Introduction: SARS-CoV-2 (COVID-19) infection has been implicated in the onset of neuropsychiatric symptoms in adults and children. While outcomes of COVID-19 infection and vaccination have been tracked in the general pediatric population, little is known of their impact on children with preexisting neuropsychiatric syndromes, including pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS). The aim of this study is to understand the prevalence and severity of COVID-19 symptoms and PANS/PANDAS symptoms following COVID-19 infection or vaccination in children with PANS/PANDAS. Methods: We analyzed retrospective COVID-19 survey data from caregivers of youth with PANS/PANDAS at Massachusetts General Hospital (MGH; n = 57) and the International PANS Registry (IPR; n = 478). Surveys were conducted online between late 2021 and early 2022 to collect COVID-19 infection and vaccination histories, side effects, and changes in PANS/PANDAS symptoms. Descriptive results are reported, stratified by case and sibling groups within the IPR sample. Results: Among patients with test-confirmed COVID-19 (MGH: n = 20, IPR: n = 65 cases, n = 16 siblings), mild/minor COVID-19 symptoms were common (62-75%). All patients with preexisting PANS/PANDAS-related symptoms at the time of COVID-19 infection experienced an exacerbation of PANS/PANDAS symptoms, while remitted patients did not report any PANS/PANDAS symptoms. Following the first COVID-19 vaccine dose (MGH: n = 45, IPR: n = 150 cases, n = 44 siblings), fatigue was the predominant side effect (30-56%). Most patients did not report new (59-81%) or worsened (71-82%) PANS symptoms post-vaccination, irrespective of symptomatic status at vaccination. Vaccine hesitancy often stemmed from concerns that the vaccination would cause an exacerbation of PANS/PANDAS symptoms. Conclusions: In two samples of children with PANS/PANDAS, symptoms of COVID-19 following infection and vaccination were common and generally mild to moderate. Children experiencing PANS/PANDAS symptoms at the time of COVID-19 infection experienced an increase in PANS/PANDAS symptom severity.

Abstract Neurofibromatosis type 1 (NF1) syndrome is an autosomal dominant cancer predisposition syndrome defined by germline deletion of one NF1 allele. Somatic loss of heterozygosity in the remaining NF1 allele in Schwann lineage cells gives rise to benign tumors known as plexiform neurofibromas. These tumors have a high risk of transforming into malignant peripheral nerve sheath tumors (MPNST) through the sequential deletion of CDKN2A/B followed by recurrent mutations in SUZ12 or EED, constituting the inactivation of polycomb repressor complex 2 (PRC2). PRC2 is a transcriptional repressor complex involved in the silencing of several development and differentiation genes. Loss of this complex leads to a depletion in trimethylation marks on Histone H3 Lysine 27 (H3K27me3) and the subsequent gain of acetylation marks on the same lysine residue (H3K27Ac). These molecular hallmarks are shared with diffuse intrinsic pontine gliomas (DIPG) harboring the H3K27M mutation which prevents effective deposition of H3K27me3, thus having similar molecular phenotypes to MPNST. However, the full range of epigenetic consequences of these events are currently not well characterized. Additionally, given that MPNSTs originate from cells of neural crest origin and DIPGs from cells of neural origin, it is not know to what degree epigenetic changes stemming from H3K27me3-loss are general across tumors or are context-dependent based on cell-of-origin. In order to contribute to this effort, the Largaespada lab has engineered Schwann cell lines to harbor deletions in NF1 and either SUZ12 or EED and assayed the H3K27ac landscape of these cells in addition to patient-derived MPNST cell lines. Utilizing the ranked ordering of super enhancers (ROSE) algorithm, we have identified common super enhancers within each MPNST cell line. These super enhancer elements are located nearby a variety of putative oncogenes responsible for the maintenance of cell identity. These elements were then compared to publicly available data from DIPG primary and patient-derived samples to understand common regulatory events driven by loss of H3K27me3 as well as molecular signatures present only in MPNST or in DIPG that may be a result of PRC2 or H3K27M alone. We further characterized these super enhancers by assessing the expression levels of their associated genes to understand their role in transcriptional activation. These efforts provide a roadmap of the super enhancer landscape of both MPNSTs and DIPGs to investigate novel mechanisms of H3K27me3-dependent tumorigenesis while also contributing to knowledge of potential effects of H3K27me3-loss that dependent on the cell-of-origin for each respective tumor. Citation Format: Christopher M. Stehn, Minu Bhunia, Kyle Williams, Alex T. Larsson, Ariel Caride, Jeong-Heon Lee, Tamas Ordog, David Largaespada. Characterizing the super enhancer landscape of H3K27me3 loss in MPNST and DIPG [abstract]. In: Proceedings of the AACR Special Conference on Brain Cancer; 2023 Oct 19-22; Minneapolis, Minnesota. Philadelphia (PA): AACR; Cancer Res 2024;84(5 Suppl_1):Abstract nr B009.

The Psychiatric Consultation Service at Massachusetts General Hospital sees medical and surgical inpatients with comorbid psychiatric symptoms and conditions. During their twice weekly rounds, Dr Stern and other members of the Consultation Service discuss diagnosis and management of hospitalized patients with complex medical or surgical problems who also demonstrate psychiatric symptoms or conditions. These discussions have given rise to rounds reports that will prove useful for clinicians practicing at the interface of medicine and psychiatry.Prim Care Companion CNS Disord 2024;26(3):23f03662.Author affiliations are listed at the end of this article.

Proteomics provides an opportunity for detection and monitoring of anorexia nervosa (AN) and its related variant, atypical-AN (atyp-AN). However, research to date has been limited by the small number of proteins explored, exclusive focus on adults with AN, and lack of replication across studies. This study performed Olink Proseek Multiplex profiling of 92 proteins involved in inflammation among females with AN and atyp-AN (N = 64), all < 90% of expected body weight, and age-matched healthy controls (HC; N=44). After correction for multiple testing, nine proteins differed significantly in the AN/atyp-AN group relative to HC group ( lower levels: CXCL1, HGF, IL-18R1, TNFSF14, TRANCE; higher levels: CCL23, Flt3L, LIF-R, MMP-1). The expression levels of three proteins ( lower IL-18R1, TRANCE; higher LIF-R) were uniquely disrupted in females with AN. No unique expression levels emerged for atyp-AN. Across the whole sample, twenty-one proteins correlated positively with BMI (ADA, AXIN1, CD5, CD244, CD40, CD6, CXCL1, FGF-21, HGF, IL-10RB, IL-12B, IL18, IL-18R1, IL6, LAP TGF-beta-1, SIRT2, STAMBP, TNFRSF9, TNFSF14, TRAIL, TRANCE) and six (CCL11, CCL23, FGF-19, IL8, LIF-R, OPG) were negatively correlated with BMI. Overall, our results replicate the prior study demonstrating a dysregulated inflammatory status in AN, and extend these results to atyp-AN (AN/atyp-AN all < 90% of expected body weight). Of the 27 proteins correlated with BMI, 18 were replicated from a prior study using similar methods, highlighting the promise of inflammatory protein expression levels as biomarkers of disease monitoring. Additional studies of individuals across the entire weight spectrum are needed to understand the role of inflammation in atyp-AN.

