Dennis McGonagle

Leeds Teaching Hospitals NHS Trust, Leeds, England, United Kingdom

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Publications (258)1429.7 Total impact

  • Rheumatology (Oxford, England) 11/2014; · 4.24 Impact Factor
  • Peggy Jacques, Dennis McGonagle
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    ABSTRACT: Given that entheses are sites of high mechanical stress that concentrate the forces of large contracting muscles down onto a small footprint of bone contact, it was recognized nearly 60 decades ago that stress and injury at such sites may play a role in the pathogenesis of mechanically related enthesopathy. In recent years, the role of mechanical stress and its related consequences on inflammatory enthesitis have also been recognized. Clinical imaging studies and experimental animal models of spondyloarthropathy including tumor necrosis factor (TNF) transgenic models and interleukin (IL)-23 overexpression systems are associated with a primary enthesitis with disease subsequently spreading to adjacent joint structures including the synovium and bone. Joint mechanical stress, without discernible microdamage or injury, leads to spondyloarthritis (SpA) in a TNF transgenic model. Normal-aged human entheses often demonstrate microdamage, but it is unclear whether an abnormal response to mechanical stress alone or the need for stress-induced microdamage is involved in human disease initiation. Clinically, the contribution of mechanical stress to SpA including psoriatic arthritis (PsA) helps conceptualize the disease in a new way and provides obvious mechanistic links to skin and nail Koebner responses. It also offers novel epidemiological explanations for why PsA develops in subjects with high body mass indices most typically in the fourth and fifth decades. Molecularly, the monogenic forms of SpA including caspase recruitment domain-containing protein 14 (CARD14) and IL36RN mutations have site-specific expression of mutated proteins in the skin, thus offering a direct molecular link between local inflammation-related pathway dysregulation and local stress or injury in disease causation. Given that many of the pathways that govern both immunity and mechanical stress including extracellular-signal-regulated kinase (ERK) and mitogen-activated protein kinase (MAPK) are shared, it may be difficult to develop strategies that selectively target mechanical stress-related pathways. However, occupational- and obesity-related factors may be potentially modifiable in susceptible individuals to prevent or ameliorate disease. Copyright © 2014 Elsevier Ltd. All rights reserved.
    Best practice & research. Clinical rheumatology. 10/2014; 28(5):703-710.
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    ABSTRACT: Dactylitis is a hallmark of psoriatic arthritis (PsA) where flexor tenosynovitis is common. This study explored the microanatomical basis of dactylitis using high-resolution MRI (hrMRI) to visualise the small entheses around the digits.
    Annals of the rheumatic diseases. 09/2014;
  • Dennis McGonagle, Kay-Geert A Hermann, Ai Lyn Tan
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    ABSTRACT: Rheumatologists have long considered OA and PsA as two completely distinct arthropathies. This review highlights how some forms of generalized OA and PsA may afflict the same entheseal-associated anatomical territories. While degeneration or inflammation may be clearly discernible at the two extremes, there may be a group of patients where differentiation is impossible. Misdiagnosis of a primary degeneration-related pathology as being part of the PsA spectrum could lead to apparent failure of disease-modifying agents, including apparent anti-TNF and apparent IL23/17 axis therapy failure. This is not a reflection of poor clinical acumen, but rather a failure to appreciate that the pathological process overlaps in the two diseases. Whether the category of OA-PsA overlap disease exists or whether it represents the co-occurrence of two common arthropathies that afflict the same anatomical territories has implications for the optimal diagnosis and management of both OA and PsA.
    Rheumatology (Oxford, England) 09/2014; · 4.24 Impact Factor
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    ABSTRACT: Objective This study explored posterior cruciate ligament (PCL) synovio-entheseal complex (SEC) microanatomy to determine whether it may participate in the early osteoarthritis (OA) disease process. Methods SEC microanatomy and OA features were evaluated in 14 non-arthritic cadaveric knees (mean age=69.9) using magnetic resonance imaging (MRI) and histology. MRI images of 49 subjects selected from the progression cohort of the Osteoarthritis Initiative were evaluated by a musculoskeletal radiologist using an original semi-quantitative method for features associated with OA at the PCL tibial enthesis. Statistical analysis was performed using chi-square and Wilcoxon signed-rank tests to evaluate associations between SEC configuration and OA features. Results The PCL formed a SEC-like structure encompassing bone- and ligament-lining intra-articular cartilages to which the posterior root of the medial meniscus contributed. Degenerative features at the PCL-SEC included: neovascularisation (44%), enthesis chondrocyte clustering (44%), collagen matrix fissuring at the enthesis (56%) and in the PCL itself (67%), tidemark duplication (44%), bone remodelling (44%) and microscopic inflammatory changes (33%). In the OAI cohort, SEC-related pathology included BMLs (69%) and osteophytosis (94%) at locations that corresponded to SEC-related cartilages. Posterior joint recess effusion (49%) was linked to MRI abnormalities at PCL-SEC cartilages (χ2 =7.27, p = 0.007). Conclusions The PCL has a prominent SEC configuration that is associated with microscopic OA changes in aged clinically non-diseased joints. MRI determined knee OA commonly exhibited pathological features at this site which was associated with adjacent joint effusion. Thus, the PCL-SEC could play a hitherto unappreciated role in the early OA disease process.
