TNFα increases the degradation of pyruvate dehydrogenase kinase 4 by the Lon protease to support proinflammatory genes.

The endothelium is a major target of the proinflammatory cytokine, tumor necrosis factor alpha (TNFα). Exposure of endothelial cells (EC) to proinflammatory stimuli leads to an increase in mitochondrial metabolism; however, the function and regulation of elevated mitochondrial metabolism in EC in response to proinflammatory cytokines remain unclear. Studies using high-resolution metabolomics and 13C-glucose and 13C-glutamine labeling flux techniques showed that pyruvate dehydrogenase activity (PDH) and oxidative tricarboxylic acid cycle (TCA) flux are elevated in human umbilical vein ECs in response to overnight (16 h) treatment with TNFα (10 ng/mL). Mechanistic studies indicated that TNFα mediated these metabolic changes via mitochondrial-specific protein degradation of pyruvate dehydrogenase kinase 4 (PDK4, inhibitor of PDH) by the Lon protease via an NF-κB-dependent mechanism. Using RNA sequencing following siRNA-mediated knockdown of the catalytically active subunit of PDH, PDHE1α (PDHA1 gene), we show that PDH flux controls the transcription of approximately one-third of the genes that are up-regulated by TNFα stimulation. Notably, TNFα-induced PDH flux regulates a unique signature of proinflammatory mediators (cytokines and chemokines) but not inducible adhesion molecules. Metabolomics and ChIP sequencing for acetylated modification on lysine 27 of histone 3 (H3K27ac) showed that TNFα-induced PDH flux promotes histone acetylation of specific gene loci via citrate accumulation and ATP-citrate lyase-mediated generation of acetyl CoA. Together, these results uncover a mechanism by which TNFα signaling increases oxidative TCA flux of glucose to support TNFα-induced gene transcription through extramitochondrial acetyl CoA generation and histone acetylation.

Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling.

BACKGROUND: Cross-talk between sterol metabolism and inflammatory pathways has been demonstrated to significantly affect the development of atherosclerosis. Cholesterol biosynthetic intermediates and derivatives are increasingly recognized as key immune regulators of macrophages in response to innate immune activation and lipid overloading. 25-Hydroxycholesterol (25-HC) is produced as an oxidation product of cholesterol by the enzyme cholesterol 25-hydroxylase (CH25H) and belongs to a family of bioactive cholesterol derivatives produced by cells in response to fluctuating cholesterol levels and immune activation. Despite the major role of 25-HC as a mediator of innate and adaptive immune responses, its contribution during the progression of atherosclerosis remains unclear. METHODS: The levels of 25-HC were analyzed by liquid chromatography-mass spectrometry, and the expression of CH25H in different macrophage populations of human or mouse atherosclerotic plaques, respectively. The effect of CH25H on atherosclerosis progression was analyzed by bone marrow adoptive transfer of cells from wild-type or Ch25h-/- mice to lethally irradiated Ldlr-/- mice, followed by a Western diet feeding for 12 weeks. Lipidomic, transcriptomic analysis and effects on macrophage function and signaling were analyzed in vitro from lipid-loaded macrophage isolated from Ldlr-/- or Ch25h-/-;Ldlr-/- mice. The contribution of secreted 25-HC to fibrous cap formation was analyzed using a smooth muscle cell lineage-tracing mouse model, Myh11ERT2CREmT/mG;Ldlr-/-, adoptively transferred with wild-type or Ch25h-/- mice bone marrow followed by 12 weeks of Western diet feeding. RESULTS: We found that 25-HC accumulated in human coronary atherosclerotic lesions and that macrophage-derived 25-HC accelerated atherosclerosis progression, promoting plaque instability through autocrine and paracrine actions. 25-HC amplified the inflammatory response of lipid-loaded macrophages and inhibited the migration of smooth muscle cells within the plaque. 25-HC intensified inflammatory responses of lipid-laden macrophages by modifying the pool of accessible cholesterol in the plasma membrane, which altered Toll-like receptor 4 signaling, promoted nuclear factor-κB-mediated proinflammatory gene expression, and increased apoptosis susceptibility. These effects were independent of 25-HC-mediated modulation of liver X receptor or SREBP (sterol regulatory element-binding protein) transcriptional activity. CONCLUSIONS: Production of 25-HC by activated macrophages amplifies their inflammatory phenotype, thus promoting atherogenesis.

