Reconsultation, self-reported health status and costs following treatment at a musculoskeletal Clinical Assessment and Treatment Service (CATS): a 12-month prospective cohort study.

OBJECTIVES: To determine (1) reconsultation frequency, (2) change in self-reported health status, (3) baseline factors associated with reconsultation and change in health status and (4) associated healthcare costs and quality-adjusted life-years (QALYs), following assessment at a musculoskeletal Clinical and Assessment Treatment Service (CATS). DESIGN: Prospective cohort study. SETTING: Single musculoskeletal CATS at the primary-secondary care interface. PARTICIPANTS: 2166 CATS attenders followed-up by postal questionnaires at 6 and 12 months and review of medical records. OUTCOME MEASURES: Primary outcome was consultation in primary care with the same musculoskeletal problem within 12 months. Secondary outcome measures were consultation at the CATS with the same musculoskeletal problem within 12 months, physical function and pain (Short Form-36), anxiety and depression (Hospital Anxiety and Depression Scale), time off work, healthcare costs and QALYs. RESULTS: Over 12 months, 507 (38%) reconsulted for the same problem in primary care and 345 (26%) at the CATS. Primary care reconsultation in the first 3 months was associated with baseline pain interference (relative risk ratio 5.33; 95% CI 3.23 to 8.80) and spinal pain (1.75; 1.09 to 2.82), and after 3-6 months with baseline assessment by a hospital specialist (2.06; 1.13 to 3.75). Small mean improvements were seen in physical function (1.88; 95% CI 1.44 to 2.32) and body pain (3.86; 3.38 to 4.34) at 6 months. Poor physical function at 6 months was associated with obesity, chronic pain and poor baseline physical function. Mean (SD) 6-month cost and QALYs per patient were £422.40 (660.11) and 0.257 (0.144), respectively. CONCLUSIONS: While most patients are appropriate for a 'one-stop shop' model, those with troublesome, disabling pain and spinal pain commonly reconsult and have ongoing problems. Services should be configured to identify and address such clinical complexity.

DNA methylation profiling of synovial fluid FLS in rheumatoid arthritis reveals changes common with tissue-derived FLS.

AIM: Alterations in DNA methylation contribute to the abnormal phenotype of fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). We profiled genome-wide DNA methylation in these cells from synovial fluid, a more readily accessible source of disease-associated cells. PATIENTS & METHODS: Genome-wide DNA methylation was interrogated in fluid-derived FLS from five RA and six osteoarthritis patients using Human Methylation 450 Bead Chip and bisulfite pyrosequencing. RESULTS: Array analysis identified 328 CpGs, representing 195 genes, that were differentially methylated between RA and osteoarthritis fluid-derived FLS. Comparison with the genes identified in two independent studies of tissue-derived FLS revealed 73 genes in common (~40%), of which 22 shared identity with both studies. Pyrosequencing confirmed altered methylation of these genes. CONCLUSION: Synovial fluid-derived RA FLS show methylation changes common with tissue-derived FLS, supporting the use of fluid-derived FLS for future investigations.

Genome-wide DNA methylation profiling in rheumatoid arthritis identifies disease-associated methylation changes that are distinct to individual T- and B-lymphocyte populations.

