Psoriasis
Conditions
Keywords
Erythema, optimization, Papule, Plaque, pretreatment, T cells, UVB laser light, psoriasis, topical administration
Brief summary
The purpose of this study is 1) to determine whether Imiquimod or Steroid pretreatment modifies UVB laser light response resulting in increased cell death compared to UVB laser light alone; 2) to determine if pretreatment of psoriatic lesions with Imiquimod or Steroid prior to UVB laser light exposure selectively effects various T cell functions; 3) to determine clinical results from the Imiquimod/Steroid/UVB laser light and correlate those changes with immuno-histochemical changes in the skin; and 4) to determine if single high dose lesion limited UVB laser light intervention combined with Imiquimod or Steroid influences T cell changes
Detailed description
The characteristic lesion of psoriasis is a sharply demarcated erythematous papule or plaque with excessive scaling due to hyperproliferating keratinocytes, infiltrating granulocytes, and a dense mononuclear infiltrate with activated T cells. To date, no one mechanism has been explanatory for the panoply of changes that occur in both the dermis and epidermis of psoriasis patients. Several key findings have shown that cutaneous T cells play a key role in the propagation of the disease; memory-type T cells home to the skin, specifically due to expression of cutaneous lymphocyte antigen (CLA), and are the main effector cells in psoriatic tissue responsible for the production of cytokines that result in exacerbated cutaneous inflammation. T cell recruitment is thought to occur in psoriasis, in part, as a result of cytokine and chemokine release from keratinocytes, macrophages, and endothelial cells. CLA-positive T cells migrate into the tissues where memory-effector T cells are activated and expand. This migration is critical to maintenance of the psoriasis lesions, because anti-LFA-1 antibodies (efalizumab) are effective in treating psoriasis, resulting in blood lymphocytosis and tissue depletion of T cells. Despite many years of using UVB phototherapy in the treatment of psoriasis, its mechanism of action is based mainly on in vitro exposures of isolated cells and on extrapolations from UV effects on normal skin, with little direct data from lesional skin. Previously, our studies determined optimal single efficacious dose using the Excimer laser, refined the mechanism of UVB action in psoriasis, developed key cytokine quantitative meth -ods to assess targeted mRNA levels in psoriatic tissue after treatment, demonstrated that regulatory T cells from psoriasis tissue and blood appear to have a functional defect, and demonstrated that UVA component of solar radiation is a critical and significant contributor to UV-induced in vivo immuno-suppression. All of these previous findings lead us to our current hypothesis that direct selective apoptotic effects on the T mem/Teff cells may result in decreased APC activation and IL-12 over-riding of Treg suppression and a re-balanced Tre:Tmem/eff cell ratio which in turn may have a sustained remittive effect (high duration multi-month clearing of a psoriasis lesion after a single UVB laser light treatment.)
Interventions
DRUGImiquimod
Each study subject served as his/her own control. For this arm of the study, topical vehicle was applied to one plaque for 5 days. Imiquimod (5% topical cream) was applied to two psoriasis plaques for 5 days. Skin biopsies were taken from half of each of the 3 plaques at specific time points after completion of topical pre-treatment. The other half of the plaques were exposed to UVB light (via Excimer laser). Biopsies were subsequently taken at a specified time point.
DRUGClobetasol
Each study subject served as his/her own control. For this arm of the study, topical vehicle was applied to one plaque for 5 days. Clobetasol propionate 0.05% was applied to two psoriasis plaques for 5 days. Skin biopsies were taken from half of each of the 3 plaques at specific time points after completion of topical pre-treatment. The other half of the plaques were exposed to UVB light (via Excimer laser). Biopsies were subsequently taken at a specified time point.
Sponsors
University Hospitals Cleveland Medical Center
VA Office of Research and Development
Study design
Allocation
NON_RANDOMIZED
Intervention model
FACTORIAL
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* The presence of plaque-type psoriasis in areas of the trunk, buttocks, or extremities that are amenable to biopsy and evaluable disease in at least 2 cm target treatment sites separated by 1 cm * Age 18-80, both genders, all ethnicities * No contraindications to phototherapy or biopsy procedures * No topical steroid, tar, phototherapy, Vitamin D, or retinoid therapy to target lesions for at least 1 week prior to the study * No systemic psoriasis therapy for at least four weeks prior to the study * Able to give informed consent under IRB approval procedures
Exclusion criteria
* Photosensitivity disorders * Active untreated diseases or medication usage which may interfere with UVB, wound healing, or immune function * Hypersensitivity to local anesthetic * Inability to provide informed consent * Pregnancy and /or lactating
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Elevated MyxA | Biopsy samples for analysis were taken 1 hour post UVB treatment | Lesions were treated with either Imiquimod or Clobetasol cream. Lesions were subsequently treated with UVB and biopsied. From the biopsy samples obtained from the Imiquimod arm, quantitative PCR was performed to measure levels of Myx A, an imiquimod response gene. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Subjects With Improvement in Lesional Psoriasis Area and Assessment (PASI) Score After Imiquimod and UVB Treatment | 2 weeks after Imiquimod and UVB | The PASI is a disease burden measure that integrates area, erythema, thickness and scale of each target lesion. The severity score for each region is calculated by adding the scores for redness, thickness and scale (each of which are graded from 0 to 4). The maximum severity score is 12. The higher the PASI, the worse the disease. Thus, an improvement in PASI score is a lower score than the pre-treatment PASI. |
| Number of Subjects With a 1.5 Fold Increase in mRNA Expression of GRAMD1A and DMXL2 | Biopsy samples for analysis were taken 1 hour post UVB treatment | Based upon upregulated mRNA expression of MyxA in 1 out of 7 patients treated with Imiquimod, a list of alternative target genes responsive to Imiquimod was generated. The target mRNAs examined included GRAMD1A, IL2RA, TGHD1, DMXL2. The target gene was consider upregulated if there was a 1.5 fold increase in the mRNA expression of the target gene. |
Countries
United States
Participant flow
Recruitment details
Subjects were recruited from the Dermatology clinics at University Hospitals Case Medical Center and the Louis Stokes Cleveland VAMC.
