Publications by authors named "Neal L Millar"

55 Publications

Targeting the CCR6/CCL20 axis in entheseal and cutaneous inflammation.

Arthritis Rheumatol 2021 Jun 3. Epub 2021 Jun 3.

Department of Dermatology, University of California, Davis, Sacramento, CA, USA.

Objectives: To assess the involvement of the CCR6/CCL20 axis in psoriatic arthritis (PsA) and psoriasis (PsO) and to evaluate its potential as a therapeutic target.

Methods: First, we quantified CCL20 levels in peripheral blood and synovial fluid of PsA patients and the presence of CCR6 cells in synovial and tendon tissue. Utilizing an IL-23 minicircle DNA (MC) mouse model exhibiting key features of both PsO and PsA, we investigated CCR6 and CCL20 expression and the preventive and therapeutical effect of CCL20 blockade. Healthy tendon stromal cells were stimulated in vitro with IL-1β to assess the production of CCL20 by qPCR and ELISA. The effect of conditioned media from stimulated tenocytes in inducing T cell migration was interrogated with a transwell system.

Results: We observed an upregulation of both CCR6 and CCL20 in the enthesis of IL-23 MC-treated mice, which was confirmed in human biopsies. Specific targeting of the CCR6/CCL20 axis with a CCL20 locked dimer (CCL20LD) blocked entheseal inflammation, leading to profound reductions in clinical and proinflammatory markers in the joints and skin of IL-23 MC-treated mice. The stromal compartment in the tendon was the main source of CCL20 in this model and accordingly, in vitro activated human tendon cells were able to produce this chemokine and to induce CCR6+ T cell migration, the latter of which could be blocked by CCL20LD.

Conclusions: Our studies highlight the pathogenic role of CCR6-CCL20 axis in enthesitis and raise the prospect of a novel therapeutic approach for treating patients with PsO and PsA.
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http://dx.doi.org/10.1002/art.41882DOI Listing
June 2021

Single cell and spatial transcriptomics in human tendon disease indicate dysregulated immune homeostasis.

Ann Rheum Dis 2021 May 17. Epub 2021 May 17.

Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK

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http://dx.doi.org/10.1136/annrheumdis-2021-220256DOI Listing
May 2021

Do we need to improve the reporting of evidence in tendinopathy management? A critical appraisal of systematic reviews with recommendations on strength of evidence assessment.

BMJ Open Sport Exerc Med 2021 23;7(1):e000920. Epub 2021 Feb 23.

Institute of Infection, Immunity and Inflammation College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Objective: To critically appraise the quality of published systematic reviews (SRs) of randomised controlled trials (RCTs) in tendinopathy with regard to handling and reporting of results with special emphasis on strength of evidence assessment.

Data Sources: Medline from inception to June 2020.

Study Eligibility: All SRs of RCTs assessing the effectiveness of any intervention(s) on any location of tendinopathy.

Data Extraction And Synthesis: Included SRs were appraised with the use of a 12-item tool devised by the authors arising from the Preferred Reporting Items in Systematic Reviews and Meta-Analyses statement and other relevant guidance. Subgroup analyses were performed based on impact factor (IF) of publishing journals and date of publication.

Results: A total of 57 SRs were included published in 38 journals between 2006 and 2020. The most commonly used risk-of-bias (RoB) assessment tool and strength of evidence assessment tool were the Cochrane Collaboration RoB tool and the Cochrane Collaboration Back Review Group tool, respectively. The mean score on the appraisal tool was 46.5% (range 0%-100%). SRs published in higher IF journals (>4.7) were associated with a higher mean score than those in lower IF journals (mean difference 26.4%±8.8%, p=0.004). The mean score of the 10 most recently published SRs was similar to that of the first 10 published SRs (mean difference 8.3%±13.7%, p=0.54). Only 23 SRs (40%) used the results of their RoB assessment in data synthesis and more than half (n=30; 50%) did not assess the strength of evidence of their results. Only 12 SRs (21%) assessed their strength of evidence appropriately.

Conclusions: In light of the poor presentation of evidence identified by our review, we provide recommendations to increase transparency and reproducibility in future SRs.
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http://dx.doi.org/10.1136/bmjsem-2020-000920DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907875PMC
February 2021

Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease.

Ann Rheum Dis 2021 Mar 10. Epub 2021 Mar 10.

Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK

Objectives: Increasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation.

Methods: T cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes.

Results: Significant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte-T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio.

Conclusions: Interaction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.
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http://dx.doi.org/10.1136/annrheumdis-2020-219335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292554PMC
March 2021

Recent advances in tendinopathy.

Fac Rev 2020 19;9:16. Epub 2020 Nov 19.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, The University of Glasgow, Glasgow, UK.

Tendinopathy refers to the clinical diagnosis of activity-related pain resulting in a decline in tendon function. In the last few years, much has been published concerning the basic science and clinical investigation of tendinopathy and debates and discussions to new questions and points of view started many years ago. This advances review will discuss the current thinking on the basic science and clinical management of tendinopathy and in particular new findings in the tendon repair space that are relevant to the pathophysiology of tendinopathy. We will further discuss potential novel therapies on the horizon in human tendon disease.
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http://dx.doi.org/10.12703/b/9-16DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7886058PMC
November 2020

Author Correction: Tendinopathy.

