Current State of Knowledge on Primary Sjögren’s Syndrome, an Autoimmune Exocrinopathy

Abstract

Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune rheumatic disease characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis, affecting 0.3–3% of the population. Women are more prone to develop pSS than men, with a sex ratio of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial cells of the salivary glands are now known to play an active role in the pathogenesis of the disease. The aetiology of the “autoimmune epithelitis” still remains unknown, but certainly involves genetic, environmental and hormonal factors. Later during the disease evolution, the subsequent chronic activation of B cells can lead to the development of systemic manifestations or non-Hodgkin’s lymphoma. The aim of the present comprehensive review is to provide the current state of knowledge on pSS. The review addresses the clinical manifestations and complications of the disease, the diagnostic workup, the pathogenic mechanisms and the therapeutic approaches.

Full text

Journal of
Clinical Medicine
Review
Current State of Knowledge on Primary Sjögren’s
Syndrome, an Autoimmune Exocrinopathy
Dorian Parisis 1,2, Clara Chivasso 1, Jason Perret 1, Muhammad Shahnawaz Soyfoo 2and
Christine Delporte 1, *
1Laboratory of Pathophysiological and Nutritional Biochemistry, UniversitéLibre de Bruxelles,
1070 Brussels, Belgium; dorian.parisis@ulb.be (D.P.); clara.chivasso@ulb.ac.be (C.C.);
jason.perret@ulb.be (J.P.)
2Department of Rheumatology, Erasme Hospital, UniversitéLibre de Bruxelles, 1070 Brussels, Belgium;
msoyfoo@ulb.ac.be
*Correspondence: christine.delporte@ulb.be; Tel.: +32-2-555-6210
Received: 25 June 2020; Accepted: 16 July 2020; Published: 20 July 2020


Abstract:
Primary Sjögren’s syndrome (pSS) is a chronic systemic autoimmune rheumatic disease
characterized by lymphoplasmacytic infiltration of the salivary and lacrimal glands, whereby sicca
syndrome and/or systemic manifestations are the clinical hallmarks, associated with a particular
autoantibody profile. pSS is the most frequent connective tissue disease after rheumatoid arthritis,
affecting 0.3–3% of the population. Women are more prone to develop pSS than men, with a sex ratio
of 9:1. Considered in the past as innocent collateral passive victims of autoimmunity, the epithelial
cells of the salivary glands are now known to play an active role in the pathogenesis of the disease.
The aetiology of the “autoimmune epithelitis” still remains unknown, but certainly involves genetic,
environmental and hormonal factors. Later during the disease evolution, the subsequent chronic
activation of B cells can lead to the development of systemic manifestations or non-Hodgkin’s
lymphoma. The aim of the present comprehensive review is to provide the current state of
knowledge on pSS. The review addresses the clinical manifestations and complications of the disease,
the diagnostic workup, the pathogenic mechanisms and the therapeutic approaches.
Keywords:
Sjögren’s syndrome; autoimmune disease; physiopathology; treatment; diagnosis; review
1. Introduction
Sjögren’s syndrome (SS) is a chronic systemic rheumatic disease characterized by lymphoplasmacytic
infiltration of the exocrine glands—especially salivary and lachrymal glands—responsible for sicca
syndrome and systemic manifestations. The dreaded complication of this dysregulated and unabated
lymphocytic activation is the development of lymphoma. SS can be “primary” if it occurs alone (pSS) or
“secondary” (sSS) when it is associated with another autoimmune disease [1].
First medical descriptions of SS date back to 1882 when the German Theodor Karl Gustav von
Leber (1840–1917) described for the first time a dry inflammation of the ocular surface under the name
of “keratitis filamentosa”. Ten years later, the Polish surgeon Jan Mikulicz-Radecki described the case of a
man with swelling of the salivary and lacrimal glands, a clinical picture still called Mikulicz syndrome
today. At the same time, several cases of patients with ocular and oral dryness were described,
whether or not associated with the existence of rheumatism or gout. Dr. W. B. Hadden (1856–1893)
described the improvement of xerostomia in one of these patients with the use of an alkaloid called
pilocarpine [
2
]. Despite the involvement of these physicians in the first medical descriptions of SS, only
two famous names have remained attached to the disease: Gougerot and Sjögren. Henri Gougerot
(1881–1955) was a French dermatologist who described in 1925 three clinical cases characterized by
J. Clin. Med. 2020,9, 2299; doi:10.3390/jcm9072299 www.mdpi.com/journal/jcm

J. Clin. Med. 2020,9, 2299 2 of 61
generalized mucous dryness (eyes, mouth, nose, trachea and vagina) associated with atrophy of the
salivary glands (SG). He was the first to describe that xerostomia and ocular dryness are part of a larger
sicca syndrome resulting from dysfunction of the exocrine glands or their autonomic innervation.
In France, the term “Gougerot(-Sjögren) syndrome” is often used to describe pSS. Henrik Samuel
Conrad Sjögren (1899–1986) was a Swedish ophthalmologist who was mainly interested in the dryness
of the ocular surface. With his wife, Maria Hellgren, daughter of a well-known oculist, he described
keratoconjunctivitis sicca (KCS)—distinct from vitamin A deficiency xerophthalmia—using Rose
Bengal and methylene blue staining techniques. In 1933, in his PhD thesis, he described the cases
of 19 women with KCS and 13 of whom had arthritis. He was therefore, the first to link KCS to a
systemic disease beyond the field of ophthalmology. Unfortunately, his thesis was not successful,
and he stopped his academic career but not his medical and scientific one. It was only in the years
1935–1943 that Sjögren’s work was recognized and that the term “Sjögren’s syndrome” has been used
since. Finally, the autoimmune origin was recognized only in early 1960s [
2
]. Sjögren was awarded the
title of “Doctor” in 1957 by the University of Gothenburg and the honorary title of “Professor” in 1961
by the Swedish Government. Henrik Sjögren died of pneumonia on 17 September 1986, several years
after a disabling stroke [3–5].
2. Epidemiology
2.1. Prevalence
pSS affects 0.1% to 4.8% of the population with a female to male ratio of 9:1, depending on
the cohort studied, classification criteria and methodology used [
6
,
7
]. Although pSS is considered a
common disorder, its prevalence seems to be overestimated in some studies. Overall, 0.5–1% seems to
be a commonly accepted estimate of the prevalence of pSS in the general population [
7
]. However
according to a more recent meta-analysis of 7 studies, prevalence rate is 0.043% with a sex ratio of 10.72.
The prevalence of pSS in Europe is higher than in Asia, 0.7122% and 0.045%. Sex ratio does not differ
according to the geographic/ethnic origin of the populations studied [8].
2.2. Incidence
There is an overt heterogeneity of SS incidence among several studies. A meta-analysis reported
an incidence rate of 6.92 per 100,000 person–years, with an overall average age of 56.2 years at diagnosis
and an incidence rate ratio between women and men estimated at 9.29. Six Asian studies reported a
relatively higher incidence ratio around 6 per 100,000 person–years. Both Slovenian and American
studies reported an incidence ratio of 3.9 per 100,000 person–years. Finally, a Greek study estimated an
incidence ratio between the two at 5.3 per 100,000 person–years. Data regarding the incidence of pSS
in Africa, Oceania and South America are lacking [8].
3. Physiopathology of Sjögren’s Syndrome
SS is considered as a multifactorial process originating from the interaction between genetic factors
and exogenous and endogenous agents able to trigger an abnormal autoimmune response mediated
in particular by T and B lymphocytes [
9
]. The inflammation sustains, perpetuates and amplifies
tissue damage and leads to a progressive functional impairment of the affected organs and a chronic
inflammatory environment. Three recurrent events are generally associated with SS: (1) a trigger
phase induced by environmental factors under specific epigenetic factors, genetic predisposition and
hormonal regulation; (2) the dysregulation of normal salivary gland epithelial cell (SGEC) function;
(3) a chronic inflammation characterized by SG infiltration made of lymphocytic cells, lymphocytes B
hyperactivity and autoantibodies production [10] (Figure 1).

J. Clin. Med. 2020,9, 2299 3 of 61
J. Clin. Med. 2020, 9, x FOR PEER REVIEW 3 of 63
Figure 1. Overview of physiopathological mechanism underlying Sjögren’s syndrome (SS).
Environmental triggers, such as viral infections, genetic predispositions, epigenetics and sex hormone
deregulation, cause the disruption of salivary gland epithelial cell (SGEC), the production of type I
interferon (IFN) and other cytokines such as B cell Activating Factor of the tumour necrosis factor
(TNF) Family (BAFF) [11] and the alteration of proteins involved in saliva secretion. Dendritic cells,
as well as SGEC acquire the characteristics of antigen-presenting cells capable of processing viral and
self-antigens, leading to the activation of autoreactive T and B cells. Autoreactive T cells induce tissue
damage through the release of cytotoxic granules and cause the exposure of autoantigens on the
surface of SGEC. In addition, activated B cells produce autoantibodies that induce SGEC apoptosis
and create an inflammatory microenvironment. This complex mechanism triggers a self-perpetuating
cycle of autoimmunity.
3.1. Trigger Phase
In SS pathogenesis, a trigger phase is induced by environmental factors such as viral infections
combined with genetic predisposition, epigenetic factors and sex hormonal regulation (Figure 2).
Figure 2. Factors involved in SS trigger phase.
Figure 1.
Overview of physiopathological mechanism underlying Sjögren’s syndrome (SS).
Environmental triggers, such as viral infections, genetic predispositions, epigenetics and sex hormone
deregulation, cause the disruption of salivary gland epithelial cell (SGEC), the production of type I
interferon (IFN) and other cytokines such as B cell Activating Factor of the tumour necrosis factor
(TNF) Family (BAFF) [
11
] and the alteration of proteins involved in saliva secretion. Dendritic cells,
as well as SGEC acquire the characteristics of antigen-presenting cells capable of processing viral
and self-antigens, leading to the activation of autoreactive T and B cells. Autoreactive T cells induce
tissue damage through the release of cytotoxic granules and cause the exposure of autoantigens on the
surface of SGEC. In addition, activated B cells produce autoantibodies that induce SGEC apoptosis and
create an inflammatory microenvironment. This complex mechanism triggers a self-perpetuating cycle
of autoimmunity.
3.1. Trigger Phase
In SS pathogenesis, a trigger phase is induced by environmental factors such as viral infections
combined with genetic predisposition, epigenetic factors and sex hormonal regulation (Figure 2).
J. Clin. Med. 2020, 9, x FOR PEER REVIEW 3 of 63
Figure 1. Overview of physiopathological mechanism underlying Sjögren’s syndrome (SS).
Environmental triggers, such as viral infections, genetic predispositions, epigenetics and sex hormone
deregulation, cause the disruption of salivary gland epithelial cell (SGEC), the production of type I
interferon (IFN) and other cytokines such as B cell Activating Factor of the tumour necrosis factor
(TNF) Family (BAFF) [11] and the alteration of proteins involved in saliva secretion. Dendritic cells,
as well as SGEC acquire the characteristics of antigen-presenting cells capable of processing viral and
self-antigens, leading to the activation of autoreactive T and B cells. Autoreactive T cells induce tissue
damage through the release of cytotoxic granules and cause the exposure of autoantigens on the
surface of SGEC. In addition, activated B cells produce autoantibodies that induce SGEC apoptosis
and create an inflammatory microenvironment. This complex mechanism triggers a self-perpetuating
cycle of autoimmunity.
3.1. Trigger Phase
In SS pathogenesis, a trigger phase is induced by environmental factors such as viral infections
combined with genetic predisposition, epigenetic factors and sex hormonal regulation (Figure 2).
Figure 2. Factors involved in SS trigger phase.
Figure 2. Factors involved in SS trigger phase.
3.1.1. Environmental Factors
According to the current physiopathogenic model of SS, environmental factors including viral
infection lead to SGEC and Toll Like Receptors (TLRs) activation [
12
,
13
]. Primary viruses involved

