Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis
Atopic dermatitis (AD) is a chronic disease associated with intense itching, which affects most aspects of everyday life in the majority of patients. Acute inflammation and extensor/facial involvement is common in infants, whereas chronic inflammation increases in prevalence with age, as do localization to flexures. AD has a complex background characterized by immune activation, increased epidermal thickness in chronic diseased skin, and defective barrier function. In normal, healthy skin, the outer layer of the epidermis, the stratum corneum is made up flattened dead cells called corneocytes held together by a mixture of lipids and proteins. The stratum corneum and, in particular, the lipid layer are vital in providing a natural barrier function that locks water inside the skin and keeps allergens and irritants out. In people with AD, the barrier function is defective, which leads to dry skin. As the skin dries out, it cracks allowing allergens and irritants to penetrate.
Mild AD can be controlled with emollients and topical medications. However, moderate to severe AD is extremely difficult to control and requires systemic treatment that is often unsatisfactory due to impracticality and lack of effectiveness. Only three therapeutic options exist for moderate to severe AD, including: 1) oral steroids 2) cyclosporine A (CsA), that is not widely used in the US as it is not FDA approved for AD and 3) ultraviolet phototherapy. Oral steroids and CsA treatments have major side effects and UV radiation therapy is highly inconvenient for patients. Several biologic medications, such as TNF-alpha inhibitors, are effective, convenient, and relatively safe therapies for psoriasis, but have thus far not shown efficacy in AD. Ustekinumab is a unique biologic medication that may specifically target AD.
The investigators study will determine whether there is a reversal of the skin thickness and the immune pathways involved in the disease during treatment with Ustekinimab and what specific immune cells are involved. The investigators are also interested to understand how the clinical reversal of the disease will correlate with tissue reversal of the disease.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||Randomized Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis Who Have Sub-optimal Response to Prior Therapy|
- A 50% or greater improvement from their baseline objective SCORAD (SCORing Atopic Dermatitis) at Week 16. [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
- Determine whether there is a reversal of the pathological epidermal phenotype during ustekinumab therapy and what immune pathways are suppressed during treatment with the drug at week 16. [ Time Frame: Week 16 ] [ Designated as safety issue: No ]
- The proportion of subjects who achieve an improvement of 50% or greater from their baseline objective SCORAD at Week 32 (If patient received placebo first). [ Time Frame: Week 32 ] [ Designated as safety issue: No ]
- Measured effects on patient quality of life using the DLQI (Dermatology Life Quality Index). [ Time Frame: Week 52 ] [ Designated as safety issue: No ]
- The change in SCORAD from week16 to week 32 for patients that were treated with Ustekinumab from weeks 0-16, to measure maintenance of response after discontinuation of treatment. [ Time Frame: Week 32 ] [ Designated as safety issue: No ]
- Ustekinumab's effect on the pathologic epidermal hyperplasia of lesional and non-lesional AD skin. [ Time Frame: Week 32 ] [ Designated as safety issue: No ]Epidermal hyperplasia pre- and post-treatment will be measured on lesional and non-lesional AD skin by: epidermal thickness, K16, and Mki67 expression (IHC, RT-PCR, and gene array will be used to determine these determinants). We will also assess for modulation of various epidermal barrier genes during treatment by similar measures.
- Ustekinumab's suppression of expression of excess p40 production in non-lesional AD skin (decreasing systemic immune activation). [ Time Frame: Week 32 ] [ Designated as safety issue: No ]
- Correlation between clinical response (measured via a decrease in SCORAD) to therapy with ustekinumab and suppression of the immune pathways (Th2, Th17, and Th22). [ Time Frame: Week 16 ] [ Designated as safety issue: No ]To determine the correlation between clinical response to therapy with ustekinumab and suppression of the immune pathways and pathologic epidermal phenotype. In the group of patients that will respond to treatment by a reduction of at least 50% of the SCORAD ("responders), we will correlate the decrease in SCORAD with suppression of Th2, and TH22 immune pathways and with the reduction in epidermal hyperplasia.
|Study Start Date:||March 2013|
|Estimated Study Completion Date:||March 2018|
|Estimated Primary Completion Date:||March 2018 (Final data collection date for primary outcome measure)|
Experimental: Treatment Arm (Ustekinumab)
Since there is a crossover design, each patient will be in the treatment arm for 16 weeks of the study.
