Volume 5 - Number 2/2014

Volume 5 - Number 2/2014 NAPOLI 17-18 Ottobre 2014

Volume 5, Number 2/2014 L ultima volta che ho visto Riccarda è stato in occasione dell Acne and Rosacea Days, a Milano, alla fine di settembre dell anno scorso. In seguito, ci siamo sentiti al telefono alcune volte. In queste occasioni l ho trovata come è sempre stata, e come la ricordo, cioè attiva, vivace, brillante. Non immaginavo che la sua fine terrena fosse così vicina, così prematura. Quando una persona muore, gli aggettivi, i pregi, le qualità si sprecano. Ma nel caso di Riccarda, questi erano e sono doverosi e dovuti. Anche se frequentavamo via Pace più o meno negli stessi anni della scuola di specialità, ho conosciuto Riccarda, e bene, solo dopo, quando abbiamo fondato insieme i Quaderni di Dermocosmetologia Medica e Chirurgica e, successivamente, Dermo Cosmo News, una rivista che ha rappresentato una piccola novità nel panorama editoriale italiano. Questi parti erano il frutto di lunghe chiacchierate accompagnate da innumerevoli sigarette (soprattutto sue ). Ho sempre riconosciuto a Riccarda non pochi meriti professionali. Riccarda ha inventato la dermocosmetologia in Italia (ricordo i congressi a Saint Vincent) e ha inventato, attra - verso le pagine del Corriere, un linguaggio scientifico, rigoroso, ma comprensibile al grande pubblico: Riccarda ha avvicinato la gente alla figura del dermatologo: non pensate sia un grande merito? Infine, ma non sarebbe finita, ha inventato una nuova scienza: la dermatologia ecologica, con tanto di associazione (Skineco) e di giornale (il Journal of Ecologic Dermatology). Mi fermo qui: sono molto, molto triste. Cara Riccarda, mi/ci mancherai. Stefano Veraldi

Volume 5, Number 2/2014 European Journal of Acne and Related Diseases Volume 3, n. 3, 2012 Editorial Board Editor Stefano Veraldi Milano Co-Editor Mauro Barbareschi Milano Scientific Board Vincenzo Bettoli Ferrara Stefano Calvieri Roma Gabriella Fabbrocini Napoli Giuseppe Micali Catania Giuseppe Monfrecola Napoli Nevena Skroza Roma Annarosa Virgili Ferrara Managing Editor Antonio Di Maio Milano Content Treatment of mild to moderate acne with a cream containing nicotinamide, potassium azeloyl diglycinate, salicylic acid and chloroxylenol. Results of a multicentre, pilot, open, sponsor-free study pag 33 Daniele Domenico Raia, Giuseppe Alessandrini, Giuseppe Borda, Gianluigi Cappelletto, Giorgio Filosa, Enrico Scaparro, Francesco Simonacci, Marco Simonacci, Stefano Veraldi Results of a multicentre, pilot, open, sponsor-free study on the efficacy, tolerability and impact on quality of life of a cream containing glycolic acid, retinaldehyde and undecyl-rhamnoside in patients with acne pag 42 Stefano Veraldi, Mauro Barbareschi Drug-induced acneiform eruptions pag 47 Vittorio Berruti, Antonia Gimma, Franca Taviti, Carla Cardinali Effects of a new multi-component in cream based on Alukina and Microsilver BG in the treatment of acne vulgaris pag 53 Antonino Di Pietro, Pietro Cazzola Abstracts NAPOLI, 17-18 Ottobre 2014 Italian Acne Club Giuseppe Alessandrini (Ugento), Mario Bellosta (Pavia), Enzo Berardesca (Roma), Carlo Bertana (Roma), Alessandro Borghi (Ferrara), Francesco Bruno (Palermo), Carla Cardinali (Prato), Maria Pia De Padova (Bologna), Paolo Fabbri (Firenze), Patrizia Forgione (Napoli), Simone Garcovich (Roma), Antonia Gimma (Prato), Gian Luigi Giovene (Perugia), Massimo Gola (Firenze), Giovanni Lo Scocco (Prato), Mario Maniscalco (Sciacca), Carlo Pelfini (Pavia), Mauro Picardo (Roma), Maria Concetta Potenza (Roma), Marco Romanelli (Pisa), Alfredo Rossi (Roma), Rossana Schianchi (Milano), Patrizio Sedona (Venezia), Aurora Tedeschi (Catania), Antonella Tosti (Bologna/Miami), Matteo Tretti Clementoni (Milano) International Editorial Board Zrinka Bukvic Mokos (Zagreb, Croatia), Tam El Ouazzani (Casablanca, Morocco), May El Samahy (Cairo, Egypt), Uwe Gieler (Giessen, Germany), Maite Gutierrez Salmerón (Granada), Marius-Anton Ionescu (Paris, France), Monika Kapinska Mrowiecka (Cracow, Poland), Nayera Moftah (Cairo, Egypt), Nopadon Noppakun (Bangkok, Thailand), Gerd Plewig (Munich, Germany), Miquel Ribera Pibernat (Barcelona), Robert Allen Schwartz (Newark, Usa), Jacek Szepietowski (Breslau, Poland), Shyam Verma (Ladodra, India) Direttore Responsabile: Pietro Cazzola Direttore Generale: Armando Mazzù Registr. Tribunale di Milano n. 296 del 01/06/2011. Scripta Manent s.n.c. Via Bassini, 41-20133 Milano Tel. 0270608091/0270608060 - Fax 0270606917 E-mail: scriman@tin.it Abbonamento annuale (3 numeri) Euro 50,00 Pagamento: conto corrente postale n. 1010097192 intestato a: Edizioni Scripta Manent s.n.c., via Bassini 41-20133 Milano Stampa: Lalitotipo s.r.l., Settimo Milanese (MI) Editorial Staff Consulenza grafica: Piero Merlini Impaginazione: Stefania Cacciaglia È vietata la riproduzione totale o parziale, con qualsiasi mezzo, di articoli, illustrazioni e fotografie senza l autorizzazione scritta dell Editore. L Editore non risponde dell opinione espressa dagli Autori degli articoli. Ai sensi della legge 675/96 è possibile in qualsiasi momento opporsi all invio della rivista comunicando per iscritto la propria decisione a: Edizioni Scripta Manent s.n.c. Via Bassini, 41-20133 Milano 31

