Gender and psychosocial context as determinants of fibromyalgia symptoms in young adults from the general population

Original article

Gender and psychosocial context as determinants of

fibromyalgia symptoms (fibromyalgia research

criteria) in young adults from the general population

Sara Lourenc¸o

, Lu´cia Costa

, Ana Maria Rodrigues

, Filomena Carnide

and

Raquel Lucas

Abstract

Objective. To quantify the prevalence of FM (FM research criteria), to describe its components—symptom

severity score (SSS) and widespread pain index (WPI)—and to identify biopsychosocial predictors of the

severity of SSS as well as WPI using a population-based sample of young adults.

Methods. Participants were part of the 21-year-old follow-up of the EPITeen cohort, which was set up

during the 2003–04 school year and comprised subjects born in 1990 attending schools in Porto, Portugal

(n = 1719, 51.4% women). Data on biopsychosocial characteristics were collected, and FM-related

infor-mation was gathered using the Fibromyalgia Survey Questionnaire. Sex-specific multivariate log-binomial

regression coefficients () and 95% CI were used to quantify the associations between adverse

biopsy-chosocial characteristics and high scores in SSS and WPI.

Results. The overall point-prevalence of FM was 1.0%. Women scored significantly higher in SSS and

WPI when compared with men. Global psychological distress was strongly and significantly associated

with high scores in SSS in women and men (respectively, low sleep quality, b = 1.44, 95% CI 1.05, 1.84

and b = 1.19, 95% CI 0.78, 1.61; depressive symptoms, b = 1.64, 95% CI 1.23, 2.06 and b = 1.14, 95% CI

0.60, 1.70; eating disorders, b = 1.17, 95% CI 0.71, 1.63 and  = 1.15, 95% CI 0.52, 1.78). In women,

adverse socioeconomic factors were predictors of high scores in SSS, whereas in men these contexts

were significantly associated with high scores in WPI.

Conclusion. In young adulthood, psychological distress was particularly consistent in predicting SSS and

may become useful as a red flag for the establishment of clinical disease.

Key words: FM, psychological stress, young adult.

Rheumatology key messages

. In young adulthood, FM-related non-pain symptoms were much more frequent than widespread pain.

. In disadvantaged socioeconomic contexts, women reported FM-related non-pain symptoms, while men reported FM-related pain symptoms.

. Early psychological distress may become useful as a red flag for FM throughout the life course.

Introduction

FM is a complex syndrome [1] that overlaps but surpasses chronic widespread pain [2]. Recently, the ACR modelled FM as a condition of progressive severity throughout the life course and where non-specific symptoms other than pain precede the establishment of clinical disease [3]. However, up to 2010, the classification of FM depended on the ascertainment of tender points, lagging behind the clinical understanding of the syndrome [4]. Given that it missed a part of the spectrum of clinical presentation, this

1

EPIUnit – Institute of Public Health, University of Porto,2

Servic¸o de

Reumatologia, Hospital de Sa˜o Joa˜o, Porto,3

Rheumatology Research Unit, Institute of Molecular Medicine, University of Lisbon Medical

School, Lisboa,4

Faculty of Human Kinetics, University of Lisbon, Cruz

Quebrada – Dafundo and5

Department of Clinical Epidemiology, Predictive Medicine and Public Health, University of Porto Medical School, Porto, Portugal

Correspondence to: Sara Lourenc¸o, EPIUnit – Institute of Public Health of the University of Porto, Rua das Taipas, 135-139, 4050-600 Porto, Portugal. E-mail: [email protected]

Submitted 1 November 2014; revised version accepted 5 March 2015

approach had suboptimal sensitivity as a tool for diagno-sis [5] and possibly also for prognodiagno-sis monitoring. Consequently, classification criteria were revised [6] so that the assessment of FM in generalist or research set-tings could objectively reflect constructs that were previ-ously restricted to clinical expertise centres.

If non-specific symptoms other than pain precede wide-spread pain in the natural history of the disease, it is likely that the clinical presentation of the syndrome itself varies throughout the life course, with younger patients present-ing primarily non-pain features [7, 8]. As the ACR classifi-cation criteria are still recent, little is known about the frequency and predictors of each component of FM in the general population of young adults [9], where the prevalence of the syndrome is expected to be low but where timely prevention and management may be more effective [10].

Up to the present, there have been two investigations measuring the prevalence of FM in the general adult population according to the FM research criteria [11], which yielded substantial differences in disease preva-lence: 2.1% in Germany [12] vs 6.4% in the USA [13]. Even though both studies provided new population-based evidence, the USA investigation measured disease presence through postal questionnaire and had a low par-ticipation rate, while the German sample, because of its representativeness, was comparatively underpowered in the youngest age groups.

