Salicylic Acid Peel Incorporating Triethyl Citrate and Ethyl Linoleate in the Treatment of Moderate Acne: A New Therapeutic Approach

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1 ORIGINAL ARTICLES Salicylic Acid Peel Incorporating Triethyl Citrate and Ethyl Linoleate in the Treatment of Moderate Acne: A New Therapeutic Approach BEATRICE RAONE, MD,* STEFANO VERALDI, MD, ROBERTA RABONI, MD,* MARCO ARDIG O, MD, ANNALISA PATRIZI, MD,* GIUSEPPE MICALI, MD,** GABRIELLA FABBROCINI, MD, AND VINCENZO BETTOLI, MD [Correction statement added after online publication 29-Apr-2013: Dr. Fabbrocini s name has been corrected.] BACKGROUND Acne affects many adolescents. Conventional therapy often results in side effects and poor adherence, and the treatment does not consider the psychological effect of acne on patients, which is comparable with that of disabling diseases. OBJECTIVES To evaluate the efficacy and tolerability of a peel (30% salicylic acid, triethyl citrate and ethyl linoleate) combined with a home therapy with three topical agents (triethyl citrate, ethyl linoleate and salicylic acid 0.5% cream, lotion) in moderate acne of the face. DESIGN Prospective, observational, multicenter, open-label, postmarketing, phase IV study. METHODS Patients were assessed by comparing Global Acne Grading System (GAGS) score and total lesion count from 15 days before the first peel (T 15 ), after four salicylic peels (every 10 2 days (T 0,T 10,T 20,T 30 ), and 20 days after of the end of the study (T 50 ). This treatment was associated to a home therapy. RESULTS Fifty-three patients completed the study. The average GAGS score fell 49% between T 15 and T 50 (p <.001). No patient withdrew for adverse events. CONCLUSIONS This therapy was effective and well-tolerated in all cases. Chemo-exfoliation sessions ensured the continuous monitoring of clinical results and improved patient quality of life. The authors have indicated no significant interest with commercial supporters. Acne is the most common chronic inflammatory dermatologic disease affecting teenagers; 1 its pathogenesis is recognized as multifactorial. It can deeply affect quality of life, but unlike other chronic diseases such as atopic dermatitis and psoriasis, the psychological comorbidity of acne is not necessarily related to the severity of the disease. 2,3 This is understandable because acne mainly occurs during adolescence, a time when body image is important, so even mild acne may lead to depression in vulnerable teenagers. Current therapies for the management of acne involve one or several pathogenic factors such as inflammation, abnormal keratinization of follicle epithelium, colonization and proliferation of Propionibacterium acnes, androgen-mediated hypersecretion of sebum, and *Division of Dermatology, Department of Internal Medicine, Aging, and Nephrologic Diseases, Sant Orsola-Malpighi Hospital, University of Bologna, Italy; Department of Anesthesiology, Intensive Care, and Dermatological Sciences, University of Milan, Italy; Division of Infective Dermatology, San Gallicano Dermatology Institute, Rome, Italy; Dermatology Section, Department of Clinical and Experimental Medicine, Hospital Sant Anna, University of Ferrara, Italy; Department of Systematic Pathology, University of Naples Federico II, Naples, Italy; **Dermatology Clinic, University of Catania, ItalyThe authors have indicated no significant interest with commercial supporters by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc. ISSN: Dermatol Surg 2013;1 9 DOI: /dsu

