Dupilumab: Mechanism of action, clinical, and translational science.

Allergic disease prevalence has increased globally with the subset of type 2 inflammatory diseases playing a substantial role. Type 2 inflammatory diseases may differ in clinical presentation, but they exhibit shared pathophysiology that is targeted by the unique pharmacology of dupilumab. Dupilumab binds to the interleukin (IL)-4 receptor alpha subunit (IL-4Rα) that blocks IL-4 and IL-13 signaling, two key drivers of type 2 inflammation. Herein, we review the mechanism of action and pharmacology of dupilumab, and the clinical evidence that led to the regulatory approvals of dupilumab for the treatment of numerous type 2 inflammatory diseases: atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis, eosinophilic esophagitis, and prurigo nodularis.

Comprehensive plasma cytokine and chemokine profiling in prurigo nodularis reveals endotypes in Type 2 inflammation.

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with variability in peripheral blood eosinophil levels and response to T-helper 2 targeted therapies (Th2). Our objective was to determine whether circulating immune profiles with respect to type 2 inflammation differ by race and peripheral blood eosinophil count. Plasma from 56 PN patients and 13 matched healthy controls was assayed for 54 inflammatory biomarkers. We compared biomarker levels between PN and HCs, among PN patients based on absolute eosinophil count, and across racial groups in PN. Eleven biomarkers were elevated in PN versus HCs including interleukin (IL)-12/IL-23p40, tumor necrosis factor-alpha (TNF-α), Thymic stromal lymphopoietin (TSLP), and macrophage-derived chemokine (MDC/CCL22). Additionally, PN patients with AEC > 0.3 K cells/µL had higher Th2 markers (eotaxin, eotaxin-3, TSLP, MCP-4/CCL13), and African American PN patients had lower eosinophils, eotaxin, and eotaxin-3 versus Caucasian and Asian PN patients (p < 0.05 for all). Dupilumab responders had higher AEC (p < 0.01), were more likely to be Caucasian (p = 0.02) or Asian (p = 0.05) compared to African Americans, and more often had a history of atopy (p = 0.08). This study suggests that blood AEC > 0.3 K and Asian and Caucasian races are associated with Th2 skewed circulating immune profiles and response to Th2 targeted therapies.

Dysregulation of the Skin-Liver Axis in Prurigo Nodularis: An Integrated Genomic, Transcriptomic, and Population-Based Analysis.

Pruritus has long been linked to hepatic dysfunction; however, there are limited data characterizing the association between liver disease and prurigo nodularis (PN), a chronic inflammatory skin disease featuring severe pruritis. We thus conducted a cross-sectional analysis of hepatic comorbidities in PN patients using TriNetX, a large global health research network. This analysis revealed that PN patients had a higher risk (p < 0.001) of developing liver cirrhosis, acute and subacute hepatic failure, inflammatory liver disease, chronic hepatitis, nonalcoholic steatohepatitis, portal hypertension, fatty liver, chronic passive congestion of the liver, and hepatocellular carcinoma compared with healthy controls. The cumulative incidence of liver disease was about three times higher in PN patients compared with healthy controls. These findings provided the basis for translational studies to investigate a genetic mechanism for this association. Cutaneous transcriptomic analysis performed on PN patients revealed the dysregulation of genes related to hepatic failure in lesional PN compared with both nonlesional PN and control skin. Similarly, gene set variation analysis (GSVA) revealed a significantly increased (p < 0.05) activation of liver metabolism, chronic hepatic failure, acute hepatic failure, cholestatic liver disease, polycystic liver disease, and hepatocellular carcinoma pathways in lesional PN compared with control skin. A subsequent genome-wide association study (GWAS) identified shared single-nucleotide polymorphisms (SNPs) in the genes AR, EDIL3, MACROD2, PCSK5, RUNX1T1, TENM4, and ZEB2 between PN and liver disease from the FinnGen cohort. Significant dysregulation of the skin-liver axis in PN patients may explain the increased incidence and severity of hepatic comorbidities and help identify future therapeutic targets for PN.

