OBJECTIVE: To clarify the evidence on the magnitude and duration of treatment effect of intra-articular corticosteroid (IAC) injections for knee osteoarthritis (OA) compared to placebo, to evaluate a treatment effect by steroid type, and to describe the reported adverse effects.
DESIGN: Cochrane Controlled Trials Register, Medline, Embase, CINAHL, Scopus, and Web of Science databases were searched. The risk of systematic bias was assessed according to the Cochrane Collaboration's domain-based evaluation framework.
RESULTS: The final sample included eight RCTs with follow-ups from 1 to 26 weeks. The risk of systematic bias was considered low in five and high in three studies. The pooled SMD was -0.58 (95% CI -0.88 to -0.27) and NNT 5.1 (95% CI 10.0 to 3.7). The heterogeneity was considerable. The pooled effect size approached the level of statistical insignificance at four months. The pooled risk ratio of adverse effects was insignificant 0.95 (95% CI 0.34 to 2.55).
CONCLUSION: The IAC had a mild to moderate effect on pain severity up to three months after the injection - much longer than it had previously been reported. The effect may vary substantially in different patient groups and appropriate patient selection is important. The risk of adverse effects was low.
INTRODUCTION: Knee osteoarthritis (KOA) is a significant health problem with lifetime risk of development estimated to be 45%. Effective nonsurgical treatments are needed for the management of symptoms.
METHODS: We designed a network meta-analysis to determine clinically relevant effectiveness of nonsteroidal anti-inflammatory drugs, acetaminophen, intra-articular (IA) corticosteroids, IA platelet-rich plasma, and IA hyaluronic acid compared with each other as well as with oral and IA placebos. We used PubMed, EMBASE, and Cochrane Central Register of Controlled Trials to perform a systematic search of KOA treatments with no date limits and last search on October 7, 2015. Article inclusion criteria considered the following: target population, randomized controlled study design, English language, human subjects, treatments and outcomes of interest, ≥30 patients per group, and consistent follow-up. Using the best available evidence, two abstractors independently extracted pain and function data at or near the most common follow-up time.
RESULTS: For pain, all active treatments showed significance over oral placebo, with IA corticosteroids having the largest magnitude of effect and significant difference only over IA placebo. For function, no IA treatments showed significance compared with either placebo, and naproxen was the only treatment showing clinical significance compared with oral placebo. Cumulative probabilities showed naproxen to be the most effective individual treatment, and when combined with IA corticosteroids, it is the most probable to improve pain and function.
DISCUSSION: Naproxen ranked most effective among conservative treatments of KOA and should be considered when treating pain and function because of its relative safety and low cost. The best available evidence was analyzed, but there were instances of inconsistency in the design and duration among articles, potentially affecting uniform data inclusion.
OBJECTIVE: The aims of this study were to systematically review clinimetrics of commonly assessed ultrasound pathologies in knee, hip and hand osteoarthritis (OA), and to conduct a meta-analysis for each clinimetric.
METHODS: MEDLINE, EMBASE, and Cochrane Library databases were searched from their inceptions to September 2016. According to the OMERACT Instrument Selection Algorithm, data extraction focused on ultrasound technical features and performance metrics. Methodological quality was assessed with modified 19-item Downs and Black score and 11-item Quality Appraisal of Diagnostic Reliability (QAREL) score. Separate meta-analyses were performed for clinimetrics: 1)inter-rater/intra-rater reliability; 2)construct validity; 3)criteria validity; and 4)internal/external responsiveness. SPSS, Excel and Comprehensive Meta-analysis were used.
RESULT: Our search identified 1126 records; of these, 100 were eligible, including a total of 8542 patients and 32373 joints. The average Downs and Black score was 13.01, and average QAREL was 5.93. The stratified meta-analysis was performed only for knee OA, which demonstrated moderate to substantial reliability [minimum kappa>0.44(0.15,0.74), minimum ICC>0.82(0.73-0.89)], weak construct validity against pain(r=0.12 to 0.27), function(r=0.15 to 0.23), and blood biomarkers(r=0.01 to 0.21), but weak to strong correlation with plain radiography(r=0.13 to 0.60), strong association with MRI [minimum r=0.60(0.52,0.67)] and strong discrimination against symptomatic patients(OR=3.08 to 7.46). There was strong criterion validity against cartilage histology [r=0.66(-0.05,0.93), and small to moderate internal(SMD=0.20 to 0.58) and external(r=0.35 to 0.43) responsiveness to interventions.