Nat Rev Dis Primers 2021 Feb 3;7(1):10. Epub 2021 Feb 3.

Hospital for Special Surgery, New York, NY, USA.

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http://dx.doi.org/10.1038/s41572-021-00251-8DOI Listing
February 2021

Short-Term Western Diet Intake Promotes IL-23‒Mediated Skin and Joint Inflammation Accompanied by Changes to the Gut Microbiota in Mice.

J Invest Dermatol 2021 Jul 22;141(7):1780-1791. Epub 2021 Jan 22.

Department of Dermatology, University of California Davis School of Medicine, Sacramento, California, USA. Electronic address:

We previously showed that exposure to a high-sugar and moderate-fat diet (i.e., Western diet [WD]) in mice induces appreciable skin inflammation and enhances the susceptibility to imiquimod-induced psoriasiform dermatitis, suggesting that dietary components may render the skin susceptible to psoriatic inflammation. In this study, utilizing an IL-23 minicircle-based model with features of both psoriasiform dermatitis and psoriatic arthritis, we showed that intake of WD for 10 weeks predisposed mice not only to skin but also to joint inflammation. Both WD-induced skin and joint injuries were associated with an expansion of IL-17A‒producing γδ T cells and increased expression of T helper type 17 cytokines. After IL-23 minicircle delivery, WD-fed mice had reduced microbial diversity and pronounced dysbiosis. Treatment with broad-spectrum antibiotics suppressed IL-23‒mediated skin and joint inflammation in the WD-fed mice. Strikingly, reduced skin and joint inflammation with a partial reversion of the gut microbiota were noted when mice switched from a WD to a standard diet after IL-23 minicircle delivery. These findings reveal that a short-term WD intake‒induced dysbiosis is accompanied by enhanced psoriasis-like skin and joint inflammation. Modifications toward a healthier dietary pattern should be considered in patients with psoriatic skin and/or joint disease.
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http://dx.doi.org/10.1016/j.jid.2020.11.032DOI Listing
July 2021

Basic Science of Tendinopathy and Novel Treatments: An Update.

Instr Course Lect 2021 ;70:551-562

Tendinopathy describes a spectrum of degenerative and inflammatory changes occurring in tendons, usually caused by mechanical loading. It is associated with pain and reduced function and can often lead to tendon rupture. Although advances have been made in recent years, it remains challenging to manage tendinopathy because its definition and the understanding of its risk factors and pathophysiology are still evolving. The objective of this chapter is to present current ideas on the basic science of tendinopathy and in particular new findings in regard to pathophysiology. Current therapies and insights into potential novel therapies for tendinopathy are also discussed.
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January 2021

Tendinopathy.

Nat Rev Dis Primers 2021 01 7;7(1). Epub 2021 Jan 7.

Hospital for Special Surgery, New York, NY, USA.

Tendinopathy describes a complex multifaceted pathology of the tendon, characterized by pain, decline in function and reduced exercise tolerance. The most common overuse tendinopathies involve the rotator cuff tendon, medial and lateral elbow epicondyles, patellar tendon, gluteal tendons and the Achilles tendon. The prominent histological and molecular features of tendinopathy include disorganization of collagen fibres, an increase in the microvasculature and sensory nerve innervation, dysregulated extracellular matrix homeostasis, increased immune cells and inflammatory mediators, and enhanced cellular apoptosis. Although diagnosis is mostly achieved based on clinical symptoms, in some cases, additional pain-provoking tests and imaging might be necessary. Management consists of different exercise and loading programmes, therapeutic modalities and surgical interventions; however, their effectiveness remains ambiguous. Future research should focus on elucidating the key functional pathways implicated in clinical disease and on improved rehabilitation protocols.
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http://dx.doi.org/10.1038/s41572-020-00234-1DOI Listing
January 2021

Vancomycin Wrap for Anterior Cruciate Ligament Surgery: Molecular Insights.

Am J Sports Med 2021 02 6;49(2):426-434. Epub 2021 Jan 6.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences University of Glasgow, Glasgow, UK.

Background: The use of the vancomycin wrap to pretreat the hamstring graft in anterior cruciate ligament reconstruction (ACLR) has grown in popularity since it was first described in 2012 and has significantly reduced rates of postoperative infection. However, it remains unknown if this antibiotic treatment affects the molecular composition of the graft.

Purpose: To establish whether treatment with vancomycin at 5 mg/mL, the most commonly used concentration, alters the molecular function of the hamstring graft in ACLR.

Study Design: Controlled laboratory study.

Methods: Surplus hamstring tendon collected after routine ACLR surgery was used for in vitro cell culture and ex vivo tissue experiments. Vancomycin was used at 5 mg/mL in RPMI or saline diluent to treat cells and tendon tissue, respectively, with diluent control conditions. Cell viability at 30, 60, and 120 minutes was assessed via colorimetric viability assay. Tendon cells treated with control and experimental conditions for 1 hour was evaluated using semiquantitative reverse transcription analysis, immunohistochemistry staining, and protein quantitation via enzyme-linked immunosorbent assay for changes in apoptotic, matrix, and inflammatory gene and protein expression.

