Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis
Condition: Atopic Dermatitis
MeSH terms: Dermatitis, Atopic; Dermatitis; Eczema
Study type: Interventional
Phase: Phase 2

Summary: 
      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 Ustekinumab 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.
    

Detailed description: 
      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 dendritic 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.
    

Intervention name(s): Ustekinumab; Placebo
Intervention type(s): Drug; Other
Intervention description(s): Injection of monoclonal antibody against the p40 subunit of IL-12/23; Injection of placebo
Other intervention name(s): Stelara
Intervention MeSH terms: Ustekinumab
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment
Keywords: Atopic Dermatitis; Eczema