(2022) - Frozen Shoulder Review

PRIMER
Frozen shoulder
Neal L. Millar 1 ✉, Adam Meakins2, Filip Struyf 3, Elaine Willmore4,
Abigail L. Campbell 5, Paul D. Kirwan6, Moeed Akbar 1, Laura Moore7,
Jonathan C. Ronquillo8, George A. C. Murrell 9 and Scott A. Rodeo 7
Abstract | Frozen shoulder is a common debilitating disorder characterized by shoulder pain
and progressive loss of shoulder movement. Frozen shoulder is frequently associated with other
systemic conditions or occurs following periods of immobilization, and has a protracted clinical
course, which can be frustrating for patients as well as health-care professionals. Frozen shoulder
is characterized by fibroproliferative tissue fibrosis, whereby fibroblasts, producing predominantly
type I and type III collagen, transform into myofibroblasts (a smooth muscle phenotype), which is
accompanied by inflammation, neoangiogenesis and neoinnervation, resulting in shoulder capsular
fibrotic contractures and the associated clinical stiffness. Diagnosis is heavily based on physical
examination and can be difficult depending on the stage of disease or if concomitant shoulder
pathology is present. Management consists of physiotherapy, therapeutic modalities such as steroid
injections, anti-inflammatory medications, hydrodilation and surgical interventions; however, their
effectiveness remains unclear. Facilitating translational science should aid in development of novel
therapies to improve outcomes among individuals with this debilitating condition.
Frozen shoulder1 (FS), also known as adhesive capsulitis, musculoskeletal conditions, such as inflammatory
is a common shoulder disorder manifesting as pain and arthritis and osteoarthritis.
progressive loss of shoulder movement. FS can be either A true evidence-based model for the management of
primary or secondary, which refers to whether the con- FS has yet to be defined, with a wide spectrum of treat-
dition has come on spontaneously with no known cause ments available. Management varies according to the
or trauma (primary FS), or whether it is associated with stage of the disease and range from early pharmaco-
trauma, surgery or other pathology, such as subacromial therapy and associated physiotherapy to later approaches
pain (secondary FS). FS typically progresses through such as surgery (manipulation under anaesthesia (MUA)
three overlapping stages, with the predominant symp- and arthroscopic capsular release (ACR)), extracor-
toms of pain and loss of motion (inflammation/‘freezing’ poreal shockwave therapy (ESWT), hydrodilation,
(stage I)), stiffness (‘frozen’ (stage II)) and then resolu- injections (sodium hyaluronate injection), collagenase
tion of symptoms (‘thawing’ (stage III)). However, this treatment and experimental approaches that require val-
classification remains contentious, as many patients still idation in clinical trials. FS therefore remains a challenge
experience symptoms and functional restrictions long to treat, with a large proportion of patients still failing to
after progression through these stages. attain complete resolution of symptoms. Indeed, while
FS is characterized by fibroproliferative tissue fibro- FS is often regarded as a self-limiting disease (1–2 year
sis (FIG. 1) of the shoulder capsule, which is thought recovery), various studies have shown that many of
to be modulated by mediators that include cytokines, the symptoms associated with FS, such as stiffness and
growth factors and enzymes, in particular, matrix pain, persist in 20–50% of patients2–4. Thus, further work
metalloproteinases (MMPs), with increasing evidence is required to identify more effective treatment options
for the involvement of inflammatory mediators and for these patients. This Primer presents the current
various immune cells. The histological characteris- knowledge of the basic and clinical science of FS and
tic of FS is the presence of a matrix of fibroblasts and highlights its clinical presentation, natural history, risk
myofibroblasts containing type I and type III collagen factors, pathoanatomy and pathogenesis. Furthermore,
that results in an imbalance between tissue extracel- we provide evidence- based treatment guidelines in
lular matrix (ECM) degradation, remodelling and the form of a proposed treatment algorithm. In addi-
✉e-mail: neal.millar@ regeneration. Although knowledge of risk factors of tion, we aim to consolidate and interpret the unmet
glasgow.ac.uk FS, pathophysiology and enhanced treatments are still needs in the field and discuss the barriers that need to
https://doi.org/10.1038/ emerging, both basic and clinical research (and conse- be overcome to attain better outcomes for all patients
s41572-022-00386-2 quently therapeutic advances) lag behind that in other with FS.
NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 1
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PRIMER
Author addresses disease26. Furthermore, FS, as identified by shoulder