    Osteoarthritis and Cartilage 09/2014; · 4.26 Impact Factor
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    ABSTRACT: Gelatinous Heberden's nodes (HNs), also termed synovial cysts, are a common form of generalised osteoarthritis (OA). We sought to determine if HN cases at clinical presentation contained multipotential stromal cells (MSCs), and to explore whether such cells were more closely related to bone marrow (BM) or synovial fluid (SF) MSCs by transcriptional analysis.
    Arthritis research & therapy. 06/2014; 16(3):R119.
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    ABSTRACT: The aims of this study were to investigate the extent of MRI-determined joint disease (erosion and synovitis) in SLE and to link this to autoantibody profiles known to be relevant to SLE, including ACPA, RF and anti-RA33 antibodies.
    Rheumatology (Oxford, England) 05/2014; · 4.24 Impact Factor
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    ABSTRACT: To monitor progression to inflammatory arthritis (IA) in individuals with non-specific musculoskeletal (MSK) symptoms and positive anticyclic citrullinated peptide (anti-CCP) antibodies. To develop a pragmatic model to predict development of IA in this patient group. In this prospective observational cohort, patients with new non-specific MSK symptoms and positive anti-CCP were recruited from regional primary care and secondary care referrals. Clinical, imaging and serological parameters were assessed at baseline. Cox regression analysis was performed to identify predictors of progression to IA and develop a risk score to stratify patients at presentation. 100 consecutive patients (73 women, mean age 51 years) were followed up for median 19.8 months (range 0.1-69.0); 50 developed IA after a median 7.9 months (range 0.1-52.4), 34 within 12 months. The majority (43/50) fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for rheumatoid arthritis. A model for progression to IA was devised using four variables: tenderness of hand or foot joints, early morning stiffness ≥30 min, high-positive autoantibodies, and positive ultrasonographic power Doppler signal. None of the five individuals at low risk (score 0) progressed to IA, compared with 31% of 29 at moderate risk (1-2) and 62% of 66 at high risk (≥3). Adding shared epitope increased the number at low risk (score 0-1; 0/11 progressed). In patients presenting with non-specific MSK symptoms and anti-CCP, the risk of progression to IA could be quantified using data available in clinical practice. The proposed risk score may be used to stratify patients for early therapeutic intervention. NCT02012764 at ClinicalTrials.gov.
    Annals of the rheumatic diseases 04/2014; · 8.11 Impact Factor
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    ABSTRACT: Aim: To enumerate and characterize multipotential stromal cells (MSCs) in a cellular bone allograft and compare with fresh age-matched iliac crest bone and bone marrow (BM) aspirate. Materials & methods: MSC characterization used functional assays, confocal/scanning electron microscopy and whole-genome microarrays. Resident MSCs were enumerated by flow cytometry following enzymatic extraction. Results: Allograft material contained live osteocytes and proliferative bone-lining cells defined as MSCs by phenotypic and functional capacities. Without cultivation/expansion, the allograft displayed an 'osteoinductive' molecular signature and the presence of CD45(-)CD271(+)CD73(+)CD90(+)CD105(+) MSCs; with a purity over 100-fold that of iliac crest bone. In comparison with BM, MSC numbers enzymatically released from one gram of cellular allograft were equivalent to approximately 45 ml of BM aspirate. Conclusion: Cellular allograft bone represents a unique nonimmune material rich in MSCs and osteocytes. This osteoinductive graft represents an attractive alternative to autograft bone or composite/synthetic grafts in orthopedics and broader regenerative medicine settings.
