ARTHRITIS & RHEUMATISM Vol. 56, No. 1, January 2007, pp 360–371 DOI 10.1002/art.22336 © 2007, American College of Rheumatology Moderation of Psychosocial Risk Factors Through Dysfunction of the Hypothalamic–Pituitary–Adrenal Stress Axis in the Onset of Chronic Widespread Musculoskeletal Pain Findings of a Population-Based Prospective Cohort Study J. McBeth, 1 A. J. Silman, 1 A. Gupta, 1 Y. H. Chiu, 1 D. Ray, 1 R. Morriss, 2 C. Dickens, 1 Y. King, 1 and G. J. Macfarlane 3 Objective. To test the hypothesis that abnormali- ties in the hypothalamic–pituitary–adrenal (HPA) stress-response system would act as an effect moderator between HPA function and the onset of chronic wide- spread pain (CWP). Methods. We conducted a population-based pro- spective cohort study. Current pain and psychosocial status were ascertained in 11,000 subjects. Of the 768 eligible subjects free of CWP but at future risk based on their psychosocial profile, 463 were randomly selected, and 267 (57.7%) consented to assessment of their HPA axis function. Diurnal function was measured by assess- ing levels of salivary cortisol in the morning (9:00 AM) and evening (10:00 PM). Serum cortisol levels were measured after an overnight low-dose (0.25 mg) dexa- methasone suppression test and a potentially stressful clinical examination. All subjects were followed up 15 months later to identify cases of new-onset CWP. Results. A total of 241 subjects (94.9%) com- pleted the followup study, and 28 (11.6%) reported the new onset of CWP. High levels of cortisol post- dexamethasone (odds ratio [OR] 3.53, 95% confidence interval [95% CI] 1.17–10.65), low levels in morning saliva (OR 1.43, 95% CI 0.52–3.94), and high levels in evening saliva (OR 2.32, 95% CI 0.64–8.42) were all associated with CWP. These 3 factors were found to be independent and additive predictors of CWP (OR for all 3 factors 8.5, 95% CI 1.5–47.9) in analyses controlling for age, sex, depression, sleep disturbance, recent trau- matic life events, and pain status. One or more of these 3 HPA factors identified 26 (92.9%) cases of new-onset CWP. Conclusion. Among a group of psychologically at-risk subjects, dysfunction of the HPA axis helps to distinguish those who will and will not develop new- onset CWP. Chronic widespread pain (CWP) affecting the musculoskeletal system, the principal symptom of fibro- myalgia, is common, with a 1-month population preva- lence of 11% (1). It is associated with loss of function and considerable disability, may be associated with increased mortality rates (2), and is a major cause of health care utilization both in primary and secondary care settings. We have previously demonstrated in the prospective Altrincham Pain Study conducted in north- west England (3) that an increased risk of CWP onset is predicted from high levels of psychological distress, other somatic symptoms, and abnormal illness behavior. These factors are indicative of the process of somatiza- tion that can be defined as the tendency to express psychological distress as physical symptoms. These re- sults confirmed for the first time that psychosocial factors preceded the onset of CWP, rather than just Supported by the Arthritis Research Campaign, Chesterfield, UK. 1 J. McBeth, PhD, A. J. Silman, MD, A. Gupta, MD, Y. H. Chiu, PhD, D. Ray, MD, C. Dickens, MD, Y. King, RGN: University of Manchester, Manchester, UK; 2 R. Morriss, MD: Royal Liverpool University Hospital, Liverpool, UK; 3 G. J. Macfarlane, MD: Univer- sity of Aberdeen, Aberdeen, UK, and University of Manchester, Manchester, UK. Address correspondence and reprint requests to J. McBeth, PhD, Arthritis Research Campaign Epidemiology Unit, School of Epidemiology and Health Sciences, Stopford Building, University of Manchester, Oxford Road, Manchester, M13 9PT, UK. E-mail: john.mcbeth@manchester.ac.uk. Submitted for publication March 31, 2006; accepted in revised form October 13, 2006. 360