Reaction Time in Fibromyalgia Patients.

BACKGROUND: Fibromyalgia has unknown aetiology and is associated with reduced information processing speed and therefore prolonged reaction time. However, the processes underlying this are unknown. OBJECTIVES: First, to compare the reaction time in a cohort of fibromyalgia patients and a matched group of normal controls. Second, to assess whether detailed symptoms of pain and autonomic function, as well as measures of tinnitus, fatigue, daytime sleepiness and Mycoplasma pneumoniae infection are predictors of reaction time in fibromyalgia. METHODS: The between-groups mean serial five-choice reaction time difference was assessed in a cohort of fibromyalgia patients and in a matched group of normal controls in an analytical casecontrolled study. With the mean serial five-choice reaction time as the dependent variable for the fibromyalgia group, a mixed stepwise multiple linear regression was performed with inputs relating to pain, dysautonomia, tinnitus, fatigue, daytime sleepiness and Mycoplasma pneumoniae infection. RESULTS: The mean (standard error) serial five-choice reaction time for the fibromyalgia group was 448.4 (23.0) ms, compared with 386.3 (8.3) ms for the control group (p = 0.007). The final multiple linear regression model (p < 0.001; adjusted R2 = 0.772) contained 13 predictors: eight sensory pain and three affective pain parameters, and Mycoplasma pneumoniae IgG and IgA assay results. CONCLUSION: Certain sensory and affective pain parameters, as well as Mycoplasma pneumoniae infection, appear to be predictors of reaction time in fibromyalgia. Further research into the pathophysiological mechanisms by which they affect information processing is warranted and may shed light on the aetiology of fibromyalgia.

T Lymphocyte Interferon-gamma Response to Anaplasmataceae-related Major Surface Proteins and Ankyrin A in Fibromyalgia.

BACKGROUND: The aetiology of fibromyalgia is unknown; its symptoms may be related to a T-lymphocyte-mediated response to infectious organisms. OBJECTIVES: First, to test the hypothesis that fibromyalgia is associated with increased interferon (IFN)-γ-secreting T-lymphocytes after stimulation with Anaplasmataceae-related major surface proteins (MSFs) and the macromolecular translocation type IV secretion system effector ankyrin repeat domain-containing protein A (AnkA). Second, to ascertain the relationship in fibromyalgia between (i) the IFN-γ-secreting T-lymphocyte response to stimulation with Anaplasmataceae-related MSFs and AnkA, and (ii) co-infection by Borrelia and Yersinia spp., and antinuclear antibodies. METHODS: Using a case-control design, patients fulfilling the American College of Rheumatology revised criteria for fibromyalgia, and controls, underwent the following blinded assessments: (i) enzyme- linked immune absorbent spot (ELISpot) IFN-γ release assay of T-lymphocyte reactivity to Anaplasmataceae-related MSFs and AnkA; (ii) ELISpot IFN-γ release assays of T-lymphocyte reactivity to three Borrelia antigens, namely Borrelia burgdorferi full antigen (B31); peptide mix (from Borrelia burgdorferi sensu stricto, Borrelia afzelii, Borrelia garinii); and Borrelia burgdorferi lymphocyte function-associated antigen-1; (iii) immunoglobulin (Ig) A assay by enzyme-linked immunosorbent assay (ELISA) of antibodies to Yersinia spp.; (iv) IgG (ELISA) antibodies to Yersinia spp.; (v) serum antinuclear antibodies (immunofluorescence). RESULTS: The groups were age- and sex-matched. The mean (standard error) value of IFN-γ release for the fibromyalgia group was 1.52 (0.26), compared with 1.00 (0.22) for the controls. Generalised linear modelling (p<0.001) of IFN-γ release in the fibromyalgia patients showed significant main effects of all three indices of Borrelia infection and of antinuclear antibodies. CONCLUSION: Anaplasmataceae may play an aetiological role in fibromyalgia.

