Shared symptomatology between atopic dermatitis, ADHD and autism spectrum disorder: a protocol for a systematic scoping review.

INTRODUCTION: Children with atopic dermatitis (AD) are more at risk for the neurodevelopmental disorders attention-deficit/hyperactivity disorder (ADHD) and autism spectrum disorder (ASD) with parallel increases in global prevalences. Children afflicted with these conditions appear to share similar problems in sensory modulation but investigational studies on the underlying aetiology are scarce. This scoping review aims to find knowledge gaps, collate hypotheses and to summarise available evidence on the shared pathophysiology of AD, ADHD and ASD in children. METHODS AND ANALYSIS: Our study will follow the methodological manual published by the Joanna Briggs Methodology for Scoping Reviews and will be reported in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews. The following electronic databases will be searched for studies focused on children with AD and symptoms of ADHD and/or ASD: Medline ALL via Ovid, Embase, Web of Science Core Collection and the Cochrane Central Register of Controlled Trials via Wiley. ETHICS AND DISSEMINATION: This review does not require ethics approval as it will not be conducted with human participants. We will only use published data. Our dissemination strategy includes peer review publication and conference reports.

From decision to reflection: understanding the experiences and unmet care needs of patients treated with immunotherapy for melanoma in the adjuvant or metastatic setting.

BACKGROUND: Despite increased use of immune checkpoint inhibitors (ICIs) in patients with advanced melanoma, little is known about patient experiences during this treatment. This study aimed to gain an in-depth understanding of experiences and unmet care needs of patients treated in the adjuvant or metastatic setting for advanced melanoma regarding their ICI treatment trajectory. METHODS: Interviews and focus groups were conducted among 35 patients treated with ICIs in the adjuvant setting for completely resected stage III (n = 14), or in the metastatic setting for irresectable stage IV (n = 21) melanoma. A thorough thematic content analysis was conducted. RESULTS: Three main themes were identified. When (1) dealing with uncertainty in the decision-making process, adjuvant patients explored the pros and cons, whereas metastatic patients considered immunotherapy their only viable option. Both groups expressed the need for additional guidance. In (2) navigating the immunotherapy course, both perceived the trajectory as intense, experienced a major impact on their and their (close) relatives' lives, and felt the need to (re)gain control. When (3) looking back on the immunotherapy experience, metastatic patients generally felt relieved, while among adjuvant patients, feelings of doubt regarding their choice for ICIs were also reported. CONCLUSIONS: ICI treatment is perceived as intensive for both patient groups, facing both comparable and distinct challenges throughout the treatment trajectory, underscoring the need for stage-specific, individualised guidance. Options regarding flexible follow-ups, low-threshold contact and psychosocial support throughout the treatment trajectory should be explored.

Lifetime prevalence and associated factors of itch with skin conditions: Atopic dermatitis, psoriasis and dry skin in individuals aged over 50.

BACKGROUND: Itch, common in dermatological conditions, is often accompanied by psychological distress and reduced quality of life. However, research on the prevalence and associated factors of itch with skin conditions in general populations is limited. OBJECTIVES: This cross-sectional study aimed to determine the lifetime prevalence of itch with skin conditions and identify its associated factors in middle-aged and elderly individuals. METHODS: Participants from the Rotterdam Study, a population-based cohort, were interviewed to assess whether they had ever had an itchy skin condition, defining lifetime itch with skin conditions. Over 20 demographic, lifestyle, dermatological, and non-dermatological factors were collected. Multivariable logistic regression analysis explored associations between these factors and itch with skin conditions, reported as odds ratios (ORs) with 95% confidence intervals (CIs). RESULTS: 5,246 eligible participants (age range: 51-100, median age: 67, female: 56.0%) revealed a lifetime prevalence of 33.7% for itch with skin conditions. Female sex (OR (95% CI): 1.26 (1.11-1.43)), body mass index (1.02 (1.01-1.03)), self-reported and presence of atopic dermatitis (4.29 (3.74-4.92), and 1.97 (1.60-2.43)), self-reported and presence of psoriasis (2.31 (1.77-3.01), and 2.11 (1.55-2.87)), self-reported dry skin (1.95 (1.73-2.29)), self-reported asthma (1.40 (1.08-1.83)), renal impairment (1.45 (1.17-1.79)), and clinically relevant depressive and anxiety symptoms (1.85 (1.52-2.25), and 1.36 (1.11-1.66)) were significantly associated with it. CONCLUSIONS: This study reveals a substantial one-third lifetime prevalence of itch with skin conditions in individuals aged over 50. Significant associations with diverse lifestyle, demographic, dermatological and, intriguingly, non-dermatological factors including renal impairment, imply additional contributors to itch induction or persistence in individuals with skin conditions.

