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Chapter 52 Topical Treatment with 52

M. Kerscher, S. Williams, P. Lehmann

52.1 21

Introduction 20

11 , the physiologically occurring adrenal , 17 and its derivatives (here referred to as glucocorticoids) 16 1 C D 9 are the most widely used topical preparations in der- 14 matology. According to Schäfer et al. there were times 2 A B when 95% of all topically applied drugs for skin dis- Fig. 52.1. Chemical 3 5 eases contained glucocorticoids[69]. No other drug has structure of cortisol 6 4 changed the treatment of a wide range of dermatoses as successfully as topical glucocorticoids. In concordance with this, Howard Maibach has differentiated the histo- effects of cortisol. Today, 2 1- 2 2-cortisol (predniso- ry of dermatology into an era before and one after cor- lone, first generation ) is one of the best ticosteroid therapy. known and still most frequently used systemically More than 50 years ago, Hench (1896–1965) first administered . Methylation in ring B in reported the therapeutic benefit of a systemically 6 q -position and in ring D in 16 q -and16[ -position ini- administered adrenal cortical (17-hydroxy- tiated a further significant increase of anti-inflamma- 11-dehydrorcorticosterone, compound E) [32]. In 1950, tory effects of . Substitution with halo- Philip S. Hench, Eduard C. Kendall, and Tadeusz Reich- gens (halogenation), e.g., through introduction of fluo- stein(thelattertwohaddiscoveredthenaturalcorti- ride (F) in position 6 [ and/or 9 [ also significantly sone of the adrenal gland in 1936) received the Nobel increased the efficiency of the molecule in comparison prize [35]. The introduction of topical to cortisol. Topical corticosteroids of the so-called sec- by Sulzberger and Witten in 1952 provided a major ond generation are characterized by single fluoridation pharmacologic breakthrough for dermatotherapy [78]. (e.g., acetonide and ), cortico- However, it was the first halogenated substance – triam- of the 3rd generation have a double fluorida- cinolone acetonide – that initiated the revolution of tion (e.g., and fluometason) [56]. How- highly potent topical corticosteroids. In the develop- ever, third-generation corticosteroids are not necessar- ment of potent corticosteroids through chemical modi- ily more effective than second-generation ones. fication of the cortisol molecule (11 q ,17 [ ,21-Trihy- Several organic acids, such as propionic or acetic droxy-4-pregnene-3,20-dione, Fig. 52.1), there have acid, can be used to form esters (esterification) with been four important steps: dehydrogenation, alkylation hydroxylgroupsofcortisol.Amorerecenttrendto (e.g., methylation), halogenation, and esterification. potentiate the efficacy of topically applied corticoste- Dehydrogenation of the molecule was the first roid preparations is the formation of di-ester com- important development in the treatment of dermatoses pounds of the molecule. The combination of different and other diseases with corticosteroids. The introduc- modifications in the cortisol molecule led – especially tion of a double bond in position C1-C2 ( 2 1- 2 2)for for topical treatment – to extremely effective prepara- example, led to a fivefold increase of the antiphlogistic tions such as clobetasol-17-propionate. 478 52 Topical Treatment with Glucocorticoids

