Re: 오십견의 새로운 병리. 뇌와 면역관계 2024!!

[문형철]

Front Physiol

. 2024 Mar 29;15:1248612. doi: 10.3389/fphys.2024.1248612

A new perspective of frozen shoulder pathology;

the interplay between the brain and the immune system

Santiago Navarro-Ledesma 1,2,*, Dina Hamed-Hamed 3, Leo Pruimboom 2

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PMCID: PMC11009429  PMID: 38617059

Abstract

Frozen shoulder (FS), also known as adhesive capsulitis of the shoulder (FS), is a fibrotic inflammatory process of unknown etiology whose main symptoms are pain, stiffness and the loss of joint mobility. These symptoms may be associated with pathologies such as diabetes, Dupuytren’s syndrome and the preval‎ence of today’s sedentary lifestyle. This literature review provides an overview of the epidemiology and pathogenesis of this pathology, as well as the mechanisms of lowgrade chronic inflammation and infection, insulin resistance, and omics-science associated with it. We also propose a new hypothesis related to the possibility that the GABAergic system could play a decisive role in the development of frozen shoulder and that therefore diabetes type 1, endocrinological autoimmune disorders and frozen shoulder are connected by the same pathophysiological mechanisms. If that is true, the combined presence of psycho-emotional stress factors and pathogenic immune challenges could be the main causes of frozen shoulder syndrome. Finally, we propose a series of possible intervention strategies based on a multifactorial etiological and mechanistic concept.

초록

동결견(FS)은 어깨의 유착성 관절낭염(FS)으로도 알려져 있으며, 원인이 불분명한 섬유성 염증 과정으로 통증, 경직 및 관절 가동 범위 상실이 주요 증상이다. 이러한 증상은 당뇨병, 뒤퓌트렌 증후군 및 현대인의 좌식 생활 방식과 같은 병리학적 요인과 연관될 수 있다.

본 문헌 고찰은

이 병리의 역학 및 병인, 그리고 이와 관련된

저등급 만성 염증 및 감염,

인슐린 저항성,

오믹스 과학의 메커니즘에 대한 개요를 제공한다.

또한,

GABAergic 시스템이

동결견 발생에 결정적 역할을 할 수 있다는 새로운 가설을 제안하며,

따라서 제1형 당뇨병, 내분비 자가면역 질환 및 동결견이

동일한 병리생리학적 기전으로 연결될 수 있음을 시사한다.

이 가설이 사실이라면,

심리정서적 스트레스 요인과 병인성 면역 도전의 복합적 존재가

동결견 증후군의 주요 원인이 될 수 있다.

마지막으로,

다인자적 병인론적 및 기전적 개념에 기반한 일련의 가능한 중재 전략을 제안한다.

Keywords: frozen shoulder (adhesive capsulitis), shoulder pain, shoulder condition, autoimmune disorder, endocrinological disease, low grade inflammation, psychosocial factors

1 Introduction

Frozen shoulder (FS) or adhesive capsulitis of the shoulder (FS) is a disorder characterized by its inflammatory and fibrotic process (Pietrzak, 2016). Codman first included the term “frozen shoulder” in 1934 (Dias et al., 2005). The predominant symptoms of this pathology in people suffering from it are stiffness, pain and a limitation in the range of active and passive mobility of the glenohumeral joint (Hannafin and Chiaia, 2000; Hagiwara et al., 2018). These symptoms have impact on personal and professional life and disturb people from performing their normal daily activities, affecting their quality of life (Chen et al., 2017). The disability in the shoulder can last over a period of one or more years during which range of motion is slowly restored in 60% of the affected population (Sarasua et al., 2021).

The other 40% of patients develop a chronic disorder (Buchbinder et al., 2007) and become increasingly more limited in their daily functions (Walmsley et al., 2014a; Chen et al., 2017). Interesting is that the quality of life seems to be solely related with purely the loss of motion of the affected shoulder and as such a successful treatment would improve both physical performance and quality of life (Fernandes, 2015).

1. 서론

동결견(FS) 또는 어깨 접착성 관절낭염(FS)은

염증 및 섬유화 과정을 특징으로 하는 질환이다(Pietrzak, 2016).

Codman은

1934년 처음으로 “동결견”이라는 용어를 사용했습니다(Dias et al., 2005).

이 병리를 앓는 사람들에게서 나타나는 주요 증상은 견관절의 경직, 통증 및 능동적·수동적 가동 범위의 제한입니다(Hannafin and Chiaia, 2000; Hagiwara et al., 2018). 이러한 증상은 개인적·직업적 생활에 영향을 미치며 일상 활동 수행을 방해하여 삶의 질을 저하시킵니다(Chen et al., 2017).

어깨 기능 장애는 1년 이상 지속될 수 있으며,

이 기간 동안 환자의 60%에서 관절 가동 범위가 서서히 회복됩니다(Sarasua et al., 2021).

나머지 40%의 환자는 만성 질환으로 발전하며(Buchbinder et al., 2007),

일상 기능이 점점 더 제한됩니다(Walmsley et al., 2014a; Chen et al., 2017).

흥미롭게도

삶의 질은 오로지 영향을 받은 어깨의 운동 범위 상실과 관련이 있는 것으로 보이며,

따라서 성공적인 치료는 신체적 기능과 삶의 질 모두를 개선할 수 있습니다(Fernandes, 2015).

It is of outmost importance to understand the reasons why FS resolves in 60% and persist in 40% of affected patients. Several factors seem to operate simultaneously in patients in which FS does not resolve and are of psychological, functional, etiological, and biological character. A retrospective study concerning the success rate of arthroscopic capsular release and relationship with functional and psychological factors showed that traumatic etiology, depression and anxiety decreased success rate after operation (Galasso et al., 2023). Another study with 210 patients (F/M = 130/80), investigated the outcome of consecutive physiotherapy, cortisone injection and, when necessary, arthroscopic release, in patients with FS and the impact of diabetes and obesity on that outcome (Barbosa et al., 2019). Interestingly, the study showed no association of BMI and successful outcome of FS treatments whereas patient with diabetes showed worse results when treated with physiotherapy and cortisone injection. The authors of this study refer to diabetes as a known risk factor for FS and conclude that mechanistic prove still lacks to explain the significant impact of diabetes on onset and resolve of FS (Barbosa et al., 2019). They refer to the fact that glycosylated Hb does not seem related with FS and so glycation and the forming of advanced glycolated end products cannot explain mechanistically the relationship between FS and persistent FS. Other explanations are therefore needed. Later we will describe a new hypothesis about the way FS develops and persists.

FS가 60%의 환자에서 해결되고

40%에서 지속되는 이유를 이해하는 것은 가장 중요합니다.

FS가 해결되지 않는 환자들에서는

심리적, 기능적, 병인학적, 생물학적 특성의 여러 요인들이 동시에 작용하는 것으로 보입니다.

관절경적 관절낭 이완술의 성공률과 기능적·심리적 요인 간의 관계를 조사한 후향적 연구에 따르면

외상성 병인, 우울증 및 불안이 수술 후 성공률을 저하시켰다(Galasso et al., 2023).

또 다른 연구(환자 210명, 여성/남성 = 130/80)에서는

FS 환자를 대상으로 연속적인 물리치료, 코르티손 주사,

그리고 필요한 경우 관절경적 방출술의 결과를 조사했으며,

당뇨병과 비만이 그 결과에 미치는 영향을 분석했다(Barbosa et al., 2019).

흥미롭게도

이 연구에서는 체질량지수(BMI)와 FS 치료 성공률 간 연관성이 나타나지 않았으나,

당뇨병 환자는 물리치료 및 코르티손 주사 치료 시

더 나쁜 결과를 보였다.

동결견에 대한 정보는 풍부함에도 불구하고, 중재 결과에 대한 대규모 전향적 연구는 제한적이다. 본 연구의 목적은 기능적 및 임상적 결과를 평가하고, 추가적으로 당뇨병과 체질량지수(BMI)의 독립적 영향을 분석하는 데 있었다.

12개월 동안 발생한 모든 원발성 동결견 210건을 대상으로 한 
전향적 코호트 연구를 분석하였다. 

기능적 결과 평가는 
개입 전후 옥스퍼드 어깨 점수(Oxford Shoulder score)를 사용하였다.
 추가 인구통계학적 데이터를 수집하였다. 

스테로이드 주사, 
관절경적 유착 박리술, 
수동적 관절 운동술을 포함한 개입의 효과를 분석하였다.

환자의 54%가 
관절내 스테로이드 주사에 반응하였다. 

난치성 증상을 보인 환자(46%)는 
관절경적 유착 박리술을 시행받았다. 

초기 주사 치료 실패율은 
당뇨병 환자[70%]에서 비당뇨병 환자[44%]보다 높았다. 

수술 후 옥스퍼드 어깨 점수는 3개월 시점에서 평균 41.6점에서 27.2점으로 개선되었다[p<0.05]. 환자의 85%에서 증상이 만족스럽게 해소되었으며, 외회전 범위는 평균 10.5°에서 61.3°로 개선되었다[p<0.05]. BMI가 30 이상인 환자와 30 미만인 환자 간 결과에 통계적 유의차는 없었다.

