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Joint appendages – the structures which have historically been overlooked in arthritis research and therapy development
Best Practice & Research Clinical Rheumatology 25 (2011) 779–784
Contents lists available at SciVerse ScienceDirect
Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh
3
Joint appendages – the structures which have historically been overlooked in arthritis research and therapy development Zoe Ash, Dennis McGonagle*,1 Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds LS7 4SA, UK
Keywords: Tendons Ligaments Synovial bursa Psoriatic arthritis
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. Ó 2011 Elsevier Ltd. All rights reserved.
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) [1]. 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 [2]. 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
* Corresponding author. E-mail addresses: [email protected] (Z. Ash), [email protected] (D. McGonagle). 1 Tel.: þ44 113 3924884; fax: þ44 113 392 4991. 1521-6942/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2011.11.009
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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 compressionrelated bony erosions [3]. Furthermore, there is evidence for age-related change in ligaments with thickening setting in after the age of 50 [4,5]. Moreover, the most conspicuous abnormality in subjects with uninvolved joints adjacent to osteoarthritic joints is the presence of ligament abnormalities [4]. However, ligaments are under-appreciated drivers in the pathogenesis of OA [3]. 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 [6]. 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’ [7]. This means that adjacent to the insertion proper, the bone surface is often lined by enthesis-associated cartilages termed ‘periosteal fibrocartilages’ [8,9]. 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 [10]. 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’ [11]. 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 [10]. 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 [12]. 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 [13]. 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 [13] and this has recently been confirmed in normal joints using high-resolution computed tomography (CT) [14]. 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’ [8]. 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 [8].
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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 [15]. 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 [16]. What is more, the suppression of inflammation with disease-modifying anti-rheumatic drugs (DMARDs) is associated with less regression of inflammation at these sites [16]. 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 [7]. Together, these form enthesis organs and synovioentheseal 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 [7]. 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. Fat pads Joint fat has only recently become appreciated in a rheumatology setting. Joint fat may be located in extra-articular sites such as around the Achilles tendon and plantar fascia where it is vital for
Fig. 1. Magnetic resonance imaging of right sided trochanteric bursitis in a female patient in her 50s with mechanical disease, there is bone oedema seen but no evident soft-tissue change. This relates to the enthesis organ concept whereby the tendon appendage exerts pressure over the bone proximal to the attachment site.
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cushioning [17]. Large conspicuous fat pads such as Hoffa’s fat pad in the knee are one type of prominent intra-articular joint adiposity in a classical synovial joint. The second type is a sub-synovial fibro-fatty tissue. It must be remembered that fat is a liquid at body temperature and therefore it is an excellent shock absorber. There is also a prominent fat pad adjacent to the retro-calcaneal bursa called ‘Kager’s fat pad’, which may contribute to shock absorption during locomotion and certainly represents an under-appreciated skeletal appendage. Fat pads also have extensive fibrous septa to contain the fat within small compartments to stop its displacement during locomotion. Joint fat has also been noted to have excellent stem cell activity, being a rich source of mesenchymal stem cells, with good chondrogenic potential [18]. Indeed, the potential of the joint fat pad with respect to chondrogenesis is much greater than that from subcutaneous fat [19].
Relevance of fat in disease Atrophy of the fat pad in the heel is a recognised factor for plantar fasciitis-type pain [20]. Hoffa’s fat pad impingement in the knee is associated with pain [21]. This can be appreciated on MRI and the excision of the fat pad can be associated with good symptomatic relief. MRI scanning shows that Kager’s fat pad is often inflamed as part of the enthesitis organ inflammatory reaction [22]. Recent studies have also shown that there may be fat pad inflammation in OA [23]. Furthermore, it is
Fig. 2. Magnetic resonance imaging of a finger distal interphalangeal joint, showing the extensor tendon attachment to the base of the distal phalanx with some fibres running towards the nail matrix (white asterisk).
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increasingly recognised that the fat pad is a source of various cytokines including adiponectin that may play prominent immunomodulatory roles [24,25]. The role of fat, both in extra-articular and intraarticular locations, is currently not fully appreciated, and is ripe for further studies.
