Yohei Kirino1, Yasushi Kawaguchi2, Yoshifumi Tada3, Hiroshi Tsukamoto4, Toshiyuki Ota5, Masahiro Iwamoto6, Hiroki Takahashi7, Kohei Nagasawa8, Shuji Takei9, Takahiko Horiuchi10, Hisae Ichida2, Seiji Minota6, Atsuhisa Ueda1, Akihide Ohta11, Yoshiaki Ishigatsubo12. 1. a Department of Stem Cell and Immune Regulation , Yokohama City University Graduate School of Medicine , Kanagawa , Japan. 2. b Institute of Rheumatology , Tokyo Women's Medical University , Tokyo , Japan. 3. c Division of Rheumatology, Department of Internal Medicine , Saga University , Saga , Japan. 4. d Department of Medicine and Biosystemic Science , Kyushu University Graduate School of Medical Sciences , Fukuoka , Japan. 5. e Department of Rheumatology , Iizuka Hospital , Fukuoka , Japan. 6. f Division of Rheumatology/Clinical Immunology, Department of Internal Medicine , Jichi Medical University , Tochigi , Japan. 7. g Department of Rheumatology and Clinical Immunology , Sapporo Medical University School of Medicine , Hokkaido , Japan. 8. h Rheumatic Disease Center , Sawara Hospital , Fukuoka , Japan. 9. i Faculty of Medicine , Kagoshima University, School of Health Sciences , Kagoshima , Japan. 10. j Department of Internal Medicine , Kyushu University Beppu Hospital , Oita , Japan. 11. k Faculty of Medicine (presently Kohokai Group Medical Corporation) , Saga University , Saga , Japan. 12. l Yokohama City University School of Medicine , Kanagawa , Japan.
Abstract
BACKGROUND: Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. METHODS: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. RESULTS: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. CONCLUSION: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria.
BACKGROUND:Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. METHODS: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. RESULTS: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. CONCLUSION: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria.
Authors: Bas M Smits; Joris van Montfrans; Samuel A Merrill; Lisette van de Corput; Mariëlle van Gijn; Andrica de Vries; Cor van den Bos; Floor Abbink; Renate G van der Molen; Natasja Dors; Caroline Lindemans; Jaap J Boelens; Stefan Nierkens Journal: J Clin Immunol Date: 2021-03-29 Impact factor: 8.317