Muscle Pressure Correlates With Pain Levels in Fibromyalgia Patients.

BACKGROUND/OBJECTIVE: We evaluated patients with fibromyalgia syndrome (FMS) to determine whether there is a correlation between pain scores based on a 0- to 10-point visual analog scale (VAS) and muscle pressure. METHODS: One hundred forty-two patients who satisfied the American College of Rheumatology classification criteria for FMS and 38 non-FMS controls comprised the study groups. Muscle pressure was measured in mm Hg using a pressure gauge attached to a no. 22 needle inserted into the midportion of the trapezius muscle. The muscle pressure was then correlated with the VAS pain score of 0 to 10, some with an increment of 0.5. A second muscle pressure was obtained from 19 patients at a subsequent visit, which was compared with their pain scores. RESULTS: The mean (SD) pain score for 142 patients with FMS was 6.6 (SD, 1.84) on a 0- to 10-point VAS. The mean pain score in the non-FMS subjects was 0.7 (SD, 1.26). The mean muscle pressure in the FMS group was 32.9 (SD, 6.57) mm Hg. The mean muscle pressure in the non-FMS subjects was 10.6 (SD, 3.85) mm Hg. The calculated Pearson correlation coefficient for muscle pressure versus pain score was 0.8312 ( p < 0.0001). This indicates a highly significant association between subjects' muscle pressure and pain scores. For the repeat muscle pressures, the change in muscle pressure was correlated with the change in pain score, and the resulting Pearson correlation coefficient was 0.9255 ( p < 0.0001). These results again indicate a highly significant association between subjects' muscle pressure and pain scores. CONCLUSION: The results show that increased muscle pressure may be a significant cause of pain in FMS, and the etiology of the pain may have a large peripheral component in addition to a centralized origin of the pain.

The Vast Majority of Patients With Fibromyalgia Have a Straight Neck Observed on a Lateral View Radiograph of the Cervical Spine: An Aid in the Diagnosis of Fibromyalgia and a Possible Clue to the Etiology.

OBJECTIVE: A straight cervical spine is an underappreciated and often overlooked finding in fibromyalgia. The aim of this medical records review study was to evaluate the cervical curvature on radiographs of patients with fibromyalgia. METHODS: A consecutive series of 270 cervical spine radiographs of patients with neck pain from 2015 to 2018 were retrospectively analyzed for cervical curvature using the Cobb angle measurement. One hundred fifty-five patients met full American College of Rheumatology criteria for fibromyalgia, whereas 115 subjects with other rheumatic diseases who were similar in age and education served as control subjects. RESULTS: Mean cervical curvature in fibromyalgia was 6.4 ± 5.2 degrees and 13.8 ± 7.4 degrees in control subjects. The more than 7-degree difference was significant ( p < 0.001). Curvature in the magnitude of 21 degrees is at the low end of normal. At ≤10 degrees, where the cervical spine is essentially straight, there were 129 fibromyalgia patients (83.2%) and 37 control subjects (32.2%). The 51% difference was significant ( p < 0.001). CONCLUSION: Most patients with fibromyalgia share an abnormality in common that is verifiable by a simple radiograph. In 83.2% of the patients, the cervical spine was essentially straight (Cobb angle ≤10 degrees). In fibromyalgia patients, the loss of cervical curvature was approximately 6.5 times greater than in control subjects (50.3% vs. 7.8%). A straight neck without other radiographic abnormalities may be a major anatomical abnormality in fibromyalgia that has gone unnoticed. It may assist in the diagnosis, as well as suggest increased muscle tension/pressure as a possible etiology.

Intramuscular Pressure Is Almost Three Times Higher in Fibromyalgia Patients: A Possible Mechanism for Understanding the Muscle Pain and Tenderness.