Daniele Domenico Raia 1, Giuseppe Alessandrini 2, Giuseppe Borda 3, Gianluigi Cappelletto 4, Giorgio Filosa 5, Enrico Scaparro 6, Francesco Simonacci 7, Marco Simonacci 7, Stefano Veraldi 1 1 Department of Pathophysiology and Transplantation, University of Milan, I.R.C.C.S. Foundation, Ca Granda Ospedale Maggiore Policlinico, Milan, Italy 2 Private Practice, Ugento (Lecce), Italy 3 Villa Erbosa, Bologna, Italy 4 Data Clinica, Zero Branco (Treviso), Italy 5 Dermatology Unit, ASUR, Marche AV2, Jesi, Italy 6 ASL 3 Genovese, Genova (Italy) 7 Dermatology Unit, ASUR Marche AV 3, Macerata (Italy) Treatment of mild to moderate acne with a cream containing nicotinamide, potassium azeloyl diglycinate, salicylic acid and chloroxylenol. Results of a multicentre, pilot, open, sponsor-free study Daniele Domenico Raia SUMMARY We present the results of a multicentre, pilot, open, sponsor-free study on the efficacy (primary endpoint) and tolerability (secondary endpoint) of a new cream containing 4% nicotinamide, 3% potassium azeloyl diglycinate, 2% salicylic acid and 1% chloroxylenol in patients with mild to moderate acne. Acne severity and treatment efficacy were evaluated by means of the Global Acne Grading System. Wash out period was at least two weeks for topical drugs, two months for oral antibiotics and six months for oral isotretinoin. The cream was applied on the face twice daily for twelve weeks. All patients were examined every four weeks. No other topical and/or systemic products or drugs were allowed, except for non-comedogenic cosmetics, moisturizers and sunscreens. Furthermore, neither chemical peelings nor sunlight exposure/phototherapy were allowed. A mean percentage of reduction 50% of GAGS from baseline was considered as a significant clinical improvement. At least one month of follow up was considered. Tolerability was assessed by means of a 0-to-3 scale severity (0 = absent; 1 = mild; 2 = moderate; 3 = severe; maximum global value = 18) of six clinical parameters: dryness, scaling, erythema, oedema, stinging/burning and pruritus. Student s t-test was used to assess statistical significance in the difference observed from the beginning to the end of the study. A mean percentage reduction of GAGS ± Standard Deviation equal to 55.7±13.6% was observed. Remission of all six tolerability parameters was achieved. This very good tolerability allowed a high adherence of patients to the treatment: this cream markedly improved compliance. Key words: Acne; Nicotinamide; Potassium azeloyl diglycinate; Salycilic acid; Chloroxylenol; Nipacide; Allantoin. Introduction We present the results of a multicentre, pilot, open, sponsor-free study on the evaluation of the efficacy and tolerability of a new cream* for the treatment of mild to moderate acne. This cream contains a novel combination of the following active compounds: 4% nicotinamide, 3% potassium azeloyl diglycinate, 2% salycilic acid and 1% chloroxylenol. *Acneffe crema Patients and Methods Fifty-six patients [23 males (41.1 %) and 33 females (58.9 %)], with a mean age of 19.1±5.7 years, with comedonal, papular, pustular, mild to moderate acne [Global Acne Grading System (GAGS 30)] 1, were treated with a cream containing 4% nicotinamide, 3% potassium azeloyl diglycinate, 2% salycilic acid and 1% chloroxylenol. Wash out period was at least two weeks for topical 33

34 antiseptics, antibiotics, azelaic acid, salycilic acid, nicotinamide and retinoids; at least two months for oral antibiotics and at least six months for oral isotretinoin. The cream was applied on the face twice daily for twelve weeks. Each application was preceded by a cleansing. No other topical and/or systemic products or drugs were allowed, except for non-comedogenic cosmetics, moisturizers and sunscreens. Furthermore, neither chemical peelings nor sunlight exposure/phototherapy were allowed. Acne severity and treatment efficacy (primary endpoint) were evaluated by means of the GAGS. All patients were examined every four weeks. A mean percentage of reduction 50% of GAGS from baseline was considered as a significant clinical improvement. At least one month of follow up was considered. Tolerability (secondary endpoint) was assessed by means of a 0-to-3 scale severity of six clinical parameters: dryness, scaling, erythema, oedema, stinging/burning and pruritus (0 = absent; 1 = mild; 2 = moderate; 3 = severe; maximum global value = 18). Student s t-test was used to assess statistical significance in the difference observed from the beginning to the end of the study and tolerability score. Results Severity of lesions measured by GAGS decreased from a mean absolute value ± SD of 25.1±4.9 at baseline to 11.2±4.1 (p < 0 001) after twelve weeks of treatment (= mean percentage reduction ±SD = 55.7± 13.6%). Further reduction to 10.3±3.9 (p < 0.001; mean percentage reduction ±SD = 59.2±13.4%) was observed after one month of follow-up (Table 1a, 1b; Figures 1a, 1b). The tolerability final mean score was 0 3 for all six parameters after 12 weeks of treatment (Table 2a). Dryness, scaling, erythema, oedema, stinging/burning and pruritus were absent after 12 weeks of treatment in 98%, 100%, 73%, 86%, 93% and 98% of patients, respectively. The sum of such parameters showed a decrease from a mean value of 4.1±3.4 at baseline to 0.5±0.9 after 12 weeks of treatment (reduction: 87.8%; p < 0 001; Table 2b; Figure 2). Discussion Table 1. Efficacy assessment. Table 1a. Mean GAGS ± SD in absolute value. GAGS T 0 25.1 ± 4.9 GAGS T 1 19.8 ± 4.3 GAGS T 2 15.2 ± 4.4 GAGS T 3 11.2 ± 4.1 GAGS T 4 10.3 ± 3.9 Table 1b. Mean percentage reduction of GAGS in comparison to baseline (GAGS T0). GAGS T 0 100% T 0 T 1 (21.1 ± 8.4)% T 0 T 2 (39.5 ± 14.3)% T 0 T 3 (55.7 ± 13.6)% T 0 T 4 (59.2 ± 13.4)% As previously mentioned, the study cream contains nicotinamide, potassium azeloyl diglycinate, salycilic acid and chloroxylenol. Nicotinamide (N) (also known as niacinamide) is a water-soluble amide of nicotinic acid (also known as niacin). They are similarly effective because they can be converted into each other. Other synonyms are vitamin B3 and vitamin pellagra preventing (vitamin PP). N is a component of two important enzymes involved in hydrogen transfer: nicotinamide adenine dinucleotide (NAD, coenzyme I) and nicotinamide adenine dinucleotide phosphate (NADP, coenzyme II) 2, 3. These two codehydrogenases supply hydrogen to the respiratory chain for oxidation and energy production 4. The clinical activity of N is likely due to the presence of a pyridine ring in the chemical structure 5. Several theories were proposed to explain the activity of topical N in acne. N acts in acne as anti-inflammatory agent. It inhibits neutrophil chemotaxis 4-7 and synthesis of phosphodiesterase: the resultant increase in cyclic AMP induces the inhibition of release of proteases from leucocytes and the inhibition of lymphocyte trans-

Figure 1. Figure 1a. Reduction of GAGS in absolute value. Figure 1b. Percentage reduction of GAGS in comparison to baseline. Table 2a. Tolerability. Mean absolute value ± SD for each parameter evaluated. T 0 T 1 T 2 T 3 T 4 Mean absolute value ± SD Dryness 0.6 ± 0.6 0.3 ± 0.5 0.1 ± 0 3 0 0 Scaling 0.6 ± 0.5 0.3 ± 0.5 0 0 0 Erythema 1.1 ± 0.7 0.1 ± 0.1 0.3 ± 0.4 0.3 ± 0.4 0.1 ± 0.3 Oedema 0.5 ± 0.9 0.3 ± 0.6 0.2 ± 0.1 0.1 ± 0.3 0 Stinging/burning 0.6 ± 0.9 0.3 ± 0.5 0.1 ± 0.3 0 0 Pruritus 0.6 ± 0.9 0.4 ± 0.6 0 0 0 Table 2b. Sum of the severity degrees of tolerability parameters (mean values of dryness + scaling + erythema + oedema + stinging/burning + pruritus for each patient). Time Mean value ± Standard Deviation T 0 4.1 ± 3.4 T 1 2.7 ± 2.5 T 2 0.8 ± 1.2 T 3 0.5 ± 0.9 T 4 0.5 ± 1.1 Figure 2. Trend of the sum of severity degrees of tolerability parameters. 35

