SKIN July 2019 Volume 3 Issue 4 Copyright 2019 The National Society for Cutaneous Medicine 279 BRIEF ARTICLES Expedited Resolution of 5-Fluorouracil-Induced Reaction and Barrier Dysfunction with White Petrolatum Melody Maarouf MHS1, Bryan W. Kromenacker MA BSN1, Eric E. Brucks MD2, Vivian Y. Shi MD3 1University of Arizona, College of Medicine, Tucson, AZ 2University of Arizona, Department of Medicine, Tucson, AZ 3University of Arizona, Department of Medicine, Division of Dermatology, Tucson, AZ Topical 5-fluorouracil (5-FU) is a commonly prescribed field treatment for diffuse actinic keratosis (AK).[1] 5-FU preferentially targets AKs, inducing inflammation and skin barrier disruption, [2] with erythema, blistering, necrosis with erosion, and re- epithelialization. Complete AK clearance can be seen in up to 90% of patients who tolerate these side effects. [3] There is no standard recommendation on post-topical 5-FU wound care to minimize skin discomfort and inflammation. Previously, Erlendsson et al. attempted to mitigate the cutaneous reactions associated with topical ingenol-mebutate. Following finalization of AK treatment, twice-daily application of topical Clobetasol proprionate 0.05% for 4 days did not show significant reduction of local skin responses, pain, or pruritus. [4] Maarouf et al., have shown that petrolatum is effective in improving post 5-FU erythema and skin hydration. [5] A 67-year-old Caucasian male with diffuse facial AK (19 by count; left: 10 right: 9) Actinic keratoses (AK) are precancerous lesions that develop on chronically sun-exposed skin. They frequently require prophylactic field treatment due to the risk of progression to squamous cell carcinoma. Topical 5-fluorouracil (5-FU) is highly effective treatment for AK, yet leaves a patient with an exuberant erythematous reaction at treatment site, which can be embarrassing and uncomfortable. We report a case of a patient with diffuse facial AK who was treated with 5-FU twice daily for 2 weeks, resulting in fiery-red erythema and disrupted barrier function. Application of pure ultra white petroleum jelly, an emollient preferred by dermatologists for post-operative wound healing, resulted in drastic decreased erythema and recovery time of post-treatment transepidermal water loss and hydration, compared to the contralateral, non- petrolatum-treated side. Additionally, petrolatum use did not disrupt the AK resolution endpoint. We suggest that petroleum jelly be used for the repair of 5-FU-induced barrier disruption and erythema to promote greater patient adherence. ABSTRACT INTRODUCTION CASE REPORT SKIN July 2019 Volume 3 Issue 4 Copyright 2019 The National Society for Cutaneous Medicine 280 underwent 5-FU treatment twice daily for 2 weeks. Within 1 week, he experienced erythema, burning, and itching, which became robust and uncomfortable during the second week of treatment. After completing his 5-FU course, he applied Vaseline Pure Ultra White Petroleum Jelly (Covidien, Mansfield, MA) to the right side of the face twice daily for 2 weeks, leaving the left side of the face untreated. Four weeks following 5-FU initiation, 95% AK lesions had resolved and no lesion was present at 3 months follow-up. Average Clinician’s Erythema Assessment (0=clear skin with no signs of erythema to 4=severe erythema/fiery redness)[6] and skin barrier biophysical properties [hydration, transepidermal water loss (TEWL)] were measured at baseline, weekly during 5-FU treatment, and for 2 more weeks during petrolatum intervention. Facial erythema, hydration, and TEWL progressively worsened during 5-FU treatment, peaking at 3-weeks. Compared to the contralateral control side, petrolatum significantly reduced erythema, increased hydration, and decreased TEWL (Figure 1A- D). Hydration steadily declined throughout treatment, and sharply rose by week 5. In mixed-effects bivariate regressions across ointment conditions using face side as the grouping variable, erythema positively correlated with TEWL (r =0.42, p=0.03) (Figure 1E) and inversely correlated with hydration (r =-0.57, p=0.004) (Figure 1F), suggesting that subjective erythema accurately reflected changes in skin barrier physiology. While