Nanoscale Three-Dimensional Imaging of Integrated Circuits Using a Scanning Electron Microscope and Transition-Edge Sensor Spectrometer.

X-ray nanotomography is a powerful tool for the characterization of nanoscale materials and structures, but it is difficult to implement due to the competing requirements of X-ray flux and spot size. Due to this constraint, state-of-the-art nanotomography is predominantly performed at large synchrotron facilities. We present a laboratory-scale nanotomography instrument that achieves nanoscale spatial resolution while addressing the limitations of conventional tomography tools. The instrument combines the electron beam of a scanning electron microscope (SEM) with the precise, broadband X-ray detection of a superconducting transition-edge sensor (TES) microcalorimeter. The electron beam generates a highly focused X-ray spot on a metal target held micrometers away from the sample of interest, while the TES spectrometer isolates target photons with a high signal-to-noise ratio. This combination of a focused X-ray spot, energy-resolved X-ray detection, and unique system geometry enables nanoscale, element-specific X-ray imaging in a compact footprint. The proof of concept for this approach to X-ray nanotomography is demonstrated by imaging 160 nm features in three dimensions in six layers of a Cu-SiO2 integrated circuit, and a path toward finer resolution and enhanced imaging capabilities is discussed.

SREBP2 regulates the endothelial response to cytokines via direct transcriptional activation of KLF6.

The transcription factor SREBP2 is the main regulator of cholesterol homeostasis and is central to the mechanism of action of lipid-lowering drugs, such as statins, which are responsible for the largest overall reduction in cardiovascular risk and mortality in humans with atherosclerotic disease. Recently, SREBP2 has been implicated in leukocyte innate and adaptive immune responses by upregulation of cholesterol flux or direct transcriptional activation of pro-inflammatory genes. Here, we investigate the role of SREBP2 in endothelial cells (ECs), since ECs are at the interface of circulating lipids with tissues and crucial to the pathogenesis of cardiovascular disease. Loss of SREBF2 inhibits the production of pro-inflammatory chemokines but amplifies type I interferon response genes in response to inflammatory stimulus. Furthermore, SREBP2 regulates chemokine expression not through enhancement of endogenous cholesterol synthesis or lipoprotein uptake but partially through direct transcriptional activation. Chromatin immunoprecipitation sequencing of endogenous SREBP2 reveals that SREBP2 bound to the promoter regions of two nonclassical sterol responsive genes involved in immune modulation, BHLHE40 and KLF6. SREBP2 upregulation of KLF6 was responsible for the downstream amplification of chemokine expression, highlighting a novel relationship between cholesterol homeostasis and inflammatory phenotypes in ECs.

Oral spleen tyrosine kinase/Janus Kinase inhibitor gusacitinib for the treatment of chronic hand eczema: Results of a randomized phase 2 study.

BACKGROUND: Gusacitinib is an oral inhibitor of Janus and Spleen tyrosine kinases. METHODS: The efficacy and safety of gusacitinib were evaluated in a double-blind, placebo-controlled, multicenter, phase 2 study in 97 chronic hand eczema patients randomized (1:1:1) to placebo or gusacitinib (40 or 80 mg) for 12 weeks (part A). Then, in part B (through week 32), the patients received gusacitinib. RESULTS: At week 16, patients receiving 80 mg gusacitinib showed a 69.5% (P <.005) decrease in the modified total lesion-symptom score versus 49.0% for 40 mg (P =.132), and 33.5% for placebo. Considerable improvement in Physician's Global Assessment was seen in 31.3% of patients receiving 80 mg versus 6.3% of placebo (P <.05). A 73.3% decrease in the hand eczema severity index versus placebo (21.7%) occurred in patients receiving 80 mg (P <.001). Patients receiving 80 mg experienced a considerable decrease in hand pain (P <.05). As early as week 2, considerable reductions over placebo in modified total lesion-symptom score (P <.005), Physician's Global Assessment (P =.04), and hand eczema severity index (P <.01) were observed (80 mg gusacitinib). Adverse events included upper respiratory infection, headache, nausea, and nasopharyngitis. CONCLUSIONS: Gusacitinib showed rapid improvement in chronic hand eczema patients and was well tolerated, warranting further investigations.

