Progress in early, sensitive and predictive determination of the atrophogenic potential will have impact on the identification and development of novel drugs. The atrophogenic potential of existing topical GC varies to some degree; however, the pro-atrophogenic potential of a given conventional GC in general closely correlates with its anti-inflammatory potency (95). To selectively address both the inflammation and atrophy components, one may consider strategies based on pharmacokinetics, i.e. temporal, histological, and spatial aspects, including those related to drug delivery, or strategies that involve pharmacodynamics, i.e. mechanistic aspects and modes of action that result from intrinsic pharmacological properties of a compound. Both types of approaches should ultimately favor suppressive effects on the relevant immunocytes, such as T cells, Langerhans cells, or various subpopulations of dendritic cells over those on keratinocytes and fibroblasts.
Optimizing treatment regimen
A relatively trivial approach to minimize GC-mediated atrophy is to simply limit the period of skin exposure by intermittent treatment schedules. Some reduction of skin atrophy can thereby be achieved even when strongly atrophogenic GCs are applied. This is indicated by reduced decrease of procollagen I and III under intermittent usage of topical hydrocortisone (96). Yet, to improve the overall outcome of anti-inflammatory treatment, interruption might not be appropriate. Rotational treatment with topical GC and an alternative regimen, e.g. topical calcineurin inhibitors, topical vitamin D3, or retinoids may, therefore be a better choice. Thus, continuous immunosuppression may be achieved by addressing complementary anti-inflammatory pathways (97). Other strategies include intermittent use of the GC only every second day (tandem therapy) (98–100) or intermittent treatment twice a week (101,102) or use of very potent GCs only for a very few days with subsequent switch to compounds from weaker classes as soon as a response is observed (103,104).
Optimizing pharmacokinetics and biotransformation
Rather than limiting the periods of exposure, selective addressing of target cells and tissues may be a more straightforward approach to achieve immunomodulation while avoiding atrophy.
The major players in atopic dermatitis, psoriasis, and allergic contact dermatitis are T cells. Those may initially be activated by antigen-presenting cells of the skin such as Langerhans cells, plasmocytoid dendritic cells, inflammatory dendritic epidermal cells, or macrophages. Atrophy, on the other hand, is caused mainly by effects on dermal fibroblasts and epidermal keratinocytes. Yet, after decades of GC research, the ostensive lack of potent anti-inflammatory but non-atrophogenic GR ligands clearly illustrates the challenge to hit the respective target cells differentially. This may partly be ascribed to the fact that, under inflammatory conditions, T cells and antigen-presenting cells are present and acting in both epidermis and dermis. Thus, a spatial separation of atrophy and inflammation is virtually not possible.
Whatsoever, atrophogenic effects of dermal fibroblasts may overweigh those of those epidermal keratinocytes, whereas epidermal T cells and antigen-presenting cells may significantly contribute to skin inflammation.
This perception underlies efforts to optimize the physico-chemical properties of topical GC towards high lipophilicity and high molecular size. Increased lipophilicity (log P > 3) may facilitate partition into the skin, whereas increased molecular weight (> 500 Da) may slow down transdermal permeation into the bloodstream, providing skin-selective treatment, especially of the upper skin layers (105,106). Retention of active drug in the tissue with comparably high inflammatory activity but relatively low contribution to atrophy may therefore lead to a superior drug profile.
This principle might explain the favorable benefit/risk ratio, e.g. of prednicarbate (PC; prednisolone 17-ethyl-carbonate, 21-propionate), a topical GC with reduced atrophogenic potential. It is assumed that the advantage of PC relies on its rapid hydrolyzation to prednisolone 17-ethylcarbonate in the epidermis, a metabolite with high GR affinity and anti-inflammatory activity (107). PC as well as this metabolite permeate the skin slowly; thus, most of the drug is decomposed before lower skin levels, the dermis with its more atrophy-sensitive fibroblasts, is ever reached. Similarly, the active metabolite of mometasone furoate was found to have higher GR-binding affinities in the epidermis than in the dermis (108).
Aiming at increased drug permeation into the skin and reduced risk of systemic side effects, optimization of PC parameters as well as the prodrug-drug-antedrug concept has extensively been pursued in topical GC development, as exemplified by PC or methylprednisolone aceponate (MPA). The prodrug properties, achieved by, e.g. esterification, generally also increase lipophilicity and therefore facilitate drug uptake into the stratum corneum (109). The prodrug may have reduced or no pharmacologic activity. Within the skin, the prodrug becomes activated by ester cleavage through cutaneous esterases or spontaneous hydrolysis, as in the case of MPA or the inhaled GC budesonid (110). To prevent the body from systemic GC-mediated effects, the active drug requires biotransformation into an inactive or significantly less active metabolite (antedrug) in the systemic circulation or, with some protraction, even within the skin. This principle is widely accepted and applied. Screening for metabolically unstable corticoids, e.g. those that contain metabolically labile carboxamide moieties on the side chain or at the C-16 position of prednisolone (111) is therefore a standard approach.
Overall, the improved physico-chemical properties and biotransformation are highly rewarding regarding reduction of systemic side effects and may also lessen a compound's atrophogenic potential. Yet, because of the obvious colocalization of atrophy-prone fibroblasts and keratinocytes with the various kinds of immunocytes in the dermis and the epidermis, both its use to counter atrophy and its effect on the pro-inflammatory milieu in the deeper skin layers is logically limited.
More sophisticated adaptations of biotransformation approaches are required to achieve intracutaneous cell type-specific activation or deactivation. PC, for instance, is metabolized and activated to only a minor degree in fibroblasts (about 1%/h), whereas it is rapidly and almost completely activated in keratinocytes in vitro (112). This example shows that cell type-specific properties can in principle be exploited. However, it is obviously not representing the perfect solution, since both cell types account for atrophy and should ideally deal with the drug similarly. Differential metabolization of the compound should clearly be sought to affect immunocytes vs. keratinocytes and fibroblasts.
So far, however, findings of this kind are fortuitous, and stringent strategies to rationally exploit such differences are not established.
In addition, keratinocytes and fibroblasts may contribute also to the pro-inflammatory cascade, e.g. by releasing stimulatory cytokines such as TNF-α and interleukin 1 (IL-1) (113,114). Complete barring of these cell populations from GC action may therefore not be appropriate.
The most ambitious and most promising approach to separate beneficial effects and side effects of GR ligands addresses differential molecular modes of action that might underlie immunosuppressive and pro-atrophogenic properties. Such mechanisms do obviously not obey clear-cut rules since GR ligands may activate and suppress gene activation in several different ways. There is evidence, however, that transactivation of GC responsive genes overweighs in side effect induction. In contrast, immunomodulation seems to primarily depend on GC-mediated transrepression, i.e. silencing of pro-inflammatory genes (119). First non-steroidal GR ligands with dissociated properties, termed selective GR agonists (SEGRA) have recently been identified (82,120,121). Such compounds show great potential to reduce side effects of GC although being equipotent regarding immunosuppression. To date, it is not unequivocally clear whether transactivation-dependent molecular events are also crucial for skin atrophy (see above). Rats, however, that were topically treated with a SEGRA compound showed significantly reduced skin atrophy when compared with prednisolone-treated animals. Dissociated GR ligands therefore bear great potential to achieve an improved benefit/risk ratio with respect to atrophy and immunomodulation, whereas epidermal immunocytes may significantly contribute to skin inflammation.