Results: Vancomycin treatment at 5 mg/mL significantly reduced tenocyte viability in vitro after 60 minutes of treatment ( < .05); however, this was not sustained at 120 minutes. Vancomycin-treated tendon tissue showed no significant increase in apoptotic gene expression, or apoptotic protein levels in tissue or supernatant, ex vivo. Vancomycin was associated with a reduction in inflammatory proteins from treated tendon supernatants (IL-6; < .05).

Conclusion: Vancomycin did not significantly alter the molecular structure of the hamstring graft. Reductions in matrix protein and inflammatory cytokine release point to a potential beneficial effect of vancomycin in generating a homeostatic environment.

Clinical Relevance: Vancomycin ACL wrap does not alter the molecular structure of the ACL hamstring graft and may improve graft integrity.
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http://dx.doi.org/10.1177/0363546520981570DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859666PMC
February 2021

Comparison of Treatments for Frozen Shoulder: A Systematic Review and Meta-analysis.

JAMA Netw Open 2020 12 1;3(12):e2029581. Epub 2020 Dec 1.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Scotland, United Kingdom.

Importance: There are a myriad of available treatment options for patients with frozen shoulder, which can be overwhelming to the treating health care professional.

Objective: To assess and compare the effectiveness of available treatment options for frozen shoulder to guide musculoskeletal practitioners and inform guidelines.

Data Sources: Medline, EMBASE, Scopus, and CINHAL were searched in February 2020.

Study Selection: Studies with a randomized design of any type that compared treatment modalities for frozen shoulder with other modalities, placebo, or no treatment were included.

Data Extraction And Synthesis: Data were independently extracted by 2 individuals. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline. Random-effects models were used.

Main Outcomes And Measures: Pain and function were the primary outcomes, and external rotation range of movement (ER ROM) was the secondary outcome. Results of pairwise meta-analyses were presented as mean differences (MDs) for pain and ER ROM and standardized mean differences (SMDs) for function. Length of follow-up was divided into short-term (≤12 weeks), mid-term (>12 weeks to ≤12 months), and long-term (>12 months) follow-up.

Results: From a total of 65 eligible studies with 4097 participants that were included in the systematic review, 34 studies with 2402 participants were included in pairwise meta-analyses and 39 studies with 2736 participants in network meta-analyses. Despite several statistically significant results in pairwise meta-analyses, only the administration of intra-articular (IA) corticosteroid was associated with statistical and clinical superiority compared with other interventions in the short-term for pain (vs no treatment or placebo: MD, -1.0 visual analog scale [VAS] point; 95% CI, -1.5 to -0.5 VAS points; P < .001; vs physiotherapy: MD, -1.1 VAS points; 95% CI, -1.7 to -0.5 VAS points; P < .001) and function (vs no treatment or placebo: SMD, 0.6; 95% CI, 0.3 to 0.9; P < .001; vs physiotherapy: SMD 0.5; 95% CI, 0.2 to 0.7; P < .001). Subgroup analyses and the network meta-analysis demonstrated that the addition of a home exercise program with simple exercises and stretches and physiotherapy (electrotherapy and/or mobilizations) to IA corticosteroid may be associated with added benefits in the mid-term (eg, pain for IA coritocosteriod with home exercise vs no treatment or placebo: MD, -1.4 VAS points; 95% CI, -1.8 to -1.1 VAS points; P < .001).

Conclusions And Relevance: The findings of this study suggest that the early use of IA corticosteroid in patients with frozen shoulder of less than 1-year duration is associated with better outcomes. This treatment should be accompanied by a home exercise program to maximize the chance of recovery.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.29581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745103PMC
December 2020

Effectiveness of isometric exercise in the management of tendinopathy: a systematic review and meta-analysis of randomised trials.

BMJ Open Sport Exerc Med 2020 4;6(1):e000760. Epub 2020 Aug 4.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Objective: To systematically review and critically appraise the literature on the effectiveness of isometric exercise in comparison with other treatment strategies or no treatment in tendinopathy.

Design: A systematic review and meta-analysis of randomised controlled trials.

Data Sources: Electronic searches of Medline, Cumulative Index to Nursing and Allied Health Literature, EMBASE and Cochrane were undertaken from inception to May 2020.

Methods: Overall quality of each study was determined based on a combined assessment of internal validity, external validity and precision. For each outcome measure, level of evidence was rated based on the system by van Tulder .

Results: Ten studies were identified and included in the review, including participants with patellar (n=4), rotator cuff (n=2), lateral elbow (n=2), Achilles (n=1) and gluteal (n=1) tendinopathies. Three were of good and seven were of poor overall quality. Based on limited evidence (level 3), isometric exercise was not superior to isotonic exercise for chronic tendinopathy either immediately following treatment or in the short term (≤12 weeks) for any of the investigated outcome measures. Additionally, for acute rotator cuff tendinopathy, isometric exercise appears to be no more effective than ice therapy in the short term (limited evidence; level 3).

Summary: Isometric exercise does not appear to be superior to isotonic exercise in the management of chronic tendinopathy. The response to isometric exercise is variable both within and across tendinopathy populations. Isometric exercise can be used as part of a progressive loading programme as it may be beneficial for selected individuals.

Prospero Registration Number: CRD42019147179.
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http://dx.doi.org/10.1136/bmjsem-2020-000760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7406028PMC
August 2020

Attenuation of Dupuytren's fibrosis via targeting of the STAT1 modulated IL-13Rα1 response.

