Re: 스테로이드 주사 후 tendon의 장력감소에 대한 논문 - 정리중...

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

Author links open overlay panelBenjamin John Floyd Dean MRCS, Emilie Lostis BSc, Thomas Oakley BM, BSc, Ines Rombach MSc, Mark E. Morrey MD, Andrew J. Carr FRCS

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https://doi.org/10.1016/j.semarthrit.2013.08.006Get rights and content

Abstract

Objective

Our primary objective was to summarise the known effects of locally administered glucocorticoid on tendon tissue and tendon cells.

Methods

We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines of the Medline database using specific search criteria. The search yielded 50 articles, which consisted of 13 human studies, 36 animal studies and one combined human/animal study.

Results

Histologically, there was a loss of collagen organisation (6 studies) and an increase in collagen 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 = 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.

목표: 

우리의 주요 목표는 

국소 투여 글루코코르티코이드가 힘줄 조직과 힘줄 세포에 미치는 

알려진 효과를 요약하는 것이었습니다. 

연구 방법: 

특정 검색 기준을 사용하여 Medline 데이터베이스의 PRISMA 및 코크란 가이드라인을 사용하여 과학 문헌을 체계적으로 검토했습니다. 

검색 결과 13개의 인간 연구, 36개의 동물 연구, 1개의 인간/동물 결합 연구로 구성된 50개의 논문이 검색되었습니다. 

결과: 조직학적으로 콜라겐 조직 손실(6건의 연구)과 콜라겐 괴사(3건의 연구)가 증가했습니다. 

섬유아세포의 증식(8개 연구)과 생존력(9개 연구)이 감소했습니다. 

17건의 연구에서 콜라겐 합성이 감소했습니다. 

4건의 연구에서 염증 세포 침윤이 증가한 것으로 나타났습니다. 

세포 독성 증가는 3건의 연구에서 입증되었습니다. 

힘줄의 기계적 특성은 18개 연구에서 조사되었습니다. 

이 중 6건의 연구에서 기계적 특성이 감소한 것으로 나타났고, 3건은 증가한 것으로 나타났으며, 나머지 9건은 큰 변화가 없는 것으로 나타났습니다. 

기계적 데이터에 대한 메타 분석 결과, 전체 효과 크기는 0.67(95% CI ¼ 0.01 ~ 1.33)로 기계적 특성이 크게 저하된 것으로 나타났습니다(9개 연구의 데이터). 

결론: 

전반적으로 

글루코코르티코이드의 국소 투여는 

세포 생존력 감소, 세포 증식 및 콜라겐 합성을 포함하여 

시험관 내 힘줄 세포에 상당한 부정적인 영향을 미친다는 것이 분명합니다. 

생체 내 연구에서 나타난 바와 같이 

콜라겐 분해와 괴사가 증가합니다. 

힘줄의 기계적 특성도 

현저히 감소합니다. 

이 리뷰는 

글루코코르티코이드 주사와 관련된 

힘줄 조직 및 세포에 장기적으로 심각한 해를 끼친다는 

새로운 임상 증거를 뒷받침합니다.

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Keywords

Glucocorticoid

Tendon

Tenocyte

Steroid

Fibroblast

Introduction

In September 1948 at the Mayo clinic, cortisone was injected into a patient for the first time in the treatment of rheumatoid arthritis to dramatic effect [1]. The 1950 Nobel Prize in Physiology or Medicine was awarded jointly to Edward Calvin Kendall, Tadeus Reichstein and Philip Showalter Hench directly relating to this work “for their discoveries relating to the hormones of the adrenal cortex, their structure and biological effects.” The use of glucocorticoid in the treatment of painful musculoskeletal disease has since proliferated to the point that now in the UK over 500,000 intra-articular glucocorticoid injections (GCIs) are administered per year in the primary care setting [2]. GCIs are used to relieve pain and/or inflammation in a wide variety of musculoskeletal disorders including osteoarthritis, inflammatory arthritis, tenosynovitis, tendinopathy 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], [4], [5], [6]. For example, in the treatment of shoulder pain, trials have shown only short-term benefits with no significant long-term gains [6], [7], [8]. Emerging high-quality evidence also points to poorer long-term outcomes associated with GCIs in the treatment of tendinopathy [9].

