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Effects of recurrent intra-articular corticosteroid injections for osteoarthritis at 3 months and beyond: a systematic review and meta-analysis in comparison to other injectables

  • R.L. Donovan
    Correspondence
    Address correspondence and reprint requests to: R.L. Donovan, Musculoskeletal Research Unit, University of Bristol, Learning & Research Building (Level 1), Southmead Hospital, Bristol, BS10 5NB, UK.
    Affiliations
    Musculoskeletal Research Unit, University of Bristol, Level 1 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK

    North Bristol NHS Trust, Southmead Road, Bristol, BS10 5NB, UK
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  • T.A. Edwards
    Affiliations
    North Bristol NHS Trust, Southmead Road, Bristol, BS10 5NB, UK
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  • A. Judge
    Affiliations
    Musculoskeletal Research Unit, University of Bristol, Level 1 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK

    National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
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  • A.W. Blom
    Affiliations
    Musculoskeletal Research Unit, University of Bristol, Level 1 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK

    North Bristol NHS Trust, Southmead Road, Bristol, BS10 5NB, UK

    National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
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  • S.K. Kunutsor
    Affiliations
    Musculoskeletal Research Unit, University of Bristol, Level 1 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK

    National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
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  • M.R. Whitehouse
    Affiliations
    Musculoskeletal Research Unit, University of Bristol, Level 1 Learning and Research Building, Southmead Hospital, Bristol, BS10 5NB, UK

    North Bristol NHS Trust, Southmead Road, Bristol, BS10 5NB, UK

    National Institute for Health Research Bristol Biomedical Research Centre, University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol, Bristol, UK
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Open AccessPublished:September 12, 2022DOI:https://doi.org/10.1016/j.joca.2022.07.011

      Summary

      Objective

      Intra-articular corticosteroid injections (IACIs) provide temporary symptom relief in osteoarthritis (OA). This meta-analysis investigated the effects of recurrent IACIs at 3 months and beyond.

      Design

      We searched Medline, Embase and Cochrane from inception to January 2021 for randomised controlled trials (RCTs) of patients with OA who received recurrent IACIs compared with other injectables, placebo or no treatment (primary outcomes: pain, function). Mean differences (MDs) with 95% confidence intervals were reported.

      Results

      Ten RCTs were included (eight knee OA (n = 763), two trapeziometacarpal OA (n = 121)). Patients received between 2 and 8 injections, varying by trial. Trials compared recurrent IACIs with hyaluronic acid (HA), platelet-rich plasma (PRP), saline or orgotein (follow-up 3–24 months). Greater improvements in pain, function and QoL at 3–24 months were noted for the comparators than with IACIs, with comparators demonstrating an equal or superior effect, or the intervention effect attenuated during follow-up. Recurrent IACIs demonstrated no benefits in pain or function over placebo at 12–24 months. No serious adverse events were recorded. No studies reported on time-to-future interventions, risk of future prosthetic joint infection or other adverse events associated with subsequent joint replacement.

      Conclusions

      Recurrent IACIs often provide inferior (or non-superior) symptom relief compared with other injectables (including placebo) at 3 months and beyond. Other injectables (HA, PRP) often yielded greater improvements in pain and function up to 24 months post-injection. Existing RCTs on recurrent IACIs lack sufficient follow-up data to assess disease progression and time-to-future interventions.