Changes to the DNA methylome have been described in patients with rheumatoid arthritis (RA). In previous work, we reported genome-wide methylation differences in T-lymphocyte and B-lymphocyte populations from healthy individuals. Now, using HumanMethylation450 BeadChips to interrogate genome-wide DNA methylation, we have determined disease-associated methylation changes in blood-derived T- and B-lymphocyte populations from 12 female patients with seropositive established RA, relative to 12 matched healthy individuals. Array data were analyzed using NIMBL software and bisulfite pyrosequencing was used to validate array candidates. Genome-wide DNA methylation, determined by analysis of LINE-1 sequences, revealed higher methylation in B-lymphocytes compared with T-lymphocytes (P ≤ 0.01), which is consistent with our findings in healthy individuals. Moreover, loci-specific methylation differences that distinguished T-lymphocytes from B-lymphocytes in healthy individuals were also apparent in RA patients. However, disease-associated methylation differences were also identified in RA. In these cases, we identified 509 and 252 CpGs in RA-derived T- and B-lymphocytes, respectively, that showed significant changes in methylation compared with their cognate healthy counterparts. Moreover, this included a restricted set of 32 CpGs in T-lymphocytes and 20 CpGs in B-lymphocytes (representing 15 and 10 genes, respectively, and including two, MGMT and CCS, that were common to both cell types) that displayed more substantial changes in methylation. These changes, apparent as hyper- or hypo-methylation, were independently confirmed by pyrosequencing analysis. Validation by pyrosequencing also revealed additional sites in some candidate genes that also displayed altered methylation in RA. In this first study of genome-wide DNA methylation in individual T- and B-lymphocyte populations in RA patients, we report disease-associated methylation changes that are distinct to each cell type and which support a role for discrete epigenetic regulation in this disease.

Development of needle trap technology for on-site determinations: active and passive sampling.

This study presents a thorough evaluation of new prototypes of extended tip needle trap devices (NT), as well as their application to in situ sampling of biological emissions and active/passive on-site sampling of indoor air. A new NT prototype was constructed with a side hole above the sorbent and an extended tip that fits inside the restriction of the narrow neck liner to increase desorption efficiency. New prototype needles were initially packed with divinylbenzene particles at SGE Analytical Science for the purpose of studying biogenic emissions of pine trees. Prior to their final application, they were evaluated in terms of robustness after multiple use (n > 10), as well as amount extracted of volatile organic compounds (VOCs). An ANOVA test for all the probes showed that at a 95% level of confidence, there were not statistical differences observed among the 9 NTs tested. In addition, the needles were also packed in laboratory with synthesized highly cross-linked PDMS as a frit to immobilize carboxen (Car) particles for spot sampling. For passive sampling, the needles were packed with Car particles embedded in PDMS to simplify calculations in passive mode. The use of NTs as spot samplers, as well as a passive sampler under controlled conditions in the laboratoryyielded a relative standard deviation of less than 15%. Finally, a new, reusable and readily deployable penlike diffusive sampler for needle traps (PDS-NT) was built and tested. Application of the PDS-NT in combination with NT-spot sampling toward the analysis of indoor air in a polymer synthesis laboratory showed good agreement between both techniques for the analyte studied, yielding averages of 0.03 and 0.025 ng/mL of toluene, respectively.

Epigenome-wide profiling identifies significant differences in DNA methylation between matched-pairs of T- and B-lymphocytes from healthy individuals.

Multiple reports now describe changes to the DNA methylome in rheumatoid arthritis and in many cases have analyzed methylation in mixed cell populations from whole blood. However, these approaches may preclude the identification of cell type-specific methylation, which may subsequently bias identification of disease-specific changes. To address this possibility, we conducted genome-wide DNA methylation profiling using HumanMethylation450 BeadChips to identify differences within matched pairs of T-lymphocytes and B-lymphocytes isolated from the peripheral blood of 10 healthy females. Array data were processed and differential methylation identified using NIMBL software. Validation of array data was performed by bisulfite pyrosequencing. Genome-wide DNA methylation was initially determined by analysis of LINE-1 sequences and was higher in B-lymphocytes than matched T-lymphocytes (69.8% vs. 65.2%, P ≤ 0.01). Pairwise analysis identified 679 CpGs, representing 250 genes, which were differentially methylated between T-lymphocytes and B-lymphocytes. The majority of sites (76.6%) were hypermethylated in B-lymphocytes. Pyrosequencing of selected candidates confirmed the array data in all cases. Hierarchical clustering revealed perfect segregation of samples into two distinct clusters based on cell type. Differentially methylated genes showed enrichment for biological functions/pathways associated with leukocytes and T-lymphocytes. Our work for the first time shows that T-lymphocytes and B-lymphocytes possess intrinsic differences in DNA methylation within a restricted set of functionally related genes. These data provide a foundation for investigating DNA methylation in diseases in which these cell types play important and distinct roles.