The Principal Components of Autonomic Dysfunction in Fibromyalgia Assessed by the Refined and Abbreviated Composite Autonomic Symptom Score.

BACKGROUND: We have recently confirmed that non-pain autonomic dysfunction symptoms occur in fibromyalgia and can be assessed with the 31-item Composite Autonomic Symptom Score (COMPASS 31) instrument. Fibromyalgia patients have been found to have higher scores than matched controls across all six domains of this instrument. OBJECTIVES: To analyse the principal components of the autonomic COMPASS 31 domain scores in fibromyalgia patients to understand better the fundamental dimensions of dysautonomia in this disorder. METHODS: A principal component analysis of fibromyalgia autonomic domain scores was carried out using a varimax orthogonal rotation with decomposition being based on the correlation matrix and setting a threshold of greater than one for the eigenvalues. RESULTS: Three mutually orthogonal principal components, accounting for over 80% of the total variance, were identified. The first was a function of the secretomotor, orthostatic intolerance and pupillomotor domains; the second was a function of the vasomotor and urinary bladder domains; and the third was a function of the gastrointestinal and orthostatic intolerance domains. There was a positive correlation between symptom domain scores of the Revised Fibromyalgia Impact Questionnaire and the first principal component scores (rs = 0.536, p = 0.006). CONCLUSION: This analysis has reduced the dimensionality of autonomic dysfunction in fibromyalgia patients from six to three. The internal structure of the fibromyalgia dysautonomia data reflected by these results may help in the elucidation of the aetiology of this complex and difficult-to-treat disorder.

Antinuclear Antibody Seropositivity in Fibromyalgia Associated with Borrelia-specific T Lymphocytes.

BACKGROUND: Our group have recently reported that there is no evidence of an association between fibromyalgia and Borrelia-specific T lymphocytes. However, a small number of case reports has suggested that infection by the bacterial genus Borrelia may be associated with the presence of antinuclear antibodies (ANAs). OBJECTIVE: To test the hypothesis that those fibromyalgia patients who are ANA seropositive are more likely to show evidence of Borrelia-specific T lymphocyte reactivity than those who are seronegative. METHODS: T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) was assessed using the enzyme-linked immunospot and serum ANA status was assessed using immunofluorescence in 27 fibromyalgia patients fulfilling the revised diagnostic criteria of the American College of Rheumatology. RESULTS: The ANA seropositive and seronegative groups were matched for age, sex and ethnicity; the T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) in the former group (mean 5.60) was significantly higher than that in the seronegative group (mean 1.77; p < 0.05). CONCLUSION: This novel study points to an association of ANA seropositivity in fibromyalgia with Borrelia-specific T lymphocytes.

The Role of Chlamydia pneumoniae in the Aetiology of Autoimmune Diseases.

Introduction The most prevalent chronic human autoimmune disorder worldwide is rheumatoid arthritis. Synovial samples from acute-phase patients are polymerase chain reaction-positive for Chlamydia pneumoniae (C. pneumoniae) DNA and express chlamydial hsp60. Furthermore, anti-cyclic citrullinated peptide (anti-CCP) antibodies promote apoptosis of mature human Saos-2 osteoblasts via cell surface binding to citrullinated heat shock protein 60 (HSP60). Hence, we hypothesised that C. pneumoniae infection is associated with anti-CCP antibodies. Methods C. pneumoniae IgA and anti-CCP antibody levels were determined in 26 healthy subjects in this cross-sectional study. Serum C. pneumoniae IgA antibody levels were assessed using an enzyme-linked immunosorbent assay. Serum anti-CCP antibody levels were assessed using fluoroenzymeimmunoassay. Results There was a highly significant positive correlation between the two sets of antibodies (rs = 0.621; P = 0.0007). Linear regression analysis showed that this correlation was not the result of age or sex. Discussion A biologically plausible mechanism is put forward for these results, involving HSP60 acting as an endogenous ligand for toll-like receptor 4 (TLR4) and the interaction of TLR4 with lipopolysaccharides, which occur in the outer membrane of the C. pneumoniae elementary body. Pronounced pro-inflammatory mediator secretion then takes place. The release of Ca2+ ions may then activate local peptidylarginine deiminases, leading to the formation of CCPs and thus the reported finding. Confirmation of these results may have potential clinical implications in terms of diagnosis, including pre-symptomatic diagnosis, and treatment.

