Itch: Epidemiology, clinical presentation, and diagnostic workup.

Itch, or pruritus, is the uncomfortable sensation underlying the desire to scratch. Itch is a very common complaint in the general population that can result from dermatologic, systemic (eg, renal, hepatobiliary, endocrine), paraneoplastic, neuropathic, and psychogenic etiologies. Chronic itch is associated with significant sleep disturbances and profoundly reduces overall quality of life. Certain populations, including elderly and African Americans, are at increased risk of experiencing heightened burden of itch. Because of the variable clinical presentation and wide-ranging etiologies, itch presents a challenge for clinicians. The initial evaluation should include a complete blood count, with differential, hepatic, renal, and thyroid function testing along with diabetes screening. Further testing should be guided by history and physical examination findings. There should be a heightened concern for underlying malignancy in individuals older than 60 years of age who have a history of liver disease and diffuse itch less than 12 months of duration. For individuals with chronic pruritus of unknown origin, increased blood eosinophils may serve as a biomarker of T helper cell type 2 polarization and response to immunomodulator therapies. In this first part of a 2-part continuing medical education series, we describe the broader epidemiology and specific conditions associated with itch and the clinical presentation and diagnostic workup for patients with itch.

Itch: Pathogenesis and treatment.

Itch pathogenesis is broadly characterized into histaminergic and nonhistaminergic pathways and transmitted via 2 main receptor families: G protein-coupled receptors and transient receptor potential channels. In the skin, itch is primarily transmitted by unmyelinated type C and thinly myelinated type Aδ nerve fibers. Crosstalk between the immune and neural systems modulates itch transmission at the skin, spinal cord, and brain. Among the many known pruritogens, Th2 cytokines, such as interleukin-4, interleukin-13, interleukin-31, and thymic stromal lymphopoietin, are particularly important mediators that signal through shared Janus kinase pathways, representing novel targets for novel itch therapeutics. Emerging evidence has also revealed that the opioidergic system is a potent modulator of itch transmission, with increased µ-opioid activity and decreased κ-opioid activity contributing to itch pathogenesis. Optimal management of itch requires that treatment approaches be tailored to specific etiologic itch subtypes. When the etiology is unknown and patients are given a diagnosis of chronic pruritus of unknown origin, treatment should be guided by the presence of Th2 polarization, often reflected by increased blood eosinophils. In the second article of this 2-part series, we outline our current understanding of itch pathogenesis and discuss available and emerging treatments for itch.

Real-world comorbidities of atopic dermatitis in the US adult ambulatory population.

BACKGROUND: Atopic dermatitis (AD) is a pruritic, inflammatory skin disease associated with various comorbidities. However, comprehensive analyses of real-world comorbidities in adult patients with AD are limited. OBJECTIVE: To characterize the real-world comorbidities associated with adult AD in an ambulatory population. METHODS: We queried the MarketScan Commercial Claims and Encounters database from January 1, 2017 to December 31, 2017. Multivariable logistic regressions were performed to compare comorbidities in adult patients with AD versus age- and sex-matched controls. RESULTS: A total of 39,779 patients with AD and 353,743 controls were identified. Increased odds of psychiatric conditions, including anxiety (odds ratio [OR] 1.44) and mood disorders (OR 1.31), were observed in patients with AD. Patients with AD had higher likelihoods of autoimmune diseases, including vitiligo (OR 4.44) and alopecia areata (OR 6.01). Adult AD was also associated with infections, including impetigo (OR 9.72), methicillin-resistant Staphylococcus aureus (OR 3.92), and cellulitis (OR 2.52). Patients with AD were more likely to have systemic conditions, including lymphoid/hematopoietic malignancy (OR 1.91), atherosclerosis (OR 1.69), and metabolic syndrome (OR 1.47). For all the above, P < .001. LIMITATIONS: Retrospective analysis of health care claims data. CONCLUSION: Adult AD is associated with various psychiatric and systemic comorbidities, emphasizing the systemic nature of AD and the need for the collaborative management of these patients.

Health-related quality of life and economic burden of prurigo nodularis.

