Fibromyalgia is a common condition, but its aetiology is not fully understood.15,21,41,43 Previous reviews have listed numerous somatic, psychological, and social factors associated with fibromyalgia in cross-sectional studies, but very few large prospective studies have been reported.4,10,15,21 As a result, too many reviews rely on prevalence data to support aetiological theories when only prospective studies can demonstrate causality.15
There are several definitions of fibromyalgia, and the prevalence varies between 1.2% and 5.4% of the population according to definition.18 Chronic widespread pain (CWP) is more common affecting 14.2% of UK population.9,18 The incidence of fibromyalgia has been measured rarely and is quoted in reviews as 5.83 per 1000 using ACR criteria in middle-aged women, and 11.28 and 6.88 per 1000 in female and male adults, respectively, using ICD-9 codes.4,39 The Forseth study found the incidence of CWP to be approximately twice that of fibromyalgia.10 The current review included studies of fibromyalgia and CWP; the incidence data are presented separately, but the risk factors have been assessed together partly to maximise numbers of studies.
There has been no previous systematic review of onset of fibromyalgia in population-based samples. One systematic review concerned physical and psychological traumatic events in fibromyalgia development, but the only prospective studies concerned follow-up of people with whiplash or other injuries.51 Another review reported an increased prevalence of fibromyalgia in patients with other medical disorders including irritable bowel syndrome, diabetes, and patients undergoing haemodialysis.16 A review concerning the transformation of regional pain to CWP was inconclusive, possibly because it included very few studies.24 A further systematic review found a bidirectional relationship between sleep disturbance and CWP.32 This review aimed to find all studies that demonstrated the incidence of fibromyalgia and CWP in population-based cohorts of adults and collate the risk factors for new onsets of both conditions.
Two reviews were performed. The first included articles that provided an incidence rate of fibromyalgia or CWP in the general population. The second concerned risk factors for a new onset of fibromyalgia or CWP. The 2 reviews overlapped, and many individual studies were included in both, which is why they are presented together. A few articles, including all birth cohort studies, provided data on risk factors without an incidence rate being calculated. The method of the search was similar for the 2 reviews.
2.1. Data sources and search strategy
A systematic search was performed of articles published between January 1998 and July 2019 using Ovid Medline, Web of Science, and Cochrane Database of Systematic Reviews. The databases were searched using the terms “incidence,” “onset,” “epidemiology,” “population,” and “risk factors” first with “fibromyalgia” and then with “chronic widespread pain.” Many studies emerged through subsequent hand searching of the selected articles.
Previous systematic reviews were searched for additional relevant studies. The searches were performed by the author only.
2.2. Selection criteria
The same selection criteria were used for both reviews. Studies were included if the following were true: (1) a population-based cohort was studied prospectively (or high-quality retrospective cohorts), so that possible risk factors were recorded well in advance of the onset of fibromyalgia, (2) there was an appropriate control group, (3) the diagnosis of fibromyalgia was made by a doctor (recorded on a research or medical insurance database) or made according to a standardised questionnaire (mostly questionnaire for ACR criteria) or self-report, and (4) the study specified that any individuals who had fibromyalgia before the study entry date were excluded. Case–control studies (with retrospective determination of risk factors), cross-sectional studies, case series, and case reports were not included.
2.3. Data extraction and quality assessment
For each article, the following were recorded: first author/year, study design, base population, control group, mode of fibromyalgia diagnosis, number of new cases/duration of study, incidence, risk factors in univariate, and in multivariate analyses and quality. The data are reported under these headings in the supplementary table (available at http://links.lww.com/PAIN/A956). To tabulate the results, the incidence rate was standardised to new cases per 1000 per annum.
Where relevant, quality of the selected studies was assessed using the Newcastle-Ottawa Scale for cohort studies. Quality was rated as high when there were 3 or 4 stars in selection domain, 1 or 2 stars in comparability domain, and 2 or 3 stars in outcome/exposure domain, fair when there were 2 stars in selection domain, 1 or 2 stars in comparability domain, and 2 or 3 stars in outcome/exposure domain, otherwise it was rated as low.
