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321 Cancer risk with topical pimecrolimus and tacrolimus for atopic dermatitis: systematic review and Bayesian meta-analysis

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Abstract

Atopic dermatitis affects millions worldwide and is effectively managed by topical treatments, including topical calcineurin inhibitors, pimecrolimus and tacrolimus. In 2005 and 2011, the FDA released reviews associating topical calcineurin inhibitors with a theoretical cancer risk, albeit an uncertain association. We systematically reviewed the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors. We systematically identified randomized controlled trials, comparative, and non-comparative non-randomized studies from database inception to 6 June 2022, from MEDLINE, EMBASE, GREAT, LILACS, ICTRP, FDA, EMA, company registers and relevant citations. We included studies in any language addressing the risk of cancer in patients with atopic dermatitis exposed to topical calcineurin inhibitors for greater than 3 weeks. We excluded split-body studies. We conducted a Bayesian meta-analysis and used the GRADE approach to determine the certainty of the evidence. A multidisciplinary panel including patients, advocacy groups and care providers, set an a priori threshold of 1 in 1000 risk difference as a clinically important effect. We analysed 121 studies (52 randomized controlled trials and 69 non-randomized studies) including 3.4 million patents followed for a mean of 11 months (range: 0.7–120). The absolute risk of any cancer with topical calcineurin inhibitor exposure was neither different from controls (absolute risk 4.70 per 1000 with topical calcineurin inhibitor exposure vs. 4.56 per 1000 without; odds ratio 1.03 [95% credible interval 0.94–1.11], moderate-certainty evidence) nor the general US population (4.6 per 1000). Findings were similar in infants, children, and adults, and were robust to trial sequential, subgroup and sensitivity analyses. Among infants, children and adults with atopic dermatitis, moderate-certainty evidence shows that topical calcineurin inhibitors do not increase the risk of cancer. These findings support the safe use of topical calcineurin inhibitors in the management of patients with atopic dermatitis. Our findings provide actional information to inform updated clinical practice guidelines, product labels and continuing education for care providers, to clarify the safe usage of topical calcineurin inhibitors.

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Background: The patient-burden and quality of life (QOL) impact of atopic dermatitis (AD) in the United States population is not wellestablished. Objective: To elucidate the patient-burden of AD in the US population. Methods: A cross-sectional, population-based study of 602 adults was performed. AD was determined using modified UK Diagnostic Criteria for AD. AD severity was assessed using self-reported global AD severity, Patient-Oriented Eczema Measure (POEM), Patient-Oriented Scoring AD (POSCORAD), PO-SCORAD-itch and sleep. QOL was assessed using short-form (SF-)12 mental and physical health scores and Dermatology Life Quality Index (DLQI). Results: Adults with AD reported higher proportions of having only fair/poor overall health (25.8% vs. 15.8%), being somewhat/very dissatisfied with life (16.7% vs. 11.4%), lower weighted mean [SD] SF-12 mental (45.9 [9.9] vs. 50.9 [9.2]) and physical health subscores (53.0 [2.5] vs. 53.5 [2.3]) and higher DLQI (4.9 [6.5] vs. 1.1 [2.8]). In multivariable regression models adjusting for socio-demographics and multiple comorbid health disorders, there were significant stepwise decreases by AD severity (self-reported, POEM, PO-SCORAD) of overall health, life satisfaction, SF-12 mental health and increases of DLQI scores. SF-12 physical health scores were only associated with moderate AD. Concurrently severe PO-SCORAD, POEM and/or PO-SCORAD-itch was associated with very low mean SF-12 mental health (34.7) and high DLQI scores (24.7). AD commonly limited lifestyle (51.3%), led to avoidance of social interaction (39.1%) and impacted activities (43.3%).The most burdensome AD symptoms were itch (54.4%), excessive dryness/scaling (19.6%) and red/inflamed skin (7.2%). Conclusion: These data support the heavy burden that AD places on patients, particularly moderate and severe AD.
