Statin use is associated with a reduced incidence of colorectal cancer expressing SMAD4.

BACKGROUND: Long-term use of statins is associated with a small reduced risk of colorectal cancer but their mechanism of action is not well understood. While they are generally believed to act on KRAS, we have previously proposed that they act via influencing the BMP pathway. The objective of this study was to look for associations between statin use and the risk of developing colorectal cancer of a particular molecular subtype. METHODS: By linking two registries unique to the Netherlands, 69,272 statin users and 94,753 controls were identified and, if they developed colorectal cancer, their specimens traced. Colorectal cancers were molecularly subtyped according to the expression of SMAD4 and the mutation status of KRAS and BRAF. RESULTS: Statin use was associated with a reduction in the risk of developing colorectal cancer regardless of molecular subtype (HR 0.77; 95% CI 0.66-0.89) and a larger reduction in the risk of developing SMAD4-positive colorectal cancer (OR 0.64; 95% CI 0.42-0.82). There was no relationship between statin use and the risk of developing colorectal cancer with a mutation in KRAS and/or BRAF. CONCLUSIONS: Statin use is associated with a reduced risk of developing colorectal cancer with intact SMAD4 expression.

Long-term sickness absence in a working population: development and validation of a risk prediction model in a large Dutch prospective cohort.

BACKGROUND: Societal expenditures on work-disability benefits is high in most Western countries. As a precursor of long-term work restrictions, long-term sickness absence (LTSA) is under continuous attention of policy makers. Different healthcare professionals can play a role in identification of persons at risk of LTSA but are not well trained. A risk prediction model can support risk stratification to initiate preventative interventions. Unfortunately, current models lack generalizability or do not include a comprehensive set of potential predictors for LTSA. This study is set out to develop and validate a multivariable risk prediction model for LTSA in the coming year in a working population aged 45-64 years. METHODS: Data from 11,221 working persons included in the prospective Study on Transitions in Employment, Ability and Motivation (STREAM) conducted in the Netherlands were used to develop a multivariable risk prediction model for LTSA lasting ≥28 accumulated working days in the coming year. Missing data were imputed using multiple imputation. A full statistical model including 27 pre-selected predictors was reduced to a practical model using backward stepwise elimination in a logistic regression analysis across all imputed datasets. Predictive performance of the final model was evaluated using the Area Under the Curve (AUC), calibration plots and the Hosmer-Lemeshow (H&L) test. External validation was performed in a second cohort of 5604 newly recruited working persons. RESULTS: Eleven variables in the final model predicted LTSA: older age, female gender, lower level of education, poor self-rated physical health, low weekly physical activity, high self-rated physical job load, knowledge and skills not matching the job, high number of major life events in the previous year, poor self-rated work ability, high number of sickness absence days in the previous year and being self-employed. The model showed good discrimination (AUC 0.76 (interquartile range 0.75-0.76)) and good calibration in the external validation cohort (H&L test: p = 0.41). CONCLUSIONS: This multivariable risk prediction model distinguishes well between older workers with high- and low-risk for LTSA in the coming year. Being easy to administer, it can support healthcare professionals in determining which persons should be targeted for tailored preventative interventions.

Bidirectional tumor/stroma crosstalk promotes metastasis in mesenchymal colorectal cancer.

