All credit to Stanjupiter on another thread associated with...

All credit to Stanjupiter on another thread associated with Stemcell
I believe it reinforces the need for Gut orientated solutions and may be of some interest to those crewing the slow boat ANR

This post contains confronting information about the reality of severe acute GvHD of the gut.I discuss and provide evidence for:Why a requirement for approval of a RCT in high risk aGvHD is disingenuousWhy the ARDS trial is an example of a RCT that was influenced by external forces and should have no bearing on GvHDThe important similarity between ARDS and GvHDThe important difference between ARDS and GvHDWhat "most severe" actually meansWhy steroids are an expensive therapy in ARDSThe bizarre real-world study in RuxolitinibWhy RUX poses risk without benefit and approval for acute GvHD should be revokedMedicine is becoming something we can't delude ourselves about any moreRUX efficacy in indications other than acute GvHD is irrelevant and a disturbing example of superficial thinking that I've seen in medical journals and written to the FDA about. It's particularly shocking when it involves such a major procedure as a BMT.Acute GvHD is a specific indication where severe diarrhea poses the greatest challenge to doctors.Rux has ZERO efficacy in survival. This has been proven by Reach2 RCT. It was even trialled against Infliximab. From reading studies, I identified this drug as the worst choice for SR aGvHD. I wrote about it here a couple of years ago. It beggars belief that 17 patients were given Infliximab as BAT in Reach2.I don't even know why it had to take a RCT to prove what's basic common sense, that a drug in tablet form would not be saving any lives when severe diarrhea comes with the highest risk of death. A common side effect of RUX is that it activates CMV, which causes diarrhea.A RCT requirement before approval in the most severe form of SR aGvHD is the most disingenuous thing I've heard. Severe acute GvHD of the gut is the easiest indication to determine cause and effect. Death rate is 80-90% for SR and spontaneous remissions do not occur. Gut healing in terms of quality and extent achieved by conventional therapy is well known. Doctors are specific about what mucosal healing is possible. Surely there's data from the trial and EAP showing consistent superior efficacy in gut healing and time to achieve it? There's high quality imaging available now and biomarkers predicting non survival.No company says the most severe cases respond best unless they know their therapy is the real deal. MSB had the confidence to include the most severe cases, including skin only ( a fail for Osiris trial), in the single-arm trial. "Most severe" doesn't mean the most refractory and difficult; it means the most severe signals of inflammation that our cells respond to. It's common sense that using multiple anti-inflammatory agents dampens inflammation and would cause the cells to not work so well. That's why the children did better when Remestemcel-L was moved up the line to just after steroid failure.ARDS TRIALThose who claim the ARDS trial proved Remestemcel-L doesn’t work or suggest it was due to 'batch inconsistency’ are imo disingenuous; they’re leaving out crucial info that the WHO, after a rushed pooled analysis with main data from an open-label trial in DEX lacking prior info about patients and follow-up, such as survival but with organ damage, issued the directive that corticosteroids be used in Covid ARDS.I referred to research here that co-administration of DEX abrogates efficacy of MSCs, use of other corticosteroids lessens efficacy. (This is perhaps the reason why the Osiris trial failed because MSCs were combined with steroids). Re. ARDS trial, it wasn’t only DEX but other corticosteroids and this was the catalyst, as the Nature article suggests, for doctors to return to what they knew, including using anti-TNF agents when our cells respond to TNFa.Mortality in ARDS: Foolish Primary Endpoint?Josh Farkas, whose blog is well known, says that mortality is a foolish primary endpoint and it’s better to go for softer endpoints, which are actually not soft. Having said that, in the emotive environment of a pandemic, I don’t see how we could have gone for any other endpoint.Unlike SR aGvHD, most patients in ARDS survive and most don’t die by 30 days because organ failure is what kills people. I provided evidence from large studies that show a consistent picture of bad survival over 25 years: 4564446647293890‘Jain et al (2006) say, “ Finally, most ARDS deaths are due to multiorgan failure. Less than 5% of patients actually die of refractory hypoxemia.48. Since the primary end point of most studies is mortality, patients may be improving from a pulmonary standpoint but may not show mortality benefit because