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Background There is a concern that topical tacrolimus and pimecrolimus, indicated for second-line treatment of atopic dermatitis, may increase the risk of lymphoma and skin cancer, particularly in children. Objective The aim of this study was to compare incidence rates (IRs) of lymphoma and skin cancer between new users of topical tacrolimus or pimecrolimus and users of moderate- to high-potency topical corticosteroids (TCSs) and untreated subjects. Methods This is a multicenter cohort study with frequency matching by strata of propensity scores in population databases in the Netherlands, Denmark, Sweden, and the UK. IR ratios (IRRs) were estimated using Mantel–Haenszel methods for stratified analysis. Results We included 19,948 children and 66,127 adults initiating tacrolimus, 23,840 children and 37,417 adults initiating pimecrolimus, 584,121 users of TCSs, and 257,074 untreated subjects. IRs of lymphoma per 100,000 person-years were 10.4 events in children and 41.0 events in adults using tacrolimus and 3.0 events in children and 27.0 events in adults using pimecrolimus. The IRR (95% confidence interval [CI]) for lymphoma, tacrolimus versus TCSs, was 3.74 (1.00–14.06) in children and 1.27 (0.94–1.71) in adults. By lymphoma type, the highest IRR was 3.17 (0.58–17.23) for Hodgkin lymphoma in children and 1.76 (95% CI, 0.81–3.79) for cutaneous T-cell lymphoma (CTCL) in adults. For pimecrolimus versus TCSs, the highest IRR was 1.31 (95% CI, 0.33–5.14) for CTCL in adults. Compared with untreated subjects, adults using TCSs had a higher incidence of CTCL (IRR, 10.66; 95% CI, 2.60–43.75). Smaller associations were found between tacrolimus and pimecrolimus use and the risk of malignant melanoma or nonmelanoma skin cancer. Conclusion Use of topical tacrolimus and pimecrolimus was associated with an increased risk of lymphoma. The low IRs imply that even if the increased risk is causal, it represents a small excess risk for individual patients. Residual confounding by severity of atopic dermatitis, increased monitoring of severe patients, and reverse causation could have affected the results.
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Background Topical tacrolimus is an effective anti-inflammatory therapy for acute and chronic states of atopic dermatitis (AD) in both adults and children. Topical tacrolimus has particular use at sensitive areas such as the face, anogenitals, and skin folds of neck and extremities. However, many AD patients also experience aggravated symptoms on trunk. Objective The aim of this study was to investigate the efficacy and safety of topical tacrolimus for AD patients with truncal lesions. Methods AD patients with truncal lesions who were aged ≥2 years were recruited from 20 centres in Korea. They received treatment with topical tacrolimus ointment twice daily during 4 weeks. The primary end point was change of the local eczema area and severity index (EASI) of the trunk from baseline to day 28. The secondary end points were changes in the patient global assessment (PGA) score and itch visual analogue scale (VAS) score of the trunk between baseline and day 28. Results Two hundred and ninety-one patients were recruited, and 176 patients completed the full 4-week treatment course. By the end of the treatment, the mean local EASI of the trunk (2.2±4.71) was significantly decreased from that at baseline (4.71±4.03, p<0.001). PGA (1.71±1.15) and itch VAS score of the trunk (2.61±2.19) on day 28 were also profoundly decreased compared with the baseline (2.96±1.07 and 5.15±2.47, respectively). No serious adverse events were observed during the study period. Conclusion Topical tacrolimus is an effective and safe therapy for truncal lesions in AD patients.
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The implementation of treatment guidelines for atopic dermatitis is challenging, in part because of different guidance documents being used by different groups of specialists and in part because the language of guidelines often reflects the evidence base rather than the practical "how to." The Atopic Dermatitis Yardstick is part of a series developed in response to the need to proactively address the loss of disease control for atopic illnesses at all levels of severity. It presents a comprehensive update on how to conduct a sustained step-up in therapy for the patient with inadequately controlled or poorly controlled atopic dermatitis. Patient profiles, based on current guidelines and the authors' combined clinical experience, provide a practical and clinically meaningful guide to aid physicians in helping their patients achieve the goal of clear to almost clear. The intent is not to replace guidelines but to complement their recommendations incorporating the latest research and therapies.
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Background: JTE-052 is a novel Janus kinase inhibitor presently under clinical development for the topical treatment of atopic dermatitis (AD). Objectives: To evaluate the efficacy and safety of JTE-052 ointment in Japanese adult patients with AD. Methods Patients with moderate-to-severe AD were randomised (2:2:2:2:1:1) to receive JTE-052 ointment at 0.25%, 0.5%, 1% or 3%, the vehicle ointment or 0.1% tacrolimus ointment (reference) twice daily for 4 weeks. The primary efficacy endpoint was the percent change in modified Eczema Area Severity Index (m-EASI) score from the baseline at the end of treatment (EOT). Secondary efficacy endpoints included change from baseline in the pruritus numeric rating scale (NRS) score. Results: A total of 327 patients were enrolled. At EOT, the least-squares mean percent change from baseline in m-EASI score for JTE-052 0.25%, 0.5%, 1%, 3% and the vehicle ointment was -41.7%, -57.1%, -54.9%, -72.9% and -12.2%, respectively. All JTE-052 groups showed significant reductions of m-EASI score versus the vehicle group (p <0.001 for all). In the tacrolimus group, the mean percent change in m-EASI score was -62.0%. JTE-052 groups also showed significant improvement in other parameters; notably, the pruritus NRS score was reduced as early as Day 1 night-time. JTE-052 ointment at doses up to 3% was safe and well tolerated. Conclusions: Topical JTE-052 markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate-to-severe AD with a favourable safety profile. The study results indicate that topical JTE-052 is a promising therapeutic option for AD. This article is protected by copyright. All rights reserved. Trial registration number: JAPICCTI-152887.