Patients with the mesenchymal subtype colorectal cancer (CRC) have a poor prognosis, in particular patients with stroma-rich tumors and aberrant SMAD4 expression. We hypothesized that interactions between SMAD4-deficient CRC cells and cancer-associated fibroblasts provide a biological explanation. In transwell invasion assays, fibroblasts increased the invasive capacity of SMAD4-deficient HT29 CRC cells, but not isogenic SMAD4-proficient HT29 cells. A TGF-ß/BMP-specific array showed BMP2 upregulation by fibroblasts upon stimulation with conditioned medium from SMAD4-deficient CRC cells, while also stimulating their invasion. In a mouse model for experimental liver metastasis, the co-injection of fibroblasts increased metastasis formation of SMAD4-deficient CRC cells (p = 0.02) but not that of SMAD4-proficient CRC cells. Significantly less metastases were seen in mice co-injected with BMP2 knocked-down fibroblasts. Fibroblast BMP2 expression seemed to be regulated by TRAIL, a factor overexpressed in SMAD4-deficient CRC cells. In a cohort of 146 stage III CRC patients, we showed that patients with a combination of high stromal BMP2 expression and the loss of tumor SMAD4 expression had a significantly poorer overall survival (HR 2.88, p = 0.04). Our results suggest the existence of a reciprocal loop in which TRAIL from SMAD4-deficient CRC cells induces BMP2 in fibroblasts, which enhances CRC invasiveness and metastasis.

Nonsteroidal Antiinflammatory Drugs for Axial Spondyloarthritis: A Cochrane Review.

OBJECTIVE: To determine the benefits and harms of nonsteroidal antiinflammatory drugs (NSAID) in axial spondyloarthritis (axSpA). METHODS: Systematic review using Cochrane Collaboration methodology. INCLUSION CRITERIA: randomized controlled trials (RCT) and quasi-RCT (to June 2014), investigating NSAID versus any control for axSpA, and observational studies of longterm effects (≥ 6 mos) of NSAID on radiographic progression or adverse events. Main outcomes were pain, Bath Ankylosing Spondylitis Disease Activity Index, Bath Ankylosing Spondylitis Functional Index, Bath Ankylosing Spondylitis Metrology Index, radiographic progression, number of withdrawals because of adverse events, and number of serious adverse events. Risk of bias was assessed. RESULTS: Thirty-five RCT, 2 quasi-RCT, and 2 cohort studies were included. Twenty-nine RCT and 2 quasi-RCT (n = 4356) were included in pooled analyses [traditional NSAID vs placebo (n = 5), cyclooxygenase-2 (COX-2) vs placebo (n = 3), COX-2 vs traditional NSAID (n = 4), NSAID vs NSAID (n = 24), naproxen vs other NSAID (n = 3), and low- vs high-dose NSAID (n = 5)]. Compared with placebo, both traditional and COX-2 NSAID were consistently more efficacious at 6 weeks and equally safe after 12 weeks. No significant differences in benefits or harms between the 2 NSAID classes and no important differences in benefits or withdrawals because of adverse events between different NSAID were found, especially if studies with high risk of bias were excluded. Single studies suggest NSAID may retard radiographic progression, especially by continuous rather than on-demand NSAID use. CONCLUSION: High-quality evidence indicates that both traditional and COX-2 NSAID are efficacious for treating axSpA, and harms are not different from placebo in the short term. Various NSAID are equally effective.

Cardiovascular Morbidity and Mortality Among Working Individuals With Rheumatic Disease: Results From a Large Prospective Cohort Study.

BACKGROUND: Cardiovascular comorbidities are common in rheumatic diseases and are associated with an increased mortality risk but have not been studied in a working population, with less severe disease. Also, the impact of premature cardiovascular mortality on work participation has been neglected until now. OBJECTIVES: The objectives of this study were to evaluate the cardiovascular risk in working individuals with inflammatory rheumatic diseases and to explore whether cardiovascular morbidity and mortality are associated with decreased work participation in this population. METHODS: Employees from 45 companies in The Netherlands (n = 12,140) were prospectively followed up from 1998 onward by annual questionnaires. Data covering 10 years of follow-up was available (1998-2008) for rheumatic and cardiovascular morbidities. Self-reported rheumatic and cardiovascular diseases were verified by clinical review in hospital records in a subsample living in 1 specific region of The Netherlands. Information on the vital status was obtained by linking our records to national registries. Cox proportional hazards models were used to determine the contribution of cardiovascular comorbidity on mortality, with adjustment for confounders. RESULTS: In the sample verified by clinical review, the 10-year risk of developing cardiovascular diseases tended to be increased in workers with inflammatory rheumatic diseases (n = 17) at baseline (relative risk, 2.30; 95% confidence interval [CI], 0.91-5.81) and was significantly increased in those with gout (n = 18) at baseline (relative risk, 3.64; 95% CI, 1.64-8.09) as compared with those without inflammatory rheumatic diseases or gout, respectively. Gout (n = 31; hazard ratio, 4.19; 95% CI, 1.33-13.25) and cardiovascular diseases (n = 206; hazard ratio, 2.19; 95% CI, 1.24-3.84) were significantly related to 10-year mortality. No deaths had occurred in individuals with inflammatory rheumatic diseases during follow-up. CONCLUSIONS: In this study, gout was significantly associated with cardiovascular comorbidity and mortality, but inflammatory rheumatic diseases were not. Decreased work participation in workers with gout and potentially inflammatory rheumatic diseases can be expected because of an increased morbidity but not mortality risk.