IMPORTANCE Maternal immune activation (MIA) leading to altered neurodevelopment in utero is a hypothesized risk factor for psychiatric outcomes in offspring. Primary antibody immunodeficiencies (PIDs) constitute a unique natural experiment to test the MIA hypothesis of mental disorders. OBJECTIVE To assess the association of maternal and paternal PIDs with psychiatric disorders and suicidal behavior in offspring. DESIGN, SETTING, AND PARTICIPANTS Cohort study of 4 294169 offspring of parents with and without PIDs living in Sweden at any time between 1973 and 2013. Data were extracted from Swedish nationwide health and administrative registers and were analyzed from May 5 to September 30, 2022. All individuals with diagnoses of PIDs identified between 1973 and 2013 from the National Patient Register were included. Offspring were included if born before 2003. Parent-offspring pairs in which both parents had a history of PIDs were excluded. EXPOSURES Lifetime records of parental PIDs according to the International Classification of Diseases, Eighth Revision (ICD-8); International Classification of Diseases, Ninth Revision (ICD-9); and International Statistical Classification of Diseases and Related Health Problems, Tenth Revision (ICD-10) diagnostic codes. MAIN OUTCOMES AND MEASURES Lifetime records of 10 psychiatric disorders and suicidal behavior identified using ICD-8, ICD-9, and ICD-10 diagnostic codes, including suicide attempts and death by suicide, among offspring. Covariates included sex, birth year, parental psychopathology, suicide attempts, and autoimmune diseases. Additional analyses excluded offspring with their own PIDs and autoimmune diseases. Poisson regression models were fitted separately for mothers and fathers to estimate incidence rate ratios (IRRs) and 95% CIs for the risk of psychiatric and suicidal behavior outcomes in the offspring of PID-exposed vs PID-unexposed mothers or fathers. RESULTS The cohort included 4294169 offspring (2 207 651 males [51.4%]) and 3 954 937 parents (1 987 972 females [50.3%]). A total of 7270 offspring (0.17%) had parents with PIDs, and 4 286 899 offspring had parents without PIDs. In fully adjusted models, offspring of mothers with PIDs had an increased risk of any psychiatric disorder, while no such risks were observed in offspring of fathers with PIDs (IRR, 1.17; 95% CI, 1.10-1.25 vs IRR, 1.03; 95% CI, 0.94-1.14; P < .001). Likewise, an increased risk of suicidal behavior was observed among offspring of mothers with PIDs but not offspring of fathers with PIDs (IRR, 1.20; 95% CI, 1.06-1.36 vs IRR, 1.10; 95% CI, 0.91-1.34; P = .01). For the offspring of mothers with PIDs, the risk of developing any psychiatric disorder was significantly higher for those with mothers with 6 of 10 individual disorders, with IRRs ranging from 1.15 (95% CI, 1.04-1.26) for anxiety and stress-related disorders and 1.15 (95% CI, 1.03-1.30) for substance use disorders to 1.71 (95% CI, 1.37-2.14) for bipolar disorders. Offspring of mothers with both PIDs and autoimmune diseases had the highest risk for any psychiatric disorder (IRR, 1.24; 95% CI, 1.11-1.38) and suicidal behavior (IRR, 1.44; 95% CI, 1.17-1.78). CONCLUSIONS AND RELEVANCE Findings of this cohort study suggest that maternal, but not paternal, PIDs were associated with a statistically significant increased risk of psychiatric disorders and suicidal behavior in the offspring, particularly when PIDs co-occur with autoimmune diseases. These findings align with the MIA hypothesis of mental disorders, but the precise mechanisms remain to be elucidated.

Postinfectious neuroinflammation has been implicated in multiple models of acute-onset obsessive-compulsive disorder including Sydenham chorea (SC), pediatric acute-onset neuropsychiatric syndrome (PANS), and pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS). These conditions are associated with a range of autoantibodies which are thought to be triggered by infections, most notably group A streptococci (GAS). Based on animal models using huma sera, these autoantibodies are thought to cross-react with neural antigens in the basal ganglia and modulate neuronal activity and behavior. As is true for many childhood neuroinflammatory diseases and rheumatological diseases, SC, PANS, and PANDAS lack clinically available, rigorous diagnostic biomarkers and randomized clinical trials. In this review article, we outline the accumulating evidence supporting the role neuroinflammation plays in these disorders. We describe work with animal models including patient-derived anti-neuronal autoantibodies, and we outline imaging studies that show alterations in the basal ganglia. In addition, we present research on metabolites, which are helpful in deciphering functional phenotypes, and on the implication of sleep in these disorders. Finally, we encourage future researchers to collaborate across medical specialties (e.g., pediatrics, psychiatry, rheumatology, immunology, and infectious disease) in order to further research on clinical syndromes presenting with neuropsychiatric manifestations.

