- Email: [email protected]
Enthesitis: The clue to the pathogenesis of spondyloarthritis?
G Model
ARTICLE IN PRESS
BONSOI-4202; No. of Pages 4
Joint Bone Spine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Review
Enthesitis: The clue to the pathogenesis of spondyloarthritis?夽 Corinne Miceli-Richard a,∗,b a b
Service de Rhumatologie, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, 75014 Paris, France Institut Pasteur, Département d’Immunologie, 75015 Paris, France
a r t i c l e
i n f o
Article history: Accepted 17 February 2015 Available online xxx Keywords: Enthesitis Spondyloarthritis Mechanical stress
a b s t r a c t The term “spondyloarthritis” designates a group of conditions whose shared characteristic is inflammation at the interface between the bone and either the tendons and ligaments or the joint capsule. This interface, known as the enthesis, can be the site of ossification in spondyloarthritis. The advent of high-performance imaging techniques such as magnetic resonance imaging has rekindled interest in the enthesis by providing new insights into the sequence that leads to entheseal ossification. These techniques have established initial inflammation and fatty metaplasia as key events that precede ossification. The pathophysiological mechanisms that trigger the initial inflammation probably involve multiple factors such as mechanical stress and the presence of resident cells responsive to interleukin-23 and capable of releasing proinflammatory cytokines. Research into the triggers of entheseal inflammation and ossification may thus provide the clue to the pathophysiology of spondyloarthritis. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction The term “spondyloarthritis” designates a group of conditions whose shared characteristic is inflammation at the interface between the bone and either the tendons and ligaments or the joint capsule. This interface is known as the enthesis. Inflammation of the entheses is a key semiological and clinical feature of spondyloarthritis. Furthermore, identifying the mechanisms that lead to entheseal ossification would very likely constitute a major breakthrough in understanding the pathogenesis of spondyloarthritis. Early work conducted by John Ball in the 1960s established the existence of a continuum from erosive lesions to exuberant bone repair. This review discusses the early pathological descriptions of the enthesis in spondyloarthritis, the valuable insights provided by contemporary imaging techniques into the sequence that leads to entheseal ossification, and the key role for the synovio-entheseal complex in inducing arthritis. Finally, recent studies indicate that
夽 This title pays homage to Sitaj J, Niepel G, and Kopecky S at the Research Institute for Rheumatic Diseases in Piestany, Czechoslovakia, whose article entitled “Enthesopathies – A clue to pathogenesis?” was published in 1979, in the Scandinavian Journal of Rheumatology (Suppl. 32), Proceedings from a symposium on Bechterew’s syndrome and allied disorders. These three authors were probably the first to use the term “enthesopathy”. ∗ Corresponding author. E-mail address: [email protected]
mechanical stress or cells residing in the enthesis can trigger inflammation of this functional organ.
2. Classification Entheses fall into two groups, fibrous entheses, in which the collagen fibers that make up the tendons or ligaments attach directly to the bone, and fibrocartilaginous entheses, which exhibit four transition zones [1–3]: a tendinous zone with longitudinally oriented fibroblasts that are parallel to the collagen fibers, a fibrocartilaginous zone containing both fibroblasts and chondrocytes but no calcifications, a zone of calcified fibrocartilage, and the subchondral bone. Fibrous entheses attach tendons and ligaments to the diaphysis and metaphysis of long bones. Fibrocartilaginous entheses, in contrast, attach to long-bone epiphyses and to the small bones of the hands and feet, and also connect a substantial number of spinal ligaments. For instance, the supraspinatus tendon attaches to the greater trochanter of the humerus by a fibrocartilaginous enthesis and the deltoid tendon to the deltoid tuberosity by a fibrous enthesis. Spondyloarthritis is characterized by endochondral ossification of the fibrocartilaginous entheses. Endochondral ossification starts within the cartilage, which is first penetrated by blood vessels. Chondrocytes in contact with the blood vessels become globular then vacuolated before eventually degenerating. The empty cavities thus created are occupied by preosteoblasts that migrate from
http://dx.doi.org/10.1016/j.jbspin.2015.02.018 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Miceli-Richard C. Enthesitis: The clue to the pathogenesis of spondyloarthritis? Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.018
G Model BONSOI-4202; No. of Pages 4
ARTICLE IN PRESS C. Miceli-Richard / Joint Bone Spine xxx (2015) xxx–xxx
2
the capillaries and gradually differentiate into osteoblasts, which produce bone matrix.
