Cochrane has been a trusted proponent of evidence-based medicine for over 20 years. Its dermatology-specific editorial team (Cochrane Skin Review Group) is the pre-eminent source of systematic reviews in dermatology . Explicit standardized Cochrane review methods can minimize bias and maximize the reliability of reported outcomes, establishing benchmarks for decision-making. Mortality is one outcome where pronounced heterogeneity in reporting may affect its utility in clinical research. We therefore explored mortality outcome expression and execution in the Cochrane Skin portfolio and concurrently analyzed mortality in core outcome sets (outcomes that, at a minimum, should be measured in clinical trials) by searching dermatology studies registered in the COMET (Core Outcome Measures in Effectiveness Trials) database [ ]. COMET contains text from core outcome sets publications, from which we extracted core outcomes and classified these according to the taxonomy developed by Dodd et al [ ] for validated standardized annotation.
All Cochrane Skin Group reviews as of March 2021 were included and exported from the Cochrane Database of Systematic Reviews , allowing descriptive analysis and characterization of mortality reporting by category of mortality terminology (all-cause, cause-specific, infant/maternal, survival). All COMET database core outcome sets classified in the published “skin” research category as of August 23, 2021, were reviewed for reporting of mortality outcomes and categorized according to the mortality terminology previously described. Core outcomes specified in terms of “death” were included in the all-cause mortality category.
Of the 113 Cochrane Skin dermatology reviews, 13 reported mortalities as an outcome measure: 10 all-cause, 2 cause-specific, 5 survival, and 1 infant/maternal ().
Four reviews (4/13) reported more than one mortality outcome. More than one-third of the total reviews (5/13) were melanoma-related. Reviews of other dermatologic conditions reporting mortality included cutaneous squamous cell carcinoma (cSCC), nonmelanoma skin cancer, pemphigus vulgaris, pemphigus foliaceus, bullous pemphigoid, toxic epidermal necrolysis (TEN), necrotizing fasciitis, drug-induced skin rash, and topical steroids used during pregnancy. The time frame of mortality outcome reporting ranged widely, from 10 days to 10 years, but generally correlated appropriately with the condition (eg, 30 days for TEN capturing acute onset and progression vs 10-year survival for melanoma).
COMET database searches revealed 13 core outcome set studies of 13 skin conditions (); only 2 (15%) included mortality as a core outcome (survival for head and neck lymphatic malformations, death from cSCC).
|Condition||Cochrane Systematic Review title||Authors||Year||DOI||PMID||Type of mortality reported||Time frame of mortality reporting|
|Toxic epidermal necrolysis||Interventions for Toxic Epidermal Necrolysis||Majumdar S, Mockenhaupt M, Roujeau J, Townshend A||2002||10.1002/14651858.CD001435||12519556||All-cause mortality||30-day follow-up time|
|Melanoma||Statins and Fibrates for Preventing Melanoma||Dellavalle RP, Drake A, Graber M, Heilig LF, Hester EJ, Johnson KR, McNealy K, Schilling L||2005||10.1002/14651858.CD003697.pub2||16235336||Disease-specific||≥7 years post-RCTa|
|Nonmelanoma skin cancers||Interventions for Preventing Nonmelanoma Skin Cancers in High-Risk Groups||Bath-Hextall F, Leonardi-Bee J, Somchand N, Webster A, Delitt J, Perkins W||2007||10.1002/14651858.CD005414.pub2||17943854||All-cause mortality||End of trial follow-up (1 year to 5 years for included RCTs)|
|Pemphigus vulgaris and pemphigus foliaceus||Interventions for Pemphigus Vulgaris and Pemphigus Foliaceus||Martin LK, Agero AL, Werth V, Villanueva E, Segall J, Murrell DF||2009||10.1002/14651858.CD006263.pub2||19160272||All-cause mortality||Variable, deaths only reported from 1 RCT over 4 weeks|
|Melanoma||Surgical Excision Margins for Primary Cutaneous Melanoma||Sladden MJ, Balch C, Barzilai DA, Berg D, Freiman A, Handiside T, Hollis S, Lens MB, Thompson JF||2009||10.1002/14651858.CD004835.pub2||19821334||All-cause mortality, survival, recurrence-free survival||5- and 10-year survival|
|Bullous pemphigoid||Interventions for Bullous Pemphigoid||Kirtschig G, Middleton P, Bennett C, Murrell DF, Wojnarowska F, Khumalo NP||2010||10.1002/14651858.CD002292.pub3||20927731||All-cause mortality||51 days (1 RCT), 10 days (1 RCT), 6 months and 3 years (1 RCT)|
