kidney function of the plasma crown in a 48 micro, most of five years. So very kidney disease at the time of diagnosis of Lupus is present and up to about two thirds of patient's. And indeed, in Children, in our UK GSLV national study that showed up to about 80%. And that's because many Children can present with inter current infections, a bit of diarrhea and vomiting and then that's how they get seen more common and more severe. Um Lupus happens non European ethnicity. So here you can see an increase in African American and Caribbean populations with the percentage affected and the incidence of end stage renal disease per million population. There is limited data on childhood sesame lupus erythematosus, but we've got a national register, we're getting more data and it's up to about one in 50,000 Children at risk for Europe. And the prevalence in Children, adults from various epidemiological studies is anywhere up to about one in 2000. So, Lupus has a variable clinical manifestation, but a very unpredictable natural history and a progressive clinical course, which can be associated with significant morbidity and mortality, especially if not treated actively up to about one in six of patient's present in childhood with more severe organ involvement. And then compared to adult counterparts, the renal disease is a major determinant of the long term outcome of Lucas and that influences our management with them in suppressive agents. But both the blood and the kidney involvement are more severe in Children. Compared to adults. There is a different spectrum between Children and adults. We see a lot more brain involvement with cerebral lupus adults see a lot more harder common involvement probably due to more after all and sclerosis, arterial sclerosis, inherent population. But there is a multi system involvement that we can see with joint involvement or thrive to salt, a new hepatitis. And we share some of our patient's jointly with the Hepatology team. But also we share many patient's with the rheumatology team that got joint involvement, macrophage activation syndrome. However, I think we need to consider Children and where they are as young adults and growing up there, skeleton their education, they're evolving identity, their quality of life, but thinking about adolescence and about their overall appearance to treatment. So, lupus probably is that one condition which is more similar between adults and Children because it's the same autoimmune process. We have very similar classification criteria and we're looking at disease markers such as er throw site sedimentation rate. The compliment see, three lymphocyte counts, double stranded DNA with the same drugs in the Armamentarium. We're doing a lot more clinical trials. Indeed, I could come back and have a chat at another time. So let's talk a little bit about the kidney involvement. But how can it present? Well, as you know, the kidneys are like sit and the cipel's can get bigger and protein molecules can lead into the urinary space. And that's called protein urea, if it leads to an extent where the total amount in the blood of the protein levels reduces. And that can change the oncotic pressure by virtue of the body to becoming an epidemic is to try and um manage the hypoglycemia. As a result of that, you can get a nephrotic syndrome, sometimes associated with the microscopic dipstick positive hematuria, very rarely microscopic. So blood that you can see in the urine or Coca Cola cola colored urine, we also see other kidney involvement with high BP, evidence of kidney dysfunction. But what we know is that the histopathology of lupus nephritis alone cannot be accurately predicted from clinical and syria logical measures. And that's why we do kidney biopsies. And I question actually whether sometimes we should do full art biopsy because if patient's have significant amount of protein urea, we don't know if that's a result of active inflammation in the past causing chronic damage or what it means today. So the original World Health Organization Classification in the seventy's, most of these happened at international meetings. Initially, Buffalo, New York and Geneva moved in the eighties to the World Health modified classification where the further sub divided the classes and then had a minor adaptation, class five and 95. And although we use the revised 2013 M I S and RPS working group classification of the prisoner practice, it's really primarily based on the 2003 that I've shown you here. So how do we consider this classification? Well, sometimes you can imagine we want to six, it's a steep incline and it's an increase and it's actually a little bit different because the terminology, for example, the class one has changed. So now with minimum as energy or lupus nephritis, by the time we do a biopsy in Children, it's very rare to see minimal changes. So, very often we've got at least a class two is not a class three or four, which has an escalation in severity which last five is different. It's just a diffuse membranous lupus nephritis that you can see from the picture of Europe. And a class six is where you usually have small shrunken kidneys that