Seminars in and Rheumatism 43 (2014) 570–576

Contents lists available at ScienceDirect

Seminars in Arthritis and Rheumatism

journal homepage: www.elsevier.com/locate/semarthrit

The risks and benefits of treatment for : A systematic review of the effects of local glucocorticoid on tendon

Benjamin John Floyd Dean, MRCSn, Emilie Lostis, BSc, Thomas Oakley, BM, BSc, Ines Rombach, MSc, Mark E. Morrey, MD, Andrew J. Carr, FRCS

Nuffield Department of Orthopaedics, and Musculoskeletal Sciences (NDORMS), Botnar Research Centre, Institute of Musculoskeletal Sciences, Nuffield Orthopaedic Centre, Windmill Rd, Oxford OX3 7LD, UK article info abstract

Objective: Our primary objective was to summarise the known effects of locally administered gluco- corticoid on tendon tissue and tendon cells. Keywords: fi Glucocorticoid Methods: We conducted a systematic review of the scienti c literature using the PRISMA and Cochrane fi Tendon guidelines of the Medline database using speci c search criteria. The search yielded 50 articles, which Tenocyte consisted of 13 human studies, 36 animal studies and one combined human/animal study. Steroid Results: Histologically, there was a loss of collagen organisation (6 studies) and an increase in collagen Fibroblast necrosis (3 studies). The proliferation (8 studies) and viability (9 studies) of fibroblasts was reduced. Collagen synthesis was decreased in 17 studies. An increased inflammatory cell infiltrate was shown in 4 studies. Increased cellular toxicity was demonstrated by 3 studies. The mechanical properties of tendon were investigated by 18 studies. Descriptively, 6 of these studies showed a decrease in mechanical properties, 3 showed an increase, while the remaining 9 showed no significant change. A meta-analysis of the mechanical data revealed a significant deterioration in mechanical properties, with an overall effect size of 0.67 (95% CI ¼ 0.01 to 1.33) (data from 9 studies). Conclusions: Overall it is clear that the local administration of glucocorticoid has significant negative effects on tendon cells in vitro, including reduced cell viability, cell proliferation and collagen synthesis. There is increased collagen disorganisation and necrosis as shown by in vivo studies. The mechanical properties of tendon are also significantly reduced. This review supports the emerging clinical evidence that shows significant long-term harms to tendon tissue and cells associated with glucocorticoid injections. & 2014 Elsevier Inc. All rights reserved.

Introduction cortex, their structure and biological effects.” The use of glucocorti- coid in the treatment of painful musculoskeletal disease has since In September 1948 at the Mayo clinic, cortisone was injected proliferated to the point that now in the UK over 500,000 intra- into a patient for the first time in the treatment of rheumatoid articular glucocorticoid injections (GCIs) are administered per year arthritis to dramatic effect [1]. The 1950 Nobel Prize in Physiology in the primary care setting [2]. GCIs are used to relieve and/or or Medicine was awarded jointly to Edward Calvin Kendall, Tadeus inflammation in a wide variety of musculoskeletal disorders Reichstein and Philip Showalter Hench directly relating to this including , inflammatory arthritis, , ten- work “for their discoveries relating to the hormones of the adrenal dinopathy and degenerative spine disease. The evidence regarding the clinical efficacy of GCIs is conflicting but broadly shows some short-term benefits in terms of pain relief [3–6]. For example, in The authors of this work are funded by the Musculoskeletal Biomedical the treatment of shoulder pain, trials have shown only short-term Research Unit of the National Institute for Health Research (B.D., M.M., E.L., T.O. benefits with no significant long-term gains [6–8]. Emerging high- and A.C.), the Jean Shanks Foundation (B.D.) and Orthopaedic Research UK (B.D.). The funding sources had no role in the study design, collection, analysis and quality evidence also points to poorer long-term outcomes asso- interpretation of data; in the writing of the article; and in the decision to submit ciated with GCIs in the treatment of tendinopathy [9]. the manuscript for publication. GCIs are frequently applied in close proximity to tendons with n Corresponding author at: Nuffield Department of Orthopaedics, Rheumatology common examples including the rotator cuff, the flexor and and Musculoskeletal Sciences (NDORMS), Botnar Research Centre, Institute of fi extensor tendon origins around the elbow, the gluteus medius, Musculoskeletal Sciences, Nuf eld Orthopaedic Centre, Windmill Rd, Oxford OX3 fl 7LD, UK. the Achilles and the patellar tendons, the exor tendons in the E-mail address: [email protected] (B.J.F. Dean). hand (i.e., trigger finger) and the extensor tendons around the

