Increased Levels of B-Type Natriuretic Peptide May be Associated With Various Types of Chronic Itch

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A recent study¹ published in the Journal of Investigative Dermatology analyzed the association of systemic B-Type natriuretic peptide (BNP) levels with itch intensity ratings related to chronic itch. In their study, Nattkemper et al found multiple examples of evidence suggesting that high levels of BNP can induce itch through central pathways in the spinal cord of mice.

“The beauty of this study is that we show that this neuropeptide is associated with itch severity, and it could be a marker for some patients on their itch severity,” said study author Gil Yosipovitch, MD, professor and Stiefel Chair of medical dermatology in the Dr. Phillip Frost department of dermatology and cutaneous surgery at the University of Miami, and director of the Miami Itch Center, in an interview with Dermatology Times.

Chronic itch significantly impacts patients’ quality of life due to correlations with dermatologic diseases, neuropathies, or systemic diseases such as kidney or liver diseases. Nattkemper et al noted that 10% of patients have chronic itch of unknown origin (CPUO). According to the study authors, the majority of CPUO patients are elderly and their itch is difficult to diagnose due to the unknown cause and the lack of a primary skin rash. Now, biomolecular targets are becoming important markers to better help clinicians with diagnosis and treatment.

Despite its difficulty, new research has emerged to better understand the neural mechanisms of itch. Sensory neuron subpopulations have been categorized and show that there are 3 classes of nonpeptidergic (NP) subtypes with unique genetic profiles of itch-associated genes, according to previous research.² BNP is typically produced by cardiomyocytes, yet it can also be secreted by endothelial cells, T-cells, and macrophages, and is crucial in supporting cardiovascular homeostasis and regulating blood pressure. The study authors noted that “when the prohormone, proBNP, is released into circulation, it is equally cleaved into the biologically active BNP, and biologically inactive NT-proBNP fragment.”

According to Nattkemper et al, “BNP has been identified as an itch specific neurotransmitter as it is released from C- primary afferent fibers to act on lamina I-II dorsal horn spinal cord interneurons via NPRA and NPRC in mice models. Although NPRA is expressed in both the epidermis and dermis, acute peripheral injection of BNP did not cause any scratching where only intrathecal administration of BNP elicited a scratch response in mice, suggesting a central activating mechanism.”

In previous literature, BNP has been evaluated in mouse models of atopic dermatitis, some human studies have shown BNP is elevated in the epidermis of pruritic skin of atopic dermatitis and prurigo nodularis when compared to healthy skin, and elevated serum BNP levels in hemodialysis patients were linked to increased pruritus in non-diabetics. Based on the lack of available data, Nattkemper et al “aimed to report the association of systemic BNP levels with the itch intensity ratings of a large cohort of chronic itch patients and its mechanism using a mouse model. Our initial findings led to further examination of whether systemic BNP can induce itch in mice beyond the peripheral effects of BNP in skin.”

Materials and Methods

For BNP testing, 77 patient blood samples were used. Patients with atopic dermatitis, prurigo nodularis, CPUO, bullous pemphigoid, neuropathic itch, and cholestatic itch were asked to rate their itch severity at the time of their blood sample draw. The association between BNP level and itch severity was assessed using Spearman correlations with linear regression, adjusting for age, sex, race/ethnicity, previous diagnosis of congestive heart disease or hypertension, or the current use of a diuretic.

For NT-proBNP testing, 33 patient blood samples were used. Patients with atopic dermatitis, prurigo nodularis, CPUO, systemic itch, or other itch were asked to rate their itch severity at the time of the blood sample draw. Similar to BNP testing, the association between BNP level and itch severity was assessed using Spearman correlations with linear regression, adjusting for age, sex, race/ethnicity, previous diagnosis of congestive heart disease or hypertension, or the current use of a diuretic. According to Nattkemper et al, only the CPUO patient population (n=14) had sufficient data for a separate analysis of NT-proBNP and itch severity correlation.

BNP or phosphate buffered saline (PBS) were intravenously administered through the tail vein of mice, and instances of scratching were counted throughout the body over 1 hour. Nattkemper et al noted that based on previously reported BNP ranges in human cohorts, 1.2 µg/kg BNP may induce pathophysiological levels in mice. Blood samples from the mice were collected after 1 hour.

Results

The study authors found that increased systemic BNP levels and NT-proBNP correlated to itch severity overall in the chronic itch patients. When diagnostic groups were individually tested, only the CPUO patient group’s BNP and NT-proBNP levels were positively correlated to itch severity. The data also showed that BNP levels significantly correlated to age and NT-proBNP levels did not. Age significantly correlated with itch severity of the BNP patient group but did not in the NT-proBNP patient group. Overall, systemic levels of BNP and NT-proBNP in chronic itch patients showed significant linear regression to itch severity when adjusted for age. The levels of BNP in the CPUO patient group maintained significant linear regression to itch severity when also adjusted for age.

