M Lunt

Incidence of vertebral fracture in europe: results from the European Prospective Osteoporosis Study (EPOS).

Vertebral fracture is one of the major adverse clinical consequences of osteoporosis; however, there are few data concerning the incidence of vertebral fracture in population samples of men and women. The aim of this study was to determine the incidence of vertebral fracture in European men and women. A total of 14,011 men and women aged 50 years and over were recruited from population‐based registers in 29 European centers and had an interviewer‐administered questionnaire and lateral spinal radiographs performed. The response rate for participation in the study was approximately 50%. Repeat spinal radiographs were performed a mean of 3.8 years following the baseline film. All films were evaluated morphometrically. The definition of a morphometric fracture was a vertebra in which there was evidence of a 20% (+4 mm) or more reduction in anterior, middle, or posterior vertebral height between films—plus the additional requirement that a vertebra satisfy criteria for a prevalent deformity (using the McCloskey‐Kanis method) in the follow‐up film. There were 3174 men, mean age 63.1 years, and 3614 women, mean age 62.2 years, with paired duplicate spinal radiographs (48% of those originally recruited to the baseline survey). The age standardized incidence of morphometric fracture was 10.7/1000 person years (pyr) in women and 5.7/1000 pyr in men. The age‐standardized incidence of vertebral fracture as assessed qualitatively by the radiologist was broadly similar—12.1/1000 pyr and 6.8/1000 pyr, respectively. The incidence increased markedly with age in both men and women. There was some evidence of geographic variation in fracture occurrence; rates were higher in Sweden than elsewhere in Europe. This is the first large population‐based study to ascertain the incidence of vertebral fracture in men and women over 50 years of age across Europe. The data confirm the frequent occurrence of the disorder in men as well as in women and the rise in incidence with age.

Population-based geographic variations in dxa bone density in Europe: The evos study

The purpose of this study was to investigate variations in bone density between 16 European populations, 13 of which were participants in the European Vertebral Osteoporosis Study (EVOS). Men and women aged 50–80 years were recruited randomly from local population registers, stratified in 5-year age bands. The other three centres recruited similarly. Random samples of 20–100% of EVOS subjects were invited for dual-energy X-ray absorptiometry (DXA) densitometry of the lumbar spine and/or proximal femur using Hologic, Lunar or Norland pencil beam machines or, in one centre, a Sopha fan-beam machine. Cross-calibration of the different machines was undertaken using the European Spine Phantom prototype (ESPp). Highly significant differences in mean bone density were demonstrated between centres, giving rise to between-centre SDs in bone density that were about a quarter of a population SD. These differences persisted when centres using Hologic machines and centres using Lunar machines were considered separately. The centres were ranked differently according to whether male or female subjects were being considered and according to site of measurement (L2–4, femoral neck or femoral trochanter). As expected, bone mineral density (BMD) had a curvilinear relationship with age, and apparent rates of decrease slowed as age advanced past 50 years in both sexes. In the spine, not only did male BMD usually appear to increase with age, but there was a highly significant difference between centres in the age effect in both sexes, suggesting a variability in the impact of osteoarthritis between centres. Weight was consistently positively associated with BMD, but the effects of height and armspan were less consistent. Logarithmic transformation was needed to normalize the regressions of BMD on the independent variates, and after transformation, all sites except the femoral neck in females showed significant increases in SD with age. Interestingly, the effect of increasing weight was to decrease dispersion in proximal femur measurements in both sexes, further accentuating the tendency in women for low body mass index to be associated with osteoporosis as defined by densitometry. It is concluded that there are major differences between BMD values in European population samples which, with variations in anthro-pometric variables, have the potential to contribute substantially to variations in rates of osteoporotic fracture risk in Europe.

BSR and BHPR rheumatoid arthritis guidelines on safety of anti-TNF therapies.

