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Is Joint Hypermobility Related to Anxiety in a Nonclinical Population Also?

Received July 10, 2003; revision received Jan. 13, 2004; accepted Jan. 30, 2004. From the Department of Psychiatry, Hospital del Mar, Barcelona; the Department of Epidemiology, Institut Municipal Investigació Mèdica, Barcelona; and the Centre de Salut Sant Pere de Riudebitlles, Barcelona. Address reprint requests to Dr. Bulbena, Institut Atenció Psiquiatrica, Universitat Autonoma Barcelona, Hospital del Mar, Paseo Marítimo 25–29, E-08003 Barcelona, Spain; abulbena{at}acmcb.es (e-mail).

ABSTRACT

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This study examines the association between joint hypermobility syndrome and anxiety in a nonclinical sample. Subjects (N=526) receiving a medical check-up were assessed with the Hospital del Mar hypermobility criteria and the State-Trait Anxiety Inventory. Scores for trait anxiety, and to a lesser extent state anxiety, were significantly higher among subjects with joint hypermobility syndrome than among subjects without this syndrome (median trait anxiety scores for women: 17 versus 11; median scores for men: 13 versus 1). These findings indicate that the association of joint hypermobility syndrome and anxiety holds even for subjects with no psychiatric diagnosis. Therefore, it seems that this benign connective tissue disorder is a predisposing factor for trait anxiety. However, it is necessary to further explore and define the biological basis of this syndrome, as well as its associations and clinical expressions, which interact with great complexity.

INTRODUCTION

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Several studies have shown a strong association between panic disorder/agoraphobia and joint laxity or joint hypermobility syndrome, a benign heritable disease of the connective tissue.^1,2 An interstitial duplication of human chromosome 15 (named DUP 25) has been identified as responsible for this association, confirming the heritability (although not strictly Mendelian) of these conditions and supporting a common biological cause.³

Joint hypermobility syndrome has an estimated prevalence of 10%–15% in the general population and is more common in women than in men (3:1). It is clinically characterized by an increased distensibility of joints in passive movements and hypermobility in active movements. Although joint hypermobility syndrome often goes unnoticed, affected individuals may suffer from repeated injuries of the musculoskeletal system. The higher incidence of mitral valve prolapse in patients with joint hypermobility is another known extra-articular association. Asthenic somatotype has been related as well, showing a higher rate in patients with panic disorder and agoraphobia than in psychiatric or medical comparison subjects.⁴

Joint hypermobility syndrome requires definite clinical criteria for its diagnosis. The most recognized scale is the well-established 9-point scoring system of Beighton et al.⁵ In 1992 the Hospital del Mar criteria for hypermobility were developed by assembling all of the items included in the Beighton,⁵ Carter and Wilkinson,⁶ and Rotés⁷ criteria, which were the most often used in clinical settings. Cluster analysis of all items in the three scoring systems was performed and studied for the elaboration of the Hospital del Mar 10-point scoring system.⁸ The new scale thus obtained showed very robust indicators of reliability, internal consistency, and predictive validity, which, incidentally, were never studied in the older scales. It also provides evidence supporting the use of different cutoff points for males and females, which results in greater suitability for the detection of joint laxity in males particularly.⁸ This reduces the rate of false negatives in the assessment of the syndrome, especially for males, who are considered hypermobile at a lower score than are females. Moreover, the results of the validation of the Hospital del Mar criteria indicate that it is suitable for use not only in screening studies but also in clinical rheumatologic settings.⁸

Grahame et al. suggested new criteria that include joint symptoms and extra-articular symptoms for a better definition of the syndrome. Grahame et al. also proposed different cutoffs for different ages as well. However, the reliability and validity studies have not yet been concluded.⁹

Finally, in light of new genetic research, clinical psychiatry will attain new clinical phenotypes that will include both psychiatric characteristics (panic disorder, agoraphobia, and social phobia) and biological information, such as the joint hypermobility syndrome and its association with the DUP 25 alteration, which may clarify predisposing factors for anxiety.^3,10