      Keywords

      Introduction

      Intra-articular corticosteroid injections (IACIs) are a well-established non-surgical treatment option for the symptoms of osteoarthritis (OA), which can provide short-term improvements in pain, disability and quality of life (QoL)
      • Juni P.
      • Hari R.
      • Rutjes A.W.
      • Fischer R.
      • Silletta M.G.
      • Reichenbach S.
      • et al.
      Intra-articular corticosteroid for knee osteoarthritis.
      . The benefits tend to be greater for those with advanced disease
      • van Middelkoop M.
      • Arden N.K.
      • Atchia I.
      • Birrell F.
      • Chao J.
      • Rezende M.U.
      • et al.
      The OA Trial Bank: meta-analysis of individual patient data from knee and hip osteoarthritis trials show that patients with severe pain exhibit greater benefit from intra-articular glucocorticoids.
      . IACIs have been used for decades, most commonly for knee OA. Given the progressive nature of OA, a proportion of these patients will later require more invasive surgical interventions. IACIs are a relatively safe non-surgical means of temporary relief of symptoms - they can be a key treatment component for patients who are not fit for surgical interventions, for those where there is diagnostic uncertainty, or for those whose current symptoms are not severe enough for them to consider undergoing joint replacement.
      Numerous alternative injectables exist including anti-inflammatories, botulinum toxin, hyaluronic acid (HA), platelet-rich plasma (PRP) and, more recently, stem cells and biologics
      • Jones I.A.
      • Togashi R.
      • Wilson M.L.
      • Heckmann N.
      • Vangsness C.T.
      Intra-articular treatment options for knee osteoarthritis.
      . All of these have been demonstrated to provide symptomatic relief in the short term, but there is often significant heterogeneity between trials
      • Orchard J.W.
      Is there a place for intra-articular corticosteroid injections in the treatment of knee osteoarthritis?.
      . Moreover, there is a strong placebo effect which may contribute to the difficulty in detecting differences between treatment groups in trials
      • Bannuru R.R.
      • McAlindon T.E.
      • Sullivan M.C.
      • Wong J.B.
      • Kent D.M.
      • Schmid C.H.
      Effectiveness and implications of alternative placebo treatments: a systematic review and network meta-analysis of osteoarthritis trials.
      • Rosseland L.A.
      • Helgesen K.G.
      • Breivik H.
      • Stubhaug A.
      Moderate-to-severe pain after knee arthroscopy is relieved by intraarticular saline: a randomized controlled trial.
      • Saltzman B.M.
      • Leroux T.
      • Meyer M.A.
      • Basques B.A.
      • Chahal J.
      • Bach B.R.
      • et al.
      The therapeutic effect of intra-articular normal saline injections for knee osteoarthritis: a meta-analysis of evidence level 1 studies.
      .
      Many contemporary studies, reviews and meta-analyses reach contrasting conclusions regarding which intra-articular injectable is superior for patients with knee OA
      • Bannuru R.R.
      • Schmid C.H.
      • Kent D.M.
      • Vaysbrot E.E.
      • Wong J.B.
      • McAlindon T.E.
      Comparative effectiveness of pharmacologic interventions for knee osteoarthritis: a systematic review and network meta-analysis.
      • Campbell K.A.
      • Saltzman B.M.
      • Mascarenhas R.
      • Khair M.M.
      • Verma N.N.
      • Bach B.R.
      • et al.
      Does intra-articular platelet-rich plasma injection provide clinically superior outcomes compared with other therapies in the treatment of knee osteoarthritis? A systematic review of overlapping meta-analyses.
      • Faundez J.
      • Cotoras P.
      • Irarrazaval S.
      Are intraarticular steroids effective for knee osteoarthritis?.
      • Gregori D.
      • Giacovelli G.
      • Minto C.
      • Barbetta B.
      • Gualtieri F.
      • Azzolina D.
      • et al.
      Association of pharmacological treatments with long-term pain control in patients with knee osteoarthritis: a systematic review and meta-analysis.
      • He W.W.
      • Kuang M.J.
      • Zhao J.
      • Sun L.
      • Lu B.
      • Wang Y.
      • et al.
      Efficacy and safety of intraarticular hyaluronic acid and corticosteroid for knee osteoarthritis: a meta-analysis.
      • Jevsevar D.S.
      • Shores P.B.
      • Mullen K.
      • Schulte D.M.
      • Brown G.A.
      • Cummins D.S.
      Mixed treatment comparisons for nonsurgical treatment of knee osteoarthritis: a network meta-analysis.
      • Shen L.
      • Yuan T.
      • Chen S.
      • Xie X.
      • Zhang C.
      The temporal effect of platelet-rich plasma on pain and physical function in the treatment of knee osteoarthritis: systematic review and meta-analysis of randomized controlled trials.
      and hip OA
      • Zhao Z.
      • Ma J.X.
      • Ma X.L.
      Different intra-articular injections as therapy for hip osteoarthritis: a systematic review and network meta-analysis.
      , often having assessed different outcomes over variable periods, and focussing on single-dose injections. Similarly, a recent meta-analysis of a variety of injectables to treat patients with trapeziometacarpal OA demonstrated a mild improvement in pain with IACIs vs HA, but the strength of the recommendation was limited, and neither was considered to be superior overall
      • Riley N.
      • Vella-Baldacchino M.
      • Thurley N.
      • Hopewell S.
      • Carr A.J.
      • Dean B.J.F.
      Injection therapy for base of thumb osteoarthritis: a systematic review and meta-analysis.
      . Another meta-analysis for this group demonstrated that IACIs were more effective at reducing pain at 24 months, but HA was more effective at improving function over the same period
      • Trellu S.
      • Dadoun S.
      • Berenbaum F.
      • Fautrel B.
      • Gossec L.
      Intra-articular injections in thumb osteoarthritis: a systematic review and meta-analysis of randomized controlled trials.
      . Again, most of the existing trials have focussed on outcomes after single-dose injections.
      Outcomes for recurrent IACIs at 3 months and beyond remain less well-researched
      • Orchard J.W.
      Is there a place for intra-articular corticosteroid injections in the treatment of knee osteoarthritis?.
      . This systematic review and meta-analysis aimed to assess the existing literature to investigate the effects of recurrent IACIs at 3 months and beyond when compared to other injectables, placebo or no treatment.

      Materials and methods

      Data sources and search strategy

      The review was registered a priori in the PROSPERO prospective register of systematic reviews (ID: CRD42020226861) and conducted according to a predefined protocol and in line with PRISMA guidelines. We searched for randomised controlled trials (RCTs) which compared longer-term outcomes (at 3 months post-injection and beyond) after recurrent IACIs were used to treat OA compared with other common injectables (e.g., botulinum toxin, HA, PRP), placebo (e.g., saline), sham treatment or no treatment. We systematically searched the databases of Medline, Embase and Cochrane from inception to 07 January 2021. The computer-based searches used a combination of free and MeSH search terms and keywords related to the population (e.g., “osteoarthritis”), and intervention (e.g., “corticosteroid,” “methylprednisolone”). There were no restrictions on language. The search was complemented by manually screening the reference lists of all retrieved articles and utilising the “Cited Reference Search” function in Web of Science to obtain any additional studies that were missed by the search strategy. Any previously published systematic reviews and meta-analyses were also screened for studies that met our eligibility criteria. The detailed search strategy has been provided in Appendix 1.

      Eligibility criteria

      We included RCTs that reported on longer-term outcomes at 3 months post-injection and beyond after recurrent (≥ two injections in the study period) IACIs in adults (age >18 years) for OA compared with other common injectables, placebo, sham treatment or no treatment. The primary outcome was patient-reported outcome measures (PROMs) including pain and function. Secondary outcomes of interest included QoL, joint stiffness, adverse events (e.g., infection, cardiovascular events), disease progression, and time-to-future interventions (e.g., arthroscopy, arthroplasty).
      We excluded any studies that only assessed outcomes after single-dose injections, studies that included patients with prosthetic joints, and patients with pathology other than OA (e.g., rheumatoid arthritis, gout). Non-RCTs were also excluded.

      Study selection and data extraction

      Once the searches were completed, the results were imported into Rayyan
      • Ouzzani M.
      • Hammady H.
      • Fedorowicz Z.
      • Elmagarmid A.
      Rayyan-a web and mobile app for systematic reviews.
      , an online bibliographic tool. One reviewer (RLD) initially screened the titles and abstracts and removed any duplicates to provide a list of potentially relevant articles. Full-text screening of these articles was then performed independently by two reviewers (RLD, TAE) against predefined eligibility criteria. Any discrepancies regarding the eligibility of an article were discussed, and a consensus was achieved through a senior author (MRW) if required. One reviewer (RLD) independently extracted data and conducted risk of bias assessments using a standardised data collection form. A second reviewer (TAE) independently repeated the process to verify the data. A data abstraction table was designed and piloted. Data were extracted on the lead author, year of publication, geographical location, study design, number of participants, mean age, percentage of males, joint treated (e.g., knee), intervention (corticosteroid (CS)), comparators, indications, duration of follow-up, and outcome measures. We also extracted data on relevant study characteristics to permit the risk of bias assessments. In circumstances of multiple publications, the study with the most up-to-date or comprehensive information was included. Authors of eligible studies were contacted to provide further information if there were missing data for the extracted fields.

