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1.  Influence of lifestyle factors on quantitative heel ultrasound measurements in middle-aged and elderly men 
Calcified tissue international  2010;86(3):211-219.
We examined the distribution of quantitative heel ultrasound (QUS) parameters in population samples of European men, and looked at the influence of lifestyle factors on the occurrence of these parameters.
Men aged between 40 and 79 years were recruited from eight European centres and invited to attend for an interviewer-assisted questionnaire, assessment of physical performance and quantitative ultrasound (QUS) of the calcaneus (Hologic - SAHARA). The relationships between QUS parameters and lifestyle variables were assessed using linear regression with adjustments for age, centre and weight.
3,258 men, mean age 60.0 years were included in the analysis. A higher PASE score (upper vs lower tertile) was associated with higher BUA (β coefficient = 2.44 dB/Mhz), SOS (β coefficient = 6.83 m/s) and QUI (β coefficient = 3.87). Compared to those who were inactive, those who walked or cycled more than an hour per day had a higher BUA (β coeff =3.71 dB/Mhz), SOS (β coeff = 6.97 m/s) and QUI (β coeff = 4.50). A longer time to walk 50 feet was linked with lower BUA (β coeff = −0.62 dB/Mhz), SOS (β coeff = −1.06 m/s) and QUI (β coeff = −0.69). Smoking was associated with a reduction in BUA, SOS and QUI. There was a U shaped association with frequency of alcohol consumption.
Modification of lifestyle, including increasing physical activity and stopping smoking may help optimise bone strength and reduce the risk of fracture in middle aged and elderly European men.
PMCID: PMC4080706  PMID: 20205346
Epidemiology; Ultrasound; Bone mineral density; Risk factors; Exercise
Calcified tissue international  2011;88(6):503-510.
The aim of this study was to determine the influence of insulin-like growth factor binding proteins (IGFBP)-1 and IGFBP-3, and IGF-1 on calcaneal ultrasound parameters in middle-aged and elderly European men.
Men aged 40 to 79 years were recruited from population registers for participation in the European Male Ageing Study (EMAS). Subjects were invited by letter to complete a postal questionnaire and to attend for an interviewer-assisted questionnaire, quantitative ultrasound (QUS) of the calcaneus and a fasting blood sample from which serum levels of IGFBP-1, IGFBP-3, IGF-1, oestradiol (E2) and SHBG were assayed. The questionnaires included the Physical Activity Scale for the Elderly (PASE) and questions about smoking and alcohol consumption. Estimated bone mineral density (eBMD) was derived as a function of the QUS parameters, speed of sound and broadband ultrasound attenuation. Height and weight were measured in all subjects.
3057 men, mean age 59.7 years (standard deviation [SD]=11.0) were included in the analysis. After adjusting for age, centre and BMI, higher levels of IGFBP-1 were associated with lower eBMD. Higher levels of both IGFBP-3 and IGF-1 were associated with higher eBMD. After further adjustment for PASE score, current smoking, alcohol consumption, free E2 and SHBG, IGFBP-3 and IGF-1, though not IGFBP-1, remained significantly associated with eBMD.
IGFBP-1 was associated with bone health though the effect could be explained by other factors. IGFBP-3 and IGF-1 were independent determinants of bone health in middle aged and elderly European men.
PMCID: PMC3920365  PMID: 21503646
insulin-like growth factor binding protein 1; insulin-like growth factor binding protein 3; calcaneus quantitative ultrasound; population-based; men
3.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
PMCID: PMC3077961  PMID: 20872596
4.  HLA‐Cw6 and HLA‐DRB1*07 together are associated with less severe joint disease in psoriatic arthritis 
Annals of the Rheumatic Diseases  2007;66(6):807-811.
Human leucocyte antigen (HLA) genes predict disease severity in psoriasis (HLA‐Cw6) and rheumatoid arthritis (shared epitope (SE)), but the situation is unclear for psoriatic arthritis (PsA).
To determine the association of the HLA‐Cw6 and HLA‐DRB1 gene with disease severity in a large UK cohort with PsA.