A monoclonal antibody against the p40 subunit of IL-12/23
Other Name: Stelara
Placebo Comparator: Placebo Arm
Since there is a crossover design, each patient will be in the placebo arm for 16 weeks of the study. If a patient begins in the placebo arm, they will switch over to the treatment arm at week 16.
In psoriasis, epidermal hyperplasia is driven by underlying immune activation, whether as a direct response to IL-20 family cytokines that induces hyperplasia and inhibits keratinocyte terminal differentiation or as an indirect response to immune-mediated injury to keratinocytes. The epidermal reaction in psoriasis is largely restored to normal with selective immune suppression. Hence, one might hypothesize that similar epidermal responses should occur in the presence of "generalized" cellular immune activation, in diseases with similar inflammatory infiltrate and epidermal hyperplasia, such as AD. In fact, psoriasis and AD share features of dense T-cells and dentritic cell infiltrates, as well as over-expression of IL-22 in skin lesions. These diseases also share similar epidermal hyperplasia in their chronic phases.
Work from the investigators group showed that IL-22 is a key cytokine in the pathogenesis of both AD and psoriasis. The investigators have demonstrated that in psoriasis, ustekinumab suppresses the production of IL-12, IL-23, and IL-22. Additionally, by RT-PCR the investigators demonstrated that the mRNA expression of p40 cytokine and the IL23R is up-regulated in AD as compared to both normal skin and psoriasis. The investigators therefore hypothesize that ustekinumab will suppress IL-22 and possibly also p40 production in AD lesions and reverse both the epidermal growth/differentiation defects and the underlying immune activation, and hence will suppress disease activity. Interestingly, p40 was also found to be significantly up-regulated in non-lesional AD skin as compared with normal skin.
Although AD is thought to be predominately a disease of Th2-type cells, in the chronic stage, there is large Th1 component. To date, the precise mechanism by which sequential activation of Th2 and Th1 cells in AD is achieved remains unknown. IL-12 induces the differentiation and maturation of human Th cells into Th1-type cells. Recent circumstantial evidence suggests that in AD patients IL-12 may facilitate a change from the Th2-type to a Th1 cytokine profile. IL-12 was recently shown to be highly elevated in pediatric AD and its levels were strongly associated with disease severity.
Expression of IL-12 p40 mRNA is significantly enhanced in lesional skin from AD, suggesting that the enhanced local production of IL-12 in dendritic cells and macrophages may be responsible for the increased production of IFN-γ in chronic lesions potentially suggesting that IL-12 may have a pivotal role in promoting inflammation in atopic dermatitis. Topical steroids which constitute a mainstay of therapy in AD are known to strongly down-regulate IL-12 expression, possibly also indicating that targeted anti IL-12 therapy might important role in treating AD.
Recently, the Th1/Th2 paradigm in autoimmunity and allergy has been revisited to include a role for a new population of IL-17-producing Th cells known as Th17. Th17 cells are characterized by the production of inflammatory cytokines such as IL-17A, IL-17F, IL-22, and IL-26. One of the key factors involved in naive Th-cell commitment to a Th17 phenotype is IL-23.
Patients with acute AD were found to have increased Th17 T-cells in peripheral blood by flow cytometry and intracellular cytokine staining 26 as well as by immunohistochemistry (IHC) in lesions. Since IL-23 is the major inducer of Th17 T-cells, as well as "T22" T-cells, neutralization of IL-23 could potentially result in both decreased Th17 signal in acute AD as well as decreased "T22/IL22" signal. Therefore the investigators postulate that ustekinumab in AD will act both inhibiting the IL-12-dependent Th1 shift in chronic AD stage as well as the pathogenic IL-22/"T22" axis in this disease.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01806662
|Contact: Recruitment Office||1-800-782-2737|
|United States, New York|
|New York, New York, United States, 10065|
|Principal Investigator: Emma Guttman, MD, PhD|