Our long experience and results in GvHD inform our trial in ARDS; they're both heterogeneous conditions and cytokine storms. Conversely, our results in ARDS could inform Ryoncil's position in clinical practice. I'd be surprised if, once approved. Ryoncil didn't go into first line position, ahead of steroids.
Incidence of ARDSARDS comes about through a variety causes. Bellani et al report on a study of patients undergoing invasive or noninvasive ventilation conducted during 4 consecutive weeks in the winter of 2014 in a convenience sample of 459 ICUs from 50 countries across 5 continents. Of 29 144 patients admitted to participating ICUs, 3022 (10.4%) fulfilled ARDS criteria. Of these, 2377 patients developed ARDS in the first 48 hours and whose respiratory failure was managed with invasive mechanical ventilation.
As ARDS is a syndrome, not a disease, there's significant overlap with pneumonia and sepsis. For the above reasons, I dismiss the argument that if an effective vaccine or anti-viral becomes available, Remestemcel-L would have a limited market (assuming a successful trial). Also, there's more to surviving ARDS and coming off ventilators; patients who survive ARDS can suffer a variety of long-term effects and if Remestemcel-L proves effective in preventing or reducing these effects then it will become the gold standard therapy.
Respiratory Failure in Hematopoietic Stem Cell TransplantThe conditioning regimen likely damages the lungs as well as the gut given the connection and cross-talk between these two mucosal sites. Wieruszewski et al (2018) say the number of HSCTs is rapidly rising worldwide and "respiratory failure in the hematopoietic stem cell transplant recipient is common and is a major contributor of morbidity, mortality, and healthcare utilization"..." Etiology may be infectious or non-infectious in nature, and in some cases these may coexist". Pulmonary complications are common in patients who have chronic GvHD and they suffer frequent bouts of pneumonia.
Endothelial Dysfunction in GvHD Endothelial dysfunction is implicated in GvHD and autoimmune diseases such as SLE and IBD. I first learned about it on this forum and I can now see it in my extended family. The endothelial dysfunction was noticed and treated but the autoimmune disease pre-dated it. Even now, I despair to hear about just the heart being treated and never any consideration of the gut, which comes from not seeing the body as a system.
Mir et al (2017) report on the endothelium damage in GvHD:
"As we have previously demonstrated, the endothelium is injured early after HCT by the consecutive effects of the conditioning regimen, the proinflammatory agents used during transplantation, the translocation of endotoxins across the damaged gastrointestinal tract and the engraftment.24, 25 Furthermore, the ED has been proposed as the prime contributor to the proinflammatory, procoagulant and proapoptotic phenotype developing in HCT recipients suffering from some early complications.7, 8, 9, 26, 27 At this point, the host vascular endothelium is also the first barrier that comes into contact with the damaging inputs occurring before the debut of aGvHD".
("The translocation of endotoxins across the damaged gastrointestinal tract" is relevant to both ARDS and GvHD, as I mentioned in a previous post; the microbiome itself plays a key role in the immune system, and disruption to the intestinal barrier lets through the Trojan Horse that is dysbiosis)
D.Luft et al report on endothelial dysfunction in SR-GvHD (Blood, 2016):"These results suggest that endothelial cell vulnerability and dysfunction, rather than refractory T-cell activity, drives treatment refractoriness of GVHD and opens new avenues for prediction and control of this devastating condition".
Endothelial Dysfunction in Covid-19@Treed pointed out the term 'endothelial dysfunction' had come up again with respect to ARDS. I first learned about that on this forum. I've been listening to doctors talking about the strange way Covid-19 behaves, the vascular aspect to it: patients present swollen with edema and blue (a patient described herself as looking like a smurf); there's lack of blood to the fingertips and in severe cases it seems to rampage around the body damaging not only the lungs but other organs such as the heart.
SI mentioned with respect to the heart our cells reduce inflammation and regulate blood flow. Dr Grossman in an interview with Fox said the following (my emphasis): "We also have
evidence that we're improving the endothelial lining of the vasculature". When discussing LVAD results, SI said that our cells had a positive effect on vessels that were ' leaky' and 'friable'. JCR has seen potential for Temcell in HIE (blue baby syndrome) which indicates they view our cells as capable of structural repair.
In addition to anti-fibrotic, antibacterial, immunomodulatory, anti-inflammatory we have MSCs improving blood flow, which is specific to severe covid-19 cases. I therefore dismiss all the drugs touted for a cytokine storm. SI has said they 'don't have a chance' in ARDS and I agree because ARDS needs a variety of actions. I particularly question the use of Actemra in Covid-19 pneumonia. STAT analyzed more than 500,000 side-effect reports on rheumatoid arthritis drugs, and found clear evidence that the risks of heart attacks, strokes, and other conditions were as high or higher for Actemra patients than for patients taking some competing drugs. Actemra has been implicated in 1,100 deaths. One common side effect is causing UTIs, which is risky for patients in ICU.