OBJECTIVE: Widespread pain in fibromyalgia syndrome (FMS) is conventionally viewed as arising from disordered central processing. This study examines intramuscular pressure in the trapezius as an alternative mechanism for understanding FMS pain. METHODS: One hundred eight patients who satisfied the American College of Rheumatology criteria for FMS and 30 patients who met the ACR criteria for another rheumatic disease comprised the study groups. Muscle pressure was measured in mmHg using a pressure gauge attached to a no. 22 needle inserted into the mid-portion of the trapezius muscle. In addition, patients with FMS and rheumatic disease controls had dolorimetry testing, digital palpation, and reported pain scores. RESULTS: Muscle pressure was substantially higher in patients with FMS with a mean value of 33.48 ± 5.90 mmHg. Only 2 of 108 patients had muscle pressure of < 23 mmHg. The mean pressure in rheumatic disease controls was 12.23 ± 3.75 mmHg, with a range from 3-22 mmHg. Patients with FMS were more tender than controls based on both dolorimetry (P < 0.001) and digital palpation (P < 0.001). The mean pain score in patients with FMS and controls was 6.68 ± 1.91 and 1.43 ± 1.79, respectively (P < 0.001). CONCLUSION: Pressure in the trapezius muscle of patients with FMS is remarkably elevated and may be an intrinsic feature of FMS that could be monitored as part of the diagnostic evaluation. The burden of the pressure abnormality may help explain the diffuse muscle pain of FMS. Therefore, FMS as a disorder of exclusively central pain processing should be revisited. Therapeutically, the reduction of muscle pressure may change the clinical picture significantly.

Immune Recognition of Citrullinated Proteoglycan Aggrecan Epitopes in Mice with Proteoglycan-Induced Arthritis and in Patients with Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disease affecting the joints. Anti-citrullinated protein antibodies (ACPA) are frequently found in RA. Previous studies identified a citrullinated epitope in cartilage proteoglycan (PG) aggrecan that elicited pro-inflammatory cytokine production by RA T cells. We recently reported the presence of ACPA-reactive (citrullinated) PG in RA cartilage. Herein, we sought to identify additional citrullinated epitopes in human PG that are recognized by T cells or antibodies from RA patients. METHODS: We used mice with PG-induced arthritis (PGIA) as a screening tool to select citrulline (Cit)-containing PG peptides that were more immunogenic than the arginine (R)-containing counterparts. The selected peptide pairs were tested for induction of pro-inflammatory T-cell cytokine production in RA and healthy control peripheral blood mononuclear cell (PBMC) cultures using ELISA and flow cytometry. Anti-Cit and anti-R peptide antibodies were detected by ELISA. RESULTS: Splenocytes from mice with PGIA exhibited greater T-cell cytokine secretion in response to the Cit than the R version of PG peptide 49 (P49) and anti-P49 antibodies were found in PGIA serum. PBMC from ACPA+ and ACPA- RA patients, but not from healthy controls, responded to Cit49 with robust cytokine production. High levels of anti-Cit49 antibodies were found in the plasma of a subset of ACPA+ RA patients. Another PG peptide (Cit13) similar to the previously described T-cell epitope induced greater cytokine responses than R13 by control (but not RA) PBMC, however, anti-Cit13 antibodies were rarely detected in human plasma. CONCLUSIONS: We identified a novel citrullinated PG epitope (Cit49) that is highly immunogenic in mice with PGIA and in RA patients. We also describe T-cell and antibody reactivity with Cit49 in ACPA+ RA. As citrullinated PG might be present in RA articular cartilage, Cit PG epitope-induced T-cell activation or antibody deposition may occur in the joints of RA patients.

Three-Quarters of Persons in the US Population Reporting a Clinical Diagnosis of Fibromyalgia Do Not Satisfy Fibromyalgia Criteria: The 2012 National Health Interview Survey.

