Development of a core outcome set for cutaneous squamous cell carcinoma trials: identification of core domains and outcomes.

BACKGROUND: The lack of uniformity in the outcomes reported in clinical studies of the treatment of cutaneous squamous cell carcinoma (cSCC) complicates efforts to compare treatment effectiveness across trials. OBJECTIVES: To develop a core outcome set (COS), a minimum set of agreed-upon outcomes to be measured in all clinical trials of a given disease or outcome, for the treatment of cSCC. METHODS: One hundred and nine outcomes were identified via a systematic literature review and interviews with 28 stakeholders. After consolidation of this long list, 55 candidate outcomes were rated by 19 physician and 10 patient stakeholders, in two rounds of Delphi exercises. Outcomes scored 'critically important' (score of 7, 8 or 9) by ≥ 70% of patients and ≥ 70% of physicians were provisionally included. At the consensus meeting, after discussion and voting of 44 international experts and patients, the provisional list was reduced to a final core set, for which consensus was achieved among all meeting participants. RESULTS: A core set of seven outcomes was finalized at the consensus meeting: (i) serious or persistent adverse events, (ii) patient-reported quality of life, (iii) complete response, (iv) partial response, (v) recurrence-free survival, (vi) progression-free survival and (vii) disease-specific survival. CONCLUSIONS: In order to increase the comparability of results across trials and to reduce selective reporting bias, cSCC researchers should consider reporting these core outcomes. Further work needs to be performed to identify the measures that should be reported for each of these outcomes.

Atopic dermatitis and bone health: a systematic review.

Atopic dermatitis (AD) is associated with systemic inflammation and systemic corticosteroid use which can lead to poor bone health. The aim of this systematic review is to investigate the relationship between AD and bone mineral density (BMD), osteoporosis and fractures. We searched Web of Science, Cochrane Database of Systematic Reviews, MEDLINE and Embase. Title, abstract and full-text screening, and data extraction were done in duplicate. Quality appraisal was performed using the Agency for Healthcare Research and Quality Methodology Checklist (cross-sectional studies) and Newcastle-Ottawa Scale (cohort studies). We screened 3800 abstracts and included fifteen studies (twelve cross-sectional, three cohort). In cross-sectional studies, AD was associated with decreased BMD and increased fractures. In cross-sectional studies and a cohort study, AD was associated with a higher prevalence of osteoporosis compared to controls. There was inconsistency across studies, with some finding no association. In a large cohort study, AD was associated with increased risk of fractures of the hip (HR: 1.06, 95% CI: 1.02 to 1.11), spine (HR: 1.14, 95% CI: 1.06 to 1.23) and wrist (HR: 1.06, 95% CI: 1.01 to 1.10), with further increased risk with more severe AD. Differences between studies precluded quantitative synthesis. There is some evidence supporting an association between AD and poor bone health. Research is needed to clarify this association, underlying mechanisms and develop strategies to improve bone health of individuals with AD.

Quality of reporting in systematic reviews published in dermatology journals.

BACKGROUND: Reporting of systematic reviews (SRs) using PRISMA increases transparency and reproducibility; adherence in the dermatology literature has not been assessed. OBJECTIVES: To assess selected, primarily methodological items from the PRISMA reporting guideline among SRs published in dermatology journals. METHODS: We reviewed SRs published from 2013 to 2017 in the five highest-impact dermatology journals according to the Science Citation Index. We descriptively assessed reporting of selected PRISMA items, the proportion of PRISMA items fully and partially reported, and whether SRs described using a preregistered protocol. We used univariate and multivariate linear regression to evaluate associations between exposures (year, protocol registration, funding source, type of included study, disease and journal), and outcomes (proportion of PRISMA items fully reported, and fully and partially reported, for each SR). RESULTS: We identified 136 SRs. All had more than one inadequately reported PRISMA item. Protocol registration (73%) and risk of bias (38%) were most often unreported. Reporting improved over time in our primary multivariate analysis [fully reported vs. partially and not reported, ß = 2·48; 95% confidence interval (CI) 0·73-4·27] and secondary analysis (fully and partially reported vs. not reported, ß = 1·28, 95% CI 0·06-2·50). Only 15% (20 of 136) of SRs stated that their protocols were registered; this was associated with PRISMA adherence to the evaluated PRISMA items in our primary multivariate analysis (ß = 10·05, 95% CI 2·89-17·2) and secondary analysis (ß = 8·87, 95% CI 3·84-13·9). CONCLUSIONS: SR reporting in dermatology journals is often inadequate but improving over time; protocol registration is associated with better reporting. What's already known about this topic? No studies to date have examined the adherence of dermatology systematic reviews (SRs) to reporting guidelines, such as PRISMA. In other medical fields, reporting is variable with some improvement in adherence to reporting standards over time. What does this study add? Among SRs published in five dermatology journals from 2013 to 2017, all (n = 136) had at least one inadequately reported PRISMA item, while 93% (127 of 136) had at least one fully nonreported item. Reporting improved over time and SRs that stated use of a preregistered protocol were associated with better reporting. Several items remain commonly underreported in dermatology SRs. Authors, reviewers, journal editors and editorial committees should encourage preregistration of SR protocols and improved SR reporting.

