Best Practice & Research Clinical Rheumatology 37 (2023) 101837

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Best Practice & Research Clinical

Rheumatology
journal homepage: www.elsevierhealth.com/berh

Lacrimal and salivary gland ultrasound - how

and when to use in patients with primary
€ gren's syndrome
Sjo
Viktoria Fana a, Lene Terslev a, b, *
a
Center for Rheumatology and Spine Diseases, Copenhagen Center for Arthritis Research, Rigshospitalet,
Copenhagen, Denmark
b
Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

a b s t r a c t
Keywords:
€gren's syndrome
Sjo This paper addresses how to perform an ultrasound assessment of
Ultrasound the salivary and lacrimal glands, how to identify pathological
Diagnosis changes, and how to score disease activity, focusing on the use for
Scoring primary Sjo € gren's syndrome (pSS). It addresses the role of salivary
Differential diagnosis gland ultrasound for diagnosing and management of patients with
Biopsy
pSS and touches upon the use for differential diagnosis, including
how and when to perform ultrasound-guided biopsies and
injections.
© 2023 The Author(s). Published by Elsevier Ltd. This is an open
access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).

Introduction

€gren's syndrome (SS) is a chronic, systemic, autoimmune disease characterized by immune-

Sjo
mediated destruction of the exocrine glands, systemic B-cell hyperactivation, and activation of in-
flammatory cells e affecting especially salivary and lacrimal glands [1]. Patients with SS have one of the
highest risks of lymphoproliferative disease as compared to patients with other autoimmune diseases
[2]. The dominating symptoms are dry mouth and/or dry eyes, in combination with extra-glandular
symptoms such as arthritis, arthralgia, and fatigue. A limited part of the patients may have concomi-
tant severe systemic involvement affecting the pulmonary, neurological, dermatological, renal, and

* Corresponding author. Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark

E-mail addresses: viktoria.fana.01@regionh.dk (V. Fana), lene.terslev.01@regionh.dk (L. Terslev).

https://doi.org/10.1016/j.berh.2023.101837
1521-6942/© 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY license (http://
creativecommons.org/licenses/by/4.0/).
V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

hematological systems. SS can occur in the absence of other systemic diseases, primary SS (pSS), or as
part of an underlying autoimmune tissue disease, secondary SS (sSS). The focus of the paper is solely on
pSS.

Epidemiology

The reported estimated incidence and prevalence of pSS differ greatly between studies as different
classification criteria for pSS are applied. This is illustrated by Qin et al. [3] where the pooled prevalence
rates in studies that applied the 1993 European Classification Criteria for pSS were reported to be
12fold higher than the pooled prevalence rates found in studies that applied the 2002 AECG classifi-
cation criteria for pSS. They therefore conducted a systematic literature review and performed a meta-
analysis based on 21 studies and estimated the prevalence of pSS in the total population to be 60.82
(95%CI 43.69 to 77.94) cases per 100.000 individuals and the pooled incidence ratio for pSS is estimated
to be 6.92 (05% CI 4.98 to 8.86) per 100.000 individuals per year. The meta-analysis provides insight
into the global incidence and prevalence rates, but the “true” prevalence and incidence are difficult to
estimate as it varies between countries [3].
The median age at time of diagnosis was reported to be 53 years of age in the 2 Big Data studies
[4e6] but varies also between countries. European cohorts of patients with pSS have a higher debut age
than non-European patients and lower in Asian than in Western populations [7e11].
All studies conducted on the incidence and prevalence of pSS have shown a very skewed gender
ratio with females having a predisposition for pSS. The Big Data Google-driven study found the female:
male prevalence to be 10:1 [6], whereas the Big Data Sjogren Project Consortium found the female:
male prevalence somewhat higher - 14:1 [5]. However, the gender ratio varies from country to country
with the highest ratio reported being 27:1 in China [7].

How to diagnose and classify patients with pSS

There are no diagnostic criteria for pSS and the diagnosis may be challenging. It is based on a
constellation of subjective symptoms, such as i.e., dry mouth and dry eyes, and clinical, serological,
histological, and functional parameters reflecting the salivary and lacrimal gland involvement. Among
the strongest indicators of pSS is the presence of autoantibodies (antieSS-A/Ro), and/or lymphocytic
infiltration on labial salivary gland biopsy but also functional tests, such as sialometry and Schirmer's
test, provide valuable information.
The heterogeneity of signs and symptoms in patients with pSS has led to the development of
classification criteria to ensure comparability between different cohorts of patients in research studies.
The first classification criteria for pSS published was the Copenhagen criteria, presented in 1986 [12]
followed by the European community classification criteria in 1993 [13] and then the American-
European Consensus group Criteria (AECG) in 2002 [14], which were revised in 2016 and renamed
the ACR/EULAR classification criteria [15] - see Table 1. In contrast to previously suggested criteria the
new criteria focused on more objective disease criteria but none of the classification criteria involve
imaging techniques.
Though salivary gland biopsy has a high specificity and positive predictive value for pSS the
sensitivity is variable with significant discrepancies in the histological evaluation [16,17]. Similarly, the
functional tests have low specificity for pSS. There is therefore an interest in other, non-invasive and
reliable diagnostic methods that can aid in the diagnosis of pSS and the focus has been on the value of
salivary gland ultrasound (SGUS) [18e20].