Non-steroidal anti-inflammatory drugs (NSAIDs) for axial spondyloarthritis (ankylosing spondylitis and non-radiographic axial spondyloarthritis).

BACKGROUND: Axial spondyloarthritis (axSpA) comprises ankylosing spondylitis (radiographic axSpA) and non-radiographic (nr-)axSpA and is associated with psoriasis, uveitis and inflammatory bowel disease. Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended as first-line drug treatment. OBJECTIVES: To determine the benefits and harms of NSAIDs in axSpA. SEARCH METHODS: We searched CENTRAL, MEDLINE and EMBASE to 18 June 2014. SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs of NSAIDs versus placebo or any comparator in adults with axSpA and observational cohort studies studying the long term effect (≥ six months) of NSAIDs on radiographic progression or adverse events (AEs). The main comparions were traditional or COX-2 NSAIDs versus placebo. The major outcomes were pain, Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Metrology Index (BASMI), radiographic progression, number of withdrawals due to AEs and number of serious AEs DATA COLLECTION AND ANALYSIS: Two review authors independently selected trials for inclusion, assessed the risk of bias, extracted data and assessed the quality of evidence for major outcomes using GRADE. MAIN RESULTS: We included 39 studies (35 RCTs, two quasi-RCTs and two cohort studies); and 29 RCTs and two quasi-RCTs (n = 4356) in quantitative analyses for the comparisons: traditional NSAIDs versus placebo, cyclo-oxygenase-2 (COX-2) versus placebo, COX-2 versus traditional NSAIDs, NSAIDs versus NSAIDs, naproxen versus other NSAIDs, low versus high dose. Most trials were at unclear risk of selection bias (n = 29), although blinding of participants and personnel was adequate in 24 trials. Twenty-five trials had low risk of attrition bias and 29 trials had low risk of reporting bias. Risk of bias in both cohort studies was high for study participation, and low or unclear for all other criteria. No trials in the meta-analyses assessed patients with nr-axSpA.Traditional NSAIDs were more beneficial than placebo at six weeks. High quality evidence (four trials, N=850) indicates better pain relief with NSAIDs (pain in control group ranged from 57 to 64 on a 100mm visual analogue scale (VAS) and was 16.5 points lower in the NSAID group (95% confidence interval (CI) -20.8 to -12.2), lower scores indicate less pain, NNT 4 (3 to 6)); moderate quality evidence (one trial, n = 190) indicates improved disease activity with NSAIDs (BASDAI in control group was 54.7 on a 100-point scale and was 17.5 points lower in the NSAID group, 95% CI -23.1 to -11.8), lower scores indicate less disease activity, NNT 3 (2 to 4)); and high quality evidence (two trials, n = 356) indicates improved function with NSAIDs (BASFI in control group was 50.0 on a 100-point scale and was 9.1 points lower in the NSAID group (95% CI -13.0 to -5.1), lower scores indicate better functioning, NNT 5 (3 to 8)). High (five trials, n = 1165) and