an important therapy for prevention of SCC, topical 5-FU is uncomfortable (Figure 1A-C). The inflammatory response severity correlates closely with the degree of barrier dysfunction that persists weeks after the initiation and cessation of 5-FU use (Figure 1D-E). Thus, facial treatment is especially intolerable and cosmetically unacceptable. This report demonstrates that white petrolatum, a bland, cheap, and widely available barrier repair ointment, can significantly reduce erythema and repair barrier dysfunction. Petrolatum is a semisolid mixture of hydrocarbons derived from heavy mineral oils, which resemble the components of intercellular epidermal lipids. In addition to forming a hydrophobic film on the skin surface, petrolatum’s hydrophobic nature allows it to diffuse into the epidermis. Intercalation into intercellular spaces promotes modification of the lipid lattices to reinforce barrier integrity. [7] The therapeutic advantage of 5-FU is in disaccord with its high rates of symptomatology dissatisfaction. The prospect of lessening adverse effects and time to erythema resolution may increase patient tolerance and compliance for 5-FU treatment. Additionally, the 100% resolution of AK count suggests that petrolatum does not reduce 5-FU efficacy. DISCUSSION SKIN July 2019 Volume 3 Issue 4 Copyright 2019 The National Society for Cutaneous Medicine 281 Figure 1. (a) Heatmap represents progressively increasing erythema during5-FU treatment (Weeks 1-3), with decreasing erythema on the petrolatum-treated (R) side as early as Week 4; Heatmap represents progressively worsening skin barrier function, characterized by (b) increased TEWL and (c) decreased hydration during 5-FU treatment (Weeks 1-3), with faster recovery detected on the petrolatum-treated (R) side as early as Week 4, compared to the non-petrolatum-treated (L) side; (d) Scatterplot represents a positive correlation (r=0.42, p=0.03) between erythema and TEWL; (e) Scatterplot represents a negative correlation (r=-0.57, p = 0.004) between erythema and hydration. SKIN July 2019 Volume 3 Issue 4 Copyright 2019 The National Society for Cutaneous Medicine 282 White petrolatum is an effective therapeutic agent in reducing erythema and expediting skin barrier recovery following topical 5-FU. Randomized controlled studies should aim to assess the erythema- and pain-reducing effects that alternative barrier repair modalities have on 5-FU-treated skin Conflict of Interest Disclosures: None. Funding: None. Corresponding Author: Vivian Y. Shi, MD Assistant Professor of Medicine, Dermatology Division University of Arizona vshi@email.arizona.edu References: 1. Moy, R.L., Clinical presentation of actinic keratoses and squamous cell carcinoma. J Am Acad Dermatol, 2000. 42(1 Pt 2): p. 8-10. 2. Maarouf M, Kromenacker B.W., Brucks E.S., Hendricks A.J., Shi, V.Y. 5-flouracil- induced erythema and transepidermal water loss associated with complete actinic keratosis resolution. J Dermatolog Ther, 2019. 32(3):e12890. Epub ahead of print. 3. Gupta, A.K., V. Davey, and H. McPhail, Evaluation of the effectiveness of imiquimod and 5-fluorouracil for the treatment of actinic keratosis: Critical review and meta-analysis of efficacy studies. J Cutan Med Surg, 2005. 9(5): p. 209-14. 4. Erlendsson, A.M., Karmisholt, K.E., Haak, C.S., Stender, I.M., Haedersal M. Topical corticosteroids has no influence on inflammation or efficacy after ingenol mebutate treatment of grade I to III actinic keratosis (AK): A randomized clinical trial. JAAD, 2016. 74(4): p/ 709- 15. 5. Maarouf M, Kromenacker B.W., Brucks E.S., Hendricks A.J., Shi, V.Y. Reducing unpleasant side effects of topical 5- Floururacial treatment for actinic keratosis: a randomized controlled trial. J Dermatolog Treat. 2019. 1:1-5. Epub ahead of print. 6. Morales-Burgos, A., M.P. Loosemore, and L.H. Goldberg, Postoperative wound care after dermatologic procedures: a comparison of 2 commonly used petrolatum-based ointments. J Drugs Dermatol, 2013. 12(2): p. 163-4. 7. Tan, J. and M. Leoni, Erythema of Rosacea: Validation of Patient's Self- Assessment Grading Scale. J Drugs Dermatol, 2015. 14(8): p. 841-4 CONCLUSION mailto:vshi@email.arizona.ed#u