    Regenerative Medicine 03/2014; · 3.87 Impact Factor
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    ABSTRACT: The vast majority of literature pertaining to mesenchymal stem cells (MSC) immunomodulation has focussed on bone marrow derived MSC that are systemically infused to alleviate inflammatory conditions. Rheumatoid arthritis (RA) is the commonest autoimmune joint disease that has witnessed significant therapeutic advances in the past decade, but remains stubbornly difficult to treat in a subset of cases. Preclinical research has demonstrated that bone marrow, adipose, synovial and umbilical cord derived MSC all suppress the functions of different immune cells thus raising the possibility of new therapies for autoimmune diseases including RA. Indeed, preliminary evidence for MSC efficacy has been reported in some cases of RA and Systemic Lupus Erythromatosis (SLE). The potential use of BM-MSC for RA therapy is emerging but the use of synovial MSC (S-MSC) to suppress the exaggerated immune response within the inflamed joints remains rudimentary. Synovial fibroblasts that are likely derived from S-MSCs, also give rise to a cell cultured progeny termed fibroblast like synoviocytes (FLS), which are key players in the perpetuation of joint inflammation and destruction. A better understanding of the link between these cells and their biology could be a key to developing novel MSC based strategies for therapy. The review briefly focuses on BM-MSC and gives particular attention to joint niche synovial MSC and FLS with respect to immunoregulatory potential therapy roles.
    QJM: monthly journal of the Association of Physicians 02/2014; · 2.36 Impact Factor
  • Annals of the rheumatic diseases 01/2014; · 8.11 Impact Factor
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    ABSTRACT: Hypervascularization in finger clubbing is recognized, but its microanatomical basis remains unclear. This pilot descriptive study used magnetic resonance imaging (MRI) to explore this further. High-resolution MRI acquired with contrast agent was carried out in 4 patients with finger clubbing and 4 healthy volunteers. The anatomy of the nail bed, capsular structures, and bony changes were described. Marked nail bed thickening and contrast enhancement was noted in all clubbed fingers, with bone edema in 3 of the 4 patients. None of the healthy subjects had similar abnormalities. This confirms that hypervascularization of the nail bed observed in the microanatomy on high-resolution MRI is associated with clubbed appearances of the nails.
    The Journal of Rheumatology 01/2014; · 3.26 Impact Factor
  • Miriam Wittmann, Dennis McGonagle, Thomas Werfel
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    ABSTRACT: This review focuses on treatment targets for the most common inflammatory skin diseases, eczema and psoriasis with an emphasis on cytokines expressed in the uppermost layer of the skin which is easily accessible for diagnostic and therapeutic approaches. Recently, a significant body of research has highlighted the influence of the skin barrier and the patients’ microbiome on skin inflammatory responses and we will comment on their impact on mediator regulation. Itch is a prominent dermatology symptom which is influenced by cytokines and can via itch–scratch cycle impact on the skin barrier and mediator expression associated with damage. Taking the contribution of pruritus and superficial skin damage into account, we address cytokines as targets for stratified treatment approaches in subgroups of eczema and psoriasis.
    Cytokine & Growth Factor Reviews. 01/2014;
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    ABSTRACT: Adult stem cells are characterised by longer telomeres compared to mature cells from the same tissue. In this study, candidate CD146 (+) umbilical cord (UC) mesenchymal stem cells (MSCs) were purified by cell sorting from UC tissue digests and their telomere lengths were measured in comparison to donor-matched CD146-negative fraction. UC tissue fragments were enzymatically treated with collagenase and the cells were used for cell sorting, colony-forming fibroblast (CFU-F) assay or for long-term MSC cultivation. Telomere lengths were measured by qPCR in both culture-expanded MSCs and candidate native UC MSCs. Immunohistochemistry was undertaken to study the topography of CD146 (+) cells. Culture-expanded UC MSCs had a stable expression of CD73, CD90 and CD105, whereas CD146 declined in later passages which correlated with the shortening of telomeres in the same cultures. In three out of four donors, telomeres in candidate native UC MSCs (CD45 (-)CD235α (-)CD31 (-)CD146 (+)) were longer compared to donor-matched CD146 (-) population (CD45 (-)CD235α (-)CD31 (-)CD146 (-)). The frequency of CD45 (-)CD235α (-)CD31 (-)CD146 (+) cells measured by flow cytometry was ~1000-fold above that of donor-matched CFU-Fs (means 10.4% and 0.01%, respectively). CD146 (+) cells were also abundant in situ having a broad topography including high levels of positivity in muscle areas in addition to vessels.
    F1000Research. 01/2014; 3:126.