Prevalence and trend of allergen sensitization in patients with cheilitis referred for patch testing, North American Contact Dermatitis Group data, 2001-2018.

BACKGROUND: An updated understanding of allergic contact cheilitis is needed. OBJECTIVES: To characterize clinical characteristics and allergen relevance in patients with cheilitis referred for patch testing. METHODS: Retrospective analysis of 43 772 patients patch tested with the North American Contact Dermatitis Group (NACDG) screening series from 2001 to 2018. RESULTS: Overall, 2094 patients (4.8%) had lips as one of three sites of dermatitis, 1583 (3.6%) had lips as the primary site and 1167 (2.7%) had lips as the sole site of dermatitis. Prevalences of cheilitis at any, primary, and sole sites significantly increased throughout the study cycle from 2001-2002 (2.7%, 2.2% and 1.7%) to 2017-2018 (7.8%, 5.2% and 3.7%). Approximately 60% of patients with any, a primary, or a sole site of cheilitis had one or more positive allergic patch-test reactions compared to 65% of those without cheilitis. CONCLUSION: Patients with cheilitis who were referred for patch testing had high rates of positive and relevant allergens. More than one in four patients with any, primary, or sole cheilitis had a positive reaction to non-NACDG screening allergens (28.0%, 26.8%, 31.1% vs. 21.6%) compared to patients without cheilitis, emphasizing the need for expanded patch test series in cheilitis.

Hand and foot dermatitis in patients referred for patch testing: Analysis of North American Contact Dermatitis Group Data, 2001-2018.

BACKGROUND: Dermatitis localized to hands (HD), feet (FD), or both hands and feet (HFD) has multiple etiologies, including atopic dermatitis, irritant contact dermatitis, and allergic contact dermatitis. Unfortunately, little is known about clinical differences between patients with HD, FD, and HFD. OBJECTIVE: To characterize differences in demographics, etiology, and patch testing results among patients presenting with HD, FD, or HFD referred for patch testing. METHODS: A retrospective analysis of patients patch tested by the North American Contact Dermatitis Group between 2001 and 2018. RESULTS: Of 43,677 patients who were patch tested, 22.8% had HD, 2.9% had FD, and 3.7% had HFD. Allergic and currently relevant patch test reactions to ≥1 North American Contact Dermatitis Group screening allergen occurred in similar proportions in all 3 study groups. However, HD (18.0%) had higher proportions of occupationally relevant reactions than HFD (8.9%) or FD (4.0%). Nickel and fragrance mix I were in the top 5 currently relevant allergens for HD, FD, and HFD. Other top allergens, as well as allergen sources, differed between HD, FD, and HFD. LIMITATIONS: No data on HD or FD morphology or distribution. CONCLUSION: HD, FD, and HFD have several differences with respect to patient characteristics, etiologies, and clinically relevant allergens.

Medical adhesive allergens: Retrospective analysis of cross-sectional data from the North American Contact Dermatitis Group, 2001-2018.

