Cosima Schiavone

Occurrence of tendon pathologies in metabolic disorders

This article reviews the pathogenetic role of metabolic disorders, which are of paramount relevance to the progression of tendon damage. In diabetes, the prevalence of rheumatological diseases is high, mainly because of the deleterious effects of advanced glycation end products that deteriorate the biological and mechanical functions of tendons and ligaments. In heterozygous familial hypercholesterolaemia, most patients develop Achilles xanthomatosis, a marker of high risk for cardiovascular disease caused by cholesterol deposition in the tendons. Tendon degeneration has also been observed in non-familial hypercholesterolaemia. Monosodium urate crystal deposition in soft tissues is a hallmark of chronic gouty arthritis. In this group of diseases, the mobilization of cholesterol and uric acid crystals is presumably followed by low-grade inflammation, which is responsible for tendon degeneration. Adiposity may contribute to tendon disorders via two different mechanisms: increased weight on the load-bearing tendons and systemic dysmetabolic factors that trigger subclinical persistent inflammation. Finally, tendon abnormalities have been observed in some rare congenital metabolism disorders such as alkaptonuria.

Limited joint mobility in diabetes and ageing: recent advances in pathogenesis and therapy.

Limited joint mobility is frequently observed in elderly people and in patients suffering from diabetes, who represent a growing segment of the population of western countries. Our review wishes to offer the “state of art” about this interesting topic, which may have important clinical implications, leading to impairment of both basic and instrumental activities of daily living. The main causes of a reduced range of motion are degenerative joint diseases and increased stiffness of collagen tissue. The main biochemical abnormality, common to aging and diabetes, is the non-enzymatic glycosilation of collagen, with advanced glycation end product (AGE) formation, which in turn leads to an increase of collagen cross-links. The most extensive accumulation of AGEs occurs in tissues that contain proteins with low turnover, such as the collagen in the extracellular matrix of articular capsule, ligaments and muscle-tendon units. The increase in collagen cross-linking alters the mechanical properties of these tissues with a decrease in elasticity and tensile strength, and an increase in mechanical stiffness. Besides this, AGEs react with specific cell surface receptors (RAGEs). The engagement of the ligand by RAGEs triggers cell-specific signalling, resulting in enhanced generation of reactive oxygen species and sustained up-regulation of pro-inflammatory mediators and adhesion molecules. An appropriate control of the glucose levels and a diet rich in antioxidant agents are recommended in patients with diabetes. Stretching and strengthening programmes are widely used, in order to prevent and to reduce joint stiffness, but the improvements with physiotherapy are little and short-lasting. Several drugs, which can interfere with AGE formation and removal, or with the cellular effects of AGEs, are under study (among them pyridoxamine, an active form of Vitamin B6, AGE-breaker compounds, glucosamine, rutin and derivatives, soluble RAGE isoforms, and statins). In experimental animal models, these drugs are effective in reducing diabetic complications due to AGE formation; however, further study is necessary before their extensive use in the clinical setting.

Sonographic evaluation of the shoulder in asymptomatic elderly subjects with diabetes.

BackgroundThe prevalence of rotator cuff tears increases with age and several studies have shown that diabetes is associated with symptomatic shoulder pathologies. Aim of our research was to evaluate the prevalence of shoulder lesions in a population of asymptomatic elderly subjects, normal and with non insulin - dependent diabetes mellitus.MethodsThe study was performed on 48 subjects with diabetes and 32 controls (mean age: 71.5 ± 4.8 and 70.7 ± 4.5, respectively), who did not complain shoulder pain or dysfunction. An ultrasound examination was performed on both shoulders according to a standard protocol, utilizing multiplanar scans.ResultsTendons thickness was greater in diabetics than in controls (Supraspinatus Tendon: 6.2 ± 0.09 mm vs 5.2 ± 0.7 mm, p < 0.001; Biceps Tendon: 4 ± 0.8 mm vs 3.2 ± 0.4 mm, p < 0.001). Sonographic appearances of degenerative features in the rotator cuff and biceps were more frequently observed in diabetics (Supraspinatus Tendon: 42.7% vs 20.3%, p < 0.003; Biceps Tendon: 27% vs 7.8%, p < 0.002).Subjects with diabetes exhibited more tears in the Supraspinatus Tendon (Minor tears: 15 (15.8%) vs 2 (3.1%), p < 0.03; Major tears: 15 (15.8%) vs 5 (7.8%), p = ns), but not in the long head of Biceps. More effusions in subacromial bursa were observed in diabetics (23.9% vs 10.9%, p < 0.03) as well as tenosynovitis in biceps tendon (33.3% vs 10.9%, p < 0.001).In both groups, pathological findings were prevalent on the dominant side, but no difference related to duration of diabetes was found.ConclusionsOur results suggest that age - related rotator cuff tendon degenerative changes are more common in diabetics.Ultrasound is an useful tool for discovering in pre - symptomatic stages the subjects that may undergo shoulder symptomatic pathologies.