Anatomy of the salivary and lacrimal glands

Anatomical knowledge of glands is important for the ultrasound (US) examination and assessment
of potential pathology. Both the salivary and lacrimal glands may be affected in pSS. The following is a
short description of the anatomy of the 2 gland types.

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

Table 1
ACR/EULAR criteria The entry criterium for the classification criteria is at least one symptom of ocular or oral dryness,
which cannot be explained by other conditions. A score
4 means that the patient can be classified as having primary
€ gren's Syndrome.
Sjo

Item Score

Labial salivary gland biopsy with focal lymphocytic sialadenitis and focus score
1 3
Anti-SSA (anti-Ro) positive 3
Positive ocular staining score (
5 (or van Bijsterfeld score
4)) in at least one eye 1
Positive Schirmer's test (5 mm/5min) in at least one eye 1
Unstimulated whole saliva flow rate 0.1 ml/min 1

The salivary glands

There are 3 main pairs of major salivary glands, located outside the oral cavity, and numerous
(600e1000) minor salivary glands, located in the mucous membranes of the oral cavity [21]. They
produce and secrete saliva into the oral cavity and the volume may range between 0.5 and 1.5 L [22].
The major salivary glands produce most of the saliva, while the minor salivary glands contribute to
about 0,8% of the total salivary production. The saliva lubricates the oral cavity to enable talking, eating,
tasting, swallowing, and initiating degustation (a-amylase, lipase). Saliva maintains oral health by oral
clearance, tooth mineralization (bicarbonate, phosphate, protein), salivary pellicle formation (pro-
teins), antimicrobial action (mucin, histains, cystatins, proteins, peroxidases, a-amylase, immuno-
globulin), and tissue repair (growth factor, water, mucin) [21].
Because the sublingual gland is too small in size to allow proper assessment by ultrasound, only the
parotid and submandibular gland is described in the following [23].

The parotid gland

The parotid gland is the largest of the major salivary glands, weighing 14e30 g, and produces 26% of
the total saliva production. It is pyramid-shaped and measures 5.8 cm craniocaudal, and 3.4 cm ven-
trodorsally. The gland is located in the retromandibular fossa. The superior border of the gland is the
zygomatic arch, the posterior border is an external acoustic canal and sternocleidomastoid muscle, and
the anterior border is masseter muscle and sternocleidomastoid muscle.
The parotid gland consists of a superficial lobe which accounts for approximately 80% of total gland
volume, and a deep lobe which represents a very small portion of the gland. The superficial and deep
parts of the parotid gland are in close proximity to the facial nerve.
The parotid gland receives its blood supply from the superficial temporal artery, maxillary artery,
and transverse facial artery branches of the external carotid artery. Venous drainage occurs through
retromandibular veins. The vessel may be seen by ultrasound. The parotid gland is the only salivary
gland that may contain lymph nodes and one to 2 lymph nodes are often seen primarily in the su-
perficial lobe [24].

The submandibular gland

The submandibular gland is the second largest major salivary gland and weighs 10e15 g and
produces 60e70% of saliva production. The submandibular gland lies in the submandibular trigonum
between the body of the mandible superiorly, the anterior belly of the digastric muscle medially, and
the posterior belly of the digastric muscle inferiorly. The submandibular gland is surrounded by a
capsule and consists of a superficial larger lobe and deep lobe - the 2 lobes are inter-sectioned by the
mylohyoid muscle.
A branch of the external carotid artery and the fascial artery provides the blood supply to the
submandibular gland and passes through the gland capsule before crossing the inferior border of the
mandible. Venous drainage occurs through the facial vein. Both artery and vein can be visualized by US
in a longitudinal view. Lymph nodes may be seen outside the gland close to the capsular border.