moderate (three trials, n = 671) quality evidence (downgraded due to potential imprecision) indicates that withdrawals due to AEs and number of serious AEs did not differ significantly between placebo (52/1000 and 2/1000) and NSAID (39/1000 and 3/1000) groups after 12 weeks (risk ratio (RR) 0.75, 95% CI 0.46 to 1.21; and RR 1.69, 95% CI 0.36 to 7.97, respectively). BASMI and radiographic progression were not reported.COX-2 NSAIDS were also more efficacious than placebo at six weeks. High quality evidence (two trials, n = 349) indicates better pain relief with COX-2 (pain in control group was 64 points and was 21.7 points lower in the COX-2 group (95% CI -35.9 to -7.4), NNT 3 (2 to 24)); moderate quality evidence (one trial, n = 193) indicates improved disease activity with COX-2 (BASDAI in control groups was 54.7 points and was 22 points lower in the COX-2 group (95% CI -27.4 to -16.6), NNT 2 (1 to 3)); and high quality evidence (two trials, n = 349) showed improved function with COX-2 (BASFI in control group was 50.0 points and was 13.4 points lower in the COX-2 group (95% CI -17.4 to -9.5), NNT 3 (2 to 4)). Low and moderate quality evidence (three trials, n = 669) (downgraded due to potential imprecision and heterogeneity) indicates that withdrawals due to AEs and number of serious AEs did not differ significantly between placebo (11/1000 and 2/1000) and COX-2 (24/1000 and 2/1000) groups after 12 weeks (RR 2.14, 95% CI 0.36 to 12.56; and RR 0.92, 95% CI 0.14 to 6.21, respectively). BASMI and radiographic progression were not reported.There were no significant differences in benefits (pain on VAS: MD -2.62, 95% CI -10.99 to 5.75; three trials, n = 669) or harms (withdrawals due to AEs: RR 1.04, 95% CI 0.60 to 1.82; four trials, n = 995) between NSAID classes. While indomethacin use resulted in significantly more AEs (RR 1.25, 95% CI 1.06 to 1.48; 11 studies, n = 1135), and neurological AEs (RR 2.34, 95% CI 1.32 to 4.14; nine trials, n = 963) than other NSAIDs, these findings were not robust to sensitivity analyses. We found no important differences in harms between naproxen and other NSAIDs (three trials, n = 646), although other NSAIDs appeared more effective for relieving pain (MD 6.80, 95% CI 3.72 to 9.88; two trials, n = 232). We found no clear dose-response effect on benefits or harms (five studies, n = 1136). Single studies suggest NSAIDs may be effective in retarding radiographic progression, especially in certain subgroups of patients, e.g. patients with high CRP, and that this may be best achieved by continuous rather than on-demand use of NSAIDs. AUTHORS' CONCLUSIONS: High to moderate quality evidence indicates that both traditional and COX-2 NSAIDs are efficacious for treating axSpA, and moderate to low quality evidence indicates harms may not differ from placebo in the short term. Various NSAIDs are equally effective. Continuous NSAID use may reduce radiographic spinal progression, but this requires confirmation.

Self-management education programmes for osteoarthritis.

