Clinical Phenotype and Response to Treatment in Adult-Onset Still's Disease with MEFV Variants

Fumiaki Nonaka¹, Toshimasa Shimizu², Katsumi Eguchi³, Masataka Umeda⁴, Yukitaka Ueki⁵, Keita Fujikawa⁶, Akinari Mizokami⁷, Munetoshi Nakashima⁸, Michio Yasunami⁹, Naoki Iwamoto⁴, Atsushi Kawakami², Yuka Jiuchi¹⁰ and Kiyoshi Migita¹⁰, ¹Department of Rheumatology and Metabloism, Sasebo City General Hospital, Sasebo, Japan, ²Department of Immunology and Rheumatology, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan, ³Department of Rheumatology, Sasebo Chuo Hospital, Sasebo, Japan, ⁴Department of Immunology and Rheumatology, Nagasaki University, Nagasaki, Japan, ⁵Kyushu multicenter rheumatoid arthritis ultrasound prospective observational cohort study group, Nagasaki, Japan, ⁶Arthritis and Connective Tissue Disease, Isahaya Health Insurance General Hospital, Isahaya, Japan, ⁷Department of Rheumatology, Isahaya Health Insurance General Hospital, Isahaya, Japan, ⁸Department of Rheumatology, Japanese Red Cross Nagasaki Genbaku Hospital, Nagasaki, Japan, ⁹Nagasaki University Institute of Tropical Medicine (NEKKEN), Nagasaki, Japan, ¹⁰Department of Rheumatology and Clinical Research Center, Nagasaki Medical Center, Omura, Japan

Meeting: 2015 ACR/ARHP Annual Meeting

Date of first publication: September 29, 2015

Keywords: adult-onset Still's disease and familial Mediterranean fever, Biologic agents

Session Information

Date: Sunday, November 8, 2015

Title: Miscellaneous Rheumatic and Inflammatory Diseases Poster I

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose:

Adult-onset Still’s disease (AOSD) is a rare inflammatory disorder that has been recently classified as a polygenic autoinflammatory disorder. Patients with Familial Mediterranean Fever (FMF) share clinical features (eg. recurrent fever, skin rash, synovitis and serositis) with the major symptoms of AOSD. FMF is considered to be caused by gain-of-function mutations in the MEFV gene. Although the pathophysiology of AOSD remains unknown, a growing number of studies support the hypothesis that dysregulation of inflammasome activation and subsequent overproduction of interleukin-1β play a pivotal role. The aim of this study was to investigate the allele frequencies of MEFV gene variants and identify clinical phenotypes as well as responses to treatments of AOSD patients with MEFV variants.

Methods:

A retrospective analysis was performed in 50 patients (9 males and 41 females) diagnosed with AOSD based on the diagnostic criteria of Yamaguchi M, et al. and 105 healthy individuals who were enrolled as controls. The study protocol was approved by the institutional review board/ethics committee of Sasebo City General Hospital. Written informed consent was obtained from each individual for their clinical records to be used in this study. Genetic DNA was extracted from peripheral blood, and exon1, 2, 3 and 10 of the MEFV gene were genotyped by direct sequencing. MEFV mutation frequencies in AOSD patients were compared with controls. Furthermore, clinical features and responses for treatments were examined in patients with or without MEFV variants.

Results:

MEFV variants were identified in 32 AOSD patients (64.0%). No significant difference was found statistically between AOSD patients and healthy subjects in terms of allele frequencies of MEFV exon1 (E84K), exon2 (L110P, E148Q, R202Q, and G304R) and exon3 (P309S and R408Q) variants. However, the carriage rate of exon10 MEFV variants (M694I and G632S) was significantly higher in AOSD patients than that of healthy subjects (6.1% versus 0%, p=0.031). The polycyclic and systemic clinical courses of AOSD disease phenotype were frequently observed in patients with MEFV variants. Biologic agents were administered to 7 patients with MEFV exon2 and/or exon3 variants who were refractory to conventional treatments such as steroid, steroid pulse and immuosuppressants. Six of them were treated with tocilizumab; one was treated with infliximab. All patients except one demonstrated rapid improvement in both clinical and laboratory parameters. The median dosage of prednisolone was reduced. However, one patient treated with tocilizumab developed macrophage activation syndrome.

Conclusion:

Our study provides preliminary evidence that FMF-related MEFV variants may be clinically implicated with the disease phenotype and treatment outcomes of AOSD. Therefore, identification of MEFV variants is beneficial to define clinical phenotypes and predict clinical responses to treatments.

Disclosure: F. Nonaka, None; T. Shimizu, None; K. Eguchi, None; M. Umeda, None; Y. Ueki, None; K. Fujikawa, None; A. Mizokami, None; M. Nakashima, None; M. Yasunami, None; N. Iwamoto, None; A. Kawakami, None; Y. Jiuchi, None; K. Migita, None.

To cite this abstract in AMA style:

Nonaka F, Shimizu T, Eguchi K, Umeda M, Ueki Y, Fujikawa K, Mizokami A, Nakashima M, Yasunami M, Iwamoto N, Kawakami A, Jiuchi Y, Migita K. Clinical Phenotype and Response to Treatment in Adult-Onset Still’s Disease with MEFV Variants [abstract]. Arthritis Rheumatol. 2015; 67 (suppl 10). https://acrabstracts.org/abstract/clinical-phenotype-and-response-to-treatment-in-adult-onset-stills-disease-with-mefv-variants/. Accessed .

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