Musculoskeletal clinical assessment and treatment services at the primary-secondary care interface: an observational study.

BACKGROUND: Management of musculoskeletal conditions in the UK is increasingly delivered in multidisciplinary clinical assessment and treatment services (CATS) at the primary-secondary care interface. However, there is little evidence concerning the characteristics and management of patients attending CATS. AIM: To describe the characteristics, investigation, and treatment of adults attending a musculoskeletal CATS. DESIGN AND SETTING: Cross-sectional analysis of cohort study baseline data from a musculoskeletal CATS in Stoke-on-Trent Primary Care Trust, UK. METHOD: All patients referred from primary care between February 2008 and June 2009 were mailed a pre-consultation questionnaire concerning pain duration, general health status, anxiety, depression, employment status, and work absence due to musculoskeletal problems. At the consultation, clinical diagnoses, body region(s) affected, investigations, and treatment were recorded. RESULT: A total of 2166 (73%) completed questionnaires were received. Chronic pain duration >1 year (55%), major physical limitation (76%), anxiety (49%), and depression (37%) were common. Of those currently employed, 516 (45%) had taken time off work in the last 6 months because of their musculoskeletal problem; 325 (29%) were unable to do their usual job. The most frequent investigations were X-rays (23%), magnetic resonance imaging (18%), and blood tests (14%): 1012 (48%) received no investigations. Injections were performed in 282 (13%) and 492 (23%) were referred to physiotherapy. CONCLUSION: Although most patients presented with musculoskeletal problems suitable for CATS, chronic pain, physical limitation, anxiety, depression, and work disability were commonplace, highlighting the need for a biopsychosocial model of care that addresses psychological, social, and work-related needs, as well as pain and physical disability.

Association of circulating levels of MMP-8 with mortality from respiratory disease in patients with rheumatoid arthritis.

INTRODUCTION: Matrix metalloproteinases (MMPs) are implicated in the destruction of the joint and have been shown to be strongly associated with inflammation in rheumatoid arthritis (RA). Circulating MMPs have also been associated with cardiovascular disease in the general population, and are predictive of cardiovascular mortality. The purpose of the present study was to determine whether circulating levels of MMPs are predictive of mortality in RA. METHODS: A multiplex suspension array system (Luminex®) was used to measure levels of MMPs (1, 2, 3, 8 and 9) in sera taken at recruitment of RA patients (n = 487) in a study of factors associated with mortality in RA. Patients were tracked on the National Health Service Central Register for notification of death, and the relationship between baseline MMP levels and mortality was analysed using Cox proportional hazards regression analysis. RESULTS: At the time of follow-up, 204/486 patients had died, of which 94 (46.1%) had died of circulatory diseases, 49 of malignancy (24.0%), and 42 (20.6%) of respiratory diseases. In a stepwise analysis which included all MMPs, only MMP-8 was significantly associated with all cause mortality (P = 0.0007, 0.6% hazard ratio increase per ng/ml). No association was found between MMP levels and mortality due to circulatory disease or malignancy. However MMP-8 levels were strongly associated with mortality due to respiratory disease (P < 0.0001, 1.3% hazard ratio increase per ng/ml). The association with respiratory disease related mortality remained highly significant in multivariate models which included smoking as well as markers of severity and disease activity such as rheumatoid factor, nodular disease, and C-reactive protein (CRP). CONCLUSIONS: The serum level of MMP-8 is a strong predictor of mortality in RA, especially that due to respiratory disease. This finding is consistent with increased activation of neutrophils in RA and identifies serum MMP-8 as a useful marker for increased risk of premature death.

A simplified approach to direct SPE-MS.

