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Introduction: Atopic dermatitis (AD) is a chronic inflammatory skin disease, placing a significant burden on patients' quality of life (QoL). The validated Atopic Dermatitis Control Tool (ADCT) is recommended to assess AD control in adults. The aim of this study was to assess AD control and explore associations with demographic characteristics, patient-reported outcome measures (PROMs), and treatment., Methods: In this cross-sectional study, questionnaires were sent to 2,066 adults from two tertiary referral centers who had previously physician-diagnosed AD and had visited the outpatient clinic at least once between 2020 and 2022. Questionnaires were completed between May and October 2022. AD control was assessed by the ADCT, with a score ≥7 indicating uncontrolled AD. AD severity, QoL, and weekly average pruritus were simultaneously measured using the Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), and numeric rating scale (NRS), respectively, with higher scores indicating more severe symptoms. Moreover, treatment-related questions were included. Associations between uncontrolled AD, age, sex, and treatment were explored using multivariate logistic regression analysis., Results: In total, 863 patients (41.8%) filled out the questionnaire and 812 were included in the analysis, of which 59% reported controlled AD. Uncontrolled AD was associated with higher PROM scores and receiving topical anti-inflammatories only (adjusted odds ratio [95% confidence interval] ranged from 1.33 [0.995-1.88] to 2.55 [2.21-2.86]). Of those treated with topical anti-inflammatories only, 54% reported uncontrolled AD., Conclusion: The majority of the patients reported controlled AD. Patients with uncontrolled AD often reported more severe symptoms and were more likely to receive topical anti-inflammatories only. It could be considered to shift patients with uncontrolled AD from topical to systemic treatment., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Importance: Limited data are available on the long-term effectiveness and safety of dupilumab for atopic dermatitis (AD) in daily practice., Objective: To evaluate clinical effectiveness and reasons for discontinuation of dupilumab treatment in children, adults, and older adults with AD with up to 5 years of treatment in daily practice., Design, Setting, and Participants: This prospective multicenter cohort study was conducted using the BioDay registry (4 academic and 10 nonacademic hospitals in the Netherlands) to identify patients with AD of all ages who were treated with dupilumab between October 2017 and December 2022., Main Outcomes and Measures: Clinical effectiveness was evaluated by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), and numeric rating scale (NRS) for pruritus, stratified by children (<18 years), adults (18-64 years), and older adults (≥65 years). In addition, time to response, treatment responders, EASI subscores, second treatment episodes, and thymus- and activation-related chemokine and eosinophil levels were assessed. For patients who discontinued dupilumab, the reason for discontinuation was evaluated., Results: In total, 1286 patients with AD (median [IQR] age, 38 [26-54] years; 726 [56.6%] male) were treated with dupilumab, including 130 children, 1025 adults, and 131 older adults. The median (IQR) follow-up time was 87.5 (32.0-157.0) weeks. Most patients maintained controlled AD, with EASI of 7 or lower and NRS for pruritus of 4 or lower varying between 78.6% and 92.3% and 72.2% and 88.2% for up to 5 years of treatment, respectively, while up to 70.5% of all patients prolonged the dosing interval to mostly 300 mg every 3 or 4 weeks. Mean EASI and NRS for pruritus were 2.7 (95% CI, 1.2-4.2) and 3.5 (95% CI, 2.7-4.3), respectively, after 5 years of treatment. Statistically significant differences between age groups were found over time for EASI and IGA; however, differences were rather small (week 52: EASI, 0.3-1.6; IGA, 0.12-0.26). No statistically significant differences between age groups were found for NRS for pruritus. Median thymus- and activation-related chemokine levels considerably decreased from 1751 pg/mL (95% CI, 1614-1900 pg/mL) to 390 pg/mL (95% CI, 368-413 pg/mL) after 6 months of treatment and remained low. Median eosinophil levels temporarily increased up to week 16, with a subsequently statistically significant decrease over time. In total, 306 patients (23.8%) discontinued dupilumab after a median (IQR) of 54.0 (29.0-110.00) weeks, with adverse events among 98 patients (7.6%) and ineffectiveness among 85 patients (6.6%) as the most frequently reported reasons. Forty-one patients (3.2%) restarted dupilumab, and most of these patients recaptured response., Conclusions and Relevance: In this cohort study with up to 5 years of follow-up, dupilumab maintained its clinical effectiveness, while two-thirds of patients tapered to a dosing interval of every 3 or 4 weeks. Treatment was discontinued in 23.8% of patients mainly due to adverse events and/or ineffectiveness.