0049-0172/$ - see front matter & 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.semarthrit.2013.08.006 B.J.F. Dean et al. / Seminars in Arthritis and Rheumatism 43 (2014) 570–576 571 wrist (i.e., De Quervain's tenosynovitis). It has been recurrently The search, selection of studies and data analysis were per- postulated that there is an increased risk of tendon rupture formed independently by 2 individuals (T.O. and BD for the articles associated with GCI [10] but no high-quality evidence exists to on humans and E.L. and B.D. for the articles on animals). Agree- adequately confirm or refute this hypothesis [11,12]. It is important ment on inclusion was achieved after review of the full-text to remember that GCI is often used in the context of an abnormal articles and a decision by both individuals based on the diseased tendon in which the risk of rupture is already increased. inclusion/exclusion criteria. The data were then extracted using a However, there is strong evidence that oral corticosteroids are spreadsheet designed by 2 authors (B.D. and E.L.), this included associated with a higher risk of tendon rupture [13], and an data relating to study heterogeneity and methodological quality. increased spinal fracture risk associated with epidural GCIs has The data extracted included study subject characteristics, gluco- also recently been reported [14]. The mechanisms of action of corticoid used, source of cultured cells and cells used method of are multiple, highly complex and incompletely tissue analysis, control group, results and statistical methods. understood [15,16]. One important pathway involves the activa- Methodological quality was assessed using an 8-point scoring tion of specific cytoplasmic glucocorticoid receptors, which then system (Appendix 2) based on the method used by Hegedus migrate to the cell nucleus to affect gene transcription. Generally, et al. [27]. glucocorticoids are thought to be anti-inflammatory, but the reality may not be so simple [17]. Study selection The tendon changes that occur in painful human tendinopathy are generally considered to be consistent with a failed healing The search strategy yielded 4424 results (Fig. 1). After the response [18,19]. Normal tendon healing occurs with sequential exclusion of duplicates and review articles, there were 1996 inflammatory, proliferative and remodelling phases [20]. Fibro- articles. Screening the articles revealed 40 articles on humans blast proliferation, angiogenesis and nerve ingrowth are all and 38 articles on animals that met the criteria based on their important in the healing process [21,22]. Tendinopathy is charac- abstracts. Further assessment of eligibility, based on full-text terised by abnormal tenocyte morphology and disorganised colla- articles, led to the exclusion of 28 of these 78 papers. The reasons gen architecture [19]. Although the presence of inflammation in for the exclusion of these 28 papers were as follows: no control tendinopathy has been proposed by some authors [23], few studies group [6], reviews [12], systemic glucocorticoid therapy [6] and have shown the presence of a “classical” inflammatory process not related to tendon [4]. This left 50 articles meeting our inclusion involving the inward migration of inflammatory cells driven by criteria, and they are summarised in Appendix 3. inflammatory mediators [24]. Therefore, the logic of using GCIs in the treatment of a tendinopathy is not convincing. Study characteristics In this context, the purpose of this review was to determine the effects of local GCI on both tendon tissue and tendon cells. We Of the 50 included articles, 36 related to animal studies, 13 to aimed to describe and summarise the histological, molecular and human studies and 1 to a study that was on both animals and mechanical changes. humans. Of the 36 animal studies, 25 were in vivo and 11 in vitro; while of the 13 human studies, 12 were in vitro,1wasin vivo, and 1 study was both in vivo and in vitro. The 1 combined human Methods and animal study was in vitro. The most common animal used was rat (19 studies), followed by rabbit (9 studies), chick embryo Search strategies (5 studies), dog (2 studies), cow (1 study) and multiple animals (1 study). The 25 in vivo animal studies used Achilles tendon This systematic review used the PRISMA-Statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and Flow chart of systemac review protocol the Cochrane handbook as guidelines in the development of the study protocol and the report of the current study [25,26]. The Papers idenfied through database searching inclusion criteria and methods of analysis were specified in (n=4424) advance and documented in a protocol. Studies were identified using the Medline electronic database. Aer removal of duplicates and review papers (n=1996) No limit was placed on the year of data entry, but in practice, there Idenficaon were no results prior to 1956. The search was undertaken in June 2013. The following search terms were used: steroid OR cortico- Screening of paper abstracts steroid OR glucocorticoid AND tendon OR rotator cuff OR Achilles OR tendinn OR tenocyte.

Additional studies were located by searching papers referenced Screening Human papers pre Animal papers pre in listed articles. The studies identified by the searches were analysis (n=40) analysis (n=38) combined, and duplicates were excluded. The abstracts were initially screened before analysis of the selected full-text articles. Full inclusion/exclusion criteria are detailed in Appendix 1. Studies Review of full text and applicaon of had to relate to the use of local glucocorticoid on tendon tissue or Analysis exclusion criteria tendon cells. Review articles and case studies were excluded. Papers pertaining to steroids other than glucocorticoids, such as anabolic steroids, were excluded. Those articles addressing steroid use other than for a peri-tendinous or tendinous injection, such as Human papers Combined Animal papers included animal and included intra-articular steroid injection, were excluded. Studies using Included (n=13) human papers (n=36) systemic steroid as opposed to injected corticosteroid were included excluded. Any study without results relating to histological, (n=1) cellular, molecular or mechanical tissue changes was excluded. If a study could not be obtained in English, it was excluded. Fig. 1. Flow chart of systematic review protocol. 572 B.J.F. Dean et al. / Seminars in Arthritis and Rheumatism 43 (2014) 570–576

(11 studies), shoulder tendon (5 studies), forearm tendon (3 Table 1 studies), peroneal tendon (2 studies), tail tendon (2 studies), Histological changes patellar tendon (1 study) and both Achilles and patellar tendon Human studies Animal studies (1 study). The human in vivo study used Achilles tendon, while the combined human in vivo/vitro study used shoulder tendon for its General cell Viability ↓ [44–51,90] Proliferation ↓ [54,55] in vivo component. characteristics Proliferation Of the 14 human studies, the glucocorticoid/s used were ↓ [45,48–50,52,53] Collagen Collagen necrosis ↑a [56] Collagen necrosis ↑ [57] ↑a[58] dexamethasone alone (6 studies), triamcinolone (3 studies), dex- morphology Collagen organisation ↓a Collagen organisation amethasone and triamcinolone (2 studies), dexamethasone and [56] ↓[29,57,59,60] ↓a [40]→[89] methylprednisolone (1 study) and hydrocortisone (1 study). Of the Cellular Inflammatory cells ↑a [56] 36 animal studies, the glucocorticoid/s used were hydrocortisone migration Inflammatory cells ↑[57,59] ↑a (9 studies), dexamethasone (8 studies), methylprednisolone [58] Fibroblast migration ↓ [52] Fibroblast migration (7 studies), betamethasone (6 studies), triamcinolone (4 studies), ↑ [60] ↓ [61] methylprednisolone and betamethasone (1 study) and predniso- Cellular toxicity ↑ [47,48] ↑a [49] ↑a [49]→[88] lone (1 study). The animal and human study used triamcinolone. Adhesions and Altered collagen Adhesions ↑ [62,63] ↓ [64] others birefringencea [56] Adipocyte clustering Study methodology and assessing the risk of bias around steroid [52] Non tenocyte All included studies stated described their study group and differentiation of hTSCs control groups and clearly described method/s of tissue analysis. [53]

