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1.  Death Receptor 3 (TNFRSF25) Increases Mineral Apposition by Osteoblasts and Region Specific New Bone Formation in the Axial Skeleton of Male DBA/1 Mice 
Journal of Immunology Research  2015;2015:901679.
Objectives. Genome wide association studies identified TNFSF member TNF-like protein 1A (TL1A, TNFSF15) as a potential modulator of ankylosing spondylitis (AS). TL1A is the only confirmed TNFSF ligand of death receptor 3 (DR3, TNFRSF25); however, its role in disease pathology is not characterised. We evaluated DR3's role in controlling osteoblast- (OB-) dependent bone formation in vitro and in vivo. Methods. Osteoprogenitor cells and OB were cultured from male DR3-deficient (DR3ko) and wild-type (DR3wt) DBA/1 mice. DR3 and RANKL expression were tested by flow cytometry. Alkaline phosphatase and mineralization were quantified. Osteopontin, osteoprotegerin, and pro MMP-9 were measured by ELISA. A fluorescent probe (BoneTag) was used to measure in vivo mineralization in 10-month-old mice. Results. DR3 was expressed on osteoprogenitors and OB from DR3wt mice. Alkaline phosphatase, osteopontin, and mineral apposition were significantly elevated in DR3wt cultures. Levels of RANKL were comparable whilst osteoprotegerin was significantly increased in DR3wt cultures. In vivo incorporation of BoneTag was significantly lower in the thoracic vertebrae of 10-month-old DR3ko mice. Conclusions. These data identify new roles for DR3 in regulating OB-dependent bone mineral apposition. They potentially begin to explain the atypical pattern of new bone formation observed in the axial skeleton of grouped, aging DBA/1 mice.
PMCID: PMC4433704  PMID: 26065008
2.  Establishing a Core Domain Set to Measure Rheumatoid Arthritis Flares: Report of the OMERACT 11 RA Flare Workshop 
The Journal of rheumatology  2014;41(4):799-809.
The OMERACT Rheumatoid Arthritis (RA) Flare Group (FG) is developing a data-driven, patient-inclusive, consensus-based RA flare definition for use in clinical trials, longterm observational studies, and clinical practice. At OMERACT 11, we sought endorsement of a proposed core domain set to measure RA flare.
Patient and healthcare professional (HCP) qualitative studies, focus groups, and literature review, followed by patient and HCP Delphi exercises including combined Delphi consensus at Outcome Measures in Rheumatology 10 (OMERACT 10), identified potential domains to measure flare. At OMERACT 11, breakout groups discussed key domains and instruments to measure them, and proposed a research agenda. Patients were active research partners in all focus groups and domain identification activities. Processes for domain selection and patient partner involvement were case studies for OMERACT Filter 2.0 methodology.
A pre-meeting combined Delphi exercise for defining flare identified 9 domains as important (> 70% consensus from patients or HCP). Four new patient-reported domains beyond those included in the RA disease activity core set were proposed for inclusion (fatigue, participation, stiffness, and self-management). The RA FG developed preliminary flare questions (PFQ) to measure domains. In combined plenary voting sessions, OMERACT 11 attendees endorsed the proposed RA core set to measure flare with ≥ 78% consensus and the addition of 3 additional domains to the research agenda for OMERACT 12.
At OMERACT 11, a core domain set to measure RA flare was ratified and endorsed by attendees. Domain validation aligning with Filter 2.0 is ongoing in new randomized controlled clinical trials and longitudinal observational studies using existing and new instruments including a set of PFQ.
PMCID: PMC4365895  PMID: 24584927
3.  Pharmacologic Modulation of Hand Pain in Osteoarthritis: A Double-Blind Placebo-Controlled Functional Magnetic Resonance Imaging Study Using Naproxen 
In an attempt to shed light on management of chronic pain conditions, there has long been a desire to complement behavioral measures of pain perception with measures of underlying brain mechanisms. Using functional magnetic resonance imaging (fMRI), we undertook this study to investigate changes in brain activity following the administration of naproxen or placebo in patients with pain related to osteoarthritis (OA) of the carpometacarpal (CMC) joint.
A placebo-controlled, double-blind, 2-period crossover study was performed in 19 individuals with painful OA of the CMC joint of the right hand. Following placebo or naproxen treatment periods, a functionally relevant task was performed, and behavioral measures of the pain experience were collected in identical fMRI examinations. Voxelwise and a priori region of interest analyses were performed to detect between-period differences in brain activity.
Significant reductions in brain activity following treatment with naproxen, compared to placebo, were observed in brain regions commonly associated with pain perception, including the bilateral primary somatosensory cortex, thalamus, and amygdala. Significant relationships between changes in perceived pain intensity and changes in brain activity were also observed in brain regions previously associated with pain intensity.
This study demonstrates the sensitivity of fMRI to detect the mechanisms underlying treatments of known efficacy. The data illustrate the enticing potential of fMRI as an adjunct to self-report for detecting early signals of efficacy of novel therapies, both pharmacologic and nonpharmacologic, in small numbers of individuals with persistent pain.
