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.

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.

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.

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.

[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.

Chronic Nodular Prurigo: A Retrospective Study of 74 Cases. / Prurigo crónico nodular: Estudio retrospectivo de 74 casos.

BACKGROUND AND OBJECTIVE: Chronic nodular prurigo (CNPG) is a recently defined and currently underdiagnosed disease with a variety of causes. It is associated with multiple comorbidities, and its management and treatment have improved with a better understanding of its pathogenesis. The aim of this study was to describe our experience with a series of patients with CNPG. MATERIAL AND METHODS: Single-center, observational, retrospective study of the sociodemographic and clinical characteristics of patients with CNPG seen at the dermatology department of a tertiary care hospital between 2009 and 2021. RESULTS: We included 74 patients, mostly women (63.5%), with a mean age of 57 years. Overall, 39.2% of patients had a concomitant skin condition, mainly atopic dermatitis (62%). Other comorbidities included endocrine disorders (54.1%), cardiovascular disease (44.4%), and psychiatric disorders (36.5%). Skin biopsy helped confirm the clinical diagnosis in 70% of cases. The mean immunoglobulin E level was higher than normal (516 IU/mL), regardless of atopic predisposition. On average, patients received 3 treatments, the most common choices being methotrexate, antihistamines, and topical and oral corticosteroids. Methotrexate was among the most effective options. CONCLUSIONS: CNPG is a complex disease associated with multiple comorbidities. It requires a multidisciplinary approach, with the dermatologist at the center. Classical treatment approaches are probably insufficient.

Transcriptomic characterization of prurigo nodularis and the therapeutic response to nemolizumab.

BACKGROUND: Prurigo nodularis (PN) is a debilitating, difficult-to-treat, intensely pruritic, chronic inflammatory skin disease characterized by hyperkeratotic skin nodules. The pathogenesis of PN is not well understood but is believed to involve cross talk between sensory nerve fibers, immune cells, and the epidermis. It is centered around the neuroimmune cytokine IL-31, driving an intractable itch-scratch cycle. OBJECTIVE: We sought to provide a comprehensive view of the transcriptomic changes in PN skin and characterize the mechanism of action of the anti-IL-31 receptor inhibitor nemolizumab. METHOD: RNA sequencing of biopsy samples obtained from a cohort of patients treated with the anti-IL-31 receptor inhibitor nemolizumab and taken at baseline and week 12. Generation and integration of patient data with RNA-Seq data generated from reconstructed human epidermis stimulated with IL-31 and other proinflammatory cytokines. RESULTS: Our results demonstrate that nemolizumab effectively decreases IL-31 responses in PN skin, leading to effective suppression of downstream inflammatory responses including TH2/IL-13 and TH17/IL-17 responses. This is accompanied by decreased keratinocyte proliferation and normalization of epidermal differentiation and function. Furthermore, our results demonstrate how transcriptomic changes associated with nemolizumab treatment correlate with improvement in lesions, pruritus, stabilization of extracellular matrix remodeling, and processes associated with cutaneous nerve function. CONCLUSION: These data demonstrate a broad response to IL-31 receptor inhibition with nemolizumab and confirm the critical upstream role of IL-31 in PN pathogenesis.

Attenuation of actinic prurigo eruptions with Polypodium leucotomos supplementation.

Actinic prurigo is a rare pruritic photodermatosis. We report the use of Polypodium leucotomos extract in an 11-year-old female patient with actinic prurigo, resulting in a significant attenuation of her disease without development of adverse effects to date. Polypodium leucotomos exerts a pleiotropic immunomodulatory and antioxidant effect by shifting the balance from pro- to an antiinflammatory cytokine environment. This counteracts the effects of UV-induced cellular damage characteristic of photodermatoses.

Lesiones en la piel causadas por ácaros de palomas / Skin lesions caused by bird mites

El prurigo agudo es una patología sumamente frecuente y con múltiples etiologías, entre las cuales se encuentran los ácaros de las aves. La incidencia de esta dermatosis ha aumentado en el último tiempo. Existen diferentes parásitos que colonizan las aves y que, al tener contacto con el ser humano, generan lesiones papulosas de tipo prurigo. El agente causal más involucrado es Dermanyssus gallinae, no siempre hallado en el momento del examen físico. Se presenta el caso de una mujer con lesiones papulosas en el tronco y las extremidades, iniciadas luego del contacto con detritos de palomas.

