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REVIEW
Concepts of Entheseal Pain
Enrico De Lorenzis,
1
Gerlando Natalello,
1
David Simon,
2
Georg Schett,
2
and Maria Antonietta D’Agostino
1
Pain is the main symptom in entheseal diseases (enthesopathies) despite a paucity of nerve endings in the
enthesis itself. Eicosanoids, cytokines, and neuropeptides released during inflammation and repeated nonphysiolo-
gic mechanical challenge not only stimulate or sensitize primary afferent neurons present in structures adjacent to
the enthesis, but also trigger a “neurovascular invasion”that allows the spreading of nerves and blood vessels into
the enthesis. Nociceptive pseudounipolar neurons support this process by releasing neurotransmitters from periph-
eral endings that induce neovascularization and peripheral pain sensitization. This process may explain the fre-
quently observed dissociation between subjective symptoms such as pain and the structural findings on imaging
in entheseal disease.
INTRODUCTION
The term “enthesopathy”refers to a disease process that
occurs at tendon insertion sites. Entheses are specialized tissues
that connect tendons, ligaments, or joint capsules with bones.
They can be classified into fibrocartilaginous entheses, which are
formed by a layered structure that gradually transforms from ten-
don fibers to bone, or fibrous entheses, which are characterized
by direct insertion through a tissue analog to a tendon or ligament
midsubstance (1,2).
Due to their biologic function, entheses are prone to
mechanical overuse with subsequent inflammation and
tissue remodeling (“degeneration”) accumulating after repeated
mechanical stress. Aging, metabolic or hormonal diseases, and
specific drugs also facilitate the development of entheseal dis-
ease (3). In addition, certain forms of arthritis (i.e., the spondyloar-
thritis (SpA) disease spectrum, including ankylosing spondylitis,
psoriatic arthritis, reactive arthritis, and inflammatory bowel
disease [IBD]–associated arthritis) are characterized by the way
they preferentially affect the entheses (4). Entheseal disease is
characterized by substantial pain that also often occurs in the
absence of major structural changes, a phenomenon that is
highly clinically relevant but still conceptually poorly explained to
date. In this review, we address this feature of entheseal disease
and suggest a mechanistic explanation based on the current
evidence.
Pain as the main symptom of entheseal disease
Entheseal disease is associated with a very high pain burden
(5). Entheseal pain is the result of a complex relationship between
the immune system and the nervous system. Clinical examination
of the entheses alone often does not reveal the reason for pain in
entheseal disease, making the clinical diagnosis of entheseal dis-
ease challenging. Therefore, ultrasound examination and mag-
netic resonance imaging (MRI) have been used to improve the
detection of entheseal disease. Inflammation and structural
changes in the entheses have been reported in professional ath-
letes prone to mechanical stress (6,7), as well as in patients with
psoriasis (8,9), IBD (10), and SpA (11). Of note, imaging studies
have shown that a fraction of asymptomatic individuals in the
general population also show signs of entheseal changes on
imaging (12). Conversely, entheseal symptoms (e.g., pain) can
also occur in the absence of significant imaging findings (13),
indicating that entheseal pain does not always need to involve
substantial inflammation and/or degeneration. This observation
indicates that entheseal pain can result from different processes.
Specifically, entheseal pain may be related to a chronic inflammatory
1
Enrico De Lorenzis, MD, Gerlando Natalello, MD, Maria Antonietta
D’Agostino, MD, PhD: Division of Rheumatology, Catholic
University of the Sacred Heart, Fondazione Policlinico Universitario
A. Gemelli IRCCS, Rome, Italy;
2
David Simon, MD, Georg Schett, MD:
Department of Internal Medicine 3, Friedrich-Alexander University
Erlangen-Nurnberg (FAU) and Universitätsklinikum Erlangen, Erlangen,
Germany.
Author disclosures are available at https://onlinelibrary.wiley.com/action/
downloadSupplement?doi=10.1002%2Fart.42299&file=art42299-sup-0001-
Disclosureform.pdf.
