The efficacy of off-label use dupilumab in dermatology: a systematic review
Creators: name: Wan, Vincent
Publisher: name: Open Science Framework
Year: 2022
Subjects: subject: Dermatology
subject: Medicine and Health Sciences
subject: Medical Specialties
subject: dermatology
subject: dupilumab
subject: dupixent
subject: IL4Ra antagonist
subject: off-label

description: The efficacy of off-label use dupilumab in dermatology: a systematic review Version 1.0 Review Question: This systematic review is designed to evaluate the efficacy of the off-label use of dupilumab for dermatological conditions. Searches: Relevant studies will be identified via a systematic search of bibliographic databases, including Medline, EMBASE, CINAHL, Web of Science, and SCOPUS. The search string “dupilumab OR dupixent” was used on April 22, 2022 for the search. Adaptations to the search string were made to fit each database where necessary. The search strategy was peer-reviewed by an expert health librarian (VK). No studies will be excluded on the basis of language or publication status. Studies on both adult and pediatric population are eligible for inclusion. Articles in languages other than English will be translated either by a team member fluent in the language, professional interpreter or through use of Google translate if the former options are unavailable. A grey literature search will be conducted using the following methods:  A search of clinical trials registries, i.e., Cochrane Central Register of Controlled Trials (CENTRAL).  Google Scholar web search.  Backwards reference searching from included studies will be examined for further review. Types of studies to be included: Experimental studies, observational studies, randomized and non-randomized trials, case studies/reports or case series are all eligible for inclusion if they contain primary data. Pure review articles will be excluded. Condition or domain being studied: Dupilumab is a monoclonal antibody that binds the IL-4 receptor subunit alpha and inhibits IL-4 and IL-13 signalling.1 As dupilumab targets the Th2 pathway, it is currently FDA approved for atopic dermatitis (AD), asthma, and chronic rhinosinusitis with nasal polyposis2. Due to its high level of efficacy, low risk, and absence of black box labeling, dupilumab has become a commonly used medication, with over 200,000 prescriptions for atopic dermatitis. Given its favorable benefit to risk ratio, it has been used and shown promise in other type 2 inflammatory dermatological conditions that have been resistant to standard treatment. A systematic review was conducted in 2019 which assembled cases of off-label use in prurigo nodularis, chronic pruritis, allergic contact dermatitis, chronic hand eczema, etc.3 Since that study, there has been a large increase in publications that have demonstrated the potential benefit using off-label dupilumab in the treatment of various other dermatological conditions such as Hailey-Hailey disease,4 Kimura disease,5 and Grover’s disease.6 More data has also come to light to support the preliminary findings of the previous systematic review. Given the potential therapeutic benefit of dupilumab in such a wide range of inflammatory dermatological disorders, it is important that dermatologists have a better understanding of the efficacy and safety profiles within contexts outside of AD. In this study, the goal is to systematically review the literature and assess the levels of evidence available in off-label uses of dupilumab in order to better characterize the efficacy of dupilumab in the treatment of inflammatory dermatological disorders. Participants/population: Studies which examine the off-label use of dupilumab to treat any dermatological condition will be considered for inclusion. Off-label use for AD under the age of 6 will not be considered for inclusion during screening. There is no limit on patient characteristics including age, gender, skin phototypes, and ethnicities. Intervention(s), exposure(s): The intervention of interest for this systematic review is dupilumab. Studies that utilize a combination of dupilumab with other pharmacological therapies will be considered. Comparator(s)/control: Studies that will be considered for inclusion may or may not have a control group. In addition, studies do not need to have a control group to be considered for inclusion. Context: N/A Main outcome(s): The primary outcomes for this review are: 1. The primary off-label indication in dermatology for treatment of dupilumab (e.g., diagnoses) 2. Treatment regime of dupilumab (e.g., dosage, frequency of treatments) 3. Previously refractive history of disease (duration, pharmacologic therapy) 4. Remission rate or change in clinical severity of symptoms with clinical photographs or any clinical rating scales including when appropriate: a. Clinician-reported measures; b. Patient reported outcome measures of severity, impairment, etc.; c. Labs, radiology, or tissue specimens that record improvement or lack thereof, etc. 5. Documentation of any ocular adverse drug reactions (e.g., conjunctivitis) Data extraction (selection and coding): The identification of studies will involve a two-step process that uses four independent reviewers. Firstly, two independent reviewers will review the literature searches to identify all potentially relevant studies for full review from the title, abstract, and descriptors. Disagreement