Association between Cardiac Atrioventricular Conduction and Antibodies to Chlamydia Pneumoniae in Fibromyalgia Patients.

BACKGROUND: Fibromyalgia patients may complain of cardiovascular symptoms, including chest pain and palpitations. It has been proposed that infection by Chlamydia pneumoniae might be common in fibromyalgia. Chlamydia pneumoniae infection has also been hypothesized to be a causative factor in cardiac disease. OBJECTIVE: This study aims to test the hypothesis that there is an association between atrioventricular conduction and antibodies to Chlamydia pneumoniae in fibromyalgia. METHODS: Thirteen female fibromyalgia patients underwent serum Chlamydia pneumoniae IgG assays and 12-lead electrocardiography in a cross-sectional study. None of the patients was taking medication which might affect atrioventricular conduction, and none suffered from hypothyroidism, renal disease, hepatic disease, or carotid hypersensitivity. RESULTS: There was a significant positive correlation between the PR interval duration and the serum Chlamydia pneumoniae IgG level (r = 0.650; p = 0.016). CONCLUSION: This study supports the hypothesis of an association between atrioventricular conduction and antibodies to Chlamydia pneumoniae in fibromyalgia patients. It suggests that the higher the level of such antibodies, the greater the electrocardiographic PR interval, and therefore the slower the atrioventricular conduction. Potential pathophysiological mechanisms include a chronic inflammatory response to Chlamydia pneumoniae and the action of the bacterial lipopolysaccharide. The latter may involve stimulators of interferon genes, activation of the cardiac NOD-like receptor protein 3 inflammasomes, and downregulation of fibroblast growth factor 5 in the heart.

Major Histocompatibility Complex Class II HLA-DRB1 Allelic Epitopes in Fibromyalgia.

BACKGROUND: Preliminary evidence has pointed an association of the gene HLA-DRB1 with fibromyalgia. HLA-DRB1 alleles carrying the shared or susceptibility epitope encoding the five-amino acid motif QKRAA, QRRAA or RRRAA in positions 70 to 74 of the major histocompatibility complex class II DRß chain are associated with several autoimmune diseases. OBJECTIVE: The objective of this study was to test the hypothesis that susceptibility epitope-encoding HLA-DRB1 alleles are associated with fibromyalgia. METHODS: Using a case-control design, the prevalence of susceptibility epitope-encoding HLADRB1 alleles in 27 white Caucasian patients fulfilling the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology was compared with that in 27 white Caucasian ageand sex-matched healthy controls. RESULTS: 13 (48%) of the fibromyalgia patients had susceptibility epitope-coding HLA-DRB1 alleles compared with 15 (56%) of the controls (P = 0.785). The DRB1*01 allele encoding the protective epitope 70-DERAA-74 motif was found in one of the control subjects; none of the fibromyalgia patients had such a protective epitope. CONCLUSION: While the present study does not provide evidence supporting the potential role of HLA-DRB1 in the etiology of fibromyalgia, it does not exclude the possibility that there is a polygenic component to a putative genetic causative role.

Is Fibromyalgia Associated with Borrelia-specific T Lymphocytes?

