University of Manchester



The efficacy of intra-articular steroids in hip osteoarthritis: A systematic review Paul S. McCabe1, Nasimah Maricar1, Matthew J. Parkes1, David T. Felson1, 2, 3, Terence W. O’Neill1,21. Arthritis Research UK Centre for Epidemiology, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester UK2. NIHR Manchester Musculoskeletal Biomedical Research Unit, Central Manchester NHS Foundation Trust, Manchester Academic Health Sciences Centre, Manchester, UK3. Clinical Epidemiology Unit, Boston University School of Medicine, Boston, Massachusetts, USAAddress for Correspondence:Paul McCabeArthritis Research UK Centre for Epidemiology Faculty of Medical and Human Sciences,University of ManchesterStopford BuildingOxford RoadManchesterM13 9PTTelephone Number 0161 306 0547 Fax 0161 275 5043Email paul.mccabe@manchester.ac.uk Running head: Intra-articular steroids in hip OAABSTRACTOBJECTIVE: International guidelines recommend intra-articular steroid injections (IASI) in the management of hip osteoarthritis (OA), though these recommendations are extrapolated primarily from studies of knee OA. The aim of this systematic review was to assess the efficacy of IASI on pain in hip OA.METHODS: MEDLINE, EMBASE, AMED, CINAHL Plus, Web of Science and the Cochrane Central Register of Controlled Trials were searched to May 2015. RCTs assessing the efficacy of hip IASI on pain were included. Pre-specified data was extracted using a standardised form. Quality was assessed using the Jadad score. RESULTS Five trials met the inclusion criteria. All had a small number of participants (≤101). All studies reported some reduction in pain at 3-4 weeks post-injection compared to control. Based on data from individual trials the treatment effect size was large at 1 week post-injection but declined thereafter. A significant (moderate effect size) reduction in pain was reported in 2 trials up to 8 weeks following IASI. Pooled results of 2 trials (N=90) showed an increased likelihood of meeting the OMERACT-OARSI response criteria at 8 weeks post-IASI, odds ratio 7.8 (95% CI 2.7-22.8). The number needed to treat to achieve one OMERACT-OARSI responder at 8 weeks post-injection was 2.4 (95% CI 1.7-4.2). Hip IASI appear to be generally well tolerated.CONCLUSIONS: Hip IASI may be efficacious in short term pain reduction in those with hip OA though the quality of the evidence was relatively poor. Further large, methodologically rigorous trials are required to verify whether intra-articular corticosteroids are beneficial and for how long. KEYWORDS: Hip, osteoarthritis, intra-articular injection, steroids, pain, function, response, systematic reviewINTRODUCTIONTo date there are no effective therapies which reduce disease progression in hip OA and management is primarily focused on optimum pain control and maintaining function. There are, however, limitations with current analgesic therapies. Oral analgesic therapy is restricted by duration, degree of efficacy and considerable associated toxicities. ADDIN EN.CITE <EndNote><Cite><Author>Jüni</Author><Year>2006</Year><RecNum>443</RecNum><DisplayText>[1]</DisplayText><record><rec-number>443</rec-number><foreign-keys><key app="EN" db-id="55s9eza5fzxpsqe9w2spae54zs9tvs9awzt2">443</key><key app="ENWeb" db-id="UayrjwrYEugAAHnefLY">408</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jüni, Peter</author><author>Reichenbach, Stephan</author><author>Dieppe, Paul</author></authors></contributors><titles><title>Osteoarthritis: rational approach to treating the individual</title><secondary-title>Best Practice &amp; Research Clinical Rheumatology</secondary-title></titles><periodical><full-title>Best Practice &amp; Research Clinical Rheumatology</full-title></periodical><pages>721-740</pages><volume>20</volume><number>4</number><keywords><keyword>osteoarthritis</keyword><keyword>pain</keyword><keyword>management</keyword><keyword>meta-analysis</keyword><keyword>effect size</keyword></keywords><dates><year>2006</year></dates><isbn>1521-6942</isbn><urls><related-urls><url>;[1] Non-steroidal anti-inflammatory drugs are associated with significant morbidity and mortality, ADDIN EN.CITE <EndNote><Cite><Author>Richy</Author><Year>2004</Year><RecNum>524</RecNum><DisplayText>[2]</DisplayText><record><rec-number>524</rec-number><foreign-keys><key app="EN" db-id="55s9eza5fzxpsqe9w2spae54zs9tvs9awzt2">524</key><key app="ENWeb" db-id="UayrjwrYEugAAHnefLY">420</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Richy, F</author><author>Bruyere, O</author><author>Ethgen, O</author><author>Rabenda, V</author><author>Bouvenot, G</author><author>Audran, M</author><author>Herrero-Beaumont, G</author><author>Moore, A</author><author>Eliakim, R</author><author>Haim, M</author><author>Reginster, J-Y</author></authors></contributors><titles><title>Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach</title><secondary-title>Ann Rheum Dis</secondary-title></titles><periodical><full-title>Ann Rheum Dis</full-title><abbr-1>Annals of the rheumatic diseases</abbr-1></periodical><pages>759-766</pages><volume>63</volume><number>7</number><dates><year>2004</year><pub-dates><date>July 1, 2004</date></pub-dates></dates><urls><related-urls><url>;[2] exacerbated by the co-morbidities that are frequent in a typical OA population, whilst other analgesic medications, for example codeine, can cause nausea, constipation and drowsiness. ADDIN EN.CITE <EndNote><Cite><Author>Peloso</Author><Year>2001</Year><RecNum>512</RecNum><DisplayText>[3]</DisplayText><record><rec-number>512</rec-number><foreign-keys><key app="EN" db-id="55s9eza5fzxpsqe9w2spae54zs9tvs9awzt2">512</key><key app="ENWeb" db-id="UayrjwrYEugAAHnefLY">418</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Peloso, P M</author></authors></contributors><titles><title>Opioid therapy for osteoarthritis of the hip and knee: use it or lose it?