INDIVIDUAL ARTICLE: Patient Journey and the Burden of Systemic Comorbidities and Sequalae in Prurigo Nodularis.

BACKGROUND: Prurigo Nodularis (PN) is a relatively rare chronic inflammatory skin disease characterized by firm pruritic nodules. PN is associated with significantly increased rates of many systemic and non-systemic comorbidities. This results in a higher burden of disease and utilization of specialty care compared to non-PN United States (US) adults. Psychiatric comorbidities associated with PN include depression and anxiety. In this article, we describe the burden of comorbidities. sequelae of disease, inflammatory disease signatures, and the impact of PN in African American and Asian patients. Furthermore, we explore challenges in the recognition and diagnosis of PN and describe methods to increase awareness of PN among dermatologists. J Drugs Dermatol. 2023;22:12(Suppl 2):s12-14.

Lichen-planus-pemphigoides-like reaction to PD-1 checkpoint blockade.

BACKGROUND: Programmed cell death protein (PD-1) and programmed death-ligand 1 (PD-L1) inhibition checkpoint blockade leads to various cutaneous adverse reactions, including bullous pemphigoid and lichen-planus-like reactions. However, lichen planus pemphigoides (LPP), manifesting histopathologic features of both lichen planus and bullous pemphigoid, has more rarely been associated with immunotherapy. METHODS: The clinical and histopathologic findings of three patients were examined, and a review of cases of LPP and bullous lichen planus secondary to PD-1 inhibitor therapy was performed. RESULTS: Three patients (two with advanced non-small-cell lung adenocarcinoma and the third with metastatic breast cancer) presented with both lichenoid eruptions and bullae. Biopsy of the lesions revealed lichenoid tissue reactions in all three patients. Together with the histopathologic findings, direct immunofluorescence (DIF) showing linear C3 and IgG deposition and positive enzyme-linked immunosorbent assay (ELISA) showing BP180 positivity supported a diagnosis of LPP in two patients. The third patient in our series also showed confirmatory ELISA testing supporting LPP. CONCLUSIONS: Lichen planus pemphigoides is a distinct cutaneous toxicity to checkpoint inhibitor therapy illustrates a possible pathogenic mechanism and the importance of dermatopathology recognition to render an accurate diagnosis.

Acute generalized exanthematous pustulosis due to terbinafine.

Acute generalized exanthematous pustulosis is a rare adverse cutaneous reaction characterized by the rapid appearance of numerous pustules arising on edematous, erythematous skin. It is commonly accompanied by fever and leukocytosis and usually resolves with discontinuation of the offending agent. Herein, acute generalized exanthematous pustulosis induced by terbinafine is described, followed by a brief review of the literature.

Psychological Interventions in the Treatment of Chronic Itch.

Patients with chronic itch suffer from higher levels of depression and anxiety than their healthy counterparts. Furthermore, psychological factors, such as stress, are known to aggravate itch. The mere act of thinking about itching can induce the sensation. Interventions like habit reversal training and arousal reduction have been shown to have positive effects on itch relief. Yet, there is still limited data on the psychological management to control the itch scratch cycle and a description of methods suitable to address itch. In this review, we describe different psychological interventions shown to be effective in the treatment of chronic itch. We also provide suggestions based on our experience of suitable interventions for patients with different types of itch.

Itch prevalence and characteristics in a Hispanic geriatric population: a comprehensive study using a standardized itch questionnaire.

A cross-sectional study of geriatric patients was performed to provide a comprehensive description of the prevalence and clinical characteristics of chronic itch affecting Hispanic geriatric subjects in Mexico. Participants were recruited from both nursing homes and geriatric ambulatory care centers. Patients without dementia were evaluated using an itch intensity and characteristic questionnaire and were assessed for itch-related dermatoses (n = 302). Data on medications and underlying systemic diseases were obtained from medical records. The prevalence of chronic itch was 25% in this population. Of those with chronic itch, 69% had xerosis, 28% had itch-related dermatoses, and 96% had documented comorbidities. The most common comorbidities were diabetes mellitus (OR = 2.3, 95% CI 1.3-3.9, p = 0.003) and chronic venous insufficiency (OR = 4.4, 95% CI 1.6-12.2, p = 0.002). The most common areas where patients experienced itch were legs (54%), back (45%), scalp (28%) and arms (27%). Patients experienced the greatest amount of itch in the winter (77%) and during the night (65%). Chronic itch is a common problem in the studied Hispanic geriatric population, and its presence significantly correlates with xerosis, diabetes, and venous insufficiency.