BACKGROUND: Prurigo nodularis (PN) is an understudied, pruritic inflammatory skin disease. Little is known about the effect of PN on quality of life and its associated economic burden. OBJECTIVE: To quantify the impact of PN on quality of life and its economic implications. METHODS: A cohort study of PN patients (n = 36) was conducted using the Health Utilities Index Mark 3 questionnaire. Control data from US adults (n = 4187) were obtained from the 2002-2003 Joint Canada/United States Survey of Health. Quality-adjusted life year loss and economic costs were estimated by comparing the Health Utilities Index Mark 3 scores of the PN patients with those of the controls. RESULTS: The PN patients had lower overall health performance compared to the controls, (mean ± SE, 0.52 ± 0.06 vs 0.86 ± 0.003, respectively, P < .001). In multivariable regression, PN was found to be associated with worse health performance (coefficient -0.34, 95% CI [-0.46 to -0.23]), most prominent in the pain subdomain (coefficient -0.24, 95% CI [-0.35 to -0.13]). This correlated to an average of 6.5 lifetime quality-adjusted life years lost per patient, translating to an individual lifetime economic burden of $323,292 and a societal burden of $38.8 billion. CONCLUSION: These results demonstrate that PN is associated with significant quality-of-life impairment, similar to the level of other chronic systemic conditions. PN is also associated with a substantial individual economic burden, emphasizing the necessity of research on effective treatment options.

GZ17-6.02 Inhibits the Growth of EGFRvIII+ Glioblastoma.

Epidermal Growth Factor Receptor (EGFR) is amplified in over 50% of glioblastomas and promotes tumor formation and progression. However, attempts to treat glioblastoma with EGFR tyrosine kinase inhibitors have been unsuccessful thus far. The current standard of care is especially poor in patients with a constitutively active form of EGFR, EGFRvIII, which is associated with shorter survival time. This study examined the effect of GZ17-6.02, a novel anti-cancer agent undergoing phase 1 studies, on two EGFRvIII+ glioblastoma stem cells: D10-0171 and D317. In vitro analyses showed that GZ17-6.02 inhibited the growth of both D10-0171 and D317 cells with IC50 values of 24.84 and 28.28 µg/mL respectively. RNA sequencing and reverse phase protein array analyses revealed that GZ17-6.02 downregulates pathways primarily related to steroid synthesis and cell cycle progression. Interestingly, G17-6.02's mechanism of action involves the downregulation of the recently identified glioblastoma super-enhancer genes WSCD1, EVOL2, and KLHDC8A. Finally, a subcutaneous xenograft model showed that GZ17-6.02 inhibits glioblastoma growth in vivo. We conclude that GZ17-6.02 is a promising combination drug effective at inhibiting the growth of a subset of glioblastomas and our data warrants further preclinical studies utilizing xenograft models to identify patients that may respond to this drug.

Real-world comorbidities of atopic dermatitis in the pediatric ambulatory population in the United States.

BACKGROUND: Increasing evidence has suggested the systemic nature of atopic dermatitis (AD), a common inflammatory skin condition in children. However, comprehensive analyses of real-world comorbidities in pediatric AD are limited. OBJECTIVE: To characterize comorbidity burden in patients with AD aged <18 years old. METHODS: The MarketScan commercial claims database was queried from January 1, 2017, to December 31, 2017. Age- and sex-matched analyses were used to compare patients with AD with general population controls. RESULTS: A total of 86,969 pediatric patients with AD and 116,564 matched controls were identified. Increased anxiety (odds ratio [OR], 1.20) and attention-deficit hyperactivity disorder (OR, 1.11) were noted in patients with AD. In addition to dermatologic/allergic diseases, AD was also associated with infections, including methicillin-resistant Staphylococcus aureus (OR, 3.76), and autoimmune conditions, including vitiligo (OR, 2.98) and alopecia areata (OR, 4.32). Pediatric patients with AD had higher likelihoods of lymphoid/hematologic malignancies (OR, 1.94), ocular disorders (OR, 1.37-2.02), metabolic syndrome (OR, 1.61), and obesity (OR, 1.81). For all the ORs mentioned above, P was <.001. LIMITATIONS: Retrospective analysis of health care claims data. CONCLUSIONS: AD in pediatric patients was associated with a wide range of psychologic and systemic comorbidities. Increased awareness can help minimize its negative effects on the quality of life and prevent long-term health consequences in young patients with AD.

