Prurigo Nodularis: A Giant Leap Forward

Prurigo nodularis (PN) is characterized by firm, extremely itchy nodules on the upper and lower extremities (Figure 1). We all see PN in our clinics and know that it dramatically reduces the quality of life for patients. The effect on health-related quality of life among patients with PN is similar to patients with heart failure and stroke.¹ PN has arguably the greatest itch intensity of all chronic pruritic diseases, with disruption of quality of life on average being significantly higher than in patients with psoriasis and atopic dermatitis.² Patients with PN also have increased levels of anxiety and depression, likely mediated by sleep disruption and psychosocial distress from the appearance of disfiguring skin nodules.³ Beyond quality of life, little was known about the epidemiology and pathophysiology of the disease until recently. Let’s start by challenging previously held dogma about PN.

Myth #1: PN Must Be Secondary to Another Systemic Condition

PN may occur in association with chronic diseases, such as type 2 diabetes, hepatitis B and C, HIV, and chronic kidney disease.³ For this reason, all patients with PN should be screened for liver and renal dysfunction, as well as type 2 diabetes. Although PN can exist alongside these comorbidities, it is important to understand that PN is a novel inflammatory skin disease associated with increased cutaneous and systemic inflammation in the blood, with increased CD4, CD8, γδ, and natural killer T cells, among other mediators.⁴ This systemic inflammation can lead to the development of comorbidities, such as chronic kidney disease, and worsening of existing comorbidities, which further highlights the importance of early treatment of PN.⁵

Myth #2: PN Is Just a Subtype of Atopic Dermatitis

This can be a confusing topic. Atopic dermatitis, especially in African American patients, can sometimes be papular, have extensor involvement, and feature secondary prurigo nodule formation in the midst of other areas of classic eczema. In contrast, classic PN occurs in middle-aged adults, often without any intervening eczematous lesions or history of atopy.⁶ Classic PN is a unique inflammatory skin disease. Indeed, transcriptomic studies have supported this by finding that PN has a unique transcriptome compared with both psoriasis and atopic dermatitis, with dysregulation of cutaneous fibroproliferative and neurovascular function.⁷ PN also features Th2 dysregulation in addition to elements of both Th17 and Th22 immune polarization.⁴ A history of atopy is not as important a feature in treating PN as understanding the relative role of type 2 inflammation in a particular patient. Many forms of PN, as well as other forms of chronic itch, feature high blood eosinophils and IgE, which are biomarkers of type 2 inflammation that predict response to immunomodulator therapy.⁸

Myth #3: PN Is a Homogeneous Disease

We are also learning that there are disease endotypes in PN along the neuroimmune spectrum and with respect to disease comorbidities. A recent analysis of comorbidity clusters in PN revealed unique subsets of patients with high levels of associated atopy, neuropsychiatric disease, and chronic cardiopulmonary disease, respectively.⁹ A recent study also demonstrated there are 2 clusters of patients with PN, those with much higher inflammatory cytokine levels and another group with a different form that is less inflammatory but has a greater association with myelopathy/spinal disc disease.⁸ A recent study suggested that there are endotypes in the degree of type 2 inflammation, with 1 group of patients with PN having increased IL-13 and IL-5 levels, and the other group having normal levels similar to healthy patients.¹⁰

There are also differences in the clinical presentation of PN, with nodules in African American patients often featuring greater thickening and tissue fibrosis.¹¹ African American patients with PN also have worse disease control and greater systemic inflammation, with higher blood levels of C-reactive protein, ferritin, and blood eosinophils than White patients.⁸ These observed clinical differences and racial disparities are likely due to a variety of factors relating to differences in health care access, environment, and socioeconomic status, as well as differences in genetic predisposition.¹²

Myth #4: PN Treatment Should Only Be Directed at Alleviating Itch in Skin Nodules