Address correspondence via email to Maria-Antonietta D’Agostino, MD,
PhD, at mariaantonietta.dagostino@unicatt.it.
Submitted for publication March 28, 2022; accepted in revised form July
7, 2022.
493
Arthritis & Rheumatology
Vol. 75, No. 4, April 2023, pp 493–498
DOI 10.1002/art.42299
© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.
This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits
use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or
adaptations are made.
process intrinsic to diseases like SpA that is characterized by
infiltration of macrophages at the fibrocartilage and by lymphocytes
in the corresponding bone marrow (14,15), and/or to a less inflam-
matory, mechanically induced process (16,17) that only shows spu-
rious signs of inflammation because of repairing mechanisms (18).
Innervation of entheseal tissues and
neurovascular response
Microscopic examinations of normal entheses in both humans
and animals have shown a paucity of nerve endings in the entheses
themselves (19,20). In fact, cartilage-related proteins like aggrecan,
which is also a major component of entheses, act as inhibitors of axo-
nal growth (21). In contrast, functionally related structures that sur-
round the entheses (e.g., the fat pad, the paratenon and endotenon,
the bone, and the periosteum at the insertion site [22]) are very richly
innervated by both small nonmyelinated C and large myelinated Aδ
nociceptive fibers (23). These nociceptive neurons can be activated
as soon as a pathologic process affecting the entheses also
affects the surrounding tissues. Entheseal stress is common both in
SpA—in which entheseal inflammation is considered a very early
abnormality—and upon exacerbated or repeated mechanical stress
that often involves the whole tendon or ligament. Moreover, repeated
and/or prolonged mechanical challenge and inflammation may trigger
a“neurovascular invasion”of the entheses from bone marrow and
the adjacent paratenon (24–28). Other pain mechanisms can also
be associated with entheseal disease, such as dysfunctional patterns
in muscle recruitment (24) or central sensitization associated with both
inflammatory (25)anddegenerative(26) entheseal diseases.
Prostaglandin E
2
as a mediator in entheseal pain
Despite the high prevalence and intensity of pain in entheseal
diseases (26), the actual nociceptive stimuli involved have not yet
been fully characterized. Different molecules, such as eicosa-
noids, cytokines, and neuropeptides, involved in musculoskeletal
pathologies can directly stimulate the primary afferent neurons or
sensitize them to mechanical stimuli. Therefore, as we will
describe below, immune cells in SpA-related enthesitis may not
be the exclusive source of algogenic substances, and mesenchy-
mal cells may also play an important role. The specific contribution
of mediators is difficult to pinpoint as their biologic signals are
widely interconnected and reciprocally amplified (Figure 1).
Given the anatomic and functional background of entheses
(27), mechanical strain is consistently deemed a pivotal factor in
the pathogenesis of entheseal disease (28), and resident mesen-
chymal cells are sensitive to changes in load. In vitro studies in
which cultured mesenchymal cells were used have shown that
osteoblasts (29), chondrocytes (30), and fibroblasts (31,32) are
mechano-sensitive and produce prostaglandin E
2
(PGE
2
) and
other inflammation markers (33) in response to repeated stretch-
ing. Considering that the entheses are subject to major stress
along the tendon–bone complex (34) and that the production of
PGE
2
is stretch-dependent, it can be postulated that the large
amounts of PGE
2
are produced locally (35). In this context,
PGE
2
production seems to be an event that happens quickly,
occurring within hours after mechanical stress and providing the
basis for pain and an inflammatory response. Notably, PGE
2
can
also promote vasodilation and angiogenesis through the produc-
tion of vascular endothelial growth factor, the differentiation of
bone marrow cells, and the migration of endothelial cells (36).