capsule volume on arthrography, is the leading cause of
1
School of Infection and Immunity, College of Medicine, Veterinary and Life Sciences, hemiplegic shoulder pain after stroke27.
University of Glasgow, Glasgow, UK.
2
Department of Trauma and Orthopaedics, West Hertfordshire Hospital Trust, Watford, UK.
Mechanisms/pathophysiology
3
Department of Rehabilitation Sciences and Physiotherapy, University of Antwerp,
From homeostasis to disease
Antwerp, Belgium.
4
Physiotherapy Department, Gloucestershire Hospitals NHS Foundation Trust, The shoulder joint capsule is a lax fibrous sheath that
Gloucester, UK. encloses the joint. The healthy capsule is collagenous in
5
Department of Orthopaedic Surgery, Kaiser Permanente West Los Angeles, Los Angeles, structure, composed primarily of dense type I collagen
CA, USA. and elastic fibre bundles with limited vessels and nerve
6
School of Medicine, Discipline of Physiotherapy, Trinity College Dublin, Dublin, Ireland. fibres. The main cell type within this membrane is fibro-
7
Department of Orthopaedic Surgery, Sports Medicine and Shoulder Service, Hospital for blasts, which maintain capsule health by producing ECM
Special Surgery, New York, NY, USA. proteins that provide a supportive yet flexible structure.
8
De La Salle University Medical Center, Health Sciences Institute & Asian Hospital and In FS, the typical collagen structure is disrupted by
Medical Center, Dasmariñas, Philippines.
gradual fibrosis of this connective tissue membrane and
9
Orthopaedic Research Institute, St George Hospital, University of New South Wales,
thickening of the adjacent synovial membrane28. These
Sydney, New South Wales, Australia.
fibrotic changes are accompanied by inflammation, neo-
angiogenesis and neoinnervation29–32. The consequence
Epidemiology is a reduced joint volume and increased stiffness of
Prevalence the capsule that cause restricted movement and pain. In the
The lifetime prevalence of FS is estimated to be 2–5% following sections we describe how the shoulder cap-
of the general population, and FS affects ~8% of men sule and associated structures progress from a lax fibrous
and ~10% of women5,6. FS is most common in the fifth and membrane to a fibrotic hypervascular structure that
sixth decades of life, with the peak age in the mid-50s7. drives the clinical course of FS.
In up to 17% of patients with FS, the other shoulder
becomes affected within 5 years4,8. Stages of FS
It is debatable whether FS as a condition is truly FS progresses through three characteristic stages1, each
unique to the shoulder. Indeed, there are case reports with associated arthroscopic and histological changes32.
of occurrences of adhesive capsulitis in the knee, hip Neviaser and Neviaser initially described four stages of
and ankle9,10, although they are exceptionally rare. disease (stages I–IV) in 1987 (REF.1), which was modified
Contractures and fibrosis do frequently occur in the in 2010 to three clinically based stages (stages I–III)33
knee and elbow, although without the potential for (FIG. 2). Stage I is characterized by pain without appre-
the spontaneous resolution seen in the shoulder. ciable limitation in motion, and is associated with an
inflammatory synovial reaction on arthroscopy, and
Risk factors with hypervascular synovitis with rare inflammatory
FS has been linked to a range of co-morbidities, including cell infiltrates and normal capsular tissue on biopsy.
cardiovascular disease, Parkinson disease, stroke, hyper- Clinically, stage II involves ongoing pain with pro-
thyroidism and, in particular, diabetes mellitus, where gressive limitation in motion. Intra-articularly, there is
the incidence of FS can reach close to 60%11–14. FS has also ongoing synovitis and progressive capsular contracture.
been linked to hypothyroidism15, hyperlipidaemia16 and On arthroscopy, there is hypervascular synovitis and
autoimmune diseases17. These co-morbidities are found loss of axillary folding. Histology shows hypertrophic,
in more than 80% of individuals diagnosed with FS, hypervascular synovitis now with perivascular and sub-
with over 35% of affected individuals having more than synovial scar formation. Stage III is marked by ongoing
three associated conditions11. Other risk factors (BOX 1) stiffness clinically, and is associated with loss of the axil-
associated with FS are smoking18, obesity7 and low levels lary recess, fibrosis and minimal synovitis on arthros-
of physical activity19. In addition, FS risk is increased in copy. Biopsy of patients with stage III FS reveals dense,
individuals with Dupuytren disease, a fibrotic disorder of hypercellular collagenous tissue to mature fibrosis with a
the palmar fascia that has a very similar pathophysiology thin synovial layer, similar to other fibrosing conditions.
to FS20–22. In addition to an association with metabolic
and hormonal changes, FS has also been associated with Inflammation
abnormal shoulder mechanics and nerve dysfunction. Recent years have seen the musculoskeletal scientific
This link between primary nerve dysfunction and FS community direct its attention to investigating the mecha-
was first proposed in 1959 by Thompson and Kopell23, nisms underlying the inflammatory and fibrotic changes
who proposed that reduced glenohumeral motion could associated with FS to elucidate the aetiological, cellular
result in exacerbated scapulothoracic motion, thereby and molecular pathways. Although a single unifying
stretching the suprascapular nerve, leading to a cycle of cause is yet to be identified, several key mechanisms have
pain and shoulder dysfunction. Since then, FS has been been implicated in the pathogenesis of FS. One of these is
identified in patients with a variety of primary neuro- chronic, unresolved inflammation. Histological analyses
logical conditions. FS is a cause of shoulder pain and of tissue biopsy samples from affected patients consistently
dysfunction in patients after radical neck dissection24, reveal chronic inflammation, which is associated with
acute cerebrovascular aneurysm surgery and subarach- increased vascularity, fibroblast proliferation, synovial
noid haemorrhage25 and in individuals with Parkinson membrane thickening and increased ECM deposition7,8.
2 | Article citation ID: (2022) 8:59 www.nature.com/nrdp
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PRIMER
a Healthy shoulder
Acromioclavicular joint
Coracoacromial ligaments
Articular capsule
Synovium
Joint cavity
Articular cartilage
Deltoid muscle Scapula

Articular capsule Humeral head
b Early-stage frozen shoulder

Inflammatory cell
infiltrate
Hypervascular
synovitis
Cytokine
secretion
c Late-stage frozen shoulder
Articular capsule thickening
Fibroplasia, some immune