36 formation 4,5,8,9. N inhibits the synthesis of polyadenosinediphosphate-ribose-polymerase 1 (PARP 1), a nuclear enzyme involved in DNA repair, which, if overactivated, causes cell necrosis 4. PARP enhances nuclear factor-kb-mediated transcription, which plays a central role in the expression of cytokines, adhesion molecules and inflammatory mediators 4. N inhibits the expression of intercellular adhesion molecule-1 and major histocompatibility complex-ii, and the synthesis of interleukins (ILs) 1 and 12, tumor necrosis factor (TNF)-α and macrophage migration inhibition factor (MIF) 4, 10. MIF inhibition may be responsible for the steroid-sparing effect of N, as MIF is upregulated by corticosteroids 4. It has been shown that Propionibacterium (P.) acnes activates IL-8 synthesis by interacting with toll-like receptor (TLR) 2 on the surface of keratinocytes. It was demonstrated that N downregulates IL-8 gene expression at transcriptional and post-transcriptional levels and IL-8 synthesis in a dose-dependent manner, through phosphorylation of the mitogen-activated protein kinase and TLR-2 degradation. In addition, N decreases the half-life of IL-8 mrna by affecting its stability 7, 11. Furthermore, N acts as an electron scavenger 4-6. Topical N improves the epidermal barrier function: the latter induces reduction in transepidermal water loss and improvement in the moisture content of the horny layer 12. N increases protein (keratin, filaggrin and involucrin), ceramide, free fatty acids and cholesterol synthesis in the stratum corneum 12 and speeds up the differentiation of keratinocytes 2. The activity of N on sebum excretion rate (SER) was studied by Draelos et al. 13. One hundred Japanese subjects were enrolled in a double-blind, placebo-controlled study. Fifty subjects applied a 2% nicotinamide product on the face for 4 weeks and 50 subjects applied a placebo moisturizer for 4 weeks. SER measurements were taken at baseline, week 2 and week 4. The group treated with N demonstrated significantly lower SER after 2 and 4 weeks of application 13. A 4% N cream contains an anti-bacterial adhesive (ABA) substance: the latter is sucrose stearate. This substance inhibits the adhesion of P. acnes on cytoplasmic membrane of corneocytes of the infrainfundibulum. Seven volunteers of both genders with acne applied once a day on one forearm, for three days, a gel containing sucrose stearate; the other forearm was considered as control. Corneocytes were isolated from the two forearms of each volunteer and incubated with P. acnes. Bacterial adhesion to corneocytes was quantified by flow-cytofluorimetry. Fluorescence intensity of corneocytes-bacteria complex was measured. ABA inhibited the adhesion of 50% P. acnes in three patients and of 82 to 97% in four patients 14. The first clinical study on the activity and tolerability of topical N in acne was published in 1995 6. In this double-blind study, 4% N gel was compared to 1% clindamycin (C) gel in the treatment of moderate inflammatory acne. Seventy-six patients were randomly assigned to apply either N (n = 38) or C (n = 38), twice daily for eight weeks. Efficacy was evaluated at weeks 4 and 8 using Physician's Global Evaluation, Acne Lesion Counts and Acne Severity Rating. After eight weeks, both treatments induced comparable (p = 0.19) beneficial results in the Physician's Global Evaluation: 82% of the patients treated with N and 68% treated with C improved. Both treatments induced statistically similar reduction in acne lesions (papules and pustules: 60% in the N group versus 43% in the C group: p = 0.168), and acne severity ( 52% in the N group versus 38% in the C group: p = 0.161) 6. In 1995, Griffiths 15 published the results of three multicentre, randomized, double-blind, vehiclecontrolled studies. A total of 969 patients with mild to moderate inflammatory acne of the face were treated twice daily for 8-12 weeks with 4% N gel (= 486 patients) or placebo (= 483 patients): 709 patients were considered evaluable at the end of the study (356 patients in the N group and 353 in the vehicle group). Three clinical criteria of evaluation were used: Acne Severity Rating, Physician s Global Evaluation and papule/pustule count. As far as Acne Severity Rating is concerned, patients treated with N experienced greater improvement over baseline at final visit compared with vehicle (p = 0.013). Physician s Global Evaluation: a significantly greater improvement at the final visit in the group treated with N compared with the group treated with the vehicle (p = 0.016) was observed.

Papule/pustule count: in the group of patients treated with N, papule/pustule count fell from 29.43 ± 0.77 at baseline to 15.40 ± 0.70 at the final visit, compared with 29.34 ± 0.78 to 16.07 ± 0.69 in the vehicle group, e.g. a non significant (p = 0.16) difference between the two groups. The high vehicle response observed in these patients was most likely a consequence of the hydro-alcoholic gel vehicle, which exerted some therapeutic effect. Side effects were local erythema and dryness 15. In 2003, two Indian studies were published 16, 17. In the study by Dos et al. 16, eighty patients with moderate acne were enrolled for the comparative evaluation of 1% C phosphate (40 patients) versus 1% C phosphate and 4% N gel (40 patients). This study did not show any added advantage of C in combination with N over C alone 16. In the other trial, 17 75 patients with inflammatory acne were divided into three groups. Group A was treated with 4% N and 1% C, group B was treated with 1% C and group C, which was considered to have resistance to local antibiotics due to no response to treatment, was treated with the combination. At the end of eight weeks, the results were compared. It was concluded that addition of N was of not much value in treating inflammatory acne 17. Weltert et al. 18 carried out a double-blind trial in which 4% N gel was compared to 4% erythromycin gel. Two groups of 80 patients each with moderate inflammatory acne of the face were treated for eight weeks. The efficacy was evaluated by means of retention and inflammatory lesion count and clinical score of seborrhoea. N and erythromycin led to equivalent regression of inflammatory lesions. Seborrhoea score presented a more significant decrease in the group treated with N 18. An Italian, multicentre, controlled, sponsor-free stu - dy, carried out by the Italian Acne Board (IAB) 19, demonstrated that 4% N cream, applied twice daily for 12 weeks, induced a significant clinical improvement ( 50% from baseline) in 21 out of 64 patients (32.8%) with mild to moderate acne. When N (applied once daily for 12 weeks) was associated with 0.1% adapalene gel (applied once daily for 12 weeks), 54 out of 106 patients (50.9%) improved. This group of patients was compared with another group of 78 patients who were treated with adapalene (1 application/day for 12 weeks) and a moisturizer (1 application/day for 12 weeks). A significant clinical improvement was observed in 32 out of 78 patients (41%). Acne severity and treatment efficacy were evaluated by means of the GAGS. Results of these three studies may be summarized as follows: a) one-third of patients significantly improved with N alone. This improvement was sometimes (approximately in 15% of patients) slow (up to three weeks). b) Tolerability was excellent. Topical N lacks of photoallergic or phototoxic potential: therefore, it can be used in complete safety also in the summertime. c) The association N-adapalene is more effective than the association adapalene-moisturizer: it is possible that N and adapalene possess a synergistic effect 19. A multicentre, double-blind, randomized study was conducted by clinical and biophysical noninvasive measurements to evaluate the efficacy and tolerability of a 4% N-phospholipidic (linoleic acid rich-phosphatidylcholine) emulsion versus 1% C phosphate, both applied once daily for 12 weeks. The N-phospholipidic association resulted to be slightly superior to C for all parameters studied (better compliance and global clinical improvement) 20. Finally, a multicentre, prospective, non-randomized, open, parallel-group study was published 21. Patients with mild to moderate acne, who had been treated with a topical retinoid for at least one month and had developed skin irritation, were assigned to one of the two following treatments: 0.2% myrtacine + 4% vitamin PP (n = 116) or a moisturizer (n = 48). Myrtacine is an ethanolic extract obtained from myrtle leaves. It showed several pharmacological properties in vitro: it inhibits keratinocyte proliferation, inhibits the growth of P. acnes, decreases the synthesis of pro-inflammatory mediators via the cyclo-oxigenase and lipo-oxigenase pathways, and decreases lipase activity. Both treatments were administered twice daily. Study endpoints were: improvement in signs and symptoms of retinoid dermatitis, global efficacy, reduction in acne severity, overall clinical outcome, 37

