Last Resort

Castleman’s disease (CD) is a rare lymphoproliferative disorder divided into unicentric (solitary enlarged lymph node) and multicentric (multifocal enlarged lymph nodes).¹ MCD typically presents with systemic inflammation, reactive proliferation of benign lymphocytes, multifocal lymphadenopathy, elevated inflammatory markers, anemia, hypoalbuminemia, and polyclonal gammaglobulinemia.¹ It is hypothesized that HHV-8 drives the systemic inflammation of MCD via high levels of interleukin-6 (IL-6) activity.¹ iMCD is an HHV-8-negative variant of MCD.¹

TAFRO syndrome was first described in 2010 in three Japanese patients demonstrating high fever, anasarca, hepatosplenomegaly, lymphadenopathy, severe thrombocytopenia, and reticulin fibrosis.² In 2015, the All Japan TAFRO Syndrome Research Group recognized TAFRO syndrome as a variant of iMCD and created diagnostic criteria and a severity classification system.³ Major criteria consist of anasarca, including pleural effusion and/or ascites identified on CT scan and general edema, thrombocytopenia (platelet count <100 k/mm³), and systemic inflammation (fever >37.5°C and/or serum CRP greater than or equal to 2 mg/dL).³ Two of four minor criteria must be met, which include (1) lymph node histology consistent with CD, (2) reticulin myelofibrosis and/or increased number of megakaryocytes in bone marrow, (3) mild organomegaly, including hepatomegaly, splenomegaly, and lymphadenopathy <1.5 cm in diameter identified on CT scan, and (4) progressive renal insufficiency (serum creatinine >1.2 mg/dL in males or >1.0 mg/dL in females).³ In addition, several patients with TAFRO syndrome demonstrate elevated ALP, low-normal LDH, elevated vascular endothelial growth factor, elevated IL-6, microcytic anemia, and slight polyclonal hypergammopathy.³ Malignancies such as lymphoma and myeloma, autoimmune diseases such as SLE and ANCA-associated vasculitis, infectious diseases such as those caused by mycobacteria, and POEMS (polyneuropathy, organomegaly, endocrine diseases, M-protein, and skin lesions) syndrome must be excluded to diagnose TAFRO syndrome.^3,4

The pathophysiology of TAFRO syndrome is unknown, and it is unclear whether the syndrome is truly a variant of iMCD or a distinct entity.³ IL-6 is typically only mildly elevated in TAFRO syndrome, without the consequent thrombocytosis and polyclonal hypergammaglobulinemia seen in MCD, which is associated with higher levels of IL-6.¹ Multiple non-HHV-8 mechanisms for TAFRO syndrome have been proposed, including (1) systemic inflammation, autoimmune/autoinflammatory mechanisms, (2) neoplastic, ectopic cytokine secretion by malignant or benign tumor cells, and/or (3) infectious, such as non-HHV-8 virus.⁵

Immunosuppression is the mainstay of treatment for TAFRO syndrome based on recommendations from the 2015 TAFRO Research Group.³ Glucocorticoids are considered first-line therapy.³ Cyclosporin A is recommended for individuals refractory to glucocorticoids.³ In patients with a contraindication to cyclosporin A, anti-IL-6 receptor antibodies such as tocilizumab (approved for treatment of iMCD in Japan) and siltuximab (approved for treatment of iMCD in North America and Europe) or the anti-CD20 antibody rituximab should be prescribed.³ There is evidence for the thrombopoietin receptor agonists romiplostim and eltrombopag to treat persistent thrombocytopenia.³ Additional treatments for refractory TAFRO syndrome include IVIG and plasma exchange, chemotherapy (cyclophosphamide, doxorubicin, vincristine, prednisolone), and thalidomide.^3,6

Little is known about the epidemiologic characterization of TAFRO syndrome as less than 40 cases of TAFRO syndrome have been reported in the United States, Asia, and Europe.