Ayaa Alkhaleefa, BHSc; Taylor Evart Woo, MD, MSc; Laurie Parsons, MD, FRCPC

Division of Dermatology, Department of Medicine, University of Calgary, Calgary, AB, Canada

Conflict of interest: Ayaa Alkhaleefa, Taylor Evart Woo, and Laurie Parsons have no relevant disclosures. Funding sources: None.

Abstract: Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by the presence of pruritic nodules. Dupilumab was approved by the US Food and Drug Administration in September 2022 and Health Canada in July 2023 for the treatment of PN. Dupilumab is a human monoclonal immunoglobulin G4 antibody that binds the interleukin (IL)-4 receptor alpha subunit, blocking intercellular signalling of IL-4 and IL-13. Inhibition of these cytokines downregulates the inflammatory response and improves disease severity and pruritus. Two randomized controlled trials have shown dupilumab to be effective in reducing pruritus and lesion count in patients with PN. The approval of dupilumab for PN represents the first approved therapy for PN and may indicate a paradigm shift in the way this condition is treated.

Keywords: dupilumab, Dupixent®, immunomodulator, biologic, prurigo nodularis, nodular prurigo, clinical trial

Introduction

Prurigo nodularis (PN) is a chronic inflammatory skin condition characterized by prurigo nodules, a cutaneous reaction pattern in which pruritus is a central component.1,2 It presents with papulonodules distributing along the trunk and extensor surfaces and ranges from few to hundreds of lesions.2,3 It is among the dermatoses that demonstrate the “butterfly sign”, where skin on the upper back is spared.4 The mean age of patients with PN is 50.9 years, and it is slightly more common in females who have darker skin phototypes.4 PN may be associated with underlying systemic diseases, including chronic obstructive pulmonary disease, congestive heart failure, chronic nephritis, type 2 diabetes mellitus, or the human immunodeficiency virus (HIV) infection. Clinical features of PN include intense pruritus that is present constantly, intermittently, or paroxysmally for ≥6 weeks. The diagnostic workup for PN includes a complete blood cell count with differential, liver and renal function tests, diabetes screening, thyroid function testing, infectious etiologies including viral hepatidies, and excluding other systemic etiologies.3

The pathogenesis of PN involves immune and neural dysregulation.3-5 Biopsy of prurigo lesions show dense dermal, interstitial, and perivascular infiltrates in the dermis.3 These infiltrates primarily consist of increased numbers of T-lymphocytes, mast cells, and eosinophilic granulocytes. These collections of immune cells generate a robust inflammatory response releasing interleukin (IL)-31, tryptase, eosinophil cationic protein, histamine, prostaglandins, and neuropeptides causing an intractable itch. In addition, there is upregulation of several neuropeptides such as calcitonin gene-related peptide and substance-P. Upregulation of neuropeptides promotes their secretion into cutaneous tissue via nerve fibers, ultimately causing neurogenic inflammation.

Treatment options for PN involve addressing potential underlying causes, providing symptomatic relief, and breaking the itchscratch cycle.3,6 The first-line topical therapy for PN is high potency topical corticosteroids, such as betamethasone valerate 0.1% tape.3 Other treatment options include topical calcineurin inhibitors, topical capsaicin, neuromodulators (gabapentinoids, cannabinoids, or anesthetics), antidepressants, phototherapy, and immunosuppressants. However, many treatments for PN are commonly used off-label and there exists variability in dosing regimens, leading to varying degrees of efficacy and clearance rates.7

Dupilumab represents the first and only US FDA and Health Canada approved medication for the treatment of PN.8 Dupilumab is a human monoclonal immunoglobulin G4 antibody that works by binding the IL-4 receptor alpha subunit shared by the IL-4 and IL-13 receptor complexes (Figure 1). Binding to this subunit inhibits both the inflammatory and pruritic processes, which are integral components in managing the itch-scratch cycle. IL-31 is a cytokine that is associated with the immune cascade and is believed to contribute towards symptoms of intense pruritus in PN.4,6

Dupilumab for the Treatment of Prurigo Nodularis - image
Figure 1. The mechanism of action of dupilumab in prurigo nodularis (PN). PN induces a type-2 inflammatory response, which involves Th2 cells. Th2 cells secrete interleukins 4, 5, and 13 and stimulate type 2 immunity, which is characterized by high immunoglobulin E antibody titers and eosinophilia. Cessation of the inflammatory response triggered by Th2 cells inhibits the ability of eosinophils and mast cells to produce neuroinflammatory peptides and begin the allergic inflammatory response, respectively. Figure created using BioRender.com.