To the Editor: Studies examining Medicare reimbursement in dermatology are limited. A comprehension of reimbursement trends could improve the understanding of changes in the clinical practice of dermatology and advance patient care. Using the Centers for Medicare and Medicaid Services website,1CMS Homepage | CMS.https://www.cms.gov/Date accessed: January 25, 2020Google Scholar we searched for commonly used dermatology services in the 2018 physician procedure/summary file. We queried the physician fee schedule look-up tool for facility and nonfacility pricing information for each current procedural terminology (CPT) code. Using the consumer price index for urban consumers, we adjusted for inflation by multiplying the 2000 reimbursement by the 2000 January inflation multiplier.2CPI Home: U.S. Bureau of Labor Statistics.https://www.bls.gov/cpi/Date accessed: January 25, 2020Google Scholar We also used weighted averages to appropriately adjust for differences in utilization. The weighted, adjusted average for physician reimbursement by Medicare for the included dermatology services decreased by 10% and 18% from 2000 to 2020 for nonfacility and facility prices, respectively. Of 20 codes included in our study, 10 decreased in nonfacility reimbursement from 2000 to 2020, while the other 10 codes increased in nonfacility reimbursement (Tables I and II).Table INonfacility reimbursement trends for commonly used dermatology services. Adjusted for inflation using consumer price index. Sorted by decreasing utilization based on 2018 Medicare utilization dataUtilization in 2018CPT codeCPT code description2000 reimbursement (unadjusted)2000 reimbursement (adjusted to 2020 USD)2020 reimbursementPercentage of change1460093217003Destruction of 2-14 skin growths13206−68%606862099213Established patient office or other outpatient visit, typically 15 minutes4772788%444874517000Destruction of skin growth507769−10%210326199214Established patient office or other outpatient visit, typically 25 minutes731111132%164986999212Established patient office or other outpatient visit, typically 10 minutes345347−10%160225117110Destruction of up to 14 skin growths517811852%86744895044Application of allergic extract skin patch, with a reaction analysis8126−55%86215699203New patient office or other outpatient visit, typically 30 minutes89136112−17%69261117004Destruction of 15 or more skin growths194296166−44%66647599202New patient office or other outpatient visit, typically 20 minutes639779−18%35104796910Skin application of tar and ultraviolet B or of petrolatum and ultraviolet B2335140302%25962613132Repair of wound (2.6-7.5 cm) of the forehead, cheeks, chin, mouth, neck, underarms, genitals, hands, and/or feet402614504−18%24002417262Destruction of malignant growth (1.1-2.0 cm) of the trunk, arms, or legs125190186−2%20810912032Repair of wound (2.6-7.5 cm) of the scalp, underarms, trunk, arms, and/or legs16725633431%19088311900Injection of up to 7 skin growths3858581%17726911602Removal of malignant growth (1.1-2.0 cm) of the trunk, arms, or legs1662532603%16149013121Repair of wound (2.6-7.5 cm) of the scalp, arms, and/or legs2894424543%15214396900Application of ultraviolet light to the skin16244171%13420011301Shaving of 0.6-1.0 cm of skin growth of the trunk, arms, or legs6610112827%12325369100Biopsy of the ear72110104−5%Average99152150−1%∗Percentage of change from average adjusted 2000 USD (weighted average adjusted 2000 USD) to average 2020 USD average (weighted average adjusted 2020 USD).Weighted average436659−10%∗Percentage of change from average adjusted 2000 USD (weighted average adjusted 2000 USD) to average 2020 USD average (weighted average adjusted 2020 USD).CPT Code, Current procedural terminology code; USD, US dollar.∗ Percentage of change from average adjusted 2000 USD (weighted average adjusted 2000 USD) to average 2020 USD average (weighted average adjusted 2020 USD). Open table in a new tab Table IIFacility reimbursement trends for commonly used dermatology services. Adjusted for inflation using consumer price index. Sorted by decreasing utilization based on 2018 Medicare utilization dataUtilization in 2018CPT codeCPT code description2000 unadjusted2000 adjusted2020Percentage of change1460093217003Destruction of 2-14 skin growths8132−83%606862099213Established patient office or other outpatient visit, typically 15 minutes3351535%444874517000Destruction of skin growth32495715%210326199214Established patient office or other outpatient visit, typically 25 minutes5482820%164986999212Established patient office or other outpatient visit, typically 10 minutes233527−24%160225117110Destruction of up to 14 skin growths34527136%86744895044Application of an allergic extract skin patch, with a reaction analysis8126−55%86215699203New patient office or other outpatient visit, typically 30 minutes7912079−35%69261117004Destruction of 15 or more skin growths151231103−55%66647599202New patient office or other outpatient visit, typically 20 minutes528052−34%35104796910Skin application of tar and ultraviolet B or of petrolatum and ultraviolet B2335123254%25962613132Repair of wound (2.6-7.5 cm) of the forehead, cheeks, chin, mouth, neck, underarms, genitals, hands, and/or feet332507324−36%24002417262Destruction of malignant growth (1.1-2.0 cm) of the trunk, arms, or legs92140118−16%20810912032Repair of wound (2.6-7.5 cm) of the scalp, underarms, trunk, arms, and/or legs1291972012%19088311900Injection of up to 7 skin growths264032−20%17726911602Removal of malignant growth (1.1-2.0 cm) of the trunk, arms, or legs122186171−8%16149013121Repair of wound (2.6-7.5 cm) of the scalp, arms, and/or legs332507276−46%15214396900Application of ultraviolet light to the skin162424−2%13420011301Shaving of 0.6-1.0 cm of skin growth of the trunk, arms, or legs477155−23%12325369100Biopsy of the ear456955−21%Avg8212595−24%Weighted Avg324840−18%∗Percentage of change from average adjusted 2000 USD (weighted average adjusted 2000 USD) to average 2020 USD average (weighted average adjusted 2020 USD).Avg, Average; CPT Code, current procedural terminology code.∗ Percentage of change from average adjusted 2000 USD (weighted average adjusted 2000 USD) to average 2020 USD average (weighted average adjusted 2020 USD). Open table in a new tab CPT Code, Current procedural terminology code; USD, US dollar. Avg, Average; CPT Code, current procedural terminology code. Our study demonstrates a substantial decrease in the weighted, adjusted average facility and nonfacility Medicare reimbursement for commonly used services in dermatology. Nonfacility Medicare payment rates experienced a smaller decrease when compared with facility payment rates. This is of note as dermatology is mainly an office-based, nonfacility specialty. Interestingly, despite decreasing Medicare reimbursement rates, dermatologist salaries maintained their growth, with a recent study conducted from 2013 to 2018 reporting an overall median salary increase of 20% for women and 9% for men.3Sachdeva M. Price K.N. Hsiao J.L. Shi V.Y. Gender and rank salary trends among academic dermatologists.Int J Womens Dermatol. 2020; 6: 324-326Google Scholar Major changes in reimbursement for individual codes are largely due to changes in valuation by the relative-value scale update committee. However, the overall 10% nonfacility and 18% facility decreases in the Medicare reimbursement observed in this study was likely influenced by an inflation rate of nearly 53% from 2000 to 2020. In tandem, the conversion factor did not keep up with inflation, decreasing from $36.61 in 2000 to $36.09 in 2020. If the conversion factor had increased according to the 52% increase in inflation from 2000 to 2020, the estimated current value of the conversion factor would have been $55.95. Besides these changes, health care policy changes have aimed to decrease reimbursement as well, such as the 2% sequestration enacted in 2012.4Davis P.A. Medicare and budget sequestration. Congr Res Serv.https://fas.org/sgp/crs/misc/R45106.pdfGoogle Scholar The decrease in the Medicare reimbursement seen in our study is not unique to dermatology. For example, emergency medicine reported an average adjusted Medicare reimbursement decrease of 29% from 2000 to 2020.5Pollock J.R. Bollig T.R. Haglin J.M. Sandefur B.J. Rappaport D.E. Lindor R.A. Medicare reimbursement to physicians decreased for common emergency medicine services from 2000 to 2020.Ann Emerg Med. 2020; 76: 615-620Google Scholar In summary, our findings demonstrate a substantial decrease in inflation-adjusted reimbursement for dermatologists from 2000 to 2020. It is imperative to evaluate how the trends in payment may continue to affect access to care in dermatology, especially in the Medicare population. A limitation of our study is the exclusion of codes that did not exist in either 2000 or 2020, such as micrographic surgery codes that were created in 2007. In addition, we recognize that dermatologists perform other medical services not included in our analysis. Lastly, our study relied on volume data from 2018 to calculate a weighted average, and we were not able to compare volume changes from 2000 to 2020. None disclosed.

