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author:("sillman, A J")
1.  Influence of age and sex steroids on bone density and geometry in middle-aged and elderly European men 
Osteoporosis International  2010;22(5):1513-1523.
The influence of age and sex steroids on bone density and geometry of the radius was examined in two European Caucasian populations. Age-related change in bone density and geometry was observed. In older men, bioavailable oestradiol may play a role in the maintenance of cortical and trabecular bone mineral density (BMD).
To examine the effect of age and sex steroids on bone density and geometry of the radius in two European Caucasian populations.
European Caucasian men aged 40–79 years were recruited from population registers in two centres: Manchester (UK) and Leuven (Belgium), for participation in the European Male Ageing Study. Total testosterone (T) and oestradiol (E2) were measured by mass spectrometry and the free and bioavailable fractions calculated. Peripheral quantitative computed tomography was used to scan the radius at distal (4%) and midshaft (50%) sites.
Three hundred thirty-nine men from Manchester and 389 from Leuven, mean ages 60.2 and 60.0 years, respectively, participated. At the 50% radius site, there was a significant decrease with age in cortical BMD, bone mineral content (BMC), cortical thickness, and muscle area, whilst medullary area increased. At the 4% radius site, trabecular and total volumetric BMD declined with age. Increasing bioavailable E2 (bioE2) was associated with increased cortical BMD (50% radius site) and trabecular BMD (4% radius site) in Leuven, but not Manchester, men. This effect was predominantly in those aged 60 years and over. In older Leuven men, bioavailable testosterone (Bio T) was linked with increased cortical BMC, muscle area and SSI (50% radius site) and total area (4% radius site).
There is age-related change in bone density and geometry at the midshaft radius in middle-aged and elderly European men. In older men bioE2 may maintain cortical and trabecular BMD. BioT may influence bone health through associations with muscle mass and bone area.
PMCID: PMC3073040  PMID: 21052641
Ageing; Epidemiology; Osteoporosis; Peripheral quantitative computed tomography; Sex hormones
2.  Pressure pain thresholds and tender point counts as predictors of new chronic widespread pain in somatising subjects 
Annals of the Rheumatic Diseases  2006;66(4):517-521.
Tender points are a general measure of distress both in the community and in clinic subjects. It has been suggested that multiple tender points should be regarded as the early stages of somatisation of distress. Similarly, recent evidence suggests that chronic widespread pain (CWP) is one manifestation of the somatisation of distress.
Given that a high tender point count and CWP are clinical hallmarks of the fibromyalgia syndrome, it was hypothesised that in somatising subjects, a high tender point count or a low pain threshold would predict the development of CWP in the future.
In this population‐based prospective study, 245 adults aged 25–65 years, free of CWP, were identified on the basis of a detailed questionnaire on pain and a psychosocial questionnaire comprising the Somatic Symptom Checklist and the Illness Behaviour subscale of the Illness Attitude Scales. These subjects took part in a pain threshold examination with a Fischer pressure algometer. Tender point counts were computed by including all areas with a pain threshold <4 kg/cm2. Individuals were followed up at 15 months, at which time 231 (93% of subjects still living at their baseline address) provided data on pain status, using the same instruments.
At follow‐up, 26 (11%) subjects developed new CWP. Although subjects with a low baseline pain threshold were not at increased risk of developing symptoms, a high tender point count, adjusted for age, sex, baseline pain status and other confounding factors, predicted the development of new CWP.
Subjects free of CWP are at an increased risk of its development if they have a high tender point count. However, a low‐pressure pain threshold does not predict the onset of symptoms. Data from this population‐based prospective study suggest that a low pain threshold in subjects with CWP is likely to be a secondary phenomenon as a result of pain or associated distress rather than the antecedent of symptoms.
PMCID: PMC1856033  PMID: 17012291
3.  Down regulation of multidrug resistance protein‐1 expression in patients with early rheumatoid arthritis exposed to methotrexate as a first disease‐modifying antirheumatic drug 
Annals of the Rheumatic Diseases  2006;65(10):1390-1393.
Methotrexate (MTX) is the current gold standard conventional disease‐modifying antirheumatic drug (DMARD) and is effluxed from cells by several transmembrane proteins, including multidrug resistance protein‐1 (MRP1). It is hypothesised that the overexpression of these proteins may mediate reduced efficacy of MTX. To date, it is unclear how expression of these proteins changes over time or after exposure to drugs.