cells, and differentiated Axillary recess volume decrease
myofibroblasts with
abundance of
type III collagen
Fig. 1 | Structural changes during frozen shoulder. a | The healthy capsule is collagenous in structure, composed primarily
of dense type I collagen and elastic fibre bundles with limited blood vessels and nerve fibres. The main cell type within this
membrane is the fibroblast, which maintains capsule health by producing extracellular matrix (ECM) proteins that provide
a supportive yet flexible structure. b | In frozen shoulder, there is fibrosis and thickening of the connective tissue membrane
as well as the adjacent synovial membrane. c | Fibroproliferation results in an increased number of fibroblasts producing
more ECM proteins, resulting in a dense and poorly organized fibrillar structure. These fibrotic changes are accompanied
by inflammation, neoangiogenesis and neoinnervation. The consequence is a reduced joint volume and increased stiffness
of the capsule, causing restricted movement and pain.
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PRIMER
Various immune cells have been identified in capsular pro-fibrotic and inflammatory responses in FS fibro-
tissue from patients with FS, including B cells, macro- blasts than in fibroblasts from healthy tissue as a result
phages, mast cells and T cells34–36. There is growing of greater levels of the IL-17A signalling receptor
evidence indicating a reciprocal homeostatic relationship (IL-17RA) on fibroblasts from diseased shoulders. The
between immune cells and stromal cells within soft tissue, potential pathological effects of IL-17A are notable due
in both health and disease, and as we enter the single- to its similar effect observed in tendinopathy43, for which
cell genomic age, there are emerging data of the pres- anti-IL-17A treatment (secukinumab) is currently being
ence of discrete subtypes of immune cells in the capsule investigated in a clinical trial44.
of patients with FS, including several subpopulations of The levels of IL-33, which can also act as an alarmin
dendritic and T cells37. Immune cells and their mediators (also known as a damage- associated molecular
have been implicated in driving the progression of many pattern), are also elevated in FS tissue 45. Alarmin
fibrotic disorders, and there are now the beginnings of a release has been described in other chronic musculo-
greater appreciation for their role in soft tissue diseases. skeletal conditions, such as rheumatoid arthritis and
While it is simple to explain the presence of immune cells osteoarthritis46,47. A study examined H&E-stained cap-
in a purely pathological context, their homeostatic and sular tissue from patients with FS and found fibroblas-
inflammation-resolving role in soft tissues is now evident. tic hypercellularity and increased vascularity as well as
For example, a subtype of macrophages (those expressing high levels of the alarmins IL-33, high-mobility group
LYVE1 and MERTK) has been identified in patients with protein B1 (HMGB1), S100A8 and S100A9; the levels
rheumatoid arthritis who are in remission38 that is pheno- of these alarmins were correlated with the severity of
typically similar to a population of macrophages present patient-reported pain45. These alarmins can be released
in healthy shoulder capsule but reduced in the capsule of from immune and stromal cells and may mediate
patients with FS37. Loss of these homeostatic or resolutory crosstalk between the two compartments.
cells could indicate a function for these macrophages in Advanced glycation end products (AGEs) have
maintaining healthy tissue. been associated with inflammation, and the increased
production and accumulation of these products is
Pro-inflammatory cytokines seen in diabetes and routine ageing. AGEs can act as
As FS has been described historically as a chronic fibrotic immune modulators by attracting cells that release pro-
disease of the shoulder capsule, the main emphasis of inflammatory cytokines to coordinate degradation and
cytokine studies has been on the role of TGFβ. Many renewal of ECM. Capsular tissue of patients with FS had
studies have unequivocally implicated TGFβ in fibrotic higher immunoreactivity, blood vessel formation and
disease, and FS is no exception. TGFβ is highly expressed perivascular adipocytes than healthy capsule tissue48.
in FS tissue39 and can induce numerous cellular fibrotic
responses, including ECM protein production, fibro- Neural and vascular changes
blast proliferation, increased myofibroblast differentia- The hypervascularity associated with inflammation has
tion and collagen gel contractility40. The link to fibrosis also been suggested to play a key role in the development
is discussed later in this section. Other inflammatory of FS symptoms18. Hypervascularity is prominent across
mediators, including IL-1, IL-6, IL-10, GM-CSF, M-CSF, histological studies in FS, particularly in the rotator
PDGF and TNF, are also dysregulated in diseased interval8. This is the result of neoangiogenesis, which is
capsule35,41 and may drive inflammatory and matrix demonstrated by overexpression of the haematopoietic
responses. Fibroblasts cultured from diseased capsule cell surface marker CD34 (REF.42) and vascular endothelial
produce elevated levels of pro-inflammatory cytokines growth factor (VEGF) in both patients with FS who have
(such as IL-6, IL-8 and CCL-20) in comparison with the diabetes and those without diabetes21. Neoangiogenesis
levels produced by healthy capsular fibroblasts42. is accompanied by neurogenesis, which is probably
Evidence suggests a prominent role for IL-17A in driven by increased expression of the nerve growth fac-
FS. FS tissue contains T cells (CD4+ and CD8+ T cells, tor receptor p75 (REF.30). In patients with FS, the degree
among other subtypes), which produce IL-17A, whereas of neoinnervation is correlated with the frequency of
T cells are predominantly absent from healthy shoul- night pain and expression of HMGB1 (REF.45). In addition
der capsule37. In this study, IL-17A induced greater to an increase in the density of nerves, there is also an
increase in acid-sensing ion channels (ASICs), calcitonin
Box 1 | Risk factors for frozen shoulder gene-related peptide (CGRP) and substance P49, which
are upregulated in hyperalgesia and chronic pain. CGRP
Systemic risk factors • Humeral fracture
in particular is a key connection between the nervous and
• Diabetes mellitus • Parkinson disease immune systems. CGRP is released by the synaptic ter-
• Hypothyroidism • Axillary surgery (breast carcinoma) minals of pain sensing neurons and acts on lymphocytes,
• Hyperthyroidism • Radiotherapy macrophages and mast cells, among others49, resulting in
• Hypoadrenalism Intrinsic risk factors increased production of pro-inflammatory mediators and
• Hyperlipidaemia • Rotator cuff tendinopathy further immune cell recruitment. In addition, expression
Extrinsic risk factors • Rotator cuff tears of the melatonin receptors MTNR1A and MTNR1B is
• Cardiopulmonary disease • Biceps tendinopathy upregulated in FS in response to the pro-inflammatory
• Cervical degenerative disc disease • Calcific tendinopathy
cytokines TNF and IL-1β50, which in turn induces ASIC3
and IL-6 expression, leading to further pain and inflam-
• Cerebrovascular disease • Acromioclavicular arthritis
mation. Combined, these features might explain why pain,
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PRIMER
Stage I Stage II Stage III
Thawing
Frozen Improvement in
Stiffness, range of motion
loss of and pain
axillary
recess, and
minimal
synovitis
Inflammation
and/or freezing
Gradually
worsening pain,
with later
decreased range
of motion
and/or stiffness
ROM
Pain
Time
Fig. 2 | The stages of frozen shoulder. Frozen shoulder is classified into three clinical stages based on pain level and
the severity of range of motion (ROM) limitation. Stage I is the inflammatory stage and includes gradually worsening pain
but limited effect on ROM. Stage II involves plateauing of shoulder pain levels but is mostly associated with increasing
stiffness that results in considerable loss of shoulder function that particularly affects patients’ normal activities of daily
living. Stage III is characterized by reduction of pain (particularly night pain), with pain usually at the end of ROM, and a
very gradual improvement in stiffness over a number of months to years.
particularly night pain, is such a prominent feature of FS. transdifferentiation of fibroblasts to myofibroblasts, and
Central sensitization in FS has not been comprehensively myofibroblasts are a hallmark of FS and other fibrotic
studied and so remains speculative, but could explain conditions53–55. In addition, there is now a greater appre-
why some patients are resistant to current interventions ciation of the potential role of other cytokines, including
and may benefit from a different approach. IL-1, IL-4, IL-13 and IL-17A, in fibrosis. One such aspect
of fibrotic disorders that may be under cytokine regula-
Matrix changes tion is the phenomenon of fibroblast activation. Activated
Fibrosis is the fundamental process manifesting in FS. fibroblasts show higher expression of CD44, CD55, CD90
Fibroblasts are the resident cell type within the joint (THY1), CD106 (also known as VCAM1), CD248 (also
capsule and are responsible for producing the ECM known as endosialin), podoplanin, uridine diphospho-
that forms the structure of the tissue. Under normal glucose dehydrogenase, prolyl-4-hydroxylase and prolyl
homeostatic conditions, type I collagen is the primary endopeptidase FAP (also known as fibroblast activation
matrix protein produced, whereas the more immature protein) compared with control healthy fibroblasts, which
and disorganized type III collagen39 is deposited under are associated with inflammatory cytokine and matrix
pathological conditions, owing to the requirement for dysregulation44. Elevated expression of these proteins by
accelerated ECM turnover. In addition, the production fibroblasts is a phenotype of several musculoskeletal dis-
of several other structural matrix proteins is increased eases including FS, and activated pathogenic fibroblasts
in FS, including vimentin, fibronectin and tenascin C51. produce more pro-inflammatory proteins than healthy
Both MMPs and tissue inhibitors of metalloproteinases fibroblasts42. However, whether the increased expression of
(TIMPs), which regulate matrix remodelling, are dysreg- these proteins is itself directly responsible for the patholog-
ulated in FS. MMPs 1–4, 7–9 and 12–14 and TIMP1 and ical effects of activated fibroblasts or whether it is just an
TIMP2 are implicated in FS51. These proteinases have a epiphenomenon of fibroblast activation remains unclear56.
vital role in ECM turnover, with the balance between
MMPs and TIMPS crucial in matrix remodelling and Metabolic factors
homeostasis, as highlighted by the development of FS Multiple researchers have proposed that certain con-
in 50% of recruited patients in an anticancer treatment ditions, such as hyperlipidaemia and hyperglycae-
trial using a TIMP analogue52. mia, predispose patients with FS to propagation of
Interestingly, many of the fibrotic facets of FS fibro- pro- inflammatory and pro- fibrotic signalling cas-
blasts have been attributed to the effects of increased cades. Multiple studies have found a strong association
TGFβ production. TGFβ has long been known to induce between diabetes mellitus and FS57,58, particularly in the
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Pro-inflammatory and pro-fibrotic