Genotyping of the HLA‐Cw and HLA‐DRB1 loci was undertaken in DNA samples from patients with PsA (n = 480). Stratification and regression analysis were used within the PsA cases to determine whether HLA‐Cw6, HLA‐DRB1 or the presence of the SE alleles predicted disease severity as measured by the Health Assessment Questionnaire score, the total number of damaged or involved joints adjusted for disease duration and disease‐modifying antirheumatic treatments.
HLA‐Cw6 was found to be in linkage disequilibrium with HLA‐DRB1*07 (r2 = 0.46). Patients with PsA who carried both HLA‐Cw6 and HLA‐DRB1*07 had fewer damaged or involved joints (41% fewer damaged (95% CI 23% to 55%, p = 0.02) and 31% fewer involved joints (95% CI 16% to 44%, p<0.001)) compared with those who carried neither HLA‐Cw6 nor HLA‐DRB1*07 alleles. Those who carried either HLA‐Cw6 or HLA‐DRB1*07 alleles alone had no evidence of a reduction in joint involvement. The SE, HLA‐DRB1*03 and HLA‐DRB1*04 alleles did not predict severity using these outcome measures.
Patients with PsA carrying both HLA‐Cw6 and HLA‐DRB1*07 alleles have a less severe course of arthritis. This suggests that a protective locus lies on a haplotype marked by these alleles. No association was detected with disease severity and SE status.
PMCID: PMC1954651  PMID: 17223660
5.  Early functional disability predicts both all‐cause and cardiovascular mortality in people with inflammatory polyarthritis: results from the Norfolk Arthritis Register 
Annals of the Rheumatic Diseases  2007;66(4):486-492.
To investigate the predictive value of early functional disability in patients with inflammatory polyarthritis (IP), for all‐cause and cardiovascular disease (CVD) mortality.
1010 subjects with new‐onset IP from the Norfolk Arthritis Register were studied. All were seen at baseline and at 1 year. Health Assessment Questionnaire (HAQ) scores were obtained at both time points. Vital status at 10 years from registration was established through central records. Mortality (all‐cause and CVD) per 1000 person‐years were calculated by HAQ stratum (HAQ scores <1, 1–2 and ⩾2). The predictive value of HAQ (per unit increase) at the two time points, adjusted for age at onset of symptom, sex and other factors found to predict mortality, was assessed using Cox regression models. The analysis was repeated for those who satisfied the 1987 American College of Rheumatology criteria for rheumatoid arthritis (RA) by 5 years.
By 10 years, 171 (16.9%) subjects had died. 89 deaths (52%) were attributed to CVD. Mortality was greatest in the highest HAQ group at both time points. Following adjustment for other predictors, HAQ score at year 1 remained a significant predictor of all‐cause mortality (HR 1.46; 95% CI 1.15 to 1.85) and CVD mortality (HR 1.49; 95% CI 1.12 to 1.97). The predictive value of HAQ at year 1 was similar in the RA subgroup.
Our data show that at 1 year of follow‐up, HAQ score is an important independent predictor of subsequent all‐cause and CVD mortalities in people with IP and RA. Baseline HAQ scores are of less value.
PMCID: PMC1856031  PMID: 17090565
7.  Lumbar disc degeneration: association between osteophytes, end‐plate sclerosis and disc space narrowing 
Annals of the Rheumatic Diseases  2006;66(3):330-333.
Lumbar disc degeneration is characterised radiologically by the presence of osteophytes, end‐plate sclerosis and disc space narrowing.
To determine the strength of the association between increasing severity of combinations of these features in a population sample of men and women.
Men and women aged ⩾50 years were recruited from a primary care‐based community health index in Aberdeen, UK. Participants had lateral spinal radiographs performed according to a standard protocol. The intervertebral disc spaces (L1/2–L4/5) were evaluated for the presence of anterior osteophytes, end‐plate sclerosis and disc space narrowing using a graded semiquantitative score (grade 0–3). Log linear modelling was used to determine the associations (pairwise) between increasing severity of these features, with the results expressed as β coefficients and 95% confidence intervals (CIs).