CONCLUSION: Ultrasound demonstrated strong criterion validity with cartilage histology, poor to strong correlation with patient findings and MRI, moderate reliability, and low responsiveness to interventions.
OBJECTIVES: Hyaluronic acid and corticosteroids are common intra-articular (IA) therapies widely used for the management of mild to moderate knee osteoarthritis (OA). Many trials evaluating the efficacy of IA administered therapies commonly use IA saline injections as a placebo comparator arm. Using a systematic review and meta-analysis, our objective was to assess the clinical benefit associated with use of IA saline in trials of IA therapies in the treatment of patients with painful knee OA.
METHODS: MEDLINE and Embase databases were searched for articles published up to and including August 14th, 2014. Two reviewers assessed the eligibility of potential reports and the risk of bias of included trials. We analyzed short (≤3 months) and long-term (6-12 months) pain reduction of the saline arm of included trials using standardized mean differences (SMDs; estimated assuming a null effect in a comparator group) that were combined and weighted using a random effects model. Treatment-related adverse events (AEs) were tabulated and presented using descriptive statistics.
RESULTS: From 40 randomized controlled trials (RCTs) eligible for inclusion only 38 provided sufficient data to be included in the meta-analysis. Based on data with moderate inconsistency IA saline was found to significantly improve short-term knee pain in 32 studies involving 1705 patients (SMD = -0.68; 95% CI: -0.78 to -0.57; P < 0.001; I(2) = 50%). Long-term knee pain was significantly decreased following IA injection with saline in 19 studies involving 1445 patients (SMD = -0.61; 95% CI: -0.76 to -0.45; P < 0.001) with a substantial degree of inconsistency (I(2) = 74%). Overall, 29 of the included trials reported on adverse events, none of which found any serious treatment-related AEs following IA injection with saline.
CONCLUSIONS: Pain relief observed with IA saline should prompt health care providers to consider the additional effectiveness of current IA treatments that use saline comparators in clinical studies, and challenges of identifying IA saline injection as a "placebo."
BACKGROUND: Placebo controls are essential in evaluating the effectiveness of medical treatments. Although it is unclear whether different placebo interventions for osteoarthritis vary in efficacy, systematic differences would substantially affect interpretation of the results of placebo-controlled trials.
OBJECTIVE: To evaluate the effects of alternative placebo types on pain outcomes in knee osteoarthritis.
DATA SOURCES: MEDLINE, EMBASE, Web of Science, Google Scholar, and Cochrane Database from inception through 1 June 2015 and unpublished data.
STUDY SELECTION: 149 randomized trials of adults with knee osteoarthritis that reported pain outcomes and compared widely used pharmaceuticals against oral, intra-articular, topical, and oral plus topical placebos.
DATA EXTRACTION: Study data were independently double-extracted; study quality was assessed by using the Cochrane risk of bias tool.
DATA SYNTHESIS: Placebo effects that were evaluated by using a network meta-analysis with 4 separate placebo nodes (differential model) showed that intra-articular placebo (effect size, 0.29 [95% credible interval, 0.09 to 0.49]) and topical placebo (effect size, 0.20 [credible interval, 0.02 to 0.38]) had significantly greater effect sizes than did oral placebo. This differential model showed marked differences in the relative efficacies and hierarchy of the active treatments compared with a network model that considered all placebos equivalent. In the model accounting for differential effects, intra-articular and topical therapies were superior to oral treatments in reducing pain. When these differential effects were ignored, oral nonsteroidal anti-inflammatory drugs were superior.
LIMITATIONS: Few studies compared different placebos directly. The study could not decisively conclude whether disease severity and co-interventions systematically differed between trials evaluating different placebos.
CONCLUSION: All placebos are not equal, and some can trigger clinically relevant responses. Differential placebo effects can substantially alter estimates of the relative efficacies of active treatments, an important consideration for the design of clinical trials and interpretation of their results.
PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.
BACKGROUND: Knee osteoarthritis is a leading cause of chronic pain, disability, and decreased quality of life. Despite the long-standing use of intra-articular corticosteroids, there is an ongoing debate about their benefits and safety. This is an update of a Cochrane review first published in 2005.