Background: Studies on wet work and hand eczema (HE) frequently rely solely on self-reports regarding wet work., Objectives: To assess the association between wet work and moderate-to-very-severe HE, within the Dutch general population, by using a (sex-specific) job exposure matrix (JEM)., Methods: Within the Lifelines Cohort Study, participants with self-reported moderate-to-very-severe HE at worst in the past year were linked to data from the Danish (sex-specific) wet work JEM, a tool that links occupations with wet work indices (including duration and probability of glove use, wet hands and total wet work for at least 2 and 4 h/working day)., Results: In total, 56 978 (41.9%) participants were included. The multivariate binary logistic regression analyses showed significant associations between all facets of wet work and moderate-to-very-severe HE. When using the sex-specific JEM, significant associations were found in females, but not in males., Conclusions: This study is the first to use a wet work-specific JEM in a general population sample, and found positive associations between wet work and HE. The sex-specific findings should be interpreted with caution, due to limitations inherent in using a JEM, and should be further explored with observational studies, with a focus on duration, frequency, and exposure type., (© 2024 The Author(s). Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Twin studies revealed that genetic effects play a role in hand eczema (HE), but the responsible genetic factors are unknown., Objectives: To identify and characterise genetic loci associated with HE and to provide insight into the genetic overlap between HE and atopic dermatitis (AD)., Methods: We used questionnaire-derived and genotype data from the European population-based Lifelines cohort and biobank. We performed a discovery genome-wide association study (GWAS) of HE (2879 cases and 16 249 controls) and of AD (1706 cases and 17 190 controls). We replicated our findings in an independent Lifelines sample for HE (1188 cases and 6431 controls) and AD (757 cases and 6747 controls). We conducted several post-GWAS analyses and performed genetic correlation analyses between our HE results and independent AD data., Results: The two-step GWAS of HE, regardless of adjusting for AD, identified one independent locus 20q13.33, likely driven by a number of causal single-nucleotide polymorphisms. For the AD GWAS, we replicated a known stop-gained rs61816761 at locus 1q21.3 (FLG, FLGAS1). We found a strong genetic correlation (p < 0.01) between HE and AD (r g  = 0.65), regardless of adjusting for AD (r g  = 0.63)., Conclusions: Locus 20q13.33 is associated with HE, and there is a large genetic overlap between HE and AD., (© 2024 The Author(s). Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Long-term daily practice data on patient-reported benefits of dupilumab for atopic dermatitis (AD) remains limited., Objective: To evaluate patient-reported outcome measures (PROMs) and the safety of dupilumab in patients with moderate-to-severe AD over a follow-up period of up to 5 years., Methods: Data were extracted from the prospective, multicenter BioDay registry (October 2017-2022) of patients with moderate-to-severe AD treated with dupilumab in daily practice., Results: In total 1223 patients, 1108 adults and 115 pediatric patients were included. After ≥1 year of treatment, mean Patient-Oriented Eczema Measure (POEM), Dermatology Life Quality Index (DLQI), Numeric rating scale (NRS)-pruritus ranged between 7.8 and 8.7, 3.5 and 4.2, and 2.9 and 3.1 in adults, respectively, whilst these patient-reported outcome measures (PROMs) ranged between 8.9 and 10.9, 4.4 and 6.4, and 3.0 and 3.7 in pediatric patients, respectively. At follow-up, overall work impairment decreased from 40.1% to 16.3% to 13.3% in adults. Furthermore, class I obesity and itch-dominant patients generally had less favorable treatment response. Of all patients, 66.8% reported ≥1 adverse event, with conjunctivitis being the most common (33.7%)., Limitations: The overall percentage of missing values for selected PROMs was 26% in adults and 46% in pediatric patients., Conclusion: In addition to favorable safety, dupilumab has demonstrated sustained effectiveness across various PROMs, underscoring the treatment benefits from patients' perspectives., Competing Interests: Conflicts of interest C.M. Boesjes is a speaker for AbbVie and Eli Lilly. L.S. Spekhorst is a speaker for AbbVie. I.M. Haeck is a consultant, advisory board member, and/or speaker for Sanofi and Regeneron Pharmaceuticals, LEO Pharma, AbbVie, Janssen, and Eli Lilly. L.F. van der Gang is a speaker for AbbVie. L.P. van der Rijst is a speaker for AbbVie. R.A. Tupker is an advisory board member of Leo Pharma, Eli Lilly, and Novartis. K.Politiek was an advisory board member and/or speaker for AbbVie, LEO Pharma, Novartis, and Sanofi. W. Touwslager is an advisor, consultant, and speaker for Sanofi, Leo Pharma, AbbVie, and Novartis. WA Christoffers is an advisory board member of Leo Pharma. M. de Graaf is a consultant, advisory board member, and/or speaker for AbbVie, Almiral, Eli Lilly, Janssen, LEO Pharma, Novartis, Pfizer, Regeneron Pharmaceuticals, and Sanofi. M.S. de Bruin-Weller is a consultant, advisory board member, and/or speaker for AbbVie, Almirall, Aslan, Amgen, Eli Lilly, Galderma, Janssen, Leo Pharma, Pfizer, Regeneron, and Sanofi. M.L.A. Schuttelaar is an advisor, consultant, speaker, and/or investigator for AbbVie, Pfizer, LEO Pharma, Regeneron, Sanofi, Eli Lilly, and Galderma. She has received grants from Regeneron, Sanofi, Novartis, and Pfizer., (Copyright © 2024 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.)

Background: To date, hand eczema (HE)-related presenteeism has never been assessed within the general population, and general population-based studies on HE-related sickness absence are limited., Objectives: To assess the prevalence of HE-related presenteeism and sickness absence, and factors associated with HE-related presenteeism, within the Dutch general population., Methods: Within the Lifelines Cohort Study, participants with HE in the last year (aged 18-65 in 2020), were identified by a questionnaire including questions regarding HE-related presenteeism and sickness absence. Socio-demographic factors were collected from 2006 to 2020., Results: Out of the 3.703 included participants with HE, 2.7% (n = 100) reported HE-related presenteeism, with 19.8% (n = 57) among those with severe-to-very-severe HE. HE-related sickness absence was reported by 0.5% (n = 20) and 5.9% (n = 17), respectively. Logistic regression analyses, adjusted for age and sex, showed negative associations between HE-related presenteeism and higher educational attainment, higher income (>€2500) and higher occupational skill level, and positive associations for high-risk occupations, chronic HE, moderate and severe-to-very-severe HE (compared to almost clear), atopic dermatitis and occupational wet exposure., Conclusions: A high prevalence of HE-related presenteeism was found among participants with severe-to-very-severe HE. Future studies should focus on longitudinal associations with the clinical course of HE, as HE-related presenteeism might aggravate symptoms of HE., (© 2024 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

