Therapeutic Interventions for Atopic Dermatitis Affecting the Lips in Adults Are Limited: A Systematic Review

Introduction: Atopic cheilitis, a localized manifestation of atopic dermatitis involving the lips, significantly affects patients' quality of life due to chronic inflammation, discomfort, and functional impairments. Despite its clinical importance, management strategies are often extrapolated from generalized atopic dermatitis treatments, lacking lip-specific evidence.

Objective: To systematically review the efficacy and safety of pharmacologic and non-pharmacologic interventions for atopic cheilitis in adults and identify gaps in the current literature.

Methods: A systematic review of MEDLINE, EMBASE, Web of Science, Scopus, and Cochrane CENTRAL was conducted through September 2024. We included randomized controlled trials, prospective cohort studies, retrospective analyses, and case series involving at least five adults (≥18 years) with clinically diagnosed atopic cheilitis. Data on therapeutic efficacy, patient-reported outcomes, adverse events, and long-term remission were extracted and narratively synthesized.

Results: Out of 3,764 screened records, 10 studies met the inclusion criteria. Conventional therapies, such as topical corticosteroids (TCS) and calcineurin inhibitors (TCIs), demonstrated short-term efficacy in reducing erythema and pruritus, though relapse was common upon discontinuation. Emerging systemic treatments, including dupilumab (a biologic targeting IL-4 and IL-13) and oral Janus kinase (JAK) inhibitors, showed substantial improvement in severe and refractory cases. Barrier repair measures, such as ceramide-based emollients, were effective as adjunctive therapies, enhancing skin hydration and comfort. However, phototherapy and allergen avoidance strategies provided mixed results. Across studies, a lack of standardized lip-specific severity scoring tools hindered direct comparisons of outcomes. Most interventions were well-tolerated, but data on long-term safety were limited.

Conclusions: While both established and novel therapies show promise in treating atopic cheilitis, significant gaps remain, particularly regarding validated lip-specific clinical measures and long-term outcomes. Future research should prioritize standardized assessment tools and high-quality trials focused on lip-targeted interventions to optimize management strategies and improve patient quality of life.

Atopic dermatitis (AD) is a chronic, relapsing-inflammatory condition characterized by eczematous lesions, pruritus, and skin barrier dysfunction. While it is often described on flexural surfaces, facial involvement is common and can include the sensitive lip region. Atopic cheilitis, defined as the presence of AD lesions on the vermilion and surrounding areas of the lips, poses unique clinical challenges: the lip skin’s thinner stratum corneum, reduced sebaceous glands, and near-constant exposure to irritants and environmental stressors can lead to persistent inflammation, painful fissuring, and functional impairment. Despite the high clinical relevance, lip-specific treatment strategies remain inadequately addressed in standard AD guidelines and the broader literature. Most clinical recommendations are extrapolated from data on facial or generalized AD. Emerging systemic treatments—such as biologic agents (e.g., dupilumab) and oral JAK inhibitors—hold promise for severe or refractory AD, yet their efficacy and safety for lip involvement specifically are not well-defined. Moreover, there is a notable lack of lip-specific severity scoring tools, making it difficult to assess treatment response accurately or compare outcomes across studies. The objective of this systematic review is to provide a comprehensive synthesis of current evidence on therapeutic interventions for atopic cheilitis in adults. We assess both established treatments (e.g., topical corticosteroids, topical calcineurin inhibitors) and novel therapies (e.g., dupilumab, JAK inhibitors), highlighting outcomes, adverse events, and knowledge gaps. By consolidating and critiquing the existing literature, this review aims to guide clinicians and researchers toward evidence-based, lip-centric strategies for managing atopic dermatitis, and to identify key priorities for future research.

Protocol and Registration

This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered with PROSPERO.

PRISMA chart

Eligibility Criteria

Studies were included if they: (1) investigated adults (≥18 years) with a clinical diagnosis of AD involving the lips; (2) examined at least one therapeutic intervention (pharmacological or non-pharmaco-logical); and (3) reported outcomes related to lip-specific disease severity, symptom improvement, patient-reported outcomes, or adverse events. RCTs, non-randomized trials, prospective or retrospective cohort studies, and case series (≥5 patients) were eligible. We excluded case reports, pediatric-only populations, and studies not reporting any lip-specific outcome or for which lip involvement could not be deduced.

