Belimumab for the Treatment of Diffuse Cutaneous Systemic Sclerosis

Belimumab for the Treatment of Diffuse Cutaneous Systemic Sclerosis: A Phase 2a, Single-centered, Randomized, Placebo-controlled, Double-blind, Proof-of-concept Pilot Study.

This is a 48 week, phase IIa, single center, randomized, double-blind, placebo-controlled, proof-of-concept pilot study. All participants will first be treated with mycophenolate mofetil (MMF, Cellcept) and titrated up to a dose of 2 grams/day. Following this period, half will be given either a belimumab (Benlysta®) or placebo intravenous infusion to treat early diffuse cutaneous systemic sclerosis. Belimumab/MMF is expected to improve disease activity measured by an improvement in skin thickening and stability of pulmonary function test measurements when compared to patients treated with placebo/MMF.

The specific objectives of this study are to:

1. Determine whether belimumab used in combination with MMF is safe and tolerable in the treatment of patients with early diffuse cutaneous systemic sclerosis (Disease duration < 3 years).
2. Determine whether belimumab used in combination with MMF is more effective in the treatment of diffuse cutaneous systemic sclerosis than MMF alone, as measured by change in modified Rodnan Skin Score (mRSS), forced vital capacity (FVC), hemoglobin corrected diffusion capacity (DLCO), Medsger Severity Scale (MSS), and by other physician and patient derived outcome measures.
3. Determine the biological activity of Belimumab/MMF as assessed by effect on histology of skin, change in B-Cell profiles, effect on BLyS levels, and effect on serological and cutaneous biomarkers of disease activity.

Inclusion Criteria:

1. Age greater than or equal to eighteen years.
2. Clinical diagnosis of diffuse systemic sclerosis by ACR criteria, with a stable modified Rodnan skin score in the one month preceding introduction of belimumab therapy.
3. Disease duration of less than or equal to 3 years as defined by the date of onset of the first non-Raynaud's symptom.

Exclusion Criteria:

1. Inability to render informed consent in accordance with institutional guidelines.
2. Disease duration of greater than 3 years.
3. Patients with mixed connective tissue disease or "overlap" (i.e. those who satisfy more than one set of ACR criteria for a rheumatic disease.)
4. Limited scleroderma.
5. Systemic sclerosis-like illness associated with environmental or ingested agents such as toxic rapeseed oil, vinyl chloride, or bleomycin.
6. Ongoing treatment with immunosuppressive therapies including cyclophosphamide, azathioprine, methotrexate, or cyclosporine, or use of those medications within 1 month of trial entry.
7. The use of other anti-fibrotic agents including colchicine, D-penicillamine, minocycline, tyrosine kinase inhibitors (nilotinib, imatinib, dasatinib), or Type 1 oral Collagen in the month prior to enrollment.
8. Use in the prior month of corticosteroids at doses exceeding the equivalent of prednisone 10 mg daily. Use of corticosteroid at < 10 mg of prednisone can continue during the course of the study.
9. Treatment with MMF at a dose of ≥ 2 grams daily for > 3 months.
10. Concurrent serious medical condition which in the opinion of the investigator makes the patient inappropriate for this study such as uncontrollable CHF, arrhythmia, severe pulmonary or systemic hypertension, severe GI involvement, hepatic impairment, serum creatinine of greater than 2.0, active infection, severe diabetes, unstable atherosclerotic cardiovascular disease, malignancy, HIV, or severe peripheral vascular disease.
11. A positive pregnancy test at entry into this study.
12. Men and women with reproductive potential will be required to use effective means of contraception through the course of the study, such as a tubal ligation or hysterectomy, condom or diaphragm used with a spermicide,or an intrauterine device (IUD). Approved hormonal contraceptives (such as birth control pills, patches, implants or injections) may interact with and reduce the effectiveness of MMF and thus, are not acceptable. Contraceptive measures such as Plan B (TM), sold for emergency use after unprotected sex, are not acceptable methods for routine use.
13. Breastfeeding. Breastfeeding is contraindicated with the use of MMF.
14. Participation in another clinical research study involving the evaluation of another investigational drug within ninety days of entry into this study.
15. The presence of severe lung disease as defined by a diffusion capacity of less than 30% of predicted or requiring supplemental oxygen.
16. History of HIV infection
17. Known active bacterial, viral, fungal, mycobacterial, or other infection r any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeks prior to screening
18. Any other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of an investigational drug or that may affect the interpretation of the results or render the patient at high risk from treatment complications
19. Prior use of Belimumab, Rituximab, or other B-Cell depleting therapies ever
20. The use of other biologics including TNF inhibitors, abatacept, or tocilizumab within 1 month of enrollment [this is a safety issue]
21. Patients with a history of severe depression, psychosis, or suicidal ideation will be excluded.