To compare MRP1 expression in newly diagnosed patients with DMARD‐naive rheumatoid arthritis with that in healthy controls and to investigate how MRP1 expression changed after exposure to MTX.
18 newly diagnosed patients with DMARD‐naive rheumatoid arthritis and 14 healthy controls were recruited. Peripheral blood mononuclear cell counts were taken at baseline and after 6 months' treatment with MTX. Cells were separated by density gradient centrifugation and MRP1 expression was measured using the QCRL‐1 monoclonal antibody.
MRP1 expression in patients did not seem to be up regulated compared with that in healthy controls. In patients who were positive for MRP1 at baseline (61%), treatment with MTX and folic acid led to a marked down regulation of MRP1 expression at 6 months.
In patients with rheumatoid arthritis expressing MRP1, treatment with MTX and folic acid led to down regulation of MRP1 expression. Further studies are required to determine the mechanism behind this observation and whether MRP1 expression mediates altered efficacy to MTX.
PMCID: PMC1798314  PMID: 16504991
4.  Predictors of persistent neck pain after whiplash injury 
Emergency Medicine Journal : EMJ  2006;23(3):195-201.
To establish the aetiological influences of persistent neck pain following a motor vehicle collision and to construct a model for use in the emergency department for identifying patients at high risk of persistent symptoms.
Prospective cohort study. Patients recruited from hospital emergency departments were sent a questionnaire to gather information on various exposures. They were followed up at 1, 3, and 12 months to identify those with persistent symptoms.
Main outcome measure
Persistent neck pain (pain at 1, 3, and 12 months after collision).
The baseline survey included 765 patients. Subsequently, 480 completed a questionnaire at each follow up time point, of whom 128 (27%) reported neck pain on each occasion. Few collision specific factors predicted persistent neck pain. In contrast, a high level of general psychological distress, pre‐collision history of widespread body pain, type of vehicle, whiplash associated symptoms, and initial neck disability best predicted the persistence of symptoms. Furthermore, these factors, in combination, accounted for more than a fivefold increase in the risk of persistent neck pain.
The greatest predictors of persistent neck pain following a motor vehicle collision relate to psychological distress and aspects of pre‐collision health rather than to various attributes of the collision itself. With these factors, and those relating to initial injury severity, it is possible to identify a subgroup of patients presenting with neck pain with the highest risk of persistent symptoms. Thus, it is possible to identify whiplash patients with a poor prognosis and to provide closer follow up and specific attention to management in these individuals.
PMCID: PMC2464416  PMID: 16498156
whiplash; prognosis; predictors; epidemiology
5.  Does physical trauma lead to an increase in the risk of new onset widespread pain? 
Annals of the Rheumatic Diseases  2005;65(3):391-393.
To determine the rate of new onset of widespread pain after a traumatic event (motor vehicle crash).
A prospective cohort study of persons registered with an insurance company who had or had not experienced a motor vehicle crash. All participants were sent a questionnaire to assess pre‐crash (or for the non‐crash group, prior) psychosocial factors and widespread pain. Participants reporting pre‐crash (prior) widespread pain were excluded. At six months, participants were sent a follow up questionnaire to ascertain new prevalent widespread pain.
597 (51%) of participants returned a baseline questionnaire (465 crash and 132 non‐crash). Among the cohort who had experienced a crash, the new onset rate of widespread pain six months later was low (8%), though in comparison with the non‐crash group there was an increased risk (RR = 1.9 (95% CI, 0.8 to 4.8, adjusted for age and sex)); this was attenuated after adjustment for pre‐crash (prior) psychological distress and somatic symptoms (RR = 1.4 (95% CI, 0.5 to 3.2)).
The findings suggest that a motor vehicle crash (as an example of a physically traumatic event) is unlikely to have a major impact on the new onset of widespread pain. Any observed relation may, in part, be explained by psychological distress.
PMCID: PMC1798040  PMID: 16014672
fibromyalgia; pain; trauma
6.  Radiographic features of lumbar disc degeneration and bone mineral density in men and women 
Annals of the Rheumatic Diseases  2005;65(2):234-238.
To determine the association between individual radiographic features of lumbar disc degeneration and bone mineral density (BMD) at the spine and hip.
Subjects were recruited from a population register for a screening survey of vertebral osteoporosis. BMD was assessed at the spine and hip using dual energy x ray absorptiometry. Lateral spinal radiographs were evaluated for features of lumbar disc degeneration. Each vertebral level from L1/2 to L4/5 was assessed for the presence and severity of osteophytes, end plate sclerosis, and disc space narrowing. Linear regression was used to determine the association between each of these features and BMD at the spine and hip, with adjustments for age, body mass index, and levels of physical activity. Analyses were done separately in men and women.