The characteristic features of PN are skin nodules with accompanying tissue fibrosis that define the disease’s skin phenotype. However, two-thirds of patients report that the intense itch associated with PN occurs both in skin nodules and nonlesional-appearing skin.¹³ Molecular markers of inflammation are present even in nonlesional PN, which has greater inflammation than the skin of healthy patients.⁴

For many years, the treatment of PN has been limited by ineffective, untargeted therapies. Topical steroids have less efficacy in PN than in other inflammatory skin conditions because of difficulty penetrating through thickened skin layers, which feature exaggerated hyperkeratosis and epidermal acanthosis. Most other topical therapies also have minimal efficacy for this reason. Intralesional steroid therapy is more effective than topical therapy, but there is a limitation to how many nodules you can treat at once and the risk of atrophy and dyspigmentation, especially for patients with skin of color. Phototherapy is an option, but often the onset of action is delayed and incomplete. Immune suppressants, such as methotrexate and cyclosporine, are untargeted options with some efficacy, but management can be complicated by frequent laboratory monitoring and renal and hepatic toxicities, which are already more common in patients with PN.

Hope on the Horizon

We now have increasing data from phase 3 trials demonstrating the efficacy of novel therapies being developed for PN. IL-31 is a key cytokine regulating itch transmission, and it also plays a role in promoting fibrosis. To target this cytokine, nemolizumab is a monoclonal antibody in development that is directed against the IL-31 receptor A. In a phase 2 trial, nemolizumab administered every 4 weeks via injection showed rapid effects on itch, with patients experiencing an over 50% reduction in itch intensity with just 1 injection.¹⁴ Similarly, a large phase 3 trial demonstrated that 56% of patients treated with nemolizumab achieved at least a 4-point reduction in itch intensity during a 16-week treatment period, with many patients having large reductions in skin nodules.¹⁵ To help explain nemolizumab’s mechanism of action, a transcriptomic study demonstrated that it downregulates both Th2 and Th17 responses in the skin of patients with PN.¹⁶

Dupilumab is a monoclonal antibody targeting IL-4 receptor alpha, which is well known to dermatologists for the treatment of atopic dermatitis. Dupilumab is also being studied for PN after many off-label case studies reporting treatment success. In the LIBERTY-PN PRIME2 phase 3 trial, 37.2% of patients treated with dupilumab achieved a 4-point or greater reduction in itch intensity at week 12 and 57.7% of patients achieved a 4-point or greater reduction in itch intensity at week 24.¹⁷

Nalbuphine extended release (ER) is a mixed kappa opioid agonist and mu opioid antagonist with study data available from a phase 2b/3 clinical trial for the treatment of PN. Twenty-five percent of patients treated with nalbuphine ER had a 4-point or greater reduction in itch intensity at week 14.¹⁸ Finally, there are several agents in phase 2 studies for PN, such as the Janus kinase 1 inhibitors INCB054707 and abrocitinib. Vixarelimab is also a monoclonal antibody targeting oncostatin M receptor beta that is progressing through clinical trials for PN.

The future is bright for PN. Studies are still needed to assess the efficacy of new agents in various endotypes of PN and investigate disease remission following breakage of the itch-scratch cycle.

References
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2. Steinke S, Zeidler C, Riepe C, et al. Humanistic burden of chronic pruritus in patients with inflammatory dermatoses: results of the European Academy of Dermatology and Venereology Network on Assessment of Severity and Burden of Pruritus (PruNet) cross-sectional trial. J Am Acad Dermatol. 2018;79(3):457- 463.e5. doi:10.1016/j.jaad.2018.04.044

3. Wongvibulsin S, Sutaria N, Williams KA, et al. A nationwide study of prurigo nodularis: disease burden and healthcare utilization in the United States. J Invest Dermatol. 2021;141(10):2530-2533.e1. doi:10.1016/j.jid.2021.02.756

4. Belzberg M, Alphonse MP, Brown I, et al. Prurigo nodularis is characterized by systemic and cutaneous T helper 22 immune polarization. J Invest Dermatol. 2021;141(9):2208-2218.e14. doi:10.1016/j.jid.2021.02.749