3. Early pathological studies The first pathological descriptions of the enthesis were reported several decades ago [4] and Niepel et al. seem to have coined the term “enthesopathy”, in 1966 [5]. The enthesis was viewed early on as a site of metabolic activity, most notably during growth. Blood vessels are found predominantly at the junction between the uncalcified and calcified fibrocartilaginous zones, known as the tidemark [4]. However, the annulus fibrosus of the intervertebral disk is devoid of blood vessels. Early pathological studies used autopsy material or biopsies from painful sites in patients with spondyloarthritis, such as the iliac crest, greater trochanter, and patella (during knee arthrodesis). These studies were conducted in the late 1960s, and the use of biopsy specimens from patients would be considered unacceptable today. Their objective was to understand the pathogenesis of ankylosing spondylitis (AS) at a time when the difference between this disease and rheumatoid arthritis was still unclear. The term “rheumatoid spondylitis” was used, based on the cervical spine involvement seen in rheumatoid arthritis. According to these early descriptions, the hallmark pathological feature of enthesopathy is the coexistence of lesions of different durations at the same site, with erosions, microscopic inflammatory foci within ligaments, and areas of bone repair [4]. The inflammatory foci contain neutrophils and lymphoplasmacytic infiltrates. These infiltrates, which predominate in the erosive lesions, extend into the ligamentous area along the main blood vessels. The lesions heal by lamellar bone apposition with bone overgrowth compared to the local architecture, leading to the production of uneven bone that extends beyond the peripheral cortical surface. Similar changes are found in the capsule of painful joints, which contains an inflammatory infiltrate composed of neutrophils and lymphoplasmacytic cells. Active fibroblastic proliferation is visible at these sites, but without local reactive bone formation. At the spine, histological studies show erosive lesions at the annulus insertion site around the rim of the intervertebral disk, with a repair process involving local bone production. Facet joint involvement has generated controversy. One hypothesis suggests that the facet joint lesions may be secondary to the adjacent intervertebral ankylosis, based on the observation that spinal tuberculosis rarely involves the facet joints directly. Thus, facet joint ankylosis may develop as a consequence of anterior vertebral ankylosis. This hypothesis is not entirely satisfactory, as some patients with spondyloarthritis have facet joint ankylosis at spinal levels free of intervertebral ankylosis. Ball puts forward an alternative hypothesis based on a case of severe facet joint synovitis characterized by both erosive lesions and excessive bone repair, replicating findings at other sites. These data support primary ossification of the joint capsule [4]. Similar abnormalities were identified at the sacroiliac joints in an autopsy study of a 22-year-old patient with spondyloarthritis of 4 years’ duration. Both sides of the sacroiliac joints were uneven on pelvic radiographs. The histological changes consisted of both erosive lesions and uneven bone growth via endochondral ossification. In 1971, Ball stated that careful attention should be directed to the enthesis in spondyloarthritis. This good advice was heeded only three decades later, when new imaging techniques provided macroscopic information on the enthesis, which was thus thrust into the research spotlight.
