Tendons – time to revisit inflammation
Jonathan D Rees1, Matthew Stride2, Alex Scott3
It is currently widely accepted among clinicians that chronic tendinopathy is caused by a degenerative process devoid of inflammation. Current treatment strategies are focused on physical treatments, peritendinous or intratendinous injections of blood or blood products and interruption of painful stimuli. Results have been at best, moderately good and at worst a failure. The evidence for non-infammatory degenerative processes alone as the cause of tendinopathy is surprisingly weak. There is convincing evidence that the inflammatory response is a key component of chronic tendinopathy. Newer anti-inflammatory modalities may provide alternative potential opportunities in treating chronic tendinopathies and should be explored further.
Case for inflammation in chronic tendinopathy
Although it was certainly progress to stop referring to all symptomatic tendons as ‘tendinitis’; does referring to all chronic tendons as ‘degenerative’ risks throwing the baby out with the bathwater? Ironically, it is now the ‘tendinosis’ paradigm that has itself become just as deeply ingrained in the medical literature as the original tendinitis concept. This has had two detrimental consequences. First, it oversimplifies our understanding of the pathological processes. Second it may lead us to ignore potentially effective treatments in chronic tendinopathy.
‘Absence’ of inflammatory cells
The ‘tendinopathy paradigm’ was developed from several historical studies that had failed to show the presence of acute inflammatory cells (such as neutrophils and macrophages) in chronic tendinopathy, or indeed in the early stages of tendon overload. From this there was an inference that both acute and chronic tendinopathies are devoid of inflammation.
One of the most common findings on US of a chronically symptomatic tendon is power Doppler blood flow generally not seen in healthy tendons. This blood flow is referred to as neovascularisation. It is difficult to know if this neovascularisation represents genuine neoangiogenesis, however in histological studies of chronic tendinopathy angiogenesis is a common finding. There is a body of evidence to suggest that neural ‘sprouting’ or neoinnervation accompanies neovessel formation, and that the neoinnervation may be a contributor or even responsible for the pain in chronic tendinopathy.
Power Doppler US assessment of, for example, an entheseal lesion or tendon body in a confirmed rheumatological inflammatory arthritis can look indistinguishable from that seen in a ‘degenerative’ tendinopathy (see figure 1).
Power Doppler ultrasound in ‘overuse’ and ‘inflammatory’ tendon disorders. Sonographically it is often impossible to determine the cause of tendinopathy from Power Doppler signals. The top row of images are all of patients without underlying rheumatological diagnosis and in whom mechanical overload or injury was the cause of the tendinopathy (from left to right insertional Achilles tendinopathy, proximal patellar tendon pathology and mid-peroneal tendon pathology). The bottom row of images is of patients with a known inflammatory rheumatological diagnosis. From left to right tibialis posterior tendinopathy (in RA) and insertional Achilles tendinopathy in a patient with reactive arthritis (longitudinal and transverse sections).
Biochemical influences on tendinopathy
There are several biochemical mediators that have been demonstrated to have an influence on the development and progression of chronic tendinopathy. These include the COX-1 and COX-2, matrix metalloprotineases (MMPs) and substance P.
The cyclooxygenase pathway is involved in classical inflammatory conditions (such as RA) and additionally processes with a more moderate degree of ongoing inflammation (such as osteoarthritis). It is known that peritendinous administration of prostaglandin E1 (PGE1) and elevated levels of PGE2may lead to tendinopathic changes in tendon models.
Tendinopathy remains both an extremely common condition and a condition with few truly effective treatments.
Over the last decade various models have been proposed to explain the pathological process underpinning tendinopathy. These models have suggested a primarily degenerative pathological process and some have clearly stated that the process of tendon overuse pathology is non-inflammatory in nature. Indeed this has become a paradigm for thinking about tendinopathy.
This paper has highlighted the limitations of this current view. More modern research tools have confirmed the presence of inflammatory cells including macrophages and lymphocytes in chronic tendinopathy, particularly in closely associated tissue (eg, bursa or paratenon). In addition to inflammatory cells, there is evidence that numerous other mediators including substance P, MMPs, VEGF and COX which play a role in chronic tendon pathology.
This does not mean that the pathology of chronic tendinopathy mirrors that of inflammatory arthritis. We do not advocate going back to the ‘tendinitis’ model, and there is no doubt that a shift away from primarily anti-inflammatory strategies has had great benefit for tendinopathy treatments, by placing the emphasis on active rehabilitation to attempt to regain function and potentially lead to enhanced tissue remodelling.
Mechanical overload is still likely to be the dominant factor involved in initiation of an inflammatory response—the point is that at least some of the damage caused by this overload is mediated through a process that involves elements of the inflammatory process.
An appreciation of the basic science involved in tendinopathy gives us a whole new potential armamentarium of treatments that we can use. It is hoped that tendon research will be driven by a greater awareness of the potential for managing and targeting the inflammatory response.
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