PMCID: PMC4365729  PMID: 25533872
4.  Functional Analysis of a Complement Polymorphism (rs17611) Associated with Rheumatoid Arthritis 
Complement is implicated in the pathogenesis of rheumatoid arthritis (RA); elevated levels of complement activation products have been measured in plasma, synovial fluid, and synovial tissues of patients. Complement polymorphisms are associated with RA in genome-wide association studies. Coding-region polymorphisms may directly impact protein activity; indeed, we have shown that complement polymorphisms affecting a single amino acid change cause subtle changes in individual component function that in combination have dramatic effects on complement activity and disease risk. In this study, we explore the functional consequences of a single nucleotide polymorphism (SNP) (rs17611) encoding a V802I polymorphism in C5 and propose a mechanism for its link to RA pathology. Plasma levels of C5, C5a, and terminal complement complex were measured in healthy and RA donors and correlated to rs17611 polymorphic status. Impact of the SNP on C5 functionality was assessed. Plasma C5a levels were significantly increased and C5 levels significantly lower with higher copy number of the RA risk allele for rs17611, suggesting increased turnover of C5 V802. Functional assays using purified C5 variants revealed no significant differences in lytic activity, suggesting that increased C5 V802 turnover was not mediated by complement convertase enzymes. C5 is also cleaved in vivo by proteases; the C5 V802 variant was more sensitive to cleavage with elastase and the “C5a” generated was biologically active. We hypothesize that this SNP in C5 alters the rate at which elastase generates active C5a in rheumatoid joints, hence recruiting neutrophils to the site thus maintaining a state of inflammation in arthritic joints.
PMCID: PMC4367161  PMID: 25725109
5.  Typology of patients with fibromyalgia: cluster analysis of duloxetine study patients 
To identify distinct groups of patients with fibromyalgia (FM) with respect to multiple outcome measures.
Data from 631 duloxetine-treated women in 4 randomized, placebo-controlled trials were included in a cluster analysis based on outcomes after up to 12 weeks of treatment. Corresponding classification rules were constructed using a classification tree method. Probabilities for transitioning from baseline to Week 12 category were estimated for placebo and duloxetine patients (Ntotal = 1188) using logistic regression.
Five clusters were identified, from “worst” (high pain levels and severe mental/physical impairment) to “best” (low pain levels and nearly normal mental/physical function). For patients with moderate overall severity, mental and physical symptoms were less correlated, resulting in 2 distinct clusters based on these 2 symptom domains. Three key variables with threshold values were identified for classification of patients: Brief Pain Inventory (BPI) pain interference overall scores of <3.29 and <7.14, respectively, a Fibromyalgia Impact Questionnaire (FIQ) interference with work score of <2, and an FIQ depression score of ≥5. Patient characteristics and frequencies per baseline category were similar between treatments; >80% of patients were in the 3 worst categories. Duloxetine patients were significantly more likely to improve after 12 weeks than placebo patients. A sustained effect was seen with continued duloxetine treatment.
FM patients are heterogeneous and can be classified into distinct subgroups by simple descriptive rules derived from only 3 variables, which may guide individual patient management. Duloxetine showed higher improvement rates than placebo and had a sustained effect beyond 12 weeks.
PMCID: PMC4364643  PMID: 25532971
Fibromyalgia; Duloxetine; Cluster analysis; Patient subgroups; Prediction
6.  Overlapping structural and functional brain changes in patients with long-term exposure to fibromyalgia 
Arthritis and rheumatism  2013;65(12):3293-3303.
There is vast evidence for brain aberrations in patients with fibromyalgia (FM) and it is possible that central plasticity is critical for the transition from acute to chronic pain. However, the relationship between brain structure and function is poorly investigated.
The present study, including 26 FM patients and 13 age- and gender-matched healthy controls, investigated the differences between patients and controls regarding functional connectivity during intermittent pressure pain and measures of brain structure. Magnetic resonance imaging (MRI) was used to obtain high-resolution anatomical images and functional MRI scans for measures of pain-evoked brain activity.
FM patients displayed a distinct overlap between decreased cortical thickness, brain volumes and measures of functional regional coherence in the rostral anterior cingulate cortex. The morphometric changes were more pronounced with longer exposure to FM pain. In addition, we found associations between structural and functional changes in the mesolimbic areas of the brain and comorbid depressive symptoms in FM patients.
The combined integration of structural and functional measures allowed for a unique characterization of the impact of FM pain on the brain. Our data may lead to the identification of early structural and functional brain alterations in response to pain, which could be used to develop markers to predict the development of FM and other pain disorders.
PMCID: PMC3984030  PMID: 23982850
Magnetic Resonance Imaging; fibromyalgia; morphology; functional connectivity; ReHo
7.  Second-line agents in myositis: 1-year factorial trial of additional immunosuppression in patients who have partially responded to steroids 
Rheumatology (Oxford, England)  2014;54(6):1050-1055.
Objective. Ciclosporin and MTX are used in idiopathic inflammatory myopathies (DM and PM) when patients incompletely respond to glucocorticoids. Their effectiveness is unproved in randomized controlled trials (RCTs). We evaluated their benefits in a placebo-controlled factorial RCT.
Methods. A 56-week multicentre factorial-design double-blind placebo-controlled RCT compared steroids alone, MTX (15–25 mg weekly) plus steroids, ciclosporin (1–5 mg/kg/day) plus steroids and all three treatments. It enrolled adults with myositis (by Bohan and Peter criteria) with active disease receiving corticosteroids.