During September and October 2021, a substantial number of Polymerase Chain Reaction (PCR) tests in England processed at a single laboratory were incorrectly reported as negative. We estimate the number of false negative test results issued and investigate the epidemiological impact of this incident. We estimate the number of COVID-19 cases that would have been reported had the sensitivity of the laboratory test procedure not dropped for the period 2 September to 12 October. In addition, by making comparisons between the most affected local areas and comparator populations, we estimate the number of additional infections, cases, hospitalisations and deaths that could have occurred as a result of increased transmission due to false negative test results.We estimate that around 39,000 tests may have been false negatives during this period and, as a direct result of this incident, the most affected areas in the South-West of England could have experienced between 6000 and 34,000 additional reportable cases, with a central estimate of around 24,000 additional reportable cases. Using modelled relationships between key variables, we estimate that this central estimate could have translated to approximately 55,000 additional infections.Each false negative likely led to around 1.5 additional infections. The incident is likely to have had a measurable impact on cases and infections in the affected areas in the South-West of England. IMPACT STATEMENT: These results indicate the significant negative impact of incorrect testing on COVID outcomes; and make a substantial contribution to understanding the impact of testing systems and the need to ensure high accuracy in testing and reporting of results., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Limited daily practice data on the effect of abrocitinib in patients with atopic dermatitis are available. The aim of this multicentre prospective study is to evaluate the effectiveness and safety of abrocitinib in patients with atopic dermatitis treated in daily practice. In a subgroup, the effectiveness of abrocitinib on hand eczema was evaluated. A total of 103 patients from the BioDay registry were included in the study: week 4 (n = 95), week 16 (n = 61) and week 28 (n = 39). At week 28, the Eczema Area and Severity Index (EASI)-50/75/90 was achieved by 81.8%, 57.6%, and 18.2%, respectively, and the weekly average pruritus numerical rating scale ≤ 4 by 62.9%. The effectiveness of abrocitinib was not significantly different between dupilumab non-responders and dupilumab-naïve patients/responders, and between upadacitinib non-responders and upadacitinib-naïve patients/responders. Mean ± standard deviation Hand Eczema Severity Index decreased from 27.4 ± 27.7 at baseline to 7.7 ± 12.1 at week 28 (n = 31). Thirty-two patients (31.1%) discontinued treatment due to ineffectiveness (n = 17), adverse events (n = 9) or both (n = 3). The most frequently reported adverse event was nausea (n = 28). In conclusion, abrocitinib is an effective treatment for atopic dermatitis and can be effective for patients with previous inadequate response to dupilumab or upadacitinib. Furthermore, hand eczema can improve in patients treated with abrocitinib for atopic dermatitis.

Background: Health literacy (HL) is defined as the degree to which individuals have the capacity to obtain, process, and understand health information and services needed to make appropriate health decisions. Patients with limited HL are less likely to manage chronic diseases appropriately., Objective: We sought to assess the prevalence of limited HL in patients with atopic dermatitis (AD) and its association with other patient-reported outcomes., Methods: A cross-sectional questionnaire-based study was conducted at a tertiary referral center for AD. Patients diagnosed with AD by a dermatologist between 2019 and 2021 were identified from medical records. Perception-based HL was assessed by the European Health Literacy Survey Questionnaire 16 and performance-based HL by the Newest Vital Sign. Patients completed the Patient-Oriented Eczema Measure, Dermatology Life Quality Index, and Atopic Dermatitis Control Tool to measure AD severity, quality of life, and AD disease control, respectively., Results: In total, 322 patients were included (response rate, 48.3%). On the basis of the European Health Literacy Survey Questionnaire 16, 32.4% had limited HL (8.4% inadequate and 24.0% problematic), which was associated with impaired quality of life. According to the Newest Vital Sign, 20.3% had inadequate HL, which was associated with older age., Conclusions: Up to one-third of the patients with AD showed signs of limited HL, which was associated with impaired health-related quality of life and older age. Further research should evaluate the influence of inadequate HL on health outcomes and focus on strategies to improve organizational HL to eventually enhance patient-centered care., (© 2024 The Author(s).)

Background: Limited research has been conducted on the measurement properties of the Recap of atopic eczema (RECAP) questionnaire, particularly in relation to interpretability., Objectives: To investigate the validity, reliability, responsiveness and interpretability of the Dutch RECAP in adults with atopic dermatitis (AD)., Methods: We conducted a prospective study in a Dutch tertiary hospital, recruiting adults with AD between June 2021 and December 2022. Patients completed the RECAP questionnaire, reference instruments and anchor questions at the following three timepoints: baseline, after 1-3 days and after 4-12 weeks. Hypotheses testing was used to investigate single-score validity and change-score validity (responsiveness). To assess reliability, both standard error of measurement (SEMagreement) and intraclass correlation coefficient (ICCagreement) were reported. To assess the interpretability of single scores, bands for eczema control were proposed. To investigate the interpretability of change scores, both smallest detectable change (SDC) and minimally important change (MIC) scores were determined. To estimate the MIC scores, four different anchor-based methods were employed: the mean change method, 95% limit cut-off point, receiver operating characteristic curve and predictive modelling., Results: In total, 200 participants were included (57.5% male sex, mean age 38.5 years). Of the a priori hypotheses, 82% (single-score validity) and 59% (responsiveness) were confirmed. Known-group analyses showed differences in the RECAP scores between patient groups based on disease severity and impairment of the quality of life. The SEMagreement was 1.17 points and the ICCagreement was 0.988. The final banding was as follows: 0-1 (completely controlled); 2-5 (mostly controlled); 6-11 (moderately controlled); 12-19 (a little controlled); 20-28 (not at all controlled). Moreover, a single cut-off point of ≥ 6 was determined to identify patients whose AD is not under control. The SDC was 3.2 points, and the MIC value from the predictive modelling was 3.9 points. Neither floor nor ceiling effects were observed., Conclusions: The RECAP has good single-score validity, moderate responsiveness and excellent reliability. This study fills a gap in the interpretability of the RECAP. Our results indicate a threshold of ≥ 6 points to identify patients whose AD is 'not under control', while an improvement of ≥ 4 points represents a clinically important change. Given its endorsement by the Harmonising Outcome Measures for Eczema initiatives, the results of this study support the integration of RECAP into both routine clinical practice and research settings., Competing Interests: Conflicts of interest: M.L.A.S. is an advisor, consultant, speaker and/or investigator for AbbVie, Pfizer, LEO Pharma, Regeneron, Sanofi Genzyme, Eli Lilly and Galderma. She has received grants from Regeneron, Sanofi Genzyme, Novartis and Pfizer., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