</title><secondary-title>J Rheumatol</secondary-title></titles><periodical><full-title>J Rheumatol</full-title><abbr-1>The Journal of rheumatology</abbr-1></periodical><pages>6-11</pages><volume>28</volume><number>1</number><dates><year>2001</year><pub-dates><date>January 1, 2001</date></pub-dates></dates><urls><related-urls><url>;[3] Intra-articular steroid therapy offers a potentially useful therapy as it is directly targeted at the affected joint with few systemic effects. 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ADDIN EN.CITE.DATA [5] A previous narrative review in 2008 concluded that, although there was a lack of evidence of efficacy and safety of IASI in hip OA, there was some evidence of short-term pain relief. ADDIN EN.CITE <EndNote><Cite><Author>Kruse</Author><Year>2008</Year><RecNum>456</RecNum><DisplayText>[8]</DisplayText><record><rec-number>456</rec-number><foreign-keys><key app="EN" db-id="55s9eza5fzxpsqe9w2spae54zs9tvs9awzt2">456</key><key app="ENWeb" db-id="UayrjwrYEugAAHnefLY">409</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kruse, DavidW</author></authors></contributors><titles><title>Intraarticular cortisone injection for osteoarthritis of the hip. Is it effective? Is it safe?</title><secondary-title>Current Reviews in Musculoskeletal Medicine</secondary-title><alt-title>Curr Rev Musculoskelet Med</alt-title></titles><periodical><full-title>Current Reviews in Musculoskeletal Medicine</full-title><abbr-1>Curr Rev Musculoskelet Med</abbr-1></periodical><alt-periodical><full-title>Current Reviews in Musculoskeletal Medicine</full-title><abbr-1>Curr Rev Musculoskelet Med</abbr-1></alt-periodical><pages>227-233</pages><volume>1</volume><number>3-4</number><keywords><keyword>Intraarticular corticosteroid injection</keyword><keyword>Hip osteoarthritis</keyword><keyword>Musculoskeletal ultrasound</keyword><keyword>Septic arthritis</keyword><keyword>Osteonecrosis</keyword></keywords><dates><year>2008</year><pub-dates><date>2008/12/01</date></pub-dates></dates><publisher>Humana Press Inc</publisher><urls><related-urls><url>;[7] To date there have been no systematic reviews of the impact of IASI in the management of hip OA. The objective of this systematic review was to assess the efficacy of IASI in reducing pain in patients with hip OA. A secondary objective was to assess the effects of hip IASI on function and also evaluate safety. METHODSLiterature searchMEDLINE, EMBASE, AMED, CINAHL Plus, Web of Science and the Cochrane Central Register of Controlled Trials were searched from inception to May 2015. No restrictions on language or date were applied. Search terms included synonyms of hip osteoarthritis, intra-articular injection, injection and steroids and common steroids used in intra-articular injections (methylprednisolone, triamcinolone and betamethasone) and associated brand names. Each database was searched individually with the search strategy optimised based on indexing method. Search terms were searched for both as free text and using terms indexed in each databases thesaurus (i.e. MeSH) where applicable. Full details of the MEDLINE search strategy appear in the supplementary data, available at Rheumatology online. To maximise the sensitivity of the search strategy no randomised controlled trial (RCT) or language filter was applied. Reference lists of relevant articles, reviews and clinical guidelines were also hand searched. To identify relevant unpublished trials the WHO Trial Search Portal and UK Clinical Trials Gateway were also searched. Eligibility assessment of trials for inclusion in the review was performed unblinded by 1 reviewer (P.S.M.) using a standardised form.Study selectionThis review included RCTs that assessed the use of hip IASI, using any steroid preparation, in patients with painful hip OA. The diagnosis of hip OA must have been based on the presence of hip pain and radiological evidence of OA. All trials must have included an intervention group which received a hip IASI and a control group who received a placebo (sham injection, normal saline or local anaesthetic intra-articular injection). Trials comparing IASI with another active treatment without a control group were excluded. Outcome measuresThe a priori outcome of interest was self-reported pain. Data was extracted for all reported pain measures and for the secondary outcome of function. Previous reports suggest that IASI in the knee have a significant, but relatively short lived effect on pain and may also have transient effects on functionPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5CZWxsYW15PC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48

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ADDIN EN.CITE.DATA [8] and therefore we extracted pain and function outcome data at all reported time points. Quality AssessmentThe quality of included trials was independently assessed by reviewers (P.S.M and N.M.) using the scoring system suggested by Jadad et al, ADDIN EN.CITE <EndNote><Cite><Author>Jadad</Author><Year>1996</Year><RecNum>434</RecNum><DisplayText>[9]</DisplayText><record><rec-number>434</rec-number><foreign-keys><key app="EN" db-id="55s9eza5fzxpsqe9w2spae54zs9tvs9awzt2">434</key><key app="ENWeb" db-id="UayrjwrYEugAAHnefLY">406</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jadad, Alejandro R.</author><author>Moore, R. Andrew</author><author>Carroll, Dawn</author><author>Jenkinson, Crispin</author><author>Reynolds, D. John M.</author><author>Gavaghan, David J.</author><author>McQuay, Henry J.</author></authors></contributors><titles><title>Assessing the quality of reports of randomized clinical trials: Is blinding necessary?</title><secondary-title>Controlled Clinical Trials</secondary-title></titles><periodical><full-title>Controlled Clinical Trials</full-title></periodical><pages>1-12</pages><volume>17</volume><number>1</number><keywords><keyword>Pain</keyword><keyword>meta-analysis</keyword><keyword>randomized controlled trials</keyword><keyword>quality</keyword><keyword>health technology assessment</keyword></keywords><dates><year>1996</year></dates><isbn>0197-2456</isbn><urls><related-urls><url>(95)00134-4</electronic-resource-num></record></Cite></EndNote>[9] a widely used and validated quality assessment tool for RCTs which includes assessment of blinding, randomisation and reporting of withdrawals and drop outs.