Targeted therapy in the treatment of nodular prurigo

Pruritus is a rare chronic recurrent polyethological skin disease characterized by severe itching, resulting in development of skin elements such as papulo-vesicles, papules, nodules and plaques. The disease is often difficult to treat with standard therapy, and patients experience debilitating symptoms for years. The article presents a clinical case of a patient who suffered from nodular pruritus for more than 20 years, which worsened over last 4 years after suffering from a mild COVID-19 infection, when the disease became continuously recurrent. Conventional treatment was virtually ineffective. Skin rashes became widespread upon admission to Clinic of Immunopathology at the Research Institute of Fundamental and Clinical Immunology (Novosibirsk) in April 2024, severe itching disrupted sleep, thus significantly reducing the quality of life. On 04/16/2024, immunotherapy was initiated with dupilumab at initial dose of 600 mg, according to the instructions, followed by 300 mg every 2 weeks. After the first administration of the drug, significant positive dynamics was noted, i.e., decrease in itching, rapid regression of rashes, and the patient’s skin was almost completely cleansed by the 4th injection. At the present time, the skin remains clean, there is no itching, and sleep has returned to normal. The patient continues to apply emollients and takes second-generation antihistamine drugs. The efficiency of dupilumab therapy, which blocks IL-4 and IL-13 signaling by specifically binding to IL-4Rα, a subunit common to IL-4 and IL-13 receptor complexes, is due to modulation of neuroimmune regulation in the skin which underlies pathogenesis of chronic itching in nodular pruritus. IL-4 and IL-13 are considered important cytokines of Th2 cells, which increase the expression of IL-31R and other pruritus-related receptors, enhance neuronal activation in inflamed skin, transmitting signals to nearby efferent neurons and the central nervous system, thus causing itching. A vicious cycle of itch-scratching is formed, with enhanced sensitization of histamine-independent sensory neurons to pruritogens, enhanced fibroblast proliferation, migration, and production of profibrous factors. Since the main goal of treating nodular pruritus is to block the vicious cycle of itching and scratching, and promote nodular healing, dupilumab therapy leads to remission of the disease, normalizing the interaction of immune and nervous systems in the skin. When treating adult patients with nodular pruritus, dupilumab was recently approved in Russia (just a year ago), and has already shown its high efficiency. The presented case demonstrates the opportunities of modern immunotherapy methods in treatment of dermatological diseases with sluggish clinical course.

1. Zadionchenko E.V., Klyuchnikova D.E., Zvezdina I.V., Denisova E.V. Special aspects of prurigo nodularis diagnosis and treatment. Klinicheskaya dermatologiya i venerologiya = Russian Journal of Clinical Dermatology and Venereology, 2022, Vol. 21, no. 5, pp. 656-662. (In Russ.)

2. Pruritus. Clinical guidelines. Moscow, 2020. [Electronic resource]. Available at: https://www.rodv.ru/klinicheskie-rekomendacii/ (date of access: November 20, 2024).

3. Chiricozzi A., Maurelli M., Gori N., Argenziano G., De Simone C., Calabrese G., Girolomoni G., Peris K. Dupilumab improves clinical manifestations, symptoms, and quality of life in adult patients with chronic nodular prurigo. J. Am. Acad. Dermatol., 2020, Vol. 83, no. 1, pp. 39-45

4. Conrad C., Schlapbach C. Prurigo nodularis forecast: Light type 2 inflammation with high chances of fibrosis. J. Allergy Clin. Immunol., 2024, Vol. 153, no. 1, pp. 93-94.

5. Huang A.H., Williams K.A., Kwatra S.G. Prurigo nodularis: Epidemiology and clinical features. J. Am. Acad. Dermatol., 2020, Vol. 83, no. 6, pp. 1559-1565.

6. Joel M.Z., Hydol-Smith J., Kambala A., Cornman H.L., Kwatra S.G. Prevalence and comorbidity burden of prurigo nodularis in United States adults enrolled in the All of Us research program. J. Am. Acad. Dermatol., 2023, Vol. 89, no. 5, pp. 1056-1058.

7. Johansson O., Liang Y., Marcusson J.A., Reimert C.M. Eosinophil cationic proteinand eosinophil-derived neurotoxin/eosinophil protein X-immunoreactive eosinophils in prurigo nodularis. Arch. Dermatol. Res., 2000, Vol. 292, pp. 371-378.