GCIs are frequently applied in close proximity to tendons with common examples including the rotator cuff, the flexor and extensor tendon origins around the elbow, the gluteus medius, the Achilles and the patellar tendons, the flexor tendons in the hand (i.e., trigger finger) and the extensor tendons around the wrist (i.e., De Quervain's tenosynovitis). It has been recurrently postulated that there is an increased risk of tendon rupture associated with GCI [10] but no high-quality evidence exists to adequately confirm‎ or refute this hypothesis [11], [12]. It is important to remember that GCI is often used in the context of an abnormal diseased tendon in which the risk of rupture is already increased. However, there is strong evidence that oral corticosteroids are associated with a higher risk of tendon rupture [13], and an increased spinal fracture risk associated with epidural GCIs has also recently been reported [14]. The mechanisms of action of glucocorticoids are multiple, highly complex and incompletely understood [15], [16]. One important pathway involves the activation of specific cytoplasmic glucocorticoid receptors, which then migrate to the cell nucleus to affect gene transcription. Generally, glucocorticoids are thought to be anti-inflammatory, but the reality may not be so simple [17].

The tendon changes that occur in painful human tendinopathy are generally considered to be consistent with a failed healing response [18], [19]. Normal tendon healing occurs with sequential inflammatory, proliferative and remodelling phases [20]. Fibroblast proliferation, angiogenesis and nerve ingrowth are all important in the healing process [21], [22]. Tendinopathy is characterised by abnormal tenocyte morphology and disorganised collagen architecture [19]. Although the presence of inflammation in tendinopathy has been proposed by some authors [23], few studies have shown the presence of a “classical” inflammatory process involving the inward migration of inflammatory cells driven by inflammatory mediators [24]. Therefore, the logic of using GCIs in the treatment of a tendinopathy is not convincing.

In this context, the purpose of this review was to determine the effects of local GCI on both tendon tissue and tendon cells. We aimed to describe and summarise the histological, molecular and mechanical changes.

1948년 9월 메이요 클리닉에서 

류마티스 관절염 치료를 위해 

처음으로 코르티손을 환자에게 주사하여 극적인 효과를 거두었습니다[1]. 

1950년 노벨 생리의학상은 

“부신 피질의 호르몬, 그 구조 및 생물학적 효과와 관련된 발견으로” 

이 연구와 직접적으로 관련된 

에드워드 캘빈 켄달, 타데우스 라이히슈타인, 필립 쇼월터 헨치에게 공동으로 수여되었습니다. 

이후 

고통스러운 근골격계 질환 치료에 글루코코르티코이드의 사용이 급증하여 

현재 영국에서는 1차 진료 환경에서 

연간 50만 건 이상의 관절 내 글루코코르티코이드 주사(GCI)가 투여되고 있습니다[2]. 

GCI는 

골관절염, 염증성 관절염, 건초염, 건병증 및 퇴행성 척추 질환을 포함한 

다양한 근골격계 질환의 통증 및/또는 염증을 완화하는 데 사용됩니다. 

GCI의 임상적 효능에 관한 증거는 상충되지만 

대체로 통증 완화 측면에서 단기적인 이점을 보여줍니다[3-6]. 

예를 들어, 

어깨 통증 치료의 경우, 

임상시험에서 단기적인 효과만 나타났을 뿐 

장기적인 이득은 크지 않은 것으로 나타났습니다 [6-8]. 

또한 

최근의 고품질 증거는 

건병증 치료에서 GCI와 관련된 장기적인 결과가 좋지 않다는 점을 지적합니다[9]. 

회전근개, 팔꿈치 주변의 굴곡근 및 신전근, 중둔근, 

아킬레스 및 슬개건, 손의 굴곡근(예: 방아쇠 손가락), 

손목 주변의 신전근(예: 드 쿠르뱅 건초염) 등 힘줄과 가까운 곳에 

GCI를 자주 적용하는 것이 일반적입니다. 

GCI와 관련된 힘줄 파열의 위험이 증가한다는 가설이 

반복적으로 제기되어 왔지만[10], 

이 가설을 적절히 확인하거나 반박할 만한 양질의 증거는 존재하지 않습니다[11,12]. 

GCI는 

파열 위험이 이미 높아진 비정상적인 질환이 있는 힘줄의 맥락에서 

자주 사용된다는 점을 기억하는 것이 중요합니다. 

그러나 

경구 코르티코스테로이드가 

힘줄 파열 위험을 높인다는 강력한 증거가 있으며[13], 

경막외 GCI와 관련된 척추 골절 위험 증가도 최근 보고되었습니다[14]. 

글루코코르티코이드의 작용 메커니즘은 

다양하고 매우 복잡하며 불완전하게 이해되고 있습니다 [15,16]. 

한 가지 중요한 경로는 

특정 세포질 글루코코르티코이드 수용체가 활성화되어 

세포 핵으로 이동하여 유전자 전사에 영향을 미치는 것입니다. 

일반적으로 

글루코코르티코이드는 항염증제로 생각되지만, 

실제로는 그렇게 간단하지 않을 수 있습니다 [17]. 

고통스러운 인간 건병증에서 발생하는 힘줄 변화는 

일반적으로 치유 반응 실패와 일치하는 것으로 간주됩니다 [18,19]. 

