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548 Original Article DOI: 10.1111/j.1610-0387.2008.06641.x

JDDG | 7˙2008 (Band 6) © The Authors • Journal compilation © Blackwell Verlag, Berlin • JDDG • 1610-0379/2008/0607-0548

JDDG; 2008 • 6:548–553 Submitted: 3.9.2007 | Accepted: 7.11.2007

Keywords• tacrolimus ointment• atopic dermatitis• ointment usage

SummaryBackground: Atopic dermatitis is a chronic or recurrent inflammatory skin dis-ease that often requires treatment over years. According to its severity, atopicdermatitis is often managed with use of emollients, topical corticosteroids, top-ical calcineurin inhibitors or systemic agents. This long-term study comparesthe efficacy of tacrolimus 0.1 % ointment with topical corticosteroids as stan-dard therapy in patients with moderate atopic dermatitis.Patients and methods: 50 patients were enrolled. They were allocated to treat-ment groups by the investigator (tacrolimus group or standard group), and fol-lowed over a period of six to twenty months. Efficacy was evaluated by theEczema Area Severity Index (EASI), the percentage of affected body surfacearea, and the score of Rajka and Langeland. In addition, ointment usage wasdocumented and analyzed.Results: The improvement of the skin condition was statistically significant inboth groups. The comparison of the two groups, however, did not show a sta-tistically significant advantage of one or the other treatment. Ointment usagewas slightly higher in the standard group.Conclusions: The efficacy of tacrolimus 0.1 % ointment was confirmed. In termsof emollient usage, no regular pattern could be demonstrated.

A single-center open-label long-term comparison of

tacrolimus ointment and topical corticosteroids for

treatment of atopic dermatitis

Ella Neumann, Dorothee Amtage, Leena Bruckner-Tuderman, Maja MockenhauptDepartment of Dermatology, University Medical Center, Freiburg, Germany

IntroductionAtopic dermatitis or neurodermatitis is achronic or chronically recurrent inflam-matory skin disease, which usuallyrequires long-term treatment. It impairswell-being and the quality of life ofpatients to a great extent [1–3, 20]. Themain goals of therapy are reduction ofinflammation and treating tormentingsymptoms such as itching and the oftenresulting disturbance of sleep.

Depending on the severity and extent ofatopic dermatitis, emollients, topicalcorticosteroids and in recent years topi-cal calcineurin inhibitors (such astacrolimus) are used for treatment. Insevere cases of atopic dermatitis, sys-temic steroids and even systemicimmunosuppressive agents are adminis-tered also successfully [2, 4, 5]. Topical corticosteroids constitute stan-dard therapy for atopic dermatitis [6],

but in long-term use can cause skin atro-phy and other side effects [7]. Topicalimmunomodulators such as Protopic®

ointment (topical preparation oftacrolimus) represent a new treatmentoption, as they possess efficacy similar tosteroids but do not induce skin atrophy[8, 9]. Individual studies from the USAand Great Britain have already shownthat the use of topical calcineurininhibitors is equally cost-effective and in

part even less costly in comparison tohigh-potency topical corticosteroids[10]. We performed a follow-up study on thequestion if there is a treatment advantagein using tacrolimus 0.1 % ointment(trade mark Protopic® 0.1 % ointment)in comparison to classical therapy withtopical corticosteroids (class I–III in theGerman classification according toNiedner) with respect to severity andextent of atopic dermatitis as well asointment usage.

Materials and methodsStudy designThis is a follow-up study over a period ofsix to twenty months in the day care cen-ter as well as the atopic dermatitis outpa-tient service of the Department ofDermatology, University MedicalCenter Freiburg, Germany. In both arms(P arm = Protopic® 0.1 % ointmentgroup; S arm = standard therapy group)a total of 50 patients was included. Thepatients were randomly assigned to botharms. The respective topical therapy wasapplied once to twice daily (dependingon condition of the skin) thinly onaffected skin. For standard therapy topi-cal steroids of class I–III (no patientreceived a steroid of class IV) wereemployed. Emollients were used as basictherapy in both groups. In this follow-up study no artificial treat-ment regimen was constructed, in whichpatients were required to treat multipletimes daily on a regular basis (even afterimprovement of clinical findings).Instead, patients were observed perform-ing their usual treatment habits. Patientswere offered the chance to present in ouratopic dermatitis outpatient service atany time. Patients who did not reportback within a period of eight weeks werecontacted by the responsible physician atfirst by telephone and then given anappointment for examination. Patientswhose data are included in this studygave written consent. This follow-upstudy was before its initiation reviewedby the ethical commission of theUniversity of Freiburg and judged posi-tively according to the ethical standardsof the Helsinki Declaration.

