Pathways driving tendinopathy and enthesitis: siblings or distant cousins in musculoskeletal medicine?

Tendinopathy and enthesitis share clinical, anatomical, and molecular parallels. However, their relationship is complex, presenting challenges in diagnosis and treatment. The biomechanics underlying these pathologies, together with relative immune and stromal contributions to pathology, are characterised by crucial comparative elements. However, methodologies used to study enthesitis and tendinopathy have been divergent, which could account for discrepancies in how these conditions are perceived and treated. In this Review, we summarise key clinical parallels between these two common presentations in musculoskeletal medicine and address factors that currently preclude development of more effective therapeutics. Furthermore, we describe molecular similarities and disparities that govern pathological mechanisms in tendinopathy and enthesitis, thus informing translational studies and treatment strategies.

Frozen shoulder.

Frozen shoulder is a common debilitating disorder characterized by shoulder pain and progressive loss of shoulder movement. Frozen shoulder is frequently associated with other systemic conditions or occurs following periods of immobilization, and has a protracted clinical course, which can be frustrating for patients as well as health-care professionals. Frozen shoulder is characterized by fibroproliferative tissue fibrosis, whereby fibroblasts, producing predominantly type I and type III collagen, transform into myofibroblasts (a smooth muscle phenotype), which is accompanied by inflammation, neoangiogenesis and neoinnervation, resulting in shoulder capsular fibrotic contractures and the associated clinical stiffness. Diagnosis is heavily based on physical examination and can be difficult depending on the stage of disease or if concomitant shoulder pathology is present. Management consists of physiotherapy, therapeutic modalities such as steroid injections, anti-inflammatory medications, hydrodilation and surgical interventions; however, their effectiveness remains unclear. Facilitating translational science should aid in development of novel therapies to improve outcomes among individuals with this debilitating condition.

Rapidly progressive crescentic diabetic nephropathy: two case reports.

Crescents are not a well recognised feature of diabetic nephropathy. We present two cases of patients presenting with a rapid decline in renal function and subacute onset of nephrotic syndrome. Glomerulonephritis screening was negative, and renal biopsy revealed non-necrotising cellular crescents and typical features of late-stage diabetic nephropathy. We review the literature for diabetic nephropathy with crescents and explore possible underlying mechanisms.

The effect of exercise on cytokines: implications for musculoskeletal health: a narrative review.

The physiological effects of physical exercise are ubiquitously reported as beneficial to the cardiovascular and musculoskeletal systems. Exercise is widely promoted by medical professionals to aid both physical and emotional wellbeing; however, mechanisms through which this is achieved are less well understood. Despite numerous beneficial attributes, certain types of exercise can inflict significant significant physiological stress. Several studies document a key relationship between exercise and immune activation. Activation of the innate immune system occurs in response to exercise and it is proposed this is largely mediated by cytokine signalling. Cytokines are typically classified according to their inflammatory properties and evidence has shown that cytokines expressed in response to exercise are diverse and may act to propagate, modulate or mitigate inflammation in musculoskeletal health. The review summarizes the existing literature on the relationship between exercise and the immune system with emphasis on how exercise-induced cytokine expression modulates inflammation and the immune response.

Tendinopathy.

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.

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

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 et al. 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.

Fibrosis of the Choroid Plexus Filtration Membrane.

We report a previously undescribed inflammatory lesion consisting of deposition of activated complement (C3d and C9neo) in association with major histocompatibility complex type II (MHC2)-positive activated microglia in choroid plexus villi exhibiting classical fibrous thickening of the pericapillary filtration membrane. The proportion of villi affected ranged from 5% to 90% in 56 adult subjects with diseases of the CNS and 11 subjects with no preexisting disease of the CNS. In 3 of the 4 children studied, 2% or less of examined villi showed stromal thickening, complement deposition, and the presence of MHC2-positive microglia; in adults, the proportion of villi affected increased with age. Other features of the lesion included loss of capillaries and failure by macrophages to clear extracellular particulate electron-dense material by clathrin-mediated phagocytosis. This choroid plexus lesion may relate pathogenetically to age-related macular degeneration and to Alzheimer disease, 2 other conditions with no known risk factors other than increasing age. All 3 conditions are characterized by the presence of damaged capillaries, inflammatory extracellular aggregates of mixed molecular composition and defective clearance of the deposits by macrophages.