BACKGROUND: Self-management education programmes are complex interventions specifically targeted at patient education and behaviour modification. They are designed to encourage people with chronic disease to take an active self-management role to supplement medical care and improve outcomes. OBJECTIVES: To assess the effectiveness of self-management education programmes for people with osteoarthritis. SEARCH METHODS: The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, PyscINFO, SCOPUS and the World Health Organization (WHO) International Clinical Trial Registry Platform were searched, without language restriction, on 17 January 2013. We checked references of reviews and included trials to identify additional studies. SELECTION CRITERIA: Randomised controlled trials of self-management education programmes in people with osteoarthritis were included. Studies with participants receiving passive recipients of care and studies comparing one type of programme versus another were excluded. DATA COLLECTION AND ANALYSIS: In addition to standard methods we extracted components of the self-management interventions using the eight domains of the Health Education Impact Questionnaire (heiQ), and contextual and participant characteristics using PROGRESS-Plus and the Health Literacy Questionnaire (HLQ). Outcomes included self-management of osteoarthritis, participant's positive and active engagement in life, pain, global symptom score, self-reported function, quality of life and withdrawals (including dropouts and those lost to follow-up). We assessed the quality of the body of evidence for these outcomes using the GRADE approach. MAIN RESULTS: We included twenty-nine studies (6,753 participants) that compared self-management education programmes to attention control (five studies), usual care (17 studies), information alone (four studies) or another intervention (seven studies). Although heterogeneous, most interventions included elements of skill and technique acquisition (94%), health-directed activity (85%) and self-monitoring and insight (79%); social integration and support were addressed in only 12%. Most studies did not provide enough information to assess all PROGRESS-Plus items. Eight studies included predominantly Caucasian, educated female participants, and only four provided any information on participants' health literacy. All studies were at high risk of performance and detection bias for self-reported outcomes; 20 studies were at high risk of selection bias, 16 were at high risk of attrition bias, two were at high risk of reporting bias and 12 were at risk of other biases. We deemed attention control as the most appropriate and thus the main comparator.Compared with attention control, self-management programmes may not result in significant benefits at 12 months. Low-quality evidence from one study (344 people) indicates that self-management skills were similar in active and control groups: 5.8 points on a 10-point self-efficacy scale in the control group, and the mean difference (MD) between groups was 0.4 points (95% confidence interval (CI) -0.39 to 1.19). Low-quality evidence from four studies (575 people) indicates that self-management programmes may lead to a small but clinically unimportant reduction in pain: the standardised mean difference (SMD) between groups was -0.26 (95% CI -0.44 to -0.09); pain was 6 points on a 0 to 10 visual analogue scale (VAS) in the control group, treatment resulted in a mean reduction of 0.8 points (95% CI -0.14 to -0.3) on a 10-point scale, with number needed to treat for an additional beneficial outcome (NNTB) of 8 (95% CI 5 to 23). Low-quality evidence from one study (251 people) indicates that the mean global osteoarthritis score was 4.2 on a 0 to 10-point symptom scale (lower better) in the control group, and treatment reduced symptoms by a mean of 0.14 points (95% CI -0.54 to 0.26). This result does not exclude the possibility of a clinically important benefit in some people (0.5 point reduction included in 95% CI). Low-quality evidence from three studies (574 people) showed no signficant difference in function between groups (SMD -0.19, 95% CI -0.5 to 0.11); mean function was 1.29 points on a 0 to 3-point scale in the control group, and treatment resulted in a mean improvement of 0.04 points with self-management (95% CI -0.10 to 0.02). Low-quality evidence from one study (165 people) showed no between-group difference in quality of life (MD -0.01, 95% CI -0.03 to 0.01) from a control group mean of 0.57 units on 0 to 1 well-being scale. Moderate-quality evidence from five studies (937 people) shows similar withdrawal rates between self-management (13%) and control groups (12%): RR 1.11 (95% CI 0.78 to 1.57). Positive and active engagement in life was not measured.Compared with usual care, moderate-quality evidence from 11 studies (up to 1,706 participants) indicates that self-management programmes probably provide small benefits up to 21 months, in terms of self-management skills, pain, osteoarthritis symptoms and function, although these are of doubtful clinical importance, and no improvement in positive and active engagement in life or quality of life. Withdrawal rates were similar. Low to moderate quality evidence indicates no important differences in self-management , pain, symptoms, function, quality of life or withdrawal rates between self-management programmes and information alone or other interventions (exercise, physiotherapy, social support or acupuncture). AUTHORS' CONCLUSIONS: Low to moderate quality evidence indicates that self-management education programmes result in no or small benefits in people with osteoarthritis but are unlikely to cause harm.Compared with attention control, these programmes probably do not improve self-management skills, pain, osteoarthritis symptoms, function or quality of life, and have unknown effects on positive and active engagement in life. Compared with usual care, they may slightly improve self-management skills, pain, function and symptoms, although these benefits are of unlikely clinical importance.Further studies investigating the effects of self-management education programmes, as delivered in the trials in this review, are unlikely to change our conclusions substantially, as confounding from biases across studies would have likely favoured self-management. However, trials assessing other models of self-management education programme delivery may be warranted. These should adequately describe the intervention they deliver and consider the expanded PROGRESS-Plus framework and health literacy, to explore issues of health equity for recipients.