Patient selectionMale and female patients with a diagno-sis of moderately severe atopic dermatitisaccording to the criteria of Hanifin and

Rajka [1] were included in the follow-upstudy. Possible exclusion criteria are list-ed in Table 1.

Treatment planAt the start of the observation the fol-lowing data and findings were collectedby use of a questionnaire (M0): patientdata, age at first manifestation, severityin terms of the Eczema Area SeverityIndex (EASI), the point score of Rajkaand Langeland, involved body surfacearea in percent (BSA%), type I and typeIV sensitizations, and date of start ofobservation. Follow-up visits occurred at regularintervals with use of a second question-naire (M1-x) which registered bouts ofdisease, disease duration, EASI score,score of Rajka and Langeland, involvedBSA% and ointment usage. A thin layerof Protopic® 0.1 % ointment or stan-dard treatment was applied 1–2 x dailyon affected skin. The efficacy of treatment was judgedusing the EASI score, BSA% and pointscore of Rajka and Langeland. In theEASI score four different skin regions(head/neck, arm, leg, trunk) were evalu-ated with respect to extent of atopic der-matitis and the morphological criteriaerythema, infiltration/ papules, excoria-tion and lichenification (0 = none, 1 =mild, 2 = moderate, 3 = severe). TheEASI score is calculated form the sum ofmorphological scores and extent (1: <10 %, 2: 10–29 %, 3: 30–49 %, 4:50–69 %, 5: 70–89 %, 6: 90–100 %),the location and age-associated ratio to

total body surface area multiplied with afactor (0.2 and 0.3).

Statistical analysisAll patients fulfilling the inclusion crite-ria were assigned to one of the treatmentgroups (P or S group) and observed overa period of at least six months. The dataof these patients were analyzed. If theobservation period was less than sixmonths or the patients participated inless than five visits, they were excludedfrom the analysis. Descriptive statistics (mean and median)were determined for all demographicand clinical parameters. Endpoints were calculated using the t-test for independent samples as well asthe Wilcoxon rank sum test.

ResultsDemographic and patient-related dataA total of 50 patients were followed-up,of which 40 were included in the dataanalysis. Ten patients had to be excludedduring the observation, as either theobservation period was too short (n = 9patients) or another form of therapy waschosen (n = 1) which was not allowed inthis protocol. The standard group (standard therapywith corticosteroids and emollients asbasic therapy) included 20 patients andthe Protopic® group (Protopic® 0.1 %ointment and emollients as basic thera-py) also included 20 patients. Minimal observation period was 146days, maximum 623 days, with a meanof 335 days (11.1 months) in the P

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Table 1: Inclusion and exclusion criteria.

Exclusion criteria Inclusion criteria

• Pregnancy• Phototherapy (high-dose

UVA therapy prohibited)• Systemic corticosteroid/

cyclosporine A in the 4 weekspreceding the start of observation

• Participation in studies• Known sensitivity towards

relevant ingredients of theointments

• Age < 16 years• Observation period < 6

months or < 5 visits

• Moderately severe atopic dermatitis

• Age � 16 years

group as well as a minimum of 146 days,maximal 586 days and a mean of 347days (11.5 months) in the S group. The two observed groups did not differin demographic and patient-related datasuch as age, gender, weight, height, bodysurface area, frequency of allergies or dis-ease duration (see Table 2).

Response rateBody surface area (BSA):In the P group at the start of observationthe 20 patients included had an average of34.45 % (median 35.5 %) of body sur-face area affected. After an average obser-vation period of 335 days a reduction ofaffected skin to 16.6 % (median 10 %)occurred. This result in the P group wasstatistically significant with p = 0.0043. For the 20 patients included in the Sgroup a mean of 46.35 % (median36 %) of body surface area was affected

at the start of observation. After a meanobservation period of 347 days affectedskin was reduced to 25.4 % (median17.5 %). The result for the standardgroup is statistically significant with p =0.0162. The difference in improvement of skinfindings between the P group and the Sgroup is not statistically significant (p =0.23) (Figure 1). If we analyze the differ-ence in involved body area in the individ-ual observation period (e. g. 30 %involved BSA at the beginning of obser-vation – 10 % involved BSA at the end ofobservation), the P group had a mean of17.85 % (median 20 %) and the S groupa mean of 20.95 % (median 20 %). Thedifference between both groups is not sta-tistically significant (p = 0.7). In the Wilcoxon rank sum test there wasno statistically significant differencebetween the P and S groups (p =