Single-Cell RNA Sequencing Reveals Dysregulated POSTN+WNT5A+ Fibroblast Subclusters in Prurigo Nodularis.

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease with a poorly understood pathogenesis. We performed single-cell transcriptomic profiling of 28,695 lesional and nonlesional PN cells. Lesional PN has increased dysregulated fibroblasts (FBs) and myofibroblasts. FBs in lesional PN were shifted toward a cancer-associated FB-like phenotype, with POSTN+WNT5A+ cancer-associated FBs increased in PN and similarly so in squamous cell carcinoma. A multicenter cohort study revealed an increased risk of squamous cell carcinoma and cancer-associated FB-associated malignancies (breast and colorectal) in patients with PN. Systemic fibroproliferative diseases (renal sclerosis and idiopathic pulmonary fibrosis) were upregulated in patients with PN. Ligand-receptor analyses demonstrated an FB neuronal axis with FB-derived WNT5A and periostin interactions with neuronal receptors melanoma cell adhesion molecule and ITGAV. These findings identify a pathogenic and targetable POSTN+WNT5A+ FB subpopulation that may predispose cancer-associated FB-associated malignancies in patients with PN.

Non-Systemic Medication for the Treatment of Prurigo Nodularis: A Systematic Review.

Prurigo nodularis (PN) is a skin disease characterized by firm, itchy, erythematous lesions. Treatment consists of systemic and non-systemic modes of therapy. Non-systemic forms of treatment are first-line and include topical corticosteroids, topical steroid-sparing agents, and phototherapy. The objective was to review the efficacy of non-systemic treatment used to treat PN. A systematic search was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with PROSPERO (CRD42023412012). The search consisted of keywords and Medical Subject Heading (MeSH) terms and translated to Ovid MEDLINE, Embase, and Scopus. Google Scholar was also searched for the first 200 articles. Article quality of evidence was scored using GRADE criteria. The search yielded 1151 results; 37 met criteria for inclusion. There were 14 studies on phototherapy, and 11 studies on topical corticosteroids, most of which were also combined with topical antihistamines, antipruritics, and/or phototherapy. There were 2 studies each on topical antipruritics used in isolation, vitamin D analogues, and intralesional triamcinolone acetonide. There was 1 study each on topical pimecrolimus, tacrolimus, 2% dinitrochlorobenzene, cryotherapy, acupuncture, and the Paul Gerson Unna boot. Most were case reports and case series, although 2 randomized controlled trials on phototherapy and topical pimecrolimus were included. Corticosteroids had varying levels of positive response in patients and appeared more effective when used in combination or under occlusive dressing. Phototherapy is likely effective, but the risk of relapse is high. Cryotherapy may also be a lesion-directed agent to circumvent challenges to adherence and avoidance of systemic medication.

Clinical Characteristics and Treatment Outcomes of Prurigo Nodularis: A Retrospective Study.

BACKGROUND: Prurigo nodularis (PN) is a complex chronic skin disease characterized by severe pruritic nodules. PN is often associated with mental health disorders and chronic medical comorbidities. Until recently, PN treatment has been challenging and difficult. OBJECTIVES: This study aims to describe the demographic, clinical characteristics, and comorbidities associated with PN. Also, we aim to describe the effectiveness of systemic therapies, including methotrexate, cyclosporine, and narrow band ultraviolet (NB-UVB) in adult patients with PN. METHODS: This is a retrospective chart review of adult patients diagnosed with PN at Hamilton Health Science Center and/or McMaster University in Hamilton, Ontario, between 2015 and 2023. RESULTS: The study included 81 patients (57% female). The mean age was 52.8 years, and the mean age of PN diagnosis was 50 years. Reported symptoms included: itching (100%), dry skin (53%), pain (17%), and burning sensation (5%). Lower and upper extremities were the most common areas involved in 93% and 69%, respectively. Mental health disorders were present in 79% of patients, with depression (58%) and anxiety (52%) being the most common. Atopic dermatitis was the most common skin comorbidity noted. Treatments used included cyclosporine, and NB-UVB, and MTX, which resulted in significant improvement of pruritus in 38%, 35%, and 31% of patients, respectively, at week 16. CONCLUSIONS: PN is associated with increased risk of mental health disorders and other medical comorbidities. Cyclosporine, methotrexate, and NB-UVB therapy may be effective treatment options, however clinicians must consider the potential short- and long-term adverse effects of these treatments.