Dupilumab improves pruritus and skin lesions in patients with prurigo nodularis: Pooled results from 2 phase 3 trials (LIBERTY-PN PRIME and PRIME2).

Background: Phase 3 PRIME/PRIME2 trials independently demonstrated efficacy and an acceptable safety profile of dupilumab adults with moderate-to-severe prurigo nodularis. Objective: To obtain a more precise estimate of onset and magnitude of treatment effect using PRIME/PRIME2 pooled data. Methods: In PRIME/PRIME2, patients were randomized to dupilumab or placebo for 24 weeks. Pooled analysis assessed proportion of patients achieving clinically meaningful improvement in itch, clear/almost-clear skin, or both; at weeks 12 and 24; overall and by demographic subgroups and changes from baseline to week 24 in symptoms, signs, and quality of life. Results: Patients receiving dupilumab (n = 153) vs placebo (n = 158) experienced significant improvements in all tested endpoints. At week 24, 90 (58.8%) dupilumab-treated vs 30 (19.0%) placebo-treated patients achieved clinically meaningful improvement in itch, 71 (46.4%) vs 27 (17.1%) clear/almost clear skin, and 54 (35.3%) vs 14 (8.9%) achieved both (P < .0001 for all). Treatment benefits were independent of baseline demographics. Safety to week 36 was generally consistent with the known dupilumab safety profile. Limitations: On-treatment data limited to 24 weeks. Conclusions: Pooled analysis confirmed improvements reported in individual trials and revealed earlier effect onset in itch and skin pain. Dupilumab treatment showed benefits across demographics.

Cutaneous T-cell lymphoma and concomitant atopic dermatitis responding to dupilumab.

Cutaneous T-cell lymphoma (CTCL) represents a diagnostic challenge because of its large symptomatic overlap with other common skin conditions such as atopic dermatitis (AD) and psoriasis. Dupilumab has offered promising results in AD treatment; however, concerns exist that its use may exacerbate undiagnosed CTCL. We present a patient with CTCL and concomitant AD who experienced improvement in both CTCL blood involvement and AD following the addition of dupilumab therapy.

Chronic Pruritus Responding to Dupilumab-A Case Series.

BACKGROUND: Chronic pruritus is defined as itch lasting for greater than six weeks. Pruritus is a burdensome manifestation of several internal and external disease states with a significant impact on quality of life. Dupilumab has shown promise in treating a number of conditions including atopic dermatitis (AD) and asthma. Its success in reducing pruritus in AD has generated interest regarding its potential application in other pruritic conditions, such as chronic pruritus of unknown origin, uremic pruritus, and pruigo nodularis. METHODS: In this retrospective analysis, we present a series of 20 recalcitrant pruritus patients seen at a tertiary center treated with off-label dupilumab at standard AD dosing. RESULTS: Dupilumab was successful at reducing itch in all treated patients, leading to complete resolution in 12/20 patients and an overall mean NRSi reduction of 7.55. Dupilumab was well tolerated with no significant adverse effects. CONCLUSIONS: Our case series suggests dupilumab may be a safe and efficacious therapeutic option in several pruritic conditions and demonstrates the need for further studies to better ascertain its place in the pruritus treatment armamentarium.

The Genetics of Chronic Itch: Gene Expression in the Skin of Patients with Atopic Dermatitis and Psoriasis with Severe Itch.