Management of limited joint mobility in diabetic patients

Several rheumatologic manifestations are more pronounced in subjects with diabetes, ie, frozen shoulder, rotator cuff tears, Dupuytren’s contracture, trigger finger, cheiroarthropathy in the upper limb, and Achilles tendinopathy and plantar fasciitis in the lower limb. These conditions can limit the range of motion of the affected joint, thereby impairing function and ability to perform activities of daily living. This review provides a short description of diabetes-related joint diseases, the specific pathogenetic mechanisms involved, and the role of inflammation, overuse, and genetics, each of which activates a complex sequence of biochemical alterations. Diabetes is a causative factor in tendon diseases and amplifies the damage induced by other agents as well. According to an accepted hypothesis, damaged joint tissue in diabetes is caused by an excess of advanced glycation end products, which forms covalent cross-links within collagen fibers and alters their structure and function. Moreover, they interact with a variety of cell surface receptors, activating a number of effects, including pro-oxidant and proinflammatory events. Adiposity and advanced age, commonly associated with type 2 diabetes mellitus, are further pathogenetic factors. Prevention and strict control of this metabolic disorder is essential, because it has been demonstrated that limited joint motion is related to duration of the disease and hyperglycemia. Several treatments are used in clinical practice, but their mechanisms of action are not completely understood, and their efficacy is also debated.

Limited joint mobility (LJM) in elderly subjects with type II diabetes mellitus

LJM is frequently observed in young subjects with insulin-dependent diabetes mellitus (IDDM). Aim of this study was to evaluate whether non-insulin-dependent diabetes mellitus (NIDDM) increases the risk of LJM in elderly subjects. Thirty patients (15 males, 15 females, mean age 73.93 ± 12.72 years) with NIDDM in good glycemic control were compared with thirty non-diabetic elderly, well matched for sex and age (15 males, 15 females, mean age 74.3 ± 4.24 years), and with ten young normal subjects (5 males, 5 females, mean age 26.3 ± 1.56 years). In these subjects, the range of motion (ROM) of ankle, knee, hip, elbow and shoulder were measured with a double-armed goniometer. Moreover, abnormalities of supraspinatus, patellar and Achilles tendons were evaluated with a standardized ultrasound (US) procedure. A significant reduction in the mobility of all joints was found in elderly subjects, compared to younger ones, with exception for the knee and elbow flexion. Elderly patients with diabetes, compared with their age-matched counterpart, showed LJM for ankle dorso- and plantar flexion, hip flexion and adduction, shoulder abduction and flexion. Moreover, tendons sonographic abnormalities were more frequently observed in diabetics. Our data confirm that diabetes worsens the LJM in the elderly, increasing the cross-linking of collagen by the non-enzymatic advanced glycation end products formation.

Achilles tendon and plantar fascia in recently diagnosed type II diabetes: role of body mass index.

Previous research has shown that plantar fascia and Achilles tendon thickness is increased in diabetes. The aims of present study were to assess whether tendon changes can occur in the early stages of the disease and to evaluate the extent of the influence of body mass index (BMI). The study population included 51 recent-onset type II diabetic subjects, who were free from diabetic complications, divided according to BMI into three groups (normal weight, overweight, and obese). Eighteen non-diabetic, normal-weight subjects served as controls. Plantar fascia and Achilles tendon thickness was measured by means of sonography. The groups were well balanced for age and sex. In all the diabetic subjects, plantar fascia and Achilles tendon thickness was increased compared to the controls (p < 0.001, p = 0.01, p = 0.003, respectively). A significant relationship was found between plantar fascia thickness and BMI values (r = 0.749, p < 0.0001), while the correlation between BMI and Achilles tendon was weaker (r = 0.399, p = 0.004). This study shows that plantar fascia and Achilles tendon thickness is increased in the early stages of type II diabetes and that BMI is related more to plantar fascia than Achilles tendon thickness. Further longitudinal studies are needed to evaluate whether these early changes can overload the metatarsal heads and increase the stress transmitted to plantar soft tissues, thus representing an additional risk factor for foot ulcer development.

Sarcoidosis vs. Sarcoid-like reactions: The Two Sides of the same Coin?