we wouldn't really undertake a biopsy in Children because the risk of bleeding and actuals advanced sclerotic lupus arthritis class, choose where you have increased is angio matrix. You've got MS angio proliferation which happens. And class three is where if you look at all of the glimmering light of filtering units, the kidneys, if up to about half of them are involved. And that's a local lupus nephritis. And if there's active and proliferative changes in the histopathology, then that would be a class three A lupus nephritis. Whereas if there was evidence of damage with chronic fibrotic sclerotic regions, and that would be denoted as a class we see. And of course, some patient's may have had some activity which has become burnt out and there's a little bit of grumbling activity and they maybe have features of both class for new business practices where we have more than 50% of the Glomar eli the filtering units involved. And within that, it can be in a segmental distribution where if you look at each individual glomerulus, how much of the individual glamorous is involved. And if it's less than 50% of an individual glimmer realist, and that would be a diffuse segmental. The business arthritis has been involved more than 50% roughly of the number of each of the glamour alive and that would be a global business privatise. And again, it can all be denoted with A R C. So active chronic by bra Tick Lesion's or an active proliferate revolution you've been seeking and this is my simplistic way of trying to work out the classification. So if you got evidence of endobiliary have similarity involves less than 50% of the glimmering lights class three, more than 50% of class four, which is either divided in six segmental or global. If there's no antic ability, hypercellularity, you've only got essential deposits only. It's plus one. If you got the true MS Angela hypercellularity, it's a class two. And if there's evidence all deposits, then you think about a class three suburb redo of deposits. So what are we trying to achieve with our treatments? We were trying to aim to induce a maintain a remission by using agents which are the least toxic but the most effective. So the patient's have reduced in affairs which we know are associated with horse prognosis. I make no apologies for this slide, which is over 13 years ago from Shirt Cameron showing that really from the sixties to the eighties, we had a great improvement with the advent of cortical steroids and is a pipe run. So by 19, early 19 nineties, we had about an 80% survival rate even up to about 10 to 15 years after the initial transplant. So let's talk a little bit about what conventional therapies that we can think of. We would aim pursue roid sparing agents, but there's a vibrant and intravenous cyclophosphamide has really gone out of labor due to issues with toxicity and fertility issues. Although the same can be said of other immunosuppressive agents, which may not have been mistrials as much, but invariably for a chastity or 40% of Francis, we've been considering giving microphone and more fertile together with intervention to map and they get cold and then following up and seeing what happens if the blood's, I think we need to think about different management strategy should be considered in different patient's. So this is one of the seminal works but Chinatown was published in the New England journal. There's a personal inferiority and studying really looking at the advent of uh the treatment with MMF compared to in this case, all cyclophosphamide showing no changes in the continent c three level of the crap man. But what you can see here is that all there are similar uh side effect profiles. There was two versus zero deaths in the cyclophosphamide group in seven versus forth and in all the infections in the cyclophosphamide period. And then we need to consider if the patient responds without flares, whether you were able to achieve remission. So if you can get remission pretty quickly, your renal survival and patient survival can be up to about 95%. But if you don't achieve remission, then the patient survival and can be as low as about third or 31% in 10 years. And the patient survival overall of than 60% of 10 years, we know that the risk of the highest order in developing in stage kidney disease is those of the ice in RVS class four and, and a few periphery of lupus nephritis, which you can see was published. Terrible. And what we also know about some of the arms data's that patient's are unable to normalize the condoms or they have ongoing low Singapore um or lupus and projects for a year or less than the fallen um proteinuria is not high, then we would worry about these patient's. If you've got questions with an abnormal complement level, they may not normalize that compliment because of an inherent complement efficiency. But if we do, it's very reassuring, we then did the arms study, which is the first study to involve Children. So it was 12, 2 75 year olds and open label study over six months just of casting to five. And it was surprised to giving cyclophosphamide every month and all 500 mg per gram and tapering down the steroids starting from 60 mg. And I think probably nowadays would give the maximum 30 mg and then you go to the primary endpoints with decreasing urine protein to creatinine ratio is stable uh or including plasma pattern. This is a scheme of the study. 