There were 286 men (mean age 65.3 years) and 299 women (mean age 65.2 years) with spinal radiographs, yielding a total of 2340 assessable lumbar vertebral levels. In all, 73% of vertebral levels had evidence of osteophytes, 26% of sclerosis and 37% of disc space narrowing. Increasing severity of osteophyte grade was associated with an increasing severity both of sclerosis and of disc space narrowing, whereas the severity of sclerosis was associated with the severity of narrowing. This was true at all vertebral levels. The strongest association, however, was between osteophytes and sclerosis (β coefficient = 2.7, 95% CI 2.4 to 3.1). For sclerosis and narrowing the β coefficient was 1.9 (95% CI 1.7 to 2.1), whereas for osteophytes and narrowing the β coefficient was much weaker at 1.2 (95% CI 1.1 to 1.3). There was no important influence of vertebral level on any of these associations.
The association between increasing severity of osteophytes and end‐plate sclerosis is stronger than for other combinations of radiographic features of lumbar disc degeneration.
PMCID: PMC1856007  PMID: 17028115
8.  Predicting the onset of knee pain: results from a 2‐year prospective study of new workers 
Annals of the Rheumatic Diseases  2006;66(3):400-406.
To determine the relative contribution of work‐related mechanical (injury) factors and psychosocial factors to the onset of a new episode of knee pain, in a cohort of newly employed workers.
A prospective cohort study of newly employed workers from 12 diverse occupational settings in England (The New Workers Study). 859 newly employed workers, free of knee pain, were identified. Information about occupational mechanical factors (manual handling and postural activities), the occupational physical environment, and psychological and psychosocial factors was collected by self‐completion questionnaires. Participants were followed up after 12 and 24 months to identify cases of knee pain onset. Generalised estimating equations were used to estimate the risk of new‐onset knee pain, with respect to the exposures previously measured.
In total, over the 2‐year follow‐up period, 108 cases of new‐onset knee pain were observed. Mechanical load, postural factors, psychological distress and work‐place psychosocial factors all influenced the risk of new‐onset knee pain over the 2‐year follow‐up period. On multivariate analysis, two factors remained independently predictive of knee pain onset: lifting or carrying heavy weights in one hand, and the level of general psychological distress.
In addition to mechanical (injury) factors, psychological factors are important risk factors for knee pain onset as shown in a population of young newly employed workers.
PMCID: PMC1856001  PMID: 16935910
9.  Influence of Inflammatory Polyarthritis on Quantitative Heel Ultrasound Measurements 
There are few data concerning the impact of inflammatory polyarthritis (IP) on quantitative heel ultrasound (QUS) measurements. The aims of this analysis were i) to determine the influence of IP on QUS measurements at the heel and, ii) among those with IP to determine the influence of disease related factors on these measurements.
Men and women aged 16 years and over with recent onset IP were recruited to the Norfolk Arthritis Register (NOAR). Individuals with an onset of joint symptoms between 1989 and 1999 were included in this analysis. At the baseline visit subjects underwent a standardised interview and clinical examination with blood taken for rheumatoid factor. A population-based prospective study of chronic disease (EPIC-Norfolk) independently recruited men and women aged 40 to 79 years from the same geographic area between 1993 and 1997. At a follow up assessment between 1998 and 2000 subjects in EPIC-Norfolk were invited to have quantitative ultrasound measurements of the heel (CUBA-Clinical) performed. We compared speed of sound (SOS) and broadband ultrasound attenuation (BUA), in those subjects recruited to NOAR who had ultrasound measurements performed (as part of EPIC-Norfolk) subsequent to the onset of joint symptoms with a group of age and sex matched non-IP controls who had participated in EPIC-Norfolk. Fixed effect linear regression was used to explore the influence of IP on the heel ultrasound parameters (SOS and BUA) so the association could be quantified as the mean difference in BUA and SOS between cases and controls. In those with IP, linear regression was used to examine the association between these parameters and disease related factors.
