Prurigo Nodularis: Pathogenesis and the Horizon of Potential Therapeutics.

Chronic pruritus that lasts for over 6 weeks can present in various forms, like papules, nodules, and plaque types, with prurigo nodularis (PN) being the most prevalent. The pathogenesis of PN involves the dysregulation of immune cell-neural circuits and is associated with peripheral neuropathies, possibly due to chronic scratching. PN is a persistent and challenging condition, involving complex interactions among the skin, immune system, and nervous system. Lesional skin in PN exhibits the infiltration of diverse immune cells like T cells, eosinophils, macrophages, and mast cells, leading to the release of inflammatory cytokines and itch-inducing substances. Activated sensory nerve fibers aggravate pruritus by releasing neurotransmitters, perpetuating a vicious cycle of itching and scratching. Traditional treatments often fail, but recent advancements in understanding the inflammatory and itch transmission mechanisms of PN have paved the way for innovative therapeutic approaches, which are explored in this review.

A review of the current management and burden of prurigo nodularis in the United States.

Prurigo nodularis (PN) is a chronic neural- and immune-mediated disease that is characterized by intense itch, history of skin scratching, and development of papulonodular lesions. These lesions can develop consequent to a cycle of itching and scratching associated with inflammation and changes in skin cells and nerve fibers (eg, pathogenic skin fibrosis, tissue remodeling, and chronic neuronal sensitization). Diagnosis of PN involves individual evaluation of clinical characteristics to identify disease and symptom severity. In the United States, adult patients with PN (estimated, < 90,000) are more likely to be older (age, 50-60 years); in addition, this disease is detected at higher rates in women and Black individuals relative to other demographic subgroups. Still, the small population of patients with PN exhibits considerably high use of health care resources and experiences considerable symptom burden and negatively impacted quality of life. Further, PN is associated with increased rates of a range of comorbid diseases compared with other inflammatory dermatoses (eg, atopic dermatitis, psoriasis). Adequate treatment must address both the neural and immunological component of the disease; there remains a great unmet need for safe and effective therapies that can reduce the burden of disease.

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.

Chronic Nodular Prurigo: An Update on the Pathogenesis and Treatment.

Chronic nodular prurigo (CNPG) is a recalcitrant chronic itchy disorder that affects the quality of life. It can be triggered by multiple etiologies, such as atopic dermatitis, diabetes, and chronic renal diseases. The mechanisms of CNPG are complicated and involved the interaction of the cutaneous, immune, and nervous systems. Diverse immune cells, including eosinophils, neutrophils, T cells, macrophages, and mast cells infiltrated the lesional skin of CNPG, which initiated the inflammatory cytokines and pruritogens release. In addition, the interaction between the immune cells and activated peripheral sensory nerve fibers by neurotransmitters caused neuroinflammation in the skin and intractable itch. This itch-scratch vicious cycle of CNPG results in disease exacerbation. CNPG is difficult to treat with traditional therapies. Recently, great advances have been made in the pathophysiology of both inflammation and pruritus transmission in CNPG. In this review, we summarize the updated mechanisms and novel therapies for CNPG.

Healthcare Utilization and Treatment Patterns in Patients with Chronic Prurigo and Chronic Pruritus in Germany.

BACKGROUND: To date, there have been no large studies describing real-world treatment of chronic prurigo (CPG) and pruritus (CPR) in Germany. OBJECTIVE: To determine the healthcare utilization, treatment patterns, and costs associated with CPG and CPR in Germany. METHODS: Retrospective analysis using anonymized claims data (German DAK-Gesundheit), based on a 40% sample of all insured adults of the DAK-Gesundheit on December 31, 2010 (N = 2,006,003). RESULTS: Patients with CPR (prevalence 2.2%) most commonly visited general medicine/general practitioners (GPs, 80.1%), followed by gynecologists (66.1%) and dermatologists (51.1%). Patients with CPG (prevalence 0.2%) most commonly visited dermatologists (85.7%), GPs (78.1%), and ophthalmologists (47.2%). Of adult patients, 44% received at least one drug prescription. Two thirds of patients with a drug prescription received ≥1 topical drug (66.2%), and 54.3% ≥1 systemic drug (total costs of approximately EUR 550,000 and 2,500,000, respectively). Of patients with CPG, 33.8% received ≥1 systemic and 45.1% ≥1 topical drug prescription (costs of approximately EUR 360,000 vs. 105,000). Of patients with CPR, 23.5% received ≥1 systemic and 28.6% ≥1 topical drug prescription (costs of approximately EUR 2,000,000 vs. 500,000). Of patients with CPG, 5.8% received ≥1 phototherapy application vs. 1.2% of patients with CPR. CONCLUSIONS: These findings reflect the reality of care and can form a basis for the identification of overuse, underuse, and misuse in order to design CPG and CPR healthcare more effectively and efficiently.