Enthusiasm for highly effective corticosteroids such related to prednisolone. However, MMF has been as fluorinated substances found its peak during the shown to offer a superior therapeutic index with low 1960s and 1970s. Together with the development of risk of skin atrophy compared to conventional haloge- appropriate vehicles, corticosteroids rapidly became nated corticosteroids [40]. The steroid nucleus of MMF mainstay of topical therapy for various inflammatory is the 16-alpha–methyl analog of beclomethasone [63]. dermatoses such as atopic eczema. However, the strong MMF contains chlorine substitutes in 9- [ - and 21- clinical efficacy of highly potent corticosteroids was positions and a furoate moiety at position 17. Among also linked to more severe unwanted effects such as all marketed corticosteroids, the 17(2’)-furoate side skin atrophy and suppression of the adrenal gland. The chain is a structural modification unique to MMF [36]. subsequent backlash of opinion and strong criticism against topical corticosteroids, in particular after 1984, has created confusion and misunderstanding among 52.2 patients as well as physicians. In recent years, much Mechanism of Action care has been invested to re-establish a legitimate image of corticosteroids in the public opinion. Further- Glucocorticoids influence the inflammatory or immu- more, strong efforts have been taken to improve the nologicprocessatdifferentpoints.Concerningthe pharmacologic and clinical aspects of topical cortico- molecular mechanism of action within the cell, not all steroids, resulting in the development of substances details have been revealed yet. However, the mecha- that exhibit a strong effectiveness, while being linked to nisms of corticosteroids can be divided into genomic less systemic and topical unwanted effects. This has (via nucleus and DNA) and nongenomic effects [85]. been achieved by trying to separate the desired activity While genomic effects take at least 1–2 h to occur, non- from unwanted properties of the molecule, which suc- genomic ones occur within minutes[35]. ceeded at least in part. Corticosteroids exhibit three main effects: vasocon- Among these newer substances with increased ther- striction, anti-inflammatory effects, and antiprolifera- apeutic index (benefit/risk ratio) there are several non- tive effects [9]. After topical application of corticoste- halogenated corticosteroid double esters (e.g. fluocor- roid preparations, the constriction of blood vessels tinbutyl, hydrocortisone double esters and prednicar- leads to blanching of the skin. There is a correlation bate) and halogenated ones such as furo- between the intensity of the pharmacodynamic effect ate [16, 38, 40, 42, 81]. The C21-butyl-ester in fluocor- of a corticosteroid formulation and the degree of skin tinbutyl was the first corticosteroid strictly adhering to blanching [68, 69, 86]. Using the vasoconstriction test, the concept of drug targeting. It is derived from the ste- it is possible to predict the therapeutic effect of a corti- roid C-21 acid by esterification with butanol leading to costeroid preparation. The vasoconstriction test was aninversearrangementoftheacidandalcoholcompo- firstintroducedindermatologybyMcKenzieandSto- nents within the side chain. After absorption into the ughton as early as 1962 [53]. Later, it was modified in skin, fluocortinbutyl is inactivated by esterases pre- various ways [50, 69, 87]. At present, the vasoconstric- venting systemic effects; however, largely at the tor assay is still the most widely used expense of potency. (a prednisolone ranking system [33]. One problem, however, is the derivative esterified in positions 17 and 21) and the well-known development of tachyphylaxis of cortico- hydrocortisone double esters hydrocortisone acepona- steroid preparations. Tachyphylaxis describes a reduc- teandhydrocortisonebuteprate,arenonhalogenated, tion (and finally abolishment) of corticosteroid effects mid-potency corticosteroids of the newest generation (including vasoconstriction) after repeated applica- (fourth generation [56]) with a favorable benefit-risk tions [14]. The exact mechanism of action of cortico- ratio [22, 39, 43, 56, 70, 73, 81]. steroid-induced vasoconstriction is not known yet. It has been shown in vivo that nonhalogenated cor- Increased sensitivity against norepinephrine inhibi- ticosteroids influence fibroblast proliferation less mar- tion of histamine-induced vasodilatation or a direct kedly than fluorinated compounds, indicating a lower action have been discussed [9]. atrophogenic risk [31]. Mometasone furoate (MMF) is Concerning anti-inflammatory effects, corticoste- a synthetic, halogenated corticosteroid structurally roids exhibit a variety of effects on different cells such related to adrenocorticoids and pharmacologically as granulocytes, lymphocytes, and mast cells. All of 52.2 Mechanism of Action 479 these cells modulate the inflammatory reaction in a The receptor mediating genomic number of ways and the influence of corticosteroids effectsispresentineverycell(invaryingnumbersof results in an overall inhibition of inflammation. Corti- 1,000–100,000) and is composed of 777 amino acids costeroids are, for example, known to reduce the num- and three functional domains [35]. It resides predomi- ber of lymphocytes, in particular T cells, in the periph- nantly in the cytoplasm in an inactive form (as complex eral blood. They also impair the phagocytic activity of withotherproteinssuchasheatshockproteins,e.g., macrophages and inhibit expression and release of HSP-90) until it binds the corticosteroid ligand, which mediatorssuchasIL-1andIL-2frommacrophagesand enters the cytoplasm through passive diffusion. The T-cells. Corticosteroids inhibit cellular reactions to a ligand binding leads to receptor activation, dissocia- greater extent than humoral ones [57]. tion from its associated proteins and translocation to Concerning the molecular basis of their anti-inflam- the nucleus [27]. In the nucleus, it interacts with spe- matory actions, it is known that corticosteroids interact cific DNA sequences (glucocorticoid-responsive ele- with specific receptor proteins in the target cell (intra- ments) and activates (or negatively regulates) the tran- cellular glucocorticoid receptors [23]). They thereby scription of target genes. Via transcription of mRNA, regulate the expression of corticosteroid-responsive an increased de novo synthesis of certain proteins takes genes and subsequently the level and array of proteins place. Corticosteroid receptors are structurally related synthesized by the cell [27]. This main intracellular to receptors for other small hydrophobic ligands such mechanism of action is of clinical significance, as most as thyroid , vitamin D and retinoids [27]. beneficial effects of corticosteroid are not immediate, The genes encoding proteins, which are directly buttakesometimetobecomeapparent.Corticoste- induced by corticosteroids, include lipocortin and roids predominantly increase the transcription of vasocortin (Fig. 52.2). Lipocortin-1 inhibits phospholi- genes, but there are also examples in which they may pases such as phospholipase A2, which reduces the decrease expression of certain target genes (e.g., the release of arachidonic acid and the synthesis of pro- proopiomelanocortin gene POMC) [27]. In addition to inflammatory mediators such as prostaglandins, leu- the genomic effects, corticosteroids are also known to kotrienes and platelet activating factor [57]. Vasocor- induce some immediate effects mediated by mem- tin inhibits histamine release and thereby exerts anti- brane-bound receptors [27]. allergic effects.

Fig. 52.2. Intracellular mechanisms of action of glucocorticoids (modi- fied from [57]). REG receptor for glucocorticoids (G), REC receptor for pro-inflammatory cytokines (C), CBG corticoid binding globulin, IκB Inhibitor kappa B, P50 50-kDa subdivision of NFκB(nuclearfactor kappa B), P65 65-kDa subdivision of κ NF B, PLA2 phospholipase A2, COX-2 cyclooxygenase 2, LOX-5 5-lipooxygenase, iNOS inducible NO synthetase, IL-1 Interleukin 1, IL-2 Interleukin 2 480 52 Topical Treatment with Glucocorticoids