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Background: Controlled studies established the efficacy and good tolerability of pimecrolimus cream 1% for the treatment of atopic dermatitis but they may not reflect real-life use. Objective: To evaluate the efficacy, tolerability and cosmetic acceptance of a pimecrolimus-based regimen in daily practice in Switzerland. Methods: This was a 6-month, open-label, multicentre study in 109 patients (55% > or = 18 years) with atopic dermatitis. Pimecrolimus cream 1% was incorporated into patients' standard treatment protocols. Results: The pimecrolimus-based treatment was well tolerated and produced disease improvement in 65.7% of patients. It was particularly effective on the face (improvement rate: 75.0%). Mean pimecrolimus consumption decreased from 6.4 g/day (months 1-3) to 4.0 g/day (months 3-6) as disease improved. Most patients (74.1%) rated their disease control as 'complete' or 'good' and 90% were highly satisfied with the cream formulation. Conclusion: The use of a pimecrolimus-based regimen in everyday practice was effective, well tolerated and well accepted by patients.
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Non-randomised studies of the effects of interventions are critical to many areas of healthcare evaluation, but their results may be biased. It is therefore important to understand and appraise their strengths and weaknesses. We developed ROBINS-I ("Risk Of Bias In Non-randomised Studies-of Interventions"), a new tool for evaluating risk of bias in estimates of the comparative effectiveness (harm or benefit) of interventions from studies that did not use randomisation to allocate units (individuals or clusters of individuals) to comparison groups. The tool will be particularly useful to those undertaking systematic reviews that include non-randomised studies.
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Background Many clinicians have concerns about the safety of atopic dermatitis (AD) treatments, particularly in children requiring long-term daily maintenance therapy. Topical corticosteroids (TCS) have been widely used for >5 decades. Long-term TCS monotherapy has been associated with adverse cutaneous effects including atrophy, rebound flares, and increased percutaneous absorption with potential for adverse systemic effects. Topical calcineurin inhibitors (TCIs), tacrolimus and pimecrolimus, available for 1–2 decades, are not associated with atrophy or increased percutaneous absorption after prolonged use and have much lower potential for systemic effects. However, since 2006 TCIs have carried a controversial Boxed Warning based on a theoretical risk of malignancy (eg, skin and lymphoma) that has limited TCI use for standard-of-care maintenance therapy. Methods A comparative systematic search of PubMed was done for long-term (≥12 week) clinical trials of TCS or TCI treatment in patients <12 years with AD. Citations were reviewed for inclusion based on MeSH terms, abstracts, and relevant article text. Studies were excluded if they did not encompass subjects <12 years, or were <12 weeks’ duration, retrospective, meta-analyses, or limited to anecdotal case reports. Results Of 27 trials meeting criteria, 21 included 5825 pediatric patients treated with TCIs, and 6 included 1999 patients treated with TCS. TCS studies were limited to low- to mid-potency products, and all but one study lacked a vehicle control. Eight TCI studies were vehicle-controlled, and safety data were well reported, with ≤5 % of patients reporting discontinuation due to adverse effects (DAEs). Cutaneous and systemic adverse events (AEs) were similar in TCI and vehicle groups, with no reports of lymphoma. Safety data in TCS trials were less well reported. DAE incidence was addressed in just 2 trials, and systemic and cutaneous AEs were mostly unreported. Conclusions Data supporting long-term use of TCIs are robust, documenting safety and efficacy, while data supporting long-term TCS use are limited to low- to mid-potency products. Our review identifies a lack of information on the safety of commonly prescribed, long-term monotherapy with mid- to high-potency TCS in pediatric AD, and supports standard-of-care maintenance therapy with TCIs and intermittent use of low- to mid-potency TCS for flares.