Sci Adv 2020 Jul 10;6(28):eaaz8272. Epub 2020 Jul 10.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences University of Glasgow, Glasgow, Scotland, UK.

Fibrotic disorders represent common complex disease pathologies that are therapeutically challenging. Inflammation is associated with numerous fibrotic pathogeneses; however, its role in the multifaceted mechanisms of fibrosis remains unclear. IL-13 is implicated in aberrant responses involved in fibrotic disease, and we aimed to understand its role in the inflammatory processes of a common fibrotic disorder, Dupuytren's disease. We demonstrated T-cells produced IFN-g, which induced IL-13 secretion from mast cells and up-regulated IL-13Ra1 on fibroblasts, rendering them more reactive to IL-13. Consequently, diseased myofibroblasts demonstrated enhanced fibroproliferative effects upon IL-13 stimulation. We established IFN-g and IL-13 responses involved STAT dependent pathways, and STAT targeting (tofacitinib) could inhibit IL-13 production from mast cells, IL-13Ra1 up-regulation in fibroblasts and fibroproliferative effects of IL-13 on diseased myofibroblasts. Accordingly, utilizing Dupuytren's as an accessible human model of fibrosis, we propose targeting STAT pathways may offer previously unidentified therapeutic approaches in the management of fibrotic disease.
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http://dx.doi.org/10.1126/sciadv.aaz8272DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351483PMC
July 2020

Treatment of periscapular tendinopathy with radiofrequency coblation: A case report.

SAGE Open Med Case Rep 2020 9;8:2050313X20930612. Epub 2020 Jul 9.

Institute of Infection, Immunity and Inflammation, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Overuse injuries of the tendon - 'tendinopathy' - account for 30%-50% of all sporting injuries and a high proportion of orthopaedic referrals from primary care physicians. Tendinopathies often have a multifactorial aetiology and injury can be due to a combination of both acute and chronic trauma which contributes to loss of tissue integrity and eventual rupture. Our incomplete understanding of the mechanisms surrounding tendon pathophysiology continues to cause difficulties in treatments beyond loading regimes which can be unsuccessful in up to 30% of cases. We describe an uncommon case of tendinopathy affecting the periscapular muscle/tendon unit in a 35-year-old female with persistent pain around the inferior posterior pole of her right scapula. Magnetic resonance imaging findings confirmed oedema of the muscles around the inferior scapular margin in keeping with enthesopathy/tendinopathy and she was treated with radiofrequency coblation to the area. This case highlights radiofrequency ablation as a surgical option should non-operative treatments fail in the rare diagnosis of periscapular tendinopathy.
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http://dx.doi.org/10.1177/2050313X20930612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350035PMC
July 2020

Distinct synovial tissue macrophage subsets regulate inflammation and remission in rheumatoid arthritis.

Nat Med 2020 08 29;26(8):1295-1306. Epub 2020 Jun 29.

Research into Inflammatory Arthritis Centre Versus Arthritis (RACE), .

Immune-regulatory mechanisms of drug-free remission in rheumatoid arthritis (RA) are unknown. We hypothesized that synovial tissue macrophages (STM), which persist in remission, contribute to joint homeostasis. We used single-cell transcriptomics to profile 32,000 STMs and identified phenotypic changes in patients with early/active RA, treatment-refractory/active RA and RA in sustained remission. Each clinical state was characterized by different frequencies of nine discrete phenotypic clusters within four distinct STM subpopulations with diverse homeostatic, regulatory and inflammatory functions. This cellular atlas, combined with deep-phenotypic, spatial and functional analyses of synovial biopsy fluorescent activated cell sorted STMs, revealed two STM subpopulations (MerTKTREM2 and MerTKLYVE1) with unique remission transcriptomic signatures enriched in negative regulators of inflammation. These STMs were potent producers of inflammation-resolving lipid mediators and induced the repair response of synovial fibroblasts in vitro. A low proportion of MerTK STMs in remission was associated with increased risk of disease flare after treatment cessation. Therapeutic modulation of MerTK STM subpopulations could therefore be a potential treatment strategy for RA.
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http://dx.doi.org/10.1038/s41591-020-0939-8DOI Listing
August 2020

Differential Requirement for CCR6 in IL-23-Mediated Skin and Joint Inflammation.

J Invest Dermatol 2020 12 24;140(12):2386-2397. Epub 2020 Apr 24.

Department of Dermatology, University of California, Davis, Sacramento, California, USA. Electronic address:

CCR6 is important for the trafficking of IL-17A-producing γδ T cells and required for the development of psoriasiform dermatitis in an IL-23 intradermal injection model. The role of CCR6, however, in IL-23-mediated joint inflammation is unclear. We herein hydrodynamically delivered IL-23 minicircle DNA into wild-type and CCR6-deficient (CCR6-knockout) mice to induce overexpression of IL-23 systemically. After IL-23 gene transfer, wild-type mice exhibited concurrent skin and joint changes that recapitulate some features found in human psoriatic skin and joints. CCR6-knockout mice were resistant to IL-23-induced skin inflammation but exhibited no changes in joint inflammation compared with wild-type mice. Depletion of neutrophils protected wild-type mice from skin and joint disease without suppressing T helper type 17 cytokine expression. In contrast, mice lacking γδ T cells showed a partial reduction in neutrophilic recruitment and a significant decrease in IL-17A expression in skin and paw tissue. Thus, in an IL-23-mediated model that allows concurrent assessment of both skin and joint disease, we showed that CCR6 is critical for inflammation in the skin but not in the joint. Furthermore, our data suggest that neutrophils and γδ T cells are key effector cells in IL-23-mediated skin and joint inflammation in mice.
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http://dx.doi.org/10.1016/j.jid.2020.03.965DOI Listing
December 2020

Isometric versus isotonic exercise for greater trochanteric pain syndrome: a randomised controlled pilot study.