460 patient's of which 370 were randomized, 185 into each group. And you can see here, they, they were analyzed for primary endpoint and randomized intentions to treat. And that was up to about 370 patient's. This is the data showing no differences between an M F and intervening cyclophosphamide. But actually, that was not 100% true that if you get to the Black and Hispanic races responded more favorably to mmf than any other races. And it worked equally well. And I SN RPS class five, a member of the strippers. And probably, although there were more deaths and dive year and then I met it was statistically significant, less nausea, vomiting and rather bishop. Uh And then this went on to perform the arms maintenance study where we took those patient's with the Finnish induction phase. We then randomized them again in the same patient's to receive either mycophenolate mofetil A is a pipe run. And this really came about because it was increasing evidence from and the adult and then the pediatric gastritis world that patient's didn't do as well. And what you can see here, Mrs then Mike Venom off to had a huge improvement of being free of treatment. And you can see here specifically different and value can hear see there in the probability from that 0.6 up to 5.9. And the same is true for the probability of being free of, of, you know, to learn. I thought I would have to try and see if I could work hard to see if there was evidence. And this is looking at the risk of treatment failure in the subgroups of patient's. And you can see that almost all the bars cross hazard ratio line of one, apart from the overall all patient's, we're looking at the total number of events you can see was statistically significantly improved in the MMF GROUP. So I went on to do the maintain represent, applied to the study. 105 patient's treated with six foreign I'll intravenous cyclophosphamide and steroids. And after that, they were randomized to either MMF aures if I print and this showed that in fact, the renal flare was much higher with fibrin, but it's not much statistically significant. The definitely will has been reported around the country. If you look at the overall met analysis comparing cyclophosphamide to Mike Finley motto, you can see here that the diamond very often crosses the one line. So let's think about difficult lupus and how to treat it well. If you go increased severity of disease, which doesn't respond to your usual treatment or non adherent patients' that don't take your treatment or a patient's don't come to clinic to know about taking the treatment and trying to work through all of these is really important. But very often the treatment may actually be very minimal at the start may get joint injection but very often the addition of cortical steroids. Historically, cyclophosphamide on is a pipe in together with hydroxychloroquine. Nowadays, we reduce more plasma exchange of mycophenolate and definitely adamant tux amount if you declares three or four lupus nephritis, we had a little discussion about the drug treatment and lupus and steroids. Very often formed the basis of all regimens but important to try and minimize and reduce the MMF can be used for induction and remission. An IV cyclophosphamide for prolonged periods is the previous gold standard. But my commanding officer was taken that place and is a pipe runs an effective drug for intravenous cyclo force for treatment. However, is a diaper and it's an effective drug for the maintenance treatment of lupus nephritis and have had a few patient's who've done very well. Having filled honest all treatment including MMF riTUXimab cyclophosphamide that you put on to lower medications such as a, as a byproduct, it's less potent, but there is some pharmacogenomics and responses which can be individualized that we definitely do see. So standard treatment and three pulses of intravenous methylprednisolone. We use 600 mg, a meter squared once daily for three days. And rheumatologists very often use 30 mg per kilogram. We think about the induction and maintenance of lupus and involving the treatment with Michael Fennelly. More fertile not to 1.2 g, you to spirit per day. And as I said, multi organ involvement, you would consider monthly cyclophosphamide pulses but maybe reducing even 23 months. So let's talk a little bit about evidence based practice. What do we know about therapies? How do we treat patient's? So this is some of the Armamentarium that you can find out there. Um Nice bedtime reading the Kid Ico guidelines, the new lower in the R E D T A C R guidelines. And we've got the updated Kadijk oh Clinical Practice guidelines for lupus nephritis. And just looking, if you remind yourself of the strength of recommendation with level one higher than level to where you're recommending most people in the situation would want to treat. And the supporting evidence is a being high evidence and being very low. And if you