To the Editor: Epidemiologic studies of adults have shown prurigo nodularis (PN) to be an intensely pruritic dermatosis associated with a greater incidence of mental health and systemic conditions.1Huang A.H. Williams K.A. Kwatra S.G. Prurigo nodularis: epidemiology and clinical features.J Am Acad Dermatol. 2020; 83: 1559-1565Google Scholar However, the available literature on pediatric PN is sparse. Our objective was to quantify the epidemiology of pediatric PN and test the hypothesis that pediatric PN also carries a disproportionate burden of comorbidities. Institutional review board approval was granted. The MarketScan Commercial Claims and Encounters Database (October 2015 through December 2017) was queried using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes to identify patients aged 17 years or younger at the time of their diagnosis with PN (L28.1). Persons without PN were also identified: age- and sex-matched controls, patients with atopic dermatitis (AD; ICD code L20.9), and patients with psoriasis (ICD code L40.9) (Table I).2Huang A.H. Canner J.K. Khanna R. Kang S. Kwatra S.G. Real-world prevalence of prurigo nodularis and burden of associated diseases.J Invest Dermatol. 2020; 140: 480-483.e4Google Scholar A weighted national sample was used to estimate the prevalence of pediatric PN using the 2016 United States population as reference. Comorbidities previously associated with PN in adults were queried in the database for the pediatric population. The threshold for statistical significance was set a priori at 0.05. Odds ratios (OR) of comorbidities were calculated using logistic regression.Table IDemographicsCharacteristicPrurigo nodularisAtopic dermatitisPsoriasisMatched controls∗Age- and sex-matched to the prurigo nodularis cohort.Total population, n60693,94632182100Age in years, Mean (SD)12.6 (3.7)5.2 (5.0)12.0 (3.9)12.6 (3.7) Median13.541313.5Age distribution in years, n (%) 0-426 (4.3)51,529 (54.9)159 (4.9)26 (4.3) 5-985 (14.0)20,776 (22.1)663 (20.6)85 (14.0) 10-14276 (45.5)15,404 (16.4)1337 (41.6)276 (45.5) 15-17219 (36.1)6237 (6.6)1059 (32.9)219 (36.1)Gender, n (%) Male290 (47.9)49,709 (53)1332 (43)1005 (47,9) Female316 (52.1)44,083 (47)1780 (57)1095 (52.1)Region, n (%) Northeast120 (19.8)19,685 (21.0)678 (21.1)318 (15.1) North Central109 (18.0)13,197 (14.1)759 (23.6)464 (22.1) South311 (41.3)43,606 (46.4)1213 (37.7)925 (44.1) West63 (10.4)17,169 (18.3)551 (17.1)375 (17.9) Unknown3 (0.5)289 (0.3)17 (0.53)18 (0.8)n, Number; SD, standard deviation.∗ Age- and sex-matched to the prurigo nodularis cohort. Open table in a new tab n, Number; SD, standard deviation. The estimated prevalence of pediatric PN was 21.6 per 100,000. Pediatric patients with PN had higher odds of anxiety (OR, 2.84; 95% confidence interval [CI], [2.17, 3.71]) and attention deficit hyperactivity disorder (OR, 2.04; 95% CI, [1.51, 2.76]) (Fig 1). Relative to controls, pediatric patients with PN also had an increased incidence of dermatologic conditions, such as psoriasis (OR, 7.30; 95% CI, [2.59, 20.6]) or AD (OR, 37.7; 95% CI, [22.1, 64.4]); allergic conditions, such as asthma (OR, 2.48; 95% CI, [1.85, 3.33]) or urticaria (OR, 3.15; 95% CI, [1.84, 5.39]); metabolic syndromes (OR, 16.7; 95% CI, [2.08, 134]); type 2 diabetes mellitus (OR, 5.44; 95% CI, [1.11, 26.6]); and obesity (OR, 1.62; 95% CI, [1.04, 2.54]). The prevalence of PN in children reported here is lower than reported results in adults (21.6 compared to 72, respectively, per 100,000).2Huang A.H. Canner J.K. Khanna R. Kang S. Kwatra S.G. Real-world prevalence of prurigo nodularis and burden of associated diseases.J Invest Dermatol. 2020; 140: 480-483.e4Google Scholar Our results demonstrate a similarly significant burden of mental health and systemic conditions in pediatric PN. Higher odds of anxiety and attention deficit hyperactivity disorder are notable, as over-responsivity to sensory stimuli and poor impulse control likely perpetuate the chronic itch-scratch cycle characteristic of PN.3Reynolds S. Lane S.J. Sensory overresponsivity and anxiety in children with ADHD.Am J Occup Ther. 2009; 63: 433-440Google Scholar,4Kwatra S.G. Breaking the itch–scratch cycle in prurigo nodularis.N Engl J Med. 2020; 382: 757-758Google Scholar Children with PN (OR, 37.7; 95% CI, [22.1, 64.4]) appeared more likely than adults with PN (OR, 9.48; 95% CI, [6.69, 13.4]) to have AD when compared with their respective matched peers.2Huang A.H. Canner J.K. Khanna R. Kang S. Kwatra S.G. Real-world prevalence of prurigo nodularis and burden of associated diseases.J Invest Dermatol. 2020; 140: 480-483.e4Google Scholar Although residual confounding is possible, this supports the hypothesis that there may be 2 forms of PN: a younger-onset atopic type and a later-onset nonatopic type.5Tanaka M. Aiba S. Matsumura N. Aoyama H. Tagami H. Prurigo nodularis consists of two distinct forms: early-onset atopic and late-onset non-atopic.Dermatology. 1995; 190: 269-276Google Scholar Study limitations include the retrospective analysis of health care claims data not initially collected for research purposes. As a convenience sample from a database of commercial insurance claims, MarketScan does not include the uninsured or publicly insured and may not be fully representative of the entire United States. Furthermore, epidemiologic studies of associations are unable to establish causality. Research is needed to elucidate underlying mechanisms for the data observed and to validate the use of ICD-10 codes to identify patients with PN. Increased awareness and understanding of pediatric PN can help minimize the impact of associated comorbidities during a critical time of growth and development. Dr Kwatra is on the scientific advisory board for Incyte Corporation, Menlo Therapeutics, Pfizer Inc, and Regeneron Pharmaceuticals, and has received grant funding from Kiniksa Pharmaceuticals , Galderma SA , and Pfizer Inc. He is also a recipient of a Dermatology Foundation Medical Dermatology Career Development Award. Drs Huang and Grossberg and Authors Roh, Sutaria, Choi, Williams, Pritchard, Alphonse, and Canner have no conflicts of interest to declare.

Objective: Few large-scale studies of pediatric acute-onset neuropsychiatric syndrome (PANS) and pediatric autoimmune neuropsychiatric disorder associated with streptococcal infections (PANDAS) have been conducted, and thus demographic data on these conditions are limited. The current study describes comorbid medical and psychiatric conditions in a self-referred cohort of children with PANS/PANDAS, along with treatment history, barriers to treatment, family medical and psychiatric history, and perceived caregiver burden in these conditions.Methods: A total of 441 primary caregivers of patients with infection-triggered PANS/PANDAS under the age of 18 were included in this online anonymous survey, reporting on a total of 490 children (due to some caregivers reporting multiple children in the family with PANS/PANDAS). Data were collected between July 2018 and May 2019. Primary caregivers completed questions pertaining to patient demographics, symptom presentation, disease course, family medical and psychiatric history, and severity of patients' obsessive-compulsive disorder (OCD) symptoms.Results: OCD was the most common psychiatric symptom reported in children at the onset of PANS/PANDAS (83.06%), along with a high percentage of medical and psychiatric comorbidities. Most psychiatric comorbidities began or worsened at the onset of PANS/PANDAS symptoms, while major depressive disorder was the most frequently reported psychiatric disorder to develop after PANS/PANDAS onset (10%). A high frequency of autoimmune and inflammatory conditions was reported in family members, with nearly 30% of mothers endorsing one or more autoimmune conditions (29.95%). Mean caregiver burden (Caregiver Burden Inventory; M = 44.0) fell above the "burnout" level, and standardized measures showed mildly elevated levels of depression, anxiety, and stress in caregivers (Depression, Anxiety, and Stress Scale-21; M = 11.85, 7.16, and 15.56, respectively).Conclusions: Primary caregivers of children with PANS/PANDAS reported a multitude of medical and psychiatric comorbidities in their children, along with a high frequency of autoimmune and psychiatric conditions in family members. Obsessive-compulsive symptoms were the most frequently reported psychiatric symptom. Caregivers of these patients experience elevated levels of burden, stress, anxiety, and depression. Further research is needed to better understand the varied disease course in PANS/PANDAS and to develop interventions to reduce caregiver burden in these disorders.