OBJECTIVES: To determine the benefits and harms of intra-articular corticosteroids compared with sham or no intervention in people with knee osteoarthritis in terms of pain, physical function, quality of life, and safety.
SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and EMBASE (from inception to 3 February 2015), checked trial registers, conference proceedings, reference lists, and contacted authors.
SELECTION CRITERIA: We included randomised or quasi-randomised controlled trials that compared intra-articular corticosteroids with sham injection or no treatment in people with knee osteoarthritis. We applied no language restrictions.
DATA COLLECTION AND ANALYSIS: We calculated standardised mean differences (SMDs) and 95% confidence intervals (CI) for pain, function, quality of life, joint space narrowing, and risk ratios (RRs) for safety outcomes. We combined trials using an inverse-variance random-effects meta-analysis.
MAIN RESULTS: We identified 27 trials (13 new studies) with 1767 participants in this update. We graded the quality of the evidence as 'low' for all outcomes because treatment effect estimates were inconsistent with great variation across trials, pooled estimates were imprecise and did not rule out relevant or irrelevant clinical effects, and because most trials had a high or unclear risk of bias. Intra-articular corticosteroids appeared to be more beneficial in pain reduction than control interventions (SMD -0.40, 95% CI -0.58 to -0.22), which corresponds to a difference in pain scores of 1.0 cm on a 10-cm visual analogue scale between corticosteroids and sham injection and translates into a number needed to treat for an additional beneficial outcome (NNTB) of 8 (95% CI 6 to 13). An I(2) statistic of 68% indicated considerable between-trial heterogeneity. A visual inspection of the funnel plot suggested some asymmetry (asymmetry coefficient -1.21, 95%CI -3.58 to 1.17). When stratifying results according to length of follow-up, benefits were moderate at 1 to 2 weeks after end of treatment (SMD -0.48, 95% CI -0.70 to -0.27), small to moderate at 4 to 6 weeks (SMD -0.41, 95% CI -0.61 to -0.21), small at 13 weeks (SMD -0.22, 95% CI -0.44 to 0.00), and no evidence of an effect at 26 weeks (SMD -0.07, 95% CI -0.25 to 0.11). An I(2) statistic of ≥ 63% indicated a moderate to large degree of between-trial heterogeneity up to 13 weeks after end of treatment (P for heterogeneity≤0.001), and an I(2) of 0% indicated low heterogeneity at 26 weeks (P=0.43). There was evidence of lower treatment effects in trials that randomised on average at least 50 participants per group (P=0.05) or at least 100 participants per group (P=0.013), in trials that used concomittant viscosupplementation (P=0.08), and in trials that used concomitant joint lavage (P≤0.001).Corticosteroids appeared to be more effective in function improvement than control interventions (SMD -0.33, 95% CI -0.56 to -0.09), which corresponds to a difference in functions scores of -0.7 units on standardised Western Ontario and McMaster Universities Arthritis Index (WOMAC) disability scale ranging from 0 to 10 and translates into a NNTB of 10 (95% CI 7 to 33). An I(2) statistic of 69% indicated a moderate to large degree of between-trial heterogeneity. A visual inspection of the funnel plot suggested asymmetry (asymmetry coefficient -4.07, 95% CI -8.08 to -0.05). When stratifying results according to length of follow-up, benefits were small to moderate at 1 to 2 weeks after end of treatment (SMD -0.43, 95% CI -0.72 to -0.14), small to moderate at 4 to 6 weeks (SMD -0.36, 95% CI -0.63 to -0.09), and no evidence of an effect at 13 weeks (SMD -0.13, 95% CI -0.37 to 0.10) or at 26 weeks (SMD 0.06, 95% CI -0.16 to 0.28). An I(2) statistic of ≥ 62% indicated a moderate to large degree of between-trial heterogeneity up to 13 weeks after end of treatment (P for heterogeneity≤0.004), and an I(2) of 0% indicated low heterogeneity at 26 weeks (P=0.52). We found evidence of lower treatment effects in trials that randomised on average at least 50 participants per group (P=0.023), in unpublished trials (P=0.023), in trials that used non-intervention controls (P=0.031), and in trials that used concomitant viscosupplementation (P=0.06).Participants on corticosteroids were 11% less likely to experience adverse events, but confidence intervals included the null effect (RR 0.89, 95% CI 0.64 to 1.23, I(2)=0%). Participants on corticosteroids were 67% less likely to withdraw because of adverse events, but confidence intervals were wide and included the null effect (RR 0.33, 95% CI 0.05 to 2.07, I(2)=0%). Participants on corticosteroids were 27% less likely to experience any serious adverse event, but confidence intervals were wide and included the null effect (RR 0.63, 95% CI 0.15 to 2.67, I(2)=0%).We found no evidence of an effect of corticosteroids on quality of life compared to control (SMD -0.01, 95% CI -0.30 to 0.28, I(2)=0%). There was also no evidence of an effect of corticosteroids on joint space narrowing compared to control interventions (SMD -0.02, 95% CI -0.49 to 0.46).