The nail When rheumatologists think of joint appendages, perhaps the most surprising aspect of all is to discover that the nail is actually intimately linked with the skeleton. It turns out that although the extensor tendon inserts into the bone of the distal phalanx, a significant proportion of fibres run forward and anchor at the nail root (Fig. 2). Fibres also run from the enthesis along the periosteum to the digital tuft [26,27]. These fibres send vertical struts, or small dermal ligaments, that in turn anchor the periosteum to the nail bed. Furthermore, some of the fibres of the collateral ligaments extend beyond the insertion point and appear to provide lateral stability and anchorage to the nail [28]. Finally, the flexor tendon inserts into the distal phalanx and is intimately integrated with the collateral ligaments and affords additional anchorage to the nail [27]. Therefore, although the nail is embryologically derived from the ectoderm, it is very much integrated to the mesoderm and is functionally part of the skeleton. This helps explain long-standing observations including the greater prevalence of nail disease in PsA compared to psoriasis and also why nail disease may be predictive of PsA development [29]. Indeed, a recent study has confirmed that psoriasis with nail disease is associated with a greater degree of subclinical enthesopathy than psoriasis with normal nails [30].
Summary The purpose of this review was to highlight how the articulating skeleton is very much functionally integrated to include a number of appendages that exert a functional and, by extension, pathological effect over a wide area of the joint. These structures include ligaments, tendons, capsules and bursae. The importance of these structures is becoming increasingly apparent with the use of sophisticated imaging techniques in routine practice including MRI and sonography. The relevance of some of these structures has also been validated in animal model studies. The role of these appendages in the pathophysiology of pain requires further study. Practice points Rheumatologists need to appreciate the role of joint appendages in both pain causation and in disease pathophysiology. Newer imaging techniques may allow further detailed study of these structures.
Research agenda The systematic assessment of the role of appendages in causing pain and inflammation needs to be placed on an even footing with synovium, cartilage and bone in arthritis research.
References [1] Felson DT. An update on the pathogenesis and epidemiology of osteoarthritis. Radiologic Clinics of North America 2004 Jan;42(1):1–9. [2] McGonagle D, Gibbon W, O’Connor P, Green M, Pease C, Emery P. Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis and Rheumatism 1998 Apr;41(4):694–700.
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*[3] McGonagle D, Tan AL, Grainger AJ, Benjamin M. Heberden’s nodes and what Heberden could not see: the pivotal role of ligaments in the pathogenesis of early nodal osteoarthritis and beyond. Rheumatology (Oxford, England) 2008 Sep;47(9): 1278–85. [4] Tan AL, Grainger AJ, Tanner SF, Shelley DM, Pease C, Emery P, et al. High-resolution magnetic resonance imaging for the assessment of hand osteoarthritis. Arthritis and Rheumatism 2005 Aug;52(8):2355–65. *[5] Tan AL, Toumi H, Benjamin M, Grainger AJ, Tanner SF, Emery P, et al. Combined high-resolution magnetic resonance imaging and histological examination to explore the role of ligaments and tendons in the phenotypic expression of early hand osteoarthritis. Annals of the Rheumatic Diseases 2006 Oct;65(10):1267–72. [6] McGonagle D, Tan AL, Carey J, Benjamin M. The anatomical basis for a novel classification of osteoarthritis and allied disorders. Journal of Anatomy 2010 Mar;216(3):279–91. [7] Benjamin M, Moriggl B, Brenner E, Emery P, McGonagle D, Redman S. The “enthesis organ” concept: why enthesopathies may not present as focal insertional disorders. Arthritis and Rheumatism 2004 Oct;50(10):3306–13. *[8] Benjamin M, McGonagle D. The anatomical basis for disease localisation in seronegative spondylarthropathy at entheses and related sites. Journal of Anatomy 2001 Nov;199(Pt 5):503–26. [9] McGonagle D, Marzo-Ortega H, Benjamin M, Emery P. Report on the second international enthesitis workshop. Arthritis and Rheumatism 2003 