BACKGROUND: Although fibromyalgia is a common cause of chronic musculoskeletal pain, its aetiology and pathophysiology are uncertain. It has recently been suggested that fibromyalgia symptomatology represents a T lymphocyte-mediated immune response to pathogens, which are known risk factors for autoimmune diseases. One major suggested candidate pathogen is the bacterial genus Borrelia. However, to date, this hypothesis has not been tested. OBJECTIVE: The aim was to carry out the first test of this hypothesis by comparing Borrelia-specific T lymphocyte reactivity in fibromyalgia patients and matched controls. METHODS: The enzyme-linked immunospot assay was used to detect T-lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen), outer surface protein (Osp) A from Borrelia burgdorferi sensu stricto, Borrelia afzelii and Borrelia garinii, native OspC plus decorin binding protein A recombinant and lymphocyte function antigen-1 (shared epitope) in 27 patients who fulfilled the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology and in 26 control subjects. The assays were carried out blind to the group status of the participants. RESULTS: The two groups did not differ by age, sex or ethnicity. They did not differ significantly in respect of T lymphocyte reactivity to Borrelia burgdorferi sensu stricto (full antigen) (p = 0.847), Osp mix (p = 0.709) or lymphocyte function antigen-1 (p = 0.367). CONCLUSION: This novel controlled study provides no evidence of an association between fibromyalgia and Borrelia-specific T lymphocytes.

Clinical Assessment of Autonomic Function in Fibromyalgia by the Refined and Abbreviated Composite Autonomic Symptom Score (COMPASS 31): A Case-Controlled Study.

BACKGROUND: It has been shown that autonomic dysfunction in fibromyalgia can be assessed by the Composite Autonomic Symptom Score (COMPASS) questionnaire. More recently, a refined and much abbreviated 31-item version of the questionnaire has been developed, the COMPASS 31. OBJECTIVES: First, to determine whether the COMPASS 31 can assess changes in autonomic function in fibromyalgia. Second, to assess whether the COMPASS 31 values in fibromyalgia patients are positively correlated with scores on the Revised Fibromyalgia Impact Questionnaire (FIQR). METHODS: A cross-sectional, case-controlled study was carried out with 25 fibromyalgia patients and 26 healthy controls. RESULTS: The two groups were matched for age, sex and ethnicity, but not for body mass index (BMI). The total mean (standard error) COMPASS 31 for the fibromyalgia patients, 37.2 (1.8), differentiated the patients from the controls (9.5 (1.4); p < 0.00000001). The scores were greater in the fibromyalgia patients across all COMPASS 31 autonomic domains, namely orthostatic intolerance (p < 0.00000001), and vasomotor (p < 0.0001), secretomotor (p < 0.000001), gastrointestinal (p < 0.000001), bladder (p < 0.00001) and pupillomotor functions (p < 0.00000001). The total COMPASS 31 values were positively correlated with FIQR scores (rs = 0.45, p < 0.05). General linear modelling of the COMPASS 31 scores showed that only group status (fibromyalgia or control) was significant (p = 3.4 × 10-16), with age, sex and BMI being non-significant. CONCLUSION: This study confirms that non-pain autonomic dysfunction symptoms occur in fibromyalgia and can be assessed with the COMPASS 31.

Human enteroviral infection in fibromyalgia: a case-control blinded study.

OBJECTIVE: This study aimed to test the hypothesis that fibromyalgia is associated with a human enteroviral infection. METHODS: Venous peripheral blood samples from 27 patients fulfilling the American College of Rheumatology revised diagnostic criteria for fibromyalgia and from 26 age- and sex-matched controls, who underwent immunofluorescence assays for coxsackievirus A7 IgG, coxsackievirus B1 IgG, coxsackievirus A7 IgA, coxsackievirus B1 IgA, echovirus IgG, and echovirus IgA. These immunological tests were performed blind to group status. RESULTS: There were no significant differences between the patient and control groups in respect of positive results for coxsackievirus A7 IgG (p=0.467), coxsackievirus B1 IgG (p=0.491), coxsackievirus A7 IgA (p=0.586), coxsackievirus B1 IgA (p=0.467), echovirus IgG (p=0.236), and echovirus IgA (p=1). CONCLUSIONS: The results of this systematic study do not support the hypothesis that fibromyalgia is associated with infection by a human enterovirus.