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.& nbsp;Objective: To quantify the impact of PN on quality of life and its economic implications.& nbsp;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.& nbsp;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.& nbsp;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.

Neurofibromatosis Type 1 syndrome (NF1) is a cancer predisposition syndrome caused by inheritance of one loss of function allele of the NF1 gene. NF1 patients can develop malignant peripheral nerve sheath tumors (MPNST), a deadly soft tissue sarcoma. MPNSTs develop after somatic loss of the wild-type NF1 allele, resulting in an increase in Ras-GTP activated signaling. This malignant transformation is still not completely understood, but loss of TP53 or CDKN2A/2B function and the polycomb repressor complex 2 (PRC2) are common events during the transition to MPNST. SUZ12, EED and EZH2 are core components of PRC2, which is responsible for trimethylation of Histone H3 at lysine 27 (H3K27me3), a repressive epigenetic mark that silences genes through formation of heterochromatin. We hypothesized loss of PRC2 has direct and indirect effects on gene expression resulting in MPNSTs. PRC2 loss may result in altered topologically associated domains, which can affect access of promoters by distal enhancers. Altered gene expression leads to deregulation of cell differentiation and proliferation controls, promoting the transition to MPNSTs. The purpose of this study is to identify epigenomic vulnerabilities of MPNSTs using multi-omics to elucidate more effective treatments. We have engineered NF1-deficient human Schwann cells with or without concomitant loss of function SUZ12 or EED mutations. We found major epigenomic changes in the histone code of SUZ12 mutants including complete loss of H3K27me3 with concomitant gain in H3K27 acetylation. SUZ12-deficient cells also become hypersensitive to histone deacetylase inhibitors. RNA sequencing has revealed many differentially expressed genes when SUZ12 and NF1 are lost in our engineered cell lines. Preliminary results show 92 differentially expressed genes that are common to PRC2-deficient MPNSTs and engineered cell lines. 824 genes are common between our engineered cell lines where 686 of these are derepressed when SUZ12 or EED are lost with NF1. We also identified an increase in differentially expressed genes when PRC2 is lost with NF1 versus NF1 loss alone. Comparing these to genes expressed in MPNST patient samples, we have identified potential drivers of MPNST generation. Pathway enrichment analysis on differentially expressed genes indicates many upregulated cancer related pathways when PRC2 is lost. We found NOTCH and Sonic Hedgehog signaling are common to all comparisons. NOTCH signaling has been implicated in Schwann cell development. These are currently being validated via Western blot. Proteomics data will also be compared to the findings. Citation Format: Minu Bhunia, Christopher M. Stehn, Mahathi Madala, Kyle Williams, Alex Larsson, Tyler Jubenville, Suganth Suppiah, Gelareh Zadeh. Integrative multiomic analysis reveals NOTCH signaling is derepressed by loss of PRC2 in malignant peripheral nerve sheath tumors. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr A007.

Chronic pruritus is a distressing symptom associated with a significant reduction in quality of life.1 Patients undergo an extensive diagnostic workup to search for underlying dermatologic, systemic, neurologic, or psychiatric conditions. In real-world practice, a specific causal disease process often is not identified, and patients are provided a diagnosis of chronic pruritus of unknown origin (CPUO). Unfortunately, there is little guidance for managing CPUO, which presents a significant clinical challenge.