Results. A total of 359 patients were screened and 58 randomized. Of the latter, 37 patients completed 12 months of treatment, 7 were lost to follow-up and 14 discontinued treatment. Patients completing 12 months of treatment showed significant improvement (P < 0.001 on paired t-tests) in manual muscle testing (14% change), walking time (22% change) and function (9% change). Intention to treat and completer analyses indicated that ciclosporin monotherapy, MTX monotherapy and ciclosporin/MTX combination therapy showed no significant treatment effects in comparison with placebo.
Conclusion. Neither MTX nor ciclosporin (by themselves or in combination) improved clinical features in myositis patients who had incompletely responded to glucocorticoids.
Trial Registration: International Standard Randomized Controlled Trial Number Register;; ISRCTN40085050
PMCID: PMC4476843  PMID: 25433040
myositis and muscle disease; rheumatic diseases; DMARDs therapies; immunosuppressant therapies; clinical trials and methods; basic and clinical sciences; quality of life; psychology and social phenomena
8.  Updating the OMERACT Filter: Core Areas as a basis for defining core outcome sets 
The Journal of rheumatology  2014;41(5):994-999.
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter pre-supposes an explicit framework for identifying the relevant core outcomes that are universal to all studies of the effects of intervention effects. There is no published outline for instrument choice or development that is aimed at measuring outcome, was derived from broad consensus over its underlying philosophy, or includes a structured and documented critique. Therefore, a new proposal for defining core areas of measurement (“Filter 2.0 Core Areas of Measurement”) was presented at OMERACT 11 to explore areas of consensus and consider whether already endorsed core outcome sets fit in to this newly proposed framework.
Discussion groups critically reviewed the extent to which case studies of current OMERACT Working Groups complied with or negated the proposed framework, whether these observations had a more general application, and what issues remained to be resolved.
Although there was a broad acceptance of the framework in general, several important areas of construction, presentation and clarity of the framework were questioned. The discussion groups and subsequent feedback highlighted 20 such issues.
These issues will require resolution in order to reach consensus on accepting the proposed Filter 2.0 framework of Core Areas as the basis for the selection of Core Outcome Domains and hence appropriate Core Outcome Sets for clinical trials.
PMCID: PMC4217644  PMID: 24634204
9.  Updating the OMERACT Filter: Implications of Filter 2.0 to select outcome instruments through assessment of ‘Truth’: content, face and construct validity 
The Journal of rheumatology  2014;41(5):1000-1004.
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter requires that criteria be met to demonstrate that the outcome instrument meets the criteria for content, face and construct validity.
Discussion groups critically reviewed the variety of ways in which case studies of current OMERACT Working Groups complied with the ‘Truth’ component of the Filter and what issues remained to be resolved.
The case studies showed that there is broad agreement on criteria for meeting the ‘Truth’ criteria through demonstration of content, face and construct validity; however several issues were identified that the Filter Working Group will need to address.
These issues will require resolution in order to reach consensus on how ‘Truth’ will be assessed for the proposed Filter 2.0 framework, for instruments to be endorsed by OMERACT.
PMCID: PMC4212637  PMID: 24692531
10.  Improving the primary care physicians’ decision making for fibromyalgia in clinical practice: development and validation of the Fibromyalgia Detection (FibroDetect®) screening tool 
Fibromyalgia diagnosis is a challenging and long process, especially among primary care physicians (PCPs), because of symptom heterogeneity, co-morbidities and clinical overlap with other disorders. The purpose was to develop and validate a screening tool in French (FR), German (DE) and English (UK) to help PCPs identify patients with fibromyalgia.
The FibroDetect questionnaire was simultaneously developed in FR, DE and UK based on information obtained from a literature review, focus groups conducted with clinicians, and face-to-face interviews with fibromyalgia patients (FR, DE and UK, n = 23). The resulting tool was comprehension-tested in patients with diagnosed or suspected fibromyalgia (n = 3 and n = 2 in each country, respectively). Acceptability and applicability were assessed and the tool modified accordingly, then assessed in clinical practice. A scoring method was created using an iterative process based on statistical and clinical considerations with American College of Rheumatology + (ACR+) patients and ACR– patients (n = 276), and validated with fibromyalgia and non-fibromyalgia patients (n = 312).
The FibroDetect included 14 questions assessing patients’ pain and fatigue, personal history and attitudes, symptoms and impact on lives. Six questions were retained in the final scoring, demonstrating satisfactory discriminative power between ACR + and ACR- patients with area under the Receiver Operating Characteristic curve of 0.74. The predictive accuracy of the tool increased to 0.86 for fibromyalgia and non-fibromyalgia patient detection, with a sensitivity of 90% and a specificity of 67% for a cut-off of 6 on the score.
The FibroDetect is a self-administered tool that can be used as a screening classification surrogate to the ACR criteria in primary care settings to help PCPs detect potential fibromyalgia patients among a population complaining of chronic widespread pain.
PMCID: PMC4221679  PMID: 25341959
Fibromyalgia; Primary health care; Screening tool; Early diagnosis; Decision making; FibroDetect
11.  Cardiovascular risk in rheumatoid arthritis: recent advances in the understanding of the pivotal role of inflammation, risk predictors and the impact of treatment 
Rheumatology (Oxford, England)  2014;53(12):2143-2154.