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    Laura J. Savage, Dennis G. McGonagle
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    ABSTRACT: The therapy of psoriatic arthritis (PsA) has blossomed in the past decade. Inhibition of tumor necrosis factor (TNF) has been at the fore of this approach and has paved the way for the investigation of many other potential pro-inflammatory and signaling pathways. Most of the initial studies of TNF inhibitors in PsA have been conducted in specific populations, largely focusing on those with established, peripheral joint disease. That said, in excess of 10 years’ worth of real world clinical experience has led to increased confidence in the wider use of these agents. We are now faced with an exciting time of discovery of many new molecules; these not only include new, large protein biological agents, but also smaller synthetic chemical molecules, many of which can be administered orally. Those currently under development are discussed within this article. Whilst there is scarce data about their real world efficacy and safety profile, it is evident that the therapeutic armamentarium for treating PsA will greatly increase in the foreseeable future and this is anticipated to improve patient outcomes.
    Biologics in Therapy. 12/2013;
  • Dennis McGonagle, Rebecca C Thomas, Georg Schett
    Annals of the rheumatic diseases 11/2013; · 8.11 Impact Factor
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    ABSTRACT: The purpose of this work was to test whether normal peri-entheseal vascular anatomy at anterior and posterior cruciate ligaments (ACL and PCL) was associated with distribution of peri-entheseal bone erosion/bone marrow lesions (BMLs) in inflammatory arthritis (IA) and osteoarthritis (OA). Normal microanatomy was defined histologically in mice and by 3 T MRI and histology in 21 cadaveric knees. MRI of 89 patients from the Osteoarthritis Initiative and 27 patients with IA was evaluated for BMLs at ACL and PCL entheses. Antigen-induced arthritis (AIA) in mice was evaluated to ascertain whether putative peri-entheseal vascular regions influenced osteitis and bone erosion. Vascular channels penetrating cortical bone were identified in knees of non-arthritic mice adjacent to the cruciate ligaments. On MRI of normal cadavers, vascular channels adjacent to the ACL (64% of cases) and PCL (71%) entheses were observed. Histology of 10 macroscopically normal cadaveric specimens confirmed the location of vascular channels and associated subclinical changes including subchondral bone damage (80% of cases) and micro-cyst formation (50%). In the AIA model, vascular channels clearly provided a site for inflammatory tissue entry and osteoclast activation. MRI showed BMLs in the same topographic locations in both patients with early OA (41% ACL, 59% PCL) and IA (44%, 33%). The findings show that normal ACL and PCL entheses have immediately adjacent vascular channels which are common sites of subtle bone marrow pathology in non-arthritic joints. These channels appear to be key determinants in bone damage in inflammatory and degenerative arthritis.
    Annals of the rheumatic diseases 10/2013; · 8.11 Impact Factor
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    ABSTRACT: Aim: To enumerate and characterize mesenchymal stem cells (MSCs) and endothelial cells (ECs) in umbilical cord (UC) tissue digests. Materials & methods: Cultured UC cells were characterized phenotypically, and functionally by using 48-gene arrays. Native MSCs and ECs were enumerated using flow cytometry. Results: Compared with bone marrow (BM) MSCs, UC MSCs displayed significantly lower (range 4-240-fold) basal levels of bone-related transcripts, but their phenotypes were similar (CD73(+), CD105(+), CD90(+), CD45(-) and CD31(-)). UC MSCs responded well to osteogenic induction, but day 21 postinduction levels remained below those achieved by BM MSCs. The total yield of native UC MSCs (CD90(+), CD45(-) and CD235α(-)) and ECs (CD31(+), CD45(-) and CD235α(-)) exceeded 150 and 15 million cells/donation, respectively. Both UC MSCs and ECs expressed CD146. Conclusion: While BM MSCs are more predisposed to osteogenesis, UC tissue harbors large numbers of MSCs and ECs; such minimally manipulated 'off-the-shelf' cellular mixtures can be used for regenerating bone in patients with compromised vascular supply.