139 men and women with IP and 278 controls (mean age 63.2 years) were studied. Among those with IP, mean BUA was 76.3 dB/MHz and SOS 1621.8 m/s. SOS was lower among those with IP than the controls (difference = −10.0; 95% confidence interval (CI) –17.4, -2.6) though BUA was similar (difference = −1.2; 95% CI −4.5, +2.1). The difference in SOS persisted after adjusting for body mass index and steroid use. Among those with IP, disease activity as determined by the number of swollen joints at baseline, was associated with a lower SOS. In addition SOS was lower in the subgroup that satisfied the 1987 ACR criteria. By contrast, disease duration, steroid use and HAQ score were not associated with either BUA or SOS.
In this general population derived cohort of individuals with inflammatory polyarthritis there is evidence from ultrasound of a potentially adverse effect on the skeleton. The effect appears more marked in those with active disease.
PMCID: PMC3441510  PMID: 22834652
14.  Influence of Polymorphisms in the RANKL/RANK/OPG Signaling Pathway on Volumetric Bone Mineral Density and Bone Geometry at the Forearm in Men 
Calcified Tissue International  2011;89(6):446-455.
We sought to determine the influence of single-nucleotide polymorphisms (SNPs) in RANKL, RANK, and OPG on volumetric bone mineral density (vBMD) and bone geometry at the radius in men. Pairwise tag SNPs (r2 ≥ 0.8) for RANKL (n = 8), RANK (n = 44), and OPG (n = 22) and five SNPs near RANKL and OPG strongly associated with areal BMD in genomewide association studies were previously genotyped in men aged 40–79 years in the European Male Ageing Study (EMAS). Here, these SNPs were analyzed in a subsample of men (n = 589) who had peripheral quantitative computed tomography (pQCT) performed at the distal (4%) and mid-shaft (50%) radius. Estimated parameters were total and trabecular vBMD (mg/mm3) and cross-sectional area (mm2) at the 4% site and cortical vBMD (mg/mm3); total, cortical, and medullary area (mm2); cortical thickness (mm); and stress strain index (SSI) (mm3) at the 50% site. We identified 12 OPG SNPs associated with vBMD and/or geometric parameters, including rs10505348 associated with total vBMD (β [95% CI] = 9.35 [2.12–16.58], P = 0.011), cortical vBMD (β [95% CI] = 5.62 [2.10–9.14], P = 0.002), cortical thickness (β [95% CI] = 0.08 [0.03–0.13], P = 0.002), and medullary area (β [95% CI] = −2.90 [−4.94 to −0.86], P = 0.005) and rs2073618 associated with cortical vBMD (β [95% CI] = −4.30 [−7.78 to −0.82], P = 0.015) and cortical thickness (β [95% CI] = −0.08 [−0.13 to −0.03], P = 0.001). Three RANK SNPs were associated with vBMD, including rs12956925 associated with trabecular vBMD (β [95% CI] = −7.58 [−14.01 to −1.15], P = 0.021). There were five RANK SNPs associated with geometric parameters, including rs8083511 associated with distal radius cross-sectional area (β [95% CI] = 8.90 [0.92–16.88], P = 0.029). No significant association was observed between RANKL SNPs and pQCT parameters. Our findings suggest that genetic variation in OPG and RANK influences radius vBMD and geometry in men.
Electronic supplementary material
The online version of this article (doi:10.1007/s00223-011-9532-y) contains supplementary material, which is available to authorized users.
PMCID: PMC3215872  PMID: 21964949
Osteoporosis; Genetic association; Genetic polymorphism; Male; QCT
15.  Elevated levels of gonadotrophins but not sex steroids are associated with musculoskeletal pain in middle-aged and older European men 
Pain  2011;152(7-2):1495-1501.
