Prurigo Nodularis Lesions Research Articles

Successful treatment of prurigo nodularis with upadacitinib.

Prurigo nodularis (PN) is a debilitating condition marked by raised, intensely itchy, often painful nodules on the skin. A 50-year-old Asian man presented with a 7-year history of PN lesions on his trunk and extremities. Observation suggests that upadacitinib could be a promising option for treating PN.

Validation of a scoring algorithm for the clinician-reported outcome tool 'prurigo activity and severity (PAS)' based on clinical studies of dupilumab in adults with prurigo Nodularis.

Prurigo nodularis (PN) also known as chronic prurigo, is a chronic inflammatory skin disease characterized by intensely itchy nodules/lesions which occur due to intensive scratching. PN management is, in part, based on clinician evaluations of PN lesions, which can be supported by clinician-reported outcomes (ClinRO) such as the Prurigo Activity and Severity (PAS) instrument. A 5-item version of PAS was included in recent phase-3 dupilumab PN trials (PRIME [NCT04183335]/PRIME2 [NCT04202679]). The PAS score was derived using the unweighted sum of 3-items of the 5-item PAS (range, 0-11; higher score indicates worse activity and severity): Item 2 (number of lesions), Item 5a (percentage of lesions with excoriations/crusts) and Item 5b (percentage of healed lesions) for use in clinical practice and for communication of treatment benefit to physicians. To evaluate the measurement properties of PAS score and derive within-patient (responder definition) and between-group improvement thresholds for interpreting changes in PAS score in patients with PN. The data source was the pooled treatment group, intention-to-treat (ITT) data from the phase-3 PRIME (NCT04183335) and PRIME2 (NCT04202679) studies evaluating the efficacy of dupilumab in adult patients with PN with ≥20 nodules and severe itch uncontrolled with topical therapies. PAS score reliability, validity and sensitivity to change were evaluated, and anchor- and distribution-based methods were applied to derive meaningful change thresholds. The pooled ITT population included 311 patients (mean age 49.5 years, 65.3% female). Adequate to good psychometric properties were demonstrated for PAS score. The within-patient meaningful improvement threshold was estimated as 3.0 points (absolute change) and 37% (per cent change). A 1.7-point (absolute change) and 20% (per cent change) improvement were estimated to reflect a between-group meaningful change in PAS score. PAS score is a simple, clinically relevant indicator of PN lesion activity and severity supported by suitable psychometric performance.

Clinical, immunological and molecular profiles of DOCK8 deficiency in six patients from a tertiary care centre in North India.

Dedicator of cytokinesis protein 8 (DOCK8) deficiency is an autosomal recessive form of combined immunodeficiency. This rare disorder is characterized by an increased predisposition to allergy, autoimmunity and malignancies. To analyse clinical, immunological and molecular profiles of patients with DOCK8 deficiency. Clinic records of all patients attending the primary immunodeficiency clinic from 2018 to 2021 were reviewed. Six patients from five families were found to have DOCK8 deficiency. Median age at diagnosis was 7.5 years (range 2-13), with a male/female ratio of 5 : 1. Among the six patients, recurrent eczematous skin lesions were the predominant cutaneous manifestation, present in five patients (83%). Warts and molluscum contagiosum were evident in two patients (33%) and one patient (16%), respectively. Two patients had recalcitrant prurigo nodularis lesions and two had epidermodysplasia verruciformis-like lesions. Food allergies and asthma were reported by one patient each. Of the six patients, recurrent sinopulmonary infections were detected in five (83%). Epstein-Barr virus-driven non-Hodgkin lymphoma with liver metastases was the only case of malignancy, in a 4-year-old boy. IgE was elevated in all patients. Lymphopenia and eosinophilia were observed in three patients (50%) and five patients (83.3%), respectively. Genetic analysis showed DOCK8 pathogenic variants in all patients: homozygous deletion mutations in two patients, compound heterozygous deletion mutations in one, and homozygous nonsense mutations in two. A novel pathogenic homozygous missense variant in the DOCK8 gene was identified in one patient. DOCK8 deficiency should be considered as a possibility in any patient with early onset eczema, cutaneous viral infections and increased predisposition to allergy, autoimmunity and malignancy.

