title: Dysregulations in circulating sphingolipids associate with disease activity indices in female patients with systemic lupus erythematosus: a cross-sectional study.
abstract: Objective The objective of this study was to investigate the association of clinical and renal disease activity with circulating sphingolipids in patients with systemic lupus erythematosus. Methods We used liquid chromatography tandem mass spectrometry to measure the levels of 27 sphingolipids in plasma from 107 female systemic lupus erythematosus patients and 23 controls selected using a design of experiment approach. We investigated the associations between sphingolipids and two disease activity indices, the Systemic Lupus Activity Measurement and the Systemic Lupus Erythematosus Disease Activity Index. Damage was scored according to the Systemic Lupus International Collaborating Clinics damage index. Renal activity was evaluated with the British Island Lupus Activity Group index. The effects of immunosuppressive treatment on sphingolipid levels were evaluated before and after treatment in 22 female systemic lupus erythematosus patients with active disease. Results Circulating sphingolipids from the ceramide and hexosylceramide families were increased, and sphingoid bases were decreased, in systemic lupus erythematosus patients compared to controls. The ratio of C16:0-ceramide to sphingosine-1-phosphate was the best discriminator between patients and controls, with an area under the receiver-operating curve of 0.77. The C16:0-ceramide to sphingosine-1-phosphate ratio was associated with ongoing disease activity according to the Systemic Lupus Activity Measurement and the Systemic Lupus Erythematosus Disease Activity Index, but not with accumulated damage according to the Systemic Lupus International Collaborating Clinics Damage Index. Levels of C16:0- and C24:1-hexosylceramides were able to discriminate patients with current versus inactive/no renal involvement. All dysregulated sphingolipids were normalized after immunosuppressive treatment. Conclusion We provide evidence that sphingolipids are dysregulated in systemic lupus erythematosus and associated with disease activity. This study demonstrates the utility of simultaneously targeting multiple components of a pathway to establish disease associations.
authors.affiliation: 1 Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE- 171 77 Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Checa
authors.affiliation: 2 Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE- 171 76 Stockholm, Sweden.
authors.forename: H
authors.initials: H
authors.lastname: Idborg
authors.affiliation: 3 Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH - Royal Institute of Technology, Stockholm, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Zandian
authors.affiliation: 1 Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE- 171 77 Stockholm, Sweden.
authors.forename: D Garcia
authors.initials: DG
authors.lastname: Sar
authors.affiliation: 4 Computational Life Science Cluster, Department of Chemistry, Umeå University, Umeå, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Surowiec
authors.affiliation: 4 Computational Life Science Cluster, Department of Chemistry, Umeå University, Umeå, Sweden.
authors.forename: J
authors.initials: J
authors.lastname: Trygg
authors.affiliation: 2 Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE- 171 76 Stockholm, Sweden.
authors.forename: E
authors.initials: E
authors.lastname: Svenungsson
authors.affiliation: 2 Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE- 171 76 Stockholm, Sweden.
authors.forename: P-J
authors.initials: PJ
authors.lastname: Jakobsson
authors.affiliation: 3 Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH - Royal Institute of Technology, Stockholm, Sweden.
authors.forename: P
authors.initials: P
authors.lastname: Nilsson
authors.affiliation: 2 Rheumatology Unit, Department of Medicine, Solna, Karolinska Institutet, Karolinska University Hospital, SE- 171 76 Stockholm, Sweden.
authors.forename: I
authors.initials: I
authors.lastname: Gunnarsson
authors.affiliation: 1 Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, SE- 171 77 Stockholm, Sweden.
authors.forename: C E
authors.initials: CE
authors.lastname: Wheelock
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D002853:Chromatography, Liquid / Q000379:methods; D003430:Cross-Sectional Studies; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008180:Lupus Erythematosus, Systemic / Q000097:blood* / Q000188:drug therapy / Q000503:physiopathology; D008875:Middle Aged; D012720:Severity of Illness Index; D013107:Sphingolipids / Q000097:blood*; D053719:Tandem Mass Spectrometry / Q000379:methods
chemical_list: D007166:Immunosuppressive Agents; D013107:Sphingolipids
keywords: Systemic lupus erythematosus; disease activity; sphingolipids