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

The lacrimal gland

The lacrimal gland is a parried almond-shaped gland for tear production and lies in the upper lateral
orbital region. The lacrimal gland consists of an orbital and a palpebral lobe with the orbital lobe being
approximately twice as large as the palpebral lobe. The lacrimal gland is responsible for about 90% of
the tear production and measures approximately 20  12  5 mm, while variable in size between
individuals. The lacrimal fluid ultimately drains through a series of ducts into the nasal cavity.
The lacrimal fluid is isotonic to plasma and contains immunologically active proteins, peptides, and
glycoproteins, including the antibacterial enzyme lysozyme. This lacrimal fluid lubricates, protects, and
provides nutrients to the conjunctiva and cornea.
The lacrimal glans is the only orbital structure, which contains mucosa-associated lymphoid tissue
(MALT) and produced IgA and IgG antibodies.
The lacrimal gland receives its blood supply from the lacrimal artery, a branch of the middle
meningeal artery. Venous drainage is via an orbital network connecting with the facial and ophthalmic
veins, that transverses the cavernous sinus.

How to identify the major salivary glands and lacrimal glands by ultrasound

Musculoskeletal US is a non-invasive, widely available, and inexpensive method to examine the

salivary glands and allows detection of parenchymal abnormalities related to pSS and may therefore
aid in the diagnosis of pSS [18e20] The normal salivary gland parenchyma is homogenous, comparable
to the thyroid gland parenchyma, with a well-defined border to the surrounding tissue, and increased
echogenicity to adjacent muscles.

Salivary glands

US examination of major salivary glands includes the assessment of the parotid and submandibular
glands. The US examination includes gland evaluation in the longitudinal and transverse plane with
the patient in a supine position with the neck hyperextended and the head turned to the opposite side
of the examination side.

Parotid gland
High-frequency probes allow visualization of the superficial lobe but for optimal evaluation of the
deeper lobe, a lower frequency is necessary. To identify the parotid gland in the longitudinal plane the
probe is placed parallel to the tragus of the ear (anatomical landmark) and then moved slowly ante-
riorly. For the deeper lobe the longitudinal plane is obtained by placing the probe with one end on the
angelus of the mandible and the other end on the mastoid process (anatomical landmarks) e see Fig. 1.
The transverse scan is obtained by turning the probe 90 and scanning the entire extent of the gland.
With the high frequency probes >20 MHz attempts have been made to identify the facial nerve inside
of the parotid gland where it runs lateral to the retromandibular vein and the external carotid artery
[25].

Submandibular gland
The submandibular gland lies in the submandibular trigonum between the body of the mandible
superiorly, the anterior belly of the digastric muscle medially, and the posterior belly of the digastric
muscle inferiorly. For identifying the gland place the probe over the mentis and move distal e the
digastricus muscle comes into view together with the mylohyoid muscle e moving further distal and
lateral the submandibular gland comes into view with the superficial part “resting” on the mylohyoid
muscle (anatomical landmark) - see Fig. 2. By sweeping the probe over the extent of the gland the
whole gland is examined and the transverse view is obtained by rotating the probe 90 . Further in-
formation on how to scan the glands can be found at: http://ultrasound.eular.org/#/app/explore.
The facial artery passes over and into the superior aspect of the gland and can be visualized in a
longitudinal view. Care should be taken to identify vessels before assessing pathology in the gland as

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

Fig. 1. Probe position and corresponding ultrasound image for the parotid gland. Image A shows the probe position for a
longitudinal assessment of the parotid gland with B as the corresponding ultrasound image. The * indicates the superficial lobe of
the gland and the white arrow a normal lymph node characterized by hypoechoic stroma and hyperechoic hilum. Image C is the
probe position for the deep lobe with one end of the probe on the mastoid process and the other on the angulus of the mandible.
Image D is the corresponding ultrasound image with Mastoid ¼ mastoid process, Angulus ¼ mandibular angle, and ** ¼ the deep
lobe of the gland.

vessels may mimic hypo/anechoic gland changes. The lymph nodes can be seen in the anterior part or
close to the gland but never inside a healthy gland.

Lacrimal glands

The patient is examined in a supine position and with their eyelids closed. The lacrimal gland is
located in the upper lateral region of the orbital region and may be found by placing the transducer
with one end on the lateral upper orbital bone (anatomical landmark) just below the lateral one-third
of the supraorbital margin. The lacrimal gland is seen between the orbital bone and the sclera as a small
hypoechoic, homogenous area [26] e see Fig. 3. It is recommended to use a high-frequency (>22 MHz)
hockey-stick probe for ultrasound assessment of lacrimal glands to ensure high enough resolution.