OBJECTIVES: Although fibromyalgia criteria have been in effect for decades, little is known about how the fibromyalgia diagnosis is applied and understood by clinicians and patients. We used the National Health Interview Survey (NHIS) to determine the prevalence of self-reported clinician diagnosed fibromyalgia and then compared demographics, symptoms, disability and medical utilization measures of persons with a clinical diagnosis of fibromyalgia that did not meet diagnostic criteria (false-positive or prior [F/P] fibromyalgia) to persons with and without criteria-positive fibromyalgia. METHODS: The National Health Interview Survey (NHIS) collected information about both clinical diagnosis and symptoms of fibromyalgia that was appropriately weighted to represent 225,726,257 US adults. Surrogate NHIS diagnostic criteria for fibromyalgia were developed based on the level of polysymptomatic distress (PSD) as characterized in the 2011 modified American College of Rheumatology criteria (ACR) for fibromyalgia. Persons with F/P fibromyalgia were compared with persons who do not have fibromyalgia and those meeting surrogate NHIS fibromyalgia criteria. RESULTS: Of the 1.78% of persons reporting a clinical diagnosis, 73.5% did not meet NHIS fibromyalgia criteria. The prevalence of F/P fibromyalgia is 1.3%. F/P fibromyalgia is associated with a mild degree of polysymptomatic distress (NHIS PSD score 6.2) and characterized by frequent but not widespread pain and insomnia. Measures of work disability and medical utilization in F/P fibromyalgia were equal to that seen with NHIS criteria positive fibromyalgia and were 6-7x greater in F/P fibromyalgia than in non-fibromyalgia persons. F/P fibromyalgia was best predicted by being female (Odds Ratio [OR] 8.81), married (OR 3.27), and white (OR 1.96). In contrast, being a white, married woman was only modestly predictive of NHIS (criteria positive) fibromyalgia (OR 2.1). CONCLUSIONS: The majority of clinically diagnosed fibromyalgia cases in the US do not reach levels of severity necessary and sufficient for diagnosis. The clinical diagnosis of fibromyalgia is disproportionally dependent on demographic and social factors rather than the symptoms themselves. Diagnostic criteria for fibromyalgia appear to be used as a vague guide by clinicians and patients, and allow for substantial diagnostic expansion of fibromyalgia.

Characterization and Localization of Citrullinated Proteoglycan Aggrecan in Human Articular Cartilage.

BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease of the synovial joints. The autoimmune character of RA is underscored by prominent production of autoantibodies such as those against IgG (rheumatoid factor), and a broad array of joint tissue-specific and other endogenous citrullinated proteins. Anti-citrullinated protein antibodies (ACPA) can be detected in the sera and synovial fluids of RA patients and ACPA seropositivity is one of the diagnostic criteria of RA. Studies have demonstrated that RA T cells respond to citrullinated peptides (epitopes) of proteoglycan (PG) aggrecan, which is one of the most abundant macromolecules of articular cartilage. However, it is not known if the PG molecule is citrullinated in vivo in human cartilage, and if so, whether citrulline-containing neoepitopes of PG (CitPG) can contribute to autoimmunity in RA. METHODS: CitPG was detected in human cartilage extracts using ACPA+ RA sera in dot blot and Western blot. Citrullination status of in vitro citrullinated recombinant G1 domain of human PG (rhG1) was confirmed by antibody-based and chemical methods, and potential sites of citrullination in rhG1 were explored by molecular modeling. CitPG-specific serum autoantibodies were quantified by enzyme-linked immunosorbent assays, and CitPG was localized in osteoarthritic (OA) and RA cartilage using immunohistochemistry. FINDINGS: Sera from ACPA+ RA patients reacted with PG purified from normal human cartilage specimens. PG fragments (mainly those containing the G1 domain) from OA or RA cartilage extracts were recognized by ACPA+ sera but not by serum from ACPA- individuals. ACPA+ sera also reacted with in vitro citrullinated rhG1 and G3 domain-containing fragment(s) of PG. Molecular modeling suggested multiple sites of potential citrullination within the G1 domain. The immunohistochemical localization of CitPG was different in OA and RA cartilage. CONCLUSIONS: CitPG is a new member of citrullinated proteins identified in human joints. CitPG could be found in both normal and diseased cartilage specimens. Antibodies against CitPG may trigger or augment arthritis by forming immune complexes with this autoantigen in the joints of ACPA+ RA patients.