Information Sources and Search Strategy

We searched MEDLINE, EMBASE, Web of Science, Scopus, and Cochrane CENTRAL from inception to September 2024. The search strategy combined terms for AD and lip involvement, including “(atopic dermatitis OR eczema) AND (lip OR cheilitis) AND (treatment OR therapy).” No language restrictions were applied, though non-English articles required an available English translation. Reference lists of included studies and relevant reviews were manually screened for additional records.

Study Selection

Titles and abstracts were independently screened by two reviewers. Full-text articles of potentially eligible studies were then assessed. Disagreements were resolved through discussion with a third reviewer.

Data Extraction

A standardized form was used for data extraction. Variables collected included study design, population characteristics, diagnostic criteria, intervention details, comparator (if any), outcome measures (clinical severity, patient-reported outcomes, safety), and main results. Two reviewers performed data extraction independently; discrepancies were resolved by consensus.

Risk of Bias Assessment

Risk of bias in RCTs was assessed using the Cochrane Risk of Bias 2.0 tool. For non-randomized studies, we employed the ROBINS-I tool. Two independent reviewers conducted quality assessments, resolving disagreements through adjudication by a third reviewer.

Data Synthesis

Given the heterogeneity in study designs, interventions, and outcome measures, a meta-analysis was not feasible. A qualitative (narrative) synthesis of the evidence was undertaken, highlighting patterns, strengths, weaknesses, and gaps in the literature.

Study Selection and Characteristics

The search identified 3,764 records, of which 194 were reviewed in full. Ultimately, 10 studies met inclusion criteria. Publication dates spanned from 1989 to 2024, with a geographical distribution including North America, Europe, and East Asia. Sample sizes ranged from 10 to 312 participants. Duration of follow-up varied widely from 4 weeks to 18 months. Most studies did not employ validated lip-specific severity scales; instead, authors adapted general AD scoring tools (EASI, SCORAD) or used subjective physician or patient assessments. This variability limited direct comparisons across studies.

Interventions Evaluated

A broad range of interventions was reported:

Topical Corticosteroids (TCS): Multiple studies, primarily observational or small RCTs, evaluated low- to mid-potency TCS. These agents were effective in reducing erythema, scaling, and fissuring in the short term. However, relapse upon discontinuation was common, and concerns about atrophy, perioral dermatitis, and depigmentation were raised. Although such adverse events were uncommon in the short-term, long-term safety data are limited.

Topical Calcineurin Inhibitors (TCIs): Tacrolimus ointment and pimecrolimus cream were frequently employed as steroid-sparing agents. Studies consistently reported moderate improvements in lip inflammation and pruritus without the atrophy risk associated with TCS. Transient burning or stinging sensations were the most common side effects.

Topical PDE4 Inhibitors: Few studies investigated crisaborole ointment. Limited data suggested mild improvement in lip eczema severity and itch. Application-site pain or burning was reported but generally mild.

Barrier Repair Measures and Emollients: Several studies examined the use of ceramide-rich lip balms, petrolatum-based ointments, and other emollients. While such interventions generally improved dryness and comfort, objective reductions in inflammation were less clear. Adjunctive use of barrier repair agents was often combined with pharmacotherapies.

Biologics (Dupilumab): Preliminary evidence, including two small prospective studies, indicated that dupilumab can produce meaningful improvements in lip lesions in patients with moderate-to-severe AD. Improvements in itch, fissuring, and quality of life were reported as early as 4-8 weeks. Mild dryness was the most frequently mentioned adverse event. No lip-specific validated outcome measures were employed, but the consistent improvement suggests a promising role for dupilumab in recalcitrant atopic cheilitis.

JAK Inhibitors (Oral and Possibly Topical): Retrospective data on upadacitinib and abrocitinib suggested benefit in lip lesions among patients with moderate-to-severe AD. Rapid reductions in itch were noted, although standardized lip severity indices were lacking. Mild adverse events, including transient acneiform eruptions, were noted but did not preclude continued therapy.