38 patient satisfaction and tolerability. At day 28, the association myrtacine-vitamin PP significantly decreased signs (erythema, dryness/scaling and oedema) and symptoms (itching, stinging and burning sensation) of retinoid dermatitis (p < 0.01), compared with the moisturizer. In addition, the association myrtacine-vitamin PP decreased acne severity in a significantly greater proportion of patients (p = 0.023) and was associated with a better clinical outcome (global improvement: p < 0.001) compared with the moisturizer. The association myrtacine-vitamin PP was also associated with greater patient satisfaction and was better tolerated than the moisturizer 21. Results of clinical studies published so far on the treatment of acne with topical N may be summarized as follows: a) N can be considered as an effective drug for the treatment of mild to moderate inflammatory acne; b) tolerability is excellent: no cases of allergic contact dermatitis were published so far. Furthermore, topical N lacks of photoallergic or phototoxic potential: therefore, it can be used in complete safety also in the summertime. When associated with 0.2% myrtacine, N is effective for prevention and treatment of retinoid dermatitis; c) topical N can be used in association with other topical antiacne drugs, although, to our knowledge, it was associated so far only with adapalene and phosphatidylcholine. A review on topical N in acne was recently published 22. Potassium azeloyl diglycinate (PAD) is a new water soluble derivative of azelaic acid. It is obtained by reacting the chloride of azelaic acid with two molecules of glycine and one molecule of potassium hydroxide 23-25. PAD, like azelaic acid, has sebostatic and whitening action; furthermore, it possesses, thanks to the presence of glycine, a moisturizing effect 23-25. An experimental study showed that the combination 5% PAD/1% hydroxypropyl chitosan has an anti-inflammatory effect that is superimposable to that of 15% azelaic acid, although with a better tolerability 24. Furthermore, a pilot, multicenter, randomized, double blind, placebo-controlled study confirmed the efficacy of this combination in erythema and dryness in patients with subtypes I and II of rosacea, using both the Mexameter and Corneometer devices 25. A sponsor-free, multicenter, open study showed that the combination PAD/hydroxypropyl chitosan is effective in reducing stinging and burning sensation in patients with erythemato-telangiectatic rosacea. It is possible that this action is due to both hydroxypropyl chitosan, that improves the skin barrier function of defense against environmental physical and chemical insults, and glycine, that provides a moisturizing effect and enhances the stratum corneum hydration 26. Salicylic acid (SA), as detergent in an alcoholic vehicle, was used for the first time in the treatment of acne in 1981 27. From then on, several studies were published 28-57. SA was used at different concentrations: 0.5% 29, 46, 50, 1% 56, 1.5% 55 and 2% 28-30, 34, 40, 42. As peel it was used at 20 39 or 30% 33, 38, 48-50, 57. SA was employed as cleanser 28, 46, 56, cream 30, 34, 50, 55, gel 36, 56, pads/solution/lotion 29, 40, 50 and peel 33, 37-39, 45, 48-50, 57. A thermoactivable foam of SA was also marketed: it is activated by skin contact, quickly evaporates with only negligible residues left on the skin and increases two times the penetration of SA through the epidermis 42. As far as the vehicles are concerned, hydroalcoholic vehicle 30, crown carrier system 35, sandalwood oil 46 and aqueous foam delivery 51 were used. Also in SA peels several vehicles were used: polyethylene glycol 37, 38, hydroethanol 48, 49, triethyl citrate and ethyl linoleate 50. SA was associated with C phosphate 36, 40, 44, C phosphate and benzoyl peroxide (BPO) 47, BPO 51, mandelic acid 39, glycolic acid 56, capryloyl SA/glycolic acid/citric acid/dioic acid 52. Clinical studies carried out so far showed that SA, as detergent in an alcoholic vehicle, was more effective (significant reduction in comedones) than 10% BPO wash 28. However, in another study, SA, as thermoactivable foam, was as affective as BPO 42. A total of 23 clinical trials on 7309 patients were considered in a meta-analysis study 43. At 2 to 4 weeks, SA/5% BPO had statistically greater percent inflammatory and noninflammatory lesion reductions over other groups. At 10 to 12- week end points, SA/5% BPO and C/5% BPO were similar in efficacy. At early time points, SA/5% BPO had the best profile. At later time

points, SA/5% BPO was similar to C/5% BPO 43. The association SA/C phosphate/bpo is superior to the association C/BPO 47 and the association SA/capryloyl SA/glycolic acid/citric acid/dioic acid is as effective as the association C/BPO 52. The association SA/C is superior to C alone 40, whereas the association SA/C phosphate showed no significant difference in terms of all lesion counts versus retinoic acid/c phosphate 44. Finally, 20% SA/10% mandelic acid peel was more effective than 35% glycolic acid 39. Twenty per cent SA was also associated with oral isotretinoin: this study showed that this association is more effective than isotretinoin alone 53, 54. Chloroxylenol (CH) (4-chloro-3.5-xylenol or parachlorometaxylenol or nipacide) is a halogenated derivative of phenol. It is soluble in water, ethanol and ether. CH is bactericidal against several Gram-positive bacteria, but it is less effective against staphylococci and Gram-negative bacteria. It is also fungicidal and viricidal, but it has little activity on spores 58, 59. CH is used as household antiseptic. In human medicine it was used as a skin and wound antiseptic. No statistically significant difference in reduction of comedones, papules and pustules was observed in two groups of patients treated, respectively, with 0.5% CH/2% SA cream and 5% BPO gel. However, erythema and photosensitivity were significantly fewer in the group treated with CH and SA 34. Forty-one patients with acne completed a doubleblind controlled, randomized study comparing a cream containing CH and zinc oxide versus 5% BPO cream and versus the vehicle of the cream containing CH and zinc oxide. Patients applied the medications twice daily for 8 weeks. At the end of the trial there was no significant difference in the reduction of inflammatory and noninflammatory lesion counts achieved by the cream containing CH and zinc oxide and the BPO cream. Both creams proved to be superior to the vehicle. Efficacy grading by patients and investigators showed no significant difference between the two creams. However, side effects, such as dryness and peeling, were significantly lower in the group treated with CH and zinc oxide 58. Conclusions The results of our study (open, although multicentre, sponsor-free and based on a high number of evaluable patients) may be summarized as follows: a) the study cream showed to be effective in the treatment of mild to moderate acne. This was demonstrated by a decrease > 50% of GAGS in comparison to baseline, after twelve weeks of twice-daily application of the cream; b) despite of the presence of SA, which is a well known irritating agent, the tolerability of the cream was very good: this was likely due to the presence of the two molecules of glycine in PAD and 0.2% allantoin (2,5-dioxoimidazolidin-4-yl)urea, the end product of purine catabolism. The latter has moisturizing and soothing effect, increasing the water content of the extracellular matrix. This good tolerability allows a high adherence of patients, mainly young patients, to the treatment: this cream markedly improves compliance. A controlled clinical study, in order to confirm these results, is mandatory. References 1.Doshi A, Zaheer A, Stiller MJ. A comparison of current acne grading systems and proposal of a novel system. Int J Dermatol 1997; 36:416-8. 2. Gehring W. Nicotinic acid/niacinamide and the skin. J Cosmet Dermatol 2004; 3:88-93. 3. Otte N, Borelli C, Korting HC. Nicotinamide biologic actions of an emerging cosmetic ingredient. Int J Cosmet Sci 2005; 27:255-61. 4. Namazi MR. Nicotinamide in dermatology: a capsule summary. Int J Dermatol 2007; 46:1229-31. 39