The results of the methodological quality assessment are detailed in a Denotes that study did not state statistical significance of result. Appendix 3. The median score of the human studies was 8 (range 5–8). The median score of the animal studies was 6 (range 4–8). Of the 50 studies, 40 produced quantitative and/or semi- increase in collagen necrosis (3 studies). The proliferation quantitative results with a stated statistical significant at p o 0.05. (8 studies) and viability (9 studies) of fibroblasts was reduced. Of the 10 studies that did not state statistical significance, 3 were An increased inflammatory cell infiltrate was shown in 4 studies. descriptive histological studies (1 human in vivo and 2 animal in vivo), Increased cellular toxicity was demonstrated by 3 studies. Results 2werequantitativemechanicalanddescriptivehistologicalstudies regarding fibroblast migration and adhesions were conflicting. (both animal in vivo) and the remaining 5 used solely quantitative Collagen synthesis was decreased in 17 studies. An increased ratio assays (all animal in vitro with 1 also involving human in vitro). of type 3 to type 1 collagen was shown in 2 studies. Apoptosis was Studies that did not have control groups for comparison were unaffected in 3 studies and increased in 3 studies. Small numbers excluded. Studies that used descriptive non-quantitative methods of studies had demonstrated changes in matrix enzymes (MMPs/ only and/or studies that did not state the statistical significance of TIMPs), proteoglycans, cytokines and other substances including their results were included in results; these results were clearly FOX-01 and Sirtuin-1. marked with “a”. This methodological assessment means that the Eighteen studies investigated the mechanical properties of results have not included studies with a large degree of bias, and tendon (Table 3). Descriptively, 6 of these studies showed a that those with higher degrees of potential bias have been high- decrease in mechanical properties, 3 showed an increase, while lighted to readers. the remaining 9 showed no significant change. Nine studies The study heterogeneity precluded a meta-analysis of the provided adequate in vivo data from which to calculate the effect histological and molecular results. However the studies relating size with upper and lower 95% confidence intervals. Three studies to mechanical properties were systematically analysed to obtain contributed more than 1 data set as they had obtained results for data sets for a meta-analysis. Nine of the 17 studies provided more than 1 group of GCI-treated animals; Mikolyzk et al. [29] adequate data from which the effect size with 95% upper and analysed 3 groups of animal at different time points; Oxlund et al. lower confidence intervals could be calculated. The data set [30] analysed the effects on 2 different tendons and Plotkin et al. extracted from each study was based upon which property of [31] analysed the effects of 2 different GCI dose. Figure 2 mechanical strength (i.e., yield stress, yield energy and modulus of stiffness) was quoted as the study's main finding in its abstract. More than 1 data set was included per study if each data set Table 2 related to a distinct experimental subgroup. Molecular changes

Human studies Animal studies Statistics Collagen synthesis ↓ [45,47–50,52,53,65] ↓ [55,66–68] a All statistics and the forest plot [28] were carried out using ↓ [69–73] TM Collagen ratio type III–I ↑ [74,75] Microsoft Excel 2007 (Microsoft Corporation, Redmond, WA). Apoptosis ↑ [47,51,90] Where appropriate, data were combined using meta-analytical - [45–47] methods. Meta-analyses and Forest Plots were performed in Stata MMPs/TIMPs ↑ TIMP [52] MMP2/9 - [75] version 12 (Stata, College Station, TX). Random effects meta- ↓MMP 2/8/9/13 [52] TIMP1/2 - [75] ↓β analysis was performed to account for the heterogeneity between -Integrin production [47] ↑ MMP 1/13 [47] studies. Cytokines and others ↑ SDF-1 [65] ↑ Aggrecan [75] ↑ ROS [48] ↑ Fibronectin [75] ↑ FOX-01 [48] ↓ TNFα [75] Results ↓ Proteoglycan [76] ↑ PPAR-γ and SOX-9 [53] ↑ Senescence [46,77] There were significant histological and molecular changes after ↓ Sirtuin-1 [77] local glucocorticoid administration (Tables 1 and 2). Histologically, there was a loss of collagen organisation (6 studies) and an a Denotes that study did not state statistical significance of result. B.J.F. Dean et al. / Seminars in Arthritis and Rheumatism 43 (2014) 570–576 573

Table 3 Mechanical changes

References Descriptive changes Overall effect on mechanical properties

Martins et al. [78] No difference in maximum failure load or absorbed energy - Haraldsson et al. [79,87] Reduction in tensile fascicle yield strength and Young's modulus; ↓ unaffected strain properties, peak stress and fascicle diameter Mikolyzk et al. [29] Reduced mechanical properties in steroid groups at 1 week ↓ Shapiro et al. [62] Increased energy and load to failure, but no difference in material stiffness or strain ↑ Hugate et al. [80] Decreased failure stress and total energy absorbed; increased total strain ↓ Martin et al. [81] No difference in elastic modulus, ultimate load and ultimate stress - McWhorter et al. [82] No difference in mean separation forces - Kapetanos [64] Reduced failure load and energy to failure, unchanged strain to failure ↓ Oxlund [66] No difference in yield load and yield stress - Oxlund [30] Increased maximum stress for peroneus brevis; increased elastic stiffness and ↑ maximum load for peroneus longus Kennedy and Willis [40] Initial reduction in failure load; no difference in failure load after 2 weeks ↓a Plotkin et al. [31] No difference in yield load, relative yield load and stiffness - Mackie et al. [83] No difference in yield load, stiffness or strain - Matthews et al. [84] No difference in failure load, stiffness or failure site - Unverferth and Olix [60] Decreased modulus of elastic stiffness ↓ Ketchum [85] Increased tensile strength ↑ Gonzalez [86] No difference in tensile strength -a

