Successful Treatment with Cyclosporin A in Tocilizumab-resistant TAFRO Syndrome

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1 CASE REPORT Successful Treatment with Cyclosporin A in Tocilizumab-resistant TAFRO Syndrome Yusuke Yamaga 1, Kiyonobu Tokuyama 1, Takehiro Kato 1,RieYamada 1, Masanori Murayama 1, Tsuneko Ikeda 2, Noriyoshi Yamakita 1 and Takeshige Kunieda 1 Abstract Thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome is a unique clinicopathologic variant of multicentric Castleman s disease that has recently been identified in Japan. Previous reports have shown that affected patients typically respond to immunosuppressive therapy, such as prednisolone and tocilizumab. However, the optimal treatment for refractory TAFRO syndrome, which can be fatal, remains unclear. We herein report a case of tocilizumab-resistant TAFRO syndrome successfully treated with cyclosporin A, indicating that cyclosporine A may be an alternative therapy for refractory TAFRO syndrome. Key words: TAFRO syndrome, cyclosporin A, tocilizumab (Intern Med 55: , 2016) () Introduction Recently, Takai et al. reported a new disease concept, TAFRO syndrome, named for concurrent thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (1). Although elevated levels of interleukin-6 (IL-6) and vascular endothelial cell growth factor are seen in the serum and effusions of patients with TAFRO syndrome, the pathogenesis remains unclear (2). Previous reports have shown that patients respond to immunosuppressive therapy, such as corticosteroid and anti-il-6 receptor antibody (tocilizumab, TCZ) (3, 4). However, TAFRO syndrome can be fatal (1, 5), and an alternative therapy for refractory TAFRO syndrome remains unclear. We herein report a case of tocilizumabresistant TAFRO syndrome successfully treated with cyclosporine A (CyA). Case Report A 61-year-old man was referred to our hospital due to a fever and dyspnea on exertion. He had been well until one week before admission, when a pitting edema and dyspnea developed. On examination, he was alert and communicative, with normal vital signs and oxygen saturation. Pale palpebral conjunctivae were consistent with anemia. Submandibular lymph nodes were swollen and less than 1.5 cm in diameter. Coarse crackles were heard over both lower lung fields. Severe pitting edema was present in both legs and the abdomen was markedly distended due to massive ascites. An abdominal computed tomography scan revealed massive ascites and pleural effusion, indicating pneumonia. He had normocytic anemia, severe thrombocytopenia, elevated levels of C-reactive protein and fibrinogen degradation product, and renal dysfunction with elevated blood urea and nitrogen-to-creatinine ratio (Table 1). His symptoms and computed tomography findings were initially suspected of being caused by severe bacterial pneumonia with disseminated intravascular coagulation. He was administered antibiotics and anticoagulant agents, however, severe thrombocytopenia and inflammation persisted (Fig. 1). In addition, the administration of diuretics and albumin did not improve the pleural effusion and ascites. Bone marrow aspiration was attempted for the thrombocytopenia, but it was a dry tap. A bone marrow biopsy revealed hyperplastic marrow with megakaryocytic hyperplasia Department of General Internal Medicine, Matsunami General Hospital, Japan and Department of Pathology, Matsunami General Hospital, Japan Received for publication December 13, 2014; Accepted for publication May 7, 2015 Correspondence to Dr. Takeshige Kunieda, kunieda_t@yahoo.co.jp 185