      Risk of bias assessment

      The risk of bias within individual RCTs was assessed using the Cochrane Risk of Bias (RoB 2.0) tool
      • Sterne J.A.C.
      • Savovic J.
      • Page M.J.
      • Elbers R.G.
      • Blencowe N.S.
      • Boutron I.
      • et al.
      RoB2: a revised tool for assessing risk of bias in randomised trials.
      , a validated tool for assessing the risk of bias of randomised studies. This tool assesses the risk of bias for the randomisation process, deviations from the intended interventions, missing outcome data, measurement of the outcome, and selective reporting. Each of these domains is assessed as low risk, some concerns or high risk, and then an overall judgement of the risk of bias is provided for each study.

      Statistical analysis

      A meta-analysis was performed using RevMan 5.4 software (Cochrane Collaboration). Summary measures were presented as mean differences (MDs) with 95% confidence intervals (CIs) for continuous outcomes and relative risks (RRs) with 95% CIs for binary outcomes. Standardised mean differences (SMDs) were employed if studies used different scales of measurement. For continuous data, if the mean or standard deviation (SD) was not reported, we estimated the mean and variance from the reported median, range, and sample size as recommended by Hozo et al.
      • Hozo S.P.
      • Djulbegovic B.
      • Hozo I.
      Estimating the mean and variance from the median, range, and the size of a sample.
      , to facilitate a consistent approach to the meta-analysis. For continuous data that only reported the mean and 95% CIs, the SD was calculated as per instructions in the Cochrane Handbook (Chapter 7.7.3.2)
      • Higgins J.P.T.
      • Deeks J.J.
      Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. Chapter 7: Selecting Studies and Collecting Data.
      . Relative risks were calculated from the extracted raw counts for the intervention and comparator. We combined comparators (non-CS) for the analysis. A narrative synthesis was performed for studies that could not be pooled. Heterogeneity was assessed using the Cochrane χ2 statistic and the I2 statistic. The inverse variance (IV) weighted method was used to combine pooled summary measures. Parallel analyses used fixed-effects (FE) models. The decision to use random-effects (RE) or FE models was based on I2 quantification of heterogeneity, as well as variability in the clinical and methodological aspects of the studies, number of studies available for pooling, and study sample sizes
      • Higgins J.P.
      • Thompson S.G.
      • Deeks J.J.
      • Altman D.G.
      Measuring inconsistency in meta-analyses.
      ,
      • Tufanaru C.
      • Munn Z.
      • Stephenson M.
      • Aromataris E.
      Fixed or random effects meta-analysis? Common methodological issues in systematic reviews of effectiveness.
      . The statistical significance was set as p < 0.05. We planned to conduct subgroup analysis to explore the origins of heterogeneity using random-effects meta-regression.

      Results

      Study selection

      Our search strategy identified 593 potentially relevant citations, and this was reduced to 439 after duplicates were removed. After the initial screening of titles and abstracts, 119 full-text articles remained for further evaluation, and a further one was obtained by manually scanning the reference lists of the retrieved articles. 110 papers failed to meet the eligibility criteria. Therefore, ten studies that contained extractable data were deemed eligible for inclusion in this systematic review and meta-analysis
      • Bisicchia S.
      • Bernardi G.
      • Tudisco C.
      HYADD4 versus methylprednisolone acetate in symptomatic knee osteoarthritis: a single-centre single blind prospective randomised controlled clinical study with 1-year follow-up.
      • Davalillo C.A.T.
      • Trueba Vasavilbaso C.
      • Navarrete Alvarez J.M.
      • Coronel Granado P.
      • Garcia Jimenez O.A.
      • Gimeno Del Sol M.
      • et al.
      Clinical efficacy of intra-articular injections in knee osteoarthritis: a prospective randomized study comparing hyaluronic acid and betamethasone.
      • Gammer W.
      • Broback L.G.
      Clinical comparison of orgotein and methylprednisolone acetate in the treatment of osteoarthrosis of the knee joint.
      • Malahias M.A.
      • Roumeliotis L.
      • Nikolaou V.S.
      • Chronopoulos E.
      • Sourlas I.
      • Babis G.C.
      Platelet-rich plasma versus corticosteroid intra-articular injections for the treatment of trapeziometacarpal arthritis: a prospective randomized controlled clinical trial.
      • McAlindon T.E.
      • LaValley M.P.
      • Harvey W.F.
      • Price L.L.
      • Driban J.B.
      • Zhang M.
      • et al.
      Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial.
      • Monfort J.
      • Rotes-Sala D.
      • Segales N.
      • Montanes F.J.
      • Orellana C.
      • Llorente-Onaindia J.
      • et al.
      Comparative efficacy of intra-articular hyaluronic acid and corticoid injections in osteoarthritis of the first carpometacarpal joint: results of a 6-month single-masked randomized study.
      • Nabi B.N.
      • Sedighinejad A.
      • Mardani-Kivi M.
      • Haghighi M.
      • Roushan Z.A.
      • Tehran S.G.
      • et al.
      Comparing the effectiveness of intra-articular platelet-rich plasma and corticosteroid injection under ultrasound guidance on pain control of knee osteoarthritis.
      • Raynauld J.P.
      • Buckland-Wright C.
      • Ward R.
      • Choquette D.
      • Haraoui B.
      • Martel-Pelletier J.
      • et al.
      Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial.
      • Skwara A.
      • Peterlein C.D.
      • Tibesku C.O.
      • Rosenbaum D.
      • Fuchs-Winkelmann S.
      Changes of gait patterns and muscle activity after intraarticular treatment of patients with osteoarthritis of the knee: a prospective, randomised, doubleblind study.
      • Tascioglu F.
      • Oner C.
      Efficacy of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis.
      . A PRISMA flow chart is provided in Fig. 1.