정상적인 힘줄 치유는 

염증, 증식 및 리모델링 단계가 순차적으로 진행됩니다 [20]. 

섬유아세포 증식, 

혈관 신생 및 신경 성장은 

모두 치유 과정에서 중요합니다 [21,22]. 

건병증은 

비정상적인 힘줄 세포 형태와 

무질서한 콜라겐 구조가 특징입니다 [19]. 

건병증에 염증이 존재한다는 사실은 

일부 저자에 의해 제안되었지만 [23], 

염증 매개체에 의해 유도된 염증 세포의 내측 이동과 관련된 “

고전적” 염증 과정이 존재한다는 사실은 거의 밝혀지지 않았습니다 [24]. 

따라서 

건병증 치료에 GCI를 사용한다는 논리는 설득력이 없습니다. 

이러한 맥락에서 이 리뷰의 목적은 

힘줄 조직과 힘줄 세포 모두에 대한 

국소 GCI의 효과를 확인하는 것이었습니다. 

조직학적, 분자적, 기계적 변화를 설명하고 

요약하는 것을 목표로 했습니다.

MethodsSearch strategies

This systematic review used the PRISMA-Statement (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and the Cochrane handbook as guidelines in the development of the study protocol and the report of the current study [25], [26]. The inclusion criteria and methods of analysis were specified in advance and documented in a protocol.

Studies were identified using the Medline electronic database. No limit was placed on the year of data entry, but in practice, there were no results prior to 1956. The search was undertaken in June 2013. The following search terms were used: steroid OR corticosteroid OR glucocorticoid AND tendon OR rotator cuff OR Achilles OR tendin⁎ OR tenocyte.

Additional studies were located by searching papers referenced in listed articles. The studies identified by the searches were 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 had to relate to the use of local glucocorticoid on tendon tissue or 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 intra-articular steroid injection, were excluded. Studies using systemic steroid as opposed to injected corticosteroid were excluded. Any study without results relating to histological, cellular, molecular or mechanical tissue changes was excluded. If a study could not be obtained in English, it was excluded.

The search, selection of studies and data analysis were performed independently by 2 individuals (T.O. and BD for the articles on humans and E.L. and B.D. for the articles on animals). Agreement on inclusion was achieved after review of the full-text articles and a joint decision by both individuals based on the inclusion/exclusion criteria. The data were then extracted using a spreadsheet designed by 2 authors (B.D. and E.L.), this included data relating to study heterogeneity and methodological quality. The data extracted included study subject characteristics, glucocorticoid used, source of cultured cells and cells used method of tissue analysis, control group, results and statistical methods. Methodological quality was assessed using an 8-point scoring system (Appendix 2) based on the method used by Hegedus et al. [27].

방법

검색 전략

이 체계적 문헌고찰은 연구 프로토콜 개발 및 본 연구 보고서의 지침으로 PRISMA-Statement(체계적 문헌고찰 및 메타분석을 위한 선호 보고 항목)와 코크란 핸드북을 사용했습니다 [25], [26]. 포함 기준과 분석 방법은 사전에 명시하고 프로토콜에 문서화했습니다.

연구는 Medline 전자 데이터베이스를 사용하여 식별되었습니다. 데이터 입력 연도에는 제한이 없었지만 실제로는 1956년 이전의 결과는 없었습니다. 검색은 2013년 6월에 수행되었습니다. 검색어는 스테로이드 또는 코르티코스테로이드 또는 글루코코르티코이드 및 힘줄 또는 회전근개 또는 아킬레스 또는 힘줄⁎ 또는 건세포를 사용했습니다.

추가 연구는 나열된 논문에서 언급된 논문을 검색하여 찾아냈습니다. 검색을 통해 확인된 연구들을 통합하고 중복된 연구들은 제외했습니다. 선별된 논문을 분석하기 전에 초록을 먼저 선별했습니다. 전체 포함/제외 기준은 부록 1 에 자세히 설명되어 있습니다. 연구는 힘줄 조직 또는 힘줄 세포에 국소 글루코코르티코이드를 사용하는 것과 관련되어야 했습니다. 리뷰 논문과 사례 연구는 제외되었습니다. 아나볼릭 스테로이드와 같은 글루코코르티코이드 이외의 스테로이드와 관련된 논문은 제외되었습니다. 관절 내 스테로이드 주사와 같은 건 주위 또는 건 주사 이외의 스테로이드 사용을 다룬 논문은 제외되었습니다. 코르티코스테로이드 주사가 아닌 전신 스테로이드를 사용한 연구는 제외되었습니다. 조직학적, 세포학적, 분자적 또는 기계적 조직 변화와 관련된 결과가 없는 모든 연구는 제외되었습니다. 영어로 된 연구를 구할 수 없는 경우 제외했습니다.