동결견 환자에게 수술적 개입의 결과를 이해시키는 것은 상담 시 중요하다. 

당뇨병 환자는 
보존적 치료 실패율이 높고 반복 수술 필요성이 증가하지만 
증상 완치는 여전히 가능하며, BMI 상태만으로는 불량한 결과를 예측할 수 없다는 점을 확인하였다.

연구 저자들은 당뇨병을 FS의 알려진 위험 요인으로 언급하며,

당뇨병이 FS 발병 및 해결에 미치는 상당한 영향력을 설명할 수 있는 기전적 증거는

여전히 부족하다고 결론지었다(Barbosa et al., 2019).

그들은 당화 헤모글로빈이 섬유근육통과 관련이 없어 보인다는 사실,

즉 당화 및 고급 당화 최종 생성물 형성이

섬유근육통과 지속성 섬유근육통 간의 관계를 기계적으로 설명할 수 없다는 점을 언급합니다.

따라서 다른 설명이 필요합니다.

후반부에서

섬유근육통이 발생하고 지속되는 방식에 대한

새로운 가설을 설명할 것입니다.

The common opinion about the pathophysiology of FS is based on a “inflammation-fibrotic cascade’ theory, characterized by fibroproliferative tissue fibrosis, whereby fibroblasts, producing predominantly type I and type III collagen and transform into myofibroblasts (a smooth muscle phenotype). This process is further accompanied by inflammation, neoangiogenesis and neoinnervation (Millar et al., 2022). Neoinnervation and the change of tissue morphology could explain the main hallmarks of FS, meaning pain and loss of range of motion (Akbar et al., 2019a). Epidemiological data reflect a preval‎ence of FS of 3%–5% in the general population (Sarasua et al., 2021).

The syndrome consists of three phases (Walmsley et al., 2014a; Cho et al., 2018): i) the painful freezing phase in which pain precedes a loss of range of motion lasting 10–36 weeks (Walmsley et al., 2014b; Zhang et al., 2021); ii) the state of freezing or adhesive phase, lasting 4–12 months where pain gradually reduces while the range of motion stays impaired (Walmsley et al., 2014b; Zhang et al., 2021); and iii) the thawing or regression phase where range of motion improves progressively (Walmsley et al., 2014b; Zhang et al., 2021). However, 40% of patients do not recover normal range of motion and keep experiencing symptoms and that makes this classification still contentious (Millar et al., 2022).

The course of FS and its impact on physical wellbeing, mental health, together with a sustained loss of productivity and global economy has been shown (Bouaicha et al., 2020). Although a common opinion about the pathophysiology exists (the above-mentioned cascade), the disparity of results observed in the literature regarding the etiology of FS, suggests that there remain mechanistic lagunes in the pathophysiology and etiology of FS (Austin et al., 2014).

New insights about the possible etiology of FS come from a recent study (de Mello et al., 2023) that shows a significant increase of FS cases during the COVID-19 pandemic. They investigated retrospectively 1.983 patients that suffered from FS and compared the number of patients that became affected from March 2019 to February 2020 and from March 2020 to February 2021 (de Mello et al., 2023). During the pandemic the incidence of FS was 2.41-fold higher compared to the previous year (de Mello et al., 2023). Data that confirmed the results of other epidemiological studies were related with a 4-fold increase of FS in patients suffering from diabetes (Whelton and Peach, 2018). The same holds for the possible association between hypothyroidism and the incidence of FS which in this study shows a 5-fold increase, again in coherence with earlier published data (Cohen et al., 2020).

FS 병리생리학에 대한 일반적 견해는 ‘염증-섬유화 연쇄 반응’ 이론에 기반하며, 이는 섬유증식성 조직 섬유화를 특징으로 한다. 이 과정에서 섬유모세포는 주로 I형 및 III형 콜라겐을 생성하며 근섬유모세포(평활근 표현형)로 전환된다. 이 과정은 염증, 신생혈관 형성 및 신생신경생성을 동반한다(Millar et al., 2022). 신경 재생과 조직 형태 변화는 FS의 주요 특징인 통증과 가동 범위 상실을 설명할 수 있다(Akbar et al., 2019a). 역학 자료에 따르면 일반 인구에서 FS 유병률은 3%~5%이다(Sarasua et al., 2021).

이 증후군은 세 단계로 구성됩니다(Walmsley et al., 2014a; Cho et al., 2018):

i) 통증이 관절 가동 범위 상실보다 선행하는 통증성 동결기(10~36주 지속)(Walmsley et al., 2014b; Zhang et al., 2021);

ii) 4~12개월 지속되는 동결 상태 또는 유착 단계로, 통증은 점차 감소하지만 운동 범위는 계속 제한됨(Walmsley et al., 2014b; Zhang et al., 2021); 그리고

iii) 관절 가동 범위가 점진적으로 개선되는 해빙 또는 퇴행 단계(Walmsley et al., 2014b; Zhang et al., 2021). 그러나 환자의 40%는 정상적인 관절 가동 범위를 회복하지 못하고 증상을 지속 경험하며, 이로 인해 이 분류는 여전히 논란의 여지가 있다(Millar et al., 2022).

FS의 경과와

신체적 웰빙,

정신 건강에 미치는 영향,

그리고 지속적인 생산성 손실과 글로벌 경제에 미치는 영향이 입증되었다(Bouaicha et al., 2020).

병리생리학에 대한 일반적인 견해(상기 연쇄 반응)가 존재함에도 불구하고, FS의 원인에 관한 문헌에서 관찰된 결과의 불일치는 FS의 병리생리학 및 원인에 대한 기전적 공백이 여전히 존재함을 시사한다(Austin et al., 2014).

FS의 가능한 원인에 대한 새로운 통찰력은

최근 연구(de Mello et al., 2023)에서 비롯되었으며,

이 연구는 COVID-19 대유행 기간 동안 FS 사례가 크게 증가했음을 보여줍니다.

이들은 FS를 앓은 1,983명의 환자를 후향적으로 조사하여

2019년 3월부터 2020년 2월까지와 2020년 3월부터 2021년 2월까지의

환자 발생 수를 비교했습니다(de Mello et al., 2023).

대유행 기간 동안 FS 발생률은

전년 대비 2.41배 더 높았습니다(de Mello et al., 2023).

다른 역학 연구 결과를 뒷받침하는 데이터는

당뇨병 환자에서 FS 발생률이 4배 증가했다는 점과 관련이 있었습니다(Whelton and Peach, 2018).

갑상선 기능 저하증과 FS 발생률 사이의 연관성 역시 마찬가지였는데,

본 연구에서는 5배 증가를 보였으며

이는 다시 한번 이전에 발표된 데이터와 일치합니다(Cohen et al., 2020).

The new findings are mainly related with psycho-emotional factors. The individuals that suffered from depression and anxiety had, respectively, 8.8 (p < 0.001) and 14 (p < 0.001) times and significant greater risk on the development of FS (Whelton and Peach, 2018). The results of an earlier systematic review (Brindisino et al., 2022) already emphasized on the impact of depression and anxiety on physical dimensions such as shoulder pain, range of motion and pain perception. These data suggest that ‘toxic’ emotions and ‘toxic’ thoughts (Pruimboom, 2023) could be part of the multifactorial etiology of FS and further research should elicit possible mechanisms of how exactly these ‘yellow flag’ factors could cause FS.

Genetic susceptibility as risk factor for FS is also proposed and suggested by results of a genome-wide association study by Scott et al. (Scott-solomon et al., 2022). Three polymorphisms of genetic loci related with cell proliferation and production of extracellular matrix and collagen fibers seem to be as associated with FS, diabetes and hypothyroidism and so genetic susceptibility should be included in the list of possible risk factors (Scott-solomon et al., 2022). One of the loci as a risk factor for FS is the Wnt gene (Scott-solomon et al., 2022). A polymorphism of the Wnt gene has also been found in people suffering from morbus Dupuytren, giving a possible explanation for the relationship between morbus Dupuytren and FS (Dolmans et al., 2011).

Further confusion about the definite causes of FS and the mechanisms behind it is caused by the fact that there exists a great disparity in success rates by interventions based on the known epidemiologic, etiological and mechanistic data known thus far (Cohen et al., 2016; Cho et al., 2019; Mertens et al., 2022). These disparities make it legitimate to state that the best way to treat people with FS is primary prevention.

새로운 발견은

주로 심리정서적 요인과 관련이 있습니다.

우울증과 불안을 겪은 개인은

각각 8.8배(p < 0.001) 및 14배(p < 0.001)

더 높은 FS 발병 위험을 보였습니다(Whelton and Peach, 2018).

이전 체계적 문헌고찰(Brindisino et al., 2022) 결과에서도

우울증과 불안이 어깨 통증, 가동 범위, 통증 인식과 같은

신체적 차원에 미치는 영향이 이미 강조된 바 있다.

