Mechanistically-based Optimization of UV Radiation Therapy in Psoriasis

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

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.)

• Drug: Imiquimod
  Topical immiquimod will be applied once daily for a period of 5 days to pre-identified psoriasis lesions. Time period of treatment is subject to change based on experiment results.
• Drug: Clobetasol (glucosteroid)
  Topical clobetasol will be applied once daily for a period of 5 days to pre-identified psoriasis lesions. Time period of treatment is subject to change based on experiment results.
• Device: Excimer laser (UVB light) treatment
  Varying does of UVB excimer laser light, based upon plaque thickness, will be applied after imiquimod or clobetasol treatment to pre-identified psoriasis lesions.

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