BMJ Open Sport Exerc Med 2019 21;5(1):e000558. Epub 2019 Sep 21.

Institute of Infection, Immunity and Inflammation, College of Medical Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Objectives: Greater trochanteric pain syndrome (GTPS) is a common cause of lateral hip pain. Limited evidence exists for the effectiveness of exercise for GTPS. This study aimed to compare the effectiveness of isometric and isotonic exercise for individuals with GTPS.

Methods: This randomised controlled pilot trial recruited 30 participants with GTPS. Both programmes consisted of daily, progressive home exercise for 12 weeks with 8 individual physiotherapy sessions over the trial period. The primary outcome measure was the Victorian Institute of Sport Assessment-Gluteal (VISA-G) and secondary outcome measures included the Numeric Pain Rating Scale (0-10) and an 11-point Global Rating of Change Scale. Outcome measures were assessed at baseline, 4 and 12 weeks.

Results: Twenty-three participants completed the trial. After 12 weeks, mean VISA-G scores improved in both groups; 55-65 in the isometric group and 62-72 in the isotonic group. 55% of the isometric group and 58% of the isotonic group achieved a reduction in pain of at least 2 points (minimally clinically important difference (MCID)) on the Numeric Pain Rating Scale. 64% of the isometric group and 75% of the isotonic group had improved by at least 2 points (MCID) on the Global Rating of Change Scale.

Conclusion: Isometric and isotonic exercise programmes appear to be effective for individuals with GTPS and should be considered in the loading management of patients with this condition.
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http://dx.doi.org/10.1136/bmjsem-2019-000558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6797310PMC
September 2019

Time to put down the scalpel? The role of surgery in tendinopathy.

Br J Sports Med 2020 Apr 25;54(8):441-442. Epub 2019 Oct 25.

School of Physiotherapy, Royal College of Surgeons in Ireland, Dublin, Ireland.

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http://dx.doi.org/10.1136/bjsports-2019-101084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7146938PMC
April 2020

Interobserver and intraobserver comparison of imaging glenoid morphology, glenoid version and humeral head subluxation.

Shoulder Elbow 2019 Jun 26;11(3):204-209. Epub 2018 Apr 26.

University of Glasgow, Glasgow, UK.

Background: Glenoid morphology, glenoid version and humeral head subluxation represent important parameters for the treating physician. The most common method of assessing glenoid morphology is the Walch classification which has only been validated with computed tomography (CT).

Methods: CT images and magnetic resonance imaging (MRI) images of 25 patients were de-identified and randomized. Three reviewers assessed the images for each parameter twice. The Walch classification was assessed with a weighted kappa value. Glenoid version and humeral head subluxation were comparted with a reproducibility coefficient.

Results: The Walch classification demonstrated almost perfect intraobserver agreement for MRI and CT images (k = 0.87). Weighted interobserver agreement values for the Walch classification were fair for CT and MRI (k = 0.34). The weighted reproducibility coefficient for glenoid version measured 9.13 (CI 7.16-12.60) degrees for CT and 13.44 (CI 10.54-18.55) degrees for MRI images. The weighted reproducibility coefficient for percentage of humeral head subluxation was 17.43% (CI 13.67-24.06) for CT and 18.49% (CI 14.5-25.52) for MRI images.

Discussion: CT and MRI images demonstrated similar efficacy in classifying glenoid morphology, measuring glenoid version and measuring posterior humeral head subluxation. MRI can be used as an alternative to CT for measuring these parameters.
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http://dx.doi.org/10.1177/1758573218768507DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6555109PMC
June 2019

How does surgery compare to sham surgery or physiotherapy as a treatment for tendinopathy? A systematic review of randomised trials.

BMJ Open Sport Exerc Med 2019 24;5(1):e000528. Epub 2019 Apr 24.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Purpose: To assess the effectiveness of surgery on all tendinopathies by comparing it to no treatment, sham surgery and exercise-based therapies for both mid-term (12 months) and long-term (> 12 months) outcomes.

Methods: Our literature search included EMBASE, Medline, CINAHL and Scopus. A combined assessment of internal validity, external validity and precision of each eligible study yielded its overall study quality. Results were considered significant if they were based on strong (Level 1) or moderate (Level 2) evidence.

Results: 12 studies were eligible. Participants had the following types of tendinopathy: shoulder in seven studies, lateral elbow in three, patellar in one and Achilles in one. Two studies were of good, four of moderate and six of poor overall quality. Surgery was superior to no treatment or placebo, for the outcomes of pain, function, range of movement (ROM) and treatment success in the short and midterm. Surgery had similar effects to sham surgery on pain, function and range of motion in the midterm. Physiotherapy was as effective as surgery both in the midterm and long term for pain, function, ROM and tendon force, and pain, treatment success and quality of life, respectively.