Acute prurigo is an extremely frequent dermatosis with multiple etiologies, including bird mites. Recently, there has been an increase in the reported cases of human infestation cases caused by bird acarus. Many parasites colonize birds and the infestation to humans produces papular lesions. Dermanyssus gallinae is the most common acarus involved. We report a woman with papular lesions in trunk and extremities after contact with a bird nest.

Prurigo excoriée treated with low dose naltrexone.

A 53-year-old woman presented with a 25-year history of acne excoriée and prurigo excoriée. Her symptoms began in 1988 coinciding with her husband's death from a brain tumour when she was 27. The pruritus affected her quality of life and disturbed her sleep. She had scarring on her face and body resulting from persistent scratching. The pruritus proved refractory to treatment despite a multi-modal treatment approach including multiple topicals, phototherapy and systemic agents such as isotretinoin, antibiotics, anxiolytic agents and neuromodulators. She was extremely frustrated that various treatments had been ineffective at controlling the itch-scratch cycle. She was commenced on low dose naltrexone (LDN), 3 mg nocte, and she became itch free within a few weeks. She reports that the LDN has had a beneficial impact on her quality of life.

High-Potency Topical Steroid Treatment of Multiple Keratoacanthomas Associated With Prurigo Nodularis.

Patients who present with multiple keratoacanthomas (KAs) associated with prurigo nodularis often pose a treatment challenge. These lesions often require aggressive treatment, such as Mohs micrographic surgery, surgical excision, electrodesiccation and curettage, intralesional steroid injection, and long-term acitretin. 5-Fluorouracil (5-FU) cream 5% has been shown to be effective; however, topical options are limited when 5-FU fails. We have found success using a high-potency topical steroid under occlusion, resulting in resolution of KAs and prurigo nodules.

Prurigo nodular crónico / Chronic nodular prurigo

El prurigo nodular crónico se caracteriza por un ciclo de prurito y excoriación en el que intervienen mecanismos neurodérmicos, asociado a diversas enfermedades. Se manifiesta con placas o nódulos hiperqueratósicos cupuliformes. El tratamiento, enfocado en reducir el prurito, representa un desafío por la frecuente resistencia a las terapéuticas habituales. Se describe el caso de un hombre de 72 años, con antecedentes psiquiátricos, que presentó una dermatosis pruriginosa recalcitrante refractaria a múltiples esquemas de tratamiento.

Chronic prurigo nodularis is characterized by a cycle of itching and excoriation involving neurodermal mechanisms, associated with various diseases. It manifests with cupuliform hyperkeratotic plaques or nodules. Treatment is focused on reducing itching and is a challengue due to the frequent resistance to the usual therapies. We present the case of a 72-year-old man with a psychiatric history, who presented a recalcitrant pruritic dermatosis refractory to multiple treatment regimens.

Eosinophilic dermatoses.

Eosinophilic dermatoses are a heterogeneous group of diseases, characterized by an eosinophil-rich infiltrate and/or degranulation of eosinophils. Blood eosinophilia may be an associated feature. Typical, albeit not specific histological findings include 'flame figures', which are caused by the accumulation of cationic proteins released by eosinophils and subsequent collagen denaturation. "Classic" eosinophilic dermatoses include eosinophilic cellulitis (Wells syndrome), granuloma faciale, eosinophilic fasciitis (Shulman syndrome) and eosinophilic folliculitis (Ofuji disease). In addition, there is a multitude of skin diseases that present with varying degrees of eosinophilic infiltration. These include atopic dermatitis, bullous pemphigoid, urticaria, allergic contact dermatitis, prurigo nodularis, arthropod bite reaction, parasitic infections, and drug hypersensitivity. Even though these disorders share a common characteristic (tissue eosinophilia), they differ greatly in their clinical presentation.