Inhibitors of TNF-a represent important treatment advances for a number of inflammatory conditions, including RA. TNF-a inhibitors offer a targeted strategy that contrasts with the non-specific immunosuppressive agents traditionally used to treat most forms of systemic inflammation. Information on who benefits from these agents and on their adverse effects continues to be collected through clinical studies, case series and reports and through national registries. In 2001 and 2005, the British Society for Rheumatology (BSR) established and updated guidelines for the use of anti-TNF drugs in RA [1, 2]. These guidelines have indicated which adult patients with RA should be eligible for treatment with anti-TNF therapies, precautions that need to be taken in their use and action that should be taken in the event of adverse effects. The previous guidelines applied to the then-available anti-TNF therapies {etanercept and infliximab in 2001 [1], and etanercept, infliximab and adalimumab (first-generation anti-TNF agents) in 2005 [2]}. Due to the large volume of information now available on these agents the BSR has, in 2010, produced separate guidelines on eligibility for anti-TNF treatment in RA (in press) These current guidelines cover the safety aspects of anti-TNF treatment in RA and apply to the first-generation products but also to the newly licensed second-generation anti-TNF drugs, certolizumab pegol and golimumab. There are relatively little safety data specifically for these second-generation agents but there are no data thus far to suggest that their side-effect profile would differ significantly from the first-generation agents. This is a rapidly changing field with new data emerging each month, so it is vital that clinicians keep up to date with this area of practice. These guidelines have Rheumatology Department, Royal Derby Hospital, Derby, Rheumatology Unit, Queen Alexandra Hospital, Portsmouth, Rheumatology Department, Nuffield Orthopaedic Centre, Oxford, Rheumatology Department, Poole Hospital, Poole, ARC Epidemiology Unit, University of Manchester, Manchester, Rheumatology Department, St George’s Healthcare, London, Rheumatology Department, Royal Lancaster Infirmary, Lancaster, Rheumatology Department, St Helens Hospital, St Helens, National Rheumatoid Arthritis Society, Maidenhead, Rheumatology Department, Addenbrooke’s Hospital, Cambridge, Rheumatology Department, Trafford General Hospital, Manchester, Rheumatology Unit, Worthing and Southlands NHS Trust, Worthing and Rheumatology Department, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK.

The Effects of Lifestyle, Dietary Dairy Intake and Diabetes on Bone Density and Vertebral Deformity Prevalence: The EVOS Study

Abstract. The risk of low and moderate energy fracture is related to bone mineral density (BMD). Yet it is uncertain whether the epidemiologic determinants of fracture risk are the same as for low bone density. The European Vertebral Osteoporosis Study was a population-based prevalence study of vertebral deformity in 36 age-stratified population samples aged 50–80 years. In nearly 4000 subjects (13 centers), BMD measurements were also made at the spine, femoral neck and femoral trochanter. To investigate whether effects of reported physical activity on spine deformity risk were mediated through BMD, we modeled these and other risk factor data with BMD as the dependent variate after adjusting for age, center, sex and body mass index (BMI). The significant determinants of vertebral deformity risk were also entered into logistic models of deformity risk that included BMD measurements as covariates. Both current and lifetime physical activity were positively associated with BMD. This effect was stronger with hip BMD than with spine BMD. Lifetime smoking exposure was associated with reduced BMD. Type 2 diabetes mellitus was associated with increased BMD. Weak positive associations were found between consumption of dairy products and BMD at the three measured sites and these were strengthened by an interaction with measures of physical activity in men. Physical activity in women had the largest beneficial effect in lean women and in women exposed to hormone replacement therapy. When fracture risk was modeled with BMD as a covariate, the lifestyle and dietary determinants became less strongly related to vertebral deformity risk, suggesting that BMD may have acted as an intermediary variable. However, heavy physical activity in men still increased spine deformity risk after adjusting for BMD. It is concluded that physical activity in both genders and milk consumption in young women might protect against vertebral deformities in later life through their effects on bone density. The adverse effect of smoking on BMD was confirmed. Heavy physical activity in men might increase spine deformity risk even when BMD is normal.