|Cutaneous squamous cell carcinoma||Interventions for Nonmetastatic Squamous Cell Carcinoma of the Skin||Lansbury L, Leonardi-Bee J, Perkins W, Goodacre T, Tweed JA, Bath-Hextall FJ||2010||10.1002/14651858.CD007869.pub2||20393962||All-cause mortality||2 years|
|Melanoma||Interferon Alpha for the Adjuvant Treatment of Cutaneous Melanoma||Mocellin S, Lens MB, Pasquali S, Pilati P, Chiarion Sileni V||2013||10.1002/14651858.CD008955.pub2||23775773||Death, disease-free survival, overall survival||5 years|
|Melanoma||Sentinel Lymph Node Biopsy Followed by Lymph Node Dissection for Localized Primary Cutaneous Melanoma||Kyrgidis A, Tzellos T, Mocellin S, Apalla Z, Lallas A, Pilati P, Stratigos A||2015||10.1002/14651858.CD010307.pub2||25978975||All-cause mortality, disease-specific, disease-free survival||10 years|
|Pregnancy||Safety of Topical Corticosteroids in Pregnancy||Chi CC, Wang SH, Wojnarowska F, Kirtschig G, Davies E, Bennett C||2015||10.1002/14651858.CD007346.pub3||26497573||Fetal death||Not specified, variable|
|Necrotizing soft tissue infections||Interventions for Necrotizing Soft Tissue Infections in Adults||Hua C, Bosc R, Sbidian E, De Prost N, Hughes C, Jabre P, Chosidow O, Le Cleach L||2018||10.1002/14651858.CD011680.pub2||29851032||Mortality, survival||30-day mortality, 28-day and 30-day study periods for survival|
|Melanoma||Systemic Treatments for Metastatic Cutaneous Melanoma||Pasquali S, Hadjinicolaou AV, Chiarion Sileni V, Rossi CR, Mocellin S||2018||10.1002/14651858.CD011123.pub2||29405038||Overall survival, progression-free survival||1 year|
|Severe drug‐induced skin rash||Genetic Testing for Prevention of Severe Drug‐Induced Skin Rash||Alfirevic A, Pirmohamed M, Marinovic B, Harcourt-Smith L, Jorgensen AL, Cooper TE||2019||10.1002/14651858.CD010891.pub2||31314143||All-cause mortality||12-month follow-up post rash|
aRCT: randomized controlled trial.
|Condition||Study title||Authors||Year||URL||DOI||Mortality as an outcome (yes/no)||Type of mortality reported|
|Acne||Identifying What to Measure in Acne Clinical Trials: First Steps Towards Development of a Core Outcome Set||Layton AM, et al||2017||http://www.comet-initiative.org/Studies/Details/1221||http://dx.doi.org/10.1016/j.jid.2017.04.017||No||N/Aa|
|Actinic keratosis||Core Outcome Set for Actinic Keratosis Clinical Trials||Reynolds KA, et al||2019||http://www.comet-initiative.org/Studies/Details/756||http://dx.doi.org/10.1001/jamadermatol.2019.4212||No||N/A|
|Cutaneous leishmaniasis||Harmonized Clinical Trial Methodologies for Localized Cutaneous Leishmaniasis and Potential for Extensive Network With Capacities for Clinical Evaluation||Olliaro P, et al||2018||http://www.comet-initiative.org/Studies/Details/1455||https://doi.org/10.1371/journal.pntd.0006141||No||N/A|
|Eczema||Core Outcome Domains for Controlled Trials and Clinical Recordkeeping in Eczema: International Multiperspective Delphi Consensus Process||Schmitt J, et al||2011||https://www.comet-initiative.org/Studies/Details/90||http://dx.doi.org/doi:10.1038/jid.2010.303||No||N/A|
|Head and neck lymphatic malformation||Standardized Outcome and Reporting Measures in Pediatric Head and Neck Lymphatic Malformations||Balakrishnan K, et al||2015||http://www.comet-initiative.org/Studies/Details/894||https://doi.org/10.1177/0194599815577602||Yes||Death|
|Hidradenitis suppurativa||A Core Domain Set for Hidradenitis Suppurativa Trial Outcomes: An International Delphi Process||Thorlacius L, et al||2018||http://www.comet-initiative.org/Studies/Details/934||http://dx.doi.org/10.1111/bjd.16672||No||N/A|
|Incontinence-associated dermatitis||Core Outcome Domains in Incontinence-Associated Dermatitis Research||Van den Bussche K, et al||2018||http://www.comet-initiative.org/Studies/Details/383||http://dx.doi.org/10.1111/jan.13562||No||N/A|
|Psoriasis||Identifying a Core Domain Set to Assess Psoriasis in Clinical Trials||Callis Duffin K, et al||2018||http://www.comet-initiative.org/Studies/Details/1464||Not available||No||N/A|
|Skin cancer||Development of a Core Outcome Set for Cutaneous Squamous Cell Carcinoma Trials: Identification of Core Domains and Outcomes||Reynolds KA, et al||2020||http://www.comet-initiative.org/Studies/Details/864||http://dx.doi.org/10.1111/bjd.19693||Yes||Progression-free survival, recurrence-free survival, disease-specific survival|