검색, 연구 선정 및 데이터 분석은 2인(인간 대상 논문의 경우 T.O. 및 BD, 동물 대상 논문의 경우 E.L. 및 B.D.)이 독립적으로 수행했습니다. 포함 여부에 대한 합의는 논문 전문을 검토하고 포함/제외 기준에 따라 두 사람이 공동으로 결정한 후 이루어졌습니다. 그런 다음 두 명의 저자(B.D. 및 E.L.)가 설계한 스프레드시트를 사용하여 데이터를 추출했으며, 여기에는 연구 이질성 및 방법론적 품질과 관련된 데이터가 포함되었습니다. 추출된 데이터에는 연구 대상자 특성, 사용된 글루코코르티코이드, 배양 세포의 출처 및 조직 분석에 사용된 세포, 대조군, 결과 및 통계적 방법이 포함되었습니다. 방법론적 품질은 Hegedus 등이 사용한 방법에 따라 8점 채점 시스템(부록 2)을 사용하여 평가했습니다 [27].

Study selection

The search strategy yielded 4424 results (Fig. 1). After the exclusion of duplicates and review articles, there were 1996 articles. Screening the articles revealed 40 articles on humans and 38 articles on animals that met the criteria based on their abstracts. Further assessment of eligibility, based on full-text articles, led to the exclusion of 28 of these 78 papers. The reasons for the exclusion of these 28 papers were as follows: no control group [6], reviews [12], systemic glucocorticoid therapy [6] and not related to tendon [4]. This left 50 articles meeting our inclusion criteria, and they are summarised in Appendix 3.

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Fig. 1. Flow chart of systematic review protocol.

Study characteristics

Of the 50 included articles, 36 related to animal studies, 13 to human studies and 1 to a study that was on both animals and humans. Of the 36 animal studies, 25 were in vivo and 11 in vitro; while of the 13 human studies, 12 were in vitro, 1 was in vivo, and 1 study was both in vivo and in vitro. The 1 combined human and animal study was in vitro. The most common animal used was rat (19 studies), followed by rabbit (9 studies), chick embryo (5 studies), dog (2 studies), cow (1 study) and multiple animals (1 study). The 25 in vivo animal studies used Achilles tendon (11 studies), shoulder tendon (5 studies), forearm tendon (3 studies), peroneal tendon (2 studies), tail tendon (2 studies), patellar tendon (1 study) and both Achilles and patellar tendon (1 study). The human in vivo study used Achilles tendon, while the combined human in vivo/vitro study used shoulder tendon for its in vivo component.

Of the 14 human studies, the glucocorticoid/s used were dexamethasone alone (6 studies), triamcinolone (3 studies), dexamethasone and triamcinolone (2 studies), dexamethasone and methylprednisolone (1 study) and hydrocortisone (1 study). Of the 36 animal studies, the glucocorticoid/s used were hydrocortisone (9 studies), dexamethasone (8 studies), methylprednisolone (7 studies), betamethasone (6 studies), triamcinolone (4 studies), methylprednisolone and betamethasone (1 study) and prednisolone (1 study). The animal and human study used triamcinolone.

연구 특성

포함된 50개의 논문 중 36개는 동물 연구, 13개는 인간 연구, 1개는 동물과 인간을 모두 대상으로 한 연구였습니다. 36건의 동물 연구 중 25건은 생체 내, 11건은 시험관 내 연구였으며, 13건의 인간 연구 중 12건은 시험관 내, 1건은 생체 내, 1건은 생체와 시험관 모두에서 수행된 연구였습니다. 인간과 동물을 결합한 연구 1건은 시험관 내 연구였습니다. 가장 많이 사용된 동물은 쥐 (19개 연구)였으며, 토끼(9개 연구), 병아리 배아 (5개 연구), 개 (2개 연구), 소(1개 연구) 및 여러 동물(1개 연구)이 그 뒤를 이었습니다. 25건의 생체 내 동물 연구에서는 아킬레스건 (11건), 어깨 힘줄(5건), 팔뚝 힘줄(3건), 복막 힘줄(2건), 꼬리 힘줄 (2건), 슬개건(1건), 아킬레스건과 슬개건 모두(1건)를 사용했습니다. 인간 생체 내 연구에서는 아킬레스건을 사용했으며, 인간 생체 내/시험관 내 복합 연구에서는 어깨 힘줄을 생체 내 구성 요소로 사용했습니다.

