A Clinical Study to Evaluate Ianalumab in Participants With Diffuse Cutaneous Systemic Sclerosis

Eligibility Criteria

• * Male and female participants \>= 18 and =\< 70 years (at the time of the screening visit).
• * Diagnosis of systemic sclerosis, as defined by the 2013 American College of Rheumatology/ European League Against Rheumatism (ACR/EULAR) classification criteria for SSc (van den Hoogen et al 2013) and meet the dcSSc subset classification according to LeRoy (LeRoy 1988)
• * Disease duration of =\< 60 months (defined as time from the first non-Raynaud phenomenon manifestation, e.g., puffy hands, scleroderma, digital ulcers, arthralgia, dyspnea)
• * mRSS units of \>= 15 and =\< 45 at the time of the screening visit
• * Active disease that meets at least one of the following criteria at screening:
• * Disease duration of =\< 18 months defined as time from the first non-Raynaud phenomenon manifestation
• * Increase in mRSS of \>= 3 units compared with the most recent assessment performed within the previous 6 months
• * Involvement of one new body area and an increase in mRSS of \>= 2 units compared with the most recent assessment performed within the previous 6 months
• * Involvement of two new body areas within the previous 6 months
• * Elevated acute phase reactants (ESR) \>= 30 mm/hr or high-sensitivity C-reactive protein (hsCRP) \>= 6 mg/dL)
• * Presence of interstitial lung disease (ILD) and ATA autoantibody positivity
• * Modified EUSTAR disease activity index (mDAI) \> 2.5
• * Participant must be positive for at least one of the following autoantibodies:
• * anti-topoisomerase I (ATA) (also known as anti-SCL-70)
• * anti-RNA polymerase III (anti-RNAP3)
• * anti-nuclear antibody (ANA) (≥ 1:80) Participants who are positive only for ANA (while being negative for both ATA /anti-RNAP3) will be limited to 30% of the overall randomized study population.
• * Rheumatic disease other than dcSSc, including limited cutaneous disease (lcSSc) or sine scleroderma at the screening visit. Secondary Sjogren's disease and scleroderma myopathy are not exclusionary.
• * Positive anti-centromere antibody (ACA+) without positive ATA or anti-RNAP3 autoantibody result at the screening visit
• * Previous improvement (decrease) in mRSS \> 10 units
• * Pulmonary disease with FVC ≤ 50% of predicted or diffusing capacity of the lung for carbon monoxide (DLCO, corrected for hemoglobin) ≤ 40% of predicted at the screening visit
• * WHO Functional Class 3 or higher assessment for pulmonary arterial hypertension (PAH, as defined on right heart catheterization), receiving IV therapy for PAH or evidence of other moderately severe pulmonary disease
• * Participants treated with cyclophosphamide within 12 weeks prior to Baseline.
• * Prior use of a B-cell depleting therapy other than ianalumab (e.g., rituximab, other anti-CD20 mAb, anti-CD22 mAb, or anti-CD52 mAb) administered within 36 weeks prior to randomization, or as long as B cell count is less than the lower limit of normal or baseline value prior to receipt of B cell-depleting therapy (whichever is lower)
• * Treatment with biologic agents, such as intravenous immunoglobulin or monoclonal antibodies, including marketed drugs, within 12 weeks or 5 half-lives (whichever is longer) prior to baseline visit, unless explicitly allowed in inclusion criteria
• * Treatment with any investigational agent within ≤ 4 weeks (or 5 half-lives of the investigational drug, whichever is longer) of the baseline visit
• * Use of anti-fibrotic agents including colchicine, D-penicillamine, pirfenidone, or tyrosine kinase inhibitors (e.g., nintedanib, nilotinib, imatinib, dasatinib) in the 4 weeks prior to baseline visit.
• * Previous treatment with chlorambucil, bone marrow transplantation or total lymphoid irradiation.