environment Mast cell
Substance P Neuropeptides
Trigger
Fibroblasts Myofibroblasts
Tissue
Growth factors fibrosis and
contracture
• Mechanical stress
• Matrix turnover imbalance
Cytokines T cell
Dendritic cell
B cell Macrophage
Fig. 3 | Molecular pathophysiology of frozen shoulder. A trigger, typically systemic (for example, altered metabolic
status), extrinsic (for example, shoulder immobilization after trauma or surgery) or intrinsic (rotator cuff pathology),
induces a pro-inflammatory, pro-fibrotic environment in which various soluble factors influence cell behaviour. Substance
P induces production and release of neuropeptides by mast cells, which affects fibroblast activation and matrix production.
Pro-inflammatory cytokines, such as IL-1, IL-6, HMGB1 and IL-17A, and growth factors stimulate fibroblast activation,
proliferation and positive feedback loops driving further cytokine and growth factor production. Cytokines also induce
T cell activation and production of IL-17A, while the abundance of macrophage subsets, B cells and dendritic cells are all
increased in biopsy samples of frozen shoulder in humans. All these factors, together with mechanical stress and matrix
turnover imbalance, induce fibroblast transdifferentiation to myofibroblasts, which leads to tissue fibrosis and contracture.
setting of long-term hyperglycaemia59. In addition, FS expression is in the peroxisome proliferator-activated

in individuals with diabetes tends to be prolonged and receptor-γ (PPARγ) pathway66, suggesting a central role
refractory to non-operative treatment compared with for altered lipid metabolism in the pathogenesis of FS.
that in individuals without diabetes13. This associa- Interestingly, patients taking lipid-lowering medications
tion is probably multifactorial, resulting from chronic (such as statins) are not at increased risk of developing
low- level inflammation in individuals with diabetes FS, unlike those taking anti-hyperglycaemic medica-
as well as the presence of AGEs. Pro- inflammatory tions16. This observation suggests that either a reduction
cytokines that are consistently elevated in patients in serum lipids or taking lipid-lowering medications
with diabetes, including TNF, IL-6 and IL-1β51, are also might be protective, which is consistent with the known
present at high levels in the capsule and synovium of anti-inflammatory and anti-fibrotic effects of statins in
patients with FS8. Furthermore, AGEs show increased other conditions62,63.
immunoreactivity in both patients with FS who have In addition to hyperlipidaemia and hyperglycaemia,
diabetes and those who do not48. AGEs contribute to both hyperthyroidism and hypothyroidism are associ-
fibrosis and inflammation across other organ systems ated with an increased risk of developing FS67. Calcitonin
in individuals with diabetes through multiple mecha- is probably the connection between thyroid dysfunc-
nisms. First, AGEs form crosslinks between collagen tion and FS, as calcitonin deficiency is a feature of both
molecules, leading to resistance to proteolysis and disorders68. The connection between calcitonin and FS
reduced tissue compliance60. Second, AGEs stimulate was first noted when postmenopausal women being
the production of pro-inflammatory and pro-fibrotic treated for osteoporosis with salmon calcitonin showed
cytokines and growth factors in stromal and immune improvements in their FS symptoms69. Salmon calci-
cells through activation of the receptor for AGEs55. tonin reduces TGFβ, type I collagen and type III colla-
Finally, AGEs may also contribute to the imbalanced gen synthesis as well as fibroblast adhesion in cultured
MMP and/or TIMP activity that is found across diabetic cells70, all of which are key mediators of fibrosis in FS.
organ systems61. These results were confirmed in a double-blind, rand-
Elevation in serum lipids and cholesterol is also asso- omized, controlled trial in which intranasal calcitonin
ciated with the development of FS, both in conjunction treatment improved shoulder pain and function faster
with diabetes and separate from it45,62,63. Inflammatory than placebo in patients with FS68.
lipoproteins, which are associated with vascular inflam- In summary, the pathophysiology of FS is not yet
mation and immune reaction, are independent risk clear but accumulating evidence is starting to clarify the
factors for the development of FS 64. Furthermore, roles of inflammation, angiogenesis, neuromodulation
the level of increase in serum lipids and glucose is and fibrosis in this disease (FIG. 3).
inversely correlated with the Constant score (a meas-
ure of patient- reported pain and shoulder function) Diagnosis, screening and prevention
in patients with early FS65, supporting the role of these Diagnosis
blood markers in disease progression. Transcriptional The diagnosis of FS is fraught with ambiguity, incon-
profiling of samples from patients with FS (using RNA sistency and confusion for clinicians. Many patients
sequencing) revealed that the greatest differential gene can present with signs and symptoms of FS (pain and
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global restriction in movement) but do not have patho- Loss of shoulder range of motion (ROM) is a key fea-
logical changes of the joint capsule71. Despite the many ture of FS pathology but objective clinical markers that
diagnostic labels and familiar patterns of presentation are deemed to constitute positive findings are rather
with FS, there are currently no formally recognized nebulous.
diagnostic criteria. Consensus studies indicate that
pain, particularly at night and with sudden or unex- Clinical assessment. Loss of passive and active ROM is
pected movements, along with a global loss of active and inherently associated with FS but criteria are conflict-
passive movement of the shoulder, are reliable clinical ing. Thresholds range from a reduction of 30% in two
identifiers72. While these are all undoubtedly character- of three unspecified directions73, to 50% loss of external
istic features of FS, they lack sufficient differential diag- rotation compared to the contralateral side74. However,
nostic capability to distinguish FS from other shoulder there is a lack of reliability in differentiating movement
pathologies (FIG. 4). loss from capsule pathology resulting from other poten-
Pain in FS is often reported in a wide and diffuse tially more serious pathologies or from self- limiting
pattern around the shoulder, scapula, chest and into movement owing to kinesiophobia and protective pain
the upper arm, usually above the elbow, which, in its guarding71,75,76.
early stages, can make FS indistinguishable from other Reliably and accurately assessing shoulder movement
shoulder pathologies, such as rotator cuff tendinopathy, in an individual with severe pain is a clinical challenge.
joint arthrosis and pain from cervicogenic sources. Pain Often, what seems to be an abnormal loss of range can be
in FS is often described as constant, deep and severe. a patient self-limiting due to pain or fear. It is therefore
recommended that movement is assessed in a variety of
positions with differing levels of support. For example,
the key movement of external rotation, if found to be
Red flags reduced in the standing position, should also be assessed
• Mass, lump, constant pain? in the supine or lying position with the arm and trunk
- Possible tumour
• Red skin, fever, unwell? supported (FIG. 5). Similarly, assessing shoulder elevation
- Possible infection by lifting the arm overhead could be compared with
• Trauma and pain and gross weakness? lowering the head and trunk below a supported arm.
- Possible fracture or cuff tear
• Trauma or seizure and pain and loss of A noticeable disparity in ROM is more likely to represent
movement? kinesiophobia and movement inhibition as opposed to
- Possible dislocation true capsular restriction.
As capsular tissue is non-contractile, isometric mus-
cle testing in the mid-range of movements should elicit
Does it hurt to move the neck or shoulder? little pain provocation in patients with FS (FIG. 5). This
can be a useful screening tool when considering other
diagnoses such as rotator cuff tendinopathy. Assessment
Neck Shoulder of the cervical spine is also essential to eliminate possi-
ble cervicogenic pathology such as nerve root irritation
Manage Any reports of instability? GHJ instability causing radicular pain.
Yes
accordingly • Dislocations or • Traumatic
subluxations • Atraumatic Imaging. The acquisition of plain radiographs of the gle-
• Feelings of apprehension
nohumeral joint is often suggested to ensure that there
No Frozen shoulder are not substantial degenerative joint changes that could
• Common age 35–65 years
Is there a substantial
or
also present with pain and motion loss and, therefore,
loss of passive external Yes
rotation compared with GHJ osteoarthritis confound the diagnosis of FS. However, in practice,
the other arm? • Common age >60 years a working diagnosis can often be made on the basis
No of a good medical history and simple clinical examina-
tion, with plain radiographs not necessarily required
Is there a painful arc of Subacromial pain
movement through Yes • Rotator cuff pathology in primary care environments77. It has been suggested
elevation or pain on - Tendinopathy that routine radiography may not confer superior accu-
resistance testing? - Calcific deposit racy in diagnosing serious pathology to good clinical
- Degenerative tear
No • Bursitis questioning and physical examination78.
• Long head of biceps The use of advanced imaging modalities such as ultra-
Is there localized pain over • SLAP lesions
sonography and MRI to diagnose FS has been proposed.
the ACJ and on
movements above Findings such as axillary capsule thickening and/or oblit-
shoulder height and/or Yes ACJ pathology eration of the axillary recess, coracohumeral ligament
horizontal abduction? • Common age >30 years
and rotator interval thickening, and/or hypervascularity
are considered indicative of FS pathology if the imag-
Fig. 4 | Proposed algorithm for differential diagnosis of frozen shoulder. This algorithm
may aid in differentiating frozen shoulder from other painful and/or motion-limiting ing results match the clinical presentation79,80. Indeed,
conditions of the shoulder, such as glenohumeral joint (GHJ) osteoarthritis, subacromial pain advanced imaging in patients with refractory FS can
and acromioclavicular joint (ACJ) pathology. Decisions are made based predominantly on be extremely important in detecting undiagnosed soft
physical examination (loss of passive external rotation) but other techniques and methods tissue tumours, although these undiagnosed tumours
also provide useful diagnostic information. SLAP, superior labrum from anterior to posterior. are present in fewer than 1% of patients with FS 76.
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Planes of movement of the shoulder joint
Abduction and adduction Flexion and extension
Abduction Flexion
Adduction Extension
Horizontal abduction and adduction Internal and external rotation
Internal External
rotation rotation
Horizontal
adduction
(flexion)
External Internal
rotation rotation
Horizontal
abduction
(extension)
Fig. 5 | Key examination techniques for frozen shoulder. Various movements of the arm of the affected shoulder are
used to assess pain and limitations of range of motion in individuals with frozen shoulder.
However, imaging does not offer superior diagnostic approach to this disease that does not consider the
information beyond a medical history and physical heterogeneity of individuals with FS.
examination and is therefore not recommended for As discussed above, FS has been associated with
routine work-up81; however, MRI may be useful if there myriad systemic diseases, such as diabetes mellitus,
is a clinical suspicion of another serious pathology with cardiovascular disease and thyroid disorders. Although
similar symptomology to FS. robust evidence of a causal relationship between these
conditions and the development of FS is lacking, there
Screening and prevention are theories regarding the potential mechanisms that
With new research and the associated understanding might underlie an increased risk of developing FS.
of the complex pathophysiology of FS, it is increasingly These conditions are associated with chronic low-grade
apparent that the lack of clarity surrounding the diagno- inflammation19, which has no mechanism of injury and
sis of FS is, in part, due to a historically oversimplified is marked by elevated levels of active pro-inflammatory
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cytokines but the absence of the increased neutrophil Non-operative management