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5PbGl2bzwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [9, 10] In the event of disagreement the reviewers discussed their assessment to reach a consensus.Data ExtractionTwo authors (P.S.M and N.M.) independently extracted data from all studies utilising a standardised proforma.Quantitative SynthesisA quantitative synthesis of the OMERACT-OARSI response status at 8 weeks post-injection incorporating the results of 2 studies was performed. Analysis was undertaken in Review Manager version 5.3 (The Cochrane Collaboration, The Nordic Cochrane Centre, Copenhagen) utilising a Mantel-Haenszel model. We used a fixed effects approach as there was little heterogeneity in the 2 studies.We also performed a further analysis, which considered the pain outcomes reported in the included studies. We took data from the highest ‘rated’ pain outcome available from each of the included trials, according to the hierarchy described by Jüni et al.[1] at the longest available reported follow-up visit. Given the likelihood of high heterogeneity between trials with different follow-up lengths, and pain outcomes, we opted to use a random-effects Mantel-Haenszel model for this analysis, since it is more robust to heterogeneity in effects. Standardised mean differences were constructed, comparing the mean change in each pain outcome, between the active and control groups featured in each trial. Where within-person standard deviations in pain outcome were not reported, we contacted authors to obtain the unreported data. Where a response was not available, we imputed the mean difference standard deviations (SDbaseline-follow-up) by combining the standard deviations reported at baseline and follow up, with an estimated correlation between baseline and follow up visits of 0.5, and sensitivity analyses using correlations of 0.25 and 0.75, as per Cochrane Collaboration recommendations, [11] using the following formula:SDbaseline-follow-up=SDbaseline2 + SDfollow-up2-(2 ×Corbaseline,follow-up)×SDbaseline ×SDfollow-up)____________________________RESULTSSearch resultsThe search of literature databases identified 488 records potentially relevant to the study question (Figure 1). After removal of duplicates, 362 records remained and screening of the record title or abstract allowed exclusion of 324. For the remaining 36 records the full text article was read with 5 studies meeting the inclusion criteria.[12-16] The reasons for exclusion included lack of randomisation,[17] no placebo control group,[18] clinical guideline only,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+PFJl

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ADDIN EN.CITE.DATA [5-7] review article,[19-32] injection methods article or review,[33-36] trial protocol only[37] and others.[38-45] A search of trial registries identified one unpublished trial (clinical trials registration number NCT01079455) which was potentially relevant to this review. A published protocol for the trial was identified[37] and if performed per protocol would have met the review inclusion criteria. However, no published results were identified and the corresponding author did not respond to a request for further information.Characteristics of included studies A summary of the characteristics of included trials is shown in Table 1. Across all 5 included trials 346 participants were randomised and 134 received a hip IASI. All trials were of a parallel design. The hip OA populations studied included those awaiting or eligible for a total hip arthroplasty (THA),[13,14,16] those refractory to simple analgesia [12] or any person meeting the ACR criteria for OA of the hip.[15] Three different steroid preparations (methylprednsiolone acetate[13,15] triamcinolone acetonide[16] and triamcinolone hexacetonide[12] were utilised and all studies used a different dose as shown in Table 1. One study did not report which triamcinolone salt was utilised.[14] All intra-articular injections were performed under image guidance either by ultrasound[13,15] or fluoroscopy.[12,14.16] All studies had patient-reported pain as a primary outcome and 4 also included some assessment of function.[12,13,15,16]. A variety of different outcome measures were employed to assess pain including: numerical rating scale (NRS) of pain in general,[14] NRS worst pain,[13] visual analogue scale (VAS) of pain on weight bearing/walking and at rest,[15,16] and the Western Ontario and McMaster Universities osteoarthritis index (WOMAC) pain subscale.[12] Objective functional assessment included passive hip range of motion (ROM) [12.16]and subjective functional assessments: modified Katz ADL index,[16] SF-36 physical and social function score[12] and subjective algo-functional assessments (Lequesne index[15] and WOMAC global score[13,15]). Additional outcome measures included the Osteoarthritis Research Society International and Outcome measures in Rheumatology Clinical Trials (OARSI/OMERACT) response criteria[13,16] and patient global assessment.[13,15] All studies reported follow up durations of at least 8 weeks. Quality AssessmentThe quality of included trials was assessed using the Jadad scoring system and results are shown in Table 2. All studies scored 3 or more indicating high quality study design. Four studies were described as double blind [12,14-16] and one as single blind.[13] The inclusion of a single blind trial is unlikely to have introduced significant bias as the patients were blinded to treatment allocation and the trial only considered self-reported outcome measures.