By using data from a population-based sample of female and male adults born in 1990, we aimed to quantify the prevalence of FM (FM research criteria), to describe its components—symptom severity score (SSS) and wide-spread pain index (WPI)—and to identify biopsychosocial predictors of the severity of SSS and WPI.

Patients and methods

Participants

This study uses cross-sectional data collected from young adults of the Epidemiological Health Investigation of Teenagers in Porto (EPITeen; 2011–13). The EPITeen was designed as a prospective cohort first assembled during the 2003–04 school year, when all public and pri-vate schools in Porto (Portugal) that provided teaching to adolescents born in 1990 were approached. In this first wave, we identified 2787 eligible adolescents, of whom 2159 agreed to participate. In 2007–08 (second wave), the initially recruited sample was re-evaluated, and 783 students born in the same year but who moved to Porto after 2003–04 were additionally recruited to the cohort. Sampling procedures and detailed methods have been described elsewhere [14].

Between 2011 and 2013, 1761 young adults (of the 2942 eligible for follow-up) attended to the third wave (evaluation at 21 years old). Among those, 23 (1.3%) sub-jects were excluded due to psychiatric disorders and 19 (1.1%) due to missing data in FM components. Therefore, 1719 participants were eligible for this investigation.

Only cross-sectional data from the third wave were used in this study. This option was based on the obser-vation that the EPITeen adolescents largely maintained their rank in the distribution of relevant characteristics throughout follow-up, such as BMI [15], depressive symp-toms [16] and parental education. In addition, other im-portant indicators were either not collected (health-related quality of life and sleep quality) or not informative due to the age of participants in previous waves (work status and individual education).

The study was approved by the Ethics Committee of the University Hospital of Sa˜o Joa˜o (Porto) and was carried out according to the Declaration of Helsinki. Written in-formed consent was obtained from all participants.

Data collection

Anthropometrics were obtained while subjects stood barefoot in light indoor clothing. Weight was measured to the nearest tenth of a kilogram (Tanita Corporation, Tokyo, Japan), and height was measured in centimetres to the nearest tenth using a portable stadiometer (Seca, Hamburg, Germany). BMI was calculated as weight (in kilograms) divided by squared height (in metres).

Chronic regional musculoskeletal pain (persistent or re-current pain during at least 3 months) in nine different anatomical regions was measured using the Nordic Musculoskeletal Questionnaire [17, 18], and the total number of regions reported as chronically painful was computed.

Data on work status, parental (parent with the highest number of schooling years) and individual education and monthly household income were also gathered. Frequencies of smoking, alcohol drinking and physical ac-tivity during leisure time were also collected.

The first question of the Medical Outcomes Study 36-Item Short Form Survey (in general would you say your health is) was used as a summary indicator of health-related quality of life [19, 20]. Quality of sleep was mea-sured as following: In general, how would you rate your sleep quality during the last month? Depressive symp-toms were assessed using the Beck Depression Inventory (second version) [21], and eating disorders were evaluated using the Eating Disorders Inventory [22].

FM and its components

The Fibromyalgia Survey Questionnaire (FSQ; Winfried Ha¨user, personal communication, 17 May 2011), adminis-tered by face-to-face interview, was used to estimate the presence of FM and the severity of its components (SSS and WPI) according to the FM research criteria [6, 11]. The SSS quantifies the severity of fatigue, trouble thinking and/or remembering and waking up tired and/or unre-freshed in the previous week (0 = no problems; 1 = slight or mild problems, generally mild or intermittent; 2 = mod-erate, considerable problems, often present and/or at a moderate level; 3 = severe, continuous, life-disturbing problems) and the presence (no, yes) of pain or cramps in the lower abdomen, depression and headache in the past 6 months. The WPI evaluates pain presence (no, yes)

in the preceding week in 19 anatomical areas (jaws, shoulders, upper arms, lower arms, hips, upper legs, lower legs, neck, chest, upper back, lower back and abdomen). The FSQ has been described in detail else-where [23]. Individuals were defined as FM cases when SSS and WPI severity scores were both above the cut-off points (SSS 5 5 and WPI 5 7 or SSS 5 9 and WPI = 3–6) and were present at a similar level for at least 3 months. In order to quantify the predictive value of a negative result in the FSQ, a consecutive subsample of female participants (n = 140) was assessed for FM using the gold-standard method (a clinical examination by a rheumatologist). Among those (all of them classified as not having FM according to the FSQ criteria and whose average score in SSS was 3.6 and 1.0 in WPI), none was classified by the rheumatologist as having clinical criteria for FM. This validated our methodological option, because a very low prevalence of clinical disease was expected at this age, and no FM cases would be screened out by the FSQ.