The epidemiology of acne vulgaris in a multiethnic adolescent population from Rotterdam, the Netherlands: A cross-sectional study.

BACKGROUND: Although acne is a prevalent multifactorial inflammatory skin condition, few studies were performed in multiethnic populations. OBJECTIVES: To study the prevalence and determinants of acne in a multiethnic study at the start of puberty. METHODS: This cross-sectional study is embedded in Generation R, a population-based prospective study from Rotterdam, the Netherlands. Three-dimensional facial photos at the center visit in 2016-2019 (of ∼13-year-olds) were used to grade acne severity using the Global Evaluation of the Acne Severity (GEA). Analyses were stratified by biological sex and explored through chi-square tests and multivariable ordinal logistic regression. RESULTS: A total of 4561 children (51% girls) with a median age of 13.5 (IQR 13.3-13.6) were included. The visible acne prevalence (GEA 2-5) for girls vs boys was 62% vs 45% and moderate-to-severe acne (GEA 3-5) 14% vs 9%. Higher puberty stages (adjusted odds ratios: 1.38 [1.20-1.59] and 2.16 [1.86-2.51] for girls and boys, respectively) and darker skin colors V and VI (adjusted odds ratios: 1.90 [1.17-3.08] and 2.43 [1.67-3.56]) were associated with more severe acne in both sexes, and being overweight in boys (adjusted odds ratio: 1.58 [1.15-2.17]). LIMITATIONS: Cross-sectional design. CONCLUSIONS: Acne prevalence was high at the age of 13 years and was associated with advanced puberty, darker skin color, and weight status.

Upadacitinib treatment in a real-world difficult-to-treat atopic dermatitis patient cohort.

BACKGROUND: Upadacitinib was the first JAK-1 selective inhibitor registered for the treatment of moderate-to-severe atopic dermatitis (AD). Although efficacy and safety have been shown in clinical trials, real-world data on the use of upadacitinib in patients that have been treated with other immunosuppressants and targeted therapies is limited. OBJECTIVES: To provide real-world evidence on the use of upadacitinib treatment in moderate-to-severe atopic dermatitis. METHODS: In this prospective observational single-centre study, all AD patients treated with upadacitinib treatment in the context of standard care were included between August 2021 and September 2022. Clinical outcome measures and adverse events (AEs) were analysed. RESULTS: Forty-eight patients were included. The majority (n = 39; 81%) had failed (ineffectiveness) on other targeted therapies, including other JAK inhibitors and biologics. Thirty-four (71%) patients were still using upadacitinib treatment at last follow up (median duration 46.5 weeks). Fourteen (29%) patients discontinued treatment due to ineffectiveness or AE. Upadacitinib treatment led to a significant decrease of disease severity during a median follow up of 37.5 weeks. Median IGA at baseline decreased from 3 (IQR 2-3) to 1.5 (IQR 1-2) at last review (p < 0.001). Median NRS itch decreased from 7 (IQR 5-8) at baseline to 2.25 (IQR 0.25-6.5) at last review (p < 0.001). Three patients discontinued treatment due to AE. Forty-eight AEs were reported, including acne-like eruptions (25%), nausea (13%) and respiratory tract infections (10%). CONCLUSIONS: In this real-world cohort, we confirmed that upadacitinib is an effective treatment in a subset of AD patients that have failed several previous systemic immunosuppressive and biologic treatments. Overall, AE were mostly well tolerated and not a reason to discontinue treatment for most patients.