How to define and score pathology in the salivary and lacrimal glands with ultrasound in
patients with pSS

Salivary glands

The use of US for evaluation of the major salivary glands in patients with pSS was suggested more
than 30 years ago [27]. The pathological changes are related to changes in morphology and therefore
the use of B-mode is the primary US modality. The initial US features were glandular heterogeneity
with hypo/anechoic areas and hyperechoic bands. Since then, other SGUS abnormalities have been
proposed to be of relevance such as calcifications or aggregates in the glands, fatty infiltration, poorly
defined salivary gland borders, presence of intra- or peri-glandular lymph nodes, and enlargement or
atrophy of the glands [28].
There is a primary focus across studies on the heterogeneity of the glandular tissue, including at-
rophy [23,29,30].

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

Fig. 2. Probe position and corresponding ultrasound image for submandibular gland. Image A shows the probe position for a
longitudinal assessment of the submandibular gland with the probe just below the mentis bone. The white arrow indicates the
probe movement distal (image B and lateral image C) Image B shows the anatomical landmarks with the open arrows ¼ digastricus
muscles and the white arrowhead ¼ the mylohyoid muscle. In image C the probe moves laterally following the mylohyoid muscle
(white arrowhead). Image D shows the probe position over the submandibular gland and image E the corresponding ultrasound
image with * ¼ the superficial lobe and ** the deep lobe and white arrowhead ¼ the mylohyoid muscle. Image E shows the division
of the gland in the superficial and the deep lobe by the mylohyoid muscle.

Fig. 3. Probe position and corresponding ultrasound image for lacrimal gland. Image A shows the probe position for a longi-
tudinal assessment of the lacrimal gland with B as the corresponding ultrasound image. The * indicates the gland, B ¼ orbital bone,
and SCL ¼ sclerae.

Ultrasound for assessing disease severity

The first scoring system for assessing the degree of pathology in the salivary gland in patients with
pSS was introduced in 1992 [27], and since then several scoring systems have been developed. A recent
meta-analysis identified more than 30 different scoring systems [31]. The many available scoring
systems hampers the use of US as a research tool in patients with pSS and impacts the generalizability
of research findings. Therefore, the Outcome Measures in Rheumatology (OMERACT) ultrasound
working group developed and validated a grey-scale semi-quantitative consensus scoring system for
the major salivary glands focusing solely on the hypo/anechoic changes in the gland and eliminating
measurements of gland size and fatty infiltration [23,32]. The scoring system graded the lesions 0e3
where: grade 0 ¼ normal parenchyma; grade 1 ¼ mild inhomogeneity without anechoic or hypoechoic
areas and hyperechogenic bands; grade 2 ¼ moderate inhomogeneity with focal anechoic or hypo-
echoic areas; and grade 3 ¼ severe inhomogeneity with diffuse an- or hypoechoic areas occupying the
entire gland or a fibrous gland (pathology examples are seen in Fig. 4).

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

€ gren's Syndrome. Images A-C are from the submandibular gland and represent
Fig. 4. Examples of gland pathology in primary Sjo
examples of the OMERACT scoring system grades 1,2 and 3, respectively. Images D-F are from the parotid gland and represent
examples of OMERACT scoring system grades 1,2 and 3, respectively. Examples of grade 0 for the 2 glands can be seen in Figs. 1 and 2.

The OMERACT grey-scale scoring system was tested in video clips and in patients. In video clips, the
scoring system showed discriminant validity with an excellent intra-reader reliability (kappa ¼ 0.81)
and a good inter-reader reliability (kappa ¼ 0.66) [23]. When tested in patients, the reliability was
lower with intra-reader reliability that varied from moderate to excellent, better for the submandibular
gland than the parotid gland (kappa 0.44 to 1) and moderate inter-reader reliability (kappa o.62 for
both glands) [32]. In reliability exercises the reliability is always better in images than in patients as
these are selected based on high quality and clarity whereas other factors affect the scoring in patients
such as image acquisition technique and probe resolution but also patient factors such as facial hair and
tissue echogenicity. However, the first step was taken to ensure a greater degree of homogeneity in
future research work. An atlas has been developed showing 4 different examples for each grade for
each gland and is available online [33]. In the HarmoncSS study, the reliability of the OMERACT scoring
system was found to be even better and slightly better than the De Vita scoring system in less trained
hands [34].
Scoring the 4 salivary glands with US is a feasible method and takes approximately less than 10 min
[33].
The OMERACT ultrasound working group has subsequently developed and validated a consensus-
based semi-quantitative scoring system for Doppler activity in the gland (0e3) for evaluation of the
vascularization of major salivary glands. The system is defined as: Grade 0 ¼ no visible vascular signals;
Grade 1 ¼ focal, dispersed vascular signals; Grade 2 ¼ diffuse vascular signals detected in less than 50%
of the gland and Grade 3 ¼ diffuse vascular signals in more than 50% of the gland. Flow detected from
normal, anatomical vessels in the salivary glands is excluded from scoring. The scorings system when
tested in static images showed good inter-reader reliability and excellent intra-reader reliability with
kappa ¼ 0.90 and 0.80 respectively and when tested in patients the intra- and inter-reader reliability
was kappa ¼ 0.84 and 0.70, respectively [35].

