Off-Label Combination Therapies for the Management of Atopic Dermatitis: A Protocol for a Scoping Review

Introduction: Atopic dermatitis (AD) is a chronic, heterogeneous and relapsing inflammatory skin disease that presents a significant global health burden, affecting up to 20% of the paediatric population and 2-10% of adults worldwide.1–3 AD is considered the skin disease with the highest non-fatal health burden due to its profound negative impact on patient quality of life, sleep and mental health.1,4–6 AD is characterised by severe pruritus and xerosis, the pathogenesis of which is multifactorial, including an interplay between genetic predisposition, immune dysregulation with aberrant Th2 responses, skin barrier disruption and cutaneous dysbiosis; each of which may be modulated by environmental factors.2,7 These cytokines play a central role in B-cell maturation, IgE class switching and the down-regulation of essential skin barrier proteins such filaggrin, loricrin and involucrin.8 Current Therapeutic Landscape: The current management of AD follows a step-wise approach based on disease severity.9 For mild forms, the cornerstone of therapy includes trigger avoidance, regular use of emollients to combat xerosis and the application of topical corticosteroids (TCS) or topical calcineurin inhibitors (TCI).9 However, patients with moderate-to-severe disease that remains recalcitrant to topical interventions often require second-line treatments, including phototherapy or systemic immunomodulatory agents.5,9 Historically, systemic options were limited to conventional immunosuppressants such as ciclosporin A (CsA), methotrexate (MTX), azathioprine (AZA) and mycophenolate mofetil (MMF).10,11 Despite extensive clinical experience for use in management of moderate-severe AD, the above therapies are not licensed by the FDA/EMA/Japan for management of moderate to severe AD. Their long-term application is often curtailed by an unfavourable risk-benefit ratio, potential organ toxicity (e.g., nephrotoxicity with CsA or bone-marrow suppression with MTX), and a lack of robust long-term data.10,12 The therapeutic landscape was revolutionised in 2017 with the approval of dupilumab, the first biologic targeting the IL-4 receptor alpha chain to inhibit the signalling of IL-4 and IL-13.13 Since then the therapeutic landscape has expanded to include other biologics such as lebrikizumab, nemolizumab and tralokinumab, as well as oral small molecule drugs such as Janus kinase (JAK) inhibitors (e.g., abrocitinib, baricitinib, and upadacitinib).14 Despite these advancements, a subset of patients, demonstrates an inadequate response or resistance to biologic monotherapy.14,15 The Challenge of Recalcitrant Disease and Off-Label Combinations: In clinical practice, dermatologists often encounter patients whose disease is not adequately controlled by a single systemic agent.16 While phase III clinical trials typically evaluate these drugs as monotherapy (or with limited TCS use), daily practice sometimes involves an off-label combination of systemic therapies.1,3,17 There are two primary clinical scenarios where these combinations occur: 1. Transitioning and tapering: patients starting a new biologic like dupilumab may continue a conventional immunosuppressant (such as CsA) for several weeks to prevent disease flares during the transition period or to induce faster clinical remission.18 2. Rescue therapy: In patients experiencing a lack of response or loss of disease control on biologic monotherapy, a second systemic agent or phototherapy may be added as a "rescue" or ‘combination’ strategy to enhance effectiveness and maintain long-term control.3 Observational data indicate that up to 45% of patients in real-world settings may continue systemic immunosuppressants during the initiation of dupilumab.1 Common combinations reported in the literature include dupilumab paired with methylprednisolone, ciclosporin, methotrexate or azathioprine.3 Rationale for a Scoping Review: Despite the increasing use of combined systemic regimens, there is neither standardized guidelines nor comprehensive evidence mapping regarding their safety and effectiveness.3 Most clinical trials exclude patients with complex histories of multiple systemic failures, meaning trial data may not reflect real-world effectiveness in the most severe patients.1 While some studies suggest that combining dupilumab with conventional drugs can be an effective and safe way to transition to monotherapy or salvage treatment, these findings are often limited by small sample sizes, retrospective designs, and short follow-up durations.1,3 With ongoing expansion of the therapeutic armamentarium for management of moderate-severe AD, this adds further complexity to potential combination strategies.5,7 As such, a scoping review is necessary to map the existing literature on the off-label use of combination systemic therapies for AD. By synthesizing data from available studies, this protocol aims to clarify the evidence base