SummaryDifferentiating between sarcoidosis as an autonomous disease and sarcoid-like reactions requires considerable efforts. The epithelioid cell granuloma is not equivalent to sarcoidosis because it may be identified in a number of infectious and noninfectious disorders, including neoplastic diseases. At the current state of knowledge, accurate distinction between different causes of epithelioid cell granulomas is in many cases not possible. Despite being characteristic of sarcoidosis and sarcoid-like reactions, the epithelioid cell granuloma is not their synonym, as numerous other causes can give rise to such a type of granulomatous infiltrate. Its etiology should be sought through careful additional investigations, including the genetic signature of both conditions.Sarcoid-like reactions may be grouped generally into several subtypes. The differentiation between each one of them requires a certain combination of diagnostic tests. The major objective of these tests is to exclude or to prove the presence of an infectious, tumoral, or immunogenic antigen on the one hand, and to characterize the genetic profile of the affected patients (for example, sarcoidosis-specific genes) on the other. Only thus may one accurately differentiate between the two pathologic conditions described earlier in the abstract.The clear differentiation between sarcoidosis as a separate disease and sarcoid-like pathologies leads to the more precise clarification of the final diagnosis, which may in turn allow for a more appropriate therapy and improvement in the quality of life of the patients. Equating sarcoid granulomas with sarcoidosis can lead to serious consequences in a number of patients. Sadly enough, after scrutinizing the current available data in the world literature, one cannot find criteria to allow such distinction in a high percentage of the investigated cases.This critical review provides a completely new pathogenetic and diagnostic algorithm, helping in the differentiation between the disease sarcoidosis and the sarcoid-like pathologies with different etiology. An update on the inclusion criteria from the ATS/ERS/WASOG (American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders) statement (which at the current state of knowledge seems to be ineffective) for the diagnosis of sarcoidosis is also suggested.In conclusion, molecular mimicry may be seen as the main pathogenic generator not only of sarcoidosis but also of sarcoid-like reactions. A completely new and exact definition of the notion of or the sarcoidosis disease itself will be possible only after 1.defining the genetic risk for the development of sarcoidosis as an autonomous disease and supplementing the sarcoidosis consensus of ATS/ERS/WASOG from 1999 with this important information, and2.defining the notion of a sarcoid-like reaction and its subforms.ZusammenfassungDie Unterscheidung von Sarkoidose als eigenständiger Erkrankung und sarkoidaler Reaktion erfordert erhebliche Anstrengungen. Der Nachweis epitheloidzelliger Granulome ist nicht der Diagnose einer Sarkoidose gleichzusetzen, da diese bei einer Vielzahl von infektiösen und nicht infektiösen Erkrankungen, einschließlich der Tumore, auftreten können. Mit unserem derzeitigen Wissensstand ist die exakte Differenzierung bezüglich ihrer Ursachen aus nicht immer möglich. Obwohl die epitheloidzelligen Granulome charakteristisch für Sarkoidose und sarkoidale Reaktionen sind, können zahlreiche andere Ursachen für ihre Entstehung verantwortlich sein. Ihre Ätiologie sollte durch sorgfältige zusätzliche Untersuchungen einschließlich der genetischen Signatur beider Erkrankungen geklärt werden.Sarkoidale Reaktionen können in verschiedene Subtypen klassifiziert werden. Deren Unterscheidung bedarf einer gewissen Kombination der Untersuchungsverfahren. Hauptanliegen dieser Untersuchungen ist die Verifizierung bzw. der Ausschluß infektiöser, tumoraler oder immunogener Antigene einerseits und die Beschreibung des genetischen Profils des betroffenen Patienten (z.B. sarkoidose-spezifische Gene) andererseits. Nur hierdurch wird eine exakte Differenzierung beider Pathologien (Sarkoidose, sarkoidal) möglich.Die eindeutige Differenzierung von Sarkoidose und sarkoidaler Reaktion als verschiedene Erkrankungen erlaubt eine präzisere Diagnose, eine zielgerichtetere Behandlung und die Verbesserung der Lebensqualität der Patienten. Umgekehrt kann die Nichtbeachtung dieses Grundsatzes zu ernsten Konsequenzen für betroffene Patienten führen. Leider ist bietet die wissenschaftliche Weltliteratur bislang keine Kriterien, die eine klare Unterscheidung beider Pathologien bei einem hohen Prozentsatz der Patienten erlaubt.Diese kritische Übersicht entwickelt einen komplett neuen pathogenetischen und diagnostischen Algorithmus zur Differenzierung von Sarkoidose und sarkoidaler Reaktion verschiedener Ätiologien. Ein Update der Einschlußkriterien der ATS/ERS/WASOG (American Thoracic Society/European Respiratory Society/World Association of Sarcoidosis and other Granulomatous Disorders) für die Sarkoidose-Diagnose wird ebenfalls vorgeschlagen.Schlußfolgerungen: Molekulare Mimikry kann als wesentlicher Motor nicht allein für die Sarkoidose, sondern auch die sarkoidale Reaktion angesehen werden. Eine komplett neue und exakte Definition der Diagnose Sarkoidose wird nur dann möglich werden, wenn: 1.Das genetische Risiko der Sarkoidoseentwicklung bestimmt und der Konsensus der ATS/ERS/WASOG von 1999 implementiert wird.2.Die sarkoidale Reaktion und ihre Subtypen bestimmt werden.