Sleep disturbance in adults with chronic pruritic dermatoses is associated with increased C-reactive protein levels.

BACKGROUND: Pruritus is a common symptom that can significantly reduce quality of life through sleep disruption. OBJECTIVE: To examine features of disturbed sleep in patients with chronic pruritic dermatoses and test the hypothesis that systemic inflammation may serve as a biomarker for impaired sleep in these patients. METHODS: Cross-sectional analysis of the National Health and Nutrition Examination Survey investigating systemic inflammation using C-reactive protein (CRP) levels. Logistic regression was used to compare patients with and without sleep disturbances, adjusting for demographics (model 1) and medical comorbidities (model 2). RESULTS: Chronic pruritic dermatoses were associated with multiple sleep disturbances, including nighttime awakenings (model 1: odds ratio [OR], 1.646; 95% confidence interval [CI], 1.031-2.627; model 2: OR, 1.329; 95% CI, 0.888-1.989) and early morning awakening (model 1: OR, 1.669, 95% CI, 1.118-2.493; model 2: OR, 1.582; 95% CI, 1.008-2.481). Mean CRP levels were 52.8% higher among patients with pruritic dermatoses reporting trouble sleeping compared with those who did not (0.663 vs 0.434 mg/dL; P = .034). Trouble sleeping was also positively correlated with CRP levels (ß = 0.142, P = .025). LIMITATIONS: Potential recall bias among participants. CONCLUSIONS: In addition to confirming sleep disturbances with pruritic dermatoses, we found these disturbances are more likely to present with elevated CRP levels. Clinicians should consider the potential risk for sleep-related and cardiac comorbidities in patients diagnosed with itchy skin conditions.

Reduced serum pyridoxine and 25-hydroxyvitamin D levels in adults with chronic pruritic dermatoses.

Little is known about the role nutritional factors play in the pathogenesis of chronic pruritic dermatoses (CPD). In this study, we analyzed nutritional deficiencies in CPD patients compared to matched controls. We conducted a population-based study from the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2006. The main outcomes of the study were laboratory data on serum vitamin levels in participants who answered affirmatively to the questionnaires on CPD as well as matched healthy controls. We identified 877 cases of CPD among 9817 adults in the US aged 20 to 59 years. These findings revealed a slightly higher percentage of females with CPD. Low vitamin B6 (OR 0.697; 95% CI: 0.696-0.699, p = 0.025) and vitamin D (OR 0.794; 95% CI: 0.789-0.799, p = 0.037) levels were associated with a higher rate of CPD compared to healthy controls. Our study suggests that low levels of Vitamin B6 and Vitamin D inversely correlates with the presence of CPD. These vitamin deficiencies suggest further studies on the effect of vitamin supplementation may help in patients with CPD.

A Polygenic Risk Score for Predicting Racial and Genetic Susceptibility to Prurigo Nodularis.

Prurigo nodularis (PN) is an understudied inflammatory skin disease characterized by pruritic, hyperkeratotic nodules. Identifying the genetic factors underlying PN could help to better understand its etiology and guide the development of therapies. In this study, we developed a polygenic risk score that predicts a diagnosis of PN (OR = 1.41, P = 1.6 × 10-5) in two independent and continentally distinct populations. We also performed GWASs, which uncovered genetic variants associated with PN, including one near PLCB4 (rs6039266: OR = 3.15, P = 4.8 × 10-8) and others near TXNRD1 (rs34217906: OR = 1.71, P = 6.4 × 10-7; rs7134193: OR = 1.57, P = 1.1 × 10-6). Finally, we discovered that Black patients have over a two-times greater genetic risk of developing PN (OR = 2.63, P = 7.8 × 10-4). Combining the polygenic risk score and self-reported race together was significantly predictive of PN (OR = 1.32, P = 4.7 × 10-3). Strikingly, this association was more significant with race than after adjusting for genetic ancestry. Because race is a sociocultural construct and not a genetically bound category, our findings suggest that genetics, environmental influence, and social determinants of health likely affect the development of PN and may contribute to clinically observed racial disparities.

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, IL1ß, 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.

Cluster Analysis of Circulating Plasma Biomarkers in Prurigo Nodularis Reveals a Distinct Systemic Inflammatory Signature in African Americans.