Skin Microbiome in Prurigo Nodularis.

Prurigo nodularis (PN) is a chronic condition characterized by the presence of nodular lesions accompanied by intense pruritus. The disease has been linked to several infectious factors, but data on the direct presence of microorganisms in the lesions of PN are scarce. The aim of this study was to evaluate the diversity and composition of the bacterial microbiome in PN lesions by targeting the region V3-V4 of 16S rRNA. Skin swabs were obtained from active nodules in 24 patients with PN, inflammatory patches of 14 patients with atopic dermatitis (AD) and corresponding skin areas of 9 healthy volunteers (HV). After DNA extraction, the V3-V4 region of the bacterial 16S rRNA gene was amplified. Sequencing was performed using the Illumina platform on the MiSeq instrument. Operational taxonomic units (OTU) were identified. The identification of taxa was carried out using the Silva v.138 database. There was no statistically significant difference in the alpha-diversity (intra-sample diversity) between the PN, AD and HV groups. The beta-diversity (inter-sample diversity) showed statistically significant differences between the three groups on a global level and in paired analyses. Staphylococcus was significantly more abundant in samples from PN and AD patients than in controls. The difference was maintained across all taxonomic levels. The PN microbiome is highly similar to that of AD. It remains unclear whether the disturbed composition of the microbiome and the domination of Staphylococcus in PN lesions may be the trigger factor of pruritus and lead to the development of cutaneous changes or is a secondary phenomenon. Our preliminary results support the theory that the composition of the skin microbiome in PN is altered and justify further research on the role of the microbiome in this debilitating condition.

Extracellular matrix and dermal nerve growth factor dysregulation in prurigo nodularis compared to atopic dermatitis.

Prurigo nodularis (PN) is a chronic, pruritic, inflammatory skin disease characterized by hyperkeratotic nodules on the trunk and extremities. While there is growing research on the immunological basis of PN, the neuropathic and structural components of PN lesions are unknown. This study examines the inflammatory, neuropathic, and structural pathways in PN compared to atopic dermatitis (AD) using RNA-sequencing of the lesional and non-lesional skin tissue of PN and AD patients, as well as immunohistochemistry analysis of nerve growth factor (NGF), a neurotrophic factor that regulates nerve development. Transcriptomic analysis of skin biopsies revealed that compared to lesional AD skin, lesional PN skin had significantly increased expression of NGF, matrix metalloproteinases, OSM, MCEMP1, IL1α, IL1β, CXCL2, CXCL5, CXCL8, and insulin-like growth factors in PN compared to AD, and decreased expression of CCL13, CCL26, EPHB1, and collagens (COL4/6). Gene set enrichment analysis demonstrated higher enrichment of keratinization, cornified envelope, myelin sheath, TGF-beta signaling, extracellular matrix disassembly, metalloendopeptidase activity, and neurotrophin-TRK receptor signaling pathways in PN. On immunohistochemistry, PN lesions demonstrated higher dermal NGF expression compared to AD. We present novel findings demonstrating increased neurotrophic and extracellular matrix remodeling signatures in PN compared to AD, possibly explaining the morphological differences in their lesions. These signatures may therefore be important components of the PN pathogenesis and may serve as therapeutic targets.

33307 Nemolizumab is associated with a rapid reduction of itch and sleep disturbance in patients with prurigo nodularis

Background: Itch and sleep disturbances are major problems for patients with prurigo nodularis (PN). The interleukin 31 receptor inhibitor nemolizumab has shown significant efficacy in improving PN lesions and itch; this post hoc analysis evaluated onset of action on pruritus and sleep disturbance.