The Use of Hyaluronic Acid after Tendon Surgery and in Tendinopathies

Viscosupplementation with hyaluronic acid is safe and effective in the management of osteoarthritis, but its use in the treatment of tendon disorders has received less attention. The aim of this review is to summarize the current knowledge on this topic, evaluating experimental and clinical trials. A search of English-language articles was performed using the key search terms “hyaluronic acid” or “viscosupplementation” combined with “tendon,” “tendinopathy,“ “adhesions,“ or “gliding,“ independently. In quite all the experimental studies, performed after surgical procedures for tendon injuries or in the treatment of chronic tendinopathies, using different hyaluronic acid compounds, positive results (reduced formation of scars and granulation tissue after tendon repair, less adhesions and gliding resistance, and improved tissue healing) were observed. In a limited number of cases, hyaluronic acid has been employed in clinical practice. After flexor tendon surgery, a greater total active motion and fingers function, with an earlier return to work and daily activities, were observed. Similarly, in patients suffering from elbow, patellar, and shoulder tendons disorders, pain was reduced, and function improved. The positive effect of hyaluronic acid can be attributed to the anti-inflammatory activity, enhanced cell proliferation, and collagen deposition, besides the lubricating action on the sliding surface of the tendon.

Ultrasound Morphology of the Achilles in Asymptomatic Patients With and Without Diabetes

Background: The prevalence of tendinopathies is increased in subjects with diabetes mellitus. However, there are few data on the structural abnormalities of Achilles tendons in asymptomatic diabetic patients. The aim of the study was to assess the morphologic characteristics of the Achilles tendon in subjects with diabetes in comparison with controls without diabetes. Methods: Participants were consecutively recruited from an outpatient population. Ultrasound longitudinal and transverse scans were performed bilaterally along the full length of Achilles tendon from the musculotendinous junction to the insertion. Degenerative features (abnormal fibrillar pattern, hypo-hyperechoic areas), signs of enthesopathy (bony erosion, enthesophytes, and bursitis), and intratendinous neovessel formation were recorded. Results: Asymptomatic sonographic abnormalities (ASA) were significantly increased in subjects with diabetes (35/136 [25.7%] vs 32/273 [11.7%], P = .0003). Sixty tendons with ASA were observed in the first group and 45 in the latter because ASA were bilateral in 25 and in 13 subjects, respectively. ASA were more frequently localized at the enthesis (32/60 [53.3%] vs 9/45 [20%], P = .0005) in the diabetes group, whereas, on the contrary, they were more prevalent at the midportion in controls (38/45 [84.4%] vs 36/60 [60%], P < .006). Conclusion: Diabetes may predispose to Achilles tendinopathy and particularly to Achilles enthesopathy. Longitudinal studies, evaluating the progression of the lesions not only in the midportion of the tendon but also at the insertion are needed to support this conclusion. Level of Evidence: Level III, comparative series.

Hepatosplenic Sarcoidosis: Contrast-Enhanced Ultrasound Findings and Implications for Clinical Practice

Sarcoidosis is a complex granulomatous disease that affects virtually every organ and tissue, with a prevalence that varies significantly among the sites involved. The role of conventional imaging, such as computed tomography and magnetic resonance imaging, in the assessment of hepatosplenic sarcoidosis is well established by revealing organ enlargement, multiple discrete nodules, and lymphadenopathy. In this review, we aim to describe contrast-enhanced ultrasound (CEUS) findings in liver and spleen involvement by sarcoidosis, reporting evidence from the literature and cases from our experience, after a brief update on safety profile, cost-effectiveness, and clinical indications of this novel technique. Furthermore, we highlight potential advantages of CEUS in assessing hepatosplenic sarcoidosis that may be useful in the clinical practice.