2 ANEW T HERAPEUTIC APPROACH alteration of sebum composition. 1 5 Topical antimicrobial agents and topical and oral antibiotics are used to reduce P. acnes colonization of the pilosebaceous unit; topical and oral retinoids mainly oppose hyperproliferation and keratosis of the ductal corneocytes. 4 Systemic estrogens and antiandrogens can be used to reduce the effect of androgens on the sebaceous gland. The choice of treatment depends on the type and severity of the disorder. In mild or moderate, mainly comedonal, acne, topical retinoids are the first-line treatment. In inflammatory acne, systemic antimicrobial agents alone or in combination with topical retinoids are used. In severe resistant cases, systemic isotretinoin should be considered, but local treatments for acne often lead to local adverse events such as erythema, scaling, dryness, itching, and burning. 6 These treatments must be employed for some weeks to achieve good therapeutic results. For these reasons, there is often poor adherence to conventional therapies for acne, which compromises the effectiveness of drug treatments, leading to treatment failure. Moreover, teenagers may often forget to follow the treatment protocol appropriately or may refuse medications in a spirit of contradiction or because of social barriers. 7 Thus, physicians must make efforts to ensure that patients adhere to the proposed treatment. Finally, the spread of antibiotic resistance, caused by the prolonged use of antibiotics for acne, has led researchers to investigate the development of new nonantibiotic treatments. New treatments for acne aim to accelerate the therapeutic outcomes and improve adherence. Based on these assumptions, our study evaluated the efficacy and tolerability of a new protocol consisting of a peel with 30% salicylic acid (SA) solution incorporating a combination of triethyl citrate and ethyl linoleate (Enerpeel SA) and a home topical therapy based on triethyl citrate, ethyl linoleate, and SA 0.5% (Aknicare lotion, Aknicare cream, Aknicare Sun, General Topics SRL, S. Felice del Benaco (BS), Italy) indicated for the management of mild to moderate acne. The choice of triethyl citrate and ethyl linoleate has been made because these compounds can modify the microenvironment of the pilosebaceous unit, attenuating seborrhea and reducing the number of comedones, papules, and pustules. 8 The active lotion containing triethyl citrate and ethyl linoleate is an effective treatment for patients with mild to moderate acne. In a double-blind, placebo-controlled, randomized study by Charakida and colleagues involving 40 patients, there was a rapid response with the topical lotion, which achieved a significant reduction in lesion count after only 4 weeks of therapy, with a significant effect on inflammatory and noninflammatory acne lesions. Sebum production was significantly less in the actively treated group, with a mean 53% less sebum production than controls. The treatment was also well-tolerated. 8 Methods This prospective, observational, multicenter (7 centers), open-label, postmarketing, phase IV study was undertaken on 60 patients to assess the efficacy and tolerability of this combined therapy in the treatment of moderate acne. This therapy consisted of 30% SA incorporating triethyl citrate and ethyl linoleate peels in the physician s clinic and a home topical therapy based on the use of triethyl citrate, ethyl linoleate, and SA 0.5%. In 10 patients, confocal microscopy, a noninvasive instrumental technique, was used to verify changes at the cellular level (efficacy of the different peels in stratum corneum reduction, evaluation of irritation and skin barrier damage after peels, correlation between the new technology and standard solutions) after a few minutes and 24 hours after the peelings. Study Population Ethical guidelines based on the Declaration of Helsinki were followed. All patients signed informed consent for recruitment to the study and photographs. Male and female patients age 12 and older with from inflammatory and noninflammatory (comedonal) facial acne for 1 or more years and with 2 DERMATOLOGIC SURGERY

