Non‐steroidal topical immunomodulators provide skin‐selective, self‐limiting treatment in atopic dermatitis

ARTICLE

Auteur(s) : Jan D. BOS

Department of Dermatology A0‐235, Academic Medical Centre, University of Amsterdam, PO Box 22700, 1100 DE Amsterdam, The Netherlands

Article accepted on 22\5\2003

Key words: Atopic dermatitis is a common chronic inflammatory skin disease associated with immunological dysfunction that is characterised by an intensely pruritic rash. In up to 90 % of patients with the truly atopic form of the disease, aberrant T‐helper‐2 responses lead to over production of allergen‐specific IgE [1‐4]. T cells appear to play an equally important pathogenic role in the minority of patients with the atopiform type of the disease, in whom neither allergen‐specific IgE nor elevated total serum IgE levels are detectable [2, 3, 5, 6]. In most cases, atopic dermatitis presents before 5 years of age. Although it may gradually resolve by adolescence, in up to 60 % of patients, atopic dermatitis persists into adulthood [7]. A complex disease with an unpredictable relapsing course, atopic dermatitis requires a multifaceted treatment programme that focuses on avoiding trigger factors and irritants, maintaining skin hydration with regular use of emollients and treating signs and symptoms with pharmacological agents.

Conventional therapy for atopic dermatitis

A variety of treatments are commonly used to reduce the inflammation and pruritus associated with atopic dermatitis, including topical corticosteroids, oral antihistamines, coal‐tar preparations, phototherapy and, in severe cases, systemic agents such as cyclosporin. With their potent anti‐inflammatory effects and good short‐term safety profile, topical corticosteroids have been the mainstay of treatment for decades. However, their clinical utility is restricted by the potential for local and systemic side effects that increases with the duration of treatment as well as the potency of the therapeutic agent. These side effects are primarily due to the non‐specific mode of action of corticosteroids. Corticosteroids exert their effects on the immune system and other cellular processes by forming complexes with cytoplasmic glucocorticoid receptors, entering the nucleus and modulating transcription through interactions with DNA sequences known as glucocorticoid‐response elements (GREs; reviewed in [8 and 9]). Additional cellular effects may occur as the result of corticosteroid ‐‐ receptor complex interactions with transcription factors, such as activator protein (AP)‐1, nuclear factor of activated T cells (NFAT) and nuclear factor (NF)‐κB. Because GREs and corticosteroid‐modulated transcription factors influence the transcription of many genes found in numerous cell types, this mode of action is not selective for the pathogenesis of atopic dermatitis. Local side effects associated with corticosteroid treatment include skin atrophy, irreversible telangiectasia and striae, dyspigmentation, acne, perioral dermatitis when applied to the face, increased intraocular pressure when applied to the eyelids, purpura and hypertrichosis. Additionally, use of potent topical corticosteroids for prolonged periods of time, particularly on areas of thin skin and in small children, can result in significant systemic absorption and adverse effects, such as suppression of the hypothalamic‐pituitary‐adrenal axis and growth retardation (reviewed in [10‐12]). Corticosteroid use may be associated with tachyphylaxis [13‐15], and in some cases treatment discontinuation may trigger rebound flares of disease [16, 17]. A final treatment challenge with these agents is steroid phobia among patients and their carers, which may lead to non‐compliance and under‐treatment of the disease [18]. Taken together, these factors indicate that there is a need for non‐steroidal therapies for chronic diseases such as atopic dermatitis that combine the efficacy of corticosteroids with an improved long‐term safety profile.

Non‐steroidal topical immunomodulators ‐‐ a new class of agent

Non‐steroidal topical immunomodulators (TIMs) are a new class of drug developed specifically for the treatment of atopic dermatitis. Tacrolimus ointment (Protopic^®, Fujisawa) was the first agent approved in this class and is available at strengths of 0.1 % and 0.03 %. A second TIM, pimecrolimus 1 % cream (Elidel^®, Novartis), is now available as well. The two TIMs are very similar in chemical structure (Fig. 1). Both block T‐cell activation and the subsequent production of inflammatory cytokines by binding to FK506‐binding protein‐12 (FKBP‐12; also known as macrophilin‐12) to form a complex that selectively inhibits the enzymatic activity of calcineurin, which is required to activate the transcription factor NFAT (reviewed in [19‐20]). The mechanism of action of the two TIMs is nearly identical, although tacrolimus appears to bind the intracellular target FKBP‐12 with three‐fold higher affinity than pimecrolimus (Novartis, data on file). In addition, a recent in vitro study has shown that pimecrolimus is slightly less effective than tacrolimus in inhibiting cytokine messenger RNA (mRNA) and protein production from stimulated human T cells [21]..

