Resistant psoriasis: what if some patients actually have a different type of psoriasis?

Psoriasis is not simply a skin disease

When we see psoriasis, we observe red plaques, scaling, inflammation, itching in some patients, and involvement of the scalp, nails, skin folds, palms, or soles. But what we see on the surface is only the visible consequence of a far more complex immunological disturbance.

Psoriasis is an immune-mediated inflammatory disease in which genetic predisposition, the immune system, and skin cells all interact. Furthermore, it is not necessarily confined to the skin: some patients may develop psoriatic arthritis, and psoriasis is also associated with various metabolic and cardiovascular comorbidities. A review published in The Lancet in 2026 continues to describe it precisely as a heterogeneous systemic disease, not as a simple disorder of the epidermis.

Today we can treat psoriasis far better than we could 20 years ago

The treatment of psoriasis has changed radically. In addition to topical treatments and phototherapy, we now have medications capable of acting on very specific inflammatory pathways — for example TNF, IL-17, IL-23, and other immunological signals.

Targeted therapies have made it possible to achieve something that was extraordinarily difficult just a few years ago: patients with moderate or severe psoriasis who are virtually lesion-free. But there is a problem.

Not all patients respond in the same way

A medication can work spectacularly in one person and much less so in another. Some patients do not respond sufficiently, others lose their response over time, and others need to try different treatments.

And this brings us to a fundamental question: are we calling 'psoriasis' diseases that look alike on the outside but are not exactly the same on the inside? Research on ADAR1 provides us with a fascinating example.

The discovery: an interferon-dependent subtype of psoriasis

In 2026, an international team published a study in the Journal of Experimental Medicine titled 'ADAR1 loss-of-function variants altering RNA editing define a new interferon-dependent psoriasis subtype'. The researchers initially studied four unrelated families in which early-onset plaque psoriasis appeared, with or without psoriatic arthritis.

There was one particularly striking feature: a strong interferon signature in both the skin and the blood. When studying the genome, they found rare variants that caused loss of function in ADAR1. They subsequently identified six additional rare variants in an independent cohort of 125 patients with psoriasis.

What exactly is ADAR1?

This is where the fascinating part begins. ADAR1 is an enzyme involved in a process called RNA editing. And to understand it, we need to spend a moment on genetics.

Our DNA contains the fundamental instructions for our cells. To use those instructions, the cell produces RNA. But that RNA is not simply a passive photocopy: it can be processed, modified, regulated, and also edited.

ADAR1 is specifically involved in a modification called adenosine-to-inosine editing. It may seem like a microscopic detail, but it has enormous importance for our immune system.

Because our immune system has to recognize an enemy

Our body has sensors capable of detecting foreign RNA. This is extremely useful, because many viruses use RNA. When our cells detect certain RNA that appears foreign, they can interpret it as a sign that a virus may be present and activate defense mechanisms, including interferons.

But there is a problem

Our own cells also produce enormous amounts of RNA. Therefore, the immune system needs to distinguish 'this is mine' from 'this could be a virus.' ADAR1 is involved in that recognition system: we can think of it as a kind of molecular proofreader. By editing certain of our own RNA molecules, it helps prevent our immune system from mistaking them for viral signals.

What happens when ADAR1 malfunctions?

If RNA editing decreases, some of our own RNA molecules can inappropriately activate the antiviral surveillance systems. The body may then behave as though a threat exists that is not actually there, and an exaggerated type I interferon response emerges. That is precisely what researchers observed in this subtype of psoriasis.

Imagine a fire alarm

We can explain it in a very simple way. Imagine that ADAR1 helps the smoke detector distinguish real smoke from water vapor. If ADAR1 malfunctions, the detector starts interpreting normal signals as dangerous: the alarm goes off, but there is no fire, and it keeps ringing.

In our body, that immunological alarm can manifest as interferon, inflammatory cytokines, activation of skin cells, and chronic inflammation.

What are interferons?

Interferons are fundamental molecules of our immune system, especially important in antiviral defense. When a cell detects a possible viral infection, it can produce interferons, which send a signal to other cells: 'Attention, there is a threat.' This activates hundreds of genes related to immune defense.

During an infection, this is extraordinarily useful. But if that signal remains activated when it should not, it can contribute to inflammatory disease.

And this is where this new type of psoriasis comes in

Researchers found that ADAR1 alterations reduced normal RNA editing. As a result, the expression of interferon-stimulated genes and various inflammatory cytokines increased. In other words, the skin remained in a state of exaggerated immunological alarm.

Which cells were involved?

Here another particularly interesting discovery for dermatology emerges. Using single-cell analysis techniques, the researchers identified keratinocytes and melanocytes as important sources of this interferon signal.

Keratinocytes make up a large part of our epidermis. Melanocytes are the cells that produce melanin — that is, pigmentation. This makes the relationship between inflammation and the skin color changes observed in some of these patients even more interesting.

Genetics was revealing the mechanism

And now comes probably the most interesting part. Once the problem had been identified, the researchers could ask themselves: can we specifically block that pathway? Because if the problem is an exaggerated interferon signal, we may not need to indiscriminately block the entire immune system — we can try to block the specific signal that is malfunctioning. That is precision medicine.

This is where JAK1 and TYK2 come in

Interferon signals use certain intracellular proteins to transmit their message, among them JAK1 and TYK2. We can think of it this way: interferon knocks on the cell's door, but for the instruction to reach the nucleus it needs a transmission chain, and JAK1 and TYK2 play a part in that transmission.

What if we cut the signal?

The researchers confirmed in functional experiments that the inflammatory effects associated with ADAR1 alterations could be reversed by upadacitinib, a JAK1 inhibitor, and deucravacitinib, which acts on TYK2. And this is where the discovery goes from being merely interesting in the laboratory to having a potential clinical impact.