Network meta-analyses of systemic treatments for psoriasis: a critical appraisal: Original Articles: Jabbar-Lopez ZK, Yiu ZZN, Ward V et al. Quantitative evaluation of biologic therapy options for psoriasis: a systematic review and network meta-analysis. J Invest Dermatol 2017; 137:1646-54. Sbidian E, Chaimani A, Garcia-Doval I et al. Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis. Cochrane Database Syst Rev 2017; 12:CD011535.

AIM: There are numerous systemic medications in use for psoriasis, with additional investigational agents being studied. However, head-to-head, randomized clinical trials are rare and cannot feasibly compare all treatments. A network meta-analysis (NMA) synthesizes the available evidence to provide estimates for all pairwise comparisons. Here, we summarize and appraise two recent NMAs that assessed systemic therapies for moderate-to-severe psoriasis. SETTING AND DESIGN: Two systematic reviews searched databases and the grey literature to identify relevant randomized clinical trials. STUDY PARTICIPANTS: The reviews mostly included trials that involved adults with moderate-to-severe psoriasis. One of the reviews also included two trials involving children. STUDY EXPOSURE: Interventions common to both reviews include adalimumab, etanercept, infliximab, ustekinumab, ixekizumab, secukinumab and methotrexate. One of the reviews included additional interventions, primarily other biological agents along with new small-molecule treatments and systemic conventional treatments. PRIMARY OUTCOMES: One review focused on 'clear/nearly clear' and withdrawals from adverse events as study outcomes, while the second review focused on improvement of ≥ 90% measured on the Psoriasis Area and Severity Index (PASI 90) and serious adverse events. OUTCOMES: Additional outcomes included quality of life, PASI 75, Physician's Global Assessment of 0/1 and any adverse event. RESULTS: Overall, both NMAs are of high quality and provide a comprehensive summary of the evidence base and treatment effects. Results, in terms of both estimates and rankings, suggest that newer biologics targeting the interleukin (IL)-12/23 and IL-17 axes appear to be more effective than older biologics and oral agents. CONCLUSIONS: Patients, clinicians and policy makers can use the relative efficacy assessments of NMAs to inform decision making regarding the clearance of psoriasis skin lesions at relevant time points and improvement in quality of life.

Diagnosis validation and clinical characterization of atopic dermatitis in Nurses' Health Study 2.

BACKGROUND: Epidemiologic studies of atopic dermatitis (AD) are often limited by case definitions that have not been validated. OBJECTIVE: In this study, we assessed the accuracy of self-report of AD in a large cohort of US female nurses, the Nurses' Health Study 2 (NHS2). We also provide clinical characteristics of AD in the cohort. METHODS: We sent an electronic questionnaire to NHS2 participants who previously reported ever having a diagnosis of AD. This questionnaire was designed to confirm cases of AD using previously validated algorithms with >85% specificity. We assessed the association of AD with asthma, comparing the results when different definitions of AD were applied. We also inquired about various aspects of participants' AD. RESULTS: Responses were received from 2509 of 5126 (49%) nurses who were sent the questionnaire, with an average age of 62. Most participants (1996/2509, 80%) reiterated their previously reported clinician diagnosis of AD. Application of the two diagnostic algorithms yielded confirmation of 1538 and 1293 prevalent cases, respectively. The association of AD with asthma was stronger when more stringent AD case definitions were applied. Participants generally reported mild disease (92% with ≤10% maximal body surface area involved) and a high proportion (57%) reported adult-onset disease. CONCLUSIONS: Self-report of AD diagnosis has good reliability, and future analyses will be strengthened by our ability to conduct sensitivity analyses with refined confirmed AD subgroups.

