Introduction

The target organ distribution in spondylarthropathies (SpA) has historically been hard to explain in terms of a specific autoantigen or autoantibody that could account for the diverse patterns of organ involvement . Inflammatory arthritis in SpA typically shows a propensity for lower limb over upper limb involvement and large joint over small joint involvement. The human leukocyte antigen (HLA)-B27-associated juvenile form of SpA typically starts in the ankle and foot and migrates to the sacroiliac joint (SIJ) and spine during teenagehood or early adulthood. The extra-articular features of uveitis and aortic root inflammation in particular spurred the eminent osteoarticular pathologist Bywaters to suggest that tension at the aortic root provided a unifying biomechanical theory for SpA .

With the complex pattern of skeletal pathology evident in tissues from subjects with later stages of SpA, the pre-eminence of entheseal disease in SpA was not fully comprehended with pathologists including Bywaters and Ball not attempting to link enthesitis to synovitis and osteitis, the other two cardinal features of SpA . In the 1990s, magnetic resonance imaging (MRI) studies showed that clinically unrecognized enthesitis was not uncommon in synovitic joints and that enthesitis was associated with adjacent osteitis . This led to the realization that other joint structures including fibrocartilaginous joints such as the SIJ and regions where tendons change direction or wrap around bone, dubbed “functional enthesis,” share similar histological and identical patterns of mechanical stress and thus a theoretical enthesis-based biomechanical model for all SpA features was proposed . The idea that mechanical stress and microdamage may be instrumental in inflammatory enthesitis as a primary driver in SpA resonated with the ideas from the 1950s where La Cava pointed out that sports injury-related enthesopathy might be linked to an inflammatory reaction characterized by fibrosis and calcification occurring at the enthesis in response to continuously recurring microtrauma .

Enthesis microanatomical configuration

It is not clear whether every arthritic joint in SpA is characterized by the co-occurrence of enthesitis and synovitis , which could reflect the limitations of the currently used imaging techniques such as ultrasonography and MRI. This is particularly the case in small joints due to the close proximity of the synovium, enthesis, and other joint structures. The prototypical enthesis of the Achilles tendon should be considered not only as a focal attachment site to bone but rather as a complex organ, including the periosteal and sesamoid fibrocartilages, the retrocalcaneal bursa, and the tip of Kager’s fat pad covered by synovium, which together form an enthesis organ . The concept of a synovio–entheseal complex illustrates the complex integration of entheses with the joint’s synovium indicating a complex anatomical link between the enthesis and synovium . The close anatomical relationship between the enthesis, prone to mechanical stress, and the vascularized synovium, in contact with a diversity of immune mediators, may provide the pathogenic basis for joint inflammation in SpA .

Entheses are, unlike the synovium, avascular structures and are composed of dense regular connective tissue that serves to minimize the chances of damage during locomotion. This is, in particular, the case for the avascular fibrocartilaginous attachment site. However, this site shows clear vascular invasion with aging, probably reflecting a tissue repair response to accumulating microdamage . Extensive microdamage and altered vascularity are present at numerous entheses in elderly individuals, which probably relates to a lifetime of mechanical loading. Imaging studies also suggest evidence of microdamage as determined by ultrasound of these fibrocartilages in younger subjects . Finally, it was shown that even in normal-aged entheses and in SpA-related enthesitis new bone and erosion occurred at different topographical locations with new bone typically occurring at the distal part of the enthesis where the bone is under more tension, strongly suggesting a role for mechanical factors in physiological and pathological enthesis remodeling in humans .

Enthesis microanatomical configuration

It is not clear whether every arthritic joint in SpA is characterized by the co-occurrence of enthesitis and synovitis , which could reflect the limitations of the currently used imaging techniques such as ultrasonography and MRI. This is particularly the case in small joints due to the close proximity of the synovium, enthesis, and other joint structures. The prototypical enthesis of the Achilles tendon should be considered not only as a focal attachment site to bone but rather as a complex organ, including the periosteal and sesamoid fibrocartilages, the retrocalcaneal bursa, and the tip of Kager’s fat pad covered by synovium, which together form an enthesis organ . The concept of a synovio–entheseal complex illustrates the complex integration of entheses with the joint’s synovium indicating a complex anatomical link between the enthesis and synovium . The close anatomical relationship between the enthesis, prone to mechanical stress, and the vascularized synovium, in contact with a diversity of immune mediators, may provide the pathogenic basis for joint inflammation in SpA .