J. Clin. Med. 2020,9, 2299 4 of 61
in SS induction include Epstein–Barr (EBV) viruses, Human T-lymphotropic virus type I (HTLVI),
hepatitis virus C (HCV) and coxsackievirus [13].
EBV is a double stranded DNA virus appertaining to Herpesviridae family, with a strong
tropism for B cells. EBV has often been associated with autoimmunity processes and diseases such as
Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and Multiple Sclerosis (MS) [
14
,
15
].
In addition, the high EBV load found in SG and lacrimal gland biopsies from SS patients as compared
to controls [
16
,
17
] suggests its role in triggering the activation of the immune system. EBV is able to
stimulate the production of proteins that mimic B cell receptor (BCR) and CD40 signalling and induce a
strong B cell hyperactivity [
18
]. Recently, a correlation was established between past EBV infection and
the presence of anti-Ro/SSA and anti-La/SSB autoantibodies in SS patients [
19
]. The RNA encoded by
EBV binds TLR3 and induces the secretion of type I IFN and proinflammatory cytokines [
20
]. Another
protein, the latent membrane protein 1 (LMP1) acting as a target for the EBV-induced cytotoxic T
lymphocytes response may cause acini atrophy and SG lobule structure destruction observed in SS
patients [21].
HTLV-1, a human endemic retrovirus in certain geographical areas such as Japan, has been reported
to be present in SGEC [
22
]. In addition, epidemiologic studies revealed anti-HTLV-1 seropositivity in
23% of SS patients as compared to 3% in controls [23].
Coxsackie virus is a single stranded RNA virus belonging to the Picornaviridae family. A study
has identified in SS patients a cross-reactivity between antibodies to the Ro60 epitope and 2B Coxsackie
protein sharing 87% sequence homology [24]. However, these data remain controversial [25].
The role of HCV, a single stranded RNA small virus belonging to Flaviviridae family, has been
examined in the initial triggering phase of SS. Clinical studies have shown that patients with
HCV infection present sicca symptomatology, positive ocular tests, SG lymphocytic infiltration,
and autoantibodies [
26
]. Therefore, HCV-associated SS (patients with HCV fulfilling SS 2002 classification
criteria) is indistinguishable from pSS. On this basis, HCV chronic infection should be considered as an
exclusion criterion for pSS as HCV infection could participate to SS development in a subset of patients.
Despite possible involvement of viral infection in SS, the most common antiviral drugs do not
seem to show real benefit in the treatment of SS [
26
]. Indeed, as a viral infection may likely trigger
onset of the disease, later antiviral treatment may manage a persistent infection but have no effect on
the ongoing disease that may no longer be dependent on the presence of the initial viral infection.
3.1.2. Genetic Predisposition
Genetic predisposition to SS plays a role in the trigger phase of the disease. A strong association
between human leucocyte antigen (HLA)-DR and HLA-DQ alleles belonging to the group of major
histocompatibility genes (MHC) class II genes and SS was observed throughout different populations
including Caucasian, Japanese and Chinese populations [
27
]. All discovered haplotypes are in strong
linkage disequilibrium, causing difficulties in establishing which of them contain the locus that
confers the risk. SS patients with HLA-DQ1/HLA-DQ2 alleles display more severe autoimmune
disease than patients with any other allelic combination at HLA-DQ [
28
]. In addition to the HLA
system, most recent studies have focused their attention on polymorphic genes that code for molecules
physiologically involved in apoptosis such as Fas and Fas ligand (FasL). Using MRL/lpr-murine
model, a retrotransposon inserted in Fas gene was identified as playing a role in cell apoptosis and
induction of progressive sialadenitis [
29
,
30
]. Fas/FasL gene polymorphisms have also been found in SS
patients [
31
] but have not clearly been identified as disease-determining factors. Ro52 gene encoding
the 52-kd Ro autoantigen display single nucleotide polymorphism (SNP) located 13bp upstream of
exon 4 identified as significantly associated with the presence of anti-Ro 52kD autoantibodies in SS
patients [
32
]. Numerous additional genes including IL-10 [
33
], TNF alpha [
34
], alpha chain of the IL-4
receptor [
35
], IRF5, STAT4 [
36
] and CXCL13 [
37
] also display a gene polymorphism possibly associated
with SS as well. Recent studies carried out in several SS cohorts of different ethnicity have revealed
additional candidate genes probably associated with the risk to develop the lymphoma in SS patients.

J. Clin. Med. 2020,9, 2299 5 of 61
The presence of a polymorphism in the tumour necrosis factor alpha induced protein 3 (TNFAIP3) gene
is associated with the risk to develop the non-Hodkin’s lymphoma in a SS Caucasian cohort [
38
–
40
].
In addition, two polymorphisms of methylene-tetrapholate reductase (MTHFR) gene are considered
risk factors for lymphoma in SS patients [
41
]. While gene polymorphism plays an indisputable role in
the triggering phase of SS, the individual contribution of each genetic factor remains to be assessed [
42
].
3.1.3. Epigenetic Factors
Several studies have analysed the contribution of epigenetics to SS and auto-antibodies
production [
43
]. The epigenetic processes more closely linked to the disease are DNA methylation,
miRNA, circular mRNA and long non-coding RNA function.
DNA methylation is a mechanism that consists in the addition of a methyl group from a methyl
donor S-adenosylmethionine (SAM) to cytosine residues in the context of the CpG dinucleotide
catalysed by DNA methyltransferases (DNMTs). In general, the addition of a methyl group onto DNA
is associated with gene silencing due to a structural modification of chromatin. DNA methylation is
one of most important mechanisms used by different type of cells to change their genetic expression
such as the transition from naïve steady to effector B- and T-cells. An epigenome-wide analysis has
identified several genes and epigenetic modification probably associated with SS [
44
]. The most
frequent modification observed is the demethylation of several sites in SS patients’ genome. Labial SG
DNA methylation is significantly reduced in SS patients as compared to the control subjects. This defect
was conserved when the SGEC were primarily cultured. Apparently, the SGEC from SS patients
were associated with a 7-fold decrease in DNMT1 and a 2-fold increase in demethylating partner
Gadd45-alpha expression. This demethylation process was also associated in part with the infiltration
of SG by B cells and the pathology severity [
45
]. Different studies have also reported a link between
demethylating drugs and SS. In fact, mice receiving an oral administration of hydralazine or isoniazid
(demethylating agents) for several weeks develop a pathology similar to SS in terms of immunological
features and autoantibodies production. The signs of SS pathology disappeared after discontinuation
of the drug [
46
]. A recent study conducted in CD19 +B cells and minor SG of SS patients has also
identified a hypomethylation site on interferon (IFN)-regulated genes which induces an increase of
IFN response activation normally observed in SS disease [
47
]. In addition, DNA demethylation of the
pro-apoptotic death associated protein kinase (DAP-kinase) gene [
48
] and the runt-related transcription
factor (RUNX1) gene in CD4 +T cells [
49
] have been associated with non-Hodgkin B cell lymphoma
predisposition in SS. In conclusion, the genome methylation analysis represents a useful tool to identify
links between epigenetic modifications in various cell types related to SS.
miRNAs are small endogenous non-coding RNAs that regulate gene-expression transcriptionally
and post-transcriptionally. Interestingly, miR-17-92 cluster, is downregulated [
50
] and associated with
a lymphoproliferative disease and autoimmunity [
51
,
52
] in SG of SS patients. Another study has
shown increased levels of miR-146a that regulates the inflammatory response, inducing the repression
of IRAK1 and the increase of TRAF6 expression which, in turn, promote NF-
κ
B expression in the
peripheral mononuclear cells of SS patients [
53
]. Aberrations in microRNA expression are often
observed in various autoimmune diseases and for this reason they could be used as a potential
diagnostic or prognostic biomarkers. Furthermore, the small size of mature miRNA offers a high level
of stability that renders them useful in disease follow-up using paraffin embedded samples stored for
long periods of time [54,55].
Circular RNA (circRNA) consist in a class of RNA generated after an alternative splicing process
of pre-mRNA named “backsplicing”, in which a downstream 5
0
donor links an upstream 3
0
acceptor
throughout a 3
0→
5
0
phosphodiester bond. circRNa are divided in three subgroups: exonic circRNAs
(ecircRNAs), intronic circRNAs (ciRNAs) and exon-intron circRNAs (EIciRNAs) [
56
]. Recent studies
have observed that circRNA could be involved in development of autoimmune diseases such as RA, MS,
SLE and SS [
57
]. A microarray analysis has identified 234 differentially expressed circRNAs between
SS patients and healthy controls, whereby 2 are significantly upregulated and 3 downregulated in SS.