[13] Flanagan et al 1988,[14] prioritised participants for THA if they reported being worse at any follow up time point after intra-articular injection and were also censored from further participation in the trial. As the participants were aware of this from the outset there may have been an incentive to report being worse after the injection, however the study was double blind and therefore it was unlikely to have significantly affected the between group comparison. In this study after 1 month follow up the effect on pain is reported at different time points for the IASI group and the bupivacaine control group rendering it impossible to compare results between groups. The results beyond 1 month have therefore not been considered in this review.In Kullenberg et al 2004,[16] a double blind trial, the entire control group (n=40) withdrew after the 3 weeks follow up which the authors report was due to inefficacy and thus there was no control group at 12 weeks, the primary end point. Only the results up to the 3 weeks post-injection have been included in the review.Effect on PainA summary of the effect on pain for individual trials is shown in Figure 2. All trials reported some reduction in pain 3-4 weeks post hip IASI compared to controls across a diverse range of pain outcome measures. Outcome beyond 4 weeks follow up was assessed in 3 trials.[12,13,15] Two trials included follow up at 8 weeks post-injection, and both reported clinically significant reductions in pain in the hip IASI group, compared to control, in either NRS of worst pain and/or WOMAC pain subscale.[12,13] At 8 weeks, across both trials, 29 of the 50 participants who received a hip IASI met the OMERACT-OARSI response criteria compared to only 6 out of 40 who received a control injection. As shown, Figure 3, a fixed-effects Mantel-Haenszel estimate of this effect gives an odds ratio of 7.8 (95% CI 2.7-22.4), favouring IASI. The risk difference for this odds ratio was 0.41 (95% CI 0.24-0.58) giving a number needed to treat to achieve 1 OMERACT-OARSI responder at 8 weeks post-injection of 2.4 (95% CI 1.7-4.2). Only one trial, Qvistgaard et al[15] reported the results beyond 8 weeks. They reported a statistically significant reduction in pain in walking in the IASI group averaged across all follow up time points (2, 4 and 12 weeks), with an overall moderate effect size (standardised mean difference, SMD) of 0.6 (95% CI: 0.1-1.1). However, the difference between steroid and placebo groups in pain on walking was only statistically significant up to 4 weeks post injection, (P2 weeks=0.006, P4 weeks=0.006, P12 weeks=0.58). In contrast to Kullenberg et al[16] no significant reduction in pain at rest was reported at 3 weeks. The magnitude of pain reduction following hip IASI appears to be initially large but deceases over time. Atchia et al[13] reported an SMD of 1.5 and 1.9 for NRS worst pain and WOMAC pain subscale respectively 1 week post-injection. However by 4 weeks this had decreased to 1.0 and 1.1 and at 8 weeks post-injection to 0.5 and 0.6 for NRS worst pain and WOMAC pain subscale respectively. Although the results reported by Lambert et al[12] suggest a less marked decrease in efficacy between 4 and 8 weeks, in keeping with all trials included in this review, insufficient data was available in the original publication to allow calculation of treatment effect size. The corresponding authors for the three published papers in the last 10 years[13,14,16] were contacted to request additional information, or anonymised raw patient data, however, no additional information was obtained. Given the limited degree of available data, it was not possible to combine trial data in a formal meta-analysis (other than the limited fixed-effects odds-ratio estimate of OMERACT-OARSI responders, using the 8 weeks time point from two of the included studies).Figure 3 depicts a forest plot summarising the overall effect for the three trials which reported data on change in pain outcomes measured on a continuous scale. Overall, the observed degree of heterogeneity in effects in these trials was very high (I2 = 97%, p<0.001). The pooled overall SMD from these three trials was generally in favour of hip IASI, however this difference was not deemed statistically significant at the 0.05 level (SMD = -1.90; 95% CI -4.07 to 0.26; p = 0.08). Data from Atchia et al[13] did not report the required information to allow inclusion in this analysis, and imputed standard deviations were generated for the Lambert and Kullenberg et al trials[12,16[. Kullenberg et al reported data at follow up at both 3 weeks and 12 weeks, however the entire control group withdrew following the 3 week follow-up visit, and so we opted to include only the 3 week data in our analyses for this reason. Sensitivity analyses found that the overall treatment effect seen in figure 4 varied greatly with the use of different estimated correlations between baseline and follow-up mean change in pain scores, This is perhaps unsurprising, given firstly that only three studies were able to be included in this analysis, and secondly since two thirds of the included studies had imputed data (and therefore were subject to change in the sensitivity analyses).Effect on functionThe secondary outcome of interest was effect of hip IASI on function. Of the 4 studies to assess function using subjective outcome measures 3 noted a statistically significant improvement in function in the steroid group compared to control.[12,13,15] These included a significant improvement in modified Katz ADL index at 3 weeks post injection,[16] WOMAC function subscale score[12,13] and SF-36 physical and social functioning subscales[12] at 8 weeks post-injection. Atchia et al[13] reported the magnitude and duration of the effect of hip IASI on WOMAC function subscale largely mirrored the effect on pain. At 1 week post-injection the SMD was large at 1.3, decreasing to 0.9 at 4 weeks, and 0.4 at 8 weeks with less marked reduction in efficacy reported by Lambert et al.[12] Two trials assessed hip ROM as an objective measure of hip function although the results were inconsistent. In one trial a very large and statistically significant increase in hip ROM was present at 3 weeks post hip IASI[16]; however, the only other study to assess ROM did not identify any significant difference at either 4 or 8 weeks post-injection.