However, there are also indirect effects via inhibi- cellular energy metabolism (e.g., reduction of ATP pro- tion of transcription factors such as AP-1 and NFκB. duction [35]). NFκB is a heterodimer (subunits p50 and p65), which The antiproliferative effects of corticosteroids refer generally forms a complex with its inhibitor IκB to an inhibition of mitosis in the basal cell layer of the (Fig. 52.2). This binding prevents translocation of epidermis and dermal fibroblasts. This obligatory anti- NFκB to the nucleus and subsequent transcription of proliferative effect of potent corticosteroids is desired genes encoding pro-inflammatory proteins such as in certain hyperproliferative dermatoses such as psori- cyclooxygenase, lipoxygenase, phospholipase A2, asis. However, in most other corticosteroid-treated inducible NO synthetase, certain cytokines (e.g., TNF- skindiseases,includingatopiceczema,itanunwanted [ and interleukins), and adhesion molecules (e.g., effect and may lead to atrophy of the dermis and the ICAM-1, ELAM-1). Corticosteroids influence the tran- epidermis, one of the most feared side effects of topical scriptional activity of NFκBbyincreasingIκB, which corticosteroid application. κ binds and inactivates NF B [72] . Phospholipase A2 is an important pro-inflammatory mediator, influencing various membrane-mediated reactions in the cell, e.g., 52.3 within the arachidonic acid metabolism. Corticosteroid Classification In addition, there are also inhibitory protein–pro- tein interactions of the with the There is a wide variety of topical corticosteroid prepa- p65 subunit of NFκB and with AP-1. This mechanism rations containing various active ingredients and base inhibits the transcription of various NFκB- and AP-1- preparations on the market, which can be ranked fol- regulated genes such as IL-2 and collagenase [57]. lowing their strength of effect. However, potency rank- Nongenomic effects of corticosteroids, which do not ings in the international literature are not always con- require the nucleus (and therefore also occur in cells sistent and classification systems vary. The most com- withoutanucleussuchaserythrocytes),arethoughtto monly employed corticosteroid classification in Ger- occur mainly (but not exclusively) after high-dose sys- many consists of four classes: 1) mild, 2) medium, 3) temic steroid administration. They include effects on potent and 4) very potent. Table 52.1 gives an overview thecellmembranesuchasreductionofthemembrane of some commonly used topical corticosteroids and permeability for kations and protection against post- their ranking following this German classification. It traumatic membrane lipid peroxidation [35]. Further- should be noted that there are age restrictions for cer- more, corticosteroids have a nongenomic influence on tain products.

Class Generic name Brand name Formulation Concen- Table 52.1. Potency ranking (examples) tration of some frequently used top- ical steroids (only products 1.Mild Hydrocortisone Hydrogalen C,O,S,L 1.0% without additional active Hydro-Wolff C 1.0% ingredients; no claim of Hydro-Wolff C, L 0.5% completeness; modified Hydrocutan mild O 0.1% from [35, 66]) Systral Hydrocort L 0.25% Hydrocortisone Ebenol 0.25% O 0.25% Ebenol 1% O 1.0% Ficortril O (Eye) 0.5% Veluopur al OPT O 0.5 % Prednisolone Prednisolon LAW C, O 0.25% Linola-H N C (O/W) 0.4% Linola-H Fett N C (W/O) 0.4% Prednisolon Augen- O(Eye) 2.5% salbe Jenapharm C , O ointment, G gel; L lotion, S solution, FC fatty Triamcinolone – acetonide Volonimat C, O 0.025% cream, FO fatty ointment, Cresa cream ointment, Dexamethason LAW C, O 0.05% Crelo cream lotion, P paste 52.3 Corticosteroid Classification 481

Table 52.1. (contin.) Class Generic name Brand name Formulation Concen- (examples) tration 2.Medium Prednicarbate Dermatop C, O, FO, S 0.25% Pandel C, O, Cresa 0.1% Delphicort C, O 0.1% Volon A C, O 0.1% Volon A Haftsalbe O (Mouth) 0.1% Volon A Tinktur N L 0.1 % butyrate Emovate C, O 0.05% Dexamethasone Cortidexason O, FO 0.1% dipropionate Delonal C, O 0.05% Flumethasone pivalate Locacorten C 0.02% Cerson C,O,S 0.02% Cerson liquidum S 0.02% acetate Decoderm C, O, P 0.1% Alfason C, O, S, 0.1% Cresa, Crelo Laticort C, O 0.1% aceponate Advantan C,O,FO, 0.1% S, L acetonide Jellisoft C 0.01%

3.Potent Mometasone furoate Ecural FC, O, S 0.1% Fluocortolonepivalateand Ultralan C, O, FO, L 0.25% hexanoate (each) valerate Cordes Beta C, O 1.22% Betnesol V crinale S 0.112%1 Betnesol V C, O, L 0.112%1 Celastan V C, O 0.112%1 Betagalen C,O,L,S 0.122%1 Betamethasone dipropionate Diprosone C, O, S 0.064%2 Diprosis O, G 0.064%2 propinate Fluivate C, O 0.005% Sicorten C, O 0.05% Jellin C, O 0.025% Topisolon O,FO,L 0.25% Diflucortolone pentanoate Nerisona C, O, FO 0.1% Topsym C, O, S 0.05% Amciderm C, O, FO, L 0.1%

4.Very Dermoxinale L 0.05% C cream, O ointment, G gel; potent L lotion, S solution, FC fatty Dermoxin C, O 0.05% cream, FO fatty ointment, Clobegalen C, O, L, S 0.05% Cresa cream ointment, Crelo cream lotion, P paste, Karison C,O,FO 0.05% 1 = 0.1% Betamethasone, Karison crinale S 0.05% 2 = 0.05% Betamethasone 482 52 Topical Treatment with Glucocorticoids