2 Table 1. Laboratory Data on Admission. Complete blood cell count White blood cell Neutrophil Lymphocyte Eosinophil Basophil Monocyte Hemoglobin Platelet counts 14,800 /μl 88.0 % 7.0 % 0.5 % 1.0 % 3.5 % 10.8 g/dl /μl Coagulation test PT 12.3 sec PT-INR 1.06 APTT 32.4 sec FDP 19.7 μg/ml Fibrinogen 688 mg/dl D-dimer 8.62 μg/ml Blood chemistry Albumin 2.3 g/dl Total bilirubin 1.3 mg/dl AST 23 U/L ALT 8 U/L -GTP 330 U/L ALP 2,103 U/L LDH 223 U/L BUN 104 mg/dl Cr 2.15 mg/dl CRP mg/dl IgG 1,145 mg/dl IgM 73 mg/dl IgA 215 mg/dl C3 118 mg/dl C4 25 mg/dl sil-2r 448 U/mL VEGF (serum) 44 VEGF (ascites) 401 pg/ml pg/ml Abbreviations; PT: prothrombin time, PT-INR: prothrombin time-international normalized ratio, APTT: activated partial thromboplastin, AST: asparate aminotransferase, ALT: alanine aminotransferase, LDH: lactate dehydrogenase, -GTP: -glutamyl transpeptidase, BUN: blood urea nitrogen, sil-2r: soluble IL-2 receptor, FDP: fibrinogen degradation products, VEGF: vascular endothelial growth factor Plt ( 10 4 / An bio mpsl TCZ TCZ Day 0 Day 7 Day 14 Day 21 Day 28 Day 35 Day 42 Day 49 Hb(g/dL) CRP(mg/dL) ALP(U/L) Ascites IL-6(pg/mL) Serum IL-6(pg/mL) Figure 1. The clinical course with TCZ and PSL therapy. TCZ with PSL was not effective for the treatment of this case. mpsl: methylprednisolone (1,000 mg/body weight 3 days), PSL: prednisolone, TCZ: tocilizumab (8 mg/kg body weight) and mild reticulin fibrosis (Fig. 2A, B). Immunopathological and flow cytometric analyses of the bone marrow showed no evidence of monoclonality (Fig. 2C, D, 3A). Additionally, serum and urine electrophoresis did not detect monoclonal protein and all serological antibody tests were (Table 2). Sixteen days after admission, the patient s respiratory distress worsened. A chest drain was inserted for draining pleural fluid and methylprednisolone (mpsl) pulse therapy (1,000 mg/day 3 days) was administered, followed by prednisolone (PSL) (60 mg daily). However, the thrombocytopenia and massive ascites did not improve. On day 22, a biopsy of a cervical lymph node was performed for a definitive diagnosis. The lymph node displayed a disrupted follicular structure and the interfollicular area was characterized by prominent vascularity and massive plasma cell infiltrations (Fig. 2E, F). The immunopathological and flow cytometric analyses of the plasma cells in the lymph node 186

3 Figure 2. Histopathological findings. The bone marrow showed hyperplastic marrow with increased megakaryocytes by Hematoxylin and Eosin staining (A) and mild reticulin fibrosis by silver staining (B). Kappa (C) and lambda (D) immunohistochemical staining of the bone marrow showed no evidence of monoclonality. The lymph node displayed a disrupted follicular structure (E) and the interfollicular area was characterized by prominent vascularity and massive plasma cell infiltrations (F). Kappa (G) and lambda (H) immunohistochemical staining of the lymph node showed no evidence of monoclonality. showed no evidence of monoclonality (Fig. 2G, H, 3B). The histological findings were consistent with manifestations of Castleman s disease (CD). According to the clinical features, TAFRO syndrome was diagnosed. On day 42, treatment was initiated with weekly TCZ therapy (8 mg/kg body weight) in addition to 60 mg of PSL daily for 2 weeks. However, the patient s general condition, including the fever, systemic inflammation, thrombocytopenia, and anasarca, steadily deteriorated (Fig. 1). As the effectiveness of CyA treatment has been previously reported (1), we obtained ethical committee approval and patient consent for using CyA. On day 51, the patient was treated with CyA (4 mg/kg of body weight/day), after which his hemoglobin concentration and platelet counts gradually increased, and the PSL dose was tapered (Fig. 4). One month later, his platelet count had increased to within 187