Phototherapy (Narrowband UVB): Phototherapy has limited reporting. One small pilot study (n=15) showed partial improvement in lip lesions, but practical challenges and patient discomfort (particularly on the sensitive lip area) limited utility.

Allergen Avoidance and Adjunctive Strategies: Several case series emphasized patch testing and allergen avoidance (e.g., fragrances, flavorings, dental materials), with approximately half of patients showing improvement after allergen elimination. These findings underscore the role of contact sensitivities in exacerbating lip lesions and highlight a potentially underrecognized management strategy.

Psychosocial and Integrative Interventions: Two exploratory studies examined mindfulness-based stress reduction and cognitive-behavioral therapy. Patients reported better coping strategies and modest clinical improvements, reflecting the psychosomatic component of AD and the lips’ importance in social interactions and self-image.

Risk of Bias and Quality of Evidence

RCTs frequently displayed moderate risk of bias due to limited blinding and lack of validated lip-specific outcomes. Non-randomized studies and case series were prone to selection bias and incomplete reporting. Overall, the quality of evidence is low to moderate, and the lack of standardized measures hinders robust conclusions.

This systematic review highlights significant gaps and challenges in treating atopic cheilitis in adults. While several interventions show efficacy, their evaluation is complicated by the absence of lip-specific severity indices. Conventional treatments like TCS and TCIs remain mainstays but often provide only transient relief. Systemic agents such as dupilumab and JAK inhibitors, although promising, require further evaluation in well-designed trials that incorporate validated, lip-targeted outcome measures. The unique anatomical and physiological properties of the lips—thin epidermis, fewer sebaceous glands, constant exposure to saliva and irritants—suggest that AD lesions here may respond differently than those on other body sites. Addressing these distinctive factors might optimize treatment strategies. Moreover, the psychosocial impact of lip involvement, which can affect speech, diet, and interpersonal interactions, remains under-explored yet critically important.

The urgent need for standardized, validated scoring tools for lip eczema is evident. Such tools should capture clinical severity (erythema, fissuring, scaling), functional impairment (pain with speech or eating), and patient-reported outcomes (itch, dryness, quality of life). Future research should prioritize:

Development of Lip-Specific Severity Indices: Standardized clinical assessment tools are essential for comparing therapies and conducting meta-analyses.

Randomized Controlled Trials with Lip-Focused Endpoints: Well-designed RCTs evaluating existing and emerging therapies can provide definitive guidance.

Long-Term Safety and Efficacy Data: Chronic use of TCS, TCIs, biologics, and JAK inhibitors must be examined over extended periods, given the recurrent and persistent nature of lip involvement.

Integrative Approaches and Allergen Avoidance: Further exploration into allergen identification, avoidance strategies, and psychosocial support is warranted, as these may enhance or complement pharmacotherapy.

Limitations

This review is limited by the scarcity of high-quality studies focused on the lips. Publication bias cannot be excluded, and many interventions were assessed in small samples with short follow-up. Nonetheless, our comprehensive search and systematic methodology minimize the risk of missing relevant data and provide a structured foundation for future investigations.

Atopic dermatitis affecting the lips poses unique treatment challenges. While traditional topicals and newer systemic agents both show potential, the evidence base is fragmented and hindered by a lack of standardized, lip-specific measures. Biologics and JAK inhibitors offer promising avenues for refractory disease, yet robust trials are needed to confirm their safety and efficacy for lip involvement. This review underscores the pressing need for lip-focused research, from the validation of severity indices to the design of controlled studies aimed at improving outcomes and quality of life for patients with atopic cheilitis.

Capsule Summary

This article integrates current findings on treatments for atopic cheilitis, revealing a lack of robust, lip-specific data.

It encourages dermatologists to consider emerging therapies carefully, and highlights the need for dedicated research to improve lip-targeted strategies.

Acknowledgments

No specific funding was received for this work. The authors thank the Indiana University School of Medicine and Midwestern University College of Osteopathic Medicine library staffs for assistance in literature retrieval and acknowledge the contributions of peer reviewers for their valuable input.

Funding Statement: No funding was received for this study.

Conflict of Interest Statement: The authors declare no conflicts of interest.