250 women and 256 men (mean age around 65 years) were studied. At the lumbar spine, after age adjustment there was an increase in BMD with increasing grade for all radiographic features of disc degeneration in both men and women. At the femoral neck, after age adjustment there was an increase in BMD with increasing osteophyte and end plate sclerosis grade though not disc space narrowing. Adjusting for body mass index and physical activity did not influence the strength of the associations.
Radiographic features of lumbar disc degeneration are associated with an increase in BMD at the spine. Osteophytes and end plate sclerosis, but not disc space narrowing, are associated with an increase in BMD at the hip.
PMCID: PMC1798008  PMID: 16014671
epidemiology; lumbar disc degeneration; radiographic features; bone mineral density
7.  Can clinical factors at presentation be used to predict outcome of treatment with methotrexate in patients with early inflammatory polyarthritis? 
Methotrexate (MTX) is the first choice conventional disease-modifying antirheumatic drug (DMARD) for rheumatoid arthritis. It is not universally effective, however; although to date it is not possible to predict with any accuracy which patients will respond to treatment. The aim of this analysis was to examine whether clinical and genetic variables could be used to predict response to MTX.
Patients recruited to the Norfolk Arthritis Register (NOAR), a primary care based inception cohort of patients with inflammatory polyarthritis, were eligible for this analysis if they were commenced on MTX as their first DMARD within 3 months of their baseline visit and had at least 2 years of follow-up data. Outcome on MTX was defined as: (1) stopped for adverse events; (2) stopped for inefficacy or second DMARD added; (3) stopped for other reasons; or (4) remained on MTX monotherapy. Multiple logistic regression was used to establish which variables (including demographics, disease activity and Health Assessment Questionnaire score) predicted stopping monotherapy for inefficacy or adverse event (with those remaining on treatment taken as the referent category). The area under the Receiver Operating Characteristic curves (AUC ROC), were used to determine how accurate the model was at predicting outcome.
309 patients were included in this analysis. At 1 year (2 years), 34 (46) patients had stopped for adverse events and 25 (49) had either stopped monotherapy for inefficacy or had a second DMARD added. 231 (188) patients remained on MTX monotherapy. The strongest predictor of inefficacy at both time points was shared epitope positivity: odds ratios (OR) 5.8 (95% confidence intervals (CI) 1.3 to 25.6) at 1 year, OR 3.0 (95% CI 1.3 to 7.3) at 2 years. High Health Assessment Questionnaire score (OR 1.84 95% CI 1.12 to 3.01) and female gender (OR 2.2, 95% CI 0.92 to 5.28) were associated with adverse events on MTX at 1 year. However, even the most optimal combinations of the factors analysed were only weakly predictive of treatment outcome: AUC ROC for adverse events 0.68 (95% CI 0.58 to 0.78) and for inefficacy AUC ROC 0.71 (95% CI 0.6 to 0.81).
Within this cohort, routine clinical and laboratory factors were poor at predicting outcome of treatment with MTX. Given the major therapeutic advantage to be derived from accurate prediction of treatment outcome, further studies will need to investigate novel biological and other markers.
PMCID: PMC2596302  PMID: 18292102
8.  Musculoskeletal pain is associated with a long-term increased risk of cancer and cardiovascular-related mortality 
Rheumatology (Oxford, England)  2008;48(1):74-77.
Objectives. To test the hypothesis that individuals with regional and widespread pain disorders have an increased risk of mortality.
Methods. We conducted a prospective cohort study of 4515 adults. Subjects were an age- and sex-stratified sample who had participated in a population study of pain occurrence during 1996. Based on those reports subjects were classified as having no pain, regional pain or widespread pain. All subjects were identified on the National Health Service Central Register and followed up until April 2005, a total of 8.2 yrs, at which time information was obtained on vital status, and if applicable, date and cause of death. The relationship between pain status and subsequent death is expressed as mortality rate ratios with 95% CIs, adjusted for age, gender, ethnicity and practice.
Results. A total of 35.2% reported regional pain and 16.9% satisfied criteria for widespread pain. In comparison with those without pain, there was a 20% and 30% increased risk of dying over the follow-up period among subjects with regional and widespread pain, respectively. The specific causes of death in excess were cancer and cardiovascular disease. In addition, the mortality risk from both cancer and cardiovascular deaths was found to increase as the number of pain sites that subjects reported increased.