Statistical analysis

All items of the FSQ were described as counts and pro-portions and were stratified by sex. Prevalence of FM and median (25th percentile, 75th percentile) scores in SSS and WPI components were estimated overall and strati-fied by sex, and the statistical significance of differences between groups was estimated using chi-square or Mann–Whitney U-tests, as appropriate. Given that a low prevalence of clinical disease was expected in this age group, young adults were categorized according to their position in relation to the median scores in SSS and WPI (non-normal distribution) obtained in the whole sample: below or at the median (low severity) vs above the median (high severity).

Both SSS and WPI distributions have returned outliers. We cannot exclude that these were the result of measure-ment error, but it is plausible that they represent the true expected variability of symptom severity in the general population. Thus, we opted for not excluding participants with outlier values. Notwithstanding, as we dichotomized the symptom scores into low or high using medians, this attenuated the impact of outlier inclusion; that is, the total score of each individual was only used to classify partici-pants as high or low scorers.

Potential biopsychosocial predictors were categorized as follows: BMI (normal weight vs overweight/obese), mul-tisite chronic pain (none or one vs two or more anatomical sites), work status (never vs ever worked), parental edu-cation (9 or less vs 10 or more schooling years), individual education (12 or less vs 13 or more schooling years), monthly household income (4E2000 vs >E2000), smok-ing (never vs ever), alcohol drinksmok-ing (less than once vs once or more per week), physical activity (low vs moderate or high), health-related quality of life (bad or fair vs good or very good or excellent), sleep quality (bad or fairly bad vs fairly good or good), depressive symptoms (no vs yes) and eating disorders (no vs yes).

Sex-specific multivariate log-binomial regression coef-ficients (b) and corresponding 95% CI were used to quan-tify the magnitude of associations between adverse biopsychosocial characteristics and high scores in SSS and WPI. Each estimate was adjusted for a priori selected confounders as follows: BMI was adjusted for individual education (proxy for socioeconomic context), smoking (proxy for lifestyles) and depressive symptoms (proxy for psychological health); multisite chronic pain was adjusted for BMI, individual education, smoking and depressive symptoms; lifestyles were adjusted for individual educa-tion and depressive symptoms; psychological health was adjusted for individual education. Data were analysed using Stata version 11.2 for Windows (Stata Corp. LP, College Station, TX, USA).

Results

Young adults enrolled in this population-based study were, on average, 21.9 years of age, and the proportion of women and men was very similar (51.4% vs 48.6%). Three-quarters of the whole sample had normal weight, and the vast majority had reported chronic pain in one or fewer anatomical sites (94.0%). Nearly two-thirds of participants had more than secondary school as edu-cational level. Most subjects had smoked at least once in life (71.8%) and had reported depressive symptoms (84.9%).

Concerning FM-related symptoms, the most frequently reported non-pain symptoms were fatigue (66.7% vs 52.3%) and waking up tired or unrefreshed (64.8% vs 60.6%) in both sexes. Women were significantly more likely to report pain or tenderness in at least one anatomical region than men (43.5% vs 33.5%, P < 0.001; Table 1).

The point-prevalence of FM was 1.0% (95% CI 0.5, 1.5). Although not significantly different, the prevalence of FM was higher in women than in men (1.4% vs 0.6%, P = 0.111, respectively). Overall, SSS and WPI scores were low (medians: 3.0 out of 12 and 0.0 out of 19, re-spectively), but both components were significantly higher in women when compared with men (Fig. 1).

Prevalence of high scores in SSS and WPI according to young adults’ characteristics is summarized in Table 2. Multisite chronic pain was significantly associated with high scores in SSS (52.0% vs 37.4%, P = 0.008). Young adults who had ever worked (vs had never worked), whose monthly household income was lower (vs higher monthly household income) and those who had ever smoked (vs had never smoked) scored more frequently high in SSS. All the adverse psychological factors in study were significantly associated with high scores in SSS.

Regarding WPI, multisite chronic pain was significantly associated with high scores in this component (71.0% vs 36.0% in participants without multisite chronic pain, P < 0.001). Except for parental education, adverse socio-economic characteristics (having ever worked, low indi-vidual education and low monthly household income) were also significantly associated with high scores in WPI. With the exception of eating disorders, adverse

psychological factors were significantly associated with higher scores in WPI, but differences were much smaller than those observed in the SSS. Figures 2 (women) and 3 (men) illustrate the sex-specific adjusted associations be-tween adverse biopsychosocial characteristics and high scores in SSS and WPI.