Apr;48(4):896–905. [10] Benjamin M, McGonagle D. Histopathologic changes at “synovio-entheseal complexes” suggesting a novel mechanism for synovitis in osteoarthritis and spondylarthritis. Arthritis and Rheumatism 2007 Nov;56(11):3601–9. [11] McGonagle D, Lories RJ, Tan AL, Benjamin M. The concept of a “synovio-entheseal complex” and its implications for understanding joint inflammation and damage in psoriatic arthritis and beyond. Arthritis and Rheumatism 2007 Aug; 56(8):2482–91. [12] Tak PP, Bresnihan B. The pathogenesis and prevention of joint damage in rheumatoid arthritis: advances from synovial biopsy and tissue analysis. Arthritis and Rheumatism 2000 Dec;43(12):2619–33. [13] McGonagle D, Tan AL, Moller Dohn U, Ostergaard M, Benjamin M. Microanatomic studies to define predictive factors for the topography of periarticular erosion formation in inflammatory arthritis. Arthritis and Rheumatism 2009 Apr;60(4): 1042–51. *[14] Stach CM, Bauerle M, Englbrecht M, Kronke G, Engelke K, Manger B, et al. Periarticular bone structure in rheumatoid arthritis patients and healthy individuals assessed by high-resolution computed tomography. Arthritis and Rheumatism 2010 Feb;62(2):330–9. *[15] Hayer S, Redlich K, Korb A, Hermann S, Smolen J, Schett G. Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis. Arthritis and Rheumatism 2007 Jan;56(1):79–88. [16] Rhodes LA, Tan AL, Tanner SF, Radjenovic A, Hensor EM, Reece R, et al. Regional variation and differential response to therapy for knee synovitis adjacent to the cartilage-pannus junction and suprapatellar pouch in inflammatory arthritis: implications for pathogenesis and treatment. Arthritis and Rheumatism 2004 Aug;50(8):2428–32. *[17] Benjamin M, Redman S, Milz S, Buttner A, Amin A, Moriggl B, et al. Adipose tissue at entheses: the rheumatological implications of its distribution. A potential site of pain and stress dissipation? Annals of the Rheumatic Diseases 2004 Dec;63(12):1549–55. [18] English A, Jones EA, Corscadden D, Henshaw K, Chapman T, Emery P, et al. A comparative assessment of cartilage and joint fat pad as a potential source of cells for autologous therapy development in knee osteoarthritis. Rheumatology (Oxford, England) 2007 Nov;46(11):1676–83. [19] Mochizuki T, Muneta T, Sakaguchi Y, Nimura A, Yokoyama A, Koga H, et al. Higher chondrogenic potential of fibrous synovium- and adipose synovium-derived cells compared with subcutaneous fat-derived cells: distinguishing properties of mesenchymal stem cells in humans. Arthritis and Rheumatism 2006 Mar;54(3):843–53. [20] Falsetti P, Frediani B, Acciai C, Baldi F, Filippou G, Marcolongo R. Heel fat pad involvement in rheumatoid arthritis and in spondyloarthropathies: an ultrasonographic study. Scandinavian Journal of Rheumatology 2004;33(5):327–31. [21] Magi M, Branca A, Bucca C, Langerame V. Hoffa disease. Italian Journal of Orthopaedics & Traumatology 1991 Jun;17(2): 211–6. [22] Gheno R, Nico MA, Buck FM, Trudell DJ, Haghighi P, Resnick D. Edematous processes within Kager fat pad: magnetic resonance imaging, gross anatomical, and histological studies in cadavers with clinical correlation. Journal of Computer Assisted Tomography 2010 Jul;34(4):621–5. [23] Clockaerts S, Bastiaansen-Jenniskens YM, Runhaar J, Van Osch GJ, Van Offel JF, Verhaar JA, et al. The infrapatellar fat pad should be considered as an active osteoarthritic joint tissue: a narrative review. Osteoarthritis and Cartilage/OARS, Osteoarthritis Research Society 2010 Jul;18(7):876–82. *[24] Distel E, Cadoudal T, Durant S, Poignard A, Chevalier X, Benelli C. The infrapatellar fat pad in knee osteoarthritis: an important source of interleukin-6 and its soluble receptor. Arthritis and Rheumatism 2009 Nov;60(11):3374–7. [25] Ushiyama T, Chano T, Inoue K, Matsusue Y. Cytokine production in the infrapatellar fat pad: another source of cytokines in knee synovial fluids. Annals of the Rheumatic Diseases 2003 Feb;62(2):108–12. [26] Frenz C, Fritsch H, Hoch J [Plastination histologic investigations on the inserting pars terminalis aponeurosis dorsalis of three-sectioned fingers]. Annals of Anatomy 2000 Jan;182(1):69–73. *[27] Tan AL, Benjamin M, Toumi H, Grainger AJ, Tanner SF, Emery P, et al. The relationship between the extensor tendon enthesis and the nail in distal interphalangeal joint disease in psoriatic arthritis–a