Article
The Food and Drug Administration (FDA) is tasked with evaluating the efficacy and safety of a drug. Despite having a regimented appraisal process in place, safety evidence can emerge during clinical trials as well as from observations and studies conducted after the drug has been on the market that might require a boxed warning. The boxed warning is the most severe warning that the FDA can give to an approved drug. It is commonly referred to as a Black Box Warning as it is outlined in the package insert by a thick black box to garner the attention of prescribers and patients. There are currently over 400 medications that have boxed warnings and the information addressing major risks associated with a particular drug may, appropriately or inappropriately, influence patient and clinician decision making. Healthcare professionals must use the best evidence and clinical judgment in determining whether to prescribe medications with these warnings. Use of an approved drug at dosages or for indications other than what it was originally licensed for is referred to as “off-label” and is legal, commonplace, and may be evidence-based. All drugs may expose patients to possible harm, so prescribers have an obligation to discuss the best available evidence regarding benefits and harms so that patients can participate in shared decision-making.
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BACKGROUND The influence of diet on atopic dermatitis (AD) is complex, and the use of dietary elimination as a treatment has conflicting views. OBJECTIVE To systematically review the benefits and harms of dietary elimination for the treatment of AD. METHODS We searched MEDLINE, EMBASE, AMED, PsycINFO and CENTRAL from inception to Jan 18, 2022, without language restrictions, for RCTs and observational studies comparing dietary elimination versus no dietary elimination for treatment of AD. We conducted random-effects meta-analysis of eczema outcomes. We used the GRADE approach to assess certainty of evidence (CRD42021237953). RESULTS Ten RCT (n = 599, baseline median of study mean ages 1.5 years, median of study mean SCORAD 20.7, range 3.5-37.6) were included in the meta-analysis. Compared to no dietary elimination, low certainty evidence showed that dietary elimination may slightly improve eczema severity (50% with versus 41% without dietary elimination improved SCORAD by a minimally important difference of 8.7 points, risk difference [RD], 9% [95%CI 0 to 17]), pruritus (daytime itch score [range 0-3], mean difference [MD] -0.21 [95%CI -0.57 to 0.15]) and sleeplessness (sleeplessness score [range 0-3], MD -0.47 [95%CI -0.80 to -0.13]). There were no credible subgroup differences based on elimination strategy (empiric versus guided by testing) or food-specific sensitization. Insufficient data addressed harms of elimination diets among included RCTs, although indirect evidence suggests elimination diets may increase the risk of developing IgE-mediated food allergy. CONCLUSION Dietary elimination may lead to a slight, potentially unimportant, improvement in eczema severity, pruritus and sleeplessness in patients with mild-moderate AD. This must be balanced against potential risks of indiscriminate elimination diets including developing IgE-mediated food allergy and withholding more effective treatment options for AD.
Article
Importance: Vaccination against SARS-CoV-2 is a highly effective strategy to prevent infection and severe COVID-19 outcomes. The best strategy for a second dose of vaccine among persons who had an immediate allergic reaction to their first SARS CoV-2 vaccination is unclear. Objective: To assess the risk of severe immediate allergic reactions (eg, anaphylaxis) to a second dose of SARS-CoV-2 mRNA vaccine among persons with immediate allergic reactions to their first vaccine dose. Data sources: MEDLINE, Embase, Web of Science, and the World Health Organization Global Coronavirus database were searched from inception through October 4, 2021. Study selection: Included studies addressed immediate allergic reactions of any severity to a second SARS-CoV-2 vaccine dose in persons with a known or suspected immediate allergic reaction (<4 hours after vaccination) after their first SARS-CoV-2 vaccine dose. Studies describing a second vaccine dose among persons reporting delayed reactions (>4 hours after vaccination) were excluded. Data extraction and synthesis: Paired reviewers independently selected studies, extracted data, and assessed risk of bias. Random-effects models were used for meta-analysis. The GRADE (Grading of Recommendation, Assessment, Development, and Evaluation) approach evaluated certainty of the evidence. Main outcomes and measures: Risk of severe immediate allergic reaction and repeated severe immediate allergic reactions with a second vaccine dose. Reaction severity was defined by the reporting investigator, using Brighton Collaboration Criteria, Ring and Messmer criteria, World Allergy Organization criteria, or National Institute of Allergy and Infectious Diseases criteria. Results: Among 22 studies of SARS-CoV-2 mRNA vaccines, 1366 individuals (87.8% women; mean age, 46.1 years) had immediate allergic reactions to their first vaccination. Analysis using the pooled random-effects model found that 6 patients developed severe immediate allergic reactions after their second vaccination (absolute risk, 0.16% [95% CI, 0.01%-2.94%]), 232 developed mild symptoms (13.65% [95% CI, 7.76%-22.9%]), and, conversely, 1360 tolerated the dose (99.84% [95% CI, 97.09%-99.99%]). Among 78 persons with severe immediate allergic reactions to their first SARS-CoV-2 mRNA vaccination, 4 people (4.94% [95% CI, 0.93%-22.28%]) had a second severe immediate reaction, and 15 had nonsevere symptoms (9.54% [95% CI, 2.18%-33.34%]). There were no deaths. Graded vaccine dosing, skin testing, and premedication as risk-stratification strategies did not alter the findings. Certainty of evidence was moderate for those with any allergic reaction to the first dose and low for those with severe allergic reactions to the first dose. Conclusions and relevance: In this systematic review and meta-analysis of case studies and case reports, the risk of immediate allergic reactions and severe immediate reactions or anaphylaxis associated with a second dose of an SARS-CoV-2 mRNA vaccine was low among persons who experienced an immediate allergic reaction to their first dose. These findings suggest that revaccination of individuals with an immediate allergic reaction to a first SARS-CoV-2 mRNA vaccine dose in a supervised setting equipped to manage severe allergic reactions can be safe.