Systemic Medication for the Treatment of Prurigo Nodularis-A Systematic Review.

IMPORTANCE: Prurigo nodularis (PN) is a debilitating inflammatory skin disease characterized by red to violaceous pruritic lesions. The goal of therapy is to break the scratch-itch cycle. Treatment varies and often requires a multimodal approach to target both immune and neural mediated aspects of disease. OBJECTIVES: To review the efficacy of systemic treatment used to treat PN. EVIDENCE REVIEW: A systematic search of keywords and Medical Subject Headings was performed in Ovid MEDLINE, Embase, Scopus, and ClinicalTrials.gov. The first 200 results of an abbreviated search in Google Scholar were also included. PRISMA guidelines were followed and the review was registered on PROSPERO (CRD42023412012). GRADE criteria were used to assess articles for quality of evidence. FINDINGS: The search resulted in 1153 articles; 382 were duplicates, 643 were irrelevant, 19 were not retrieved, 21 were abstract only, and 88 are included in this review. There were 24 studies on dupilumab, 16 on thalidomide, 8 on cyclosporin, 7 on methotrexate, 3 each on lenalidomide and aprepitant, 2 each on alitretinoin, apremilast, baricitinib, gabapentin, intravenous (IV) immunoglobulins, pregabalin, tofacitinib, and 1 each on amitriptyline, azathioprine, butorphanol, isoquercitin, IV dexamethasone-cyclophosphamide/ oral cyclophosphamide, ketotifen, metronidazole, montelukast, nalbuphine, nemolizumab, serolopitant, tacrolimus, and herose derma zima capsule. CONCLUSIONS AND RELEVANCE: Dupilumab reduces pruritus and appearance of lesions and is associated with the fewest number of side effects. Thalidomide and pregabalin are also effective, but their long-term use is limited by muscle and nerve pain. Janus Kinase inhibitors may be beneficial, but large population studies are lacking.

Clinical and Pathological Spectrum of Prurigo Pigmentosa in Central European Individuals.

Importance: Based on early studies, prurigo pigmentosa (PP) was considered a rare inflammatory dermatosis affecting primarily Asian individuals. However, several case reports subsequently showed that the disease is not restricted to those of Asian origin. Large studies on PP in central European individuals, on the other hand, are missing. Objective: To increase awareness of PP by describing the clinical, histopathological, and immunohistochemical features in central European individuals. Design, Setting, and Participants: This observational, retrospective case series analyzed clinicopathological features of 20 central European patients diagnosed with PP. Data collection was performed by means of archive material, including physician's letters, clinical photographs, and histopathological records, at the Department of Dermatology at the Medical University of Graz in Austria from January 1998 to January 2022. Main Outcomes and Measures: Demographic, clinical, histopathological, and immunohistochemical characteristics for patients diagnosed with PP were recorded. Results: Of the 20 patients included, 15 (75%) were female, and the mean (range) age was 24.1 (15-51) years. The study cohort consisted entirely of European patients. The most common site of involvement of PP was the breast, followed by the neck and back. Other involved clinical sites were the abdomen, shoulders, face, head, axillae, arms, and genital region and groin. Clinically, lesions were characterized by a symmetric pattern in 90% (n = 18) of all cases. Marked hyperpigmentation was observed only in 25% (n = 5) of patients. In some cases, triggers such as malnutrition, long-term pressure, and friction were noted. Histologic findings revealed presence of neutrophils in all cases and necrotic keratinocytes in 67% (n = 16) of cases. Immunohistochemistry results showed predominance of CD8+ lymphocytes in the epidermis, as well as the presence of plasmacytoid dendritic cells and myeloid cell nuclear differentiation antigen-positive neutrophil precursors. Conclusions and Relevance: This case series found that most clinical features observed in Asian patients were also observed in central European patients, but hyperpigmentation was primarily mild to moderate. Histopathological features were similar to those reported in the literature with the additional presence of myeloid cell nuclear differentiation antigen-positive precursor neutrophils. These results expand previous knowledge about PP in central European individuals.