GvHD, the Bird in the Hand.Ruxolitinib has been approved for SR acute GvHD and would be a competitor in the 12+ age group. The side effects of this drug have been well documented. I will focus on efficacy. As I said in a previous post, the issue imo is the real world multi-centre study by Zeiser et al which is highly cited and said to have got excellent results in SR acute and chronic GvHD including gut and skin. Acute cohort was 54 patients and complete response reported as 46%
I've been comparing the above study with other ones around the world. Below are studies in acute SR RUX listed according to first authors. The numbers refer to the number of patients of total cohort who attained a complete response or complete remission:
Assouan 5/10
Khandelwhal 1/13
Neumann 3/9
Gomez 5/23
Toama 9/36
Vicent 4/13
In total out of 104 patients 27 patients achieved complete response or remission, so therefore a combined CR of 25.9%, which is slightly lower than I said in a previous post. If these results were from a clinical trial it would be a fail. The results of the study by Gomez et al are imo particularly of note because this was a multi centre study including 7 children.
The study by Khandelwhal et al was in children and the authors explain the disparity of response to the study by Zeiser et al:
"In the adult report of ruxolitinib as salvage treatment for steroid-refractory acute GVHD [7], the authors did not use the time point of 4 weeks from starting ruxolitinib to assess responses. Instead, this above-mentioned study mandated that a response needed to last for 3 weeks, and patients were scored for their best response at any time after starting treatment with ruxolitinib, with follow-up censored at the onset of any subsequent systemic immunosuppressive therapy".
When I've mentioned these poor results to friends the answer I got is that without RUX some patients would have died. I don't deny that, but I think this is an example of superficial thinking. Steroids set the bar low (1/3 of cases getting a durable response) and so we're already aiming low and now a drug with less efficacy for gut and bad side effects has been approved. Also, in the study by Assouan et al, which best reflects the one by Zeiser et al, two patients recorded as treatment failures were alive at the longest time measured.
RUX gets best results for skin and I know patients with chronic skin GvHD do report relief. I'm not saying it's ineffective. The study by Zeiser et al, says the photos are representative. The chronic skin GvHD isn't like the extensive lichenoid and sclerodermatous cases I've seen in journals. The arm is light pink and not angry red; the skin looks to be a barrier in the before photo. The photo of the leg in acute GvHD is EXACTLY like red skin syndrome caused by addiction to topical steroids. I've seen this in person and photos on social media The soles are not affected in RSS. I'm not saying this is RSS (As far as I'm aware I don't think RSS can arise from IV or oral steroids).That's a good result; the skin is a barrier but looks to me as if edema is still there. Authors report on a severe case of gut GvHD and provide a photo of a biopsy but there are no photos of a scope. I posted a link to the paper below.
Can MSCs Prevent Chronic Illness?The TWST March 23 2020 SI is quoted:
"Patients with skin disease respond reasonably well to existing therapies, but when the attack involves the gut and the liver — otherwise known as stage C/D or grade 3/4 disease— unfortunately the mortality rates approach 90%"
.It's not enough to aim to reasonably get on top of things; Failure to get on top of the acute stage leads to long-term complications. I think skin GvHD, because it has the best prognosis is being seriously underestimated. Perhaps in the acute stage the cells' deeper healing of connective tissue, which seems likely if JCR saw potential application in EB, could prevent development of chronic skin disease.
Where the gut is concerned, steroids are not known for mucosal healing. I think of it like painting over rotten wood.
Khan et al (2019) say, "The secretome of MSC contains both pro-inflammatory (e.g., TNF-alpha, IFN-gamma, and IL-1B) and anti-inflammatory cytokines (e.g., TGF-beta 1, IL-13, and IL-18 binding protein), with the net effect likely to be the result of a balance between the two".
From the same interview above SI is quoted:
"But there is a limit to how much benefit you get from inflammation versus the excessive tissue destruction that is a by product of the inflammatory response".
So am I right in thinking acute inflammation is the cure but the key is not to let it overshoot? SI has used the word 'cured' with respect to GvHD. That must surely mean not going on to develop chronic GvHD. The cells
regulate inflammation and that's what leads to a cure? Perhaps steroids interfere with this process because of their too broad action.
GI-GvHD and IBDThe connection between GI GvHD and IBD is well known. I've been banging on about this for years, feeling like I've been talking to myself. Seattle Children's Hospital is running a trial comparing the two. Ryoncil could be used off label for Crohn's Disease and ulcerative colitis. Our cells were called in on compassionate grounds for a little girl called London who had acute GvHD grade 4 intestinal hemorrhaging her father said would need a miracle to cure. Word would have got around that London was running up down the hospital corridors a mere three weeks after receiving our cells. IBD in children and young adults can also be a terrifying fire storm and gastroenterologists will be desperate to get their hands on this therapy.
I sent my email (essay) to the FDA and got a reply that wasn't automated, so someone managed to struggle through to the end. First position should be what's best for healing the gut and our cells win hands down on this. Gut-skin, gut-lung connection is well known and chronic skin and lung GvHD are a huge problem which necessitates a change of approach in the acute stage. Covid-19 is all the more reason not to delay approval of Ryoncil.
Feel free to make any corrections as my intention is as much to learn. All IMO GLTAH
https://www.jstage.jst.go.jp/article/hct/6/3/6_16-031/_pdfhttps://jamanetwork.com/journals/jama/fullarticle/2492877https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6201323/https://www.nature.com/articles/leu2015212/
(20min delay)