J. Clin. Med. 2020,9, 2299 6 of 61
Functional analysis has also shown that these circRNAs are related to arthritis and the presence of
autoantibodies [
58
]. All this data taken into account, we can conclude that circRNAs could be used as
biomarkers for a potentially valuable diagnostic tool for SS disease, but supplementary investigations
assessing which of them is the most specific of pathology are necessary.
Long non-coding RNAs (lncRNA) are a novel class of functional non-translated RNAs with a
length of over 200 nucleotides. Several studies revealed a strong link between lncRNAs and the
immune responses [
59
]. The expression analysis of lncRNAs in SS patients has shown lncRNAs
LINC00657, LINC00511 and CTD-2020K17.1 potentially associated with the disease. These 3 lncRNAs
target different genes involved in B cell physiology and malignancy, including IL15, WDR5, GNAI2,
LTßR, CBX8, BAK1, BAX ext [
60
]. IL15 and WDR5 play an important role in B cell proliferation
and differentiation; GNAI2 regulates B cell trafficking to the lymph nodes [
61
]; LTßR and CBX8 are
involved in GC formation in inflamed tissues [62,63], and BAK1 and BAX are overexpressed in B cell
lymphoma [
64
]. These results illustrate an important role of lncRNAs in multiple processes and the
understanding of their modulation and function could provide deeper insight into the pathogenesis of
SS and facilitate the identification of novel therapeutic strategies.
3.1.4. Sex Hormones Deregulation and X-Chromosome Linked Factors
Nine out of ten SS patients are women and generally during menopause [
65
]. The strong
predisposition of women to develop SS clearly demonstrates the role of sex hormones as a risk factor
of the disease. In a recent case-control study, pSS in women was associated with lower oestrogen
exposure and lower cumulative menstrual cycling time compared to sicca controls. Conversely,
an increasing oestrogen exposure was negatively associated with development of pSS [
66
]. Finally,
an effect of X chromosome per se is also evoked since men with Klinefelter’s syndrome have a higher
risk of developing pSS—20 times higher—compared to healthy men, despite normal sex hormone
levels [
67
,
68
]. Similarly, the association between pSS and mixed connective tissue disease has been
reported in a 16-year-old Japanese patient with trisomy X [69].
Androgens suppress the inflammation and enhance the function of lacrimal glands in female
SS mouse models (MRL/MpJ-Tnfrsf6lpr[MRL/lpr]) [
70
]. The androgens could help maintaining acini
structure in healthy SG, while their reduction observed in SS patients could cause a decrease in integrin
expression and probably a dysregulation of acini architecture [
71
]. SS patients present low levels of
androgen hormones both in the bloodstream and in SG [
72
]. In Klinefelter’s syndrome associated SS
and SLE, correction of hypogonadism by testosterone therapy for 60 days leads to remission in one
case-series report [73].
Healthy ovariectomized C57BL/6 mice display an exocrinopathy with autoimmune characteristics
similar to SS including SG focal adenitis, lacrimal glands lesions, Ro/SSA, La/SSB and
α
-fodrin
autoantibodies [
74
]. Similarly to ovariectomized mice, both mice rendered deficient in aromatase,
an enzyme important in the biosynthesis of oestrogens, as well as mice that received an aromatase
inhibitor develop a lymphoproliferative autoimmune disease resembling SS [
75
,
76
]. How oestrogen
deficiency promotes autoimmune lesions remains unclear. However, one putative explanation could
be that oestrogen deficiency stimulates SGEC to secrete IFN-
α
and IL-8, and to express MHC class
II, enabling them to act as antigen-presenting cells. Oestrogen deficiency is responsible for RbAp48
overexpression, which induces p53-mediated apoptosis in exocrine glands [
77
]. In another study,
transgenic mice overexpressing RbAp48 develop SS-like exocrinopathy characterized by an increased
propensity to apoptosis and the acquisition of an active immunocompetent role by epithelial cells,
producing IFN-
γ
and IL-18 [
78
]. In primary cultures of human SG cells, pre-treatment with 7
β
-estradiol
impede IFN
γ
-induced upregulation of ICAM-1 in control group but not in pSS group. These data
suggest a protective role of oestrogens on epithelial activation and the existence of a deficient estrogenic
responsiveness in pSS [
79
]. Not surprisingly, the use of aromatase inhibitors in the treatment of breast
cancer is associated with arthralgia or even authentic SS [80–82].

J. Clin. Med. 2020,9, 2299 7 of 61
Humans and other primates, secrete large amount of sex steroid precursors, such as
dehydroepiandrosterone (DHEA) and DHEA-sulphate precursors, metabolic intermediates in the
biosynthesis of androgens and oestrogens. According to tissue needs, the prohormones are directly
processed within tissues. DHEA is present in low concentrations in patients with SS as compared to
age-matched healthy controls [
83
]. Several studies have shown that human MSG possess an organized
intracrine machinery capable to convert DHEA(-sulphate) pro-hormone to its active metabolites,
dihydrotestosterone (DHT) and 17
β
-oestradiol [
84
] (Figure 3). However, the non- functionality of this
enzymatic machinery in MSG from SS patients could account for the diminished local concentrations of
DHT and androgen-regulated biomarker Cysteine-Rich Secretory Protein 3 (CRISP-3) in SS patients [
85
].
J. Clin. Med. 2020, 9, x FOR PEER REVIEW 7 of 63
use of aromatase inhibitors in the treatment of breast cancer is associated with arthralgia or even
authentic SS [80–82].
Humans and other primates, secrete large amount of sex steroid precursors, such as
dehydroepiandrosterone (DHEA) and DHEA-sulphate precursors, metabolic intermediates in the
biosynthesis of androgens and oestrogens. According to tissue needs, the prohormones are directly
processed within tissues. DHEA is present in low concentrations in patients with SS as compared to
age-matched healthy controls [83]. Several studies have shown that human MSG possess an
organized intracrine machinery capable to convert DHEA(-sulphate) pro-hormone to its active
metabolites, dihydrotestosterone (DHT) and 17β-oestradiol [84] (Figure 3). However, the non-
functionality of this enzymatic machinery in MSG from SS patients could account for the diminished
local concentrations of DHT and androgen-regulated biomarker Cysteine-Rich Secretory Protein 3
(CRISP-3) in SS patients [85].
Taken together, these data suggest that women affected by SS at menopause, when the levels of
testosterone produced by the ovaries has already declined, may be particularly vulnerable to
androgen deficiency because the only source of DHT in SG is dependent on local conversion of
DHEA. Whereas in men, the level of systemic androgens produces by gonads may satisfy the specific
needs of SG, not requiring the intermediate metabolite.
Figure 3. Intracrine steroidogenic machinery in healthy acinar cells. The figure shows the conversion
of dehydroepiandrosterone (DHEA) to active sex steroids. STS: steroid sulphatase, SULT2B1:
sulfotransferase 2B1, HSD: hydroxy steroid dehydrogenase, 5-α-R: 5α-reductase, TEST: testosterone,
DHT: dihydrotestosterone. DHEA-S: DHEA-sulphate.
3.2. SGEC Deregulation
3.2.1. Upregulation of Adhesion Molecules
According to recent observations, several SS pathogenic models could explain the role of SGEC
in glandular damage. The current SS pathogenic model is the “autoimmune epithelitis”. This model
considers SGEC as a crucial player in the initial triggering phase of the disease [86]. SGEC from SS
Figure 3. Intracrine steroidogenic machinery in healthy acinar cells. The figure shows the conversion
of dehydroepiandrosterone (DHEA) to active sex steroids. STS: steroid sulphatase, SULT2B1:
sulfotransferase 2B1, HSD: hydroxy steroid dehydrogenase, 5-
α
-R: 5
α
-reductase, TEST: testosterone,
DHT: dihydrotestosterone. DHEA-S: DHEA-sulphate.
Taken together, these data suggest that women affected by SS at menopause, when the levels of
testosterone produced by the ovaries has already declined, may be particularly vulnerable to androgen
deficiency because the only source of DHT in SG is dependent on local conversion of DHEA. Whereas
in men, the level of systemic androgens produces by gonads may satisfy the specific needs of SG, not
requiring the intermediate metabolite.
3.2. SGEC Deregulation
3.2.1. Upregulation of Adhesion Molecules
According to recent observations, several SS pathogenic models could explain the role of SGEC in
glandular damage. The current SS pathogenic model is the “autoimmune epithelitis”. This model
considers SGEC as a crucial player in the initial triggering phase of the disease [
86
]. SGEC from SS
patients express significantly higher levels of TLRs mRNA levels, including TLR-1, TLR-2, TLR-3 and
TLR-4 as compared to control SGEC [
87
]. Under physiological conditions, TLRs are activated by the