The aim of this study was to determine the association of hormone levels with the occurrence of musculoskeletal pain. Men ages 40 to 79 years were recruited from population registers in 8 European centres. Subjects were asked to complete a postal questionnaire, which enquired about lifestyle and the occurrence of musculoskeletal pain over the past month. Total testosterone (T), oestradiol (E2), luteinising hormone (LH), and follicle-stimulating hormone (FSH) were assayed from a fasting blood sample. The association between pain status and hormone levels was assessed using multinomial logistic regression with results expressed as relative risk ratios (RRR) and 95% confidence intervals (CI). A total of 3206 men had complete data on pain status. Of these, 8.7% reported chronic widespread pain (CWP), whereas 50% had some pain although not CWP and were classified as having some pain. T and E2 were not associated with musculoskeletal pain, whereas significant differences in LH and FSH levels were found between pain groups. After adjustment for age and other possible confounders, the association between pain status and both LH and FSH persisted. Compared with those in the lowest tertile of LH, those in the highest tertile were more likely to report some pain (vs no pain, RRR = 1.28; 95% CI 1.09 to 1.50) and also CWP (vs no pain, RRR = 1.51; 95% CI 1.10 to 2.07). Similar results were found for FSH. Gonadotrophins, but not sex steroid hormone levels, are associated with musculoskeletal pain in men.
Higher levels of gonadotrophins but not androgens were significantly associated with musculoskeletal pain in men. Alterations in hypothalamic–pituitary–testicular feedback mechanisms may play a role in the onset of chronic widespread pain.
PMCID: PMC3183223  PMID: 21421286
Musculoskeletal pain; Reproductive hormones; American College of Rheumatology; European Male Ageing Study; Epidemiology
16.  A validation of the first genome-wide association study of calcaneus ultrasound parameters in the European Male Ageing Study 
BMC Medical Genetics  2011;12:19.
A number of single nucleotide polymorphisms (SNPs) have been associated with broadband ultrasound attenuation (BUA) and speed of sound (SOS) as measured by quantitative ultrasound (QUS) at the calcaneus in the Framingham 100K genome-wide association study (GWAS) but have not been validated in independent studies. The aim of this analysis was to determine if these SNPs are associated with QUS measurements assessed in a large independent population of European middle-aged and elderly men. The association between these SNPs and bone mineral density (BMD) measured using dual-energy X-ray absorptiometry (DXA) was also tested.
Men aged 40-79 years (N = 2960) were recruited from population registers in seven European centres for participation in an observational study of male ageing, the European Male Ageing Study (EMAS). QUS at the calcaneus was measured in all subjects and blood was taken for genetic analysis. Lumbar spine (LS), femoral neck (FN) and total hip (TH) BMD were measured by DXA in a subsample of 620 men in two centres. SNPs associated with BUA or SOS in the Framingham study with p < 10-4 were selected and genotyped using SEQUENOM technology. Linear regression was used to test for the association between SNPs and standardised (SD) bone outcomes under an additive genetic model adjusting for centre. The same direction of effect and p < 0.05 indicated replication.
Thirty-four of 38 selected SNPs were successfully genotyped in 2377 men. Suggestive evidence of replication was observed for a single SNP, rs3754032, which was associated with a higher SOS (β(SD) = 0.07, p = 0.032) but not BUA (β(SD) = 0.02, p = 0.505) and is located in the 3'UTR of WDR77 (WD repeat domain 77) also known as androgen receptor cofactor p44. A single SNP, rs238358, was associated with BMD at the LS (β(SD) = -0.22, p = 0.014), FN (β(SD) = -0.31,p = 0.001) and TH (β(SD) = -0.36, p = 0.002) in a locus previously associated with LS BMD in large-scale GWAS, incorporating AKAP11 and RANKL.
We found suggestive evidence of association between a single SNP located in the 3'UTR of WDR77 with calcaneal ultrasound parameters. The majority of SNPs, associated with QUS parameters in the Framingham Study, were not replicated in an independent population sample of European men.
PMCID: PMC3042372  PMID: 21276240
17.  Influence of arthritis and non-arthritis related factors on areal bone mineral density (BMDa) in women with longstanding inflammatory polyarthritis: a primary care based inception cohort 
The aim of this analysis was to determine the relative influence of disease and non-disease factors on areal bone mineral density (BMDa) in a primary care based cohort of women with inflammatory polyarthritis.