a Denotes that study did not state statistical significance of result. represents this forest plot. The overall effect size was 0.67 (95% postulated [33–36]. The histological and molecular changes in confidence interval 0.01 to 1.33, p ¼ 0.046), demonstrating tendinopathy are undoubtedly consistent with mechanical tendon that in these 9 studies there was a clear trend towards reduced failure and a persistent failed healing response [18,19,37]. The mechanical properties in tendon after glucocorticoid injection. inflammatory element of tendinopathy appears more consistent with a failing attempt to heal than a classical “inflammatory response” involving an inward migration of inflammatory cells. Discussion This apparent attempt at healing involving an inflammatory component appears to be more likely present in early tendinop- Overall the results are broadly negative, both in terms of the athy [38] and decreasingly present as disease progresses, as effects on several specific cellular characteristics and on the tendon becomes progressively hypoxic and abnormal [39]. In this mechanical properties of tendon. While some studies have shown context, the consistent negative findings summarised in this short-term pain relief, these results provide plausible mechanisms review, both in terms of the changes to the cellular and tendon by which glucocorticoid treatment may result in adverse patient properties, should be of great cause for concern. outcomes in the treatment of degenerative tendinopathy partic- Overall glucocorticoid appears to have a negative effect on ularly in the long term [9]. tendon homoeostasis with increased collagen disorganisation and The cause of tendinopathy has been the subject of much heated collagen necrosis seen after treatment. Indeed it may be hypoth- debate over the years, [32] and many different theories have been esised that the increased number of inflammatory cells present may

Author Measure SMD (95% CI)

Haraldsson 2009 yield stress -2.38 (-3.44, -1.31) Kapetanos 1982 yield load -1.41 (-2.40, -0.42) Martin 1999 yield stress -0.46 (-1.39, 0.48) Martins 2011 yield load -1.00 (-1.76, -0.24) Matthews 1974 yield load -0.39 (-1.01, 0.23) Mikolyzk 2009 yield load (timepoint 1) -12.73 (-16.76, -8.70) Mikolyzk 2009 yield load (timepoint 3) 0.00 (-0.86, 0.86) Mikolyzk 2009 yield load (timepoint 5) -1.67 (-2.70, -0.63) Oxlund 1980 yield load (peroneus brevis) 3.52 (1.82, 5.22) Oxlund 1980 yield load (peroneus longus) 1.76 (0.45, 3.08) Plotkin 1976 yield load (high dose) -0.17 (-0.58, 0.24) Plotkin 1976 yield load (low dose) -0.44 (-0.86, -0.02) Unverfeth 1973 modulus of stiffness -1.18 (-2.55, 0.19) Overall (I-squared = 87.3%, p = 0.000) -0.67 (-1.33, -0.01)

NOTE: Weights are from random effects analysis

-16.8 0 16.8 Mechanical properties reduced Mechanical properties increased

Fig. 2. Forest plot of studies analysing effects of glucocorticoid on the mechanical properties of tendon (X axis—effect size (standardised mean difference) and Y axis—studies included). 574 B.J.F. Dean et al. / Seminars in Arthritis and Rheumatism 43 (2014) 570–576 be the result of a reparative response to the glucocorticoid-induced observers undertaking the semi-quantitative tissue grading does tendon damage. This explanation is consistent with the result of the increase the risk of study bias towards positive findings. The mechanical studies that show a short-term deterioration in the measurement of multiple mechanical characteristics of tendon, mechanical properties [29,40] which then recovers in the longer and the absence of defining a primary study outcome, combined to term as a result of the healing response to the glucocorticoid- result in some likely bias in terms of obtaining false-positive induced damage. The mechanisms for such changes in tendon are results. unclear with the classical description of glucocorticoid as an “anti- inflammatory” agent appearing to be an over simplification [17]. Glucocorticoid-induced senescence is one mechanism by which Conclusions long-term degenerative changes in tendon tissue may be worsened. The glucocorticoid reduction in collagen synthesis is another Overall it is clear that the local administration of glucocorticoid important mechanism by which altered homoeostasis may lead to has significant negative effects on tendon cells in vitro, including deterioration in the mechanical properties of tendon, thus poten- reduced cell viability, cell proliferation and collagen synthesis. tially increasing levels of future degeneration. There is increased collagen disorganisation and necrosis as shown It is worth noting that there is still a clear role for GCI in the by in vivo studies. The mechanical properties of tendon are also treatment of tendinopathy, but that it is vital to consider the significantly reduced. This review supports the emerging clinical potential negative effects highlighted by this review when making evidence that shows significant long-term harms to tendon tissue one's clinical decision on a case-by-case basis. Given the huge and cells associated with glucocorticoid injections. variability in terms of both patient characteristics and the patho- geneses of the different , it is beyond the scope of this review to give prescriptive management advice to clinicians regarding the use of GCIs. Certainly the repeated use of GCIs in Appendix 1 younger patients with an “overuse” type of tendinopathy appears unwise and potentially harmful, given the negative effects of See below for Table A1. glucocorticoid on the tendon healing. However, the use of GCIs for short-term clinical gains in older patients with degenerate Table A1 tendons who are not suitable surgical candidates still appears a Full inclusion and exclusion criteria very appropriate treatment strategy. While the judicious use of Inclusion Exclusion GCIs for specific conditions such as trigger finger and De Quer- vain's tenosynovitis, in which the anti-proliferative and anti- Studies must relate to tendon tissue or tendon No control group inflammatory effects are of definite therapeutic benefit, is still a cells following the local administration of steroid very effective and justifiable treatment strategy [41,42]. The use of Steroid is defined as glucocorticoid Case reports, case radiologically guided injections is becoming more commonplace series and review and evidence suggests that they are significantly more accurate articles than “blind” injections [43]. Whether this increased accuracy Animal and human tendon cells or tendon Systemic and not translates into reduced complication rates and better clinical tissue local steroid administration outcomes is something that needs to be determined by future In vivo and in vitro studies Studies relating to research. anabolic steroid Glucocorticoid Limitations of this review treatment alone Fibroblasts not derived from The results and generalisable meaning of this review are both tendon limited by the quality and heterogeneity of the included studies. Not available in the There was significant study heterogeneity in terms of study type English language (animal/human or in vivo/vitro), the anatomical source of tendon/ tendon cells, glucocorticoid used, dose of glucocorticoid, mode of Appendix 2 tissue analysis, time points and control type. It is particularly important to appreciate that several assumptions have been made See below for Table A2. in carrying out the meta-analysis of the mechanical studies. One had to assume that the extracted data was accurate (means and standard deviations) and that their underlying distributions were normal. As a result, some caution should be exercised when Table A2 interpreting the results of the meta-analysis. Methodological quality assessment document (the number of “yes” answers was For the purposes of this review, we have asked a specific but counted for each study to give a total score out of 8) general research question and included only studies that met Number Criteria Yes/No/Unclear criteria specific to this. However, our objective was to synthesise the overall research findings in this broad area and a degree of 1 Study population clearly described (animals/humans) study heterogeneity had to be accepted in order to achieve this. 2 Control group clearly described ' The degree to which this review s results are generalisable to 3 Sampling method clearly described human patients is certainly open to debate. In vitro findings often 4 Steroid clearly described (name/dose) conflict with in vivo findings; however, our review's key findings 5 Quantitative method or semi-quantitative appear broadly consistent between the different study types. method using minimum of 2 independent observers The degree to which the results of the studies were descriptive, 6 Validity and/or reliability of methods semi-quantitative or quantitative was highly variable. As a result, it described has been made clear when results have not been shown to be 7 Statistical significance stated for results statistically significant (Tables 1–3). The variable blinding of the 8 Study limitations mentioned B.J.F. Dean et al. / Seminars in Arthritis and Rheumatism 43 (2014) 570–576 575