AUTHORS' CONCLUSIONS: Whether there are clinically important benefits of intra-articular corticosteroids after one to six weeks remains unclear in view of the overall quality of the evidence, considerable heterogeneity between trials, and evidence of small-study effects. A single trial included in this review described adequate measures to minimise biases and did not find any benefit of intra-articular corticosteroids.In this update of the systematic review and meta-analysis, we found most of the identified trials that compared intra-articular corticosteroids with sham or non-intervention control small and hampered by low methodological quality. An analysis of multiple time points suggested that effects decrease over time, and our analysis provided no evidence that an effect remains six months after a corticosteroid injection.
OBJECTIVE: IA steroid injections (IASIs) have been shown to relieve pain in knee OA and are widely used in clinical practice. There is, however, evidence of some variation in response. Knowledge of predictors of response could aid in the selection of patients for this therapy. The aim of this systematic review was to determine factors associated with response to IASI in knee OA.
METHODS: Medline, Embase, AMED, CINAHL, Web of Science and Cochrane Central Registers for Controlled Trials up to January 2012 were searched with additional hand searches of relevant articles. Studies included were those that involved adults diagnosed with knee OA in whom IASIs were administered and factors that predicted treatment response were investigated.
RESULTS: Eleven publications meeting these criteria were reviewed and relevant information extracted. It was not possible to pool the results because of the different predictors studied, variable outcome measures, different criteria for symptom change and missing data. Given the relative paucity of data and small heterogeneously designed studies, it was difficult to identify predictors of response. Data from individual publications, although not consistent across studies, suggest that the presence of effusion, withdrawal of fluid from the knee, severity of disease, absence of synovitis, injection delivery under US guidance and greater symptoms at baseline may all improve the likelihood of response to IASI.
CONCLUSION: Further larger-scale studies using standardized methods are required to characterize predictors of response and should focus on synovitis, effusion, pain and structural severity of disease. Such data would help in better targeting therapy to those most likely to benefit.
Objectives: Variations in the degree of pain relief reported by patients with osteoarthritis following intra-articular corticosteroid injections are well recognized but the reasons for this are not widely understood and factors which might predict variations in response have not been subjected to systematic review. We set out to review systematically the literature relating to predictors of pain reduction following intra-articular corticosteroid injections in patients with knee and hip osteoarthritis. Methods: Searches were performed using Medline, EMBASE, Web of Knowledge and MeSH search of Pubmed, the last search being performed in August 2012. Search terms included knee osteoarthritis, hip osteoarthritis, corticosteroid and related terms, and intra-articular injection. Papers were selected and reviewed by 2 reviewers. For inclusion, papers were required to describe studies in which patients with osteoarthritis of the knee or hip received intra-articular corticosteroid injection as an intervention, contain clearly defined outcome measures relating to pain and contain analysis relating to predictors of clinical response to treatment. Results: Twenty-one studies met criteria for inclusion from a total of 54 papers reviewed in full. Eight of these related to hip OA and 13 related to knee OA. No factors that were investigated as potential predictors of response, including radiographic grade and clinical or sonographic evidence of inflammation or synovial hypertrophy were supported by strong evidence. The review also identified that several plausible potential predictors had not been studied to date. Conclusions: Previous research has not identified reliable predictors of response to IA corticosteroid injections, a widely practised intervention in knee and hip OA. Further studies are required if this question is to be answered.