Conclusions. This study supports a previous observation that persons with regional and widespread pain are at an increased risk of cancer death. Possible mechanisms should be explored.
PMCID: PMC2639482  PMID: 19056799
Pain; Musculoskeletal; Mortality; Cancer; Cardiovascular; Epidemiology; Population-based study; Prospective; Mechanisms
9.  Reduction in the incidence of myocardial infarction in patients with rheumatoid arthritis who respond to anti–tumor necrosis factor α therapy: Results from the British Society for Rheumatology Biologics Register 
Arthritis and Rheumatism  2007;56(9):2905-2912.
Rheumatoid arthritis (RA) is associated with an increased risk of coronary artery disease, possibly acting via shared mechanisms of inflammation. This study was undertaken to test the hypothesis that the powerful antiinflammatory effect of anti–tumor necrosis α (anti-TNFα) therapy might lead to a reduction in the incidence of myocardial infarction (MI) in patients with RA.
Using data from the British Society for Rheumatology Biologics Register, a national prospective observational study, we compared MI rates in 8,670 patients with RA treated with anti-TNFα and 2,170 patients with active RA treated with traditional disease-modifying antirheumatic drugs (DMARDs).
Through July 2006, 63 MIs occurred in the anti-TNFα cohort during 13,233 person-years of followup and 17 MIs occurred in the DMARD cohort during 2,893 person-years of followup, equivalent to a rate of 4.8 events per 1,000 person-years and 5.9 events per 1,000 person-years, respectively. After adjustment for baseline risk factors, there was no reduction in the rate of MI in the anti-TNFα cohort compared with the DMARD cohort (incidence rate ratio 1.44 [95% confidence interval 0.56–3.67]). In an analysis of anti-TNFα–treated patients who responded to the treatment within 6 months versus those who did not, MI rates were found to be 3.5 events per 1,000 person-years in responders and 9.4 events per 1,000 person-years in nonresponders. The adjusted incidence rate ratio (95% confidence interval) for responders compared with nonresponders was 0.36 (0.19–0.69).
These results indicate that RA patients treated with anti-TNFα do not have a lower incidence of MI compared with RA patients treated with traditional DMARDs. However, the risk of MI is markedly reduced in those who respond to anti-TNFα therapy by 6 months compared with nonresponders. This finding supports the notion that inflammation plays a pivotal role in MI.
PMCID: PMC2435427  PMID: 17763428
10.  Serious Infection Following Anti–Tumor Necrosis Factor α Therapy in Patients With Rheumatoid Arthritis: Lessons From Interpreting Data From Observational Studies 
Arthritis and Rheumatism  2007;56(9):2896-2904.
In a recent observational study, we found that the risk of serious infection following anti–tumor necrosis factor α (anti-TNFα) therapy in patients with rheumatoid arthritis (RA) was not importantly increased compared with the background risk in routinely treated RA patients with similar disease severity. Observational data sets are, however, subject to a number of important biases related to selection factors for the timing of starting and stopping therapy. Infection risk is also likely to vary with duration of therapy. This study was undertaken to examine the influences of these biases and of the method of analysis on the risk of infection.
We compared the risk of serious infection in 8,659 patients treated with anti-TNFα with that in 2,170 patients treated with traditional disease-modifying antirheumatic drugs (DMARDs) recruited to the British Society for Rheumatology Biologics Register. We applied a number of statistical models in which we varied the length of the followup period by using different definitions of the date of discontinuation of treatment and different lag periods of risk following drug cessation.
When the at-risk period was defined as “receiving treatment”, the adjusted incidence rate ratio comparing patients receiving anti-TNFα therapy with patients receiving DMARD therapy was 1.22 (95% confidence interval [95% CI] 0.88–1.69). Limiting followup to the first 90 days, however, revealed an adjusted incidence rate ratio of 4.6 (95% CI 1.8–11.9). Rates of infection were increased in the 90 days immediately following drug discontinuation and beyond, explained by selection factors for drug discontinuation.
These findings show that overall, the way in which UK rheumatologists select patients for starting and discontinuing anti-TNFα therapy explains our previous finding of no increase in risk. However, there may be important increases in true risk, notably early in the course of treatment, that would become more evident depending on the definition of at-risk period.
PMCID: PMC2435418  PMID: 17763441
11.  Non-steroidal anti-inflammatory drug use does not appear to be associated with increased cardiovascular mortality in patients with inflammatory polyarthritis: results from a primary care based inception cohort of patients 
Annals of the Rheumatic Diseases  2008;68(3):367-372.