Microextraction by packed sorbent (MEPS) has been directly hyphenated with ESI-MS for the rapid screening of opiates and codeine metabolites in urine. This study introduces a novel format of MEPS that incorporates a two-way valve in the barrel of the syringe enabling the direction of liquid flow to be manipulated. Controlled directional flow (CDF) MEPS allows sharp, concentrated sample bands to be delivered directly to the MS in small volumes and effectively eliminates the need to optimize elution. The method optimization assessed the recovery, matrix effects, and the speed of infusion, all critical variables for optimum ESI performance. Matching extraction workflows demonstrated a reduction in carryover from 65% for conventional MEPS to only 1% for CDF MEPS. The recovery (<89% for 50 µL sample), matrix effects (<42%), linearity (r(2) > 0.99), and LODs (<5 ng/mL) were determined to demonstrate method performance. The optimized approach was employed for the screening of codeine metabolites in urine. The ion trace revealed sharp sample bands corresponding to the codeine metabolites. At-line MEPS-ESI-MS allowed both sample preparation and analysis to be completed in only 5 min facilitating high throughput and alleviating the burden of method development.

Interaction between smoking and functional polymorphism in the TGFB1 gene is associated with ischaemic heart disease and myocardial infarction in patients with rheumatoid arthritis: a cross-sectional study.

INTRODUCTION: Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that plays important roles in immunity and inflammation. Some studies have suggested that polymorphism in the TGFB1 gene is associated with heart disease in the general population. The purpose of the present study was to determine whether common single-nucleotide polymorphisms (SNP) in the TGFB1 gene are associated with ischaemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and to investigate the influence of smoking on any association. METHODS: PCR-based assays were used to determine the genotypes of TGFB1 SNPs including TGFB1-509 C/T (rs1800469, in the promoter region), +868 T/C (rs1800470, in exon 1) and +913 G/C (rs1800471, in exon 1) in 414 subjects with established RA. Genotyping for the +868 SNP was also carried out on a second study population of RA patients (n = 259) with early disease. Serum levels of TGF-beta1 were measured using a commercial ELISA kit. Smoking history and IHD/MI status were obtained on each patient. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses. RESULTS: The heterozygous genotype of TGFB+868 was associated with an increased risk of IHD (OR 2.14, 95% CI 1.30 - 3.55) and MI (OR 2.42, 95% CI 1.30-4.50), compared to the homozygous genotypes combined. Smoking was an independent risk for IHD and MI, and evidence of interaction between smoking and TGFB+868 was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the TGFB1+868 TC genotype and smoking (OR 2.75, 95% CI 1.59-4.75; and OR 2.58 95% CI 1.33-4.99, respectively), independent of other cardiovascular risk factors. The association of the +868 TC genotype and evidence of +868 TC-smoking interaction with IHD were replicated in a second population of RA patients with early disease. Serum TGF-beta1 levels were not associated with TGFB1 genetic variations, smoking or IHD/MI status. CONCLUSIONS: Interaction between smoking and polymorphism in the TGFB1 gene may influence the risk of IHD and MI in patients with RA.

Polymorphism in the vascular endothelial growth factor A (VEGFA) gene is associated with serum VEGF-A level and disease activity in rheumatoid arthritis: differential effect of cigarette smoking.

OBJECTIVE: To assess the impact of common genetic variants in the vascular endothelial growth factor A (VEGFA) gene on circulating VEGF-A levels and disease activity in patients with rheumatoid arthritis (RA). METHODS: A cohort (n=419) of consecutively recruited RA patients of Caucasian origin was studied. Disease activity (DAS28) was recorded on a regular basis (0, 12 and 24 months). Smoking history (never, past and current) was obtained. PCR-RFLP assays were used to determine the genotypes of VEGFA single-nucleotide polymorphisms (SNP) including VEGFA-2578 (rs699947), -460 (rs833061), +405 (rs2010963) and +936 (rs3025039). Circulating levels of VEGF-A were measured in serum samples using a fluorescent bead-based assay system (Luminex®). Associations were analyzed using univariate and multivariate statistics. RESULTS: VEGFA-2578 AA genotype was associated with lower serum VEGF-A levels, as was the most frequent haplotype (A(-2578)-C(-460)-G(+405), 48.1%) within the 5'-flanking region of the gene. The same genotype and haplotype were also associated with decreased disease activity in RA. This was seen only in patients who had never smoked. In multivariate multiple regression models, the VEGFA-2578 SNP was shown to be associated with disease activity at presentation (p=0.029) and over time (p=0.016) in patients who never smoked, independent of serum VEGF-A levels and other confounding factors. CONCLUSION: Genetic variation in the VEGFA gene is associated with serum VEGF-A levels in RA, and shows an association with disease activity in RA patients who have never smoked, independent of serum VEGF-A levels.

