Evaluate Reversal of Pathological Epidermal Phenotype in Severe Atopic Dermatitis (AD) With Suppression of Immune Activation During Cyclosporine A Therapy

Patients will be first screened to be sure they are healthy (aside from atopic dermatitis)
with a physical exam, and lab tests. These lab tests consist of CBC, biochemical profile,
hepatitis B and C profile, urine analysis, HIV, PPD, and urine pregnancy test (if
applicable). Patients will return in 2 to 3 days for PPD reading. A repeat serum
creatinine will be drawn at this time so as to have 2 baseline values. Patient will begin
taking cyclosporine at 5 mg/kg of body weight in 2 divided daily doses for 12 weeks, and
after this period the dose will be reduced by 1mg/kg per week (the tapering down will start
at 12 weeks of treatment), so that cessation of treatment will occur after 16 weeks from the
start of treatment. Patients will then be followed in clinic for an additional 8 weeks for
a potential relapse, and if a relapse will occur topical treatment with corticosteroids,
immune-modulators or phototherapy may be instituted. Patients will be seen in the outpatient
clinic at baseline, wks 1,2, 4, 6, 8, 10, and 12 and every 2weeks until completion of a
24-week study. Biopsies (of lesional and non-lesional skin) will be done to assess
histological response at baseline, week 2, week 6 (optional), week 12 and at relapse
(optional). Bloods for safety analysis and pregnancy test (if applicable) will be done at
each visit, and vital signs will be measured at that time. Serum IgE, eosinophils, and
serum cytokines will be done at baseline, and every 2 weeks until week 16, and at week 24.
At each visit patients will be assessed for adverse events. Clinical assessment, and
ultrasound, will be done at each visit. The most widely accepted clinical assessment tool
is known as SCORAD (SCORing for Atopic Dermatitis). This tool combines clinical features of
AD such as erythema, dryness, lichenification, percent body surface area, as well as quality
of life issues such as pruritus and loss of sleep due to disease. Another assessment tool
we will be using is the static IGA (investigator global assessment). The IGA represents an
overall evaluation of dermatitis performed by the investigator at every visit. IGA scores
utilize a 6-point scale, ranging from 0 (clear) to 5 (very severe disease). IGA scores
measure disease severity based on morphology, without referring back to the baseline state.
Ultrasound study provides an alternate, non-invasive method of assessing disease activity in
the skin. Clinical photos will be done at weeks 0, 6, 12, 16, and 24.In this study, we
would like to determine whether AD, like psoriasis, is an immune-driven disease of epidermal
hyperplasia and differentiation. To establish the immune contribution to AD, we will treat
patients with standard doses of CsA and measure the extent of immune suppression in skin
lesions by quantitative measures of pathological leukocytes and expression of inflammatory
gene products. At the end of 12 weeks of treatment we will determine whether pathological
epidermal hyperplasia is reversed by quantitative and qualitative measures of epidermal
hyperplasia and aberrant epidermal differentiation. In addition, we will correlate the
extent to which the epidermal phenotype is modulated with the extent to which skin
inflammation is suppressed, as the effect of suppression of specific inflammatory molecules
on resulting keratinocyte responses is not known. The alternative hypothesis in AD is that
it is not an immune-mediated disease, but instead a disease of primary epidermal
differentiation due to germline alterations (gene deletions) in filaggrin and other genes
that cooperate to differentiate a normal epidermal barrier at the level of stratum corneum.
The alternative hypothesis is considered to be the most likely patho-mechanism in AD by a
number of current researchers. The alternative hypothesis would be supported by this study
if pathologic epidermal hyperplasia persists in the skin regions with significant
suppression of the immune/inflammatory pathways induced by CsA treatment.

Inclusion Criteria:

- Severe AD (defined as having a mean SCORAD score> 40,, with significant disease
activity, pruritus, and sleep disturbances (13), suitable for treatment with
Cyclosporine, and have failed or unsuitable for other treatment modalities, including
topical and or systemic steroids or phototherapy. Patients must also have an IGA
score of 3 or greater,

- Males and females age 18 and above (if females are of child-bearing potential they
must agree to use acceptable contraception during the study).

- No systemic treatment contraception must commence 2 weeks prior to initiating the
drug.

- No systemic treatment for 4 weeks, no topical treatment or phototherapy for 2 weeks

Exclusion Criteria:

- Previously treated with cyclosporine and had unacceptable toxicity

- Past or current history of malignancy (except for treated isolated skin cancers)

- Renal, hepatic, and hematologic laboratory values greater than CTC grade 1 toxicity,
such as but not limited to creatinine >1.5 ULN, SGOT>2.5 ULN. Values greater then
grade 1 would most likely represent clinically significant renal, hepatic or
hematologic disease

- Stage I hypertension is defined as >140/90. Patients with this blood pressure or
higher on two separate occasions, whether on medications or not, will be excluded
(JNC guidelines www.nhlbi.nih.gov/guidelines/hypertension )

- Significant lipid panel abnormality (any grade 1 toxicity on CTC scale)

- Lactating females

- Other medical condition that would increase the risk of cyclosporine toxicity

- Positive PPD

- Primary or secondary immune deficiency (including known HIV status)

- Possible or known pregnancy

- Serious infection (such as active hepatitis)

- Drug or alcohol abuse

- Inability or lack of willingness to co-operate with regular monitoring

- Severe photodamage/precancerous skin lesions due to previous sunlight exposure, or
photo/photochemotherapy

- Concurrent use of PUVA or UVB, other radiation therapy,

- Concurrent use of other immunosuppressive agents such as MTX, Immuran,
Cyclophosphamide, Cellcept, etc.(because of the possibility of excessive
immunosuppression and the subsequent risk of malignancies)

- Active infections, infections or history of serious infection requiring
hospitalization, antibiotics, antivirals,or antifungals within 30 days of baseline

- History of other inflammatory skin conditions (such as psoriasis, pemphigus, etc.

- Patients with background skin conditions that might be directly related to atopic
dermatitis (such as post inflammatory hyperpigmentation) will not be excluded as well
as common background non-inflammatory skin conditions such as seborrheic keratosis,
benign pigmented lesions, acne, etc