Jan W. Schoones

Synovial inflammation, immune cells and their cytokines in osteoarthritis: a review.

OBJECTIVE Although osteoarthritis (OA) is considered a non-inflammatory condition, it is widely accepted that synovial inflammation is a feature of OA. However, the role of immune cells and their cytokines in OA is largely unknown. This narrative systematic review summarizes the knowledge of inflammatory properties, immune cells and their cytokines in synovial tissues (STs) of OA patients. DESIGN Broad literature search in different databases was performed which resulted in 100 articles. RESULTS Of 100 articles 33 solely investigated inflammation in OA ST with or without comparison with normal samples; the remaining primarily focussed on rheumatoid arthritis (RA) ST. Studies investigating different severity stages or cellular source of cytokines were sparse. OA ST displayed mild/moderate grade inflammation when investigated by means of haematoxylin and eosin (H&E) staining. Most frequently found cells types were macrophages, T cells and mast cells (MCs). Overall the number of cells was lower than in RA, although the number of MCs was as high as or sometimes even higher than in RA ST. Cytokines related to T cell or macrophage function were found in OA ST. Their expression was overall higher than in normal ST, but lower than in RA ST. Their cellular source remains largely unknown in OA ST. CONCLUSION Inflammation is common in OA ST and characterized by immune cell infiltration and cytokine secretion. This inflammation seems quantitatively and qualitatively different from inflammation in RA. Further research is needed to clarify the role of inflammation, immune cells and their cytokines in the pathogenesis of OA.

What is the evidence for the presence of a therapeutic window of opportunity in rheumatoid arthritis? A systematic literature review

Objective Initiation of DMARD-therapy in the ‘window of opportunity’ is thought to result in a more effective modification of the processes underlying rheumatoid arthritis (RA). We questioned whether this effect is true or hyped and performed a systematic literature review. Methods Medical literature databases up to June 2012 were systematically reviewed for cohort studies and randomised controlled trials reporting outcome data of early RA in relation with symptom duration at treatment initiation. The quality of these studies was assessed by two independent reviewers using a criteria scoring system of 15 items. Studies were dichotomised with the median score (79%) as cut-off. Best-evidence synthesis was applied to determine the level of evidence per outcome category. A meta-analysis was performed on the studies reporting on achieving DMARD-free sustained remission (the reverse of disease persistency). Results Out of 836 screened articles, 18 fulfilled the selection criteria and were not duplicates. Ten were scored as high quality. Remission (various definitions) and radiographic progression were frequently studied outcomes. There was strong evidence for an association between symptom duration and radiographic progression. A meta-analysis on datasets evaluating DMARD-free sustained remission showed that symptom duration was independently associated with such remission; HR 0.989 (95% CI 0.983 to 0.995) per week increase in symptom duration. A moderate level of evidence was observed for other remission outcomes. Conclusions Even when heterogeneity of patients is taken into account, prolonged symptom duration is associated with radiographic progression and a lower chance on DMARD-free sustained remission. These data may support the presence of a ‘window of opportunity’.

Ectopic fat and insulin resistance: pathophysiology and effect of diet and lifestyle interventions.

The storage of triglyceride (TG) droplets in nonadipose tissues is called ectopic fat storage. Ectopic fat is associated with insulin resistance and type 2 diabetes mellitus (T2DM). Not the triglycerides per se but the accumulation of intermediates of lipid metabolism in organs, such as the liver, skeletal muscle, and heart seem to disrupt metabolic processes and impair organ function. We describe the mechanisms of ectopic fat depositions in the liver, skeletal muscle, and in and around the heart and the consequences for each organs function. In addition, we systematically reviewed the literature for the effects of diet-induced weight loss and exercise on ectopic fat depositions.

Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality.

CONTEXT IGF-I plays a central role in metabolism and growth regulation. High IGF-I levels are associated with increased cancer risk and low IGF-I levels with increased risk for cardiovascular disease. OBJECTIVE Our objective was to determine the relationship between circulating IGF-I levels and mortality in the general population using random-effects meta-analysis and dose-response metaregression. DATA SOURCES We searched PubMed, EMBASE, Web of Science, and Cochrane Library from 1985 to September 2010 to identify relevant studies. STUDY SELECTION Population-based cohort studies and (nested) case-control studies reporting on the relation between circulating IGF-I and mortality were assessed for eligibility. DATA EXTRACTION Data extraction was performed by two investigators independently, using a standardized data extraction sheet. DATA SYNTHESIS Twelve studies, with 14,906 participants, were included. Overall, risk of bias was limited. Mortality in subjects with low or high IGF-I levels was compared with mid-centile reference categories. All-cause mortality was increased in subjects with low as well as high IGF-I, with a hazard ratio (HR) of 1.27 (95% CI = 1.08-1.49) and HR of 1.18 (95% CI = 1.04-1.34), respectively. Dose-response metaregression showed a U-shaped relation of IGF-I and all-cause mortality (P = 0.003). The predicted HR for the increase in mortality comparing the 10th IGF-I with the 50th percentile was 1.56 (95% CI = 1.31-1.86); the predicted HR comparing the 90th with the 50th percentile was 1.29 (95% CI = 1.06-1.58). A U-shaped relationship was present for both cancer mortality and cardiovascular mortality. CONCLUSIONS Both low and high IGF-I concentrations are associated with increased mortality in the general population.