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

Due to the presence of arteries and veins also in the normal gland (see anatomy section) it is
possible to detect Doppler activity in healthy glands and the detectable amount varies from patient to
patient and increases postprandially [35].
The role of scoring Doppler activity for diagnosing and managing patients with pSS has yet to be
determined.

Lacrimal glands

There is limited experience with scoring pathology in the lacrimal gland using US.
The US lesions in the lacrimal gland in patients with pSS have been reported as glandular paren-
chyma visibility (yes/no), glandular size (normal or increased), glandular parenchyma homogeneity
(homogenous or inhomogeneous), hypoechoic areas (absent or present), hyperechoic spots (absent or
present), fibrous gland appearance (absent or present), fatty deposition (absent or present) and these
features showed good to excellent intra and inter-rater reliability when assessed in static images [36].
Nevertheless, the dichotomous score is very subjective and insensitive to changes in morphology, and
more work is needed for developing a relevant scoring system for lacrimal gland pathology in these
patients with pSS.

How to apply ultrasound for the diagnosis of salivary glands and lacrimal glands

The role of US in the diagnostic set-up for pSS has been hampered by the different applied scorings
systems using different US cut-offs for pathology. In addition, studies have also applied different
classification criteria resulting in differences in the value of SGUS findings for fulfilling pSS classifi-
cation criteria with sensitivities ranging from 46 to 92% and specificities from 73 to 98% [37]. A recent
systemic review and meta-analysis based on 54 included studies showed that SGUS for the diagnosis of
pSS had a pooled sensitivity of 80% and a pooled specificity of 90%. The pooled positive and negative
likelihood ratio was 8 and 0.22, respectively, and as the diagnostic estimates were found to be robust to
sensitivity analyses by quality criteria, pSS diagnostic criteria, and US scoring systems, it suggests a
future role in the classification criteria [38]. This supports the existing knowledge from several studies
that have assessed the role of SGUS in the classification criteria. They have found that SGUS improves
the fulfillment of the ACR/EULAR classification criteria when given the same weight as other minor
items - increasing the sensitivity when using the clinical diagnosis as reference standard and without
compromising the specificity [39,40]. The improved performance of the ACR/EULAR classification
criteria could also be found if adding ultrasound as an item in the classification criteria but if replacing
the labial biopsy with SGUS the sensitivity and specificity decreased slightly suggesting that SGUS
should be included as an additional item rather than substituting another item in the classification
criteria [41,42].
But if SGUS cannot replace the salivary gland biopsy in the classification criteria, can it minimize the
need for invasive procedures such as labial biopsies? If it is possible to diagnose the patients based on
clinical, autoantibodies, and functional tests alone then neither SGUS nor labial biopsies are relevant.
However, recent studies have suggested that SGUS in combination with the presence or absence of
antibodies may indicate when labial biopsies are irrelevant. If both SGUS and anti-SSA/Ro antibodies
are compatible with pSS or when both SGUS and anti-SSA/Ro antibodies are not compatible with pSS,
then a salivary gland biopsy was not needed, and the patient could correctly be classified as having or
not having pSS [43,44] suggesting clinical relevance of SGUS in the diagnostic set up in routine care.
What constitutes a pathological score? There is a general agreement that a score
2 is indicative of
pathology when found in at least one gland independent of the applied scoring system [20,23,33,45,46].
The consensus-based OMERACT scoring system has shown a good sensitivity (0.70) and an excellent
specificity (0.94) for the diagnosis of pSS (fulfilling the ACR/EULAR classification criteria) when applying
a cut-off of score >2 in two glands with only minimal changes in the specificity if found in only one
gland. In addition, the scoring system had a high positive predictive value (PPV) and negative predictive
value (NPV) of 88% and 82%, respectively [33].