abundance associated with acute inflammation82. The There is consensus that non- operative manage-
influence of hyperglycaemia on the risk of developing ment is the initial treatment of choice for FS98. Many
FS is mediated by pro-inflammatory cytokines, which non-operative management strategies have been sug-
are elevated in the capsule and synovium of patients gested for use in patients with FS. One of the reasons
with FS 83. Raised levels of serum cholesterol and for this is that patients present with a wide array of
pro-inflammatory lipoproteins have also been detected symptoms and varied levels of disability, which may
in FS and are risk factors for cardiovascular disorders64. relate to disease stage. Consequently, it is suggested that
Thyroid- stimulating hormone levels also seem to be a treatment intervention suitable for the disease stage
correlated with the severity of FS15. and pain level of the patient be adopted, and there is
Routine haematological analyses and blood bio- growing evidence for the value of this approach99,100. In
chemical tests to assess for the presence of inflamma- addition, as patients with FS often have high pain levels
tory or metabolic markers are not routinely performed and functional limitation in combination with a long
in patients with FS. Although these markers have been duration of symptoms, they are often motivated to try
shown to be risk factors, their prevalence across the FS every possible intervention that might help them. As
population and the impact they may have on disease tra- symptoms may improve with time in a large proportion
jectory and their relation to causal mechanisms remains of those with FS, it is easy to consider the intervention
unknown. as the reason for improvement, when in fact this may
A process that has received little attention to date not be the case.
is the role of chronic or persistent pain. Chronic pain is
now viewed as a long-term condition in its own right Patient education. Informing the patient about FS and
and has been identified as a global health priority46,84. discussing the natural history is one of the most impor-
Central pain mechanisms are known to be present in tant initial interventions. The mysterious and uncertain
long- standing shoulder pain and could potentially nature of FS can be worrisome and perplexing. Good
play a greater role in FS than previously considered85,86. advice and education reduces patient anxiety and results
Chronic pain could be compounded by low self-efficacy, in subjective improvement of symptoms101; therefore,
pain perceptions and health behaviours such as fear clearly explaining the evidence-based knowledge of FS
avoidance and kinesiophobia, which can be associated natural history, such as expected duration, can have sub-
with poor outcomes87. stantial effects on pain and function. It is important to
Individuals with traits of anxiety and depression inform patients of the options available to manage FS
might be at higher risk of a longer duration of symp- themselves and to give them simple and clear strategies
toms and a poorer prognosis88. The independent FS risk to modify their occupational or recreational activities as
factors smoking and obesity have the potential to further required. It is therefore paramount that all health-care
exacerbate levels of disability, as their presence, along providers provide the same message to reduce confu-
with sleep deprivation, lower pain thresholds89–93. sion, contradiction and negative stress factors. Another
Individuals with recalcitrant symptoms in whom important factor in patient education is noting the
traditional, mechanically driven treatments have been response to interventions or activity, which differs for
unsuccessful often require multispecialty, multimodal each stage; for example, in early FS, no increase in pain
input to address the complex physical, emotional and inflammation should be allowed, whereas in the
and social dimensions that are the consequences of middle and late stages, 24 h of pain increase could be
chronic pain conditions. Like screening for existing allowed102.
co-morbidities, validated screening measures for dimen-
sions such as fear avoidance beliefs, pain self-efficacy, Physiotherapy. Physiotherapy provides accelerated pain
sleep disturbance and mood are not routinely used in relief 103 and/or improvement in ROM33,103–105 compared
this cohort of patients94–97. Further research in this area with no treatment. However, these improvements are
is needed to determine whether such screening tools mostly short-term, without a demonstrated reduction
would be of value when determining individual patient in disease duration. It is suggested that the level of irri-
treatments and likely outcomes. tability of the patient be used to define the appropriate
intensity of the chosen management strategy102,106,107.
Management Irritability levels are mainly based on the intensity of
The pathogenesis of FS remains incompletely under- pain. For example, in patients with high irritability (pain
stood. It is therefore unsurprising that well- defined, level at least 7 out of 10), the intervention should be at
evidence- based management guidelines are lacking. an intensity that does not induce extra pain, while in
In general, a patient with FS can seek non- surgical patients with moderate irritability (pain level 4–6 out
treatments, such as physiotherapy, medications and cor- of 10) the intervention will increase in duration and
ticosteroid injections (CSIs), or more invasive options, intensity, and in patients with low irritability (pain <3 out
such as surgical interventions. Whether disease duration of 10) increased duration stretches will be possible, with
can be influenced by treatment, and the efficacy of each allowance for some pain or discomfort108.
intervention, is unclear, as the evidence for most inter- Several mobilization and stretching techniques
ventions is mixed33. Therefore, current treatment of FS (for example, four-direction shoulder stretching109 and
focuses primarily on symptom reduction; that is, pain inferior capsular stretching110) are effective in early
relief and restoring mobility and function. and late stages of FS for pain relief 111,112 and can be
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recommended for increasing ROM and function102,106. outcomes than oral prednisolone. A systematic review
One of the proposed mechanisms that might explain pain of 20 randomized controlled trials found some evidence
reduction in patients with FS involves the sensory input in favour of ESWT for reduction of pain in FS, although
that activates the endogenous pain inhibitory systems113. the authors of the review highlighted issues around the
Further study is clearly warranted to determine if endog- quality of evidence and were unable to perform a meta-
enous pain inhibitory systems are indeed involved in analysis. For now, definitive conclusions about the
manual therapeutic interventions around the shoul- efficacy of ESWT as an adjunct to treatment in FS cannot
der. However, in patients with FS who are in their first be drawn128.
high irritability stage, the use of passive mobilization or Other physiotherapy modalities, such as cold, heat,
capsular stretching can be counterproductive and can electrical modalities such as transcutaneous nerve
even increase the inflammatory response114. However, stimulation, pulsed electromagnetic field therapy and
a study comparing a combination of manual mobiliza- low-level laser therapy, have been suggested to have posi-
tions and shoulder exercises to a glucocorticoid injec- tive effects on pain in patients with FS. However, as these
tion found that the physiotherapeutic combination modalities are typically applied as adjunctive interven-
probably results in less improvement in the short term tions, the individual effect of each technique on the natu-
but a similar number of adverse events115, although ral course of FS is difficult to define. Consequently, there
no clinically important differences were noted at is only weak evidence in favour of techniques such as
6 and 12 months. Other mobilization techniques, such shockwave therapy, shortwave diathermy, pulsed electro-
as Codman’s pendulum exercises (passive mobili- magnetic field therapy, low-level laser therapy, therapeu-
zation of the shoulder while bent over), do not result tic ultrasound and electrical stimulation in reducing pain
in a substantial difference in pain or ROM116 com- and improving shoulder ROM in patients with FS106,129.
pared with other techniques. Unfortunately, there is Mirror therapy is a promising mode of exercise ther-
insufficient evidence to quantify the ideal frequency apy that seems to be effective in the treatment of FS. This
of mobilization. The intensity of stretching exercises approach aims to restore the congruence between motor
should be determined by the patient’s irritability level, output and sensory output130 and has been beneficial in
as stretching beyond painful limits in a highly irritable patients with FS for improving pain, function, ROM
patient results in poorer outcomes102,106. In addition in flexion and abduction and general health, although
to a patient’s irritability level, the total end range time further research is needed131.
(TERT) can be used to report the dose applied to Besides exercises that specifically target the shoulder,
the patient and evaluate progression117. TERT is the general physical activity is recommended for general
total amount of time that the joint is positioned at its health, well-being102, improving mood and sleep132, and
end range and is proportional to the increase in pas- the prevention of depression132. Physical activity can help
sive ROM118. The importance of the right treatment to reduce or reverse the effects of a sedentary lifestyle,
intensity is highlighted again by a prospective study which is often associated with an increase in chronic
that compared intensive passive stretching and manual low-grade inflammation and the development of insulin
mobilization to supportive therapy and exercises within resistance133.
the pain limits, which demonstrated better shoulder
function in the supportive group at the end of the Pharmacotherapy. Common medications for patients
2-year follow-up period119. However, currently there is with FS include paracetamol or acetaminophen, NSAIDs
little evidence to support joint mobilizations over other and corticosteroids. The evidence for the use of par-
non-operative interventions106. As such, the exact effects acetamol in patients with FS is limited, but it may be
of exercises, the extent to which they are effective, and useful when there are contraindications to the use of
the format of exercise therapy that is the most effec- other medications134–136. Paracetamol inhibits cycloox-
tive are uncertain105. Preliminary evidence shows that ygenase and is active both peripherally and centrally. FS
supervised exercise therapy is more effective than has been shown to be an inflammatory process followed
unsupervised exercise therapy at home120. by fibrosis, and therefore theoretically NSAIDs should
Resistance-based exercise may also have an impor- be more effective in the early inflammatory stage than
tant role in patients with FS, although this approach has in the later fibrotic stage12. However, this has not yet
been poorly researched. The addition of strengthening been shown clinically. NSAIDs might be used for pain
exercises to a multimodal programme with mobilization relief, but do not have an effect on ROM33. In addition,
and electrostimulation seems to result in improvements NSAIDs influence the serotonergic system, which may
in pain, ROM, function and muscle strength121,122. These provide some benefit in modulating perceived pain
improvements were not seen with the addition of scap- in addition to their direct anti-inflammatory effect134.
ulothoracic exercises, mobilization and electromagnetic Oral corticosteroids provide quicker pain relief com-
therapy to a similar multimodal programme123–125. pared with placebo, but this effect has not been seen
The role of ESWT has been investigated in the in the long term, and in some cases this treatment can
treatment of FS. In a randomized, double-blind, exacerbate symptoms owing to rebound pain after their
placebo-controlled trial comparing radial ESWT to pla- discontinuation33,99,111,112.
cebo shockwave therapy in 106 participants126, substantial Intra-articular CSIs are recommended in the inflam-
improvement in function, pain and ROM occurred in the matory or early stages of FS, before the emergence of
group who received shockwave. In a trial in patients with capsular contraction, to provide pain relief and reduce
primary FS127, focused ESWT produced superior pain inflammation 137–140. Histologically, intra-articular
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CSIs have been associated with decreased fibrosis in a rat model of FS revealed less fibrosis with CCH
proliferation140. CSIs are more effective than placebo, injection than with CSI or saline160. These data support
but do not change long-term (6-month and 12-month) a potential role for CCH in the management of FS.
outcomes 141. CSIs are more effective than physi- In conclusion, while many interventions have been
cal therapy in decreasing pain in the early stages of described, the most reliable benefits are from steroid
FS33,99,111,112,142, but the difference is minimal in the long injection and NSAIDs in stage I FS, physiotherapy in
term103. CSI alone has no effect on ROM but a combina- stage II–III FS, and advancement of physiotherapy to
tion of CSI and physiotherapy improves ROM111. In gen- mirror or resistance exercises in stage III FS (TABLE 1).
eral, CSI in early stage (stage I or II) FS results in greater
improvement in pain and function than in late (stage III Operative management
or IV) FS 143. Although the risks are low, there are After ruling out other causes of pain and stiffness of the
potential complications with the use of intra-articular shoulder, the patient should be informed that the natural
CSI, including avascular necrosis, infection, muscle history of the condition is eventual resolution in most
complaints and pain increase144–146. Intra-articular CSI patients. However, symptoms and disability persist in
can also lead to a transient increase in serum glucose, some patients, and surgical management may provide
which may be relevant in patients with FS who have a faster, more complete recovery. The aim of surgical
diabetes. approaches in FS is to release the fibrous, thickened
and tightened glenohumeral joint capsule and asso-
Alternative interventions. There are limited and mixed ciated contracted ligaments to improve ROM of the
data for several other interventions, including sodium glenohumeral joint, and to decrease pain.
hyaluronate injection147,148, suprascapular nerve block149,150,
collagenase treatment 151, botulinum toxin 152 and MUA. The aim of MUA is to stretch the shoulder joint
hydrodilation153,154 for use in FS, with the most supporting capsule and thereby improve ROM. In an anaesthetized
evidence for botulinum toxin and hydrodilation. shoulder, the procedure involves applying a passive
Hydrodilation therapy refers to intra-articular injec- stretch to the glenohumeral joint, in all shoulder ROM
tion of a large volume of sterile saline with or without directions. There are conflicting opinions as to the ideal
corticosteroid to distend the capsule. Hydrodilation time to perform MUA in patients with idiopathic FS,
therapy is a promising intervention that has gained from as soon as FS is diagnosed161,162 to up to 12 months
popularity over the past 10 years155–157. A meta-analysis after failed non-operative treatment1,100,163. Several stud-
found that both CSI and hydrodilation with corticos- ies have cited improved outcomes from MUA in more
teroids provide superior short-term pain relief, ROM than 80% of patients112,162,164–166.
improvement and function compared with placebo, with
ROM improvements persisting to beyond 24 months157. ACR with or without MUA manipulation. ACR involves
Hydrodilation with corticosteroids was found to have a cutting and removing the thickened, swollen, inflamed
greater benefit than CSI158. abnormal capsule under direct arthroscopic con-
Following its successful use in Dupuytren disease, trol. ACR is a safe and effective modality in treating
collagenase clostridium histolyticum (CCH) has also FS163,164,167–171 and may offer distinct advantages when
been utilized to treat FS. CCH is typically given as a series compared with other methods of treatment. For exam-
of three injections over 6 weeks. A randomized study ple, direct visualization of the affected joint allows diag-
showed improvement in subjective function with CCH nostic confirmation and enables additional pathology to
but no notable increase in ROM compared with be ruled out. The effectiveness of ACR has been demon-
placebo159. Another study found a greater improvement strated in multiple studies, with a dramatic reduction in
in ROM at 3 months with CCH than with exercise ther- pain scores, increased ROM as well as overall increased
apy alone151. Histological examination of capsular tissue shoulder function169–173.
Comparison of ACR and MUA. UK FROST174 is the larg-