8. Jørgensen K. M., Egeberg A., Gislason G. H., Skov L., Thyssen J.P. Anxiety, depression and suicide in patients with prurigo nodularis. J. Eur. Acad. Dermatol. Venereol., 2017, Vol. 31, no. 2, pp. e106-e107.

9. Kolkhir P., Akdis C.A., Akdis M., Bachert C., Bieber T., Canonica G.W., Guttman-Yassky E., Metz M., Mullol J., Palomares O., Renz H., Ständer S., Zuberbier T., Maurer M. Type 2 chronic inflammatory diseases: Targets, therapies and unmet needs. Nat. Rev. Drug Discov., 2023, Vol. 22, no. 9, pp. 743-767.

10. Kwatra S.G. Breaking the Itch-Scratch Cycle in Prurigo Nodularis. N. Engl. J. Med., 2020, Vol. 382, no. 8, pp. 757-758.

11. Nguyen J.K., Austin E., Huang A., Mamalis A., Jagdeo J. The IL-4/IL-13 axis in skin fibrosis and scarring: Mechanistic concepts and therapeutic targets. Arch. Dermatol. Res., 2020, Vol. 312, no. 2, pp. 81-92.

12. Park K., Mori T., Nakamura M., Tokura Y. Increased expression of mRNAs for IL-4, IL-17, IL-22 and IL-31 in skin lesions of subacute and chronic forms of prurigo. Eur. J. Dermatol., 2011, Vol. 21, pp. 135-136.

13. Parthasarathy V., Cravero K., Deng J., Sun Z., Engle S.M., Auxier A.N., Hahn N., Sims J.T., Okragly A.J., Alphonse M.P., Kwatra S.G. Circulating plasma IL-13 and periostin are dysregulated type 2 inflammatory biomarkers in prurigo nodularis: A cluster analysis. Front. Med., 2022, Vol. 9, 1011142. doi: 10.3389/fmed.2022.1011142.

14. Schuhknecht B., Marziniak M., Wissel A., Phan N.Q., Pappai D., Dangelmaier J., Metze D., Stander S. Reduced intraepidermal nerve fibre density in lesional and nonlesional prurigo nodularis skin as a potential sign of subclinical cutaneous neuropathy. Br. J. Dermatol., 2011, Vol. 165, no. 1, pp. 85-91.

15. Stander S., Zeidler C., Riepe C., Steinke S., Fritz F., Bruland P., Soto-Rey I., Storck M., Agner T., Augustin M., Blome C., Dalgard F., Evers A.W., Garcovich S., Gonçalo M., Lambert J., Legat F.J., Leslie T., Misery L., Raap U., Reich A., Şavk E., Streit M., Serra-Baldrich E., Szepietowski J., Wallengren J., Weisshaar E., Dugas M. European EADV network on assessment of severity and burden of Pruritus (PruNet): First meeting on outcome tools. J. Eur. Acad. Dermatol. Venereol., 2016, Vol. 30, no. 7, pp. 1144-1147.

16. Sutaria N., Adawi W., Goldberg R., Roh Y.S., Choi J., Kwatra S.G. Itch: Pathogenesis and treatment. J. Am. Acad. Dermatol., 2022, Vol. 86, no. 1, pp. 17-34.

17. Williams K.A., Huang A.H., Belzberg M., Kwatra S.G. Prurigo nodularis: Pathogenesis and management. J. Am. Acad. Dermatol., 2020, Vol. 83, no. 6, pp. 1567-1575.

18. Yook H.J., Lee J.H. Prurigo nodularis: pathogenesis and the horizon of potential therapeutics. Int. J. Mol. Sci., 2024, Vol. 25, no. 10, 5164. doi: 10.3390/ijms25105164.

19. Yosipovitch G., Mollanazar N., Ständer S., Kwatra S.G., Kim B.S., Laws E., Mannent L.P., Amin N., Akinlade B., Staudinger H.W., Patel N., Yancopoulos G.D., Weinreich D.M., Wang S., Shi G., Bansal A., O’Malley J.T. Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials. Nat. Med., 2023, Vol. 29, no. 5, pp. 1180-1190. doi: 10.1038/s41591-023-02320-9.