      Study characteristics

      Table I provides a summary of the characteristics of the ten included RCTs. Eight studies assessed injections into knee joints (n = 763), and two studies assessed injections into trapeziometacarpal joints (n = 121). Six studies were performed in Europe (Germany, Greece, Italy, Spain, Sweden, Turkey), three in North America (USA, Canada, Mexico), and one in the Middle East (Iran). Regarding recurrent injections for knee OA, four studies compared CS with HA
      • Bisicchia S.
      • Bernardi G.
      • Tudisco C.
      HYADD4 versus methylprednisolone acetate in symptomatic knee osteoarthritis: a single-centre single blind prospective randomised controlled clinical study with 1-year follow-up.
      ,
      • Davalillo C.A.T.
      • Trueba Vasavilbaso C.
      • Navarrete Alvarez J.M.
      • Coronel Granado P.
      • Garcia Jimenez O.A.
      • Gimeno Del Sol M.
      • et al.
      Clinical efficacy of intra-articular injections in knee osteoarthritis: a prospective randomized study comparing hyaluronic acid and betamethasone.
      ,
      • Skwara A.
      • Peterlein C.D.
      • Tibesku C.O.
      • Rosenbaum D.
      • Fuchs-Winkelmann S.
      Changes of gait patterns and muscle activity after intraarticular treatment of patients with osteoarthritis of the knee: a prospective, randomised, doubleblind study.
      ,
      • Tascioglu F.
      • Oner C.
      Efficacy of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis.
      , two with saline (placebo)
      • McAlindon T.E.
      • LaValley M.P.
      • Harvey W.F.
      • Price L.L.
      • Driban J.B.
      • Zhang M.
      • et al.
      Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial.
      ,
      • Raynauld J.P.
      • Buckland-Wright C.
      • Ward R.
      • Choquette D.
      • Haraoui B.
      • Martel-Pelletier J.
      • et al.
      Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial.
      , one with PRP
      • Nabi B.N.
      • Sedighinejad A.
      • Mardani-Kivi M.
      • Haghighi M.
      • Roushan Z.A.
      • Tehran S.G.
      • et al.
      Comparing the effectiveness of intra-articular platelet-rich plasma and corticosteroid injection under ultrasound guidance on pain control of knee osteoarthritis.
      , and one with an anti-inflammatory agent (orgotein)
      • Gammer W.
      • Broback L.G.
      Clinical comparison of orgotein and methylprednisolone acetate in the treatment of osteoarthrosis of the knee joint.
      . Regarding recurrent injections for trapeziometacarpal OA, one study compared CS with HA
      • Monfort J.
      • Rotes-Sala D.
      • Segales N.
      • Montanes F.J.
      • Orellana C.
      • Llorente-Onaindia J.
      • et al.
      Comparative efficacy of intra-articular hyaluronic acid and corticoid injections in osteoarthritis of the first carpometacarpal joint: results of a 6-month single-masked randomized study.
      and one with PRP
      • Malahias M.A.
      • Roumeliotis L.
      • Nikolaou V.S.
      • Chronopoulos E.
      • Sourlas I.
      • Babis G.C.
      Platelet-rich plasma versus corticosteroid intra-articular injections for the treatment of trapeziometacarpal arthritis: a prospective randomized controlled clinical trial.
      . Most patients included in the studies were female, and the mean age was in the fifth or sixth decade of life. The maximum follow-up duration was 24 months (range 6–24 months), and no study reported a mean or median follow-up duration.
      Table ICharacteristics of the included studies
      Author Year

      Location
      Study DesignParticipants (n)JointIntervention (corticosteroid)ComparatorAge (years)

      Mean ± SD (range)
      Sex (male, %)Main OutcomesMaximum Follow-Up (months)
      Bisicchia

      2016

      Italy
      Single-centre single-blinded prospective RCT150KneeMP 40 mg

      2 injections

      1 week apart
      HA

      2 injections

      1 week apart
      MP: 68.6 ± 9.9 (54–80)

      HA: 71.5 ± 10.6 (48–84)
      MP: 33.3

      HA: 29.3
      WOMAC, VAS, SF-3612
      Davalillo

      2015

      Mexico
      Single-centre single-blinded prospective RCT200KneeBM 7 mg

      2 injections

      4 weeks apart
      HA

      5 injections

      1 week apart
      BM: 62.8 ± 0.6

      HA: 62.7 ± 0.6
      BM: 41.8

      HA: 39.2
      VAS, WOMAC12
      Gammer

      1984

      Sweden
      Single-centre double-blinded prospective RCT36KneeMP 40 mg

      4 injections

      Weeks 1/2/4/6
      Orgotein 8 mg

      4 injections

      Weeks 1/2/4/6
      Overall: 63 (48–72)NRStiffness, VAS, adverse events6
      Malahias

      2018

      Greece
      Mutli-centre single-blinded prospective RCT33Trapezio-metacarpalMP 125 mg + LA

      2 injections

      2 weeks apart
      PRP

      2 injections

      2 weeks apart
      MP: 63 ± 11.8

      PRP: 62.8 ± 10.6
      MP: 19

      PRP: 19
      VAS, Q-DASH, patient satisfaction12
      McAlindon

      2017

      USA
      Single-centre double-blinded prospective RCT140KneeTA 40 mg

      8 injections

      3 months apart
      Saline 0.9% 1 mL

      8 injections

      3 months apart
      TA: 59.1 ± 8.3

      Saline: 57.2 ± 7.6
      TA: 47.1

      Saline: 45.7
      ROM, BP, WOMAC, VAS, adverse events, function, SF-3624
      Monfort

      2015

      Spain
      Single-centre single-blinded prospective RCT88Trapezio-metacarpalBM 3 mg

      3 injections

      1 week apart
      HA

      3 injections

      1 week apart
      Overall: 62.8 ± 8.7 (45–92)Overall: 12.5VAS, FIHOA, SF-366
      Nabi