Table 1 | Treatment approaches for frozen shoulder based on stage of the
condition est multicentre randomized trial in FS, which compared
early structured physiotherapy116, MUA and ACR. Early
Stage Characteristics Treatment approaches structured physiotherapy and post-procedural physio-
Pharmacological Physical Other adjuncts therapy programmes were standardized at 12 sessions
I Inflammation NSAIDs Home exercises Patient education over 12 weeks. At the 12- month primary end point,
CSI Hydrodilation most participants had improved to near full function,
as determined by the Oxford Shoulder Score (43 out
TENS
of 48), a quality of life outcome score. Oxford Shoulder
II Freezing and NSAIDs Physiotherapy: Patient education Scores were significantly higher in the ACR group than
frozen mobilization in the MUA and early structured physiotherapy groups
Hydrodilation
Shockwave therapy (P < 0.01), and were higher in the MUA group than in
the early structured physiotherapy group. Economic
III Thawing NA Physiotherapy: Surgical manage-
resistance-based ment if symptoms analysis in the UK FROST study174 showed that MUA
do not dissipate is more costly (£276) and ACR is substantially more
CSI, corticosteroid injection; NA, not applicable; TENS, transcutaneous electrical nerve costly (£1,734) than early structured physiotherapy.
stimulation. All three treatments led to substantial patient recovery,
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with no clear superiority for any approach. ACR resulted Outlook