Interaction between smoking and polymorphism in the promoter region of the VEGFA gene is associated with ischemic heart disease and myocardial infarction in rheumatoid arthritis.

OBJECTIVE: To determine whether variants in the vascular endothelial growth factor A (VEGFA) gene are associated with ischemic heart disease (IHD) and/or myocardial infarction (MI) in patients with rheumatoid arthritis (RA), and whether there is evidence of a gene-smoking interaction. METHODS: PCR-RFLP assays were used to determine the genotypes of VEGFA single-nucleotide polymorphisms (SNP) including VEGFA-2578A/C (rs699947), -460C/T (rs833061), +405C/G (rs2010963), and +936C/T (rs3025039) in 418 subjects with RA. Smoking history was obtained on each patient, and IHD and MI status was recorded. Associations with IHD/MI were assessed using contingency tables and logistic regression analyses. RESULTS: Strong linkage disequilibrium was detected among VEGFA-2578, -460, and +405. SNP located in the VEGFA promoter region (-2578, -460) were found to be associated with IHD and MI, whereas +405 and +936, in the 5'-untranslated region (UTR) and 3'-UTR, respectively, were not. Haplotype analysis suggested that the A/C/G haplotype was associated with increased risk of IHD (OR 2.37, 95% CI 1.22-4.62) and MI (OR 4.10, 95% CI 1.45-11.49). Smoking was also independently associated with IHD and MI, and evidence of interaction between smoking and the VEGFA promoter SNP was found. Multivariate analyses indicated that the strongest associations with IHD and MI were due to the combined effect of the VEGFA-2578 A allele and smoking (OR 3.52 and 7.11, respectively), independent of risk factors such as age, sex, diabetes, C-reactive protein, hypercholesterolemia, and hypertension. CONCLUSION: Interaction between smoking and polymorphism in the VEGFA gene is associated with IHD and MI in patients with RA.

Beach lifeguards: visual search patterns, detection rates and the influence of experience.

PURPOSE: Lifeguard surveillance is critical to any water safety program. This study determined the rates of detection of a 'drowning' individual by beach lifeguards, and whether scanning patterns differed between groups of lifeguards (experienced/less experienced, male/females, surf/non-surf). It was hypothesized that (1) Experienced lifeguards would perform better and produce less fixations of longer duration than inexperienced; (2) A greater detection rate would be seen in a 'biased' compared to a 'non-biased' condition; (3) There would be no differences between the surf compared to non-surf lifeguards, and male compared to female lifeguards with regard to scanning patterns or detection rates. METHOD: A mobile eye tracker was worn by each lifeguard (n = 69, 52 males, 17 females) as they watched 12 min of animated beach footage projected onto a screen in two conditions: a. 'Non-biased' (uniform scene). b. 'Biased' (uniform scene with presumed 'rip' on right side of screen). The lifeguards were informed that at any point during the 12 min a person may or may not disappear and to highlight if and where, a person disappeared. Unknown to the participants, a person always disappeared after 10 min at the same position within, but not between, conditions. Data were analysed using anova, t-tests and binary logistic regression. RESULTS: Experienced lifeguards were five times (p < 0.05) more likely to detect the drowning individual than inexperienced lifeguards. There were no significant differences between the visual search patterns of the groups between 2 and 10 min. The detection rates averaged 16% in the non-biased condition and 29% in biased conditions (p < 0.1), probably because lifeguards searched more on the right of the water. Furthermore, 40% (biased) and 42% (non-biased) did not detect the person disappearing, even though they fixated in the correct location in the 3.5 s before the person completely disappeared. This suggests that some lifeguards may have fixated on, but not processed, relevant visual data ('looked at but not seen'). 25% (biased) and 36% (non-biased) of the lifeguards did not fixate in the location of the person disappearing, but were able to identify their disappearance. CONCLUSIONS: Visual search patterns used by lifeguards can be altered by instruction and detection rates improve as a consequence. Peripheral vision is used effectively by some lifeguards, but cue extraction may be problematic for others.