and identify critical research gaps that must be addressed to optimise personalised management for patients with recalcitrant AD. Objective: The primary objective of this scoping review is to identify and map the evidence concerning the off-label use of combination systemic therapies in the treatment of moderate-to-severe atopic dermatitis in adults and children. This review will identify the types of combinations currently utilised, the clinical rationales for their use (e.g., rescue/combination vs. bridging), and the reported outcomes regarding physician-rated severity, patient-reported outcome measures, and safety concerns. Methods and Analysis Search strategy: A comprehensive electronic search of MEDLINE, the Cochrane Library, and Web of Science will be conducted from database inception to January 2026. The search strategy will combine controlled vocabulary (i.e. MeSH terms) and free-text keywords relating to atopic dermatitis and systemic therapies, including but not limited to: systemic therapy, immunosuppressive agent, atopic dermatitis, eczema, methotrexate, cyclosporine, azathioprine, mycophenolate mofetil, abrocitinib, baricitinib, dupilumab, tralokinumab, lebrikizumab, nemolizumab, and upadacitinib. Synonyms and alternative spellings will be incorporated as appropriate. The search will not be restricted by language; however, studies will only be included if an English translation is available, either locally or through artificial intelligence–assisted translation. Reference lists of included studies will be hand-searched to identify additional relevant publications. Corresponding authors of included studies will be contacted where necessary to identify further published or unpublished data relevant to the review question. Grey literature will be searched by reviewing published online abstracts from the British Association of Dermatologists Annual Scientific Meeting, American Academy of Dermatology Annual Meeting, and the European Academy of Dermatology and Venereology Biannual Symposium and Congress. Draft search strategy: (systemic therapy OR immunosuppressive agent) AND (atopic dermatitis OR eczema) AND (methotrexate OR cyclosporine OR azathioprine OR mycophenolate mofetil OR abrocitinib OR baricitinib OR dupilumab OR tralokinumab OR lebrikizumab OR nemolizumab OR upadacitinib) Types of studies to be included: Experimental and observational study designs will be eligible, including randomised controlled trials, cohort studies, case–control studies, cross-sectional studies, and case series. Condition or domain being studied: This scoping review will examine the off-label use of combination systemic therapies for the management of moderate-severe atopic dermatitis. Currently, there are no head-to-head trials evaluating the efficacy of different combinations of systemic treatments, and evidence in this area remains limited. Despite this, anecdotal reports suggest such combinations are commonly used in patients with severe or treatment-refractory disease. Participants or population: Children and adults aged 0–99 years with a diagnosis of atopic dermatitis made by a medical practitioner will be eligible. Participants must be receiving at least one systemic agent for the management of atopic dermatitis. Studies from all geographical regions and both hospital and community settings will be included. Interventions and exposures: Combination systemic therapies used for the management of atopic dermatitis. Comparator: Single-agent systemic therapy or standard systemic treatment where applicable. Outcomes: Primary outcome Efficacy of combination systemic therapies in the management of atopic dermatitis. Secondary outcomes • Identification of the most effective combination systemic therapies • Safety and tolerability of combination systemic therapies in patients with atopic dermatitis. Risk of bias: The Joanna Briggs Institute (JBI) critical appraisal tools will be used to assess methodological quality and risk of bias for cohort, case–control, cross-sectional, and case series studies. The Cochrane Risk of Bias tool will be used for randomised controlled trials. Eligibility criteria: Inclusion criteria • Studies including male and/or female participants aged 0–99 years with atopic dermatitis. • Participants receiving systemic therapy for the management of atopic dermatitis. Exclusion criteria: • Studies in which participants are not treated with systemic agents. • Studies for which no English-language translation is available. Study selection: Two reviewers will independently screen titles and abstracts for eligibility. Full-text articles will be obtained for any study deemed potentially relevant by either reviewer. Full-text screening will be conducted independently by both reviewers. Disagreements will be resolved through discussion or adjudication by a third reviewer if necessary. Data extraction: Two reviewers will independently chart data from included studies using a standardised data extraction form. Discrepancies will be resolved by refer