in patients requiring the least amount of further treat- Research in recent decades has improved our under-
ment, but was the most expensive, and was associated standing of known risk factors and disease progression,
with higher risks, suggesting it should only be utilized and, importantly, insights into the basic mechanisms
when less- costly and less- invasive interventions fail. driving the disease process, with the potential for new
Early structured physiotherapy was accessed faster, but therapeutic targets. Despite affecting 5% of the world’s
more patients required further treatment. population164, research into FS lags behind that of other
In summary, the surgical options of MUA and ACR musculoskeletal conditions, and integration of new find-
may provide an earlier, potentially more complete ings into a comprehensive treatment strategy that can be
resolution of pain and restoration of ROM and func- applied across the spectrum of disease (from early-stage
tion, although these interventions should be considered through to late-stage disease) and medical practition-
only after non-operative management approaches have ers (physiotherapists, primary care physicians and sur-
failed. geons) remains elusive. Of note, emerging basic science
research needs to be assimilated into clinical practice
Quality of life to provide clinicians with a picture of the principal
FS results in significant functional disability and reduc- pathophysiological processes involved in FS.
tion in quality of life, as shown using various question-
naires and scores, such as the visual analogue scale, Physiotherapy advances
disabilities of the arm, shoulder and hand (DASH) The component of physiotherapy that includes mobili-
score, the 36-item Short-Form (SF-36) health survey, zation techniques beyond the threshold of pain in early
and the Hamilton depression rating scale and anxiety disease can be detrimental to patient engagement and is
scores87. It is not clear what factors predict the severity explained by the unique mechanosensitive properties of
of pain and disability as well as quality of life in patients fibroblasts and the fact that the inflammatory response
with FS175. The prolonged disease course in FS results makes fibroblasts more sensitive to progressive mechan-
in greatly impaired sleep and everyday activities and, ical stress119. However, progressive stretching exercises
therefore, markedly affects the physical, psychological up to tolerable pain levels results in an increase in the
and social quality of life of patients175–177. FS has been MMP to TIMP ratio, thus favouring collagen remodel-
linked to anxiety and depression177. Co-morbidities are ling, and importantly is superior to supervised neglect179.
associated with increased disability and reduced quality Therefore, some mechanical stress is advantageous in
of life in these patients but not with the severity of pain. promoting remodelling of the ECM, especially in the
Psychiatric disorders can also affect pain, disability and later stage of the condition. Thus, further research is
quality of life as well as patients’ characteristic and objec- required on the role of precision ‘tailored’ physiotherapy
tive symptoms178, but the effect of these parameters on guidelines for the treatment of FS.
FS requires further study.
The patient’s perspective and experience has been Translational advances
largely overlooked in FS research. This is startling, Novel bench to bedside treatment strategies have been
particularly when considering the vast numbers affected suggested for intervening in the inflammation–fibrosis
by this condition and the subsequent health-care cost, cascade in different ways. Given the dominant role of
and the implications of long- term symptoms and the TGFβ pathway in FS, gene silencing (with small
reduced quality of life as a result of FS. A study101 explor- interfering RNAs) was utilized to knockdown Smad4
ing patients’ perceptions of FS treatment highlighted (a central mediator of TGFβ signalling) in a rat model
the severe pain and loss of function that impacted their of FS induced by immobilization180. Suppression of the
daily life, alongside sleep disturbance and inability to TGFβ pathway impaired the inflammatory response
perform work duties. Delay in diagnosis was a cause of and myofibroblast differentiation and resulted in bet-
frustration and worry for the patients interviewed, as the ter shoulder ROM and an increased joint volume in
severity of pain often led patients to suspect that there a rodent model of FS compared with control rats. In a
might be a more sinister cause of their pain. Patients also placebo-controlled, double-blind, randomized trial, the
highlighted a lack of a definitive diagnosis alongside thyroid hormone calcitonin (delivered by nasal spray)
unclear pathways for management of their condition was moderately efficacious in improving pain and func-
and emphasized a mismatch between their perception of tional outcomes in FS68. Another study found an asso-
the impact of FS and that of the clinician. Although only ciation between expression of alarmins (such as IL-33,
involving a small number of patients, this study stresses IL-17A and HMGB1) and pain levels45, highlighting a
the need for a better understanding of FS, for both cli- potential role for anti-cytokine therapies in treating FS;
nicians and patients. To improve a patient’s experience however, additional preclinical work is required before
with FS, a prompt diagnosis, a clear understanding of progressing towards potential first-in-human trials in FS.
the treatment options available and an explanation of the
course of this painful condition are priorities. Aligning Clinical advances
treatment goals with those of patients suffering with FS Clinically, knowledge about pain management and
should underpin clinicians’ interaction with patients the association between pain and other psychological
who present with FS and future research into this con- disorders, such as depression and anxiety, is expand-
dition. Clearly, the patient’s voice has not been heard ing. In addition, the central element of night pain in
enough in studies thus far. FS has a major impact on patients’ overall well- being
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owing to interruption of sleep, and the emotional and avoidable risk factors involved. Population health mes-
societal implications of these factors are not well under- sages delivered consistently by health-care professionals
stood. These issues may play an important role in the across all sectors should be considered core tenets within
management of FS in the future as these associations musculoskeletal care. This should include an honest and
are clarified. open, yet compassionate, discussion and acknowledge-
The lack of well-conducted prospective longitudinal ment that it may take weeks, months or years for the
studies to adequately investigate prognostic risk factors benefits of lifestyle changes to make any demonstrable
for FS is a barrier to furthering our understanding of impact on patient outcomes186.
this pathology. Although none of the risk factors dis- Clinical trials in FS remain challenging, with incon-
cussed earlier are known to have a direct causative sistencies in outcome measures, heterogeneity of patient
role, their high prevalence in the FS population indi- stage at recruitment and the requirement for prolonged
cates that reducing or improving them would be useful. follow-up. Although advances have been made towards
Therefore, clear, simple and actionable health promotion a consensus in terms of a core set of outcome domains
advice regarding smoking cessation, physical activity, for use in trials in shoulder disorders187, several impor-
stress and sleep levels, diet and weight management is tant issues need to be addressed, including heteroge-
recommended. Even slight increases in physical activity neity in study design, stage-specific or patient-specific
and exercise can substantially reduce the relative risks treatment protocols, and how we classify response to
of both morbidity and mortality associated with many of any treatment regimen — specifically those altering
the proposed risk factors for FS181. Increasing walking specific physiotherapy regimes. Further research is now
time to just 2 h a week significantly reduces the risk of required to link the genetic, epigenetic, environmental
cardiovascular disease in individuals with diabetes182 and therapeutic factors together so that curative or pre-
and both aerobic and resistance-based exercise demon- ventive therapies for FS can be obtained. These findings
strably reduces morbidity risk183–185. In the near future, should give impetus to the development of new diag-
‘frozen shoulder’ could be considered an umbrella term nostic techniques, evidence-based screening methods
for emerging subgroups of this pathology, each with its and more targeted personalized interventions, which
own aetiology, disease progression, prognosis and man- underscore the need for a multidisciplinary approach to
agement strategies. While novel therapeutic modalities the management of FS.
to treat FS are evolving, there should also perhaps be
a concomitant focus on preventing the important and Published online xx xx xxxx
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PRIMER