A flexible loop-type flow modulator for comprehensive two-dimensional gas chromatography.

The present investigation is focused on a simple flow modulator (FM), for comprehensive two-dimensional gas chromatography (GC×GC). The interface is stable at high temperatures, and consists of a metallic disc (located inside the GC oven) with seven ports, which are connected to an auxiliary pressure source via two branches, to the first and second dimension, to a waste branch (linked to a needle valve) and to an exchangeable modulation loop (2 ports). The ports are connected via micro-channels, etched on one of the inner surfaces of the disc. Modulation is achieved using a two-way electrovalve, connected on one side to the additional pressure source, and to the two metal branches, on the other. An FM enantio-GC×polar-GC method (using a flame ionization detector) was optimized (a 40-µL loop was employed), for the analysis of essential oils. As an example, an application on spearmint oil is shown; the method herein proposed was subjected to validation. Finally, an FM GC×GC diesel experiment was carried out, using an apolar-polar column combination, to demonstrate the effectiveness of the modulator in the analysis of a totally different sample-type.

Effect of psychological distress on continuation of anti-tumor necrosis factor therapy in patients with rheumatoid arthritis.

OBJECTIVE: To investigate the relationship of psychological distress and associated factors with continuation of tumor necrosis factor (TNF) antagonist therapy in patients with rheumatoid arthritis (RA). METHODS: Patients about to start therapy with TNF antagonists (n = 166) were assessed for psychological distress using the Hospital Anxiety and Depression Scale (HADS). A core set of demographic and clinical variables, including comorbidities from medical records and cigarette smoking history by questionnaire, were recorded at baseline and regular intervals thereafter. Cox proportional hazards regression analysis was used to assess the likelihood of patients discontinuing therapy over a 36-month followup period. RESULTS: The number of years smoked was associated with anxiety (HADS-A; p for trend = 0.008) and general psychological distress (HADS-Total; p for trend = 0.03). In univariate analyses, earlier discontinuation was associated with these variables at baseline: anxiety (HADS-A), depression (HADS-D), abnormal mood (HADS-Total), smoking history (> 30 pack-yrs), years smoked (> 30 yrs), current smoking, high Disease Activity Score 28-joint count (DAS28), poor patient global assessment, and evidence of cardio/cerebrovascular disease (CVD). In multivariate analyses, the strongest predictors of discontinuation were HADS-Total, smoking history (> 30 pack-yrs), DAS28, and evidence of CVD at baseline. CONCLUSION: Discontinuation of therapy with TNF antagonists is independently associated with psychological distress, heavy smoking, and CVD at baseline.

Ofatumumab, a human anti-CD20 monoclonal antibody, for treatment of rheumatoid arthritis with an inadequate response to one or more disease-modifying antirheumatic drugs: results of a randomized, double-blind, placebo-controlled, phase I/II study.