The Prevalence and Characteristics of Fibromyalgia in the 2012 National Health Interview Survey.

BACKGROUND: Most knowledge of fibromyalgia comes from the clinical setting, where healthcare-seeking behavior and selection issues influence study results. The characteristics of fibromyalgia in the general population have not been studied in detail. METHODS: We developed and tested surrogate study specific criteria for fibromyalgia in rheumatology practices using variables from the US National Health Interview Survey (NHIS) and the modification (for surveys) of the 2010 American College of Rheumatology (ACR) preliminary fibromyalgia criteria. The surrogate criteria were applied to the 2012 NHIS and identified persons who satisfied criteria from symptom data. The NHIS weighted sample of 8446 persons represents 225.7 million US adults. RESULTS: Fibromyalgia was identified in 1.75% (95% CI 1.42, 2.07), or 3.94 million persons. However, 73% of identified cases self-reported a physician's diagnosis other than fibromyalgia. Identified cases had high levels of self-reported pain, non-pain symptoms, comorbidity, psychological distress, medical costs, Social Security and work disability. Caseness was associated with gender, education, ethnicity, citizenship and unhealthy behaviors. Demographics, behaviors, and comorbidity were predictive of case status. Examination of the surrogate polysymptomatic distress scale (PSD) of the 2010 ACR criteria found fibromyalgia symptoms extending through the full length of the scale. CONCLUSIONS: Persons identified with criteria-based fibromyalgia have severe symptoms, but most (73%) have not received a clinical diagnosis of fibromyalgia. The association of fibromyalgia-like symptoms over the full length of the PSD scale with physiological as well as mental stressors suggests PSD may be a universal response variable rather than one restricted to fibromyalgia.

The Use of Polysymptomatic Distress Categories in the Evaluation of Fibromyalgia (FM) and FM Severity.

OBJECTIVE: The polysymptomatic distress (PSD) scale is derived from variables used in the 2010 American College of Rheumatology (ACR) fibromyalgia (FM) criteria modified for survey and clinical research. The scale is useful in measuring the effect of PSD over the full range of pain-related clinical symptoms, not just in those who are FM criteria-positive. However, no PSD scale categories have been defined to distinguish severity of illness in FM or in those who do not satisfy the FM criteria. We analyzed the scale and multiple covariates to develop clinical categories and to further validate the scale. METHODS: FM was diagnosed according to the research criteria modification of the 2010 ACR FM criteria. We investigated categories in a large database of patients with pain (2732 with rheumatoid arthritis) and developed categories by using germane clinic variables that had been previously studied for severity groupings. By definition, FM cannot be diagnosed unless PSD is at least 12. RESULTS: Based on population categories, regression analysis, and inspections of curvilinear relationships, we established PSD severity categories of none (0-3), mild (4-7), moderate (8-11), severe (12-19), and very severe (20-31). Categories were statistically distinct, and a generally linear relationship between PSD categories and covariate severity was noted. CONCLUSION: PSD categories are clinically relevant and demonstrate FM type symptoms over the full range of clinical illness. Although FM criteria can be clinically useful, there is no clear-cut symptom distinction between FM (+) and FM (-), and PSD categories can aid in more effectively classifying patients.

Cross-sectional neurocognitive data do not support a transition from fibrofog to Alzheimer disease in fibromyalgia patients.