Appendix 3 [6] Coombes BK, Bisset L, Vicenzino B. Efficacy and safety of corticosteroid injec- tions and other injections for management of tendinopathy: a systematic review of randomised controlled trials. Lancet 2010;376:1751–67 [Epub 2010/ See below for Table A3. 10/26]. [7] Buchbinder R, Green S, Youd JM. Corticosteroid injections for shoulder pain. Cochrane Database Syst Rev 2003 [CD004016, Epub 2003/01/22]. [8] Scott A, Docking S, Vicenzino B, Alfredson H, Zwerver J, Lundgreen K, et al. Table A3 Sports and exercise-related tendinopathies: a review of selected topical issues Summary of included studies and methodological scores by participants of the second International Scientific Tendinopathy Sympo- sium (ISTS) Vancouver 2012. Br J Sports Med 2013;47:536–44 [Epub 2013/04/ References Human/ Study type Methdological 16]. animal score [9] Coombes BK, Bisset L, Brooks P, Khan A, Vicenzino B. Effect of corticosteroid injection, physiotherapy, or both on clinical outcomes in patients with uni- Akpinar et al. [59] Animal In vivo 6 lateral lateral epicondylalgia: a randomized controlled trial. J Am Med Assoc Balasubramaniam and Prathap Animal In vivo 3 2013;309:461–9 [Epub 2013/02/07]. [58] [10] Mahler F, Fritschy D. Partial and complete ruptures of the Achilles tendon and Buck and Wilhelm [73] Animal In vivo 3 local corticosteroid injections. Br J Sports Med 1992;26:7–14 [Epub 1992/03/ Dombi and Halsall [68] Animal In vitro 4 01]. Gonzalez [86] Animal In vivo 4 [11] Shrier I, Matheson GO, Kohl HW 3rd. Achilles tendonitis: are corticosteroid Haraldsson et al. [79] Animal In vivo 8 injections useful or harmful? Clin J Sport Med 1996;6:245–50 [Epub 1996/10/ Haraldsson et al. [87] Animal In vitro 7 01]. Hugate et al. [80] Animal In vivo 6 [12] Maffulli N, Wong J. Rupture of the Achilles and patellar tendons. Clin Sports – Kapetanos [64] Animal In vivo 6 Med 2003;22:761 76 [Epub 2003/10/17]. [13] van der Linden PD, Sturkenboom MC, Herings RM, Leufkens HM, Rowlands S, Kempka et al. [49] Human/ In vitro 7 Stricker BH. Increased risk of achilles tendon rupture with quinolone anti- animal bacterial use, especially in elderly patients taking oral corticosteroids. Arch Kennedy and Willis [40] Animal In vivo 4 Intern Med 2003;163:1801–7 [Epub 2003/08/13]. Ketchum [85] Animal In vivo 7 [14] Mandel S, Schilling J, Peterson E, Rao DS, Sanders W. A retrospective analysis Kim et al. [65] Human in vitro 8 of vertebral body fractures following epidural steroid injections. J Bone Joint Koeke et al. [89] Animal In vivo 8 Surg 2013;95:961–4. Lee et al. [75] Animal In vivo 8 [15] Barnes PJ. Corticosteroid effects on cell signalling. Eur Respir J 2006;27:413–26 Lee and Ling [56] Human In vivo 5 [Epub 2006/02/03]. Mackie et al. [83] Animal In vivo 8 [16] Payne DN, Adcock IM. Molecular mechanisms of corticosteroid actions. Martin et al. [81] Animal In vivo 8 Paediatr Respir Rev 2001;2:145–50 [Epub 2003/01/18]. Martins et al. [78] Animal In vivo 8 [17] Lannan EA, Galliher-Beckley AJ, Scoltock AB, Cidlowski JA. Proinflammatory Matthews et al. [84] Animal In vivo 6 actions of glucocorticoids: glucocorticoids and TNFalpha coregulate gene – McWhorter et al. [82] Animal In vivo 7 expression in vitro and in vivo. Endocrinology 2012;153:3701 12 [Epub Mikolyzk et al. [29] Animal In vivo 8 2012/06/08]. [18] Dean BJ, Franklin SL, Carr AJ. The peripheral neuronal phenotype is important Muto et al. [90] Human In vitro 8 in the pathogenesis of painful human tendinopathy: a systematic review. Bone Oikarinen [69] Animal In vitro 5 Joint Res 2012;1:158–66 [Epub 2013/04/24]. Oikarinen [70] Animal In vitro 5 [19] Dean BJF, Franklin SL, Carr AJ. A systematic review of the histological and Oikarinen et al. [71] Animal In vitro 5 molecular changes in rotator cuff disease. BoneJoint Res 2012;1:158–66. Oikarinen et al. [67] Animal In vitro 6 [20] Sharma P, Maffulli N. Biology of tendon injury: healing, modeling and Oikarinen [72] Animal In vitro 4 remodeling. J Musculoskelet Neuronal Interact 2006;6:181–90 [Epub 2006/ Oxlund [30] Animal In vivo 8 