will be resolved by adjudication by a third-party. Secondly, a standardized form with pre-defined inclusion/exclusion criteria will be developed based on the research question and scope. Two independent reviewers will review the full text of potentially relevant studies using the standardized form to remove articles that do not fit the inclusion criteria. Disagreement will be resolved by discussion or third-party adjudication with documentation of reasons for exclusion. Inclusion criteria: 1. Use of dupilumab or dupilumab in combination with other treatment 2. Use of dupilumab in the treatment of dermatological conditions 3. Observational or experimental studies Exclusion criteria: 1. Studies without any primary data 2. Unspecified regimen/dose of dupilumab 3. Lack of reported outcome 4. Use of dupilumab for the treatment of moderate-severe atopic dermatitis without any concurrent dermatological diagnosis. Risk of bias (quality) assessment: For intervention studies that used a randomized study design, risk of bias will be assessed using the Cochrane Handbook’s risk of bias (RoB) tool. For non-randomized studies, risk of bias assessment will be completed using the Newcastle-Ottawa Scale (NOS). For case series and reports, the JBI critical appraisal checklist will be used. Two reviewers will independently complete the assessment of the included studies. Disagreements in the risk of bias scoring will be resolved by consensus or third-party adjudication. Strategy for data synthesis: Studies will be grouped by dermatological condition and further stratified by level of evidence. With the same skin condition and similar dupilumab treatment regimen, studies will be pooled given that the research team has judged that heterogeneity is sufficiently low. Statistical analysis for the data will be performed using SPSS statistical software and RevMan, Version 5.3 (if the interventions can be pooled). Meta-analysis will be performed if appropriate. Descriptive data will be reported using proportions, and means with standard deviations (SD) or medians with interquartile range (IQR) as appropriate. Pooled statistics for dichotomous variables will be calculated as relative risks (RR) with 95% confidence intervals (CI) using a random effect model. For continuous outcomes, individual trial results will be reported using mean differences (MD) or standardized mean differences (SMD) and pooled results as weighted mean differences (WMD) with 95% CIs using a random effects model. The weights given to each study in the pooled analysis will be based on the inverse variance method. Heterogeneity between studies will be examined using Q and I2. A Q statistic will be employed to provide a test of statistical significance indicating whether the differences in effects sizes are due to subject-level sampling error alone or other sources. As for I2, as a generic metric, I2 values of 25% indicate low heterogeneity, 50% indicate moderate heterogeneity, and 75% indicate high levels of heterogeneity. Analysis of subgroups or subsets: Each dermatological condition will be stratified by level of evidence (e.g., case report, randomized trial, etc.) and analyzed separately where possible. Contact details for further information: Dr. David Rosmarin DRosmarin@tuftsmedicalcenter.org Organisational affiliation of the review: University of British Columbia Tufts University School of Medicine Review team members and their organisational affiliations: Vincent Wan, University of British Columbia Jeffrey Toy, University of British Columbia Kaiyang Li, McGill University Dr. Harry (Chaocheng) Liu, University of British Columbia Dr. David Rosmarin, Tufts University Acknowledgement: Vanessa Kitchin – expert health librarian Qian (Tracy) Zhang – biostatistical analyst Type and method of review: Systematic review (intervention) Anticipated or actual start date: May 1, 2022 Anticipated completion date: Oct 1, 2022 Funding sources/sponsors: None Conflicts of interest: None Language: English Country: USA Subject index terms: Dupilumab, dupixent, monoclonal antibody, inflammatory dermatosis, dermatology, safety, efficacy, hand eczema, allergic contact dermatitis, chronic idiopathic pruritus, prurigo nodularis, chronic spontaneous urticaria, HIV, bullous pemphigoid, pemphigus vulgarus, EB prurignosa, Hailey-Hailey, Kimura Disease, perforating collagenosis, Job syndrome, Netherton Syndrome, alopecia areata, Grover’s disease, psoriasis. Details of any existing review of the same topic by the same authors None Stage of review at time of submission: The search strategies are currently being developed. References: 1. Harb H, Chatila TA. Mechanisms of Dupilumab. Clinical and experimental allergy. 2020;2019;50:5-14. 2. Shirley M. Dupilumab: First Global Approval. Drugs (New York, N.Y.). 2017;77:1115-1121. 3. Hendricks AJ, Yosipovitch G, Shi VY. Dupilumab use in dermatologic conditions beyond atopic dermatitis - a systematic review. The Journal of dermatological treatment. 2021;2019;32:19-28. 4. Alzahrani N, Grossman‐Kranseler J, Swali R, et al. Hailey–Hailey disease treated with dupilumab: a case series. British journal of dermatology (1951). 2021;185:680-682. 5. Teraki Y, Terao A. Treatment of Kimura Disease With Dupilumab. JAMA dermatology (Chicago, Ill.). 2022;158:329-330. 6. Butler DC, Kollhoff A, Berger T. Treatment of Grover Disease With Dupilumab. JAMA dermatology (Chicago, Ill.). 2021;157:353-356.