4 Figure 3. Flow cytometric analysis. A flow cytometric analysis of the bone marrow (A) and lymph node (B) showed no evidence of clonality. FSC-H: forward scatter, SSC-H: side scatter Table 2. Serological Antibody Tests. Serological tests Antinuclear Antibody Anti-dsDNA antibody Anti-Sm Antibody HIV-1/2 Antigen and Antibodies HHV-8 Antibody HTLV-1 Antibody Abbreviations; Anti-dsDNA Antibody: Anti double strand DNA Antibody, Anti-Sm Antibody: Anti-Smith Antibody, HIV: Human Immunodeficiency Virus, HHV-8: Human Herpes Virus 8, HTLV-1: Human T- cell Leukemia Virus Type 1 the normal range and the ascites and pleural effusion completely diminished. Discussion Multicentric Castleman s disease (MCD) is thought to comprise several disease states, including idiopathic and secondary MCD in conditions such as polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome, autoimmune diseaseassociated lymphadenopathy, and malignant lymphoma (6, 7). In contrast to its prevalence in Western countries (7, 8), MCD associated with HIV and/or HHV-8 is uncommon in Japan, where the disease generally demonstrates a relatively chronic course. Recently, Kojima et al. revealed that MCD cases can be classified into two variants according to the clinicopathologic findings: idiopathic plasmacytic lymphadenopathy with polyclonal hyperimmunoglobulinemia (IPL) type and non-ipl type CD (9, 10). IPL is identical to MCD in Western countries, whereas non-ipl type CD was histologically characterized by mixed-type or hyaline vascular-type CD and suspected to include various lymphoproliferative disorders. Takai et al. reported three case series of thrombocytopenia with mild myelofibrosis and systemic symptoms, such as a fever, effusion, hepatosplenomegaly, and lymphadenopathy, and thereafter proposed a new distinct entity, which they named TAFRO syndrome (1). In the present case, thrombocytopenia, pleural effusions, ascites, and the histological findings were consistent with non-ipl CD. The bone marrow histology, which showed hyperplastic marrow with megakaryocytic hyperplasia and mild reticulin fibrosis, strongly indicated TAFRO syndrome. The existence of thrombocytopenia, exudative pleural effusion, and renal dysfunction suggested a possible diagnosis of systemic lupus erythematosus (SLE). However, the patient s symptoms and laboratory data did not fulfill 188

5 Plt ( 10 4 / L) PSL 60mg 30mg CyA 20mg 15mg Day 49 Day 63 Day 77 Day 91 Day 105 Hb(g/dL) CRP(mg/dL) ALP(U/L) Figure 4. The clinical course with CyA and PSL therapy. CyA with PSL successfully treated with tocilizumab-resistant TAFRO syndrome. PSL: prednisolone, CyA: cyclosporine A (4 mg/kg of body weight) the criteria for the classification of SLE (Table 2) (11). Although POEMS syndrome was another possible diagnosis, it was ruled out because of the absence of monoclonal gammopathy, skin changes and polyneuropathy. Malignant lymphoma, such as angioimmunoblastic T-cell lymphoma (AITL) and intravascular lymphoma (IVL), was also a possible diagnosis according to the patient s symptoms and laboratory data. AITL is a peripheral T-cell lymphoma characterized by a polymorphous infiltrate involving lymph nodes with a prominent proliferation of high endothelial venules and follicular dendritic cells. However, these specific changes were not seen in the lymph nodes. In addition, a normal level of serum LDH and the pathological findings of intravascular proliferation and/or sinusoidal involvement of lymphoma cells were not observed in the lymph node, which could rule out IVL. Although the standard therapeutic strategy for TAFRO syndrome has yet to be established, all patients in the previous reports were treated with steroids and some improved with the addition of CyA or TCZ with rituximab therapy (12). Unfortunately, some patients died, indicating that this syndrome sometimes results in a fatal outcome despite