BACKGROUND: Identification of allergens causing medical adhesive contact allergy is difficult. OBJECTIVE: To characterize the demographics, clinical characteristics, patch test results, and occupational data for North American Contact Dermatitis Group patients with medical adhesive contact allergy. METHODS: A retrospective study of 43,722 North American Contact Dermatitis Group patients patch tested from 2001 to 2018 with medical adhesive (tapes/bandaids/adhesive aids/suture glue) sources, positive patch test results, and final primary diagnoses of allergic contact dermatitis. RESULTS: In total, 313 (0.7%) patients met the inclusion criteria. Compared with other patients with final primary diagnoses of allergic contact dermatitis, patients with a medical adhesive allergy were less likely to be male (odds ratio, 0.58; 95% CI, 0.45-0.77) and/or aged >40 years (odds ratio, 0.76; 95% CI, 0.60-0.96). The most common North American Contact Dermatitis Group screening series allergens were colophony (80.7%), balsam of Peru (3.9%), 2-hydroxyethyl methacrylate (2.7%), and carba mix (2.7%). One-fourth of the patients (79/313, 25.2%) had positive patch test reactions to supplemental allergens/materials, and 54 (17.3%) of the 313 patients only had reactions to supplemental allergens/materials. LIMITATIONS: Results of comprehensive patch testing may be prone to referral population selection bias and may not be representative of the general dermatology population. CONCLUSION: Colophony was the most common allergen. Supplemental allergens and materials should be tested in the evaluation of a suspected medical adhesive contact allergy.

Patch testing with glucosides: The North American Contact Dermatitis Group experience, 2009-2018.

BACKGROUND: Alkyl glucosides are nonionic surfactants that are increasingly used in personal care products. OBJECTIVE: To characterize positive patch test reactions to decyl glucoside (5% petrolatum, tested 2009-2018) and lauryl glucoside (3% petrolatum, tested 2017-2018). METHODS: Retrospective analysis of patients tested by the North American Contact Dermatitis Group. RESULTS: Of 24,097 patients patch tested to decyl and/or lauryl glucoside, 470 (2.0%) had positive reactions. Compared with glucoside-negative patients, glucoside-positive patients had higher odds of occupational skin disease (13.4% vs 10.1%; P = .0207), history of hay fever (38.5% vs 31.6%; P = .0014), atopic dermatitis (39.0% vs 28.6%; P < .0001), and/or asthma (21.8% vs 16.5%; P = .0023). Most glucoside reactions (83.9%) were currently relevant. The most common source was personal care products (63.0%), especially hair products (16.5%) and skin cleansers (15.2%). Of 4933 patients tested to decyl and lauryl glucoside, 134 (2.7%) were positive to 1 or both; 43.4% (43 of 99) of decyl-positive patients were also positive to lauryl glucoside and 55.1% (43/78) of lauryl glucoside patients were also positive to decyl glucoside. LIMITATIONS: The cohort predominantly reflects a referral population, and follow-up after testing was not captured. CONCLUSION: Glucoside positivity occurred in 2.0% of the tested patients. Reactions were often clinically relevant and linked to personal care products. Cross-reactivity was >40%.

Patch testing with ammonium persulfate: The North American Contact Dermatitis Group Experience, 2015-2018.

BACKGROUND: Ammonium persulfate (APS), an oxidizing agent used in hair products, manufacturing, and pool/spa water, can cause skin reactions, including allergic contact dermatitis. OBJECTIVE: To characterize positive patch test reactions to APS (2.5% petrolatum). METHODS: Retrospective analysis of patients tested to the North American Contact Dermatitis Group screening series from 2015 to 2018. RESULTS: Of 10,526 patients, 193 (1.8%) had positive patch test reactions to APS. Compared with APS-negative patients, APS-positive patients were significantly more likely to be male (43.2% vs 28.0%; P < .0001); have primary hand dermatitis (30.2% vs 22.0%; P = .0064), scattered generalized dermatitis (25.5% vs 17.9%; P = .0064), or trunk dermatitis (8.9% vs 4.9%; P = .0123); and have dermatitis that is occupationally related (22.2% vs 10.9%; P < .0001). More than half of the APS-positive reactions were currently relevant (57.0%); 19 (9.8%) were related to occupation, especially hairdressers (68.4%). Swimming pools/spas (23.3%) and hair care products (19.2%) were the most common sources of APS. LIMITATIONS: Immediate reactions and follow-up testing were not captured. CONCLUSION: The proportion of patients positive to APS was 1.8%. APS positivity was significantly associated with male sex and hand dermatitis. Swimming pool/spa chemicals were important sources of APS exposure.

