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CorrespondenceDiagnostic Relevance of Antibodies to Serotonin and Phospholipids in Fibromyalgia SyndromeTo the Editor: In their communication, Werle, et al reported that antibodies to serotonin can be detected in patients with fibromyalgia syndrome (FM) in a significantly higher incidence (20%) than in healthy controls (5%; p < 0.003); nevertheless they state that "antibodies against serotonin have no diagnostic relevance in patients with fibromyalgia syndrome"1. We do not agree with this interpretation, and would like to add further data. Indeed, in 1992, we reported that antibodies to serotonin could be detected in 74% of 50 FM patients2, and in 1994 we described for the first time the association of antiserotonin antibodies with antibodies to phospholipids. Among 100 FM patients 73% had antibodies to serotonin and 54% to phospholipids3. These patients had been followed in our outpatient department for 6-10 years (P.A. Berg), and several serum samples were available from these patients during that time. As mentioned by Werle, et al1, in the meantime several point analysis studies have been performed by us and other authors observing an incidence of antiserotonin antibodies in the range of 20-61% and of antiphospholipid antibodies in the range of 26-36%. To clarify these discrepancies with respect to our previous findings, we started another point analysis in 1997 in 72 additional patients seen in our outpatient department (R. Klein). The incidence of the antibodies to serotonin was low, reaching only 28% (Table 1). However, following these patients in a longitudinal study, i.e., testing sera at different time intervals during a period of 4 years, we observed that up to 58% have been found positive (unpublished observation). Therefore, one has to postulate that antibodies to serotonin in particular can fluctuate. Analyzing more than 200 controls, only 11-15% were found to be positive, and this was statistically significant compared to the patients with FM (p < 0.01).
Concerning the incidence of antiphospholipid antibodies (aPL), our previous finding3 was confirmed by the group in Heidelberg, who detected aPL in 43% of their patients with FM1. These observations are of interest with respect to a recent report demonstrating a hypercoagulable state in 92% of 54 patients with FM and chronic fatigue syndrome (CFS) similar to that in patients with antiphospholipid antibody syndrome4. Considering the concept that FM may belong to a wider syndrome, labelled "functional somatic syndrome"5, we tested, using a different approach, sera from patients with other disorders that have been attributed to this syndrome, such as CFS or irritable bowel disease. We also included patients with disorders representing single symptoms of FM such as depression, migraine, endometriosis, restless legs syndrome, or inner ear diseases (reference 6 and unpublished observations). Interestingly, also in these patients we found antibodies to serotonin in 25-68% and aPL in 25-50%. In contrast, in patients with inflammatory rheumatic disorders, the antibodies to serotonin were detected in only 11-15%2,6, and this frequency was similar to that in healthy individuals (Table 1). Taken together these data argue in favor of the diagnostic relevance of antibodies to serotonin and phospholipids. As for many autoantibody associated diseases, the triggering events responsible for these characteristic serological phenomena remain unknown. One explanation often discussed is molecular mimicry leading to the loss of tolerance towards autoantigens7. That FM and especially CFS can be precipitated also by infectious agents8 fits this concept. It is well documented that autoreactivity is a physiological condition9, and therefore it is not surprising that the FM associated antibodies are also found in healthy individuals, although at a low incidence. The concept of the existence of a physiological autoimmune reaction towards serotonin is substantiated by our recent finding that also autoreactive T lymphocytes recognizing tryptophan and serotonin can be detected in healthy individuals and in an enhanced incidence in FM patients10. It seems therefore most likely that the antibodies are part of the pool of naturally occurring antibodies, which are mainly involved in the first line defence to bacterial or viral infections or chemical xenobiotics9. Further, it is not at all unlikely that FM is a heterogeneous disease, and that the demonstration of autoantibodies may reflect a subgroup with a possible autoimmune origin. This would also explain variations in the incidence of FM associated antibodies reported by different authors. In any case, the observation of a defined group of antibodies in association with specific clinical manifestations is considered in many instances as an indicator for a particular autoimmune disorder10, and therefore there is no reason to reject the significantly increased antibodies to serotonin as diagnostically relevant for FM. REINHILD KLEIN, MD; PETER A. BERG, MD, PhD, Department of Internal Medicine II, University of Tübingen, Tübingen, Germany. REFERENCES 1. Werle E, Fischer HP, Muller A, Fiehn W, Eich W. Antibodies against serotonin have no diagnostic relevance in patients with fibromyalgia syndrome. J Rheumatol 2001;28:595-600. 