Conclusion: We recommend that healthcare professionals who treat tendinopathy encourage patients to comply with loading exercise treatment for at least 12 months before the option of surgery is seriously entertained.
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http://dx.doi.org/10.1136/bmjsem-2019-000528DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6539146PMC
April 2019

Fibroblast activation and inflammation in frozen shoulder.

PLoS One 2019 23;14(4):e0215301. Epub 2019 Apr 23.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences University of Glasgow, Glasgow, Scotland, United Kingdom.

Introduction: Frozen shoulder is a common, fibro-proliferative disease characterised by the insidious onset of pain and progressively restricted range of shoulder movement. Despite the prevalence of this disease, there is limited understanding of the molecular mechanisms underpinning the pathogenesis of this debilitating disease. Previous studies have identified increased myofibroblast differentiation and proliferation, immune cell influx and dysregulated cytokine production. We hypothesised that subpopulations within the fibroblast compartment may take on an activated phenotype, thus initiating the inflammatory processes observed in frozen shoulder. Therefore, we sought to evaluate the presence and possible pathogenic role of known stromal activation proteins in Frozen shoulder.

Methods: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients undergoing shoulder stabilisation surgery. Fibroblast activation marker expression (CD248, CD146, VCAM and PDPN, FAP) was quantified using immunohistochemistry. Control and diseased fibroblasts were cultured for in vitro studies from capsule biopsies from instability and frozen shoulder surgeries, respectively. The inflammatory profile and effects of IL-1β upon diseased and control fibroblasts was assessed using ELISA, immunohistochemistry and qPCR.

Results: Immunohistochemistry demonstrated increased expression of fibroblast activation markers CD248, CD146, VCAM and PDPN in the frozen shoulder group compared with control (p < 0.05). Fibroblasts cultured from diseased capsule produced elevated levels of inflammatory protein (IL-6, IL-8 & CCL-20) in comparison to control fibroblasts. Exposing control fibroblasts to an inflammatory stimuli, (IL-1ß) significantly increased stromal activation marker transcript and protein expression (CD248, PDPN and VCAM).

Conclusions: These results show that fibroblasts have an activated phenotype in frozen shoulder and this is associated with inflammatory cytokine dysregulation. Furthermore, it supports the hypothesis that activated fibroblasts may be involved in regulating the inflammatory and fibrotic processes involved in this disease.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0215301PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6478286PMC
February 2020

Targeting the NF-κB signaling pathway in chronic tendon disease.

Sci Transl Med 2019 02;11(481)

Department of Orthopedic Surgery, Columbia University, 650 W 168th St, New York, NY 10032, USA.

Tendon disorders represent the most common musculoskeletal complaint for which patients seek medical attention; inflammation drives tendon degeneration before tearing and impairs healing after repair. Clinical evidence has implicated the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway as a correlate of pain-free return to function after surgical repair. However, it is currently unknown whether this response is a reaction to or a driver of pathology. Therefore, we aimed to understand the clinically relevant involvement of the NF-κB pathway in tendinopathy, to determine its potential causative roles in tendon degeneration, and to test its potential as a therapeutic candidate. Transcriptional profiling of early rotator cuff tendinopathy identified increases in NF-κB signaling, including increased expression of the regulatory serine kinase subunit IKKβ, which plays an essential role in inflammation. Using cre-mediated overexpression of IKKβ in tendon fibroblasts, we observed degeneration of mouse rotator cuff tendons and the adjacent humeral head. These changes were associated with increases in proinflammatory cytokines and innate immune cells within the joint. Conversely, genetic deletion of IKKβ in tendon fibroblasts partially protected mice from chronic overuse-induced tendinopathy. Furthermore, conditional knockout of IKKβ improved outcomes after surgical repair, whereas overexpression impaired tendon healing. Accordingly, targeting of the IKKβ/NF-κB pathway in tendon stromal cells may offer previously unidentified therapeutic approaches in the management of human tendon disorders.
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http://dx.doi.org/10.1126/scitranslmed.aav4319DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6534967PMC
February 2019

The epidemiology of acromioclavicular joint excision.

J Orthop Surg (Hong Kong) 2019 Jan-Apr;27(1):2309499018816521

1 Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Background: With the development of arthroscopic procedures such as subacromial decompression (ASAD) and rotator cuff repair (RCR), it is hypothesized that there may have been a similar rise in the performance of acromioclavicular joint excision (ACJE). The purpose of this study was to investigate the epidemiology of ACJE to examine incidence, surgical technique, age, gender of patients and associated procedures in an urban population.

Methods: A prospectively collected surgical database was retrospectively examined to identify patients undergoing ACJE. Associated procedures such as ASAD or RCR were determined from these records. The demographic details (age and gender) were also recorded.

Results: A total of 411 ACJEs were performed over the study period (n = 216 males, n = 195 female). The overall incidence increased from 9.3 per 100,000 in 2009, to a peak of 19.6 per 1,00,000 in 2013. In 349 patients, ACJE was undertaken as part of an arthroscopic procedure, of which 332 were ASAD+ACJE alone. The prevalence of arthroscopic ACJE in ASADs was 23.7% (349/1400). ACJE was performed as an open procedure in 62 (15%) cases. Those undergoing open ACJE were younger than those undergoing an arthroscopic procedure (mean difference 6.2 years, 95% CI 3.2-9.2, p < 0.001).

