Successful Treatment of TAFRO Syndrome, a Variant of Multicentric Castleman’s Disease, with Cyclosporine A: Possible Pathogenetic Contribution of Interleukin-2

Abstract

Multicentric Castleman's disease is a systemic inflammatory disorder characterized by lymphadenopathy and excessive interleukin-6 production. A unique clinicopathologic variant of multicentric Castleman's disease, TAFRO (i.e., thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis, and organomegaly) syndrome, was recently proposed in Japan. Despite the successful use of anti-interleukin-6 therapy in some patients with TAFRO syndrome, not all patients achieve remission. The pathophysiological etiology of and suitable therapeutic strategies for this variant have not been established. Here, we present our experience of a unique case of TAFRO syndrome in a 78-year-old woman whose symptoms responded differently to several therapies. Tocilizumab, an anti-interleukin-6 receptor antibody, successfully induced remission of fever and lymphadenopathy. However, severe thrombocytopenia persisted and she developed anasarca, ascites, and pleural effusion shortly thereafter. Rituximab, an anti-CD20 antibody, and glucocorticoid therapy provided no symptom relief. In contrast, cyclosporine A, an immunosuppressive agent that blocks T cell function by inhibiting interleukin-2, yielded immediate improvements in systemic fluid retention and a gradual increase in platelet count, with complete resolution of disease symptoms. Excessive serum interleukin-2, when used as an anti-cancer agent, has been reported to cause side effects such as fluid retention, thrombocytopenia, and renal failure. Our case was unique because the antiinterleukin-2 therapy successfully improved symptoms that were not relieved with anti-interleukin-6 therapy. The present report therefore provides insight into the possible role of interleukin-2, in addition to interleukin-6, in TAFRO syndrome. This report will certainly help to clarify the pathogenesis of and optimal treatment strategies for TAFRO syndrome.

Two Cases of Thrombocytopenia, Anasarca, Fever, Reticulin Fibrosis/Renal Failure, and Organomegaly (TAFRO) Syndrome with High Serum Procalcitonin Levels, Including the First Case Complicated with Adrenal Hemorrhaging

“…In the 2015 treatment strategy for TAFRO syndrome (26), treatments with high-dose glucocorticoids, cyclosporin A, tocilizumab, and rituximab are recommended, based on the clinical experiences of Japanese research teams. In previous reports describing the clinical courses of six TAFRO syndrome cases (7,11,15-17,19), treatment with rituximab was effective, except in one case (15). To our knowledge, our Case 2 is the second case of tocilizumab-resistant TAFRO syndrome successfully treated with rituximab (19).…”

“…These findings suggested that IL-6 may not be the primary pathological cytokine (20). Konishi et al (15) also suggested the involvement of an IL-2-dependent pathway in addition to IL-6-related pathways in the etiology of TAFRO syndrome, based on their clinical experience.…”

“…For the treatment of TAFRO syndrome, immunosuppressive drugs including high-dose corticosteroids and cyclosporin A have been used (20). Tocilizumab (anti-IL-6 receptor antibody) (7,9,10,12,14,15,17,19-22,24,25) and rituximab (anti-CD20 antibody) (7,11,15-17,19,20) have also been used. However, despite these treatments, some patients exhibit a rapidly deteriorating clinical course and died (4).…”

Successful treatment by tocilizumab without steroid in a very severe case of TAFRO syndrome

“…Our case thus represented a very rare case of successful treatment for grade 5 TAFRO syndrome. Some patients with TAFRO syndrome have been successfully treated with steroid, immunosuppressants, including cyclosporine A (CyA), TCZ and rituximab, and/or immunomodulatory drugs like thalidomide [2][3][4][5][6]. According to the 2015 treatment strategy for TAFRO syndrome, steroid is the first-line treatment, with CyA as the second-line therapy.…”

“…Konishi et al suggested that IL-2-related immunological abnormality plays a role in the pathogenesis of TAFRO syndrome, in addition to IL-6 [4]. Their case achieved remission with CyA and CyA interferes in T cell activity via inhibition of calcineurin which is responsible for activating IL-2 encoding gene transcription [10].…”