Conjunctivitis in atopic dermatitis patients with and without dupilumab therapy - international eczema council survey and opinion.

BACKGROUND: Conjunctivitis is common in patients with atopic dermatitis (AD) in general and a commonly reported adverse event in AD clinical trials with dupilumab. OBJECTIVE: To survey opinions and experience about conjunctivitis occurring in AD, including those during dupilumab treatment in a group of AD experts from the International Eczema Council (IEC). METHODS: Electronic survey and in-person discussion of management strategies. RESULTS: Forty-six (53.5%) IEC members from 19 countries responded to the survey. Consensus was reached for several statements regarding diagnostic workup, referral and treatment. IEC members suggest that patients with AD should (i) routinely be asked about ocular complaints or symptoms, (ii) obtain information about the potential for conjunctivitis before starting dupilumab therapy and (iii) if indicated, be treated with dupilumab despite previous or current conjunctivitis. In cases of new-onset conjunctivitis, there was consensus that dupilumab treatment should be continued when possible, with appropriate referral to an ophthalmologist. LIMITATIONS: The study relies on expert opinion from dermatologists. Responses from few dermatologists without dupilumab access were not excluded from the survey. CONCLUSION: The IEC recommends that dermatologists address conjunctivitis in patients with AD, especially during treatment with dupilumab.

Use of systemic corticosteroids for atopic dermatitis: International Eczema Council consensus statement.

BACKGROUND: Guidelines discourage the use of systemic corticosteroids for atopic dermatitis (AD), but their use remains widespread. OBJECTIVES: To reach consensus among an international group of AD experts on the use of systemic corticosteroids for AD. METHODS: A survey consisting of statements accompanied by visual analogue scales ranging from 'strongly disagree' to 'neutral' to 'strongly agree' was distributed to the International Eczema Council (IEC). Consensus was reached in agreement on a statement if < 30% of respondents marked to the left of 'neutral' towards 'strongly disagree'. RESULTS: Sixty of 77 (78%) IEC members participated. Consensus was reached on 12 statements, including that systemic corticosteroids should generally be avoided but can be used rarely for severe AD under certain circumstances, including a lack of other treatment options, as a bridge to other systemic therapies or phototherapy, during acute flares in need of immediate relief, in anticipation of a major life event or in the most severe cases. If used, treatment should be limited to the short term. Most respondents agreed that systemic corticosteroids should never be used in children, but consensus was not reached on that statement. The conclusions of our expert group are limited by a dearth of high-quality published evidence. If more stringent consensus criteria were applied (e.g. requiring < 20% of respondents marking towards 'strongly disagree'), consensus would have been reached on fewer statements. CONCLUSIONS: Based on expert opinion from the IEC, routine use of systemic corticosteroids for AD is generally discouraged and should be reserved for special circumstances.

Incident alopecia areata and vitiligo in adult women with atopic dermatitis: Nurses' Health Study 2.

We aimed to determine the risk of alopecia areata (AA) and vitiligo associated with atopic dermatitis (AD) in a large cohort of US women, the Nurses' Health Study 2. We used logistic regression to calculate age- and multivariate-adjusted odds ratios to determine the risk of incident AA and vitiligo associated with AD diagnosed in or before 2009. A total of 87 406 and 87 447 participants were included in the AA and vitiligo analyses, respectively. A history of AD in 2009 was reported in 11% of participants. There were 147 incident cases of AA and 98 incident cases of vitiligo over 2 years of follow-up. AD was associated with increased risk of developing AA (OR 1.80, 95% CI 1.18-2.76) and vitiligo (OR 2.14, 95% CI 1.29-3.54) in multivariate models. In this study of US women, AD was associated with increased risk of incident vitiligo and AA in adulthood.

What's in a name? Atopic dermatitis or atopic eczema, but not eczema alone.