Patients with prurigo nodularis (PN) suffer from intractable itch and dramatic reduction in QOL. Although there is significant clinical heterogeneity in the presentation of PN, disease endotypes remain unknown. We assayed circulating plasma cytokine concentrations in patients with PN (n = 20) along with matched healthy controls and utilized an unsupervised machine learning algorithm to identify disease endotypes. We found two distinct clusters of patients with PN with noninflammatory (cluster 1) and inflammatory (cluster 2) plasma profiles. Cluster 2 had more African Americans (82%, n = 9 vs. 33%, n = 3; P = 0.028), higher Worst Itch Numeric Rating Scale scores (9.5 ± 0.9 vs. 8.3 ± 1.2; P = 0.036), and lower QOL as reflected by higher Dermatology Life Quality Index scores (21.9 ± 6.4 vs. 13.0 ± 4.1; P = 0.015). In addition, cluster 1 had a higher rate of myelopathy (67%, n = 6 vs. 18%, n = 2; P = 0.028). Compared with cluster 1, cluster 2 had higher levels of IL-1α, IL-4, IL-5, IL-6, IL-10, IL-17A, IL-22, IL-25, and IFN-α. With population-level analysis, African American patients with PN had higher erythrocyte sedimentation rate, C-reactive protein, ferritin, and eosinophils and lower transferrin than Caucasian patients with PN. These findings indicate discrete clusters of patients with PN with plasma biomarker profiles corresponding to distinct demographic and clinical characteristics, potentially allowing for precision medicine approaches to treat PN.

Risk of Hematologic Cancer in Patients With Undifferentiated Pruritus.

Importance: Although pruritus is common in patients with hematologic cancers, it is unknown whether patients with undifferentiated pruritus have higher risk of developing hematologic cancer. Furthermore, it is unclear whether serum lactate dehydrogenase (LDH) level, commonly ordered for cancer workup, has diagnostic utility in patients with pruritus. Objective: To assess the risk of hematologic cancer and the diagnostic utility of LDH level in patients with undifferentiated pruritus. Design, Setting, and Participants: This retrospective population-level cohort analysis was conducted using the TriNetX Research Network, a global health records database encompassing more than 69 million patients, from 2002 to 2020. The study included 327 502 eligible patients diagnosed with unspecified pruritus, excluding those with existing chronic pruritic dermatoses or systemic diseases known to cause pruritus, along with 327 502 matched controls. Exposures: Development of hematologic cancer within 1 year, 5 years, and 10 years following unspecified pruritus diagnosis. Main Outcomes and Measures: Primary study outcomes were 1-year, 5-year, and 10-year relative risks (RRs) for development of 9 hematologic cancers in patients with pruritus compared with control patients. Secondary outcomes were 1-year, 5-year, and 10-year RRs for any hematologic cancer at different LDH cutoffs (250 U/L and 500 U/L). Results: After matching, the pruritus and control cohorts each had 327 502 patients (68.1% female patients; 0.4% American Indian or Alaska Native patients; 3.5% Asian patients; 22.2% Black patients; 0.1% Native Hawaiian or Pacific Islander patients; 59.3% White patients; mean [SD] age, 42.2 [22] years). Patients with pruritus had increased 1-year risk of Hodgkin lymphoma (RR, 4.42; 95% CI, 2.83-6.88), myeloid leukemia (RR, 2.56; 95% CI, 1.79-3.67), multiple myeloma (RR, 2.38; 95% CI, 1.66-3.41), non-Hodgkin lymphoma (RR, 2.35; 95% CI, 1.96-2.82), monoclonal gammopathy (RR, 1.90; 95% CI, 1.55-2.32), myelodysplastic syndrome (RR, 1.74; 95% CI, 1.14-2.64), and lymphocytic leukemia (RR, 1.47; 95% CI, 1.07-2.02). After 12 months, the cancer risk was comparable with that of controls. Patients with pruritus had increased LDH levels, which were not associated with increased hematologic cancer risk. Conclusions and Relevance: In this cohort study, the RR of hematologic cancer in patients with undifferentiated pruritus was highest in the first 12 months, and LDH level had limited diagnostic utility in these patients. Clinicians should consider a thorough review of symptoms and assessment of cancer risk factors when deciding on workup for patients presenting with undifferentiated pruritus.