Article
Optimal evidence-based clinical practice requires systematic summaries of the best available evidence, including ratings of the quality of that evidence, and is facilitated by the availability of trustworthy guidelines. In this review, we describe the GRADE approach to rating quality of evidence and moving from evidence to recommendations using examples from Allergy-Immunology. GRADE focuses on systematic summaries of the best evidence, systematic reviews and trustworthy guidelines, and emphasizes a structured approach to determining quality (certainty) of bodies of evidence, absolute magnitude of effects of desirable and undesirable consequences (benefits and harms) and use of evidence to develop clinical recommendations. Adopted by over 110 organizations worldwide, including the American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma & Immunology Joint Task Force on Practice Parameters, GRADE is foundational to the optimal interpretation of research evidence and its application in clinical practice. This review supports the clinician’s ability to find and utilize the information in GRADE guidelines to help care for patients in clinic.
Article
Meta-analyses contribute critically to cumulative science, but they can produce misleading conclusions if their constituent primary studies are biased, for example by unmeasured confounding in nonrandomized studies. We provide practical guidance on how meta-analysts can address confounding and other biases that affect studies’ internal validity, focusing primarily on sensitivity analyses that help quantify how biased the meta-analysis estimates might be. We review a number of sensitivity analysis methods to do so, especially recent developments that are straightforward to implement and interpret and that use somewhat less stringent statistical assumptions than do earlier methods. We give recommendations for how these newer methods could be applied in practice and illustrate using a previously published meta-analysis. Sensitivity analyses can provide informative quantitative summaries of evidence strength, and we suggest reporting them routinely in meta-analyses of potentially biased studies. This recommendation in no way diminishes the importance of defining study eligibility criteria that reduce bias and of characterizing studies’ risks of bias qualitatively. Expected final online publication date for the Annual Review of Public Health, Volume 43 is April 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.
Article
Objective This article describes GRADE guidance for assessing imprecision when rating the certainty of the evidence from network meta-analysis. Study design and setting A project group within the GRADE working group conducted iterative discussions, computer simulations, and presentations at GRADE working group meetings to produce and obtain approval for this guidance. Results When addressing imprecision of a network estimate, reviewers should consider the 95% confidence or credible interval, and the optimal information size. If the 95% confidence or credible interval crosses a pre-specified threshold, reviewers should rate down the certainty of the evidence. If the 95% confidence interval does not cross any pre-specfied threshold, reviewers should consider the optimal information size. Because addressing the optimal information size may be challenging, reviewers can use the effect size to decide if any calculations are necessary. When the size of the effect is modest or the optimal information size is met, reviewers should not rate down for imprecision. Conclusions Reviewers should use this guidance when to appropriately address imprecision in the context of the assessment of certainty of evidence from network meta-analysis.