Women aged 16 years and over with recent onset inflammatory polyarthritis were recruited to the Norfolk Arthritis Register (NOAR) between 1990 and 1993. Subjects were examined at both baseline and follow up for the presence of tender, swollen and deformed joints. At the 10th anniversary visit, a sub-sample of women were invited to complete a bone health questionnaire and attend for BMDa (Hologic, QDR 4000). Linear regression was used to examine the association between BMDa with both (i) arthritis-related factors assessed at baseline and the 10th anniversary visit and (ii) standard risk factors for osteoporosis. Adjustments were made for age.
108 women, mean age 58.0 years were studied. Older age, decreasing weight and BMI at follow up were all associated with lower BMDa at both the spine and femoral neck. None of the lifestyle factors were linked. Indices of joint damage including 10th anniversary deformed joint count and erosive joint count were the arthritis-related variables linked with a reduction in BMDa at the femoral neck. By contrast, disease activity as determined by the number of tender and or swollen joints assessed both at baseline and follow up was not linked with BMDa at either site.
Cumulative disease damage was the strongest predictor of reduced femoral bone density. Other disease and lifestyle factors have only a modest influence.
PMCID: PMC2889849  PMID: 20509941
18.  Why are women predisposed to autoimmune rheumatic diseases? 
The majority of autoimmune diseases predominate in females. In searching for an explanation for this female excess, most attention has focused on hormonal changes - both exogenous changes (for example, oral contraceptive pill) and fluctuations in endogenous hormone levels particularly related to menstruation and pregnancy history. Other reasons include genetic differences, both direct (influence of genes on sex chromosomes) and indirect (such as microchimerism), as well as gender differences in lifestyle factors. These will all be reviewed, focusing on the major autoimmune connective tissue disorders: rheumatoid arthritis, systemic lupus erythematosus and scleroderma.
PMCID: PMC2787267  PMID: 19863777
19.  What epidemiology has told us about risk factors and aetiopathogenesis in rheumatic diseases 
This article will review how epidemiological studies have advanced our knowledge of both genetic and environmental risk factors for rheumatic diseases over the past decade. The major rheumatic diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, scleroderma, osteoarthritis, gout, and fibromyalgia, and chronic widespread pain, will be covered. Advances discussed will include how a number of large prospective studies have improved our knowledge of risk factors, including diet, obesity, hormones, and smoking. The change from small-scale association studies to genome-wide association studies using gene chips to reveal new genetic risk factors will also be reviewed.
PMCID: PMC2714091  PMID: 19490599
20.  The association between neighbourhood socio-economic status and the onset of chronic widespread pain: Results from the EPIFUND study 
Cross-sectional studies have reported an inverse relationship between socio-economic status and the prevalence of chronic widespread pain (CWP). However, the extent to which this relationship is explained by psychological factors is unknown. The aim of this study was to examine the hypothesis that socio-economic status predicts the onset of CWP but that this relationship would be explained by psychological factors.
Subjects from three diverse socio-economic areas were recruited into a population-based prospective survey of pain. Subjects completed a questionnaire at baseline that assessed pain status and psychological factors and occupation. Fifteen months later subjects completed a follow-up questionnaire which assessed pain status.
A total of 3489 subjects were free of CWP at baseline and eligible for follow-up, of whom 2782 (79.7%) participated. Of those, 281 (10%) subjects were classified as having new CWP. Logistic regression analysis revealed that compared to subjects from the most affluent socio-economic area, those from the moderate and least affluent areas were respectively, 1.47 (95% CI: 1.08–2.01) and 1.35 (95% CI: 1.00–1.82) times more likely to have new CWP. However, in a stepwise multivariate logistic regression analysis, controlling for psychological factors, the relationship between new onset CWP and socio-economic status was no longer evident.