3 BEATRICE ET AL a Global Acne Grading System (GAGS) of moderate acne (score 19 30) were recruited. 9,10 Exclusion criteria were mild or severe acne, pregnancy, breastfeeding, and known allergy to salicylic acid or other treatment ingredients. Concomitant treatments with topical or systemic corticosteroids, antibiotics, immunosuppressants (e.g., cyclophosphamide, azathioprine), ultraviolet (UV) B, psoralen plus UVA, photodynamic therapy, and radiotherapy were avoided. Individual predisposition to development of hypertrophic scars or keloids, active herpetic lesions, and phototypes IV to VI were also considered grounds for exclusion. Patients who were undergoing treatment with systemic antibiotics or topical antiacne medications were included in the study after a washout period of variable duration depending on their current treatment (1 month for systemic antibiotics, 2 weeks for topical treatments). Study Protocol Before starting the study, a medical history was taken for each patient, their acne was graded (according to GAGS), and total lesions were counted (number of papules, pustules, and open and closed blackheads). Patients who met the inclusion criteria were instructed to apply lotion containing triethyl citrate and ethyl linoleate and SA 0.5% twice daily for 2 weeks. This period was defined as the preparatory phase (T 15 ). During the active treatment phase, patients underwent four peeling sessions involving the application of 30% SA solution and the adjuvant activity of triethyl citrate and ethyl linoleate every 10 2 days (T 0,T 10,T 20,T 30 ). After and between each chemoexfoliating treatment, patients applied a triethyl citrate, ethyl linoleate, and SA 0.5% cream twice a day; in the morning, the cream also included a special sunscreen containing UVB and UVA chemical filters with sun protection factor 30. During the maintenance phase (T 30 T 50 ), patients applied the same topical treatments (cream and cream with sunscreen). The total duration of the study was 65 days. Patients were examined at recruitment (T 15 ), at baseline (T 0 ), every 10 days during the active phase (T 0,T 10, T 20,T 30 ), and 20 days after the maintenance phase (T 50 ), at the end of the study. During each examination, patients were clinically assessed according to their acne grade; new counts of inflammatory and noninflammatory acne lesions were taken, and any side effects were recorded. Digital photographs were taken. Study Endpoints The primary endpoint of the study was the assessment of changes in acne severity after the four sessions of peels and to the end of the study (T 50 ). The T 30 GAGS score was compared with that at T 0, and a comparison was made of the photographs. Secondary endpoints were changes in total inflammatory and noninflammatory lesions count at T 50 and the level of maintenance of clinical results from T 30 to T 50. The safety and tolerability of the study were assessed according to the adverse events at each consultation. Statistical Analysis Data were analyzed according to the analysis of variance (ANOVA) between the repeated measurements of the GAGS at each visit. Each parameter was also evaluated independently. Mean changes were determined between visits (T 10,T 20,T 30,T 50 )andat every visit in relation to baseline (p <.05 significant). Results Sixty patients were recruited, but seven did not attend follow-up and were therefore considered to be drop-outs. Fifty-three patients (28 male, 25 female) ages were included in the efficacy

4 ANEW T HERAPEUTIC APPROACH assessment. The majority of patients were teenagers or young adults. All patients were of Caucasian origin, and all had previously received treatment with topical antibiotics, retinoids, systemic antibiotics, or some combination of the three. No patient had been treated with systemic isotretinoin. For each center, there was an investigator who followed all visits and performed the peeling treatment. At recruitment (T 15 ), mean GAGS score was 21. At the end of the study (T 50 ), mean GAGS score was 10.8, which was a statistically significant decrease (p <.001; Figure 1). A significant decrease of 45.5% in mean GAGS score was also registered from baseline (T 0 ) to the end of the study (T 50 ) (p <.001; Figure 2). Figure 3 shows the comparison of changes in mean GAGS score using ANOVA. As can be seen in the figure, a significant improvement was already observed after the first SA peel. The improvement continued throughout the active phase and follow-up. The mean number of closed and open blackheads at baseline were respectively 18.6 and At the end of the study (T 50 ), there was a significant decrease in the mean number of blackheads (8.0 closed blackheads, a change of 57.1% (p <.001) and 6.9 open blackheads, a change of 64.0% (p <.001) (Figures 4 and 5). The mean number of papules at baseline was 16.5; a statistically significant decrease to 6.5 was observed (a 60.8% reduction, p <.001) (Figure 6). The mean number of pustules at baseline was 6.3; at the end of the study, the mean number had significantly decreased to 1.1 (an 82.3% improvement, p <.001) (Figure 7). A marked improvement in GAGS and inflammatory and noninflammatory lesion count was observed after the first peeling session and continued for the duration of the study (Figures 8 11). Figure 1. Comparison of mean global acne scores before and after treatment. No patients reported adverse events: no rashes and no itching. Patients experienced a mild burning sensation during the peel, followed by mild erythema that lasted for a few hours, and only slight perceptible desquamation in the days after each peel. All patients declared satisfaction with the treatment performed. Confocal microscopy confirmed these results, confirming the effectiveness of the chemoexfoliation in removing the stratum corneum and the usefulness of this technology in treating inflammatory disorders (Figure 12). Conclusions Figure 2. Comparison of mean Global score baseline to T 0, T 30, and T 50. The widespread clinical opinion of 25% to 30% SA peel solutions is that these treatments are 4 DERMATOLOGIC SURGERY