Tralokinumab treatment for patients with moderate-to-severe atopic dermatitis in daily practice.

BACKGROUND: Evidence about tralokinumab treatment for moderate-to-severe atopic dermatitis (AD) in daily practice is limited. AIM: To report the first evidence, to our knowledge, from daily practice of treatment with tralokinumab in patients with AD. METHODS: In this observational prospective study, patients with AD who received tralokinumab treatment in the context of routine care at the Erasmus Medical Centre were included between November 2021 and February 2022. This included 28 patients who had previously been treated with dupilumab, and 14 patients who had been treated with a Janus kinase inhibitor (JAKi). The Investigator's Global Assessment (IGA; 0-4) and the numeric rating scale peak pruritus during the past 7 days (NRS itch 7d: 0-10), adverse events and reasons for discontinuation were analysed. A good clinical response was defined as any decrease in IGA and NRS itch 7d and if a patient was satisfied with the treatment and wished to continue with therapy. RESULTS: In total, 37 patients were treated with tralokinumab. Twenty-two (59%) patients showed a good response to tralokinumab treatment. Fifteen (41%) patients discontinued treatment because of inadequate AD control or adverse events. Treatment-related adverse events were mild in most patients. Half of the patients where treatment with dupilumab had failed had a good clinical response to tralokinumab. CONCLUSIONS: Tralokinumab was found to be effective in most patients in this cohort with difficult-to-treat, severe AD from daily practice. Interestingly, tralokinumab was also found to be effective in 50% of patients who had previously experienced insufficient response or adverse events with dupilumab treatment.

Bacterial Contamination Is Involved in the Etiology of Soft-Tissue Filler, Late-Onset, Inflammatory Adverse Events.

BACKGROUND: The treatment algorithm in late-onset inflammatory adverse events with soft-tissue fillers depends primarily on the assumed causative factor: immunologic or bacterial. METHODS: The authors included 29 patients, 13 of whom experienced late-onset inflammatory adverse events to fillers (inflammatory group) and 16 who did not (reference group). Biopsies were acquired from both groups with an 18-G needle. Before taking the biopsy, the authors acquired skin swabs for 25 of the 29 patients. The IS-pro method-a new and very sensitive method to detect microbiota-was used. This is a novel broad-range polymerase chain reaction technique based on length and sequence variations of the 16S to 23S ribosomal interspacer region. IS-pro can detect bacteria at low abundances and identify them up to species level. To exclude contamination from skin microbiota, the authors compared the microbiota found on skin swabs with that found in the corresponding biopsies. RESULTS: A high level of Gram-positive bacteria was found in biopsies of soft-tissue fillers, predominantly in patients from the inflammation group. This suggests that these bacteria were introduced during the primary filler injection treatment. The composition of the microbiota on the skin differed markedly from that in the filler, indicating that contamination during the sampling process did not influence results. CONCLUSIONS: Bacteria adherent to soft-tissue fillers or bacteremia probably play a causative role in adverse events. Contamination of samples in the biopsies with skin microbiota was excluded. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

A randomized clinical trial of isolated ambulatory phlebectomy versus saphenous thermal ablation with concomitant phlebectomy (SAPTAP Trial).