07/20]. Oxlund [66] Animal In vivo 7 [21] Ackermann PW, Li J, Lundeberg T, Kreicbergs A. Neuronal plasticity in relation Piper et al. [88] Animal In vitro 7 to nociception and healing of rat achilles tendon. J Orthop Res 2003;21: Plotkin et al. [31] Animal In vivo 7 432–41 [Epub 2003/04/23]. Poulsen et al. [48] Human In vitro 8 [22] Sharma P, Maffulli N. Tendon injury and tendinopathy: healing and repair. – Poulsen et al. [77] Human In vivo/ 8 J Bone Joint Surg Am 2005;87:187 202 [Epub 2005/01/07]. — fl in vitro [23] ReesJD,StrideM,ScottA.Tendons time to revisit in ammation. Br J Scutt et al. [55] Animal In vitro 7 Sports Med 2013, http://www.ncbi.nlm.nih.gov/pubmed/23476034 [Epub 2013/03/12]. Sendzik et al.[47] Human In vitro 8 [24] Alfredson H, Lorentzon R. Chronic tendon pain: no signs of chemical inflam- Shapiro et al. [62] Animal In vivo 5 mation but high concentrations of the neurotransmitter glutamate. Implica- Tatari et al. [63] Animal In vivo 4 tions for treatment? Current Drug Targets 2002;3:43–54 [Epub 2002/03/20]. Tempfer et al. [52] Human In vitro 8 [25] Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gotzsche PC, Ioannidis JP, et al. The Tillander et al. [57] Animal In vivo 5 PRISMA statement for reporting systematic reviews and meta-analyses of Tsai et al. [54] Animal In vitro 5 studies that evaluate healthcare interventions: explanation and elaboration. Tsai et al. [61] Animal In vitro 5 Br Med J 2009;339:b2700 [Epub 2009/07/23]. Unverferth and Olix [60] Animal In vivo 5 [26] Cochrane Handbook for Systematic Reviews of Interventions. 〈http://www. Wei et al. [74] Animal In vivo 6 cochraneorg/training/cochrane-handbook〉;2012. Wong et al. [44] Human In vitro 7 [27] Hegedus EJ, Cook C, Brennan M, Wyland D, Garrison JC, Driesner D. Vascularity Wong et al. [50] Human In vitro 7 and tendon pathology in the rotator cuff: a review of literature and implica- – Wong et al. [76] Human In vitro 8 tions for rehabilitation and surgery. Br J Sports Med 2010;44:838 47 [Epub Wong et al. [45] Human In vitro 8 2009/03/19]. Zargar Baboldashti et al. [46] Human In vitro 8 [28] Neyeloff JL, Fuchs SC, Moreira LB. Meta-analyses and Forest plots using a microsoft excel spreadsheet: step-by-step guide focusing on descriptive data Zhang et al. [53] Human In vitro 8 analysis. BMC Res Notes 2012;5:52 [Epub 2012/01/24]. [29] Mikolyzk DK, Wei AS, Tonino P, Marra G, Williams DA, Himes RD, et al. Effect of corticosteroids on the biomechanical strength of rat rotator cuff tendon. References J Bone Joint Surg Am 2009;91:1172–80. [30] Oxlund H. The influence of a local injection of cortisol on the mechanical properties of tendons and ligaments and the indirect effect on skin. Acta [1] Glyn J. The discovery and early use of cortisone. J R Soc Med 1998;91:513–7 Orthop Scand 1980;51:231–8. [Epub 1999/03/10]. [31] Plotkin MB, Foss ML, Goldin B, Ellis DG. Dose-response effects of anti- [2] Authority NBS. Electronic Prescribing & Financial Information for Practices inflammatory steroid injections on mechanical properties of rat tail tendons. (ePFIP), http://wwwnhsbsanhsuk/PrescriptionServices/963aspx; 2009. Med Sci Sports 1976;8:230–4. [3] Arroll B, Goodyear-Smith F. Corticosteroid injections for osteoarthritis of the [32] Lewis JS. Rotator cuff tendinopathy. Br J Sports Med 2009;43:236–41 [Epub knee: meta-analysis. Br Med J 2004;328:869. 2008/09/20]. [4] Arroll B, Goodyear-Smith F. Corticosteroid injections for painful shoulder: a [33] Neer CS 2nd. Impingement lesions. Clin Orthop Relat Res 1983:70–7 [Epub meta-analysis. Br J Gen Prac 2005;55:224–8 [Epub 2005/04/06]. 1983/03/01]. [5] Staal JB, de Bie R, de Vet HC, Hildebrandt J, Nelemans P. Injection therapy for [34] Fredberg U, Stengaard-Pedersen K. Chronic tendinopathy tissue pathology, subacute and chronic low-. Cochrane Database Syst Rev 2008 pain mechanisms, and etiology with a special focus on inflammation. Scand J [CD001824, Epub 2008/07/23]. Med Sci Sports 2008;18:3–15 [Epub 2008/02/26]. 576 B.J.F. Dean et al. / Seminars in Arthritis and Rheumatism 43 (2014) 570–576