14건의 인체 연구 중 사용된 글루코코르티코이드는 덱사메타손 단독(6건), 트리암시놀론 (3건), 덱사메타손과 트리암시놀론 (2건), 덱사메타손과 메틸프레드니솔론 (1건), 하이드로코르티손 (1건)이었습니다. 36건의 동물 연구 중 사용된 글루코코르티코이드는 하이드로코르티손 (9건), 덱사메타손 (8건), 메틸프레드니솔론 (7건), 베타메타손 (6건), 트리암시놀론 (4건), 메틸프레드니솔론 및 베타메타손 (1건), 프레드니솔론 (1건)이었습니다. 동물 및 인체 연구에는 트리암시놀론이 사용되었습니다.

Study methodology and assessing the risk of bias

All included studies stated described their study group and control groups and clearly described method/s of tissue analysis. The results of the methodological quality assessment are detailed in 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-quantitative results with a stated statistical significant at p < 0.05. Of the 10 studies that did not state statistical significance, 3 were descriptive histological studies (1 human in vivo and 2 animal in vivo), 2 were quantitative mechanical and descriptive histological studies (both animal in vivo) and the remaining 5 used solely quantitative assays (all animal in vitro with 1 also involving human in vitro).

Studies that did not have control groups for comparison were excluded. Studies that used descriptive non-quantitative methods only and/or studies that did not state the statistical significance of their results were included in results; these results were clearly marked with “a”. This methodological assessment means that the results have not included studies with a large degree of bias, and that those with higher degrees of potential bias have been highlighted to readers.

The study heterogeneity precluded a meta-analysis of the histological and molecular results. However the studies relating to mechanical properties were systematically analysed to obtain data sets for a meta-analysis. Nine of the 17 studies provided adequate data from which the effect size with 95% upper and lower confidence intervals could be calculated. The data set extracted from each study was based upon which property of 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 related to a distinct experimental subgroup.

Statistics

All statistics and the forest plot [28] were carried out using Microsoft Excel 2007TM (Microsoft Corporation, Redmond, WA). Where appropriate, data were combined using meta-analytical methods. Meta-analyses and Forest Plots were performed in Stata version 12 (Stata, College Station, TX). Random effects meta-analysis was performed to account for the heterogeneity between studies.

Results

There were significant histological and molecular changes after local glucocorticoid administration (Table 1, Table 2). Histologically, there was a loss of collagen organisation (6 studies) and an increase in collagen necrosis (3 studies). The proliferation (8 studies) and viability (9 studies) of fibroblasts was reduced. An increased inflammatory cell infiltrate was shown in 4 studies. Increased cellular toxicity was demonstrated by 3 studies. Results regarding fibroblast migration and adhesions were conflicting. Collagen synthesis was decreased in 17 studies. An increased ratio of type 3 to type 1 collagen was shown in 2 studies. Apoptosis was unaffected in 3 studies and increased in 3 studies. Small numbers of studies had demonstrated changes in matrix enzymes (MMPs/TIMPs), proteoglycans, cytokines and other substances including FOX-01 and Sirtuin-1.

결과

국소 글루코코르티코이드 투여 후

상당한 조직학적 및 분자학적 변화가 있었습니다(표 1, 표 2).

조직학적으로

콜라겐 조직의 손실(6건의 연구)과

콜라겐 괴사(3건의 연구)가 증가했습니다.

섬유아세포의 증식(8개 연구) 및 생존력(9개 연구)이 감소했습니다.

섬유아세포 : 콜라겐, 탄성섬유, extracellular matrix, 히알루론산, 성장인자, 각종 효소 생성...

4건의 연구에서 염증 세포 침윤이 증가한 것으로 나타났습니다.

세포 독성 증가는 3건의 연구에서 입증되었습니다.

섬유아세포 이동 및 유착에 관한 결과는 상반된 결과를 보였습니다.

17건의 연구에서콜라겐 합성이 감소했습니다.

2건의 연구에서 3형 콜라겐과 1형 콜라겐의 비율이 증가한 것으로 나타났습니다.

세포 사멸은 3건의 연구에서 영향을 받지 않았고 3건의 연구에서 증가했습니다. 소수의 연구에서 매트릭스 효소(MMP/TIMP), 프로테오글리칸, 사이토카인 및 FOX-01과 시르투인-1을 포함한 기타 물질의 변화가 입증되었습니다.

Table 1. Histological changes

Human studiesAnimal studies

Empty Cell

a

Denotes that study did not state statistical significance of result.

Table 2. Molecular changes

Human studiesAnimal studies

Empty Cell

a

Denotes that study did not state statistical significance of result.

Eighteen studies investigated the mechanical properties of tendon (Table 3). Descriptively, 6 of these studies showed a decrease in mechanical properties, 3 showed an increase, while the remaining 9 showed no significant change. Nine studies provided adequate in vivo data from which to calculate the effect size with upper and lower 95% confidence intervals. Three studies contributed more than 1 data set as they had obtained results for more than 1 group of GCI-treated animals; Mikolyzk et al. [29] analysed 3 groups of animal at different time points; Oxlund et al. [30] analysed the effects on 2 different tendons and Plotkin et al. [31] analysed the effects of 2 different GCI dose. Figure 2 represents this forest plot. The overall effect size was −0.67 (95% confidence interval −0.01 to −1.33, p = 0.046), demonstrating that in these 9 studies there was a clear trend towards reduced mechanical properties in tendon after glucocorticoid injection.

