Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder

doi:10.1016/j.jse.2012.06.014

Journal of Shoulder and Elbow Surgery

Volume 22, Issue 5, May 2013, Pages 666-672

https://doi.org/10.1016/j.jse.2012.06.014 Get rights and content

Background

Frozen shoulder is a debilitating condition characterized by gradual loss of glenohumeral motion with chronic inflammation and capsular fibrosis. Yet its pathogenesis remains largely unknown. We hypothesized that the subacromial bursa may be responsible for the pathogenesis of frozen shoulder by producing inflammatory cytokines.

Materials and methods

We obtained joint capsules and subacromial bursae from 14 patients with idiopathic frozen shoulder and from 7 control subjects to determine the expression levels of interleukin (IL) 1α, IL-1β, IL-6, tumor necrosis factor α (TNF-α), cyclooxygenase (COX) 1, and COX-2 by real-time reverse transcriptase–polymerase chain reaction, immunohistochemistry, and enzyme-linked immunosorbent assay.

Results

IL-1α, IL-1β, TNF-α, COX-1, and COX-2 were expressed at significantly high levels in the joint capsules of the frozen shoulder group compared with those of the control group. Intriguingly, IL-1α, TNF-α, and COX-2 were also expressed at significantly high levels in the subacromial bursae of the frozen shoulder group compared with those of the control group. Immunohistochemical analysis showed increased expression of COX-2 in both the joint capsules and subacromial bursae of the frozen shoulder group.

Conclusions

These findings imply that elevated levels of inflammatory cytokines in the subacromial bursa may be associated with the pathogenesis of inflammation evolving into fibrosis.

Section snippets

Tissue samples

We studied 14 patients undergoing arthroscopic capsular release for idiopathic frozen shoulder after conservative treatment failed. Inclusion criteria included global restriction of passive shoulder motion with normal findings on plain radiographs; no pathologic findings regarding the rotator cuff, labrum, long head of the biceps, or acromioclavicular joint on magnetic resonance imaging; and no risk factors such as diabetes, cardiovascular disease, or thyroid disease. The diagnosis of frozen

Inflammatory cytokines are increased in both joint capsule and subacromial bursa

We first assessed the mRNA expression levels of cytokines in both joint capsules and subacromial bursae. IL-1α levels in patients with frozen shoulder were elevated in both the joint capsule (1.5 ± 0.15, P < .05) and the subacromial bursa (2.3 ± 0.24, P < .05) compared with those in the control group (1.0 ± 0.01 in joint capsule and 2.0 ± 0.06 in subacromial bursa) (Fig. 1, A, left panel). However, expression levels of IL-1β were increased only in the joint capsule (4.3 ± 0.3, P < .05) compared

Discussion

It has generally been accepted that inflammation and fibrosis of the joint capsule together are the main source of pain and limited motion in frozen shoulder.11, 17, 23 Despite much research, the etiology and pathologic mechanisms that lead to the development of frozen shoulder are poorly understood, and there is no consensus on the optimal treatment.17, 21, 22, 26 Current efforts are focused on determining both an immunologic basis for frozen shoulder and the role of cell signaling and

Conclusions

We showed that IL-1α, IL-6, TNF-α, and COX-2 were expressed at significantly high levels in the subacromial bursae in patients with frozen shoulder. These findings imply that elevated levels of inflammatory cytokines in the subacromial bursa as well as joint capsule may contribute to generate pain in frozen shoulder and may be associated with the pathogenesis of inflammation evolving into fibrosis.

Acknowledgment

English-language editing was provided by Katharine O'Moore-Klopf, ELS (East Setauket, NY, USA).

Disclaimer

The authors, their immediate families, and any research foundations with which they are affiliated have not received any financial payments or other benefits from any commercial entity related to the subject of this article.

The biospecimens for this study were provided by the Keimyung Human Bio-Resource Bank, a member of the National Biobank of Korea, which is supported by the Ministry of Health, Welfare, and Family Affairs.