high-resolution MRI and histological study. Rheumatology (Oxford, England) 2007 Feb;46(2):253–6. *[28] Guero S, Guichard S, Fraitag SR. Ligamentary structure of the base of the nail. Surgical and Radiologic Anatomy: SRA 1994; 16(1):47–52. *[29] Wilson FC, Icen M, Crowson CS, McEvoy MT, Gabriel SE, Kremers HM. Incidence and clinical predictors of psoriatic arthritis in patients with psoriasis: a population-based study. Arthritis and Rheumatism 2009 Feb 15;61(2):233–9. [30] Ash ZR, Tinazzi I, Castillo-Gallego C, Kwok C, Wilson C, Goodfield M, et al. Psoriasis patients with naill disease have a greater magnitude of underlying systemic subclinical enthesopathy than those with normal nails. Annals of the Rheumatic Diseases; 2011 Dec 9 [Epub ahead of print].
Contents lists available at SciVerse ScienceDirect
Best Practice & Research Clinical Rheumatology journal homepage: www.elsevierhealth.com/berh
3
Joint appendages – the structures which have historically been overlooked in arthritis research and therapy development Zoe Ash, Dennis McGonagle*,1 Section of Musculoskeletal Disease, Leeds Institute of Molecular Medicine, University of Leeds and NIHR Leeds Musculoskeletal Biomedical Research Unit, Leeds Teaching Hospitals NHS Trust, Chapel Allerton Hospital, Leeds LS7 4SA, UK
Keywords: Tendons Ligaments Synovial bursa Psoriatic arthritis
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. Ó 2011 Elsevier Ltd. All rights reserved.
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) [1]. 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 [2]. 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
* Corresponding author. E-mail addresses: [email protected] (Z. Ash), [email protected] (D. McGonagle). 1 Tel.: þ44 113 3924884; fax: þ44 113 392 4991. 1521-6942/$ – see front matter Ó 2011 Elsevier Ltd. All rights reserved. doi:10.1016/j.berh.2011.11.009
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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 compressionrelated bony erosions [3]. Furthermore, there is evidence for age-related change in ligaments with thickening setting in after the age of 50 [4,5]. Moreover, the most conspicuous abnormality in subjects with uninvolved joints adjacent to osteoarthritic joints is the presence of ligament abnormalities [4]. However, ligaments are under-appreciated drivers in the pathogenesis of OA [3]. 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 [6]. 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’ [7]. This means that adjacent to the insertion proper, the bone surface is often lined by enthesis-associated cartilages termed ‘periosteal fibrocartilages’ [8,9]. 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 [10]. 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’ [11]. 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 [10]. 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 [12]. 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 [13]. 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 [13] and this has recently been confirmed in normal joints using high-resolution computed tomography (CT) [14]. 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’ [8]. 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 [8].
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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 [15]. 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 [16]. What is more, the suppression of inflammation with disease-modifying anti-rheumatic drugs (DMARDs) is associated with less regression of inflammation at these sites [16]. 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 [7]. Together, these form enthesis organs and synovioentheseal 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 [7]. 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. Fat pads Joint fat has only recently become appreciated in a rheumatology setting. Joint fat may be located in extra-articular sites such as around the Achilles tendon and plantar fascia where it is vital for
Fig. 1. Magnetic resonance imaging of right sided trochanteric bursitis in a female patient in her 50s with mechanical disease, there is bone oedema seen but no evident soft-tissue change. This relates to the enthesis organ concept whereby the tendon appendage exerts pressure over the bone proximal to the attachment site.