52.4 Table 52.2. Potential unwanted effects of topically applied Local and Systemic Unwanted Effects of Topical glucocorticoids Glucocorticoids Suppression of proliferation Atrophy of the epithelium After the initial enthusiasm for topical corticosteroid Disturbances of pigmentation Striae distensae ointments (see “Introduction”), they were often applied over prolonged periods of time without critical Purpura and ecchymosis assessment of unwanted effects, especially as long- Impaired wound healing term data was still missing. In the following decades, Pseudo-anetoderma many of the undesired effects of corticosteroids –most Cutis linearis punctata colli Rubeosis faciei often referred to as side effects – became increasingly Milia evident and gradually well known to the general pub- Atrophy of the subcutaneous fat tissue (in particular after lic. The consequence of the somewhat overestimated intralesional injection of crystalline corticosteroid for- role of unwanted effects in the public opinion was that mulations) Embolia medicamentosa cutis or embolia arteriae centralis today many patients completely reject corticosteroid retinae (after injection of crystalline corticosteroid for- treatment in any form. However, in particular with the mulations) newest, fourth-generation of topical corticosteroids Distal phalangeal atrophy such as prednisolone, hydrocortisone buteprate, or Interactions with skin appendages mometasone furoate, unwanted effects of corticoste- (steroid acne) roid preparations can be avoided in the majority of cases (if employed sensibly and with ground knowl- Hair loss edge of possible undesired effects). Therangeofunwantedeffectsorsideeffectsoftopi- Immunosuppression Pyoderma cal corticosteroid application differ depending on the duration of administration. Short-term application is Tinea (e.g. Candida ) in general less often associated with severe unwanted Herpes simplex effects, while they are more likely to develop in long- Aggravation of term use. Allergic reactions Overall, most of the side effects of corticosteroid Allergic contact Photoallergic applications are local problems, including various types of skin damage (epidermal and dermal atrophy), Miscellaneous Granuloma gluteale infantum striae distensae, purpura, impaired wound healing, , aggravation of perioral dermatitis and telangiectasia (see Table 52.2 for details) [37]. One Increased light sensitivity of the most dangerous effects during treatment with Suppression of the physiological adrenal function corticosteroids is an increased susceptibility to infec- tionsoftheskin.Thisdoesnotonlyoccurafterlong- term use, but can also potentially be observed already In 1989, Akers summarized the risk of unoccluded aftershort-termapplication.Infectionscausedbyfun- treatment of corticosteroid-containing preparations gi, , viruses, or others are more frequent in (betamethasone-benzoate, -dipropionate, -valerate, patients with atopic eczema compared to most other fluocinolone, , hydrocortisone, and triam- skin diseases or healthy individuals (e.g., tinea, pyoder- cinolone acetonide) in an overview of 2,849 patients [1]. ma, or herpes) or can be worsened by topical applica- Inhis14-pairedcomparison,heusedtheabove-men- tion of corticosteroids (e.g., scabies). Today nearly all tioned seven steroid preparations in six corticosteroid- of these can be treated easily with appropri- sensitive skin disorders including . In ate topical or in severe cases systemic drugs (e.g., fun- summary, after 5,698 treatments, 248 adverse reactions gicidal azoles in tinea, in pyoderma and were demonstrated corresponding to a total frequency acyclovir in herpes). With very few exceptions, there is of 4.4%. In detail, he reported irritation (1.39%), - usually no need for directly adding or anti- ing (0.95%), burning (0.81%), dryness (0.46%), scaling mycotic agents to corticosteroid preparations. (0.30%), and vesicle formation (0.16%). 52.4 Local and Systemic Unwanted Effects of Topical Glucocorticoids 483

Relatively rare unwanted effects of corticosteroid asthefaceandtheanogenitalregionandunderocclu- administration that have been published more recently sive conditions. In addition, significant interindividual are, for example, milia (especially on the neck and the absorption differences (up to factor >10) of identical supraclavicular region)[ 80], distal phalangeal atrophy topical corticosteroid preparations in the same ana- [10] and photocontact dermatitis [75]. tomical region have been observed [49]. Systemic effects are not very common after topical However, a reduction of plasma cortisol levels or a application of corticosteroids. However, in rare cases of disturbance of the circadian cortisol rhythm do not significant systemic absorption, it is possible that cor- necessarily mean hypocorticism. It has been shown, ticosteroid levels higher than the Cushing dose (i.e., for example, that systemic corticosteroid treatment >7.5 mg prednisolone equivalent per day in adults) beyond the Cushing level may reduce plasma cortisol occur. This may lead to adrenal insufficiency or hyper- levels without a disturbance of the regulation of the corticism (Cushing syndrome) [9, 76]. Carruthers et al. pituitary-adrenal axis and without an actual conse- have shown that, for example, topical application of quence for adrenal function. Therefore, a small reduc- 45–90 g (weekly) 0.05% clobetasol propionate cream tion of cortisol plasma level or shift of circadian corti- or ointment suppressed the hypothalamic-pituitary- sol peaks in the peripheral blood do not necessarily adrenal axis in both normal individuals and patients indicate a pronounced disturbance of adrenal func- with diseased skin [7]. tion.However,thefactremainsthatitiscertainly The penetration and percutaneous absorption of important to avoid any influence on adrenal function the corticosteroid is primarily dependent on the mole- and its regulation via pituitary hormones, even though culestructure,thetypeofvehicle,additionofpotential it is not very probable that this will happen with topi- penetration enhancers and the anatomical region cal, nonocclusive corticosteroid therapy, especially in treated (Fig. 52.3). The risk of systemic effects of topi- adults. Table 52.2 summarizes some of the most com- cally applied corticosteroids is also higher in very mon unwanted effects of topical corticosteroid use. young children and in patients with significantly Onepotentialadversereactionoftopicalcorticoste- impaired barrier function of the skin. Naturally, the roid application that should not be forgotten, as it is larger the body area treated and thus the more cortico- probably more frequent than generally expected, is the steroid preparation is applied onto the skin, the higher development of allergic reactions to the corticosteroid the risk of systemic side effects. Percutaneous absorp- compound. Most commonly, allergic reactions against tion is also increased in certain body areas such the steroid molecule in external preparations are type

1400 1300 %

1200

1000

800

( compared to the forearm = 100 % ) ) compared forearm 100 % ( the = to 600 350 % 360 %

400 250 % Fig. 52.3. Percutaneous pene- tration of topical corticoste- 200 100 % 83 % roids in different body 42 % 50 % regions compared to the penetration Percutaneous volar aspect of the forearm 0 (modified from [17, 24]) Forearm Ankle L eg P alm Trunk S calp Axilla Face 484 52 Topical Treatment with Glucocorticoids