Genetic variants in pre-eclampsia: a meta-analysis

BACKGROUND Pre-eclampsia has a clear familial component, suggesting that the condition may be partly attributable to genetic susceptibility. The search for susceptibility genes has led to a drastic increase in the number of published studies associating genetic factors with pre-eclampsia. However, attempts to replicate these findings have yielded inconsistent results. This meta-analysis assessed the pooled effect of each genetic variant that is reproducibly associated with pre-eclampsia. METHODS Studies that assessed the association between genes and pre-eclampsia were searched in PubMed, Embase and Web of Science. We selected all genetic variants that were significantly associated with pre-eclampsia in an initial study and were subsequently independently reproduced in at least one additional study. All studies that assessed these reproduced variants were then included. The association between genetic variants and pre-eclampsia was calculated at the allele level, and the main measure of effect was a pooled odds ratio in a random-effects model. RESULTS The literature search yielded 2965 articles, of which 542 investigated genetic associations in pre-eclampsia. We identified 22 replicated genetic variants, of which 7 remained significantly associated with pre-eclampsia following meta-analysis. These variants were in or near the following genes: ACE, CTLA4, F2, FV, LPL and SERPINE1. CONCLUSIONS This meta-analysis identified seven genetic variants associated with pre-eclampsia. Importantly, many of these variants are also risk factors for developing cardiovascular disease, revealing that pre-eclampsia and cardiovascular disease have shared genetic risk factors. The contribution of the identified genetic variants in the pathogenesis of pre-eclampsia should be the focus of future studies.

Risk of Hypothyroidism following Hemithyroidectomy: Systematic Review and Meta-Analysis of Prognostic Studies

CONTEXT The reported risk of hypothyroidism after hemithyroidectomy shows considerable heterogeneity in literature. OBJECTIVE The aim of this systematic review and meta-analysis was to determine the overall risk of hypothyroidism, both clinical and subclinical, after hemithyroidectomy. Furthermore, we aimed to identify risk factors for postoperative hypothyroidism. DATA SOURCES A systematic literature search was performed using several databases, including PubMed. STUDY SELECTION Original articles in which an incidence or prevalence of hypothyroidism after primary hemithyroidectomy could be extracted were included. DATA EXTRACTION Study identification and data extraction were performed independently by two reviewers. In case of disagreement, a third reviewer was consulted. DATA SYNTHESIS A total of 32 studies were included in this meta-analysis. Meta-analysis was performed using logistic regression with random effect at study level. The overall risk of hypothyroidism after hemithyroidectomy was 22% (95% confidence interval, 19-27). A clear distinction between clinical (supranormal TSH levels and subnormal thyroid hormone levels) and subclinical (supranormal TSH levels and thyroid hormone levels within the normal range) hypothyroidism was provided in four studies. These studies reported on an estimated risk of 12% for subclinical hypothyroidism and 4% for clinical hypothyroidism. Positive anti-thyroid peroxidase status is a relevant preoperative indicator of hypothyroidism after surgery. Effect estimates did not differ substantially between studies with lower risk of bias and studies with higher risk of bias. CONCLUSIONS This meta-analysis showed that approximately one in five patients will develop hypothyroidism after hemithyroidectomy, with clinical hypothyroidism in one of 25 operated patients.

Minimal clinically important differences in health-related quality of life after total hip or knee replacement: A systematic review

Objectives We aimed first to summarise minimal clinically important differences (MCIDs) after total hip (THR) or knee replacement (TKR) in health-related quality of life (HRQoL), measured using the Short-Form 36 (SF-36). Secondly, we aimed to improve the precision of MCID estimates by means of meta-analysis. Methods We conducted a systematic review of English and non-English articles using MEDLINE, the Cochrane Controlled Trials Register (1960–2011), EMBASE (1991–2011), Web of Science, Academic Search Premier and Science Direct. Bibliographies of included studies were searched in order to find additional studies. Search terms included MCID or minimal clinically important change, THR or TKR and Short-Form 36. We included longitudinal studies that estimated MCID of SF-36 after THR or TKR. Results Three studies met our inclusion criteria, describing a distinct study population: primary THR, primary TKR and revision THR. No synthesis of study results can be given. Conclusions Although we found MCIDs in HRQoL after THR or TKR have limited precision and are not validated using external criteria, these are still the best known estimates of MCIDs in HRQoL after THR and TKR to date. We therefore advise these MCIDs to be used as absolute thresholds, but with caution.