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

When assessing the agreement between SGUS findings and histology, one study reported SGUS to
have a PPV of 85% and an NPV of 96% for the histology results - with an overall concordance between
the ultrasound and the histology of 91% (Kappa ¼ 0.826) [47] as also reported in other studies [45,48].
Studies have found abnormal SGUS scores to be associated with the presence of SSa and/or SSb
autoantibodies in patients with pSS [43,49,50].
€ gren's Syndrome Disease Activity Index (ESSDAI)
Clinical disease activity scores are the EULAR Sjo
[51]containing measures of both disease activity and potential measures of tissue damage and where
low disease activity is an ESSDAI score <5. Another activity score is the EULAR Sjo € gren's Syndrome
Patient Reported Index (ESSPRI) [51] which scores the severity of patients' symptoms. The correlation
between the disease activity indices and abnormal SGUS are varying showing either a good correlation
or a lack of [20,49,52,53] e one potential explanation is the application of different scoring systems.
Another is that the composite index measures other aspects of the disease than mere gland pathology.

Other ultrasound techniques for pSS

Elastography is a US technique that measures the mechanical properties of the investigated tissue
by registering the response to acoustic energy thereby obtaining information on tissue stiffness.
Currently, available elastography techniques are categorized by the measured physical quantity and are
strain imaging and shear wave imaging. Both techniques have been applied in patients with pSS for
diagnostic purposes [54,55], but the role is unclear and will not be further addressed in this paper.

How to monitor pSS using ultrasound examination

To date, pSS is a challenging disorder, as the underlying pathophysiological mechanisms are not
fully understood, assessing disease activity is challenging, and there is currently no specific treatment
available to ensure disease control or improvement though several drugs are being tested in clinical
trials and others are in the pipeline.
The clinical measures for assessing disease activity are the ESSDAI for systemic activity [51] and the
ESSPRI for the severity of patients’ symptoms [56]. SGUS is another potential tool for assessing disease
activity and the consensus-based scoring system may be relevant for clinical trials [32].
SGUS has been used for assessing the potential treatment effect in patients with pSS when treated
with fx. rituximab or abatacept [57e59], but as the treatment effects have been doubtful [60] the role of
SGUS remains unclear. Currently, longitudinal studies are ongoing and may be able to provide infor-
mation on the role of SGUS for monitoring purposes (the REgistry of Sjo € gren's Syndrome LongiTudinal
(RESULT) cohort [52] and the HarmonicSS trial (https://www.harmonicss.eu) (2017e2020) and
NECESSITY trial (https://www.necessity-h2020.eu) (2019e2024).

Ultrasound for the stratification of patients with different phenotypes of pSS

Normal SGUS can be seen in patients with pSS fulfilling ACR/EULAR classification criteria and this
has led to investigating if this difference could be beneficial for identifying different phenotypes of pSS.
One study found that patients with pSS with positive SGUS were different in almost all aspects of the
disease as compared to the patients with pSS with a normal SGUS. They had longer disease duration,
ESSDAI, and ESSPRI. In addition, they were more likely to have a positive parotid gland biopsy, positive
anti-SSA/SSB antibodies, and abnormal unstimulated whole saliva and ocular staining score. They also
scored significantly lower for fatigue than in patients with normal SGUS [52]. These findings were
further supported by another study demonstrating that patients with pSS with normal SGUS had lower
disease activity (ESSDAI<5), negative labial biopsy results, a lack of anti-La/SSB antibodies, and normal
unstimulated salivary flow rate [46].

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

The data are promising but whether the differences indeed indicate different phenotypes and hence
the possibility of identifying patients with a milder disease course needs to be established in future
studies.

How to use ultrasound for differential diagnosis

A wide range of diseases may have sicca symptoms and swelling of the lacrimal and salivary glands
without having pSS. This is diseases such as active hepatitis C, light-chain amyloidosis, sarcoidosis,
systemic sclerosis, IgG4-related disease, graft-versus-host disease, AIDS, history of head and neck ra-
diation treatment, and lymphoproliferative disease (benign tumors as pleomorphic adenomas, War-
thin tumors, and MALT lymphoma. Though there may be other ultrasound features in the different
conditions as compared to pSS there may however also be overlaps. Therefore, the diagnosis of pSS
cannot be made solely on SGUS findings but must be put into the context with the patient's medical
history, clinical exam, blood samples including serology, and other imaging techniques, such as scin-
tigraphy, MRI, or biopsy when relevant. In any case of doubt, gland biopsies are necessary.
Sarcoidosis and amyloidosis are infiltrative diseases that can affect the salivary glands and cause
swelling of the glands. The SGUS lesions found in these conditions may be similar to the SGUS findings
in patients with pSS [61]. Sarcoidosis may also affect the lacrimal gland and is reported in 7e15% of the
patients [62].
The SGUS lesions found in patients with sSS in other autoimmune tissue diseases such as rheu-
matoid arthritis, SLE, systemic sclerosis, and other connective tissue disease are the same as for pSS and
here clinical features are important for a correct diagnosis [63].
The IgG4-related disease is characterized by bilateral but painless salivary gland swelling and is
caused by infiltration of IgG4þlymphocytes. A subtype is IgG4-related Mikulicz's disease that involves
both the salivary and lacrimal glands. The SGUS lesions may mimic pSS but can be characterized by
nodal changes and/or by multiple hypoechoic areas with varying sizes in enlarged glands and this
pattern can be helpful to suspect IgG4-related disease e see example in Fig. 5A.
Focal lesions are rare in the salivary glands overall but when they are present they are more
commonly seen in the parotid gland and rarely found in the submandibular gland and are most
frequently benign [64,65]. However, lymphoproliferative disease is the most severe complication of
pSS and occurs in around 5e10% of the patients, with MALT lymphoma being the most common
subtype of non-Hodgkin lymphomas [66]. When applying SGUS the lymphoma may be seen as a
diffuse change in the glandular pattern simulating an OMERACT grade 3 or it may be focal lesions e see
example in Fig. 5B. The focal lesions in the gland are often hypoechoic and homogenous with possible