결과의 통계적 유의성을 명시하지 않은 연구를 나타냅니다.

18개의 연구에서 힘줄의 기계적 특성을 조사했습니다(표 3). 이 중 6개 연구는 기계적 특성이 감소한 것으로 나타났고, 3개 연구는 증가한 것으로 나타났으며, 나머지 9개 연구는 유의미한 변화가 없는 것으로 나타났습니다.

9개 연구는 95% 신뢰 구간 상하로 효과 크기를 계산할 수 있는 충분한 생체 내 데이터를 제공했습니다. 3개 연구는 1개 이상의 GCI 처리 동물 그룹에 대한 결과를 얻었기 때문에 1개 이상의 데이터 세트를 제공했으며, Mikolyzk 등 [29]은 서로 다른 시점의 3개 동물 그룹을 분석했고, Oxlund 등 [30]은 2개의 다른 힘줄에 대한 효과를 분석했으며, Plotkin 등 [31]은 2개의 다른 GCI 용량에 따른 효과를 분석했습니다. 그림 2는 이 포레스트 플롯을 나타냅니다. 전체 효과 크기는 -0.67 (95% 신뢰구간 -0.01 ~ -1.33, p = 0.046)로, 이 9개의 연구에서 글루코코르티코이드 주사 후 힘줄의 기계적 특성이 감소하는 경향이 분명하게 나타났습니다.

Table 3. Mechanical changes

ReferencesDescriptive changesOverall 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.

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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).

Discussion

Overall the results are broadly negative, both in terms of the effects on several specific cellular characteristics and on the mechanical properties of tendon. While some studies have shown short-term pain relief, these results provide plausible mechanisms by which glucocorticoid treatment may result in adverse patient outcomes in the treatment of degenerative tendinopathy particularly in the long term [9].

The cause of tendinopathy has been the subject of much heated debate over the years, [32] and many different theories have been postulated [33], [34], [35], [36]. The histological and molecular changes in tendinopathy are undoubtedly consistent with mechanical tendon failure and a persistent failed healing response [18], [19], [37]. The 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. This apparent attempt at healing involving an inflammatory component appears to be more likely present in early tendinopathy [38] and decreasingly present as disease progresses, as tendon becomes progressively hypoxic and abnormal [39]. In this context, the consistent negative findings summarised in this review, both in terms of the changes to the cellular and tendon properties, should be of great cause for concern.

Overall glucocorticoid appears to have a negative effect on tendon homoeostasis with increased collagen disorganisation and collagen necrosis seen after treatment. Indeed it may be hypothesised that the increased number of inflammatory cells present may be the result of a reparative response to the glucocorticoid-induced tendon damage. This explanation is consistent with the result of the mechanical studies that show a short-term deterioration in the mechanical properties [29], [40] which then recovers in the longer term as a result of the healing response to the glucocorticoid-induced damage. The mechanisms for such changes in tendon are 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 long-term degenerative changes in tendon tissue may be worsened. The glucocorticoid reduction in collagen synthesis is another important mechanism by which altered homoeostasis may lead to deterioration in the mechanical properties of tendon, thus potentially increasing levels of future degeneration.

It is worth noting that there is still a clear role for GCI in the treatment of tendinopathy, but that it is vital to consider the potential negative effects highlighted by this review when making one's clinical decision on a case-by-case basis. Given the huge variability in terms of both patient characteristics and the pathogeneses of the different tendinopathies, 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 younger patients with an “overuse” type of tendinopathy appears unwise and potentially harmful, given the negative effects of glucocorticoid on the tendon healing. However, the use of GCIs for short-term clinical gains in older patients with degenerate tendons who are not suitable surgical candidates still appears a very appropriate treatment strategy. While the judicious use of GCIs for specific conditions such as trigger finger and De Quervain's tenosynovitis, in which the anti-proliferative and anti-inflammatory effects are of definite therapeutic benefit, is still a very effective and justifiable treatment strategy [41], [42]. The use of radiologically guided injections is becoming more commonplace and evidence suggests that they are significantly more accurate than “blind” injections [43]. Whether this increased accuracy translates into reduced complication rates and better clinical outcomes is something that needs to be determined by future research.

토론

전반적인 결과는

몇 가지 특정 세포 특성과 힘줄의 기계적 특성에 대한 영향 측면에서 전반적으로 부정적입니다.

