Rosacea Core Domain Set for Clinical Trials and Practice: A Consensus Statement.

Importance: Inconsistent reporting of outcomes in clinical trials of rosacea is impeding and likely preventing accurate data pooling and meta-analyses. There is a need for standardization of outcomes assessed during intervention trials of rosacea. Objective: To develop a rosacea core outcome set (COS) based on key domains that are globally relevant and applicable to all demographic groups to be used as a minimum list of outcomes for reporting by rosacea clinical trials, and when appropriate, in clinical practice. Evidence Review: A systematic literature review of rosacea clinical trials was conducted. Discrete outcomes were extracted and augmented through discussions and focus groups with key stakeholders. The initial list of 192 outcomes was refined to identify 50 unique outcomes that were rated through the Delphi process Round 1 by 88 panelists (63 physicians from 17 countries and 25 patients with rosacea in the US) on 9-point Likert scale. Based on feedback, an additional 11 outcomes were added in Round 2. Outcomes deemed to be critical for inclusion (rated 7-9 by ≥70% of both groups) were discussed in consensus meetings. The outcomes deemed to be most important for inclusion by at least 85% of the participants were incorporated into the final core domain set. Findings: The Delphi process and consensus-building meetings identified a final core set of 8 domains for rosacea clinical trials: ocular signs and symptoms; skin signs of disease; skin symptoms; overall severity; patient satisfaction; quality of life; degree of improvement; and presence and severity of treatment-related adverse events. Recommendations were also made for application in the clinical setting. Conclusions and Relevance: This core domain set for rosacea research is now available; its adoption by researchers may improve the usefulness of future trials of rosacea therapies by enabling meta-analyses and other comparisons across studies. This core domain set may also be useful in clinical practice.

Factors associated with the melanoma diagnostic interval in Ontario, Canada: a population-based study.

BACKGROUND: Protracted times to diagnosis of cancer can lead to increased patient anxiety, and in some cases, disease progression and worse outcomes. This study assessed the time to diagnosis for melanoma, and its variability, according to patient-, disease-, and system-level factors. METHODS: This is a descriptive, cross-sectional study in Ontario, Canada from 2007-2019. We used administrative health data to measure the diagnostic interval (DI)-and its two subintervals-the primary care subinterval (PCI) and specialist care subinterval (SCI). Multivariable quantile regression was used. RESULTS: There were 33,371 melanoma patients. The median DI was 36 days (interquartile range [IQR]: 8-85 days), median PCI 22 days (IQR: 6-54 days), and median SCI 6 days (IQR: 1-42 days). Increasing comorbidity was associated with increasing DI. Residents in the most deprived neighbourhoods and those in rural areas experienced shorter DIs and PCIs, but no differences in SCI. There was substantial variation in the DI and SCI across health regions, but limited differences in the PCI. Finally, patients with a history of non-melanoma skin cancer, and those previously established with a dermatologist experienced significantly longer DI, PCI, and SCI. DISCUSSION: This study found variability in the melanoma DI, notably by system-level factors.

A population-based validation study of the 8th edition UICC/AJCC TNM staging system for cutaneous melanoma.

BACKGROUND: The 8th edition UICC/AJCC TNM8 (Tumour, Nodes, Metastasis) melanoma staging system introduced several modifications from the 7th edition (TNM7), resulting in changes in survival and subgroup composition. We set out to address the limited validation of TNM8 (stages I-IV) in large population-based datasets. METHODS: This retrospective cohort-study included 6,414 patients from the population-based Ontario Cancer Registry diagnosed with cutaneous melanoma between January 1, 2007 and December 31, 2012. Kaplan-Meier curves estimated the melanoma-specific survival (MSS) and overall survival (OS). Cox proportional hazard models were used to estimate adjusted hazard ratios for MSS and OS across stage groups. The Schemper-Henderson measure was used to assess the variance explained in the Cox regression. RESULTS: In our sample, 21.3% of patients were reclassified with TNM8 from TNM7; reclassifications in stage II were uncommon, and 44.1% of patients in stage III were reclassified to a higher subgroup. Minimal changes in MSS curves were observed between editions, but the stage IIB curve decreased and the stage IIIC curve increased. For TNM8, Stage I (n = 4,556), II (n = 1,206), III (n = 598), and IV (n = 54) had an estimated 5-year MSS of 98.4%, 82.5%, 66.4%, and 14.4%, respectively. Within stage III, IIIA 5-year MSS was 91.7% while stage IIID was 23.5%. HRs indicated that TNM8 more evenly separates subgroups once adjusted for patient- and disease-characteristics. The variance in MSS explained by TNM7 and TNM8 is 18.9% and 19.7%, respectively. CONCLUSION: TNM8 performed well in our sample, with more even separation of stage subgroups and a modest improvement in predictive ability compared to TNM7.