J. Clin. Med. 2020,9, 2299 8 of 61
recognition of pathogen-associated molecular patterns (PAMPs) derived from microorganisms and
endogenous mediators of inflammation known as danger-associated molecular patterns (DAMPs) [
88
].
TLR signalling pathway acts as link between innate and adaptive immunity in autoimmune diseases.
Indeed, upon activation, TLRs recruit adapter proteins in order to propagate the intracellular signal that
results in the transcription of genes involved in inflammation, immune regulation, cell survival and
proliferation and subsequent activation of the immune system. TLR signalling in SGEC upregulates
several molecules such as MHC class I and class II, costimulatory molecules such as B7.1 (CD80) and
B7.2 (CD86) and adhesion molecules 1 (ICAM-1) [89].
3.2.2. Antigen-Presenting Cell Properties
The expression of MHC class I, MHC class II, costimulatory molecules and adhesion molecules on
SGECs empower them to present antigen to T cells (acting as non-professional antigen presenting cells).
3.2.3. Chemokines Production
The activation of Interferon Regulatory Factor (IRF) and nuclear factor kappa-light-chain-enhancer
of activated B cells (NFkB) pathways increases the production of inflammatory cytokines, including
type I IFN, tumour necrosis factor-α(TNF-α), interleukin(IL)-1, IL-6 and BAFF [90].
3.2.4. Apoptosis and Expression of Self-Antigens
In addition to chemokines production, the ribonucleoproteins, normally hidden from the immune
system, are exposed on the cell surface. In particular, the expression of antigen Ro/SSA and La/SSB
proteins on apoptotic SGEC promotes the initiation of autoimmunity.
3.2.5. Alteration of Proteins Involved in Saliva Secretion
Apoptosis of the acinar epithelial cells and altered expression and distribution of proteins involved
in saliva secretion has been proposed as possible mechanisms responsible for the impairment of
secretory function of SS SG. For example, an increase in AQP3 expression was observed at the apical
membrane of acinar cell of SG from SS [
91
], while AQP1 [
92
] and AQP4 [
93
] expression was decreased in
myoepithelial cells. Rituximab treatment, used in SS patients to deplete B cells, increases AQP1 protein
expression in myoepithelial cell and induces an improvement of saliva flow [
94
]. These data could
suggest a crucial role to AQP1 in saliva secretion. However, AQP1-null mice model has shown that this
protein is not essential for saliva production [
95
]. Nevertheless, one cannot exclude a compensatory
effect in such mouse models, whereby other AQPs could be alternatively used. In contrast, AQP5 is
today considered the most important protein involved in saliva secretion [
96
]. Under physiological
conditions, AQP5 translocates from the intracellular vesicular compartments to the apical membrane
of SG acinar cells after activation of muscarinic and adrenergic receptors [
97
]. In SS patients and SS
mice models, aberrant localization of AQP5 has been observed [
98
], which is predominately basolateral
instead of apical [
99
–
101
]. The reason why the AQP5 localization is altered is still unknown but several
hypotheses have been proposed.
The presence of autoantibodies against M3 receptor could impair its activation and block the
translocation signal normally sent to AQP5 [
102
]. Another possible mechanism could be the alteration
of protein–protein interactions between AQP5 and its partner proteins [
103
]. Prolactin inducible
protein (PIP) is a known AQP5 protein partner in lacrimal glands in mice models. Aberrant binding
of PIP to the c-terminal domain of AQP5 impairs AQP5 trafficking to the apical membrane of
epithelial cells [
104
]. Lastly, the inflammatory environment that characterizes SS disease could also
directly or indirectly be involved in these modifications [
105
,
106
]. IFN-
γ
for example, contributes
to SS pathogenesis inducing SG apoptosis and expression of several chemoattractant cytokines and
enhancing the antigen presenting function of epithelial cells [
107
–
109
]. IFN-
γ
administration leads to
increased production of anti-M3R antibody, which affect the SG secretory function in response to an
adequate stimulus [
110
]. Neutralization of IFN-
γ
in anti-programmed death ligand 1 (PDL1)-treated

J. Clin. Med. 2020,9, 2299 9 of 61
non-obese diabetic (NOD)/ShiLtJ mice improves AQP5 expression and saliva secretion [
111
]. TNF-
α
is
another pro-inflammatory cytokine that is increased in SS [
112
]. Elevated TNF-
α
levels in both serum
and SG has been observed in SS patients compared to controls [
113
]. In human SG acinar cells, TNF-
α
treatment down-regulates the expression of AQP5 [
114
]. The injection of antibodies against TNF-
α
in
NOD mice reduces SG inflammatory foci and increases AQP5 protein expression [
115
]. It seems clear
that correct expression, trafficking and localization of AQP5 are essential to overcome the impaired
salivary secretion process and the combination of inflammation, antibodies production, protein–protein
interaction and salivary epithelial cells deregulation are probably involved in the hypofunction of SG
of SS patients.
3.3. Chronic Inflammation
3.3.1. T-Cell Infiltration
In the early stages of SS, the lymphocytic infiltrates, present in SG from SS patients, are constituted
by a vast majority (>75%) of T lymphocytes being mostly CD4 T cells [
116
]. However, saliva from
SS patients contains greater Th1 cytokines than saliva from controls [
109
,
117
], including IL-1
β
, IL-6,
tumour necrosis factor (TNF)-
α
, and IFN-
γ
[
118
]. Th2-derived cytokines, such as IL-10 and IL-4,
were also found in greater quantity in SG tissue from SS patients than in controls [
119
]. The two T cell
responses are in a dynamic balance with a predominance of Th1 activity in patients suffering from
SS [
120
]. In patients with SS, the activated T cells respond to an intense antigenic stimulus, such as
the recognition of Ro and La autoantigens expressed on blebs of apoptotic cells [
121
], which induces
a proliferative response [
122
]. Therefore, T-cell recognition of self-antigens and their subsequent
activation are crucial for the cascade of events leading to the development of SS pathology. T cells
may proliferate locally in SG or be re-directed by chemokines from the circulation to the glands.
Two chemokines involved in the attraction of T-cells in SS SG are CXCL9 and CXCL10 [
123
]. In SS SG,
T cells are likely to be involved in the disruption of the glandular architecture throughout the apoptosis
mechanism mediated by FasL pathway [
124
], by a direct cytotoxic activity involving the release of
perforin and/or secretion of cytokines and by the activation of B cells [
125
]. Th17 cells represent another
subpopulation of T-cells strongly activated in SS patients [
126
]. In general, Th17 plays an important
physiological role in mucosal defence in healthy individuals. In SS patients, the activated Th17 cells
promote inflammation by secreting IL-6, IL-17, IL-21, IL-22 and IL-23 [
127
–
129
]. Follicular helper T cells
have been shown to play an important role in lymphoid follicle formation and ectopic germinal centre
formation in SS SG [
130
]. During pathology, SGEC induce activation and differentiation of T helper to
T follicular helper by the release of IL6 and ICOS ligand expression. The activated follicular cells in
turn secrete IL-21 cytokine which mediates B cell maturation and proliferation [
131
]. In conclusion,
the combined activation of T-cell subtypes creates an optimal environment for detrimental B cell
activation and the breakdown of tolerance.
3.3.2. Breakdown of B Cells Tolerance
Under physiological condition, B cells originate in the bone marrow from haematopoietic stem
cells and during their development undergo several stages of selection because of a large portion of
self-reactive and polyreactive B cell are normally generated [
132
]. The first checkpoint removes the
polyreactive B cells in the bone marrow (central tolerance checkpoint), the second in the periphery
ensures that only a small amount of self-reactive, and polyreactive mature naïve B cells survive. Finally,
a third tolerance checkpoint called pre-germinal centre checkpoint, excludes self-reactive naïve B cells
from entering B cell follicles [133].
A recent study has revealed the existence of deficiencies in both early and late B cell tolerance
checkpoints in patients with SS. Indeed, the accumulation of circulating autoreactive naïve B cells in
SS suggests an impairment of the autoreactive B cell clearance during the early peripheral tolerance
checkpoints and an increased frequency of autoreactive unswitched and switched memory B cells

J. Clin. Med. 2020,9, 2299 10 of 61
reveals a possible impairment also in pre- and/or post-germinal centre tolerance checkpoints [
134
].
These observations have also been made in patients with SLE, RA and type 1 diabetes [
135
,
136
]. B cell
depletion using anti-CD20 antibodies in Id3 knockout mice model leads to a significant histological
improvement associated with a recovery of saliva secretory function and corroborate the hypothesis
that B cells could play an important role in SS disease [137].
B cell hyperactivity is an important hallmark of SS. Two cytokines have been shown to be
fundamental in B cell survival and proliferation: B cell Activating Factor of the TNF Family (BAFF)
and APRIL (A proliferating ligand) [
138
]. Once SG tissue infiltration is established, a large number
of cells such as dendritic cells, monocytes and macrophages but also SGEC and T lymphocytes can
secrete BAFF. BAFF overexpression has indeed been documented in SS as well as in other systemic
autoimmune diseases and has been correlated with autoantibodies [139].
3.3.3. Formation of Germinal-Like Structures
Germinal centres (GCs) were described for the first time by Walther Flemming in 1884 [
140
].
GCs are specific region in secondary lymphoid tissues such lymph nodes and spleen. GCs provide the
environment for proliferation of mature B cells, differentiation and mutation of their immunoglobulin
variable-region gene segments during a process called somatic hypermutation, which generates a
diversity of clones. Following this process, the cells migrate from the dark zone to the lighter zone
of the lymphoid tissues, where the affinity of immunoglobulins is tested on follicular dendritic cells
(FDC) and follicular helper T cells (TFH) cells presenting the antigens. The non-selected cells undergo
apoptosis while the selected cells are stimulated by T cells to undergo class switch recombination
and differentiation into antibody-producing plasma cells or memory B cells [
141
,
142
]. SG from SS
patients can contain similar GC structures made of T, B, and plasma cells, macrophages, and follicular
dendritic cells [
143
]. Given the strong similarity of SG GC with the lymphoid organ GC, the SG GC
observed in SS patients were defined as ectopic GC-like structures, also known as “tertiary lymphoid
organs” [
144
]. Several studies have reported the association between GCs and the immunopathological
features of SS [
145
]. Other important studies have observed a 6.5- to 15.6-fold increased risk to develop
non-Hodgkin lymphomas in SS with an elevated presence of GCs [146,147].
3.3.4. Local Production of Autoantibodies
The most common and studied antibodies in SS patients are those directed against the autoantigens
Ro/SSA and La/SSB [
148
]. Anti-Ro, Anti-La, anti-SSA and anti-SSB were originally described as four
antibodies directed against antigens expressed by salivary and lacrimal glands tissues from SS
patients. Later, anti-Ro and anti-La were shown to be the same antibodies as anti-SSA and anti-SSB,
respectively [149,150].
Ro antigen is constituted of two distinct Ro proteins of 52 and 60 kDa, with the latter binding to
small cytoplasmic RNAs known as hY RNAs. The Ro52 protein, also known as TRIM21, is frequently
targeted by SS antibodies, which makes it a useful diagnostic marker, but its function and why it
becomes a target protein in a lot of rheumatic diseases is not completely understood. Ro52 is a member
of the tripartite motif (TRIM) protein family, and it plays an important role in the ubiquitination of
proteins. Several targets have been suggested as substrate of Ro52 activity, including various members
of the IFN-regulatory factor (IRF) transcription factor family. The most speculated hypothesis attributes
to Ro52 a role of IFN negative regulator. Indeed, in a Ro52-null mouse, the lack of ubiquitination
mediated by Ro52 leads to an aberrant expression of type I IFNs and proinflammatory cytokines,
such as IL-6, IL-12, IL-23, and TNF-
α
[
151
]. La/SSB antigen is a 48 kDa phosphorylated protein located
in the nucleus and the cytoplasm. La/SSB binds to many RNA molecules newly synthesized by RNA
polymerase III [
152
]. These two antibodies are detected in 50% to 70% of primary SS patients, but the
anti-La/SSB alone is observed in only 2% of patients [153,154].