2. Klein R, Bansch M, Berg PA. Clinical relevance of antibodies against serotonin and gangliosides in patients with primary fibromyalgia syndrome. Psychoneuroendocrinology 1992;17:593-8. 3. Klein R, Berg PA. A comparative study on autoantibodies to nucleoli and 5-hydroxytryptamine in patients with fibromyalgia syndrome and tryptophan-induced eosinophilia-myalgia syndrome. Clin Invest 1994;72:541-9. 4. Berg D, Berg LH, Couvaras J, Harrison H. Chronic fatigue syndrome and/or fibromyalgia as a variation of antiphospholipid antibody syndrome: an explanatory model and approach to laboratory diagnosis. Blood Coagul Fibrinolysis 1999;10:435-8. 5. Barsky AJ, Borus JF. Functional somatic syndromes. Ann Intern Med 1999;130:910-21. 6. Klein R, Berg PA. High incidence of antibodies to 5-hydroxytryptamine, gangliosides and phospholipids in patients with chronic fatigue and fibromyalgia syndrome and their relatives: evidence for a clinical entity of both disorders. Eur J Med Res 1995;1:21-6. 7. Naparstek Y, Plotz PH. The role of autoantibodies in autoimmune disease. Ann Rev Immunol 1993;11:79-104. 8. Goldenberg DL. Fibromyalgia and other chronic fatigue syndromes: Is there any evidence for chronic viral diseases? Semin Arthritis Rheum 1988;18:111-20. 9. Avrameas S, Ternynck T. Natural autoantibodies: the other side of the immune system. Res Immunol 1995;146:235-48. 10. Barth H, Klein R, Berg PA. L-tryptophan contamination "peak E" induces the release of IL-5 and IL-10 by peripheral blood mononuclear cells from patients with functional somatic syndromes. Clin Exp Immunol 2001;126:187-92. Drs. Werle, et al reply To the Editor: We appreciate the investigations of our colleagues Klein and Berg in the field of fibromyalgia (FM), and their sophisticated pathophysiological considerations. From our point of view, the results of the different studies cited in their letter are not contradictory; however, the interpretation and clinical conclusion are quite different and conflicting. The question we discussed in our paper1 was: What is the diagnostic power of antiserotonin antibodies? Is the detection of these autoantibodies clinically useful for decision making? Should we routinely measure these antibodies? How can these results influence the treatment of our patients? In their letter, Klein and Berg summarize that the prevalence of antiserotonin antibodies varies in a broad range of 20-61%. They state that this is due to a high level but considerable fluctuation of antiserotonin antibodies over time. A similar gap of antibody prevalence (25-68%) was observed by Klein and Berg in patients with other functional disorders. These data strengthen our opinion that a positive antiserotonin antibody test result has no clinical relevance for differential diagnosis of FM. These antibodies are not useful to discriminate patients from nonpatients in FM or to identify clinically relevant subgroups of FM patients, since there is no evidence that the variation of concentration of antiserotonin antibody over time is related to progression of symptom severity. The clinician has to decide on diagnosis and therapy, and antibody testing offers no help in this respect. Figure 1 illustrates the association of disease prevalence and the positive predictive value of antiserotonin antibodies for the diagnosis of FM based on a sensitivity of 20% and a specificity of 95% based on the data of our study. This plot demonstrates that, for example, at a prevalence of about 5%, which has been reported for females at an age of about 50 years2, the positive predictive value is 0.17. This means that only one of 5 positive test results is likely to indicate an FM patient, and vice versa 4 out of 5 positive results were received from non-FM subjects. At a given prevalence of 30%, which might occur only in very specialized outpatient clinics, the probability to obtain a positive test result in FM patients would still be only about 50%. Moreover the negative predictive value is not a useful criterion for decision making. 