2.4. Outcome measure
The primary outcome was a diagnosis of fibromyalgia or CWP. For clinical diagnosis of the former this was usually a research database that included all patient contacts (for all diagnoses) in a given population ensuring complete data collection. For most studies, the diagnosis of fibromyalgia was made according to ICD-9 diagnosis of fibromyalgia or a GP diagnostic code (read code in United Kingdom). A few studies included only those patients who had at least 2 medical encounters when a diagnosis of fibromyalgia was recorded. Two studies used self-report (Have you been diagnosed with fibromyalgia by a physician?); most other studies used a questionnaire to elicit widespread pain according to the ACR criteria (but without clinical examination of tender points). Studies that used a criterion of pain for “at least 1 week” were excluded as pain, which has persisted for 3 months or more is used in the ACR definitions. In view of the different ways of making the diagnosis (physician-diagnosis v self-administered questionnaire), the incidence rates are reported separately.
Many studies assessed a large population sample as a comparison group to a cohort with a specific medical condition under test as a potential risk factor for fibromyalgia. For these studies, an adjustment was made to represent the total population (ie, including the relevant proportion with the medical disorder under study).
The strength of the association between risk factor and fibromyalgia/CWP onset was assessed in 3 ways, the strength of the relationship in terms of adjusted odds (or hazard), a reported bidirectional association, and an exposure–response relationship.
As this review is only concerned with secondary data which would have been anonymised in the primary articles, no ethical approval was sought.
The search of the databases yielded 1653 articles once duplicates had been eliminated. Of the 1653 abstracts, 1577 were excluded, 76 full articles were screened, and 37 met the inclusion criteria. Twelve studies used a physician diagnosis of fibromyalgia, 3 used self-report, and 14 used a questionnaire/manikin diagram to make a diagnosis of CWP according to ACR criteria; 8 were birth cohorts (details in supplementary table, available at http://links.lww.com/PAIN/A956). The studies of fibromyalgia were larger (median number of new-onset cases = 2590 [range 12-20,984]) than those of CWP (median of 237 new cases [range 21-2494]).
3.1. Incidence of chronic widespread pain and fibromyalgia
In 11 cohorts of new-onset chronic widespread pain that included both sexes (Table 1), the median incidence was 12.5 per 1000 person-years (range: 7.2-81.6). There were 3 outliers (incidence of 58, 61 and 81.6 per 1000 person-years); these 3 studies had a short follow-up duration (1-3 years). The remaining 8 studies had a longer follow-up (3-13 years) and reported a median incidence of 9.4 (range 7.2-16.4) per 1000 person years. Half of the studies of CWP showed no significant female predominance.
Twelve articles provided an incidence rate for fibromyalgia (Table 2). Excluding 4 studies which included predominantly one sex only, the median incidence of physician diagnosed fibromyalgia in 8 general population cohorts was 3.6 per 1000 person-years (range = 0.33-18.8). After adjustment in the studies which excluded participants with a specific medical disorder, the incidence was 4.3 per 1000 person-years. All except 2 studies showed a higher incidence among women compared with men (Table 2). In 6 population-based cohorts of people with a specific medical diagnosis (Table 3), the median incidence of physician diagnosis fibromyalgia was 14 (range 1.2-32.7); there was no clear female predominance in these cohorts; in one study, men with inflammatory bowel disease (IBD) showed a higher risk of fibromyalgia (FM) than women with IBD.6
Six of the CWP studies provided separate data for participants who, at baseline, had “some” or “severe” regional pain. The median incidence for these studies was 67 per 1000 person-years (range 14.8-124) compared with a median incidence of 14 per 1000 person-years [range 3.3-26] for those pain-free at baseline.3,13,29,30,34,37
3.2. Risk factors for new-onset fibromyalgia and chronic widespread pain
There were 12 studies, which provided data concerning risk factors for developing fibromyalgia and 22 for CWP (details in the supplementary table, available at http://links.lww.com/PAIN/A956). The risk factors mentioned at least twice in the literature are shown in Figure 1, which concerns the risk factors that emerged from univariate analyses. Studies assessing physician-diagnosed fibromyalgia on medical record databases (blue in Fig. 1) included limited demographic data with full data on a range of medical disorders, including sleep disorders and depression. By contrast, studies of CWP (red in Fig. 1) assessed a much wider range of risk factors. There were inadequate data to show whether the risk factors for fibromyalgia and CWP are similar; they are considered together in this description of risk factors.