There is controversy about the effects of non-steroidal anti-inflammatory drugs (NSAIDs) on cardiovascular disease (CVD) mortality. The aim of this study was to explore associations between NSAID use and mortality in patients with inflammatory polyarthritis (IP).
Subjects and methods:
A total of 923 patients with new onset (IP), recruited to the UK Norfolk Arthritis Register (NOAR) between 1990–1994, were followed up to the end of 2004. Current medication was recorded annually for the first 6 years and then every 2–3 years. Rheumatoid factor (RF) and C-reactive protein (CRP) were measured. Logistic regression was used to calculate all cause and CVD mortality odds ratios (OR) for NSAID use at baseline and during follow-up, adjusting for gender and time-varying covariates: RF, CRP, joint counts, smoking, steroid use, DMARD use and other medication use.
By 2004 there were 203 deaths, 85 due to CVD. At baseline, NSAIDs were used by 66% of patients. In final multivariate models, baseline NSAID use was inversely associated with all cause mortality (adjusted OR 0.62, 95% CI 0.45 to 0.84) and CVD mortality (adjusted OR 0.54, 95% CI 0.34 to 0.86). Interval NSAID use had weaker mortality associations: all cause mortality (adjusted OR 0.72, 95% CI 0.52 to 1.00), CVD mortality (adjusted hazard ratio (HR) 0.66, 95% CI 0.40 to 1.08).
No excess CVD or all cause mortality was observed in NSAID users in this cohort of patients with IP. This is at variance with the literature relating to NSAID use in the general population. It is unclear whether this represents unmeasured confounders influencing a doctor’s decision to avoid NSAIDs in the treatment of IP.
PMCID: PMC2633631  PMID: 18408253
12.  Investigating the role of the HLA-Cw*06 and HLA-DRB1 genes in susceptibility to psoriatic arthritis: comparison with psoriasis and undifferentiated inflammatory arthritis 
Annals of the Rheumatic Diseases  2007;67(5):677-682.
Psoriasis of early onset (type I; age of onset ⩽40 years) is associated with HLA-Cw*06 while the shared epitope (SE) is associated with rheumatoid arthritis susceptibility. Our aim was to investigate the role of HLA-Cw*06 and HLA-DRB1 genes (including SE) with psoriatic arthritis (PsA) susceptibility.
In a case–control association study, HLA-Cw*06 phenotype frequencies were compared between patients with PsA (n = 480), psoriasis alone (n = 611) and healthy controls (n = 166). Similarly, at the HLA-DRB1 locus, phenotype and SE frequencies were compared in patients with PsA (n = 480), early undifferentiated inflammatory arthritis alone (n = 1621) and healthy controls (n = 537).
The HLA-Cw*06 phenotype was associated with type I psoriasis (OR 6.9, 95% CI 4.4, 11.1, p = 2.2×10−21) and with patients with PsA having type I psoriasis (OR 5.0, 95% CI 3.2, 7.9, p = 4.39×10−13), but not with patients with PsA having type II psoriasis (age of onset >40 years). HLA-DRB1*07, in linkage disequilibrium with HLA-Cw*06, was also associated with patients with PsA having type I psoriasis (OR 2.7, 95% CI 2.1, 3.7, p<0.00001). HLA-DRB1*04 alleles and the SE were associated with undifferentiated inflammatory arthritis but not with PsA.
The SE is not a PsA susceptibility locus. HLA-Cw*06 and HLA-DRB1*07 are associated with patients with PsA having type I psoriasis, suggesting that the primary association is with age of onset of psoriasis. Patients with PsA having type I psoriasis, therefore, have a genetic background different to those with type II psoriasis, and adjustment for this is necessary in future studies that investigate the genetic susceptibility of PsA.
PMCID: PMC2563264  PMID: 17728335
13.  Hospital referrals for low back pain: more coherence needed. 
Low back pain is a common reason for hospital referral but little is known of the resulting workload in different specialties. All new outpatient attendances for conditions with low back pain were recorded over one month in a teaching hospital and a district general hospital. The patients were seen in at least ten specialties and two-fifths of them had been seen previously with the same symptom in another department. In the two hospitals, low back pain accounted for 15% and 12% of all new outpatient attendances. A more coherent referral policy is needed.
PMCID: PMC1297950  PMID: 10741313
14.  Obstetric and gynaecological factors in susceptibility to peripheral joint osteoarthritis. 
Annals of the Rheumatic Diseases  1996;55(9):671-673.