Age-related differences in patch testing results among children: Analysis of North American Contact Dermatitis Group Data, 2001-2018.

BACKGROUND: An updated understanding of allergic contact dermatitis is needed, particularly in children. OBJECTIVES: To compare positive and clinically relevant reactions in children versus adults referred for patch testing. METHODS: Retrospective analysis of 1871 children and 41,699 adults from the North American Contact Dermatitis Group (NACDG) from 2001-2018. RESULTS: Both final diagnosis of allergic contact dermatitis (55.2% versus 57.3%; chi square, P = .0716) and prevalence of ≥ 1 currently relevant reaction to a NACDG screening allergen (49.2% vs 52.2%; P = .1178) were similar between children and adults. Currently in children, the most common relevant allergens were nickel sulfate (17.3%), hydroperoxides of linalool (7.8%), methylisothiazolinone (7.7%), cobalt chloride (7.0%), and fragrance mix I (4.9%). Approximately a fifth of children had a positive reaction to a non-NACDG allergen. CONCLUSION: Over half of children referred for patch testing were diagnosed with allergic contact dermatitis. The most common relevant allergens in children were nickel sulfate, cobalt chloride, and hydroperoxides of linalool. Twenty percent of children had at least 1 positive reaction to allergens/substances not on the NACDG screening series, underscoring the need for comprehensive testing.

Occupational contact dermatitis: Retrospective analysis of North American Contact Dermatitis Group Data, 2001 to 2016.

BACKGROUND: Patch testing is an important diagnostic tool for suspected allergic contact dermatitis (ACD) in occupational settings. OBJECTIVE: Provide an overview of occupational skin disease (OSD) and an analysis of occupational ACD in North American patients undergoing patch testing between 2001and 2016. METHODS: Patients with OSD were analyzed for frequency of allergic reactions to a screening series of allergens, occupational relevance, location of skin disease, and exposure sources. Demographic, occupation, and industry information were recorded. RESULTS: Of 38,614 patients evaluated, 4471 (11.6%) had OSD, of whom 3150 (70.5%) had ACD. The most common occupationally related allergens included rubber accelerators, preservatives, and bisphenol A epoxy resin. Hands (75.8%), arms (30.0%), and face (15.9%) were common sites of dermatitis. The occupations most affected were service workers and machine operators. LIMITATIONS: Our cohort may not reflect the general working population. CONCLUSION: This study identified common occupational allergens, exposure sources, and occupations/industries at risk. This information may help the clinician evaluate and manage patients with occupational contact dermatitis.

Patch testing with cobalt in children and adolescents: North American contact dermatitis group experience, 2001-2018.

BACKGROUND: Allergic contact dermatitis (ACD) to cobalt is more common in children and adolescents than adults. However, detailed information on sites and sources of cobalt ACD is limited. OBJECTIVES: To assess trends in positive and clinically relevant patch test reactions to cobalt in children and associated patient characteristics, common sources and body sites affected. METHODS: A retrospective analysis of children (<18 years) patch tested to cobalt by the North American Contact Dermatitis Group between 2001 and 2018. RESULTS: Of 1919 children patch tested, 228 (11.9%) and 127 (6.6%) had a positive/allergic or currently relevant patch test reaction to cobalt, respectively. The most common primary body sites affected were scattered generalized (30.0%), face, not otherwise specified (10.6%) and trunk (10.1%). Patients with allergic and currently relevant allergic patch test reactions were more likely to have a primary site of trunk (p = 0.0160 and p = 0.0008) and ears (p = 0.0005 and p < 0.0001). Affected body site(s) varied by cobalt source among patients with currently relevant reactions, especially for less common sources. The most commonly identified sources of cobalt included jewellery, belts and clothing. CONCLUSIONS: Positive patch test reactions to cobalt were common in children. The most common body site was scattered generalized and the sources of cobalt varied by body site.