Prurigo nodularis (PN) is an intensely pruritic, inflammatory skin disease characterized by symmetrically distributed hyperkeratotic nodules (Kwatra, 2020Kwatra S.G. Breaking the itch–scratch cycle in prurigo nodularis.N Engl J Med. 2020; 382: 757-758Crossref PubMed Scopus (46) Google Scholar; Kwon et al., 2019Kwon C.D. Khanna R. Williams K.A. Kwatra M.M. Kwatra S.G. Diagnostic workup and evaluation of patients with prurigo nodularis.Medicines (Basel). 2019; 6: 97Crossref PubMed Google Scholar). The intense pruritus associated with PN often severely impacts QOL (Huang et al., 2020cHuang A.H. Williams K.A. Kwatra S.G. Prurigo nodularis: epidemiology and clinical features.J Am Acad Dermatol. 2020; 83: 1559-1565Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar; Iking et al., 2013Iking A. Grundmann S. Chatzigeorgakidis E. Phan N.Q. Klein D. Ständer S. Prurigo as a symptom of atopic and non-atopic diseases: aetiological survey in a consecutive cohort of 108 patients.J Eur Acad Dermatol Venereol. 2013; 27: 550-557Crossref PubMed Scopus (120) Google Scholar; Pereira et al., 2020Pereira M.P. Hoffmann V. Weisshaar E. Wallengren J. Halvorsen J.A. Garcovich S. et al.Chronic nodular prurigo: clinical profile and burden. A European cross-sectional study.J Eur Acad Dermatol Venereol. 2020; 34: 2373-2383Crossref PubMed Scopus (37) Google Scholar). In our previous experience as well as in a European cohort, patients with PN had a greater severity of disease, greater itch intensity, and more dramatic reduction in QOL than other patients with chronic pruritus (Whang et al., 2021bWhang K.A. Khanna R. Williams K.A. Mahadevan V. Semenov Y. Kwatra S.G. Health-related QOL and economic burden of chronic pruritus.J Invest Dermatol. 2021; 141: 754-760.e1Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar; Williams et al., 2021Williams K.A. Roh Y.S. Brown I. Sutaria N. Bakhshi P. Choi J. et al.Pathophysiology, diagnosis, and pharmacological treatment of prurigo nodularis.Expert Rev Clin Pharmacol. 2021; 14: 67-77Crossref PubMed Scopus (29) Google Scholar; Zeidler et al., 2021Zeidler C. Pereira M.P. Dugas M. Augustin M. Storck M. Weyer-Elberich V. et al.The burden in chronic prurigo: patients with chronic prurigo suffer more than patients with chronic pruritus on non-lesional skin: a comparative, retrospective, explorative statistical analysis of 4,484 patients in a real-world cohort.J Eur Acad Dermatol Venereol. 2021; 35: 738-743Crossref PubMed Scopus (20) Google Scholar). Thus, we hypothesized that patients with PN experience higher rates of disease comorbidities and healthcare utilization than patients who have other pruritic, inflammatory skin conditions. To address the current gaps in the understanding of PN, we employed national claims data to describe the epidemiology, comorbidities, and healthcare utilization of patients with PN. Using anonymized, nationally representative, private insurance claims data (October 2015‒December 2019), we defined patients with PN as individuals with ≥2 medical claims for PN using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) codes. For comparison to patients with inflammatory skin diseases, ICD-10-CM codes were also used to identify patients with atopic dermatitis (AD) and psoriasis. Matched controls (age- and gender-matched to patients with PN) were selected from individuals without any ICD-10-CM codes for PN, AD, and psoriasis. Further details are provided in Supplementary Materials and Methods. In our analysis of nationwide claims data, we identified the number of cases of PN, AD, and psoriasis annually. In 2016, there were 2,658 patients with PN, 21,482 patients with AD, and 21,073 patients with psoriasis. In 2017, there were 4,823 patients with PN, 38,805 patients with AD, and 35,193 patients with psoriasis. In 2018, there were 6,992 patients with PN, 54,593 patients with AD, and 47,382 patients with psoriasis. In 2019, there were 9,426 patients with PN, 70,298 patients with AD, and 59,509 patients with psoriasis. The annual period prevalence estimates in the claims database are shown in Table 1. The prevalence estimates for PN in 2016 were 18 per 100,000 overall, 22 per 100,000 for adults, and 2 per 100,000 for children, and the estimates rose to 58 per 100,000 overall, 70 per 100,000 for adults, and 7 per 100,000 for children in 2019. The mean (SD) age of patients with PN was 57.5 (17.0) years in 2016 and increased to 59.8 (16.9) years in 2019. The gender breakdown ranged from 44.5% male in 2016 to 46.5% male in 2019. The demographics for the controls and for patients with AD and psoriasis are also shown in Table 2.Table 1Period Prevalence Estimates (Per 100,000) for PN, AD, and PsoriasisPNADPsoriasis201620172018201920162017201820192016201720182019Overall18324558146255348432144232302366Children24674197421,0161,27515263340Adults2239547074127178227178286370445Abbreviations: AD, atopic dermatitis; PN, prurigo nodularis. Open table in a new tab Table 2Demographics for PN, Controls (Matched to Patients with PN), AD, and Psoriasis2016PNControlsADPsoriasisn2,65813,29021,48221,073Age, mean (SD)57.5 (17.0)57.5 (17.0)22.0 (24.2)52.1 (16.2)Gender, male (%)1,183 (44.5)5,915 (44.5)10,367 (48.3)10,284 (48.8)CCI1.53 (2.27)0.98 (1.82)0.53 (1.16)1.16 (1.88)2017PNControlsADPsoriasisn4,82324,11538,80535,193Age, mean (SD)57.7 (16.9)57.7 (16.9)21.9 (23.7)52.3 (16.3)Gender, male (%)2,197 (45.6)10,985 (45.6)18,610 (48.0)17,075 (48.5)CCI1.84 (2.52)1.21 (2.09)0.61 (1.31)1.38 (2.10)2018PNControlsADPsoriasisn6,99234,96054,59347,382Age, mean (SD)58.6 (17.0)58.6 (17.0)22.6 (23.8)53.0 (16.4)Gender, male (%)3,220 (46.1)16,100 (46.1)25,971 (47.8)22,684 (47.9)CCI2.04 (2.64)1.34 (2.26)0.68 (1.42)1.53 (2.26)2019PNControlsADPsoriasisn9,42647,13070,29859,509Age, mean (SD)59.8 (16.9)59.8 (16.9)23.7 (24.3)53.9 (16.5)Gender, male (%)4,383 (46.5)21,915 (46.5)33,216 (47.3)28,124 (47.3)CCI2.32 (2.84)1.57 (2.42)0.75 (1.52)1.71 (2.40)Abbreviations: AD, atopic dermatitis; CCI, Charlson Comorbidity Index; PN, prurigo nodularis. Open table in a new tab Abbreviations: AD, atopic dermatitis; PN, prurigo nodularis. Abbreviations: AD, atopic dermatitis; CCI, Charlson Comorbidity Index; PN, prurigo nodularis. For a comprehensive analysis of the comorbidity burden, we quantified the overall comorbidity burden with the Charlson Comorbidity Index. We also examined the comorbidity profiles using the individual components of the Charlson Comorbidity Index (Figure 1). Patients with PN had the highest Charlson Comorbidity Index of these groups, with a mean (SD) of 1.53 (2.27) compared with 0.98 (1.82) for the controls (age- and gender-matched to patients with PN), 0.53 (1.16) for patients with AD, and 1.16 (1.88) for patients with psoriasis in 2016 and a mean (SD) of 2.32 (2.84) compared with 1.57 (2.42) for the controls, 0.75 (1.52) for patients with AD, and 1.71 (2.40) for patients with psoriasis in 2019 (Table 2). The top five specialties seen by patients with PN, by the estimated number of visits per year per patient, were internal medicine (2.01), dermatology (1.87), family practice (1.60), cardiology or cardiovascular disease (0.85), and orthopedics or orthopedic surgery (0.49). For comparison, the estimates of the most visited specialties for the controls and the patients with AD and psoriasis are provided in Table 3.Table 3Estimates of Healthcare Utilization Per Person for the Top Five Specialties Utilized by Patients with PN Compared with Controls (Matched to Patients with PN) and Patients with AD or PsoriasisPNControlsADPsoriasisSpecialtyVisits Per YSpecialtyVisits Per YSpecialtyVisits Per YSpecialtyVisits Per YInternal medicine2.01Internal medicine1.41Pediatrics2.02Internal medicine1.60Dermatology1.87Family practice1.33Allergy and immunology0.93Family practice1.41Family practice1.60Cardiology or cardiovascular disease0.63Dermatology0.75Dermatology1.38Cardiology or cardiovascular disease0.85Orthopedics or orthopedic surgery0.34Family practice0.64Cardiology or cardiovascular disease0.55Orthopedics or orthopedic surgery0.49Dermatology0.31Internal medicine0.62Rheumatology0.51Abbreviations: AD, atopic dermatitis; PN, prurigo nodularis. Open table in a new tab Abbreviations: AD, atopic dermatitis; PN, prurigo nodularis. Patients with PN had a higher burden of several cardiovascular, pulmonary, and other systemic diseases than those with AD and those with psoriasis (Boozalis et al., 2018Boozalis E. Tang O. Patel S. Semenov Y.R. Pereira M.P. Ständer S. et al.Ethnic differences and comorbidities of 909 prurigo nodularis patients.J Am Acad Dermatol. 2018; 79: 714-719.e3Abstract Full Text Full Text PDF PubMed Scopus (86) Google Scholar; Huang et al., 2020aHuang A.H. Canner J.K. Khanna R. Kang S. Kwatra S.G. Real-world prevalence of prurigo nodularis and burden of associated diseases.J Invest Dermatol. 2020; 140: 480-483.e4Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar; Whang et al., 2019Whang K.A. Kang S. Kwatra S.G. Inpatient burden of prurigo nodularis in the United States.Medicines (Basel). 2019; 6: 88Crossref PubMed Google Scholar). Patients with PN may experience a higher disease burden because the itch in PN is thought to be the most severe of chronic pruritic dermatoses (Steinke et al., 2018Steinke S. Zeidler C. Riepe C. Bruland P. Soto-Rey I. Storck M. et al.Humanistic burden of chronic pruritus in patients with inflammatory dermatoses: Results of the European Academy of Dermatology and Venereology Network on Assessment of Severity and Burden of pruritus (PruNet) cross-sectional trial.J Am Acad Dermatol. 