Figure 1. Association of disease prevalence and positive predictive value (PPV) of antiserotonin antibodies for the diagnosis of FM based on sensitivity of 20% and specificity of 95%. At a prevalence of 0.05 the PPV is 0.17 (broken line).
However, the scientific question of why there are significant differences in autoantibody patterns between FM patients and normal controls needs further clarification. Prof. Dr. WOLFGANG EICH; Priv. Doz. Dr. EGON WERLE; Dipl. Psych. AUNETTE MÜLLER, Department of Internal Medicine II, University of Heidelberg, Heidelberg, Germany. REFERENCES 1. Werle E, Fischer HP, Muller A, Fiehn W, Eich W. Antibodies against serotonin have no diagnostic relevance in patients with fibromyalgia syndrome. J Rheumatol 2001;28:595-600. 2. Wolfe F, Ross K, Anderson J, Russell IJ, Hebert L. The prevalence and characteristics of fibromyalgia in the general population. Arthritis Rheum 1995;38:19-28.
Is Hypermobility a Factor in Fibromyalgia? To the Editor: I read with great interest the comments by Dr. Fitzcharles regarding hypermobility and its possible association with fibromyalgia1 (FM). Unfortunately, evaluation and documentation of hypermobility is difficult in uncomfortable patients with a tendency toward deconditioning and generalized muscle spasm from nonrestorative sleep. Beyond improving our ability to recognize hypermobility in this challenging patient subset, considering other associations with hypermobility may provide different insight into this question. Hypermobility is associated with specific, important mechanical stresses at the joints and entheses, often resulting in a presentation of migratory, nondeforming musculoskeletal pain in children and adults. Overuse syndromes, possibly more common due to altered local enthesopathic stresses during repetitive or transient microtrauma from joint hyperflexion and hyperextension under duress, may account for some of these presentations. "Repeated minor traumatic episodes" may be an important consideration and a treatment focus, but I suspect that a larger issue underlies the hypothesis that FM is associated with hypermobility. Evidence of altered autonomic function, whether primary or secondary, in patients with FM is building2,3. Also, the relevance of autonomic regulation4 as it relates to many maladies has not yet been fully explored. Hypermobility is associated with anxiety5, panic attack6, and unexplained chest pain, which may all be linked by dysregulation of autonomic function. Patients with FM often exhibit many stimulatory issues interfering with sleep quality, such as nighttime restlessness7, racing thoughts, and busy dreams. Options to decrease this nighttime restlessness with lorazepam, clonazepam8, and pramipexole9 in doses used for restless legs syndrome, all decreased FM pain scores, at least in preliminary open label analyses of 166-202 consecutive patients. Posttraumatic stress disorder commonly accompanies FM10, and may be another manifestation of excessive sympathetic tone. This fight-or-flight response should be expected to inhibit deep, restorative sleep through hypervigilance, i.e., a fundamental, primitive, survival mechanism. Why hypermobility would cluster with or be a marker for a tendency to have excessive sympathetic tone is unclear. If one believes that FM is an expected and predictable consequence of significant, persistent stage IV sleep disturbance, whether through torture or experimentally induced, then an effective inhibitor of deep sleep, such as excessive sympathetic tone, may be important. If so, it is interesting that hypermobility may simply be a musculoskeletal marker for a potential to develop autonomic dysregulation especially in the setting of intense or prolonged sympathetic/fight-or-flight stimuli. Hypermobility may be difficult to document, but understanding its implications as an important risk factor for more than local mechanical enthesopathic stress may provide meaningful insight into prevention and treatment of autonomically mediated gastrointestinal, cardiac, psychiatric, and musculoskeletal disorders. ANDREW J. HOLMAN, MD, Clinical Assistant Professor of Medicine, Division of Rheumatology, University of Washington, Private Practice, Valley Medical Center, Renton, Washington, USA REFERENCES 1. Fitzcharles M. Is hypermobility a factor in fibromyalgia? J Rheumatol 2000;27:1587-8. 