4. Imaging studies: visualizing the sequence responsible for entheseal ossification The imaging-study features of enthesopathy are not the focus of this article and are discussed elsewhere. However, to some extent, a detailed analysis of magnetic resonance imaging (MRI) findings has shed light on the sequence of events that lead to entheseal ossification in spondyloarthritis. Much is owed to the research group headed by W. Maksymowych at the University of Alberta in Canada. The two main MRI changes are subchondral inflammation on either side of the intervertebral disk, indicating inflammatory discitis; and inflammation of the anterior and posterior vertebral body corners at the sites where Romanus lesions are seen histologically. TNF␣ antagonists, a therapeutic option when nonsteroidal antiinflammatory drugs fail, can extinguish the inflammatory lesions at the spine and sacroiliac joints. Nevertheless, despite the potent antiinflammatory action of TNF␣ antagonists as assessed by MRI, these drugs have no structural effects after 2 years of use [6–8]. This finding suggested uncoupling of the inflammatory and bone-formation processes, a hypothesis that can now be revisited based on recent data from longitudinal spinal MRI studies in patients with spondyloarthritis. In these studies, serial MRI and standard radiography of the spine established that subchondral inflammation of the vertebral body corners visible by MRI predicted new syndesmophyte formation at the same sites 2 years later [9–13]. Maksymowych et al. have suggested the co-existence at the spine of two types of inflammatory lesions: mild inflammation that dies out without inducing a repair process (type A) and a complex advanced inflammatory process that can be extinguished only by a repair process that creates the conditions for syndesmophyte formation (type B) [14]. The same research group demonstrated that the combination of type B lesions and fatty metaplasia was the strongest predictor of syndesmophyte formation [14]. According to this hypothesis, TNF␣ antagonists should provide longer term benefits by extinguishing type A lesions and preventing the development of further Romanus lesions, thus suggesting a window of opportunity for TNF␣ antagonist therapy in spondyloarthritis [14]. Thus, detailed analyses of spinal MRI findings provide information on the role for fatty metaplasia and marked inflammation in the entheseal ossification process.
5. The synovio-entheseal complex In psoriatic arthritis, concomitant psoriasis of the nail and inflammation of the distal interphalangeal joint is highly characteristic. Although uncommon, this combination provides insight into the pathophysiology of entheseal inflammation. The nail is part of the integumentary system, as it is formed in the embryo by invagination of the epidermis into the dermis. The nail has three parts: the root, plate, and free edge (Fig. 1). The nail plate rests on the highly vascular nail bed. At the nail root, a groove in the skin contains the matrix, which is also highly vascular and the site of keratin production (Fig. 1). In patients with psoriatic arthritis, MRI shows major inflammation of the distal interphalangeal joint involving the synovial membrane, base of the nail, subchondral bone, and adjacent extensor tendons. MRI and histological studies of this synovio-entheseal complex show that the extensor tendon fibers are tightly intertwined with the base of the nail (Fig. 2) [15]. Thus, the nail is functionally integrated into the musculoskeletal system, as it is connected by entheses to the bone. This integration explains the global inflammation seen by MRI at this site in psoriatic arthritis [15]. The concept that the synovio-entheseal complex is an entity affected by an inflammatory process also explains the occurrence of periostitis in psoriatic arthritis [16]. This extensive local inflammation differs markedly from findings in rheumatoid
Please cite this article in press as: Miceli-Richard C. Enthesitis: The clue to the pathogenesis of spondyloarthritis? Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.018
G Model BONSOI-4202; No. of Pages 4
ARTICLE IN PRESS C. Miceli-Richard / Joint Bone Spine xxx (2015) xxx–xxx
3
limited the development of enthesophytes. This finding suggests links between mechanical stress, inflammation, and bone formation. 7. Role for cells residing in the entheses
Fig. 1. Anatomy of the nail.
A study reported 2 years ago by Sherlock et al. demonstrated that cells residing in the entheses played a key role in joint inflammation [19]. The study used a murine model of arthritis secondary to entheseal inflammation. In this model, an antibody to interleukin (IL)-23 (targeting the p19 subunit of IL-23) prevented the development of clinical joint symptoms. Detailed cell studies documented the presence within the entheses of double-negative (CD4–/CD8–) T cells that carried the IL-23 receptor. These IL-23-responsive cells induced the release of proinflammatory cytokines including TNF, IL-17, and IL-22. Interestingly, and in relation with observational data from humans, these double-negative T cells were also found in the aortic arch and valves. 8. Conclusions
Fig. 2. Synovio-entheseal complex.