Risk of cardiovascular (CV) disease is increased among RA patients. High inflammatory burden associated with RA appears to be a key driver of the increased cardiovascular risk. Inflammation is linked with accelerated atherosclerosis and associated with a paradoxical inversion of the relationship between CV risk and lipid levels in patients with untreated RA, recently coined the lipid paradox. Furthermore, the inflammatory burden is also associated with qualitative as well as quantitative changes in lipoproteins, with the anti-inflammatory and atheroprotective roles associated with high-density lipoprotein cholesterol significantly altered. RA therapies can increase lipid levels, which may reflect the normalization of lipids due to their inflammatory-dampening effects. However, these confounding influences of inflammation and RA therapies on lipid profiles pose challenges for assessing CV risk in RA patients and interpretation of traditional CV risk scores. In this review we examine the relationship between the increased inflammatory burden in RA and CV risk, exploring how inflammation influences lipid profiles, the impact of RA therapies and strategies for identifying and monitoring CV risk in RA patients aimed at improving CV outcomes.
PMCID: PMC4241890  PMID: 24907149
rheumatoid arthritis; cardiovascular disease; inflammation; atherosclerosis; dyslipidaemias; anti-rheumatic agents
12.  Safety, tolerability, pharmacokinetics and pharmacodynamics of an anti- oncostatin M monoclonal antibody in rheumatoid arthritis: results from phase II randomized, placebo-controlled trials 
Arthritis Research & Therapy  2013;15(5):R132.
Oncostatin M (OSM) has been implicated in the pathophysiology of rheumatoid arthritis (RA) through its effect on inflammation and joint damage. GSK315234 is a humanised anti-OSM Immunoglobulin G1 (IgG1) monoclonal antibody (mAb). This 3-part study examines the safety, tolerability and efficacy of GSK315234 in patients with active RA.
This was a 3-part (Parts A, B and C), multicenter study. Part A and Part B were randomised, double-blind, placebo-controlled, Bayesian adaptive dose finding studies to investigate the safety, tolerability, efficacy, pharmacokinetics and pharmacodynamics of single (Part A) and 3 repeat (Part B) intravenous infusions of GSK315234 in patients with active RA on a background of methotrexate (MTX). Part C was a single dose, randomised, single-blind, placebo-controlled study to assess subcutaneously administered GSK315234 to patients with active RA on a background of MTX.
The primary endpoint of the study was mean change in DAS28 at Day 28 in Part A and Day 56 in Part B and C. All patients receiving at least one dose of GSK315234 were included in safety analysis. In Part A, there were statistically significant differences in DAS28 between 3 mg/kg and placebo at Day 56, 84 and 91. There was also a statistically significant difference in DAS28 between 0.3 mg/kg, 3 mg/kg and 10 mg/kg, as compared to placebo, at Day 84. Although these changes were small and occurred late, they supported progression to Part B and C to determine the therapeutic potential of GSK315234. For Part B, no significant difference was observed between 6 mg/kg and placebo. For Part C, a statistically significant difference in DAS28 was observed at Day 40, Day 84 and Day 100 between the 500 mg subcutaneous group, as compared to placebo. No significant findings were observed at any of the time points for EULAR response criteria, ACR20, ACR50 or ACR70. An exploratory analysis of clinical, pharmacokinetic and pharmacodynamics data suggests the lack of efficacy may be due to moderate binding affinity and rapid off-rate of GSK315234 as compared to the higher affinity OSM receptor causing a protein carrier effect prolonging the half life of OSM due to accumulation of the OSM/antibody complex in the serum and synovial fluid.
Our data highlighted the importance of binding affinity and off-rate effect of a mAb to fully neutralize the target and how this may influence its efficacy and potentially worsen disease activity. Using an anti-OSM mAb with high affinity should test this hypothesis and examine the potential of OSM as a therapeutic target in RA.
Trial registration no: NCT00674635
PMCID: PMC3978888  PMID: 24286335
13.  Survey of physician experiences and perceptions about the diagnosis and treatment of fibromyalgia 
Fibromyalgia (FM) is a condition characterized by widespread pain and is estimated to affect 0.5-5% of the general population. Historically, it has been classified as a rheumatologic disorder, but patients consult physicians from a variety of specialties in seeking diagnosis and ultimately treatment. Patients report considerable delay in receiving a diagnosis after initial presentation, suggesting diagnosis and management of FM might be a challenge to physicians.
A questionnaire survey of 1622 physicians in six European countries, Mexico and South Korea was conducted. Specialties surveyed included primary care physicians (PCPs; n=809) and equal numbers of rheumatologists, neurologists, psychiatrists and pain specialists.
The sample included experienced doctors, with an expected clinical caseload for their specialty. Most (>80%) had seen a patient with FM in the last 2 years. Overall, 53% of physicians reported difficulty with diagnosing FM, 54% reported their training in FM was inadequate, and 32% considered themselves not knowledgeable about FM. Awareness of American College of Rheumatology classification criteria ranged from 32% for psychiatrists to 83% for rheumatologists. Sixty-four percent agreed patients found it difficult to communicate FM symptoms, and 79% said they needed to spend more time to identify FM. Thirty-eight percent were not confident in recognizing the symptoms of FM, and 48% were not confident in differentiating FM from conditions with similar symptoms. Thirty-seven percent were not confident developing an FM treatment plan, and 37% were not confident managing FM patients long-term. In general, rheumatologists reported least difficulties/greatest confidence, and PCPs and psychiatrists reported greatest difficulties/least confidence.
