title: Cause-effect relations between 55 kD soluble TNF receptor concentrations and specific and unspecific symptoms in a patient with mild SLE disease activity: an exploratory time series analysis study.
abstract: BACKGROUND
  This integrative single-case study investigated the 12 h-to-12 h cause-effect relations between 55 kD soluble tumor necrosis factor receptor type 1 (sTNF-R55) and specific and unspecific symptoms in a 52-year-old Caucasian woman with mild systemic lupus erythematosus (SLE) disease activity.
  
  
  METHODS
  The patient collected her entire urine for 56 days in 12 h-intervals to determine sTNF-R55/creatinine and protein/creatinine levels (ELISA, HPLC). Additionally, twice a day, she took notes on oral ulceration and facial rash; answered questionnaires (VAS) on fatigue, weakness, and joint pain; and measured body temperature orally. Time series analysis consisted of ARIMA modeling and cross-correlational analyses (significance level = p < 0.05).
  
  
  RESULTS
  Time series analysis revealed both a circadian and a circasemiseptan rhythm in the urinary sTNF-R55 data. Moreover, several significant lagged correlations between urinary sTNF-R55 concentrations and SLE symptoms in both directions of effect were identified. Specifically, increased urinary sTNF-R55 concentrations preceded decreased urinary protein levels by 36-48 h (r = -0.213) and, in the opposite direction of effect, increased protein levels preceded increased sTNF-R55 concentrations by 24-36 h (r = +0.202). In addition, increased urinary sTNF-R55 levels preceded increased oral ulcers by 36-48 h (r = +0.277) and, conversely, increased oral ulceration preceded decreased sTNF-R55 levels by 36-48 h (r = -0.313). Moreover, increased urinary sTNF-R55 levels preceded decreased facial rash by 36-48 h (r = -0.223) and followed increased body temperature after 36-48 h (r = +0.209). Weakness, fatigue and joint pain were not significantly correlated with urinary sTNF-R55 levels.
  
  
  CONCLUSIONS
  This study gathered first evidence of real-life, long-term feedback loops between cytokines and SLE symptoms in mild SLE disease activity. Such insights into the potential role of sTNF-R55 in SLE would not have been possible had we applied a pre-post design group study. These findings require replication before firm conclusions can be drawn.
authors.affiliation: Clinical Department of Medical Psychology, Innsbruck Medical University, Schöpfstraße 23a, 6020, Innsbruck, Austria. christian.schubert@i-med.ac.at.
authors.forename: Christian
authors.initials: C
authors.lastname: Schubert
authors.affiliation: Clinical Department of Medical Psychology, Innsbruck Medical University, Schöpfstraße 23a, 6020, Innsbruck, Austria. julia.haberkorn@uki.at.
authors.forename: Julia
authors.initials: J
authors.lastname: Haberkorn
authors.affiliation: Department of Statistics and Operations Research, University of Granada, Granada, Spain. fmocan@ugr.es.
authors.forename: Francisco M
authors.initials: FM
authors.lastname: Ocaña-Peinado
authors.affiliation: Clinical Department of Internal Medicine, Innsbruck Medical University, Innsbruck, Austria. paul.koenig@i-med.ac.at.
authors.forename: Paul
authors.initials: P
authors.lastname: König
authors.affiliation: Clinical Department of Dermatology, Innsbruck Medical University, Innsbruck, Austria. norbert.sepp@i-med.ac.at.
authors.forename: Norbert
authors.initials: N
authors.lastname: Sepp
authors.affiliation: Central Institute of Medical and Chemical Laboratory Diagnostics, University Clinics, Innsbruck, Austria. mirjam.schnapka-koepf@uki.at.
authors.forename: Mirjam
authors.initials: M
authors.lastname: Schnapka-Köpf
authors.affiliation: Division of Biological Chemistry, Biocenter, Innsbruck Medical University, Innsbruck, Austria. dietmar.fuchs@i-med.ac.at.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Fuchs
mesh_terms: D005260:Female; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000378:metabolism*; D008875:Middle Aged; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*
chemical_list: D018124:Receptors, Tumor Necrosis Factor