855 Cutaneous transcriptomics identifies fibroproliferative and neurovascular gene dysregulation in prurigo nodularis compared to psoriasis and atopic dermatitis

Prurigo nodularis (PN) is a chronic inflammatory skin disease that is associated with several systemic comorbidities, suggesting dysregulation of cutaneous and systemic inflammatory processes. Th2, 17, and 22 immune signatures have been identified in PN lesions, highlighting shared cutaneous gene signatures between PN, psoriasis (PsO), and atopic dermatitis (AD). We aimed to identify pathways specific to PN by comparing the skin transcriptomes of PN, PsO, and AD. RNA-seq was performed on lesional and nonlesional biopsies from PN patients without a history of atopy or PsO.

Racial differences in dysregulation of the renin-angiotensin-aldosterone system in patients with prurigo nodularis

BackgroundThere are limited data characterizing the association between renal disease and prurigo nodularis (PN). ObjectiveTo characterize the association and describe mechanistic disease linkages between PN and renal comorbidities. MethodsWe conducted a cross-sectional analysis of renal comorbidities in PN using TriNetX, a global health research network providing access to medical records. Epidemiological findings provided the basis for translational studies on plasma and skin biopsy samples from PN patients stratified by race. ResultsPN was associated with stages 1–5 of chronic kidney disease (CKD), end-stage renal disease, nephritic syndrome, nephrotic syndrome, glomerular disease, and tubulointerstitial disease, but the associations were significantly stronger in black patients. Compared to controls, CKD progression was faster (HR 2.88, 95% CI: 1.01–8.26) only in black PN (10-year survival: 63.5% black vs. 85.5% white). Circulating plasma angiotensinogen levels were dysregulated (P < 0.001) only in black PN patients. Cutaneous transcriptomic analysis of genes related to the renin-angiotensin-aldosterone system (RAAS) revealed considerable dysregulation in PN lesions with greater dysregulation in black patients. ConclusionsSignificant dysregulation of the cutaneous and systemic RAAS in black PN patients may explain the increased incidence and severity of renal disease.

Increased IL-31 expression in serum and tissue protein in prurigo nodularis.

Background:Prurigo nodularis (PN) is a chronic pruritic skin disease which can greatly impact patients’ quality of life. Moreover, the pathogenesis remains unclear, making it a difficult-to-treat condition.Aims:To investigate the expression of interleukin-31 (IL-31) in serum and skin biopsy specimens of PN patients and healthy subjects and identify its possible correlation to disease severity and itch intensity.Methods:Patients with PN and healthy volunteers were recruited for the study. Expression levels of IL-31 were measured by enzyme-linked immunosorbent assay and immunohistochemistry. Baseline characteristics, disease activity, itch intensity, and related laboratory results were collected.Results:Forty-three PN patients and 31 healthy subjects participated in our study. The PN patients had significantly higher mean serum IL-31 levels than the healthy subjects (52.9 ± 18.2 versus 36.3 ± 10.7 pg/ml, p < 0.001). Epidermal and dermal PN lesions also exhibited significantly higher IL-31 expression compared with the healthy skin (p < 0.001 and p = 0.01, respectively). However, there was no significant difference in serum or lesional expression of IL-31 by disease severity or itch intensity.Conclusion:Increased IL-31 expression in serum and PN lesions suggests that IL-31 has a potential role in the pathogenesis of PN.