J. Clin. Med. 2020,9, 2299 11 of 61
In most cases, anti-Ro/SSA and anti-La/SSB are correlated with severe dysfunction of the exocrine
glands, associated with parotid gland enlargement and large number of lymphocytic infiltrates in the
MSG [155,156].
Other antibodies believed to be pathogenic in SS are anti-centromere antibodies (ACA),
anti-citrullinated protein antibodies (ACPA), anti-carbonic anhydrase II antibodies, anti-aquaporin-5,
anti-muscarinic receptor 3 (anti-M3R) and anti-fodrin antibodies. ACA are directed against six antigens
associated with the centromere (complex of kinetochore proteins). The incidence of ACA antibody
ranges from 3.7% to 4% [
157
,
158
]. ACPA are directed against fibrin and fibrinogen, vimentine and
alpha-enolase (CEP-1). In general, ACPA antibodies are the marker most observed in rheumatoid
arthritis but are usually present in low concentrations in pSS as well, in about 3–22% of cases [
159
].
Anti-carbonic anhydrase II antibodies have been detected in 12.5–20.8% of SS patients and also play a
pathogenic role in renal tubular acidosis (RTA) [
160
,
161
]. In fact, immunization of mice with human
carbonic anhydrase II resulted in autoimmune sialadenitis, production of anti-carbonic-anhydrase-II
antibodies and urinary acidification defect [
162
,
163
]. Anti-AQP5 antibodies were observed to be
associated with serologic and histopathological features of SS [
164
]. Anti-M3R antibodies are present
in serum of up to 90% of subjects with SS [
165
]. Antibodies against alpha-fodrin are detected in serum
samples from patients with primary or secondary SS, especially in patients with sicca symptoms.
However, anti-alpha-fodrin antibodies do not represent a sensitive nor a specific serological marker of
SS [
166
]. Other novel tissue-specific autoantibodies are currently under investigation: autoantibodies
against salivary protein 1 (SP-1), parotid secretory protein (PSP) and carbonic anhydrase 6 have
been described in pSS and non-pSS patients with chronic pain, which may help to understand and
diagnose early pSS and pSS-associated widespread pain syndrome in the future [
167
]. Anti-cofilin-1,
anti-alpha-enolase and anti-RGI2 antibodies are associated with pSS MALT lymphoma [
168
]. Other
autoantibodies have also been described to be more frequently found in pSS patients and variously
associated with the clinical and biological characteristics of the disease [
168
]. Table 1summarizes the
novel autoantibodies that have been detected in pSS patients.

J. Clin. Med. 2020,9, 2299 12 of 61
Table 1. Rapid overview of original publications describing novel autoantibodies in pSS.
Autoantigen Targeted by
Autoantibody
Number of Patients (N Total/Pooled) Autoantibody Prevalence (% of Total) Clinical Associations
pSS pSS MALT Sicca FM Sicca Crtl pSS pSS MALT Sicca FM Sicca Crtl
Salivary protein 1 (SP1) 270 _ 29 151 148 46.3 _ 75.9 45.7 27 Early disease, low focus-score, SSA−/SSB−[169–173]
Found in non-pSS dry eye and fibromyalgia with sicca
syndrome [167,174,175]
Carbonic anhydrase 6 (CA6) 13 _ _ 151 23 53.8 _ _ 7.3 4.3
Parotid secretory protein (PSP) 13 _ _ 151 23 15.4 _ _ 11.3 4.3
Interferon-inducible protein-16 250 _ _ _ 255 37.2 _ _ _ 2.7 High focus-score and GC, hyperγ, ANA >1:320 [176]
Mouse double minute 2 (MDM2) 100 _ _ _ 74 21 _ _ _ 5.4

disease duration, ESSDAI,

focus-score, anaemia,
thrombocytopenia, SSB+[177]
Nuclear autoantigen 14 kDa (NA-14) 204 _ _ _ 144 12.7 _ _ _ 0

IgA level, ANA <1:320, ANA−, shorter disease
duration [178,179]
Stathmin-4 72 _ _ _ 128 15 _ _ _ 5 Polyneuropathy, vasculitis [180]
Poly(U)-binding splicing factor 60 kDa 84 _ _ _ 38 30 _ _ _ 5.3 Asian or African descent, ANA+, RF+, hyperγ, SSA+,
SSB+[181]
NR2 66 _ _ _ 99 20 _ _ _ 7.6

memory function,

depression rate [182]

hippocampal grey matter [183]
50 _ _ _ _ 12 * _ _ _ _
TRIM38 235 _ _ _ 50 10 _ _ _ 4

ocular stain scores,

Schirmer’s test, focus-score ≥3,
SSA+, RF+, hyperγ[184]
Saccharomyces cerevisiae 104 _ _ _ _ 5 _ _ _ _ Triple Ro52+/Ro60+/La+, hypocomplementemia,
cutaneous involvement [185]
Calponin-3 209 _ _ _ 46 11 _ _ _ 2.2 Peripheral neuropathy [186]
Ganglionic acetylcholine receptor 39 _ _ _ 39 23 _ _ _ 0 Autonomic neuropathy [187]
Aquaporin-4 109 _ _ _ _ 10 _ _ _ _ NMOSD overlap [188]
Aquaporin-5 112 _ _ _ 53 73 _ _ _ 32 Low resting salivary flow [164]
Other aquaporins (1, 3, 8, 9) 34 _ _ _ _ 38 _ _ _ _

ocular stain scores [189]
P-selectin 70 _ _ _ 35 21 _ _ 0 Low platelet count [190]
Carbamylated proteins 123 _ _ _ 172 28.5 _ _ _ 3.5

total IgG, IgM, RF+,β2-microglobulin,

focus-score
and GC [191,192]
Moesin 50 _ _ _ 50 42 _ _ _ 4 [193]
Cofilin-1 50 20 _ _ 50 76 80 _ _ 18 Association with pSS lymphoma [194]
IgA isotype of anti-Ro/SSA
ACPA+and high urine pH for anti-alpha-enolase [195]
Alpha-enolase 50 20 _ _ 50 82 90 _ _ 26
Rho GDP-dissociation inhibitor 2 50 20 _ _ 50 86 90 _ _ 26
*=antibody positivity in cerebrospinal fluid; Sicca =non-pSS Sicca syndrome; FM =fibromyalgia with non-pSS sicca syndrome similar to “Sicca Asthenia Polyalgia” syndrome; Crtl =
healthy controls; hyper
γ
=hypergammaglobulinemia; ANA =antinuclear antibodies; GC =germinal centre; SSA and SSB =anti-Ro/SSA (Ro52 and/or Ro60) and anti-La/SSB; ESSDAI =
Eular Sjögren Syndrome Disease Activity Index; RF+ = rheumatoid factor positivity; NMOSD =Neuromyelitis Optica Spectrum Disorder; ACPA+ = anti-citrullinated protein antibodies
positivity;

=increase(d)/higher;

=decrease(d)/lower; “−”=negativity.

J. Clin. Med. 2020,9, 2299 13 of 61
3.3.5. Damage of Salivary Acini Architecture
One of the pathomorphological characteristics of SG from SS patients is the presence of focal
infiltration made of lymphocytic cells. The focus infiltrate is defined as the “focus score” and “focus
score =1” is a group of 50 or more lymphocytes per 4 mm
2
of tissue [
196
]. SG infiltration is
normally associated with destruction and fragmentation of the glandular tissue, acinar hyperplasia
and replacement of acinar cells with fatty or fibrotic infiltrations [
197
]. These events lead to a deep
modification and impaired function of the glandular tissue. An architectural disorganization of the
epithelial cells has been described in the pSS: detachment of the basement membrane, alterations of
the apical microvilli and disorganization of the tight junctions separating the apical and basolateral
poles [
198
]. Several studies have shown that SS labial SG (LSG) display significant increase in proteolytic
activity of matrix metalloproteinases (MMPs) and higher expression of MMP-3 and MMP-9 exclusively
in acinar and ductal cells [
199
]. Some of the cytokines synthesized by the inflammatory cells, acinar and
ductal cells of SS LSG can induce increased MMPs expression [
108
,
200
]. In turn, high MMPs expression
triggers a high level of remodelling activity in the basal lamina that enhances the vulnerability of SGEC
to direct contact with cytotoxic inflammatory cells [
201
]. The disorganisation of the basal lamina of
acini and ducts of LSG from patients with SS is the most frequent modification observed that positively
correlates with the number of inflammatory cells within the gland.
4. Clinical Manifestations
Although often reduced to its sicca syndrome due to its tropism for glandular tissue, pSS remains
a systemic disease that can affect virtually all organs. These clinical manifestations can be
due to various mechanisms: dryness secondary to exocrinopathy, autoimmune epithelitis with
periepithelial lymphocytic infiltration of target organs, associated organ-specific autoimmunity with
specific autoantibodies, systemic manifestations linked to the presence of immune complexes or
cryoglobulinemia and clonal lymphocytic expansion. Three-quarters of pSS patients will have at
least one extraglandular manifestation, ranging from mild inflammatory arthralgia to life-threatening
manifestations. The clinical manifestations can occur at diagnosis or during follow-up, even after
more than 10 years, which must justify careful monitoring of patients. In general, the manifestations
due to lymphocytic infiltration around an epithelium of a target organ have a stable and indolent
course (e.g., sicca syndrome, renal tubular acidosis, pulmonary involvement) while the autoimmune
disorders linked to immune complexes or autoantibodies have a more unpredictable course, with flares
and remissions.
4.1. General Manifestations
More than half of pSS patients report disabling fatigue and non-restful sleep [
202
], partly related
to poor sleep quality due to dryness, night pain and an increased prevalence of obstructive sleep
apnoea [
203
]. Low-grade fever is found in 6% to 41% of pSS patients [
204
], while periodic fever
is found more anecdotally [
204
]. Weight loss and night sweats may also be due to the systemic
activity of the disease, autonomic involvement or lymphoma development. B symptoms—the triad of
fever, night sweating and weight loss classically described in lymphomas—are found only in 15% of
low-grade lymphomas associated with pSS [205].
4.2. Ocular Manifestations
Dry eye is a classic manifestation of pSS, part of the sicca syndrome affecting more than 95% of
pSS patients. Patients can report inability to tear, foreign-body sensation, conjunctival inflammation,
eye fatigue and decreased visual acuity. Ocular dryness can be complicated by keratoconjunctivitis
sicca, blepharitis, bacterial keratitis or corneal ulcer [
206
]. Uveitis, episcleritis and orbital pseudotumor
are rare but possible systemic manifestations [207].

