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Introduction Systemic sclerosis (SSc) is associated with the highest case-related mortality of all rheumatic diseases. B cell-targeting has shown efficacy in SSc but failed to eliminate the anti-topoisomerase-I autoantibody-producing plasma cell niches.Material and Methods We treated five cases of severe, progressive, treatment-refractory SSc with the plasma cell-depleting bispecific antibody teclistamab ( table 1). After six cycles of teclistamab, 1g of rituximab was administered to prevent recovery of autoantibody-producing cells. Four patients were positive for anti-topoisomerase-I antibodies, and one patient was positive for anti-fibrillarin autoantibodies. All patients had diffuse cutaneous SSc, interstitial lung disease and primary heart involvement and have been refractory to at least three immunomodulatory and/or antifibrotic therapies. Immunosuppressive and antifibrotic therapies were discontinued prior to baseline (BL). Patients were followed for up to 15 months.Results Treatment with teclistamab depleted all plasma cells in the skin. Anti-topoisomerase-I-autoantibody titers seroconverted in two patients and dropped by 83% and 33% in the third and fourth patient, respectively. This immunological response was associated with strong decreases of the modified Rodnan skin score, stabilization of SSc-ILD, resolution of tendon friction rubs and decreases in the EUSTAR-AI in all patients. The effect on SSc-associated primary myocardial involvement was heterogeneous. Treatment with teclistamab was associated with several adverse events including cytokine release syndrome, hypogammaglobulinemia and mild infections (despite regular immunoglobulin replacement).Conclusions Teclistamab may offer potential as a rescue therapy for selected patients suffering from severe, treatment-refractory dcSSc, including those with advanced disease.Abstract OC.52 Figure 1Abstract OC.52 Figure 2Abstract OC.52 Table 1