IVreactionssuchasallergiccontactdermatitis.Apart Which corticosteroid molecule, which concentra- from the development of allergic contact dermatitis, tion,andwhichvehicleshouldbeusedforpatchtestsis there have also been reports of contact urticaria caused discussed controversially in the literature [11–13, 29, by ingredients of topical preparations [49, 59, 64]. 64]. One protocol, for example, implies the use of tixo- Since the first reports on allergic contact dermatitis cortol pivalate, hydrocortisone-21-acetate, and bude- to corticosteroid compounds by Burckhardt, Kooij, sonide in petrolatum in addition to the preparation Church, Sönnichen, O’Hara, and Bandmann et al., suspected to be the cause of the patient’s contact der- more than 100 patients with such allergic reactions matitis. have been described [3, 5, 8, 41, 58, 64, 74]. Dooms- However, an allergic contact dermatitis to a cortico- Goossens assumed for Belgium that allergic skin reac- steroid-containing formulation does not necessarily tions induced by corticosteroids might be as frequent have to be caused by the steroid molecule itself. Many as allergic reactions against PABA ( R -aminobenzoic of the constituents of the vehicle (e.g., emulgator, anti- acid) and its esters [12]. Since corticosteroids suppress oxidant, or stabilizer) or additional active ingredients allergic contact dermatitis, the patch test reaction is of the product (e.g., antibiotics, antimycotics, antisep- often difficult to interpret. Overall however, especially tics) can cause allergic contact reactions. considering the frequency of corticosteroid applica- tions, allergic reactions to corticosteroid-containing preparations are still comparably rare. This is remark- 52.5 able since the cortisol molecule has been modified Influence of the Vehicle on the Effect of Topical extensively in the past 40 years such that only the ring Corticosteroid Preparations structure of the mother substance remained. The exclusively topically applied corticosteroid derivative It has been shown by Stoughton and co-workers that pivalate (pregn-4-ene-3,20-dione-21-thiol- the same steroid preparation offered by different com- 11 q ,17[ -dihydoxy-21-pivalte), however, seems to be panies can potentially exert very different therapeutic anexceptioninthiscontext.HausenandFoussereau effects[77].Thisisduetothecomplexinfluencesof demonstrated that is a potent aller- various factors of the formulation on clinical effects of geninguineapigs[30].Itisinterestingthatallergic the product. The affinity between the corticosteroid patch test reactions were found to be positive even in molecule and its vehicle, for example, is an important patients who had never been treated with tixocortol factor determining the penetration into the skin (if the pivalate. The reason for this might be a cross-reactivity barrier function of the horny layer is intact) and clini- of tixocortol pivalate and hydrocortisone [44]. In fact, cal efficacy [46–48, 62, 69]. The higher the degree of most corticosteroid-allergic patients react to several corticosteroid saturation in a vehicle, the greater its corticosteroids because of cross-reactions [44]. Four therapeutic effect. However, this is only correct if the groups of cross-reactions have been proposed [44]. drug is in solution (solution-type ointment). If on the However, reactions to are correlated with other hand the corticosteroid is suspended in the base reactions to both the acetonide group (group B) and preparation – suspension-type ointment – (under the theestergroup(groupD)[44]. prerequisites that (a) the corticosteroid concentration Apart from anti-inflammatory glucocorticoids, is sufficient to guarantee a constant flux and (b) there is modifications of the steroid structure cyclopentano- a fast corticosteroid liberation without changes of the perhydrophenanthrene (e.g., in androgens, cardiaca skin barrier), its maximum effect is independent of the [digitalis glycosides] and vitamin D) are used for base preparation [34, 46, 47, 50, 51, 60]. numerous other indications in medicine. Most fre- Malzfeldt and co-workers demonstrated that a beta- quently, allergic reaction to this substance group are -17-benzoate solution-type ointment (e.g., seen after topical application. However, cyclopentano- neutral oil gel) was less effective compared to an identi- perhydrophenanthrene itself is a weak . Only cally concentrated (5.6 mg per 100 g ointment) suspen- exceptionally do allergic reactions occur after systemic sion-type ointment (e.g., paraffin gel) in the treatment administration, e.g., urticaria or drug of atopic eczema and allergic contact dermatitis [50]. eruption after digitalis glycosides have been described This is in accordance with findings showing that corti- [4, 89]. costeroid liberation and skin blanching are stronger 52.6 Additional Active Ingredients in Topical Corticosteroid Preparations 485 after topical application of betamethasone-17-benzo- and a reduction of S. aureus on the skin surface may ate in suspension-type ointment (paraffin gel) than in improve clearing of the disease [2, 18, 45]. Further- solution-type ointment (neutral oil gel) of the same more, atopic dermatitis is frequently associated with concentration [46–48, 51]. Without knowledge of the skin infections, especially those caused by bacteria degree of saturation, the solubility, and liberation of (e.g., impetiginized atopic dermatitis). Therefore, anti- the corticosteroid from the base preparation into the septics or antibiotics are often added to corticosteroid skin, the therapeutic effect of the applied product can- products for atopic dermatitis. It has been shown, for not be precisely predicted. example, that a preparation containing betamethasone It is also possible that a dilution of the corticosteroid valerate and gentamycin was more effective than either in certain ointment bases does not reduce its potency compound alone [82]. However, one should be very equivalently [19, 51], and may as a consequence cause careful with the use of combination products and the unexpected side effects. Gibson et al. could not confirm addition of topical antibiotics should be avoided. The significant differences in blanching activity of clobeta- reason for this is the risk of allergic reactions to the sol after a tenfold dilution [19]. This finding can only antibiotic and the development of resistance against be understood by assuming that a solution-type oint- topically applied antibiotics. ment was used as vehicle [51]. Furthermore, the results is frequently used as a topical antibiotic, of Watson and Findlay revealing nearly identical liber- since it is not administered systemically. However, an ation of clobetasol from a propylene glycol and a paraf- against neomycin can be associated with aller- fin ointment can be interpreted insomuch that clobeta- gic cross-reactions against other aminoglycoside anti- sol was most likely suspended in the concentration biotics such as gentamycin, a very important systemic used [84]. In these experiments, it was also demon- drug. is an antibiotic preparation developed strated that a very high amount (90%) of the drug was exclusively for topical use. As no other drug with a found in the gauze which covered the skin after appli- comparable chemical structure is used in human medi- cation of the ointment [84]. cine, the danger of antibiotic cross-reactions with While W/O emulsions have been shown to improve potent systemic drugs is comparably low for this mole- the stratum corneum barrier, many O/W emulsions cule. Therefore mupirocin can be used safely in impeti- (e.g., nonionic hydrophilic cream DAB, hydrophilic ginized atopic dermatitis. However, it is preferable to skin emulsion base NRF and base cream DAC) may apply mupirocin ointment on its own for a couple of themselves compromise the epidermal barrier func- hours followed by a conventional corticosteroid prepa- tion [21]. This might lead to enhanced drug penetra- ration. Alternatively, a combination of an antiseptic tion, as has been shown for hydrocortisone in a study substance (e.g., Triclosan) and a corticosteroid or a by Gloor et al. [21]. Additional ingredients such as corticoid ointment underneath wet wraps with aque- moisturizers or other drugs (e.g., salicylic acid, urea, ous antiseptic solutions (e.g., chinosol solution) can be ) are also able to influence the pene- used. If a more severe bacterial or superinfec- tration of corticosteroids and thereby alter the effects tion such as strong pyoderma occurs, systemic admin- of the product in a manner that is difficult to predict [7, istration of an antibiotic is warranted. This can be per- 25, 56]. In summary, free formulations with unknown formed either according to an antibiogram or using a liberation and penetration characteristics of the active broad spectrum antibiotic against those bacteria most ingredient should be used with caution, as the entire frequently found in infectious skin disorders (e.g., pen- formulation has an important influence on the efficacy icillin derivatives, erythromycin or gyrase inhibitor). and safety of the product. Many additional active ingredients such as tar deri- vates, salicylic acid, (H1-receptor block- ers), or fungicides have been incorporated into cortico- 52.6 steroid preparations, especially in products for atopic Additional Active Ingredients in Topical eczema. However, the clinical effect of these prepara- Corticosteroid Preparations tions is in most cases largely caused by the efficacy and potency of the corticosteroid itself. It is known today that Staphylococcus aureus plays an Since unpredictable interactions between the corti- important role in the pathogenesis of atopic dermatitis costeroid and additives are possible, caution must be 486 52 Topical Treatment with Glucocorticoids