BACKGROUND: Current treatment of patients with saphenous trunk and tributary incompetence consists of truncal ablation with concomitant, delayed or no treatment of the tributary. However, reflux of the saphenous trunk may be reversible after treatment of the incompetent tributary. The aim of this study was to determine whether single ambulatory phlebectomy with or without delayed endovenous truncal ablation (SAP) is non-inferior to thermal endovenous ablation with concomitant phlebectomy (TAP), and whether SAP is a cost-effective alternative to TAP. METHODS: A multicentre, non-inferiority RCT was conducted in patients with an incompetent great saphenous vein or anterior accessory saphenous vein with one or more incompetent tributaries. Participants were randomized to receive SAP or TAP. After 9 months, additional truncal treatment was considered for SAP patients with remaining symptoms. The primary outcome was VEnous INsufficiency Epidemiological and Economic Study Quality of Life/Symptoms (VEINES-QOL/Sym score) after 12 months. Secondary outcomes were, among others, cost-effectiveness, perceived improvement of symptoms, and anatomical success. RESULTS: Some 464 patients received the allocated treatment (SAP 227, TAP 237). VEINES-QOL scores were 52.7 (95 per cent c.i. 51.9 to 53.9) for SAP and 53.8 (53.3 to 55.1) for TAP; VEINES-Sym scores were 53.5 (52.6 to 54.4) and 54.2 (54.0 to 55.6) respectively. Fifty-eight patients (25.6 per cent) in the SAP group received additional truncal ablation. Treatment with SAP was less costly than treatment with TAP. CONCLUSION: One year after treatment, participants who underwent SAP had non-inferior health-related quality of life compared with those who had TAP. Treatment with SAP was a cost-effective alternative to TAP at 12 months. REGISTRATION NUMBER: NTR 4821 (www.trialregister.nl).

Akkermansia muciniphila and Faecalibacterium prausnitzii in Immune-Related Diseases.

Probiotics and synbiotics are used to treat chronic illnesses due to their roles in immune system modulation and anti-inflammatory response. They have been shown to reduce inflammation in a number of immune-related disorders, including systemic lupus erythematosus (SLE), human immunodeficiency virus (HIV), and chronic inflammatory skin conditions such as psoriasis and atopic dermatitis (AD). Akkermansia muciniphila (A. muciniphila) and Faecalibacterium prausnitzii (F. prausnitzii) are two different types of bacteria that play a significant part in this function. It has been established that Akkermansia and Faecalibacterium are abundant in normal populations and have protective benefits on digestive health while also enhancing the immune system, metabolism, and gut barrier of the host. They have the potential to be a therapeutic target in diseases connected to the microbiota, such as immunological disorders and cancer immunotherapy. There has not been a review of the anti-inflammatory effects of Akkermansia and Faecalibacterium, particularly in immunological diseases. In this review, we highlight the most recent scientific findings regarding A. muciniphila and F. prausnitzii as two significant gut microbiota for microbiome alterations and seek to provide cutting-edge insight in terms of microbiome-targeted therapies as promising preventive and therapeutic tools in immune-related diseases and cancer immunotherapy.

Using a Clinicopathologic and Gene Expression (CP-GEP) Model to Identify Stage I-II Melanoma Patients at Risk of Disease Relapse.

Background: The current standard of care for patients without sentinel node (SN) metastasis (i.e., stage I−II melanoma) is watchful waiting, while >40% of patients with stage IB−IIC will eventually present with disease recurrence or die as a result of melanoma. With the prospect of adjuvant therapeutic options for patients with a negative SN, we assessed the performance of a clinicopathologic and gene expression (CP-GEP) model, a model originally developed to predict SN metastasis, to identify patients with stage I−II melanoma at risk of disease relapse. Methods: This study included patients with cutaneous melanoma ≥18 years of age with a negative SN between October 2006 and December 2017 at the Sahlgrenska University Hospital (Sweden) and Erasmus MC Cancer Institute (The Netherlands). According to the CP-GEP model, which can be applied to the primary melanoma tissue, the patients were stratified into high or low risk of recurrence. The primary aim was to assess the 5-year recurrence-free survival (RFS) of low- and high-risk CP-GEP. A secondary aim was to compare the CP-GEP model with the EORTC nomogram, a model based on clinicopathological variables only. Results: In total, 535 patients (stage I−II) were included. CP-GEP stratification among these patients resulted in a 5-year RFS of 92.9% (95% confidence interval (CI): 86.4−96.4) in CP-GEP low-risk patients (n = 122) versus 80.7% (95%CI: 76.3−84.3) in CP-GEP high-risk patients (n = 413; hazard ratio 2.93 (95%CI: 1.41−6.09), p < 0.004). According to the EORTC nomogram, 25% of the patients were classified as having a 'low risk' of recurrence (96.8% 5-year RFS (95%CI 91.6−98.8), n = 130), 49% as 'intermediate risk' (88.4% 5-year RFS (95%CI 83.6−91.8), n = 261), and 26% as 'high risk' (61.1% 5-year RFS (95%CI 51.9−69.1), n = 137). Conclusion: In these two independent European cohorts, the CP-GEP model was able to stratify patients with stage I−II melanoma into two groups differentiated by RFS.