J. Clin. Med. 2020,9, 2299 14 of 61
4.3. Stomatologic Manifestations
Lymphocytic infiltration of SG generates exocrinopathy with hyposialia responsible for soreness,
adherence of food to the mucosa, dysphagia, difficulties in speaking or eating, dental caries,
tooth loss, periodontal involvement, lip dryness and nonspecific ulcerations and aphthae [
206
,
208
].
Oral candidiasis and angular cheilitis are mycotic complications related to the loss of antimicrobial
action of saliva [
209
]. Parenchymal involvement can be complicated by recurrent parotid enlargement
of infectious, lithiasic, inflammatory or lymphomatous origin [
210
]. SG may be the site of bilateral
multicystic parotid masses and lymphoma.
4.4. Musculoskeletal Manifestations
Joint inflammatory manifestations are, after sicca syndrome, the most frequent manifestations of
pSS (50% of patients) [
211
]. Patients may have arthralgia with inflammatory characteristics (morning
stiffness >30 min) or less frequently true symmetric polysynovitis mimicking rheumatoid arthritis
(RA). Joint involvement of the pSS is generally moderate (<5 affected joints) and preferentially
affects the small joints of the hands and upper limbs [
211
,
212
]. Joint involvement is conventionally
non-erosive—except in case of an overlap with RA—but can be deforming (Jaccoud arthropathy) [
211
].
More rarely, pSS can be responsible for myositis. Finally, widespread pain is frequent—nearly 50% of
pSS patients—resembling primary fibromyalgia [213,214].
4.5. Neurological Manifestations
Neurological manifestations of pSS are relatively frequent (18–45% of patients) and affect both
the central and peripheral (sensitivomotor and autonomic included) nervous systems, with a higher
prevalence of peripheral manifestations [215].
The peripheral manifestations are polymorphic and can be differentiated according to
electromyographic examinations in mixed polyneuropathy, axon sensory polyneuropathy, sensory
ataxic neuronopathy, axon sensorimotor polyneuropathy, pure sensory neuronopathy, mononeuritis
multiplex or rarely chronic demyelinating polyradiculoneuropathy. The mechanisms mentioned are
mainly lymphocytic infiltration of the dorsal root ganglia (for sensory ganglioneuronopathy), vasculitic
lesions of the vasa nervorum and/or the presence of axon-specific autoantibodies. The cranial nerves
can also be involved, essentially the trigeminal nerve by involvement of the Gasser ganglion (associated
or not with a more extensive ganglionopathy) and the facial nerve (uni- or bilateral paralysis). The other
cranial nerves are affected anecdotally. Finally, damage to non-myelinated fibres can be responsible of
autonomic neuropathy or small-fibre neuropathy.
In the central nervous system, pSS may be responsible for encephalic or spinal manifestations,
with stroke-like or Multiple Sclerosis-like damage secondary to cerebral vasculitis. Some demyelinating
manifestations combining myelitis and optic neuritis are part of an associated neuromyelitis optica
spectrum disorder (NMOSD), a condition linked to the presence of anti-aquaporin 4 autoantibodies.
Neuro-pSS can also manifest as a recurrent aseptic lymphocytic meningitis. Rarely, the association of
upper and lower motor neuron diseases resulting in an amyotrophic lateral sclerosis-like syndrome
has been described during pSS.
Finally, cognitive dysfunction (“brain frog”), restless leg syndrome and psychiatric abnormalities
are classically linked to pSS, but it is not clear whether these manifestations are reactive or directly
linked to the pathophysiology of the disease.
4.6. Pulmonary Manifestations
The prevalence of clinically significant lung disease in pSS is 9–20% although subclinical
manifestations can be found in more than 50% of patients by CT-scan or bronchoalveolar lavage
findings. pSS exocrinopathy also affects the lower airways causing coughing, tracheobronchitis
sicca, bronchial hyperresponsiveness (mimicking late-onset asthma), cylindrical bronchiectasis and

J. Clin. Med. 2020,9, 2299 15 of 61
bronchiolitis (mainly follicular bronchiolitis). This involvement of the small airway epithelium is rarely
responsible for an obstructive ventilatory syndrome (11–14%) but can be complicated by recurrent
pulmonary infections or atelectasis [216,217].
Nonspecific interstitial pneumonia (NSIP) and usual interstitial pneumonia (UIP) are the most
frequent interstitial lung diseases (ILD) patterns during pSS, corresponding to 45% and 16% of cases
respectively. Lymphocytic interstitial pneumonitis (LIP) arrives in 3rd position (15% of ILD cases) and
can be considered as a more specific benign diffuse lymphoproliferative disorder of pSS, probably
starting from the follicular bronchiolitis. It must be differentiated from pulmonary lymphoma, which is
found in 2% of pSS-ILD. Other patterns such as organizing pneumonitis are less frequent (11%) or
even rare such as pulmonary amyloidosis, alveolar haemorrhage, Langerhans’ histiocytosis, cavitary
lung disease and/or combined pulmonary fibrosis and emphysema syndrome. However, presence of
multifocal cysts on CT-scan should raise clinical suspicion for pSS-ILD [211,216,217].
Pleural involvement is rare. In fact, pSS manifests by pleurisy only in less than one percent of
cases [207]. Shrinking lung syndrome occurs in extremely rare cases in pSS patients [218–223].
4.7. Dermatological Manifestations
Cutaneous involvement in pSS is relatively common and multiple manifestations are described
such as xeroderma, eyelid dermatitis, annular erythema/subacute cutaneous lupus-like lesions
and vascular purpura (caused by cutaneous vasculitis, urticarial vasculitis, cryoglobulinemia or
hypergammaglobulinemic purpura of Waldenström) [
211
]. More rarely pSS can be responsible for
cutaneous ulcer, livedo, erythema nodosum, panniculitis, amyloidosis or granuloma annulare [209].
4.8. Cardiovascular Manifestations
Raynaud phenomenon is the most frequent vascular manifestation, affecting 15% of patients [
207
].
Fortunately, cardiac manifestations such as pericarditis, pulmonary hypertension and cardiomyopathy
are very rare, affecting <1% of pSS patients, respectively [
207
]. Cardiac rhythm disturbances have
been described, secondary to ionic disorders, dysautonomia or direct impairment of the electrical
conduction system of the heart [224,225].
4.9. Oeso-Gastrointestinal Manifestations
Dysphagia is a frequent complaint in pSS patients generally related to inadequate lubrication of the
upper aerodigestive tract and food bolus resulting from hyposalivation. Oesophageal dysmobility is also
mentioned in certain cases, explaining the lack of correlation between xerostomia and dysphagia
[226,227]
.
Dyspepsia is frequent, occurring in 23% of pSS patients, and often linked to chronic atrophic gastritis
where inflammatory infiltrates similar to those of the SG are found following tissue histological
examination. Antibodies against parietal cells or intrinsic factor can be found, but pernicious anaemia
remains rare [
226
]. Manifestations such as diffuse abdominal pain, diarrhoea or malabsorption can occur
as part of a protein losing enteropathy or in case of overlap with Celiac disease [
226
,
227
]. Interestingly,
pSS patients with Primary Biliary Cirrhosis overlap (PBC) are at higher risk of developing duodenal
ulcers (85% of cases) [
226
]. The digestive tract can be the site of acute and serious complications in the
context of cryoglobulinaemic vasculitis.
4.10. Pancreatic and Hepatobiliary Manifestations
The pancreas being an exocrine gland, it is not surprising to find cases of acute pancreatitis, chronic
pancreatitis or pancreatic insufficiency in 0–7% of pSS patients. Moreover, 25% to 33% prevalence of
chronic pancreatitis-like morphologic changes suggest that there are many asymptomatic cases [226].
Hepatomegaly is found in 10–20% of patients. Liver tests are disrupted in 10–50% of patients, usually
mildly and with no particular clinical significance. pSS can be associated with Primary Biliary Cirrhosis
(PBC)—another autoimmune epithelitis—or with autoimmune hepatitis (AH). Pseudolymphoma has
been described to occur in liver like it may occur in salivary or lacrimal glands [226,227].

