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Kynurenine pathway is altered in patients with SLE and associated with severe fatigue
  1. Karolina Åkesson1,
  2. Susanne Pettersson2,3,
  3. Sara Ståhl4,
  4. Izabella Surowiec5,
  5. Mattias Hedenström5,
  6. Susanna Eketjäll6,
  7. Johan Trygg5,
  8. Per-Johan Jakobsson1,
  9. Iva Gunnarsson1,
  10. Elisabet Svenungsson1 and
  11. Helena Idborg1
  1. 1 Rheumatology Unit, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
  2. 2 Theme Inflammation and Infection, Karolinska University Hospital, Stockholm, Sweden
  3. 3 Department of Neurobiology, Care Sciences and Society, Karolinska Institutet, Stockholm, Sweden
  4. 4 Personalized Healthcare and Biomarkers Laboratories, Innovative Medicines, Science for Life Laboratory, Translational Science Centre, AstraZeneca, Stockholm, Sweden
  5. 5 Department of Chemistry, Computational Life Science Cluster, Umeå University, Umeå, Sweden
  6. 6 Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development Biotech Unit, AstraZeneca, Integrated Cardio Metabolic Centre (ICMC), Karolinska Institutet, Huddinge, Sweden
  1. Correspondence to Dr Helena Idborg; Helena.idborg{at}ki.se

Abstract

Objective Fatigue has been reported as the most disturbing symptom in a majority of patients with SLE. Depression is common and often severe. Together these symptoms cause significant morbidity and affect patients with otherwise relatively mild disease. Tryptophan and its metabolites in the kynurenine pathway are known to be important in several psychiatric conditions, for example, depression, which are often also associated with fatigue. We therefore investigated the kynurenine pathway in patients with SLE and controls.

Methods In a cross-sectional design plasma samples from 132 well-characterised patients with SLE and 30 age-matched and gender-matched population-based controls were analysed by liquid chromatography tandem mass spectrometry to measure the levels of tryptophan and its metabolites kynurenine and quinolinic acid. Fatigue was measured with Fatigue Severity Scale and depression with Hospital Anxiety and Depression Scale. SLE disease activity was assessed with Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

Results The kynurenine/tryptophan ratio, as a measure of indoleamine 2,3-dioxygenase (IDO) activity, was increased in patients with SLE. Patients with active disease (SLEDAI ≥6) showed lower tryptophan levels compared with controls (54 µM, SD=19 vs 62 µM, SD=14, p=0.03), although patients with SLE overall did not differ compared with controls. Patients with SLE had higher levels of tryptophan metabolites kynurenine (966 nM, SD=530) and quinolinic acid (546 nM, SD=480) compared with controls (kynurenine: 712 nM, SD=230, p=0.0001; quinolinic acid: 380 nM, SD=150, p=0.001). Kynurenine, quinolinic acid and the kynurenine/tryptophan ratio correlated weakly with severe fatigue (rs =0.34, rs =0.28 and rs =0.24, respectively) but not with depression.

Conclusions Metabolites in the kynurenine pathway are altered in patients with SLE compared with controls. Interestingly, fatigue correlated weakly with measures of enhanced tryptophan metabolism, while depression did not. Drugs targeting enzymes in the kynurenine pathway, for example, IDO inhibitors or niacin (B12) supplementation, which suppresses IDO activity, merit further investigation as treatments in SLE.

  • systemic lupus erythematosus
  • autoimmune diseases
  • autoimmunity
  • disease activity

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Footnotes

  • KÅ and SP contributed equally.

  • Contributors KÅ: statistical analysis and manuscript writing. SP: FSS data collection and analysis and manuscript writing. SS: LC-MS analysis of metabolites in the kynurenine pathway. IS: GC-MS analysis and manuscript writing. MH: NMR analysis and manuscript writing. SE: cytokine measurements and manuscript writing. JT and P-PJ: manuscript writing/approval. IG and ES: SLE cohort responsible and manuscript writing. HI: study design, statistical analyses and manuscript writing.

  • Funding This study was supported by the AstraZeneca–Karolinska Institutet Joint Research Program in Translational Science, Swedish Research Council, Stockholm County Council (ALF), Swedish Heart-Lung foundation, King Gustaf Vs 80th Birthday Fund, Swedish Rheumatism Association, Swedish Society of Medicine and Karolinska Institutet’s Foundations.

  • Competing interests SE is employed by AstraZeneca.

  • Patient consent Obtained.

  • Ethics approval The local research ethics committee approved the study.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement No additional data are available.

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