[12]Safety of hip IASIFour trials reported safety data.[12.13,15,16] Only one serious adverse event, a deep venous thrombosis 3 months post-injection, was reported in the IASI group.[12] The injection procedure itself was noted to be well tolerated.[12,13,15,16] No adverse events in the IASI group were reported by two trials.[12,15] The third trial found similar rates of adverse events (52% placebo group vs. 51% in the IASI group), and noted that ‘most were mild and/or considered unrelated to treatment.’[12] Qvistgaard et al noted that 3 patients (out of a total sample of 101) experienced a flare in pain post-injection but did not allocate these to a specific treatment group.[15] DiscussionThe evidence from this review suggests that hip IASI may be efficacious in delivering short term, but clinically significant, pain reduction in those with hip OA, and may also lead to transient improvement in function. The treatment effect appears to be of rapid onset with a large treatment effect size reported at 1 week post-injection. The magnitude of pain reduction and functional improvement decreases thereafter, although two trials report clinically significant differences in both pain and function at 8 weeks post-injection.[12,13] This pattern is similar to that observed in studies of IASI at other sites in OA, such as the knee.[8] Because each trial used a different preparation or dose of steroid it was not possible to determine the effect of any particular dose on outcome. The injection procedure itself was well tolerated by trial participants[12,13,15,16] and only 1 serious adverse event in those receiving an IASI was reported.[12] This is the first systematic review to address the effect of hip IASI on pain and function. It utilised a broad and systematic search strategy to identify all the available evidence. There were nonetheless some limitations which need to be considered. 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ADDIN EN.CITE.DATA [5] and the review’s conclusions are based on the results of 5 trials containing only 346 participants in total. Small trials are recognised to potentially over-estimate treatment effect sizes,[46] or report a significant effect when none is present.[47] Thus a degree of caution is required in interpreting the results and it is not possible to draw firm conclusion on the efficacy of IASI in hip OA. The lack of available data made it difficult to undertake any formal assessment of this potential bias on treatment effect. All of the included trials were also of short duration and it remains unclear for how long hip IASI exert a clinically meaningful effect. Additionally, the majority of participants were awaiting, or eligible for, a THA, which suggests that these participants had severe OA and so caution is needed in generalising these findings to those with less severe disease. The trial populations, consisting predominantly of those with severe hip OA, and the availability of an alternative effective treatment (THA) for this group, resulted in challenges in the conduct of the included trials. These included difficulties in recruitment leading to trials being stopped prior to recruiting the pre-specified sample size,[12] withdrawal of all controls prior to the primary end point due to inefficacy of the control treatment[16] and reduction in follow up duration due to participants undergoing THA[13] potentially increasing the risk of bias. We also cannot exclude publication bias in which trials that failed to show a treatment effect for IASI may have been less likely to have been published. Although we did search clinical trial registers and found only one, potentially ongoing, unpublished trial suggesting there is unlikely to be significant recent publication bias, we cannot exclude publication bias pre-dating the requirement for clinical trial registration. A large number of different pain and function outcome measures were utilised across the included trials. This significant heterogeneity in methodology between trials, coupled with the limited reporting of trial statistics, particularly for individual time points, limited the pooling of results into treatment effect sizes (standardised mean difference), in turn rendering it difficult to compare results between trials other than the limited fixed-effects odds-ratio estimate of OMERACT-OARSI responders, using the 8 week time point from two of the included trials and for an overall SMD in only three trials.. This highlights the importance of developing and use of core outcomes for clinical trials in this area.This review only included RCTs which incorporated a placebo group and thus did not consider trials comparing different doses of steroid or those comparing steroids with other treatments such as hyaluronic acid (HA) preparations. Whilst this did reduce the number of included trials, placebo effects are expected to be large in trials of injections in osteoarthritis, and this (large) effect would confound any observed treatment effect, making results less clear than in the present review.