TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis, 2018, Conrad et al.

jnmaciuch

jnmaciuch

Senior Member (Voting Rights)

TNF blockade induces a dysregulated type I interferon response without autoimmunity in paradoxical psoriasis​


Although anti-tumor necrosis factor (TNF) agents are highly effective in the treatment of psoriasis, 2–5% of treated patients develop psoriasis-like skin lesions called paradoxical psoriasis. The pathogenesis of this side effect and its distinction from classical psoriasis remain unknown. Here we show that skin lesions from patients with paradoxical psoriasis are characterized by a selective overexpression of type I interferons, dermal accumulation of plasmacytoid dendritic cells (pDC), and reduced T-cell numbers, when compared to classical psoriasis. Anti-TNF treatment prolongs type I interferon production by pDCs through inhibition of their maturation. The resulting type I interferon overexpression is responsible for the skin phenotype of paradoxical psoriasis, which, unlike classical psoriasis, is independent of T cells. These findings indicate that paradoxical psoriasis represents an ongoing overactive innate inflammatory process, driven by pDC-derived type I interferon that does not lead to T-cell autoimmunity.

Link (open access)
 
I hope others don't mind me posting papers as a way to collect things that caught my interest and potentially spark discussion on them. I've recently been interested in the capability of type I interferons to induce symptoms without the involvement of T cells.

Psoriasis might be relevant given potential genetic associations with HLA-C from Zhang et al. HLA-C is one of the most frequent sites of mutation in psoriasis, though interestingly I don't think I've ever heard mention of skin issues in ME/CFS.
 
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Explain like I'm brain foggy:

Skin pathology in psoriasis is commonly associated with T-cell infiltration and T-cell mediated tissue damage. This paper explores cases of psoriasis induced by a TNF blocker (such as humira/adalimumab used for treatment of many immune diseases, including psoriasis itself).

Since TNF blockers induce cell death in T cells (among others), this is a case of "paradoxical" psoriasis where damage must be mediated by another cell type. The findings show that type I interferon production by plasmacytoid dendritic cells, an innate immune cell type, are sufficient to create psoriasis-like pathology in certain individuals.
 
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It is highly relevant. Keep the papers coming. I agree that this sort of 'paradoxical' signal effect could well be a clue to the MECFS situation.

I had patients with minimal psoriasis plus arthritis who got gross palmar keratosis on Humira. I hate the old 'cytokine balance' idea but these paradoxical kick backs are very real and may be telling us something crucial
 
V.R.T. said:
Do you mean a general one or one specific to psoriasis?
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Either! I’m not sure how limited a psoriasis-specific screen might be, though I think there is room for many of the most commonly mutated pathways in psoriasis to also be relevant in ME/CFS (besides HLA-C).

Just figured I’d ask on the off chance someone in your family had already had it done for one reason or another. It’s not always informative but can sometimes be an interesting tidbit.
 
jnmaciuch said:
Either! I’m not sure how limited a psoriasis-specific screen might be, though I think there is room for many of the most commonly mutated pathways in psoriasis to also be relevant in ME/CFS (besides HLA-C).

Just figured I’d ask on the off chance someone in your family had already had it done for one reason or another. It’s not always informative but can sometimes be an interesting tidbit.
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I can certainly ask my Dad whether he's done one tomorrow.
 
V.R.T. said:
I can certainly ask my Dad whether he's done one tomorrow.
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Only if you’re so inclined, certainly not important! I’m just always interested by cases of families where a high proportion seem to end up afflicted with some chronic debilitating issue, but the specifics differ person to person (especially if there happens to be some specific information about triggers for the various individuals)
 
We have the HLA profile – or whatever it is that mediates susceptibility to psoriasis – but only one person in each generation seems to get it.

My mam and I were the, erm, lucky ones and I got the arthritis too (disabling because it wrecks your hands), but no one else.

So I suspect that either other triggers are required, or that penetrance is low. We also have genetic haemochromatosis, but even with two mutated copies of the gene people don't necessarily develop that.
 
Kitty said:
So I suspect that either other triggers are required, or that penetrance is low. We also have genetic haemochromatosis, but even with two mutated copies of the gene people don't necessarily develop that.
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Yes that seems to be common—from what I remember in psoriasis/lupus/etc., there are very few mutations that get within the range of virtually guaranteeing those diseases.

There’s a commonly used mouse model that nearly always develops psoriasis, and it is a knockout for IRF2, which is an interferon-stimulated gene that negatively regulated interferon. I’m pretty sure IRF2 is a strong risk gene in humans as well. In lupus, interferon kappa mutations are pretty highly predictive for skin manifestations of lupus.

The rest of them only seem to increase risk a bit, so will result in a few more people in the family being afflicted.
 
jnmaciuch said:
I hope others don't mind me posting papers as a way to collect things that caught my interest and potentially spark discussion on them. I've recently been interested in the capability of type I interferons to induce symptoms without the involvement of T cells.

Psoriasis might be relevant given potential genetic associations with HLA-C from Zhang et al. HLA-C is one of the most frequent sites of mutation in psoriasis, though interestingly I don't think I've ever heard mention of skin issues in ME/CFS.
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My skin issues started when I got sick. Not psoriasis as far as I know. But what it is has never been confirmed with certainty.

I have heard from others who have skin issues.
 
If severe, hygiene etc would probably be a confounding factor. Bacterial or fungal infections as well.
 
jnmaciuch said:
Thanks for sharing, this is the first I’ve heard. Do you happen to know if those other people are all severe or not?
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I know one was very severe and tubefed but now seems to be in remission

Here are some quotes of other people on the forum, do not know their severity


Mithriel said:
Problem with all these studies is they most likely predict chronic fatigue not ME. Chronic fatigue is not to be taken lightly but it is not the same and the confusion will not be helpful to anyone.

I can see why a disordered immune system would lead to fatigue and it is an interesting study from that point of view.

I developed psoriasis after decades of ME and have heard this is not unusual though I did not expect it! It gets worse and better in line with my ME.
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lansbergen said:
Me too.
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Forbin said:
I was diagnosed with scalp eczema a couple of years prior to ME. This seemed to morph into a diagnosis of scalp psoriasis about 10 years after the onset of ME. Fortunately it is intermittent and confined to the scalp.

It seems that people who have psoriasis are more likely to have Crohn's disease. I mention this because a study of the microbiome in MECFS found...



I was also once diagnosed with chronic ulcerative colitis (after ME onset), but it seemed to vanish after a month on sulfasalazine, making the initial diagnosis questionable. On the other hand, my mother developed chronic ulcerative colitis in her 30's and had it for the rest of her life.

I would not be surprised if some imbalance in the microbiome has something to do with all of this, including ME.
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If I remember correctly read on X and another forum of skin issues as well.
 
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