J. Clin. Med. 2020,9, 2299 16 of 61
4.11. Uronephrologic Manifestations
Schematically, renal involvement linked to pSS can be divided into 3 groups: (1) tubulointerstitial
nephritis linked to autoimmune epithelitis characterized by peritubular lymphocyte infiltration,
(2) glomerulonephritis associated with immune complexes and (3) disorders linked to the presence
of specific autoantibodies. According to different cohorts, about 5% of pSS patients have a renal
involvement. However, this figure seems clearly underestimated if occult tubular involvement is
systematically assessed [211,228].
Tubular involvement can be associated with dysfunction of any part of the renal tubule and can
be responsible for polyuropolydypsic syndrome, low molecular weight proteinuria, aminoaciduria,
euglycemic glycosuria, acidosis with normal anion gap, hypokalaemia that may be complicated by
paralysis or disturbed heart rhythm, hypophosphoremia linked to increased phosphate excretion
that may be complicated by osteomalacia, nephrocalcinosis or the formation of recurrent kidney
stones [
228
,
229
]. More anecdotally, acquired Gitelman or Bartter syndrome has been described,
possibly linked to the presence of specific autoantibodies targeting transporters (ie NaCl co-transporter
in Gitelman syndrome) [
228
,
230
]. Glomerular disease occurs later in the history of the disease and most
often corresponds to a mesangioproliferative glomerulonephritis (MPGN) caused by the deposition of
immune complexes, usually cryoglobulinemia, which should be looked for [211,228].
Interstitial cystitis is a chronic inflammatory disease of the bladder that can be found in pSS
patients. This rare manifestation is characterized by complaints such as pollakiuria, lower abdominal
pain, urinary urgency, painful micturition, haematuria and dysuria [
231
]. Interstitial cystitis can be
complicated by bilateral hydronephrosis and obstructive renal failure [231].
4.12. Haematological Manifestations
Anaemia is present in 20% of pSS cases, usually normochromic normocytic, of various mechanisms:
anaemia of chronic disease or haemolytic, more rarely secondary to aplastic or pernicious anaemia
or myelodysplastic syndrome [
232
,
233
]. Leukopenia is found in 15% of patients and most often
corresponds to lymphocytopenia. Agranulocytosis is rare. Thrombocytopenia is found in 15% of
patients, of peripheral origin, whether or not involved in Evans syndrome [
232
,
233
]. Rare cases of
Thrombotic Thrombocytopenic Purpura (TTP) [
234
–
236
] and Hemophagocytic lymphohistiocytosis
(HLH) [237] have been described.
Reactive multiple lymphadenopathy is possible, statistically associated with the presence of
synovitis [
212
]. The intense stimulation of B cells explains the occurrence of hypergammaglobulinemia,
hyperviscosity syndrome, monoclonal gammapathy, cryoglobulinemia and amyloidosis [
232
,
238
].
The formation of immune complexes leads to complement fraction consumption.
CD4-Lymphocytopenia is mainly found in anti-Ro-SSA positive patients and is associated with
an increased risk of non-Hodgkin’s lymphoma (NHL) [
232
]. NHL has a prevalence of 4.3% in pSS
patients [
205
]. Schematically, pSS-associated NHL can be divided into two main categories: the first
has an indolent course and is dominated by the extranodal marginal zone (MZ) B cell lymphomas of
MALT-type, and the second corresponds to the high-grade lymphomas such as de novo or secondary
diffuse large B cell lymphoma (DLBCL). In pSS patients, MALT lymphomas are indolent diseases
characterized by a good performance status, small tumour burden and infrequent B symptoms.
They are preferably located in one or more extranodal sites such as SG, stomach, nasopharynx, lung,
liver, kidney, orbit and skin [
205
]. It is interesting to note that almost all of these sites are organs
involved in autoimmune epithelitis. Locoregional nodal involvement can be observed while bone
marrow infiltration is rare. DLBCL are aggressive and have a poor prognosis. A certain proportion of
them probably come from a transformation from a low-grade lymphoma. NHL mainly occurs in pSS
patients with cryoglobulinemia, palpable purpura and C4 fraction consumption [205].

J. Clin. Med. 2020,9, 2299 17 of 61
4.13. Ear–Nose–Throat (ENT) Manifestations
ENT complaints are common (40–50%) in pSS patients but objective fibroscopic abnormalities
are less frequent (20%) [
239
]. Exocrinopathy can generate rhinitis sicca—reported by about 40% of pSS
patients—which is a source of discomfort, nasal crusting, sinusitis, epistaxis or smell and taste disorders [
240
].
pSS patients are more likely to develop laryngopharyngeal reflux (LPR) because oesophageal involvement
impairs anti-reflux mechanisms. LPR—in addition to pharyngitis sicca—manifests itself through various
ENT complaints such as dysphonia, throat pain, chronic throat clearing or Eustachian tube dysfunction [
241
].
As with other systemic vasculitides, pSS may be responsible for sensorineural hearing loss or
chondritis [
242
], responding to corticosteroid treatments. In an appealing way, pSS is associated with a
sensorineural hearing loss in a significant proportion of patients, mainly affecting high frequencies,
but whose clinical impact is not obvious [243].
4.14. Gynaecological and Obstetrical Manifestations
pSS does not have a negative impact on fertility, but chronic pain and vaginal dryness can be
the cause of dyspareunia having a negative impact on the sexuality of female patients [
244
]. During
pregnancy, pSS can be responsible for two rare but classic manifestations: autoimmune congenital
heart block and neonatal lupus [
245
–
247
]. These two manifestations are linked to the transplacental
passage of anti-Ro/SSA autoantibodies. Congenital heart block occurs in 2% of anti-Ro/SSA positive
pregnancies but with a 10 to 20% risk of recurrence in subsequent pregnancies. More rarely, neonatal
lupus can be associated with endocardial fibroelastosis, valvular malformations or septal defects.
Neonatal lupus—affecting one fifth of anti-Ro/SSA positive pregnancies—is characterized by an
erythematous rash and photosensitivity that can be associated with hepatic, haematological and
neurological involvement. Compared with healthy pregnancy, patients with pSS had significantly
higher chance of pregnancy loss or neonatal death. However, there were no significant associations
between pSS and premature birth, spontaneous or artificial abortion or stillbirth [
248
]. These data
should be taken with caution because they are based on a limited number of heterogeneous—and not
necessarily recent—studies.
5. Diagnosis Workup
5.1. Diagnosis Versus Classification Criteria
Faced with one or more compatible manifestations, the diagnosis of pSS must be evoked and
investigated. Making a diagnosis is the basis of medical care. For the patient, it represents the end of
questioning and diagnostic wandering. For the physician, the diagnosis makes it possible to clarify
the management. Finally, for the researcher, the diagnosis makes it possible to create homogeneous
groups around a consensus definition. Unfortunately, there is no single diagnostic test to confirm
the diagnosis of pSS. Due to its protean and willingly insidious presentation, pSS is sometimes
difficult to recognize and may delay diagnosis by more than 10 years. Sicca syndrome, fatigue and
unspecific musculoskeletal pain can be wrongly taken for manifestations of age, anxio-depression or
perimenopause in people with pSS. Systemic manifestations can sometimes precede sicca syndrome,
resulting in an “occult pSS” [
249
]. For these various reasons, the gold standard for individual diagnosis
of pSS remains the opinion of an expert clinician. To allow the study of the disease in groups of pSS
patients, several consensuses have defined classification criteria allowing a common definition of
what pSS is. The 3 most recent sets of classification criteria are presented in Table 2. By definition,
classification criteria are specific but may lack sensitivity and should not be used blindly as diagnostic
criteria but as a guide in clinical practice.

J. Clin. Med. 2020,9, 2299 18 of 61
Table 2.
Modern pSS Classification Criteria—comparisons of items, definitions and diagnosis
performance compared to experts’ opinions.
AECG Classification Criteria
(2002) [250]
SICCA Classification Criteria
(2012) [251]
ACR-EULAR Classification
Criteria (2016) [252]
Domain Item Definition Value Item Definition Value Item Definition Value
Subjective
eye dryness ≥1/3 specific questions
minor
/_/_
Subjective
oral dryness ≥1/3 specific questions
minor
/_/_
Ocular signs
Schirmer (≤5 mm/5 min)
OR
Van Bijsterveld ≥4
minor
OSS ≥31
Schirmer (<5 mm/5 min) 1
OSS ≥5
OR
Van Bijsterveld ≥4
1
SG dysfunction
UWSF (≤1.5 mL/15 min)
OR
Compatible parotid
sialography
OR
Anormal salivary
scintigraphy
minor
/_ UWSF (≤0.1 mL/min) 1
MSGB Focus-score ≥1
Major
Focus-score ≥1 1 Focus-score ≥1 3
Auto
antibodies
Anti-Ro/SSA or
Anti-La/SSB
Major
Anti-Ro/SSA or
Anti-La/SSB
OR
RF(+) with
ANA(+)≥1:320
1 Anti-Ro/SSA 3
pSS definition 4 out of 6 with ≥1 Major
(or 3 out of 4 objectives findings)
pSS signs and/or symptoms
with ≥2/3 criteria
Sicca or ESSDAI manifestation
with a total score ≥4
Exclusions
criteria
-
Past head and neck radiation
- Hepatitis C infection
- AIDS
- Pre-existing lymphoma
- Sarcoidosis
- Graft-versus-host disease
- Current use of
anticholinergic drugs
-
Past head and neck radiation
- Hepatitis C infection
- AIDS
- Sarcoidosis
- Graft-versus-host disease
-
Past head and neck radiation
- Hepatitis C infection
- AIDS
- Pre-existing lymphoma
- Sarcoidosis
- Graft-versus-host disease
- Amyloidosis
- IgG4-related disease
- Current use of
anticholinergic drugs
Sensitivity 93.5% 92.5% 96%
Specificity 94.0% 95.4% 95%
AECG =American European Consensus Group, SICCA =Sjögren’s International Collaborative Clinical Alliance,
ACR-EULAR =American College of Rheumatology—European League Against Rheumatism, UWSF =unstimulated
whole saliva flow, RF =rheumatoid factor, ANA =antinuclear antibodies, ESSDAI =EULAR Sjögren’s syndrome
disease activity index.
5.2. Sicca Syndrome and Glandular Assessment
The investigation for objective dysfunction of the salivary and lacrimal glands is useful for the
diagnosis and symptomatic management of the patient. Anatomical or functional imaging can be used
to assess changes in the major SG during pSS.
The evaluation of dry eyes requires a simple ophthalmological examination. The Schirmer test
consists of positioning a small strip of filter paper inside the inferior fornix of each eye. The eyes are
then closed for 5 min. After this time, the strips are removed, and the amount of tears absorbed by
capillarity is measured in millimetres from the edge of the strip in contact with the ocular surface.
Dryness is significant if
≤
5 mm/5 min. The evaluation then continues with the evaluation of the
stability of the tear film by the Break-up Time (BUT) and the search for conjunctival or corneal lesions
linked to dryness (keratoconjunctivitis sicca). These various tests use the slit lamp and the ocular
instillation of dyes. BUT is measured by placing a drop of fluorescein in each eye and measuring the
time during which the coloured tear film uniformly covers the ocular surface, before the appearance of