Background: Limited data are available regarding patient-centred dosing of dupilumab for atopic dermatitis (AD) in daily practice., Objectives: To evaluate our patient-centred dupilumab dosing regimen in daily practice, to assess prognostic factors for successful tapering and to estimate medication-related cost savings., Methods: This prospective multicentre study included adult patients with AD, participating in the BioDay registry, treated with dupilumab for ≥ 1.3 years. Interval prolongation was considered in the case of dupilumab standard dose for ≥ 1 year and persistent controlled AD [Eczema Area and Severity Index (EASI) ≤ 7; ≥ 6 months]. Primary endpoints were the mean EASI and Numeric Rating Scale (NRS)-pruritus after the start of tapering. Prognostic factors for successful tapering were analysed with logistic regression and a cost-savings analysis was performed., Results: A total of 595 patients were included, of whom 401 patients [mean EASI 2.5 (SD 2.3); NRS-pruritus of 2.4 (SD 1.9) at the start of tapering] prolonged their dupilumab interval. In 83.3% of these patients tapering was successful; most patients used dupilumab every 3 or 4 weeks (Q3W/Q4W). A significant small increase was observed for EASI (highest mean 3.5) and NRS-pruritus (highest mean 3.2) (P < 0.001); however, scores remained low. Predicting successful tapering showed nonsignificant odds ratios for all incorporated variables. The estimated cost savings was €3 977 033.98 for 401 patients between January 2019 and June 2022., Conclusions: This study showed successful tapering of dupilumab in 83.3% of patients with AD who attempted tapering, while maintaining controlled disease and with the majority using Q3W/Q4W. Interval prolongation can be beneficial both for the patient and from a socio-economic perspective., Competing Interests: Conflicts of interest L.S.S. is a speaker for AbbVie. C.M.B. is a speaker for AbbVie and Eli Lilly. D.S.B. is a speaker for Janssen, LEO Pharma, Novartis and Sanofi. I.M.H. is a consultant, advisory board member and/or speaker for AbbVie, Eli Lilly, Janssen, LEO Pharma, Regeneron Pharmaceuticals and Sanofi. R.A.T. is an advisory board member of Eli Lilly, LEO Pharma and Novartis. F.M.G. was an advisory board member and/or speaker for AbbVie, LEO Pharma, Novartis and Sanofi. W.R.H.T. is an advisor, consultant and/ot speaker for AbbVie, LEO Pharma, Novartis and Sanofi. M.S.d.B.-W. is a consultant, advisory board member and/or speaker for AbbVie, Almirall, Arena, Aslan, Eli Lilly, Galderma, Janssen, LEO Pharma, Pfizer, Regeneron and Sanofi. M.-L.A.S. is an advisor, consultant, speaker and/or investigator for AbbVie, Eli Lilly, Galderma, LEO Pharma, Pfizer, Regeneron and Sanofi. She has received grants from Novartis, Pfizer, Regeneron and Sanofi. M.d.G. is a consultant, advisory board member and/or speaker for AbbVie, Eli Lilly, LEO Pharma, Novartis, Pfizer and Sanofi. The authors not listed here declare no conflicts of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of British Association of Dermatologists.)

There is a lack of knowledge concerning loneliness and psychiatric disorders other than anxiety and depression in patients with atopic dermatitis. This cross-sectional study was conducted within the Lifelines Cohort Study, in the Netherlands, by sending an atopic dermatitis questionnaire to adult participants (n = 135,950) in 2020. Psychiatric disorders were measured with a self-reported question and validated instrument (Mini International Neuropsychiatric Interview; M.I.N.I.), and loneliness was assessed with the validated 6-item De Jong Gierveld Loneliness Scale. In total, 56,896 subjects (mean age 55.8 years, 39.7% males) were included. Atopic dermatitis showed positive associations with self-reported chronic fatigue syndrome, burnout, depression, social phobia, panic disorder, attention deficit hyperactivity disorder, and eating disorder in the participants' lifetimes. Based on the M.I.N.I., atopic dermatitis was positively associated with panic disorder and at least 1 anxiety disorder. In addition, subjects with atopic dermatitis were more likely to experience loneliness compared with those without atopic dermatitis. These associations were observed only in the moderate-to-severe, but not mild, atopic dermatitis group. This study raises awareness that a significant proportion of adults with atopic dermatitis feel lonely and are affected by several psychiatric disorders, especially those severely affected by atopic dermatitis. Further studies are required to evaluate if interdisciplinary care, such as the collaboration between dermatologists and psychiatrists, could optimize medical care for this vulnerable patient group.