Economic burden of food allergy in Canada: Estimating costs and identifying determinants.

BACKGROUND: Limited data exist on the economic burden of food allergy (FA). OBJECTIVE: To assess FA-related direct (healthcare and out-of-pocket) and indirect (lost productivity) costs and their determinants in Canadian children and adults self-reporting FA. METHODS: FA-individuals self-reporting a convincing history or physician diagnosis were recruited through FA registries, an anaphylaxis registry, and advocacy associations, and electronically surveyed regarding FA-related healthcare use, out-of-pocket expenditures, and time lost from paid and unpaid labor. Direct and indirect costs (2020 Canadian dollars [CAD]) were stratified on severe reaction vs mild, moderate or no reaction, and children vs adults; multivariate regressions assessed the association between costs and sociodemographic and disease characteristics. RESULTS: Between May 2018 and July 2019, 2692 eligible individuals responded (2189 convincing history and 503 physician diagnosis only); 1020 experienced a severe reaction; 1752 were children. Per FA-individual, annual healthcare, out-of-pocket, and indirect costs were $1267, $2136, and $7950. Those with a severe reaction had higher healthcare and out-of-pocket costs than those with mild, moderate or no reaction. FA-children vs FA-adults had higher healthcare and out-of-pocket costs, and lower indirect costs. Multivariate results showed that lower age, a severe reaction ever, multiple FAs, and fair or poor general health were associated with higher healthcare and out-of-pocket costs. Higher age, lower household education and income, and fair or poor general health were associated with higher indirect costs. CONCLUSION: The economic burden of FA in Canada is substantial, particularly for those with a severe reaction ever, multiple FAs, and fair or poor general health. It is crucial that those most adversely affected are allocated appropriate resources to support disease management.

It is no skin off my nose: The relationship between the skin and allergic rhinitis.

OBJECTIVE: Evidence supports the relationship between the skin barrier and allergic conditions. This narrative review evaluates what role the cutaneous barrier may play in the pathogenesis, disease course, and management of allergic rhinitis (AR). DATA SOURCES: A literature review of the MEDLINE (PubMed), Embase, Cochrane, and SCOPUS Sciverse databases was conducted to identify available evidence. Reference lists of pertinent papers were searched using a snowball technique. STUDY SELECTIONS: Papers published in English from all years until December 2020 were included. Papers that did not address the relationship between AR and the skin and hypothesis papers were excluded. RESULTS: The cutaneous barrier shares histologic characteristics with the sinonasal epithelial barrier, which may explain commonalities between AR and atopic dermatitis. A disruption in the epithelial barrier could be a common pathway in the development of multiple allergic conditions. The skin is a common target for the treatment of AR. Available data that look at the relationship between the skin and AR often include other topics such as other atopic disorders and the role of the epithelial barrier. Increased understanding of how the cutaneous barrier affects AR may lead to new innovations in its management. CONCLUSION: The connection between the cutaneous barrier and AR holds possibilities for further investigation, and these may lead to a better understanding and future innovations for all atopic diseases.

Impact of the COVID-19 pandemic on skin cancer diagnosis: A population-based study.