이러한 데이터는 ‘독성’ 감정과 ‘독성’ 사고(Pruimboom, 2023)가

FS의 다인성 병인학의 일부일 수 있으며,

이러한 ‘경고 신호’ 요인들이 정확히 어떻게 FS를 유발하는지에 대한

가능한 메커니즘을 규명하기 위한 추가 연구가 필요함을 시사합니다.

Scott 등(Scott-solomon et al., 2022)의

게놈 전체 연관성 연구 결과에서도 FS의 위험 요인으로 유전적 취약성이 제안되고 제시되었습니다.

세포 증식과 세포외 기질 및 콜라겐 섬유 생성과 관련된 유전자 좌위의

세 가지 다형성이

섬유근육통, 당뇨병 및 갑상선 기능 저하증과 연관되어 있는 것으로 보이며,

따라서 유전적 취약성은 가능한 위험 요인 목록에 포함되어야 합니다(Scott-Solomon et al., 2022).

섬유근육통의 위험 요인으로 작용하는 좌위 중 하나는

Wnt 유전자입니다(Scott-Solomon et al., 2022).

Wnt 유전자의 다형성은

듀피트렌병(morbus Dupuytren) 환자에서도 발견되어,

듀피트렌병과 FS 간의 연관성에 대한 가능한 설명을 제시한다(Dolmans et al., 2011).

FS의 명확한 원인과 그 기전에 대한 추가적인 혼란은 지금까지 알려진 역학적, 병인학적 및 기전적 데이터를 기반으로 한 중재의 성공률에 큰 차이가 존재한다는 사실에서 비롯됩니다(Cohen et al., 2016; Cho et al., 2019; Mertens et al., 2022). 이러한 차이로 인해 FS 환자를 치료하는 최선의 방법은 1차 예방이라고 주장하는 것이 타당합니다.

Psychological factors were already identified as risk factors for the development of FS and for worse outcome in patients who underwent chirurgical repair of a rotator cuff injury (Aïm et al., 2022). The authors of the latter study conclude that although significant worse outcome was measured for patients suffering from anxiety and depression, it was not clear if the psychological state was cause or consequence (Aïm et al., 2022). Anxiety, depression and pain, the latter a hallmark of FS, do not only share psychological characteristics, but also biological ones.

Spontaneous pain, as initiating symptom for idiopathic FS, is often part of a cluster of syndromes including depression, pain and chronic fatigue (Mokhtari et al., 2019). Several pathways have been described to explain the comorbidity between the three syndromes, although the common opinion about the connections is mostly based on the presence of a chronic neuroinflammation causing hippocampal atrophy, accompanied with decreased neurogenesis, decreased neuroplasticity and less presence of neurotrophic factors (Raison et al., 2006; Jain et al., 2011; Mokhtari et al., 2019). Causes of neuroinflammation range from endotoxemia (De and Pruimboom, 2015; Mohammad and Thiemermann, 2021), and metabolic syndrome (Van Dyken and Lacoste, 2018) via acute brain trauma and stroke (Leung et al., 2007) to sleep disturbances (Zhu et al., 2012a) and high calorie diet (Robbins and Solito, 2022). Stroke and acute brain trauma have also been associated with FS (Leung et al., 2007) and the same holds for sleep disturbances (Jankowska-Polańska et al., 2021). Overall, psychological and immunological factors are related with onset and prognosis of FS and so treatment should account interventions improving functioning of the brain, the immune system and the shoulder.

심리적 요인은

이미 FS 발병 위험 인자로 확인되었으며,

회전근개 손상 수술을 받은 환자의 예후 악화와도 연관성이 보고되었습니다(Aïm et al., 2022).

후자의 연구 저자들은

불안과 우울증을 겪는 환자들에게서 유의미하게 나쁜 결과가 측정되었지만,

심리적 상태가 원인인지 결과인지는 명확하지 않다고 결론지었다(Aïm et al., 2022).

불안, 우울증 및 통증(후자는 FS의 특징)은

심리적 특성뿐만 아니라 생물학적 특성도 공유한다.

특발성 FS의 초기 증상인 자발적 통증은

우울증, 통증, 만성 피로 증후군을 포함한 복합 증후군의 일부로 나타나는 경우가 많다(Mokhtari et al., 2019). .

세 증후군 간의 동반발생(comorbidity)을 설명하기 위한 여러 경로가 제시되었으나,

이 연결에 대한 일반적인 견해는

주로 만성 신경염증(chronic neuroinflammation)의 존재에 기반한다.

이 염증은 해마 위축(hippocampal atrophy)을 유발하며,

신경생성(neurogenesis) 감소,

신경가소성(neuroplasticity) 저하,

그리고 신경영양인자(neurotrophic factors)의 감소와 동반된다(Raison et al., 2006; Jain et al., 2011; Mokhtari et al., 2019).

신경염증의 원인은

내독소혈증(De and Pruimboom, 2015; Mohammad and Thiemermann, 2021),

대사증후군(Van Dyken and Lacoste, 2018)을 거쳐 급성 뇌 외상 및 뇌졸중(Leung et al., 2007),

수면 장애(Zhu et al., 2012a),

고칼로리 식이(Robbins and Solito, 2022)에 이르기까지 다양하다.

뇌졸중과 급성 뇌 외상 역시 FS와 연관성이 확인되었으며(Leung et al., 2007),

수면 장애 역시 마찬가지입니다(Jankowska-Polańska et al., 2021).

전반적으로

심리적·면역학적 요인은 FS의 발병 및 예후와 관련이 있으므로,

치료에는 뇌 기능, 면역 체계 및 어깨 기능 개선을 위한 중재가 포함되어야 합니다.

If we could identify the sum of non-confounding risk factors as cause of FS than the use of for instance lifestyle medicine would be indicative. Primary prevention is more than early detection of a disease. Nevertheless, measurements that help to recognize the disease in its early stage before symptoms appear and fibrosis sets in, helps to slow the development of FS and supports faster healing (Pietrzak, 2016). In this regard, metabolic factors (diabetes mellitus and thyroid disorders, metabolic syndrome), autonomic symptoms and pain sensitivity may contribute to the prognosis in terms of shoulder pain, disability, and quality of life in patients with FS (Nathan, 2002). Therefore, inflammation control has been proposed to be the best option when the etiology of a pathology is unknown (Hand et al., 2008). The diagnosis of frozen shoulder is classified into primary and secondary. Primary FS is characterized by a progressive and painful loss of the active and passive mobility range in the shoulder with its causes being unknown (Walmsley et al., 2014b); secondary FS is of a known intrinsic or extrinsic cause with stiffness in the shoulder being established for instance after surgery (Hannafin and Chiaia, 2000).

The care of musculoskeletal health is often based on the recognition of patient-reported findings, physical examination and evidence of an initial inflammatory state leading to fibrosis (Hand et al., 2008).

만약 FS의 원인으로 혼란 요인이 없는 위험 요인들을 종합적으로 규명할 수 있다면,

예를 들어 생활습관 의학의 활용이 시사점이 될 수 있습니다.

1차 예방은

질병의 조기 발견 그 이상입니다.

그럼에도 증상이 나타나고

섬유화가 진행되기 전 초기 단계에서 질병을 인식하는 데 도움이 되는 측정법은

FS의 진행을 늦추고 더 빠른 회복을 지원합니다(Pietrzak, 2016).

이와 관련하여 대사 인자(당뇨병 및 갑상선 장애, 대사 증후군), 자율신경계 증상 및 통증 민감도는 동결견 환자의 어깨 통증, 장애, 삶의 질 측면에서 예후에 기여할 수 있다(Nathan, 2002). 따라서 병리의 원인이 알려지지 않은 경우 염증 조절이 최선의 선택으로 제안되어 왔다(Hand et al., 2008). 동결견 진단은 원발성과 속발성으로 분류됩니다. 원발성 동결견은 원인이 알려지지 않은 상태에서 어깨의 능동적 및 수동적 가동 범위가 점진적이고 통증을 동반하며 감소하는 것이 특징입니다(Walmsley et al., 2014b). 속발성 동결견은 알려진 내인성 또는 외인성 원인이 있으며, 예를 들어 수술 후 어깨의 경직이 확립된 경우를 말합니다(Hannafin and Chiaia, 2000).

근골격계 건강 관리는

주로 환자 보고 증상, 신체 검사 및 섬유화로 이어지는

초기 염증 상태의 증거를 바탕으로 이루어집니다(Hand et al., 2008).

However, some patients with FS (between 7% and 50%) have symptoms for a long period of time with 6% having them for more than 7 years (Eljabu et al., 2016), which again can be explained by an incomplete understanding of frozen shoulder’s etiology (Mertens et al., 2022). In this sense, FS is currently understood in a multifactorial way, in which chronic low-grade inflammation (LGI), alterations in glucose metabolism (especially insulin resistance with compensatory hyperinsulinemia), chronic ischemia and endotoxemia are important factors of great scientific interest. Perhaps adding omics sciences could shed light on the understanding of the mechanisms and causes that lead to FS and we will therefore add some data related with metabolomics and proteomics (Nathan, 2002; de la Serna et al., 2021). We will further propose a new perspective of the etiology and possible treatment of patients suffering from FS through the description of the interplay of the brain and immune system in people suffering from FS, diabetes type 1 and even morbus Hashimoto.