can see in our chapter that we recommend initial therapy with corticosteroids combined with either cyclophosphamide around man. And you can see here that you recommend that after initial therapy is complete, patient's with class three and 40% of fighters receive maintenance therapy with his apartment. Mmf is divided those and then low dose oral cortical. She goes less than 10 mg. We then went on to publish, I was the only pediatric nephrologist in this adult group over singular E R E T T A guidelines in the management of Children. And I've spoken to colleagues about the overall management of pediatric lupus nephritis. And compared to adult onset disease, we know that lupus nephritis and Children is more severe with increased damage, a cruel and more common presentation. But the diagnosis management monitoring is very similar to that of adults. And we need to think about adolescents than moving over to the adult programming, just writing a manuscript on that, thinking about how to have the best co ordinated transition program. So compared to adult onset disease, lupus, so privatise and Children is more severe increased damage. A cruel and more common presentation with the diagnosis management to monitoring is fairly similar to that of adults. A coordinator transition program to adult specialists is important assessing concordance two treatments and optimizing long term outcomes. But if you look at all of the evidence base, you can see here the majority was either graded or not graded at all. So graded two D was about half and you can see here 13% were not graded. So actually, if you look at those which were graded one ab you're talking about 16% and a total of about a third being classified from one a down to two seen. We then did an update in 2019 of the recommendations and we looked and find that the 2012 recommendations remained fairly unchanged. Then you can look at the Cochrane collaboration and some data which has also been published where again, very often you start training with cortical steroids. As I said, you can use 30 mg per kilogram per day or cyclophosphamide. Er mmf generally, if you go through the maintenance which you would use, mmf potentially somebody would use azaTHIOprine depending on ethnicity. And pharmacogenomics and kinetics consider swapping conduction therapy or adding in the tux amount if not given. And again, for many patient's even with the class to your class, border business colitis, we'll be thinking about mycophenolate, mofetil and tacrolimus to try and get them off the cortical steroids fairly early to reduce the side effects. And then we could consider um other costs in your inhibitors such as cyclists, foreign attack. The line is especially if you've got membranous nephropathy or if you've got no response to other treatment. So what other treatments will I sometimes call it sex drugs and rock and roll. Talk to adolescents talking about contraception, about future pregnancies but treating with hydroxychloroquine, making sure your aggressively treat hypertension proteinuria and hyperlipidemia. Thinking about aspirin, advance possible Lipitor anticardiolipin antibody positive and anti coagulate if they are positive, especially for nephrotic and considering non live vaccines and treating vitamin D deficiency intravenous immunoglobulin. I've definitely seen have a response for hematological involvement especially for thrombocytopenia. But you need to get approval locally plasma exchange. Again, I use for those with the rapidly progressive present YCL Ameren arthritis together with, for example, patient's with the palmer vasculitis and um pommery bleeding with evidence of um oxus and infliximab has been reported in a few cases, we've not had much positive outcome and stem cell transplantation has a significant morbidity and mortality. There was something to be considered here. You can see the difference in member nous lupus know privatised treatment with cyclophosphamide compared to intravenous cyclophosphamide. So actually showing here the probability of being in remission is much better. The cyclosporin, as you can see here compared to cyclophosphamide. So, if you've got a class five Lupus nope, riotous and you've got featured a class three or four, we would treat as a class three or four. Lupus nephritis usually with microphone, um a photo and riTUXimab with naive. But if there's no features, a class three or four, the adult literature would say that if you've got mild protein urea underground per day, then you would treat jia's conservatively with ace inhibitor or angiotensin receptor blocker or manage hypertension. If you've obviously got significant protein urea, then it would be potentially differently wanting to re get a different agent. So I'm just going to consider B cell depletion of been two large studies. The explorer in Lunar, which didn't actually show much improvement with the addition of riTUXimab, which we can talk about. But I think there were some issues with the study. We know that anti nuclear antibodies and antidouble stranded DNA are both important diagnostically and prognostically in can be related to the severity arenal damage. And we