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 1

Author addresses disease26. Furthermore, FS, as identified by shoulder

2 | Article citation ID: (2022) 8:59 www.nature.com/nrdp

Deltoid muscle Scapula

b Early-stage frozen shoulder

c Late-stage frozen shoulder

Articular capsule thickening

Fibroplasia, some immune

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 3

4 | Article citation ID: (2022) 8:59 www.nature.com/nrdp

Stage I Stage II Stage III

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 5

Pro-inﬂammatory and pro-ﬁbrotic

setting of long-term hyperglycaemia59. In addition, FS expression is in the peroxisome proliferator-activated

6 | Article citation ID: (2022) 8:59 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 7

Planes of movement of the shoulder joint

Abduction and adduction Flexion and extension

Horizontal abduction and adduction Internal and external rotation

8 | Article citation ID: (2022) 8:59 www.nature.com/nrdp

cytokines but the absence of the increased neutrophil Non-operative management

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 9

10 | Article citation ID: (2022) 8:59 www.nature.com/nrdp

Comparison of ACR and MUA. UK FROST174 is the larg-

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 11

with no clear superiority for any approach. ACR resulted Outlook

12 | Article citation ID: (2022) 8:59 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 13

14 | Article citation ID: (2022) 8:59 www.nature.com/nrdp

NATURE REVIEWS | DISEASE PRIMERS | Article citation ID: (2022) 8:59 15

16 | Article citation ID: (2022) 8:59 www.nature.com/nrdp

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