Entheses are boney insertion sites of tendons and ligaments. Enthesopathies are defined as the pathologies that affect the entheses. Although somewhat controversial, there appear to be two main classifications of entheses: 1) fibrous and 2) fibrocartilaginous. The difference is that fibrous entheses insert directly onto the periosteum, whereas fibrocartilaginous enthesis lack periosteum.
Anatomically, the entheses are usually found outside the joint capsule with exceptions, including the sacroiliac, sternoclavicular, and distal interphalangeal joints. Entheses have two main roles: stability of the joint, and to transduce mechanical forces. A unique aspect of the entheses is also the relative lack of vascularity. Enthesitis, a subset of enthesopathy, is the inflammation of the insertion sites for the tendons and ligaments on the bone. It is associated with diffuse inflammatory disorders such as psoriatic arthritis (PsA) and spondyloarthropathies (SpA).
Enthesopathies can be separated into two broad categories 1) repetitive mechanical stress and 2) diffuse inflammatory response. Enthesopathies from repetitive mechanical stress can be seen in common sports-related injuries such as lateral and medial epicondylitis, Achilles, and shoulder enthesopathy. Diffuse inflammatory responses that lead to enthesopathies and enthesitis tend to affect multiple entheses. The repetitive local microtrauma allows innate immune cells to invade the local area and cause inflammation triggered by chemokines. Chemokines involved in the local inflammatory response include CXCL1, CCL2, IL-17, TNF-alpha, and prostaglandin E2 (PGE2).
The prevalence and incidence of enthesopathies from a diffuse inflammatory disease are difficult to assess and calculate given the varied nature, presentation, and etiology of the enthesopathies. It has been reported the prevalence of enthesitis in patients with PsA is approximately 35%. In patients with SpA, 10 to 60% of patients that are diagnosed with SpA have enthesitis.
Enthesopathies can be due to a loss of fibrillar structure secondary to edema, mineralization, which leads to calcification and ossification, diffuse inflammatory disease, or altered structure of collagen fibers leading to a thickened enthesis. Moreover, enthesopathies themselves can lead to other manifestations such as enthesophytes. Enthesophytes are due to new bone formation secondary to seronegative SpA, diabetes mellitus, local trauma, and calcium pyrophosphate deposition disease.  Often times, mechanical stress is the inciting event that triggers the cascade and repetitive cycle of inflammation. Common examples of mechanical stress enthesitis include lateral epicondylitis and medial epicondylitis of the elbow.
Enthesitis is a common finding in both PsA and the SpA. The key difference between enthesitis from mechanical stress and that from a diffuse inflammatory process such as PsA and SpA is that the diffuse inflammatory processes tend to affect multiple entheses. Mechanical stress, albeit theorized to be at a lower threshold, seems to be an inciting event in both localized enthesitis from repetitive stress and diffuse enthesitis from an inflammatory disease.
The history and physical of enthesopathies depends on the location of the affected entheses. The patient may complain of decreased range of motion of the affected area as well as localized pain. Inspection may reveal localized swelling or erythema. Pain may be elicited by palpating the affected area as well as ranging the affected joint. Range of motion should be assessed both actively and passively for mechanical deficits and pain limitations.
If a diffuse inflammatory disease is suspected, a more thorough physical exam should include the evaluation of commonly affected areas such as the sacroiliac joints, Achilles tendon, and distal interphalangeal joints. Moreover, asking a broad review of systems may reveal the underlying cause of enthesitis, such as weight loss, night sweats, chills, or any other constitutional symptoms.
The evaluation includes a thorough history and physical exam, depending on the underlying etiology of the enthesopathy. For enthesopathies secondary to repetitive use with a low likelihood of underlying inflammatory disease, the evaluation is primarily through physical examination, with imaging as needed. X-rays can be used to evaluate for bony pathology and calcifications. Diagnostic ultrasound or magnetic resonance imaging can be used to visualize soft tissue, including the enthesis itself.
