A Study Using The Experimental Drug Called Imatinib (Gleevec) in Subjects With Systemic Sclerosis

The purpose of this study is to assess the safety and tolerability of imatinib (gleevec) in subjects who have systemic sclerosis. Imatinib has been approved by the FDA for the treatment of newly diagnosed adult patients with CML (newly diagnosed adult patients and for the treatment of patients with an accelerated phase. Imatinib is also approved for the treatment of patients with a certain type of gastrointestinal cancer (called stromal tumors) but it has not been approved to treat systemic sclerosis. Imatinib works by interfering with an enzyme called tyrosine phosphatase resulting in suppression of the immune system. It als interferes with a protein called platelet derived growth factor receptor (PDGFr) that has been linked to increased fibrosis.

Systemic sclerosis is a rare, progressive disease that leads to hardening and tightening of the skin and connective tissues. It usually begins with a few dry patches of skin on the hands or face that begin getting thicker and harder. These patches then spread to other areas of the skin. In some cases, systemic sclerosis also affects the blood vessels an internal organs. Systemic sclerosis is one of a group of arthritic conditions called connective tissue disorders, a person's antibodies are directed against their own tissues.

Eligibility Criteria:
Inclusion Criteria:

1. All patients must fulfill the criteria for SSc by ACR criteria
2. Age of entry into the study ≥ 18 yrs
3. FVC \<85% of predicted.
4. Able to complete the 6MWT with a walking distance ≥ 150 m
5. Patients must have dyspnea on exertion (grade ≥ 2 on the Magnitude of Task component of the Mahler Modified Dyspnea Index).
6. SSc for ≤ 10 years, with onset defined as the date of the first non-Raynaud manifestation typical of systemic sclerosis.
7. Patients may have limited (cutaneous thickening distal but not proximal to elbows and knees, with or without facial involvement) or diffuse (cutaneous thickening proximal to elbows and knees, often involving the chest or abdomen) cutaneous SSc (Medsger 1995).
8. Patients must show some evidence of alveolitis as defined by an HRCT of the lung which shows ground glass opacification as a radiographic marker of "alveolitis" or finely reticulated fibrosis or they must have alveolitis by BAL ( ≥ 3% PMN's or ≥ 2% eosinophils).
9. Female patients of childbearing potential must have negative pregnancy test within 7 days before initiation of study drug dosing.
10. Patients must be able to provide written voluntary informed consent.

Exclusion Criteria:

1. FVC ≤ 50% of predicted or DLCO (corrected for Hgb but not for alveolar volume) ≤ 35% of predicted (suggesting severe probably irreparable disease and/or significant pulmonary vascular involvement by SSc).
2. FEV1/FVC ratio \<65% (to exclude significant airflow obstruction)
3. Clinically significant abnormalities on HRCT not attributable to SSc (e.g., lung mass, extensive scarring due to previous infection, etc.)
4. Clinically significant pulmonary hypertension documented on right heart catheterization (i.e., right ventricular systolic pressure of \>50 mm Hg and/or mean PAP ≥30 mm Hg) pulmonary pressure or echocardiographic evidence of PAH (if echo cardiographic systolic pressure ≥ 55 mmHg) or FVC/DLCO ratio \>1.6 on pulmonary function testing
5. Persistent unexplained hematuria (\>10 RBCs/hpf).
6. History of persistent leukopenia (white blood cell count \<3500), neutropenia (absolute neutrophil count \< 1500) or thrombocytopenia (platelet count \<100,000).
7. Clinically significant anemia (\<9.0 gm/dl)
8. Serum creatinine \>ULN.
9. Pregnancy (documented by urine pregnancy test), breast feeding
10. If of child-bearing potential, failure regularly to employ a reliable means of contraception
11. Active infection of the lung or elsewhere, whose management would be compromised by Imatinib
12. Unreliability, drug abuse (including active alcoholism)
13. Any chronic, debilitating illness (other than SSc)
14. Smoking of cigars, pipes or cigarettes during the past 6 months
15. Baseline liver function tests (ALT or AST or bilirubin \>1.5 x upper limit of normal
16. Previous use of prednisone \> 10 mg per day. If on prednisone ≤10 mg/d, dose must have been stable for \> 1 month.
17. All other medication with putative disease-modifying properties (e.g., D-penicillamine, cyclophosphamide, azathioprine, methotrexate, colchicine, Potaba) must be discontinued 1 month prior to beginning study medication.
18. Patient is \< 5 years since she/he had a primary malignancy except: if the other primary malignancy is not currently clinically significant nor requiring active intervention, or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in situ. Existence of any other malignant disease is not allowed except after consultation with the PI.
19. Patient with Grade III/IV cardiac problems as defined by the New York Heart Association Criteria. (i.e., congestive heart failure, myocardial infarction within 6 months of study)
20. Patient has a severe and/or uncontrolled medical disease (i.e., uncontrolled diabetes, chronic renal disease, or active uncontrolled infection).
21. Patient has known chronic liver disease (i.e., chronic active hepatitis and cirrhosis).
22. Patient has a known diagnosis of human immunodeficiency virus (HIV) infection.
23. Use of contraindicated medications at baseline.