Appraisal of evidence base for introduction of new implants in hip and knee replacement: a systematic review of five widely used device technologies

Objective To determine the evidence of effectiveness and safety for introduction of five recent and ostensibly high value implantable devices in major joint replacement to illustrate the need for change and inform guidance on evidence based introduction of new implants into healthcare. Design Systematic review of clinical trials, comparative observational studies, and registries for comparative effectiveness and safety of five implantable device innovations. Data sources PubMed (Medline), Embase, Web of Science, Cochrane, CINAHL, reference lists of articles, annual reports of major registries, summaries of safety and effectiveness for pre-market application and mandated post-market studies at the US Food and Drug Administration. Study selection The five selected innovations comprised three in total hip replacement (ceramic-on-ceramic bearings, modular femoral necks, and uncemented monoblock cups) and two in total knee replacement (high flexion knee replacement and gender specific knee replacement). All clinical studies of primary total hip or knee replacement for symptomatic osteoarthritis in adults that compared at least one of the clinical outcomes of interest (patient centred outcomes or complications, or both) in the new implant group and control implant group were considered. Data searching, abstraction, and analysis were independently performed and confirmed by at least two authors. Quantitative data syntheses were performed when feasible. Results After assessment of 10 557 search hits, 118 studies (94 unique study cohorts) met the inclusion criteria and reported data related to 15 384 implants in 13 164 patients. Comparative evidence per device innovation varied from four low to moderate quality retrospective studies (modular femoral necks) to 56 studies of varying quality including seven high quality (randomised) studies (high flexion knee replacement). None of the five device innovations was found to improve functional or patient reported outcomes. National registries reported two to 12 year follow-up for revision occurrence related to more than 200 000 of these implants. Reported comparative data with well established alternative devices (over 1 200 000 implants) did not show improved device survival. Moreover, we found higher revision occurrence associated with modular femoral necks (hazard ratio 1.9) and ceramic-on-ceramic bearings (hazard ratio 1.0-1.6) in hip replacement and with high flexion knee implants (hazard ratio 1.0-1.8). Conclusion We did not find convincing high quality evidence supporting the use of five substantial, well known, and already implemented device innovations in orthopaedics. Moreover, existing devices may be safer to use in total hip or knee replacement. Improved regulation and professional society oversight are necessary to prevent patients from being further exposed to these and future innovations introduced without proper evidence of improved clinical efficacy and safety.

Functional outcomes after radiotherapy or laser surgery in early glottic carcinoma: A systematic review†

Early glottic carcinoma is treated with laser surgery or radiotherapy, but which treatment has better functional outcomes is unclear. This systematic review compared functional outcomes (voice, swallowing, quality of life [QOL]) in more extended T1a and limited T2 tumors (1) between treatments and (2) between greater and lesser laser resections.

The effects of pre- and postoperative fibrinogen levels on blood loss after cardiac surgery: a systematic review and meta-analysis

OBJECTIVES Fibrinogen concentrate is increasingly used in cardiac surgery when bleeding is anticipated or ongoing. Since randomized clinical studies to support this are lacking, it is relevant to know whether lower fibrinogen levels are associated with excessive bleeding. We performed a systematic review and meta-analysis to define the association between fibrinogen levels and blood loss after cardiac surgery. METHODS A database search (January 2013) was performed on publications assessing the association between pre- and postoperative fibrinogen levels and postoperative blood loss in adult patients undergoing cardiac surgery. Cohort studies and case-control studies were eligible for inclusion. The main outcome was the pooled correlation coefficient, calculated via Fishers Z transformation scale, in a random-effects meta-analysis model stratified for the time point at which fibrinogen was measured. RESULTS A total of 20 studies were included. The pooled correlation coefficient of studies (n = 9) concerning preoperative fibrinogen levels and postoperative blood loss was -0.40 (95% confidence interval: -0.58, -0.18), pointing towards more blood loss in patients with lower preoperative fibrinogen levels. Among papers (n = 16) reporting on postoperative fibrinogen levels and postoperative blood loss, the pooled correlation coefficient was -0.23 (95% confidence interval: -0.29, -0.16). CONCLUSIONS Our meta-analysis indicated a significant but weak-to-moderate correlation between pre- and postoperative fibrinogen levels and postoperative blood loss in cardiac surgery. This moderate association calls for appropriate clinical studies on whether fibrinogen supplementation will decrease postoperative blood loss.