Here, we report 2 cases of TAFRO syndrome, where 1 with cardiomyopathy, successfully treated with tacrolimus. In case 2, tacrolimus completely reversed TAFRO syndrome and was also effective in cardiomyopathy. Lessons: This report suggests that tacrolimus is potentially effective and safe as an initial treatment and a glucocorticoid-sparing agent. Our literature review INCB8761 (PF-4136309) shows that calcineurin inhibitors, including tacrolimus, may be effective in TAFRO syndrome. Since previous studies indicate a role of Th1 inflammation in TAFRO syndrome pathogenesis, tacrolimus may, therefore, be effective in treating TAFRO syndrome. strong class=”kwd-title” Keywords: calcineurin inhibitors, cardiomyopathy, cyclosporine A, multicentric Castleman disease, tacrolimus, TAFRO syndrome 1.?Introduction TAFRO syndrome was first described in Japan in 2010 2010 as a unique variant of multicentric Castleman disease (MCD) with an aggressive clinical course and comprised thrombocytopenia, anasarca, INCB8761 (PF-4136309) fever, reticulin fibrosis, renal dysfunction, and organomegaly (TAFRO). MCD constitutes a heterogeneous group of lymphoproliferative disorders characterized by excessive systemic inflammatory features, including frequent fever, generalized peripheral lymphadenopathy, hepatosplenomegaly, polyclonal hypergammaglobulinemia, and elevated levels of serum C-reactive protein (CRP), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF). These clinical manifestations of MCD are possibly driven by excessive proinflammatory hypercytokinemia, particularly in association with elevated levels of IL-6. On the contrary, MCD is strongly associated with human herpesvirus-8 (HHV-8), which infects B cells and expresses a viral homolog of IL-6; TAFRO syndrome is considered as a subgroup of HHV-8-negative MCD or idiopathic MCD group. Although IL-6 levels in TAFRO syndrome are elevated, many of its features differ considerably from classical MCD features, including severe thrombocytopenia and absence of hypergammaglobulinemia, which is difficult to explain owing to hyper-IL-6 syndrome because IL-6 overexpression typically results in thrombocytosis and hypergammaglobulinemia. In addition, IL-6 targeting strategies seem to be ineffective for some TAFRO syndrome cases, whereas they are highly effective for MCD (91% complete response rate). These findings suggest that not only IL-6 but also other proinflammatory conditions may play roles in the pathogenesis of TAFRO syndrome. Furthermore, the combination of glucocorticoids and tocilizumab, an anti-IL-6 receptor antibody, increases the risk of severe infections. In terms of effectiveness and adverse events, IL-6-targeting agents may not be the best choice for TAFRO syndrome; however, the optimal treatment remains unclear. To the best of our knowledge, this is the first report of 2 cases of TAFRO syndrome successfully treated with tacrolimus, where 1 with a rare complication of cardiomyopathy, ALK7 which was also completely resolved after treatment. We also discuss the relationship between the action mechanism of tacrolimus and possible pathogenesis of TAFRO syndrome. 2.?Case reports 2.1. Case 1 A 68-year-old Japanese woman without medical history was admitted to our hospital with a 4-week history of abdominal distension and fever of 38.1C. Physical examination revealed swollen cervical and axillary lymph nodes ( 1?cm in diameter) and abdominal tenderness. Laboratory studies revealed anemia (hemoglobin, 7.3?g/dL); thrombocytopenia (38,000/L); reduced immunoglobulin G (IgG, 770?mg/dL); elevated levels of alkaline phosphatase (ALP, 720?U/L), soluble interleukin-2 receptor (sIL-2R, 3060?U/mL), and CRP (2.7?mg/dL); and renal dysfunction (serum creatinine 1.6?mg/dL) with microhematuria. Test results for autoantibodies, including antinuclear antibody (ANA) and antineutrophil cytoplasmic antibody (ANCA); and viruses, including HHV-8 and human immunodeficiency virus (HIV), were negative. Computed tomography (CT) revealed systemic lymphadenopathy, bilateral pleural effusion, massive ascites, and hepatosplenomegaly. IL-6 and VEGF levels in serum (24 and 390?pg/mL, respectively) and in ascitic fluid (1800 and 63?pg/mL, respectively) were elevated. Cervical lymph node biopsy revealed atrophic germinal centers, expanded mantle zones, and proliferated high endothelial venules and small number of plasma cells in the interfollicular zones (Fig. ?(Fig.1A,1A, B). Bone marrow biopsy revealed hyperplasia of megakaryocytes and reticulin fibrosis. These symptoms and histopathologic findings met the diagnostic criteria for TAFRO syndrome.[3,7] Open in a separate window Figure 1 Histologic findings of the cervical lymph node. (A) Lymph node with proliferated high endothelial venules and small number of plasma cells in the interfollicular zone. Hematoxylin and eosin staining (40 magnification). (B) Atrophic germinal centers with enlarged nuclei of high endothelial cells and expanded mantle zones. Hematoxylin and eosin staining INCB8761 (PF-4136309) (100 magnification)..