Rheumatologists have largely conceptualised joint disease in inflammatory and degenerative arthritis in terms of bone, cartilage and the synovial lining, but have tended to overlook other integral components of the joints which are attached close to joint margins. We discuss these structures under the umbrella term of ‘appendages’. These structures include ligaments, tendons, entheses or joint insertions, regional fibrocartilages, bursae and other peri-articular joint structures including fat pads and nails. In this review, we highlight how these structures play key pathophysiological roles in inflammatory arthritis and we emphasise how an understanding of these structures is collectively important for both clinical practice and future rheumatological research.
Introduction
Rheumatologists are well versed in the importance of synovium, for example, in the pathogenesis of joint destruction in rheumatoid arthritis (RA). Likewise, all involved in musculoskeletal research also appreciate the importance of bone and articular cartilage in the pathogenesis of joint destruction in osteoarthritis (OA) . In these last 15 years, the third major category of inflammatory arthritis, namely the ‘spondyloarthropathies (SpA)’, has been shown to be intimately associated with inflammation at the enthesis, or site of ligament and tendon insertions . However, the role of these and other structures around joints is less well appreciated. The purpose of this article is to review the role of what we collectively term as ‘appendages’ in the pathophysiology of joint destruction. We will cover ligaments and tendons, and then peri-articular structures, namely bursae, joint fat pads and nails.
Ligaments and tendons
The role of ligaments has recently gained interest with high-resolution magnetic resonance imaging (MRI) studies into hand OA, where the earliest abnormality seen is diffuse thickening of the ligaments associated with adjacent peri-articular inflammatory change, adjacent synovitis and compression-related bony erosions . Furthermore, there is evidence for age-related change in ligaments with thickening setting in after the age of 50 . Moreover, the most conspicuous abnormality in subjects with uninvolved joints adjacent to osteoarthritic joints is the presence of ligament abnormalities . However, ligaments are under-appreciated drivers in the pathogenesis of OA . This has led to the recent proposal for an anatomical re-classification of OA whereby the idiopathic category of disease is now thought to be anatomically intimately linked to ligament abnormalities .
It is now well recognised that certain key structures play vital roles in joint physiology, and predispose to arthritis. Whilst insertions have been historically viewed as focal, it is now evident that some entheses actually form what are termed ‘enthesis organs’ . This means that adjacent to the insertion proper, the bone surface is often lined by enthesis-associated cartilages termed ‘periosteal fibrocartilages’ . Moreover, the undersurface of ligaments and tendons is also often lined by similar fibrocartilage. Because ligaments and tendons are usually inserted into bones, and run in a curved angle over rounded bone surfaces, this allows the pressure on joint loading to be distributed over a much wider area than simply the insertion proper. Consequently, ligaments and tendons have cartilages that are intra-articular, but are not involved in direct cartilage-on-cartilage load bearing, as has been the traditionally envisaged model of cartilage function in joints.
These cartilages are subject to extensive micro-damage in healthy aged subjects . Furthermore, these cartilages, just like articular cartilage, require lubrication by synovial fluid, and they also rely on the synovial fluid to remove microdebris. Given that these ligament and tendon-related cartilages are located intra-articularly, they are intimately associated with the joint synovium in what have been termed ‘synovio-entheseal complexes’ . These structures likely play a very significant role in the pathogenesis of intra-articular synovitis not only in the seronegative SpA but also in OA .
Ligaments and tendons
The role of ligaments has recently gained interest with high-resolution magnetic resonance imaging (MRI) studies into hand OA, where the earliest abnormality seen is diffuse thickening of the ligaments associated with adjacent peri-articular inflammatory change, adjacent synovitis and compression-related bony erosions . Furthermore, there is evidence for age-related change in ligaments with thickening setting in after the age of 50 . Moreover, the most conspicuous abnormality in subjects with uninvolved joints adjacent to osteoarthritic joints is the presence of ligament abnormalities . However, ligaments are under-appreciated drivers in the pathogenesis of OA . This has led to the recent proposal for an anatomical re-classification of OA whereby the idiopathic category of disease is now thought to be anatomically intimately linked to ligament abnormalities .