Effects of cardiovascular comorbidities on work participation in rheumatic diseases: a prospective cohort study among working individuals.

OBJECTIVE: To determine the risk of sick leave and work disability in relation to rheumatic diseases and cardiovascular comorbidities among working individuals. METHODS: Employees (n = 12,140) from 45 companies in The Netherlands were prospectively followed up from 1998-2008. Questionnaires were used to assess self-reported diseases and employment status. Company records provided individual sick leave data for the first 2.5 years of followup. For a selected sample of the cohort (50%), verification of self-reported diseases was sought through hospital record linkage. Poisson regressions and Cox proportional hazards models were applied to determine the impact of both self-reported and verified diseases on sick leave and work disability, respectively. RESULTS: The number of days and frequency of sick leave were increased in working individuals with self-reported rheumatic and cardiovascular disease (P < 0.001), but self-reported cardiovascular comorbidity did not result in more sick leave in those who also self-reported rheumatic disease. Work disability was also increased for both self-reported rheumatic disease and cardiovascular disease (P < 0.001), but again, no additive effects were found. In the sample verified by clinical review, the frequency or number of days of sick leave was significantly higher in employees with cardiovascular disease (P < 0.001), inflammatory rheumatic disease (P < 0.05), and osteoarthritis (P < 0.05) compared to employees without these diseases. Work disability in the verified sample occurred especially in patients with osteoarthritis (hazard ratio [HR] 12.36 [95% confidence interval (95% CI) 1.59-13.66]), fibromyalgia (HR 14.24 [95% CI 2.02-16.54]), and cardiovascular disease (HR 4.88 [95% CI 1.70-14.01]). CONCLUSION: Rheumatic and cardiovascular diseases increased the risk of sick leave and work disability in a working population, but there was no indication that these effects convey an additive risk.

Effect of biological therapy on work participation in patients with ankylosing spondylitis: a systematic review.

OBJECTIVES: To review systematically the effect of biological treatment in patients with ankylosing spondylitis (AS) on three work outcomes: work status, absence from paid work and at-work productivity. METHODS: A systematic literature search was performed (Pubmed, Embase, Cochrane Library) to identify relevant articles. Risk of bias of included studies was assessed using the Cochrane guidelines for cohorts and randomised controlled trials (RCTs). Data were extracted using a self-composed data extraction form. Owing to extensive interstudy heterogeneity, narrative summaries were used to present the data. RESULTS: Nine studies were included (six uncontrolled cohorts, one population-controlled cohort and two RCTs) that reported on 39 comparisons. Overall, 961 patients were treated with three different tumour necrosis factor α inhibitors (etanercept, infliximab, adalimumab). For presenteeism and absence from work, most comparisons showed improvement in favour of biological agents, but not all comparisons were statistically significant and they usually concerned before-after analyses. For work status, changes were less often positive, but studies dealt with patients with longstanding AS, lacked power and had a relatively short follow-up. CONCLUSIONS: Although trends towards beneficial effects of biological agents in longstanding AS were seen on all work outcomes, the methodological limitations in the studies included hampers clear conclusions. Since the majority of studies were (extensions of) controlled trials, the generalisability of the effect of biological agents on work participation in real life should be further studied in larger (population-controlled) studies. The effect of biological agents in patients with early disease has not yet been examined.