      2018

      Iran
      Single-centre single-blinded prospective RCT67KneeTA 40 mg

      3 injections

      4 weeks apart
      PRP

      3 injections

      4 weeks apart
      TA: 58.6 ± 8.8

      PRP: 59.1 ± 7.8
      TA: 20.6

      PRP: 15.2
      VAS, KOOS6
      Raynauld

      2003

      Canada
      Single-centre double-blinded prospective RCT68KneeTA 40 mg

      8 injections

      3 months apart
      Saline 0.9% 1 mL

      8 injections

      3 months apart
      TA: 63.1 ± 9.1

      Saline: 63.3 ± 9.0
      TA: 26

      Saline: 39
      WOMAC, VAS, ROM, adverse events24
      Skwara

      2009

      Germany
      Single-centre single-blinded prospective RCT42KneeTA 10 mg

      5 injections

      1 week apart
      HA

      5 injections

      1 week apart
      TA: 61.3 ± 6.7

      HA: 60.8 ± 7.0
      TA: 42.9

      HA: 38.1
      KSS, Lequesne, VAS3
      Tascioglu

      2003

      Turkey
      Single-centre single-blinded prospective RCT60KneeMP 40 mg

      3 injections

      1 week apart
      HA

      3 injections

      1 week apart
      MP: 60.1 ± 6.9

      HA: 57.4 ± 6.5
      MP: 0

      HA: 0
      VAS, Lequesne, ROM, adverse events6
      Key (alphabetical): BM, betamethasone; BP, blood pressure; FIHOA, functional index of hand osteoarthritis; HA, hyaluronic acid; KOOS, knee injury and osteoarthritis outcome score; KSS, knee society score; LA, local anaesthetic; MP, methylprednisolone; NR, not reported; PRP, platelet-rich plasma; Q-DASH, disabilities of the arm, shoulder and hand questionnaire; ROM, range of motion; SF-36, 36-item short-form survey; TA, triamcinolone; VAS, visual analogue scale; WOMAC, western Ontario and McMaster universities arthritis index.

      Risk of bias

      According to the RoB 2.0 tool, nine RCTs were deemed to be of low risk of bias, and one was deemed to have some concerns. The risk of bias assessment for individual articles is included in Appendix 2.

      Knee OA

      CS vs ‘other’ in patients with knee OA
      • Bisicchia S.
      • Bernardi G.
      • Tudisco C.
      HYADD4 versus methylprednisolone acetate in symptomatic knee osteoarthritis: a single-centre single blind prospective randomised controlled clinical study with 1-year follow-up.
      • Davalillo C.A.T.
      • Trueba Vasavilbaso C.
      • Navarrete Alvarez J.M.
      • Coronel Granado P.
      • Garcia Jimenez O.A.
      • Gimeno Del Sol M.
      • et al.
      Clinical efficacy of intra-articular injections in knee osteoarthritis: a prospective randomized study comparing hyaluronic acid and betamethasone.
      • Gammer W.
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      Clinical comparison of orgotein and methylprednisolone acetate in the treatment of osteoarthrosis of the knee joint.
      ,
      • McAlindon T.E.
      • LaValley M.P.
      • Harvey W.F.
      • Price L.L.
      • Driban J.B.
      • Zhang M.
      • et al.
      Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial.
      ,
      • Nabi B.N.
      • Sedighinejad A.
      • Mardani-Kivi M.
      • Haghighi M.
      • Roushan Z.A.
      • Tehran S.G.
      • et al.
      Comparing the effectiveness of intra-articular platelet-rich plasma and corticosteroid injection under ultrasound guidance on pain control of knee osteoarthritis.
      • Raynauld J.P.
      • Buckland-Wright C.
      • Ward R.
      • Choquette D.
      • Haraoui B.
      • Martel-Pelletier J.
      • et al.
      Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial.
      • Skwara A.
      • Peterlein C.D.
      • Tibesku C.O.
      • Rosenbaum D.
      • Fuchs-Winkelmann S.
      Changes of gait patterns and muscle activity after intraarticular treatment of patients with osteoarthritis of the knee: a prospective, randomised, doubleblind study.
      • Tascioglu F.
      • Oner C.
      Efficacy of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis.

      Pain

      All eight studies assessed pain using the Visual Analogue Scale (VAS) pain scores (scale 0–10 or 0–100, where the lower limit represents no pain and the upper limit represents extreme pain). At 3 months, there was no difference in VAS (SMD 0.33; 95% CI –0.44, 1.10; p = 0.40; Fig. 2(A)). Greater improvements in VAS were noted in the ‘other’ group at 6 months (SMD 1.05; 95% CI 0.54, 1.56; p < 0.0001; Fig. 2(B)) and 9 months (SMD 2.06; 95% CI 1.71, 2.40; p < 0.00001; Fig. 2(C)). However, there was no difference between treatment groups at 12 months (SMD 0.83; 95% CI –0.58, 2.24; p = 0.25; Fig. 2(D)) nor 24 months (SMD –0.01; 95% CI –0.30, 0.28; p = 0.94; Fig. 2(E)).
      Fig. 2
      Fig. 2Forest plots demonstrating differences in VAS pain scores for CS vs ‘other’ in patients with knee OA at 3 months (2A), 6 months (2B), 9 months (2C), 12 months (2D) and 24 months (2E).

      Function

      Davalillo et al., McAlindon et al. and Raynauld et al. assessed function using the WOMAC function scale (scale 0–68, where the lower limit represents no disability and the upper limit represents extreme disability), and Skwara et al. and Tascioglu et al. used the Lequesne functional index to assess function (scale 0–24, where the lower limit represents no disability and the upper limit represents extreme disability). At 3 months, function scores had improved in both groups but greater improvements in function were noted in the ‘other’ group (SMD 0.82; 95% CI 0.19, 1.45; p = 0.01; Fig. 3(A)). This trend continued at 6 months (SMD 1.98; 95% CI 1.66, 2.30; p < 0.00001; Fig. 3(B)), 9 months (SMD 3.52; 95% CI 3.07, 3.97; p < 0.00001; Fig. 3(C)) and 12 months (SMD 1.61; 95% CI 1.30, 1.93; p < 0.00001; Fig. 3(D)). At 24 months, there was no difference between treatment groups (SMD –0.10; 95% CI –0.39, 0.19; p = 0.51; Fig. 3(E)).
      Fig. 3
      Fig. 3Forest plots demonstrating differences in WOMAC function scores for CS vs ‘other’ in patients with knee OA at 3 months (3A), 6 months (3B), 9 months (3C), 12 months (3D) and 24 months (3E).
      Nabi et al. measured function using the KOOS activities of daily living (ADLs) scale (scale 0–100, where the lower limit represents extreme disability and the upper limit represents no disability). Improvements in scores were seen in both treatment groups, but greater improvements in scores were noted in the ‘other’ group at 3 months (MD –8.02; 95% CI –11.24, −4.80; p < 0.00001; Fig. 4(A)) and 6 months (MD –18.55; 95% CI –21.81, −15.29; p < 0.00001; Fig. 4(B)).
      Fig. 4
      Fig. 4Forest plots demonstrating differences in KOOS ADLs scores for CS vs ‘other’ in patients with knee OA at 3 months (4A) and 6 months (4B).