Approximately 10 minutes after tail vein injection of BNP, the mice began to persistently itch their flank, face, hind quarters, and abdomens. Their itching almost completely stopped approximately 1 hour after injection.

“To our very interesting surprise, you could block BNP in the periphery but induce it in the spinal cord, meaning that this neuropeptide can cause itch systemically; you don't have to have inflammation in the skin to induce itch, which is kind of an eye-opener because our previous understanding was you have to have inflammation in the skin or some kind of a response in the skin to induce itch,” said Yosipovitch.

Conclusion

Nattkemper et al noted that their evidence shows that high levels of BNP can induce itch through central pathways in the spinal cord of mice, and that certain concentrations of systemic BNP can access the spinal cord to stimulate central itch sensory pathways.

“Since BNP is a small molecule, it is not unreasonable that it can cross the blood brain barrier similar to other small peptides, such as endogenous opioids, that have been reported to gain access to the central nervous system from the periphery. Furthermore, our results suggest that a BNP receptor antagonist might be a therapeutic option for the treatment of CPUO and itch in systemic diseases,” concluded the study authors.

Q&A With Gil Yosipovitch, MD

Gil Yosipovitch, MD

Credit: University of Miami

Dermatology Times: Can you please provide a background on chronic pruritus of unknown origin and its clinical features?

Yosipovitch: This is a disease process that we see in our clinics. Every dermatologist would see patients who have chronic itch, and we don't know the cause. That's how I coined this term 11 years ago as chronic pruritis of unknown origin, just like there's chronic pain of unknown origin or chronic fever of unknown origin. Now we know that about 10% of patients who have chronic itch suffer from chronic pruritus of unknown origin. Most of these patients are elderly. What does it mean that if you do a workup on them, they don't have atopic eczema, they didn't have any primary rash, but they get itch with secondary skin changes that appear? This is usually in the elderly, but it could be in any age group, more in adults. They're miserable and they suffer. We as dermatologists want to have a diagnosis or a rash, but there isn't one. It's an unmet need with quite a few patients in my clinics. There are no treatments for it at this stage. The FDA acknowledges that there is such a disease. Therefore, it's important to better understand what this disease is composed of.

Dermatology Times: What inspired this study regarding the evaluation of B-Type natriuretic peptide levels?

Yosipovitch: BNP was found a couple of years ago by my colleague, Dr. Santosh Mishra, also an author of this paper, and he found it in mice. It's a neuropeptide that is important in itch transmission. He recently found it in atopic eczema in animal models and there have been reports of some kidney patients that had elevated BNP, and kidney diseases can cause chronic itch with chronic itchy patients. But what initiated the study was a patient of mine who was difficult to treat and failed so many treatments. One day, he really had a big edema of his leg, so I took BNP because I was concerned about it's a marker, this brain natriuretic peptide, for congestive heart failure, and his BNP levels were sky high. I was very concerned that he had congestive heart failure. However, he didn't have it. He was given treatment to reduce his edema which also reduced his BNP levels, and he comes 2 weeks later, and he says, "Dr. Yosipovitch, you saved my life. I'm not itching anymore." What I gave him as a treatment was just a diuretic, a treatment that reduces edema. Since then, I came to the idea that no one really did a study on the levels of BNP wherever they do correlate because we know that this neuropeptide is in mice. We have a large blood bank of patients where we collect different types of chronic itch. Also, I have an itch-specific clinic, so we started collecting data. We analyzed more than 100 patients' blood for BNP and another metabolite called NT-proBNP, and interestingly, there was a very nice correlation between the itch severity of a patient's and BNP levels. Is it for everyone? No. Interestingly, most associations were in different types of chronic itch, but the most striking was in patients who are elderly with CPUO.

That led me to go back to my colleague Dr. Mishra to ask what can we do to understand where this peptide is inducing? Because he published that the periphery can cause itch, but my question to him was could it have a systemic effect? It was also related to other systemic itch; itch could be associated not just with skin diseases, but with systemic diseases such as chronic kidney disease, lymphoma, and so forth. Dr. Mishra first injected the dose response to the mice and found that BNP is dose dependent. The question we had was whether we block. We know that in the periphery it is in the skin, it is evident that there is BNP, but if we block it in the periphery, does it still affect the spinal cord or the dorsal root ganglion? And to our very interesting surprise, you could block BNP in the periphery but induce it in the spinal cord, meaning that this neuropeptide can cause itch systemically; you don't have to have inflammation in the skin to induce that itch, which is kind of an eye-opener because all our previous understanding was you have to have inflammation in the skin or some kind of a response in the skin to induce itch. I think that's the beauty of this study.