[35] Seitz AL, McClure PW, Finucane S, Boardman ND III, Michener LA. Mechanisms [64] Kapetanos G. The effect of the local corticosteroids on the healing and of rotator cuff tendinopathy: intrinsic, extrinsic, or both? Clin Biomech biomechanical properties of the partially injured tendon. Clinical Orthop Relat 2011;26:1–12. Res 1982;163:170–9 [Epub 1982/03/01]. [36] Xu Y, Murrell GA. The basic science of tendinopathy. Clin Orthop Relat Res [65] Kim YS, Bigliani LU, Fujisawa M, Murakami K, Chang SS, Lee HJ, et al. Stromal 2008;466:1528–38 [Epub 2008/05/15]. cell-derived factor 1 (SDF-1, CXCL12) is increased in subacromial [37] Riley G. The pathogenesis of tendinopathy. A molecular perspective. Rheu- and downregulated by steroid and nonsteroidal anti-inflammatory agents. – matology (Oxford) 2004;43:131 42 [Epub 2003/07/18]. J Orthop Res 2006;24:1756–64. fl [38] Millar NL, Hueber AJ, Reilly JH, Xu Y, Fazzi UG, Murrell GA, et al. In ammation [66] Oxlund H. Long term local cortisol treatment of tendons and the indirect effect on – is present in early human tendinopathy. Am J Sports Med 2010;38:2085 91 skin. An experimental study in rats. Scand J Plast Reconstr Surg 1982;16:61–6. [Epub 2010/07/03]. [67] Oikarinen A, Mäkelä J, Vuorio T, Vuorio E. Comparison on collagen gene [39] Abate M, Silbernagel KG, Siljeholm C, Di Iorio A, De Amicis D, Salini V, et al. expression in the developing chick embryo tendon and heart. Tissue and Pathogenesis of tendinopathies: inflammation or degeneration? Arthritis Res development time-dependent action of dexamethasone. Biochim Biophys Ther 2009;11:235 [Epub 2009/07/14]. Acta 1991;1089:40–6. [40] Kennedy JC, Willis RB. The effects of local steroid injections on tendons: a [68] Dombi GW, Halsall HB. Collagen fibril formation in the presence of dexame- biomechanical and microscopic correlative study. Am J Sports Med 1976;4: thasone disodium phosphate. Connect Tissue Res 1986;15:257–68. 11–21. [69] Oikarinen A. Effect of betamethasone-17-valerate on synthesis of collagen and [41] Peters-Veluthamaningal C, van der Windt DA, Winters JC, Meyboom-de Jong B. prolyl hydroxylase activity in chick embryo tendon cells. Biochem Pharmacol Corticosteroid injection for trigger finger in adults. Cochrane Database Syst – Rev 2009 [CD005617, Epub 2009/01/23]. 1977;26:875 9. [42] Peters-Veluthamaningal C, Winters JC, Groenier KH, Meyboom-DeJong B. [70] Oikarinen A. Effect of cortisol acetate on collagen biosynthesis and on the Randomised controlled trial of local corticosteroid injections for de Quervain's activities of prolyl hydroxylase, lysyl hydroxylase, collagen galactosyltransfer- tenosynovitis in general practice. BMC Musculoskelet Disord 2009;10:131 ase and collagen glucosyltransferase in chick-embryo tendon cells. Biochem J [Epub 2009/10/29]. 1977;164:533–9. [43] Lee DH, Han SB, Park JW, Lee SH, Kim KW, Jeong WK. Sonographically guided [71] Oikarinen AI, Vuorio EI, Zaragoza EJ, Palotie A, Chu ML, Uitto J. Modulation of tendon sheath injections are more accurate than blind injections: implications collagen metabolism by glucocorticoids. Receptor-mediated effects of dexa- for trigger finger treatment. J Ultrasound Med 2011;30:197–203 [Epub 2011/ methasone on collagen biosynthesis in chick embryo fibroblasts and chon- 01/27]. drocytes. Biochem Pharmacol 1988;37:1451–62. [44] Wong MW, Lui WT, Fu SC, Lee KM. The effect of glucocorticoids on tendon cell [72] Oikarinen J. Cortisol induces (2′-5′)oligoadenylate synthetase in cultured chick viability in human tendon explants. Acta Orthop 2009;80:363–7 [Epub 2009/ embryo tendon fibroblasts. Biochem Biophys Res Commun 1982;105:876–81 05/08]. [Epub 1982/04/14]. [45] Wong MW, Tang YY, Lee SK, Fu BS, Chan BP, Chan CK. Effect of dexamethasone [73] Buck RC, Wilhelm DL. The influence of cortisone on the regeneration of tendon and on cultured human tenocytes and its reversibility by platelet-derived growth tracheal epithelium in the rat. Br J Exp Pathol 1952;33:562–6 [Epub 1952/12/01]. factor. J Bone Joint Surg Am 2003;85–A:1914–20 [Epub 2003/10/18]. [74] Wei AS, Callaci JJ, Juknelis D, Marra G, Tonino P, Freedman KB, et al. The effect [46] Zargar Baboldashti N, Poulsen RC, Franklin SL, Thompson MS, Hulley PA. of corticosteroid on collagen expression in injured rotator cuff tendon. J Bone Platelet-rich plasma protects tenocytes from adverse side effects of dexame- Joint Surg Am 2006;88:1331–8. fl – thasone and cipro oxacin. Am J Sports Med 2011;39:1929 35. [75] Lee H-J, Kim Y-S, Ok J-H, Lee Y-K, Ha MY. Effect of a single subacromial [47] Sendzik J, Shakibaei M, Schafer-Korting M, Lode H, Stahlmann R. Synergistic prednisolone injection in acute rotator cuff tears in a rat model. 