0.2965). With respect to the initial valueof affected skin in % (BSA%), no statis-tically significant difference existedbetween both groups (Table 2).EASI score:At the start of observation the meanEASI score in the P group was 14.35(median 15) and 17.4 (median 15.5) inthe S group. At the end of observation amean improvement to 6.4 (median 3) inthe P group and 9.8 (median 6.5) in theS group was seen. The improvement within the P groupwas statistically significant with p =0.0057; the improvement within the Sgroup was statistically significant with p= 0.0137. In comparing the P and Sgroups, no statistically significant differ-ence was found (p = 0.2816) (Figure 2).No statistically significant difference ininitial EASI score existed between thetwo observation groups.

550 Original Article Tacrolimus ointment and topical steroids in atopic dermatitis

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Table 2: Patient characteristics and descriptive results.

Characteristics Protopic® group Standard group

Gender MenWomen

911

MenWomen

812

Age (years) MeanMedianRange

37.637.4

17.5–64.7

MeanMedianRange

36.332.4

17–73.3

Weight (kg) MeanRange

69.253–94

MeanRange

68.550–100

Height (cm) MeanRange

172.2160–188

MeanRange

169.5155–188

Body surface area(m2)

MeanRange

1.821.58–2.14

MeanRange

1.791.5–2.1

Type I allergies 16 patients 18 patients

Involved skin (%) atstart of observation

MeanMedianRange

34.4535.55–70

MeanMedianRange

46.3536.0

15–90

EASI score at start ofobservation

MeanMedianRange

14.3515.01–29

MeanMedianRange

17.415.55–34

Total previous diseaseduration (years)

MeanMedianRange

17.516.0

0.6–35.4

MeanMedianRange

19.320.0

0.3–37.7

Ointment use perweek (mean in grams)

Protopic® 0.1 %

RangeEmollients

Range

10.21

0.69–16.3633.28

8.73–137.63

Steroid cl. I–III

RangeEmollients

Range

12.72

1.22–32.0530.33

6.16–58.97

By dividing the standard groups into twosub-groups (group S-1 topical corticos-teroids of class I + II and group S-2 topi-cal corticosteroids of class III), a meanEASI score of 19.5 (median 18) at thebeginning of observation and 11.3 (medi-an 8.5) at the end of observation for the S-1 group was found. The comparison ofthe P with the S-1 group showed no statis-tically significant difference (p = 0.2549). For the S-2 group the mean initial EASIscore was 18.44 (median 15.5) and atthe end of observation 8.44 (median6.5).No statistically significant differ-

ence in comparison to the P group exist-ed (p = 0.5029). If we analyze the change in EASI scoresin the individual observation periods (e.g. EASI score of 28 at the beginning ofobservation – EASI score of 12 at theend of observation) the mean value forthe P group was 7.95 (median 10) andfor the S group 7.6 (median 11). Neitherthe t-test (p = 0.9) nor the Wilcoxonrank sum test (p = 0.1823) were able tofind a statistically significant differencebetween the P and the S group.Score of Rajka and Langeland:

At the start of observation the P grouphad a mean score according to Rajka andLangeland of 5.47 points (median 5)and the S group a mean of 6 points(median 6). At the end of observationthe P group had a mean of 4.35 points(median 4) and the S group a mean of5.25 points (median 5). A significant improvement in the skinfindings (measured in terms of BSA%,EASI score and score of Rajka andLangeland) was found during the obser-vation period in both groups with nosignificant difference between thegroups.

