Prurigo nodularis

I had heard an earlier statement that prurigo nodularis is too heterogenous to be classified as one disease. I ask Sonja and Jesper their opinion on that. They agree that the clinical presentation and histology are quite clear, but we are still learning a lot about the pathophysiology.

“Typical morphology is unique, and one can make a diagnosis even without knowing full range of phenotypes”, Sonja explains.

Typical elements are the nodules, sometimes also papules, the tendency of hyperkeratosis and hyperpigmentation, the distribution of the nodules and the pattern of excoriation^2,3.

“Different aspects add to the disease in different patients even though it is the same disease”, Jesper says. I’m excited to learn more.

Sonja states that “the disease is complex but also not complex” and I believe that both have already made it clear that the presentation on the skin is the “not complex” part. To get to the complexity, they lead the discussion back to the pathophysiology of the disease. New evidence, such as transcriptome data, is piling up and indicating that fibrotic, vascular, epithelial, immune, and neuronal cells all play part in this disease^4,5. Sonja foresees that

Uncovering the genetic factors promoting the onset of fibrosis and hypervascularization due to mechanical stress and scratching will be the key to understanding who will get the disease. Jesper continues to reflect on the subject:

“Maybe the genetic background is present in a few percent of the population, and if those patients get itchy dermatoses, they will get chronic prurigo. If a group of people would scratch themselves repeatedly, most wouldn’t get the disease.”

What also adds to the heterogeneity of the disease, is the broad variation between aetiologies. – “What is an aetiology and what is a comorbidity?” Sonja asks. She explains that it’s not always possible to find the aetiology behind a patient’s pruritus.

“If the patient is undergoing dialysis, it is easy to identify. But if a dialysis patient also has atopic dermatitis and diabetes, what will the aetiology then be?” she asks.

Sonja and Jesper also discuss that prurigo itself might induce comorbidities via systemic inflammation, adding one layer more to the total picture.

We go on to discuss predisposing factors to this disease. Jesper sees that prurigo nodularis is three to four times more prevalent in black skin as compared to white skin and explains what the reason for that might be. The explanation starts with Mas-related G-protein coupled receptors (Mrgprs), a receptor family with different subtypes implicated as pruriceptors on sensory neurons in humans. According to Jesper, there are known characteristics in some people with black skin, for example that it starts itching when hydroxychloroquine or cloroquine is given for malaria treatment, due to a specific Mrgpr variant.

“Perhaps genetic variations or polymorphisms in Mrgprs are also behind the susceptibility to prurigo nodularis”, he suggests.

Sonja gets excited and agrees that mutation in this kind of receptor leading to nerve dysfunction would make perfect sense. “We love this scientific speculation”, they laugh together.

Our discussion moves towards the nerve fibres’ role in prurigo nodularis. What is known, is that nerves are hypersensitized ⁶.

“If itch is induced in these patients with a known pruritogen such as cowhage, they get more intense itch than patients without prurigo nodularis, which shows that nerves are hypersensitized”, Sonja tells.

“Yes, this is hyperknesis, meaning that increased itch is perceived in response to normally itch-evoking stimuli”, Jesper explains in detail.

It is known that the number of epidermal nerve fibres is reduced in prurigo nodularis, but the remaining ones are more sprouted ^6,7,8. The experts describe how changes in neuroanatomy might take place: continuous scratching induces stress on the keratinocytes and nerve fibres, which leads to changes in the cellular metabolism and possible nerve fibre injury.

“The change in function associated to that would be more than understandable”, Sonja and Jesper reflect. “Still, that itchy dermatoses have decreased nerve density is somewhat strange and shows how complex these diseases are”, Jesper says.

One interesting player might be the Merkel cell, which is involved in the regulation of itch: if Merkel cells didn’t exist, we would constantly itch from touch. Animal models have shown that dry skin or older age leads to less Merkel cells and less inhibition from touch ^{9, 10}.

“We would expect fewer Merkel cells in prurigo nodularis patients, but instead it is the opposite”, Jesper reveals. “Maybe the dysfunction is on the spinal cord level, or with interneuron regulation.”
 

After a deep dive into pathological mechanisms with these two experts, I’d like to guide the discussion back to the more general level and ask their opinion on the classification on prurigo nodularis as a disease. Sonja states that it is a neuroimmune disease, part of the spectrum of inflammatory diseases.

“The fact that one can shut down the disease by shutting down some inflammatory molecules justifies that”, Jesper states.

Sonja continues that the disease could even be called neuro-fibro-inflammatory disease to be even more exact.

Psychological problems, returning to the complexity of the disease, also belong to prurigo nodularis.

“Most patients will get psychological problems from such an itchy dermatosis, which is in addition also visible and stigmatizing”, Jesper explains. The unpredictability of the itch has a role in the development of anxiety. “The patient is left wondering when the itch will start and when it will come back”.

Jesper continues to call prurigo “a disease that invites psychological problems” and Sonja agrees. She is astonished to be asked sometimes why dermatologists treat prurigo nodularis as “it is a psychiatric disease”.  “This is not true!” she says. According to Sonja, the only psychiatric dermatological disease to be mentioned is skin-picking disease.

“The conditions might look similar but can be distinguished as the tissue in prurigo is elevated and fibrotic, while in skin-picking disease there are just bizarre excoriations”, Sonja says.

In skin-picking disease, there are first psychiatric problems that lead to skin scratching, and itch might be associated with the healing process. That contrasts with prurigo, which is an itch disease — what is seen in the skin is secondary. “This claim might sound dramatic, but it has been shown that if scratching is stopped, the skin will heal”, Jesper says.

 “If this is not chronic, I don’t know what should be called chronic in dermatology”