A previous study of rheumatologic outpatients showed that subjects with joint hypermobility syndrome have a greater lifetime risk of suffering from some type of anxiety disorder (in particular, panic disorder, agoraphobia, and simple phobia) than do rheumatologic comparison subjects (rheumatologic outpatients without joint hypermobility); the age- and sex-adjusted odds ratio was 10.7, and the 95% confidence interval (CI) was 4.8–23.8.¹¹ Furthermore, subjects with joint hypermobility syndrome and mitral valve prolapse appeared to be three times as likely to suffer from anxiety disorders as were subjects with joint hypermobility without mitral valve prolapse.

Conversely, in a psychiatric population, when patients with panic disorder and/or agoraphobia were compared with age- and sex-matched psychiatric and medical comparison subjects, joint hypermobility syndrome was found in 67.7% of the patients with anxiety disorder but in only 10.1% of the psychiatric and 12.5% of the medical comparison subjects.¹² Moreover, the patients with anxiety disorder were more likely to have joint hypermobility syndrome than both groups of comparison subjects (odds ratio=16.9, 95% CI=8.8–32.2). Nevertheless, no significant differences were found in the prevalence of mitral valve prolapse between the patients with anxiety disorder and the comparison subjects.

It seems clear that joint hypermobility syndrome is associated with anxiety disorders, mainly panic and agoraphobia, but it is still unknown whether subjects with joint hypermobility syndrome who have no clinical criteria for these psychiatric conditions are also more likely to suffer from anxiety than subjects without joint hypermobility. Therefore, the main aim of this study was to assess whether the relationship between joint hypermobility syndrome and anxiety (trait and state anxiety in this case) holds in a group of nonclinical subjects.

METHOD

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The study was carried out at the medical department of a large audit consultant and legal services company in Barcelona, Spain, that periodically examines all workers in the company during a routine medical checkup. All subjects who attended the medical office consecutively over 4 months were admitted to the study. Informed consent was obtained after the study had been fully explained to all patients. Patients suffering from joint conditions that could hamper the examination for joint hypermobility were excluded. Patients suffering from anxiety disorders and those treated with antianxiety drugs were excluded as well.

All subjects were interviewed and examined by the occupational physician, who was especially trained in the assessment of the criteria for hypermobility of Beighton et al.⁵ and the Hospital del Mar.⁸ Both scoring systems were used in the assessment of joint hypermobility syndrome in order to find the maximum number of cases. However, in light of their high correlation (rho=0.9) and the similarity of the results, those obtained by using the Beighton criteria have not been included.

The Beighton system includes five criteria describing nine maneuvers to explore the degree of joint mobility. The scores range from 0 to 9 and depend on the degree of movement. The Hospital del Mar system consists of 10 criteria, each scoring 1 point, that describe the degree of joint movements (Appendix 1).

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APPENDIX 1. Hospital del Mar Criteria for the Clinical Assessment of Joint Hypermobility

In both systems, joint hypermobility syndrome is determined by different cutoff scores. This is due to the fact that there is no gold standard to define hypermobility. The choice of a cutoff point to determine whether or not a person meets the criteria for a case of hypermobility according to any scale can be arbitrarily made on clinical grounds. When previous studies applied any of the three scoring systems—Beighton et al.,⁵ Carter and Wilkinson,⁶ or Rotés⁷—to determine which subjects met the criteria for a case, the cutoff decision was made on the basis of the author's opinion, the target group, and the difficulty of the procedure. We proposed cutoff points after applying multivariate techniques.⁸ These cutoffs were 3/4 scores (3 indicating a noncase, 4 or higher indicating a case) for males and 4/5 for females to determine joint hypermobility.

The interrater reliability (kappa) for agreement between the medical researcher and the standard rheumatologist for the joint hypermobility items ranged between 0.68 and 1.00. The medical examination also included a variety of measures such as weight, height, blood pressure, and general blood tests.

