Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still’s disease: A multicenter retrospective study

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.

Keywords:

• Adult-onset Still’s disease
• ferritin
• heme oxygenase-1

Acknowledgements

We wish to thank Ms. Keiko Yaba (Yokohama City University Hospital Clinical Laboratory Center), and Dr. Mitsuhiro Takeno (Department of Rheumatology and Allergy, Nippon Medical University) for helping the measurement of serum ferritin. We also thank Drs. Yosuke Kunishita, Atsushi Ihata, Shohei Nagaoka (Yokohama Minami Kyosai Hospital), Kaoru Minegishi, and Shigeru Ohno (Center for Rheumatic Diseases, Yokohama City University Medical Center) for providing serum samples and clinical information, and Ryusuke Yoshimi (Department of Stem Cell and Immune Regulation, Yokohama City University) for supporting clinical and laboratory works. We would like to thank Mr. Tom Kiper for his review of the article.

Conflict of interest

None.

Additional information

Funding

Y.K. is supported by grants from Japan Society for the Promotion of Science Grant-in-Aid for Scientific Research [Grant Nos 26713036 and 15K15374], the Kanae Foundation for the Promotion of Medical Science, Takeda Science Foundation, and Yokohama Foundation for Advancement of Medical Science.