OBJECTIVE: To investigate the safety and efficacy of ofatumumab, a novel human anti-CD20 monoclonal antibody (mAb), in patients with active rheumatoid arthritis (RA) whose disease did not respond to > or = 1 disease-modifying antirheumatic drug. METHODS: This combined phase I/II study investigated the safety and efficacy of 3 doses of ofatumumab. In part A (phase I), 39 patients received 2 intravenous (i.v.) infusions of ofatumumab (300 mg, 700 mg, or 1,000 mg) or placebo in a 4:1 ratio 2 weeks apart, using a specified premedication and infusion regimen. In part B (phase II), 225 patients received study treatment as per phase I in a 1:1:1:1 ratio. Safety was assessed by adverse events (AEs) and laboratory parameters. Efficacy was assessed by the American College of Rheumatology 20% criteria for improvement (ACR20), the Disease Activity Score in 28 joints, and the European League Against Rheumatism (EULAR) response criteria. B cell pharmacodynamics were also investigated. RESULTS: AEs were predominantly reported at the first infusion and were mostly mild to moderate in intensity. Rapid and sustained peripheral B cell depletion was observed in all dose groups. In phase II, patients in all ofatumumab dose groups had significantly higher ACR20 response rates (40%, 49%, and 44% for the 300 mg, 700 mg, and 1,000 mg doses, respectively) than did patients receiving placebo (11%) at week 24 (P < 0.001). Overall, 70% of patients receiving ofatumumab had a moderate or good response according to the EULAR criteria at week 24. CONCLUSION: Our findings indicate that ofatumumab, administered as 2 i.v. infusions of doses up to 1,000 mg, is clinically effective in patients with active RA.

The Staffordshire arthritis, musculoskeletal, and back assessment (SAMBA) study: a prospective observational study of patient outcome following referral to a primary-secondary care musculoskeletal interface service.

BACKGROUND: Recent healthcare policy has shifted the management of musculoskeletal conditions in the UK away from secondary care towards Clinical Assessment and Treatment Services at the primary-secondary care interface. However, little is known about the outcome of patients with musculoskeletal conditions referred from primary care to Clinical Assessment and Treatment Services or how best to identify those patients at high risk of poor outcome in this setting. We describe the protocol for a twelve-month prospective observational study which aims to describe the outcome of patients referred to musculoskeletal and back pain services at the primary-secondary care interface and to develop simple prognostic measures to guide clinical prioritisation and triage. METHODS/DESIGN: All patients referred over a twelve-month period from primary care to musculoskeletal and back pain clinics in the primary-secondary care interface Clinical Assessment and Treatment Service in North Staffordshire will be mailed a postal questionnaire prior to their consultation. This will collect information on quality of life, general health, anxiety and depression, pain, healthcare utilisation including medication use, occupational characteristics, and socio-demographics. At the consultation in the interface clinic, the clinical diagnosis, investigations requested, and clinical interventions will be recorded. Follow-up data for the twelve-month period subsequent to recruitment will be collected via mailed follow-up questionnaires at 6 and 12 months, and review of medical records. DISCUSSION: This twelve-month prospective observational study of patients referred to a musculoskeletal Clinical Assessment and Treatment Service will assess the management and outcome of musculoskeletal care at the primary-secondary care interface as proposed in the Musculoskeletal Services Framework.

Relationship between pack-year history of smoking and response to tumor necrosis factor antagonists in patients with rheumatoid arthritis.

OBJECTIVE: To determine whether there is a quantitative relationship between smoking history and response to therapy with tumor necrosis factor (TNF) antagonists. METHODS: A history of cigarette smoking was obtained from a questionnaire completed by each patient starting therapy with TNF antagonists since 2002 (n=154). A core set of demographic and clinical variables was recorded at baseline and at 3 and 12 months. The extent of smoking was quantified in pack-years (py), with 1 py equivalent to 20 cigarettes per day for 1 year. The association between smoking intensity and response was assessed using contingency tables and logistic regression analysis. Response to therapy was defined according to the European League Against Rheumatism improvement criteria. RESULTS: There was an increasing trend of no response at 3 and 12 months with increasing py history [p (trend)=0.008 and 0.003, respectively]. The change in Disease Activity Score (DAS)28 over the first 3 months was inversely associated with the number of py (r=-0.28, p=0.002). The association of py history with response failure was independent of age, sex, disease duration, baseline disease activity score (DAS28), Health Assessment Questionnaire (HAQ) score, IgM rheumatoid factor, and smoking at baseline. The most significant effect was seen in patients treated with infliximab. CONCLUSION: RA patients with a history of smoking were more likely to show a poor response to TNF antagonists. Response failure was associated with the intensity of previous smoking, irrespective of smoking status at initiation of anti-TNF therapy.