The various types of data available from histological, imaging, and basic-science studies converge to identify the enthesis as a fully functional organ and the initial site of inflammation, which creates the conditions for enthesophyte formation. The degree of extension of the inflammatory process governs the clinical expression of the characteristic symptoms, which vary according to the enthesis involved: heel pain, axial pain in the spine or sacroiliac joints, and joint involvement. Mechanical stress may be among the triggers of local inflammation, together with IL-23-responsive cells residing in the enthesis. Disclosure of interest
arthritis, where the inflammation is confined to the synovial membrane [17].
The author declares that he has no conflicts of interest concerning this article.
6. Role for mechanical stress in triggering entheseal inflammation
References
Clinical observations suggesting that mechanical stress may trigger enthesopathy in spondyloarthritis include the predominant involvement of the lower limbs, particularly in the peripatellar region and Achilles tendon, and the onset of axial lesions at the thoracolumbar junction. A proof-of-concept study directed by Dirk Elewaut in Ghent supports this possibility [18]. The investigators used a mouse model characterized by primary entheseal inflammation. TNFARE mice have a deletion of 69 base pairs in the adenylate-uridylate (AU)-rich part of the TNF-encoding gene. This deletion increases the stability of the mRNA for TNF. TNFARE mice exhibit the features of human spondyloarthritis, including arthritis and inflammation of the peripheral and sacroiliac entheses. They also have inflammatory bowel disease resembling human Crohn’s disease. Interestingly, in this model, the joint inflammation starts at the entheses at 4 weeks of age then extends to the synovial membrane, leading to erosive arthritis by 6–8 weeks of age. The enthesopathy in this model developed independently from B cells and T cells but was dependent on stromal cells. Under the hypothesis that entheseal inflammation might be triggered by mechanical stress, the investigators compared Achilles tendon enthesitis in TNFARE mice moving around freely in their cage or suspended from their tail to eliminate mechanical loading of the limbs. Arthritis developed in the freely moving mice but not in the suspended mice. These data support a role for mechanical stress in triggering entheseal inflammation in spondyloarthritis. In another mouse model, the same investigators demonstrated that tail suspension
[1] Rufai A, Ralphs JR, Benjamin M. Structure and histopathology of the insertional region of the human Achilles tendon. J Orthop Res 1995;13:585–93. [2] Benjamin M, Ralphs JR. Tendons and ligaments – an overview. Histol Histopathol 1997;12:1135–44. [3] Benjamin M, Rufai A, Ralphs JR. The mechanism of formation of bony spurs (enthesophytes) in the Achilles tendon. Arthritis Rheum 2000;43:576–83. [4] Ball J. Enthesopathy of rheumatoid and ankylosing spondylitis. Ann Rheum Dis 1971;30:213–23. [5] Niepel GA, Kostka D, Kopecky S, et al. Enthesopathy. Acta Rheumatologica et Balneologica Pistiniana 1966;1:1–64. [6] van der Heijde D, Landewé R, Einstein S, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum 2008;58:1324–31. [7] van der Heijde D, Landewé R, Baraliakos X, et al. Radiographic findings following two years of infliximab therapy in patients with ankylosing spondylitis. Arthritis Rheum 2008;58:3063–70. [8] van der Heijde D, Salonen D, Weissman BN, et al. Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years. Arthritis Res Ther 2009;11:R127. [9] Baraliakos X, Listing J, Rudwaleit M, et al. The relationship between inflammation and new bone formation in patients with ankylosing spondylitis. Arthritis Res Ther 2008;10:R104. [10] Maksymowych WP, Chiowchanwisawakit P, Clare T, et al. Inflammatory lesions of the spine on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis: evidence of a relationship between inflammation and new bone formation. Arthritis Rheum 2009;60:93–102. [11] van der Heijde D, Machado P, Braun J, et al. MRI inflammation at the vertebral unit only marginally predicts new syndesmophyte formation: a multilevel analysis in patients with ankylosing spondylitis. Ann Rheum Dis 2012;71:369–73. [12] Chiowchanwisawakit P, Lambert RG, Conner-Spady B, et al. Focal fat lesions at vertebral corners on magnetic resonance imaging predict the development of new syndesmophytes in ankylosing spondylitis. Arthritis Rheum 2011;63:2215–25.