    Regenerative Medicine 09/2013; 8(5):569-81. · 3.87 Impact Factor
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    ABSTRACT: Objective To determine the prevalence, on magnetic resonance imaging (MRI), of bone marrow edema lesions in symptomatic axial psoriatic arthritis (PsA), and to compare this prevalence with that in nonradiographic axial spondyloarthritis (SpA) and ankylosing spondylitis (AS) and its relationship to HLA–B27 status. Methods We performed a cross-sectional audit of MRI scans of lumbar spine (L-spine) and sacroiliac (SI) joints. Using the semiquantitative Leeds Scoring System in which bone marrow edema is graded from 0 to 3 according to severity of the lesions, MRI scans were scored independently by 2 expert readers who were blinded to the clinical characteristics of the patients. Concordant data from the 2 readers were used to report on definite lesions. ResultsMRIs from 76 patients with comparable age ranges were categorized into 3 groups: those from PsA patients, those from patients with nonradiographic axial SpA, and those from AS patients. HLA–B27 positivity was similar in PsA patients (10 of 33) and patients with nonradiographic axial SpA (10 of 24) and higher in AS patients (18 of 19). Total MRI scores (L-spine plus SI joints) were higher in AS patients than in PsA patients (P = 0.025) or in patients with nonradiographic axial SpA (P = 0.007). A relationship was seen between the severity and extent of disease and HLA–B27 positivity in PsA patients, which was comparable to that in AS patients. HLA–B27–negative PsA patients had lower MRI scores than HLA–B27–positive PsA patients (P = 0.03) and AS patients (P = 0.006), whereas scores were similar in HLA–B27–positive PsA patients and AS patients. Similarly, MRI scores of HLA–B27–negative patients with nonradiographic axial SpA were lower than those of AS patients (P = 0.01). ConclusionHLA–B27 positivity defines a group of patients with more severe axial bone marrow edema that is likely related to the classic AS phenotype. Clinically, HLA–B27–negative PsA is more likely to be reported as a “negative” MRI examination result.
    Arthritis & Rheumatology 09/2013; 65(9). · 7.48 Impact Factor
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    ABSTRACT: Ultrasonography (US) and magnetic resonance imaging (MRI) are increasingly used imaging techniques for visualising entheses, however few studies have made a direct comparison of each. This study aimed to compare each technique for the detection of enthesitis in patients with spondyloarthritis (SpA) related knee swelling in order to make a lesion by lesion comparison. Consecutive SpA patients with knee synovitis were recruited: each had clinical assessment for enthesitis at 8 sites in the involved knee joint followed by US and MRI examinations. Inflammatory and structural changes at tendon and ligament insertions were scored and a lesion by lesion comparison was made. 21 patients were recruited. Clinically defined involved knee joint enthesitis was evident in 18 of 21 (86%) patients in 61 of 168 (36%) evaluated sites. Clinical enthesitis was associated with more hypoechogenicity (16 vs. 4%, p=0.007) and thickening (16 vs. 6%, p=0.03) by US compared to non-tender sites. Considering all MRI findings only increased signal in the surrounding tissues was higher at tender sites (41 vs. 20%, p=0.01) and the insertions points themselves showed little abnormality. The positive agreements between individual lesions by both methods was very low (10-26%) with low kappa values (0.06-0.18) with no correlations between the MRI and US scores (r²= 0.059). The difficulty in procuring 'gold standard' histological validation is synovial joints makes the assessment of enthesitis using clinical and current imaging protocols of limited utility for diagnostic purposes.
    Clinical and experimental rheumatology 08/2013; · 2.66 Impact Factor

Publication Stats

7k Citations
1,429.70 Total Impact Points

Institutions

  • 2004–2014
    • Leeds Teaching Hospitals NHS Trust
      • • Department of Trauma and Orthopaedics
      • • Department of Radiology
      Leeds, England, United Kingdom
    • Ludwig-Maximilian-University of Munich
      • Institute for Anatomy and Cell Biology
      München, Bavaria, Germany
  • 1997–2014
    • University of Leeds
      • • Leeds Institute of Rheumatic and Musculoskeletal Medicine
      • • Leeds Institute of Molecular Medicine (LIMM)
      • • School of Medicine
      Leeds, England, United Kingdom
  • 2011–2013
    • Istanbul Medical University
      İstanbul, Istanbul, Turkey
    • Université René Descartes - Paris 5
      Lutetia Parisorum, Île-de-France, France
    • NIHR Oxford Biomedical Research
      Oxford, England, United Kingdom
  • 2012
    • University of Verona
      Verona, Veneto, Italy
  • 2010–2012
    • Institute of Genetics and Molecular Medicine
      Edinburgh, Scotland, United Kingdom
    • U.S. Food and Drug Administration
      • Center for Biologics Evaluation and Research
      Washington, D. C., DC, United States
  • 2009
    • Imperial College London
      Londinium, England, United Kingdom
  • 2001–2009
    • Cardiff University
      • School of Biosciences
      Cardiff, Wales, United Kingdom