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Improved range of motion after manipulation under anesthesia versus physiotherapy for stage two frozen shoulder: a randomized controlled trial
2024, JSES International
Frozen shoulder (FS) is a common cause of shoulder pain and stiffness. Conservative treatment is sufficient for the majority of patients with long-term recovery of shoulder function. Manipulation under anesthesia (MUA) is known as a well-established treatment option if conservative treatment fails. It is unknown whether MUA does indeed shorten the duration of symptoms or leads to a superior outcome compared to conservative treatment. The objective of the current trial is to evaluate the effectiveness of MUA followed by a physiotherapy (PT) program compared to a PT program alone in patients with stage 2 FS.
A prospective, single-center randomized controlled trial was performed. Patients between 18 and 70 years old with stage 2 FS were deemed eligible if an initial course of conservative treatment consisting of PT and intra-articular corticosteroid infiltration was considered unsatisfactory. Patients were randomized, and data was collected with an online data management platform (CASTOR). MUA was performed by a single surgeon under interscalene block, and intensive PT treatment protocol was started within 4 hours after MUA. In the PT group, patients were referred to instructed physiotherapist, and treatment was guided by tissue irritability. The primary outcome was the Shoulder Pain and Disability Index (SPADI) score. Secondary outcomes were pain, range of motion (ROM), Oxford Shoulder Score, quality of life, and ability to work.
In total, 82 patients were included, 42 in the PT group and 40 in the MUA group. There was a significant improvement in SPADI, Oxford Shoulder Score, pain, ROM, and quality of life in both groups at 1-year follow-up. SPADI scores at three months were significantly improved in favor of MUA. MUA showed a significantly bigger increase in anteflexion and abduction compared to PT at all points of follow-up. No significant differences between both groups were found for all other parameters. No fractures, dislocations, or brachial plexus injuries occurred in this trial.
MUA in stage 2 FS can be considered safe and results in a faster recovery of ROM and improved functional outcome, measured with SPADI scores, compared to PT alone in the short term. After 1 year, except for slightly better ROM scores for MUA, the result of MUA is equal to PT.
Type 2 diabetes and fasting glycemic traits are causal factors of frozen shoulder: a 2-sample Mendelian randomization analysis
2024, Journal of Shoulder and Elbow Surgery
The causal relationship between type 2 diabetes (T2D) and frozen shoulder is unclear. This study aims to explore the genetic causal association between T2D and glycemic traits (fasting glucose [FG], fasting insulin [FI], glycated hemoglobin [HbA_1c], and 2-hour postprandial glucose [2hGlu]) on frozen shoulder.
Using 2-sample Mendelian randomization (MR), we analyzed nonconfounded estimates of the effects of T2D and glycemic traits on frozen shoulder. Single-nucleotide polymorphisms (SNPs) strongly associated (P < 5 × 10^–8) with exposures from genome-wide association studies (GWAS) were identified. We employed fixed effect mode inverse variance weighting (IVW-FE), random effect mode IVW (IVW-MRE), MR-Egger, and weighted median to assess the association of exposures and outcome. Sensitivity analysis was conducted to test for heterogeneity and multidirectionality bias in MR.
We found a significant genetic causal correlation between T2D (IVW-MRE P = .007, odds ratio [OR] 1.093, 95% confidence interval [CI] 1.03-1.16), FG (IVW-FE P < .001, OR 1.455, 95% CI 1.173-1.806), and frozen shoulder, but no evidence for causal correlation between FI, HbA_1c, and 2hGlu and frozen shoulder. Although there was certain heterogeneity, sensitivity analysis reveals no deviation from the MR assumptions.
This study supports a genetic causal relationship between T2D and FG and frozen shoulder.
Effect of angiotensin converting enzyme inhibitors and angiotensin II receptor blockers on need for operative intervention for idiopathic adhesive capsulitis
2023, JSES International
The exact pathogenesis of idiopathic adhesive capsulitis (IAC) is not fully understood, but an inflammatory profibrotic cascade, largely mediated by transforming growth factor-beta 1 (TGF- β1) has been implicated. Angiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACE-Is) both decrease the activity of TGF-β1. The aim of this study was to determine the impact of ACE-Is or ARBs use on the need for operative intervention in IAC.
This was a retrospective cohort study of patients from a single institutional database with IAC, divided into two cohorts, with and without ACE-I and/or ARB use as the primary exposure and a minimum 2-year follow-up. The primary outcome measured was the incidence of operative intervention including manipulation under anesthesia (MUA) and arthroscopic capsular release (ACR). Additional multivariable logistic regression analysis was performed to evaluate associations between ACE-I/ARB use and likelihood of undergoing an operative procedure.
A total of 17,645 patients met inclusion criteria, with 5424 patients in the ACE-I/ARB cohort and 12,221 in the non-ACE-I/ARB cohort. Overall, 422 (2.4%) patients underwent surgical treatment, 378 (2.1%) ACR, and 74 (0.4%) MUA. There was no significant difference between cohorts in the frequency of surgical procedures or time to procedure since diagnosis. There were no significant differences between individual ACE-Is or ARBs, although Losartan was found to have a trend of decreased rate of intervention (31.7% vs. 36.8%, P = .209) when compared to patients not on losartan that did not reach statistical significance. Patient factors predictive of undergoing MUA/ACR were diabetes (P = .013), obesity (P < .001), and male sex (P < .001). Increasing patient age reduces the likelihood of undergoing operative intervention, with patients aged 50-70 years (P = .022) and age >70 years (P < .001) demonstrating reduced odds as compared to patients aged <30 years.