Article
Importance Topical calcineurin inhibitors (TCIs) are commonly used as second-line treatment for atopic dermatitis. In 2006, the US Food and Drug Administration issued a black box warning against TCI use, citing data from case reports and animal studies indicating a potential risk of cancer. Objective To evaluate the association between TCI use and risk of malignant neoplasms compared with nonactive and active comparator groups. Data Sources Electronic searches were conducted in MEDLINE via Ovid, Embase via Ovid, and Web of Science from database inception to August 21, 2020. Study Selection Observational studies investigating the association between treatment with TCIs (ie, tacrolimus and pimecrolimus) and the development of cancer with nonactive or active comparators were included. The population of interest was not limited to any specific disease state, age, or sex. All articles were assessed independently and in duplicate by 2 reviewers. Risk of bias was assessed using the Newcastle-Ottawa scale. Of 2464 nonduplicate records retrieved from the search, 11 studies met the inclusion criteria. Data Extraction and Synthesis Data extraction was conducted independently by 2 reviewers according to Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Random-effects meta-analyses were used to derive pooled relative risk (RR) estimates. Data were analyzed from July 25 to October 25, 2020. Main Outcomes and Measures Risk of cancer overall and risk of specific cancer types (lymphoma, melanoma, and keratinocyte carcinoma). Results Eight unique cohort studies (408 366 treated participants [55.1% female], 1 764 313 nonactive comparator controls, and 1 067 280 controls using topical corticosteroids) and 3 unique case-control studies (3898 cases [55.0% male] and 14 026 cancer-free controls [52.4% male]) were included. There was no association between TCI use and cancer overall compared with nonactive comparators (RR, 1.03; 95% CI, 0.92-1.16). Lymphoma risk was elevated with TCI use with both nonactive (RR, 1.86; 95% CI, 1.39-2.49) and topical corticosteroid comparators (RR, 1.35; 95% CI, 1.13-1.61). No significant association was found between TCI use and increased skin cancer (melanoma and keratinocyte carcinoma). Conclusions and Relevance The findings of this systematic review and meta-analysis suggest an association between TCI use and risk of lymphoma but not other cancers. Combined with the low absolute risk of lymphoma, the potential increased risk attributable to TCI use for any individual patient is likely very small.
Article
Background Little is known about the current global prevalence of atopic dermatitis (AD) in the pediatric population. Objective To estimate the real-world global prevalence of AD in the pediatric population and by disease severity. Methods This international, cross-sectional, web-based survey of children/adolescents (6 months to <18 years old) was conducted in 18 countries: North America (Canada, United States), Latin America (Argentina, Brazil, Columbia, Mexico), Europe (France, Germany, Italy, Spain, United Kingdom), Middle East/Eurasia (Israel, Saudi Arabia, Turkey, United Arab Emirates, Russia), and East Asia (Japan, Taiwan). Prevalence was determined using two defintions: 1) diagnosed AD according to the International Study of Asthma and Allergies in Childhood (ISAAC) criteria and self/parent-report of ever being told by a physician that they/their child had AD (eczema); 2) reported AD based on ISAAC crtieria only. Severity was assessed using the Patient Global Assessment (PtGA) and Patient Oriented Eczema Measure (POEM). Results Among 65,661 responders, the 12-month diagnosed AD prevalence (ISAAC+self-reported diagnosis) ranged from 2.7% to 20.1% across countries; reported AD (ISAAC only) was 13.5% to 41.9%. Severe AD assessed with both PtGA and POEM was generally <15%; more subjects rated AD as mild on PtGA than suggested by POEM. No trends in prevalence were observed based on age or sex; prevalence was generally lower in rural residential settings relative to urban/suburban. Conclusion This global survey in 18 countries showed that AD affects a substantial proportion of the pediatric population. Although prevalence and severity varied across age groups and countries, <15% had severe AD.
Article
Background Most previously published trials of topical tacrolimus in atopic dermatitis were of relatively short duration and comprised a limited population with moderate-to-severe disease. Objective The goal of the study was to evaluate the safety and efficacy over a 6-month period of tacrolimus 0.1% ointment in children and adults with a broader severity spectrum of atopic dermatitis. Methods An open-label multicenter trial in patients 2 years and older was used. Primary safety and tolerability assessments included skin infection and application site adverse events. Efficacy parameters were body surface area involvement, pruritus score, and overall reponse. Results There were 240 patients recruited at 23 study sites. Significant improvement from baseline was noted for all efficacy endpoints in both pediatric and adult patients. Skin infections occurred in 26% of patients. Burning sensation with product application, reported by 38% of patients, was transient and of mild-to-moderate severity in the majority. Conclusion Tacrolimus 0.1% ointment was safe, well tolerated, and efficacious in treatment of atopic dermatitis in children and adults over six months.