of extrapulmonary organ failure"In one post above, I provided evidence from a large study from 2019 that acute kidney injury, a common complication of ARDS, did not happen until day 28, and data from recent large studies that found ARDS survivors don’t do well, have high use of health care, return to ICU and are at risk of death many months after discharge.Referring to a large study in ARDS survivors, published in Thorax (2017), Dr Brown’s statement is imo an accurate reflection of the state of affairs:"If you had ARDS 25 years ago, we thought we saved your life in the intensive care unit, so we'd say, 'All is well, off you go -- you'll be fine,'" said Dr. Brown. "We had no idea as doctors how wrong we were about life after ARDS".We’re told SOC improved during the pandemic. I’d like to know how that could be after 25 years of prone positioning, fluid management and a host of failed pharmacological agents described by my Horse’s Mouth experts in ARDS, Drs Calfee and Matthay.Nature seems to be some kind of oracle in the scientific world, so I have to be careful here. According to the article, SOC improved because doctors worked out how to best use steroids in Covid ARDS. They were not able to do this in 25 years? Did they definitely know from the tests that Covid caused ARDS? Even if that was the case, once you get to the stage of ARDS, how is the virus still relevant? Even if the virus is relevant, severe Covid has been compared to MAS, which is far from uncommon, and massive doses of steroids are the mainstay.Long Covid and MIS-C are spoken of in the media as if they’re new and uncommon phenomena. They’re not. After surviving ARDS, it’s not uncommon to be readmitted to ICU for pneumonia and patients remain at significant risk of death even up to a year. Before our trial was influenced, I was anticipating significant efficacy in mortality but I was thinking the difference would be most visible after many months.In conclusion, all may not be lost imo for our ARDS trial. We could still be in with a chance of significance in overall mortality. We could still see dramatic success in meeting the primary end point from the first half of the trial. And if there’s a clear difference between the first half and second half of our trial, then perhaps this could be the catalyst to end our self-delusion about our best buddies corticosteroids, which are very expensive drugs because they turn acute cases into chronic ones, at least in the condition of ARDS, and this is where the burden of cost lies.GvHD: The Important DifferenceThe most important and different thing about GvHD is that it's a complication caused by a medical procedure, and with that comes the onus on doctors to take responsibility for it. GvHD can even attack teeth, eyes, joints and genitals, which is why a gynaecologist needs to be on board. Patients are finding out such important things from one another. They’ve been putting up with symptoms of GvHD thinking the graft has 'taken' and found out from social media that this isn't true. The consensus is that patients undergo a BMT not knowing what’s involved. The FH article (link below) confirms this and it's important to know what pressure clinicians are under. I know at least one doctor has heard the following:"You did this to me. You fix it".GvHD of the gut is excruciating. The colon can be swollen with edema and it's difficult to give effective pain killers because they can interfere with the rhythm of the bowel. Diarrhea needs to be monitored.Severe inflammation of the gut is a literal torture that I've personally witnessed. Below are the words from recent public blogs of a patient and a parent whose child suffered from severe GvHD of the gut. I put the links below. From the research I’ve done, these words reflect the reality of what's going on:"Whilst so many sophisticated measures are instituted to address the suffering from pain and nausea in paediatric patients, it floors me that there is no alternative to the treatment of gut GvHD"."Torture, 24/7; the horror of which is behind closed doors and rarely witnessed by any healthcare staff, and only mildly placated by cuddles"."The torture I endured is indescribable. Over a year after my discharge, the effects of my treatment permeate every single moment of every single day".RuxolitinibRUX does a reasonable job with less severe skin GvHD and can enable patients to come off systemic steroids. The reasonable, but not complete, job it does is putting patients with skin GvHD, who have the best prognosis, at risk.The mainstay of cutaneous skin GvHD is topical steroids. With RUX doing a reasonable job with skin, I’d expect to see the combining of that with the upping of topical treatments, which would seem sensible. That’s exactly what I’m seeing ( Sarantopoulos et al., Blood, 2019) and other sources recommending