Factors predicting pain and early discontinuation of tumour necrosis factor-α-inhibitors in people with rheumatoid arthritis: Results from the British Society for Rheumatology Biologics Register

Background: We examined pain levels in 2 cohorts assembled from the British Society for Rheumatology Biologics Register (BSRBR), and investigated which factors predicted Bodily Pain scores and discontinuation of TNFα-inhibitors. Method: Data were retrieved from BSRBR-RA databases for up to 1 year after commencing TNFα-inhibitors (n=11995) or being treated with non-biologic therapies (n=3632). Bodily Pain scores were derived from the Short Form-36 (SF36) questionnaire and norm-transformed to allow comparison with UK population averages. Discontinuation data were from physician reports. Other data, including 28-joint disease activity score (DAS28) measurements, were from clinical examination, interview, medical records and self-report questionnaires. DAS28-P was derived as the proportion of DAS28 attributed to patient-reported factors (tender joint count and visual analogue score). Missing baseline variables from both cohorts were imputed into 20 replicate datasets. Odds ratios (OR) and adjusted OR were calculated for higher than median pain within each cohort. Results: Participants reported moderate to severe pain at baseline, and pain scores remained >1SD worse than normal population standards at 1 year, even when disease activity responded to treatment. Baseline pain was associated with DAS28-P, worse physical function, worse mental health, and DAS28. After logistic regression, independent predictors of higher than median pain at follow up were baseline Bodily Pain score, higher DAS28-P, worse physical function or mental health and co-morbidities. Higher age, male gender, and higher BMI were additional independent predictors of higher pain in participants who received TNFα-inhibitors. Baseline pain was also one of the predictors of discontinuation of the first TNFα-inhibitor within 1 year, as were female gender, current smoking, co-morbidities, extra-articular manifestations and worse function. Conclusion: Pain persists in people with treated RA, even in those for whom inflammation responds to treatment. Worse pain outcomes are predicted by factors different to those typically found to predict inflammatory disease activity in other studies. Worse pain at baseline also predicts discontinuation of TNFα-inhibitors. Improved pain management should complement inflammatory disease suppression in RA

Potential role of endocrine gastrin in the colonic adenoma carcinoma sequence

The role of hyper-gastrinaemia in the incidence of colonic cancer remains to be clarified. The aim of this study was to determine whether cholecystokinin-2 (CCK-2) receptor expression predicts the sensitivity of human colonic adenomas to the proliferative effects of serum hyper-gastrinaemia. Gene expression of the classical (74 kDa) CCK-2 receptor in human colonic adenoma specimens and cell lines, was quantified by real-time PCR. Western blotting, using a CCK-2 receptor antiserum, confirmed protein expression. A transformed human colonic adenoma was grown in SCID mice, with hyper-gastrinaemia induced by protein pump inhibitors. CCK-2 receptor blockade was achieved by using neutralising antiserum. Both human colonic adenoma cell lines and biopsies expressed CCK-2 receptor mRNA at levels comparable with CCK-2 receptor transfected fibroblasts and oxyntic mucosa. Western blotting confirmed immunoreactive CCK-2 receptor bands localised to 45, 74 and 82.5 kDa. Omeprazole and lansoprazole-induced hyper-gastrinaemia (resulting in serum gastrin levels of 34.0 and 153.0 pM, respectively) significantly increased the weight of the human adenoma grafts (43% (P=0.016) and 70% (P=0.014), respectively). The effect of hypergastrinaemia on tumour growth was reversed by use of antiserum directed against the CCK-2 receptor. Hyper-gastrinaemia may promote proliferation of human colonic adenomas that express CCK-2 receptor isoforms

Relative efficacy of topical non-steroidal anti-inflammatory drugs and topical capsaicin in osteoarthritis: protocol for an individual patient data meta-analysis

Background Pain is the most troubling issue to patients with osteoarthritis (OA), yet current pharmacological treatments offer only small-to-moderate pain reduction. Current guidelines therefore emphasise the need to identify predictors of treatment response. In line with these recommendations, an individual patient data (IPD) meta-analysis will be conducted. The study aims to investigate the relative treatment effects of topical non-steroidal anti-inflammatory drugs (NSAIDs) and topical capsaicin in OA and to identify patient-level predictors of treatment response. Methods IPD will be collected from randomised controlled trials (RCTs) of topical NSAIDs and capsaicin in OA. Multilevel regression modelling will be conducted to determine predictors for the specific and the overall treatment effect. Discussion Through the identification of treatment responders, this IPD meta-analysis may improve the current understanding of the pain mechanisms in OA and guide clinical decision-making. Identifying and prescribing the treatment most likely to be beneficial for an individual with OA will improve the efficiency of patient management