BACKGROUND: The COVID-19 pandemic has been unprecedented and has led to drastic reductions in non-urgent medical visits. Deferral of these visits may have critical health impact, including delayed diagnosis for melanoma and other skin cancers. We examined the influence of the pandemic on skin biopsy rates in a large population-based cohort. METHODS: Using a universal health care claims dataset from Ontario, we examined skin biopsies from January 6, 2020 to September 27, 2020, and compared these to the same period for 2019. Those diagnosed with anogenital cancers, younger than 20 years, residing out-of-province and with lapses in coverage were excluded. The sensitivity and specificity of claims diagnoses compared to a validated algorithm to identify keratinocyte carcinoma (KC), or to the cancer registry for melanoma was evaluated. Factors associated with biopsy during the early pandemic were investigated with modified Poisson regression. RESULTS: A precipitous drop in total skin biopsies (15% of expected), biopsies for KC (18%) and melanoma (27%) was seen with the onset of COVID-19 cases (p<0.01). Claims diagnoses were of high specificity for KC (99%), and for melanoma (98%), though sensitivity was less (61%, 28% respectively). In adjusted analysis, the elderly (80+ years), females and residents of certain regions were less likely to be biopsied during the pandemic. Subsequently, there were substantial improvements in biopsy rates over 10 weeks. However, compared to 2019, a large backlog of expected cases still remained 28 weeks after lockdown (45,710 all biopsy, 9,104 KC, 595 melanoma). INTERPRETATION: A drastic reduction in skin biopsies is noted early in the COVID-19 pandemic; this disproportionately affected the elderly, females and certain geographic regions. Though biopsies subsequently increased, a large backlog of cases remained after almost half a year. This will have implications for downstream care of skin cancer. Efforts should be made to limit diagnostic delay.

Filaggrin expression via immunohistochemistry in basal cell carcinoma and squamous cell carcinoma.

BACKGROUND: Filaggrin is a protein integral to the structure and function of the epidermis. Filaggrin (FLG) loss-of-function (LOF) mutations are common and increase the risk of developing atopic dermatitis (AD) and ichthyosis vulgaris (IV). Epidemiologic data suggest a link between skin cancer and AD. We examined if FLG staining pattern can be used to characterize cutaneous squamous cell carcinomas (SCC), basal cell carcinomas (BCC), and reactive squamous epithelium. METHODS: Tissue microarrays (TMAs) were created from 196 cases of formalin-fixed paraffin-embedded (FFPE) SCC and 144 BCC cases. TMAs and sections of reactive squamous epithelium were stained with optimized anti-FLG antibody and evaluated for FLG expression (normal, abnormal, or negative). RESULTS: FLG was absent in poorly differentiated (PD) compared to well-differentiated (WD) SCC (P < .0001) and moderately-differentiated (MD) (P = .0231) SCC, and in MD compared to WD SCC (P = .0099). Abnormal staining was significantly increased in PD compared to WD cases (P = .0039) and in MD compared to WD cases (P = .0006). Most BCC did not exhibit FLG expression (P < .05). Reactive squamous epithelium demonstrated normal, but exaggerated FLG expression. CONCLUSIONS: Our findings demonstrate the differences in FLG expression patterns in types of keratinocyte carcinomas and their mimickers.

Systematic Review of Interventions to Increase Awareness of Ultraviolet Radiation-Induced Harm and Protective Behaviors in Post-Secondary School Adults.

College and university students are a group known for excessive sun exposure and indoor tanning. Health education campaigns for avoidance of ultraviolet (UV) radiation have been relatively unsuccessful in this population. This systematic review examines interventions aimed at post-secondary school young adults on college and university campuses for skin cancer awareness, photoprotection, and change in UV-exposure-related behavior. Fifty-nine studies were identified for inclusion according to predetermined criteria. Study heterogeneity was high; methods of intervention were individual or group-based, and were mostly visually delivered and/or passive learning. Most interventions occurred at a single time point. Intervention success was assessed by evaluating subject behavior, intention, attitudes, knowledge, and emotion. Multicomponent interventions, generally consisting of UV photography and a passively delivered educational component, may be more effective than a single component alone. Overall, study quality was poor. Sample size of the majority of studies was <150 subjects. Most studies used self-report of behavior and had a short follow-up time. Generalizability of findings may be impacted as women, particularly white/Caucasian women, were overrepresented in the studies identified by this systematic review. For this specific target population, themes arising from the review include the importance of self-relevance and message framing. Self-affirmation was identified as a potential challenge in designing interventions for this target group, which can lead to defensiveness and a negative reaction to the health message. The findings of this systematic review may inform future research in this field, as well as guide planning of effective interventions in this target population.