In women, adverse socioeconomic contexts (having ever worked, b = 0.50, 95% CI 0.22, 0.78; and low individ-ual education, b = 0.26, 95% CI 0.03, 0.54) were pre-dictors of high SSS, whereas smoking (b = 0.36, 95% CI 0.00, 0.71) and low physical activity (b = 0.35, 95% CI 0.04, 0.67) were associated with high SSS in men. All the psychological indicators were strongly and signifi-cantly associated with high scores in SSS in women and men (respectively, poor health-related quality of life,

b= 1.15, 95% CI 0.72, 1.58 and b = 1.26, 95% CI 0.72, 1.80; low sleep quality, b = 1.44, 95% CI 1.05, 1.84 and b= 1.19, 95% CI 0.78, 1.61; depressive symptoms, b= 1.64, 95% CI 1.23, 2.06 and b = 1.14, 95% CI 0.60, 1.70; eating disorders, b = 1.17, 95% CI 0.71, 1.63 and b= 1.15, 95% CI 0.52, 1.78).

In both sexes, significant strong associations between multisite chronic pain and high scores in WPI were found (b = 1.69, 95% CI 1.00, 2.38 and b = 1.41, 95% CI 0.62, 2.20, in women and men, respectively). In men only, ad-verse socioeconomic factors (having ever worked, b= 0.22, 95% CI 0.07, 0.52; low individual education, b= 0.37, 95% CI 0.08, 0.67; and low monthly household income b = 0.34, 95% CI 0.04, 0.35) were significantly associated with WPI.

TABLE1 Frequency of non-pain and pain symptoms and their chronicity as assessed in the Fibromyalgia Survey Questionnaire in 21-year-old young female and male adults

Women Men

Severity of symptoms over the past week

No problem Slight Moderate Severe No problem Slight Moderate Severe

Fatigue 294 (33.3) 354 (40.1) 197 (22.3) 38 (4.3) 399 (47.7) 295 (35.3) 126 (15.1) 16 (1.9) Trouble thinking or remembering 457 (51.8) 272 (30.8) 121 (13.7) 33 (3.7) 518 (62.0) 226 (27.0) 79 (9.4) 13 (1.6) Waking up tired and/or unrefreshed 311 (35.2) 273 (30.9) 226 (25.6) 73 (8.3) 329 (39.4) 308 (36.8) 165 (19.7) 34 (4.1)

Symptoms in the past 6 months No Yes No Yes

Pain or cramps in lower abdomen

645 (73.1) 238 (26.9) 756 (90.4) 80 (9.6)

Depression 808 (95.5) 75 (8.5) 812 (97.1) 24 (2.9)

Headache 340 (38.5) 543 (61.5) 548 (65.6) 288 (34.4)

Pain or tenderness over the past week

Pain in any region 499 (56.5) 384 (43.5) 556 (66.5) 280 (33.5)

Left jaw 879 (99.5) 4 (0.5) 833 (99.6) 3 (0.4)

Right jaw 878 (99.4) 5 (0.6) 833 (99.6) 3 (0.4)

Neck 806 (91.3) 77 (8.7) 785 (93.9) 51 (6.1)

Left shoulder 818 (92.6) 65 (7.4) 790 (94.5) 46 (5.5)

Right shoulder 818 (92.6) 65 (7.4) 789 (94.4) 47 (5.6)

Left upper arm 862 (97.6) 21 (2.4) 811 (97.0) 25 (3.0)

Right upper arm 863 (97.7) 20 (2.3) 812 (97.1) 24 (2.9)

Left lower arm 874 (99.0) 9 (1.0) 827 (98.9) 9 (1.1)

Right lower arm 874 (99.0) 9 (1.0) 829 (99.2) 7 (0.8)

Chest 863 (97.7) 20 (2.3) 811 (97.0) 25 (3.0) Abdomen 823 (93.2) 60 (6.8) 812 (97.1) 24 (2.9) Upper back 789 (89.4) 94 (10.6) 777 (92.9) 59 (7.1) Lower back 713 (80.8) 170 (19.2) 736 (88.0) 100 (12.0) Left hip 871 (98.6) 12 (1.4) 829 (99.2) 7 (0.8) Right hip 872 (98.8) 11 (1.2) 830 (99.3) 6 (0.7)

Left upper leg 840 (95.1) 43 (4.9) 790 (94.5) 46 (5.5)

Right upper leg 846 (95.8) 37 (4.2) 789 (94.4) 47 (5.6)

Left lower leg 836 (94.7) 47 (5.3) 805 (96.3) 31 (3.7)

Right lower leg 837 (95.8) 46 (5.2) 797 (95.3) 39 (4.7)

Symptoms and/or pain/tendernessa

for at least 3 months

Chronicity 636 (72.0) 247 (28.0) 645 (77.2) 191 (22.8)

a_{Considering all symptoms described in this table that were marked as being present by participants during the face-to-face}

Discussion

In this population-based sample of young adults, we found a 1.0% point-prevalence of FM according to the FM research criteria, slightly (but not significantly) higher in females. Although SSS and WPI were on average low in this sample, both FM components were significantly higher in women.