Interpretation of DAS28 and its components in the assessment of inflammatory and non-inflammatory aspects of rheumatoid arthritis

Background: DAS28 is interpreted as the inflammatory disease activity of RA. Non-inflammatory pain mechanisms can confound assessment. We aimed to examine the use of DAS28 components or DAS28-derived measures that have been published as indices of non-inflammatory pain mechanisms, to inform interpretation of disease activity. Methods: Data were used from multiple observational epidemiology studies of people with RA. Statistical characteristics of DAS28 components and derived indices were assessed using baseline and follow up data from British Society for Rheumatology Biologics Registry participants [1] commencing anti-TNF therapy (n = 10813), or [2] changing between non-biologic DMARDs (n=2992), [3] Early Rheumatoid Arthritis Network participants (n=813), and [4] participants in a cross-sectional study exploring fibromyalgia and pain thresholds (n=45). Repeatability was tested in 34 patients with active RA. Derived indices were the proportion of DAS28 attributable to patient-reported components (DAS28-P), tender-swollen difference and tender:swollen ratio. Pressure pain detection threshold (PPT) was used as an index of pain sensitisation. Results: DAS28, tender joint count, visual analogue scale, DAS28-P, tender-swollen difference and tender:swollen ratio were more strongly associated with pain, PPT and fibromyalgia status than were swollen joint count or erythrocyte sedimentation rate. DAS28-P, tender-swollen difference and tender:swollen ratio better predicted pain over 1 year than did DAS28 or its individual components. Conclusions: DAS28 is strongly associated both with inflammation and with patient-reported outcomes. DAS28-derived indices such as tender-swollen difference are associated with non-inflammatory pain mechanisms, can predict future pain and should inform how DAS28 is interpreted as an index of inflammatory disease activity in RA

Rapid Diagnosis of Smear-Negative Tuberculosis Using Immunology and Microbiology with Induced Sputum in HIV-Infected and Uninfected Individuals

Rationale and Objectives. Blood-based studies have demonstrated the potential of immunological assays to detect tuberculosis. However lung fluid sampling may prove superior as it enables simultaneous microbiological detection of mycobacteria to be performed. Until now this has only been possible using the expensive and invasive technique of broncho-alveolar lavage. We sought to evaluate an immunoassay using non-invasive induced-sputum to diagnose active tuberculosis. Methods and Results. Prospective cohort study of forty-two spontaneous sputum smear-negative or sputum non-producing adults under investigation for tuberculosis. CD4 lymphocytes specific to purified-protein-derivative of Mycobacterium tuberculosis actively synthesising interferon-gamma were measured by flow cytometry and final diagnosis compared to immunoassay using a cut-off of 0.5%. Sixteen subjects (38%) were HIV-infected (median CD4 count [range] = 332 cells/mu l [103748]). Thirty-eight (90%) were BCG-vaccinated. In 27 subjects diagnosed with active tuberculosis, the median [range] percentage of interferon-gamma synthetic CD4+ lymphocytes was 2.77% [0-23.93%] versus 0% [0-2.10%] in 15 negative for active infection (p<0.0001). Sensitivity and specificity of the immunoassay versus final diagnosis of active tuberculosis were 89% (24 of 27) and 80% (12 of 15) respectively. The 3 positive assays in the latter group occurred in subjects diagnosed with quiescent/latent tuberculosis. Assay performance was unaffected by HIV-status, BCG-vaccination or disease site. Combining this approach with traditional microbiological methods increased the diagnostic yield to 93% (25 of 27) alongside acid-fast bacilli smear and 96% (26 of 27) alongside tuberculosis culture. Conclusions. These data demonstrate for the first time that a rapid immunological assay to diagnose active tuberculosis can be performed successfully in combination with microbiological methods on a single induced-sputum sample

The Scottish Early Rheumatoid Arthritis (SERA) Study:an inception cohort and biobank