know that adults and Children with active lupus have profound B cell abnormalities. And this is the monoclonal antibody riTUXimab. It binds to the CD 20 antigen located on the pre be in mature B lymphocytes undergoes license of the B cells and used for patient's with autoimmune disease, EBV driven lymphoproliferative disorder. And we now use it for the prophylaxis and treatment problem form a of post transplant and then forklift of disorder. And we generally give Rituxan number 375 another grams, three to square. This is a slow infusion when we were considering of the regime. And to start, we thought that instead of giving four weekly dose is actually giving two doses apart, night apart, giving the same total dose might be beneficial. And the reasons for treatment that we employed usually for multiple systemic presentation, blue prison of life or organ threatening disease, or those with the active treatment, active disease after previous treatment, for example, with intravenous cyclophosphamide. So we published the person in the world of using this regimen. Here, you can see seven patient's. You can see the reduction and you can see here on the immuno suppression being able to be weaned, there was no reported effects, but we did show an improvement in the disease activity by using the Bushell who was assessment group showing scores decreasing from trans two at baseline. And this was followed shortly our publication by the French Canadian group who looked at 11 patient's that were treated with 2 to 12 infusions of cyclophosphamide. And you can see here that B cell divisions achieved in all but one but there were adverse effects with blood infection. Um So lymphopenia and entrepreneur reduced white cell counts, thrombocytopenia on evidence of a rash and empathetic. They did see more human theological abnormalities in the French Canadian group, but they were checking the results more regularly because of the potential risks. So if you look at the safety and efficacy, we look at the 1st 21 treatments in 19 Children with refractor lupus, uh median age of 17 who had had lupus between six and 16.7 years had lupus for one month to over nine years and a follow up from six months to over three years. Four out of five of these patient's had biopsy proven lupus nephritis and had been treated with lots of other immunosuppressants during the time. But this was the first time that we were going to really pave way for riTUXimab want to be used. And what we showed is a reduction and the disease activity with the Lupus assessment group and the reduction also in the albuminuria that you can see here with your own argument, crown ratio and improvement and both the G fro the kidney function as well as a serum albumin or album levels. If you look at the immunological parameters, a reduction in the N A and increased the complement C three C four and reduction in the double stranded D N A as there was an ESR and an increase in the hemoglobin platelets and lymphocytes subsets. Here we show that most patient's B cell deplete by six months, but most of it effect then goes that you can see subsequently and patient's had clinically significant improvements in their symptoms and signs. But for some of these patient's, that really caught me that I've seen them for years and they've never felt so good. They've had lupus for 11 years, so much energy rash is gone and they were all feeling great, but just a caveat, remember that by one in four will develop herpes zoster. So make sure you're recording everything, make sure you know, if they've had chicken pox in the past and you tend to see a cytokine release syndrome and lymphoma, which we don't see in lupus because basically you got a big clump of cells which is slowly breaking down in the event of confusion related adverse events, then you can stop and restart, which is important to recommend some very often and reduced doors. Who you can see about one and a quarter patient's, as I said to public, the herpes austin. So he showed that we sell, depletion was safe and effective in 21 episodes of 19 Children and went on to do a cohort study with Liverpool where we looked at 63 patient's all of whom had the improved biochemical hematological and ecological parameters that we talked about. I really do worry about the selfie generation. You can see here patient's making themselves in the mirror. And to be honest, the cortical steroid side effects really empowers patient's not to take their medications, which of course is the wrong news for them. I just wanted to share a couple of patient's who've moved over to adults. This young lady was very complicated, registration her up, she had pawned me hypertension together with sickle cell anemia. She does sick whole and sell diagnosed very young age and her lupus was diagnosed before she hit 10. She had lots of joint problems with receiving multiple intraarticular joint injections previously treated with cyclophosphamide and riTUXimab we instituted every six months giving adores irrespective of uh the longer term issues and treated with the alternate day, prayed and methotrexate. This girl was managed in another adult centers on plasma