Diagnosis and managing FM is challenging for physicians, especially PCPs and psychiatrists, but other specialties, including rheumatologists, also express difficulties. Improved training in FM and initiatives to improve patient-doctor communication are needed and may help the management of this condition.
PMCID: PMC3502453  PMID: 23051101
14.  Fibromyalgia Syndrome Module at OMERACT 9 
The Journal of rheumatology  2009;36(10):2318-2329.
(1) Establish a core domain set for fibromyalgia (FM) assessment in clinical trials and practice, (2) review outcome measures’ performance characteristics, (3) discuss development of a responder index for the assessment of FM in clinical trials, (4) review objective markers, (5) review the domain of cognitive dysfunction, (6) establish a research agenda for work regarding outcomes research.
(1) Results of univariate and multivariate analysis of 10 different FM clinical trials of four different drugs, mapping key domains identified in previously presented patient focus group: Delphi exercises and a clinician/researcher Delphi exercise, breakout discussions to vote on possible essential domains and reliable measures. (2) Updates presented regarding outcome measures’ status. (3) Presented update on objective markers to measure FM disease state. 4) The issue of cognitive dysfunction (dyscognition) in FM was reviewed.
(1) Greater than 70% of OMERACT participants agreed that pain, tenderness, fatigue, patient global, multidimensional function and sleep disturbance domains should be measured in all FM clinical trials, dyscognition and depression in some trial, and domains of research interest include stiffness, anxiety, functional imaging, and cerebrospinal fluid biomarkers. (2) FM domains’ outcome measures have generally proven to be reliable, discriminative, and feasible. More sophisticated and comprehensive measures are in development, as is a responder index for FM. (3) Increasing number of objective markers are being developed for FM assessment. (4) Cognitive dysfunction assessment by self-assessed and applied outcome measures is being developed.
A multidimensional symptom core set is proposed for the evaluation of FM in clinical trials. There is ongoing research on improved measures of single domains and composite measures.
PMCID: PMC3419373  PMID: 19820221
Fibromyalgia; OMERACT; outcome measures; clinical trials
15.  Content and Criterion Validity of The Preliminary Core Dataset for Clinical Trials in Fibromyalgia Syndrome 
The Journal of rheumatology  2009;36(10):2330-2334.
Increasing research interest and emerging new therapies for treatment of fibromyalgia (FM) have led to a need to develop a consensus on a core set of outcome measures that should be assessed and reported in all clinical trials, to facilitate interpretation of the data and understanding of the disease. This aligns with the key objective of the Outcome Measures in Rheumatology (OMERACT) initiative to improve outcome measurement through a data driven, interactive consensus process. Through patient focus groups and Delphi processes, working groups at previous OMERACT meetings identified potential domains to be included in the core data set. A systematic review has shown that instruments measuring these domains are available and at least moderately sensitive to change. Most of instruments have been validated in multiple languages. This pooled analysis study aims to develop the core data set by analysing data from 10 randomised controlled trials (RCTs) in FM. Results from this study provide support for the inclusion of the following in the core data set: pain, tenderness, fatigue, sleep, patient global assessment and multi-dimensional function/health related quality of life. Construct validity was demonstrated with outcome instruments showing convergent and divergent validity. Content and criterion validity were confirmed by multivariate analysis showing R square values between 0.4 and 0.6. Low R square value is associated with studies in which one or more domains were not assessed. The core data set was supported by high consensus among attendees at OMERACT 9. Establishing an international standard for RCTs in FM should facilitate future meta-analyses and indirect comparisons.
PMCID: PMC3412585  PMID: 19820222
Fibromyalgia; OMERACT; outcome measures; clinical trials; core data set
16.  Patients with fibromyalgia display less functional connectivity in the brain’s pain inhibitory network 
Molecular Pain  2012;8:32.
There is evidence for augmented processing of pain and impaired endogenous pain inhibition in Fibromyalgia syndrome (FM). In order to fully understand the mechanisms involved in FM pathology, there is a need for closer investigation of endogenous pain modulation. In the present study, we compared the functional connectivity of the descending pain inhibitory network in age-matched FM patients and healthy controls (HC).
We performed functional magnetic resonance imaging (fMRI) in 42 subjects; 14 healthy and 28 age-matched FM patients (2 patients per HC), during randomly presented, subjectively calibrated pressure pain stimuli. A seed-based functional connectivity analysis of brain activity was performed. The seed coordinates were based on the findings from our previous study, comparing the fMRI signal during calibrated pressure pain in FM and HC: the rostral anterior cingulate cortex (rACC) and thalamus.
FM patients required significantly less pressure (kPa) to reach calibrated pain at 50 mm on a 0–100 visual analogue scale (p < .001, two-tailed). During fMRI scanning, the rACC displayed significantly higher connectivity to the amygdala, hippocampus, and brainstem in healthy controls, compared to FM patients. There were no regions where FM patients showed higher rACC connectivity. Thalamus showed significantly higher connectivity to the orbitofrontal cortex in healthy controls but no regions showed higher thalamic connectivity in FM patients.
Patients with FM displayed less connectivity within the brain’s pain inhibitory network during calibrated pressure pain, compared to healthy controls. The present study provides brain-imaging evidence on how brain regions involved in homeostatic control of pain are less connected in FM patients. It is possible that the dysfunction of the descending pain modulatory network plays an important role in maintenance of FM pain and our results may translate into clinical implications by using the functional connectivity of the pain modulatory network as an objective measure of pain dysregulation.