2. Raj SR, Brouillard D, Simpson CS, Hopman WM, Abdollah H. Dysautonomia among patients with fibromyalgia: a noninvasive assessment. J Rheumatol 2000;27:2660-5. 3. Martinez-Lavin M, Hermosillo AG, Rosas M, Soto ME. Circadian studies of autonomic nervous balance in patients with fibromyalgia: a heart variability analysis. Arthritis Rheum 1998;41:1966-71. 4. Coghlan H, Natello G. Erythrocyte magnesium in symptomatic patients with primary mitral valve prolapse: relationship to symptoms, mitral valve leaflet thickness, joint hypermobility and autonomic regulation. Magnes Trace Elem 1991;10:205-14. 5. Bulbena A, Duro J, Porta M, et al. Anxiety disorders in the joint hypermobility syndrome. Psychiatry Res 1993;46:59-68. 6. Martin-Santos R, Bulbena A, Porta M, Gago J, Molina L, Duro J. Association between joint hypermobility syndrome and panic disorder. Am J Psychiatry 1998;155:1578-83. 7. Yunus M, Aldag J. Restless legs syndrome and leg cramps in fibromyalgia syndrome: a controlled study. BMJ 1996;312:1339. 8. Holman AJ. Safety and efficacy of lorazepam for fibromyalgia after one year [abstract]. Arthritis Rheum 1999;42 Suppl:S152. 9. Holman AJ. Safety and efficacy of the dopamine agonist, pramipexole, on pain score for refractory fibromyalgia [abstract]. Arthritis Rheum 2000;43 Suppl;S333. 10. Culclasure T, Enzenauer R, West S. Post-traumatic stress disorder presenting as fibromyalgia. Am J Med 1993;94:548-9. Dr. Fitzcharles replies To the Editor: Dr. Holman's interesting comments regarding fibromyalgia (FM), hypermobility, and recent findings indicating altered autonomic function in this group of patients are appreciated. We agree with Dr. Holman that the role of the central nervous system (CNS) is increasingly recognized in FM. The focus towards dysregulation of central pain processing mechanisms, including changes in autonomic function, is seemingly more plausible in the light of recent research1. The puzzling mechanisms of function of the CNS are slowly becoming clearer as variables such as autonomic function, levels of neuromodulators, and even changes in cerebral blood flow are now measurable. The findings of autonomic dysregulation in illnesses not manifesting prominent chronic pain such as severe liver disease2, Parkinson's disease3, and postmyocardial infarction4, as well as other conditions commonly associated with pain such as irritable bowel syndrome5, chronic headaches6, and recently FM7 calls into question the precise role of the autonomic nervous system in pain perception and expression. We do not yet know whether these observations represent simply an associated finding or have influence upon the expression of the condition. We should therefore exercise caution in not too readily attributing a single factor such as autonomic dysfunction as a cause of pain in FM. Our current understanding of FM suggests that multiple factors are likely operative. To date, there are two measurements that appear to show consistent abnormality: abnormalities of substance P in the cerebral spinal fluid and reduction of thalamic regional blood flow as measured by resting single photon emission computed tomography (SPECT) brain scan, with precise anatomical localization by superimposition of magnetic resonance imaging (MRI) scan8,9. Autonomic dysregulation likely represents some component of this central pain mechanism, and further study is needed to clarify the importance of this finding. The sleep disturbance in FM is also perplexing. Great hopes were held