[48] Additionally, there is a lack of evidence on the efficacy of HA compared to placebo in the hip[49] and studies of HA in the knee suggest there are marked variations in treatment effect size for different preparations[50] adding significantly to the heterogeneity. This review, is consistent with the recent Cochrane review of IASI in knee OA with regards the overall quality of the evidence, heterogeneity between trials and evidence of small study effects[8] and highlights the need for further research to confirm both the efficacy and the short and long term safety in IASI in the management of hip OA. Future trials should be sufficiently large and include a placebo group. Standardised outcomes such as those such as those recommended by OARSI[51] should be used and the results should be presented in a manner which will facilitate inclusion in future meta-analyses. In conclusion, hip IASIs, when performed with image guidance appear to be well tolerated and may be effective in reducing pain and improving function in the short term in those with severe hip OA, though the quality of the evidence is relatively poor. Further large, methodologically rigorous trials are required to verify whether intra-articular corticosteroids are beneficial and for how long.ACKNOWLEDGMENTSThe authors wish to thank Mary Ingram for her assistance in developing the search strategy. AUTHOR CONTRIBUTIONConception and design: PSM, DF, TWO, Literature search: PSM, Data extraction: PSM, NMAnalysis and interpretation of data: PSM, MJP, NM, DF, TWO, Drafting of article: PSM, MJP, TWO. All authors contributed to the critical revision of the manuscript and approved the final version.ROLE OF FUNDING SOURCE PSM and NM are supported by National Institute of Health Research (NIHR) fellowships. Support was also provided by Arthritis Research UK [Grant 20380] and the NIHR Manchester Musculoskeletal Biomedical Research Unit. The funding agencies that supported this work had no role in the design, completion or reporting of this work. CONFLICT ON INTERESTSThe authors declare they have no conflicts of interest.REFERENCES ADDIN EN.REFLIST 1.Jüni P, Reichenbach S, Dieppe P: Osteoarthritis: rational approach to treating the individual. Best Pract Res Clin Rheumatol 2006, 20(4):721-740.2.Richy F, Bruyere O, Ethgen O, Rabenda V, Bouvenot G, Audran M et al: Time dependent risk of gastrointestinal complications induced by non-steroidal anti-inflammatory drug use: a consensus statement using a meta-analytic approach. Ann Rheum Dis 2004, 63(7):759-766.3.Peloso PM: Opioid therapy for osteoarthritis of the hip and knee: use it or lose it? The J Rheumatol 2001, 28(1):6-11.4.Zhang W, Doherty M, Arden N, Bannwarth B, Bijlsma J, Gunther KP et al: EULAR evidence based recommendations for the management of hip osteoarthritis: report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT). Ann Rheum Dis 2005, 64(5):669-681.5.Hochberg MC, Altman RD, April KT, Benkhalti M, Guyatt G, McGowan J et al: American College of Rheumatology 2012 recommendations for the use of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee. Arthritis Care Res (Hoboken) 2012, 64(4):465-474.6.Zhang W, Moskowitz RW, Nuki G, Abramson S, Altman RD, Arden N et al: OARSI recommendations for the management of hip and knee osteoarthritis, Part II: OARSI evidence-based, expert consensus guidelines. Osteoarthritis Cartilage 2008, 16(2):137-162.7.Kruse D: Intraarticular cortisone injection for osteoarthritis of the hip. Is it effective? Is it safe? Curr Rev Musculoskelet Med 2008, 1(3-4):227-233.8.Juni P, Hari R, Rutjes AWS, Fischer R, Silletta MG, Reichenbach S et al: Intraarticular corticosteroid for knee osteoarthritis. Cochrane Database Syst Rev 2015(10):CD005328.9.Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJM, Gavaghan DJ et al: Assessing the quality of reports of randomized clinical trials: Is blinding necessary? Control Clin Trials 1996, 17(1):1-12.10.Olivo SA, Macedo LG, Gadotti IC, Fuentes J, Stanton T, Magee DJ: Scales to Assess the Quality of Randomized Controlled Trials: A Systematic Review. Physical Therapy 2008, 88(2):156-175.11.Higgins JPT, Green S (editors).?Cochrane Handbook for Systematic Reviews of Interventions?Version 5.1.0 [updated March 2011]. The Cochrane Collaboration, 2011. Available from cochrane-.12.Lambert RG, Hutchings EJ, Grace MG, Jhangri GS, Conner-Spady B, Maksymowych WP: Steroid injection for osteoarthritis of the hip: a randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2007, 56(7):2278-2287.13.Atchia I, Kane D, Reed MR, Isaacs JD, Birrell F: Efficacy of a single ultrasound-guided injection for the treatment of hip osteoarthritis. Ann Rheum Dis 2011, 70(1):110-116.14.Flanagan J, Casale FF, Thomas TL, Desai KB: Intra-articular injection for pain relief in patients awaiting hip replacement. Ann R Col Surg Engl 1988, 70(3):156-157.15.Qvistgaard E, Christensen R, Torp-Pedersen S, Bliddal H: Intra-articular treatment of hip osteoarthritis: a randomized trial of hyaluronic acid, corticosteroid, and isotonic saline. Osteoarthritis Cartilage 2006, 14(2):163-170.16.Kullenberg B, Runesson R, Tuvhag R, Olsson C, Resch S: Intraarticular corticosteroid injection: Pain relief in osteoarthritis of the hip? J Rheumatol 2004, 31(11):2265-2268.17.Leveaux VM, Quin CE: Local injection of hydrocortisone and procaine in osteo-arthritis of the hip joint. Ann Rheum Dis 1956, 15(4):330-337.18.Spitzer AI, Bockow BI, Brander VA, Yates JW, Maccarter DK, Gudger GK et al: Hylan g-f 20 improves hip osteoarthritis: a prospective, randomized study. Phys Sportsmed 2010, 38(2):35-47.19.Stitik TP, Kumar A, Foye PM: Corticosteroid injections for osteoarthritis. Am J Phys Med Rehabil 2006, 85(11 Suppl):S51-65.20.Kruse DW: Intraarticular cortisone injection for osteoarthritis of the hip. Is it effective? Is it safe? Curr Rev Musculoskelet Med 2008, 1(3-4):227-233.21.Stephens MB, Beutler AI, O'Connor FG: Musculoskeletal injections: a review of the evidence. Am Fam Physician 2008, 78(8):971-976.22.Desay J: Advisor forum. Breaking down injectable steroids. Clinical Advisor 2002, 5(1):57-57.23.Gossec L, Dougados M: Do intra-articular therapies work and who will benefit most? Best Pract Res Clin Rheumatol 2006, 20(1):131-144.24.Gray RG, Gottlieb NL: Intra-articular corticosteroids. An updated assessment. Clin Orthop Relat Res 1983, 177(177):235-263.25.Dickson DJ: A rational approach to osteoarthritis. Practitioner 1997, 241(1581):763-766.26.Creamer P: Intra-articular corticosteroid treatment in osteoarthritis. Curr Opin Rheumatol 1999, 11(5):417-421.27.Ayral X: Injections in the treatment of osteoarthritis. Best Pract Res Clin Rheum 2001, 15(4):609-626.28.Foye PM, Castro C, Stitik TP, Kim JH, Dorri MH, Campos JS et al: The Hip. In: Injection Procedures, Stitik TP Ed. New