PMCID: PMC3404927  PMID: 22537768
17.  Psychological factors and their relation to osteoarthritis pain 
We assessed associations between mental health and osteoarthritis (OA) pain
Two hundred and sixty-six subjects with hip and/or knee OA from the Longitudinal Examination of Arthritis Pain (LEAP) study were interviewed weekly for 12 weeks, measuring WOMAC pain subscale and 5-item Mental Health Inventory (MHI-5).
We examined associations between MHI-5 and its change, divided into quartiles, to WOMAC pain and its change (occurring one week later) using linear regression, adjusting for age, sex, body mass index, medication use. Generalized estimating equations were used to account for repeated measurements correlation. We also assessed the relation of MHI-5 to the risk of pain flare using conditional logistic regression in a case crossover study.
Seventy-five men and 191 women were included. Mean age was 65.0, mean BMI 31.5. 82% had knee as their primary site. The mean WOMAC score was 2.93 in the quartile with the highest MHI-5 as compared with a mean WOMAC of 4.57 in the quartile with the lowest MHI-5 (p for trend across quartiles <0.001). In the case crossover analysis (91 subjects), periods with the worst MHI-5 quartile had 2.1 times the odds of a pain flare the subsequent week as compared to periods with the best MHI-5 quartile (p<0.001).
We demonstrate an association between worsened measures of mental health and OA pain and risk of pain flares. General mental health is a modifiable component of health and may represent a new avenue for prevention of OA pain flares.
PMCID: PMC2912218  PMID: 20346403
osteoarthritis; pain; mental health
18.  A Multistate Transition Model for Osteoarthritis Pain Change 
Pain severity of knees is assessed using an ordinal scale in patients with musculoskeletal diseases and often changes over time. Assessment of the effect of a particular risk factor on the change in pain severity will shed light on our understanding of biological mechanisms and provide guidance for rational clinical intervention for recurrent pain. The multistate transition model allows transitions between several different states of pain severity and estimates the transitional intensity using an extension of the Cox proportional hazards model. Using data from a longitudinal study, we applied this model to assess the relation of two psychological factors to the change in knee pain severity over time among patients with osteoarthritis and demonstrated that the multistate transition model can be a valuable tool for rheumatic disease studies.
PMCID: PMC3039455  PMID: 21331303
Multistate transition; Pain; Proportional hazards model
19.  The Role of Interleukin 6 in the Pathophysiology of Rheumatoid Arthritis 
Interleukin 6 (IL-6) is a pleiotropic cytokine with a pivotal role in the pathophysiology of rheumatoid arthritis (RA). It is found in abundance in the synovial fluid and serum of patients with RA and the level correlates with the disease activity and joint destruction. IL-6 can promote synovitis and joint destruction by stimulating neutrophil migration, osteoclast maturation and vascular endothelial growth factor (VEGF)-stimulated pannus proliferation. IL-6 may also be mediating many of the systematic manifestations of RA including inducing the acute-phase reaction [including C-reactive protein (CRP)], anaemia through hecipidin production, fatigue via the hypothalamic—pituitary—adrenal (HPA) axis) and osteoporosis from its effect on osteoclasts. In addition, IL-6 may contribute to the induction and maintenance of the autoimmune process through B-cell maturation and TH-17 differentiation. All of the above makes IL-6 blockade a desirable therapeutic option in the treatment of RA. Following successful animal studies, a humanized anti-interleukin-6 receptor (anti-IL-6R) monoclonal antibody, tocilizumab (TCZ), entered into clinical trials and it has been shown to be an effective treatment in several large phase III clinical trials in RA with rapid and sustained improvement in disease activity, reducing radiographic joint damage and improving physical function.
PMCID: PMC3383508  PMID: 22870451
interleukin 6; pathophysiology; receptor blockade; rheumatoid arthritis
20.  Risk factors for radiographic progression in psoriatic arthritis: subanalysis of the randomized controlled trial ADEPT 
Arthritis Research & Therapy  2010;12(3):R113.
To identify independent predictors of radiographic progression in psoriatic arthritis (PsA) for patients treated with adalimumab or placebo in the Adalimumab Effectiveness in PsA Trial (ADEPT).
Univariate analyses and multivariate linear regression analyses assessed risk for radiographic progression (change in modified total Sharp score, ΔmTSS > 0.5) from baseline to week 24 for C-reactive protein (CRP) and other baseline variables, and for 24-week time-averaged CRP (univariate analysis only). Subanalyses determined mean ΔmTSS for CRP subgroups. Analyses were post hoc, with observed data.
One hundred and forty-four adalimumab-treated patients and 152 placebo-treated patients were assessed. Mean CRP was 64% lower by week 2 with adalimumab and essentially unchanged with placebo. Univariate analyses indicated that elevated CRP at baseline and time-averaged CRP were strongly associated with radiographic progression for placebo-treated patients but not for adalimumab-treated patients. Multivariate analysis confirmed that elevated baseline CRP was the only strong independent risk factor for radiographic progression (for CRP ≥1.0 mg/dl: odds ratio = 3.28, 95% confidence interval = 1.66 to 6.51, P < 0.001). Adalimumab treatment reduced risk of progression approximately fivefold. The difference between mean ΔmTSS for adalimumab versus placebo was greatest for patients with baseline CRP ≥2.0 mg/dl (-0.5 vs. 2.6).