BACKGROUND: Cognitive dysfunction is a signature feature of fibromyalgia. Many who develop cognitive problems in their middle years are concerned that it is prodromal to Alzheimer's disease. OBJECTIVE: To determine if deficits in episodic memory and progressive cognitive decline, hallmarks of Alzheimer's disease, are prominent in the cognitive makeup of fibromyalgia patients. METHODS: In a cross-sectional study, performance on 15 neurocognitive (NC) measures was evaluated in 2 cohorts of fibromyalgia subjects. The first cohort contained 94 subjects with a short duration of cognitive problems (≤12 months). The second cohort contained 55 subjects with a long duration of cognitive problems (≥84 months). RESULTS: The 2 groups were similar in education (14.9 ± 2.3 vs 14.9 ± 2.4), vocabulary scale score (11.2 ± 2.3 vs 11.6 ± 2.7), and depression (17.9 ± 9.8 vs 17.7 ± 9.4). The mean durations of cognitive problems in the short- and long-term group were 7.3 ± 3.9 months and 13.3 ± 7.1 years, respectively. There was no evidence of decline on 14 of 15 measures in the fibromyalgia group with an additional 12.6 years of cognitive dysfunction. Normality of function was in evidence on 4 measures of episodic memory in both cohorts. CONCLUSIONS: Fibromyalgia patients' fear of developing Alzheimer's disease was not borne out by the data. The cognitive pattern of fibromyalgia appears distinct from that of Alzheimer's disease. Fibrofog is not associated with either episodic memory loss on standard tests of episodic memory or progressive cognitive decline. Patients with fibrofog remember personally experienced events termed episodic memory at a normal rate in quiet, distraction-free conditions. Patients with Alzheimer's disease do not. They forget the essential elements of short stories just read to them in environments free of distractions. In Alzheimer's disease, the brain mechanisms responsible for encoding personally experienced events into memory are irreversibly impaired. In fibrofog, the encoding mechanisms are intact. At the heart of memory loss in fibromyalgia is the inability to appropriately filter out relevant distractions. Encoding mechanisms that otherwise operate normally in forming episodic memories for everyday events in fibromyalgia appear to malfunction when 2 streams of information operate concurrently (relevant information and a source of distraction overlap). The findings should allay the worries of many with fibromyalgia who fear that fibrofog is the start of a dementing process.

Fibrofog and fibromyalgia: a narrative review and implications for clinical practice.

Patients with fibromyalgia often report forgetfulness as well as declines in cognitive function, memory, and mental alertness-symptoms that have been termed "fibrofog" in popular and electronic media as well as in professional literature. "Fibrofog" is the subjectively experienced cognitive dysfunction associated with fibromyalgia and is a clinically important yet comparatively less well-studied aspect of the disorder; it includes loss of mental clarity (mental fogginess) as well as attention and memory impairment. Although until recently cognitive symptoms have been largely ignored, these symptoms can be more disturbing than the widespread pain and can change these patients' lives, sometimes dramatically so. Whereas widespread musculoskeletal pain, tenderness, and fatigue may be the hallmark symptoms of fibromyalgia, patients rank cognitive dysfunction highly in terms of disease impact. This review addresses (1) the prevalence of self-reported cognitive disturbances in fibromyalgia, (2) the clinical presentation of fibrofog, (3) neuropsychological test performance, with particular attention to discrepancies between self-report and test results, (3) clinical correlates of impaired cognitive function in fibromyalgia, (4) neurobiology relevant to cognitive disturbances in fibromyalgia, and (5) clinical management of fibrofog. Although the pathophysiology of fibromyalgia remains an enigma, evidence suggests that it may be a brain disorder, with cognitive deficits ("fibrofog") reflecting disturbed centrally mediated processes.

Cognitive dysfunction in fibromyalgia: slow access to the mental lexicon.

Lexical access speed, the time needed for the brain to access the catalogue of words in long-term memory, is assumed to provide a foundation for a broad array of cognitive operations. It was hypothesized that deficits in lexical speed are likely to play a central role in deficiencies in cognitive performance of patients with fibromyalgia, who as a group show deficits in lexical speed. This was tested in a sample of 209 patients with fibromyalgia and in 72 control patients with memory deficits. Participants completed the Stroop word-naming measure of lexical access speed and 12 neurocognitive measures. Deficit in lexical access speed occurred at approximately twice the frequency (48.3% vs 25.0%) in fibromyalgia. The average delay in speed of lexical access was 171 msec. in fibromyalgia and 163 msec. in controls. Those with deficits in lexical access speed displayed deficiencies on 10 of 12 cognitive measures in the fibromyalgia group, and on 8 of 12 cognitive measures in the control group. The premise that lexical access speed is disproportionately present in fibromyalgia and serves as a foundation for a wide array of cognitive operations is supported.

