Barbareschi, M

Berardesca, E

Pimpinelli, Nicola

Veraldi, S

English

Florence Research

Contact Dermatitis, 2001, 45, 280–285 Copyright C Munksgaard 2001Printed in Denmark . All rights reservedISSN 0105-1873Evaluation of efficacy of a skin lipid mixture inpatients with irritant contact dermatitis, allergiccontact dermatitis or atopic dermatitis:a multicenter studyE. Berardesca1, M. Barbareschi2, S. Veraldi2 and N. Pimpinelli31Department of Dermatology, IRCCS Policlinico S. Matteo, Pavia, Italy2Institute of Dermatological Sciences IRCCS, Milan, Italy3Department of Dermatological Sciences, University of Florence, Medical School, ItalyDisturbances of skin barrier function occur in several skin diseases, e.g., atopic dermatitis (AD),irritant/allergic contact dermatitis (ICD, ACD). Skin barrier damage triggers the production ofcytokines that stimulate lipogenesis which may also cause inflammatory processes. The aim of thisstudy was to evaluate the efficacy of a topical skin lipid mixture in the treatment of ICD, ACDand AD. 580 consecutive patients suffering from ICD, ACD or AD were treated with a skin lipidmixture containing ceramide-3 and patented nanoparticles. Patients received the lipid mixturealone or in combination with topical corticosteroids until clearance or for 8 weeks. Both treatmentgroups statistically improved all parameters considered at week 4 and 8 as compared to baseline.Between the 2 treatment groups, there was a statistically significant difference in favour of com-bined therapy for (ICD, ACD, AD, respectively): erythema, pruritus and overall disease severity;erythema and pruritus; erythema, pruritus, fissuring and overall disease severity. No statisticallysignificant difference was found for (ICD, ACD, AD, respectively): dryness, scaling and fissuring;scaling, fissuring and overall disease severity; dryness and scaling. Between the 2 ACD treatmentgroups, there was a statistically significant difference in favour of the skin lipid mixture for dryness.In conclusion, the study shows that balanced lipid mixtures are effective in improving barrierproperties and the clinical condition of the skin in contact dermatitis.Key words: barrier function; allergic contact dermatitis; stratum corneum intercellular lipids; atop-ic dermatitis; irritant contact dermatitis. C Munksgaard, 2001.Accepted for publication 27 July 2001The cutaneous permeability barrier, localized inthe stratum corneum (SC) interstices, is consti-tuted by lamellar bilayers, rich in cholesterol, freefatty acids and ceramides (1–4). Topical treatmentwith either an organic solvent, acetone, detergentsor other irritants, disrupts this barrier by removalof these lipids (2–5). In response to barrier disrup-tion, a homeostatic repair response is initiatedwithin the nucleated epidermis, which results in therapid restoration of lipids in the SC and normal-ization of barrier function; this homeostatic re-sponse includes an increase in epidermal synthesisof all 3 of the above-mentioned skin lipid classes(6–8). The requirement for an increase in lipid syn-thesis for barrier repair is shown by the obser-vation that inhibition of either cholesterol, fattyacid or sphingolipid synthesis alone, leads to a de-lay in barrier repair (9–11). Thus, lipid productionin the nucleated layers of the epidermis providesthe lipids required for barrier restoration.Recent studies have shown that application ofany 1 or 2 of these lipid classes to damaged skinimpedes rather than facilitates the rate of barrierrepair, as can be detected by transepidermal waterloss (TEWL) (11). In contrast, when members ofall 3 key lipid classes are supplied together, normalrates of barrier repair occur. Furthermore, follow-ing acute barrier disruption, exogenous physiol-ogic lipids, whether in complete or incompletemixtures, quickly permeate the SC, are taken upby the nucleated layers of the epidermis, and areincorporated into lamellar bodies (LB).Then, depending on the lipid composition andproportion, normal or abnormal LB are formed,281EVALUATION OF A SKIN LIPID MIXTURETable 1. Sex and age profiles of the patients participating to thestudySkin lipid CombinedVariable mixture therapysex (M/F), ACD group 11/24 61/104age, ACD group 36.8∫9.18 35.7∫12.7sex (M/F), ICD group 34/89 64/90age, ICD group 38.2∫13.9 38.5∫14.7sex (M/F), AD group 13/11 33/32age, AD group 31.4∫11.1 27.3∫11.6Table 2. Number