title: Association between stressful life events and autoimmune diseases: A systematic review and meta-analysis of retrospective case-control studies.
abstract: BACKGROUND
  Evidence of a relationship between stressful life events and the onset of autoimmune diseases is not univocal and there are no meta-analyses in the literature on the question.
  
  
  OBJECTIVE
  To look for differences in the number and type of stressful life events in the premorbid period between patients with autoimmune diseases and healthy subjects.
  
  
  METHODS
  Review of the literature in PubMed and Scopus (January 1963-May 2015).
  
  
  METHODS
  We included retrospective case-control studies that compared patients diagnosed with autoimmune disorders and controls regarding the incidence of stressful events occurring before diagnosis, and investigated said events with validated questionnaires.
  By random effect meta-analysis, two independent researchers calculated effect-size indexes as the difference between the means of the clinical groups and the control group in relation to the combined standard deviation.
  
  
  RESULTS
  The database searches produced 2490 articles, 14 of which were selected (3201 patients). Analysis showed a moderate but significant mean effect-size index [d=0.63, p<0.01], suggesting that autoimmune disorders are effectively associated with major stressful events in the premorbid period. The relationship between stressful events and autoimmune disease was weaker in studies with a high proportion of female subjects [β=-0.004, p<0.01] and stronger in studies that considered a longer interval between stressors and onset of disease [β=0.16, p<0.01].
  
  
  CONCLUSIONS
  The results of this meta-analysis suggest that stressors may play an important role in the etiopathogenesis of autoimmune disorders. Only prospective studies can provide more certain inference about the causality of this relationship.
authors.affiliation: Dipartimento Biotecnologie Mediche, Università degli Studi di Siena, Siena, Italy. Electronic address: brunetta.porcelli@unisi.it.
authors.forename: Brunetta
authors.initials: B
authors.lastname: Porcelli
authors.affiliation: Dipartimento Scienze Mediche, Chirurgiche e Neuroscienze, Università degli Studi di Siena, Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Pozza
authors.affiliation: Laboratorio di Patologia Clinica, Ospedale S. Antonio, Tolmezzo, Italy.
authors.forename: Nicola
authors.initials: N
authors.lastname: Bizzaro
authors.affiliation: Dipartimento di Medicina Molecolare e dello Sviluppo, Università degli Studi di Siena, Siena, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Fagiolini
authors.affiliation: Biblioteca Area Medico Farmaco Biologica, Università degli Studi di Siena, Siena, Italy.
authors.forename: Maria-Cristina
authors.initials: MC
authors.lastname: Costantini
authors.affiliation: Dipartimento Biotecnologie Mediche, Università degli Studi di Siena, Siena, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Terzuoli
authors.affiliation: Dipartimento Scienze Mediche, Chirurgiche e Neuroscienze, Università degli Studi di Siena, Siena, Italy.
authors.forename: Fabio
authors.initials: F
authors.lastname: Ferretti
mesh_terms: D001327:Autoimmune Diseases / Q000276:immunology*; D016022:Case-Control Studies; D006801:Humans; D008016:Life Change Events; D012189:Retrospective Studies; D011795:Surveys and Questionnaires
keywords: Autoimmune disease; Meta-analysis; Stress; Stressful life events