Article
Importance Topical calcineurin inhibitors (TCIs), primarily used to treat atopic dermatitis (AD), carry a black box label warning users about the potential for increased skin cancer risk. The risk associated with keratinocyte carcinoma (KC), the most common cancer, defined as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), remains poorly defined because findings from large-scale postmarketing surveillance studies have not been reported. Objectives To examine KC risk overall and by subtype (BCC and SCC) among adults with AD exposed to TCIs compared with those exposed to topical corticosteroids (primary comparator group) and those unexposed to TCIs or topical corticosteroids (alternative comparator group) as well as alterations in risk with TCI dose, frequency, and duration of exposure. Design, Setting, and Participants A retrospective cohort study was conducted at Kaiser Permanente Northern California, a large, integrated health care delivery system, of adults 40 years or older (n = 93 746) with a physician-rendered diagnosis of AD or dermatitis. Patients who were diagnosed from January 1, 2002, to December 31, 2013, were included, with follow-up through December 31, 2017. Data analysis was conducted from June 1, 2016, to October 1, 2018. Exposures Time-varying pharmacy-dispensed TCI exposure (n = 7033) over the study period was compared with topical corticosteroids (n = 73 674) and no TCI or topical corticosteroid exposure (n = 46 141). Main Outcomes and Measures Electronic pathologic testing–validated incident KCs (n = 7744). Results Among a cohort of 93 746 members, the mean (SD) age was 58.5 (12.7) years, and 55 023 patients (58.7%) were women. Multivariable Cox proportional hazards regression revealed no association between TCI exposure and KC risk (adjusted hazard ratio [aHR], 1.02; 95% CI, 0.93-1.13) compared with topical corticosteroid exposure. Similarly, there were no significant differences in BCC risk (aHR, 1.01; 95% CI, 0.90-1.14, TCI vs topical corticosteroids) or SCC risk (aHR, 0.94; 95% CI, 0.82-1.08, TCI vs topical corticosteroids). Changing the comparator group to unexposed individuals yielded similar findings (aHR, 1.04; 95% CI, 0.91-1.19, TCI vs unexposed for basal cell carcinoma). There were no associations between TCI dose, frequency, and duration of use and BCC, SCC, or overall KC risk. Conclusions and Relevance The results of this postmarketing surveillance study of adult health plan members with AD revealed no apparent association between TCI exposure and overall KC, BCC, or SCC risk. Secondary analyses examining dose, frequency, and duration of TCI exposure revealed no associations. These findings suggest that use of TCIs may be safe with respect to KC risk among adults with AD.
Article
Assessment of risk of bias is regarded as an essential component of a systematic review on the effects of an intervention. The most commonly used tool for randomised trials is the Cochrane risk-of-bias tool. We updated the tool to respond to developments in understanding how bias arises in randomised trials, and to address user feedback on and limitations of the original tool.
Article
Background: Though adherence is low among caregivers of children with atopic dermatitis (AD), the reasons for it are poorly understood. This study aims to assess the self-reported prevalence of non-adherence and reasons for changing prescription regimens among parents of children with AD. Methods: A link to a 15-question online survey was posted to social media sites engaging parents of children with eczema, worldwide. Items included a scale related to physician trust. Results were analyzed using R 3.4 and summarized using normal and nonparametric descriptive statistics as appropriate for each item. Results: Eighty-six eligible parents responded to the survey and provided information about medication adherence. The mean age of respondents' children was 6.2 years (SD 4.4 years), and the majority were children with moderate or severe eczema (40.5% moderate and 42.9% severe). Just over half (54.7%) reported taking or applying eczema medications as directed by their physician. Of those that did not, 30.2% took or applied less medications, and 12.8% stopped taking or applying medications altogether. The top reasons for deviating from directions were as follows: (a) worry about side effects, (b) symptom resolution, and (c) perception that the medication was not working. Trust toward physician was significantly associated with taking medication as directed. Conclusions: Decisions about adherence to medications are made in the context of perceived benefits versus anticipated side effects. Findings highlight opportunities for improving adherence, and thereby improving outcomes for children with moderate-severe AD.
Article
Background Atopic dermatitis (AD) is an extremely common childhood disease, with considerable impact on the quality of life of affected children and their families. While pruritus is the hallmark symptom of this disease, AD has been well‐documented to impact patients beyond physical symptoms, resulting in behavior problems, mood disorders, and sleep disturbance. Objective This literature review outlines how atopic dermatitis impacts the quality of life of families of children affected by AD. Methods A total of 3436 articles were identified via an online search of the MEDLINE health literature database and were screened for relevance to quality of life impacts on families with children affected by AD. Results Caring for children affected by AD can be an extremely time‐consuming task that can impair personal relationships, decrease psychosocial functioning, and cause sleep loss among family members of affected patients. Additionally, AD may result in work absence or decreased work productivity for caregivers. Special diets, irritant and allergen avoidance strategies, and alternative therapies are commonly used by patients to manage their disease and require large amounts of family involvement. Conclusions Atopic dermatitis can greatly decrease quality of life of families of affected children in various domains, including sleep, finances, and relationships. Early intervention and psychotherapy may be needed in some patients to address these quality of life impairments.