treatment. Including the present case, TCZ with PSL therapy was reported in five cases; of these, three patients were successfully treated, one died due to sepsis (5), and the condition of the remaining patient was not improved by TCZ with PSL therapy. On the other hand, all three patients treated with CyA with PSL showed improvements (1, 2). The present case is the first report of TCZ-resistant TAFRO syndrome successfully treated with CyA. Although the detailed mechanism by which CyA improves TAFRO syndrome is unclear, the effectiveness strongly suggests the association of helper T cells. Moreover, a previous report showed that IL-2 levels increased in the ascites, which supports our hypothesis (12). Therefore, CyA with PSL therapy may be an alternative therapy for refractory TAFRO syndrome. The etiology of TAFRO syndrome remains unknown, however, it may be associated with a strong cytokine storm, including IL-6 (3, 4). The findings from the present case suggest that the elevation of IL-6 may not be the main problem in TAFRO syndrome, and another unknown causal factor may be involved in the disease etiology. Successful treatment with CyA may provide new insights into the essential etiology of TAFRO syndrome. The authors state that they have no Conflict of Interest(COI). References 1. Takai K, Nikkuni K, Shibuya H, Hashidate H. Thrombocytopenia with mild bone marrow fibrosis accompanied by fever, pleural effusion, ascites and hepatosplenomegaly. Rinsho Ketsueki (Japanese Journal of Clinical Hematology) 51: , 2010 (in Japanese, Abstract in English). 2. Inoue M, Ankou M, Hua J, Iwaki Y, Hagihara M, Ota Y. Complete resolution of TAFRO syndrome (thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly) after immunosuppressive therapies using corticosteroids and cyclosporine A: a case report. J Clin Exp Hematop 53: 95-99, Iwaki N, Sato Y, Takata K, et al. Atypical hyaline vascular-type 189

6 Castleman s disease with thrombocytopenia, anasarca, fever, and systemic lymphadenopathy. J Clin Exp Hematop 53: 87-93, Kawabata H, Kotani S, Matsumura Y, et al. Successful treatment of a patient with multicentric Castleman s disease who presented with thrombocytopenia, ascites, renal failure and myelofibrosis using tocilizumab, an anti-interleukin-6 receptor antibody. Intern Med 52: , Masaki Y, Nakajima A, Iwao H, et al. Japanese variant of multicentric Castleman s disease associated with serositis and thrombocytopenia: a report of two cases: is TAFRO syndrome (Castleman- Kojima Disease) a distinct clinicopathological entity? J Clin Exp Hematop 53: 79-85, Kojima M, Nakamura S, Nishikawa M, Itoh H, Miyawaki S, Masawa N. Idiopathic multicentric Castleman s disease. A clinicopathologic and immunohistochemical study of five cases. Pathol Res Pract 201: , Van Rhee F, Stone K, Szmania S, Barlogie B, Singh Z. Castleman disease in the 21st century: an update on diagnosis, assessment, and therapy. Clin Adv Hematol Oncol 8: , Cesaman E, Knowles DM. The role of Kaposi s sarcomaassociated herpes virus (KSHV/HHV-8) in lymphoproliferative diseases. Semin Cancer Biol 9: , Kojima M, Nakamura N, Tsukamoto N, et al. Clinical implications of idiopathic multicentric Castleman disease among Japanese: a report of 28 cases. Int J Surg Pathol 16: , Kojima M, Nakamura N, Tsukamoto N, et al. Multicentric Castleman s disease representing effusion at initial clinical presentation: clinicopathological study of seven cases. Lupus 20: 44-50, Tan EM, Cohen AS, Fries JF, et al. The 1982 revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum 25: , Kubokawa I, Yachie A, Hayakawa A, et al. The first report of adolescent TAFRO syndrome, a unique clinicopathologic variant of multicentric Castleman s disease. BMC Pediatr 14: 139, The Japanese Society of Internal Medicine 190