Tinnitus in Fibromyalgia.

OBJECTIVE: To assess the impact of tinnitus in fibromyalgia. METHODS: A quantitative controlled study was carried out. The 25-item Tinnitus Handicap Inventory (THI) and the Revised Fibromyalgia Impact Questionnaire (FIQR) were administered to 27 patients who fulfilled the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology and to 26 healthy controls who had no history of suffering from fibromyalgia or any other rheumatological or neurological illness. RESULTS: The two groups were matched for age, sex and ethnicity. The fibromyalgia patients were significantly more likely to suffer from tinnitus than the controls: 16 (59.3%) of the patients suffered from tinnitus, compared with two (7.7%) of the controls (p < 0.001). The median (interquartile range) total THI score for the fibromyalgia group was 6 (44), which was significantly higher than that of 0 (0) for the control group (p < 0.001). The fibromyalgia group scored significantly higher than the control group for 24 of the 25 THI items. The total THI score across all subjects was positively correlated with the FIQR scores (rs = 0.408, p = 0.002). CONCLUSION: Fibromyalgia is associated with a relatively high prevalence of tinnitus.

Overactive Bladder Symptoms in Patients with Fibromyalgia: A Systematic Case-Controlled Study.

BACKGROUND: A recent survey reported an association between fibromyalgia and overactive bladder. OBJECTIVE: To carry out the first systematic case-controlled study to compare the level of overactive bladder symptoms in a group of fibromyalgia patients and a group of matched controls. METHODS: The symptom-bother OAB-q8 questionnaire and Revised Fibromyalgia Impact Questionnaire (FIQR) were administered to 27 patients who fulfilled the revised diagnostic criteria for fibromyalgia of the American College of Rheumatology and to 26 healthy controls who had no history of suffering from fibromyalgia or any other rheumatological or neurological illness. RESULTS: The groups were matched in respect of age, sex and ethnicity. None of the 53 subjects was taking medication, which might cause urinary urgency, none was suffering from, or had recently suffered from, a urinary tract infection and none had undergone a previous operative procedure on the lower urinary tract. Twenty-five (93%) patients had evidence of an overactive bladder during the previous four weeks, compared with five (19%) of the control group (p < 0.001). In terms of symptom severity, the mean (standard error) OAB-q8 score was 24.4 (1.5) in the fibromyalgia patients and 10.8 (4.5) in the controls (p < 0.001). Furthermore, the total OAB-q8 and FIQR scores were positively correlated (rs = 0.727, p < 0.001). CONCLUSION: This systematic controlled study confirms that fibromyalgia is associated with overactive bladder symptoms. The relatively high prevalence of 93% indicates that overactive bladder is an important urological association of fibromyalgia and should be routinely assessed in these patients.

Human enteroviral infection in fibromyalgia: a case-control blinded study

SUMMARY OBJECTIVE: This study aimed to test the hypothesis that fibromyalgia is associated with a human enteroviral infection. METHODS: Venous peripheral blood samples from 27 patients fulfilling the American College of Rheumatology revised diagnostic criteria for fibromyalgia and from 26 age- and sex-matched controls, who underwent immunofluorescence assays for coxsackievirus A7 IgG, coxsackievirus B1 IgG, coxsackievirus A7 IgA, coxsackievirus B1 IgA, echovirus IgG, and echovirus IgA. These immunological tests were performed blind to group status. RESULTS: There were no significant differences between the patient and control groups in respect of positive results for coxsackievirus A7 IgG (p=0.467), coxsackievirus B1 IgG (p=0.491), coxsackievirus A7 IgA (p=0.586), coxsackievirus B1 IgA (p=0.467), echovirus IgG (p=0.236), and echovirus IgA (p=1). CONCLUSIONS: The results of this systematic study do not support the hypothesis that fibromyalgia is associated with infection by a human enterovirus.