Fig. 5. IgG4 gland and gland with focal lesion e longitudinal scans. Image A shows an IgG4 submandibular gland ¼ open arrow
characterized by hypoechoic areas of different sizes and a nodal appearance of the stroma. The white arrowhead ¼ mylohyoid
muscle. Image B shows a parotid gland with OMERACT grade 3 (open arrow) and a focal lesion (white arrow) with posterior acoustic
enhancement and septa. M ¼ bone of the mandible.

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

acoustic enhancement, the borders may be either well or poorly defined, there may be septa inside and
the tumor may exhibit Doppler activity [67,68]. Focal lesions should always result in a biopsy and here
ultrasound may be valuable in guiding the procedure.
Primary lacrimal gland tumors are relatively common, but the role of ultrasound is unclear.

How to use ultrasound for guided biopsies in the salivary glands

The need for salivary gland biopsies has been to obtain material for cytological and histological
evaluation in patients with malignant and benign tumors [69,70]. (ref). The role of US is to guide the
biopsies e ensuring the relevant positioning of the needle and avoiding structures like vessels and
nerves. US-guided biopsies provide an alternative to open surgery that is far more invasive and with
potentially persistent complications such as facial anesthesia, pain, and swelling at the biopsy site [71].
The way to obtain material for histological evaluation are fine-needle aspiration (FNA) and core
needle biopsy (CNB) of the glands and both biopsy techniques have been shown to be safe, cost-
effective, rapid, and accurate for ensuring relevant material for diagnosis - especially in patients
with gland swelling [69,71]. The biopsy may be from anywhere in a swollen gland with diffusely
inhomogeneous glandular tissue but when focal lesions are present the focal lesion should be targeted.
Despite several disadvantages, labial biopsy has been perceived as the gold standard for ensuring
salivary gland tissue for diagnosing pSS with a focus score >1 per 4 mm2 labial salivary gland tissue,
including fatty tissue is possible [72]. It is an invasive procedure with reported side effects such as
permanent sensory loss of the lower lip mucosa in 1%e10% of the patients [73] tissue necrosis and pain
and positive biopsies may even be found in up to 15% of the general population affecting the specificity
of the test [74]. The labial biopsy result weighs highly in the classification criteria and has been shown
to be comparable to incisional biopsy of the parotid gland for diagnosing pSS suggesting that they
reflect the same aspects of the disease [75e77]. Recent studies, however, have demonstrated that US-
guided biopsies of the parotid gland may also be used for diagnosing pSS as it is able to ensure adequate
amounts of glandular tissue for focus score analysis, although the tissue obtained may have an area
>4 mm2 and with results that appear to be equivalent to incisional biopsies of the parotid gland [69,78].
This suggests a far less invasive procedure for obtaining relevant tissue for focus score assessment and
could potentially replace labial biopsies.

Biopsy-choice

FNA is used to ensure material for cytological analysis. It has a high sensitivity (85.2%) and specificity
(96.2%), and a high NPV for diagnosing malignancies in the parotid gland [79].
CNB is used to obtain adequate tissue samples for histological evaluation and is superior to US-
guided FNA for diagnosing and characterizing malignant tumors of the salivary gland with excellent
sensitivity and specificity of 96% and 100%, respectively [80,81] and is, therefore, the preferred diag-
nostic method [71,82]. Furthermore, only CNB can be used for obtaining material relevant to focus
score analyses for pSS. The complications of US-guided CNB are hematomas, facial weakness secondary
to anesthesia, or, in theory, facial nerve injury. Finally, though rare, tumor seeding may be seen.