Background: The Scottish Early Rheumatoid Arthritis (SERA) study is an inception cohort of rheumatoid (RA) and undifferentiated arthritis (UA) patients that aims to provide a contemporary description of phenotype and outcome and facilitate discovery of phenotypic and prognostic biomarkers Methods: Demographic and clinical outcome data are collected from newly diagnosed RA/UA patients every 6 months from around Scotland. Health service utilization data is acquired from Information Services Division, NHS National Services Scotland. Plain radiographs of hands and feet are collected at baseline and 12 months. Additional samples of whole blood, plasma, serum and filtered urine are collected at baseline, 6 and 12 months Results: Results are available for 1073 patients; at baseline, 76 % were classified as RA and 24 % as UA. Median time from onset to first review was 163 days (IQR97-323). Methotrexate was first-line DMARD for 75 % patients. Disease activity, functional ability and health-related quality of life improved significantly between baseline and 24 months, however the proportion in any employment fell (51 to 38 %, p = 0.0005). 24 % patients reported symptoms of anxiety and/or depression at baseline. 35/391 (9 %) patients exhibited rapid radiographic progression after 12 months. The SERA Biobank has accrued 60,612 samples Conclusions: In routine care, newly diagnosed RA/UA patients experience significant improvements in disease activity, functional ability and health-related quality of life but have high rates of psychiatric symptoms and declining employment rates. The co-existence of a multi-domain description of phenotype and a comprehensive biobank will facilitate multi-platform translational research to identify predictive markers of phenotype and prognosis

Foot posture in people with medial compartment knee osteoarthritis

<p>Abstract</p> <p>Background</p> <p>Foot posture has long been considered to contribute to the development of lower limb musculoskeletal conditions as it may alter the mechanical alignment and dynamic function of the lower limb. This study compared foot posture in people with and without medial compartment knee osteoarthritis (OA) using a range of clinical foot measures. The reliability of the foot measures was also assessed.</p> <p>Methods</p> <p>The foot posture of 32 patients with clinically and radiographically-confirmed OA predominantly in the medial compartment of the knee and 28 asymptomatic age-matched healthy controls was investigated using the foot posture index (FPI), vertical navicular height and drop, and the arch index. Independent t tests and effect size (Cohen's d) were used to investigate the differences between the groups in the foot posture measurements.</p> <p>Results</p> <p>Significant differences were found between the control and the knee OA groups in relation to the FPI (1.35 ± 1.43 vs. 2.46 ± 2.18, p = 0.02; <it>d </it>= 0.61, medium effect size), navicular drop (0.02 ± 0.01 vs. 0.03 ± 0.01, p = 0.01; <it>d </it>= 1.02, large effect size) and the arch index (0.22 ± 0.04 vs. 0.26 ± 0.04, p = 0.04; <it>d </it>= 1.02, large effect size). No significant difference was found for vertical navicular height (0.24 ± 0.03 vs. 0.23 ± 0.03, p = 0.54; <it>d </it>= 0.04, negligible effect size).</p> <p>Conclusion</p> <p>People with medial compartment knee OA exhibit a more pronated foot type compared to controls. It is therefore recommended that the assessment of patients with knee OA in clinical practice should include simple foot measures, and that the potential influence of foot structure and function on the efficacy of foot orthoses in the management of medial compartment knee OA be further investigated.</p

Evaluation of the XRCC1 gene as a phenotypic modifier in BRCA1/2 mutation carriers. Results from the consortium of investigators of modifiers of BRCA1/BRCA2

Item does not contain fulltextBACKGROUND: Single-nucleotide polymorphisms (SNPs) in genes involved in DNA repair are good candidates to be tested as phenotypic modifiers for carriers of mutations in the high-risk susceptibility genes BRCA1 and BRCA2. The base excision repair (BER) pathway could be particularly interesting given the relation of synthetic lethality that exists between one of the components of the pathway, PARP1, and both BRCA1 and BRCA2. In this study, we have evaluated the XRCC1 gene that participates in the BER pathway, as phenotypic modifier of BRCA1 and BRCA2. METHODS: Three common SNPs in the gene, c.-77C>T (rs3213245) p.Arg280His (rs25489) and p.Gln399Arg (rs25487) were analysed in a series of 701 BRCA1 and 576 BRCA2 mutation carriers. RESULTS: An association was observed between p.Arg280His-rs25489 and breast cancer risk for BRCA2 mutation carriers, with rare homozygotes at increased risk relative to common homozygotes (hazard ratio: 22.3, 95% confidence interval: 14.3-34, P<0.001). This association was further tested in a second series of 4480 BRCA1 and 3016 BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2. CONCLUSIONS AND INTERPRETATION: No evidence of association was found when the larger series was analysed which lead us to conclude that none of the three SNPs are significant modifiers of breast cancer risk for mutation carriers