patients/disease and corresponding assignedtreatmentTreatment groups ACD ICD ADmissing 5 6 2skin lipid mixture 35 123 24combined therapy 166 154 65total patients/disease 206 283 91total patients 580leading to the formation of either normal or ab-normal lamellar unit structures in the SC inters-tices (11, 12).The present study was designed to evaluate theefficacy of a skin lipid mixture in the treatment ofconditions involving barrier damage, such as atop-ic dermatitis (AD), and irritant/allergic contactdermatitis (ICD, ACD).Materials and Methods580 consecutive patients (206 with ACD, 283 withICD and 91 with AD) entered the study (Table 1).Fig. 1. *Ωp,0.05 in favour of group B versus group A. AΩpatients treated with skin lipid mixture alone; BΩpatients treated withskin lipid mixturepitopical corticosteroids.Patients were divided into 2 treatment groups: skinlipid mixture alone and skin lipid mixture plus top-ical corticosteroids. 13 patients (5 with ACD, 6with ICD and 2 with AD) were excluded from stat-istical analysis due to missing assigned treatmentgroup.All patients were treated with a skin lipid mix-ture containing ceramide-3, cholesterol, palmiticacid and oleic acid in a water-in-oil vehicle con-taining a patented nanoparticles technology (Re-positolA/AlfasonA Repair/Locobase RepairA/Nou-rivaTM Repair; Yamanouchi). The product wastopically applied 1–2¿ a day, alone (group A) orin combination with topical corticosteroids (e.g.,hydrocortisone-17-butyrate, betamethasone-valer-ate, prednicarbate, desoxymethasone, mometa-sone-furoate, prednisolone-aceponate, budesonide)(group B). The different topical corticosteroidpreparations were selected in the centers partici-pating to the study on the basis of the clinical se-verity of symptoms. The skin lipid mixture was ap-plied until healing occurred or for a maximumperiod of 8 weeks. Dermatologists randomly as-signed the patient to single or combined therapy.The severity of skin lesions was evaluated at base-line and after 4 and 8 weeks. The following symp-toms were evaluated: dryness, scaling, erythema,pruritus, fissuring and overall disease severity,using a visual 4-score rating scale (0Ωnone, 1Ωmild, 2Ωmoderate, 3Ωsevere).Statistical analysisAll data were summarized using a descriptive stat-istical technique. The results were expressed as a282 BERARDESCA ET AL.Fig. 2. *Ωp,0.05 in favour of group A versus group B; piΩp,0.05 in favour of group B versus group A. AΩpatients treated withskin lipid mixture alone; BΩpatients treated with skin lipid mixturepitopical corticosteroids.mean∫SD. The 2-way ANOVA test was used forstatistical evaluation at scheduled visits versusbaseline in each group; for multiple comparisont-Dunnet test was used. Between the 2 treatmentgroups, the comparison of the median values onthe differences observed at each scheduled visitversus baseline was performed using t-test for inde-pendent data. Non-parametric statistics were alsoused where appropriate. Statistical significance wasdefined as p,0.05.ResultsIrritant contact dermatitisBoth treatment groups (Table 2) had a statisticallysignificant improvement in all parameters con-sidered at week 4 and at week 8 versus baseline(Fig. 1, Fig. 4).The mean values of the differences after 4 and 8weeks versus baseline showed no statistically-sig-nificant difference between the 2 treatment groupsfor dryness (pΩ0.281 and pΩ0.300, respectively;ns), scaling (pΩ0.589 and pΩ0.261, respectively;ns) and fissuring (pΩ0.097 and pΩ0.390, respec-tively; ns), (Fig. 1).A statistically-significant difference in favour ofcombined therapy was shown for erythema(p,0.001 and p,0.001, respectively), pruritus(p,0.001 and p,0.001, respectively) and overallseverity disease (pΩ0.008 and pΩ0.031, respec-tively), (Fig. 1, Fig. 4).Allergic contact dermatitisBoth treatment groups had a statistically signifi-cant improvement in all parameters considered atweek 4 and at week 8 versus baseline (Fig. 2,Fig. 4). The mean values of the differences after4 and 8 weeks versus baseline showed no statisti-cally-significant difference between the 2 treat-ment groups for scaling (pΩ0.086 and pΩ0.355,respectively; ns), fissuring (pΩ0.847 and pΩ0.726,respectively; ns) and overall disease severity (pΩ0.528 and pΩ0.600, respectively; ns), (Fig. 2, Fig.4).A statistically-significant difference in favour ofthe skin lipid mixture was shown in dryness atweek 4 (p,0.001; pΩns at