Usually, we go from mice to humans, but this time we went from the humans back to the mice. I found it very exciting when Dr. Mishra collaborated with us, and Dr. Brian Kim, who provided some samples of his patients with lymphoma, and Dr. Mark Hoon who is a researcher at the NIH, and the primary author is my researcher Leigh Nattkemper who is a neuroscientist, but also very translational. The beauty of this study is that we show that this neuropeptide is associated with itch severity, and it could be a marker for some patients on the itch severity. Since then, I've started taking BNP levels in patients and want to see how they correlate with the itch intensity because itch is very subjective; it's a sensation. It's nice to have something that could be associated. It may not be for everyone. There are some conditions where it's not associated. We found that patients who had neuropathies, it wasn't related; the level of BNP didn't really differ. But it's an eye-opener. I think we'll hopefully see others replicating this study or in a larger group of patients. But I clearly have a new kind of lab test which is easy to assess. We don't need tissue for that, and we can see whether it is a marker. We all love biomarkers, and there aren't many for chronic diseases.

The beauty of this study is that it's coming from the clinic and is going back to basics, but I think we need to do more. We are clearly interested in understanding who would benefit from reducing BNP, and it's interesting because BNP is a ligand, it's a neuropeptide. But it has receptors. We've looked at different receptors and the NPR-A is a receptor for BNP and if you block that receptor, there's no itch. The other receptors for BNP that are very common in congestive heart failure are not associated with this itch. It's interesting to see whether we will find a more specific target. But it opens up to me the understanding that there's a lot more to study and see whether we can block this receptor and benefit our patients. We are just at the beginning of a new area. I'd love to see that it will advance.

Dermatology Times: What key findings are most important for dermatologists to know about BNP as a biomarker of chronic pruritus of unknown origin?

Yosipovitch: I think that doing a blood test to correlate it to age and specific disease is important. With every patient who has chronic pruritus of unknown origin, I think it would be good to have that blood test as a marker of the severity of itch, and possibly to establish that this is connected to this specific disease. However, it's not just this disease. But the fact that it's so strongly associated with chronic pruritus of unknown origin suggests to us that we have to look into it, and in the elderly, in particular. We're looking now at patients with end stage renal failure and chronic itch, or patients with chronic liver disease who have itch systemically. We didn't know how in the skin it causes itch. But it's possible these neuropeptides are increased, and they induce this itch. There's a lot more to study yet. It's just the beginning of looking into it. But for a practicing dermatologist, the simple test is to look at BNP levels in patients where you're not sure what the cause is and maybe it's chronic pruritus of unknown origin. Second is that it could explain why sometimes you have itch without any rash. A lot of dermatologists are always looking for the rash. Well, you can have itch without a rash, and this study explains why it can happen. BNP affects itch pathways, so you don't have to have inflammation or a rash to get the itch.

Dermatology Times: What other work are you involved in regarding chronic pruritus of unknown origin or other conditions such as prurigo nodularis?

Yosipovitch: I'd like to highlight but this area is going to be hopefully soon, an advance. Why? Because in chronic pruritus of unknown origin, we, and my other colleagues such as Brian Kim, believe that there is some skew in many of the patients to a type 2 inflammation that led to a study that will be hopefully published this year. The results of this phase 3 study will be released. Why is it so important? As I mentioned, these patients are so miserable, and there aren't any treatments that they can receive at this stage. If the drug dupilumab is successful, a lot of patients will thank us. These are not controlled studies. These are patients who were so miserable and received a drug like dupilumab and possibly other drugs that will target the immune type. If that's going to be approved in the future, there is a possibility that many patients, so be very thankful to dermatologists because we'll be able to help them which we have difficulty nowadays to do. This opens the field because if dupilumab is approved for it, there are a lot of new drugs in the pipeline that target type 2 inflammation so it's quite exciting. It's also possible there will be drugs that would target neuropeptides like BNP or other neuropeptides that will be found, which will be very helpful for patients so that not all the patients will need biologics, they will just need a pill.

References

1. Nattkemper LA, Kim BS, Yap QV, Hoon MA, Mishra SK, Yosipovitch G. Increased systemic levels of centrally acting B-type Natriuretic Peptide are associated with chronic Itch of different types. J Invest Dermatol. Published online March 22, 2024. doi:10.1016/j.jid.2024.02.026
2. Usoskin D, Furlan A, Islam S, et al. Unbiased classification of sensory neuron types by large-scale single-cell RNA sequencing. Nat Neurosci. 2015;18(1):145-153. doi:10.1038/nn.3881