It is now well recognised that certain key structures play vital roles in joint physiology, and predispose to arthritis. Whilst insertions have been historically viewed as focal, it is now evident that some entheses actually form what are termed ‘enthesis organs’ . This means that adjacent to the insertion proper, the bone surface is often lined by enthesis-associated cartilages termed ‘periosteal fibrocartilages’ . Moreover, the undersurface of ligaments and tendons is also often lined by similar fibrocartilage. Because ligaments and tendons are usually inserted into bones, and run in a curved angle over rounded bone surfaces, this allows the pressure on joint loading to be distributed over a much wider area than simply the insertion proper. Consequently, ligaments and tendons have cartilages that are intra-articular, but are not involved in direct cartilage-on-cartilage load bearing, as has been the traditionally envisaged model of cartilage function in joints.
These cartilages are subject to extensive micro-damage in healthy aged subjects . Furthermore, these cartilages, just like articular cartilage, require lubrication by synovial fluid, and they also rely on the synovial fluid to remove microdebris. Given that these ligament and tendon-related cartilages are located intra-articularly, they are intimately associated with the joint synovium in what have been termed ‘synovio-entheseal complexes’ . These structures likely play a very significant role in the pathogenesis of intra-articular synovitis not only in the seronegative SpA but also in OA .
Pathophysiological implications of ligament and tendon appendages
Historically, the pathogenesis of erosion formation was conceptualised in relationship to pannus that invaded the so called ‘bare area’ between synovium and peri-articular cartilage . However, these sites of erosion formation in RA, psoriatic arthritis (PsA) and inflammatory OA are often immediately adjacent to tendons and ligaments, where they compress the joint as they run towards the enthesis . In health, these regions are often lined by cartilage and, consequently, erosion formation may occur at a site where there is actually no bare area. Therefore, it appears that in addition to synovitis, the pressure effects of ligaments and tendons are key players in the development of erosion formation. Indeed, normal joints have evidence of microscopic erosions histologically and this has recently been confirmed in normal joints using high-resolution computed tomography (CT) . Not only are ligament and tendon appendages important for peri-articular erosion formation but also they are likely to be vital to explaining the long-recognised periosteal reaction that is often a feature of PsA in locations such as the ankle joint. Where periostitis and new bone formation outside joints is well recognised, it now appears that the basis for this at the ankle entails tendon pressure over the malleolus, which has been termed a ‘functional enthesis’ . These functional entheses, where there is extensive compression of the bone by the tendon as it changes course, are associated with an underlying osteitis in SpA. We believe that this osteitis is then associated with a reaction in the periosteum, which leads to spiculated new bone appearances and periostitis. Therefore, these appendages may play a significant role in the pathophysiology of pain, inflammation and radiographic changes outside actual synovial joints along bony surfaces. This historically difficult-to-understand pattern of disease in PsA can now potentially be explained .
These observations are also important in animal models, where in the tumour necrosis factor (TNF) transgenic model, the earliest erosion formation occurs where the long peroneal tendon exerts pressure over the bone around the ankle joint . The effect of these structures on inflammation extends well beyond academic observation and may be of great clinical relevance. For example, the magnitude of synovitis is much greater adjacent to these appendages in the knee joint, and particularly in the suprapatellar pouch at the quadriceps tendon insertion . What is more, the suppression of inflammation with disease-modifying anti-rheumatic drugs (DMARDs) is associated with less regression of inflammation at these sites . This means that these structures may be key players in providing the micro-environment for residual synovitis which could be relevant to help sustain and perpetuate disease.
Bursae
Bursae are usually located outside joints and can serve to minimise friction adjacent to tendon insertions. Bursae are actually quite complex structures which can sometimes have fibrocartilaginous walls adjacent to the points of tendon insertions . Together, these form enthesis organs and synovio-entheseal complexes. This arrangement is present at several sites throughout the body. As described previously, there are two types of enthesis organs, intra-articular and extra-articular . This anatomical configuration likely explains why bone oedema reactions are evident in trochanteric bursitis proximal to the insertion point of the tendons, where pressure is exerted over the bone ( Fig. 1 ). It has not yet been fully appreciated how these complex extra-articular enthesis organs contribute to inflammation and pain.