Fibromyalgia and physical trauma: the concepts we invent.

Despite weak to nonexistent evidence regarding the causal association of trauma and fibromyalgia (FM), literature and court testimony continue to point out the association as if it were a strong and true association. The only data that appear unequivocally to support the notion that trauma causes FM are case reports, cases series, and studies that rely on patients' recall and attribution - very low-quality data that do not constitute scientific evidence. Five research studies have contributed evidence to the FM-trauma association. There is no scientific support for the idea that trauma overall causes FM, and evidence in regard to an effect of motor vehicle accidents on FM is weak or null. In some instances effect may be seen to precede cause. Alternative causal models that propose that trauma causes "stress" that leads to FM are unfalsifiable and unmeasurable.

Identification of myeloid-derived suppressor cells in the synovial fluid of patients with rheumatoid arthritis: a pilot study.

BACKGROUND: Myeloid-derived suppressor cells (MDSCs) are a heterogeneous population of innate immune cells with a granulocyte-like or monocyte-like phenotype and a unique ability to suppress T-cell responses. MDSCs have been shown to accumulate in cancer patients, but recent studies suggest that these cells are also present in humans and animals suffering from autoimmune diseases. We previously identified MDSCs in the synovial fluid (SF) of mice with experimental autoimmune arthritis. The goal of the present study was to identify MDSCs in the SF of patients with rheumatoid arthritis (RA). METHODS: RA SF cells were studied by flow cytometry using antibodies to MDSC cell surface markers as well as by analysis of cell morphology. The suppressor activity of RA SF cells toward autologous peripheral blood T cells was determined ex vivo. We employed both antigen-nonspecific (anti-CD3/CD28 antibodies) and antigen-specific (allogeneic cells) induction systems to test the effects of RA SF cells on the proliferation of autologous T cells. RESULTS: SF from RA patients contained MDSC-like cells, the majority of which showed granulocyte (neutrophil)-like phenotype and morphology. RA SF cells significantly suppressed the proliferation of anti-CD3/CD28-stimulated autologous T cells upon co-culture. When compared side by side, RA SF cells had a more profound inhibitory effect on the alloantigen-induced than the anti-CD3/CD28-induced proliferation of autologous T cells. CONCLUSION: MDSCs are present among RA SF cells that are commonly regarded as inflammatory neutrophils. Our results suggest that the presence of neutrophil-like MDSCs in the SF is likely beneficial, as these cells have the ability to limit the expansion of joint-infiltrating T cells in RA.

Social security work disability and its predictors in patients with fibromyalgia.

OBJECTIVE: To determine prevalence and incidence of US Social Security Disability and Supplemental Security Income (SSD) in patients with fibromyalgia and to investigate prediction of SSD. METHODS: Over a mean of 4 years (range 1-13 years), we studied 2,321 patients with physician-diagnosed fibromyalgia (prevalent cases) and applied modified American College of Rheumatology (ACR) 2010 research criteria to identify criteria-positive patients. RESULTS: During the study, 34.8% (95% confidence interval [95% CI] 32.9-36.8%) of fibromyalgia patients received SSD. The annual incidence of SSD among patients not receiving SSD at study enrollment was 3.4% (95% CI 3.0-3.9%), and 25% were estimated to be work disabled at 9.0 years of followup. By comparison, the prevalence of SSD in rheumatoid arthritis (RA) patients with concomitant fibromyalgia was 55.6% (95% CI 54.3-57.0%) and was 42.4% in osteoarthritis (OA). By study conclusion, 31.4% of SSD awardees were no longer receiving SSD. In univariate models, incident SSD in patients with fibromyalgia was predicted by sociodemographic measures and by symptom burden; but the strongest predictor was functional status (Health Assessment Questionnaire disability index [HAQ DI]). In multivariable models, the HAQ DI and the Short Form 36-item health survey physical and mental component summary scores, but no other variables, predicted SSD. Fibromyalgia criteria-positive patients had more SSD, but the continuous scale, polysymptomatic distress index derived from the ACR criteria was a substantially better predictor of SSD than a criteria-positive diagnosis. CONCLUSION: The prevalence of SSD is high in fibromyalgia, but not higher than in RA and OA patients who satisfy fibromyalgia criteria. The best predictors of work disability are functional status variables.