While the role of immune cells in pain related to degenerative
enthesopathies is rather controversial, the specific role of neuro-
nal mediators in proper inflammatory diseases has been margin-
ally addressed (37). PGE
2
is an eicosanoid that can easily cross
cell membranes and reach surrounding tissues (38). It is consid-
ered an early algogenic mediator that binds receptors on Aδfibers
and small C fibers, promoting the activity of the transient receptor
potential cation channel V1, P2X
3
purinergic receptors, voltage-
gated T-type calcium channels (Ca
V
3.2), and the voltage-gated
sodium channels Na
V
1.8 and Na
V
1.9 (39). Moreover, PGE
2
can
promote the recruitment of macrophages and T-cells from the
bone marrow into the entheseal compartment, which are sources
of tumor necrosis factor and interleukin-17, both of which have
been shown to amplify pain responses (40–43). The reason the
influx of immune cells is more pronounced and prolonged in SpA
than in mechanically induced entheseal disease is unclear. This
may be due to genetic predisposition as well as barrier changes,
such as in the setting of intestinal inflammation, which is charac-
terized by an exaggerated immune response.
Neuropeptides in entheseal pain
Primary nociceptive pseudounipolar neurons can release
neurotransmitters from peripheral endings. The term neurogenic
inflammation defines the release of mediators that can induce
vasodilation, neovascularization, and peripheral pain sensitization
(44). Substance P, calcitonin gene-related peptide (CGRP), and
glutamate are key mediators of neurogenic inflammation. The role
of neurogenic inflammation in entheseal pain has mainly been
studied in degenerative entheseal disease. Neuronal sprouting
with enhanced expression of substance P and CGRP has been
reported in common insertional tendinopathies such as jumper’s
knee (45), Achilles tendinopathy (46,47), and tennis elbow (48).
Findings of animal model studies also suggest that mechanical
strain has a role in neurogenic inflammation (49) and that it can
lead to a mutual enhancement of PGE
2
and neuropeptides (50).
Similarly, symptomatic degenerative changes in tendon tissue
have been associated with high local levels of glutamate (51,52)
and higher expression levels of its N-methyl-D-aspartate receptor
on peripheral nerve ends and on tenocytes themselves (53). Periph-
eral glutamate and its receptors also play an important role in the
activation of nociceptors that are enhanced by substance P (54).
The role of neurogenic inflammation in a proper inflammatory disease
DE LORENZIS ET AL494
such as SpA has not been specifically investigated. However, studies
of murine models of inflammatory arthritis have identified nociceptive
nerve fibers expressing substance P and CGRP sprouting in the
entheses, a finding that is analogous to the observations in models
of overuse injuries (55–58).
Anatomic structures involved in entheseal
disease
To better understand the relationship between symptoms
(pain) and anatomic changes in entheseal disease, imaging of
anatomic structures and their respective changes are of seminal
importance. While standardized imaging criteria for mechanically
induced entheseal disease are lacking to date, the Outcome
Measures in Rheumatology (OMERACT) Ultrasound Working
Group has defined inflammatory entheseal disease in the setting
of SpA. In ultrasound, such lesions appear as hypoechoic
(water-rich) and/or thickened insertions of the tendon close to
the bone (a Doppler signal may be present if increased vasculari-
zation is exhibited), which may be associated with erosions and
bony spurs (enthesophytes) or calcifications (a sign of structural
damage) (59). Similarly, the key features of enthesitis on MRI
according to the OMERACT MRI Working Group are intratendon
hyperintensity (entheseal tendonitis), peritendon hyperintensity
Figure 1. An illustration of the biologic mechanisms occurring in entheses affected by entheseal disease. PGE
2
= prostaglandin E
2
;
TNF-α= tumor necrosis factor α; IL-17/IL-23 = interleukin-17/interleukin-23; CGRP = calcitonin gene-related peptide; SP = substance P;
Glu = glutamate.