5 BEATRICE ET AL Figure 3. Comparison of changes in the mean Global Acne Grading score according to analysis of variance. Figure 4. Comparison in mean number of closed comedones at T 0,T 30, and T 50. Figure 6. Comparison of changes in mean papule numbers at T 0,T 30, and T 50. Figure 5. Comparison in mean open comedones at T 0,T 30, and T 50. Figure 7. Comparison of changes in mean pustules numbers at T 0,T 30, and T 50. helpful in treating inflammatory and noninflammatory acne. Chemo-exfoliation has many clinical advantages, being effective, economical, and easy to perform, but supporting evidence for this approach is not widely documented in the scientific literature. The use of superficial SA peels in inflammatory acne is well-documented Their efficacy is due to: (1) Keratolytic activity providing selective action on the corneocyte cell layer without affecting the basal membrane: SA increases

6 ANEW T HERAPEUTIC APPROACH Figure 8. Mean number of Global Acne Grading score, closed and open blackheads, papules, and pustules before each examination. Figure 9. Mild inflammatory acne before and after the peel sessions. Figure 10. Moderate inflammatory acne in adolescents before and after the peel sessions. 6 DERMATOLOGIC SURGERY

7 BEATRICE ET AL Figure 11. Adult acne before and after the peel sessions. Figure 12. Confocal Microscopy. epidermal activity of enzymes, leading to exfoliation (2) Comedolytic action triggered by the lipophilic nature of the acid (3) Reduction and removal of interlamellar lipids that surround corneocytes (4) Anti-inflammatory activity (inhibition of arachidonic acid cascade) Salicylic acid (SA) peels also improve the penetration of other active topical ingredients used for treating acne and can be used in addition to topical drugs or as maintenance therapy. Dreno and colleagues examined clinical trials using chemical peels in acne treatment. 11 From 1999 to 2009, six studies of 25% to 30% SA peels were reported; all of these trials demonstrated a significant decrease in acne lesions. One of the blinded studies, considered the best by the authors, 11,12 reported a mean reduction in total lesions counts of 43% after 12 weeks of the treatment, whereas 77% of patients showed moderate or good improvement. At the end of the 65th day of our study, a decrease of 45.5% in mean GAGS score was observed, a result similar to those reported in the literature. It is also important to emphasize that all of our patients had been treated with conventional therapy for acne (systemic antibiotics or topical anti-acne) and were included in the study after a wash-out period. This wash-out had not been reported in previous studies of SA peel efficacy. The comedolytic effect of superficial peeling and its indication for treating noninflammatory acne was evaluated. Controlled studies showed a 35% decrease in comedones. 11 By the end of this trial, a

