Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis
| Status: | Completed |
|---|---|
| Conditions: | Psoriasis, Dermatology |
| Therapuetic Areas: | Dermatology / Plastic Surgery |
| Healthy: | No |
| Age Range: | 18 - 75 |
| Updated: | 4/17/2018 |
| Start Date: | March 2013 |
| End Date: | March 2015 |
Randomized Pilot Study of Ustekinumab for Subjects With Chronic Atopic Dermatitis Who Have Sub-optimal Response to Prior Therapy
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.
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.
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.
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.
Inclusion Criteria:
- Are male or female and ages 18-75.
- Have moderate to severe AD (as determined using the Objective SCORAD scale ≥15) and a
history of therapeutic failure with at least two of the three different treatment
categories as listed within the inclusion criteria.
- Patients must have tried and failed at least two of the three treatment categories of
the following treatment modalities:
Category 1 : Hydration plus topical steroids and/or antibiotics Category 2: Systemic
Steroids and/or Phototherapy Category 3: Cyclosporine and/or Other Immunomodulators
(Methotrexate, CellCept, Immuran, topical Calcineurin inhibitors)
- Patients who initially respond to cyclosporine but cannot sustain a response after the
drug is discontinued will also be eligible.
- Patients that have contraindications to category 3 drugs will also be allowed to
participate in the study.
- A washout period prior to screening will be required for the following medications:
- Cyclosporine/Oral Steroids/Imuran/Mycophenolate Mofetil/Other systemic
immunosuppressants: 4 weeks
- Phototherapy/Moderate to High Potency Topical Corticosteroids: 2 weeks
- Women of childbearing potential must test negative for pregnancy and be using adequate
birth control measures (e.g., Abstinence, oral contraceptives, intrauterine device,
barrier method with spermicide, or have had a tubal ligation or a hysterectomy) during
the study and for 6 months after receiving the last treatment. Likewise, men capable
of fathering children must also use appropriate methods of birth control (e.g.,
abstinence, barrier methods with spermicide, or have had surgical sterilization such
as vasectomy).
- Patients must be in general good health in the opinion of the investigator.
- Patients with stable chronic asthma, treated with inhaled corticosteroids, will be
eligible.
- The screening laboratory tests must meet the following criteria:
Hemoglobin >9 g/dl WBC count >3.5 x 109 cells/L Neutrophils >1.5 x 109 cells/L Platelets
>100 x 109 cells/L AST/SGOT and ALT/SGPT levels must be within 2 times the upper limit of
normal for the laboratory conducting the test. Alkaline phosphatase levels must be within 2
times the upper limit of normal for the laboratory conducting the test.
- Are PPD negative at the time of screening.
- The patients will be allowed to use topical therapy during the washout period. These
will include emollients, and mild steroids (class 6 or 7), except on one target area
that will be the site for the skin biopsies.
Exclusion Criteria:
- Previous treatment with ustekinumab or other agent that specifically targets IL-12 or
23
- Have a history of latent or active granulomatous infection, including TB,
histoplasmosis, or coccidioidomycosis, prior to screening, or are frequently in
contact with individuals who carry active TB infection or a non-tubercular
mycobacterial infection or an opportunistic infection
- Are HIV positive by history or POCT on the screening visit
- Have documented current active hepatitis B (surface antigen positive or asymptomatic
chronic carriers) or hepatitis C infection (anti-HCV positive), by history and/or
screening test
- Have a history of substance abuse (drug or alcohol) within the past year before
screening
- Have any serious concomitant illness that could require the use of systemic
corticosteroids or otherwise interfere with the patient's participation in the trial
- Pregnant women or women that are breast-feeding or plan to breast feed. Women of
childbearing age who plan to get pregnant within 15 weeks of stopping study agent
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