40 5. Lawrence ID. Nicotinamide gel: preclinical aspects. J Dermatol Treat 1995; 6 (Suppl 1):S5-7. 6. Shalita AR, Smith JG, Parish LC, Sofman MS, Chalker DK. To pical nicotinamide compared with clindamycin gel in the treatment of inflammatory acne vulgaris. Int J Dermatol 1995; 34:434-7. 7. Valins W, Amini S, Berman B. The expression of toll-like receptors in dermatological diseases and the therapeutic effect of current and newer topical toll-like receptor modulators. J Clin Aesthet Dermatol 2010; 3:20-29. 8. Shimoyama M, Kawai M, Hoshi Y, Ueda I. Nicotinamide inhibition of 3',5'-cyclic amp phosphodiesterase in vitro. Biochem Biophys Res Commun 1972; 49:1137-41. 9. Burger DR, Vandenbark AA, Daves D, Anderson WA Jr, Vetto RM, Finke P. Nicotinamide: suppression of lymphocyte transformation with a component identified in human transfer factor. J Immunol 1976; 117:797-801. 10. Shimizu T. Role of macrophage migration inhibitory factor (MIF) in the skin. J Dermatol Sci 2005; 37:65-73. 11. Grange PA, Raingeaud J, Calvez V, Dupin N. Nicotinamide inhibits Propionibacterium acnes-induced IL-8 production in keratinocytes through the NF-kappaB and MAPK pathways. J Dermatol Sci 2009; 56:106-12. 12. Tanno O, Ota Y, Kitamura N, Katsube T, Inoue S. Nicotinamide increases biosynthesis of ceramides as well as other stratum corneum lipids to improve the epidermal permeability barrier. Br J Dermatol 2000; 143:524-31. 13. Draelos ZD, Matsubara A, Smiles K. The effect of 2% niacinamide on facial sebum production. J Cosmetol Laser Ther 2006; 8:96-101. 14. Rougier N, Verdy C, Chesne C. Pouvoir inhibiteur d un gel anti-adhésion bactérienne sur l adhésion de Propionibacterium acnes aux cornéocytes de sujets acnéiques. Nouv Dermatol 2003; 22:1-4. 15. Griffiths CEM. Nicotinamide 4% gel for the treatment of inflammatory acne vulgaris. J Dermatol Treat 1995; 6 (Suppl 1):S8-10. 16. Dos SK, Barbhuiya JN, Jana S, Dey SK. Comparative evaluation of clindamycin phosphate 1% and clindamycin phosphate 1% with nicotinamide gel 4% in the treatment of acne vulgaris. Indian J Dermatol Venereol Leprol 2003; 69:8-9. 17. Sardesai VR, Kambli VM. Comparison of efficacy of topical clindamycin and nicotinamide combination with plain clindamycin for the treatment of acne vulgaris and acne resistant to topical antibiotics. Indian J Dermatol Venereol Leprol 2003; 69:138-9. 18. Weltert Y, Chartier S, Gibaud C, Courau S, Pechenart P, Sirvent A, Girard F. Évaluation clinique en double aveugle de l efficacité d un gel de nicotinamide 4% (Exfoliac NC Gel) versus gel d érythromycine 4% dans la prise en charge des acnés modérées à composante inflammatoire prédominante. Nouv Derma - tol 2004; 23:385-94. 19. Veraldi S., Barbareschi M., Fabbrocini G., Innocenzi D., Bettoli V., Micali G., Monfrecola G., Schianchi R. Trattamento dell acne lieve-intermedia con nicotinamide topica. Risultati di due studi clinici italiani multicentrici I parte. J Acne 2009; 4:26-8. 20. Morganti P, Berardesca E, Guarneri B, Guarneri F, Fabrizi G, Palombo P, Palombo M. Topical clindamycin 1% vs. linoleic acidrich phosphatidylcholine and nicotinamide 4% in the treatment of acne: a multicentre-randomized trial. Int J Cosmet Sci 2011; 33:467-76. 21. Veraldi S, Giovene GL, Guerriero C, Bettoli V: Efficacy and tolerability of topical 0.2% Myrtacine and 4% vitamin PP for prevention and treatment of retinoid dermatitis in patients with mild to moderate acne. G Ital Dermatol Venereol 2012; 147: 491-7. 22. Veraldi S, Micali G, Barbareschi M, Tedeschi A, Schianchi R. Topical nicotinamide in acne: a critical review. Eur J Acne 2012; 3: 21-6. 23. Maramaldi G, Esposito M. Potassium azeloyl diglycinate. Cosm & Toil 2002; 117: 43-50. 24. Celleno L, Bussoletti C, Caserini M, Palmieri R. Instrumental assessment of the soothing effect of a new product based on hydroxypropyl chitosan and potassium azeloyl diglycinate. J Plast Dermatol 2012;8: 33-35. 25. Berardesca E, Iorizzo M, Abril E, Guglielmini G, Caserini M, Palmieri R, Piérard GE. Clinical and instrumental assessment of the effects of a new product based on hydroxypropyl chitosan and potassium azeloyl diglycinate in the management of rosacea. J Cosmet Dermatol 2012; 11:37-41. 26. Veraldi S, Raia DD, Schianchi R, De Micheli P, Barbareschi M. Treatment of symptoms of erythemato-telangiectatic rosacea with topical potassium azeloyl diglycinate and hydroxypropyl chitosan: results of a sponsor-free, multicenter, open study. J Dermatolog Treat 2014; 27:1-2. 27. Shalita AR. Treatment of mild and moderate acne vulgaris with salicylic acid in an alcohol-detergent vehicle. Cutis 1981; 28:556-8, 561. 28. Shalita AR. Comparison of a salicylic acid cleanser and a benzoyl peroxide wash in the treatment of acne vulgaris. Clin Ther 1989; 11:264-7. 29. Zander E, Weisman S. Treatment of acne vulgaris with salicylic acid pads. Clin Ther 1992; 14:247-53. 30. Davis DA, Kraus AL, Thompson GA, Olerich M, Odio MR. Percutaneous absorption of salicylic acid after repeated (14-day) in vivo administration to normal, acnegenic or aged human skin. J Pharm Sci 1997; 86:896-9. 31. Rougier A, Richard A. Efficacy and safety of a new salicylic acid derivative as a complement of vitamin A acid in acne treatment. Eur J Dermatol 2002; 12:XLIX-L. 32. Bréno B, Khammari A, Richard A, Rougier A. Interest of a new salicylic acid derivative in the prevention of acne relapses. Eur J Dermatol 2002; 12:LI-LIII. 33. Lee HS, Kim IH. Salicylic acid peels for the treatment of acne vulgaris in Asian patients. Dermatol Surg 2003; 29:1196-9.