Ointment usageThe patients used a mean of 10.21 gProtopic® 0.1 % ointment and 33.28 gemollients weekly (median 10.86 gProtopic® 0.1 % and 29.7 g emollients)in the P group as well as 12.72 g topicalcorticosteroids (class I–III) and 30.33 gemollients (median 7.95 g topical corti-costeroids and 31.36 g emollients) in theS group. If we divide the corticosteroids into theindividual classes, mean usage of class I +II topical corticosteroids was 5.41 gweekly and 7.31 g of class III topical cor-ticosteroids. The results show thatpatients on average used less Protopic®

0.1 % ointment than topical corticos-teroids. In the S group less emollientswere used. When viewing the median,more Protopic® 0.1 % ointment but lessemollients were applied in the P groupand less topical corticosteroids but moreemollients in the S group. This discrep-ancy existed, because in the P groupindividual patients used a large amountof emollients and in the S group somepatients used a large amount of topicalcorticosteroids.

DiscussionThe treatment spectrum of atopic der-matitis includes in addition to emol-lients for basic therapy topical and sys-temic corticosteroids, systemic immuno-suppressants (e. g. cyclosporine A) aswell as topical immunomodulators (e. g.calcineurin inhibitors) [11–13]. In ourfollow-up study of 40 patients, we want-ed to compare the efficacy of Protopic®

0.1 % ointment with that of topical cor-ticosteroids of class I and II as well asclass III. We were also interested inusage of Protopic® 0.1 % ointment incomparison to topical corticosteroids

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Figure 2: Means of EASI scores in both groups (S = standard therapy; P = Protopic®) in comparisonat the start and end of observation.

Figure 1: Means of involved body surface area (%) in both groups (S = standard therapy; P = Proto-pic®) in comparison at the start and end of observation.

and the usage of emollients as basic ther-apy. The results show that topical therapywith corticosteroids and Protopic®

0.1 % ointment led to a statistically sig-nificant improvement of skin conditions(measured as EASI score, involvedBSA% and score of Rajka andLangeland) in each group. This confirmsprevious reports of good efficacy ofProtopic® ointment in the literature[11–13, 20]. When comparing the average improve-ment in the standard group with theaverage improvement in the Protopic®

group, no statistically significant superi-ority of one of both therapy forms isfound. Viewing the efficacy of varioussteroids separately, here again no statisti-cally significant difference is found. Reitamo et al. [12, 14] observed in sev-eral studies a marked improvement ofatopic dermatitis in children throughtopical application of tacrolimus 0.03 %and 0.1 % in comparison to hydrocorti-sone (class I). The initial skin conditionsin the corticosteroid group were worse.In other studies by Reitamo and cowork-ers [15], Schnopp and coworkers [16] aswell as Alomar and coworkers [17] from2002 and 2003 no significant differencewas found between the use of Protopic®

ointment and topical steroids (hydrocor-tisone butyrate ointment, mometasonefuroate) in the treatment of atopic der-matitis and in the treatment of handeczema (including contact sensitizationtowards nickel sulfate). The use of pime-crolimus 1 % cream for atopic dermati-tis was less efficacious in comparison to0.1 % betamethasone valerate [18].Combination treatment with corticos-teroids and tacrolimus ointment led togreater improvement in comparison tothe respective monotherapy [19]. In day-to-day practice such comparisonsare of limited value as each patient has adiffering expression of atopic dermatitisand responds differently to various topi-cal therapies [20].Against the background of past publica-tions on this subject, our results are mostcomparable to those of Reitamo andcoworkers 2002 [15] and Schnopp andcoworkers [16]. It must be taken intoconsideration that in these studies a tem-porally strict treatment protocol existed,while in our follow-up study the actualtreatment behavior of the patients wasdocumented.

Remarkable in our study was the lowusage of topical products containingactive ingredients (Protopic® ointmentand topical corticosteroids) in bothobserved groups. As we left it up to thepatient to decide the amount and fre-quency of application in adaptation toskin conditions and we also observedvery frugal behavior, we can explain theremarkably low amounts used at least inpart. Significantly more emollients wereused than topical products with activeingredients. Altogether less emollientswere used than recommended by derma-tologists or reported in the literature. In the study of Reitamo and theEuropean Tacrolimus Ointment StudyGroup an equally high use of Protopic®

ointment and topical corticosteroids isreported [12]. In the study of Hanifin et al. [11] amean daily use of 4.7 g tacrolimus oint-ment was found. In the literature little data on ointmentusage and treatment habits of patientsare reported, so that further studies arenecessary here.In summary, good efficacy of Protopic®