Predictors of end stage lung disease in a cohort of patients with scleroderma

Objectives: To estimate the incidence of severe lung disease in patients with scleroderma and identify the combination(s) of features present at first assessment which would be useful to predict future risk of severe lung disease. Methods: Data were analysed on 561 patients with disease onset occurring on or after 1 January 1982 and disease duration of less than five years before the first assessment. Detailed clinical and laboratory assessments were undertaken at the initial visit. End stage lung disease was defined as pulmonary hypertension requiring continuous ambulatory iloprost, or pulmonary fibrosis requiring continuous oxygen, or death from a scleroderma related lung disease. Patient status was determined at 31 December 1997. The best subset of predictors was identified by Cox regression analysis. Results: In all, 24 patients reached end stage lung disease. The cumulative incidences were 4%, 6%, and 12% at five, seven, and 14 years respectively. As expected, the lung function tests at baseline, including being in the lowest third of either diffusing lung capacity (hazard ratio (HR) = 18.2, 95% confidence interval (CI) 3.5 to 93.8) or of forced vital capacity (HR=4.1, 95% CI 1.1 to 15.2), were highly significant predictors of end stage lung disease. Interestingly, apart from the presence of proteinuria, none of the other baseline variables, including the extent of skin disease and serological markers, were predictive of severe lung disease. Conclusion: End stage lung disease was infrequent in this large cohort, but the cumulative incidence increased importantly with time. The risk can be predicted from baseline assessment of pulmonary function. In particular, those with normal pulmonary function at baseline are at very low risk.

MTHFR gene polymorphisms and outcome of methotrexate treatment in patients with rheumatoid arthritis: analysis of key polymorphisms and meta-analysis of C677T and A1298C polymorphisms.

Association of two key variants mapping to the MTHFR gene (C677T (rs1801133) and A1298C (rs1801131)) with response to methotrexate (MTX) remains controversial. We investigated these and other markers spanning the gene as predictors of MTX efficacy and adverse events in a UK rheumatoid arthritis (RA) patient cohort and performed a meta-analysis of the two key variants using all published data. The tagging single nucleotide polymorphisms (SNPs) were genotyped in 309 patients with well-defined outcomes to MTX treatment and 17 studies were included in the meta-analysis. No association of the SNPs tested was detected with MTX efficacy or toxicity in our UK cohort. After combining our data with previous studies by meta-analysis, the random effects pooled odds ratios (OR) for both C677T and A1298C showed no association with efficacy or toxicity for either of the SNPs (efficacy: OR=1.05 (95% confidence interval (CI) 0.83–1.32) and OR=0.81 (95% CI 0.53–1.24), respectively; toxicity: OR=1.38 (95% CI 0.90–2.12) and OR=1.19 (95% CI 0.80–1.78), respectively). The available evidence suggests that the MTHFR C677T and A1298C gene polymorphisms are not reliable predictors of response to MTX treatment in RA patients.

BSR and BHPR rheumatoid arthritis guidelines on eligibility criteria for the first biological therapy.

Chris Deighton1, Kimme Hyrich2, Tina Ding1, Jo Ledingham3, Mark Lunt2, Raashid Luqmani4, Patrick Kiely5, Marwan Bukhari6, Rikki Abernethy7, Andrew Ostor8, Ailsa Bosworth9, Kate Gadsby1, Frank McKenna10, Diana Finney11 and Josh Dixey12, on behalf of BSR Clinical Affairs Committee & Standards, Audit and Guidelines Working Group and the BHPR 1Rheumatology Department, Royal Derby Hospital, Derby; 2ARC Epidemiology Unit, University of Manchester, Manchester; 3Rheumatology Unit, Queen Alexandra Hospital, Portsmouth; 4Rheumatology Department, Nuffi eld Orthopaedic Centre, Oxford; 5Rheumatology Department, St George’s Healthcare, London; 6Rheumatology Department, Royal Lancaster Infi rmary, Lancaster; 7Rheumatology Department, St Helens Hospital, St Helens; 8Rheumatology Department, Addenbrooke’s Hospital, Cambridge; 9National Rheumatoid Arthritis Society, Maidenhead; 10Department of Rheumatology, Trafford General Hospital, Manchester; 11Rheumatology Unit, Worthing and Southlands NHS Trust, Worthing; 12Department of Rheumatology, Robert Jones and Agnes Hunt Orthopaedic Hospital, Oswestry, UK

Contribution of patient related differences to multidrug resistance in rheumatoid arthritis

