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    The Case for MSCs First Line in aGvHD
     

    Steroids in GvHD 

    Macmillan et al, Journal of the American Society for Blood and Bone Marrow Transplantation, 2002 did a retrospective analysis of the response of 443 patients  to steroids as primary therapy for acute GvHD at a single institution. 40% of patents were less than 20 years old.  At day 28 complete response was 35% and partial response was 20% There was a higher incidence of corticosteroid-failure in patients with gut GvHd. 1 year after HSCT the probability of survival was 53%.Chronic GvHD developed in 42%.

    Authors say:

    "These data suggest that steroids provide an active but inadequate therapy for acute GVHD, especially with higher grade GVHD. More effective prophylaxis and therapy for acute GVHD is needed for mismatched unrelated donor recipients and for those with severe GVHD."

    Steroids in IBD 

    I mentioned before that GI-GvHD has features of IBD and that Seattle CH is running a clinical trial comparing the two. 

    Bradley et al (2012) report on a multi-centre study on children with ulcerative colitis treated with steroids first line: 

    In the study, "89% of the corticosteroid-treated children had either inactive or mild disease by 3 months after the start of therapy.However, at 1 year, 45% of children who had required early use of corticosteroids were considered corticosteroid-dependent because they needed either continuous or repeated courses of the medication."

    Rutgeerts (2008) reports on the limitations of corticosteroid therapy in Crohn's Disease. The limitations being dependency: Franchimont et al (1998) found those who became dependent tended to be younger at diagnosis (P < 0.001); frequency of relapse; lack of efficacy to prevent endoscopic recurrence: In one study only 13% of patients showed complete healing of mucosal lesions. In another study the authors attribute this to the inability of steroids to modify submuosal inflammatory response. 

    It's not just mucosal healing but early mucosal healing that's the key to better long-term outcomes in IBD, whether this is achieved through exclusive enteral nutrition (Grover et al, 2016) or Infliximab (Colombel, 2011). 

    Do MSCs heal the gut better than steroids?I

    I'm quite confident our cells have good action on gut inflammation but I don't know the sort of healing there is at an endoscopic level. I have to speculate. My thinking is that it's likely they deliver superior healing to steroids because of signalling to ISCs.

    From another thread: Karine Kleinhaus MD:  "Effective cell therapies foster regeneration and repair of injured cells and tissues, thereby restoring health. They are designed to trigger the body to use its own systems to heal."

    I suggest this past five years this fundamental truth, that the body has its own systems to heal,  has become well documented in mainstream medicine and is informing paediatric clinical practice, where the gut is concerned anyway. 

     Ashton et al (2018) say all societies recommend exclusive enteral nutrition (EEN) first-line for Crohn's Disease. Adoption in clinical practice is more common in Europe, Australasia and Canada.  The reason is EEN is far superior to steroids in healing the mucosa. There's plenty of data on this, but the study by Borellis et al (2006) is a good place to start.

    EEN is a difficult therapy because the child has to temporarily give up eating and once stopped, relapse rates are very high.  I imported a quality product from the US. A light bulb moment was when I realised it didn't have to be liquid.   I note Dr Suskind from Seattle CH came up with the same strategy of inducing remission with EEN then kicking into the Specific Carbohydrate Diet. Seattle CH  have their own chef to cook for the children. My child's case of CD couldn't have been worse. When the entire digestive tract is affected it means a significant chance of repeated surgeries and ending up with short bowel syndrome.  It's possible to be symptom free and have endoscopic disease. This is not just symptom free. A decade later, this is microscopic healing, no scarring. It's like it was never there.  

    Why does EEN produce superior mucosal healing? Some think that it alters the microbiome or repairs the epithelium but no one really knows, myself included.  I didn't send in any kind of repair team. I removed food without removing nutrition. Then I removed food that's difficult for an injured gut to digest. My view is that after two years, the gut eventually got on top of things itself. My child's case is no fluke. Dr Haas found that most children who followed the diet strictly for at least a year could go back to a 'regular' diet and the disease never returned. 

    Regardless of whether or not one believes in a cure, the evidence is there that supporting the body to heal in a natural way gives superior and durable results, particularly with children.  It's reasonable to think imo that MSCs give a dramatic boost to this process. This view, however,  is likely too simplistic for the scientists on the forum. 

    Clinical Practice.

    If my child had aGvHD and steroids were advised, these are questions I would ask clinicians:

    Using a broad immune suppressant first line we have risk of:  fatal infection; return of cancer due to compromising graft v cancer; steroid-dependency; chronic GvHD if we don't quite get on top of things the first time.  Overall, won't this reduce my child's odds of making a full recovery?

    What if my child is a partial responder to steroids? I learned that MSCs respond to inflammatory signals. If you've dampened the inflammation with prior steroids, could that, to an extent, reduce my child's response to the MSCs?

    If Temcell wasn't doing a good job there wouldn't be the suggestion to study for prophylaxis. If steroids were doing a good job. the cost of MSCs wouldn't cause distress to doctors. And there's one aspect I never considered: the issue of timing, particularly with the gut, seems to be emerging as a key factor.  

    I hope Temcell continues to do well. I also hope we get approval for US because it looks to me like there currently isn't even an adequate first line therapy for GvHD.


 
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