34. Boutli F, Zioga M, Koussidou T, Ioannides D, Mourellou O. Comparison of chloroxylenol 0.5% plus salicylic acid 2% cream and benzoyl peroxide 5% gel in the treatment of acne vulgaris: a randomized double-blind study. Drugs Exp Clin Res 2003; 29:101-5. 35. De Souza A, Christiansen C, Jamie S. The use of salicylic acid in a new delivery system as a co-adjuvant topical treatment for acne vulgaris. Aesthet Surg J 2005; 25:40-3. 36. Touitou E, Godin B, Shumilov M, Bishouty N, Ainbinder D, Shouval R, Ingber A, Leibovici V. Efficacy and tolerability of clindamycin phosphate and salicylic acid gel in the treatment of mild to moderate acne vulgaris. JEADV 2008; 22:629-31. 37. Hashimoto Y, Suga Y, Mizuno Y, Hasegawa T, Matsuba S, Ikeda S, Monma T, Ueda S. Salicylic acid peels in polyethylene glycol vehicle for the treatment of comedogenic acne in Japanese patients. Dermatol Surg 2008; 34:276-9. 38. Dainichi T, Ueda S, Imayama S, Furue M. Excellent clinical results with a new preparation for chemical peeling in acne: 30% salicylic acid in polyethylene glycol vehicle. Dermatol Surg 2008; 34:891-9 39. Garg VK, Sinha S, Sarkar R. Glycolic acid peels versus salicylic-mandelic acid peels in active acne vulgaris and post-acne scarring and hyperpigmentation: a comparative study. Dermatol Surg 2009; 35:59-65. 40. Nilfroushzadeh MA, Siadat AH, Baradaran EH, Moradi S. Clindamycin lotion alone versus combination lotion of clindamycin phosphate plus tretinoin versus combination lotion of clindamycin phosphate plus salicylic acid in the topical treatment of mild to moderate acne vulgaris: a randomized control trial. Indian J Dermatol Venereol Leprol 2009; 75:279-82. 41. Bissonnette R, Bolduc C, Seité S, Nigen S, Provost N, Maari C, Rougier A. Randomized study comparing the efficacy and tolerance of a lipophillic hydroxy acid derivative of salicylic acid and 5% benzoyl peroxide in the treatment of facial acne vulgaris. J Cosmet Dermatol 2009; 8:19-23. 42. Micali G, Innocenzi D, Veraldi S. A new topical salicylic acid in a thermoactivable foam for mild acne treatment. Results of a pilot trial. Eur Bull Drug Res 2009; 17:1-4. 43. Seidler EM, Kimball AB. Meta-analysis comparing efficacy of benzoyl peroxide, clindamycin, benzoyl peroxide with salicylic acid, and combination benzoyl peroxide/clindamycin in acne. J Am Acad Dermatol 2010; 63:52-62. 44. Babayeva L, Akarsu S, Fetil E, Güneş AT. Comparison of tretinoin 0.05% cream and 3% alcohol-based salicylic acid preparation in the treatment of acne vulgaris. JEADV 2011; 25:328-33. 45. Levesque A, Hamzavi I, Seite S, Rougier A, Bissonnette R. Randomized trial comparing a chemical peel containing a lipophilic hydroxy acid derivative of salicylic acid with a salicylic acid peel in subjects with comedonal acne. J Cosmet Dermatol 2011; 10:174-8. 46. Moy RL, Levenson C, So JJ, Rock JA. Single-center, openlabel study of a proprietary topical 0.5% salicylic acid-based treatment regimen containing sandalwood oil in adolescents and adults with mild to moderate acne. J Drugs Dermatol 2012; 11: 1403-8. 47. Akarsu S, Fetil E, Yücel F, Gül E, Güneş AT. Efficacy of the addition of salicylic acid to clindamycin and benzoyl peroxide combination for acne vulgaris. J Dermatol 2012; 39:433-8. 48. Bae BG, Park CO, Shin H, Lee SH, Lee YS, Lee SJ, Chung KY, Lee KH, Lee JH. Salicylic acid peels versus Jessner's solution for acne vulgaris: a comparative study. Dermatol Surg 2013; 39:248-53. 49. Monheit G. Commentary: salicylic acid peels versus Jessner's solution peels for acne vulgaris: a comparative study. Dermatol Surg 2013; 39:253-4. 50. Raone B, Veraldi S, Raboni R, Ardigò M, Patrizi A, Micali G. Salicylic acid peel incorporating triethyl citrate and ethyl linoleate in the treatment of moderate acne: a new therapeutic approach. Dermatol Surg 2013; 39:1243-51. 51. 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Stefano Veraldi, Mauro Barbareschi Department of Pathophysiology and Transplantation, University of Milan, IRCCS Foundation, Ca Granda Ospedale Maggiore Policlinico, Milan, Italy Results of a multicentre, pilot, open, sponsor-free study on the efficacy, tolerability and impact on quality of life of a cream containing glycolic acid, retinaldehyde and undecyl-rhamnoside in patients with acne SUMMARY Stefano Veraldi The aim of this multicentre, pilot, open, sponsor-free study was to assess the efficacy, tolerability and impact on quality of life of a cream containing glycolic acid, retinaldehyde and undecylrhamnoside, in patients with mild to moderate acne. Epidemiological data, as well as data on the efficacy of the cream on scars, were also studied. 252 Italian patients were included and treated once daily for a mean period of 61 days. Changes from baseline in acne severity, seborrhoea, acne scar and quality of life were evaluated by means of specific scales. Acne severity, evaluated by means of the Global Evaluation of Acne (GEA), decreased from 2.5 to 1.5 (improvement of 39.6%, p<0.0001). Seborrhoea improved in 59% of patients. The overall percentage of patients with acne scars, evaluated by means of the Echelle Clinique des Cicatrices d Acné (ECCA), decreased from baseline (40.9%) to visit 1 (34.3%; p=0.0003). Impact of acne on quality of life, measured by means of the Cardiff Acne Disability Index (CADI), decreased from 5 to 3 (p<0.0001). Treatment was very well tolerated. The fixed combination of glycolic acid, retinaldehyde and undecyl-rhamnoside is an effective and well tolerated treatment option for mild to moderate acne. Key words: Acne; Glycolic acid; Retinaldehyde; Undecyl-rhamnoside; Quality of life; Scars. Introduction 42 The addition of an alpha-hydroxy acid, such as glycolic acid, to a retinoid, such as retinaldehyde, results in a better bioavailability of the retinoid, thus a higher delivery, which potentiates the biological activities of the retinoid. This combination therefore allows a delivery of higher amounts of retinaldehyde in the skin 1. The combination of glycolic acid with retinaldehyde showed to be effective in both non inflammatory and inflammatory acne lesions with a very good tolerability 2-4. Retinaldehyde differs from other topical retinoids, such as retinol and retinoic acid, because it possesses a specific anti-propionibacterium acnes activity. This is likely due to the presence of an aldehyde group in the isoprenoic lateral chain 5. Undecyl-rhamnoside (characterized by the presence of 11 atoms of carbonium) is derived from pentyl-rhamnoside (with 5 atoms of carbonium) and rhamnosium (with 6 atoms of carbonium). Both of these molecules inhibit the synthesis and release from keratinocytes of proinflammatory cytokines; however, they have a low skin bioavailability 6. A 24 hours treatment with undecyl-rhamnoside prior to the P. acnes stimulation down-regulated the P. acnes-induced overexpressed cytoki - nes (interleukins-1α and 8, and matrix metalloproteinase 9 ) and up-regulated interleukin-1 receptor antagonist levels in a similar modality than zinc gluconate 6. Undecyl-rhamnoside possesses a good skin bioavailability: this is likely due to the fact that this molecule is highly lipophilic 6. The aim of this multicentre, pilot, open, sponsorfree study was to assess the efficacy and tolerability of a cream containing 6% glycolic acid, 0.1% retinaldehyde, 0.1% undecyl-rhamnoside (Efectiose ), 5% Avène thermal water and 5% arginine, at a ph of 3.5 (TriAcneal Avène - Pierre Fabre Laborato -

ries) in patients with mild to moderate acne. To our knowledge, this is the first study investigating the role of this treatment combination in acne. Patients and methods Two hundred and fifty-two patients (males: 28.4%, females: 71.6%; mean age: 22 years), with mixed (comedonal and inflammatory), mild to moderate acne of the face, were treated with the cream. Wash out period was at least two weeks for topical antiseptics, antibiotics, azelaic acid, salycilic acid, nicotinamide and retinoids; at least two months for oral antibiotics and at least six months for oral isotretinoin. The cream was applied once daily for 6-12 weeks. Each application was preceded by a cleansing. No other topical and/or systemic products or drugs were allowed, except for non-comedogenic cosmetics and sunscreens. Furthermore, neither chemical peelings nor sunlight exposure/phototherapy were allowed. All patients were examined every six weeks. The aims of the study were to assess the efficacy (first endpoint) and tolerability (second endpoint) of this fixed combination and the impact on quality of life (third endpoint). Acne epidemiology was evaluated at baseline (V0) by means of a questionnaire assessing patients medical history and lifestyle. At baseline (V0) and after 6 weeks of treatment (V1), the following measures were assessed: a) acne severity by means of the Global Evalu a - tion of Acne (GEA) 7 : 0-5 points score; at base - line all patients should have a GEA score 2 to be included in the trial; b) acne scar by means of the Echelle Clinique des Cicatrices d Acné (ECCA) 8 and c) impact of acne on quality of life by means of the Cardiff Acne Disability Index (CADI) (0-15 score) 9. Tolerability and patients global satisfaction were also evaluated at V1. Results Two hundred and fifty-two patients were enrolled: 94.7% of these patients completed the study and were therefore considered as evaluable. Mean treatment duration was 61 days. Medical history revealed that a family history of acne was present in 50.8% of patients; these had a history of acne for nearly 5.1 years. Mean age of acne appearance and of first oral treatment was 16.6 and 19.4 years, respectively. 26.9% of patients were affected by acne also in areas of the skin surface other than the face. Acne severity at baseline was 2.5. Severity decreased to 1.5 (39.6% of improvement: p < 0.0001) after a mean duration of the treatment of 61 days (Figure 1). 43.8% of patients had at baseline a moderate acne severity; Figure 1. Acne severity change (n=252 patients) from baseline (V0) to V1. (After 61 days of mean treatment duration). 43