Systemic inflammation in PsA, as indicated by elevated baseline CRP, was the only strong independent predictor of radiographic progression. This association was observed predominantly for placebo-treated patients. Adalimumab treatment substantially reduced the overall risk of radiographic progression, and provided greatest radiographic benefit for patients with the greatest CRP concentrations at baseline.
Trial Registration
Trial registration: NCT00195689.
PMCID: PMC2911906  PMID: 20537151
21.  A patient survey of the impact of fibromyalgia and the journey to diagnosis 
Fibromyalgia is a painful, debilitating illness with a prevalence of 0.5-5.0% that affects women more than men. It has been shown that the diagnosis of fibromyalgia is associated with improved patient satisfaction and reduced healthcare utilization. This survey examined the patient journey to having their condition diagnosed and studied the impact of the condition on their life.
A questionnaire survey of 800 patients with fibromyalgia and 1622 physicians in 6 European countries, Mexico and South Korea. Patients were recruited via their physician.
Over half the patients (61%) were aged 36-59 years, 84% were women, and the mean time since experiencing fibromyalgia symptoms was 6.5 years. Patients had experienced multiple fibromyalgia symptoms (mean of 7.3 out of 14), with pain, fatigue, sleeping problems and concentration difficulties being the most commonly reported. Most patients rated their chronic widespread pain as moderate or severe and fibromyalgia symptoms were on average "fairly" to "very" disruptive, and had a "moderate" to "strong" impact on patients' lives. 22% were unable to work and 25% were not able to work all the time because of their fibromyalgia. Patients waited on average almost a year after experiencing symptoms before presenting to a physician, and it took an average of 2.3 years and presenting to 3.7 different physicians before receiving a diagnosis of fibromyalgia. Patients rated receiving a diagnosis as somewhat difficult on average and had difficulties communicating their symptoms to the physician. Over one third (35%) felt their chronic widespread pain was not well managed by their current treatment.
This survey provides further evidence that fibromyalgia is characterized by multiple symptoms and has a notable impact on quality of life and function. The diagnosis of fibromyalgia is delayed. Patients wait a significant period of time before presenting to a physician, adding to the prolonged time to diagnosis. Patients typically present with a multitude of symptoms, all resulting in a delay in diagnosis and eventual management. Helping clinicians to diagnose and manage patients with fibromyalgia should benefit both patients and funders of healthcare.
PMCID: PMC2874550  PMID: 20420681
22.  Therapeutic targets in rheumatoid arthritis: the interleukin-6 receptor 
Rheumatology (Oxford, England)  2009;49(1):15-24.
RA is a chronic, debilitating disease in which articular inflammation and joint destruction are accompanied by systemic manifestations including anaemia, fatigue and osteoporosis. IL-6 is expressed abundantly in the SF of RA patients and is thought to mediate many of the local and systemic effects of this disease. Unlike a number of other cytokines, IL-6 can activate cells through both membrane-bound (IL-6R) and soluble receptors (sIL-6R), thus widening the number of cell types responsive to this cytokine. Indeed, trans-signalling, where IL-6 binds to the sIL-6R, homodimerizes with glycoprotein 130 subunits and induces signal transduction, has been found to play a key role in acute and chronic inflammation. Elevated levels of IL-6 and sIL-6R in the SF of RA patients can increase the risk of joint destruction and, at the joint level, IL-6/sIL-6R can stimulate pannus development through increased VEGF expression and increase bone resorption as a result of osteoclastogenesis. Systemic effects of IL-6, albeit through conventional or trans-signalling, include regulation of acute-phase protein synthesis, as well as hepcidin production and stimulation of the hypothalamo-pituitary-adrenal axis, the latter two actions potentially leading to anaemia and fatigue, respectively. This review aims to provide an insight into the biological effects of IL-6 in RA, examining how IL-6 can induce the articular and systemic effects of this disease.
PMCID: PMC2789585  PMID: 19854855
Interleukin-6; Rheumatoid arthritis; Trans-signalling; Joint destruction; Systemic effects; Immune response; Receptor inhibition
23.  Patients' experiences of living with and receiving treatment for fibromyalgia syndrome: a qualitative study 
Fibromyalgia syndrome (FMS) presents a challenge for patients and health care staff across many medical specialities. The aetiology is multi-dimensional, involving somatic, psychological and social factors. Patients' views were obtained to understand their experience of living with this long-term condition, using qualitative interviews.
12 patients were recruited and stratified by age, gender and ethnicity from one rheumatology outpatient clinic, and a departmental held database of patients diagnosed with FMS.
Patients' accounts of their experience of FMS resonated well with two central concepts: social identity and illness intrusiveness. These suggested three themes for the analytical framework: life before and after diagnosis (e.g. lack of information about FMS, invisibility of FMS); change in health identity (e.g. mental distress, impact on social life) and perceived quality of care (e.g. lack of contact with nurses, attitudes of specialists). The information provided from one male participant did not differ from the female patients, but black and ethnic community patients expressed a degree of suspicion towards the medication prescribed, and the attitudes displayed by some doctors, a finding that has not been previously reported amongst this patient group. Patients expected more consultation time and effective treatment than they received. Subjective experiences and objective physical and emotional changes were non-overlapping. Patients' accounts revealed that their physical, mental and social health was compromised, at times overwhelming and affected their identity.