Procedure

For US-guided CNB, the patient is placed in a supine position with hyperextension of the neck. For
parotid biopsies, the patient's head is turned slightly toward the contralateral side, and biopsy is
performed in the superficial lobe area keeping the needle superficially to avoid the facial nerve which
lies deeper e approximately 1.5e2 cm below the gland surface. The optimal entry site has been
described to be caudal to the ear lobe with a posterior-to-anterior needle approach [71,72,78]. For
submandibular gland biopsies, the patient's head is instead turned toward the biopsy site and an
anterior-posterior approach [71].
The biopsies can be obtained with a 14e18-gauge semi-automatic core biopsy needle after having
infiltrated the skin and subcutaneous fat with local anesthesia followed by a small skin incision with a
scalpel [78].

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V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

Ultrasound for guided injections in salivary and lacrimal glands

US-guided therapeutic injection in the salivary and lacrimal glands has not been introduced as a
treatment form for patients with pSS. However, US-guided injections in salivary and lacrimal glands
have been used in patients with increased secretory production and are a safe method [83,84]. Sia-
lorrhea is a pathologically increased production of saliva among patients with severe neurological
diseases where injection of botulinum toxin type A has been reported effective. US ensures correct
needle and drug position [83].
Similarly, the injection of botulinum toxin A into the lacrimal gland is used for treating hyperse-
cretion of tear fluid (crocodile tears syndrome) [85]. The injection technique for the lacrimal gland is
performed with the patient in a supine position with the head in the neutral position with their eyelids
closed. By placing the transducer with one end on the lateral upper orbital bone the lacrimal gland
becomes visible between the orbital bone and the sclera. Using an in-plane approach the needle di-
rection is from medial to lateral. The technique is well accepted by the patients and reduces the risk of
injury to the eye and adjacent structures [26].
Injections with stem cells into the lacrimal and salivary glands in an animal model resulted in
regeneration of glandular tissue and hold the potential for future treatment for patients with pSS [86].

Summary

SGUS can detect parenchymal changes in the salivary and lacrimal glands in patients with pSS and
severity scores
2 are accepted as signs of pathology in the salivary glands. Despite the good diagnostic
performance, SGUS is not included in the pSS classification criteria. Studies have demonstrated that
SGUS improves the performance of the 2016 ACR-EULAR classification criteria by increasing the
sensitivity when giving the weight of 1 as other minor items, and is suggested to be included as an
additional item. SGUS may in combination with the presence or absence of autoantibodies help
minimize the need for labial biopsies as the presence of both SGUS pathology and anti-SSA/Ro anti-
bodies are compatible with the pSS diagnosis and the absence of both SGUS pathology and anti-SSA/Ro
antibodies are compatible with not having pSS.
Several scoring systems exist for assessing disease activity, but the OMERACT consensus-based
scoring system has been developed to ensure a greater degree of homogeneity across studies in pa-
tients with pSS with good reliability, sensitivity, specificity, PPV, and NPV for pSS according to the ACR/
EULAR classification criteria. The role of monitoring purposes needs further investigation.
Apart from diagnosing and assessing disease activity SGUS may also aid in the differential diagnosis
of other conditions, including lymphomas, and provides a valuable tool for US-guided gland biopsies
and gland injections. The future role of US-guided salivary gland biopsies for diagnostic purposes re-
mains unclear.

Practice points

 OMERACT ultrasound working group has developed and validated a reliable consensus-
based semi-quantitative scoring system for morphological (grey-scale) and Doppler
changes in the salivary glands in patients with pSS to ensure a greater homogeneity in future
studies.
 A grey-scale score
2 is indicative of pathology when found in at least one salivary gland.
 SGUS-detected pathology appears relevant as a future additional item in the classification
criteria for pSS.
 US-guided biopsy is a safe and well-tolerated technique for providing relevant tissues for
tumor diagnostics.

12
V. Fana, L. Terslev Best Practice & Research Clinical Rheumatology 37 (2023) 101837

Research agenda

 A scoring system for the lacrimal gland changes is needed.

 The role of SGUS in monitoring treatment effects and disease development needs to be
established.
 The role of normal-appearing glands in patients with pSS for identifying different phenotypes
of the disease needs further exploration.
 The role of US-guided biopsies as a substitute for labial biopsies in the diagnosis of pSS
needs to be determined.

Funding

This review paper has received no funding.

Declaration of competing interest

Viktoria Fana: no conflicts of interest.

Lene Terslev: Speakers fee from Janssen, Roche, Novartis, Pfizer, UCB, and Eli- Lilly, consultancy fee
from Janssen and UCB.

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