This study has demonstrated that socio-economic status is related to new onset CWP, but the association is explained by psychological factors. Understanding the factors underlying the association between socio-economic status and pain should help to design intervention strategies which may reduce the burden of chronic pain in identified high risk population groups.
PMCID: PMC2701988  PMID: 18782674
Chronic widespread pain; Socio-economic status; Psychological distress
21.  Aspects of early arthritis. What determines the evolution of early undifferentiated arthritis and rheumatoid arthritis? An update from the Norfolk Arthritis Register 
Over 3500 patients with recent onset inflammatory polyarthritis (IP) have been recruited by the Norfolk Arthritis Register (NOAR) since 1990. Longitudinal data from this cohort have been used to examine the prevalence and predictors of remission, functional disability, radiological outcome, cardiovascular mortality and co-morbidity and the development of non-Hodgkin's lymphoma. Rheumatoid factor titre, high baseline C-reactive protein and high baseline HAQ score are all predictors of a poor outcome. There is a strong association between possession of the shared epitope and the development of erosions. Patients who satisfy the American College of Rheumatology criteria for rheumatoid arthritis (RA) have a worse prognosis than those who do not. However, it appears that these patients are a poorly defined subset of all those with IP rather than having an entirely separate disease entity. New statistical techniques offer exciting possibilities for using longitudinal datasets such as NOAR to explore the long-term effects of treatment in IP and RA.
PMCID: PMC1779379  PMID: 16817941
22.  In adult onset myositis, the presence of interstitial lung disease and myositis specific/associated antibodies are governed by HLA class II haplotype, rather than by myositis subtype 
The aim of this study was to investigate HLA class II associations in polymyositis (PM) and dermatomyositis (DM), and to determine how these associations influence clinical and serological differences. DNA samples were obtained from 225 UK Caucasian idiopathic inflammatory myopathy patients (PM = 117, DM = 108) and compared with 537 randomly selected UK Caucasian controls. All cases had also been assessed for the presence of related malignancy and interstitial lung disease (ILD), and a number of myositis-specific/myositis-associated antibodies (MSAs/MAAs). Subjects were genotyped for HLA-DRB1, DQA1 and DQB1. HLA-DRB1*03, DQA1*05 and DQB1*02 were associated with an increased risk for both PM and DM. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype demonstrated strong association with ILD, irrespective of myositis subtype or presence of anti-aminoacyl-transfer RNA synthetase antibodies. The HLA-DRB1*07-DQA1*02-DQB1*02 haplotype was associated with risk for anti-Mi-2 antibodies, and discriminated PM from DM (odds ratio 0.3, 95% confidence interval 0.1–0.6), even in anti-Mi-2 negative patients. Other MSA/MAAs showed specific associations with other HLA class II haplotypes, irrespective of myositis subtype. There were no genotype, haplotype or serological associations with malignancy. The HLA-DRB1*03-DQA1*05-DQB1*02 haplotype associations appear to not only govern disease susceptibility in Caucasian PM/DM patients, but also phenotypic features common to PM/DM. Though strongly associated with anti-Mi-2 antibodies, the HLA-DRB1*07-DQA1*02-DQB1*02 haplotype shows differential associations with PM/DM disease susceptibility. In conclusion, these findings support the notion that myositis patients with differing myositis serology have different immunogenetic profiles, and that these profiles may define specific myositis subtypes.
PMCID: PMC1526560  PMID: 16507114
23.  Hypothalamic-pituitary-adrenal stress axis function and the relationship with chronic widespread pain and its antecedents 
Arthritis Research & Therapy  2005;7(5):R992-R1000.