Female sex and middle/older age were reported as risk factors in 12 and 11 studies, respectively, although, for each of these variables, there were 4 negative studies, which found these variables were not associated with onset. Musculoskeletal disorders were commonly reported as risk factors (13 studies) as were several other medical disorders: Irritable bowel syndrome (IBS) (2 studies), gastroesophageal reflux disease 1, peptic ulcer 2, diabetes 3, hypertension 3, hyperlipidaemia 4, stroke 1, multiple sclerosis 1, coronary heart disease 1, and “Medical comorbidities” 3. Sleep disorders (13 studies) and anxiety/depression (11 studies) were reported frequently, but stress, somatic symptoms, and illness behaviour (negative perception of one's health and frequent medical consultations) were reported less frequently because they have only been included in a few studies. For few years of education (5 positive and 2 negative studies) and/or low socioeconomic status (5 positive and 2 negative), the results were more conflicting.
Among lifestyle factors, a high BMI was a risk factor in 7 studies, but in 2, it was reported as protective (red and green bars in Fig. 1, respectively). Smoking was a risk factor in 8 studies. Drinking no alcohol was a risk factor in 2 studies, and moderate alcohol consumption was protective in 3 studies. Heavy or repetitive work was a risk factor in 4 studies; physical inactivity was a risk factor in one study but not in another.
3.3. Strength of the association between risk factor and onset
In multivariate analyses including all relevant variables, the pattern of risk factors was similar to that of univariate analyses, but the number of variables significantly associated with onset (in brackets) was fewer. In descending order of frequency, they were musculoskeletal disorders, including pain (11 studies), other medical disorders (9), sleep disorder (9), smoking (6), raised BMI (5), older/middle age (5), female (4), anxiety/depression (4), illness behaviour (4), somatic symptoms (3), heavy work (2) allergy (2), stress (1), and few years of formal education (1). Moderate alcohol was protective in 3 studies. The odds or hazard ratios (and 95% confidence intervals), of these risk factor, where available, are shown graphically in Figures 2 and 3. In several articles the odds or hazard ratios were not available, so in Figure 2, for example, data were available for age in 4 studies, represented by red diamonds; 2 studies each had data for female sex (blue) and allergy (green), etc. Except in one study, the odds ratios were just over one for age, sex, and medical disorders, whereas raised BMI, allergy, smoking, and childhood factors show higher odds ratios. Moderate alcohol consumption is protective. Figure 3 shows that for sleep problems, anxiety/depression, and illness behaviours, many of the odds ratios were above 2; the highest odds ratios were recorded for pain disorders, headaches, and somatic symptoms. Three studies reported that the effect of multiple risk factors was additive: somatic symptoms, illness behaviour, pre-existing regional pain, sleep problems, and heavy or repetitive work.13,28,30
A bidirectional relationship was found between fibromyalgia and the following: depression, gastroesophageal reflux disorder, headache, migraine, insomnia, and irritable bowel syndrome (IBS); each of these 6 disorders predicted fibromyalgia, which, in turn, was a risk factor for each of them.5,14,38,44,46,50
In multivariate analyses which included all relevant variables, an exposure–response relationship was observed between severity of risk factor and likelihood of developing CWP for the following: number of pain sites at baseline, no. of sleep problems, headache, frequency, no. of somatic symptoms, illness behaviour score, allergy, number of serious illnesses when young, and severity of osteomyelitis.1,3,7,8,13,14,33,35 A linear relationship was reported between IQ at age 11 years and risk of CWP at 45 years of age.11 The Tromso study found an exposure–response relationship between lack of physical activity and increased chance of developing CWP only in women; mental health complaints were a predictor only in men.2 The association between osteomyelitis and fibromyalgia onset was found only in those younger than 60 years; the strongest association occurred in those younger than 35 years of age.7 Similarly, IBD was a risk factor only for participants under 50 or 60 years of age.6
3.4. Other findings
Two studies reported on the interaction with biological or genetic factors. One found that low morning cortisol, high cortisol in the evening, or postdexamethasone predicted CWP 1 year later, and these relationships were independent of the psychosocial factors or sleep disturbance.31 The other study found that sleeping problems and high BMI were predictors of fibromyalgia and were influenced by familial factors symptoms, whereas headache and regional pain were predictors independent of family background.27 No other studies were found, which replicated these findings. A single study found that neither pain threshold nor tender point count at baseline predicted onset of CWP.12