Filaggrin gene loss-of-function mutations constitute a factor in patients with multiple contact allergies.

BACKGROUND: Polysensitivity is defined as three or more positive patch test reactions. The role of filaggrin gene (FLG) loss-of-function mutations in patients with polysensitivity has not been studied when barrier bypass and possible preceding barrier damage have been excluded. OBJECTIVES: To determine whether FLG loss of function mutations play a role in patients with multiple contact sensitivities when barrier bypass is excluded. METHODS: One hundred and sixty-nine patients with three or more, non-cross-reacting, positive patch test reactions were prospectively enrolled in this study. Exclusion criteria were a history of hand dermatitis, nickel and metal implants, and stasis dermatitis. Subjects were patch tested with the North American extended patch test series, and with other relevant haptens. DNA was obtained and sequenced for the following FLG loss-of-function mutations: R501X, 2282del4, R2447X, and S3247X. RESULTS: One hundred and sixty-five patients were genotyped for the four FLG mutations. There was a significant association between R501X mutation and polysensitivity. For the other three tested mutations, there were no significant associations with polysensitivity. When all mutations were combined, there was a significant association between loss-of-function FLG mutations and polysensitivity in patients with a history of atopic dermatitis. CONCLUSION: When skin barrier bypass is excluded, there is a significant association between polysensitivity and FLG loss-of-function mutations.

Disparities in diagnosis of advanced melanoma: a population-based cohort study.

BACKGROUND: International studies have observed inequities in stage at diagnosis of melanoma. As this has not been sufficiently studied in Canada, the purpose of this study was to investigate whether there are disparities in the diagnosis of advanced-thickness melanoma in the province of Ontario. METHODS: In this retrospective population-based cohort study, we obtained, abstracted and linked pathology reports for a 65% random sample of all cases of invasive cutaneous melanoma in Ontario from 2007 to 2012 in the Ontario Cancer Registry. Cases without pathology reports or with unreported thickness were excluded from the primary analysis. Associations between advanced melanoma (thickness > 2.0 mm) and patient, health-system and tumour factors were described and analyzed using multivariable modified Poisson regression. RESULTS: In total, 8042 patients had histologically confirmed melanoma and thickness information. Of these, 46.7% (n = 3755) were female, the median age at diagnosis was 62 years and 25.7% (n = 2069) had advanced melanoma. In multivariate analyses, advanced age (relative risk [RR] 1.53; 95% confidence interval [CI] 1.37-1.72), male sex (RR 1.12, 95% CI 1.05-1.20), lowest socioeconomic status quintile (RR 1.24; 95% CI 1.12-1.38) and health region (RR range 0.92-1.34, p = 0.005 for variable) were significantly associated with advanced melanoma. Presence of ulceration significantly modified many of these associations. INTERPRETATION: Disparate rates of advanced melanoma according to patient and health system factors suggest there may be inequitable access to timely diagnosis of melanoma in Ontario. This highlights a potential opportunity for system improvement to ensure timely and equitable access to melanoma care.

Brief Report: Increase in Melanoma Incidence in Ontario.