week 8); in favour ofcombined therapy for erythema at week 8 only (pΩ0.034; pΩns at week 4) and for pruritus at week 4and at week 8 (respectively pΩ0.019 and pΩ0.041)(Fig. 2).Atopic dermatitisBoth treatment groups had a statistically-signifi-cant improvement in all parameters considered atweek 4 and at week 8 versus baseline (Fig. 3, Fig.4). The mean values of the differences after 4 and8 weeks versus baseline showed no statistically-sig-nificant difference between the 2 treatment groupsfor dryness (pΩ0.612 and pΩ0.613, respectively;ns) and scaling (pΩ0.125 and pΩ0.166, respec-tively; ns) (Fig. 3).A statistically-significant difference in favour ofcombined therapy was shown for erythema at week4 (pΩ0.041; pΩns at week 8), pruritus at week 8(pΩ0.018; pΩns at week 4), fissuring at week 4 andweek 8 (pΩ0.002 and pΩ0.031), and overall sever-ity disease at week 4 (pΩ0.007; pΩns at week 8)(Fig. 3, Fig. 4).283EVALUATION OF A SKIN LIPID MIXTUREFig. 3. *Ωp,0.05 in favour of group B versus group A. AΩpatients treated with skin lipid mixture alone; BΩpatients treated withskin lipid mixturepitopical corticosteroids.Fig. 4. *Ωp,0.05 in favour of group B versus group A. AΩpatients treated with skin lipid mixture alone; BΩpatients treated withskin lipid mixturepitopical corticosteroids.DiscussionDisturbance of skin barrier function occurs in anumber of skin diseases, including atopic derma-titis (AD) and irritant/allergic contact dermatitis(ICD, ACD).The skin barrier can be damaged in severalways, such as by frequent exposure to mechanicalstress (construction workers, carpenters), lipid ex-traction by oils, grease or organic solvents, long-term exposure to water (cleaners, kitchen workers,fish or paper industry workers), detergents orliquid soap (housewives). As a consequence ofTEWL increase, the skin becomes dry. Skin barrierdisturbance triggers the production of cytokineswhich stimulate lipogenesis but can also increaseinflammatory responses and induce the appear-ance of eczema. As a result of a damaged skin bar-rier, irritant and sensitizing substances can moreeasily penetrate the skin, increasing the risk of de-velopment of ICD/ACD. Topically, application ofa lipid mixture has been shown to be useful in pro-284 BERARDESCA ET AL.viding ‘‘ready to use’’ lipids to the SC in order topromote repair of a deranged barrier; however, theusefulness of this model has been mainly shown inanimal models and few data in humans are avail-able (13–16). Furthermore, these studies have beenperformed using standardized irritation models,but not in real clinical conditions, where many en-vironmental and in-use cofactors can influence theoutcome of therapy.Our study shows how an optimized lipid mixtureincluded in nanoparticles (17) can be helpful inpromoting barrier repair and improving skin con-dition in different dermatoses characterized bybarrier damage.Both treatment groups improved significantly atweeks 4 and 8 both in AD and ICD/ACD. In par-ticular, no significant differences between the treat-ments at weeks 4 and 8 were detected for dryness,scaling, fissuring (ICD/ACD only) and overall dis-ease severity (ACD only) (i.e., the clinical par-ameters more related to SC efficiency) in all thepathologies investigated. The combined treatment(lipidspitopical corticosteroids) leads to a moresignificant effect on erythema, presumably due tothe corticosteroid’s vasoactive characteristics, andon pruritus as a probable consequence of a sup-pressed release of inflammatory mediators. Theoverall disease severity was in favour of the com-bined treatment in ICD and AD. These findingssupport the view that optimized lipid mixtures canbe helpful in improving barrier properties in clin-ical conditions, even though not exerting a phar-macological effect. Therefore, their use could beindicated as a support for barrier restructuringduring the acute phases of ICD/ACD or AD inassociation with pharmacological therapy, or as apreventive maintenance measure to counteract bar-rier disruption and reduce risk factors before theonset of clinical signs of irritant contact derma-titis.AcknowledgementsAcri R., Jasser A., Alloi I.E., Altobella L., Andri-ani G.C., Antonelli C., Baldini F., Bardone G.S.,Barone R., Bartalini P., Bassi A., Belli M.A.,Bencini P.L., Betti R., Bianchini S., Biondi M.,Confitto M.R., Borgognoni S., Borrelli D., Bozzet-ti M., Cambiagli S., Capilungo C., Caputo A.,Carbone