Birth cohort studies have shown that childhood difficulties by the age of 7 years (multiple headache and abdominal symptoms, maternal death, periods in local authority care, and family financial difficulties), lower IQ at 11 years, and persistent school behaviour problems throughout childhood were all associated with CWP in mid-life.11,19,20,36 These effects were partly modified by adjustment for confounders, but they remained predictors of CWP after adjustment for age, sex, socioeconomic status, anxiety, depression, health behaviours, and chronic illness during adult life. The same was true of serious physical illness requiring hospitalisation for more than a month before the age of 25 years, especially when there had been 2 such episodes.35 One study reported that there was no association between preterm birth or low birthweight and CWP.25
4.1. Statement of principal findings
Thirty-seven population-based studies met the inclusion criteria for this review of fibromyalgia and CWP; this represents a considerable body of knowledge not previously documented.4,15,39,41 As expected, the incidence of CWP was greater than that of physician-diagnosed fibromyalgia, which is associated with chronic, severe pain and treatment seeking.15 The incidence of fibromyalgia was highest in participants with pre-existing painful conditions and somewhat raised in the medically ill. A higher incidence in females was obvious in fibromyalgia, less obvious in CWP, and not evident in fibromyalgia developing in the medically ill. The review reveals a wide range of risk factors for these disorders, including difficulties during childhood, aspects of an adverse lifestyle, pre-existing medical disorders, regional or other pain disorders, sleep problems, somatic symptoms, negative health perception, and depression. Most of these variables have been associated with fibromyalgia in studies of prevalent cases with gastrointestinal, hepatic, rheumatic, and psychological disorders being most clearly associated with fibromyalgia.47 The importance of demonstrating that these are true risk factors lies in their contribution to establishing aetiological pathways.15 The data reviewed here were inadequate to compare the risk factors for fibromyalgia and CWP.
4.2. Strengths and limitations
This review has strengths and limitations, which must be recognised. The strengths include the restriction to prospective (and sound retrospective) studies of population-based cohorts with exclusion of people who had fibromyalgia before the commencement of the study. Especially in the fibromyalgia studies, the risk factors were measured well before the onset of fibromyalgia, so there was no doubt as to the temporal sequence of risk factor and onset. The cohorts were large and nearly half of the studies included over 1000 new-onset cases of fibromyalgia or CWP.
The main limitation of this review is the heterogeneous nature of the studies because of variability of diagnostic criteria, duration of follow-up period, and selection of predictor variables. The advantages of studying physician-diagnosed fibromyalgia include the clinical assessment and exclusion of other medical diseases that might lead to widespread pain. The use of medical records data ensures the exposed and comparison cohorts are comparable, and the follow-up rate is very high; most of these studies were rated high quality on this basis. On the other hand, medical records data studies include very few of the relevant lifestyle and psychosocial variables, so they assess a much narrower range of risk factors than the population-based case ascertainment studies. A more important problem is the fact that not all sufferers of the disorder see a doctor, so this method underestimates incidence. The alternative, case determination by questionnaire, may overestimate the incidence of fibromyalgia/CWP because it may include mild and transient cases and pain caused by other medical disorders.47 There is very poor agreement between the 2 methods of ascertaining cases of fibromyalgia/CWP. Only a quarter of those considered to have fibromyalgia have a physician-based diagnosis of FM.47 On the other hand, most people who say they have physician-diagnosed fibromyalgia do not fulfil the criteria for the disorder.48 In addition population-based case ascertained studies have limited response rates at follow-up, which contributed to lower quality ratings than for physician-rated fibromyalgia studies.
The small number of predictor variables included in some studies is a limitation; in the Taiwanese studies demonstrating IBD and osteomyelitis as risk factors for fibromyalgia, the database did not include smoking that may mediate the association between fibromyalgia onset and medical comorbidities.6–8 Finally, it is a limitation that the study was performed by a single reviewer; the results might be incomplete or biased in some way. The study did not include genetic studies, which are important in these disorders.
Because case ascertainment in the population is likely to be more accurate than case ascertainment in medical records, the incidence data for CWP were presented first in the results section. The fact that physician-diagnosed fibromyalgia is much more common in women, whereas polysymptomatic distress is a more pronounced feature of CWP suggests that fibromyalgia and CWP are subtly different conditions.42,48 In addition, the fact that fibromyalgia developing in the context of medical comorbidities lacks a clear female predominance suggests that there are different aetiological paths into fibromyalgia.