A prospective study examining the expression of STAT 1, 3, 6 in prurigo nodularis lesions with its immunopathogenic and therapeutic implications

Prurigo nodularis (PN) is a chronic dermatologic condition manifesting as multiple papulonodular lesions occurring on the background of intense pruritus. PN could be primary or secondary. The exact immune pathogenesis of PN is not yet clear, and multiple pathways are proposed with the JAK-STAT pathway rarely being investigated. In this study, our aim was to assess the role of Th cells in PN by comparing the expression of STAT 1, 3, and 6 in involved and normal skin of primary prurigo nodularis. A total of 49 clinico-histopathologically proven cases of primary prurigo nodularis were included. Two skin biopsies for each patient from lesional and non-lesional skin were stained with STAT 1, 3, and 6, and the nuclear staining pattern in the epidermis was graded as strong, moderate, weak, or none. Statistically significant expression of STAT 3 and STAT 6 staining was seen in the epidermis of the lesional skin as compared to non-lesional skin. Our study showed a marked dominance of STAT 3 and STAT 6 staining in the epidermis which signifies that the keratinocytes play an important role in PN and suggest that Th2, Th17, and Th22 cytokines mediate the tissue response in PN.

Abnormal keratin expression pattern in prurigo nodularis epidermis.

BackgroundPrurigo nodularis (PN) is a highly pruritic, chronic dermatosis and difficult to treat. PN lesions are characterized by existence of many hyperkeratotic, erosive papules and nodules. However, the pathogenesis of PN still remains unelucidated.AimTo clarify the keratin role in the epidermis hyperproliferation, the keratin expression pattern in the PN lesional skin.MethodsIn this study, we enrolled 24 patients with PN and 9 healthy control volunteers. K1/K10, K5/K14, K6/K16/K17 expression pattern were investigated by using immunohistochemical staining.ResultsThe lesional skin consists of the thickened spinous layers, in which active cell division was found. K5/K14 were upregulated in PN lesional epidermis, the staining signal localized in the basal layer and lower suprabasal layers. Hyperproliferation‐associated K6 was found in all layers of epidermal lesional skin, especially in the spinous layers. In contrast, K16 was only detected in the basal and lower suprabasal layers, K17 was observed in the basal and spinous layers. Terminal differential keratins K1/K10 were upregulated, detected in the pan‐epidermis, but spared in the basal and low suprabasal layers.ConclusionThe keratinocytes enter an alternative differentiation pathway, which are responsible for the activated keratinocyte phenotype, abnormal keratins expression potentially contributes to the keratinocytes proliferation, subsequently lead to increased lesional skin epidermis thickness, hyperkeratiosis and alteration of skin barrier properties.

Keratin 17 is Not Always a Marker of Proliferation of Keratinocytes in Skin Diseases.

PurposeKeratin 17 (K17) is an embryonic keratin and overexpression is seen in psoriasis, which is a hyperproliferation skin disease. Nonetheless, whether it is also highly expressed in other proliferative skin diseases remains unclear. The aim of this study is to explore the expression of K17 in cutaneous lichen planus (CLP), lichen simplex chronicus (LSC), and prurigo nodularis (PN).MethodsA total of 20 skin samples from CLP lesions, 20 from LSC lesions, 20 from PN lesions, and 10 healthy adult skin tissues were obtained. Then, the expression of K17 was analyzed using immunohistochemistry on paraffin-embedded tissue sections. Furthermore, quantitative and semi-quantitative immunohistochemical scores of K17 were independently evaluated under a microscope by 2 dermatologists.ResultsImmunohistochemical analysis revealed that in normal skin, K17 was minimally expressed. Nevertheless, it was highly expressed in all epidermal layers in CLP lesions (P-value <0.01), and negatively expressed in LSC and PN lesions (all P-value >0.05). The average gray value of K17 in CLP was 151.153±13.985 (P-value <0.001), while the average values of K17 in LSC and PN were 178.720±12.001 and 181.316±8.920, respectively (all P-value >0.05).ConclusionK17 is potentially expressed in certain inflammatory skin diseases, including psoriasis and lichen planus. Besides, it is not always a marker of hyperproliferation of keratinocytes in skin diseases.

28367 A case of chronic prurigo nodularis, angiolymphoid hyperplasia with eosinophilia, and reactive lymphadenopathy: Intersection of multiple processes, or a novel clinical entity?