R.L., Carboni A., Carvignese A.R.,Castelli F., Castelli V., Castellani L., Cecca E., Ces-pa M., Chiarpenello M., Cichetti A., Cogo M.,Colombo R., Colonna C., Croci S., Crupi A., DeFilippi C., De Luca T., De Natale F., De Rosa S.,De Zio A., Del Grande C., Della Corte G., DellaFornace F., Di Caprio N., Di Capua M., Di Giam-battista M., Di Iorio S., Bindelli A., Donato L.,Dozzani S., Dragonetti E., Fai D., Fenizi G., Fer-randi G., Ferri F., Filippelli A., Filosa G., ForteP., Franzoia P.R., Frattini L., Fusi M., Fuzio E.,Gadaleta R., Gaio L., Garofalo A.M., Gennaro P.,Germino M., Giorgi F., Goffredo A., Greco R.,Guerra S., Guida M., Landi G., Lega M., Lo Vas-to M., Lodi A., Lombardo M., Longhi F., LucianoS., Lui P., Macchione U., Marano S., Mariani M.,Marino N., Marsili F., Martora L., Maruccia A.,Mazzei V., Mazzocchi S., Monaco G., MontesanoM., Morabito S., Mozzicafreddo G., NapolitanoM., Natale R., Natalizi A., Nazzari G., Negri M.,Nume A., Orifici C., Orizio F., Palma W., Pannun-zio P.A., Pasquini F.A., Passarella M.G., PastenaS., Perotta E., Petronelli M., Pini M., Pirastu V.,Pompoli F., Pravettoni C., Puglisi A., Quadrini C.,Quercia G., Radaelli A., Rambaldi C., Raschi R.,Ricciuti F., Rivara G., Roatis M.L., Sabbioni L.,Sagramoso Z., Sarno A., Sartore P., Savarese M.,Scalzo A., Simonelli P., Soatti L., Soltani S., Som-ma M., Spedicato A., Spitaleri S., Stevanin L.,Stocchi F., Tomidei M., Tortora G., Trischitta A.,Trotta A., Vaiano V., Vaj U.N., Velluzzi M., VerrinaF., Vignoli G.P., Villa L., Zamperini C., ZangheriM., Zoccali A. Inphaser S.r.l. for statistical assist-ance.References1. Scheuplain R J et al. Permeability of the skin. Physiol Rev1971: 41: 701–747.2. Elias P M. Epidermal lipids, barrier function and desqua-mation. J Invest Dermatol 1983: 80: 44–49.3. Elias P M et al. Lipid-related barriers and gradients in theepidermis. NY Acad Sci 1988: 548: 4–13.4. Downing D T. Lipid and protein structures in the per-meability barrier of mammalian epidermis. J Lipid Res1992: 33: 301–313.5. Grubauer G et al. Lipid content and lipid type has determi-nants of the epidermal permeability barrier. J Lipid Res1989: 30: 89–96.6. Feingold K R. The regulation and role of epidermal lipidsynthesis. Adv Lipid Res 1991: 24: 57–82.7. Elias P M et al. Lipids and the epidermal water barrier:metabolism, regulation and pathophysiology. SeminDermatol 1992: 11: 176–182.8. Proksch E et al. Barrier function regulates epidermal lipidsand DNA synthesis. Br J Dermatol 1993: 128: 473–482.9. Feingold K R et al. Cholesterol synthesis is required forcutaneous barrier function in mice. J Clin Invest 1990: 86:1783–1795.10. Hollerand W M et al. Sphingolipids are required for mam-malian barrier function (II). Inhibition of sphingolipidssynthesis delays barrier recovery after acute perturbation.J Clin Invest 1991: 88: 1338–1345.11. Mao-Qiang M et al. Fatty acids are required for epidermalpermeability barrier function. J Clin Invest 1993: 92: 791–798.12. Mao-Qiang M et al. Exogenous non physiological vsphysiological lipids: divergent mechanism for correction ofpermeability barrier dysfunctions. Arch Dermatol 1995:131: 809–876.13. Erlandsen M et al. The skin barrier restoring performance285EVALUATION OF A SKIN LIPID MIXTUREof experimental topical formulations studied with an in-vivoTEWL mouse model. 4th ESCD Congress, Helsinki, 1998.14. Mao-Qiang M et al. Optimisation of physiological lipidmixture for barrier repair. J Invest Dermatol 1996: 106:1096–1101.15. Summers R S et al. The effect of lipids, with and withouthumectant, on skin xerosis. J Soc Cosmet Chem 1996: 47:27–39.16. Halkier-Sorensen L et al. Occupational skin diseases. Con-tact Dermatitis 1996: 35 (suppl. 1): 1–120.17. De Vringer T, De Ronde H A G. Preparation and structureof a water-in-oil cream containing lipid nanoparticles. JPharmac Sci 1995: 84: 466–472.Address:Enzo BerardescaDepartment of DermatologyUniversity of PaviaIRCCS Policlinico S. Matteo27100 PaviaItaly

Evaluation of efficacy of a skin lipid mixture in patients with irritant contact dermatitis, allergic contact dermatitis or atopic dermatitis: a multicenter study.

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Evaluation of efficacy of a skin lipid mixture in patients with irritant contact dermatitis, allergic contact dermatitis or atopic dermatitis: a multicenter study.

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