Experiences of resuming life after immunotherapy and associated survivorship care needs: a qualitative study among patients with metastatic melanoma.

BACKGROUND: Immune checkpoint inhibitors (ICIs) have significantly improved the overall survival of patients with metastatic melanoma. It is unclear how the growing group of metastatic melanoma survivors resume their lives after treatment, and which needs they have regarding survivorship care (SSC). OBJECTIVES: To gain an in-depth understanding of metastatic melanoma survivors' experiences of resuming life after ICIs and their associated SSC needs. METHODS: A qualitative study was conducted among 20 patients with metastatic melanoma in whom ICIs had been discontinued after ongoing tumour response. One focus group (n = 9) was held, which was complemented by 11 individual interviews. Purposive sampling was used to select a variable sample in terms of sex, age, time since discontinuation of ICIs, and perceived impact of the disease. A topic guide was used to structure the (group) interviews, which were transcribed verbatim and analysed in a thematic content analysis, using several phases of coding. RESULTS: In resuming life after ICIs, the prognosis switch often caused mixed feelings among patients, mainly because of the uncertainty about the future. Demands and expectations from self and others, persistent complaints and new problems in different life domains often make it challenging to proceed with life as it was prior to metastatic cancer. Patients indicated they needed to find a new balance, which included learning to cope with uncertainty and a changed perspective on life and close relationships. In terms of SSC needs, patients particularly stressed the need for more tailored patient information, available at one location. In addition, they emphasized the need to know who to turn to in case of questions and indicated the need for psychosocial support, also for their close relatives. CONCLUSIONS: Metastatic melanoma survivors face various challenges in resuming life after ICIs and are left with several unmet SSC needs. Efforts should be focused on offering psychosocial supportive care in addition to medical care, from diagnosis onwards, taking into account the patient's close relatives. A single point of contact and personalized survivorship care plan (SCP) could be of added value in guiding them through the patient journey, which is, given its multidisciplinary nature, particularly important in melanoma care. What is already known about this topic? Since the introduction of immune checkpoint inhibitors (ICIs) the overall survival of patients with metastatic melanoma has improved significantly, leading to a growing group of melanoma survivors. Melanoma survivors may face various problems and challenges in resuming life after treatment, which may be associated with unmet survivorship care (SSC) needs. An in-depth understanding of their experiences with resuming life and the associated SSC needs is currently lacking. What does this study add? Metastatic melanoma survivors experience various challenges after immunotherapy, from the uncertain prognosis switch to the struggle of finding a new balance in life. Besides negative aspects, such as complaints in different life domains, the patient journey is often accompanied by positive outcomes, for example a changed perspective on life. They stress the need for tailored patient information and broader supportive care, also for their close relatives. What are the clinical implications of this work? In addition to medical care, efforts should be focused on offering psychosocial supportive care, including return-to-work issues, from diagnosis onwards, ideally taking into account the patient's close relatives. To guide them through the patient journey, a single point of contact and a personalized survivorship care plan (SCP) could be of added value. The latter is particularly important in melanoma care, given its multidisciplinary nature.