BMP-9 and LDL crosstalk regulates ALK-1 endocytosis and LDL transcytosis in endothelial cells.

Bone morphogenetic protein-9 (BMP-9) is a circulating cytokine that is known to play an essential role in the endothelial homeostasis and the binding of BMP-9 to the receptor activin-like kinase 1 (ALK-1) promotes endothelial cell quiescence. Previously, using an unbiased screen, we identified ALK-1 as a high-capacity receptor for low-density lipoprotein (LDL) in endothelial cells that mediates its transcytosis in a nondegradative manner. Here we examine the crosstalk between BMP-9 and LDL and how it influences their interactions with ALK-1. Treatment of endothelial cells with BMP-9 triggers the extensive endocytosis of ALK-1, and it is mediated by caveolin-1 (CAV-1) and dynamin-2 (DNM2) but not clathrin heavy chain. Knockdown of CAV-1 reduces BMP-9-mediated internalization of ALK-1, BMP-9-dependent signaling and gene expression. Similarly, treatment of endothelial cells with LDL reduces BMP-9-induced SMAD1/5 phosphorylation and gene expression and silencing of CAV-1 and DNM2 diminishes LDL-mediated ALK-1 internalization. Interestingly, BMP-9-mediated ALK-1 internalization strongly re-duces LDL transcytosis to levels seen with ALK-1 deficiency. Thus, BMP-9 levels can control cell surface levels of ALK-1, via CAV-1, to regulate both BMP-9 signaling and LDL transcytosis.

Contact dermatitis to personal care products is increasing (but different!) in males and females: North American Contact Dermatitis Group data, 1996-2016.

BACKGROUND: Personal care products (PCPs) are commonly responsible for allergic contact dermatitis and irritant contact dermatitis. PCP use was historically associated with females, but male-targeted PCPs are increasingly being marketed. OBJECTIVE: To characterize and compare males with PCP-related contact dermatitis (MPCPs) and females with PCP-related contact dermatitis (FPCPs). METHODS: This was a retrospective cross-sectional analysis of North American Contact Dermatitis Group data (1996-2016). RESULTS: Four thousand six hundred eighty of 16,233 men (28.8%) and 12,730 of 32,222 (39.5%) women had a PCP identified as a source of irritant contact dermatitis or a positive patch test reaction. The proportion of PCP-related dermatitis in both sexes significantly increased (>2.7-fold) over the decade of study. Compared with FPCPs, a larger proportion of MPCPs were older or had trunk or extremity dermatitis (P < .0001). MPCPs were twice as likely to have soaps as a source while FPCPs were twice as likely to have hair care products (P < .0001). The most common PCP-related North American Contact Dermatitis Group allergens for both sexes were methylisothiazolinone (MPCP 28.8% and FPCP 21.5%), fragrance mix I (MPCP 22.3% and FPCP 20.1%), balsam of Peru (MPCP 18.5% and FPCP 14.1%), quaternium-15 (MPCP 16.1% and FPCP 12.3%), and paraphenylenediamine (MPCP 11.5% and FPCP 11.1%). LIMITATIONS: Patient population referred for suspected contact dermatitis. CONCLUSIONS: PCP-related dermatitis is increasing. Sites of involvement and relevant PCP sources are distinct between sexes. Male and female variation in exposure history may explain differences in reactivity to some allergen groups.

Scalp involvement in patients referred for patch testing: Retrospective cross-sectional analysis of North American Contact Dermatitis Group data, 1996 to 2016.

