Atopic dermatitis (AD), a chronic and relapsing inflammatory skin condition, is often
the first manifestation of atopy in children [1,2]. Up to 71.3% of children with AD report allergic rhinitis and/or asthma [3]. Managing AD is therefore of utmost importance to the practicing clinical immunologist
and allergist.

The hallmarks of AD include pruritus and ill-defined erythema, with edema and/or vesicles
if acute, and lichenification if chronic. It has a predilection for the flexural creases,
or, in the case of children under 4 years of age, the cheeks, forehead and extensor
surfaces of the limbs [4]. AD is characterized by both structural abnormalities and immune dysregulation, with
evidence of both innate and adaptive dysfunction [5]. Effective management of AD involves measures to avoid exacerbating triggers, maintenance
of skin barrier function and therefore hydration, management of pruritus, and treatment
of inflammation with anti-inflammatory medications.

Low to intermediate-potency topical corticosteroids have long been utilized as first-line
therapy for AD not adequately managed by emollients alone. However, potent fluorinated
corticosteroids are not indicated for use on the face, eyelids, genitalia, intertriginous
areas, or in young infants. Topical calcineurin inhibitors (TCIs), such as tacrolimus
and pimecrolimus, are alternatives to corticosteroids for AD on the face, eyelids
and skin folds that is unresponsive to low potency topical steroids [6].

TCIs exert their anti-inflammatory action by inhibiting calcineurin-dependant T-cell
activation, thus inhibiting the activation of pro-inflammatory cytokines and mediators
of the allergic inflammatory reaction [7]. They have also been demonstrated to exert effects on mast cell activation [8], resulting in relief of pruritus and erythema as early as within three days of initiating
treatment [9]. Topical tacrolimus has also been shown to decrease both the number and co-stimulatory
ability of epidermal dendritic cells [10]. However, it is these anti-inflammatory mechanisms of action which have caused concern
that high or prolonged use may lead to malignancy much like those related to oral
use of these immunosuppressives.

A recent review article by Frankel et al. concluded that tacrolimus 0.1% ointment
has been demonstrated to be as effective as mid to high potency class III-V steroids
in the treatment of AD [10]. Both tacrolimus and pimecrolimus have been associated with an increased frequency
of application-site reactions (namely, localized transient burning), but also with
a decreased risk of skin atrophy as compared to topical corticosteroids [10].

Despite evidence demonstrating efficacy, resistance to using the TCIs in management
of AD is prevalent among clinicians. This anxiety arises in part from the release
of an FDA Black Box warning in 2005, citing concerns that chronic intermittent use
of TCIs could lead to an increased incidence of Hodgkin’s and non-Hodgkin’s lymphoma,
as well as melanoma and non-melanoma skin cancers [11]. Following the release of this warning, many physician groups, including the American
Academy of Allergy, Asthma and Immunology (AAAAI), American College of Allergy, Asthma
and Immunology (ACAAI), and the Canadian Dermatology Association (CDA), released position
statements, promoting the safety of the TCIs, and arguing against the FDA warning
[12–14]. In an effort to promote appropriate use of the TCIs in Canadian clinical practice,
the CSACI has developed this position statement.

Importantly, the FDA warning was one of a theoretical risk of increased malignancy with the use of TCIs. This was based primarily on animal
data, case reports and the mechanism of action of the drugs (where tacrolimus, in vitro, has been demonstrated to inhibit spontaneous DNA repair [15]). Of note, however, there has been no strong evidence published that this could represent
a similar risk in humans. In fact, in 2005, the spontaneous reporting system described
fewer cases of malignancy in patients treated with TCIs than would be expected in
the population over the same period of time [13]. More recent data continue to show similar incidence rates [16]. To date, no evidence has been published that concludes a causal relationship between
malignancy in patients with AD, and the use of TCIs [13,14,17]. This includes several nested case–control studies demonstrating no increased risk
of lymphoma in AD patients being treated with TCIs, compared to those without TCI
exposure [18,19]. Preliminary data from long-term safety studies have demonstrated similar safety
profiles, though these studies are ongoing [20]. A recent retrospective cohort observational study did show a possible risk of increased
incidence of T-cell lymphoma in patients with AD treated with TCIs, however, this
was possibly attributed to a bias in its use early in this condition. There was no
increase in other malignancies demonstrated in this study [21]. Notably, the alternatives for patients with AD refractory to low-moderate potency
corticosteroids (i.e. switching to high potency topical steroids and/or leaving AD
untreated) carry an even higher risk profile and/or will lead to ongoing patient suffering.
It is important to note, however, that younger subjects with a higher body surface
area per weight, and subjects with abnormal epidermis (ie. Netherton’s syndrome),
can have significant percutaneous absorption of topically applied calcineurin inhibitors,
which may result in systemic serum concentrations known to cause immunosuppression.
This is why these drugs are not indicated for use in children under 2 years of age,
or patients with severely impaired skin barrier function (ie. patients with Netherton’s
syndrome).

In summary, topical calcineurin inhibitors are effective treatments for atopic dermatitis,
and the benefits of their use in the appropriately selected patient population outweighs
the theoretical risk of increased malignancy.