Figure 2. Distribution of patients (n=252) along acne severity GEA score: change from baseline (V0) to V1. 0= no lesion; 1= almost no lesion; 2= mild lesions; 3= moderate lesions; 4= severe lesions; 5= very severe lesions. Table 1. Patients (n=252) with acne scars, according to ECCA. Grading scale: change from baseline to V1 (61 mean days of treatment). Kind of scars Baseline V1 V-shaped 72.7% 68.2% U-shaped 37.0% 31.5% M-shaped 10.3% 5.9% Superficial elastolysis 14.5% 11.6% Hypertrophic inflammatory (< 2 years of age) 7.1% 2.9% Keloid (< 2 years of age) 0% 0% 44 at V1, 39.9% and 41.8% of patients showed complete remission or a mild severity, respectively (Figure 2). The overall percentage of patients with acne scars decreased from baseline (40.9%) to V1 (34.3%; p = 0.0003). This decrease was reported for each kind of scar (Table 1). As far as the efficacy on scars is concerned, 54.2% of patients stated to observe an improvement that was judged as moderate, good or very good in 22.9%, 17.6% and 13.7% of cases, respectively. A total of 86.6% of patients reported a global efficacy that was judged as moderate (34.4%), good (41.1) and excellent (11.2%). Concerning patients quality of life, mean CADI score decreased from baseline (5) to V1 (3: p < 0.0001): 79.2% patients reported an improvement in their quality of life. At V1, 95.1% of the dermatologists reported that tolerability was good (35%) or very good (60.1%). 14.1% of patients reported adverse events; in 5.6% of them, it was necessary to stop the treatment. According to the investigators opinion, 9.9% of the reported adverse effects were related to the treatment. Overall, 89.7% of patients and 93.3% of physicians were satisfied or very satisfied with treatment. On a 0-10 points scale, patients rated >8 the acceptance level of treatment (consistency of the cream, time of penetration and skin comfort after

the application); 92.4% of patients expressed their willingness to continue to use this cream after the end of the study. Discussion Our study showed, for the first time, that the fixed combination glycolic acid, retinaldehyde and undecyl-rhamnoside is effective in decreasing acne lesions severity, improving seborrhoea and acne scar, and it is well tolerated. Previous studies demonstrated the efficacy as well as the good tolerability of the combination glycolic acid/retinaldehyde. In a multicentre, doubleblind, randomized, vehicle-controlled trial, Poli et al. 3 demonstrated a significant decrease in both non inflammatory and inflammatory lesions with a very good tolerability (only one patient stopped the treatment). In another study on more than 1700 patients, a very high compliance of the combination glycolic acid/retinaldehyde was shown 2. These data were confirmed in a population of adult women with acne 4. Our study provides the first in vivo data of the role of undecyl-rhamnoside, in combination with glycolic acid and retinaldehyde, in the treatment of acne and in the potential reduction of scar formation. As previously mentioned, the overall percentage of patients with acne scar decreased from baseline (40.9%) to V1 (34.3%; p=0.0003). This decrease was reported for each kind of scar. Although in this analysis the change is not statistically significant, it has a great relevance from the clinical point of view. However, a controlled study is necessary in order to confirm these observations. Acne is associated with a greater psychological burden than other chronic skin disorders. Several studies demonstrated psychological abnormalities, including depression and anxiety. Effective treatment of acne is accompanied by improvement in self-esteem, body image, social assertiveness and self-confidence 10. In our study, the treatment has proven to be effective also in significantly improving patients quality of life, as measured by the CADI index. The high tolerability of the study cream has been confirmed not only by physicians judgment, but also by the adherence rate (almost 95%). Patients and physicians high level of global satisfaction by means of this treatment confirms the favorable profile of this combination. In conclusion, the fixed combination glycolic acid, retinaldehyde and undecyl-rhamnoside is an effective and well tolerated treatment option for mild to moderate acne. Declaration of interest. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. The following dermatologists attended this study: Giuseppe Alessandrini (Ugento, Lecce) Vincenzo Bettoli (Ferrara) Federica Dall Oglio (Catania) Gabriella Fabbrocini (Naples) Massimo Gola (Florence) Giuseppe Micali (Catania) Giuseppe Monfrecola (Naples) Monica Pau (Cagliari) Nevena Skroza (Rome) Aurora Tedeschi (Catania) Ersilia Tolino (Rome) 45

References 1. Tran C, Kasraee B, Grand D, Carraux P, Didierjean L, Sorg O, Saurat JH. Pharmacology of RALGA, a mixture of retinaldehyde and glycolic acid. Dermatology 2005; 210 (Suppl. 1):6 13. 2. Dréno B, Nocera T, Verrière F, Vienne MP, Ségard C, Vitse S, Carré C. Topical retinaldehyde with glycolic acid: study of tolerance and acceptability in association with anti-acne treatments in 1709 patients. Dermatology 2005; 210 (Suppl. 1):22 9. 3. Poli F, Ribet V, Lauze C, Adhoute H, Morinet P. Efficacy and safety of 0.1% retinaldehyde / 6% glycolic acid (Diacneal) for mild to moderate acne vulgaris. A multicentre, double-blind, randomized, vehicle-controlled trial. Dermatology 2005; 210 (Suppl 1):14 21. 4. Dréno B, Castell A, Tsankov N, Lipozencic J, Serdaroglu S, Gutierrez V, Gadroy A, Merial-Kieny C, Mery S. Interest of the association retinaldehyde/glycolic acid in adult acne. J Eur Acad Dermatol Venereol 2009; 23:529-32. 5. Pechère M, Germanier L, Siegenthaler G, Pechère JC, Saurat JH. The antibacterial activity of topical retinoids: the case of retinaldehyde. Dermatology 2002; 205:153 8. 6. Isard O, Lévêque M, Knol AC, Ariès MF, Khammari A, Nguyen JM, Castex-Rizzi N, Dréno B. Anti-inflammatory properties of a new undecyl-rhamnoside (APRC11) against P. acnes. Arch Dermatol Res 2011; 303:707-13. 7. Dréno B, Poli F, Pawin H, Beylot C, Faure M, Chivot M, Auffret N, Moyse D, Ballanger F, Revuz J. Development and evaluation of a Global Acne Severity Scale (GEA Scale) suitable for France and Europe. J Eur Acad Dermatol Venerol 2011; 25:43-8 8. Dréno A, Khammari A, Orain N, Noray C, Mérial-Kieny C, Méry S, Nocera T. ECCA grading scale: an original validated acne scar grading scale for clinical practice in dermatology. Dermatology 2007; 214:46-51. 9. Dréno B, Finley AY, Nocera T, Verrière F, Taïeb C, Myon E. The Cardiff Acne Disability Index: cultural and linguistic validation in French. Dermatology 2004; 208:104-8. 10. Tan JK. Psychosocial impact of acne vulgaris: evaluating the evidence. Skin Therapy Lett 2004; 9:1-3, 9. LA NUOVA FRONTIERA DELLA COMUNICAZIONE SCIENTIFICA www.europeanjournalofacne.it In https://itunes.apple.com/it/app/acne-planet/id499557708?l=it&mt=8 News, articoli, professionisti, libri... Il meglio dell informazione internazionale sull Acne e Rosacea nell App per ipad, iphone, ipod Touch free download ACNE & ROSACEA PLANET 46