8 ANEW T HERAPEUTIC APPROACH 64.4% and 57.1% reduction in open comedones and closed comedones, respectively, was observed. The literature has reported contradictory results regarding the treatment of inflammatory acne with chemical exfoliating solutions. 11 By the end of this study, a statistically significant reduction of inflammatory acne lesions was achieved. The decrease in the mean number of papules and pustules was 60.8% and 82.3%, respectively. Moreover, the effectiveness of peels appears to be directly proportional to the number of sessions, and the clinical improvement became more evident with repeated treatments, suggesting that several sessions were beneficial. 11 In contrast, this study trial showed that the marked decrease in mean GAGS score was achieved quickly, even after the first treatment (Figure 3). The explanation for this result could be the technology used in the formulation of the acidic solution used in this study, which uses a carrier molecule that is able to deliver the acid and other ingredients in such a way that a homogeneous absorption profile is achieved. The carrier reduces any interaction between the dissociated acid and polar and nonpolar structures in the skin, allowing more-thorough absorption and delivering greater exfoliant efficiency with less surface trauma. To evaluate the strength of the acid solution, the electrochemical effect of organic acids on skin biology was evaluated. The chemical composition of this acidic solution causes a decreased mobility of the protons. Once absorbed into the skin, the mobility of these protons starts to increase. In a simple acid aqueous solution, the mobility of the protons is at its highest level; this carrier solution was chosen for the study so that the relationship between surface trauma and chemo-exfoliant efficiency was skewed toward the latter. The presence of the other active ingredients (triethyl citrate and ethyl linoleate), which act synergistically with the acid, also enhanced the rapid effect of this treatment. In conclusion, 30% SA solution and the adjuvant activity of triethyl citrate and ethyl linoleate appear to be a useful medical device for the management of mild to moderate comedogenic and inflammatory acne. This therapy has an excellent safety and tolerability profile. In our cases, erythema and desquamation were mild. Moreover, good results were rapidly obtained, and none of the patients reported any adverse events. The treatment did not affect patients daily routine, and their social, home, and work life was not restricted. Chemo-exfoliation sessions every 10 days ensured continuous monitoring of clinical results. In this way, the necessary relationship of trust with the patient was established, which improved therapy adherence. Frequent visits during the study also helped improve patients quality of life by developing their awareness of their condition and the need for body care. References 1. Gollnick HP, Finlay AY, Shear N. Can we define acne as a chronic disease? If so, how and when? Am J Clin Dermatol 2008;9: Gupta MA, Schork NJ, Gupta AK, Kirkby S, et al. Suicidal ideation in psoriasis. Int J Dermatol 1993;32: Gupta MA, Gupta AK. Depression and suicidal ideation in dermatology patients with acne, alopecia areata, atopic dermatitis and psoriasis. Br J Dermatol 1998;139: Thiboutot D, Gollnick H, Bettoli V, Dreno B, et al. New insights into the management of acne: an update from the Global Alliance to Improve Outcomes in Acne group. J Am Acad Dermatol. 2009;60(5 Suppl):S Nast A, Dreno B, Bettoli V, Degitz K, et al. European Evidencebased (S3) Guidelines for thetreatment of Acne. J Eur Acad Dermatol Venereol 2012;26(Suppl. 1): Veraldi S, Schianchi R. Short contact therapy of acne with tretinoin. Eur J Acne 2011;2:(suppl1) Huang-Tz Ou, Feldman SR, Balkrishnan R. Understanding and improving treatment adherence in pediatric patients. Semin Cutan Med Surg. 2010; 29: Charakida A, Charakida M, Chu AC. Double-blind, randomized, placebo-controlled study of a lotion containing triethyl citrate and ethyl linoleate in the treatment of acne vulgaris. Br J Dermatol 2007;157: Doshi A, Zaheer A, Stiller MJ. A comparison of current acne grading systems and proposal of a novel system. Int J Dermatol 1997;36: DERMATOLOGIC SURGERY

9 BEATRICE ET AL 10. Allen BS, Smith G Jr. Various parameters for grading acne vulgaris. Arch Dermatol 1982;1982: Dreno B, Fischer TC, Perosino E, Poli F, et al. Expert Opinion: efficacy of superficial chemical peels in active acne management what can we learn from the literature today? Evidence-based recommendations. J Eur Acad Dermatol Venereol 2011;25: Lee HS, Kim IH. Salicylic acid peels for the treatment of acne vulgaris in Asian patients. Dermatol Surg 2003;29: Zakopoulou N, Kontochristopoulos G. Superficial chemical peels. J Cosmet Dermatol 2006;5: Address correspondence and reprint request to: Annalisa Patrizi, Department of Internal Medicine, Aging and Nephrologic Diseases, Division of Dermatology, Sant Orsola-Malpighi Hospital, University of Bologna, Via Massarenti 1, Bologna, Italy, or annalisa.patrizi@unibo.it