한국인 성인형 스틸병의 임상 양상과 질병 활성을 반영하는 바이오마커

Abstract

Background and Objectives: Adult onset Still’s disease (AOSD) is a rare inflammatory disorder of unknown etiology characterized by fever, evanescent rash, arthritis and leukocytosis. However, the clinical manifestations and laboratory findings are not disease-specific. Although many various cytokines which play important roles in the pathogenesis of AOSD and correlate with disease activity, the utility of serum cytokines in clinical medicine is still controversial. Treatment of AOSD has been also empirical, and the information of disease course and predicted outcome is still lacking. The first objective of this study is a description of the clinical features and managements in a large Korean registry with AOSD patients. The second aim is the investigation of serum cytokines as biomarkers for reflecting disease activity among AOSD patients, especially in the inactive state.

Patients and Methods: Chapter I: One hundred thirty-seven patients who fulfilled Yamaguchi’s criteria and followed up at Hanyang University Hospital for Rheumatic Diseases between January 2005 and December 2011 were enrolled. Collected data were demographic findings, clinical features, laboratory findings at initial diagnosis or first flare in this hospital, disease pattern and managements. Chapter II: Total thirty-four patients with samples available from both active and inactive states were enrolled between 2008 and July 2012. Twenty-six healthy volunteers were also recruited as controls. Clinical manifestations, laboratory findings and modified Pouchot’s score were investigated in both disease states. Serum interleukin (IL)-18 by using ELISA and IL-1β, IL-6, macrophage migration inhibitory factor (MIF), tumor necrosis factor (TNF)-α and interferon (INF)-γ by multiplex bead-based cytokine immunoassay were analyzed.

Results: Chapter I: Total 83.2% of patients were female and the meanage of onset was 37.1 years. Polycyclic systemic pattern (48.2%), monocyclic pattern (27.0%) and chronic articular pattern (24.8%) were classified. The clinical manifestations were fever (89.8%), rash (62.8%), arthralgia or arthritis (62.4%), myalgia (38.7%) and hepatomegaly (28.5%). The laboratory findings did not differ according to disease pattern except for serum ferritin. However, initial hyperferritinemia and high modified Pouchot’s score showed a good prognosis. Polyarticular involvement andarticular manifestation in the shoulder and hip had a poor prognosis and an increased risk of joint damage. Glucocorticoid with/without methotrexate was an initial drug of most use and responders of this medication had a good prognosis. However, combinations with other disease modifying anti-rheumatic drugs such as cyclosporine, leflunomide and/or biologics were needed in mainly poor prognosis. Chapter II: The baselinecharacteristics were similar between patients with AOSD and healthy controls. Serum levels of IL-18, IL-1β, IL-6 and MIF were higher in the active state than in the inactive state and in healthy controls. Using ROC curve, differentiation cutoff points of disease and activity were estimated. Many patients had higher serum levels of IL-18, IL-6 and/or MIF above than disease or activity cutoff points. In addition, they had tendencies of increased clinical activity within several months of observation. Especially, patients with serum MIF > 977.8 pg/mL or patients with simultaneously elevated level of all three cytokines such as IL-18, IL-6 and MIF in the inactive state had a risk of worsening clinical activity soon.

Conclusions: Korean AOSD patients showed similar clinical findings compared to previous studies with partial differences. Although treatment also depends on the individuals involved, glucocorticoid with/without methotrexate may be considered the best initial treatment choice. However, early addition of other immunosuppressants or biologics should be considered when patients are unresponsive to conventional therapies. Moreover, it may be considered for applying serum cytokine as a reference of remnant disease activity in each patient at the decision of treatment intensity. Serum cytokine such as IL-18, IL-6 and especially MIF may be useful markers to monitor disease activity in the inactive state.