Evaluation of enthesopathies secondary to a diffuse inflammatory response leading to enthesitis may include a complete blood count, HLA-B27 assessing for seronegative SpA, rheumatoid factor, anti-nuclear antibody, and other autoimmune factors that may reveal the underlying cause. Additionally, imaging studies may be ordered similar to those when evaluating enthesopathies from repetitive use.
Treatment depends on the underlying etiology. For an overuse enthesopathy, the mainstay of treatment is ice, rest, and nonsteroidal anti-inflammatory drugs (NSAIDs) for 7-10 days.  However, NSAID use is somewhat controversial in the acute period, as they may inhibit healing by blunting the inflammatory response. Adjunct therapies for enthesopathies also include skilled physical therapy, glucocorticoid injections, topical nitrate therapy, and platelet-rich plasma (PRP).
Skilled physical therapy has been shown to improve pain, increase function, and increase active range of motion in a broad form range of pathologies, which include shoulder, hip, elbow, and Achilles enthesopathy. From a biomechanics perspective, different joint position exercises may provide alternate stress on the tendon, which is theorized to stimulate healing after an injury.
Although routinely used in clinical practice, glucocorticoid injections are somewhat controversial. There is no clear evidence to support their use. Moreover, glucocorticoids into the tendon are tenotoxic and may lead to further injury.
Topical nitrates are theorized to increase neovascularization, fibroblast activity, and promote collagen synthesis. Studies show promising results with topical glyceryl trinitrate (GTN) for being a good adjunct therapy for chronic tendinopathies such as wrist extensors, Achilles, patellar tendon, and rotator cuff. GTN comes in a patch form with dosages ranging from .72mg/day – 5mg/day for tendinopathies.
PRP is proposed to have its effect via directly introducing a concentrate of growth factors, as well as establishing a rich microenvironment that recruits additional cells and growth factors to promote healing. Although still being researched, promising studies have shown that PRP may help in multiple enthesopathies such as gluteal tendinopathy and elbow tendinopathies.
For calcific enthesopathies, a technique called barbotage can be used. Under direct visualization via ultrasound or fluoroscopy, a calcific lesion is repeatedly injected and aspirated, typically with saline. This has been shown to be effective in lateral epicondylopathy and rotator cuff calcific tendonitis.
Enthesopathies caused by diffuse inflammatory diseases can be treated with disease-modifying antirheumatic drugs (DMARDs) such as methotrexate and hydroxychloroquine. Additionally, biologics such as rituximab, etanercept, and infliximab may be used to specifically act on inflammatory markers to help reduce the overall burden of disease.
The differential diagnosis of enthesopathies can include avulsions, fractures, ligament or tendon rupture, localized infection, contusions, muscle strains, and malignancy.
The prognosis of enthesopathies is generally favorable, given the underlying etiology. With adequate rest and rehabilitation, most cases of enthesopathies will resolve over 2-4 weeks.
Enthesopathies from diffuse inflammatory disease may result in prolonged recovery times and is relative to the severity and etiology of the underlying disease.
Tendon or ligament tear is a complication of both repetitive use and diffuse inflammatory disease enthesopathies.
Multiple subspecialties may be presented with the initial presentation of enthesopathies, and an astute clinician will need to discern where the patient may need to be referred. Education for localized enthesopathies from repetitive use can be safely done in the clinician’s office or with a skilled physical or occupational therapist. Educating on joint protective measures may also greatly benefit the patient with overuse enthesopathies. For patients with an underlying systemic inflammatory disease, a more thorough and comprehensive educational approach may be necessary. Discussions with subspecialists such as physiatrists, rheumatologists, internal medicine, and immunologists may all be needed to adequately educate and treat select patients.
An interprofessional team approach provides the best outcome for patients with enthesopathies. Teamwork and coordination are quintessential in patients with enthesopathies from inflammatory diseases. Multiple sub-specialties are involved in the coordination of care, which includes primary care clinicians, physiatrists, rheumatologists, physical therapists, and occupational therapists. Such an approach allowed for comprehensive evaluation and treatment, especially in those suffering from spondyloarthropathy. [Level 2]
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