medium- to high-potency TCSs.51 Addiction occurs with TCS misuse, resulting in physical or psychological dependence.52 The most common sign of steroid withdrawal is erythema; other symptoms include burning/stinging, pain, pruritus, facial hot flashes, and exacerbation with heat or sun.51 The recurrence of AD symptoms and/or the signs of steroid withdrawal when TCS use is stopped often leads patients to restart TCS.52 As a consequence of the safety concerns associated with TCS treatment and steroid withdrawal syndrome, many patients develop steroid phobia, which can hinder adherence and can result in undertreatment.53-55
The lack of consistent reporting of AEs makes it difficult to compare AEs among TCSs (Tables 1 and 2). Common local adverse reactions reported by those who received TCS in the trials summarized herein included secondary infections, eczema herpeticum, contact dermatitis, burning, itching, and skin atrophy ranging in incidence from 0% to 12% (Table 2).16,17,19- 23 Skin atrophy and telangiectasia were reported in few trials; incidence was low when reported (maximum reported: <1% for skin atrophy and 2% for telangiectasia) (Table 2).16,17,19,23
Few studies evaluated systemic AEs, likely as a result of the short duration of the trials (2‑4 weeks), reflecting current treatment guidelines.7,8 One study evaluated the effect of TCS on serum cortisol.22 In the clobetasol propionate group, 15% of patients experienced ≥50% decrease in serum cortisol level, compared with 11% in the vehicle group (P=0.737) (Table 2).22 In addition, 3 patients (8%) in the clobetasol propionate arm experienced serum cortisol below the normal range compared with 0 patients in the vehicle arm (P=0.240) (Table 2).22
Topical Calcineurin Inhibitors
The addition of TCIs to the treatment paradigm in the early 2000s provided an alternative for situations in which the safety of TCSs was of concern, such as in patients with steroid-induced atrophy, for those who required long-term uninterrupted topical anti-inflammatory treatment, and for the treatment of sensitive skin areas.7 The most frequently reported local TEAEs associated with TCIs include application site burning or pruritus, which typically improve as lesions resolve.7 The more significant concern with TCIs is the possibility that their use is associated with immune system-mediated malignancy. In 2006, the US Food and Drug Administration required that a boxed warning regarding the theoretical risk for malignancy be included in TCI prescribing information in response to widespread off-label use in children <2 years of age.7,56,57 Even though no causative link between TCI use and malignancy has been established,57-60 the boxed warning remains.
Unlike in the TCS studies, extensive safety data were reported in the TCI trials identified in this search. Tacrolimus was well tolerated when applied once or twice daily at least 3 times weekly for up to 40 weeks in those aged ≥2 years,24-27 and pimecrolimus was well tolerated in those aged ≥2 years for up to 26 weeks28-31,33-38 and in those aged <2 years for up to 3 years39,40 (and up to 5 years in an open-label study,61 which is outside the scope of this review) (Tables 1 and 2). Application site AEs were most frequently reported for tacrolimus (although causality was not often reported), and incidence ranged from 1.4% to 49% for burning, 0.8% to 29.5% for pruritus, and 0% to 11.8% for erythema (Table 2).24-27 Among those who received pimecrolimus, application site burning was reported by 1.2% to 10.4% of patients; application site pruritus and erythema were less likely to be reported (Table 2).
The lack of consistent reporting of AEs makes it difficult to compare AEs among TCSs (Tables 1 and 2). Common local adverse reactions reported by those who received TCS in the trials summarized herein included secondary infections, eczema herpeticum, contact dermatitis, burning, itching, and skin atrophy ranging in incidence from 0% to 12% (Table 2).16,17,19- 23 Skin atrophy and telangiectasia were reported in few trials; incidence was low when reported (maximum reported: <1% for skin atrophy and 2% for telangiectasia) (Table 2).16,17,19,23
Few studies evaluated systemic AEs, likely as a result of the short duration of the trials (2‑4 weeks), reflecting current treatment guidelines.7,8 One study evaluated the effect of TCS on serum cortisol.22 In the clobetasol propionate group, 15% of patients experienced ≥50% decrease in serum cortisol level, compared with 11% in the vehicle group (P=0.737) (Table 2).22 In addition, 3 patients (8%) in the clobetasol propionate arm experienced serum cortisol below the normal range compared with 0 patients in the vehicle arm (P=0.240) (Table 2).22
Topical Calcineurin Inhibitors
The addition of TCIs to the treatment paradigm in the early 2000s provided an alternative for situations in which the safety of TCSs was of concern, such as in patients with steroid-induced atrophy, for those who required long-term uninterrupted topical anti-inflammatory treatment, and for the treatment of sensitive skin areas.7 The most frequently reported local TEAEs associated with TCIs include application site burning or pruritus, which typically improve as lesions resolve.7 The more significant concern with TCIs is the possibility that their use is associated with immune system-mediated malignancy. In 2006, the US Food and Drug Administration required that a boxed warning regarding the theoretical risk for malignancy be included in TCI prescribing information in response to widespread off-label use in children <2 years of age.7,56,57 Even though no causative link between TCI use and malignancy has been established,57-60 the boxed warning remains.