Background: Chronic hand eczema (CHE) is a very common skin disease among the European population. It causes itch and pain and, in more severe cases, seriously impairs hand functioning at work and in private life., Objectives: To explore perspectives of people with lived experience on CHE-related problems, wishes and goals., Methods: Following a qualitative approach, we conducted topic-guided interviews in five European countries and applied template analysis to identify recurrent themes among patients with CHE., Results: We interviewed 60 patients in seven outpatient dermatological and occupational medicine clinics in Croatia, Denmark, Germany, the Netherlands and Spain. Five main themes were identified: (1) knowledge about the disease and its course, (2) preventive behaviour, (3) hand eczema therapy, (4) impact on everyday life and (5) attitudes towards CHE and healthcare. Participants did not feel well informed about CHE, especially about causes, triggers and treatment options. Preventive measures were experienced as more or less effective but also cumbersome. Experiences with therapy were diverse. Treatment satisfaction depended on the results and on the perceived support from the treatment teams. Participants found it important to be taken seriously, to receive practical advice, to try out additional treatments or examinations, find new hope and have occupational perspectives. They wished that others could better understand the physical and emotional burden of CHE. Patient support groups were not mentioned. Participants found it important to learn to take care of themselves and accept life with CHE., Conclusions: Due to its annoying symptoms, high visibility and impaired functioning at work and in private life, CHE has a high emotional and social impact. Some people may require support to learn coping with CHE and its prevention. Patients wish for information about causes and triggers. They value physicians who listen to them and keep looking for solutions., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Hand eczema (HE) is a common skin disease characterized by itch, pain and visible skin changes such as fissures, erythema and vesicles. It is not yet clear which outcome domains are most important for patients. The Hand Eczema Core Outcome Set (HECOS) initiative is developing a consented set of core domains and suitable measurement instruments for the future application in all HE trials. This includes an online Delphi survey about core domains, which requires a 'Long List' of all domains that might be important to measure., Objectives: To compile a 'Long List' of candidate outcome domains for therapeutic HE trials with suggestions from patients and experts., Methods: First, 60 patients with chronic HE were interviewed at seven study sites in Croatia, Denmark, Germany, the Netherlands and Spain. Patients were asked about domains that were important from their perspectives. Second, 185 HE experts were invited by email to complete an online survey. With an open question, they were asked to suggest up to six domains., Results: Suggestions were provided by 58 patients and 82 experts. Most patients and experts suggested to measure the domains 'signs', 'symptoms' and 'HE-related quality of life'. Specifically, >25% of patients said that less itch, pain or fissures indicated a successful treatment. Among experts, >25% suggested 'itch' and 'ability to work' as core sub-domains. Further outcomes from the domains 'HE control over time', 'patient-reported treatment experience' and 'skin barrier function' were mentioned., Conclusion: 'Itch' was rated high among patients with HE and professional HE experts. While patients emphasized fissures as important, experts underlined the ability to work. This investigation allowed us to define a 'Long List' of 7 candidate outcome domains with 58 sub-domains. From this list, a panel of stakeholders will select core domains during an online Delphi survey., (© 2023 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Background: Health literacy (HL) is essential for patients with multiple atopic diseases to improve their health, given the complexity of their disease and treatment regimens., Objective: To estimate the proportion of adults with multiple atopic diseases (at least 2 of atopic dermatitis, asthma, allergic rhinitis, and food allergy) in the Dutch general population and to evaluate the prevalence of limited HL, and its association with socioeconomic status (SES), lifestyle factors, and health-related quality of life (HR-QoL) in this patient population., Methods: This cross-sectional study was conducted within the Lifelines Cohort Study via sending an add-on digital questionnaire, including (among others) questions on atopic dermatitis, to all adult participants (n = 135,950) between February and May 2020. Data on asthma, allergic rhinitis, lifestyle factors, HR-QoL, and SES were extracted from baseline assessment between 2006 and 2013. Functional, communicative, and critical HL were measured by validated items from Chew and the Dutch Functional Communicative and Critical Health Literacy questionnaires between 2012 and 2016. Food allergy was measured by the Food Allergy Questionnaire between 2014 and 2016., Results: In total, 11.8% of the overall study population reported ever having multiple atopic diseases; of those, 23.6% reported having limited functional HL, with a higher prevalence among those with a low SES. Limited functional HL showed positive associations with smoking, obesity, chronic stress, a low diet quality, and decreased HR-QoL among subjects with multiple atopic diseases., Conclusions: We identified an HL deficit, and its association with a low SES and poor health outcomes among patients with multiple atopic diseases. Further research is warranted to utilize a more extensive assessment to measure HL and include more health outcomes, such as treatment adherence and disease control., (Copyright © 2023. Published by Elsevier Inc.)

Background: Real-world data on the effectiveness of upadacitinib on atopic dermatitis (AD), hand eczema (HE) and HE in the context of AD are limited., Objectives: To evaluate the effectiveness and safety of upadacitinib on AD and on HE in patients with AD., Methods: This prospective observational cohort study includes clinical outcomes: Eczema Area and Severity Index (EASI), Investigator's Global Assessment (IGA), Hand Eczema Severity Index (HECSI), Photographic guide; and PROMs: average pruritus and pain Numeric Rating Scale (NRS) score of the past week, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Eczema, Dermatology Life Quality Index (DLQI), Atopic Dermatitis Control Tool (ADCT), Patient Global Assessment of Disease (PGAD), Quality Of Life Hand Eczema Questionnaire (QOLHEQ) at baseline, Week 4, and Week 16 of upadacitinib-treated patients. Adverse events were monitored during each visit., Results: Thirty-eight patients were included, of which 32 patients had HE. At Week 16, EASI-75 was achieved by 50.0%. Absolute cutoff score NRS-pruritus ≤4 was reached by 62.5%, POEM ≤7 by 37.5%, DLQI ≤5 by 59.4%, ADCT <7 by 68.8%, and PGAD rating of at least 'good' by 53.1%. HECSI-75 was achieved by 59.3% and (almost) clear on the Photographic guide by 74.1%. The minimally important change in QOLHEQ was achieved by 57.9%. Sub-analysis in patients with concomitant irritant contact dermatitis showed no differences. Safety analysis showed no new findings compared to clinical trials., Conclusions: Upadacitinib can be an effective treatment for patients with AD and concomitant HE in daily practice. Future studies should focus on the effectiveness of upadacitinib on chronic HE, especially on the different etiological subtypes of HE, including HE in non-atopic individuals., (© 2023 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Dupilumab has proven to be an effective and safe treatment for atopic dermatitis (AD) in pediatric patients in clinical trials. However, few daily practice studies are available. The aim of this study is to evaluate the effect of 28 weeks dupilumab treatment on effectiveness, safety, and serum biomarkers in pediatric patients with moderate-to-severe AD in daily practice., Methods: Patients visited the outpatient clinic at baseline, 4, 16, and 28 weeks of treatment. Disease severity was assessed by the Eczema Area and Severity Index (EASI), Investigator Global Assessment (IGA), Numeric Rating Scale (NRS)-pruritus and -pain, and the Patient-Oriented Eczema Measure (POEM). Side effects were evaluated. Nineteen severity-associated serum biomarkers were measured. Predicted-EASI (p-EASI) was calculated., Results: Sixty-one patients were included. Respectively 75.4%, 49.2%, and 24.6% reached EASI-50, EASI-75, and EASI-90 and 36.1% achieved an IGA-score (almost) clear. Improvement of ≥4 points on POEM, NRS-pruritus, and NRS-pain was reached by 84.7%, 45.3%, and 77.4%, respectively. Most reported side effects were conjunctivitis (n = 10) and headache (n = 4). Biomarkers TARC, PARC, periostin, sIL-2Ra, and eotaxin-3 significantly decreased during treatment. The p-EASI showed a significant correlation with disease severity., Conclusion: Dupilumab treatment significantly improved disease severity and disease-associated symptoms and decreased severity-associated serum biomarkers in pediatric AD patients in daily practice., (© 2022 The Authors. Pediatric Allergy and Immunology published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Clinical trials have shown that baricitinib, an oral selective Janus kinase 1/2 inhibitor, is effective for the treatment of moderate-to-severe atopic dermatitis. However, daily practice data are limited. Therefore, this multicentre prospective study evaluated the effectiveness and safety of 16-weeks' treatment with baricitinib in adult patients with moderate-to-severe atopic dermatitis in daily practice. A total of 51 patients from the BioDay registry treated with baricitinib were included and evaluated at baseline and after 4, 8 and 16 weeks of treatment. Effectiveness was assessed using clinician- and patient-reported outcome measurements. Adverse events and laboratory assessments were evaluated at every visit. At week 16, the probability (95% confidence interval) of achieving Eczema Area and Severity Index ≤ 7 and numerical rating scale pruritus ≤ 4 was 29.4% (13.1-53.5) and 20.5% (8.8-40.9), respectively. No significant difference in effectiveness was found between dupilumab non-responders and responders. Twenty-two (43.2%) patients discontinued baricitinib treatment due to ineffectiveness, adverse events or both (31.4%, 9.8% and 2.0%, respectively). Most frequently reported adverse events were nausea (n = 6, 11.8%), urinary tract infection (n = 5, 9.8%) and herpes simplex infection (n = 4, 7.8%). In conclusion, baricitinib can be an effective treatment option for moderate-to-severe atopic dermatitis, including patients with non-responsiveness on dupilumab. However, effectiveness of baricitinib is heterogeneous, which is reflected by the high discontinuation rate in this difficult-to-treat cohort.