Conclusions: We demonstrate an increasing incidence of ACJE in the general population. The groups of patients most likely to undergo ACJE are women aged between 45 and 54 years old, men aged 55-64 years and the most socioeconomically deprived. The higher incidence of ACJE in the most deprived socioeconomic quintile may have public health implications. Level of Evidence: II; retrospective design: prognosis study.
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http://dx.doi.org/10.1177/2309499018816521DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391558PMC
April 2020

S100A8 & S100A9: Alarmin mediated inflammation in tendinopathy.

Sci Rep 2019 02 6;9(1):1463. Epub 2019 Feb 6.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences University of Glasgow, Glasgow, Scotland, UK.

Alarmins S100A8 and S100A9 are endogenous molecules released in response to environmental triggers and cellular damage. They are constitutively expressed in immune cells such as monocytes and neutrophils and their expression is upregulated under inflammatory conditions. The molecular mechanisms that regulate inflammatory pathways in tendinopathy are largely unknown therefore identifying early immune effectors is essential to understanding the pathology. Based on our previous investigations highlighting tendinopathy as an alarmin mediated pathology we sought evidence of S100A8 & A9 expression in a human model of tendinopathy and thereafter, to explore mechanisms whereby S100 proteins may regulate release of inflammatory mediators and matrix synthesis in human tenocytes. Immunohistochemistry and quantitative RT-PCR showed S100A8 & A9 expression was significantly upregulated in tendinopathic tissue compared with control. Furthermore, treating primary human tenocytes with exogenous S100A8 & A9 significantly increased protein release of IL-6, IL-8, CCL2, CCL20 and CXCL10; however, no alterations in genes associated with matrix remodelling were observed at a transcript level. We propose S100A8 & A9 participate in early pathology by modulating the stromal microenvironment and influencing the inflammatory profile observed in tendinopathy. S100A8 and S100A9 may participate in a positive feedback mechanism involving enhanced leukocyte recruitment and release of pro-inflammatory cytokines from tenocytes that perpetuates the inflammatory response within the tendon in the early stages of disease.
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http://dx.doi.org/10.1038/s41598-018-37684-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6365574PMC
February 2019

Topical glyceryl trinitrate for the treatment of tendinopathies: a systematic review.

Br J Sports Med 2019 Feb 9;53(4):251-262. Epub 2018 Oct 9.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.

Objective: To produce a best evidence synthesis of the clinical effects of topical glyceryl trinitrate (GTN) in the treatment of tendinopathies.

Design: A systematic review of published randomised controlled trials (RCTs) of the use of GTN in patients with tendinopathy.

Data Sources: MEDLINE, Embase, Scopus and CINAHL from database inception to January 2018.

Methods: We examined RCTs comparing the effects of topical GTN with either placebo or other treatments on tendinopathy. Overall quality of each eligible study was determined based on a combined assessment of internal validity, external validity and precision. The level of evidence for each assessed parameter was rated based on the system by van Tulder .

Results: A total of 10 eligible RCTs were identified including patients with tendinopathy of the rotator cuff (n=4), wrist extensors (n=3), Achilles (n=2) and patellar (n=1) tendons. For all tendinopathies, improvements in pain were significant when comparing GTN versus placebo in the short term (<8 weeks; poor evidence). Significant improvements in midterm outcomes for treatment with GTN versus placebo included the following: patient satisfaction (strong evidence); chances of being asymptomatic with activities of daily living (strong evidence); range of movement (moderate evidence); strength (moderate evidence); pain (at night and with activity; poor evidence) and local tenderness (poor evidence). Patients treated with topical GTN reported a higher incidence of headaches than those who received placebo (moderate evidence).

Conclusions And Relevance: Treatment of tendinopathies with topical GTN for up to 6 months appears to be superior to placebo and may therefore be a useful adjunct to the treating healthcare professions.
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http://dx.doi.org/10.1136/bjsports-2018-099552DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6362607PMC
February 2019

Why did IL-23p19 inhibition fail in AS: a tale of tissues, trials or translation?

Ann Rheum Dis 2019 08 8;78(8):1015-1018. Epub 2018 Oct 8.

Institute of Infection Immunity and Inflammation, University of Glasgow, Glasgow, UK

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http://dx.doi.org/10.1136/annrheumdis-2018-213654DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6691857PMC
August 2019

Alarmins in Frozen Shoulder: A Molecular Association Between Inflammation and Pain.

Am J Sports Med 2018 03 30;46(3):671-678. Epub 2017 Nov 30.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.

Background: The pathophysiological mechanisms behind proliferation of fibroblasts and deposition of dense collagen matrix in idiopathic frozen shoulder remain unclear. Alarmins (also known as danger signals) are endogenous molecules that are released into the extracellular milieu after infection or tissue injury and that signal cell and tissue damage.

Purpose: To investigate whether the presence of alarmins is higher in patients with idiopathic frozen shoulder than in control subjects.

Study Design: Controlled laboratory study.