Unlike in the TCS studies, extensive safety data were reported in the TCI trials identified in this search. Tacrolimus was well tolerated when applied once or twice daily at least 3 times weekly for up to 40 weeks in those aged ≥2 years,24-27 and pimecrolimus was well tolerated in those aged ≥2 years for up to 26 weeks28-31,33-38 and in those aged <2 years for up to 3 years39,40 (and up to 5 years in an open-label study,61 which is outside the scope of this review) (Tables 1 and 2). Application site AEs were most frequently reported for tacrolimus (although causality was not often reported), and incidence ranged from 1.4% to 49% for burning, 0.8% to 29.5% for pruritus, and 0% to 11.8% for erythema (Table 2).24-27 Among those who received pimecrolimus, application site burning was reported by 1.2% to 10.4% of patients; application site pruritus and erythema were less likely to be reported (Table 2).
CONCLUSIONS
Topical drugs to treat AD include PDE4 inhibitors, TCSs, and
TCIs. In the absence of head-to-head trials, comparison among
available agents is difficult because of the different study
designs, endpoints, and methodologies used across published
clinical studies. A lack of precise outcome definitions and
consistent safety reporting further complicate comparison
among trials. For example, in the current literature analysis, 12 of
28 publications did not report total AEs (Table 1), and individual
AE reporting and causality assessments varied. This is in part
because of changes in guidelines for reporting of clinical trial
results over the duration of the literature search, including the
adoption of guidelines such as the CONSORT statement62 and
the Recommendations for the Conduct, Reporting, Editing, and
Publication of Scholarly work in Medical Journals adopted by
the International Committee of Medical Journal Editors.63 The
topical PDE4 inhibitor crisaborole represents a novel therapy
targeting proinflammatory factors involved in AD pathogenesis.
The completed clinical studies for crisaborole demonstrate
efficacy and a favorable safety profile, enabling health care
providers to include crisaborole among topical therapeutic
options available for the treatment of mild-to-moderate AD.
DISCLOSURES
Lawrence Eichenfield has been a consultant, investigator, data safety monitoring board member, or speaker for Pfizer Inc., Allergan, Anacor, Arcutis, Dermavant, Dermira, Eli Lilly, Galderma, LEO Pharma, Medimetriks, Novartis, Otsuka, Regeneron, Sanofi-Genzyme, OrthoDerm/Valeant, and UCB.
Thomas Luger has no conflicts of interest to disclose.
Kim Papp has been a consultant, scientific adviser, investigator, scientific officer, and/or speaker for Pfizer Inc., AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Bausch Health, Boehringer Ingelheim, BMS, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, Gilead, GlaxoSmithKline, Janssen, Kyowa Hakka Kirin, LEO Pharma, Medimmune, Meiji Seika Pharma, Merck Sharp & Dahme, Merck-Serano, Mitsubishi
Thomas Luger has no conflicts of interest to disclose.
Kim Papp has been a consultant, scientific adviser, investigator, scientific officer, and/or speaker for Pfizer Inc., AbbVie, Akros, Allergan, Amgen, Anacor, Arcutis, Astellas, AstraZeneca, Baxalta, Baxter, Bausch Health, Boehringer Ingelheim, BMS, CanFite, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly, Forward Pharma, Galderma, Genentech, Gilead, GlaxoSmithKline, Janssen, Kyowa Hakka Kirin, LEO Pharma, Medimmune, Meiji Seika Pharma, Merck Sharp & Dahme, Merck-Serano, Mitsubishi