Pre-assignment details
Subjects with moderate to severe psoriasis were recruited from May 2007 to July 2012. 23 subjects were screened but only 9 were assigned to a study arm and received treatment. Per protocol, subjects underwent a washout period of 1 week for topical treatments and 1 month for systemic treatments prior to pre-treatment with Imiquimod or Clobetasol.
Participants by arm
| Arm | Count |
|---|---|
| Imiquimod Each study subject served as his/her own control. For this arm of the study, topical vehicle was applied to one plaque for 5 days. Imiquimod (5% topical cream) was applied to two psoriasis plaques for 5 days. Skin biopsies were taken from half of each of the 3 plaques at specific time points after completion of topical pre-treatment. The other half of the plaques were exposed to UVB light (via Excimer laser). Biopsies were subsequently taken at a specified time point. | 7 |
| Clobetasol Each study subject served as his/her own control. For this arm of the study, topical vehicle was applied to one plaque for 5 days. Clobetasol propionate 0.05% was applied to two psoriasis plaques for 5 days. Skin biopsies were taken from half of each of the 3 plaques at specific time points after completion of topical pre-treatment. The other half of the plaques were exposed to UVB light (via Excimer laser). Biopsies were subsequently taken at a specified time point. | 2 |
| Total | 9 |
Baseline characteristics
| Characteristic | Clobetasol | Total | Imiquimod |
|---|---|---|---|
| Age, Customized <=18 years | 0 participants | 0 participants | 0 participants |
| Age, Customized >=80 years | 0 participants | 0 participants | 0 participants |
| Age, Customized Between 18 and 80 years | 2 participants | 9 participants | 7 participants |
| Sex: Female, Male Female | 0 Participants | 4 Participants | 4 Participants |
| Sex: Female, Male Male | 2 Participants | 5 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 7 | 2 / 2 |
| serious Total, serious adverse events | 0 / 7 | 0 / 2 |
Outcome results
Primary
Number of Subjects With Elevated MyxA
Lesions were treated with either Imiquimod or Clobetasol cream. Lesions were subsequently treated with UVB and biopsied. From the biopsy samples obtained from the Imiquimod arm, quantitative PCR was performed to measure levels of Myx A, an imiquimod response gene.
Time frame: Biopsy samples for analysis were taken 1 hour post UVB treatment
Population: Per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imiquimod | Number of Subjects With Elevated MyxA | 1 participants |
Secondary
Number of Subjects With a 1.5 Fold Increase in mRNA Expression of GRAMD1A and DMXL2
Based upon upregulated mRNA expression of MyxA in 1 out of 7 patients treated with Imiquimod, a list of alternative target genes responsive to Imiquimod was generated. The target mRNAs examined included GRAMD1A, IL2RA, TGHD1, DMXL2. The target gene was consider upregulated if there was a 1.5 fold increase in the mRNA expression of the target gene.
Time frame: Biopsy samples for analysis were taken 1 hour post UVB treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imiquimod | Number of Subjects With a 1.5 Fold Increase in mRNA Expression of GRAMD1A and DMXL2 | 1 participants |
Secondary
Number of Subjects With Improvement in Lesional Psoriasis Area and Assessment (PASI) Score After Imiquimod and UVB Treatment
The PASI is a disease burden measure that integrates area, erythema, thickness and scale of each target lesion. The severity score for each region is calculated by adding the scores for redness, thickness and scale (each of which are graded from 0 to 4). The maximum severity score is 12. The higher the PASI, the worse the disease. Thus, an improvement in PASI score is a lower score than the pre-treatment PASI.
Time frame: 2 weeks after Imiquimod and UVB
Population: Per protocol.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Imiquimod | Number of Subjects With Improvement in Lesional Psoriasis Area and Assessment (PASI) Score After Imiquimod and UVB Treatment | 4 participants |