Article
This article presents official guidance from the Grading of Recommendations Assessments, Development, and Evaluation (GRADE) working group on how to address incoherence when assessing the certainty in the evidence from network meta-analysis. Incoherence represents important differences between direct and indirect estimates that contribute to a network estimate. Bias due to limitations in study design or publication bias, indirectness, and intransitivity may be responsible for incoherence. Addressing incoherence requires a judgment regarding the importance of the impact on the network estimate. Reviewers need to be alert to the possibility of misguidedly arriving at excessively low ratings of certainty by rating down for both incoherence and other closely related GRADE domains. This article describes and illustrates each of these issues and provides explicit guidance on how to deal with them.
Article
When direct and indirect estimates of treatment effects are coherent, network meta-analysis (NMA) estimates should have increased precision (narrower confidence or credible intervals compared with relying on direct estimates alone), a benefit of NMA. We have, however, observed cases of sparse networks in which combining direct and indirect estimates results in marked widening of the confidence intervals. In many cases, the assumption of common between-study heterogeneity across the network seems to be responsible for this counterintuitive result. Although the assumption of common between-study heterogeneity across paired comparisons may, in many cases, not be appropriate, it is required to ensure the feasibility of estimating NMA treatment effects. This is especially the case in sparse networks, in which data are insufficient to reliably estimate different variances across the network. The result, however, may be spuriously wide confidence intervals for some of the comparisons in the network (and, in the GRADE approach, inappropriately low ratings of the certainty of the evidence through rating down for serious imprecision). Systematic reviewers should be aware of the problem and plan sensitivity analyses that produce intuitively sensible confidence intervals. These sensitivity analyses may include using informative priors for the between-study heterogeneity parameter in the Bayesian framework, and the use of fixed effects models.
Article
This article describes conceptual advances of the Grading of Recommendations Assessments, Development, and Evaluation (GRADE) working group guidance to evaluate certainty of evidence (confidence in evidence, quality of evidence) from network meta-analysis (NMA). Application of the original GRADE guidance, published in 2014, in a number of NMAs has resulted in advances that strengthen its conceptual basis and make the process more efficient. This guidance will be useful for systematic reviewer authors who aim to assess the certainty of all pairwise comparisons from an NMA and who are familiar with the basic concepts of NMA and the traditional GRADE approach for pairwise meta-analysis. Two principles of the original GRADE NMA guidance are that we need to rate the certainty of the evidence for each pairwise comparison within a network separately, and that in doing so we need to consider both the direct and indirect evidence. We present, discuss, and illustrate four conceptual advances: 1) Consideration of imprecision is not necessary when rating the direct and indirect estimates to inform the rating of NMA estimates, 2) There is no need to rate the indirect evidence when the certainty of the direct evidence is high and the contribution of the direct evidence to the network estimate is at least as great as that of the indirect evidence, 3) We should not trust a statistical test of global incoherence of the network to assess incoherence at the pairwise comparison level, and 4) In the presence of incoherence between direct and indirect evidence, the certainty of the evidence of each estimate can help decide which estimate to believe.
Article
Background: Atopic dermatitis (AD) is often the first step in the atopic march leading to the development of asthma or allergic rhinitis. The goal of this study was to determine whether early intervention with pimecrolimus limits the atopic march in infants with AD and to evaluate its efficacy and safety. Methods: This was a 3-year double-blind study in which patients were randomized to pimecrolimus or vehicle and then open-label pimecrolimus for a planned further 3 years. Rescue topical corticosteroid was permitted if 3 days of study medication led to no improvement; investigators made decisions on rescue medication until week 14 and caregivers thereafter. Efficacy assessments included disease-free days, Eczema Area and Severity Index, and body surface area affected. Results: Infants ages 3 to 18 months with recent-onset AD (≤3 months) were observed for a mean of 2.8 years (N = 1,091). No significant differences between pimecrolimus- and placebo-treated groups were found in the percentage of patients with AD who developed asthma (10.7%) or other allergic conditions (allergic rhinitis, 22.4%; food allergy, 15.9%; allergic conjunctivitis, 14.1%; one or more atopic comorbidities, 37.0%) by study end. Allergic rhinitis, food allergy, and having one or more atopic comorbidities (but not asthma or allergic conjunctivitis alone) developed significantly more often in infants with greater AD severity at baseline. Pimecrolimus was significantly more effective than vehicle for AD treatment at week 14. Adverse event incidences were similar. Conclusions: This longitudinal observation of infants with AD provides evidence of the atopic march. Pimecrolimus was safe and effective in infants with mild to moderate AD.