high potency topical steroids and wet wraps to increase absorption. This puts patients at risk of red skin syndrome, a cytokine storm in itself, a torture in its own right, that can take years to recover from. Australian GPs are aware of RSS and were giving out literature on it while dermatologists were claiming it didn’t exist or was rare. It’s still not well known in the US. I wrote to the FDA about this back in March last year.Rux most common side effect is that it increases risk of viral and bacterial infections. Even if bacterial infections are cured by antibiotics, it puts long-term survival at risk even for patients who have the best prognosis because more diverse gut flora is strongly linked to long-term survival. This fact is well known in the GvHD community.While I've long been concerned about delay, I was confident of Ryoncil approval because my bet was on sanity. Coping with this world as it is requires a degree of self-delusion and denial if we can’t do anything about the situation. It’s not just that SR aGVHD predicts a tortured death. I also didn't think the FDA would risk doing psychological damage to clinicians who will be aware of 'distressing' Reach2 results and also ODAC vote on Ryoncil efficacy.As for the children receiving our cells for free, Khandelwhal et al report on 119 centres where allogeneic BMTs are performed. Most up-to-date info I have is that EAP encompasses 50 centres. Approval will increase access to Ryoncil, as occurred with Temcell in Japan.RUX is still being given to patients with severe SR acute GvHD, including very young children. I’ve come across recent studies in it.Giving RUX to anyone with grades 3 and 4 acute GvHD of the gut is a distressing action in the light of knowing for a fact that it is and that it doesn’t have to be.RUX: Real World StudyDoctors go a lot on real-world data and imo they’re right to do so because, as Goldacre says, pharma trial their drugs on patients who don’t represent those in clinical practice. It was obvious two years ago we were headed for a showdown with RUX, which is why I started looking into it. Early last year when the article was posted that the FDA would be going more on clinical trials, I immediately thought of the study by Zeiser et al. I’ve referred to it often here because I find it bizarre.You’d think investigators would present their best data, which is fair enough. Take a look at the photos in the link below. For the arm, the drug was given at the point the skin looks to be regenerating. The skin’s a barrier in the before photo. No way is that a severe case. The lower leg doesn’t show the extent of the GvHD and the after photo shows even less of it. The angle is completely different but the edema is still visible. Most strange of all, in the era of high quality imaging from scopes, there's only a photo of a biopsy. Authors say these cases are ‘representative’. What doctor familiar with GvHD would be impressed by this study? How did these authors even think they would?I’ve done my own pooled analysis of other studies in RUX in SR GvHD and come up with a CR well below that quoted by the study above. Add to this the recent publicity accusing Incyte of illegal marketing of this drug and speaking purely from the way things look, it would be difficult to imagine a 'competitor' that could be any worse.RUX approval for acute GvHD should be immediately revoked or it should be relegated to the position of last resort. I’m writing to the FDA, no mention of MSB. I’ll send a copy to as many transplant centres as I can. GvHD is a common complication for which there's no adequate first-line therapy and no effective approved second-line therapy.Perhaps @Southoz is right that there are no dead certs in life, particularly when it comes to the FDA. My approach is to research from all angles to the deepest level I can. The one thing I'm certain of is the brokenness of medicine in its current state. My view is harsher than that of Goldacre.I believe the science works and is safe. MSB, despite its major flaws in communications, has imo the technology to make medicine into something actually good. It's hard to make sense of what's going on because so much is surprising, frustrating, shocking and just plain weird. I'm inclined to think that in every way MSB should not look like what it is - a reinvention vehicle for all of medicine.Or else it’s exactly the way it looks and medicine is going to stay the way it is.All IMO GLTAHhttp://www.edwardisham.com/journal/2018/9/29/success-at-what-costhttps://www.stbaldricks.org/blog/post/a-survivor-speaks-dont-find-my-silver-linings-for-mehttps://ashpublications.org/blood/article/133/11/1191/260481/How-I-treat-refractory-chronic-graft-versus-hosthttps://www.nature.com/news/2009/090909/full/news.2009.894.htmlhttps://www.nature.com/articles/leu2015212