Background: Prurigo nodularis (PN) is a chronic skin disease characterized by intensely pruritic, hyperkeratotic nodules that can have significant deleterious effects on patient quality of life and are often difficult to treat. Various etiologies have been shown to trigger the development of PN lesions by initiating the itch-scratch cycle. Angiolymphoid hyperplasia with eosinophilia (AHLE) is a rare benign vascular tumor which may cause pain, bleeding or pruritus. We present a case of PN-like lesions with features of AHLE on pathology, which has been recalcitrant to several topical and systemic therapies.

434 The study design of two trials of dupilumab in patients with prurigo nodularis inadequately controlled with topical therapies: LIBERTY PN PRIME and PRIME 2

Multiple case series suggest dupilumab should be studied further in patients with prurigo nodularis (PN). We describe the study design of two phase 3 trials to assess if dupilumab can improve itch and resolve PN lesions. PRIME (NCT04183335) and PRIME2 (NCT04202679) are 2 double-blind, placebo-controlled, multicenter, parallel-group studies consisting of 2–4 weeks screening, 24 weeks randomized treatment with dupilumab or placebo, and 12 weeks follow-up. Low-/medium-potency topical corticosteroids (TCS)/topical calcineurin inhibitors are permitted.

Clinicopathological Differences between Acquired Reactive Perforating Collagenosis and Prurigo Nodularis

Background: Acquired reactive perforating collagenosis (ARPC) is a skin disease characterized by multiple itchy nodules, which is notably similar to the skin eruptions of prurigo nodularis (PN). The aim of this study was to prove the clinicopathological differences between ARPC and PN. Methods: We examined 22 patients with ARPC (6 males and 16 females) and 38 patients with PN (27 males and 11 females), diagnosed clinically and histologically. Transepidermal elimination of collagen which is characteristic histological findings for ARPC was found in all ARPC patients, but not in PN patients even in a serial section. Clinical findings, laboratory data, histological findings, immunohistochemical results, and efficacy of the therapies were compared between the two groups. Results: On evaluation of laboratory data, thymus and activation-regulated chemokine (TARC) levels and peripheral eosinophil counts were lower in ARPC than in PN. Histologically, we observed greater infiltration of neutrophils, histiocytes, and lymphocytes and more extensive capillaries in ARPC than in PN. Upon immunohistochemical analysis, CD163+ macrophages were found to be more abundant in the upper-to-deep dermis of ARPC, and both CD4+ T cells and CD8+ T cells were significantly increased in the mid-to-deep dermis of ARPC. The efficacies of topical steroid and antihistamines were improved by the addition of emollients in ARPC. Conclusion: This is the first report to show the histological differences in cell infiltration between the lesions of ARPC and PN. It is likely that inflammation mediated by neutrophils and M2 macrophages may be involved in the formation of ARPC lesions, as against PN lesions mediated by epidermal changes such as spongiosis. It is suggested that the addition of emollients can increase the efficacy of treatments for ARPC. However, further studies are necessary to define the precise pathomechanisms of ARPC and the effects of emollients on ARPC.

Long-term dupilumab treatment for chronic refractory generalized prurigo nodularis: A retrospective cohort study

Long-term dupilumab treatment for chronic refractory generalized prurigo nodularis: A retrospective cohort study

Prurigo nodulaire réfractaire : apport de la psychothérapie chez trois patients marocains

Prurigo nodularis is a chronic skin disorder with an important impact on patients’ quality of life. Treatment of prurigo nodularis is difficult and often disappointing. Psychological and emotional distress are concurrent factors in some cases of prurigo nodularis. Our objective was to propose a psychotherapeutic management in patients with a refractory prurigo nodularis. In the course of our work, patients were able to verbalize an important mental suffering. By listening to our patients, we have been able to alleviate their suffering. This led to the resolution of the pruritus and the regression of prurigo nodularis lesions. These results confirm the importance of psychological management in the care of every patient suffering from nodular prurigo nodularis, in addition to classic treatments.