2018; 79: 457-463.e5Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar). PN is also associated with a broad range of diseases such as liver disease, renal disease, HIV, and malignancies, among others (Dazzi et al., 2011Dazzi C. Erma D. Piccinno R. Veraldi S. Caccialanza M. Psychological factors involved in prurigo nodularis: a pilot study.J Dermatolog Treat. 2011; 22: 211-214Crossref PubMed Scopus (36) Google Scholar; Kwatra, 2020Kwatra S.G. Breaking the itch–scratch cycle in prurigo nodularis.N Engl J Med. 2020; 382: 757-758Crossref PubMed Scopus (46) Google Scholar). The higher disease burden of PN translates to higher healthcare utilization of specialty care by the patients. Patients with PN saw dermatologists more frequently than the controls as well as more frequently than those with AD and psoriasis. Consistent with our findings of the higher rates of comorbid cardiovascular disease in patients with PN, these patients also had the highest estimated utilization of cardiology or cardiovascular disease specialty visits in this study. Our results support previous findings indicating that patients with PN had a higher utilization of care from specialists (Huang et al., 2020bHuang A.H. Canner J.K. Williams K.A. Grossberg A.L. Kwatra M.M. Kwatra S.G. Healthcare resource utilization and payer cost analysis of patients with prurigo nodularis.Br J Dermatol. 2020; 183: 182-184Crossref PubMed Scopus (11) Google Scholar). In addition, patients with PN are more likely to be hospitalized, more likely to have longer inpatient stays, and more likely to have higher inpatient costs of care than the general population (Whang et al., 2021aWhang K. Gabriel S. Chavda R. Kwatra S. Emergency department utilization by patients with prurigo nodularis in the United States.J Am Acad Dermatol. 2021; 84: 1138-1140Abstract Full Text Full Text PDF PubMed Scopus (5) Google Scholar, Whang et al., 2019Whang K.A. Kang S. Kwatra S.G. Inpatient burden of prurigo nodularis in the United States.Medicines (Basel). 2019; 6: 88Crossref PubMed Google Scholar). In summary, patients with PN had higher healthcare utilization of specialty care and comorbidity burden than age- and gender-matched controls as well as patients with AD and psoriasis. Patients with PN often remain recalcitrant to treatment and suffer from impaired QOL due to their chronic itch‒scratch cycle and associated comorbidity burden. Limitations of this study include the retrospective nature of the analysis and the identification of patients with PN using the ICD-10-CM code. To increase the validity of PN identification through ICD-10-CM codes for this study, we defined patients with PN as those who had at least two claims with the corresponding ICD-10-CM code on the basis of the methodology that has been previously published (Huang et al., 2020aHuang A.H. Canner J.K. Khanna R. Kang S. Kwatra S.G. Real-world prevalence of prurigo nodularis and burden of associated diseases.J Invest Dermatol. 2020; 140: 480-483.e4Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar, Huang et al., 2020bHuang A.H. Canner J.K. Williams K.A. Grossberg A.L. Kwatra M.M. Kwatra S.G. Healthcare resource utilization and payer cost analysis of patients with prurigo nodularis.Br J Dermatol. 2020; 183: 182-184Crossref PubMed Scopus (11) Google Scholar). However, the ICD-10-CM code for PN requires further validation. Furthermore, the increase in annual prevalence estimates for PN, AD, and psoriasis observed in this study could also be a result of increasing coding of these diagnoses in the claims data along with rising awareness by the medical profession. Since the study is based on retrospective claims data, the findings presented in this study should be considered preliminary and the foundation for further research. Overall, this study provides a nationwide description of the epidemiology of PN and the comorbidities and healthcare utilization of patients with PN compared with those of control patients and patients with other similar pruritic, inflammatory skin diseases at the national level. Under law and regulations, the database used in this study cannot be made available. Owing to data use agreements, the claims data must remain private; inquiries regarding the data can be directed to the corresponding author (SGK). Shannon Wongvibulsin: http://orcid.org/0000-0002-1390-7440 Nishadh Sutaria: http://orcid.org/0000-0002-6804-6983 Kyle A. Williams: http://orcid.org/0000-0003-3969-3548 Amy H. Huang: http://orcid.org/0000-0003-2510-6269 Justin Choi: http://orcid.org/0000-0002-8388-6876 Youkyung Sophie Roh: http://orcid.org/0000-0003-1755-2146 Michael Hong: http://orcid.org/0000-0001-5987-4616 Davis Kelley: http://orcid.org/0000-0002-4477-8098 Vartan Pahalyants: http://orcid.org/0000-0003-4671-620X William Murphy: http://orcid.org/0000-0002-8884-3760 Martin Prince Alphonse: http://orcid.org/0000-0003-3447-1284 Pegah Bakhshi; http://orcid.org/0000-0002-5985-9878 Anant Walia: http://orcid.org/0000-0002-6314-5798 Yevgeniy R. Semenov: http://orcid.org/0000-0002-7387-3094 Shawn G. Kwatra: http://orcid.org/0000-0003-3736-1515 SGK is an advisory board member and/or consultant for AbbVie, Galderma, Incyte Corporation, Pfizer, Regeneron Pharmaceuticals, and Kiniksa Pharmaceuticals and has received grant funding from Galderma, Pfizer, and Kiniksa Pharmaceuticals. The remaining authors state no conflict of interest. SW is funded by the National Institutes of Health (NIH) F30HL142131 and 5T32GM007309 grants. SGK is a recipient of a Dermatology Foundation Medical Dermatology Career Development Award and has received a research grant from the Skin of Color Society. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH, Dermatology Foundation, or Skin of Color Society. We thank Susanne Churchill, Erica Meyer, and Nathan Palmer of the Department of Biomedical Informatics at Harvard Medical School (Boston, MD) for providing assistance with the claims data access. Conceptualization: SGK, YRS, SW; Data Curation: SW; Formal Analysis: SW; Investigation: SGK, YRS, SW; Methodology: SGK, YRS, SW; Project Administration: SGK, YRS, SW; Resources: SGK, YRS, SW; Supervision: SGK, YRS; Validation: SGK, YRS, SW; Visualization: SGK, YRS, SW; Writing – Original Draft Preparation: SW, NS, YSR, JC, DK; Writing – Review and Editing: SW, NS, KAW, AHH, JC, YSR, MH, DK, VP, WM, MPA, PB, AW, YRS, SGK The content of this paper is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Unidentifiable claims data from a nationwide United States health insurance plan between October 2015 and December 2019 were analyzed. The data include deidentified medical claims, pharmacy claims, and enrollment, and demographic information. We defined patients with prurigo nodularis (PN) as individuals with ≥2 medical claims (on different dates) for PN using the International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) code L28.1. For further comparison, patients with atopic dermatitis (AD) and patients with psoriasis were also identified. Patients with AD were defined as those with ≥2 medical claims (on different dates) for AD using the ICD-10-CM code L20.9. Patients with psoriasis were defined as those with ≥2 medical claims (on different dates) for psoriasis using the ICD-10-CM code L40.9. Control patients were selected as PN age- and gender-matched individuals without any ICD-10-CM codes for PN, AD, and psoriasis. Due to the deidentified nature of the database, the study was exempt from Institutional Review Board approval. Funding sources for this project had no role in the design and/or conduct of the study; data collection, management, and analysis; manuscript preparation, or in the decisions about submitting the manuscript for publication. The period prevalence of PN, AD, and psoriasis overall and by age groups (age <18 years and ≥18 years) was estimated annually from the claims data using the ICD-10-CM definitions for PN, AD, and psoriasis as described earlier. Demographic information, including age and gender, was determined from the enrollment ata. Comorbidity burden and the Charlson Comorbidity Index were estimated annually using ICD-9-CM and ICD-10-CM codes on the basis of previously published methodology (Charlson et al., 1994Charlson M. Szatrowski T.P. Peterson J. Gold J. Validation of a combined comorbidity index.J Clin Epidemiol. 1994; 47: 1245-1251Abstract Full Text PDF PubMed Scopus (4976) Google Scholar; Quan et al., 2005Quan H. Sundararajan V. Halfon P. Fong A. Burnand B. Luthi J.C. et al.Coding algorithms for defining comorbidities in ICD-9-CM and ICD-10 administrative data.Med Care. 2005; 43: 1130-1139Crossref PubMed Scopus (7386) Google Scholar). The period prevalence for the comorbidities in each group was estimated annually and is expressed as percentages. The claims data regarding provider specialty were used to estimate the utilization rates of the top five specialties visited for controls over the entire study period and starting at the time corresponding to the second ICD-10-CM diagnosis of patients with PN, AD, and psoriasis. The rates were calculated in units of visits per year per patient. Control patients without PN, AD, and psoriasis were selected with 1:5 exact matching by age and gender with patients with PN. Analyses were conducted in R, version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria).

