Rituximab Reduces Anti-UL94 and Anti-NAG-2 Antibodies Titer and Is Effective against Skin-Chronic Graft Versus Host Disease Resembling Scleroderma.

Abstract 4654

We previously described a potential pathogenetic link between human Cytomegalovirus (hCMV) infection and scleroderma-like skin chronic graft versus host disease (cGVHD) in allogeneic stem cell transplant patients (HCT), through a mechanism of molecular mimicry between UL-94 viral protein and NAG-2 molecule. Antibodies against UL-94 and NAG-2 induce apoptosis of endothelial cells and fibroblasts proliferation as observed in Systemic Sclerosis ( SSc ) patients (ASH 2009, Abstract 1169; EBMT 2009, oral comunication 377). The observation that the anti-CD20 chimaeric monoclonal antibody Rituximab induces a significant clinical response in a proportion of HCT patients with refractory cGVHD prompted us to evaluate in our CMV IgG positive HCT patients, who developed scleroderma-like skin cGVHD, first the efficacy of Rituximab, second weather the potential effect of Rituximab would correlate with the anti-viral and anti-NAG-2 antibodies titer. Among 18 patients undergone HCT for hematological malignancies between 2003 and 2006 at Bone Marrow Transplant Unit of Division of Hematoncology, European Institute of Oncology, Milan, Italy, two of them (patients #2 and #3) both positive for anti-UL94 and anti-NAG-2 antibodies and with clinical evidence of diffuse SSc-like skin cGVHD following HCT were treated with Rituximab. Rituximab was administered with the following schedule: 375 mg/msq weekly for 4 weeks and then monthly up to 4 months. Patient #2 complited the schedule, patient #3 discontinued the therapy, after the second monthly dose, due to infectious pneumonia. Patients' plasma was monitored for anti-UL94 and anti-NAG-2 antibodies titer, by direct and competitive ELISA assays, before starting Rituximab administration, after the weekly therapy, and at the end of the schedule of treatment (patient #2) or after the last Rituximab infusion, in case of discontinuation (patient #3). In patient #2 we observed a dramatic reduction of the anti-NAG-2 antibodies titer immediately after completing the weekly administration of Rituximab, reaching a stable plateau after the monthly administration of the monocolonal therapy in parallel with an excellent clinical response. In the same patient anti-UL94 antibodies titer was already low after HCT and before Rituximab, and it kept stable low values during all the administration period. Worth of note, this patient is now off any immunosuppressive treatment. We observed also a reduction of both anti-CMV and anti-NAG-2 antibodies titer in patient #3 following Rituximab, however without reaching a plateau, mainly due to the early discontinuation of the treatment. This patient had also a good clinical response, even though he is still under immunosuppression therapy. In conclusion, our data show that Rituximab reduces anti-UL94 and anti-NAG2 antibodies titer in hCMV positive HCT patients in parallel with the clinical response of skin cGVHD resembling scleroderma.