그러나

일부 동결견 환자(7~50%)는

장기간 증상을 경험하며, 6%는 7년 이상 증상이 지속됩니다(Eljabu et al., 2016).

이는 동결견의 병인에 대한 불완전한 이해로 설명될 수 있습니다(Mertens et al., 2022).

이러한 점에서 동결견은 현재 다인자적 방식으로 이해되고 있으며,

만성 저등급 염증(LGI),

포도당 대사 이상(특히 보상성 고인슐린혈증을 동반한 인슐린 저항성),

만성 허혈 및 내독소혈증이 과학적으로 매우 중요한 요인으로 주목받고 있습니다.

오믹스 과학을 추가하면

동결견으로 이어지는 메커니즘과 원인에 대한 이해에 도움이 될 수 있으므로,

우리는 대사체학과 단백질체학 관련 데이터를 추가할 것이다(Nathan, 2002; de la Serna et al., 2021). .

또한 FS, 제1형 당뇨병, 심지어 하시모토병을 앓는 환자들에서

뇌와 면역 체계의 상호작용을 설명함으로써

FS 환자의 병인론과 가능한 치료법에 대한 새로운 관점을 제시할 것이다.

2 Epidemiology

The preval‎ence of FS in the entire population is 2%–5% (Dias et al., 2005; Hand et al., 2008; Austin et al., 2014). Most patients suffering from FS are women (70%) (Hannafin and Chiaia, 2000) with the most frequent age range being between 40 and 60 (Hand et al., 2008). Although the exact etiology is unknown, the risk factors are: diabetes, Dupuytren’s syndrome, heart and neck surgery, Parkinson’s disease, smoking, thyroid disease and chronic regional pain syndrome (Bridgman, 1972; Hannafin and Chiaia, 2000; Thomas et al., 2007; Chan et al., 2017).

FS has been clearly demonstrated to be associated with diabetes (Thomas et al., 2007; Austin et al., 2014; Chan et al., 2017), with type 1 diabetes being the most frequent risk factor for its development. Its incidence in the diabetic population is 10%–36% higher than in the general population, which indicates that poor glucose control is related to the development of FS in the long term (Thomas et al., 2007). A key factor in this association is the level of hemoglobin (Bridgman, 1972). In the literature, there is a hypothesis which suggests that hyperglycemic levels associated with diabetes can incite changes in the collagen of the joints thereby unleashing fibrotic and inflammatory variations, and these changes in the joint have been observed in pathological studies of the disease (Austin et al., 2014). Chronic hyperglycemic levels increase the possibility of the production of advanced glycation end products which are known to cause cross linking of collagen fibers that can result in fibrosis of the capsules of the shoulder (Li et al., 2015). One of the most susceptible substances for glycation caused by chronic hyperglycemia is hemoglobin (Malka et al., 2016) and therefore HbAc1 could be a valid parameter of AGE products as part of the etiology of FS. A relevant study including 201,531 patients with diabetes of which 1,150 suffered from frozen shoulder did not support any association of HbAc1 with the incidence of FS (Yian et al., 2012). This study confirm‎s that people suffering from diabetes have an increased risk for FS but glycation of HbAc1 does not seem to have influence on that risk (Yian et al., 2012). It is surprising that people suffering from diabetes type 1 are at greater risk for suffering FS than patients suffering from diabetes type 2 (Thomas et al., 2007). Both groups of patients show repetitive hyperglycemia periods and both show signs from inflammation and metabolic disturbances at the level of lipid physiology including LDL, VLDL and triglycerides values in the bloodstream (Razi et al., 2017; Tell et al., 2020). Dyslipidaemia is part of the pathophysiological changes in FS and therefore the metabolic state resulting from diabetes one and two could explain partly the association between diabetes and FS. What it does not explain is the difference between the impact of diabetes type 1 and 2 on FS. COVID-19 has perhaps given a new perspective to explain this difference. FS is also associated with axial spondylarthritis (axSA), according to a study investigating 2,859 patients suffering from axSA (Huang et al., 2020). SA is associated with increased risk and early onset in patients human leukocyte antigen B27 (HLA-B27)-positive (Huang et al., 2020). A recent meta-analysis and systematic review found that FS is also strongly associated with the presence of HLA-B27 (Prodromidis and Charalambous, 2016). These findings further support the possibility that FS has an auto-immune origin or shares certain pathophysiological mechanisms with all the auto-immune diseases with which FS risk is associated.

2 역학

전체 인구에서 FS의 유병률은

2%–5%이다(Dias et al., 2005; Hand et al., 2008; Austin et al., 2014).

대부분의 FS 환자는

여성(70%)이며(Hannafin and Chiaia, 2000),

가장 흔한 발병 연령대는 40~60세이다(Hand et al., 2008) .

정확한 병인은 알려지지 않았으나,

위험 요인으로는 당뇨병, 뒤퓌트렌 증후군,

심장 및 목 수술, 파킨슨병, 흡연, 갑상선 질환,

만성 국소 통증 증후군이 있다(Bridgman, 1972; Hannafin and Chiaia, 2000; Thomas et al., 2007; Chan et al., 2017).

FS는

당뇨병과 관련이 있는 것으로 명확하게 입증되었습니다(Thomas et al., 2007; Austin et al., 2014; Chan et al., 2017).

제1형 당뇨병이 FS 발병의

가장 흔한 위험 요소입니다.

당뇨병 환자군에서 FS 발생률은

일반 인구보다 10%~36% 더 높으며,

이는 장기적으로 당 조절 불량이 FS 발병과 관련이 있음을 시사합니다(Thomas et al., 2007).

이러한 연관성의 핵심 요인은 헤모글로빈 수치입니다(Bridgman, 1972).

문헌에는 당뇨병과 관련된 고혈당 수치가 관절의 콜라겐 변화를 유발하여

섬유화 및 염증 변화를 일으킬 수 있다는 가설이 있으며,

이러한 관절 변화는 질병의 병리학적 연구에서 관찰되었습니다(Austin et al., 2014).

만성 고혈당 상태는

고급 당화 최종 생성물(AGEs)의 생성 가능성을 증가시키며,

이는 콜라겐 섬유의 가교를 유발하여 어깨 관절낭의 섬유화를 초래할 수 있다(Li et al., 2015).

초록

동결견(FS)은
어깨 통증이 자발적으로 시작되고 점진적인 관절 가동 범위 감소를 동반하는 흔한 질환이다.

동결견의 원인은 아직 명확하지 않으며,
근본적인 치료법도 확립되지 않았다.

동결견을 조기에 예방하거나 치료하는 것을 최종 목표로,
본 연구에서는 이 질환의 병리학적 및 생물학적 특징을 검토하였다.

많은 연구에 따르면 동결견의 주요 병리학적 변화는
초기에는 염증,
이후에는 섬유화로 나타난다.

활막과 관절낭에는
염증성 사이토카인, 면역 세포, 섬유화 성장 인자, 제3형 콜라겐이 존재한다.

면역 세포 구성은
대식세포에서 T 세포로 전환된다.

활성화된 섬유아세포는
염증 및 섬유화 과정을 조절하는 것으로 보인다.

매트릭스 메탈로프로테아제와 조직 메탈로프로테아제 억제제 간의 불균형이
섬유화를 촉진할 수 있다.

또한 동결견 활막에서
고급 당화 최종 생성물이 관찰된다.

당뇨병과 갑상선 기능 저하증은
FS 발병과 밀접한 관련이 있습니다.

비수술적 치료 측면에서 경구 또는 관절 내 글루코코르티코이드는 초기 효과를 제공하는 유일한 약물입니다. 일부 다른 항염증제나 항섬유화제는 FS를 잠재적으로 조절할 수 있으나, 임상 환경에서 효과성이 입증되지는 않았습니다. 향후 연구는 FS에서 생물학적 사건을 억제하는 스테로이드 절약제 개발을 목표로 해야 합니다.

만성 고혈당에 의한 당화 작용에 가장 취약한 물질 중 하나는

헤모글로빈 (Malka et al., 2016)이며,

따라서 HbAc1은 동결견(FS) 발병 기전의 일부로서

AGE 생성물의 유효한 지표가 될 수 있습니다.