exerted, especially when the prescription is composed a corticosteroid therapy for their child [26]. Most of individually without being thoroughly evaluated. these patients also felt they were not well enough informed by their physician concerning this matter andmorethan50%hadacquiredtheir“knowledge” 52.7 from the public press. Among 1,409 Swiss patients, who Acceptance of the Use of Topical Corticosteroids visited their physician for different health reasons, 79% stated they would have doubts about whether to The first topical application of a corticosteroid prepa- accept a corticosteroid therapy [88]. It is interesting ration was given as treatment for atopic eczema [78]. that even patients who had never received corticoste- Since then, the treatment of atopic eczema with topical roid therapy had reservations against these substances, corticosteroids has been mainstream therapy and until while patients who already had been treated with corti- very recently the only powerful topical alternative for costeroids were generally less anxious. In comparison active flare-ups of the disease. Only a few years ago, the tothesehighnumbers,only10%of66patientswith therapeutic armamentarium of topical agents for atop- asthma stated they were anxious of corticosteroids ic dermatitis was enriched by another group of potent, [61]. anti-inflammatory substances, the calcineurin inhibi- There are even significant numbers of physicians, tors. in particular physicians with an interest in alternative Calnan stated nearly 30 years ago that the value of a healing methods, who are against any form of treat- drug or of a topically applied substance can be mea- ment with topical corticosteroids in atopic eczema as sured by three main requisites: (a) efficacy, (b) harm- well as other corticosteroid-responsive skin diseases. lessness, and (c) acceptance [6]. This statement is still However, one has to accept that potent treatment validtoday.Itisstillthecasethattherearefewtopical modalities, which are highly effective, usually do not drugs in the treatment of atopic eczema that are as come without any potential unwanted effects. But effective as corticosteroids. However, we have to be with the newer generations of corticosteroids and cautious concerning the judgment of their harmless- when used sensibly, these can usually be avoided ness and potential side effects. The acceptance of corti- completely. costeroids in the general population is certainly still The treatment of atopic dermatitis with corticoste- not at its best. The acceptance history of treatment of roid preparations is complicated by the fact that after atopic eczema with topical corticosteroids can be systemic administration of the drug, a dosage reduc- divided into two main periods. At first it was assumed tion and final conclusion of therapy may induce a enthusiastically that topical corticosteroid therapy relapse, which is often stronger than the previous one could be given without any side effects. In comparison (rebound phenomenon), is harder to treat, and to other topical alternatives for atopic dermatitis such requires higher doses of corticosteroids to ameliorate as coal tar preparations, they also offered the advan- the symptoms. The same phenomenon is well known tage of being cosmetically highly acceptable. However, in the treatment of other chronic, steroid-responsive when the undesired influences of topical steroids on disorders such as . Therefore, oral or paren- the skin and potentially the entire organism became teral corticosteroid administration is only indicated in gradually better known, a period of major antipathy atopic dermatitis if severe complications are present. toward corticosteroid therapy started. Today, despite In contrast to the undesired effects after systemic major efforts to inform patients about the realistic risk corticosteroid treatment, topical application is only of unwanted effects and, on the other hand, great bene- exceptionally accompanied by significant systemic re- fits of intermittent corticosteroid treatment, there is sorption and a rebound phenomenon can be avoided still a considerable amount of unjustified “cortico-pho- in most cases by gradual withdrawal of the cortico- bia” among patients and parents of children with atop- steroid. ic dermatitis. This empiric observation has been confirmed in many studies. In 1993, Haggenmüller, for example, described that among 200 questioned mothers, 70% stated that they had apprehensive reservations against 52.8 Principles of Topical Treatment with Corticosteroids in Atopic Eczema 487