There is clear evidence that the age period coinciding with the peak age of the menopause is associated with an increased prevalence of osteoarthritis and this fits in with clinical observation of high likelihood of presentation at this age. A number of pieces of biological evidence also support the notion that changes in sex hormone status might influence risk of degenerative disease at peripheral joint sites. There do not appear, however, to be any important epidemiological predictors based on menstrual or obstetric history that might be useful in predicting who these women might be.
PMCID: PMC1010274  PMID: 8882147
16.  Interobserver reliability in measuring flexion, internal rotation, and external rotation of the hip using a plurimeter. 
Annals of the Rheumatic Diseases  1996;55(5):320-323.
OBJECTIVE: To determine reliability of the measurement of hip movements (flexion, internal rotation, and external rotation) between medical practitioners. METHODS: Six clinicians carried out measurements of hip movements on each of six patients with osteoarthritis of one hip, using a specifically designed plurimeter. RESULTS: There was no evidence of any systematic difference between medical practitioners in the measurement of hip flexion, internal rotation, or external rotation. The degree of agreement was greatest for hip flexion. CONCLUSIONS: This study has shown that measurement of range of movement at the hip is repeatable between practitioners using a simple plurimeter and may represent an examination that is suitable for monitoring progress and treatment.
PMCID: PMC1010170  PMID: 8660107
17.  Occurrence of rheumatoid arthritis is not increased in the first degree relatives of a population based inception cohort of inflammatory polyarthritis. 
OBJECTIVE: To determine the risk of rheumatoid arthritis (RA) in first degree relatives of a true population based sample of probands with inflammatory polyarthritis. METHODS: In a case-control study, a two stage screening procedure was used to ascertain the prevalence of RA in 518 first degree relatives of 207 Norfolk Arthritis Register cases registered in 1990 and 414 first degree relatives of 180 local controls. An initial joint symptom and medical history questionnaire was followed by a physical examination, and serological and radiological evaluation of those with symptoms. RESULTS: The prevalence of RA in the first degree relatives of all the Norfolk Arthritis Register cases was 7.7/1000, compared with 4.8/1000 in the first degree relatives of the controls, with a risk ratio of 1.6 (95% confidence interval 0.3 to 8.7). This very modest increase was also seen when the analysis was restricted to the first degree relatives of Norfolk Arthritis Register cases who satisfied the American Rheumatism Association criteria for RA: prevalence rate 7.2/1000. CONCLUSION: There was no evidence of an important increased familial risk of RA in this community based sample. These data are compatible with others from immunogenetic studies showing only weak HLA associations with community ascertained RA.
PMCID: PMC1010100  PMID: 8712872
18.  Lack of influence of non-inherited maternal HLA-DR alleles on susceptibility to rheumatoid arthritis. 
Annals of the Rheumatic Diseases  1995;54(4):311-313.
OBJECTIVE--To reproduce findings from previous reports that non-inherited maternal HLA class II antigens might contribute to rheumatoid arthritis (RA) susceptibility in the offspring. METHODS--Families were recruited from the Arthritis and Rheumatism Council's National Repository of RA families and HLA-DRB1 alleles were examined in these individuals and their first degree relatives using DNA typing methods. RESULTS--There was no evidence of an increase in either non-inherited maternal HLA-DR4 or the HLA-DRB1 shared epitope as a whole compared with the frequency expected using the non-inherited paternal antigens as controls. CONCLUSIONS--The numbers of probands who were shared epitope negative were small, but we are unable to confirm in these families the findings that non-inherited maternal HLA contributes an additional susceptibility factor to rheumatoid arthritis.
PMCID: PMC1005580  PMID: 7763111
19.  Age and sex influences on fall characteristics. 
Annals of the Rheumatic Diseases  1994;53(11):773-775.
OBJECTIVE--To investigate age and sex influences on fall characteristics. METHODS--A total of 1243 subjects (517 males and 726 females) aged 50 years and over and drawn from population based sampling frames were invited to complete an interviewer administered questionnaire concerning descriptive characteristics of falls experienced in the previous four months. Information collected included details about the part of the body to strike the ground, direction of the fall, level of trauma and whether or not injury or fracture was sustained. RESULTS--One hundred and seventy two subjects reported a fall in the previous four months. Restricting analysis to the 142 subjects who fell from a standing height or less, females aged 50-64 years were more than twice as likely to fall onto their hand compared with older females (odds ratio (OR) = 2.2; 95% confidence interval (CI) 0.8 to 6.2) and at all ages (50+) were more than three times as likely to fall on their hip compared with males (OR = 3.4; 95% CI 1.0 to 11.5). Compared with older males, males aged 50-64 were more likely to fall sideways (OR = 5.1; 95% CI 1.5 to 17.4) and less likely to fall forwards (OR = 0.4; 95% CI 0.1 to 1.1). CONCLUSION--There is a potentially clinically important variation in fall type by age and sex. In particular, this variation might explain patterns of occurrence of hip and Colles' fracture.