당뇨병 환자 201,531명(이 중 1,150명이 동결견을 앓고 있음)을 대상으로 한 관련 연구에서는 HbAc1과 동결견 발생률 간 연관성을 지지하지 않았습니다(Yian et al., 2012). 본 연구는 당뇨병 환자가 동결견 발병 위험이 높다는 점을 확인했으나, HbAc1의 당화 과정은 해당 위험에 영향을 미치지 않는 것으로 보인다(Yian et al., 2012). 당뇨병 1형 환자가 2형 당뇨병 환자보다 동결견 발병 위험이 더 높다는 점은 놀랍습니다(Thomas et al., 2007). 두 환자군 모두 반복적인 고혈당 기간을 보이며, 혈중 LDL, VLDL 및 중성지방 수치를 포함한 지질 생리학적 수준에서 염증 및 대사 장애 징후를 나타냅니다 (Razi et al., 2017; Tell et al., 2020). 이상지질혈증은 강직성 척추염의 병리생리학적 변화의 일부이므로, 제1형 및 제2형 당뇨병으로 인한 대사 상태가 당뇨병과 강직성 척추염의 연관성을 부분적으로 설명할 수 있습니다. 그러나 1형과 2형 당뇨병이 FS에 미치는 영향의 차이를 설명하지는 못한다. COVID-19는 아마도 이 차이를 설명하는 새로운 관점을 제시했을 수 있다. 축성 척추관절염(axSA)을 앓고 있는 2,859명의 환자를 대상으로 한 연구에 따르면, FS는 축성 척추관절염(axSA)과도 연관되어 있다(Huang et al., 2020). SA는 인간 백혈구 항원 B27(HLA-B27) 양성 환자에서 위험 증가 및 조기 발병과 관련이 있습니다(Huang et al., 2020). 최근 메타분석 및 체계적 문헌고찰에 따르면, FS는 HLA-B27의 존재와도 강한 연관성을 보였습니다(Prodromidis and Charalambous, 2016). 이러한 결과는 FS가 자가면역 기원을 가질 가능성 또는 FS 위험과 연관된 모든 자가면역 질환과 특정 병리생리학적 기전을 공유할 가능성을 더욱 뒷받침합니다.

One of those mechanisms could be related with the GABA-ergic dependent nervous system. Diabetes type 1 is considered an autoimmune disease and the main autoimmune response is against glutamic acid decarboxylase (GAD65) (Towns and Pietropaolo, 2011). GAD65 is a super autoantigen with high level of presence in the brain (Nataf, 2017).

GAD65 is a synaptic enzyme that catalyzes y-aminobutyric acid (GABA) from glutamate. Its expression‎ in inhibitory terminals is essential for functioning of the GABAergic system (Mende et al., 2016). The immune reaction against GAD65 resulting in the production of antibodies is not only evidenced in diabetes type 1 but also in several central nervous system disorders grouped as GAD-antibody spectrum disorders (Tsiortou et al., 2021). These disorders are characterized by severe anxiety, depressed mood, and specifically anxiety and phobias for physical challenges (Tsiortou et al., 2021). The study of Pires (de Mello et al., 2023) showed that anxiety and depression during the COVID-19 pandemic increases the risk for FS with a factor 8.8 which is even greater than other associations (de Mello et al., 2023). GAD65 antibodies that can lead to diabetes type 1 and central nervous disorders are often a consequence of two synergistic risk factors, according to Nataf (Nataf, 2017). The simultaneous exposure of an immune challenge combined with psycho-emotional stress increases the risk of T cell priming against GAD65 and this can produce both diabetes type 1 and central nervous system disorders (Nataf, 2017). SARS-COV-2 has brought fear, anxiety an depression to many affected and non affected COVID-19 individuals (Kupcova et al., 2023), and these psycho-emotion state in combination with viral challenges could be responsible for an increases of antoantibodies GAD65 in persons already suffering from diabetes type 1. It is even possible that COVID-19 can elicit diabetes type 1 according to a case study by Genç (Genç et al., 2021). During the pandemic cases of hyperglycemia, diabetic ketoacidosis and diabetes type 1 increased and so SARS-CoV-2 seems to trigger or unmask DM1 (Wang et al., 2013). Could autoantibodies against GAD65, which are associated with diabetes type 1, brain disorders, anxiety, and depression, also have a significant role in the development of Frozen Shoulder (FS), especially considering its higher occurrence in patients with hypothyroidism and Hashimoto’s disease (Brindisino et al., 2022), and the elevated risk of endocrinological autoimmune diseases related to these autoantibodies (Gambelunghe et al., 2000)? The GABAergic system has multiple functions related with hallmarks of inflammatory diseases such as rheumatoid arthritis (Shan et al., 2023), pain (Jasmin et al., 2004), and GABA-disorders as seen in people suffering from autoimmune activity against GAD65 develop a stiff body disease (Tsiortou et al., 2021). These data, although speculative, support the development of the hypothesis that FS related with diabetes type 1 is of autoimmune origin. Antibody spreading is a known mechanism in autoimmune diseases and spreading of GAD65 has been evidenced in people suffering from diabetes type 1, although the level of auto-antibodies was not high enough to predict auto-reactivity in the infiltrated tissues (Söhnlein et al., 2000). Nevertheless, disturbances of the GABA-system could lead to fear of physical challenges and movement neglect is one of the evidenced risk factors for the development of FS (de la Serna et al., 2021) (Figure 1).

이러한 기전 중 하나는

GABA-의존성 신경계와 관련될 수 있다.

제1형 당뇨병은

자가면역 질환으로 간주되며,

주요 자가면역 반응은 글루탐산 탈카복실효소(GAD65)를 대상으로 한다(Towns and Pietropaolo, 2011).

GAD65는

뇌에서 높은 수준으로 존재하는 초자가항원이다(Nataf, 2017).

 super autoantigen

GAD65는

글루타메이트로부터 γ-아미노부티르산(GABA)을 촉매하는 시냅스 효소입니다.

억제성 말단에서의 발현은

GABAergic 시스템 기능에 필수적입니다(Mende et al., 2016).

GAD65에 대한 면역 반응으로 인한 항체 생성은

제1형 당뇨병뿐만 아니라 GAD 항체 스펙트럼 장애(GAD-antibody spectrum disorders)로 분류되는

여러 중추신경계 장애에서도 확인된다(Tsiortou et al., 2021).

이러한 장애는

심각한 불안, 우울한 기분,

특히 신체적 도전 상황에 대한 불안 및 공포증을 특징으로 한다(Tsiortou et al., 2021).

Pires의 연구(de Mello et al., 2023)에 따르면,

COVID-19 팬데믹 기간 중 불안과 우울은 FS 위험을 8.8배 증가시키며,

이는 다른 연관성보다 훨씬 높은 수치이다(de Mello et al., 2023).

제1형 당뇨병 및 중추신경계 장애를 유발할 수 있는 GAD65 항체는

종종 두 가지 시너지적 위험 요인의 결과물이다

동시에 면역적 도전과 정신정서적 스트레스에 노출되면

GAD65에 대한 T 세포 프라이밍 위험이 증가하며,

이는 제1형 당뇨병과 중추신경계 장애를 모두 유발할 수 있다(Nataf, 2017).

SARS-COV-2는 많은 COVID-19 감염자와 비감염자에게 공포, 불안 및 우울증을 가져왔으며(Kupcova et al., 2023), 이러한 정신-정서적 상태가 바이러스적 도전에 결합되면 이미 제1형 당뇨병을 앓고 있는 사람에서 GAD65 항체 증가의 원인이 될 수 있습니다. Genç의 사례 연구에 따르면 COVID-19가 제1형 당뇨병을 유발할 가능성도 있습니다(Genç et al., 2021). 팬데믹 기간 동안 고혈당, 당뇨병성 케톤산증 및 제1형 당뇨병 사례가 증가했으며, SARS-CoV-2가 제1형 당뇨병(DM1)을 유발하거나 발현시키는 것으로 보입니다(Wang et al., 2013).

제1형 당뇨병, 뇌 장애, 불안, 우울증과 연관된 GAD65에 대한

자가항체가 동결견(FS) 발생에도 중요한 역할을 할 수 있을까?

특히 갑상선기능저하증 및 하시모토병 환자에서 동결견 발생률이 높다는 점(Brindisino et al., 2022), 그리고 이러한 자가항체와 관련된 내분비 자가면역 질환의 위험 증가(Gambelunghe et al., 2000)를 고려할 때 말이다. ? GABAergic 시스템은 류마티스 관절염(Shan et al., 2023), 통증(Jasmin et al., 2004)과 같은 염증성 질환의 특징 및 GAD65에 대한 자가면역 활동으로 인해 경직성 질환을 앓는 사람들에게서 관찰되는 GABA 장애와 관련된 다중 기능을 가집니다(Tsiortou et al., 2021) . 이러한 데이터는 추측적이지만, 제1형 당뇨병과 관련된 FS가 자가면역 기원을 가질 수 있다는 가설을 뒷받침한다. 항체 확산은 자가면역 질환에서 알려진 메커니즘이며, 제1형 당뇨병 환자에게서 GAD65 확산이 확인되었으나, 침윤 조직에서의 자가반응성을 예측할 만큼 자가항체 수준이 높지는 않았다(Söhnlein et al., 2000) . 그럼에도 GABA 시스템의 장애는 신체적 도전 상황에 대한 두려움으로 이어질 수 있으며, 운동 소홀은 FS 발병의 입증된 위험 요소 중 하나이다(de la Serna et al., 2021) (그림 1).

FIGURE 1.