Patients with IAC have an overall low (2.4%) rate of requiring surgical intervention. While the antifibrotic mechanism of ACE inhibitors and ARBs did not significantly affect the rate of requiring surgical intervention, male gender, obesity, younger age, and diabetes, all increased the risk for operative intervention. Losartan, specifically, may have a disease modifying effect on IAC that should be investigated with larger controlled trials.
What is the most predictive magnetic resonance imaging finding of rotator cuff tear concomitant with shoulder stiffness?
2023, JSES International
Common magnetic resonance imaging (MRI) findings in adhesive capsulitis are not often evident in rotator cuff tear concomitant with shoulder stiffness. This study aimed to determine the most predictive MRI finding of rotator cuff tear with shoulder stiffness to differentiate from that without stiffness.
The data of patients who underwent arthroscopic rotator cuff repair between January 2014 and October 2019 were retrospectively reviewed. Stiffness was defined as forward flexion <120°, external rotation at side <30°, and internal rotation at back <L3 in the active range of motion. Propensity score matching (1-to-1) was performed between the stiff and control groups by sex, age, and tear size, and 76 patients per group were matched. Anterior capsular thickness, maximal humeral/glenoid capsular thickness in the axillary recess, coracohumeral ligament thickness, the presence of hyperintensity in the anterior capsule and humeral/glenoid capsule in the axillary recess, and hyperintensity and obliteration of the subcoracoid fat triangle were evaluated.
Anterior capsular thickness, glenoid capsular thickness in the axillary recess, and anterior and axillary capsular hyperintensities were significantly more dominant in the stiff group (all P < .05) than in the control group. Anterior capsular thickness and anterior capsular abnormal hyperintensity could be used to differentiate between the stiff and control groups (P < .05). Anterior capsular thickness showed high diagnostic performance with an area under the receiver operating characteristic curve of 0.993. The cut-off value for stiffness was 3.07 mm (sensitivity, 96.1%; specificity, 100%).
Anterior capsular thickening and abnormal hyperintensity were the most predictive MRI findings for stiffness in patients with rotator cuff tear and stiffness to differentiate from patients with rotator cuff tear without stiffness.
Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors Have No Significant Relationship With Postoperative Arthrofibrosis After Shoulder Arthroscopy
2023, Arthroscopy, Sports Medicine, and Rehabilitation
To determine the effect of perioperative angiotensin II receptor blocker (ARB) or angiotensin-converting enzyme inhibitors (ACEi) on postoperative arthrofibrosis, as defined by requiring manipulation under anesthesia (MUA) or new diagnosis of adhesive capsulitis (AC) following arthroscopic shoulder procedures.
Patients were retrospectively identified using Current Procedural Terminology surgical billing codes to identify patients who underwent any shoulder arthroscopic procedure at a single urban academic institution from 2012 to 2020 with a minimum 2-year follow-up. Patients were excluded if <30 years old at time of surgery, as these patients rarely use ARB and ACEi medications, or if they had pre-existing AC. Demographics, active medication prescriptions at the time of surgery, and medical comorbidities were recorded. Multivariable logistic regression was performed to determine the effect of ARB/ACEi on subsequent MUA or AC by 90 days, 1 year, and 2 years.
In total, 5,559 patients were included in the final analysis. A majority of the cohort (53.4%) underwent arthroscopic surgery between the ages of 50 to 69 years. Most patients were male (61.8%) and without obesity (67.3%). In total, 18.9% and 15.0% were taking an ARB or ACEi medication perioperatively, respectively. Within 2 years’ postoperatively, 51 patients (0.9%) underwent subsequent ipsilateral MUA, and 174 patients (3.1%) developed AC. Patients taking ARBs had a 17.5% rate of postoperative arthrofibrosis within 2-years compared with 19.1% in those not on ARBs, although this difference was not significant (P = .58). Likewise, no significant difference was found between those taking ACEi versus not (15.0% vs 15.0%, P = .99). Individual generic ARB/ACEi subgroup analysis did not demonstrate any significant associations with rate of postoperative arthrofibrosis (P > .05).
ARBs or ACEi did not significantly affect the rate of postoperative arthrofibrosis following shoulder arthroscopy, however female sex, diabetes mellitus, and Black/African American race were associated with an increased rate of necessitating MUA or developing AC within 2 years postoperatively.
Level III, retrospective cohort study.
Adhesive Capsulitis
2023, Physical Medicine and Rehabilitation Clinics of North America

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: The authors obtained the approval of Keimyung University Dongsan Medical Center Institutional Review Board (No. 11267).

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Basic scienceInflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder

Background

Materials and methods

Results

Conclusions

Section snippets

Tissue samples

Inflammatory cytokines are increased in both joint capsule and subacromial bursa

Discussion

Conclusions

Acknowledgment

Disclaimer

J Orthop Res

J Orthop Sci

Arch Phys Med Rehabil

J Shoulder Elbow Surg

J Shoulder Elbow Surg

J Shoulder Elbow Surg

Arthroscopy

Orthop Clin North Am

J Shoulder Elbow Surg

Adhesive capsulitis of the shoulder: therapeutic contribution of subacromial bursography

Rev Rhum Engl Ed

The molecular pathophysiology of subacromial bursitis in rotator cuff disease

J Shoulder Elbow Surg

Frozen shoulder: prospective clinical study with an evaluation of three treatment regimens

Ann Rheum Dis

Expression of growth factors, cytokines and matrix metalloproteinases in frozen shoulder

J Bone Joint Surg Br

Injections and physiotherapy for the painful stiff shoulder

Ann Rheum Dis

Basic science
Inflammatory cytokines are overexpressed in the subacromial bursa of frozen shoulder