PMCID: PMC1005461  PMID: 7826141
20.  Low prevalence of rheumatoid arthritis in black-Caribbeans compared with whites in inner city Manchester. 
Annals of the Rheumatic Diseases  1994;53(5):293-297.
OBJECTIVE--To compare the prevalence of rheumatoid arthritis (RA) in Black-Caribbeans and Whites living in the same urban area. METHODS--Cases of inflammatory joint disease were ascertained initially from a postal screening survey of 1851 Black and 1829 age and sex-matched non-Blacks identified from general practice age-sex registers of seven general practices in the Moss Side and Hulme districts of Manchester. The ethnicity of respondents was confirmed using data from a postal screening questionnaire. Those reporting joint swelling or a history of arthritis were reviewed by a rheumatologist at surgeries held in each practice. The clinical records of the questionnaire non-responders and questionnaire-positive non-attenders at surgery were reviewed. RESULTS--In an adjusted denominator population of 1046 Black-Caribbeans and 997 Whites, the cumulative prevalence of RA was 2.9/1000 in Black-Caribbeans and 8/1000 in Whites, representing a prevalence in Black-Caribbeans of 0.36 times that found in Whites (95% confidence interval 0.1-1.3). CONCLUSIONS--Rheumatoid arthritis occurs less commonly in Black-Caribbeans than in Whites. The findings are consistent with published studies showing a low RA prevalence in rural African Black populations.
PMCID: PMC1005326  PMID: 8017981
21.  Occupational factors related to shoulder pain and disability. 
OBJECTIVES: To determine, in a population based study, the influence of occupational factors on the occurrence of shoulder pain and disability. METHODS: A random sample of patients was selected from the register of a general practice in the Greater Manchester area of the United Kingdom. Information was collected by a posted questionnaire with specific enquiries about symptoms in the shoulder region and related disability. A lifetime occupational history was obtained including physical exposures, working conditions, and psychosocial aspects of each workplace. Analysis has been conducted as a case-control study, comparing occupational exposures at the time of onset of symptoms in those with shoulder pain and disability with corresponding occupational exposures in those without shoulder pain and disability. RESULTS: An increased risk of shoulder pain and disability in men was associated with carrying weights on one shoulder (relative risk (RR) 5.5, 95% confidence interval (95% CI) 1.8 to 17), whereas those who reported working with hands above shoulder level, using wrists or arms in a repetitive way, or stretching down to reach below knee level had about twice the risk of shoulder pain and disability. Men working frequently in very cold or damp conditions had a fourfold and sixfold risk respectively of shoulder pain and disability. Reporting of shoulder pain and disability was also more common among men and women who reported that their work caused a lot of stress (RR 1.9, 95% CI 0.9 to 4.1) or was very monotonous (RR 2.7, 95% CI 1.3 to 5.4). The relations between physical exposures, working conditions, and psychosocial factors were independent. CONCLUSIONS: This population based study has shown that physical activities carried out at work, the physical conditions under which the work is conducted, psychosocial aspects of work, or the working environment are all independently related to the occurrence of shoulder symptoms and disability, emphasising the multifactorial nature of this condition.
PMCID: PMC1128779  PMID: 9196453
22.  Influence of previous exposure to human parvovirus B19 infection in explaining susceptibility to rheumatoid arthritis: an analysis of disease discordant twin pairs. 
Annals of the Rheumatic Diseases  1994;53(2):137-139.