All adverse psychological characteristics were strong and significant predictors of high scores in SSS. These findings were consistent between females and males. Adverse socioeconomic contexts were associated with WPI only in men.

Within the musculoskeletal system, FM is second only to OA as the most common disorder seen in clinical set-tings [24]. However, until recently, a skilled physical exam-ination was warranted in order to apply the 1990 ACR classification criteria (tender points count) for the ascer-tainment of FM, which limited its applicability to popula-tion-based research. The recent revision of the ACR classification criteria widened case ascertainment beyond clinical examination and fuelled the development of a set of FM research criteria designed for epidemiolo-gical purposes [11].

The extent to which this modification interferes with population estimates of prevalence—and mainly with the assessment of FM determinants—remains to be clarified [6]. To our knowledge, there have been only two studies that applied the FM research criteria in the general popu-lation. The first one was performed in a sample of German adults (age range 18–93 years old), in whom the overall prevalence of FM was 2.1%, without significant differ-ences between sexes [12]. The second study was con-ducted through a mailed survey in a population-based

sample of adults (83% of subjects were 540 years old) and living in Olmsted County (MN, USA), where the age-and sex-adjusted point-prevalence of FM was 6.4% [13]. These estimates may reflect true differences in disease frequency between geographical settings, but varying de-grees of participation bias cannot be excluded (56.7% participation rate in the German study and 27.7% in the USA), because persons with more severe symptoms are reportedly more willing to participate in such investiga-tions [25]. Our finding of a lower prevalence of FM using the same classification criteria as in those studies is con-sistent with our sample being substantially younger. Nevertheless, in a study that estimated the age-specific frequency of FM in five European countries (including Portugal), the prevalence in the 15–24 year age category was below 2% [26]. Even though this investigation did not use the FM research criteria to define FM cases, its esti-mate is similar to that found in our study.

In line with the current understanding of FM, the main added value of using the FM research criteria is the possibility of investigating psychosomatic symptoms other than pain. Particularly in early adulthood, non-pain symptoms are probably more clearly detectable than pain, as corroborated by our results: average SSS was 3 (out of 12), whereas average WPI was 0 (out of 19).

An additional priority research issue beyond disease frequency is the identification of the determinants of both pain and non-pain components of the redefined FM syndrome from early stages in the life course, as most knowledge about determinants of this condition has been gained in middle-aged populations, where the condition was already established and in which reverse causation is more likely [27]. In contrast, there has been

FIG. 1 Boxplots presenting the sex-specific distribution of the symptom severity and widespread pain scores (FM components) in 21-year-old young female and male adults

0 10 2 4 6 8 12 Symp to m se ve ri ty sco re n e M n e m o W Sex-specific

Symptom severity score

0 10 20 2 4 6 8 12 14 16 18 Wi de sp re ad p a in in de x n e M n e m o W Sex-specific

Widespread pain index

Dashed lines represent the mean values of symptom severity and widespread pain scores obtained in the whole sample. Diamonds illustrate the sex-specific means of symptom severity and widespread pain scores. Horizontal lines represent the sex-specific median values and corresponding interquartile ranges of symptom severity and widespread pain scores. The bottom and top of vertical lines (whiskers) illustrate the sex-specific lower and upper adjacent values of symptom severity and widespread pain scores. Dots represent the sex-specific outliers of symptom severity and widespread pain scores.

lack of distinction between the predictors of pain and non-pain FM components [6].

Gender is probably the most evident determinant of FM [27, 28]. While differences in social and psychological fea-tures may partly explain gender disparity in symptom

reporting and subsequent disease frequency, the genetic and biochemical markers also suggest sex-specific pathophysiological mechanisms that pattern FM and its clinical manifestations [29–31]. Our results corroborate sex differences that are observable from

TABLE2 Proportion of high symptom severity score and high widespread pain index according to biopsychosocial characteristics of 21-year-old young female and male adults

Fibromyalgia Survey Questionnaire All participants High symptom severity scorea P-value High widespread pain indexb P-value n (%) n (%) n (%) Total 1719 664 (38.6) 664 (38.6) Sex Female 883 (51.4) 430 (48.7) <0.001 384 (43.5) <0.001 Male 836 (48.6) 234 (28.0) 280 (33.5) BMI Normal weight 1284 (75.5) 511 (39.8) 0.072 497 (38.7) 0.929 Overweight or obese 416 (24.5) 145 (34.9) 160 (38.5)