Background: At present, no real-world studies are available on different dupilumab dosing regimens in controlled atopic dermatitis (AD). The aim of this study was to clinically evaluate a patient-centered dupilumab dosing regimen in patients with controlled AD and to relate this to serum drug levels and serum biomarkers., Methods: Ninety adult AD patients from the prospective BioDay registry were included based on their dupilumab administration interval according to a predefined patient-centered dosing regimen. Group A (n = 30) did not fulfill the criteria for interval prolongation and continued using the standard dupilumab dosage (300 mg/2 weeks), group B (n = 30) prolonged dupilumab interval with 50% (300 mg/4 weeks), and group C (n = 30) prolonged dupilumab interval with 66%-75% (300 mg/6-8 weeks). AD severity score, patient-reported outcomes, serum dupilumab levels, and serum biomarkers were analyzed over time., Results: Disease severity scores did not significantly change over time during the tapering period in any of the groups. In groups B and C, the Numeric Rating Scale (NRS)-pruritus temporarily significantly increased after interval prolongation but remained low (median NRS-pruritus≤4). Median dupilumab levels remained stable in group A (standard dosage), but significantly decreased in groups B and C (24.1 mg/L (IQR = 17.1-45.6); 12.5 mg/L (IQR = 1.7-22.3)) compared with the levels during the standard dosage (88.2 mg/L [IQR = 67.1-123.0, p < .001]). Disease severity biomarker levels (CCL17/CCL18) remained low in all study groups during the whole observation period., Conclusions: This study showed that dose reduction was successful in a subgroup of patients with controlled AD by using a patient-centered dosing regimen. These patients showed stable low disease activity and low severity biomarkers over time., (© 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.)

Evidence regarding the association between lifestyle factors and hand eczema is limited.To extensively investigate the association between lifestyle factors (smoking, alcohol consumption, stress, physical activity, body mass index, diet, and sleep) and the prevalence, incidence, subtype, severity, and prognosis of hand eczema, a systematic review and meta-analysis were conducted in accordance with the Meta-analysis Of Observational Studies in Epidemiology consensus statement. MEDLINE, Embase, and Web of Science were searched up to October 2021. The (modified) Newcastle-Ottawa Scale was used to judge risk of bias. Quality of the evidence was rated using the Grades of Recommendation, Assessment, Development and Evaluation approach. Eligibility and quality were blindly assessed by two independent investigators; disagreements were resolved by a third investigator. Data were pooled using a random-effects model, and when insufficient for a meta-analysis, evidence was narratively summarized. Fifty-five studies were included. The meta-analysis (17 studies) found very low quality evidence that smoking is associated with a higher prevalence of hand eczema (odds ratio 1.18, 95% confidence interval 1.09-1.26). No convincing evidence of associations for the other lifestyle factors with hand eczema were found, mostly due to heterogeneity, conflicting results, and/or the limited number of studies per outcome., (© 2022 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Importance: Long-term data on dupilumab drug survival in patients with atopic dermatitis (AD) are scarce. Furthermore, little is known about the factors associated with drug survival of dupilumab in AD., Objective: To describe the drug survival of dupilumab in patients with AD and to identify associated predictors., Design, Setting, and Participants: This cohort study was based on data from the multicenter prospective daily practice BioDay registry, in which 4 university and 10 nonuniversity hospitals in the Netherlands participated. Analysis included patients (age ≥18 years) participating in the BioDay registry with a follow-up of at least 4 weeks. The first patient treated with dupilumab was recorded in the BioDay registry in October 2017; data lock took place in December 2020, and data analysis was performed from October 2017 to December 2020., Main Outcomes and Measures: Drug survival was analyzed by Kaplan-Meier survival curves and associated characteristics by using univariate and multivariate Cox regression analysis., Results: A total of 715 adult patients with AD (mean [SD] age, 41.8 [16.0] years; 418 [58.5%] were male) were included with a 1-year, 2-year, and 3-year overall dupilumab drug survival of 90.3%, 85.9%, and 78.6%, respectively. Characteristics associated with shorter drug survival owing to ineffectiveness were the use of immunosuppressant drugs at baseline (hazard ratio [HR], 2.64; 95% CI, 1.10-6.37) and being a nonresponder at 4 weeks (HR, 8.68; 95% CI, 2.97-25.35). Characteristics associated with shorter drug survival owing to adverse effects were the use of immunosuppressant drugs at baseline (HR, 2.69; 95% CI, 1.32-5.48), age 65 years or older (HR, 2.94; 95% CI, 1.10-7.87), and Investigator Global Assessment score of very severe AD (HR, 3.51; 95% CI, 1.20-10.28)., Conclusions and Relevance: This cohort study demonstrated a good overall 1-year, 2-year, and 3-year dupilumab drug survival. Patients using immunosuppressive therapy at baseline and those with an absence of treatment effect at week 4 tended to discontinue treatment owing to ineffectiveness more frequently. Using immunosuppressant drugs at baseline, older age, and Investigator Global Assessment score of very severe AD were characteristics associated with an increased risk for discontinuation owing to adverse effects. These data provide more insight and new perspectives regarding dupilumab treatment in AD and can contribute to the optimization of patient outcomes.