ointment and topical corticosteroids wasshown. With ever increasing numbers ofpatients a cortisone phobia (not justifiedwith proper use) is observed in depart-ments of dermatology and dermatologists’offices. Therefore new immunomodula-tors such as topical calcineurin inhibitorsare welcomed by physicians andpatients. Side effects such as an initialburning sensation of the skin are usuallywell tolerable. In our follow-up study nopatient discontinued therapy withProtopic® ointment due to this or otherside effects. To assess long-term sideeffects of Protopic® ointment, as areknown for topical corticosteroids, suffi-cient experience and long-term studiesare still lacking. Our results – with very good efficacy ineach case – were unable to show a treat-ment advantage neither for topical corti-costeroids nor Protopic® 0.1 % oint-ment with respect to the parameters weexamined such as EASI score, affectedbody surface area in percent as well asscore of Rajka and Langeland. As tomean ointment usage a trend to greateruse of topical steroids but to less use ofemollients was observed in the standardtherapy group. Patients with atopic dermatitis knowtheir skin very well and adapt the use of

topical products with active ingredientsand emollients to the actual daily skincondition and not to the orders of thephysician. Our open follow-up study shows thatpatients do not behave in terms of treat-ment measures as in “artificial” studyconditions. This should be taken intoconsideration in future studies.Dermatologists welcome very much hav-ing an effective alternative to topical cor-ticosteroids in the form of topical cal-cineurin inhibitors such as Protopic®

ointment for monotherapy as well as forcombination with topical corticosteroids[21].

AcknowledgmentsWe would like to thank all patients whoparticipated in the follow-up study. Wealso thank all colleagues of the outpa-tient clinic, the atopic dermatitis serviceand the day care center of theDepartment of Dermatology of theUniversity Medical Center Freiburg,who were actively engaged in patientrecruitment. Many thanks to PD Dr.Christian Termeer, former coworker ofthe Fujisawa company for mutual plan-ning of the study as well as to OliverPfeiffer, medical documentalist of theDocumentation Center for Severe SkinReactions (dZh) for support in the sta-tistical analysis. The Astellas company (formerlyFujisawa) financially supported the fol-low-up study; the cooperation agreementwas reviewed by the center for researchaid and technology transfer (ZFT) of theUniversity of Freiburg. <<<

Conflict of interestNone.

Correspondence toPD Dr. Maja MockenhauptDepartment of Dermatology Hauptstr. 7D-79104 Freiburg, GermanyTel.: +49-76 1-27 0-67 23Fax: +49-76 1-27 0-68 34E-mail: dzh@uniklinik-freiburg.de

References1 Hanifin JM, Rajka G. Diagnostic features

of atopic dermatitis. Acta Derm VenereolSuppl (Stockh) 1980; 92: 44–47.

2 Bos JD, Sillevis Smitt JH. Atopic der-matitis. J Eur Acad Dermatol Venereol1996; 7: 101–114.

552 Original Article Tacrolimus ointment and topical steroids in atopic dermatitis

JDDG | 7˙2008 (Band 6)

Tacrolimus ointment and topical steroids in atopic dermatitis Original Article 553

JDDG | 7˙2008 (Band 6)

3 Su JC, Kemp AS, Varigos GA, NolanTM. Atopic eczema: its impact on thefamily and financial cost. Arch DisChild 1997; 76: 159–162.

4 Rudikoff D, Lebwohl M. Atopic der-matitis. Lancet 1998; 351: 1715–1721.

5 Sidbury R, Hanifin JM. Old, new, andemerging therapies for atopic dermati-tis. Dermatol Clin 2000; 18: 1–11.

6 Cornell RC, Maibach HI . Clinicalindications: real and assumed. In:Maibach HI, Surber C: Topical corti-costeroids. Basel: Karger, 1992:154–162.

7 Lubach D, Bensmann A, BornemannU. Steroid induced dermal atrophy.Investigations on discontinuous appli-cation. Dermatologica 1989; 179:67–72.

8 Nghiem P, Pearson G, Langley RD.Tacrolimus and pimecrolimus: Fromclever prokaryotes to inhibiting cal-cineurin and treating atopic dermatitis.J Am Acad Dermatol 2002; 46:228–241.

9 Reitamo S, Rissanen J, Remitz A,Granlund H, Erkko P, Elg P, Autio P,Lauerma AI. Tacrolimus ointment doesnot affect collagen synthesis: results of asingle-center randomized trial. J InvestDermatol 1998; 111: 396–398.

