title: Sequential therapy with belimumab followed by rituximab in Sjögren's syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy.
abstract: OBJECTIVE
  The overexpression of B-cell activating factor (BAFF) in mucosa-associated lymphoid tissue (MALT) may decrease the efficacy of rituximab treatment in Sjögren's syndrome (SS). Anti-CD20 therapy was effective on marginal zone B cells, in the murine model for human CD20 expression only when preceded by anti-BAFF therapy. The possible efficacy of a sequential anti-BAFF/anti-CD20 therapy in SS was investigated.
  
  
  METHODS
  We treated with belimumab, a monoclonal anti-BAFF antibody, and soon after with rituximab a patient with severe, refractory SS, parotid low-grade B-cell MALT lymphoma and cryoglobulinaemic vasculitis. Previous treatments with rituximab and with rituximab plus high dose glucocorticoids, as well as with cyclophosphamide, azathioprine, plasma exchange, hyperbaric therapy, VAC therapy, prostacyclin, mycophenolate mofetil and surgery, had previously failed. Treatment with belimumab was then given, but it also failed. A new course of rituximab (375 mg/m2; four weekly infusions) was started 49 days after the last infusion of belimumab.
  
  
  RESULTS
  This sequential belimumab-rituximab treatment was followed by a marked amelioration, with the complete and persistent regression of lymphoma and healing of a refractory skin ulcer. A full cycle of rituximab was then repeated 6 and 12 months later; no further treatment was given in the following 22 months up to now. Serum cryoglobulins and rheumatoid factor became persistently negative and serum BAFF and C4 persistently normal. No relevant side effects were noticed, except for a marked decrease in serum IgM. The follow up after belimumab-rituximab sequential therapy is now three and a half years.
  
  
  CONCLUSIONS
  Therapy with belimumab followed by rituximab may be effective for SS-related B-cell lymphoproliferation. The efficacy and safety of the sequential or concomitant targeting of BAFF and CD20 deserves further evaluation in SS.
authors.affiliation: Clinic of Rheumatology, Department of Medical and Biological Sciences, University Hospital 'S. Maria della Misericordia' of Udine, Italy. devita.salvatore@aoud.sanita.fvg.it.
authors.forename: Salvatore
authors.initials: S
authors.lastname: De Vita
authors.forename: Luca
authors.initials: L
authors.lastname: Quartuccio
authors.forename: Sara
authors.initials: S
authors.lastname: Salvin
authors.forename: Luca
authors.initials: L
authors.lastname: Picco
authors.forename: Cathryn Anne
authors.initials: CA
authors.lastname: Scott
authors.forename: Maurizio
authors.initials: M
authors.lastname: Rupolo
authors.forename: Martina
authors.initials: M
authors.lastname: Fabris
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D058846:Antibodies, Monoclonal, Murine-Derived / Q000008:administration & dosage*; D053264:B-Cell Activating Factor / Q000378:metabolism*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D004334:Drug Administration Schedule; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D018442:Lymphoma, B-Cell, Marginal Zone / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D012074:Remission Induction; D000069283:Rituximab; D012720:Severity of Illness Index; D012859:Sjogren's Syndrome / Q000150:complications / Q000175:diagnosis / Q000188:drug therapy* / Q000276:immunology; D013997:Time Factors; D016896:Treatment Outcome; D015854:Up-Regulation
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D053264:B-Cell Activating Factor; D007166:Immunosuppressive Agents; C505719:TNFSF13B protein, human; D000069283:Rituximab; C511911:belimumab