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cushioning [17]. Large conspicuous fat pads such as Hoffa’s fat pad in the knee are one type of prominent intra-articular joint adiposity in a classical synovial joint. The second type is a sub-synovial fibro-fatty tissue. It must be remembered that fat is a liquid at body temperature and therefore it is an excellent shock absorber. There is also a prominent fat pad adjacent to the retro-calcaneal bursa called ‘Kager’s fat pad’, which may contribute to shock absorption during locomotion and certainly represents an under-appreciated skeletal appendage. Fat pads also have extensive fibrous septa to contain the fat within small compartments to stop its displacement during locomotion. Joint fat has also been noted to have excellent stem cell activity, being a rich source of mesenchymal stem cells, with good chondrogenic potential [18]. Indeed, the potential of the joint fat pad with respect to chondrogenesis is much greater than that from subcutaneous fat [19].
Relevance of fat in disease Atrophy of the fat pad in the heel is a recognised factor for plantar fasciitis-type pain [20]. Hoffa’s fat pad impingement in the knee is associated with pain [21]. This can be appreciated on MRI and the excision of the fat pad can be associated with good symptomatic relief. MRI scanning shows that Kager’s fat pad is often inflamed as part of the enthesitis organ inflammatory reaction [22]. Recent studies have also shown that there may be fat pad inflammation in OA [23]. Furthermore, it is
Fig. 2. Magnetic resonance imaging of a finger distal interphalangeal joint, showing the extensor tendon attachment to the base of the distal phalanx with some fibres running towards the nail matrix (white asterisk).
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increasingly recognised that the fat pad is a source of various cytokines including adiponectin that may play prominent immunomodulatory roles [24,25]. The role of fat, both in extra-articular and intraarticular locations, is currently not fully appreciated, and is ripe for further studies.
The nail When rheumatologists think of joint appendages, perhaps the most surprising aspect of all is to discover that the nail is actually intimately linked with the skeleton. It turns out that although the extensor tendon inserts into the bone of the distal phalanx, a significant proportion of fibres run forward and anchor at the nail root (Fig. 2). Fibres also run from the enthesis along the periosteum to the digital tuft [26,27]. These fibres send vertical struts, or small dermal ligaments, that in turn anchor the periosteum to the nail bed. Furthermore, some of the fibres of the collateral ligaments extend beyond the insertion point and appear to provide lateral stability and anchorage to the nail [28]. Finally, the flexor tendon inserts into the distal phalanx and is intimately integrated with the collateral ligaments and affords additional anchorage to the nail [27]. Therefore, although the nail is embryologically derived from the ectoderm, it is very much integrated to the mesoderm and is functionally part of the skeleton. This helps explain long-standing observations including the greater prevalence of nail disease in PsA compared to psoriasis and also why nail disease may be predictive of PsA development [29]. Indeed, a recent study has confirmed that psoriasis with nail disease is associated with a greater degree of subclinical enthesopathy than psoriasis with normal nails [30].
Summary The purpose of this review was to highlight how the articulating skeleton is very much functionally integrated to include a number of appendages that exert a functional and, by extension, pathological effect over a wide area of the joint. These structures include ligaments, tendons, capsules and bursae. The importance of these structures is becoming increasingly apparent with the use of sophisticated imaging techniques in routine practice including MRI and sonography. The relevance of some of these structures has also been validated in animal model studies. The role of these appendages in the pathophysiology of pain requires further study. Practice points Rheumatologists need to appreciate the role of joint appendages in both pain causation and in disease pathophysiology. Newer imaging techniques may allow further detailed study of these structures.
Research agenda The systematic assessment of the role of appendages in causing pain and inflammation needs to be placed on an even footing with synovium, cartilage and bone in arthritis research.
References [1] Felson DT. An update on the pathogenesis and epidemiology of osteoarthritis. Radiologic Clinics of North America 2004 Jan;42(1):1–9. [2] McGonagle D, Gibbon W, O’Connor P, Green M, Pease C, Emery P. Characteristic magnetic resonance imaging entheseal changes of knee synovitis in spondylarthropathy. Arthritis and Rheumatism 1998 Apr;41(4):694–700.
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