Chronic regional pain

41 anatomical site 1576 (94.0) 589 (37.4) 0.004 567 (36.0) <0.001 52 anatomical sites 100 (6.0) 52 (52.0) 71 (71.0) Work status Never worked 1069 (62.4) 387 (36.2) 0.007 394 (36.9) 0.046 Ever worked 645 (37.6) 276 (42.8) 269 (41.7) Parental education 49 schooling years 680 (39.8) 267 (39.3) 0.277 274 (40.3) 0.248 510 schooling years 1029 (60.2) 391 (38.0) 386 (37.5) Individual education 412 schooling years 601 (35.0) 233 (38.8) 0.941 254 (42.3) 0.022 513 schooling years 1117 (65.0) 431 (38.6) 409 (36.6)

Monthly household income

42000E 920 (60.3) 373 (40.5) 0.040 383 (41.6) 0.004 >2000_E 606 (39.7) 214 (35.3) 208 (34.3) Smoking Never smoked 484 (28.2) 169 (34.9) 0.045 176 (36.4) 0.218 Ever smoked 1233 (71.8) 495 (40.2) 488 (39.6) Alcohol drinking

Less than once per week 1104 (64.3) 439 (39.8) 0.203 439 (39.8) 0.203

Once or more per week 614 (35.7) 225 (36.6) 225 (36.6)

Physical activity

Low 565 (32.9) 228 (40.4) 0.316 205 (36.3) 0.155

Moderate or high 1152 (67.1) 436 (37.9) 459 (39.8)

Health-related quality of life

Poor/fair 192 (11.2) 122 (63.5) <0.001 95 (49.5) 0.001

Good/very good or excellent 1524 (88.8) 539 (35.4) 567 (37.2)

Sleep quality

Very poor or reasonably poor 282 (17.1) 187 (66.3) <0.001 142 (50.4) <0.001

Reasonably good or very good 1367 (82.9) 445 (32.6) 493 (36.1) Depressive symptoms No 1222 (84.9) 388 (31.8) <0.001 441 (36.1) 0.004 Yes 218 (15.1) 157 (72.0) 101 (46.3) Eating disorders No 1068 (87.7) 354 (33.2) <0.001 387 (36.2) 0.292 Yes 150 (12.3) 97 (64.7) 61 (40.7)

Sample size is not constant due to missing data on BMI (n = 19), chronic regional pain (n = 43), work status (n = 5), parental education (n = 10), individual education (n = 1), monthly household income (n = 193), smoking (n = 2), alcohol drinking (n = 1), physical activity (n = 2), quality of life (n = 3), sleep quality (n = 70), depressive symptoms (n = 279) and eating disorders (n = 501).

a

High symptom severity score represents the young adults who scored higher than the median score, obtained in the whole

sample, in the symptom severity component.bHigh widespread pain index represents the young adults who scored higher

early adulthood, in that SSS and WPI were significantly higher in women when compared with men, especially when considering psychosomatic symptoms other than pain.

Overweight has been suggested as an aggravating comorbid condition of FM [32], but we found that BMI was not evidently associated with the severity of FM com-ponents in women and men. This may be the result of

FIG. 2 Adjusted associations between adverse biopsychosocial characteristics and high scores in symptom severity and widespread pain (FM-related components) in 21-year-old young female adults

*β =0.02 †β =0.10 β =0.50 β =0.13 β=0.26 _β=0.14 ‡β =0.24 ‡β =-0.15 ‡β =0.13 §β =1.15 §β =1.44 §β =1.64 §β =1.17 *β =0.35 †β =1.69 β =0.19 _β=0.18 β =0.20 _β=0.18 ‡β =0.20 ‡β =0.02 ‡β =-0.28 §β =0.51 §β =0.43 §β =0.18 §β =0.05 -1 0 1 2 3 Overweight/ o besity M u lti si

te chronic pain Ever

worked Low pa rental ed ucation Low individual educ ation Low m onthly household incom e Ever smoked Alco hol drink in g Low physical ac tivity Poor health-relate d quality of life Poor slee p quality Depressive sy mptom s Ea ting disorders Overweight/ o besity M u lti si

te chronic pain Ever

worked Low pa rental ed ucation Low individual educ ation Low m onthly household incom e Ever smoked Alco hol drink in g Low physical ac tivity Poor health-relate d quality of life Poor slee p quality Depressive sy mptom s Ea ting disorders Adjusted log-binom ial regression coefficients (β) and 95% confidence intervals

Symptom severity score (SSS) Widespread pain index (WPI)

Triangles and squares represent the multivariate log-binomial regression coefficients (b) and lines the corresponding 95% CIs, using as reference category (b = 0) women whose score was lower than or equal to sex-specific median scores in SSS and WPI, respectively. *Adjusted for individual education, smoking and depressive symptoms.yAdjusted for body mass index, individual education, smoking and depressive symptoms.z

Adjusted for individual education and depressive symptoms.§Adjusted for individual education.

