Brentuximab Vedotin for Systemic Sclerosis

Inclusion Criteria

• Classification of Systemic Sclerosis (SSc), as defined using the 2013 American College of Rheumatology/European Union League Against Rheumatism classification of SSc;
• Diagnosis of Diffuse Cutaneous Systemic Sclerosis (dcSSc), as defined by LeRoy and Medsger, Criteria for the classification of early systemic sclerosis. J Rheumatol, 2001. 28(7): p. 1573-6;
• Disease duration ≤ 60 months (defined as time from the first non-Raynaud phenomenon manifestation);
• Modified Rodnan Skin Score (mRSS) units ≥ 15 and ≤ 45, and both of the following:
• At least mild skin thickening (≥ 1+ mRSS) of the forearm, and
• At least moderate skin thickening (≥ 2+ mRSS) at the planned forearm skin biopsy site.
• Documentation of at least 12 weeks of ongoing immunosuppressive therapy for SSc at the time of enrollment, and at least 4 weeks at a stable dose, of one of the following:
• Methotrexate ≤ 25 mg/week, or
• Mycophenolate mofetil ≤3 grams/day or mycophenolate sodium ≤2.16 grams/day, or
• Azathioprine ≤3mg/kg/day.
• Ability to provide informed consent.

Exclusion Criteria

• Rheumatic disease other than Diffuse Cutaneous Systemic Sclerosis (dcSSc); it is acceptable to include patients with osteoarthritis, fibromyalgia, sicca symptoms, and scleroderma-associated myopathy;
• Limited cutaneous Systemic Sclerosis (SSc) or sine scleroderma;
• Pulmonary disease with Forced Vital Capacity (FVC) ≤60% of predicted, or Diffusing Capacity of the Lung for Carbon Monoxide (DLCO) (corrected for hemoglobin) ≤60% of predicted;
• Pulmonary hypertension (PH) or moderate to severe left ventricular dysfunction, defined as one of the following:
• Transthoracic echocardiography demonstrating at least one of the following (unless subsequent right heart catheterization does not demonstrate PH; or unless prior right heart catheterization within one year did not demonstrate PH and echocardiography results are not significantly changed):
• Tricuspid regurgitation jet >2.8 m/sec or estimated right ventricular systolic pressure > 42 mm Hg. or
• At least one of the following:
• Abnormality of right atrial size, shape, or wall thickness consistent with PH, or
• Abnormality of right ventricular size, shape, or wall thickness consistent with PH, or
• Abnormal septal wall shape consistent with PH.
• Left Ventricular Ejection Fraction (LVEF) 10 mg/day of prednisone or equivalent within 2 weeks prior to enrollment;
• Treatment with Intravenous Immunoglobulin (IVIG) within 12 weeks prior to enrollment;
• Treatment with cyclophosphamide within 6 months prior to enrollment;
• Use of investigational biologic or non-biologic medication within the past 90 days, or 5 half-lives prior to enrollment, whichever is greater;
• Use of anti-TNF medication or other biologic medications within the past 90 days, or 5 half-lives prior to enrollment, whichever is greater;
• Prior treatment with anti-CD20 if either of the following are true:
• B cells ≤ lower limit of normal (LLN), or
• Treatment with anti-CD20 has been within 12 months prior to enrollment.
• Any prior treatment with cell-depleting therapies other than anti-CD20, including investigational agents, including but not limited to, CAMPATH(R), anti- CD4, anti-CD5, anti-CD3, anti-CD19; or
• Any prior treatment with chlorambucil, bone marrow transplantation, or total lymphoid irradiation.
• Receipt of a live-attenuated vaccine within 3 months of study enrollment;
• Concomitant malignancies or a history of malignancy, with the exception of adequately treated basal and squamous cell carcinoma of the skin, or carcinoma in situ of the cervix;
• Major surgery (including joint surgery) within 8 weeks prior to enrollment;
• History of solid organ or hematopoietic stem cell transplantation;
• History of primary immunodeficiency;
• Comorbidities requiring systemic corticosteroid therapy, including those which have required three or more courses of systemic corticosteroids within the 12 months prior to enrollment;
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