Keratin 17 is induced in prurigo nodularis lesions

AbstractPrurigo nodularis (PN) is a highly pruritic chronic inflammatory dermatosis with unknown pathogenesis. It is characterized by the existence of many hyperkeratotic, erosive papules and nodules, and the development of lesions may be associated with hyperproliferation and aberrant differentiation of keratinocytes. Keratin 17 (K17) is overexpressed selectively in human proliferative skin diseases, promoting keratinocyte proliferation not found in normal epidermis. In this study, we investigated the mRNA levels and protein levels of K17 in lesional and perilesional skin using quantitative real-time polymerase chain reaction and western blot. We demonstrate that K17 is induced in lesional and perilesional skin in PN. The mRNA expression level of K17 was upregulated in PN lesions (P &lt; 0.01), with multifold changes in the PN lesion (normalized to glyceraldehyde-3-phosphate dehydrogenase as the housekeeping gene) showing a median positive correlation with PRUNOSI (P &lt; 0.05). The protein level of K17 was also markedly increased in PN lesions (P &lt; 0.01). In conclusion, K17 is highly induced in PN lesions, which may contribute to the proliferation of keratinocytes and the pathogenesis of PN.

Prurigo nodularis as a sweat gland/duct-related disorder: resolution associated with restoration of sweating disturbance.

Little attention has been given to the involvement of sweat glands/ducts in the pathogenesis of prurigo nodularis (PN). According to recent studies, PN is likely to develop under conditions characterized by dry skin, such as atopic dermatitis (AD), suggesting a strong impact of skin dryness on PN development. No therapeutic modalities produced complete resolution of PN without exacerbations. We previously reported that increases in skin dryness by sweating disturbance could initiate the development of AD. We investigated whether sweating responses were impaired in refractory PN lesions; and, if so, we asked whether the PN lesions could resolve by restoring sweating disturbance. Using the impression mold technique, which allows an accurate quantification of individual sweat gland/duct activity, we examined basal sweating under quiescent conditions and inducible sweating responses to thermal stimulus in PN lesions and normal-appearing skin in the same patients before and after treatment with a moisturizer or topical corticosteroids. Sweating disturbance, either basal or inducible, was most profoundly detected in the "hub" structure corresponding to the center of PN papule before the treatment. This sweating disturbance was immunohistochemically associated with the leakage of sweat into the dermis. This disturbance was restored by treatment with a moisturizer. Our limitations include a relatively small patient cohort and lack of blinding. Sweating disturbance could be one of the aggravating factors of PN development. Refractory PN with low skin hydration may resolve by restoring sweating disturbance.

Serlopitant reduced pruritus in patients with prurigo nodularis in a phase 2, randomized, placebo-controlled trial

Anecdotal evidence suggests that neurokinin 1 receptor antagonism reduces pruritus intensity in chronic pruritic conditions such as prurigo nodularis (PN). This study assessed safety and efficacy of the neurokinin 1 receptor antagonist serlopitant for treatment of pruritus in PN. In this randomized, double-blind, placebo-controlled study, 128 patients with chronic, treatment-refractory PN for more than 6weeks received serlopitant, 5mg, or placebo orally once daily for 8weeks. The primary end point was change in average itch visual analog scale score at weeks 4 and 8. Average itch visual analog scale scores significantly improved with serlopitant versus with placebo at weeks 4 and 8: the least squares mean difference (serlopitant minus placebo) was -1.0 at week 4 (P=.02) and -1.7 at week 8 (P<.001). The least squares mean difference between serlopitant and placebo reached statistical significance at week 2 (-0.9 [P=.011]). The most frequently reported treatment-emergent adverse events in the serlopitant group were nasopharyngitis, diarrhea, and fatigue. The 8-week duration may be insufficient to assess clinically relevant resolution of PN lesions. Serlopitant reduced pruritus in patients with treatment-refractory PN and was well tolerated.