      QoL

      Bisicchia et al. quantified QoL using the 36-Item Short Form Survey (SF-36) score (scale 0–100, where the lower limit represents extreme disability and the upper limit represents no disability). Greater improvements in QoL were noted in the ‘other’ group at 3 months (MD –8.00; 95% CI –12.61, −3.39; p = 0.0007; Supplementary Material Fig. A) and 6 months (MD –11.40; 95% CI –15.64, −7.16; p < 0.00001; Supplementary Material Fig. B). At 12 months, the ‘other’ group had returned to baseline and a small improvement in the CS group was maintained (MD –2.70; 95% CI –7.10, 1.70; p = 0.23; Supplementary Material Fig. C).
      Nabi et al. assessed QoL using the KOOS QoL scale (scale 0–100, where the lower limit represents extreme impact on QoL and the upper limit represents no effect of QoL). Improvements in KOOS scores were seen in both treatment groups, but greater improvements in QoL were noted in the ‘other’ group at 3 months (MD –6.35; 95% CI –11.70, −1.00; p = 0.02; Supplementary Material Fig. D) and 6 months (MD –10.26; 95% CI –15.30, −5.22; p < 0.0001; Supplementary Material Fig. E).

      Trapeziometacarpal OA

      CS vs ‘other’ in patients with trapeziometacarpal OA
      • Malahias M.A.
      • Roumeliotis L.
      • Nikolaou V.S.
      • Chronopoulos E.
      • Sourlas I.
      • Babis G.C.
      Platelet-rich plasma versus corticosteroid intra-articular injections for the treatment of trapeziometacarpal arthritis: a prospective randomized controlled clinical trial.
      ,
      • Monfort J.
      • Rotes-Sala D.
      • Segales N.
      • Montanes F.J.
      • Orellana C.
      • Llorente-Onaindia J.
      • et al.
      Comparative efficacy of intra-articular hyaluronic acid and corticoid injections in osteoarthritis of the first carpometacarpal joint: results of a 6-month single-masked randomized study.

      Pain

      Malahias et al. and Monfort et al. assessed VAS pain scores (scale 0–10 or 0–100). Although both treatments led to improvements in pain, there was no difference in VAS between treatment groups at 3 months (SMD –0.11; 95% CI –0.47, 0.26; p = 0.57; Fig. 5(A)) or 6 months (SMD 0.95; 95% CI –0.06, 0.79; p = 0.09; Fig. 5(B)). However, at 12 months, greater improvements in VAS were noted in the ‘other’ treatment group (SMD 3.95; 95% CI 2.71, 5.20; p < 0.00001; Fig. 5(C)).
      Fig. 5
      Fig. 5Forest plots demonstrating differences in VAS pain scores for CS vs ‘other’ in patients with knee OA at 3 months (5A), 6 months (5B) and 12 months (5C).

      Function

      Malahias et al. evaluated function using the Disabilities of the Arm, Shoulder and Hand Questionnaire (Q-DASH) score (0–100, where the lower limit represents no disability and the upper limit represents extreme disability) and Monfort et al. used the Functional Index of Hand Osteoarthritis (FIHOA) score (scale 0–30, where the lower limit represents no disability and the upper limit represents extreme disability). Improvements in functional scores were seen in both treatment groups, but greater improvements in function were noted in the ‘other’ group at 3 months (SMD 0.80; 95% CI 0.42, 1.18; p < 0.0001; Fig. 6(A)), 6 months (SMD 0.82; 95% CI 0.38, 1.26; p = 0.0002; Fig. 6(B)), and 12 months (SMD 0.80; 95% CI 0.07, 1.52; p = 0.03; Fig. 6(C)).
      Fig. 6
      Fig. 6Forest plots demonstrating differences in VAS pain scores for CS vs ‘other’ in patients with knee OA at 3 months (6A), 6 months (6B) and 12 months (6C).

      QoL

      Monfort et al. evaluated QoL using the SF-36 physical score (scale 0–100). Although both treatments led to improvements in QoL, there was no difference in scores between treatment groups at 3 months (MD –0.01; 95% CI –3.52, 3.50; p = 1.00; Supplementary Material Fig. F) and 6 months (MD 1.77; 95% CI -2.22, 5.76; p = 0.38; Supplementary Material Fig. G).

      Adverse events

      Adverse events were uncommon in all treatment groups for patients with knee OA and trapeziometacarpal OA. Some patients experienced mild symptoms of pain/discomfort, swelling, stiffness, pruritis or erythema but these were short-lived and self-resolving after hours/days. No severe adverse events or complications were reported across the ten studies.

      Subgroup analysis

      CS vs HA in patients with knee OA
      • Bisicchia S.
      • Bernardi G.
      • Tudisco C.
      HYADD4 versus methylprednisolone acetate in symptomatic knee osteoarthritis: a single-centre single blind prospective randomised controlled clinical study with 1-year follow-up.
      ,
      • Davalillo C.A.T.
      • Trueba Vasavilbaso C.
      • Navarrete Alvarez J.M.
      • Coronel Granado P.
      • Garcia Jimenez O.A.
      • Gimeno Del Sol M.
      • et al.
      Clinical efficacy of intra-articular injections in knee osteoarthritis: a prospective randomized study comparing hyaluronic acid and betamethasone.
      ,
      • Skwara A.
      • Peterlein C.D.
      • Tibesku C.O.
      • Rosenbaum D.
      • Fuchs-Winkelmann S.
      Changes of gait patterns and muscle activity after intraarticular treatment of patients with osteoarthritis of the knee: a prospective, randomised, doubleblind study.
      ,
      • Tascioglu F.
      • Oner C.
      Efficacy of intra-articular sodium hyaluronate in the treatment of knee osteoarthritis.