In clinic studies, altered hypothalamic-pituitary-adrenal (HPA) axis function has been associated with fibromyalgia, a syndrome characterised by chronic widespread body pain. These results may be explained by the associated high rates of psychological distress and somatisation. We address the hypothesis that the latter, rather than the pain, might explain the HPA results. A population study ascertained pain and psychological status in subjects aged 25 to 65 years. Random samples were selected from the following three groups: satisfying criteria for chronic widespread pain; free of chronic widespread pain but with strong evidence of somatisation ('at risk'); and a reference group. HPA axis function was assessed from measuring early morning and evening salivary cortisol levels, and serum cortisol after physical (pain pressure threshold exam) and chemical (overnight 0.25 mg dexamethasone suppression test) stressors. The relationship between HPA function with pain and the various psychosocial scales assessed was modelled using appropriate regression analyses, adjusted for age and gender. In all 131 persons with chronic widespread pain (participation rate 74%), 267 'at risk' (58%) and 56 controls (70%) were studied. Those in the chronic widespread pain and 'at risk' groups were, respectively, 3.1 (95% CI (1.3, 7.3)) and 1.8 (0.8, 4.0) times more likely to have a saliva cortisol score in the lowest third. None of the psychosocial factors measured were, however, associated with saliva cortisol scores. Further, those in the chronic widespread pain (1.9 (0.8, 4.7)) and 'at risk' (1.6 (0.7, 3.6)) groups were also more likely to have the highest serum cortisol scores. High post-stress serum cortisol was related to high levels of psychological distress (p = 0.05, 95% CI (0.02, 0.08)). After adjusting for levels of psychological distress, the association between chronic widespread pain and post-stress cortisol scores remained, albeit slightly attenuated. This is the first population study to demonstrate that those with established, and those psychologically at risk of, chronic widespread pain demonstrate abnormalities of HPA axis function, which are more marked in the former group. Although some aspects of the altered function are related to the psychosocial factors measured, we conclude that the occurrence of HPA abnormality in persons with chronic widespread pain is not fully explained by the accompanying psychological stress.
PMCID: PMC1257426  PMID: 16207340
24.  Psychological stress and fibromyalgia: a review of the evidence suggesting a neuroendocrine link 
Arthritis Research & Therapy  2004;6(3):98-106.
The present review attempts to reconcile the dichotomy that exists in the literature in relation to fibromyalgia, in that it is considered either a somatic response to psychological stress or a distinct organically based syndrome. Specifically, the hypothesis explored is that the link between chronic stress and the subsequent development of fibromyalgia can be explained by one or more abnormalities in neuroendocrine function. There are several such abnormalities recognised that both occur as a result of chronic stress and are observed in fibromyalgia. Whether such abnormalities have an aetiologic role remains uncertain but should be testable by well-designed prospective studies.
PMCID: PMC416451  PMID: 15142258
fibromyalgia; hormone; neurotransmitter; psychological stress
25.  Predictors of hip joint replacement in new attenders in primary care with hip pain. 
BACKGROUND: Studies investigating the factors associated with need for total hip replacement should ideally be based on prospective investigation of new attenders in primary care. AIM: To determine the incidence of listing for total hip replacement, and its predictors, among attenders in primary care with a new episode of hip pain. DESIGN OF STUDY: Prospective multicentre cohort study. SETTING: One hundred and ninety-five patients (mean age = 63 years, 68% female) with new episode of hip pain, attending primary care between November 1994 and October 1997. At the first visit, patients were evaluated for indices of pain and disability, range of hip movement, and radiographic changes of osteoarthritis. METHOD: General practitioner participants were recruited from the membership of the Primary Care Rheumatology Society to recruit all consecutive attenders with a new episode of hip pain. Annual follow-up was carried out to determine which patients were being 'put on a waiting list' for total hip replacement. RESULTS: Seven per cent of patients were put on a waiting list for total hip replacement within 12 months and 23% of patients within four years. At presentation, pain duration, pain severity, (including the need to use a stick) and restriction of internal rotation were the major clinical predictors of being put on a waiting list. Radiographic predictors of osteoarthritis performed similarly to the clinical measures. A simple scoring system based on both radiographic severity and two of the clinical measures was derived that identified groups at high likelihood of being put on a waiting list (sensitivity = 76%) with a low false-positive rate (specificity = 95%). CONCLUSION: New primary care attenders with pain are frequently accepted for total hip replacement soon after their first attendance--a decision that can be predicted by simple clinical measures.
PMCID: PMC1314488  PMID: 12564273

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