The efficacy of non‐steroidal TIMs compares well with conventional topical therapy for atopic dermatitis. Short‐term, double‐blind, randomised, controlled trials have shown that the efficacy of tacrolimus ointment is equivalent to a mid‐potent to potent topical corticosteroid typically used to treat adult patients (hydrocortisone butyrate 0.1 % ointment) and is greater than a mild corticosteroid commonly prescribed for the treatment of children and delicate areas of skin (hydrocortisone acetate 1 % ointment) [22, 23]. In addition, recent findings from a 6‐month, comparative study with more than 950 adult patients indicate that tacrolimus 0.1 % ointment provides superior efficacy over a hydrocortisone‐based regimen (hydrocortisone butyrate 0.1 % ointment applied to all affected areas except the head and neck, which were treated with hydrocortisone acetate 1 % ointment) [24]. Separately, in a short‐term, adult study, pimecrolimus cream was more effective than vehicle, but less effective than a mid‐potent to potent corticosteroid (betamethasone valerate 0.1 % cream) [25]. While these data suggest that the efficacy of the two TIMs may differ [26], further clinical trials are required to compare the efficacy of pimecrolimus and tacrolimus in a controlled setting.

In terms of safety, clinical trials with more than 20,000 patients have demonstrated that TIMs are well tolerated in both paediatric and adult patients and do not cause the side effects associated with corticosteroids. The most common adverse event associated with both TIMs is a transient sensation of warmth or burning at the site of application [25, 27‐29]. Transient application‐site pruritus is also associated with tacrolimus ointment treatment. These side effects are typically mild to moderate in severity, decrease in frequency after the first few days of treatment and rarely led to withdrawals from clinical studies.

The physiochemical properties of TIMs provide skin‐selectivity

The skin is a selectively permeable structure that acts as a frontline of the immune system. Its barrier function is primarily due to the keratinised epithelial cells on the outermost surface of the skin that form the stratum corneum [30]. With most substances, diffusion across the stratum corneum is the main rate‐limiting factor impeding percutaneous absorption. Although hair follicles and sweat glands run through the skin providing an alternative pathway for diffusion, these structures comprise only a fraction of the total surface area of the skin and do not contribute significantly to the diffusion of most compounds.

Ideally, topical medications for atopic dermatitis should be skin‐selective ‐‐ penetrating the stratum corneum and then remaining within the epidermis and dermis rather than diffusing into the bloodstream and subcutis. Physiochemical characteristics such as molecular size and lipophilicity influence skin penetration and permeation, affecting the safety and efficacy of topical agents, and are important considerations in the design and development of treatments for dermatological diseases.

Molecular size

Although healthy human skin is an effective barrier impermeable to many substances, small molecules, such as contact allergens and many topical agents, pass freely through the epidermis. As described by the 500 Da rule, molecular size is an important factor governing the passage of substances through the skin, and penetration tends to decrease markedly when the size of a compound exceeds 500 Da (Fig. 2) [31].

Lipophilicity

The lipophilicity of a substance influences its bodily absorption, distribution, metabolism and excretion. It also correlates with the affinity of a compound for skin, and high lipophilicity may slow permeation of a topical drug from the lipid‐rich stratum corneum to the hydrated lower epidermis and reduce the potential for systemic absorption. A compound‘s lipophilicity can be described by an oil:water partition coefficient (log P) determined by partitioning techniques. In general, drugs with log P values of 2 or more are considered lipophilic. Both tacrolimus and pimecrolimus are very lipophilic, with log P values of 6.09 and 6.99, respectively, measured by determining octanol:water partition coefficients with a reversed‐phase high‐performance liquid chromatography (HPLC) method [35]. As such, they have minimal potential for systemic absorption. In a separate study using the same method, pimecrolimus had a log P of 6.99, while betamethasone‐17‐valerate and clobetasol‐17‐propionate had log P values of 4.74 and 4.34, respectively [36]. These and other commonly used corticosteroids are considerably less lipophilic than TIMs, and in some cases, adequate epidermal concentrations may not be achieved without also producing significant levels of corticosteroids in the bloodstream [37].