OBJECTIVES--To assess the association between exposure to parvovirus B19 and susceptibility to rheumatoid arthritis (RA). METHODS--One hundred and fifty five twin pairs (76 monozygotic (MZ) and 79 dizygotic (DZ)), discordant for RA, were tested for the presence of IgG antiparvovirus antibodies using ELISA. The data obtained were analysed using conditional logistic regression, from which odds ratios and 95% confidence intervals were calculated. RESULTS--Overall, there was no association between exposure to parvovirus and RA (OR = 1.2, 95% CI: 0.7-1.7). However, in two subgroups there was a suggestion of an association. These were: (1) pairs where the affected twin was rheumatoid factor (RF) seronegative (OR = 2.0, 95% CI: 0.9-12.4) and (2) in opposite-sexed twin pairs where the affected twin was female (OR = 3.0, 95% CI: 0.9-11.6). CONCLUSION--Previous exposure to parvovirus infection did not explain disease susceptibility in both MZ and DZ discordant pairs with rheumatoid arthritis. This infection, however, might be relevant in some subgroups.
PMCID: PMC1005267  PMID: 8129459
23.  Unexpected HLA haplotype sharing in dizygotic twin pairs discordant for rheumatoid arthritis. 
Journal of Medical Genetics  1996;33(12):1015-1018.
Dizygotic twins are generally believed to be no more genetically similar than sibs born from separate pregnancies. In the present study, a panel of 93 dizygotic twin pairs discordant for rheumatoid arthritis were typed for HLA-A, -B, -Cw, and -DR antigens. HLA haplotype sharing identical by descent between the twins showed a trend towards increased sharing of both HLA haplotypes; this increased sharing was statistically significant when the female/female twin pairs were considered separately. In contrast, the pattern of HLA haplotype sharing in sib pairs (n = 128) was consistent with a 1:2:1 ratio of 2, 1, or 0 haplotypes shared. An analysis of 16 normal dizygotic twin pairs was consistent with these results raising the possibility that dizygotic twins in general are genetically more similar at the HLA complex than sibs born from separate pregnancies.
PMCID: PMC1050813  PMID: 9004134
24.  Lack of association of increased antibody levels to mycobacterial hsp65 with rheumatoid arthritis: results from a study of disease discordant twin pairs. 
Annals of the Rheumatic Diseases  1993;52(7):542-544.
OBJECTIVES--To investigate the role of humoral immunity to mycobacterial hsp65 in the aetiology of rheumatoid arthritis. METHODS--Levels of IgG antibodies to recombinant mycobacterial hsp65 were measured by enzyme linked immunosorbent assay (ELISA) in serum samples of 152 twin pairs discordant for RA and in serum samples from 62 normal blood donors. RESULTS--No significant differences between antibody levels in the subjects with RA compared either with their unaffected twins or with a group of normal blood donors was observed. In the monozygotic twins there was a strong but negative association between levels of antibody to hsp65 and disease status. Zygosity, sex, and HLA status did not significantly affect levels of antibody to hsp65. CONCLUSION--Previous reports of an association between hsp65 and RA were not confirmed.
PMCID: PMC1005096  PMID: 8346983
25.  Risk factors, falls, and fracture of the distal forearm in Manchester, UK. 
OBJECTIVE: To determine the risk factors associated with fracture of the distal forearm, and to evaluate the influence of falls on these risks. DESIGN: This was a case-control study. SETTING: Manchester, UK. PARTICIPANTS: The cases were 62 white women aged 45-82 years who had sustained a fracture of the distal forearm and had attended local hospitals. Two control groups were studied - 50 women who had fallen onto the hand but had not sustained a fracture (recruited from the same source as those with fracture) and 116 women randomly selected from primary care age and sex registers in the catchment area of the hospitals. Both cases and controls were sent a letter inviting them to take part in the study. Data were collected by questionnaire completed by an interviewer. MAIN RESULTS: Compared with the population control group, those with fracture were more likely to walk at a brisk pace (odds ratio (OR) = 3.5; 95% confidence interval (CI) 1.3, 9.6) though they had undertaken less physical activity at home or work on a daily basis throughout life (OR = 0.4; 95% CI 0.2, 0.9). The risk associated with brisk walking was less marked when the cases were compared with fall controls. Other lifestyle factors including calcium intake, smoking, and alcohol consumption were not associated with fracture. Analysis of gynaecological and hormonal factors suggested that compared with population controls, those with fracture of the distal forearm had had fewer fertile years (OR = 0.4; 95% CI 0.1, 0.9) and were less likely to have used oral contraceptives (OR = 0.3; 95% CI 0.1, 0.9). CONCLUSIONS: The data highlight the need for caution when advising middle aged and elderly subjects about exercise. Such advice should be combined with practical information about the prevention of falls. Hormonal factors seem to be additional determinants of fracture. Other lifestyle interventions seem unlikely to play an important part in preventing distal forearm fracture.
PMCID: PMC1060285  PMID: 8935460

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