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[13] Pedersen SJ, Chiowchanwisawakit P, Lambert RG, et al. Resolution of inflammation following treatment of ankylosing spondylitis is associated with new bone formation. J Rheumatol 2011;38:1349–54. [14] Maksymowych W, Morency N, Conner-Spady B, et al. Suppression of inflammation and effects on new bone formation in ankylosing spondylitis: evidence for a window of opportunity in disease modification. Ann Rheum Dis 2013;72:23–8. [15] Tan A, Benjamin M, Toumi H, 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 2007;46:253–6. [16] McGonagle D, Lories RJU, Tan AL, et al. The concept of a ‘synovioentheseal complex’ and its implications for understanding joint inflammation
and damage in psoriatic arthritis and beyond. Arthritis Rheum 2007;56: 2482–91. [17] Jevtic V, Watt I, Rozman B, et al. Distinctive radiological features of small hand joints in rheumatoid arthritis and seronegative spondyloarthritis demonstrated by contrast-enhanced (Gd-DTPA) magnetic resonance imaging. Skeletal Radiol 1995;24:351–5. [18] Jacques P, Lambrecht S, Verheugen E, et al. Proof of concept: enthesitis and new bone formation in spondyloarthritis are driven by mechanical strain and stromal cells. Ann Rheum Dis 2014;73:437–45. [19] Sherlock J, Joyce-Shaikh B, Turner S, et al. IL-23 induces spondyloarthropathy by acting on ROR-␥t+CD3+CD4–CD8– entheseal resident T cells. Nat Med 2012;18:1069–76.
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ARTICLE IN PRESS
BONSOI-4202; No. of Pages 4
Joint Bone Spine xxx (2015) xxx–xxx
Available online at
ScienceDirect www.sciencedirect.com
Review
Enthesitis: The clue to the pathogenesis of spondyloarthritis?夽 Corinne Miceli-Richard a,∗,b a b
Service de Rhumatologie, Hôpital Cochin, Hôpitaux Universitaires Paris Centre, 75014 Paris, France Institut Pasteur, Département d’Immunologie, 75015 Paris, France
a r t i c l e
i n f o
Article history: Accepted 17 February 2015 Available online xxx Keywords: Enthesitis Spondyloarthritis Mechanical stress
a b s t r a c t The term “spondyloarthritis” designates a group of conditions whose shared characteristic is inflammation at the interface between the bone and either the tendons and ligaments or the joint capsule. This interface, known as the enthesis, can be the site of ossification in spondyloarthritis. The advent of high-performance imaging techniques such as magnetic resonance imaging has rekindled interest in the enthesis by providing new insights into the sequence that leads to entheseal ossification. These techniques have established initial inflammation and fatty metaplasia as key events that precede ossification. The pathophysiological mechanisms that trigger the initial inflammation probably involve multiple factors such as mechanical stress and the presence of resident cells responsive to interleukin-23 and capable of releasing proinflammatory cytokines. Research into the triggers of entheseal inflammation and ossification may thus provide the clue to the pathophysiology of spondyloarthritis. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction The term “spondyloarthritis” designates a group of conditions whose shared characteristic is inflammation at the interface between the bone and either the tendons and ligaments or the joint capsule. This interface is known as the enthesis. Inflammation of the entheses is a key semiological and clinical feature of spondyloarthritis. Furthermore, identifying the mechanisms that lead to entheseal ossification would very likely constitute a major breakthrough in understanding the pathogenesis of spondyloarthritis. Early work conducted by John Ball in the 1960s established the existence of a continuum from erosive lesions to exuberant bone repair. This review discusses the early pathological descriptions of the enthesis in spondyloarthritis, the valuable insights provided by contemporary imaging techniques into the sequence that leads to entheseal ossification, and the key role for the synovio-entheseal complex in inducing arthritis. Finally, recent studies indicate that
夽 This title pays homage to Sitaj J, Niepel G, and Kopecky S at the Research Institute for Rheumatic Diseases in Piestany, Czechoslovakia, whose article entitled “Enthesopathies – A clue to pathogenesis?” was published in 1979, in the Scandinavian Journal of Rheumatology (Suppl. 32), Proceedings from a symposium on Bechterew’s syndrome and allied disorders. These three authors were probably the first to use the term “enthesopathy”. ∗ Corresponding author. E-mail address: [email protected]
mechanical stress or cells residing in the enthesis can trigger inflammation of this functional organ.