TIM skin‐selectivity in preclinical studies

Skin permeation studies

The rate and extent of percutaneous absorption of TIMs through isolated human cadaver skin preparations have been assessed in vitro using Franz diffusion cells in various studies. It should be noted that absolute rates determined with this method are highly variable. Experiments with tacrolimus ointment showed that tacrolimus penetration through intact skin was low, and penetration rates increased with increasing concentrations of tacrolimus ointment (Fujisawa, data on file). When the stratum corneum was absent, average rates of tacrolimus penetration were approximately seven‐fold higher. In a similar experiment carried out with topical agents in alcohol solutions, dermal permeation rates of the corticosteroids clobetasol propionate and diflucortolon valerate through intact human skin were found to be 70‐‐110‐fold higher than those of pimecrolimus [36]. Although an alternative formulation, such as an ointment or a cream, would have provided data more relevant to clinical practice, these results support predictions based on the molecular size and lipophilicity of TIMs and corticosteroids, indicating that corticosteroids permeate skin to a greater extent than do TIMs.

In another series of experiments, the permeation rates of tacrolimus and pimecrolimus were both low when the TIMs were applied to human, porcine or rat skin as 1 % solutions in alcohol [35, 37]. Relative to pimecrolimus, the same concentration of tacrolimus permeated nine‐fold faster through human skin and 10‐fold faster through pig skin as well as rat skin. However, these results should be interpreted with care for several reasons. First, the TIMs were applied to the skin as an alcohol solution, rather than as a cream or ointment, which would be more meaningful when considering clinical implications. Second, in clinical practice, tacrolimus is used at 10‐ and 33‐fold lower concentrations than pimecrolimus, and percutaneous penetration of TIMs has been shown to be concentration‐dependent [38]. Taken together, these results suggest that the skin permeability of commercial preparations of topical tacrolimus and pimecrolimus may be similar.

Tissue distribution in a preclinical model

A preclinical study was carried out with orally administered pimecrolimus and tacrolimus to evaluate the affinity of these compounds for skin and other tissues [39]. Rats received two oral doses of either tacrolimus or pimecrolimus, and the tissue distribution of each TIM was analysed by HPLC coupled with mass spectrometry using a chemical ionisation detection system. Area‐under‐the‐concentration ‐‐ time curve (AUC)0 ‐‐ 24 values were greatest for tacrolimus in lymph nodes and for pimecrolimus in lung. In skin, higher AUC0 ‐‐ 24 values were observed with pimecrolimus than tacrolimus. However, the clinical relevance of these results to the topical treatment of atopic dermatitis is not clear, particularly as the TIMs were administered orally.

TIM skin‐selectivity and self‐limiting treatment in clinical trials

Systemic exposure and blood levels

Pharmacokinetic studies in patients with atopic dermatitis have shown that systemic absorption of pimecrolimus and tacrolimus is low, variable and depends on the body surface area (BSA) treated [32, 33, 40‐42]. To date, pharmacokinetic studies involving both paediatric and adult patients have been reported with tacrolimus 0.3 % ointment, which is three to ten times more potent than commercially available preparations, and tacrolimus 0.1 % ointment. In the trial with the higher strength ointment, patients received 14 applications over an 8‐day period. Systemic exposure to tacrolimus was low and decreased over time, with reductions in both maximum blood concentrations (Cmax) and AUC values observed during the course of treatment (Table I) [32]. Systemic exposure was also low during 14 days of treatment with tacrolimus 0.1 % ointment, with mean AUC0 ‐‐ 24 values ranging from 11.0 to 11.35 ng·h\mL in children with a treatment area of 3,000‐‐5,000 cm² (approximately 70 % of the total BSA), and AUC0 ‐‐ 12 values of 4.8‐5.4 ng·h\mL in adults with a treatment area of 6,000‐10,000 cm² (approximately 60 % of the total BSA) [40, 41]. Comparisons with historical data show that AUC values on the last day of each study were  3 % of those observed following oral administration of tacrolimus in transplant patients. In the adult study, systemic exposure to tacrolimus decreased by almost 50 % from day 4 to day 14 (Fig. 3A). This reduction was accompanied by clinical improvement assessed as a decline in mean affected BSA (Fig. 3B). As ointment was applied to the same designated treatment area(s) throughout the study, these data indicate that tacrolimus treatment is self‐limiting, with tacrolimus blood levels decreasing as treatment continues and improvement in the skin condition occurs. This property is likely to be due to restoration of the corneal layer during therapy, and may also be related to the lack of excoriations observed with clinical improvement in disease.Table I. Pharmacokinetic profile of tacrolimus 0.3 % ointment in adult and paediatric patients with moderate to severe atopic dermatitis [24].