What happened in the patients?

In the patients identified with this molecular mechanism, treatment targeting this pathway produced particularly significant clinical responses. The authors describe a specific response to JAK1 and TYK2 inhibitors, which supports the idea that they were not simply treating 'just another case of psoriasis,' but rather acting on the molecular pathway that appeared to be driving that specific subtype of the disease.

Does this mean we have discovered a cure for psoriasis?

No. And this is probably the most important point in this entire article. It does not mean that ADAR1 is the cause of psoriasis in general, nor that all treatment-resistant patients carry an ADAR1 mutation, nor that every patient with psoriasis should receive a JAK1 or TYK2 inhibitor.

We are talking about a rare subtype. The initial research arose precisely from families with early-onset psoriasis, familial aggregation, particular genetic characteristics, and a strong interferon signature.

So why is this discovery so important?

Because it changes the question. Until now we have often said: 'This patient has psoriasis and this medication isn't working. Let's try another one.' The future may be: 'This patient has psoriasis. But what molecular mechanism is driving THEIR psoriasis?' And then selecting the treatment based on that answer.

Two patients can have virtually identical plaques

Same scaling. Same erythema. Same location. Same clinical diagnosis. But beneath those plaques, the predominant molecular pathways may not be exactly the same. And that may explain why they respond differently to treatments.

This is what we call precision medicine

Traditional medicine classifies diseases primarily based on symptoms, physical examination, histology, and laboratory tests. Precision medicine adds another dimension: molecular biology, genetics, transcriptomics, and biomarkers.

It does not only ask 'What disease do you have?' It also asks 'What mechanism is causing that disease in you?'.

And this could change dermatology

Imagine that in a few years we are able to analyse certain characteristics of a blood or skin sample and discover that this case of psoriasis is driven mainly by one particular pathway, this other case by another, this patient has a specific molecular signature, and this other patient carries a genetic variant that completely alters their immune response.

We could then select the treatment before spending months trying different medications. That is one of the great goals of personalised medicine.

But we are not there yet for every patient

And this must also be said. The ADAR1 study is extraordinarily interesting, but it does not mean that tomorrow we need to perform genetic sequencing on every patient with psoriasis.

We need to know what real proportion of patients presents these alterations, how to identify them efficiently, which biomarkers are sufficiently reliable, whether these responses are reproduced in larger cohorts, and what the best long-term therapeutic strategy is. The 2026 publication defines a new biological subtype and opens a research avenue; it does not yet make ADAR1 a routine test for all psoriasis cases.

And another important point: 'resistant' does not automatically mean 'genetic'

When a treatment for psoriasis does not work, we must review many things: the diagnosis, the severity, adherence, the dose, the duration of treatment, weight and certain comorbidities, the type of psoriasis, the presence of psoriatic arthritis, and previous treatments. Only in particular contexts will we be able to consider exceptionally rare biological mechanisms.

Psoriasis remains a complex disease

There is no 'psoriasis gene'. We have known for years that there is a significant genetic predisposition, but the typical disease is polygenic and multifactorial: numerous genetic variants are involved alongside immunological, environmental, metabolic, and probably other factors that we do not yet fully understand. The current literature continues to describe psoriasis as a heterogeneous immune-mediated disease with a complex genetic architecture.

ADAR1 now adds another piece to the puzzle.

And perhaps this is the true revolution

It is not about having discovered 'a new drug for psoriasis': the drugs used to block JAK1 or TYK2 already exist. What is truly interesting is having managed to connect gene → mechanism → treatment.

A genetic alteration (ADAR1) produces an alteration in RNA editing, which triggers excessive interferon activation, which uses certain signalling pathways, and those pathways can be pharmacologically blocked. That is precision medicine.

What should a person with psoriasis do now?

Not immediately ask: 'Doctor, I want you to test my ADAR1 gene.' For the vast majority of patients, this is not indicated as a routine investigation. What remains important is carrying out a proper evaluation of the psoriasis: extent, severity, location, nails, joints, quality of life, comorbidities and previous treatments. And choosing the most appropriate treatment based on the available evidence.

But if you have psoriasis that is difficult to control…

The answer should not be 'There is nothing to be done.' Today we have far more therapeutic options than we did a few years ago. And research is beginning to teach us something even more important: perhaps some therapeutic failures do not mean that the psoriasis is simply 'stronger.' Perhaps in certain patients we are blocking the wrong pathway.

What I want you to remember

In 2026, researchers identified rare loss-of-function variants in the ADAR1 gene in a subgroup of patients with psoriasis presenting particular characteristics. These alterations reduce a process called RNA editing and may cause the immune system to incorrectly interpret the body's own signals as danger signals. The result is an exaggerated activation of interferon, inflammation, activation of keratinocytes and melanocytes, and psoriatic disease.

The researchers also demonstrated that this inflammatory signal could be blocked by targeting JAK1 or TYK2, opening a very interesting pathway towards treatments selected according to each patient's molecular mechanism. But we are talking about a rare subtype, not all patients with psoriasis.

I am Dr. Florian Vallecillo, and if there is just one idea I want to leave you with today, it is this: two cases of psoriasis that look the same on the outside may not be the same on the inside. For years we have classified diseases primarily by what we can see; the dermatology of the future will likely add another question: what is happening molecularly beneath that lesion? Because perhaps the future of psoriasis treatment will not consist solely of having more drugs available, but rather of something far more intelligent: knowing which drug each patient needs before administering it. And this research on ADAR1 offers us a magnificent example of the direction dermatology may take: less trial and error, more biology, more biomarkers, and ultimately, an ever more personalised medicine.