      Pain

      All four studies assessed pain using VAS pain scores (scale 0–10 or 0–100). At 3 months, there was no difference in VAS (SMD 0.23; 95% CI –0.85, 1.31; p = 0.68). At 6 months (SMD 1.03; 95% CI 0.25, 1.81; p = 0.01), 9 months (MD 1.9; 95% CI 1.64, 2.16; p < 0.00001) and 12 months (MD 1.78; 95% CI 1.55, 2.01; p < 0.00001) VAS was lower in the HA group.

      Function

      Davalillo et al. assessed function using the WOMAC function scale (scale 0–68). At 3 months, WOMAC function scores had improved in both groups but were lower in the HA group (MD 5.80; 95% CI 4.48, 7.12; p < 0.00001). This trend was also seen at 6 months (MD 12.40; 95% CI 11.12, 13.68; p < 0.00001), 9 months (MD 16.80; 95% CI 15.47, 18.13; p < 0.00001), and 12 months (MD 14.10; 95% CI 12.77, 15.43; p < 0.00001).

      CS vs saline in patients with knee OA
      • McAlindon T.E.
      • LaValley M.P.
      • Harvey W.F.
      • Price L.L.
      • Driban J.B.
      • Zhang M.
      • et al.
      Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial.
      ,
      • Raynauld J.P.
      • Buckland-Wright C.
      • Ward R.
      • Choquette D.
      • Haraoui B.
      • Martel-Pelletier J.
      • et al.
      Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial.

      Pain

      Both studies assessed VAS pain scores (scale 0–100). Although improvements were seen in both the CS and saline groups, no differences were noted between treatment groups at 12 months (MD –0.40; 95% CI 9.65, 8.85; p = 0.93), and 24 months (MD –0.52; 95% CI –8.85, 7.81; p = 0.90).

      Function

      Both studies assessed function using the WOMAC function scale (scale 0–68). Overall function improved in both the CS and saline groups; however, there were no differences between the groups at 12 months (MD –6.00; 95% CI –16.23, 4.23; p = 0.25) and 24 months (SMD –0.10; 95% CI –0.39, 0.19; p = 0.51).

      Radiographic outcomes

      McAlindon et al. evaluated several radiographical parameters. At 24 months, the total mean cartilage thickness (mm) was lower in the CS group (MD –0.19; 95% CI –0.37, −0.01; p = 0.04), as was the total cartilage damage index (mm3) (MD –119.28; 95% CI –228.08, −10.48; p = 0.03). However, at 24 months, there was no difference in the total area of denudation (mm2) (MD –0.05; 95% CI –1.27, 1.17; p = 0.94), the bone marrow lesion volume (log(mm
      • Jones I.A.
      • Togashi R.
      • Wilson M.L.
      • Heckmann N.
      • Vangsness C.T.
      Intra-articular treatment options for knee osteoarthritis.
      )) (MD 0.77; 95% CI –1.23, 2.77; p = 0.45) nor the effusion volume (log(mm
      • Jones I.A.
      • Togashi R.
      • Wilson M.L.
      • Heckmann N.
      • Vangsness C.T.
      Intra-articular treatment options for knee osteoarthritis.
      )) (MD 0.13; 95% CI –0.32, 0.58; p = 0.57).

      Discussion

      Key findings

      To our knowledge, this is the first comprehensive meta-analysis of the longer-term outcomes (at 3 months and beyond)of the effects of recurrent IACIs compared to other intra-articular treatments, placebo, or no treatment. Only ten RCTs were identified in the literature: eight for knee OA and two for trapeziometacarpal OA. Whilst the risk of bias for the individual studies was assessed as low, there was significant heterogeneity between studies which created challenges for the meta-analysis. Our analysis was segregated by the index joint, and then by different groups of interventions and comparators to reduce heterogeneity in the results.
      Whilst the RCTs demonstrated improvements from baseline in pain, function, QoL, stiffness and radiographical attributes for recurrent IACIs beyond 3 months and up to 24 months, in many cases, the comparators (including placebo) demonstrated an equal or superior effect, or the effect attenuated at the maximal duration of follow-up. In many cases, alternative injectables (particularly HA and PRP) provided greater symptomatic benefits over the longer-term. Recurrent IACIs failed to demonstrate superiority over placebo (saline) for pain and function after 12- and 24-months post-injection. Most notably, none of the included studies assessed important longer-term outcomes such as the systemic side-effects of recurrent IACIs, whether recurrent IACIs accelerate OA, the time-to-future surgical interventions (e.g., arthroscopy or arthroplasty), or the risk of future prosthetic joint infection (PJI).