exchange for thrombotic thrombocytopenia purpura. But she required to come over for methylprednisolone and plasma freezes. She's, you know, induced insulin dependent diabetes and actually very significant cutaneous folliculitis. And this means let's go on to try the tax salute study where as an open label study, you can see here in all the senators and what we're trying to do is to get rid of all the steroids that you possibly can. There are um your biological agents in the horizon. Pertuzumab with C D 20 to a Tazicef cocculusm average produce a lot in COVID times a batter set which um induces the B cell tolerance. And you can see here and modulating the C D 18 G D 86. There's a long list of different agents in the pipeline. Very happy to come back and have another chat. L J P 394 was uh anti uh anti D N A that was trial but didn't make it to conclusion to manufacture. And there are lots of complement inhibitors that we're looking at and I did talk about stem cell transplantation and he's spoken to our unit. And really there's been 34 patient's published strength, the registered and basil three died one worse. And the current opinion is that there are other available options. So we really feel that transplantation is less appealing. So to conclude, lupus is a multi system disease, very subspecialty involvements and unpredictable course disease activity and damage is important. And we talk some members are rolling, treating active disease, but we need to collaborate with adult colleagues for long term outcomes in transition. Mmf has taken the role of cyclophosphamide and there's a diaper and in my views, both first line induction animation and therapy. But although reduction matters effective, it's really not been proven in because we really do talk about the bile ag and different people assessing it whether that's the best way to look at trial outcomes and it can be quite difficult to tease out because if I do a bilateral score and someone else does it a few hours later, we might get a different result. Belimumab is now registered with the use of lipids and we've tried using it in lips, replied suspicions and there's many other drugs in the pipeline. So I thought I'd lead you with the quotation and we have a patient on the zoom. But without Lupus, this was one of the first patient journeys published in the British Medical journal and I have no qualms in reporting it. But very interesting patient perspective. Without Lupus, I would not have learned so much about myself and about life in general with support from family, friends and clinicians, dancing with the roof is not all doing bloom. Here's some of the slides I'm showing our publications that we've got, which we've talked about. This is the sheer initiative which you can also see here. I'm very happy to take any thoughts. Thank you very much. Indeed. For your time and your attention. If you want, please put your hand up or ask any questions in the chat. I've got the question here that I can see about. Yes, are being raised yet. So typically in lupus, you'll have an elevated growth of sight sedimentation rate. The c reactive protein is usually normal unless you grow an infection. And so if you've got an infection, which was positive for COVID as selectivity, you may then get an elevator, the S R N C R A P. There's also a question about what is the right heart risk of pulmonary hypertension, second regions, official lung disease in those treated for lupus or other multi system pathologies. It's a very interesting question and actually, we've just had a publication looking at pulmonary hypertension is very much under reported and sometimes difficult to estimate exactly how many patient's there potentially be that could have um could have pulmonary involvement. And so I think it's a really interesting way to try and work out. We had a look at our patient who are and trying to work out what would be the best management and to try and think of and for these patient's. Um and, and it really, it really does vary that you can see here. Um And, and that it was very often the case reports. And I think one of the cases that I showed you just now and that you saw, you could actually see there was evidence um where the patient's have a secondary disease which causes the ongoing issue. Please remember to complete the feedback form that you can find. And so if you just click on the link and that you can get that, um and also we'll be able to then send you and your um certificate, your CPD, which will be able to log on. But if you just click on the link for the Google Google Docks, that will take you to the feedback form. And if you just hand it into the crisis Rescue Foundation and that would be great. Really want to thank you all for joining as well. And now it's still a difficult time. I've got some colleagues to from Ukraine. Some, some people have gone to America, but also knowing that it's a difficult time still back in Ukraine. And that's what the situation. And soon I know that some of you seeing are spread around the world and hope that you're all doing relatively well. So if you go into the chat just now, then you should be able to download the form.