일부 연구에서는

글루코코르티코이드 치료가 단기적인 통증 완화를 보여주었지만,

이러한 결과는 특히 장기적으로 퇴행성 건병증 치료에서

글루코코르티코이드 치료가 환자에게 부

정적인 결과를 초래할 수 있는 그럴듯한 메커니즘을 제공합니다 [9].

건병증의 원인은

수년 동안 많은 논쟁의 대상이 되어 왔으며 [32], [33], [34], [35], [36]

다양한 이론이 제기되어 왔습니다 [9] .

건 병증의 조직 학적 및 분자 적 변화는 의심 할 여지없이

기계적 힘줄 실패 및 지속적인 치유 실패 반응과 일치합니다 [18], [19], [37].

건병증의 염증 요소는

염증 세포의 내부 이동과 관련된 고전적인 “염증 반응”보다

치유 시도의 실패와 더 일치하는 것으로 보입니다.

염증 성분과 관련된 이러한 치유 시도는

초기 건병증에서 더 많이 나타나고[ 38],

건이 점진적으로 저산소 상태가 되고

비정상적으로 변하면서 질병이 진행됨에 따라 감소하는 것으로 보입니다 [39].

이러한 맥락에서

이 리뷰에 요약된 세포 및 힘줄 특성의 변화 측면에서 일관된 부정적인 결과는

큰 우려를 불러일으킬 수 있습니다.

전반적으로

글루코코르티코이드는 치료 후 나타나는

콜라겐 파괴와 콜라겐 괴사를 증가시켜

힘줄 항상성에 부정적인 영향을 미치는 것으로 보입니다.

실제로 존재하는 염증 세포의 증가는

글루코코르티코이드에 의한 힘줄 손상에 대한 회복 반응의 결과일 수 있다는

가설이 제기될 수 있습니다.

이 설명은

기계적 특성의 단기적 악화를 보여주는

기계적 연구 결과와 일치합니다 [29], [40]

글루코 코르티코이드 유발 손상에 대한 치유 반응의 결과로 장기적으로 회복됩니다.

힘줄의 이러한 변화에 대한 메커니즘은

“항염증제”로서의 글루코 코르티코이드에 대한

고전적인 설명이 지나치게 단순화 된 것으로 보이며 불분명합니다 [17].

글루코코르티코이드에 의한 노화는

힘줄 조직의 장기적인 퇴행성 변화를 악화시킬 수 있는 한 가지 메커니즘입니다.

글루코코르티코이드에 의한 콜라겐 합성의 감소는

변화된 항상성이 힘줄의 기계적 특성을 악화시켜 잠재적으로

향후 퇴행 수준을 증가시킬 수 있는 또 다른 중요한 메커니즘입니다.

건병증 치료에서 GCI의 역할은 여전히 분명하지만,

사례별로 임상적 결정을 내릴 때는

이 리뷰에서 강조한 잠재적인 부정적인 영향을 고려하는 것이 중요하다는 점에 유의할 필요가 있습니다.

환자 특성과 다양한 건병증의 병원체 측면에서 매우 다양한 변수를 고려할 때,

GCI 사용에 관해 임상의에게 처방적 관리 조언을 제공하는 것은 이 검토의 범위를 벗어납니다.

글루코코르티코이드가 힘줄 치유에 미치는 부정적인 영향을 고려할 때

“과용” 유형의 건병증이 있는 젊은 환자에게 GCI를 반복적으로 사용하는 것은

현명하지 않고 잠재적으로 해로울 수 있습니다.

그러나

수술 후보에 적합하지 않은 퇴행성 힘줄을 가진 고령 환자의 단기 임상적 이득을 위해

GCI를 사용하는 것은 여전히 매우 적절한 치료 전략으로 보입니다.

항증식 및 항염증 효과가 확실한 치료 효과가 있는

방아쇠 손가락 및 드 쿠르뱅 건초염과 같은 특정 질환에 GCI를 신중하게 사용하는 것은

여전히 매우 효과적이고 정당한 치료 전략입니다 [41], [42].

방사선 유도 주사의 사용은 점점 더 보편화되고 있으며,

“맹목적인” 주사보다 훨씬 더 정확하다는 증거가 있습니다 [43].

이러한

정확도 향상이 합병증 발생률 감소와

임상 결과 개선으로 이어지는지는 향후 연구를 통해 확인해야 할 사항입니다.

Limitations of this review

The results and generalisable meaning of this review are both limited by the quality and heterogeneity of the included studies. There was significant study heterogeneity in terms of study type (animal/human or in vivo/vitro), the anatomical source of tendon/tendon cells, glucocorticoid used, dose of glucocorticoid, mode of tissue analysis, time points and control type. It is particularly important to appreciate that several assumptions have been made 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 interpreting the results of the meta-analysis.