Methods: Shoulder capsule samples were collected from 10 patients with idiopathic frozen shoulder and 10 patients with unstable shoulders (control). The samples were stained with hematoxylin and eosin (H&E) and analyzed by immunohistochemistry using antibodies against alarmin molecules including high-mobility group protein B1 (HMGB1), interleukin 33, S100A8, S100A9, and the peripheral nerve marker PGP9.5. Immunoreactivities were rated in a blinded fashion from "none" to "strong." Immunohistochemical distribution within the capsule was noted. Before surgery, patient-ranked pain frequency, severity, stiffness, and the range of passive shoulder motion were recorded and statistically analyzed.

Results: Compared with control patients, patients with frozen shoulder had greater frequency and severity of self-reported pain ( P = .02) and more restricted range of motion in all planes ( P < .05). H&E-stained capsular tissue from frozen shoulder showed fibroblastic hypercellularity and increased subsynovial vascularity. Immunoreactivity of alarmins was significantly stronger in frozen shoulder capsules compared with control capsules ( P < .05). Furthermore, the expression of the alarmin molecule HMGB1 significantly correlated ( r > 0.9, P < .05) with the severity of patient-reported pain.

Conclusion: This study demonstrates a potential role for key molecular danger signals in frozen shoulder and suggests an association between the expression of danger molecules and the pain experienced by patients.
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http://dx.doi.org/10.1177/0363546517741127DOI Listing
March 2018

Targeting danger molecules in tendinopathy: the HMGB1/TLR4 axis.

RMD Open 2017 28;3(2):e000456. Epub 2017 Jul 28.

Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary and Life Sciences, University of Glasgow, Glasgow, Scotland, UK.

Objectives: To seek evidence of the danger molecule, high-mobility group protein B1 (HMGB1) expression in human tendinopathy and thereafter, to explore mechanisms where HMGB1 may regulate inflammatory mediators and matrix regulation in human tendinopathy.

Methods: Torn supraspinatus tendon (established pathology) and matched intact subscapularis tendon (representing 'early pathology') biopsies were collected from patients undergoing arthroscopic shoulder surgery. Control samples of subscapularis tendon were collected from patients undergoing arthroscopic stabilisation surgery. Markers of inflammation and HMGB1 were quantified by reverse transcriptase PCR (RT-PCR) and immunohistochemistry. Human tendon-derived primary cells were derived from hamstring tendon tissue obtained during hamstring tendon anterior cruciate ligament reconstruction and used through passage 3. In vitro effects of recombinant HMGB1 on tenocyte matrix and inflammatory potential were measured using quantitative RT-PCR, ELISA and immunohistochemistry staining.

Results: Tendinopathic tissues demonstrated significantly increased levels of the danger molecule HMGB1 compared with control tissues with early tendinopathy tissue showing the greatest expression. The addition of recombinant human HMGB1 to tenocytes led to significant increase in expression of a number of inflammatory mediators, including interleukin 1 beta (IL-1β), IL-6, IL-33, CCL2 and CXCL12, in vitro. Further analysis demonstrated rhHMGB1 treatment resulted in increased expression of genes involved in matrix remodelling. Significant increases were observed in Col3, Tenascin-C and Decorin. Moreover, blocking HMGB1 signalling via toll-like receptor 4 (TLR4) silencing reversed these key inflammatory and matrix changes.

Conclusion: HMGB1 is present in human tendinopathy and can regulate inflammatory cytokines and matrix changes. We propose HMGB1 as a mediator driving the inflammatory/matrix crosstalk and manipulation of the HMGB1/TLR4 axis may offer novel therapeutic approaches targeting inflammatory mechanisms in the management of human tendon disorders.
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http://dx.doi.org/10.1136/rmdopen-2017-000456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5574425PMC
July 2017

MicroRNA29a Treatment Improves Early Tendon Injury.

Mol Ther 2017 10 28;25(10):2415-2426. Epub 2017 Jul 28.

Institute of Infection, Immunity, and Inflammation, College of Medicine, Veterinary, and Life Sciences, University of Glasgow, Glasgow G12 8TA, UK. Electronic address:

Tendon injuries (tendinopathies) are common in human and equine athletes and characterized by dysregulated collagen matrix, resulting in tendon damage. We have previously demonstrated a functional role for microRNA29a (miR29a) as a post-transcriptional regulator of collagen 3 expression in murine and human tendon injury. Given the translational potential, we designed a randomized, blinded trial to evaluate the potential of a miR29a replacement therapy as a therapeutic option to treat tendinopathy in an equine model that closely mimics human disease. Tendon injury was induced in the superficial digital flexor tendon (SDFT) of 17 horses. Tendon lesions were treated 1 week later with an intralesional injection of miR29a or placebo. miR29a treatment reduced collagen 3 transcript levels at week 2, with no significant changes in collagen 1. The relative lesion cross-sectional area was significantly lower in miR29a tendons compared to control tendons. Histology scores were significantly better for miR29a-treated tendons compared to control tendons. These data support the mechanism of microRNA-mediated modulation of early pathophysiologic events that facilitate tissue remodeling in the tendon after injury and provides a strong proof of principle that a locally delivered miR29a therapy improves early tendon healing.
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http://dx.doi.org/10.1016/j.ymthe.2017.07.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5628866PMC
October 2017
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