York. Springer 2011:315-346.29.Pandit S, Pritchard CH, Eisner E, Naglak M: Ultrasound Guided Hip Joint Injection, Its Safety and Efficacy. Arthritis Rheum 2011, 63(10):S415-S415.30.Hameed F, Ihm J: Injectable medications for osteoarthritis. PM R 2012, 4(5 Suppl):S75-81.31.Hirsch G, Kitas G, Klocke R: Intra-articular corticosteroid injection in osteoarthritis of the knee and hip: factors predicting pain relief--a systematic review. Semin Arthritis Rheum 2013, 42(5):451-473.32.Charalambous CP, Prodromidis AD, Kwaees TA: Do intra-articular steroid injections increase infection rates in subsequent arthroplasty? A systematic review and meta-analysis of comparative studies. J Arthroplasty 2014, 29(11):2175-2180.33.Shankar H, Simhan S: Ultrasound-Guided Hip Injections; 2011.34.Lawson A, Kelsberg G, Safranek S: Does ultrasound guidance improve outcomes for steroid joint injections? J Fam Pract 2013, 62(12):763a-763c.35.Peterson C, Hodler J: Evidence-based radiology (part 2): Is there sufficient research to support the use of therapeutic injections into the peripheral joints? Skeletal Radiology 2010, 39(1):11-18.36.Qvistgaard E, Kristoffersen H, Terslev L, Danneskiold-Samsoe B, Torp-Pedersen S, Bliddal H: Guidance by ultrasound of intra-articular injections in the knee and hip joints. Osteoarthritis Cartilage 2001, 9(6):512-517.37.Colen S, van den Bekerom MP, Bellemans J, Mulier M: Comparison of intra-articular injections of hyaluronic acid and corticosteroid in the treatment of osteoarthritis of the hip in comparison with intra-articular injections of bupivacaine. Design of a prospective, randomized, controlled study with blinding of the patients and outcome assessors. BMC Musculoskelet Disord 2010, 11(264):264.38.Hollander JL, Brown EM, Jr., Jessar RA, Brown CY: Hydrocortisone and cortisone injected into arthritic joints; comparative effects of and use of hydrocortisone as a local antiarthritic agent. JAMA 1951, 147(17):1629-1635.39.Desmarais MHL: Value of Intra-Articular Injections in Osteo-Arthritis - a Controlled Series. Ann Rheum Dis 1952, 11(4):277-281.40.Neustadt DH: Local steroid injections: comment on the American College of Rheumatology guidelines for the management of osteoarthritis of the hip and on the letter by Swezey. Arthritis Rheum 1997, 40(10):1914-1915.41.Karim Z, Brown AK, Quinn M, Wakefield RJ, Conaghan PG, Emery P, O'Connor PJ, Margules KR: Ultrasound-guided steroid injections in the treatment of hip osteoarthritis: Comment on the letter by Margules (multiple letters). Arthritis Rheum 2004, 50(1):338-340.42.Conrozier T: Intraraticular Therapies in the Medical Management of Oa. Osteoarthritis Cartilage 2010, 18:S2-S2.43.Iagnocco A, Naredo E: Ultrasound-guided corticosteroid injection in rheumatology: accuracy or efficacy? Rheumatology (Oxford) 2010, 49(8):1427-1428.44.Atchia I, Kane D, Birrell F: Comment on: steroid injection for hip osteoarthritis: efficacy under ultrasound guidance. Rheumatology (Oxford) 2011, 50(4):812-813; author reply 813.45.Micu MC, Fodor D: Comment on: Steroid injection for hip osteoarthritis: efficacy under ultrasound guidance: reply. Rheumatology (Oxford) 2011, 50(4):813-813.46.Nuesch E, Trelle S, Reichenbach S, Rutjes AW, Tschannen B, Altman DG et al: Small study effects in meta-analyses of osteoarthritis trials: meta-epidemiological study. Brit Med J 2010, 341:c3515.47.Ioannidis JPA: Why Most Published Research Findings Are False. PLoS Med 2005, 2(8):e124.48.Zhang W, Robertson J, Jones AC, Dieppe PA, Doherty M. The placebo effect and its determinants in osteoarthritis: meta-analysis of randomised controlled trials. Ann Rheum Dis 2008;67(12):1716-23.49.Fernández López JC, Ruano-Ravina A. Efficacy and safety of intraarticular hyaluronic acid in the treatment of hip osteoarthritis: a systematic review. Osteoarthritis Cartilage 2006;14(12):1306-11.50.Bellamy N, Campbell J, Robinson V, Gee T, Bourne R, Wells G. Viscosupplementation for the treatment of osteoarthritis of the knee. Cochrane Database Syst Rev 2006(2):CD005321.51.Pham T, van der Heijde D, Altman RD, et al. OMERACT-OARSI Initiative: Osteoarthritis Research Society International set of responder criteria for osteoarthritis clinical trials revisited. Osteoarthritis Cartilage 2004;12(5):389-99. ADDIN EN.REFLIST FIGURE LEGENDSFigure 1. PRISMA flow diagramFigure 2. Summary of pain outcome measures results by time since injection for included trials Figure 3. Forest plot of fixed-effects Mantel-Haenszel estimate of number of OMERACT-OARSI Responders at 8 weeks post hip intra-articular steroid injection Figure 4. Forest plot of random-effects Mantel-Haenszel estimate of mean pain outcome change post hip intra-articular steroid injection, in the 3 studies providing appropriate data. FIGURE 1. 365760489041Medline43EMBASE138CINAHL95CENTRAL45AMED12Web of science143Others12Number of records screened362Duplicate results126Number of abstracts read98Not relevant to study question264Number of full text read36Not relevant to study question 62Number of included studies5Number of full text articles excluded 31 Not randomised1 No placebo control group 1 Clinical guideline3 Review article14 Injection methods article/review4 Trial protocol only1 Other 7Medline43EMBASE138CINAHL95CENTRAL45AMED12Web of science143Others12Number of records screened362Duplicate results126Number of abstracts read98Not relevant to study question264Number of full text read36Not relevant to study question 62Number of included studies5Number of full text articles excluded 31 Not randomised1 No placebo control group 1 Clinical guideline3 Review article14 Injection methods article/review4 Trial protocol only1 Other 7Table 1. Summary of the characteristics and results of studies meeting the inclusion criteria. ReferenceSettingSample Size[number receiving IASI]Mean age, yearsStudy populationOA definition Intervention groupsInjection guidanceFollow up, weeksPrimary pain outcome*FundingFlanagan et al 1988 [14]Essex, UK35 [12]range 46-79Awaiting THR for OACharnley 20mg