Renal connective tissue growth factor correlates with glomerular basement membrane thickness and prospective albuminuria in a non-human primate model of diabetes: possible predictive marker for incipient diabetic nephropathy.

UNLABELLED: Diabetic renal disease is characterized by accumulation of extracellular matrix, glomerulosclerosis, and tubulointerstitial fibrosis. Connective tissue growth factor (CTGF) is implicated in these changes, as it contributes to new matrix synthesis and is increased in the diabetic kidney. CTGF also inhibits mesangial matrix degradation through up-regulation of the tissue inhibitor of matrix metalloproteinase 1 (TIMP-1). In a non-human primate model of diabetes, we determined whether the level of renal CTGF protein before development of albuminuria correlated with renal matrix and TIMP-1 changes and whether renal CTGF predicts progression to albuminuria. METHODS: In a group of diabetic (n=9) and control (n=6) baboons after a 5-year duration of diabetes, renal tissue CTGF and TIMP-1 were detected by immunohistochemistry and compared with glomerular basement membrane (GBM) thickness and mesangial volume measurements from electron photomicrographs of renal biopsies. Urinary albumin levels were measured at 5 and 10 years of diabetes. RESULTS: GBM thickness, CTGF protein, and TIMP-1 protein were increased after 5 years of diabetes (each P<.05). Tubular fibronectin scores correlated with tubular CTGF scores (r=0.72, P=.002). In diabetic animals, GBM thickness correlated with tubular and total CTGF levels (P=.002 and P=.04, respectively), whereas mesangial cell and total matrix volume correlated with glomerular TIMP-1 (P=.02 and P=.01, respectively). Tubular CTGF scores (P=.008) and GBM thickness (P=.03) at 5 years in diabetes each predicted the degree of albuminuria at 10 years. CONCLUSIONS: These results suggest that early increases in renal CTGF protein contribute to incipient diabetic nephropathy and that renal CTGF may have utility as an early marker for progression to dysfunction in the diabetic kidney.

Mycobacteria, an environmental enhancer of lupus nephritis in a mouse model of systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is a chronic systemic autoimmune disease characterized by the production of antibodies directed against self antigens. Immune complex glomerulonephritis (GN) is one of the most serious complications of this disorder and can lead to potentially fatal renal failure. The aetiology of SLE is complex and multifactorial, characterized by interacting environmental and genetic factors. Here we examine the nature of the renal pathology in mycobacteria-treated non-obese diabetic (NOD) mice, in order to assess its suitability as a model for studying the aetiopathogenesis of, and possible treatment options for, lupus nephritis (LN) in humans. Both global and segmental proliferative lesions, characterized by increased mesangial matrix and cellularity, were demonstrated on light microscopy, and lesions varied in severity from very mild mesangiopathic GN through to obliteration of capillary lumina and glomerular sclerosis. Mixed isotype immune complexes (IC) consisting of immunoglobulin G (IgG), IgM, IgA and complement C3c were detected using direct immunofluorescence. They were deposited in multiple sites within the glomeruli, as confirmed by electron microscopy. The GN seen in mycobacteria-treated NOD mice therefore strongly resembles the pathology seen in human LN, including mesangiopathic, mesangiocapillary and membranous subclasses of LN. The development of spontaneous mixed isotype IC in the glomeruli of some senescent NOD mice suggests that mycobacterial exposure is accelerating, rather than inducing, the development of GN in this model.