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Social defeat and psycho-emotional distress lead to increased presentation of brain super autoantigens, which are presented to pro-inflammatory T lymphocytes present in the meninges of the brain. Immune challenges such as virus, bacteria and leaky gut, sedentary lifestyle, and obesity, produce a LGI and activity of both the innate and acquired immune system. The heightened activity of the T lymphocytes increases the susceptibility for the development of Teffector cells primed for multiple super autoantigens like GAD65. Active Teffector cells respond to GAD65 (antigen) presented by antigen presenting cells in the meninges inducing the primus movens of a possible autoimmune reaction. Teffector cells primed for GAD65, migrate to the peripheral body and specifically the pancreas, where they find a high level of GAD65 inducing a severe auto-immune response that ultimately leads to diabetes type 1. Antigen spreading to specific sites attract Teffector cells into the susceptible shoulder (non-dominant neglected), the thyroid gland, and the hand muscles, whereas immune activity in the brain causes a neuroinflammation, leading to depression, fear and anxiety.

When eliminating the difference of incidence between DM1 and FS and DM2 and FS, it seems plausible that components of the metabolic syndrome and the metabolic syndrome as part of DM1 and two are (co) responsible for increased pro-inflammatory cytokine production (Austin et al., 2014), causing a state of chronic low-grade inflammation as part of the pathophysiology of FS (Hutcheson and Rocic, 2012). This chronic low-grade inflammation is further related with increased oxidative stress, caused by the production of excessive reactive oxygen species (ROS) and oxidative stress is also part of FS (Vicente, 2016).

2.1 A short resume of the literature related with the shoulder pathogenesis in FS

Stiffness, pain, and limited range of motion are common symptoms in people suffering from frozen shoulder (FS). The accumulation of advanced glycation end products (AGEs) in the shoulder, associated with insulin resistance, compensatory hyperinsulinemia, chronic hypoxia, and endotoxemia, are also characteristic (Bridgman, 1972). Cytokines play a fundamental role in the development of the disease and could possibly be used as diagnostic markers. Interleukin cytokine IL-1 is involved in key functions such as immune cell recruitment, cell proliferation and tissue destruction (Chen et al., 2017). The presence of activated mast cells, T and B lymphocytes and inflammatory mediators (including cytokines) found in synovial biopsies in patients suffering from FS, support the pathophysiological role of pro-inflammatory cytokines in FS (Bridgman, 1972). These cytokines further can cause persistent capsular fibrosis and thus, the development of FS. Next to infiltrated immune cells, fibroblasts and myofibroblasts are present in great amounts (Bunker et al., 2000), whose main function are the maintenance of the extracellular connective tissue matrix. Overactivation of myofibroblasts gives raise to formation of fibrotic tissue and tissue contraction, whereas they normally have an important repair function (Ramos et al., 2004). When the matrix contracts, pain and stiffness occur. Myofibroblasts and immune cells influence each other and by their cytokines and growth factors (Bunker et al., 2000).

3 Low grade inflammation and subclinical infection

Modern life is characterized by high calorie intake, sedentary lifestyle and many other toxic factors brought by the development of culture (Ramos et al., 2004). Culture should not been seen as some reaction on evolution, it is just its logical result (Ramos et al., 2004). The factors that killed humans millions of times have been responsible for the search for solutions and humans have achieved many benefits by using their intelligence. Today people in developed countries hardly die of starvation, dehydration, heat or cold because of respectively agriculture, a sanitary system, air conditioning and central heating (Al-Amrani et al., 2021). Nature shaped survival strategies and intelligence and the end-result is culture. The need for physical activity is almost fully eliminated by motorizing transport, food is brought by a courier and so too much food and a chronic lack of physical activity are logical consequences of culture as a result of nature (Ramos et al., 2004; Pruimboom, 2023). Culture, as result of nature, developed based on the ultimate law of evolution, meaning save energy for survival and reproduction (Casanova et al., 2023).

Modern lifestyle is a direct cause of many detrimental health effects and that probably means we have had too much of culture (Pruimboom et al., 2015). Factors such as light pollution, air pollution, sleep disturbances, alcohol abuse, smoking, sitting time, high calorie diet, increase loneliness and social defeat factors such a poverty, all produce a chronic stress response, with multiple consequences (McEwen et al., 2015). Chronic stress leads to activation of the immune system. Lifestyle can also directly cause inflammation by the production of a lifestyle associated molecular pattern that consists of increased LDL and uric acid. Both are immunogenic compounds producing a pro-inflammatory state (Zindel and Kubes, 2020). Chronic stress was recently defined as chronic irritation (Navarro et al., 2023) and chronic irritation produces low-grade inflammation that, on its turn, increases permeability of multiple mucosal barriers including the gut (Fasano and Shea-Donohue, 2005; de Punder and Pruimboom, 2015; Fasano, 2020; Zindel and Kubes, 2020; Navarro et al., 2023). The translocation of bacterial debris and other toxins to the blood stream, and present in those mucosal organs, are co-responsible for the observed low-grade inflammation (Fasano and Shea-Donohue, 2005; Fasano, 2020). During any type of inflammation barrier break-down is observed where any form of injury can start with low-grade inflammation and may lead to systemic inflammation (Bunker et al., 2014). LGI activates the stress systems chronically and cortisol, noradrenalin and pro-inflammatory cytokines can cause (severe) damage to tight junctions of systemic barriers (de Punder and Pruimboom, 2015). The blood-brain barrier, the blood-retinal barrier, the blood-nerve barrier, the blood-lymph barrier and the blood-cerebrospinal fluid barrier increase their permeability or are damaged by LGI, possibly causing a systemic inflammation of all vital organs (Bridgman, 1972; Rönnbäck and Hansson, 2019). The systemic inflammation caused by LGI can easily explain the presence of an inflammatory state in the frozen shoulder of affected people (Hagiwara et al., 2018). Some cytokines, such as HMGB1, have been shown to play a role in FS pathology; they are thought to be needed for the onset and perpetuation of FS since their release during stress bolsters the inflammatory tissue response seen in patients (Akbar et al., 2019a; de la Serna et al., 2021; Millar et al., 2022).

LGI can be produced by many chronic stress factors of both sterile and non-sterile character. Non-sterile etiological factors for FS include possible infiltration of bacteria that normally inhabit human skin, such as Propionibacterium acne (P. acne), that recently has been identified in people suffering from FS (Bunker et al., 2014; Cucchi et al., 2017). A recent study showed the presence of multiple alarmins (IL-33, S100A9, S100A8 and HMGB1) in the joint capsule in FS, and these alarmins are associated with an infective response against P. acne (Cucchi et al., 2017; Akbar et al., 2019b). P. acne could not only be a possible cause of FS, it is also the most frequent bacteria that causes infection in the affected shoulder after surgical procedures (Cher et al., 2018). Corynebacterium propinquum and Streptococcus epidermis are commonly found in the affected shoulder and are also part of etiological factors of disc herniation as shown in several studies (Lavergne et al., 2017). The postulated mechanism by which these bacteria reach the shoulder capsule is through the mouth, mainly during tooth brushing (Bhanji et al., 2002; Capoor et al., 2017). Oral dysbiosis, which mediates local and peripheral inflammatory pathologies, can be the origin of the development of a pathological atopobiome in different tissues including the brain (Kelly et al., 2015), the spine and discs (Teichtahl et al., 2015) and the shoulder (Hajishengallis, 2015). The way the bacteria reach the infiltrated organs is still in debate although data suggest that they migrate in an ‘invisible state of dormancy’ (Malka et al., 2016). The dormant state of the bacteria prevents immune detection and facilitates migration and infiltration in organs with a low pO2 level such as the intervertebral disc and the shoulder capsule, and even more in sedentary people (de la Serna et al., 2021). Therefore, a combination of low-grade inflammation and the possible presence of a subclinical infection could explain the observed inflammation-fibrotic cascade in FS.

The inflammatory phase can be considered a protective event but it can become a threat when it is exacerbated (Potgieter et al., 2015); for this reason, inflammation has been linked to several degenerative diseases as well as mitochondrial alterations, with mitochondria playing an important role in pro-inflammatory signaling (Campos et al., 2003). Strategies aimed at controlling excessive oxidative stress in mitochondria may represent preventive and therapeutic interventions in inflammation (López-Armada et al., 2013). Impaired mitochondrial function is associated with several acute and chronic inflammatory diseases (López-Armada et al., 2013). A recent review has shown how mitochondrial dysfunction can end up appearing in many different pathologies, such as fibromyalgia, chronic fatigue syndrome, diabetes, some types of cancer, and neurodegenerative diseases (e.g., Parkinson’s or Alzheimer’s). In patients with FS, it seems logical to suspect mitochondrial dysfunction as a consequence of the observed alterations in glucose metabolism, insulin resistance, lack of shoulder mobility, a low oxygen level and the level of free radicals as all known risk factors for mitochondrial dysfunction (Casanova et al., 2023), as well as in chronic shoulder pain (Hamed-Hamed et al., 2023).