To identify itch-related mediators and receptors that are differentially expressed in pruritic skin, we used RNA sequencing to analyze the complete transcriptome in skin from paired itchy, lesional and nonitchy, nonlesional skin biopsies from 25 patients with atopic dermatitis and 25 patients with psoriasis and site-matched biopsies from 30 healthy controls. This analysis identified 18,000 differentially expressed genes common between itchy atopic and psoriatic skin compared with healthy skin. Of those, almost 2,000 genes were differentially expressed between itchy and nonitchy skin in atopic and psoriatic subjects. Overexpression of several genes, such as phospholipase A2 IVD, substance P, voltage-gated sodium channel 1.7, and transient receptor potential (TRP) vanilloid 1, in itchy skin was positively correlated with itch intensity ratings in both atopic dermatitis and psoriasis. Cytokines such as IL-17A, IL-23A, and IL-31 had elevated gene transcript levels in both itchy atopic and psoriatic skin. However, expression of genes for TRP vanilloid 2, TRP ankyrin 1, protease-activated receptor 2, protease-activated receptor 4, and IL-10 was found to be increased only in pruritic atopic skin, whereas expression of genes for TRP melastatin 8, TRP vanilloid 3, phospholipase C, and IL-36α/γ was elevated only in pruritic psoriatic skin. This "itchscriptome" analysis will lead to an increased understanding of the molecular mechanisms of chronic pruritus and provide targets for itch treatment irrespective of disease state.

Validation and Banding of the ItchyQuant: A Self-Report Itch Severity Scale.

Because of the significant emotional and psychosocial impact of chronic pruritus, it is important to accurately assess and measure itch severity. This study aims to validate and apply clinically meaningful bands to the ItchyQuant, an illustrated self-report numeric rating scale (NRS) for itch severity. A total of 76 adults with chronic pruritus were recruited. Participants rated their itch on the ItchyQuant, on a traditional 11-point NRS, and with verbal categorizations (no, mild, moderate, or severe). There was a significant, high correlation between the ItchyQuant and NRS (>0.92, P < 0.0001), demonstrating concurrent validity. Significantly more patients (47.2%) preferred the ItchyQuant than the NRS (23.6%) or had no preference (29.2%), P = 0.0015. Significantly more patients found the ItchyQuant easier to use (45.8%) than the NRS (20.8%) or had no preference (33.3%), P = 0.008. The set of clinically meaningful bands with the highest weighted kappa coefficient of agreement (κ = 0.69) was as follows: 0 (no itch), 1-3 (mild itch), 4-7 (moderate itch), 8-10 (severe itch). The ItchyQuant is a clinically meaningful measure of itch severity, demonstrating face and concurrent validity, that many patients prefer and find easier to use when compared with a traditional NRS. We suggest that the ItchyQuant can be added to the existing armamentarium of itch severity scales. We plan to investigate the ItchyQuant further in cognitively challenged populations.

Mediators of Chronic Pruritus in Atopic Dermatitis: Getting the Itch Out?

For centuries, itch was categorized as a submodality of pain. Recent research over the last decade has led to the realization that itch is in fact a separate and distinct, albeit closely related, sensation. Chronic itch is a common complaint and has numerous etiologies. Various receptors (TRPA1, TRPV1, PAR2, gastrin-releasing peptide receptor (GRPR), Mas-related G proteins), secreted molecules (histamine, nerve growth factor (NGF), substance P (SP), proteases), and cytokines/chemokines (thymic stromal lymphopoietin (TSLP), IL-2, IL-4, IL-13, and IL-31) are implicated as mediators of chronic pruritus. While much remains unknown regarding the mechanisms of chronic itch, this much is certain: there is no singular cause of itch. Rather, itch is caused by a complex interface between skin, keratinocytes, cutaneous nerve fibers, pruritogenic molecules, and the peripheral and central nervous systems. Atopic dermatitis is one of the most itchy skin dermatoses and affects millions worldwide. The sensation of atopic itch is mediated by the interplay between epidermal barrier dysfunction, upregulated immune cascades, and the activation of structures in the central nervous system. Clinicians are in possession of an arsenal of different treatment options ranging from moisturizers, topical immunomodulators, topical anesthetic ion channel inhibitors, systemic immunomodulators, as well as oral drugs capable of reducing neural hypersensitization. Emerging targeted therapies on the horizon, such as dupilumab, promise to usher in a new era of highly specific and efficacious treatments. Alternative medicine, stress reduction techniques, and patient education are also important treatment modalities. This review will focus on the mediators of chronic pruritus mainly associated with atopic dermatitis (atopic itch), as well as numerous different therapeutic options.