Entheses are, unlike the synovium, avascular structures and are composed of dense regular connective tissue that serves to minimize the chances of damage during locomotion. This is, in particular, the case for the avascular fibrocartilaginous attachment site. However, this site shows clear vascular invasion with aging, probably reflecting a tissue repair response to accumulating microdamage . Extensive microdamage and altered vascularity are present at numerous entheses in elderly individuals, which probably relates to a lifetime of mechanical loading. Imaging studies also suggest evidence of microdamage as determined by ultrasound of these fibrocartilages in younger subjects . Finally, it was shown that even in normal-aged entheses and in SpA-related enthesitis new bone and erosion occurred at different topographical locations with new bone typically occurring at the distal part of the enthesis where the bone is under more tension, strongly suggesting a role for mechanical factors in physiological and pathological enthesis remodeling in humans .

Animal models

Although the hypothesis of a mechanical-based origin of SpA can be easily appreciated from a conceptual point of view, formal proof is difficult to obtain from human research. With the knowledge about the enthesis organ and synovio–entheseal complex anatomy, the mechanical stress paradigm for the pathogenesis of axial and peripheral SpA has been recently tested in animal models. The tumor necrosis factor (TNF) ^ΔARE SpA model-related inflammation starts at the enthesis before spreading to adjacent tissues . Enthesitis also appeared as the first pathological finding in the spontaneous ankylosing enthesitis model of male DBA/1 mice and in collagen II-antibody-induced arthritis , indicting the key role of this structure in experimental SpA pattern arthritis.

We recently demonstrated in the TNF ^ΔARE model for SpA that mechanical stress is involved in the development of Achilles tendon enthesitis ( Fig. 1 ). In this model, deregulated TNF due to deletion of adenylate-uridylate (AU)-rich elements in the TNF genome causes systemic inflammation, axial and peripheral arthritis, enthesitis, and Crohn’s-like ileitis. Our previous work showed that the joint inflammation commenced in the Achilles enthesis and spread to the adjacent tissues and, furthermore, the enthesis fibroblasts were the key early disease initiations . In recent studies, we showed that hind limb unloading could efficiently prohibit enthesitis development at the Achilles tendon .

Experimental models including TNF overexpression and IL-23 overexpression are associated with the development of SpA phenotypes that start at the Achilles enthesis. The TNF model is associated with stromal production of TNF as an early disease initiator. Mechanical stress leads to activation of the MAPK and p38 kinases. The IL-23 overexpression appears to be dependent on the presence of a novel population of innate lymphoid-like cells at the enthesis. In normal healthy condition, these cells may be involved in homeostatic tissue repair in response to microdamage.

No animal model completely mimics human disease, and the major drawback of the TNF ^ΔARE model is the lack of new bone formation. However, we showed that new bone formation is equally linked to mechanical stress in the collagen-antibody-induced arthritis model . After resolution of the acute inflammation phase, leading to polyarthritis of wrists and ankles, hind limb unloading largely prohibited the development of bone formation at the affected joints, supporting a role for mechanical strain in their development. In addition, tail suspension was able to prevent the development of osteophytes when only minimal signs of inflammation were present, and could minimize enthesophyte size in more advanced-stage arthritis. Of note, numerous trials have shown the efficacy of TNF blockade in human SpA indicating the key role of this cytokine related to enthesitis. Imaging studies post TNF has consistently shown impressive enthesitis resolution confirming the translational relevance of the animal model findings in humans .

Recently, a landmark study provided convincing evidence that interleukin (IL)-23 overexpression induces enthesitis, including involvement of the aortic valve, by acting on double-negative, enthesis-resident T lymphocytes . Enthesitis was the earliest pathological finding. In this model, IL-23 overexpression also leads to a severely destructive polyarthritis ( Fig. 1 ). Ustekinumab (Stelara( ^® )), a human monoclonal antibody that binds to the shared p40 subunit of IL-12 and IL-23, blocking signaling of their cognate receptors, has shown significantly greater efficacy than placebo with regard to enthesitis in psoriatic arthritis (PsA) . Of note, this particular animal model also developed aortitis and is highly reminiscent of the observations of Bywaters for the mechanical stress basis of joint disease and aortic involvement .