Supporting Evidence for Dupilumab Monotherapy

The clinical trials involved in the regulatory approvals of dupilumab for PN, PRIME and PRIME2, showed significant improvement in the treatment of extreme pruritus and reduction in lesion count. The clinical investigations included two 24-week randomized, double-blind, placebo controlled, multicenter, parallel-group trials.9,10 Adults aged 18-80 years (n=311) with ≥20 nodules and pruritus were included. Pruritus was graded using the Worst-Itch Numeric Rating Scale (WI-NRS), where 0 indicated no itch and 10 indicated insupportable itch. Only patients with WI-NRS score of ≥7 prior to commencement of dupilumab were investigated. Additional inclusion criteria included a history of failing a 2-week course of medium-to-superpotent topical corticosteroid or when topical corticosteroids were not medically advisable. Both clinical trials assessed the effect of dupilumab in reducing the number of lesions along with pruritus improvement. Efficacy was assessed by a reduction in WI-NRS by ≥4 points and Investigator’s Global Assessment PN-Score (IGA PN-S) of 0-1, which is equivalent to a reduction in the number of nodules down to 0-5. Patients received either dupilumab 600 mg subcutaneously on day 1 followed by 300 mg once every other week for 24 weeks on a background therapy of topical corticosteroids/topical calcineurin inhibitors at a stable dose, or a matching placebo drug. The mean age of patients was 49.5 years, and 65% of subjects were female. At baseline, the WI-NRS score was 8.5, and 66% of patients had 20-100 nodules while 34% had more than 100 nodules. In addition, 43% of patients had a history of atopy.

The first clinical trial (PRIME) showed that 38.7% of patients had an improvement in both their WI-NRS score (≥4 points) and reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) versus 9.2% of patients who received placebo (Table 1).9 The second clinical trial (PRIME2) showed that 32.1% of patients had an improvement in both their WI-NRS score (≥4 points) and reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) versus 8.5% of patients who received placebo (Table 2).10 Overall, dupilumab demonstrated efficacy in treating both the extreme pruritus and for reducing the number of PN nodules over a 24- week period.

PRIME Dupilumab (n=75) Placebo (n=76)
Reduction in both WI-NRS scores by ≥4 points and an IGA PN-S scores of 0 or 1 from baseline at week 24 38.7% 9.2%
Improvement in WI-NRS score by ≥4 points 60% 18.4%
Reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) 48% 18.4%

Table 1. Outcomes assessing efficacy of dupilumab for the treatment of PN (PRIME).

PRIME2 Dupilumab (n=78) Placebo (n=82)
Reduction in both WI-NRS scores by ≥4 points and an IGA PN-S scores of 0 or 1 from baseline at week 24 32.1% 8.5%
Improvement in WI-NRS score by ≥4 points 57.7% 19.5%
Reduction in the number of nodules down to 0-5 (IGA PN-S of 0-1) 44.9% 15.9%

Table 2. Outcomes assessing efficacy of dupilumab for the treatment of PN (PRIME2).

Safety

Dupilumab appears to be safe for the treatment of PN. The most common side effects include 1-2% of patients who developed injection site reactions, which was more likely to occur with the initial loading dose. In addition, 8.6% of patients (n=152) had headache, 5.3% of patients (n=152) had nasopharyngitis, 4% (n=152) of patients developed conjunctivitis, and 3% (n=152) of patients developed herpes infection, dizziness, myalgias, and diarrhea.9,10 Serious adverse events, including neurodermatitis occurred in 1.3% of patients (n=152). The following serious adverse events occurred in <1% of the patient sample: coronavirus disease of 2019 pneumonia, musculoskeletal chest pain, papillary thyroid cancer, asthma, interstitial lung disease, pelvic inflammatory disease, acute pyelonephritis, lipoma, and uterine leiomyoma. The aforementioned adverse effects were not considered related to the study intervention, except for sepsis and mesenteritis which occurred in one patient in the placebo group.11

Combination Therapy Studies

Studies exploring combination therapies with dupilumab are limited. Kabbani et al. shared a case study of a 49-year-old woman who had psoriasis and PN and was successfully treated with a combination of dupilumab and ustekinumab.12 Ustekinumab is a human monoclonal antibody that is used to treat plaque psoriasis, psoriatic arthritis, and inflammatory bowel disease.13 It specifically inhibits the inflammatory response caused by IL-12 and IL-23. After 3 months of ustekinumab 45 mg every 12 weeks and dupilumab 600 mg loading dose followed by 300 mg every 2 weeks, the patient had complete resolution in her pruritus. After 10 months on this combination therapy, she achieved complete clearance of her nodules. The patient has been on this combined therapy for 4 years, and has maintained her clinical response in remission. The combination therapy has been well tolerated, and there have been no safety concerns reported.

Special Populations

Safety and efficacy of dupilumab for pediatric patients younger than 18 years of age with PN have not been established.9,10 PN has an incidence of 21.6 per 100,000 children and is commonly associated with atopic dermatitis.14 Few case reports have highlighted the use of dupilumab in pediatric patients. For example, a 7-year-old boy who had PN was treated with dupilumab 400 mg followed by 200 mg every 2 weeks. He was also using topical corticosteroids at the time. After 4 weeks of dupilumab therapy, the patient noted improvement in his prurigo lesions and no new lesions developed. By 12 weeks, the patient reported resolution of pruritus, and at the 1 year follow-up there were only a minimal number of active skin lesions and almost no excoriations. Overall, further clinical trials are required to determine the efficacy and safety of using dupilumab for PN in the pediatric population.

Conclusion

Dupilumab is an effective treatment for adult patients who have PN. Most notably, therapy improves the severe pruritus associated with this condition. Dupilumab has been shown to have a promising safety-profile and represents a paradigm shift in the way patients with PN are treated. However, further research is also required to determine the efficacy and safety of dupilumab for PN in the pediatric population.

References



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