|Vascular malformations||Development of an International Core Outcome Set for Peripheral Vascular Malformations (OVAMA Project)||Horbach SER, et al||2018||http://www.comet-initiative.org/Studies/Details/767||http://dx.doi.org/10.1111/bjd.16029||No||N/A|
|Vasculitis (small-vessel/ ANCAb-associated)||Clinicians’ Perspective on Key Domains in ANCA-Associated Vasculitis: a Delphi Exercise||Milman N, et al||2017||http://www.comet-initiative.org/Studies/Details/1041||http://dx.doi.org/10.1080/03009742.2016.1188980||No||Death discussed (from OMERACTc, to which this study adds—but was not directly included in this study)|
|Vitiligo||Developing Core Outcome Set for Vitiligo Clinical Trials: International e-Delphi Consensus||Eleftheriadou V, et al||2015||http://www.comet-initiative.org/Studies/Details/357||http://dx.doi.org/10.1111/pcmr.12354||No||N/A|
|Vulval skin disorders||Outcome Measures for Vulval Skin Conditions: a Systematic Review of Randomised Controlled Trials||Simpson R, et al||2013||https://www.comet-initiative.org/Studies/Details/271||http://dx.doi.org/DOI:%2010.1111/bjd.12391||No||N/A|
aN/A: not applicable.
bANCA: antineutrophil cytoplasmic autoantibody.
cOMERACT: Outcome Measures in Rheumatoid Arthritis Clinical Trials.
Although limited in the number of studies appraised, our results illustrate substantial variability in the reporting and timing of mortality outcomes in Cochrane Skin reviews and COMET dermatology-related core outcome sets. Allowance of potentially unclear metrics (eg, “death”) and fluctuations in the time frame considered (especially within studies of a particular disease) may be detrimental to the downstream harmonization and generalizability of research findings. Guidelines to assist researchers during trial design and registration would encourage the selection of clear metrics and facilitate consistent outcome reporting at the later stages. Increased guidance and communication among stakeholders in this area, including further refinement of reporting guideline statements such as CONSORT (Consolidated Standards of Reporting Trials)  and PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [ ], could promote much-needed standardization in mortality reporting, facilitating comparison across studies and helping decision makers effectively use dermatology research.
The authors wish to acknowledge Eve Tomlinson, Jordi Pardo, Susanna Dodd, Nicole Skoetz, and George Wells, whose contributions to a Cochrane health equity priority-setting pilot exercise laid the foundation for examining mortality outcomes across the entire Cochrane Library and provided the impetus for this smaller scale study of dermatology-related Cochrane reviews and core outcome sets.
Conflicts of Interest
RPD is Editor in Chief of the JMIR Dermatology, a Joint Coordinating Editor for Cochrane Skin, a dermatology section editor for UpToDate, a Social Media Editor for the Journal of the American Academy of Dermatology (JAAD), and a Podcast Editor for the Journal of Investigative Dermatology (JID). He is a coordinating Editor Representative on Cochrane Council. TES is an Editorial Board Member-at-Large for JMIR Dermatology. RPD receives editorial stipends (JAAD, JID), royalties (UpToDate), and expense reimbursement from Cochrane Skin. TES receives fellowship funding from the Pfizer Global Medical Grant (58858477) Dermatology Fellowship 2020 (principal investigator RPD), and fees for serving as a Medical Advisor and Investigator for Antedotum Inc. MDS is a member of the Cochrane Collaboration.
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|COMET: Core Outcome Measures in Effectiveness Trials|
|CONSORT: Consolidated Standards of Reporting Trials|
|cSCC: cutaneous squamous cell carcinoma|
|JAAD: Journal of the American Academy of Dermatology|
|JID: Journal of Investigative Dermatology|
|PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses|
|TEN: toxic epidermal necrolysis|
Edited by G Eysenbach; submitted 07.10.21; peer-reviewed by F Beyer, M Mahmic Kaknjo; comments to author 10.12.21; revised version received 17.12.21; accepted 20.12.21; published 01.02.22Copyright
©Torunn E Sivesind, Mindy D Szeto, Shahzeb Hassan, Peter Tugwell, Robert P Dellavalle. Originally published in JMIR Dermatology (http://derma.jmir.org), 01.02.2022.
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