52.8 should be avoided in the face, anogenital, and intertri- Principles of Topical Treatment with ginous areas. Corticosteroids in Atopic Eczema After disappearance of acute inflammatory signs, theskinwillbecomedryandscaly,andaformulation The choice of a topical corticosteroid preparation has to containing more lipophilic and less hydrophilic constit- be adjusted to several factors such as acuity of the dis- uents (e.g., a lipid-rich W/O cream or ointment) should ease, body location, and . The acuity of be applied. At this stage, the potent corticosteroid dermatitis determines the choice of the corticosteroid as should be changed to a less potent one. In the following well as the vehicle. In an acute phase, a light corticoste- 1–4 days, the treatment should stabilize the skin condi- roid preparation (e.g., water-rich O/W cream) should be tion, which results in a corticosteroid treatment phase used, while lipid-rich formulations and occlusive oint- of 2–8 days in total. A placebo-controlled study has ments should be avoided. Usually the corticosteroid for shown that intermittent continuation of the corticoste- acute phases should be potent (e.g., 0.1% mometasone roid (2 days per week) is advantageous concerning sta- furoate or 0.05% clobetasol-17-propionate). However, in bilization of the remission. Intermittent application some patients a medium-strength preparation (e.g. also reduces the risk of potential local and systemic 0.25% prednicarbate) is preferable (dependent on body unwanted effects [20]. Whether continued daily appli- location, age of the patient, etc.) in order to prevent cation of a weaker corticosteroid instead of intermittent unwanted effects. If a potent or very potent corticoste- applicationofastrongeronewouldhavethesameben- roid (class III or IV) is administered to a large body area, efit in terms of delay of relapses is doubted [20]. Con- it makes sense to adjust the application time to the phys- trolled studies comparing different corticosteroid iological circadian cortisol rhythm (i.e., apply the prepa- application schemes at the end of therapy, i.e., intermit- ration early in the morning before 8:00 a.m.) in order to tent application vs tapering (step therapy), are needed. avoid adrenal suppression. In atopic eczema, this also Alternatively, it is possible to introduce the topical makes sense, as the physiological maximum of mitotic application of a calcineurin inhibitor such as pimecro- activity takes place in the early morning hours [56]. limus or after the initial strong anti-inflam- The initial application of a medium to potent corti- matory action of a potent corticosteroid. In our experi- costeroid is preferable to (prolonged) administration ence, this scheme optimizes clinical efficacy with rapid of a weaker substance. Schalla discussed the possibility clearing of the disease, minimizes the risk of rebound of initially applying a weak steroid, because a disturbed phenomenon after cessation of the corticosteroid and epidermal barrier function in the acute inflammatory therefore increases patient compliance. The latter phase of atopic dermatitis may increase percutaneous scheme has proven to be of high value in practice. absorptionandthustheriskofsideeffects[71].How- Treatment of atopic dermatitis should never exclu- ever, findings of Malzfeldt et al. have shown that differ- sively consist of topical corticosteroid application, but encesinepidermalbarrierfunctionintheacute should be embedded in various additional measures. inflammatory phase of atopic dermatitis do not influ- Other topical principles such as anti-pruritic drugs ence the efficacy of a corticosteroid preparation [51]. (e.g., or urea), salicylic acid, tannic acid, In addition, tachyphylaxis, which means that the prep- tar preparations, bathing with various additives such aration becomes significantly less effective after as salt and long-term application of emollients can be repeated applications, has to be taken into account [14, added. The purpose of initial anti-inflammatory treat- 49].Therefore,itisreasonabletostarttherapywitha ment with corticosteroids is to reduce pathological rather potent corticosteroid in order to induce a quick inflammation, while the following skin care regimen is remission;usually,oncedailyapplicationissufficient, aimed at delaying acute relapses. In addition, systemic as the corticosteroid will form a reservoir within the antihistamines can be of value in order to disrupt the stratumcorneum[56].Insomecases,applicationtwice vicious cycle of scratching and inflammation. Ta- daily will be preferred. The exact frequency and dura- ble 52.3 summarizes recommended guidelines for topi- tion of corticosteroid therapy have to be adjusted indi- cal corticosteroid therapy in order to avoid unwanted vidually. In most cases, however, remission is achieved effectsandcomplicationsoftherapy.Systemictreat- after 1–4 days of treatment with a potent corticoste- ment with glucocorticoids is discussed elsewhere in roid. In children potent corticosteroid preparations this book. 488 52 Topical Treatment with Glucocorticoids

Table 52.3. Guidelines for topical corticosteroid therapy in 52.9 order to avoid unwanted effects Topical Corticosteroids Versus Topical Inhibitors “As short as possible, as long as necessary” of Calcineurin Short-term application of potent steroids is preferable to long-term application of weaker preparations Topical corticosteroids have significantly influenced Frequent re-evaluation and cessation of corticosteroid ther- dermatological therapy of atopic dermatitis for the apy, if possible after a maximum of 2–3 weeks past five decades. Before the venue of topical cortico- Combination with other topical measures steroids, therapy for atopic eczema was extremely diffi- In children only mild or medium-strength corticosteroids cult and often frustrating. Due to the proven efficacy in No potent preparations in the face, in intertriginous areas inflammatory skin diseases, the use of topical cortico- or anogenital region steroids quickly became a first-line treatment for many Thetreatedbodysurfaceshouldbekeptassmallaspossible dermatoses including atopic eczema. The prescribed amount of corticosteroid-containing prepa- After the development of highly potent topical corti- ration should be adjusted to the treated body surface costeroids in the decades after Hench’s first therapeutic (Fig. 52.4) use of an adrenal cortical hormone[32], overzealous The patient has to be informed that the prescribed formula- tion contains a corticosteroid application of these without basic knowledge of the Application of the corticosteroid in atopic dermatitis pref- side effects led to uncontrolled use and induction of erably early in the morning the well-known undesired effects in thousands of In children and intertriginous areas, no therapy under patients. This resulted in the aforementioned period of occlusion fear toward topical corticosteroid treatment. Due to Adjustment of base preparation to skin condition, acuity the newest generation of topical corticosteroids with of disease, and body location improved benefit-risk ratio and a more cautious appli- Preferably no combination with topical antibiotics cation strategy by physicians, most of the side effects Enhanced percutaneous absorption by certain additives are no longer seen in daily practice. Today, it is a very (e.g., salicylic acid and urea) rare event to encounter epidermal or dermal atrophy, At the end of therapy intermittent continuation (e.g., 2 days disturbances of pigmentation, striae distensae, pyo- per week) or slow tapering derma, and folliculitis, purpura and ecchymosis, hy-