Symptoms, the nature of fibromyalgia, and diagnostic and statistical manual 5 (DSM-5) defined mental illness in patients with rheumatoid arthritis and fibromyalgia.

PURPOSE: To describe and evaluate somatic symptoms in patients with rheumatoid arthritis (RA) and fibromyalgia, determine the relation between somatization syndromes and fibromyalgia, and evaluate symptom data in light of the Diagnostic and Statistical Manual-5 (DSM-5) criteria for somatic symptom disorder. METHODS: We administered the Patient Health Questionnaire-15 (PHQ-15), a measure of somatic symptom severity to 6,233 persons with fibromyalgia, RA, and osteoarthritis. PHQ-15 scores of 5, 10, and 15 represent low, medium, and high somatic symptom severity cut-points. A likely somatization syndrome was diagnosed when PHQ-15 score was ≥10. The intensity of fibromyalgia diagnostic symptoms was measured by the polysymptomatic distress (PSD) scale. RESULTS: 26.4% of RA patients and 88.9% with fibromyalgia had PHQ-15 scores ≥10 compared with 9.3% in the general population. With each step-wise increase in PHQ-15 category, more abnormal mental and physical health status scores were observed. RA patients satisfying fibromyalgia criteria increased from 1.2% in the PHQ-15 low category to 88.9% in the high category. The sensitivity and specificity of PHQ-15≥10 for fibromyalgia diagnosis was 80.9% and 80.0% (correctly classified = 80.3%) compared with 84.3% and 93.7% (correctly classified = 91.7%) for the PSD scale. 51.4% of fibromyalgia patients and 14.8% with RA had fatigue, sleep or cognitive problems that were severe, continuous, and life-disturbing; and almost all fibromyalgia patients had severe impairments of function and quality of life. CONCLUSIONS: All patients with fibromyalgia will satisfy the DSM-5 "A" criterion for distressing somatic symptoms, and most would seem to satisfy DSM-5 "B" criterion because symptom impact is life-disturbing or associated with substantial impairment of function and quality of life. But the "B" designation requires special knowledge that symptoms are "disproportionate" or "excessive," something that is uncertain and controversial. The reliability and validity of DSM-5 criteria in this population is likely to be low.

Polysymptomatic distress in patients with rheumatoid arthritis: understanding disproportionate response and its spectrum.

OBJECTIVE: Fibromyalgia (FM) in rheumatoid arthritis (RA) can cause consternation because symptoms are seen to be out of proportion to physician and laboratory assessments, and composite RA activity scores such as the 28 joint Disease Activity Score, Clinical Disease Activity Index, and Routine Assessment of Patient Index Data 3 (RAPID-3) can yield apparently "wrong" results. We explored the effect of polysymptomatic distress (PSD), a measure of fibromyalgianess and a quantity derived from the American College of Rheumatology 2010 FM diagnostic criteria, to explain the relationship of patient to physician variables. METHODS: We obtained PSD scores on 300 RA patients prior to ordinary clinical care, and assessed the associations of PSD with tender and swollen joints, physician global estimate of RA activity, pain, Health Assessment Questionnaire score, and composite RA activity measures during routine clinic assessments. RESULTS: PSD scores greater than the sample mean (8.8) were associated with increased patient symptoms regardless of the presence or absence of FM, while scores below the mean were associated with better patient outcomes. PSD scores predicted all patient outcomes and less strongly predicted physician outcomes. The discrepancy between patient and physician measures was greatest at low levels of physician-estimated disease activity. CONCLUSION: PSD rather than FM diagnosis more usefully identifies and predicts disproportionate responses. Just as there are patients who lean disproportionately toward greater severity, there are also patients who disproportionately report milder symptoms. Composite measures used to assess RA are flawed, as they confound RA inflammation and patient distress, and more consideration should be given to disaggregated assessments. PSD also appears to be influenced weakly by RA disease activity.

