Dupilumab As a Novel Treatment Option for Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic inflammatory cutaneous disorder characterized by profound pruritus, indurated papules, and nodules that are distributed primarily on the trunk or extremities.1Pereira M.P. Steinke S. Zeidler C. Forner C. Riepe C. Augustin M. et al.European Academy of Dermatology and Venereology European Prurigo Project: expert consensus on the definition, classification and terminology of chronic prurigo.J Eur Acad Dermatol Venereol. 2018; 32: 1059-1065Crossref PubMed Scopus (128) Google Scholar Pruritus, which is triggered by diverse underlying causes in the induction phase, elicits the act of scratching. Consequently, this process leads to development of a chronicity phase that is accompanied by the development of papules, nodules, or plaques, signifying the progression of the disease stage.1Pereira M.P. Steinke S. Zeidler C. Forner C. Riepe C. Augustin M. et al.European Academy of Dermatology and Venereology European Prurigo Project: expert consensus on the definition, classification and terminology of chronic prurigo.J Eur Acad Dermatol Venereol. 2018; 32: 1059-1065Crossref PubMed Scopus (128) Google Scholar The persistent itch in PN initiates an itch-scratch cycle, exacerbating disease severity.1Pereira M.P. Steinke S. Zeidler C. Forner C. Riepe C. Augustin M. et al.European Academy of Dermatology and Venereology European Prurigo Project: expert consensus on the definition, classification and terminology of chronic prurigo.J Eur Acad Dermatol Venereol. 2018; 32: 1059-1065Crossref PubMed Scopus (128) Google Scholar The impact of PN on patients' quality of life is profound, resulting in physical debilitation, impaired mental health, and substantial socioeconomic burdens.2Janmohamed S.R. Gwillim E.C. Yousaf M. Patel K.R. Silverberg J.I. The impact of prurigo nodularis on quality of life: a systematic review and meta-analysis.Arch Dermatol Res. 2021; 313: 669-677Crossref PubMed Scopus (11) Google Scholar The treatment of PN aims to disrupt the perpetual itch-scratch cycles. Nevertheless, the management of PN remains challenging because of the limited efficacy of conventional therapies, including topical corticosteroids, phototherapy, and immunosuppressants such as cyclosporine, which often fail to yield satisfactory responses.3Wong L.S. Yen Y.T. Chronic Nodular Prurigo: An update on the pathogenesis and treatment.Int J Mol Sci. 2022; 23: 833-843Crossref Scopus (4) Google Scholar The pathophysiology of PN has yet to be fully elucidated. Nevertheless, previous investigations have shed light on a complex interplay between inflammatory responses and neural dysregulation that may underlie the development of PN. The lesional skin of patients with PN has been shown to exhibit infiltration of various immune cells, such as eosinophils, neutrophils, macrophages, mast cells, and T cells.3Wong L.S. Yen Y.T. Chronic Nodular Prurigo: An update on the pathogenesis and treatment.Int J Mol Sci. 2022; 23: 833-843Crossref Scopus (4) Google Scholar One of the major cellular pathways associated with PN is type 2 TH2 cells.4Fukushi S. Yamasaki K. Aiba S. Nuclear localization of activated STAT6 and STAT3 in epidermis of prurigo nodularis.Br J Dermatol. 2011; 165: 990-996Crossref PubMed Scopus (78) Google Scholar Elevated levels of type 2 cytokines, including IL-4, IL-5, IL-10, IL-13, and IL-31, are observed in the lesional dermis of patients with PN.3Wong L.S. Yen Y.T. Chronic Nodular Prurigo: An update on the pathogenesis and treatment.Int J Mol Sci. 2022; 23: 833-843Crossref Scopus (4) Google Scholar Chronic scratching in PN triggers the release of alarmins such as IL-25, IL-33, and thymic stromal lymphopoietin (TSLP) from damaged keratinocytes.5Roan F. Obata-Ninomiya K. Ziegler S.F. Epithelial cell-derived cytokines: more than just signaling the alarm.J Clin Invest. 2019; 129: 1441-1451Crossref PubMed Scopus (237) Google Scholar The presence of IL-25 and TSLP leads to the stimulation of dendritic cells, resulting in the expression of OX40L, which in turn activates naive CD4+ T cells expressing OX40, thereby driving their differentiation into TH2 cells.5Roan F. Obata-Ninomiya K. Ziegler S.F. Epithelial cell-derived cytokines: more than just signaling the alarm.J Clin Invest. 2019; 129: 1441-1451Crossref PubMed Scopus (237) Google Scholar Additionally, group 2 innate lymphoid cells produce type 2 cytokines such as IL-5 and IL-13.5Roan F. Obata-Ninomiya K. Ziegler S.F. Epithelial cell-derived cytokines: more than just signaling the alarm.J Clin Invest. 