FMS is a condition that intrudes upon many aspects of patients' lives and is little understood. At the same time, it is a syndrome that evokes uneasiness in health care staff (as current diagnostic criteria are not well supported by objective markers of physiological or biochemical nature, and indeed because of doubt about the existence of the condition) and places great demands on resources in clinical practice. Greater attention needs to be paid to the links between the explanatory models of patients and staff, and most important, to the interrelationship between the complex physical, psychological and social needs of patients with FMS. Taking a less medical but more holistic approach when drawing up new diagnostic criteria for FMS might match better individuals' somatic and psycho-social symptom profile and may result in more effective treatment.
PMCID: PMC2762955  PMID: 19811630
24.  Safety and tolerability of duloxetine in the treatment of patients with fibromyalgia: pooled analysis of data from five clinical trials 
Clinical Rheumatology  2009;28(9):1035-1044.
The purpose of this report is to describe the overall safety profile of both short- and longer-term duloxetine treatment of fibromyalgia. Data from four double-blind, randomized, placebo-controlled studies (two with 6-month open-label extension phases) and a 1-year, open-label safety study were included. Safety measures included treatment-emergent adverse events (TEAEs), adverse events leading to discontinuation, serious adverse events (SAEs), clinical laboratory tests, vital signs, and electrocardiograms. The most common TEAEs for short-term treatment with duloxetine were nausea (29.3%), headache (20.0%), dry mouth (18.2%), insomnia (14.5%), fatigue (13.5%), constipation (14.5%), diarrhea (11.6%), and dizziness (11.0%; all p < 0.05 vs. placebo). Most TEAEs emerged early and were mild to moderate in severity. The profile of adverse events in patients enrolled at least 6 months, and for patients in the 1-year study, was similar to that found in the short-term treatment studies, with no new adverse events emerging at a notable rate. About 20% of patients discontinued due to adverse events in the short-term treatment studies and in the 1-year study. SAEs were uncommon, and none occurred at a significantly higher frequency for duloxetine compared with placebo. Mean changes in vital signs and weight were small. Rates of treatment-emergent potentially clinically significant (PCS) vital sign, laboratory, and electrocardiogram measures were low, with only PCS rates of alanine aminotransferase being significantly higher for duloxetine compared with placebo in the placebo-controlled treatment studies. In the 1-year study, four patients (1.1%) had suicide-related behavior. The data provided here summarize short- and long-term safety from five clinical studies in patients treated with duloxetine for fibromyalgia. In addition, postmarketing surveillance continues for adverse events reported with duloxetine in fibromyalgia, as in other indications.
PMCID: PMC2721139  PMID: 19533210
Adverse events; Duloxetine; Fibromyalgia; Safety
25.  Cardiovascular disease in patients with rheumatoid arthritis: results from the QUEST-RA study 
We analyzed the prevalence of cardiovascular (CV) disease in patients with rheumatoid arthritis (RA) and its association with traditional CV risk factors, clinical features of RA, and the use of disease-modifying antirheumatic drugs (DMARDs) in a multinational cross-sectional cohort of nonselected consecutive outpatients with RA (The Questionnaires in Standard Monitoring of Patients with Rheumatoid Arthritis Program, or QUEST-RA) who were receiving regular clinical care.
The study involved a clinical assessment by a rheumatologist and a self-report questionnaire by patients. The clinical assessment included a review of clinical features of RA and exposure to DMARDs over the course of RA. Comorbidities were recorded; CV morbidity included myocardial infarction, angina, coronary disease, coronary bypass surgery, and stroke. Traditional risk factors recorded were hypertension, hyperlipidemia, diabetes mellitus, smoking, physical inactivity, and body mass index. Unadjusted and adjusted hazard ratios (HRs) (95% confidence interval [CI]) for CV morbidity were calculated using Cox proportional hazard regression models.
Between January 2005 and October 2006, the QUEST-RA project included 4,363 patients from 48 sites in 15 countries; 78% were female, more than 90% were Caucasian, and the mean age was 57 years. The prevalence for lifetime CV events in the entire sample was 3.2% for myocardial infarction, 1.9% for stroke, and 9.3% for any CV event. The prevalence for CV risk factors was 32% for hypertension, 14% for hyperlipidemia, 8% for diabetes, 43% for ever-smoking, 73% for physical inactivity, and 18% for obesity. Traditional risk factors except obesity and physical inactivity were significantly associated with CV morbidity. There was an association between any CV event and age and male gender and between extra-articular disease and myocardial infarction. Prolonged exposure to methotrexate (HR 0.85; 95% CI 0.81 to 0.89), leflunomide (HR 0.59; 95% CI 0.43 to 0.79), sulfasalazine (HR 0.92; 95% CI 0.87 to 0.98), glucocorticoids (HR 0.95; 95% CI 0.92 to 0.98), and biologic agents (HR 0.42; 95% CI 0.21 to 0.81; P < 0.05) was associated with a reduction of the risk of CV morbidity; analyses were adjusted for traditional risk factors and countries.
In conclusion, prolonged use of treatments such as methotrexate, sulfasalazine, leflunomide, glucocorticoids, and tumor necrosis factor-alpha blockers appears to be associated with a reduced risk of CV disease. In addition to traditional risk factors, extra-articular disease was associated with the occurrence of myocardial infarction in patients with RA.
PMCID: PMC2453774  PMID: 18325087

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