Background: There is a wide variation in responses to standard disease modifying antirheumatic drug (DMARD) treatment in rheumatoid arthritis (RA). Whether multidrug resistance, failure to respond to several DMARDs, is a specific entity over and above that expected by chance alone is unclear. Objective: To identify patients with RA who demonstrate a multidrug resistant phenotype and to determine what proportion of the variance in drug responses is due to patient related factors. Methods: Patients with RA (1987 American College of Rheumatology criteria) were identified from clinics at Manchester Royal Infirmary and through the Arthritis Research Campaign National RA Repository. The clinic records were reviewed and multidrug resistance was defined as stopping three or more DMARDs owing to lack of efficacy after an adequate trial of the drug. Logistic regression measured by a random effects model was used to determine the relative contribution of the drug and subject related differences to the multidrug resistance. Results: 265 patients (210 (79.3%) female) were studied. The mean (SD) age and disease duration were 52.2 (12.9) and 10.7 (8.8) years, respectively. Patients had a median (range) of 2 (1–8) DMARD courses. Failure of at least one DMARD due to inefficacy occurred in 105 (40%) and 13 (5%) were multidrug resistant. Overall, 35% of the variance in drug responses was due to between-subject differences (p=0.02). Rheumatoid factor (RF) status contributed significantly to this (OR=2.15, 95% confidence interval (95% CI) 1.00 to 4.62) but explained only 3% of the total variance in drug inefficacy. Conclusion: Multidrug resistance occurs in an uncommon (5%) but important subgroup of patients with RA. The between-subject variance is not fully explained by demographics and RF status. Understanding the biological mechanisms that contribute to multidrug resistance may suggest new therapeutic approaches and targets in RA.

BSR and BHPR guidelines on the use of rituximab in rheumatoid arthritis

The Standards, Audit and Guidelines Working Group (SAGWG) of the British Society for Rheumatology (BSR) have recently updated the guidelines on eligibility for anti-TNF drugs in RA [1] and have updated the anti-TNF safety and efficacy guidelines [2] for general use of the rheumatology community. The National Institute for Heath and Clinical Excellence (NICE) in the UK, which is the is an independent organization responsible for providing national guidance in the UK on promoting good health and preventing and treating ill health, has published a technology appraisal guidance [3] for use of rituximab in RA in 2007. Furthermore, a consensus statement from EULAR [4] was also published in 2007. Therefore, it was felt appropriate to undertake a review of the currently available data as new evidence was available. The group did not wish to duplicate the guidance in those documents, but wished to review the more recent evidence and supplement what is already known.

Biologic treatment response among adults with juvenile idiopathic arthritis: results from the British Society for Rheumatology Biologics Register

Objective. To describe the use of and response to biologic therapies commenced in adults with JIA. Methods. Patients with arthritis onset <16 years were identified from the British Society for Rheumatology Biologics Register for rheumatoid arthritis (BSRBR-RA) and stratified into ILAR JIA subtypes. Patterns of biologic use and treatment persistence were explored, with disability levels (HAQ) and remission rates [28-Joint Disease Activity Score (DAS28)] evaluated at 6 and 12 months. Results. Arthritis with an onset of <16 years was confirmed in 225 patients and the ILAR subtype was determined in 154 (68%). Only 58 (26%) patients had a diagnosis of JIA recorded in the BSRBR-RA. The median age at biologic commencement was 31 years [interquartile range (IQR) 23–39] and 76% were female. The biologic therapies were etanercept (49%), infliximab (28%), adalimumab (22%) and anakinra (1%). Fifty per cent of patients received more than one biologic during follow-up (2 agents, n = 64; ≥3 agents, n = 49). Treatment persistence at 1 year was 78% (95% CI 71%, 82%), falling to 42% (95% CI 34%, 49%) at 5 years. Both the HAQ and DAS28 improved significantly at 6 months, with 21% and 28% of patients in remission (DAS28 < 2.6) at 6 and 12 months, respectively. Conclusion. This study describes patterns and identifies outcomes of biologic use in a national cohort of adults with JIA. With no national guidance currently available in this area, the choice of first biologic was inconsistent, although treatment outcomes were good. These data confirm that biologic therapies are an important treatment option in adults with active JIA in adulthood.