10 Ellis CN, Drake LA, Prendergast MM,Abramovits W, Boguniewicz M, DanielCR, Lebwohl M, Paller AS, Stevens SR,Whitaker-Worth DL, Tong KB. Cost-effectiveness analysis of tacrolimusointment versus high-potency topicalcorticosteroids in adults with moderateto severe atopic dermatitis. J Am AcadDermatol 2003; 48: 553–563.

11 Hanifin JM, Ling MR, Langley R,Breneman D, Rafal E. Tacrolimus oint-

ment for the treatment of atopic der-matitis in adult patients: part I, effica-cy. J Am Acad Dermatol 2001; 44:28–38.

12 Reitamo S, Harper J, Bos JD,Cambazard F, Bruijnzeel-Koomen C,Valk P, Smith C, Moss C, Dobozy A,Palatsi R, European TacrolimusOintment Group. 0,03 % Tacrolimusointment applied once or twice daily ismore efficacious than 1 % hydrocorti-sone acetate in children with moderateto severe atopic dermatitis: results of arandomized double-blind controlledtrial. Br J Dermatol 2004; 150:554–562.

13 Ruzicka T, Bieber T, Schöpf E, Rubins A,Dobozy A, Bos JD, Jablonska S, AhmedI, Thestrup-Pedersen K, Daniel F, FinziA, Reitamo S. A short-term trial oftacrolimus ointment for atopic dermati-tis. European Tacrolimus MulticenterAtopic Dermatitis Study Group. N EnglJ Med 1997; 337: 816–821.

14 Reitamo S, Ortonne JP, Sand C,Cambazard F, Bieber T, Fölster-HolstR, Vena G, Bos JD, Fabbri P,Groenhoej Larsen C, EuropeanTacrolimus Ointment Study Group. Amulticentre, randomized, double-blind, controlled study of long-termtreatment with 0,1 % tacrolimus oint-ment in adults with moderate to severeatopic dermatitis. Br J Dermatol 2005;152: 1282–1289.

15 Reitamo S, Rustin M, Ruzicka T,Cambazard F, Kalimo K, FriedmannPS, Schöpf E, Lahfa M, Diepgen TL,Judodihardjo H, Wollenberg A, Berth-Jones J, Bieber T, European TacrolimusOintment Study Group. Efficacy andsafety of tacrolimus ointment com-

pared with hydrocortisone butyrateointment in adult patients with atopicdermatitis. J Allergy Clin Immunol2002;109: 547–555.

16 Schnopp C, Remling R, MöhrenschlagerM, Weigl L, Ring J, Abeck D. Topicaltacrolimus (FK506) and mometasonefuroate in treatment of dyshidrotic palmareczema: A randomized, observer-blindedtrial. J Am Acad Dermatol 2002; 46: 73–77.

17 Alomar A, Puig L, Gallardo CM,Valenzuela N. Topical tacrolimus0,1 % ointment (protopic) reversesnickel contact dermatitis elicited byallergen challenge to a similar degree tomometason furoate 0,1 % with greatersuppression of late erythema. ContactDermatitis 2003; 49: 185–188.

18 Luger T, Van Leent EJ, Graeber M,Hedgecock S, Thurston M, Kandra A,Berth-Jones J, Bjerke J, Christophers E,Knop J, Knulst AC, Morren M, Morris A,Reitamo S, Roed-Petersen J, Schöpf E,Thestrup-Pedersen K, Van Der Valk PG,Bos JD. SDS ASM 981: an emerging safeand effective treatment for atopic dermati-tis. Br J Dermatol 2001; 144: 788–794.

19 Torok HM, Maas-Irslinger R, SlaytonRM. Clocortolone pivalate cream0,1 % used concomitantly withtacrolimus ointment 0,1 % in atopicdermatitis. Cutis 2003; 72: 161–166.

20 Luger TA, Bieber T, Meurer M, MrowietzU, Schwarz T, Simon J, Werfel T,Zuberbier T. AWMF-Leitlinie: Therapiedes atopischen Ekzems mit Calcineurin-Inhibitoren. AWMF-Leitlinien-RegisterNr. 013/037, Dezember 2004.

21 Werfel T, Aberer W, Bieber T, Buhles N,Kapp A, Vieluf D. AWMF-Leitlinie:Atopische Dermatitis. AWMF-Leitlinien-Register Nr. 013/027, Juli 2002.