FIG. 3 Adjusted associations between adverse biopsychosocial characteristics and high scores in symptom severity and widespread pain (FM-related components) in 21-year-old young male adults

*β=-0. 0 3 †β=0.62 β=-0. 0 3 β=-0. 1 7 β=-0. 1 6 β=0.05 ‡β=0.36 ‡β=0.21 ‡β=0.35 §β=1.26 §β=1.19 §β=1.14 §β=1.15 *β=-0. 2 9 †β=1.41 β=0.22 β=-0. 0 2 _β=0.37 β=0.34 ‡β=0.04 ‡β=-0. 2 5 ‡β=-0. 0 7 §β=0.24 §=0.72 §β=0.56 §β=0.09 -1 0 1 2 3 Overweight/ o besity M u lti si

te chronic pain Ever

worked Low pa rental ed ucation Low individual educ ation Low m onthly household incom e Ever smoked Alco hol drink in g Low physical ac tivity Poor health-relate d quality of life Poor slee p quality Depressiv e sy mptom s Ea ting disorders Overweight/ o besity M u lti si

te chronic pain Ever

worked Low pa rental ed ucation Low individual educ ation Low m onthly household incom e Ever smoked Alco hol drink in g Low physical ac tivity Poor health-relate d quality of life Poor slee p quality Depressiv e sy mptom s Ea ting disorders Adjusted log-binom ial regression coefficients (β) and 95% confidence intervals

Symptom severity score (SSS) Widespread pain index (WPI)

Triangles and squares represent the multivariate log-binomial regression coefficients (b) and lines the corresponding 95% CIs, using as reference category ( = 0) men whose score was lower or equal to sex-specific median scores in SSS and WPI, respectively. *Adjusted for individual education, smoking and depressive symptoms.yAdjusted for BMI, individual education, smoking and depressive symptoms.z

Adjusted for individual education and depressive symptoms.§_Adjusted

the comparatively low prevalence of obesity in the EPITeen cohort (5.4%) as well as of the short-term expos-ure to the mechanisms that explain the association be-tween obesity and FM in older adults.

Previous evidence has supported the spreading of chronic pain from regional to widespread [25]. We found that subjects of both sexes reporting multisite chronic pain were significantly more likely to score highly in WPI, which suggests that the number of painful regions and the chronicity of pain may function as a marker of chronic widespread pain later in life. Nevertheless, we recognize that such high correlation may be due to the obvious similarity between the two constructs.

Socioeconomic disadvantage has also been associated with a wide number of negative health out-comes, namely widespread pain [33]. In the present study, earlier beginning of working life and low individual education were important predictors of higher SSS among women. In men, associations were found be-tween negative socioeconomic contexts and the report of higher scores in WPI. These findings suggest important gender differences in mechanisms of soma-tization related to social disadvantage, whereby men may be more likely to report pain and women non-pain symptoms.

Adverse lifestyles have also been associated with FM in middle-aged adults [34, 35], which was not consistently observed in our study among young adults. Lifestyles adopted during the early stages of adulthood will not ne-cessarily persist throughout adulthood [36]. Thus, the adoption of adverse lifestyles in young adulthood might not be a reliable marker of psychological malaise as it is typically described in later stages of the life course, which may explain the lack of associations found between this vector of young adults’ life and FM components.

All markers of psychological distress in analysis were significantly and consistently predictive of high scores in SSS in both sexes (fewer and weaker associations were found for WPI). This is in line with previous research that has shown that adverse psychological factors are fre-quently present in FM patients in later stages of the life course [37–40]. Therefore, these findings corroborate that psychological distress as assessed in our sample of young adults may be an accurate marker of increased risk of developing FM throughout life.

To the best of our knowledge, this is the first study to estimate the prevalence of FM according to the FM re-search criteria and to describe its components in a large population-based sample of young adults. This investiga-tion pioneers the identificainvestiga-tion of a wide spectrum of early biopsychosocial correlates of the severity of FM-related pain and non-pain symptoms. Another major strength of the present study is that our population-based sample included a broad spectrum of severity of FM-related symptoms, as expected for the general population. Additionally, all participants were born in the same year, which eliminates several sources of confounding.

