To our knowledge, this is the first large study to prospectively assess somatic predictors of FM. Previous prospective studies mainly focused on the outcome of FM,5, 23, 27
psychosocial predictors of CWP31, 42
or health service utilization among subjects with FM.66
A dose-response relationship was found between prevalent allergic disease at baseline and development of FM. One cross-sectional and one case-control study have also reported an association between allergy and FM.15, 60
Allergic conditions were three times more common in primary FM patients than in controls60
and FM was diagnosed in 38% of chronic allergic rhinitis patients, suggesting chronic allergic rhinitis as a possible causative factor of FM.15
Several others have reported an association between FM, allergy, and common co-morbid clinical entities, e.g. back pain, anxiety disorders, depression, irritable bowel disorder, and migraine3, 23, 27, 66
suggesting that FM may share a common physiologic abnormality with other disease entities. This is supported by cross-sectional findings that subjects with a history of allergy were more likely to report low-back pain, be diagnosed with major depression and much more likely to have both major depression and low-back pain, compared to subjects with no history of allergy.36
A similar association was found in a prospective study where immunologically mediated disorders in childhood were strongly associated with onset of major depression in adulthood.16
Further, persons with chronic fatigue syndrome have been found to be more likely to have a history of childhood allergic disease.33
Asthma subjects not treated with glucocorticoids12
and infants genetically predisposed to allergic diseases have been reported to have alterations in the hypothalamic-pituitary-adrenal (HPA) axis with potential significant effects on the maturing immune system.4
These findings suggest that allergic disease may prime the HPA axis to respond aberrantly to stressors, creating a potential etiologic link to FM.4
Several studies have reported disturbed HPA axis function in subjects with FM, including reduced 24-hour free cortisol excretion and loss of their circadian fluctuation,18–19
exaggerated adrenocorticotropin hormone (ACTH), but blunted cortisol response to exogenous administration of human corticotrophin releasing hormone (CRH) and to insulin-induced hypoglycemia.29
CWP has been associated with altered HPA axis function,43
and among a group of psychologically at-risk subjects, dysfunction of the HPA axis helped distinguish between those who did and did not develop new onset CWP.44
Holliday also report that subjects with a genetic variation in the primary stress-response system genes in the HPA axis are more prone to develop musculoskeletal pain.35
Reduced HPA axis activity is often associated with symptoms of fatigue, myalgias, disturbed sleep, and depressed mood.1
Thus, alteration of the HPA axis may be one of the main pathophysiologies of FM.
Central sensitization may also play a role in abnormal widespread pain sensitivity57–58
and such dysregulation/sensitization of central sensory processing provides a pathophysiological model for the explanation of pain in FM/CWP.14, 22, 34
The specific linkage between HPA axis alteration and central sensitization, however, is unclear. In a recent focus article, Chapman et al.14
suggest that chronic pain conditions stem from dysregulation of a “supersystem” where nervous, endocrine and immune systems interact reciprocally through hormones, neurotransmitters and cytokines causing dysregulation of neuroendocrine-immune systems, including the HPA axis, resulting in central sensitization.
In our study, after adjusting for all potential confounders, smoking was independently associated with increased risk of FM. This association was not altered by inclusion of psychosocial predictors in our third sensitivity analysis. Both cross-sectional studies among FM/CWP patients48, 69
as well as in population-based studies2, 8, 37, 47
have reported higher prevalence of pain at all sites among current and ex-smokers, with several also reporting dose-response relationships. The temporal relationships between smoking and FM, however, could not be ascertained in these studies. The subjects of the present study, on the other hand, reported their smoking history in 1976, well before the diagnosis of FM. By 1976, virtually all (99.5%) were non-smokers. Thus, our findings suggest a strong effect of past smoking on later development of FM. Our results are in line with a 5-year prospective study of metal industry workers where a dose-response association was found between smoking intensity and future musculoskeletal symptoms.40
A possible underlying mechanism could be that smoking may cause resetting of the threshold for central pain tolerance.52
Both smokers and patients with FM have been found to have alterations of the HPA axis19, 21, 28
affecting endogenous opioid activity in pain modulating regions of the brain.32, 53
A single dose of nicotine is sufficient to activate the HPA axis, whereas chronic cigarette smoking results in a blunted HPA axis responsiveness to acute psycho-social stress.19, 29, 51
A possible confounding factor in the relationship between FM and smoking is depression which is associated with both smoking9–10
and FM.10, 46
Adjusting for depression in our study, did not change the results, suggesting a causal association between smoking and risk of FM.