2020 guidelines for the diagnosis and treatment of prurigo.

Prurigo is a treatment-resistant skin disease characterized by multiple isolated papules/nodules that cause severe itch. Prurigo papules/nodules occur either as primary lesions or as secondary lesions due to persistent scratching. The fundamental concepts and classifications of prurigo have not been sufficiently established, and considerable confusion remains regarding this topic. Clinical guidelines for chronic prurigo in Japan were published in 2012 in an attempt to reduce confusion regarding the concepts of prurigo and to standardize laboratory tests and treatments. However, the diagnostic terms for prurigo and associated concepts have changed over time, and new forms of treatment are under development. We have, thus, updated and revised the guidelines to classify prurigo based on clinical forms and causes, and disease name classifications based on the clinical form have been further simplified, such as prurigo nodularis, prurigo chronica multiformis, and prurigo (not otherwise specified). Expressions for acute, subacute, and chronic forms are not used. These guidelines outline the current concepts and specify treatments for prurigo.

Prurigo nodularis comparative treatment outcome in patients attending a tertiary hospital in northern Tanzania.

Prurigo nodularis (PN) is a chronic, benign neurodermatitis of unclear etiology characterized by excoriated, intensely pruritic nodules secondary to an intense itch-scratch cycle. PN treatment is still a challenge, and it is frustrating for both dermatologists and patients. The evidence for the effectiveness of a readily available treatment like cryotherapy is limited. To compare the efficacy of cryotherapy vs 0.05% clobetasol propionate in PN patients attending the RDTC, Northern Tanzania, from October 2018 to July 2019. Based on previous year data, it was expected to enroll nine patients. Assent and consent were obtained. Fourteen patients were enrolled, 11 analyzed; intra-subject control done each one-half of the body received either intervention randomly. The cryotherapy was given in two cycles from 5 to 10 s in one session and clobetasol propionate was applied twice daily for 4 weeks. The patients were followed-up weekly by telephone reminded them to apply clobetasol. Data entry and analysis was done in SPSS version 20. Ethical considerations were observed. Eleven patients were analyzed; four (36%) males and seven (64%) females. Cryotherapy had nodule clearance in the 11 patients of 75% to 100% in 11 (100%) and clobetasol propionate only in three of the patients. Seven patients (63.6%) preferred cryotherapy. Cryotherapy preferred above clobetasol propionate.

Prurigo Pigmentosa: Demographics and Characteristics in 14 Caucasian Patients.

BACKGROUND: Prurigo pigmentosa (PP) is an inflammatory dermatosis typically reported in young Asian women and characterized by recurrent papulovesicular lesions resolving with a postinflammatory reticulated hyperpigmentation. METHODS: We have included all consecutive patients with PP diagnosed in our tertiary center between 2013 and 2020. The clinical information was retrospectively collected from medical records. RESULTS: We identified 14 patients with PP. The median age at the time of diagnosis was 29.5 years (range 17-43 years), while the female-to-male ratio was 13:1. Diagnostic delay varied from 10 days to 10 years (mean of 25 months). Light microscopy studies consistently showed presence of a lymphohistiocytic infiltrate in combination in 40% of cases with neutrophils. Interface changes were found in 60% of cases. In 6 (43%) of 14 cases, there was a chronological relationship between the starting of a new diet and the development of the first flares. Treatment with doxycycline in 9 patients resulted in a complete regression of the lesions. LIMITATION: This was a retrospective study in a tertiary referral hospital. CONCLUSIONS: Our observations indicate that PP is not so rare in Europe as previously thought and is often diagnosed after a long delay. Demographics, clinical characteristics and triggering factors in Caucasian patients are similar to those described in the Asian population. Diagnosis is based on the peculiar recurrent course and distinctive clinicopathological features. Tetracyclines represent the first-line therapy in PP.

Phototherapy for Prurigo Nodularis: Our Experience and a Review of the Literature. / Fototerapia en el prurigo nodular. Experiencia propia y revisión de la literatura.

BACKGROUND AND OBJECTIVE: Prurigo nodularis is a chronic inflammatory skin disease characterized by highly pruritic nodular lesions that cause constant itching and scratching and significant quality-of-life impairment. It has been described in a range of conditions, including skin diseases (mainly atopic dermatitis) and metabolic, neurological, and psychiatric disorders. The pathophysiological mechanisms are largely unknown. Various modalities of phototherapy have been described as appropriate and safe treatments for achieving clinical control and alleviating symptoms. In this article, we describe our experience with phototherapy in patients with prurigo nodularis. MATERIAL AND METHODS: Retrospective observational study of patients who received their first cycle of phototherapy to treat prurigo nodularis between March 2011 and October 2019. Information was collected on epidemiological and clinical characteristics, concomitant treatments, type and duration of phototherapy, maximum dose reached, and response to treatment. RESULTS: We studied 44 patients (30 women and 14 men) with a median age of 65.5years. The most common form of phototherapy used was narrowband UV-B phototherapy (34 cycles, 77.27%) followed by a combination of UV-B and UV-A phototherapy (8 cycles). Response to treatment was considered satisfactory (clearance rate of ≥75%) in 24 patients (55.4%). CONCLUSIONS: Phototherapy is a suitable treatment for prurigo nodularis in a considerable proportion of patients. It can be used as monotherapy or combined with other treatments.