Before knowing their joint mobility status, all subjects were asked to complete the Spanish version of the self-rated Spielberger State-Trait Anxiety Inventory (STAI) in order to assess their anxiety levels.¹³

Nonparametric statistics (Spearman's rho and Mann-Whitney z) were chosen, since a normal distribution has not been clearly established for joint laxity measurements.

RESULTS

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A total of 553 individuals attended the medical office to receive a medical checkup during 4 consecutive months. Twenty-seven subjects (4.9%) met the exclusion criteria: eight (1.4%) had traumatic osteoarticular conditions that made joint examination difficult and unreliable, 10 (1.8%) were receiving treatment for different anxiety conditions, four (0.7%) undiagnosed subjects were found to suffer from simple phobias and were referred to a psychiatrist, and finally, five (0.9%) subjects were not clearly suffering at that time from anxiety features but were taking 10 mg/day or more of diazepam.

The final sample included 526 subjects, 323 (61.4%) men and 203 (38.6%) women, with mean ages of 25.2 years (SD=2.9) and 25.6 years (SD=3.2), respectively. No subject refused to participate. Most (93.7%) had received higher education (lawyers, economists, business consultants, etc.), whereas the rest were administrative workers.

The median score for trait anxiety, assessed with the STAI, was 12 (interquartile range=10), with significant sex differences: 11 (interquartile range=9) in men and 14 (interquartile range=12) in women (Mann-Whitney z=3.85, p<0.0001). The median state anxiety score was 11 (interquartile range=7), with no significant sex differences. The median score for joint hypermobility according to the Hospital del Mar criteria (range 0–10) also differed significantly between the sexes: it was 1 (interquartile range=2) for men and 3 (interquartile range=4) for women (Mann-Whitney z=11.19, p<0.0001).

Both trait and state anxiety showed modest but significant correlations with joint hypermobility. The trait anxiety score correlated with the Hospital del Mar laxity score (r_s=0.16, N=526, p=0.0002). State anxiety also showed a minor, but significant, positive correlation with joint laxity (r_s=0.10, N=526, p=0.01). Similar results were obtained for both men (r_s=0.14, p=0.05 for trait anxiety and r_s=0.08, p=0.22 for state anxiety, N=323) and women (r_s=0.11, p=0.07 for trait anxiety and r_s=0.13, p=0.02 for state anxiety, N=203).

The prevalence of joint laxity varied according to the cutoff point applied. It was 31.6% when the 2/3 Hospital del Mar cutoff point was used (53.7% for women and 17.6% for men), 21.1% with the 3/4 Hospital del Mar cutoff point (43.3% for women and 7.1% for men), and 10.6% with the 4/5 Hospital del Mar cutoff point (26.6% for women and 0.6% for men). Since the Hospital del Mar criteria suggest that different cutoff points for men and women facilitate more accurate detection, 4/5 was chosen for women and 2/3 for men in order to identify the most index cases.

In the comparisons of state and trait anxiety in the groups with and without hypermobility, significant results emerged. Hypermobile women showed significantly higher trait anxiety than did nonhypermobile women (median scores=17 and 11, respectively; z=3.33, p=0.0008). The difference in state anxiety was not significant (13 versus 12; z=1.08, p=0.30). Among the men, hypermobile subjects also showed significantly higher trait anxiety scores (median=13) than nonhypermobile men (median=11) (z=2.22, p=0.03), whereas the difference in median state anxiety scores (12 versus 11, respectively) was not achieved (z=1.94, p=0.053). Pooled data for both sexes gave a significant difference for trait anxiety (z=4.07, p<0.0001) (Figure 1) but not for state anxiety. A general trend toward higher scores on trait anxiety among the subjects with joint hypermobility than among those without hypermobility was found at different cutoff points of the Hospital del Mar hypermobility scale (Figure 2).

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FIGURE 1.  Trait Anxiety in Nonclinical Subjects With or Without Joint Hypermobility According to the Hospital del Mar Criteria aThick black lines are medians. Boxes are interquartile ranges. Error bars are standard deviations.