5. Sutaria N, Marani M, Choi J, et al. Racial differences in dysregulation of the renin-angiotensin-aldosterone system in patients with prurigo nodularis. J Dermatol Sci. 2022;105(2):130-136. doi:0.1016/j.jdermsci.2022.02.004

6. Huang AH, Canner JK, Khanna R, Kang S, Kwatra SG. Real-world prevalence of prurigo nodularis and burden of associated diseases. J Invest Dermatol. 2020;140(2):480-483.e4. doi:10.1016/j.jid.2019.07.697

7. Sutaria N, Alphonse MP, Roh YS, et al. Cutaneous transcriptomics identifies fibroproliferative and neurovascular gene dysregulation in prurigo nodularis compared with psoriasis and atopic dermatitis. J Invest Dermatol. 2022;142(9):2537-2540. doi:10.1016/j.jid.2022.02.010

8. Sutaria N, Alphonse MP, Marani M, et al. Cluster analysis of circulating plasma biomarkers in prurigo nodularis reveals a distinct systemic inflammatory signature in African Americans. J Invest Dermatol. 2022;142(5):1300-1308.e3. doi:10.1016/j.jid.2021.10.011

9. Wongvibulsin S, Parthasarathy V, Pahalyants V, et al. Latent class analysis identification of prurigo nodularis comorbidity phenotypes. Br J Dermatol. 2022;186(5):903-905. doi:10.1111/bjd.20957

10. Parthasarathy V, Cravero K, Deng J, et al. Circulating plasma IL-13 and periostin are dysregulated type 2 inflammation biomarkers in prurigo nodularis: a cluster analysis. bioRxiv. 2022.06.07.495051. doi:https://doi. org/10.1101/2022.06.07.495051

11. Kwatra SG. Prurigo nodularis. JAMA Dermatol. 2022;158(3):336. doi:10.1001/ jamadermatol.2021.5307

12. Sutaria N, Semenov YR, Kwatra SG. Understanding racial disparities in prurigo nodularis. J Am Acad Dermatol. 2022;87(3):e111-e112. doi:10.1016/j. jaad.2022.05.014

13. Aggarwal P, Choi J, Sutaria N, et al. Clinical characteristics and disease burden in prurigo nodularis. Clin Exp Dermatol. 2021;46(7):1277-1284. doi:10.1111/ ced.14722

14. Ständer S, Yosipovitch G, Legat FJ, et al. Trial of nemolizumab in moderate-to-severe prurigo nodularis. N Engl J Med. 2020;382(8):706-716. doi:10.1056/ NEJMoa1908316

15. Positive phase III trial results for nemolizumab in prurigo nodularis. The Pharma Letter. June 22, 2022. Accessed August 26, 2022. https://www.thepharmaletter.com/article/positive-phaseiii-trial-results-for-nemolizumab-in-prurigo-nodularis

16. Tsoi LC, Hacini-Rachinel F, Fogel P, et al. Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab. J Allergy Clin Immunol. 2022;149(4):1329-1339. doi:10.1016/j.jaci.2021.10.004

17. Dupilumab produces significant improvements in itch, lesions among patients with prurigo nodularis. Pharmacy Times. March 28, 2022. Accessed August 26, 2022. https://www.pharmacytimes.com/view/dupilumab-produces-significant-improvements-in-itchlesions-among-patients-with-prurigo-nodularis

18. Trevi Therapeutics announces multiple late-breaking abstracts accepted for presentation at upcoming medical conferences on analysis of oral nalbuphine extended release. News release. PR Newswire. August 24, 2022. Accessed August 26, 2022. https://www.prnewswire.com/newsreleases/trevi-therapeutics-announces-multiple-late-breaking-abstracts-accepted-forpresentation-at-upcoming-medical-conferences-on-analysis-of-oral-nalbuphine-extendedrelease-301611299.html