4.3. Wide range of risk factors
Any theory of causation must account for the fact that events in childhood predict onset of fibromyalgia many years later; this remained true even after adjustment for adult risk factors.21 On the other hand, there are risk factors, such as headache, somatic symptoms, and unsatisfactory sleep, which are so closely associated with fibromyalgia onset that they may be considered part of the fibromyalgia/CWP illness process.49 In between these 2 extremes is a wide range of risk factors that supports the concept of multiple causal pathways to fibromyalgia/CWP.15,41,43 These risk factors may be conceptualised as distal (eg, childhood problems, smoking, and low IQ), intermediate (eg, medical comorbidities), and proximal (including somatic symptoms). A very close association between somatic symptoms, illness behaviour, and fibromyalgia is to be expected with the recent definition of fibromyalgia, which includes “somatic” symptoms (fatigue, waking unrefreshed, cognitive symptoms, headaches, abdominal cramps, and depression). These would not therefore be regarded as risk factors.
The intermediate risk factor of medical illnesses is interesting—there was no female predominance and medical illness predicted fibromyalgia only in younger age groups or only in one sex. This suggests a specificity, which indicates that medical illness is a risk factor only in certain subgroups. Smoking seems also to be a risk factor primarily in those under 50 years of age.23
The distal, childhood risk factors may make an individual more susceptible to develop fibromyalgia in later life, but this “early pain pathway” may be relevant only to a minority of people, as only a small proportion of the population have experienced these childhood difficulties.20 Such susceptibility may be a direct effect or one which is mediated through subsequent adult risk factors; these may represent discrete causal pathways into fibromyalgia.19–21,36 It has been suggested that childhood adversities may lead to long-term hypothalamic–pituitary–adrenal (HPA) axis dysfunction; there is evidence that such dysfunction only occurs in those people who have both a functional somatic syndrome and a history of childhood adversity; this would be a subgroup of fibromyalgia patients.17 Alternatively, heightened sensitivity to bodily sensations and reduced ability to interpret bodily symptoms are possible mechanisms as seen in people with comorbid medical illnesses.11,22
There are many possible mechanisms mentioned by the articles in this review including central sensitisation of pain neurones, hypothalamic neuroendocrine dysfunction, hyperlipidaemia, allergies, immunological, and inflammatory factors, but the literature lacks specificity between risk factor and mechanism. For example, the association between gastrointestinal disorders and fibromyalgia may be explained by altered intestinal permeability, which results from infection/inflammation, microscopic colitis, non-steroidal anti-inflammatory drugs, and proton-pump inhibitors.40,46 In addition, the risk of both IBS and fibromyalgia is reduced by tramadol suggesting a common pain perception pathway in these 2 syndromes.50 Although many patients report gastrointestinal problems as the first indictor of FM, prospective data indicate limited association between new-onset fibromyalgia and pre-existing IBS.40,50 This example shows how putative mechanisms would be best studied in relation to particular risk factors.
In addition, it would be advantageous to study causal pathways and mechanisms in relation to specific subgroups of FM rather than assuming a single pathway into the disorder.15,41,43 One cluster analysis revealed how subgroups of fibromyalgia patients may be related to specific risk factors.45 Increased levels of anxiety and depression were confined to 2 clusters of younger patients; only one of these clusters had raised BMI associated with severe fibromyalgia and sleep difficulties. The older participants in another cluster had a raised mean BMI and severe impairment due to physical causes, ie, comorbidity.6,7 In this way, risk factors may be associated with specific subgroups and a specific causal pathway. The medical comorbidities that precede fibromyalgia in some subgroups may explain the higher mortality associated with CWP.26
In conclusion, this review demonstrates a wide variety of risk factors for fibromyalgia/CWP, which fits better with multiple rather than a single causal pathway into fibromyalgia/CWP. It raises a number of questions for future research, including testing the possibility that some risk factors may differ by sex and by age group; the causal pathway may differ in older people with medical comorbidity compared with young, otherwise healthy people. There may be some risk factors that are common to everyone developing fibromyalgia; this might include somatic symptoms, sleep disturbance, and fatigue, although these are now regarded as part of the syndrome because they are included in the more recent ACR diagnostic criteria. If fibromyalgia is conceptualised as a continuum from a purely peripherally driven painful condition to a centrally driven one, then different risk factors might be associated with particular points on this continuum.3 This could be one way to conceptualise and study risk factors in future research.
Conflict of interest statement
The author has no conflicts of interest to declare.
All analyses were secondary, and the primary data were anonymised.
Appendix A. Supplemental digital content
Supplemental digital content associated with this article can be found online at http://links.lww.com/PAIN/A956.
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