Background: Studies on the association between severity of atopic dermatitis (AD) and lifestyle factors in adults have not been conducted in the Netherlands to date., Aim: To explore the association between moderate to severe AD and lifestyle factors in adults in the Dutch general population., Methods: We conducted this cross-sectional study within the Lifelines Cohort Study by sending a digital AD questionnaire to 135 950 adults in 2020. We extracted data on lifestyle factors from baseline, collected between 2006 and 2013. We analysed the association between lifestyle factors and presence of AD of any severity and of moderate to severe AD, using binary logistic regression and linear regression models., Results: We enrolled 56 896 participants (mean age 55.8 years, 39.7% males). The lifetime prevalence of self-reported physician-diagnosed AD was 9.1%, and the point prevalence of any AD and of moderate to severe AD was 3.3% and 2.3%, respectively. We found that moderate to severe AD was associated with smoking habit of > 15 pack-years, alcohol consumption of > 2 drinks per day, chronic stress, Class I obesity, and both shorter and longer sleep duration. Moreover, we found dose-response associations with increases in smoking pack-years and level of chronic stress. We observed no associations with abdominal obesity, physical activity, diet quality or a vegetarian/vegan diet., Conclusion: We found associations between moderate to severe AD and some modifiable lifestyle factors. Our findings indicate that more screening and counselling for lifestyle factors, particularly smoking, alcohol use, stress, obesity and sleep disturbances, appears warranted in patients with moderate to severe AD. Further longitudinal studies are required to better characterize the direction of these associations and to develop strategies for prevention., (© 2022 The Authors. Clinical and Experimental Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Background: Hand eczema (HE) is the most frequently occurring occupational skin disease. However, studies on non-occupational wet exposure, occupations not considered as high-risk, and socioeconomic factors regarding HE are scarce., Objectives: To investigate the association between HE and occupational and non-occupational wet exposure and work-related factors in the Dutch general population., Methods: Within the Lifelines Cohort Study, participants with HE were identified by a digital, add-on questionnaire that included questions regarding exposure. Data on work-related and socioeconomic factors were collected from baseline., Results: Overall, 57 046 participants (42.0%) were included. Occupational and non-occupational wet exposure were positively associated with HE in the past year (odds ratios (ORs) 1.35, [95% confidence interval (CI): 1.22-1.49] and 1.34, [95%CI: 1.17-1.53], respectively). Positive associations for high-risk occupations (OR 1.20, [95%CI: 1.06-1.36] for personal care workers in health services and OR 1.25, [95%CI: 1.06-1.48] for nursing and midwifery professionals), occupations not considered as high-risk (OR 1.19, [95%CI: 1.03-1.39] for legal, social and religious associate professionals) and higher levels of education were found (OR 1.17, [95%CI: 1.04-1.32] and OR 1.18, [95%CI: 1.04-1.34] for middle and high level, respectively)., Conclusion: Preventive strategies for HE should focus on avoidance of all wet exposure, regardless of origin. In addition, job tasks instead of job title should be taken into account. As previous results on the association between HE and socioeconomic factors differ, future research should focus on a uniform definition of socioeconomic status., (© 2022 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Competing Interests: Dr Schuttelaar received consultancy fees from Sanofi Genzyme and Regeneron Pharmaceuticals; and is advisory board member for Sanofi, Regeneron, Pfizer, LEO Pharma, Lilly. Authors Zhang, Loman, and Kamphuis have no conflicts of interest to declare.

Background: Hand eczema (HE) has a significant impact on patients' quality of life and work-related activities. However, little is known about the patients' perspectives on quality of care for HE., Objectives: To evaluate the patient perspective of the HE care process in a tertiary referral center., Methods: Qualitative, semi-structured focus groups were carried out, recorded, transcribed, and analysed using an inductive-deductive thematic approach., Results: Fifteen patients participated in four focus groups. Time and attention, together with being listened to and understood by the health care professional, were the most important aspects of care for HE mentioned by participants. Other aspects of care that were regarded as important were that diagnoses, causes and follow-up of HE were not always clear to the participant; more psychosocial support was needed, and that participants experienced frequent changes in doctors. Information provided by nurses was valuable, but more individualized advice was needed., Conclusions: To better meet the needs of patients, more explanation should be given about the causes of HE and the final diagnosis. Besides focusing on the treatment, it is also important to focus on its impact on the patient and options for psychosocial and peer support should be discussed. Furthermore, the beneficial role of the specialized nurse as part of integrated care was emphasized., (© 2021 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Several risk factors, among other lifestyle factors, have been suggested for hand eczema (HE)., Objectives: To investigate a possible association between HE and lifestyle factors, including smoking, alcohol consumption, stress, body mass index (BMI), waist circumference, physical activity, diet, and amount of sleep in the Dutch general population., Methods: Data from the large population-based LifeLines Cohort Study was used. Individuals with HE in the past year were identified by a cross-sectional questionnaire in 2020. At baseline, information on lifestyle factors was collected., Results: In total 57 046 individuals were included in the present analysis. Smoking ≥8 cigarettes/day, and smoking ≥15 pack years showed a positive association with HE in the past year. In addition, chronic stress, a BMI >30 kg/m 2 , and a waist circumference of >90 cm were positively associated with HE in the past year., Conclusions: The current study indicates that lifestyle factors are associated with HE. Advice regarding lifestyle factors might contribute to enhance overall health, of which HE might possibly benefit in conjunction. Further studies should also focus on the association between lifestyle factors and the severity and prognosis of HE rather than on occurrence alone., (© 2021 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Data on chronic hand eczema and severity of hand eczema in the general population is scarce. In this cross-sectional study, a questionnaire was sent to 135,950 Lifelines Cohort Study participants, in order to investigate the prevalence and severity of hand eczema in the Dutch general population. In total, 57,798 subjects were included. The lifetime prevalence of hand eczema was 15.0% (95% confidence interval 14.7-15.3), the 1-year prevalence 7.3% (95% confidence interval 7.1-7.6), and the self-reported physician-diagnosed prevalence 6.1% (95% confidence interval 5.9-6.3). The 1-year prevalence of chronic hand eczema was 4.7% (95% confidence interval 4.5-4.9). The majority (56.9%) of the subjects with hand eczema had almost clear at worst ever and the prevalence of severe to very severe hand eczema at worst ever in the general population was 1.9% (95% confidence interval 1.8-2.1). Future epidemiological studies in the general population should include data about chronic hand eczema and severity of hand eczema, as this can provide perspective on the burden of hand eczema.

