The Immunological Basis for Treatment Resistance to Anti-TNF Treatments

Hypothesis: The balance between type I IFN and TNF determines the response to anti-TNF
treatment. The goal of the proposed study is to address this hypothesis and demonstrate that
the strength of the type I IFN signature in psoriatic skin is the major determinant of the
clinical response to anti-TNF treatment.

Purpose: Determine the strength of the type I interferon and TNF signal in psoriatic skin
prior to and during treatment with etanercept and correlate with degree of clinical
improvement.

Study Population: up to 50 subjects, men or women over the age of 18 with clinically stable
plaque psoriasis, who meet the wash out requirements and other exclusion criteria

Psoriatic patients will receive 100 mg etanercept per week (2 separate single-use pre-filled
50 mg subcutaneous injections taken on two separate days) for 3 months.

Procedures: Urine pregnancy test, TB test, photography, Physical Examinations, Skin
Examinations, Study Drug, Peripheral blood and biopsies

Anticipated Results: We expect that patients with strong IFN-α signature in psoriatic skin
along with weak TNF-α signature will have minimal response to anti-TNF treatment, while
patients with the opposite pattern, weak IFN and strong TNF signature, will have significant
clinical improvement.

Inclusion Criteria:

- At least 18 years of age at screening.

- Clinically stable moderate to severe plaque psoriasis at screening and baseline.

- Subject must be:

- A man or

- A woman who is surgically sterile or at least 3 years postmenopausal or

- A woman of childbearing potential who has had a negative pregnancy test within 7
days before the first dose of study drug.

- If the subject is sexually active, (s)he must agree to use a medically acceptable form
of contraception during screening and throughout the study.

Exclusion Criteria:

- Grade 3 or 4 adverse events or infections within 28 days before screening, or between
the screening visit and drug initiation.

- Active or chronic infection within 4 weeks before screening visit, or between the
screening and baseline visits.

- Evidence of skin conditions other than psoriasis that would interfere with the
evaluations of the effect of study medication on psoriasis.

- Use of oral psoralen with ultraviolet A (PUVA), oral retinoids, cyclosporine,
alefacept, or any other systemic anti-psoriasis therapy within 28 days study drug
initiation.

- Use of ulltraviolet B (UVB) therapy, topical steroids at no higher than moderate
strength, topical vitamin A or D analog preparations, or anthralin with 14 days of
study initiation.

- Prior or concurrent use of cyclophosphamide therapy

- Concurrent sulfasalazine therapy.

- Known hypersensitivity to Enbrel® (etanercept) or any of its components or known to
have antibodies to etanercept.

- Current enrollment in any other investigational device or investigational drug
trial(s), or receipt of any other investigational agent(s) within 28 days before
baseline visit.

- Use of any biologic drugs within 28 days of study drug initiation.

- Concurrent use of Anakinra.

- Severe comorbidities (diabetes mellitus requiring insulin; congestive heart failure
(CHF) of any severity or myocardial infarction or cerebrovascular accident or
transient ischemic attack within 3 months of screening visit; unstable angina
pectoris, uncontrolled hypertension (sitting systolic blood pressure (BP) <80 mm Hg or
> 160 or diastolic BP > 100 mm Hg), oxygen-dependent severe pulmonary disease, history
of cancer within 5 years (other than resected cutaneous basal or squamous cell
carcinoma of the skin or in situ cervical cancer)

- Known history of tuberculosis (TB), or previous positive purified protein derivative
(PPD) test. Any mycobacterial disease or high risk factors for tuberculosis (TB), such
as family member with TB, positive purified protein derivative (PPD) or taking
anti-tuberculosis medication.

- Known HIV-positive status or known history of any other immuno-suppressing disease.

- Concurrent or history of psychiatric disease that would interfere with ability to
comply with study protocol or give informed consent.

- History of alcohol or drug abuse within 12 months of screening visit.

- Latex sensitivity [Nota Bene: only applicable if they are using prefilled syringe or
prefilled SureClick™ autoinjector presentations]

- Exposure to hepatitis B or hepatitis C or to high risk factors for hepatitis B or C,
such as intravenous drug use in patient.

- Systemic lupus erythematosus, history of multiple sclerosis, transverse myelitis,
optic neuritis or seizure disorder.

- Use of a live vaccine 90 days prior to screening visit, or concurrent use of a live
vaccine.

- Any condition or circumstances judged by the patient's physician[or the investigator
or medically qualified study staff] to render this clinical trial detrimental or
otherwise unsuitable for the patient's participation.

- History of non-compliance with other therapies.

- Pregnant or nursing females.

- Diagnosis of multiple sclerosis in first degree family relationship (parent, sibling
or child)