The aryl hydrocarbon receptor (AhR), which is key to this discovery, appears to be super relevant to psoriasis, another autoimmune disease.
AhR has been known for a long time, but it seems it's been somewhat mysterious until a series of recent breakthroughs. In 2022, an AhR inhibitor called tapinarof, sold as VTAMA, was launched, and has shown itself to be one of the most effective treatments for psoriasis to date. It's also unique in that it appears to have the ability to bring lasting remission. In the main clinical trial, patients who used VTAMA for one year and then stopped had a mean remission duration of 4 months until their psoriasis returned. That is unheard of for any topical medication used on psoriasis.
Blocking AhR has also shown promise in treating MS [1].
I haven't read the lupus paper, but often with papers like these, the "cause" turns out not to be the actual origin, but some cytokine or other protein that is more disease-specific than current drug targets. This lupus discovery appears to identify an imbalance that may be compensated for, but we still don't know what triggers the imbalance in the first place.
In some cases diseases turn out to be a genetic fault, but my money is on pathogens acting as the initial triggering event, which then spins the immune system into a vicious cycle of autoimmunity. In psoriasis we see this with strep bacteria, for example, but the exact mechanisms are not well understood. However, the mechanism that makes psoriasis chronic has been identified, a type of T-cell called a tissue-resident memory (TRM) T-cell. This type of cell acts as a kind of biological memory for infections.
Good post. One small correction: Tapinarof isn't an AhR inhibitor, it's an AhR activator, an agonist.
Interestingly, tapinarof is a natural product -- a sort of bacterially-modified stilbene, a chemical cousin of resveratrol and pterostilbene -- and several other natural products also activate AhR. (Though perhaps not exactly in the same way.) The most potent and readily available of these is probably 3,3'-diindolylmethane.
Ah, thanks. I assumed tapinarof was an inhibitor, as the papers on its mechanism describe it as downregulating cytokines. It appears the exact mechanism isn't quite clear. Bissonette et al 2021 [1]:
Tapinarof was found to bind directly to AhR, resulting in
downregulation of inflammatory cytokines, regulation of
skin barrier protein expression, and antioxidant activity
... In a T-cell polarization assay, tapinarof markedly
inhibited T-cell expansion and Th17-cell differentiation
and reduced the production of IL-17, while also reducing
IL-17A and IL17F levels in a CD4 T-cell assay.
It looks like tapinarof modulates the signaling behaviour of AhR, but so far the precise mechanisms are educated guesses.
The story of tapinarof's discovery is fascinating. It's produced by a bioluminescent (!) bacillus P. luminescens that (quoting from the paper) "lives symbiotically within parasitic, soil-living entomopathogenic nematodes." It was observed in the 1950s that "the nematode did not putrefy once dead, in contrast to the rapid decay seen in the absence of the nematode," leading to the idea that the bacillus' metabolites had antimicrobial activity — which turned out to include what is now synthesized as tapinarof.
Coal tar is another semi-natural substance that is thought to act on AhR.
And, yeah, good point re coal tar. AhR was once thought to be a toxin or junk receptor that activated liver enzymes for clearance of environmental waste and other chemical byproducts. The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) were, at one time, thought to be very similar. That might still be the case with respect to PXR and CAR, but I'm thinking that the way to bet is that there's more to them than was once thought...
I don’t have any particular point to this post, just tossing out that resveratrol itself seems to be an antagonist of AhR, as it seems to compete with and block agonists.
Also of note for those curious since I haven’t seen it mentioned yet, Dioxins are potent agonists of AhR.
My own interest in AhR is that it seems to play a role in metabolism. Lower levels of exposure to AhR activators seems to kick off a complicated series of effects that seem to ultimately lower metabolism, potentially being a factor in obesity. Higher levels of exposure to dioxins however results in wasting. AhR is poster child for hideously complicated biochemical relationships, so do be careful of simple summaries of exposure/response relationships.
I would be cautious of AhR agonists though, I recall coming across a number of potential negative associations in regards to cardiovascular health.
Thanks for posting this. My doc just prescribed vtama for me a month ago and my psoriasis was gone in less than a week. I didn’t even finish the sample tube he gave me. Far more effective than the steroid topical cream I was using before. I had no idea what vtama was until reading your post.
Yep. The nice thing about VTAMA is that it can be used continuously, unlike steroid creams. And it's unique among current topical meds in that it can provide sustained remission.
It may be that VTAMA reduces TRM cells in the skin, which are the T-cells responsible for relapse. There's is an ongoing clinical trial right now called KNOCKOUT [1] that gives patients a "megadose" of Skyrizi, an IL-23 inhibitor that has, like VTAMA, been shown to reduce TRM cells. The idea is that a single huge dose could effectively cure psoriasis, or at least suppress it for a very long time. The results so far show that 83% of patients achieved complete clearance after six months, which was sustained throughout the trial period. I'm confident it will be a game changer. Here [2] is an interview with the main researcher.
Among new psoriasis drugs, there is also Zoryve, a PDE4 inhibitor (same mechanism as Otezla) as a cream or foam, which has a different mechanism of action.
This is a great response. I tapped out something longer about not being as particularly impressed with the paper and the headline here on HN, but as an rheumatologist just wanted to say your last two paragraphs well said.
Hi @zeagle, sorry to hijack the thread (didn’t see a way to DM you)
I'm a PhD student working on a new lupus diagnostic blood test approach [1]. Hoping to steer the project towards true clinical needs.
I'd love to ask for your feedback as a technologist + rheumatologist on a few lupus + RA diagnostic directions we're considering. Would they actually be useful in your practice?
Would you be open to a quick chat? My email is maximz@stanford.edu.
AhR has been known for a long time, but it seems it's been somewhat mysterious until a series of recent breakthroughs. In 2022, an AhR inhibitor called tapinarof, sold as VTAMA, was launched, and has shown itself to be one of the most effective treatments for psoriasis to date. It's also unique in that it appears to have the ability to bring lasting remission. In the main clinical trial, patients who used VTAMA for one year and then stopped had a mean remission duration of 4 months until their psoriasis returned. That is unheard of for any topical medication used on psoriasis.
Blocking AhR has also shown promise in treating MS [1].
I haven't read the lupus paper, but often with papers like these, the "cause" turns out not to be the actual origin, but some cytokine or other protein that is more disease-specific than current drug targets. This lupus discovery appears to identify an imbalance that may be compensated for, but we still don't know what triggers the imbalance in the first place.
In some cases diseases turn out to be a genetic fault, but my money is on pathogens acting as the initial triggering event, which then spins the immune system into a vicious cycle of autoimmunity. In psoriasis we see this with strep bacteria, for example, but the exact mechanisms are not well understood. However, the mechanism that makes psoriasis chronic has been identified, a type of T-cell called a tissue-resident memory (TRM) T-cell. This type of cell acts as a kind of biological memory for infections.
[1] https://newsroom.uvahealth.com/2023/02/15/multiple-sclerosis...