BACKGROUND: Scalp conditions are often multifactorial. OBJECTIVE: To characterize patients with scalp involvement and patch-testing outcomes. METHODS: Retrospective cross-sectional analysis of North American Contact Dermatitis Group data (1996-2016). Study groups included patients with scalp involvement (≤3 anatomic sites coded) with or without additional sites. RESULTS: A total of 4.8% of patients (2331/48,753) had scalp identified as 1 of up to 3 affected anatomic sites. Approximately one-third of "scalp-only" individuals had a specific primary diagnosis of allergic contact dermatitis (38.6%), followed by seborrheic dermatitis (17.2%) and irritant contact dermatitis (9.3%). When adjacent anatomic sites were affected, allergic contact dermatitis was more frequently identified as the primary diagnosis (>50%). The top 5 currently clinically relevant allergens in scalp-only patients were p-phenylenediamine, fragrance mix I, nickel sulfate, balsam of Peru, and cinnamic aldehyde. Methylisothiazolinone sensitivity was notable when adjacent anatomic sites were involved. The top 3 specifically identified sources for scalp-only allergens were hair dyes, shampoo/conditioners, and consumer items (eg, hair appliances, glasses). LIMITATIONS: Tertiary referral population. CONCLUSION: Isolated scalp involvement was less likely to be associated with allergic contact dermatitis than when adjacent anatomic sites were involved. Overlap with multiple diagnoses was frequent, including seborrheic dermatitis, irritant dermatitis, other dermatoses, or all 3. p-Phenylenediamine was the most common allergen.

Eyelid dermatitis in patients referred for patch testing: Retrospective analysis of North American Contact Dermatitis Group data, 1994-2016.

BACKGROUND: Eyelid dermatitis is a common dermatologic complaint. OBJECTIVE: To characterize patients with eyelid dermatitis. METHODS: Retrospective analysis (1994-2016) of North American Contact Dermatitis Group data. RESULTS: Of 50,795 patients, 2332 (4.6%) had eyelid dermatitis only, whereas 1623 (3.2%) also had dermatitis of the eyelids and head or neck. Compared with patients without eyelid involvement (n = 26,130), groups with eyelid dermatitis only and dermatitis of the eyelid and head or neck were significantly more likely to be female, white, and older than 40 years, and to have a history of hay fever, atopic dermatitis, or both (P < .01). Final primary diagnoses included allergic contact dermatitis (eyelid dermatitis only: 43.4%; dermatitis of the eyelid and head or neck: 53.5%), irritant contact dermatitis (eyelid dermatitis only: 17.0%; dermatitis of the eyelid and head or neck: 9.8%), and atopic dermatitis (eyelid dermatitis only: 13.1%; dermatitis of the eyelid and head or neck: 13.8%). Top 5 currently relevant allergens included nickel sulfate (eyelid dermatitis only: 18.6%; dermatitis of the eyelid and head or neck: 22.5%), fragrance mix I (eyelid dermatitis only: 16.5%; dermatitis of the eyelid and head or neck: 18.3%), methylisothiazolinone (eyelid dermatitis only: 16.5%; dermatitis of the eyelid and head or neck: 17.7%), gold sodium thiosulfate (eyelid dermatitis only: 14.7%; dermatitis of the eyelid and head or neck: 11.4%), and balsam of Peru (eyelid dermatitis only: 11.9%; dermatitis of the eyelid and head or neck: 12.6%). Both eyelid-involvement groups were significantly more likely to react to gold sodium thiosulfate, carmine, shellac, dimethylaminopropylamine, oleamidopropyl dimethylamine, and thimerosal (P < .05) compared with the no eyelid involvement group. LIMITATIONS: Lack of specific distribution patterns of eyelid dermatitis and no long-term follow-up data. CONCLUSION: Patch testing remains a critical tool in evaluating patients with eyelid dermatitis.

Hand dermatitis in adults referred for patch testing: Analysis of North American Contact Dermatitis Group Data, 2000 to 2016.