2. Classification Entheses fall into two groups, fibrous entheses, in which the collagen fibers that make up the tendons or ligaments attach directly to the bone, and fibrocartilaginous entheses, which exhibit four transition zones [1–3]: a tendinous zone with longitudinally oriented fibroblasts that are parallel to the collagen fibers, a fibrocartilaginous zone containing both fibroblasts and chondrocytes but no calcifications, a zone of calcified fibrocartilage, and the subchondral bone. Fibrous entheses attach tendons and ligaments to the diaphysis and metaphysis of long bones. Fibrocartilaginous entheses, in contrast, attach to long-bone epiphyses and to the small bones of the hands and feet, and also connect a substantial number of spinal ligaments. For instance, the supraspinatus tendon attaches to the greater trochanter of the humerus by a fibrocartilaginous enthesis and the deltoid tendon to the deltoid tuberosity by a fibrous enthesis. Spondyloarthritis is characterized by endochondral ossification of the fibrocartilaginous entheses. Endochondral ossification starts within the cartilage, which is first penetrated by blood vessels. Chondrocytes in contact with the blood vessels become globular then vacuolated before eventually degenerating. The empty cavities thus created are occupied by preosteoblasts that migrate from
http://dx.doi.org/10.1016/j.jbspin.2015.02.018 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
Please cite this article in press as: Miceli-Richard C. Enthesitis: The clue to the pathogenesis of spondyloarthritis? Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.018
G Model BONSOI-4202; No. of Pages 4
ARTICLE IN PRESS C. Miceli-Richard / Joint Bone Spine xxx (2015) xxx–xxx
2
the capillaries and gradually differentiate into osteoblasts, which produce bone matrix.
3. Early pathological studies The first pathological descriptions of the enthesis were reported several decades ago [4] and Niepel et al. seem to have coined the term “enthesopathy”, in 1966 [5]. The enthesis was viewed early on as a site of metabolic activity, most notably during growth. Blood vessels are found predominantly at the junction between the uncalcified and calcified fibrocartilaginous zones, known as the tidemark [4]. However, the annulus fibrosus of the intervertebral disk is devoid of blood vessels. Early pathological studies used autopsy material or biopsies from painful sites in patients with spondyloarthritis, such as the iliac crest, greater trochanter, and patella (during knee arthrodesis). These studies were conducted in the late 1960s, and the use of biopsy specimens from patients would be considered unacceptable today. Their objective was to understand the pathogenesis of ankylosing spondylitis (AS) at a time when the difference between this disease and rheumatoid arthritis was still unclear. The term “rheumatoid spondylitis” was used, based on the cervical spine involvement seen in rheumatoid arthritis. According to these early descriptions, the hallmark pathological feature of enthesopathy is the coexistence of lesions of different durations at the same site, with erosions, microscopic inflammatory foci within ligaments, and areas of bone repair [4]. The inflammatory foci contain neutrophils and lymphoplasmacytic infiltrates. These infiltrates, which predominate in the erosive lesions, extend into the ligamentous area along the main blood vessels. The lesions heal by lamellar bone apposition with bone overgrowth compared to the local architecture, leading to the production of uneven bone that extends beyond the peripheral cortical surface. Similar changes are found in the capsule of painful joints, which contains an inflammatory infiltrate composed of neutrophils and lymphoplasmacytic cells. Active fibroblastic proliferation is visible at these sites, but without local reactive bone formation. At the spine, histological studies show erosive lesions at the annulus insertion site around the rim of the intervertebral disk, with a repair process involving local bone production. Facet joint involvement has generated controversy. One hypothesis suggests that the facet joint lesions may be secondary to the adjacent intervertebral ankylosis, based on the observation that spinal tuberculosis rarely involves the facet joints directly. Thus, facet joint ankylosis may develop as a consequence of anterior vertebral ankylosis. This hypothesis is not entirely satisfactory, as some patients with spondyloarthritis have facet joint ankylosis at spinal levels free of intervertebral ankylosis. Ball puts forward an alternative hypothesis based on a case of severe facet joint synovitis characterized by both erosive lesions and excessive bone repair, replicating findings at other sites. These data support primary ossification of the joint capsule [4]. Similar abnormalities were identified at the sacroiliac joints in an autopsy study of a 22-year-old patient with spondyloarthritis of 4 years’ duration. Both sides of the sacroiliac joints were uneven on pelvic radiographs. The histological changes consisted of both erosive lesions and uneven bone growth via endochondral ossification. In 1971, Ball stated that careful attention should be directed to the enthesis in spondyloarthritis. This good advice was heeded only three decades later, when new imaging techniques provided macroscopic information on the enthesis, which was thus thrust into the research spotlight.