Background: Irritant contact dermatitis (ICD) is caused by the acute locally toxic effect of a strong irritant, or the cumulative exposure to various weaker physical and/or chemical irritants., Objectives: To describe the characteristics of patients with ICD in the population patch tested in the European Surveillance System on Contact Allergies (ESSCA; www.essca-dc.org) database., Methods: Data collected by the ESSCA in consecutively patch-tested patients from January 2009 to December 2018 were analyzed., Results: Of the 68 072 patients, 8702 were diagnosed with ICD (without concomitant allergic contact dermatitis [ACD]). Hand and face were the most reported anatomical sites, and 45.7% of the ICD was occupational ICD (OICD). The highest proportions of OICD were found in metal turners, bakers, pastry cooks, and confectionery makers. Among patients diagnosed with ICD, 45% were found sensitized with no relevance for the current disease., Conclusions: The hands were mainly involved in OICD also in the subgroup of patients with contact dermatitis, in whom relevant contact sensitization had been ruled out, emphasizing the need for limiting irritant exposures. However, in difficult-to-treat contact dermatitis, unrecognized contact allergy, or unrecognized clinical relevance of identified allergies owing to incomplete or wrong product ingredient information must always be considered., (Contact Dermatitis© 2021 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

Background: Hyperkeratotic hand eczema (HHE) is a typical clinical hand eczema subtype with a largely unknown pathophysiology., Objective: To investigate histopathology, expression of keratins (K), epidermal barrier proteins, and adhesion molecules in HHE., Methods: Palmar skin biopsies (lesional and perilesional) were obtained from seven HHE patients and two healthy controls. Moreover, 135 candidate genes associated with palmoplantar keratoderma were screened for mutations., Results: Immunofluorescence staining showed a significant reduction of K9 and K14 in lesional skin. Upregulation was found for K5, K6, K16, and K17 in lesional skin compared with perilesional and healthy palmar skin. Further, upregulation of involucrin and alternating loricrin staining, both in an extracellular staining pattern, was found. Filaggrin expression was similar in lesional, perilesional, and control skin. No monogenetic mutations were found., Conclusion: Currently, the phenotype of HHE is included in the hand eczema classification system; however, it can be argued whether this is justified. The evident expression of filaggrin and involucrin in lesional skin does not support a pathogenesis of atopic eczema. The upregulation of K6, K16, and K17 and reduction of K9 and K14 might contribute to the underlying pathogenesis. Unfortunately, comparison with hand eczema studies is not possible yet, because similar protein expression studies are lacking., (© 2020 The Authors. Contact Dermatitis published by John Wiley & Sons Ltd.)

CellMinerCDB provides a web-based resource (https://discover.nci.nih.gov/cellminercdb/) for integrating multiple forms of pharmacological and genomic analyses, and unifying the richest cancer cell line datasets (the NCI-60, NCI-SCLC, Sanger/MGH GDSC, and Broad CCLE/CTRP). CellMinerCDB enables data queries for genomics and gene regulatory network analyses, and exploration of pharmacogenomic determinants and drug signatures. It leverages overlaps of cell lines and drugs across databases to examine reproducibility and expand pathway analyses. We illustrate the value of CellMinerCDB for elucidating gene expression determinants, such as DNA methylation and copy number variations, and highlight complexities in assessing mutational burden. We demonstrate the value of CellMinerCDB in selecting drugs with reproducible activity, expand on the dominant role of SLFN11 for drug response, and present novel response determinants and genomic signatures for topoisomerase inhibitors and schweinfurthins. We also introduce LIX1L as a gene associated with mesenchymal signature and regulation of cellular migration and invasiveness., (Published by Elsevier Inc.)

An outcome analysis was conducted based on an extended follow-up of the implementation of differential response program reforms in Child Protective Services offices in 10 counties in a Midwestern U.S. State. Random assignment was conducted of families that were first determined to be appropriate for family assessments. Experimental families (n=2,382) were each assigned to a non-forensic family assessment, and control families (n=2,247) each received a forensic investigation. Families were assigned continuously over a 15-month period and then tracked from 45 to 60 months from the date of assignment. Detailed information on services provided and family responses was obtained via two subsamples of experimental and control families. Measures of family engagement and service reception and utilization were utilized to determine instrumental outcomes introduced through family assessments. Improved family engagement and increased and broadened services were found to have occurred, and it was theorized that these changes mediated extended outcomes. Extended outcomes included reductions of rates of subsequent screened-in reports of child maltreatment, proportions of families that experienced child removals, and instances of new safety threats and problems in parenting. Differences in outcomes were found among the participating counties with 4 counties accounting for most outcome differences. The relationships between instrumental and extended outcomes were discussed with suggestions for further research., (Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.)

To study how changes in the [ATP]/[ADP] ratio affect the level of DNA supercoiling in Escherichia coli, the cellular content of H(+)-ATPase was modulated around the wild-type level. A relatively large drop in the [ATP]/[ADP] ratio from the normal ratio resulted in a small increase in the linking number of our reporter plasmid (corresponding to a small decrease in negative supercoiling). However, when cells depleted their carbon and energy source, the ensuing drop in energy state was accompanied by a strong increase in linking number. This increase was not due to reduced transcription of the DNA in the absence of growth substrate, since rifampin had virtually no effect on the plasmid linking number. To examine whether DNA supercoiling depends more strongly on the cellular energy state at low [ATP]/[ADP] ratios than at high ratios, we used cells that were already at a low energy state after substrate depletion; after the addition of an uncoupler to these cells, the [ATP]/[ADP] ratio decreased further, which resulted in a strong increase in plasmid linking number. Our results suggest that the strong thermodynamic control of DNA supercoiling takes over at low [ATP]/[ADP] ratios, whereas at high ratios homeostatic control mechanisms attenuate thermodynamic control.