A significant dose-response relationship was also found between hyperemesis gravidarum and incident FM. Others have reported an association between hyperemesis gravidarum and psychiatric illness, a co-morbidity of FM.24, 59
Psychologic factors (somatization disorder or response to stress) or hormonal changes have been proposed11, 38, 55
while others have reported an association with overactivity of the HPA axis.62
In our study, the association with hyperemesis gravidarum remained unchanged when adjusting for psychosocial factors, suggesting an independent effect. The pathogenesis of hyperemesis gravidarum is still unclear and more studies are needed.
Previous cross-sectional reports have found associations between FM and education,49, 65
and an “overactive” lifestyle.61
We found no such associations in this prospective study. The lack of association with FM for these demographic factors in our prospective study as opposed to the findings in the cross-sectional studies, could suggest that these factors may be the results, rather than predictors, of FM.
In demographics adjusted models, the association between incident FM and a history of surgeries, peptic ulcer, and use of symptom controlling medications are in line with the findings of others.7, 66
Berger et al. reported that FM patients have comparatively high levels of co-morbidities and high levels of healthcare utilization.7
In a prospective study of subjects with FM, Wolfe found high rates of lifetime as well as current utilization of all types of medical services including lifetime surgical interventions.66
Also, significant relationships have been reported between depression, hostility and social alienation and later ulcer development.41
Our findings became non-significant when adjusting for smoking and other diseases, suggesting that surgeries, peptic ulcer, and use of symptom controlling medication are not true risk factors for FM.
The majority (60.4%) of our incident cases were diagnosed between the ages of 51 to 70 years which is broadly in line with previous reports.63
These 136 new cases of FM occurred among 3,136 women during 25 years follow-up with a cumulative incidence of 4.3% or 1.7/1,000 per year. This is significantly lower than studies from southern Norway which found a 5.5 year cumulative incidence of FM of 3.2% or 5.8/1,000 per year in females aged 20–49 years at baseline.26
This high incidence rate was explained by having used a highly sensitive method for diagnosis and the fact that the study was conducted in a high risk region. Another study reported incidence rates from 10.8 (25–29 yrs) to about 20.5 (45–64 yrs) cases per 1,000 person-years for females.63
This retrospective cohort study of a health insurance claims database, identified FM cases using the International Classification of Disease, 9th Revision, Clinical Modification (ICD9-CM). On ICD9-CM codes, however, there is no single specific code for FM. According to the coding rules, FM is coded as 729.1 which is labeled “Myositis and Myalgia, unspecified” and may therefore include other conditions as well, resulting in overestimates for FM.
The two major limitations of our study are that all variables are self-reported and some of the FM cases were diagnosed before the American College of Rheumatology (ACR) diagnostic criteria were established in 1990. Even though the diagnosis was self-reported, it was based on “doctor told” diagnosis and not self assessment. Our study population has a high level of education and easy access to health care. It is therefore likely that the validity of the physician diagnosis is fairly good compared to other population studies. Even so, our findings need to be confirmed in other studies where the diagnosis of FM is based on objective criteria rather than self-reported physician diagnosis.
In summary, after adjustment for potential confounders, ever-smoking and a history of allergies and hyperemesis gravidarum were major independent predictors of FM even after adjusting for psychosocial variables. The study findings give yet another strong rationale for avoiding smoking. Further studies are needed to assess the associations between smoking, allergies and hyperemesis gravidarum and risk of FM and to shed light on possible underlying mechanisms.
Smoking as well as prevalent allergies, and a history of hyperemesis gravidarum seem to predict development of FM in women during 25 years of follow-up. This information may help in identifying persons at high risk of developing FM and thus initiate effective prevention strategies.