4. Imaging studies: visualizing the sequence responsible for entheseal ossification The imaging-study features of enthesopathy are not the focus of this article and are discussed elsewhere. However, to some extent, a detailed analysis of magnetic resonance imaging (MRI) findings has shed light on the sequence of events that lead to entheseal ossification in spondyloarthritis. Much is owed to the research group headed by W. Maksymowych at the University of Alberta in Canada. The two main MRI changes are subchondral inflammation on either side of the intervertebral disk, indicating inflammatory discitis; and inflammation of the anterior and posterior vertebral body corners at the sites where Romanus lesions are seen histologically. TNF␣ antagonists, a therapeutic option when nonsteroidal antiinflammatory drugs fail, can extinguish the inflammatory lesions at the spine and sacroiliac joints. Nevertheless, despite the potent antiinflammatory action of TNF␣ antagonists as assessed by MRI, these drugs have no structural effects after 2 years of use [6–8]. This finding suggested uncoupling of the inflammatory and bone-formation processes, a hypothesis that can now be revisited based on recent data from longitudinal spinal MRI studies in patients with spondyloarthritis. In these studies, serial MRI and standard radiography of the spine established that subchondral inflammation of the vertebral body corners visible by MRI predicted new syndesmophyte formation at the same sites 2 years later [9–13]. Maksymowych et al. have suggested the co-existence at the spine of two types of inflammatory lesions: mild inflammation that dies out without inducing a repair process (type A) and a complex advanced inflammatory process that can be extinguished only by a repair process that creates the conditions for syndesmophyte formation (type B) [14]. The same research group demonstrated that the combination of type B lesions and fatty metaplasia was the strongest predictor of syndesmophyte formation [14]. According to this hypothesis, TNF␣ antagonists should provide longer term benefits by extinguishing type A lesions and preventing the development of further Romanus lesions, thus suggesting a window of opportunity for TNF␣ antagonist therapy in spondyloarthritis [14]. Thus, detailed analyses of spinal MRI findings provide information on the role for fatty metaplasia and marked inflammation in the entheseal ossification process.
5. The synovio-entheseal complex In psoriatic arthritis, concomitant psoriasis of the nail and inflammation of the distal interphalangeal joint is highly characteristic. Although uncommon, this combination provides insight into the pathophysiology of entheseal inflammation. The nail is part of the integumentary system, as it is formed in the embryo by invagination of the epidermis into the dermis. The nail has three parts: the root, plate, and free edge (Fig. 1). The nail plate rests on the highly vascular nail bed. At the nail root, a groove in the skin contains the matrix, which is also highly vascular and the site of keratin production (Fig. 1). In patients with psoriatic arthritis, MRI shows major inflammation of the distal interphalangeal joint involving the synovial membrane, base of the nail, subchondral bone, and adjacent extensor tendons. MRI and histological studies of this synovio-entheseal complex show that the extensor tendon fibers are tightly intertwined with the base of the nail (Fig. 2) [15]. Thus, the nail is functionally integrated into the musculoskeletal system, as it is connected by entheses to the bone. This integration explains the global inflammation seen by MRI at this site in psoriatic arthritis [15]. The concept that the synovio-entheseal complex is an entity affected by an inflammatory process also explains the occurrence of periostitis in psoriatic arthritis [16]. This extensive local inflammation differs markedly from findings in rheumatoid
Please cite this article in press as: Miceli-Richard C. Enthesitis: The clue to the pathogenesis of spondyloarthritis? Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.018
G Model BONSOI-4202; No. of Pages 4
ARTICLE IN PRESS C. Miceli-Richard / Joint Bone Spine xxx (2015) xxx–xxx
3
limited the development of enthesophytes. This finding suggests links between mechanical stress, inflammation, and bone formation. 7. Role for cells residing in the entheses
Fig. 1. Anatomy of the nail.