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FIGURE 2.  Trait Anxiety in 203 Women With or Without Joint Hypermobility According to All Possible Cutoff Scores on the Hospital Del Mar Hypermobility Criteria

DISCUSSION

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To our knowledge, this is the first report on the relation between joint hypermobility and anxiety in subjects not diagnosed with any anxiety disorder. Correlations of joint laxity with trait anxiety were significant, and so were correlations between joint laxity and state anxiety, but to a lesser extent. However, the magnitude of these correlations is very low, which may be due to the unlikely linear relation between the two groups of variables. In other words, the relation between scores for joint hypermobility syndrome and anxiety might not be strictly linear. Therefore, a categorical approach (hypermobile subjects versus nonhypermobile subjects) was applied to further analyze the association. Compared with nonhypermobile subjects, those with joint laxity (even when different cutoff points were used) always had higher trait anxiety scores, although, as previously stated, differences in state anxiety were slightly less significant, a finding that may be expected in nonclinical subjects.

Some methodological limitations of the study deserve comment. First, no structured psychiatric interview was applied to the subjects, and therefore, the final sample might still contain people suffering from panic, either undetected or simply hidden. To control for such bias, all subjects declaring anxiety conditions or receiving active treatment were excluded; they constituted 3.4% of the original sample (19 of 553). This figure is similar to the 3%–6% described in the literature.^14,15 It seems unlikely, however, that a significant number of subjects with undiagnosed anxiety would still remain in the sample. Second, anxiety was measured by a self-applied questionnaire, which by its nature was subjective; however, this situation was identical for the subjects with and without joint hypermobility syndrome. Furthermore, the sample was highly educated, which makes misunderstanding of the STAI very unlikely. Finally, the subjects were unaware of their joint status when they filled out the questionnaire. Training for assessment of joint hypermobility syndrome was very strict, and the study did not commence until item kappa values were at least 0.6.

It is widely accepted that the STAI is a good questionnaire to measure trait anxiety. Some authors have proposed the Anxiety Sensitivity Index¹⁶ or the Social Interaction Anxiety Scale,¹⁷ both self-applied questionnaires, as good predictors of anxious response to a social challenge. However, Sandin et al. have found empirical evidence related to differentiation between the constructs of anxiety sensitivity and trait anxiety.¹⁸

There is evidence that joint hypermobility syndrome and panic are both heritable conditions and that there is a genetic link between them. However, subclinical anxiety assessed by questionnaire scores for anxiety, as used in this study, has no clear nosological status; therefore, it is remarkable that the results found in this study are similar to those obtained in the clinical population. Several hypotheses may explain these findings. First, it is possible that most hypermobile people are potentially unnoticed anxiety subjects who might later develop clinical panic or some minor form, such as nonfearful panic. This explanation would be consistent with the more recent genetic findings.³ However, the age at onset of panic disorder is lower than the mean age of our study sample, and from epidemiological studies it is also known that not all hypermobile subjects develop panic or agoraphobia.² Second, people with hypermobility may include many with "nonclinical panic"¹⁹: although they suffer real but nonsevere panic, they never seek treatment. Here, too, genetic findings could explain the association, but then this would allow the presence of subclinical panic; thus, subjects with hypermobility would be more vulnerable to anxiety episodes, but only severe or idiosyncratic forms would reach the level of disease. Third, a dimensional model could explain the relationship: joint hypermobility syndrome could be linked to innate forms of excessive response to fear^20,21 or behavioral inhibition²² that, along with rearing factors, would develop as symptoms at different degrees of severity. Contrary to this is evidence that the experience of extreme fear is different from panic,²³ and therefore a simple continuum is unclear. If subjects with joint hypermobility syndrome are more anxious than those without joint hypermobility, then new biological cues for fear, conditioning, and panic could be pursued and integrative models for fear (innate versus acquired) and anxiety might be built.

In conclusion, the clinical association between some anxiety disorders and a collagen condition has been replicated in a nonclinical sample by means of a common measure of trait anxiety. This might be a step toward a better understanding of the biological basis of anxiety and warrants further research on its genetic component.

REFERENCES

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