BACKGROUND: Melanoma is a serious, potentially lethal disease. It is one of very few common cancers whose incidence is rising in North America. OBJECTIVES: The objective of this study was to examine trends in melanoma incidence in Ontario, Canada's most populous province, over the past 20 years. METHODS: Using data from the Ontario Cancer Registry (OCR), this retrospective cohort examined all incident cases of melanoma in Ontario from 1990 to 2012. Generalized linear modeling was used to evaluate changes in melanoma incidence over time, adjusting for age and sex using direct standardization with the 1991 Canadian census population. Tests for trend for changes in the distribution of cases by age, sex, socioeconomic status, and rurality status were also calculated. RESULTS: Our results show a statistically significant increasing incidence of melanoma in Ontario from 9.3 cases per 100 000 in 1990 to 18.0 cases per 100 000 in 2012 ( P for trend <.001, adjusted for age and sex). Incidence rates show stabilization from 2010 to 2012. CONCLUSION: Our study reveals a marked increase in melanoma incidence in Ontario, more than doubling over the past 20 years but with a stabilization more recently. Adequate availability of dermatology services may be important to ensure satisfactory care for the increased caseload and to ensure that cases may detected at an early stage with a good prognosis.

Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes C11orf30/EMSY as a genetic risk factor for food allergy.

BACKGROUND: Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously, PA loci were identified in filaggrin (FLG) and HLA in candidate gene studies, and loci in HLA were identified in a genome-wide association study and meta-analysis. OBJECTIVE: We sought to investigate genetic susceptibility to PA. METHODS: Eight hundred fifty cases and 926 hyper-control subjects and more than 7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. A meta-analysis of 2 phenotypes (PA and food allergy) was conducted by using 7 studies from the Canadian, American (n = 2), Australian, German, and Dutch (n = 2) populations. RESULTS: An SNP near integrin α6 (ITGA6) reached genome-wide significance with PA (P = 1.80 × 10-8), whereas SNPs associated with Src kinase-associated phosphoprotein 1 (SKAP1), matrix metallopeptidase 12 (MMP12)/MMP13, catenin α3 (CTNNA3), rho GTPase-activating protein 24 (ARHGAP24), angiopoietin 4 (ANGPT4), chromosome 11 open reading frame (C11orf30/EMSY), and exocyst complex component 4 (EXOC4) reached a threshold suggestive of association (P ≤ 1.49 × 10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, C11orf30, and EXOC4 were significant (P ≤ 1.49 × 10-6). When a phenotype of any food allergy was used for meta-analysis, the C11orf30 locus reached genome-wide significance (P = 7.50 × 10-11), whereas SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, and EXOC4 and additional C11orf30 SNPs were suggestive (P ≤ 1.49 × 10-6). Functional annotation indicated that SKAP1 regulates expression of CBX1, which colocalizes with the EMSY protein coded by C11orf30. CONCLUSION: This study identifies multiple novel loci as risk factors for PA and food allergy and establishes C11orf30 as a risk locus for both PA and food allergy. Multiple genes (C11orf30/EMSY, SKAP1, and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.

The Risk of Recurrent Anaphylaxis.

OBJECTIVES: To determine the recurrence rate of anaphylaxis in children medically attended in an emergency department (ED), we performed a prospective cohort study to evaluate prehospital and ED management of children with recurrent anaphylaxis and to assess factors associated with recurrent anaphylaxis. STUDY DESIGN: As part of the Cross-Canada Anaphylaxis Registry, parents of children with anaphylaxis identified prospectively in 3 EDs and through an emergency medical response service were contacted annually after presentation and queried on subsequent reactions. Cox regression analysis determined factors associated with recurrence. RESULTS: Among 292 children who were registered as having had medical attended anaphylaxis, 68.5% completed annual follow-up questionnaires. Forty-seven patients experienced 65 episodes of anaphylaxis during 369 patient-years of follow-up. Food was the trigger in 84.6% of cases, and epinephrine was used in 66.2%. In 50.8%, epinephrine was used outside the health care facility, and 81.7% were brought to a health care facility for treatment. Asthma, reaction triggered by food, and use of epinephrine during the index episode increased the odds of recurrent reaction. Patients whose initial reaction was triggered by peanut were less likely to have a recurrent reaction. CONCLUSIONS: We report a yearly anaphylaxis recurrence rate of 17.6% in children. There is substantial underuse of epinephrine in cases of anaphylaxis. Educational programs that promote effective avoidance strategies and prompt use of epinephrine are required.