Published Online: March 1, 2016
Atopic dermatitis (AD) or eczema is the most common chronic inflammatory skin disease, affecting about 20% of children and up to 10% of adults. Its moderate-to-severe form is still a therapeutic challenge, and clinical trials are needed to develop new therapies that are both efficacious and safe. Due to the debilitating nature of this disease, pure placebo-controlled trials over extended periods are a challenge, and background therapy, usually with topical glucocorticosteroids (GCS), is often used to enhance patient retention. Surprisingly, despite the frequent use of GCS, there have been no studies analyzing their effects on key disease circuits over an extended period of weeks-to-months.
In an article recently published in The Journal of Allergy and Clinical Immunology (JACI), Brunner and colleagues investigated the effects of triamcinolone acetonide 0.025% cream, a low-potency GCS, on the molecular and cellular skin phenotype of patients with moderate-to-severe AD. The topical GCS was used as background treatment in all patients that participated in a placebo-controlled clinical trial (NCT01806662) and for the current study they analyzed the effects of up to twice-daily applications of topical GCS only in the “placebo” group. The authors found that this background therapy had profound clinical and molecular treatment effects not only during the first four weeks, but improvements progressed even more through 16 weeks of treatment in most patients, with continuous improvements at the molecular level in the majority of study participants, resulting in a significant “placebo” response. Tachyphylaxis, which is a rapid decrease in treatment efficacy and has long been attributed to prolonged GCS use, was absent in most patients. Interestingly, the extent of disease activity at baseline predicted the clinical response to GCS, with lower disease activity at baseline showing higher responses to topical steroids.
This study shows that even low-potency topical GCS have progressive effects on atopic dermatitis clinical and molecular disease activity after several months of treatment, and that tachyphylaxis is not existent in the majority of patients. This notion has great relevance to clinical trial design for AD patients. In order to enhance patient retention, clinical trials often include a mild or even moderate background GCS therapy during the entire study period, and sometimes have a several week “run-in” phase before randomization. This “run in” period is suggested from the erroneous assumption that after a short period of topical GCS use (i.e. within a few weeks), a “steady state” is reached within the skin, allowing for the reliable evaluation of a study drug in a “placebo-controlled” fashion. Our data strongly suggest that such a baseline activity is not reached, and that GCS progressively improve the disease phenotype during months of treatment. For this reason, the authors believe that background treatment with GCS in clinical studies add a level of complexity that is detrimental to efficacy readouts, and that such trial designs need to be avoided. We strongly advocate for monotherapy study designs for a period of 4-12 weeks (depending on the expected maximal drug efficacy). This will be able to allow for a clear evaluation of drug effect, “unmasked” by the large placebo/”steroid” effect we are now facing with topical steroids as a background treatment.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.