For the purposes of this review, we have asked a specific but general research question and included only studies that met criteria specific to this. However, our objective was to synthesise the overall research findings in this broad area and a degree of study heterogeneity had to be accepted in order to achieve this. The degree to which this review's results are generalisable to human patients is certainly open to debate. In vitro findings often conflict with in vivo findings; however, our review's key findings appear broadly consistent between the different study types.

The degree to which the results of the studies were descriptive, semi-quantitative or quantitative was highly variable. As a result, it has been made clear when results have not been shown to be statistically significant (Table 1, Table 2, Table 3). The variable blinding of the observers undertaking the semi-quantitative tissue grading does increase the risk of study bias towards positive findings. The measurement of multiple mechanical characteristics of tendon, and the absence of defining a primary study outcome, combined to result in some likely bias in terms of obtaining false-positive results.

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.

Appendix 1.

See below for Table A1.

Table A1. Full inclusion and exclusion criteria

InclusionExclusion

Studies must relate to tendon tissue or tendon cells following the local administration of steroid	No control group
Steroid is defined as glucocorticoid	Case reports, case series and review articles
Animal and human tendon cells or tendon tissue	Systemic and not local steroid administration
In vivo and in vitro studies	Studies relating to anabolic steroid
	Glucocorticoid treatment alone
	Fibroblasts not derived from tendon
	Not available in the English language

Appendix 2.

See below for Table A2.

Table A2. Methodological quality assessment document (the number of “yes” answers was counted for each study to give a total score out of 8)

NumberCriteriaYes/No/Unclear

1	Study population clearly described (animals/humans)
2	Control group clearly described
3	Sampling method clearly described
4	Steroid clearly described (name/dose)
5	Quantitative method or semi-quantitative method using minimum of 2 independent observers
6	Validity and/or reliability of methods described
7	Statistical significance stated for results
8	Study limitations mentioned

Appendix 3.

See below for Table A3.

Table A3. Summary of included studies and methodological scores

ReferencesHuman/animalStudy typeMethdological score

Akpinar et al. [59]	Animal	In vivo	6
Balasubramaniam and Prathap [58]	Animal	In vivo	3
Buck and Wilhelm [73]	Animal	In vivo	3
Dombi and Halsall [68]	Animal	In vitro	4
Gonzalez [86]	Animal	In vivo	4
Haraldsson et al. [79]	Animal	In vivo	8
Haraldsson et al. [87]	Animal	In vitro	7
Hugate et al. [80]	Animal	In vivo	6
Kapetanos [64]	Animal	In vivo	6
Kempka et al. [49]	Human/animal	In vitro	7
Kennedy and Willis [40]	Animal	In vivo	4
Ketchum [85]	Animal	In vivo	7
Kim et al. [65]	Human	in vitro	8
Koeke et al. [89]	Animal	In vivo	8
Lee et al. [75]	Animal	In vivo	8
Lee and Ling [56]	Human	In vivo	5
Mackie et al. [83]	Animal	In vivo	8
Martin et al. [81]	Animal	In vivo	8
Martins et al. [78]	Animal	In vivo	8
Matthews et al. [84]	Animal	In vivo	6
McWhorter et al. [82]	Animal	In vivo	7
Mikolyzk et al. [29]	Animal	In vivo	8
Muto et al. [90]	Human	In vitro	8
Oikarinen [69]	Animal	In vitro	5
Oikarinen [70]	Animal	In vitro	5
Oikarinen et al. [71]	Animal	In vitro	5
Oikarinen et al. [67]	Animal	In vitro	6
Oikarinen [72]	Animal	In vitro	4
Oxlund [30]	Animal	In vivo	8
Oxlund [66]	Animal	In vivo	7
Piper et al. [88]	Animal	In vitro	7
Plotkin et al. [31]	Animal	In vivo	7
Poulsen et al. [48]	Human	In vitro	8
Poulsen et al. [77]	Human	In vivo/in vitro	8
Scutt et al. [55]	Animal	In vitro	7
Sendzik et al.[47]	Human	In vitro	8
Shapiro et al. [62]	Animal	In vivo	5
Tatari et al. [63]	Animal	In vivo	4
Tempfer et al. [52]	Human	In vitro	8
Tillander et al. [57]	Animal	In vivo	5
Tsai et al. [54]	Animal	In vitro	5
Tsai et al. [61]	Animal	In vitro	5
Unverferth and Olix [60]	Animal	In vivo	5
Wei et al. [74]	Animal	In vivo	6
Wong et al. [44]	Human	In vitro	7
Wong et al. [50]	Human	In vitro	7
Wong et al. [76]	Human	In vitro	8
Wong et al. [45]	Human	In vitro	8
Zargar Baboldashti et al. [46]	Human	In vitro	8
Zhang et al. [53]	Human	In vitro	8

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