BACKGROUND: The ideal nomenclature of atopic dermatitis (AD) / atopic eczema (AE) has long been contested. However, it is becoming increasingly clear that the disparate nomenclature of this disease may have important deleterious ramifications for clinical care and research. MATERIALS AND METHODS: An electronic questionnaire regarding the preferred nomenclature for AD was sent to councilors of the International Eczema Council (IEC) (n=77), an international group of clinicians and researchers with expertise in AD/AE. The survey consisted of 2 questions for consensus regarding the preference for an atopic prefix, and preference for the term AD or AE, and an exploratory question about the acceptability of the terms AD, AE or eczema. Consensus was defined a priori as at least 90% agreement for each question with a response rate of at least 90%. RESULTS: Seventy-one of 77 (92.2%) IEC councilors and associates responded to the survey, with all respondents completing the entire survey. Consensus was reached for question 1, with 69 of 71 respondents (97.2%) preferring the atopic prefix. However, consensus was not reached for question 2, with 40 respondents (58.0%) preferring the term AD and 30 (43,5%) preferring AE. Sixty-three respondents (88.7%) and 55 (77.5%) felt that the terms AD and AE were acceptable, whereas only 11 (15.5%) felt that eczema was acceptable. CONCLUSIONS: The IEC noted that the term eczema is imprecise, and its use is confusing. The consensus of the IEC was to recommend use of the prefix "atopic" (i.e., AD or AE) in all publications, presentations and discussions about the disorder.

Evaluation of the measurement properties of symptom measurement instruments for atopic eczema: a systematic review.

BACKGROUND: Symptoms have been identified as a core outcome domain for atopic eczema (AE) trials. Various instruments exist to measure symptoms in AE, but they vary in quality and there is a lack of standardization between clinical trials. Our objective was to systematically evaluate the quality of the evidence on the measurement properties of AE symptom instruments, thereby informing consensus discussions within the Harmonising Outcome Measures for Eczema (HOME) initiative regarding the most appropriate instruments for the core outcome domain symptoms. METHODS: Using the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist and predefined criteria for good measurement properties on identified development and validation studies of AE symptom instruments, a best evidence synthesis was performed to draw an overall conclusion on quality of the instruments and to provide recommendations. RESULTS: Eighteen instruments were identified and evaluated. When the quality and results of the studies were considered, only five of these instruments had sufficient validation data to consider them for the core outcome set for the core outcome domain symptoms. These were the paediatric Itch Severity Scale (ISS), Patient-Oriented Eczema Measure (POEM), Patient-Oriented SCOring Atopic Dermatitis (PO-SCORAD), Self-Administered Eczema Area and Severity Index (SA-EASI) and adapted SA-EASI. CONCLUSIONS: ISS (paediatric version), POEM, PO-SCORAD, SA-EASI and adapted SA-EASI are currently the most appropriate instruments and therefore have the potential to be recommended as core symptom instrument in future clinical trials. These findings will be utilized for the development of a core outcome set for AE.

Measurement properties of quality-of-life measurement instruments for infants, children and adolescents with eczema: a systematic review.

BACKGROUND: Quality of life (QoL) is one of the core outcome domains identified by the Harmonising Outcome Measures for Eczema (HOME) initiative to be assessed in every eczema trial. There is uncertainty about the most appropriate QoL instrument to measure this domain in infants, children and adolescents. OBJECTIVES: To systematically evaluate the measurement properties of existing measurement instruments developed and/or validated for the measurement of QoL in infants, children and adolescents with eczema. METHODS: A systematic literature search in PubMed and Embase, complemented by a thorough hand search of reference lists, retrieved studies on measurement properties of eczema QoL instruments for infants, children and adolescents. For all eligible studies, we judged the adequacy of the measurement properties and the methodological study quality with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. Results from different studies were summarized in a best-evidence synthesis and formed the basis to assign four degrees of recommendation. RESULTS: Seventeen articles, three of which were found by hand search, were included. These 17 articles reported on 24 instruments. No instrument can be recommended for use in all eczema trials because none fulfilled all required adequacy criteria. With adequate internal consistency, reliability and hypothesis testing, the U.S. version of the Childhood Atopic Dermatitis Impact Scale (CADIS), a proxy-reported instrument, has the potential to be recommended depending on the results of further validation studies. All other instruments, including all self-reported ones, lacked significant validation data. CONCLUSIONS: Currently, no QoL instrument for infants, children and adolescents with eczema can be highly recommended. Future validation research should primarily focus on the CADIS, but also attempt to broaden the evidence base for the validity of self-reported instruments.