Serum Interleukin 6 Level and Nutrition Status as Potential Predictors of Clinical Leprosy Development Among Household Contacts in Endemic Areas.

BACKGROUND: Leprosy is a chronic infectious disease that can lead to severe lifelong disabilities. Close contacts of patients with leprosy have a higher risk of acquiring the disease. Nevertheless, there is a lack of reliable markers to predict Mycobacterium leprae infection. We aimed to identify new potential markers for developing clinical leprosy among contacts. METHODS: Serum levels of interleukin (IL) 6, IL-8, IL-10, hemoglobin, ferritin, and transferrin saturation were measured in 67 patients with multibacillary leprosy (MB), 65 household contacts (HHCs) of MB patients, and 127 endemic controls (ECs). By means of multivariate logistic regression and receiver operating characteristic (ROC) analyses, we analyzed baseline variables and laboratory parameters that showed significant differences between MB in the HHC and EC groups and obtained the respective areas under the curve (AUC). Optimal cutoff values of the associated cytokines were also determined. RESULTS: Elevated IL-6 level was observed in MB patients compared to HHCs and ECs (P = .022 and .0041, respectively). Anemia and iron deficiency were also higher in the MB group compared to HHCs or ECs (P < .001). Likewise, we observed an increased risk of having MB leprosy in underweight HHCs (odds ratio [OR], 2.599 [95% confidence interval {CI}, .991-6.820]) and underweight ECs (OR, 2.176 [95% CI, 1.010-4.692]). Further ROC analysis showed that high serum IL-6 level, underweight, anemia, and iron deficiency can discriminate leprosy from their HHCs (AUC, 0.843 [95% CI, .771-.914]; P = .000; optimal cutoff value of IL-6 = 9.14 pg/mL). CONCLUSIONS: Our results suggest that serum IL-6 and nutrition status could serve as potential prognostic markers for the development of clinical leprosy in infected individuals.

Efficacy, cost-minimization, and budget impact of a personalized discharge letter for basal cell carcinoma patients to reduce low-value follow-up care.

BACKGROUND: The incidence of keratinocyte carcinomas is high and rapidly growing. Approximately 80% of keratinocyte carcinomas consist of basal cell carcinomas (BCC) with 50% of these being considered as low-risk tumors. Nevertheless, 83% of the low-risk BCC patients were found to receive more follow-up care than recommended according to the Dutch BCC guideline, which is one visit post-treatment for this group. More efficient management could reduce unnecessary follow-up care and related costs. OBJECTIVES: To study the efficacy, cost-utility, and budget impact of a personalized discharge letter for low-risk BCC patients compared with usual care (no personalized letter). METHODS: In a multi-center intervention study, a personalized discharge letter in addition to usual care was compared to usual care in first-time BCC patients. Model-based cost-utility and budget impact analyses were conducted, using individual patient data gathered via surveys. The outcome measures were number of follow-up visits, costs and quality adjusted life years (QALY) per patient. RESULTS: A total of 473 first-time BCC patients were recruited. The personalized discharge letter decreased the number of follow-up visits by 14.8% in the first year. The incremental costs after five years were -€24.45 per patient. The QALYs were 4.12 after five years and very similar in both groups. The national budget impact was -€2,7 million after five years. CONCLUSIONS: The distribution of a personalized discharge letter decreases the number of unnecessary follow-up visits and implementing the intervention in a large eligible population would results in substantial cost savings, contributing to restraining the growing BCC costs.

Practice Variation in Skin Cancer Treatment and Follow-Up Care: A Dutch Claims Database Analysis.

