Enthesopathy refers to the involvement of the entheses in any pathological process, whether inflammatory, metabolic, traumatic, or degenerative, and has been well recognized as a feature of a variety systemic rheumatic disorders . In clinical practice, enthesopathy is frequently a secondary or subordinate issue. Recent data cast a new light on the role of enthesopathy in the large body of rheumatic disorders.
Entheses are sites of attachment of tendons, ligaments, fasciae, and articular capsules to bones. Fibrous entheses are usually associated with massive muscle bodies which attach directly to large areas of the diaphyses or metaphyses of long bones and dissipate stress from tendons over bone tissue. The deltoid muscle or adductor magnus, for example, attach to bones via fibrous entheses. Fibrocartilaginous entheses have more sophisticated architecture, attach to epiphyseal or apophyseal long bone ends, often in the vicinity of synovial joints, and in addition to the dispersion of contractile force, allow for precise limb movement about the joint . The majority of entheses in the body are fibrocartilaginous. These may incorporate uncalcified as well as calcified fibrocartilage, fat pads, bursae, and synovium in addition to tendon, composed from dense fibrous connective tissue, and adjacent bone. The term “enthesis organ” has been suggested to reflect the complex anatomy and multi-functionality of fibrocartilaginous entheses .
In spondyloarthropathies, enthesitis has been appreciated as a significant clinical manifestation and important to pathogenesis. It reinforces the diagnosis of psoriatic arthropathy or juvenile enthesitis-related arthritis, for example, even in the absence of articular involvement. In our experience, however, the entheseal disease in other rheumatic disorders is frequently relegated to a role subsidiary to joint pathology or even neglected. Nonetheless, recent advances in imaging abilities in rheumatology suggest that entheses may be primary, the main target of disease process in many prevalent rheumatic conditions.
Polymyalgia rheumatica (PMR) is a highlighted example. PMR, putatively a mysterious disease of the elderly, manifests in morning stiffness and inflammatory type pain in the shoulder and pelvis girdles and accompanied by elevated serum markers of inflammation, turns out to be a widespread enthesitis/bursitis on magnetic resonance imaging (MRI) (Fig. 1) . In this cited study, the majority of patients with rheumatologist-diagnosed PMR had an “extracapsular” pattern of MRI inflammation and complete glucocorticoid responsiveness, while others demonstrated more capsular-based inflammation on MRI and less impressive response to glucocorticoids; but meaningful entheseal involvement was revealed in virtually all PMR patients . This understanding of the substrate of PMR, while still not uncovering the etiology of the disease, can be of major clinical importance, facilitating the differential diagnosis with elderly onset rheumatoid arthritis, vasculitis, and other systemic diseases. Furthermore, if confirmed in other studies, the precise localization of enthesis/bursae in PMR may help with treatment planning and strategies.
Another example of a condition with entheses/bursae being the major disease target may be crystal-associated enthesopathy. It is, in our experience, one of the most prevalent rheumatic conditions. With the aging of the population and an increased prevalence of metabolic syndrome, both serving as a backdrop to crystal-associated enthesopathy, we see this quantitatively as a major rheumatologic condition to be dealt with. Yet, paradoxically, the majority of these patients are treated by orthopedic surgeons. In most patients with crystal-induced enthesopathy/tendinopathy, entheseal or tendineal calcifications can be easily seen on X-ray films or ultrasonographic examination. Diagnosed with acute calcific tendonitis, these patients usually receive short-term treatment with nonsteroidal anti-inflammatory drugs, glucocorticoid injection, and/or a course of physical therapy. Such episode is widely believed to be a self-limiting condition, which does not necessitate prolonged follow-up or treatment. However, a recent study, examining the long-term outcome in rotator cuff calcific tendonitis, demonstrated that after the mean follow-up of 14 years, about 55% of 194 subjects had impaired shoulder function, with more than 40% severely impaired . The worst prognosis was in patients with bilateral disease, multiple calcifications, and longer duration of symptoms . These data suggest that calcific tendonitis/enthesopathy may not be just a single acute episode, but, in many patients, represent rather a remitting or even chronic inflammatory process. As such, we presuppose that crystal-induced enthesopathy of the rotator cuff, Achilles entheses, entheses of elbows, knee joints, and other locations may impact on morbidity and quality of life, both in the short- and long-term, at a level at least equal to crystal-induced arthropathy, and should be treated accordingly.
In a large study on 1219 adults, the prevalence of rotator cuff calcific deposits alone has been appreciated as up to 7.8% in asymptomatic persons and 42.5% in patients with shoulder pain . In addition to pain, limited shoulder motion and function, tears of rotator cuff structures, and/or cortical bone erosions adjacent to calcifications, all can be manifestations of uncontrolled inflammation triggered by calcium deposits. All too frequently, such patients present with enthesitis at multiple sites dubbed systemic enthesopathy. For more than a decade, we have been treating these patients in a manner similar to patients with crystal-induced arthropathy, using daily colchicine, 0.5 mg bid, as a first line therapy. Indeed, keeping in mind the ability of colchicine to constrain the activity of inflammasome, potentially activated by the pathogenic crystals, its clinical use seems at least reasonable. In practice, we have observed fair or good efficacy of colchicine, noted as improvement in both pain and range of motion, in about 70% of patients with crystal-induced enthesopathy, usually apparent very slowly over a 2–4-month period (personal unpublished data). Analogous to reports in CPPD, methotrexate was used in patients with chronic course of crystal-induced enthesopathy resistant to colchicine.
Diffuse idiopathic skeletal hyperostosis (DISH), similar to peripheral calcific entheso/tendinopathy, such as rotator cuff or trochanteric enthesopathies, becomes more prevalent with aging, typically in patients with abnormal metabolism, is asymptomatic in the majority of patients, and can cause persistent and disabling back pain and limitation in others . The anterior longitudinal ligament (ALL), the primary tissue involved in DISH, is a thick band that spans the entire length of the spine, being bound to the periosteum over the vertebral bodies, the margins of the vertebrae, the hyaline cartilage vertebral end plates, and the fibrocartilage disc. As such, the whole ALL can be regarded as an enthesis, and DISH as an axial enthesopathy (Fig. 2). Viewed as such, we posit that if we understood the fundamental difference between silent and clinically significant or pro-inflammatory calcifications in the setting of peripheral calcific enthesopathy and DISH, and/or their activation pathways, this would benefit additional countless patients worldwide.
Finally, the lesser appreciation of enthesopathy in general may be partly responsible for the less than desirable outcome in the management of osteoarthritis (OA), despite ample evidence in the studies of McConagle and others of enthesopathy’s role in OA pathogenesis [8, 9].
In summary, the involvement of entheses/tendons/bursae can be central to the course of the most prevalent rheumatic disorders. The wide spectrum of rheumatic conditions mentioned here reflects the diversity of pathogenetic mechanisms, anatomical changes, clinical presentations, imaging features, and prognosis of enthesopathies. The study of enthesopathies turns out to be unexpectedly appealing. We put forward that it is time to move enthesopathy to center stage as a major focus in rheumatology. The further study of entheses’ biology, pathology, and imaging should be prioritized.
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Slobodin, G., Rosner, I. Enthesis as a target organ in rheumatic diseases: an expanding frontier. Clin Rheumatol 36, 2163–2165 (2017). https://doi.org/10.1007/s10067-017-3749-8