Systemic adverse events and immunocompetence

Consistent with their negligible systemic absorption during the treatment of atopic dermatitis, no adverse events or changes in laboratory values indicative of systemic effects have been observed in patients with atopic dermatitis receiving topical tacrolimus or pimecrolimus (reviewed in [19, 49, 50]). Likewise, TIM does not reduce immunocompetence. In clinical studies with both agents including more than 11,000 patients, non‐application‐site adverse events such as flu‐like symptoms and fever occurred with equal frequency to that of the general population and were not correlated with treatment duration or dose [22, 23, 25, 27, 28, 43, 44, 46, 47, 51‐55]. Additionally, long‐term therapy with TIMs does not reduce cellular immune responses measured in the recall‐antigen test [43, 53]. In a 12‐month, adult, open‐label study with tacrolimus 0.1 % ointment, patients with atopic dermatitis had depressed cell‐mediated immunity at baseline, but the mean number of positive reactions to antigens and the proportion of patients with no positive reactions remained similar after 1 day, 6 months and 12 months of treatment [43]. Similarly, there were no significant differences in skin recall‐antigen responses between pimecrolimus‐treated and vehicle‐treated children in a 12‐month, controlled, double‐blind trial [53].

A final concern with TIMs is the potential for local changes in the skin immune system that could lead to an increased incidence of skin infections and skin malignancies. During clinical trials with both pimecrolimus and tacrolimus, actual skin infections were a reason for exclusion, while new infections were recorded on an ongoing basis. Short‐ or long‐term treatment with TIMs did not increase the incidence of bacterial, viral or fungal infections [22, 23, 53‐56]. Recently, data from five clinical trials with more than 1,500 paediatric and adult patients has been evaluated to determine the risk of cutaneous infections in atopic dermatitis patients treated with tacrolimus ointment [56]. In three 12‐week, vehicle‐controlled studies, the adjusted incidence of all cutaneous infections was not significantly different with vehicle, tacrolimus 0.03 % or tacrolimus 0.1 %, ranging from 18‐25 % in adults and 20‐24 % in children. When the incidence of individual infections was examined, only folliculitis rates in adult patients had a higher incidence with tacrolimus compared with vehicle. The incidence of cutaneous infections in two long‐term, open‐label safety studies with paediatric and adult patients was similar to that of the short‐term trials, and either decreased or remained the same as cumulative exposure to tacrolimus increased from treatment month 3 to month 12 in both trials. In addition, hazard rates for all skin infections, which predict the probability of an infection event occurring per unit of time, remained constant or declined during each trial with continued use of tacrolimus. Likewise, in a paediatric, 12‐month, controlled, double‐blind study with over 470 pimecrolimus‐treated patients, there were no significant differences in the incidence of individual bacterial and viral skin infections with pimecrolimus and vehicle. However, the incidence of grouped viral infections was significantly higher in pimecrolimus‐treated patients compared with vehicle [53]. In a separate 12‐month trial with 251 infants aged 3‐23 months, there were no differences in the adjusted incidence or time to first event for any skin infection, with the exception of an increase in both viral rash that was not otherwise specified and erysipelas in the vehicle group [55].

The incidence of skin malignancies, especially spinal cell carcinomas, has not been reported to increase during TIM therapy. This might be related to the fact that patients included in TIM studies are not particularly prone to their development, as excessive photoexposure is extremely rare in atopic dermatitis patients. This is in contrast with patients with psoriasis, where excessive photoexposure is common, and the incidence of spinal cell carcinomas is increased during systemic cyclosporin therapy.

Lastly, the possibility of immunusuppression‐related development of B‐cell lymphoma is a theoretical concern. Due to the extremely low or even absent systemic exposure, there is no systemic immunosuppression in TIM‐treated patients, and there is no reason to expect an increased incidence of the hematological neoplasms.

Conclusions

Non‐steroidal TIMs have similar chemical structures, molecular weights and lipophilicities and differ significantly from corticosteroids in these properties. With their relatively high lipophilicities and molecular weights, tacrolimus and pimecrolimus provide skin‐selective treatment, with negligible systemic absorption. In addition, the physiochemical characteristics of TIMs appear to regulate percutaneous penetration according to skin condition, with penetration greatest through damaged skin and least through healthy skin. These attributes contribute to the good safety profile of TIMs and suggest that these agents may improve long‐term atopic dermatitis management.

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20th World Congress in Dermatology, Paris, France, 1‐5 July 2002: Poster presentation P214.

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