Tocilizumab for Antibody-Mediated Rejection in the Setting of Cardiac Allograft Vasculopathy

Introduction IL-6 is a pro-inflammatory cytokine that potentiates the effect of plasma cells, immunoglobulins, T-cells, and macrophages. IL-6 levels are associated with atherosclerotic plaque progression and graft fibrosis; IL-6 blockade may have a role in therapy for cardiac allograft vasculopathy (CAV). Preclinical data has also implicated IL-6 signaling in graft rejection. Tocilizumab, an IL-6 receptor antagonist, has successfully decreased donor-specific antibodies (DSAs) in renal transplant patients with antibody-mediated rejection (AMR). Herein, we report on the use of tocilizumab in a heart transplant recipient with treatment-refractory AMR and established CAV. Case Report A 65 year old male who underwent heart transplantation 13 years ago presented with dyspnea. His history was significant for AMR 5 years post-transplant and CAV 10 years post-transplant. On admission, studies revealed reduced LV ejection fraction (LVEF, 70% to 50%) and cardiac index (CI, 1.27 L/min/m 2 ), severe 3-vessel CAV, and elevated pulmonary capillary wedge pressure (PCWP, 28 mmHg). He had new DSAs against HLA-A, -B, -DQ, and -DR antigens (MFI 5,792-24,748); biopsy grade was 1R/1A. He was treated with steroids, plasmapheresis, IVIg, and rituximab; maintenance immunosuppression was revised to tacrolimus, everolimus, mycophenolate, and prednisone. He was readmitted twice within the next month with acute decompensation requiring inotropes. He had a further decline in LVEF to 45%, CAV progression, and largely unchanged DSAs. He was again treated with steroids, plasmapheresis, and IVIg. Given progressive decline despite traditional AMR and CAV therapy, we initiated tocilizumab 800 mg monthly. He has received tocilizumab for one year without significant complications or hospitalizations; he reports NYHA class II symptoms. HLA screen showed resolution of HLA-A, -B, and -DR DSAs and MFI reduction of HLA-DQ DSA (24,748 to 14,994). Right heart catheterization was significantly improved (CI 2.06 L/min/m 2 and PCWP 18 mmHg); LVEF remains unchanged and coronary angiography shows CAV progression. Summary To our knowledge, this represents the first report of using tocilizumab for refractory cardiac AMR and CAV. Additional studies are warranted to evaluate the safety and efficacy of tocilizumab in heart transplant recipients and to elucidate the mechanism of DSA clearance by tocilizumab.