Belimumab and Rituximab Combination Therapy for the Treatment of Diffuse Cutaneous Systemic Sclerosis

Inclusion Criteria:

1. Age greater than or equal to eighteen years and less than or equal to 80.

2. Classification of systemic sclerosis (SSc), as defined using the 2013 AmericanCollege of Rheumatology/European Union League Against Rheumatism classification ofSSc.

3. Diagnosis of dcSSc, as defined by LeRoy and Medsger.

4. Disease duration of less than or equal to 3 years as defined by the date of onset ofthe first non-Raynaud's symptom.

5. A modified Rodnan Skin Score (mRSS) of > 14

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" unless the dominantfeatures of the illness are diffuse systemic sclerosis.

4. Limited scleroderma.

5. Systemic sclerosis-like illness associated with environmental or ingested agentssuch as toxic rapeseed oil, vinyl chloride, or bleomycin.

6. The use of other anti-fibrotic agents including colchicine, D-penicillamine, ortyrosine kinase inhibitors (nilotinib, imatinib, dasatinib) in the month prior toenrollment.

7. Use in the prior month of corticosteroids at doses exceeding the equivalent ofprednisone 10 mg daily. Use of corticosteroid at < 10 mg of prednisone can continueduring the course of the study.

8. Concurrent serious medical condition which in the opinion of the investigator makesthe patient inappropriate for this study such as uncontrollable CHF, arrhythmia,severe pulmonary or systemic hypertension, severe GI involvement, hepaticimpairment, serum creatinine of greater than 2.0, active infection, severe diabetes,unstable atherosclerotic cardiovascular disease, malignancy, HIV, or severeperipheral vascular disease.

9. A positive pregnancy test at entry into this study. Men and women with reproductivepotential will be required to use effective means of contraception through thecourse of the study, such as (1) surgical sterilization (such as a tubal ligation orhysterectomy), (2) double-barrier methods (such as a condom and occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent (foam/gel/film/cream/suppository)(3) an intrauterine device (IUD) or intrauterinesystem (IUS) (4) estrogenic vaginal ring (5) percutaneous contraceptive patches, or (6) implants of levonorgestrel or etonogestrel. Approved hormonal contraceptives (such as birth control pills, patches, implants or injections) may interact with andreduce the effectiveness of MMF so women receiving MMF who are using oralcontraceptives for birth control should employ an additional method (e.g. barriermethod). Contraceptive measures such as Plan B (TM), sold for emergency use afterunprotected sex, are not acceptable methods for routine use.

10. Women not willing to use effective birth control for the duration of the study

11. Breastfeeding.

12. Participation in another clinical research study involving the evaluation of anotherinvestigational drug within ninety days of entry into this study.

13. The presence of severe lung disease as defined by a diffusion capacity of less than 30% of predicted or requiring supplemental oxygen and forced vital capacity (FVC) ofless than 45% of predicted.

14. Grade 3 hypogammaglobulinemia

15. Have a significant IgG deficiency (IgG level < 400 mg/dL)

16. Have an IgA deficiency (IgA level < 10 mg/dL)

17. Have a historically positive HIV test or test positive at screening for HIV

18. Neutrophils <1.5X10E9/L

19. Hepatitis status:

20. Serologic evidence of current or past Hepatitis B (HB) infection based on theresults of testing for HBsAg and HBcAb as follows:

21. Patients positive for HBsAg or HBcAb are excluded b) Positive test for Hepatitis Cantibody 20. Known active bacterial, viral, fungal, mycobacterial, or otherinfection or any major episode of infection requiring hospitalization or treatmentwith IV antibiotics within 4 weeks of screening, or oral antibiotics within 2 weeksprior to screening 21. Infection history:

22. Currently on any suppressive therapy for a chronic infection (such as tuberculosis,pneumocystis, cytomegalovirus, herpes simplex virus, herpes zoster and atypicalmycobacteria)

23. Hospitalization for treatment of infection within 60 days of Day 0.

24. Use of parenteral (IV or IM) antibiotics (antibacterials, antivirals, anti-fungals,or anti-parasitic agents) within 60 days of Day 0 22. Suppressive therapy for achronic infection (such as tuberculosis, pneumocystis, cytomegalovirus, herpeszoster and atypical mycobacteria) 23. Any other disease, metabolic dysfunction,physical examination finding, or clinical laboratory finding giving reasonablesuspicion of a disease or condition that contraindicates the use of aninvestigational drug or that may affect the interpretation of the results or renderthe patient at high risk from treatment complications 24. Prior use of Belimumab,Rituximab, or other B-Cell depleting therapies ever 25. The use of other biologicsincluding TNF inhibitors, abatacept, or tocilizumab within the washout period belowfor each particular drug: Tocilizumab - 1 month for patients on 2mg/kg or 4 mg/kg. 2 months for patients on 8mg/kg. Cyclophosphamide (oral or IV) - 3 months. Abatacept - 2.5 months. TNF Inhibitors :Etanercept - 1 mo, Infliximab - 2 mo, Adalimumab - 2.5 mo. Any biologicinvestigational agent (e.g., abetimus sodium, anti CD40L antibody, BG9588/ IDEC 131)

• 365 days prior to belimumab. Any non-biologic investigational agent - 30 days prior to belimumab.

26. Have evidence of serious suicide risk including any history of suicidalbehavior in the last 6 months and/or any suicidal ideation in the last 2 monthsor who in the investigator's judgment, pose a significant suicide risk.

27. Current drug or alcohol abuse or dependence, or a history of drug or alcoholabuse or dependence within 364 days prior to Day 0.

28. History of an anaphylactic reaction to parenteral administration of contrastagents, human or murine proteins or monoclonal antibodies 29. Live vaccineswithin 30 days prior to baseline 30. Have a history of malignant neoplasmwithin the last 5 years with the exception of basal cell or squamous cellcarcinoma of the skin treated with local resection only or carcinoma in situ ofthe uterine cervix treated locally and with no evidence of metastatic diseasefor 3 years 31. Have a history of a primary immunodeficiency 32. Have any otherclinically significant abnormal laboratory value in the opinion of theinvestigator 33. Have any intercurrent significant medical or psychiatricillness that the investigator considers would make the candidate unsuitable forthe study 34. Non English speakers