Investigator's Global Assessment of Chronic Prurigo: A New Instrument for Use in Clinical Trials.

Chronic prurigo is a pruritic disease characterized by the development of pruriginous lesions due to scratching. The number of lesions is representative of the stage of the disease, while the presence of excoriations reflects the scratching activity. Aim of this study was to validate a new developed tool for the objective assessment of chronic prurigo. Investigator's Global Assessment scales for stage and activity were completed for 187 patients with chronic prurigo, who also reported patient-reported outcomes for itch intensity and quality of life. To assess the reliability and objectivity of the Investigator's Global Assessment, 5 independent raters completed the Investigator's Global Assessment scales for 8 patients twice. The scores increased with increased intensity of pruritus. The Investigator's Global Assessment stage scales correlated strongly with each other (Kendall's-tau-b 0.62) and moderately with the Investigator's Global Assessment activity scale (Kendall's-tau-b 0.47). Intra-rater test-retest reliability was excellent for all items, while the congruence among raters was very good for Investigator's Global Assessment - chronic prurigo activity (Kendall's W 0.84) and good for Investigator's Global Assessment stage scales (Kendall's W 0.747). Investigator's Global Assessment - chronic prurigo stage and activity are thus the best Investigator's Global Assessment instruments for use in assessing chronic prurigo.

Prurigo nodularis: Pathogenesis and management.

Prurigo nodularis is a chronic skin condition characterized by severely pruritic nodules that cause a profound negative impact on quality of life. The second article in this 2-part continuing medical education series focuses on reviewing the pathogenesis of prurigo nodularis and exploring management algorithms for this condition. In addition, we discuss some emerging and novel therapies for treating prurigo nodularis. The first article in this 2-part series describes the broader epidemiology, patient demographics, physical examination findings, and symptoms to aid in the timely recognition and diagnosis of prurigo nodularis.

Treatment and Burden of Disease in a Cohort of Patients with Prurigo Nodularis: A Survey-based Study.

Prurigo nodularis is a pruritic dermatosis with poor treatment options. To describe treatment patterns, comorbidities, pruritus, and quality of life a survey was administered to 92 patients with prurigo nodularis. A total of 52 patients completed the survey. The most frequently used treatments were topical corticosteroids, which were prescribed to 49/52 patients, with positive effect in 13/49. A total of 46/52 patients were treated with ultraviolet B, and 9/46 reported a positive effect. A positive effect was reported for topical corticosteroids under occlusion in 21/40, for zinc dressing treatment in 17/37, for steroid injection in 9/14, for methotrexate in 5/16, and for thalidomide in 4/12 of treated patients. Thirty-six patients reported a Pittsburgh Sleep Quality Index >5, indicating poor sleep. Patients with prurigo nodularis are severely bothered by pruritus negatively affecting quality of life. Various treatments are prescribed; most frequently topical corticosteroids and ultraviolet B. Surprisingly, patients reported topical corticosteroids under occlusion, zinc-dressing treatment and steroid injection as the most effective.

Chronic prurigo: A retrospective study of 168 cases.

Chronic prurigo is classified into two clinical subtypes: prurigo nodularis (PN) and prurigo chronica multiformis (PCM) in Japan. In this study, we retrospectively investigated the clinical features of 168 patients with chronic prurigo (103 with PN and 65 with PCM) diagnosed at the Tokyo Medical and Dental University, and compared age, sex, prevalence of comorbidities, blood test results, histology and treatment efficacy in both groups. We found that patients with PCM were significantly older than those with PN. Males were more frequently diagnosed with PCM than females; however, both sexes were similarly affected by PN. Chronic infection was more prevalent in PN, whereas diabetes was more common in PCM. For both subtypes, serum immunoglobulin E levels were elevated above the normal range. However, serum thymus and activation-regulated chemokine/CCL17 levels and the number of blood eosinophils were significantly higher in patients with PCM than in those with PN. Histologically, much higher numbers of CD4+ cells than CD8+ cells were distributed in the lesions of both subtypes. Eosinophils were distributed predominantly in intracollagenous lesions in PCM but were observed mainly in perivascular lesions in PN. There were no differences in basophil and mast cell distributions in the lesions of the two groups. Treatment efficacy was also similar in both subtypes. Together, both subtypes exhibit inflammation patterns predominantly driven by T-helper 2 cells. With respect to PCM, elevated numbers of blood eosinophils and the recruitment of these cells into intracollagenous areas may be important for pathogenesis.