A study reported 2 years ago by Sherlock et al. demonstrated that cells residing in the entheses played a key role in joint inflammation [19]. The study used a murine model of arthritis secondary to entheseal inflammation. In this model, an antibody to interleukin (IL)-23 (targeting the p19 subunit of IL-23) prevented the development of clinical joint symptoms. Detailed cell studies documented the presence within the entheses of double-negative (CD4–/CD8–) T cells that carried the IL-23 receptor. These IL-23-responsive cells induced the release of proinflammatory cytokines including TNF, IL-17, and IL-22. Interestingly, and in relation with observational data from humans, these double-negative T cells were also found in the aortic arch and valves. 8. Conclusions
Fig. 2. Synovio-entheseal complex.
The various types of data available from histological, imaging, and basic-science studies converge to identify the enthesis as a fully functional organ and the initial site of inflammation, which creates the conditions for enthesophyte formation. The degree of extension of the inflammatory process governs the clinical expression of the characteristic symptoms, which vary according to the enthesis involved: heel pain, axial pain in the spine or sacroiliac joints, and joint involvement. Mechanical stress may be among the triggers of local inflammation, together with IL-23-responsive cells residing in the enthesis. Disclosure of interest
arthritis, where the inflammation is confined to the synovial membrane [17].
The author declares that he has no conflicts of interest concerning this article.
6. Role for mechanical stress in triggering entheseal inflammation
References
Clinical observations suggesting that mechanical stress may trigger enthesopathy in spondyloarthritis include the predominant involvement of the lower limbs, particularly in the peripatellar region and Achilles tendon, and the onset of axial lesions at the thoracolumbar junction. A proof-of-concept study directed by Dirk Elewaut in Ghent supports this possibility [18]. The investigators used a mouse model characterized by primary entheseal inflammation. TNFARE mice have a deletion of 69 base pairs in the adenylate-uridylate (AU)-rich part of the TNF-encoding gene. This deletion increases the stability of the mRNA for TNF. TNFARE mice exhibit the features of human spondyloarthritis, including arthritis and inflammation of the peripheral and sacroiliac entheses. They also have inflammatory bowel disease resembling human Crohn’s disease. Interestingly, in this model, the joint inflammation starts at the entheses at 4 weeks of age then extends to the synovial membrane, leading to erosive arthritis by 6–8 weeks of age. The enthesopathy in this model developed independently from B cells and T cells but was dependent on stromal cells. Under the hypothesis that entheseal inflammation might be triggered by mechanical stress, the investigators compared Achilles tendon enthesitis in TNFARE mice moving around freely in their cage or suspended from their tail to eliminate mechanical loading of the limbs. Arthritis developed in the freely moving mice but not in the suspended mice. These data support a role for mechanical stress in triggering entheseal inflammation in spondyloarthritis. In another mouse model, the same investigators demonstrated that tail suspension
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Please cite this article in press as: Miceli-Richard C. Enthesitis: The clue to the pathogenesis of spondyloarthritis? Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.018
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Please cite this article in press as: Miceli-Richard C. Enthesitis: The clue to the pathogenesis of spondyloarthritis? Joint Bone Spine (2015), http://dx.doi.org/10.1016/j.jbspin.2015.02.018