If LGI and subclinical infection contribute to FS, interventions targeting both entities should prevail in patients suffering from FS. Although common opinion is that the use of NSAIDs as anti-inflammatory intervention could help to resolve FS, data are confounding (Ewald, 2011). NSAIDs have been part of medicine since decades and their role is based on the assumption that the metabolites produced out of arachidonic acid (AA) (as part of the debris in tissue injuries) are deleterious for wound healing and cause inflammation (Wang et al., 2021). NSAIDs inhibit COX-2 enzymes responsible for the production of different metabolites of AA, including prostaglandin E2 (PgE2, 82). PgE2 has long been considered a pro-inflammatory eicosanoid (Kawahara et al., 2015). Studies from Hangai (Hangai et al., 2016) and more recently Avramia (Avramia et al., 2021) show that PgE2 should be considered an immune-suppressive damage associated molecular pattern (DAMP) and is probably therefore the most abundant eicosanoid in an acute inflammatory environment (Hangai et al., 2016). The notion that inflammation is some ‘bad’ invention of evolution has been the driver of the search for anti-inflammatory drugs for decades. Serhan (Serhan, 2017) warns for the possible immune-suppressive activities of anti-inflammatory drugs and its iatrogenic effect on the development of chronic inflammation by preventing resolution (Serhan, 2017). Parisien et al. (Parisien et al., 2022) showed the possible negative impact of NSAIDs use after acute injury on resolution and possibly causing chronic pain syndromes (Parisien et al., 2022). The study performed a transcriptome-wide analysis in peripheral immune cells of 98 individuals suffering from acute low back pain, and followed up for 3 months (Parisien et al., 2022). The main finding was that neutrophil activity in inflammation was protective against the development of chronic pain and thousands of genetic transcriptional changes were observed only in those participants with resolved pain and none in those with persistent pain (Parisien et al., 2022). Further research elicited that mice receiving NSAIDs showed the same absence of transcriptional activity as the immune cells of the participants with persistent pain. Retrospective analysis of individuals reporting acute low back pain in the UK Biobank identified an increased risk of the development of chronic pain in patients using NSAIDs (Parisien et al., 2022).

To our knowledge, there is no research done on the possible negative effects of the use of NSAIDs in persons suffering from FS. Despite pain relief at start, the use of NSAIDs and its anti-inflammatory effects could be counteractive for long outcome of FS. Already in 2011 (Ewald, 2011) evidence of the use of NSAIDs in people suffering from FS was limited and hard evidence still lacks.

We propose to use a much more integrative approach in the treatment of patients suffering from FS. In line with other disciplines, it is perhaps time to recover the knowledge about the way the immune system normally solves injury and infection successful (Truchetet and Pradeu, 2018).

As knowledge advances about the way fatty acids influence immune activity, new lipid formulas with beneficial effects have been developed. Those lipids are nutritionally adapted and are useful for improving inflammation-based pathologies promoting a faster recovery and reducing the use of anti-inflammatory drugs that can produce serious adverse effects (Serhan, 2017). This benefit has led fatty acids, especially n-3 PUFAs and oleic, to be considered as immuno-nutrients (Mesa et al., 2006). Likewise, olive oil phenolics have been shown to reduce the generation of reactive oxygen species (ROS) in phagocytic cells, in vitro, and inhibit the activity of the enzyme 5-lipoxygenase involved in pro-inflammatory events (Shibutami and Takebayashi, 2021). This approach may allow for the identification of dietary biomarkers and a deeper understanding of metabolic dynamics and the resulting impact on health (Vazquez-Aguilar et al., 2023). The use of omics-science could help to find the exact immunological players in people suffering from FS. The search for the presence of super autoantigens and their antibodies is needed to support our new hypothesis presented earlier in this paper.

4 Metabolomics and proteomics in pain and chronic conditions as proxy for FS

The science of metabolomics studies low molecular weight chemical compounds that exist in biological tissues or cells because of genetic changes or physiological or pathological metabolic conditions (Cui et al., 2017).

Proteomics is defined as the complete eval‎uation of the structure and function of proteins to understand the nature of an organisms. The main purpose of proteomics is to find essential biomarkers that support mechanistic pathways in health and disease (Al-Amrani et al., 2021). Proteomics provides a better understanding of the structure and the function of an organism than genomics. Nevertheless, it is much more complicated than genomics because of the immense number of estimated proteins in humans (>million) opposite to the relative small number of genes (22.000). Proteomics could be used to verify our hypothesis about why DM1 is more associated with FS than DM2. That research should find proteins of an immune reaction related with T lymphocytes and the presence of GAD65 or other super autoantigens and their antibodies. To our knowledge such research is lacking in the international scientific literature and so for now it is still speculative.

One manuscript describes the proteomics of FS in different parts of the shoulder capsule and in different types of patients (Kawahara et al., 2015). Protein spectrum was measured in different compartments of the shoulder capsule in twelve patients suffering from primary FS with severe stiffness compared with seven patients presenting FS with a rotator cuff tear as the control group (Kawahara et al., 2015). There were important differences found between the two groups of patients and several proteins were highlighted as clinical important (Kawahara et al., 2015). Firstly, there are significant differences in presence of proteins related with P13K-Akt and PPAR signaling which are essential compounds in insulin and leptin metabolism (Giorgino et al., 2009; Thon et al., 2016). Patients with primary FS present increased P13K-Akt and PPAR signaling compared with the rotator cuff group (Hagiwara et al., 2018). Increased activity of both signaling pathways suggest greater presence/activity of insulin and leptin as part of the pathophysiology of primary FS and related with insulin and leptin resistance (Thon et al., 2016; Huang et al., 2018). Persons with rotator cuff damage present a proteome much more related with direct damage and less with metabolic disturbances. The latter conclusion is based on the presence of proteins that signal staphylococcus aureus infection, antigen processing/presentation, and lysosome and phagosome activity (Kawahara et al., 2015). Phagosome and lysosome activity elicit the presence of damage associated molecular patterns and pathogen associated molecular patterns (Roh and Sohn, 2018; Khorshidian et al., 2022). Damage and possible pathogen infiltration by opening the blood/capsule barrier seem to be the main causes of the symptomatology of FS after rotator cuff damage. This could mean that patients suffering from primary FS need treatment much more focused on lifestyle changes and specific metabolic interventions to solve insulin and leptin resistance, whereas people with traumatic FS demand a much more orthopedic treatment. The writers of this study also conclude that primary and secondary FS show different etiology and pathophysiology, meaning that interventions should also differ (Kawahara et al., 2015).

It is obvious that only one proteomics study in people suffering from FS cannot be used as golden standard. Much more studies are necessary to determine and identify the exact mechanisms and etiology of primary and secondary FS, but the first step has been made.

Not published as a proteomics research paper but as a pathology manuscript, Hand et al. (Hand et al., 2007) showed the presence of multiple immune cells in the shoulder of 22 conservative therapy resistant patients suffering from primary FS. Mast cells presence was highest followed by T lymphocytes, B lymphocytes and macrophages, evidencing a state of chronic inflammation in primary FS (Hand et al., 2007). Mast cells regulate fibroblast proliferation, an interaction that suggests that the inflammatory state leads to fibrosis through intermediation of mast cells (Hand et al., 2007). The presence of T and B lymphocytes as part of the acquired immune system gives rise to the existence of an autoimmune reaction in the frozen shoulder against the fibrotic tissue (Hand et al., 2007), although other hypotheses could be emphasized. More research will shed light on our hypothesis in which anxiety, fear and depression are related with increased risk for the activation of T lymphocytes against GAD65, diabetes type 1, Hashimoto and perhaps FS (Nataf, 2017).

Proteomics science in FS is still very limited, so metabolomics can add only limited knowledge to the etiology and pathophysiology of FS. Perhaps the best way to identify biomarkers for FS is the use of metabolomics studies related with global chronic pain conditions and translate those studies in comparative pathology to FS (Aroke and Powell-Roach, 2020). Mantyselka et al. observed that in a group of individuals with chronic musculoskeletal pain the circulating levels of ornithine and amino acids were increased when compared to another group where individuals reported no pain or their pain was not persistent (Mäntyselkä et al., 2017). These results are consistent with a 2019 study investigating biomarkers and glutamate changes in fibromyalgia patients suffering from chronic musculoskeletal pain. The metabolites found to be altered included ornithine, L-arginine, Nε-methyl-L-lysine, L-glutamate, L-glutamine and asymmetric dimethylarginine (ADMA) (Clos-Garcia et al., 2019). Moreover, metabotropic glutamate receptors could also play a role in neuropathic pain (Osikowicz et al., 2013). In the study by Finco et al. higher levels of choline and phosphocholine, citrate, alanine and taurine were seen in patients with neuropathic pain when compared to patients with nociceptive pain (Finco et al., 2016).

Further studies show that lipid metabolism dysregulation is involved in the persistence of pain (Ma et al., 2022). The study by González et al. suggests that serum lipid markers, specifically sphingomyelins and triacylglycerols, are associated with chronic pain (Gonzalez et al., 2022).

These findings could eventually be used to develop primary preventive interventions (Teckchandani et al., 2021).

The evidence that idiopathic FS is associated with glucose and lipid metabolic diseases is increasing. One study observed that some proteins, such as adipokines, adiponectin, leptin and resistin, which are involved in metabolism, have been linked to the development of frozen shoulder (Mäntyselkä et al., 2017).