Atopic dermatitis and risk of hypertension, type 2 diabetes, myocardial infarction and stroke in a cross-sectional analysis from the Canadian Partnership for Tomorrow Project.

BACKGROUND: Atopic dermatitis (AD) has been associated with cardiovascular risk factors and diseases, but epidemiological studies to date have found conflicting results. OBJECTIVES: To determine the associations of AD with hypertension, type 2 diabetes (T2D), myocardial infarction (MI) and stroke. METHODS: We conducted a cross-sectional analysis of baseline data from the Canadian Partnership for Tomorrow Project, which includes Canadian residents aged 30-74 years living in British Columbia, Alberta, Ontario, Quebec and the Atlantic Provinces. We excluded participants with incomplete data on AD, hypertension, T2D, MI or stroke, who had type 1 or gestational diabetes or who developed any of the outcomes at an age prior to a diagnosis of AD. This left 259 119 participants in our analysis. We used logistic regression to calculate age- and sex-, and multivariable-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between AD and subsequent hypertension, T2D, MI and stroke. RESULTS: AD was reported by 21 379 (8·4%) participants. In total, 52 787 cases of hypertension, 12 739 cases of T2D, 4390 cases of MI and 2235 cases of stroke were reported by participants at enrolment. In the multivariable-adjusted model, AD was associated with decreased odds of hypertension (OR 0·87, 95% CI 0·83-0·90), T2D (OR 0·78, 95% CI 0·71-0·84), MI (OR 0·87, 95% CI 0·75-1·00) and stroke (OR 0·79, 95% CI 0·66-0·95). CONCLUSIONS: We did not find evidence of a positive association between AD and subsequent hypertension, T2D, MI or stroke; AD was inversely associated with these outcomes in our study. Given our findings and the conflicting literature, AD is likely not a major risk factor for cardiovascular disease.

Atopic dermatitis is not independently associated with nonfatal myocardial infarction or stroke among US women.

We aimed to determine the association between atopic dermatitis (AD) and cardiovascular events in the Nurses' Health Study 2, a cohort of US women. We used logistic regression models to calculate age- and multivariate-adjusted odds ratios (OR) and 95% confidence intervals (CI) for the associations between history of AD and nonfatal MI and nonfatal stroke. Of the 78 702 participants in our analysis, 7916 (10%) had a history of AD. There were 392 and 391 cases of nonfatal MI and stroke, respectively. AD was not associated with MI in age- or multivariate-adjusted analyses. AD was significantly associated with stroke in the age-adjusted analysis (OR 1.38, 95% CI 1.03-1.85). This was no longer significant in multivariate models that adjusted for hypertension, hypercholesterolemia and diabetes (OR 1.31, 95% CI 0.98-1.76) and atopic comorbidities (OR 1.17, 95% CI 0.86-1.58). AD was not independently associated with nonfatal MI or stroke in this study.

Measurement properties of adult quality-of-life measurement instruments for eczema: a systematic review.

BACKGROUND: The Harmonising Outcome Measures for Eczema (HOME) initiative has identified quality of life (QoL) as a core outcome domain to be evaluated in every eczema trial. It is unclear which of the existing QoL instruments is most appropriate for this domain. Thus, the aim of this review was to systematically assess the measurement properties of existing measurement instruments developed and/or validated for the measurement of QoL in adult eczema. METHODS: We conducted a systematic literature search in PubMed and Embase identifying studies on measurement properties of adult eczema QoL instruments. For all eligible studies, we assessed the adequacy of the measurement properties and the methodological quality with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist. A best evidence synthesis summarizing findings from different studies was the basis to assign four degrees of recommendation (A-D). RESULTS: A total of 15 articles reporting on 17 instruments were included. No instrument fulfilled the criteria for category A. Six instruments were placed in category B, meaning that they have the potential to be recommended depending on the results of further validation studies. Three instruments had poor adequacy in at least one required adequacy criterion and were therefore put in category C. The remaining eight instruments were minimally validated and were thus placed in category D. CONCLUSIONS: Currently, no QoL instrument can be recommended for use in adult eczema. The Quality of Life Index for Atopic Dermatitis (QoLIAD) and the Dermatology Life Quality Index (DLQI) are recommended for further validation research.