Vittorio Berruti, Antonia Gimma, Franca Taviti, Carla Cardinali Dermatology department, USL 4, Prato, Italy Drug-induced acneiform eruptions SUMMARY Vittorio Berruti Drug-induced acneiform eruptions are a frequently observed condition for dermatologists. Diagnosis is often difficult and requires a thorough search for the drug involved, since multiple medications are often administered. There are no specific criteria to diagnose drug-induced acne; there are, however, specific characteristics that may help to relate skin eruption to the administration of a specific drug. Key words: Drug-induced acneiform eruptions; Drug-induced acne. Introduction Drug-induced acneiform eruptions are acne-like skin manifestations occurring after the intake of a wide range of medications (Table 1). They should be suspected in the absence of a previous history of acne or in patients with a mild form of acne who show a sudden worsening of the clinical picture. The clinical pattern is of papulopustular type, with a monomorphic appearance. There are no cysts and comedones at the onset, although they may appear at a later stage. Pruritus is often present. Localization may involve not only the seborrhoeic areas, but also limbs, trunk, lower back and genitals. If a clinical remission is achieved after discontinuation of the drug and lesions recur after the reinstatement of the medication, the drug can be considered as the etiological agent of the acneiform eruption 1. Table 1 Drug-induced acneiform eruptions. Hormones Vitamins B 1, B 6, B 12, D Antidepressants Antiepileptics Antipsicotics Tetracyclines Isonicotinic acid Phenobarbiturics Thyroid-stimulating hormone Disulfiram Chloroquine Azathioprine Halogen drugs EGFR-inhibitors PUVA 47

48 Differential diagnosis Acne vulgaris Pseudofolliculitis barbae Rosacea and perioral dermatitis (also steroid-induced) Acneiform secondary syphiloderm/syphilis Demodicosis Behçet s disease Infective folliculitis Lupus miliaris disseminatus Eosinophilic pustular folliculitis Papular sarcoidosis Hormonal therapies Hormonal therapies are one of the most frequent causes of acneiform eruptions; a distinction should be made between those induced by topical and systemic corticosteroids, by corticotropin (ACTH), by androgens and anabolic steroids, by hormonal contraceptives and by other hormones, such as danazol and thyroid-stimulating hormone. Steroids The onset of symptoms begins 2 to 4 weeks after their administration. The eruption is monomorphic, with small dome-shaped inflammatory papulae and pustules on the seborrhoeic areas (face and trunk), extending to the proximal region of the limbs. After resolution of the initial inflammatory phase, comedones or small keratin cysts may appear. The application of topical corticosteroids may increase the concentration of free fatty acids on the skin, leading to an increase of bacteria in the pilosebaceous unit. Manifestations may be more severe on the face, where the absorption of liposoluble corticosteroid is greater, as the stratum corneum is thinner and there is a larger number of sebaceous follicles. The molecular mechanism that can explain the steroid-induced acneiform eruption has been described in the literature 2 : the addition of corticosteroids to cultures of keratinocytes enhances the expression of the Toll-like receptors 2 (TRL2), which when activated by P. Acnes would induce an inflammatory response. This TRL2- P.Acnes receptor activation mechanism may be responsible both for the exacerbation of acne vulgaris and for the induction of steroid-related acneiform eruptions. Anabolic androgenic steroids (AAS) 3 Testosterone represents the treatment of choice for hypogonadism, azoospermia and male menopause. After administration, it is converted into its active metabolite, 5 α-dihydrotestosterone, capable of stimulating the sebaceous glands and leading to their hypertrophy and to hypersecretion of sebum. The clinical manifestation consists in an eruption of follicular monomorphic papulae and pustules, located on the face, trunk and limbs, followed by the appearance of comedones. If the drug cannot be discontinued, the conventional therapy for acne should be started. Acne induced by anabolic steroids, also called body building acne or doping acne, is frequent in athletes who take high doses of AASs and affects up to 50% of the individuals 4. Its clinical manifestations are variable and may consist of hypersecretion of sebum, papulae-pustules, up to conglobate acne and acne fulminans. It may occur de novo or develop on preexisting acne. The clinical signs that may accompany an acneiform eruption are gynaecomastia, decrease in testicular volume, appearance of striae, oedema and increase in body mass 1. Cases of acneiform eruptions along the jawline and/or back line have been reported in women using etonogestrel or levonorgestrel-releasing intrauterine systems after 1-3 months of their implanting. Neuropsychiatric drugs Several classes can be responsible for the development of acneiform eruption (Table 2). Amineptine is a non-halogenated tricyclic antidepressant. Even after several years of treatment, it may trigger an acneiform clinical manifestation consisting in the appearance of retentional monomorphic lesions, such as microcysts, macro-

Table 2 Neuropsychiatric drugs. Non-halogenated tricyclic antidepressant: amineptina, maprotilina, imipramina Lithium Antiepileptics Aripiprazolo Serotonin reuptake inhibitors Antipsicotics cysts and comedones of varying size 1. The clinical picture may evolve to actual facial disfigurement ( monstrous acne ). The drug and its metabolites are often found in the sebaceous secretions and in cyst content, as well as in plasma and urine 1. Since the drug may be found in sebaceous secretions and sweat, there could be metaplastic keratinization in the papulokeratotic lesions in both eccrine gland (syringometaplasia) and the sebaceous gland. We can therefore suspect a toxic action of the drug on the appendages or a chronic inflammatory action, with dose-dependent severity of the clinical picture. Therapy should consist in the discontinuation of the drug and, if necessary, surgical removal of macrocysts and systemic administration of isotretinoin 5. Lithium It is considered one of the key drugs in the treatment of depression. It is used in patients suffering from severe depression and from bipolar disorders. The onset of acneiform eruption is rapid and not dose-dependent and, in some cases, it may be accompanied by hidradenitis and conglobate acne. The most affected areas are face, armpits, groin, upper and lower limbs, buttocks, and in males often the extremities. By accumulating in the skin, lithium causes superficial follicular occlusion, leading to dilatation of apocrine and sebaceous glands with hypersecretion of sebum, and with resulting trigger of mechanisms of neutrophilic chemotaxis, inflammation and bacterial infection. Antiepileptics and serotonin reuptake inhibitors They are used to treat depression. Acnei - form manifestations 7, 8 usually affect the face and upper part of the trunk, with prevalence of pustular lesions and sometimes folliculitis while comedonal lesions occur in case of prolonged treatment 1. A few cases, described in the literature, 7-9 report acneiform skin manifestations following the administration of aripiprazole. These cases have been explained on the basis of Type III allergic mechanisms in an already sensitized individual, and Type IV in a subject with delayed hypersensitivity, which triggered a foreign-body granulomatous reaction in the skin 7. Vitamins Cases of drug-induced acneiform eruptions caused by vitamins, such as those of the B group (B 1, B 6, B 12 ), have been described in the literature, although their pathogenetic mechanisms are not yet completely understood. A causal role played by the iodate particles used for extraction of Vitamin B 12 can be assumed, as described by Dupré et al. 10 It is a sudden eruption in the face of large-sized monomorphic papulae and pustules with hypersecretion of sebum. It is rapidly reversible after the discontinuation of the drug. Cytostatics and immunosuppressants Actinomycin D has a tricyclic structure, similar to that of antidepressant drugs, and is used in the treatment of rabdomyosarcoma, Wilms tumor, Ewing, Kaposi, sarcoma, corioncarcinoma. It can increase the levels of androgen hormones by directly, or possibly indirectly, stimulating an increase in ACTH. Inflammatory lesions occur after approximately 5 days of treatment with the drug, in the typical locations of acne vulgaris, with comedones appearing at a later stage. The effect is dose-dependent 11. Cases of acneiform eruptions accompanied by systemic manifestations caused by immunomodulating molecules, such as topical ciclosporin, azathioprine, sirolimus, tacrolimus and pimecrolimus and interferon, 12, 13 have been reported in the literature. 49