2013 [Epub effects of dexamethasone and quinolones on human-derived tendon cells. Int J 2013/01/31]. – Antimicrob Agents 2010;35:366 74. [76] Wong MW, Tang YY, Lee SK, Fu BS. Glucocorticoids suppress proteoglycan [48] Poulsen RC, Carr AJ, Hulley PA. Protection against glucocorticoid-induced production by human tenocytes. Acta Orthop 2005;76:927–31 [Epub 2006/ damage in human tenocytes by modulation of ERK, Akt, and forkhead 02/14]. signaling. Endocrinology 2011;152:503–14 [Epub 2011/01/07]. [77] Poulsen RC, Watts AC, Murphy RJ, Snelling SJ, Carr AJ, Hulley PA. Glucocorti- [49] Kempka G, Ahr HJ, Ruther W, Schluter G. Effects of fluoroquinolones and coids induce senescence in primary human tenocytes by inhibition of sirtuin glucocorticoids on cultivated tendon cells in vitro. Toxicol In Vitro 1996;10: 1 and activation of the p53/p21 pathway: in vivo and in vitro evidence. Ann 743–54. [50] Wong MW, Tang YN, Fu SC, Lee KM, Chan KM. Triamcinolone suppresses Rheum Dis 2013 [Epub 2013/06/04]. human tenocyte cellular activity and collagen synthesis. Clin Orthop Relat Res [78] Martins CA, Bertuzzi RT, Tisot RA, Michelin AF, do Prado JM, Stroher A, et al. 2004;421:277–81 [Epub 2004/05/05]. Dextrose prolotherapy and corticosteroid injection into rat Achilles tendon. – [51] Moosmayer S, Tariq R, Stiris M, Smith HJ. The natural history of asymptomatic Knee Surg Sports Traumatol Arthrosc 2012;20:1895 900. rotator cuff tears: a three-year follow-up of fifty cases. J Bone Joint Surg Am [79] Haraldsson BT, Aagaard P, Crafoord-Larsen D, Kjaer M, Magnusson SP. 2013;95:1249–55 [Epub 2013/07/19]. Corticosteroid administration alters the mechanical properties of isolated [52] Tempfer H, Gehwolf R, Lehner C, Wagner A, Mtsariashvili M, Bauer HC, et al. collagen fascicles in rat-tail tendon. Scand J MedSci Sports 2009;19:621–6. Effects of crystalline glucocorticoid triamcinolone acetonide on cultered [80] Hugate R, Pennypacker J, Saunders M, Juliano P. The effects of intratendinous and human supraspinatus tendon cells. Acta Orthop 2009;80:357–62. retrocalcaneal intrabursal injections of corticosteroid on the biomechanical [53] Zhang J, Keenan C, Wang JH. The effects of dexamethasone on human patellar properties of rabbit Achilles tendons. J Bone Joint Surg Am 2004;86-A:794–801. tendon stem cells: implications for dexamethasone treatment of tendon [81] Martin DF, Carlson CS, Berry J, Reboussin BA, Gordon ES, Smith BP. Effect of injury. J Orthop Res 2013;31:105–10. injected versus iontophoretic corticosteroid on the rabbit tendon. South Med J [54] Tsai W-C, Tang F-T, Wong M-K, Yen H-C, Pang J-HS. Decreased expression of 1999;92:600–8. proliferating cell nuclear antigen is associated with dexamethasone inhibition [82] McWhorter JW, Francis RS, Heckmann RA. Influence of local steroid injections of the proliferation of rat tendon fibroblasts. J Rheumatol 2002;29(11): on traumatized tendon properties. A biomechanical and histological study. 2397–402. Am J Sports Med 1991;19:435–9. [55] Scutt N, Rolf CG, Scutt A. Glucocorticoids inhibit tenocyte proliferation and [83] Mackie JW, Goldin B, Foss ML, Cockrell JL. Mechanical properties of rabbit tendon progenitor cell recruitment. J Orthop Res 2006;24:173–82. tendons after repeated anti-inflammatory steroid injections 1974;6:198–202. [56] Lee SK, Ling CM. The response of human tendon to hydrocortisone injection. [84] Matthews LS, Sonstegard DA, Phelps DB. A biomechanical study of rabbit – Singapore Med J 1975;16:259 62 [Epub 1975/12/01]. patellar tendon: effects of steroid injection. J Sports Med 1974;2:349–57. [57] Tillander B, Franzen LE, Karlsson MH, Norlin R. Effect of steroid injections on [85] Ketchum LD. Effects of triamcinolone on tendon healing and function. the rotator cuff: an experimental study in rats. J Shoulder Elbow Surg A laboratory study. Plast Reconstr Surg 1971;47:471–82. – 1999;8:271 4. [86] Gonzalez RI. Experimental tendon repair within the flexor tunnels; the use of [58] Balasubramaniam P, Prathap K. The effect of injection of hydrocortisone into hydrocortisone without improvement of function in the dog. J Bone Joint Surg rabbit calcaneal tendons. J Bone Joint Surg Br 1972;54:729–34 [Epub 1972/11/01]. Am 1953;35-A:991–3. [59] Akpinar S, Hersekli MA, Demirors H, Tandogan RN, Kayaselcuk F. Effects of [87] Haraldsson BT, Langberg H, Aagaard P, Zuurmond AM, van El B, Degroot J, methylprednisolone and betamethasone injections on the rotator cuff: an et al. Corticosteroids reduce the tensile strength of isolated collagen fascicles. experimental study in rats. Adv Ther 2002;19:194–201. The American journal of sports medicine 2006;34(12):1992–7. [60] Unverferth LJ, Olix ML. The effect of local steroid injections on tendon. J Sports [88] Piper SL, Laron D, Manzano G, Pattnaik T, Liu X, Kim HT, et al. A comparison of Med 1973;1:31–7. lidocaine, ropivacaine and dexamethasone toxicity on bovine tenocytes in [61] Tsai WC, Tang FT, Wong MK, Pang JH. Inhibition of tendon cell migration by dexamethasone is correlated with reduced alpha-smooth muscle actin gene culture. The Journal of bone and joint surgery British volume 2012;94(6): – expression: a potential mechanism of delayed tendon healing. J Orthop Res 856 62 Epub 2012/05/26. 2003;21:265–71. [89] Koeke PU, Parizotto NA, Carrinho PM, Salate AC. Comparative study of the fi [62] Shapiro PS, Rohde RS, Froimson MI, Lash RH, Postak P, Greenwald AS. The ef cacy of the topical application of hydrocortisone, therapeutic ultrasound effect of local corticosteroid or ketorolac exposure on histologic and bio- and phonophoresis on the tissue repair process in rat tendons. Ultrasound in mechanical properties of rabbit tendon and cartilage. Hand (New York, NY) medicine & biology 2005;31(3):345–50. 2007;2:165–72. [90] Muto T, Kokubu T, Mifune Y, Sakata R, Nagura I, Nishimoto H, Harada Y, [63] Tatari H, Kosay C, Baran O, Ozcan O, Ozer E. Deleterious effects of local Nishida K, Kuroda R, Kurosaka M. Platelet-rich plasma protects rotator cuff- corticosteroid injections on the Achilles tendon of rats. Arch Orthop Trauma derived cells from the deleterious effects of triamcinolone acetonide. Orthop Surg 2001;121:333–7. Res 2013 Jun;31(6):976–82.