Triamcinolone? + 0.5% Bupivicaine Fluoroscopy4, 8, 12, 26NRS 1-5Not stated0.5% BupivicaineSalineKullenberg et al 2004 [16]Karlshamn, Sweden80 [40]70Awaiting THRAhlb?ck 80mg TAFluoroscopy3, 12VAS - pain on weight bearingNot statedAhlback criteria ≥2 and JSN with cartilage destruction ≥ 50%1% Mepivacaine???Pain at rest and on weight bearing ≥ 3 VAS??Qvistgaard et al 2006 [15]Copenhagen, Denmark101 [32]66Pain at randomisationACR40mg MP + 2 sham injections Ultrasound2, 4, 12VAS-pain on walkingOak Foundation, Erna Hamilton Foundation and Fidia Inc.Stable medication for 3 week3x Hyalgan3x Saline??????Injection repeated at 14 day intervals????Lambert et al 2007 [12]Alberta, Canada52 [31]62Symptoms for ≥ 6 monthsACR40mg TH + 0.5% BupivcaineFluoroscopy4, 8WOMAC20CHAR/NycoMed, MSI foundation, Arthritis Society of Canada, University of Alberta FoundationPersistent pain despite paracetamol±NSAIDs0.5% Bupivicaine + SalineAtchia et al 2011 [13]North Tyneside, UK77 [19]69Unilateral hip OAACR120mg MP + 1% LidocaineUltrasound1, 4, 8NRS worst painNational institute of Health Research and National Health ServicePain >1 monthDurolane + 1% LidocaineListed for THR or NZ priority score ≥20 Normal saline + 1% Lidocaine?????Standard care - no injection????* Where no primary pain outcome was specified the highest ranked pain measures reported in the hierarchy suggested by Juni et al ADDIN EN.CITE <EndNote><Cite><Author>Jüni</Author><Year>2006</Year><RecNum>443</RecNum><DisplayText>[1]</DisplayText><record><rec-number>443</rec-number><foreign-keys><key app="EN" db-id="55s9eza5fzxpsqe9w2spae54zs9tvs9awzt2">443</key><key app="ENWeb" db-id="UayrjwrYEugAAHnefLY">408</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Jüni, Peter</author><author>Reichenbach, Stephan</author><author>Dieppe, Paul</author></authors></contributors><titles><title>Osteoarthritis: rational approach to treating the individual</title><secondary-title>Best Practice &amp; Research Clinical Rheumatology</secondary-title></titles><periodical><full-title>Best Practice &amp; Research Clinical Rheumatology</full-title></periodical><pages>721-740</pages><volume>20</volume><number>4</number><keywords><keyword>osteoarthritis</keyword><keyword>pain</keyword><keyword>management</keyword><keyword>meta-analysis</keyword><keyword>effect size</keyword></keywords><dates><year>2006</year></dates><isbn>1521-6942</isbn><urls><related-urls><url>;[1]was utilised. ? Triamcinolone salt not specified. Abbreviation: IASI – intra-articular steroid injection, MP – Methylprednisolone Acetate, NRS - Numerical rating scale, OARSI-Osteoarthritis research society international, THR - total hip replacement, TA - Triamcinolone Acetonide, TH - Triamcinolone Hexacetonide, MP – Methylprednisolone ?acetate, NSAIDs – Non-steroidal anti-inflammatory drugs, JSN – joint space narrowing, ACR – American College of Rheumatology, VAS - Visual analogue scale, NRS – Numerical rating scale, WOMAC- Western Ontario and McMaster University osteoarthritis index. WOMAC20, 20 % reduction from baseline in WOMAC pain subscale.Table 2. Quality assessment of included trial using the Jadad scoring method.ReferenceRandomisedRandomisiation is described and appropriateDouble blindMethod of double blinding described and appropriateDescription of withdrawals and drop outsTotal Jadad ScoreFlanagan et al 1988 [14]YesNot reportedYesYesNo3Kullenberg et al 2004 [16]YesYesYesYesNo4Qvistgaard et al 2006 [15]YesNot reportedYesYesYes4Lambert et al 2007 [12]YesYesYesYesYes5Atchia et al 2011 [13]YesYesNoN/AYes3FIGURE 2. 3-4 weeks8 weeks12 weeksVAS pain on walkingVAS pain at restWOMAC painNRS worst painLequesne scorePatient global assessmentOARSI responder criteriaVAS pain on walkingVAS pain at restWOMAC painNRS worst painLequesne scorePatient global assessmentOARSI responder criteriaVAS pain on walkingVAS pain at restWOMAC painLequesne scorePatient global assessmentOARSI responder criteriaReferenceSummaryFlanagan et al 1988*9/12 in steroid group vs. 14/24 control reported pain improved at 4 weeks. No statistics reported.??Kullenberg et al 2004???Steroid group VAS pain on walking and at rest reported to be significantly different to control at 3 weeks. No p value reported.??Qvistgard et al 2006??????????Pain on walking steroid group effect size 0.6 (95% CI:0.1-1.1) across all time points. Difference between placebo and steroid P4 weeks=0.006 P12 weeks=0.58.??Lambert et al 2007?????OARSI responder criteria: 22/31 in the steroid group vs. 4/21 control at 8 weeks, p<0.01.??Atchia et al 2011??????OARSI responder criteria: 7/19 in steroid group vs. 2/19 in control group at week 8, p=0.02.? statistically significant improvement compared to control (at an alpha level of 0.05). ? no statistically significant improvement compared to control . Grey box – results not considered at this time point. * No statistical comparison between controls and steroid group reported ? Data from subsequent time points excluded due to absence of control group at later time points. Abbreviations: NRS - Numerical rating scale, OARSI-Osteoarthritis research society international, VAS - Visual analogue scale, WOMAC- Western Ontario and McMaster University osteoarthritis index.FIGURE 3.Hip IASIControlOdds RatioStudyRespondersTotalRespondersTotalWeightM-H, Fixed, 95% CIM-H, Fixed, 95% CIAtchia et al 201171921947.70%4.96 [0.87, 28.15]-304801460500Lambert et al 2007223142152.30%10.39 [2.73, 39.56]Total (95% CI)5040100%7.80 [2.70, 22.48]Total responders296Heterogeneity: Chi2 =0.44, df=1 (p=0.51); I2=0%Test for overall effect Z=3.80 (P=0.0001)Favours controlFavours Hip IASIResponders were those meeting the OMERACT-OARSI response criteria. Abbreviations: IASI - intra-articular steroid injection, M-H Mantel Haenszel.FIGURE 4. LINK Excel.Sheet.12 "C:\\Users\\WorkPC\\Desktop\\Figure 4.xlsx" Sheet1!R2C1:R13C8 \a \f 5 \h \* MERGEFORMAT LINK Excel.Sheet.12 "C:\\Users\\WorkPC\\Desktop\\Figure 4.xlsx" Sheet1!R2C1:R13C5 \a \f 4 \h ................
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