Differentially expressed epigenome modifiers, including aurora kinases A and B, in immune cells in rheumatoid arthritis in humans and mouse models.

OBJECTIVE: To identify epigenetic factors that are implicated in the pathogenesis of rheumatoid arthritis (RA), and to explore the therapeutic potential of the targeted inhibition of these factors. METHODS: Polymerase chain reaction (PCR) arrays were used to investigate the expression profile of genes that encode key epigenetic regulator enzymes. Mononuclear cells from RA patients and mice were monitored for gene expression changes, in association with arthritis development in murine models of RA. Selected genes were further characterized by quantitative reverse transcription-PCR, Western blot, and flow cytometry methods. The targeted inhibition of the up-regulated enzymes was studied in arthritic mice. RESULTS: A set of genes with arthritis-specific expression was identified by the PCR arrays. Aurora kinases A and B, both of which were highly expressed in arthritic mice and treatment-naive RA patients, were selected for detailed analysis. Elevated aurora kinase expression was accompanied by increased phosphorylation of histone H3, which promotes proliferation of T lymphocytes. Treatment with VX-680, a pan-aurora kinase inhibitor, promoted B cell apoptosis, provided significant protection against disease onset, and attenuated inflammatory reactions in arthritic mice. CONCLUSION: Arthritis development is accompanied by changes in expression of a number of epigenome-modifying enzymes. Drug-induced down-regulation of the aurora kinases, among other targets, seems to be sufficient to treat experimental arthritis. Development of new therapeutics that target aurora kinases can potentially improve RA management.

The longitudinal outcome of fibromyalgia: a study of 1555 patients.

OBJECTIVE: To describe the diagnosis status and outcome of patients diagnosed with fibromyalgia (FM) by US rheumatologists. METHODS: We assessed 1555 patients with FM with detailed outcome questionnaires during 11,006 semiannual observations for up to 11 years. At entry, all patients satisfied American College of Rheumatology preliminary 2010 FM criteria modified for survey research. We determined diagnosis status, rates of improvement, responder subgroups, and standardized mean differences (effect sizes) between start and study completion scores of global well-being, pain, sleep problems, and health related quality of life. (QOL) RESULTS: The 5-year improvement rates were pain 0.4 (95% CI 0.2, 0.5), fatigue 0.4 (95% CI 0.2, 0.05), and global 0.0 (95% CI -0.1, 0.1). The standardized mean differences were patient global 0.03 (95% CI -0.02, 0.08), pain 0.22 (95% CI 0.16, 0.28), sleep problems 0.20 (95% CI 0.14, 0.25), physical component summary of the Short-form 36 (SF-36) 0.11 (95% CI -0.14, -0.07), and SF-36 mental component summary 0.03 (95% CI -0.07, 0.02). Patients switched between criteria-positive and criteria-negative states, with 716 patients (44.0%) failing to meet criteria at least once during 4228.5 patient-years (7448 observations). About 10% of patients had substantial improvement and about 15% had moderate improvement of pain. Overall, FM severity worsened in 35.9% and pain in 38.6%. CONCLUSION: Although we found no average clinically meaningful improvement in symptom severity overall, 25% had at least moderate improvement of pain over time. The result that emerged from this longitudinal study was one of generally continuing high levels of self-reported symptoms and distress for most patients, but a slight trend toward improvement.