POS1353\u2005SERUM PROTEOMICS REVEALS INSULIN-LIKE GROWTH FACTOR BINDING PROTEINS-1 AS BIOMARKERS FOR IDIOPATHIC MULTICENTRIC CASTLEMAN’S DISEASE

Abstract

Castleman’s disease (CD) is a lymphoproliferative disorder1 and presents as two distinct clinical entities: the localized form, unicentric CD (UCD) and the multicentric form, multicentric CD (MCD)2. MCD without human herpesvirus-8 (HHV-8) infection is defined idiopathic MCD (iMCD)3 and most MCDs in Japan are iMCDs. TAFRO syndrome is a group of disease that present with T: thrombocytopenia, A: anasarca, F: fever, R: reticulin fibrosis/renal dysfunction, O: organomegaly4. iMCD-TAFRO is present in the TAFRO syndrome and it is thought that pathology of lymph node biopsy shows an MCD-like appearance, and some clinical features overlap with MCD5. That do not belong to any of the above categories is classified as iMCD-not otherwise specified (iMCD-NOS). No biomarkers stratifying iMCD-NOS and iMCD-TAFRO have been identified, and no biomarkers defining treatment response have been identified for iMCD.We will identify biomarkers that discriminate iMCD-NOS and iMCD-TAFRO or predict the treatment responsiveness.We performed a comprehensive analysis of serum proteins using the L-Series Human Antibody Array L-507 on the 4 iMCD-NOS and 2 iMCD-TAFRO patients from which pre- and post-tocilizumab treatment samples were obtained. An analysis by L-507 identified insulin-like growth factor binding proteins-1 (IGFBP-1) as a protein with a high rate of reduction post treatment. Sera from 28 healthy controls, 8 patients with iMCD-NOS, and 6 patients with iMCD-TAFRO were used to validate IGFBP-1 by ELISA. The mean ages of healthy controls, iMCD-NOS, and iMCD-TAFRO used in the validation ELISA were 50, 56, and 47 years, respectively, with no significant differences among the groups. The ratio of male to female was almost 1:1.The 4 patients who responded well to treatment with tocilizumab all had a high rate of IGFBP-1 reduction by L-507 serum protein arrays. In ELISA, serum IGFBP-1 was significantly higher (p=0.0016) before the introduction of treatment in iMCD patients than healthy controls. In addition, serum IGFBP-1 level of iMCD-TAFRO was significantly higher than iMCD-NOS (p=0.024). Furthermore, post-treatment serum IGFBP-1 was decreased in many cases.Serum IGFBP-1 may play a particularly important role in the pathogenesis of iMCD-TAFRO and may be useful in discriminating between iMCD-NOS and iMCD-TAFRO. In the future, we will accumulate more cases, compare it with other inflammatory diseases, and examine the difference in response to treatment.[1]CASTLEMAN, et al. 1954. CASE records of the Massachusetts General Hospital Weekly Clinicopathological Exercises: Case 40011. N Engl J Med, 250, 26-30.[2]WATERSTON, et al. 2004. Fifty years of multicentric Castleman’s disease. Acta Oncol, 43, 698-704.[3]FAJGENBAUM D, et al. 2014. HHV-8-negative, idiopathic multicentric castleman disease (iMCD): A description of clinical features and therapeutic options through a systematic literature review. Blood (ASH Annual Meeting Abstracts), 124, 4861.[5]TAKAI K, et al. 2010. Thrombocytopenia with mild bone marrow fibrosis accompanied by fever, pleural effusion, ascites and hepatosplenomegaly [in Japanese]. Rinsho Ketsueki, 51, 320-325.[6]IWAKI N, et al. 2016. Clinicopathologic analysis of TAFRO syndrome demonstrates a distinct subtype of HHV-8-negative multicentric Castleman disease. Am J Hematol, 91, 220-226.None declared