BACKGROUND: Hand eczema (HE) is a heterogeneous and burdensome disorder. OBJECTIVE: To characterize the clinical characteristics, etiologies and allergen relevance in adults with HE referred for patch testing. METHODS: Retrospective analysis (2000-2016) of North American Contact Dermatitis Group data (n = 37,113). RESULTS: Overall, 10,034 patients had HE, with differences of overlap between allergic contact, irritant contact, and atopic dermatitis. Allergic contact HE fluctuated, whereas atopic HE steadily increased, and irritant HE decreased over time. HE was associated with higher proportions of positive patch tests (67.5% vs 63.8%; χ2, P < .0001). The five most common clinically relevant allergens were methylisothiazolinone, nickel, formaldehyde, quaternium-15, and fragrance mix I. HE was associated with significantly higher odds of positive patch test reactions and clinical relevance in 13 and 16 of the 25 most common allergens, respectively, including preservatives, metals, topical medications, and rubber accelerators. LIMITATIONS: No data on HE phenotype. CONCLUSION: HE in adults was associated with higher proportions of positive patch tests, with a heterogeneous profile of allergens. Patch testing remains an important tool in the evaluation of patients with HE.

Contact dermatitis associated with preservatives: Retrospective analysis of North American Contact Dermatitis Group data, 1994 through 2016.

BACKGROUND: Preservatives are often necessary components of commercial products. Large-scale North American studies on preservative allergy are limited. OBJECTIVE: To evaluate demographics, positive patch test reactions (PPTRs), clinical relevance, and trends for preservatives tested by the North American Contact Dermatitis Group. METHODS: We conducted a retrospective cross-sectional analysis of North American Contact Dermatitis Group patch testing results of preservatives from 1994 through 2016. RESULTS: A total of 50,799 patients were tested; 11,338 (22.3%) had a PPTR to at least 1 preservative. The most frequent reactions were to methylisothiazolinone 0.2% aqueous (aq) (12.2%), formaldehyde 2% aq (7.8%), formaldehyde 1% aq (7.8%), quaternium-15 2% petrolatum (pet) (7.7%), and methyldibromo glutaronitrile/phenoxyethanol 2% pet (5.1%). Paraben mix 12% pet (1%), iodopropynyl butylcarbamate 0.1% pet (0.4%), benzyl alcohol 1% pet (0.3%), and phenoxyethanol 1% pet (0.2%) had the lowest PPTRs. Linear regression analysis of preservatives tested showed that only methylchloroisothiazolinone/methylisothiazolinone 0.01% aq (parameter estimate, 0.42; 95% CI, 0.17-0.66; P < .005) had a significant increase in PPTRs over time. LIMITATIONS: Collected variables are dependent on clinical judgment. Results may be prone to referral selection bias. CONCLUSIONS: This large North American study provides insight on preservative PPTRs and trends from 1994 through 2016.

Inter-rater variability in patch test readings and final interpretation using store-forward teledermatology.

BACKGROUND: Data regarding teledermatology for patch testing are limited. OBJECTIVES: Compare patch test readings and final interpretation by two in-person dermatologists (IPDs) with eight teledermatologists (TDs). METHODS: Patch tested patients had photographs taken of 70 screening series of allergens at 48 hours and second readings. Eight TDs reviewed photos and graded reactions (negative, irritant, doubtful, +, ++, +++) at 48 hours and second readings; in addition, they coded a final interpretation (allergic, indeterminant, irritant, negative) for each reaction. TDs rated overall image quality and confidence level for each patient and patch test reaction, respectively. Percentage of TD-IPD agreement based on clinical significance (success, indeterminate, and failure) was calculated. Primary outcome was agreement at the second reading. RESULTS: Data were available for 99, 101, and 66 participants at 48 hours, second reading, and final interpretation, respectively. Pooled failure (+/++/+++ vs negative) at second reading was 13.6% (range 7.9%-20.4%). Pooled failure at 48 hours and final interpretation was 5.4% (range 2.9%-6.8%) and 24.6% (range 10.2%-36.8%), respectively. Confidence in readings was statistically correlated with quality of images and disagreement. CONCLUSION: For patch testing, teledermatology has significant limitations including clinically significant pooled failure percentages of 13.6% for second readings and 24.6% for final interpretation.