45

40 30-60 g y

35

30

25

20

15 6 g 8 g 6 g

10 2 g Fig. 52.4. Required amounts 5 of cream/ointment for topi- Appr. amount of cream / ointment required per da cal therapy of certain areas 0 ofthebodyperday(once Whole body F ace Arms L egs T runk daily application) References 489 pertrichosis, or granuloma gluteale infantum follow- corticosteroids, a variety of vehicles with many differ- ingthecorrectapplicationoftopicalcorticosteroids. ent corticosteroid molecules are available and can The only clinically significant side effect that may expertly be chosen for a given indication, body interfere with topical corticosteroids therapy is ste- region, and phase of the disease. Now we have one roid-induced rosacea and steroid-induced perioral tacrolimus ointment preparation and one pimecroli- dermatitis. In this situation, the development of a new mus cream preparation available on the market, class of anti-inflammatory drugs will be highly wel- which makes treatment difficult for certain areas such comed, namely the topical inhibitors of calcineurin, as the scalp and intertrigo. Another advantage of topi- which can apparently also be used safely for inflamma- cal corticosteroids is the quicker onset of clinical effi- tory dermatoses of the face. cacy. However, although calcineurin inhibitors are a valu- able and indispensable new therapy for atopic eczema, topical therapy with corticosteroids still remains an References extremely important therapeutic strategy for atopic eczema. Their advantage is a very rapid onset of action 1. Akers W (1980) Risks of unoccluded topical steroids in (highly potent corticosteroid preparations can initiate clinical trials. Arch Dermatol 116:786–788 2. Arima Y, Nakai Y, Hayakawa R, Nishino T (2003) Antibac- relief of symptoms within 0.5 h after application), a terial effect of beta-thujaplicin on staphylococci isolated well-established profile (evaluated over many years), of from atopic dermatitis: relationship between changes in long-term effects and risks, and the availability of a thenumberofviablebacterialcellsandclinicalimprove- variety of different base preparations. ment in an eczematous lesion of atopic dermatitis. J Anti- microb Chemother 51:113–122 Topical inhibitors of calcineurin is a relatively newly 3. Bandmann HJ, Huber-Riffeser G, Woyton A (1966) Kon- developed substance class for which long-term experi- taktallergie gegen Triamcinolonacetonid. Hautarzt 17:183– ence (>10 years) is lacking. Undoubtedly, very thor- 185 oughly designed and accomplished studies have dem- 4. Bork K (1985) Kutane Arzneimittelnebenwirkungen. Schat- tauer, Stuttgart onstrated a very good efficacy of topical calcineurin 5. Burckhardt W (1959) Kontakekzem durch Hydrocortison. inhibitors in atopic eczema with only few side effects Hautarzt 10:42–43 [15, 54, 55, 65, 67, 79, 83]. However, the use of topical 6. Calnan CD (1976) Use and abuse topical steroids. Derma- inhibitors of calcineurin in atopic eczema of children tologica 152 [Suppl 1]:247–251 and adults has only been observed for 5–10 years. This 7. Carruthers JA, August PJ, Stoughton RCS (1975) Observa- tions on the systemic effect of topical clobetasol propio- is comparable to the era of topical corticosteroid treat- nate (Dermovate). BMJ 4:203–204 ment in the 1960s. Accordingly, long-term evaluation 8. Church R (1969) Sensitivity to has to be carried out carefully in order to assess defini- ointment. Br J Dermatol 72:431–444 tive tolerability and safety. Until this important task is 9. Cornell RC, Stoughton RB (1985) Topical corticosteroids: guidelines of therapy. Hoechst (Hoechst up- concluded, it seems premature to declare the postcorti- date) sone era in clinical dermatology. For the time being, 10. Deffer TA, Goette DK (1987) Distal phalangeal atrophy topical corticosteroids remain the first-line treatment secondary to topical steroid therapy. Arch Dermatol 123: option for acute exacerbated atopic eczema and also for 571–572 the long-term management of this disease, with the 11. Dooms-Goossens A, Vanhee J, Vanderheyden D, Gevers D, Willems L, Degreef H (1983) Allergic contact dermatitis to mentioned exception of dermatitis occurring in the topical corticosteroids: clobetasol propionate and clobeta- facial region. sol butyrate. Contact Dermatitis 9:470–478 Despite the lack of long-term experience, topical 12. Dooms-Goossens A (1988) Identification of undetected inhibitors of calcineurin have another disadvantage in corticosteroid allergy. Contact Dermatitits 18:124–125 13. Dooms-Goossens A, Degreef H, Coopmann S (1989) Cor- the treatment of atopic dermatitis compared to topical ticosteroid contact allergy: a reality. In: Frosch PJ, Dooms- corticosteroids. For experienced dermatological topi- Goossens A, Lachapell JM, Rycroft RJG. Scheper RJ (eds) cal treatment strategies, the base of the drug has an Current topics in contact dermatitis. Springer, Berlin Hei- almost as important value as the effective ingredient. delberg New York, pp 233–237 14. DuVivier A, Stoughton RB (1975) Tachyphylaxis to the Thus, the base has to be chosen according to the acu- action of topically applied corticosteroids. Arch Dermatol ity of the disease, the body region where the drug is to 111:581–583 be applied, and the skin type of the patient. For topical 15. Eichenfield LF, Lucky AW, Boguniewicz M, Langley RG, 490 52 Topical Treatment with Glucocorticoids

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