for the effect of the tricyclic antidepressants on the sleep disorder in FM and therefore relief of symptoms. The modification of the sleep abnormality has, however, not proved successful in relieving the symptoms of pain in the majority of patients with FM, and these agents are often discontinued by patients over time. In addition, FM was found to occur at the same rate as in population studies when patients attending a sleep disorders clinic were examined, suggesting that sleep disturbance alone is not a major factor in the expression of FM10. The notion of hypermobility associating with panic disorders and anxiety is intriguing and difficult to understand. The studies from Barcelona have described a strong association of hypermobility in patients with anxiety disorders, and also a high rate of anxiety disorder in rheumatology patients exhibiting hypermobility11,12. These findings from a single tertiary care center require confirmation in other patient populations. The association between physical changes of connective tissue and disordered psychological status defies our current understanding. We have, however, learned that the psyche does have important influence upon physical manifestations in humans, such as stress induced bronchospastic disease or possibly even the diffuse pain of FM. Needless to say there are likely many compounding factors influencing the expression of FM. Among the numerous factors being explored, physical changes such as hypermobility, neuroendocrine abnormalities, the effect of previous pain experience, overall deconditioning, and possibly even some genetic components are currently in vogue. The exact role of each of these factors may soon be elucidated. MARY-ANN FITZCHARLES, MB, ChB, FRCPC, Montreal General Hospital, Division of Rheumatology, and McGill Pain Centre, 1650 Cedar Avenue, Montreal, Quebec H3G 1A4, Canada. REFERENCES 1. Russell IJ. Is fibromyalgia a distinct clinical entity? The clinical investigator's evidence. Baillieres Best Pract Res Clin Rheumatol 1999;13:445-54. 2. Barron HV, Alam I, Lesh MD, Strunk A, Bass NM. Autonomic nervous system tone measured by baroreflex sensitivity is depressed in patients with end-stage liver disease. Am J Gastroenterol 1999;94:986-9. 3. Sandyk R, Awerbuch GI. Dysautonomia in Parkinson's disease: relationship to motor disability. Int J Neurosci 1992;64:23-31. 4. Pitzalis MV, Iacoviello M, Todarello O, et al. Depression but not anxiety influences the autonomic control of heart rate after myocardial infarction. Am Heart J 2001;141:765-71. 5. Heitkemper M, Jarrett M, Cain KC, et al. Autonomic nervous system function in women with irritable bowel syndrome. Dig Dis Sci 2001;46;1276-84. 6. Sliwka U, Harscher S, Diehl RR, van Schayck R, Niesen WD, Weiller C. Spontaneous oscillations in cerebral blood flow velocity give evidence of different autonomic dysfunctions in various types of headache. Headache 2001;41:157-63. 7. Buskila D. Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol 2001;13:117-27. 8. Russell IJ, Orr MD, Littman B, et al. Elevated cerebrospinal fluid levels of substance P in patients with the fibromyalgia syndrome. Arthritis Rheum 1994;37:1593-601. 9. Kwiatek R, Barnden L, Tedman R, et al. Regional cerebral blood flow in fibromyalgia: single-photon-emission computed tomography evidence of reduction in the pontine tegmentum and thalami. Arthritis Rheum 2000;43:2823-33. 10. Donald F, Esdaile JM, Kimoff JR, Fitzcharles MA. Musculoskeletal complaints and fibromyalgia in patients attending a respiratory sleep disorders clinic. J Rheumatol 1996;23:1612-6. 11. Martin-Santos R, Bulbena A, Porta M, Gago J, Molina L, Duro JC. Association between joint hypermobility syndrome and panic disorder. Am J Psychiatry 1998;155:1578-83. 12. Bulbena A, Duro JC, Porta M, et al. Anxiety disorders in the joint hypermobility syndrome. Psych Res 1993;46:59-68.
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