2019; 129: 1441-1451Crossref PubMed Scopus (237) Google Scholar Furthermore, TH2 cell–related inflammation is promoted by impaired barrier function via the activation of epidermal STAT6 in an IL-4- and IL-13–dependent manner in PN.4Fukushi S. Yamasaki K. Aiba S. Nuclear localization of activated STAT6 and STAT3 in epidermis of prurigo nodularis.Br J Dermatol. 2011; 165: 990-996Crossref PubMed Scopus (78) Google Scholar In the dermis of patients with PN, increased numbers and size of peripheral nerve fibers are observed.3Wong L.S. Yen Y.T. Chronic Nodular Prurigo: An update on the pathogenesis and treatment.Int J Mol Sci. 2022; 23: 833-843Crossref Scopus (4) Google Scholar Of note, fibroblasts are stimulated by type 2 cytokines, and they produce an extracellular matrix protein, including periostin.6Hashimoto T. Mishra S.K. Olivry T. Yosipovitch G. Periostin, an emerging player in itch sensation.J Invest Dermatol. 2021; 141: 2338-2343Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar In addition, periostin promotes TSLP production from keratinocytes, amplifying type 2 inflammation, and it directly stimulates peripheral nerve fibers and multiple immune cell populations, such as eosinophils and macrophages, through integrins to produce itch mediators.6Hashimoto T. Mishra S.K. Olivry T. Yosipovitch G. Periostin, an emerging player in itch sensation.J Invest Dermatol. 2021; 141: 2338-2343Abstract Full Text Full Text PDF PubMed Scopus (20) Google Scholar Subsequently, the binding of cytokines, including IL-4, IL-13, IL-31, IL-33, and TSLP, to their receptors on the terminal end of peripheral nerves triggers the activation of specific subsets of transient receptor potential (TRP) cation channels, specifically TRPA1 and TRPV1. This activation process triggers the perception of itch, consequently resulting in increased scratching and thus perpetuating the itch-scratch cycle.7Yosipovitch G. Rosen J.D. Hashimoto T. Itch: from mechanism to (novel) therapeutic approaches.J Allergy Clin Immunol. 2018; 142: 1375-1390Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar Yosipovitch et al conducted 2 randomized, double-blind, placebo-controlled phase 3 trials (NCT04183335 and NCT04202679), known as LIBERTY-PN PRIME and PRIME2; the aim of these studies was to assess the effectiveness and safety of dupilumab in adult patients with PN.8Yosipovitch G. Mollanazar N. Stander S. Kwatra S.G. Kim B.S. Laws E. et al.Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials.Nat Med. 2023; 29: 1180-1190Crossref PubMed Scopus (16) Google Scholar The participants were randomly assigned in a 1:1 ratio to receive either 300-mg biweekly subcutaneous doses of dupilumab or placebo for a duration of 24 weeks. The primary end point of the study was the improvement of pruritus, measured by the proportion of patients achieving at least a 4-point reduction in score on the Worst Itch Numeric Rating Scale (WI-NRS) from baseline to week 24 (PRIME) or week 12 (PRIME2). The key secondary end point was a reduction in nodule count by at least 5 at week 24. In all, 151 and 160 patients were enrolled in PRIME and PRIME2, respectively. Both trials successfully achieved all predefined primary and key secondary end points. In PRIME, a reduction of at least 4 points on the WI-NRS at week 24 was observed in 60.0% of patients receiving dupilumab versus in 18.4% of patients in the placebo group (95% CI = 27.8-57.7; P < .001). In PRIME2, at week 12, a reduction of at least 4 points on the WI-NRS was observed in 37.2% of patients receiving dupilumab versus in 22.0% of patients in the placebo group (95% CI = 2.3-31.2; P =.022). In both trials, dupilumab was well tolerated and exhibited an overall safety profile consistent with its known profile. Treatment-emergent serious adverse events were reported in 6.7 % and 8.0 % of patients in the dupilumab and placebo groups in PRIME, respectively, and 2 cases in each group in PRIME2. Conjunctivitis occurred equally in the dupilumab and placebo groups in PRIME (in 2 patients [2.7 %] in each) and was more frequent with dupilumab in PRIME2 (in 3 patients (3.9 %) vs in zero). None of the cases were serious or severe, and none led to study drug discontinuation. In these clinical studies, improvement in WI-NRS score increased progressively without plateauing during the 24-week treatment period, suggesting that further treatment may lead to continued improvement. One limitation of this study8Yosipovitch G. Mollanazar N. Stander S. Kwatra S.G. Kim B.S. Laws E. et al.Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials.Nat Med. 2023; 29: 1180-1190Crossref PubMed Scopus (16) Google Scholar is that it was not possible to assess maintenance of efficacy beyond 24 weeks owing to the short duration of PN treatment in the study. Furthermore, within the enrolled atopic population, the percentage of individuals with mild active AD was restricted to 10%, which imposed a limitation on the robustness of the statistical analysis conducted for this particular subgroup. Dupilumab, which is a fully human mAb targeting the IL-4 receptor subunit-α (IL-4Rα) of IL-4 and IL-13 receptors, may exert multifaceted effects on the pathogenesis of PN (Fig 1). Indeed, IL-4Rα is upregulated in PN lesions, and plasma levels of IL-13 are elevated in patients with PN versus in healthy subjects.3Wong L.S. Yen Y.T. Chronic Nodular Prurigo: An update on the pathogenesis and treatment.Int J Mol Sci. 2022; 23: 833-843Crossref Scopus (4) Google Scholar Treatment with dupilumab blocks the IL-4/IL-13 signaling pathway, potentially halting the pathologic itch-scratch cycle in PN. Moreover, as IL-4Rα is expressed by fibroblasts, dupilumab treatment may mitigate cutaneous fibrosis in PN. Additionally, the efficacy of dupilumab might be attributed to PN serving as a clinical manifestation of underlying atopic conditions, with approximately half of the cases associated with an atopic diathesis. There is a significant unmet need for effective, long-term treatments for PN. In the absence of US Food and Drug Administration–approved therapies for PN, physicians have used a wide range of therapies, including corticosteroids, phototherapies, neuromodulators, and immunosuppressants, all with potential for significant toxic effects. The favorable results observed in these 2 clinical trials provide important evidence for the crucial involvement of type 2 cytokines and inflammation in the pathogenesis of PN and led to US Food and Drug Administration approval of dupilumab for the treatment of adult patients with PN in 2022. Furthermore, these findings underscore the efficacy of directing therapeutic interventions toward the IL-4/IL-13 axis, and hey provide a new treatment modality for patients with PN. The efficacy of targeting type 2 cytokines and inflammation in PN, in addition to dupilumab, also raises the potential efficacy of alternative therapies centered on type 2 cytokines. Indeed, previous clinical trials have already demonstrated the efficacy of nemolizumab, an anti–IL-4Rα agent, in PN.9Stander S. Yosipovitch G. Legat F.J. Lacour J.P. Paul C. Narbutt J. et al.Trial of nemolizumab in moderate-to-severe prurigo nodularis.N Engl J Med. 2020; 382: 706-716Crossref PubMed Scopus (152) Google Scholar,10Stander S. Yosipovitch G. Lacour J.P. Legat F.J. Paul C. Reich A. et al.Nemolizumab efficacy in prurigo nodularis: onset of action on itch and sleep disturbances.J Eur Acad Dermatol Venereol. 2022; 36: 1820-1825Crossref PubMed Scopus (13) Google Scholar Furthermore, promising prospects exist for the potential efficacy of oral Janus kinase inhibitors and other agents currently used for atopic dermatitis in the management of PN. It should be noted that the etiology of PN involves factors beyond type 2 cytokines and inflammation, necessitating additional research for a comprehensive understanding of their contributions. In the meantime, the clinical trial results presented in this study8Yosipovitch G. Mollanazar N. Stander S. Kwatra S.G. Kim B.S. Laws E. et al.Dupilumab in patients with prurigo nodularis: two randomized, double-blind, placebo-controlled phase 3 trials.Nat Med. 2023; 29: 1180-1190Crossref PubMed Scopus (16) Google Scholar provide substantial evidence supporting the efficacy of interventions targeting type 2 inflammation in the management of PN, thus highlighting the significant potential of controlling type 2 inflammation as a therapeutic approach to PN. Disclosure of potential conflict of interest: K. Kabashima has received consulting fees or advisory board honoraria from Japan Tobacco Inc, Kao, LEO Pharma, Torii, Chugai Pharmaceutical, Maruho, Pola Pharma, Abbvie, Eli Lilly, Sanofi, and Pfizer, and has received research grants from LEO Pharma, Japan Tobacco Inc, P&G Japan, Eli Lilly Japan, Tanabe Mitsubishi, Ono Pharmaceutical, Kyowa Kirin, Pola Pharma, AbbVie, Sanofi, Kose, Maruho, and Kyorin Pharmaceutical. The rest of the authors declare that they have no relevant conflicts of interest.