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.

OBJECTIVE:Pediatric obsessive-compulsive disorder (OCD) sometimes appears rapidly, even overnight, often after an infection. Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections, or PANDAS, describes such a situation after infection with Streptococcus pyogenes. PANDAS may result from induced autoimmunity against brain antigens, although this remains unproven. Pilot work suggests that IgG antibodies from children with PANDAS bind to cholinergic interneurons (CINs) in the striatum. CIN deficiency has been independently associated with tics in humans and with repetitive behavioral pathology in mice, making it a plausible locus of pathology. The authors sought to replicate and extend earlier work and to investigate the cellular effects of PANDAS antibodies on cholinergic interneurons.METHODS:Binding of IgG to specific neurons in human and mouse brain slices was evaluated ex vivo after incubation with serum from 27 children with rigorously characterized PANDAS, both at baseline and after intravenous immunoglobulin (IVIG) treatment, and 23 matched control subjects. Binding was correlated with symptom measures. Neural activity after serum incubation was assessed in mouse slices using molecular markers and electrophysiological recording.RESULTS:IgG from children with PANDAS bound to CINs, but not to several other neuron types, more than IgG from control subjects, in three independent cohorts of patients. Post-IVIG serum had reduced IgG binding to CINs, and this reduction correlated with symptom improvement. Baseline PANDAS sera decreased activity of striatal CINs, but not of parvalbumin-expressing GABAergic interneurons, and altered their electrophysiological responses, in acute mouse brain slices. Post-IVIG PANDAS sera and IgG-depleted baseline sera did not alter the activity of striatal CINs.CONCLUSIONS:These findings provide strong evidence for striatal CINs as a critical cellular target that may contribute to pathophysiology in children with rapid-onset OCD symptoms, and perhaps in other conditions.

Atopic dermatitis (AD) often presents more severely in African Americans (AAs) and with greater involvement of extensor areas. To investigate immune signatures of AD in AAs with moderate to severe pruritus, lesional and non-lesional punch biopsies were taken from AA patients along with age-, race-, and sex-matched controls. Histology of lesional skin showed psoriasiform dermatitis and spongiotic dermatitis, suggesting both Th2 and Th17 activity. Gene Set Variation Analysis showed upregulation of Th2 and Th17 pathways in both lesional versus non-lesional and lesional versus control (p < 0.01), while Th1 and Th22 upregulation were observed in lesional versus control (p < 0.05). Evidence for a broad immune signature also was supported by upregulated Th1 and Th22 pathways, and clinically may represent greater severity of AD in AA. Furthermore, population-level analysis of data from TriNetX, a global federated health research network, revealed that AA AD patients had higher values for CRP, ferritin, and blood eosinophils compared to age-, sex-, and race-matched controls as well as white AD patients, suggesting broad systemic inflammation. Therefore, AA AD patients may feature broader immune activation than previously thought and may derive benefit from systemic immunomodulating therapies that modulate key drivers of multiple immune pathways.

To the Editor: With our nation's growing diversity, there is increased focus on how dermatologic conditions present among various racial and ethnic populations.1,2 Census estimations project skin of color to compose nearly 50% of the US population by 2050.3 Few studies, however, have examined the occurrence of cutaneous diseases across racial and ethnic groups.4 Our study characterizes the racial and ethnic distribution of common dermatologic conditions observed at a US tertiary care center.

Prurigo nodularis (PN) is an understudied, chronic inflammatory skin disease that disproportionately affects African Americans and presents with intensely pruritic nodules of unknown etiology. To better characterize the immune dysregulation in PN, PBMCs and skin biopsies were obtained from patients with PN and healthy subjects (majority African American) matched by age, race, and sex. Flow cytometric analysis of functional T-cell response comparing patients with PN with healthy subjects identified increased γδT cells (CD3+CD4-CD8-γδTCR+) and Vδ2+ γδT enrichment. Activated T cells demonstrated uniquely increased IL-22 cytokine expression in patients with PN compared with healthy controls. CD4+ and CD8+ T cells were identified as the source of increased circulating IL-22. Consistent with these findings, RNA sequencing of lesional PN skin compared with nonlesional PN skin and biopsy site‒matched control skin demonstrated robust upregulation of T helper (Th) 22‒related genes and signaling networks implicated in impaired epidermal differentiation. Th22‒related cytokine upregulation remained significant, with stratifications by race and biopsy site. Importantly, the expression of the IL-22 receptors IL22RA1 and IL22RA2 was significantly elevated in lesional PN skin. These results indicate that both systemic and cutaneous immune responses in patients with PN are skewed toward a Th22/IL-22 profile. PN may benefit from immunomodulatory therapies directed at Th22‒mediated inflammation.