BACKGROUND: Quality indicators are used to benchmark and subsequently improve quality of healthcare. However, defining good quality indicators and applying them to high-volume care such as skin cancer is not always feasible. OBJECTIVES: To determine whether claims data could be used to benchmark high-volume skin cancer care and to assess clinical practice variation. METHODS: All skin cancer care-related claims in dermatology in 2016 were extracted from a nationwide claims database (Vektis) in the Netherlands. RESULTS: For over 220,000 patients, a skin cancer diagnosis-related group was reimbursed in 124 healthcare centres. Conventional excision reflected 75% of treatments for skin cancer but showed large variation between practices. Large practice variation was also found for 5-fluorouracil and imiquimod creams. The practice variation of Mohs micrographic surgery and photodynamic therapy was low under the 75th percentile, but outliers at the 100th percentile were detected, which indicates that few centres performed these therapies far more often than average. On average, patients received 1.8 follow-up visits in 2016. CONCLUSIONS: Claims data demonstrated large practice variation in treatments and follow-up visits of skin cancer and may be a valid and feasible data set to extract quality indicators. The next step is to investigate whether detected practice variation is unwarranted and if a reduction improves quality and efficiency of care.

Objectives, design and main findings until 2020 from the Rotterdam Study.

The Rotterdam Study is an ongoing prospective cohort study that started in 1990 in the city of Rotterdam, The Netherlands. The study aims to unravel etiology, preclinical course, natural history and potential targets for intervention for chronic diseases in mid-life and late-life. The study focuses on cardiovascular, endocrine, hepatic, neurological, ophthalmic, psychiatric, dermatological, otolaryngological, locomotor, and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. Since 2016, the cohort is being expanded by persons aged 40 years and over. The findings of the Rotterdam Study have been presented in over 1700 research articles and reports. This article provides an update on the rationale and design of the study. It also presents a summary of the major findings from the preceding 3 years and outlines developments for the coming period.

The association between dietary and skin advanced glycation end products: the Rotterdam Study.

BACKGROUND: Advanced glycation end products (AGEs) accumulate in tissues with age and in conditions such as diabetes mellitus and chronic kidney disease (CKD), and they may be involved in age-related diseases. Skin AGEs measured as skin autofluorescence (SAF) are a noninvasive reflection of long-term AGE accumulation in tissues. Whether AGEs present in the diet (dAGEs) contribute to tissue AGEs is unclear. OBJECTIVES: Our aim was to investigate the association between dietary and skin AGEs in the Rotterdam Study, a population-based cohort of mainly European ancestry. METHODS: In 2515 participants, intake of 3 dAGEs [carboxymethyl-lysine (CML), N-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MGH1), and carboxyethyl-lysine (CEL)] was estimated using FFQs and the content of AGEs measured in commonly consumed foods. SAF was measured 5 y (median value) later using an AGE Reader. The association of dAGEs with SAF was analyzed in linear regression models and stratified for diabetes and chronic kidney disease (CKD, defined as estimated glomerular filtration rate ≤60 mL/min) status. RESULTS: Mean ± SD intake was 3.40 ±0.89 mg/d for CML, 28.98 ±7.87 mg/d for MGH1, and 3.11 ±0.89 mg/d for CEL. None of them was associated with SAF in the total study population. However, in stratified analyses, CML was positively associated with SAF after excluding both individuals with diabetes and individuals with CKD: 1 SD higher daily CML intake was associated with a 0.03 (95% CI: 0.009, 0.05) arbitrary units higher SAF. MGH1 and CEL intake were not significantly associated with SAF. Nevertheless, the associations were stronger when the time difference between dAGEs and SAF measurements was shorter. CONCLUSIONS: Higher dietary CML intake was associated with higher SAF only among participants with neither diabetes nor CKD, which may be explained by high AGE formation in diabetes and decreased excretion in CKD or by dietary modifications in these disease groups. The dAGE-SAF associations were also modified by the time difference between measurements. Our results suggest that dAGEs can influence tissue AGE accumulation and possibly thereby age-related diseases. This trial was registered at the Netherlands National Trial Register as NTR6831 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=6831) and at the WHO International Clinical Trials Registry Platform as NTR6831 (http://www.who.int/ictrp/network/primary/en/).