Moreover, Bunker T. et al. focused on hyperlipidemia as a possible risk factor for frozen shoulder after observing clinical relationships between it and Dupuytren’s contracture (Al-Amrani et al., 2021); this aforementioned study supports the hypothesis that elevated serum lipid levels are associated with frozen shoulder, and demonstrates that low-density hypercholesteremia and lipoprotein hypercholesteremia are progressively associated with frozen shoulder (Al-Amrani et al., 2021).

Again another study found higher expression‎ levels of TNC, which is a lipoprotein involved in cell adhesion, fibroblast migration and other processes related to tissue remodeling and wound healing, in synovial capsule samples from patients with adhesive capsulitis (Mertens et al., 2022).

Molecular biology studies have shown frozen shoulder capsular changes indicating that angiogenesis, inflammatory cell infiltration and expression‎ levels of inflammatory cytokines, such as interleukin (IL1-IL6) increase in frozen shoulder (Hagiwara et al., 2018).

To the best of our knowledge, preliminary results have only been reported in one study regarding this and it showed that the serum total cholesterol level may be related to shoulder stiffness (de La Puerta Vázquez et al., 2004; Sung et al., 2014; Lee et al., 2019).

Etiological and mechanistic research currently lack new hypothesis explaining the spontaneous occurrence of primary FS whereas traumatic secondary FS is much less mystical. Our new perspective of the development of FS, based on the interaction between the brain and the immune holds promise when confirmed by further investigations (Nataf, 2017; Dantzer, 2018).

5 Proposed interventions for frozen shoulder

Current therapies for the treatment of FS are both surgical and non-surgical, although no definitive management model is available yet (Challoumas et al., 2020).

Treatment choice depends mostly on expert opinions and is mostly based on qualitative experience instead of quantitative and recent research (Bridgman, 1972). There is no consensus about the best common treatment for patients with FS (Johnson et al., 2007) and therefore new perspectives are urgently needed.

We propose to use a drug-free treatment protocol based on the different mechanisms and etiological factors known to be part of FS. As chronic anti-inflammatory pharmacological interventions can be deleterious (Johnson et al., 2007; Challoumas et al., 2020), the use of nutrition as medicine could provide valid effects on the inflammatory state or even on the mental state of patients suffering from FS (Brain et al., 2019). Furthermore, experimental and epidemiological data indicate that changes in the source of lipids consumed in the diet can modify the fatty acid composition of many cell types, including cells involved in the development of many inflammatory and immunological diseases (Shibutami and Takebayashi, 2021; Hamed-Hamed et al., 2023). Hence, the use of dietary strategies as part of the FS treatment could be indicated.

The use of pre- and/or certain probiotics, as remedy against disturbances of the microbiome, could provide both acute and chronic inflammatory relief (Ho et al., 2014) through regulation of the immune response and increase in the production of IL-10 (Ho et al., 2014). IL10 is capable of inhibition of cytokine and inflammatory chemokine production (Akdis and Akdis, 2014). Lactobacillus plantarum (L. plantarum), a common used probiotic bacterial strain, inhibits the production of pro-inflammatory cytokines such as TNF- α and IL-6 (Ahn et al., 2019). The possibility of infiltration of pathogenic virus or bacteria as part of the pathophysiology of FS makes it legitimate to propose the use of lactoferrin as a natural antimicrobial, anticarcinogenic, antioxidant, and anti-inflammatory substance (Zimecki and Kruzel, 2007).

Other less known interventions could serve multiple purposes of which the use of therapeutic hypercapnia is perhaps the most indicated one (Tolstun et al., 2022). The use of therapeutic hypercapnia, the search for short term increase of CO2 in the bloodstream up to 50 mmHG by breathing exercises or CO2 devices with a partial pressure of 60–70 mmHG, has shown surprising effects on diet related behavior, blood circulation in the brain, integrity of the blood-brain barrier and immune activity in mice and human (Yang et al., 2019; Tolstun et al., 2022; Tzeng et al., 2022).

The life of the naked mole rat, known for its longevity and resistance against multiple diseases, was used as a model for life expectancy enhancing in rodents (Tolstun et al., 2022). The naked mole rat lives in a natural intermittent hypoxia/hypercapnia environment. Imitating this environment, other rodents also slowed down their metabolism, presented accelerated skin wound healing and reduced their calorie intake with 30%–40% spontaneously (Tolstun et al., 2022). If these results would be confirmed in human we would have a simple way to reduce over-eating as one of the most important deleterious lifestyle factors in modern life. Therapeutic hypercapnia further has profound effects on the immune system. The study of Tzeng (Tzeng et al., 2022), shows that the use of therapeutic hypercapnia ameliorates acute cellular rejection in the skin of a mouse acute allograft rejection model by suppressing the expression‎ of proinflammatory cytokines and neutrophil infiltration, inhibiting T cell activation and accumulation, and inducing Treg cell differentiation (Tzeng et al., 2022). If these effects are confirmed in humans, then the use of a plastic bag rebreathing strategy could be effective to (partially) counter chronic inflammation and reduce calorie intake spontaneously. Already in 1995 (Yang et al., 2019) it was shown that 1–2 min rebreathing in a plastic bag could by slightly increasing CO2 levels in the blood, improve retinal arterial obstructive diseases in young patients (Harino et al., 1995).

Therapeutic and permissive hypercapnia are often used in the same context although there are important differences between them. Therapeutic hypercapnia is based on active inspiration of air with higher pCO2 than normal, whereas permissive hypercapnia is the tolerated CO2 level when lungs are less stressed (Lee et al., 2019). We propose ‘plastic bag rebreathing technics’ as a simple and effective way to increase pCO2 in blood and produce the beneficial effects of hypercapnia. The possibility that this technic causes any damage when controlled for time and tolerance is minimum. Nevertheless, hypercapnia can be damaging as evidenced during the COVID-19 pandemic. During the pandemic, health professionals came in situations in which they used a plastic bag over their head to protect themselves against possible infection with SARS-CoV-2 (Bakirtzi et al., 2016). This way rebreathing their own breath was forced. Three volunteers were used as a model for tolerance measurements and negative effects of forced ‘therapeutic’ hypercapnia (Lee et al., 2020). CO2 levels in the bag increased almost immediately and resulted in significant hypercapnia at termination. Tolerance was reached at 5 min and was produced by breathlessness, anxiety and feelings of distress (Lee et al., 2020). We propose intermittent therapeutic hypercapnia exercises with a length of 90 s and several times per day.

The proposed interventions are drug free, under control of the patients and promising when combined with knowledge transfer about pain, fear, anxiety and depression as assessed by multiple studies of the group of Lorimer Mosely and David Butler (Moseley and Butler, 2015).

6 Conclusion

This study features an integrative view based on the current scientific evidence on FS pathology. Frozen shoulder has been observed to share mechanisms, such as low-grade inflammation and multiple metabolic disturbances, with pathologies such as diabetes and Hasimoto syndrome. Etiology of FS with autoimmune diseases also share essential topics such as the simultaneous presence of immune challenges and psycho-emotional distress at the start of the disease. Knowledge about the interplay between the immune system and the brain gives rise to the development of new treatments for people suffering from FS. Identification of the mechanisms that explain the association between an increased risk for the development of FS in people suffering from type 1 diabetes, Dupuytren, Hashimoto, and axial Spondylarthritis are missing, although several hypotheses have been elaborated in this review. Disorders of the GABA-ergic nervous could be (co-) responsible for the possible association between the mentioned maladies and FS risk. The COVID-19 pandemic increased the incidence of the development of FS, type 1 diabetes, Hashimoto and Dupuytren significantly (de Mello et al., 2023). Fear, anxiety and depression seem were associated with the increased incidence of the mentioned maladies and all three states are related changes in the GABA-ergic nervous system (Kupcova et al., 2023). A possible neurogenic background of FS has recently been elucidated in a small study with 10 patients who received a central nervous system combined treatment with significant improvement (Mena-Del Horno et al., 2022). We further propose the possibility that FS, just as the associated maladies has an autoimmune background. The striking increase of FS when suffering from several autoimmune diseases, including but less mentioned axSA, suggests a possible auto-immune background for FS. Both explanations do not exclude one of them. The opposite is true. The way the brain and the immune system interplay when faced with simultaneous immune and psycho-emotional challenges increased the possibility that immune cells are primed against super-autoantigens in the brain and it are these antigens that are also present in peripheral tissues and organs. If those primed T lymphocytes can destroy Beta-cells of Langerhans, it is plausible that these Teffector cells can destroy other tissues when faced with the same antigen. There are important indications for the presence of a possible neuroimmune connection as cause for FS and several other diseases; nevertheless this new perspective about the etiology of FS has to be confirmed with new mechanistic research.

Funding Statement

The author(s) declare that financial support was received for the research, authorship, and/or publication of this article. This study was partially funded by University Chair in Clinical Psychoneuroimmunology, University of Granada, Spain.

Author contributions

Study conception (SN-L and DH), design (SN-L and DH), acquisition of data (SN-L), analysis and interpretation of data (SN-L, DH, and LP) drafting of manuscript (SN-L, DH, and LP) and critical revision (SN-L, DH, and LP). All authors contributed to the article and approved the submitted version.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

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