Clinical aspects and management of chronic itch.

Chronic pruritus (CP) (ie, itch that persists for more than 6 weeks) poses significant challenges to patients' health and quality of life. It is a common reason for visits to dermatologists and general practitioners and can be caused by a range of conditions, including systemic diseases such as chronic kidney disease or liver diseases, malignancies, neuropathic conditions, and dermatoses such as atopic dermatitis. CP often does not develop in parallel with the course of the disease and can become an entity of its own, which must be treated with antipruritic drugs, even if the underlying cause is already under therapy. Depending on the etiology of CP, different pathways in the pathogenesis have been analyzed recently, following which new treatments have been developed and tested in randomized controlled trials. This article discusses the recent results of these studies and highlights how best to manage health care for patients with CP.

[An unexpected discovery in a patient suffering from chronic prurigo]. / Eine unerwartete Entdeckung bei einer Patientin mit chronischer Prurigo.

We report on a 61-year-old woman with a sudden onset of itching and nodules on the skin for the last year. Chronic prurigo (CPG) was diagnosed. An extensive and interdisciplinary check-up revealed metastasized ovarian cancer. Radical surgery and chemotherapy followed. The CPG has completely healed and has not relapse. We believe this case to represent paraneoplastic CPG. This case report also demonstrates that the etiology of CPG can be identified and that a detailed workup is worthwhile and can be life-saving.

Pruritic Rash in a Woman With Endometrial Cancer.

A woman in her 60s presents with a pruritic rash that initially developed on the legs and progressed to her feet, arms, hands, and trunk, with associated symptoms of a burning sensation and occasional pain. What is your diagnosis?

The blood proteomic signature of prurigo nodularis reveals distinct inflammatory and neuropathic endotypes: A cluster analysis.

BACKGROUND: Prurigo nodularis (PN) is an extremely pruritic, chronic inflammatory skin disease. Little is known about systemic inflammation in PN. OBJECTIVE: To characterize plasma inflammatory biomarkers in patients with PN and investigate the presence of disease endotypes. METHODS: In this cross-sectional study, Olink proteomic analysis was performed on plasma samples from patients with PN (n = 29) and healthy controls (n = 18). RESULTS: Patients with PN had increased levels of 8 circulating biomarkers compared to controls, including tumor necrosis factor, C-X-C Motif Chemokine Ligand 9, interleukin-12B, and tumor necrosis factor receptor superfamily member 9 (P < .05). Two PN clusters were identified in cluster 1 (n = 13) and cluster 2 (n = 16). Cluster 2 had higher levels of 25 inflammatory markers than cluster 1. Cluster 1 had a greater percentage of patients with a history of myelopathy and spinal disc disease compared with cluster 2 (69% vs 25%, P = .03). Patients in cluster 2 were more likely to have a history of atopy (38% in cluster 2 vs 8% in cluster 1, P = .09). LIMITATIONS: Small sample size precludes robust subgroup analyses. CONCLUSION: This study provides evidence of neuroimmune-biased endotypes in PN and can aid clinicians in managing patients with PN that are nonresponsive to traditional therapies.