CONCEPTS OF ENTHESEAL PAIN 495
(entheseal peritendonitis), and bone marrow edema (entheseal
osteitis), as well as the presence of tendon thickening, entheso-
phytes, or bone erosions (signs of structural changes) (60). Such
alterations have also been described in degenerative entheseal
disease, although hypoechoic areas on ultrasound and hyperin-
tensity on MRI may reflect collagen degeneration rather than
ongoing inflammation (61), and changes to entheses—including
power Doppler signal—are overall more diffuse and distant from
the bone compared to entheseal changes seen in inflammatory
entheseal disease (62). Also, the degeneration associated with
perientheseal osteitis seems to be less extensive compared to
the degeneration associated with inflammatory entheseal dis-
eases (63).
Lessons on entheseal pain from imaging studies
Overall, imaging studies have shown that perientheseal tis-
sues are substantially affected by inflammation and structural
changes in entheseal disease, providing the basis for pain, as
structures such as peritendon tissue, bone, and bone marrow
are densely innervated. Moreover, the signal changes in tendons
observed on ultrasound and MRI clearly suggest that entheseal
disease is associated not only with neovascularization, but also
with the neoinnervation of previously oligotrophic and highly
collagen-rich tissue (turning them into “nociceptive tissues”).
Conversely, the paucity of nociceptive nerve fibers at the insertion
of healthy tendons supports the observation that early forms of
mechanically induced entheseal disease can remain asymptom-
atic. It can be hypothesized that only later when neurovascular
invasion occurs does entheseal disease become symptomatic.
Consistent with this concept, it has been shown that the presence
of subclinical entheseal disease predicts the onset of articular
symptoms in patients with psoriasis (64) or chronic overuse
related to sport activities (65). Moreover, imaging studies have
shown that signs of neoangiogenesis are specifically associated
with pain in mechanically induced entheseal disease (66–68),
while the findings from an imaging study by Feydy et al on inflam-
matory entheseal disease were inconclusive with regard to the
relationship (69).
The idea that eicosanoids such as PGE
2
have a role in the
process of neoangiogenesis in entheseal disease is supported
by the evidence that nonsteroidal antiinflammatory drugs
(NSAIDs) dampen the detection of vascular signals in contrast-
enhanced ultrasonography (70). It is therefore not surprising that
NSAIDs are the first choice of treatment for both inflammatory
and degenerative forms of entheseal disease (71).
Conclusions
Taken together, these findings suggest that pain in the con-
text of entheseal disease is triggered by the involvement of well-
innervated perientheseal structures, as well as by a neurovascular
response that leads to the spreading of blood vessels and
nerves into the oligotrophic tissues of the tendon and the
entheses. Future research should focus more closely on the
relationship between symptoms and anatomic structures
involved in entheseal disease by utilizing both imaging tech-
niques and biopsy-based histopathologic examinations of the
entheseal structures affected by vascularization and innervation.
The apparent dissociation between anatomic changes and clin-
ical symptoms may be linked to the different underlying mecha-
nisms leading to entheseal disease in inflammatory and
mechanically induced musculoskeletal conditions. Mechanically
induced entheseal disease may initially be asymptomatic
because the extent of innervation and vascularization at the
affected enthesis is not severe enough to produce symptoms.
This silent phase of the disease may facilitate the accrual of fur-
ther damage and ultimately lead to perientheseal involvement
and a neurovascular response that allows for the transition to
symptomatic disease. Conversely, inflammatory entheseal dis-
ease involves periarticular tissues early in the disease course
and therefore becomes symptomatic at an early stage, trigger-
ing fast neurovascular responses. After the cessation of inflam-
mation, this neurovascular invasion of the enthesis persists,
thereby triggering pain as well as a higher sensitivity to the recur-
rence of inflammation, explaining the “uncoupling”of pain from
structural changes in the affected enthesis.
AUTHOR CONTRIBUTIONS
All authors drafted the article, revised it critically for important intel-
lectual content, and approved the final version to be published.
ACKNOWLEDGMENT
Open Access Funding provided by Universita Cattolica del Sacro
Cuore within the CRUI-CARE Agreement.
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