      Comparison to existing work

      The recommendations made by several national and international bodies include the use of intra-articular injections for the non-surgical treatment of OA but the detail of what should be injected for which conditions appear to be inconsistent. The 2019 Osteoarthritis Research Society International (OARSI) guidelines on the non-surgical management of OA suggest that IACIs may provide short-term pain relief; however, intra-articular HA injections may have beneficial effects on pain at, and beyond, 3 months of treatment, and a more favourable long-term safety profile than recurrent IACIs
      • Bannuru R.R.
      • Osani M.C.
      • Vaysbrot E.E.
      • Arden N.K.
      • Bennell K.
      • Bierma-Zeinstra S.M.A.
      • et al.
      OARSI guidelines for the non-surgical management of knee, hip, and polyarticular osteoarthritis.
      . The 2014 National Institute for Health and Care Excellence guidelines recommend that IACIs should be considered as an adjunct to other core treatments for the relief of moderate-to-severe pain for OA, but do not recommend intra-articular HA injections for the management of OA
      National Institute for Health and Care Excellence (NICE)
      Osteoarthritis: Care and Management in Adults.
      . They also acknowledged that steroid-induced arthropathy remains controversial and poorly understood. The 2013 American Academy of Orthopaedic Surgeons (AAOS) guidelines do not promote or discourage the use of IACIs (or PRP) in patients with OA, stating that the existing literature remains inconclusive, but did not recommend the use of intra-articular HA injections
      American Academy of Orthopaedic Surgeons (AAOS)
      Treatment of Osteoarthritis of the Knee.
      . The 2018 European League Against Rheumatism (EULAR) recommendations for the management of hand OA advised against the use of IACIs except in patients with painful interphalangeal OA
      • Kloppenburg M.
      • Kroon F.P.
      • Blanco F.J.
      • Doherty M.
      • Dziedzic K.S.
      • Greibrokk E.
      • et al.
      2018 Update of the EULAR recommendations for the management of hand osteoarthritis.
      .
      There is a growing body of evidence to suggest that IACIs may not be as safe as previously thought, leading to complications including accelerated OA progression, subchondral insufficiency fractures, osteonecrosis, and rapid joint destruction, albeit the evidence is not robust
      • Kompel A.J.
      • Roemer F.W.
      • Murakami A.M.
      • Diaz L.E.
      • Crema M.D.
      • Guermazi A.
      Intra-articular corticosteroid injections in the hip and knee: perhaps not as safe as we thought?.
      . A 2017 observational study suggested that patients who were administered IACIs before undergoing a total knee replacement (TKR) were at an increased risk of postoperative infection and that there was a time-dependent relationship with an increased risk of infection if the time between interventions was lower
      • Bedard N.A.
      • Pugely A.J.
      • Elkins J.M.
      • Duchman K.R.
      • Westermann R.W.
      • Liu S.S.
      • et al.
      The John N. Insall award: do intraarticular injections increase the risk of infection after TKA?.
      . A 2015 review also raised concerns regarding IACIs having time- and dose-dependent catabolic effects on cartilage morphology, histology and viability in both in vivo and in vitro studies
      • Wernecke C.
      • Braun H.J.
      • Dragoo J.L.
      The effect of intra-articular corticosteroids on articular cartilage: a systematic review.
      . Further longitudinal data is required to assess longer-term harms and benefits to patients undergoing recurrent IACIs.

      Implications of our findings

      The existing literature is limited by insufficient follow-up and has not sought to adequately measure outcomes such as the time-to-future surgical interventions. The RecUrrent IACIs in Osteoarthritis (RUbICOn) study designed by our group intends to establish the long-term safety and outcomes of the use of recurrent IACIs using linkage of large datasets (Clinical Practice Research Datalink (CPRD) with linkage to Hospital Episode Statistics (HES) and National Patient-Reported Outcomes Measures (PROMs)), as well as establishing the views and experiences of patients and clinicians
      National Institute for Health Research (NIHR)
      Funding and Awards: RecUrrent Intra-articular Corticosteroid Injections in Osteoarthritis; the RUbICOn Study.
      ,
      University of Bristol (UoB)
      RecUrrent Intra-articular Corticosteroid Injections in Osteoarthritis; the RUbICOn Study.
      . This may provide further insight on the longer-term effects of recurrent IACIs, and help to inform existing guidelines and future research.

      Limitations

      There were numerous limitations to this meta-analysis. First, the number of patients in the intervention and comparator groups were generally small, with seven of the ten included RCTs having fewer than 50 patients in each treatment arm. Second, seven of the ten included studies were single-blinded (mostly blinding of the observer but not the patient), thus increasing the risk of bias. Third, as Table I demonstrates, there was heterogeneity concerning the medicines injected, their doses, their frequency, and the duration of follow-up, hence the results should be interpreted with caution. Fourth, no study attempted to detail the minimal clinically important difference (MCID) for outcome measures, i.e., the smallest difference in the score that patients perceive as beneficial, since the MCID and statistical significance do not always correlate. Finally, it should also be noted that one study
      • Gammer W.
      • Broback L.G.
      Clinical comparison of orgotein and methylprednisolone acetate in the treatment of osteoarthrosis of the knee joint.
      dates back to 1984 and the quality of research processes has drastically improved since then. Three studies
      • McAlindon T.E.
      • LaValley M.P.
      • Harvey W.F.
      • Price L.L.
      • Driban J.B.
      • Zhang M.
      • et al.
      Effect of intra-articular triamcinolone vs saline on knee cartilage volume and pain in patients with knee osteoarthritis: a randomized clinical trial.
      ,
      • Nabi B.N.
      • Sedighinejad A.
      • Mardani-Kivi M.
      • Haghighi M.
      • Roushan Z.A.
      • Tehran S.G.
      • et al.
      Comparing the effectiveness of intra-articular platelet-rich plasma and corticosteroid injection under ultrasound guidance on pain control of knee osteoarthritis.
      ,
      • Raynauld J.P.
      • Buckland-Wright C.
      • Ward R.
      • Choquette D.
      • Haraoui B.
      • Martel-Pelletier J.
      • et al.
      Safety and efficacy of long-term intraarticular steroid injections in osteoarthritis of the knee: a randomized, double-blind, placebo-controlled trial.
      received local/national funding; the remaining studies declared no conflicts of interest.

      Conclusion

      This study demonstrates that recurrent IACIs often provide inferior (or non-superior) symptom relief compared with other injectables (including placebo). Whilst mild improvements in pain, function and QoL were noted after recurrent IACIs up to 3–24 months post-injection compared to baseline symptoms, other injectables (HA and PRP) often yielded greater improvements. Recurrent IACIs did not outperform placebo (saline) for pain and function at 12- and 24-months. Existing RCTs on recurrent IACIs lack sufficient follow-up data to assess disease progression and time-to-future intervention. Future research should seek to identify whether recurrent IACIs pose significant long-term harms.

      Conflict of interest statement

      All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: support from NIHR Biomedical Research Centre at University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol for the submitted work. AJ, AWB and MRW disclose financial activities, outside the remit of the submitted work (AJ: personal fees; AWB: research grants; MRW: research grants, lecturing, textbook royalties); no other relationships or activities that could appear to have influenced the submitted work.

      Acknowledgements

      This study is funded by the National Institute for Health Research (NIHR) [Health Technology Assessment (Grant reference number NIHR129011)]. The study was also supported by the NIHR Biomedical Research Centre at the University Hospitals Bristol and Weston NHS Foundation Trust and the University of Bristol. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. The funders had no role in considering the study design or in the collection, analysis, and interpretation of data, the writing of the report, or the decision to submit the article for publication.

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