Some methodological concerns need to be addressed. Although FSQ has demonstrated good psychometric properties in other European samples of adults [41], the instrument was not previously validated in our source population. However, to ensure that the instrument would not screen out participants with clinical disease, one of the co-authors (L.C., rheumatologist) examined a consecutive subsample of 140 females. None of the women screened out by the questionnaire had clinical evidence of a chronic widespread pain syndrome, sug-gesting a very high negative predictive value, which should be a fundamental feature of any valid screening instrument.

As we were testing a wide spectrum of potential biop-sychosocial determinants, multiple testing issues and consequent random effects may have occurred. However, the probability of random findings in our study was expected to be low because all hypotheses were defined a priori. In addition, we found a pattern of consistent and significant predictors of FM in both sexes (psychological distress indicators) that were not expected if the effects were a result of multiple testing alone.

The cross-sectional design of this investigation does not allow the establishment of the temporal sequence be-tween exposures and outcomes. The prospective follow-up of the EPITeen cohort into adulthood will be fundamen-tal for empirically confirming our hypotheses regarding the early determinants of clinical FM.

Finally, the extent to which any cohort represents its source population is likely to decrease over time because of differential losses to follow-up. Nevertheless, at baseline, subjects who attended the third wave of the EPITeen cohort were similar to those lost to follow-up in a wide range of individual characteristics (sex distribution, BMI, smoking and depressive symptoms), which supports the representativeness of the cohort.

In conclusion, the prevalence of newly defined FM in young adults from the general population was 1.0%. Non-pain symptoms were much more frequent than wide-spread pain. In the presence of adverse socioeconomic context, men were more likely to report pain and women non-pain symptoms. Early psychological distress was par-ticularly consistent in predicting SSS and may become useful as a red flag for the establishment of clinical disease.

Acknowledgements

S.L. gratefully acknowledges a doctoral grant from the Portuguese Foundation for Science and Technology (FCT; reference SFRH/BD/77965/2011). We gratefully acknowledge Dr Winfried Ha¨user for kindly providing the Fibromyalgia Survey Questionnaire used in this study. Funding: This work was supported by the Portuguese Foundation for Science and Technology (FCT, references: FCOMP-01-0124-FEDER-015750, FCT – PTDC/SAU-EPI/ 115254/2009).

Disclosure statement: The authors have declared no conflicts of interest.

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Clinical vignette

Primary synovial osteochondromatosis of the knee

A 60-year-old man was referred to our clinic with mild inter-mittent pain and progressive swelling of the right knee for the past 4 years. On physical examination, he had a swollen right knee with crepitus on palpation resembling s.c. emphysema, tenderness on flexion but no warmth. Radiographs (Fig. 1) and a CT scan from the knee showed moderate joint effusion with multiple free calcified bodies. These findings were absent from radiographs of the hips and ankles. A s.c. artefact from past lead shot injury in the lower limbs was also present. SF

analysis revealed 180 leucocytes/mm3_{and was negative for}

crystals, malignant cells, bacteria and fungi.

Primary synovial osteochondromatosis is a rare benign neoplastic disease, usually monoarticular, affecting males in the third to fifth decades of life. The main joint affected is the knee (50%), followed by the hip, elbow and glenohumeral joint [1]; extra-articular involvement (e.g. tendons and bursae) and malignant transformation to chondrosarcoma have also been described [2]. The multiple round calcified bodies may be identified easily on plain radiographs, but atypical presenta-tions with erosions or unmineralized lesions may require fur-ther investigation with a CT scan or MRI. Surgical excision is usually necessary for pain relief and functional movement re-covery [1].

Acknowledgements

All authors contributed equally, examined the patient, contributed to the acquisition and interpretation of data,

wrote or critically revised the article and approved the final version.

Funding: No specific funding was received from any fund-ing bodies in the public, commercial or not-for-profit sec-tors to carry out the work described in this manuscript. Disclosure statement: The authors have declared no conflicts of interest.

Clarissa de Queiroz Pimentel1, Leonardo

Santos Hoff1, Luiz Felipe Adsuara de Sousa1, Rafael

Alves Cordeiro1and Rosa Maria Rodrigues Pereira1

1_{Division of Rheumatology, University of Sao Paulo Medical}

School, Sao Paulo, State of Sao Paulo, Brazil

Correspondence to: Leonardo Santos Hoff, Universidade de Sa˜o Paulo, Faculdade de Medicina da Universidade de Sa˜o

Paulo, Av Dr Arnaldo, 455 3_{andar – sala 3131, 01246903,}

Cerqueira Cesar, Sa˜o Paulo, SP, Brasil.

E-mail: [email protected]

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FIG. 1 Multiple equal-sized calcified opacities within the knee; pathognomonic appearance for primary synovial osteochondromatosis