J. Clin. Med. 2020,9, 2299 19 of 61
dry spots. A tear BUT test of less than 10 s (averaged over 3 testings’) is considered pathological but is
not specific of pSS manifestations. Finally, damage to the conjunctiva and cornea is highlighted by
ocular surface staining techniques (fluorescein and lissamine green) [
253
]. The anomalies are scored
using standardized scores: van Bijsterveld scale or the SICCA Ocular Staining Score (OSS). Respective
cut-offs of
≥
4 and
≥
5 correspond to pathological situations suggestive of pSS. Those tests are more
specific of pSS than Schirmer and Break-up time tests. Rose Bengal dye is no longer used because of its
poor tolerance and local toxicity.
The evaluation of hyposalivation can be easily performed by sialometry. In its simplest form,
sialometry consists of measuring the Unstimulated Whole Salivary Flow rate (UWSF) and the Stimulated
Whole Salivary Flow rate (SWSF). UWSF is performed by asking the patient—fasted for minimum
2 h—to passively drain all the saliva produced in a tared jar for 15 min. The jar is then weighed
and the saliva volume estimated. UWSF less than 0.1 mL/min is considered pathological (normal
range 0.3–0.4 mL/min). UWSF represents a minor classification criterion. SWSF is measured in the
presence of mechanical stimulation. SWSF can be measured using the Saxon test or Gum test protocols.
Saxon test is performed by asking the patient to chew for 2 min a tared compress which will then
be weighed. Gum test is performed as USWF, but in this case, the patient chews chewing gum and
then spits saliva in a container. A diagnosis of hyposalivation is made if SWSF is
≤
0.5–0.7 mL/min
(normal range 1.5–2.0 mL/min). It is also possible to measure the salivary flow specific to each major
SG by aspiration or cannulation. However, these techniques are of little use to the rheumatologist and
especially uncomfortable for the patient.
Radiosialography is an X-ray imaging technique requiring the retrograde injection of a contrast
solution into the excretory ducts of the major SG. This technique indirectly highlights glandular damage
by studying changes in the “tree structure” of the excretory ducts [
254
]. Given the invasive nature and
the complications of this technique, it has been abandoned in favour of other non-invasive techniques.
SG scintigraphy (SGS) studies the uptake, the concentration and the basal or stimulated secretion of
a radioactive tracer by the parotid and submandibular glands following an infusion of Technethium-99
pertechnetate. SGS interpretation is mainly based on Schall’s classification [
255
], a qualitative score
classifying anomalies in 4 grades—from grade 1 (normal) to grade 4 (the total absence of uptake and
mouth activity). With
≥
3 as cut-off, sensitivity and specificity are 54–87% and 78–98%, respectively [
256
].
Salivary scintigraphy is one of the classification criteria of 2002 for pSS but has disappeared from the
most recent classification criteria of 2016. An abnormal scintigraphy makes it possible to objectify a
dysfunction of the SG but does not allow etiological diagnosis as no image is specific of pSS. However,
it may be of interest for treatment: if the examination shows SG with normal uptake but with a major
dysfunction of excretion (possibly due to an autonomic disorder), the patient could benefit from a
sialagogue treatment. In case of a scintigraphy demonstrating no uptake of the tracer, the parenchyma
is probably totally destroyed and a sialagogue treatment will be useless.
Ultrasound is a simple, non-invasive way to assess the parenchyma of parotid and submandibular
glands for diagnostic and prognostic evidence for pSS. Mode-B ultrasound using a high frequency linear
probe allows characterization of size, homogeneity, presence of hypo-/anechoic areas, hyperechoic
bands and clearness of SG borders. These different items were included in several diagnostic scores [
257
].
The OMERACT group, in an attempt to standardize, developed in 2019 a semi-quantitative scoring
(0–3) based on the presence of hypoechoic/anechoic zones within the parenchyma of the parotid and
submandibular glands [
258
]. A score
≥
2 is abnormal and suggestive of pSS. At present, SG ultrasound
(SGUS) is not part of classification criteria but may well be in the future [
259
]. Unfortunately,
correlations between histological abnormalities (lymphocytic infiltration, diseased parenchyma or
ductal ectasia/cysts) and SGUS lesions have not been corroborated [
254
]. SGUS scores improvement
after treatment with Rituximab prove that part of the abnormalities are correlated with the disease
activity and not only damage accrual [
260
,
261
]. To date, there is currently insufficient evidence to use
SGUS as a prognostic or treatment response factor. Thanks to its high spatial and contrast resolution,
low cost and accessibility, SGUS has replaced MRI in the diagnosis of the pSS patient.

J. Clin. Med. 2020,9, 2299 20 of 61
5.3. Labial Minor SG Biopsy
The minor SG biopsy (MSGB) is a simple procedure that can be performed with little equipment.
Several biopsy techniques have been described in the literature [
262
,
263
]. After disinfection,
the reappearance of small drops of saliva makes it possible to identify the accessory SG at the
level of the lateral third of the lower lip. The mucosa above these glands is anesthetized with an
injection of lidocaine. The mucosa is then opened with a scalpel over 5–10 mm and the glands removed
with forceps. The individualization and extraction of the glands is made easier by the hydrodissection
that occurs during local anaesthesia and by the eversion of the lip. Lobules are herniated towards the
surface of the wound by the application of pressure—digital or instrumental—on the external part of
the lip. For quality concerns, the removal of 4–6 glands—allowing the study of minimum 8 mm
2
of
glands—is recommended [
264
]. A parotid biopsy is only exceptionally performed because technically
more complex with a theoretical risk of damage to the facial nerve, for a diagnostic contribution
identical to MSGB based on focus-score. On the other hand, the detection of lymphoepithelial lesions
and early stage lymphomas—having a prognostic value—is more frequent/easier to detect on parotid
biopsies [263].
The central element of MSGB pathology is the presence of clusters of more than 50 mononuclear
cells (mainly lymphocytes) called foci. These foci in periductal or perivascular areas adjacent to normal
acini are counted, reported to the area investigated and expressed as a Chisholm–Mason score [
265
] or
a Focus-score [
266
]. Compared to the initial descriptions of those scores, some experts recommend
counting all foci, including those associated with areas of fibrosis or atrophy, for fear of changing the
Focus-score [
264
]. The Focus-score corresponds to the average number of foci per 4 mm
2
of gland.
It goes from 0 to 12, 12 corresponding by convention to the coalescence of the foci. The Chisholm
score ranks chronic sialadenitis from 0 to 4. Grade 0 corresponds in the absence of infiltration;
grade 1 corresponds to a slight infiltration of mononuclear cells, however not forming a focus; grade 2
corresponds to the presence of an infiltrate of mononuclear cells organizing in foci but whose density is
<1 focus per 4 mm
2
; grades 3 and 4 correspond to the presence of 1 or >1 focus per 4 mm
2
, respectively.
The presence of focal sialadenitis characterized by a Focus-score
≥
1 (Chisholm grade
≥
3) is a major
diagnostic argument for pSS and is included in the different classification criteria. Due to its sensitivity
and specificity >80% and its significant positive predictive value [
267
], the presence of a chronic focal
sialadenitis (Focus-score
≥
1) is particularly useful in the diagnosis of early pSS, even with specific
manifestations and autoantibodies negativity [249].
Although not part of the classification criteria, other anomalies can be described: fibrosis, acinar
atrophy, ectasia or metaplasia of the excretory ducts, histiocytic granulomas, presence of germinal
centre-like structures, lymphoepithelial or myoepithelial sialadenitis (LESA/MESA) [
268
,
269
]. LESA/MESA
are characterized by lymphocytic infiltration of ducts and basal cell hyperplasia, resulting in a multilayered
epithelium. In addition, pathology allows differential diagnosis with sarcoidosis, IgG4-related disease,
amyloidosis and lymphoma. Finally, MSGB provides information on the patient’s prognosis: a Focus-score
≥
3 and the presence of germinal centre-like structures or LESA/MESA are associated with more severe
disease and an increased frequency of local and systemic manifestations, including lymphoma. For this
reason, we recommend doing MSGB even if the diagnosis can be made based on anti-Ro/SSA positivity
with objective sicca syndrome.
The parotid biopsy has fallen somewhat into disuse due to the ease of performing a minor
SG biopsy with equivalent diagnostic performance. On the other hand, the possible discrepancies
with MSGB [
270
,
271
], the possibility of early detection of lesions associated with a poor prognosis,
the possibility of biopsying the same gland again to monitor the disease and the possibility of correlating
it with SGUS semiology make parotid biopsy a tool that would need to be reassessed in the future [
263
].
5.4. Antinuclear Antibodies (ANA) Profile
The other major element in the diagnosis of pSS is the presence of anti-Ro/SSA and/or anti-La/SSB
autoantibodies. The Ro/La system is a heterogeneous antigenic complex, composed by three different

J. Clin. Med. 2020,9, 2299 21 of 61
proteins (52kDa Ro, 60kDa Ro and La) and four small RNAs particles [
272
]. The search for antinuclear
antibodies (ANA) by Immunofluorescence (IF) on HEp-2/HeLa cells is therefore an important element
in the diagnosis of pSS. ANA is positive in 70% of pSS patients, usually with a fine speckled
fluorescence [
273
]. Anti-Ro/SSA and/or anti-La/SSB autoantibodies are identified in 50–90% and
25–60% of patients, respectively [
274
]. It should be borne in mind that the Hep-2 cells do not sufficiently
express Ro/SSA antigen, explaining the fact that 10% of patients anti-Ro/SSA-positive in ELISA have
negative ANA in IF on HEp-2 cells [
274
]. Therefore, in case of suspicion of pSS, it is necessary
to request the anti-Ro/SSA antibodies identification by ELISA, even in the presence of a negative
ANA IF screening. Two types of anti-Ro/SSA autoantibodies can be differentiated: anti-Ro52 and
anti-Ro60 [
272
]. Anti-Ro52/SSA have no specific ANA fluorescence staining pattern (might even exhibit
a cytoplasmic pattern [
274
]), is precipitin negative and is not detected by ELISAs based on natural
SSA/Ro. Ro52+Ro60+patients are likely to have pSS while Ro52+Ro60- patients are not [
275
]. Isolated
anti-Ro52/SSA positivity is statistically linked to primary myositis and systemic sclerosis. On the
other hand, anti-Ro52/SSA and anti-La/SSB have the highest relative risks of congenital heart block in
offspring from anti-Ro/SSA positive patients because these two antigens are expressed in foetal cardiac
tissue from the 18th to 24th week [
272
]. Anti-La/SSB is mainly found in the presence of an anti-Ro/SSA,
evoking a mechanism of epitope spreading. In only 2–3% of cases, pSS patients present with an
isolated Anti-La/SSB antibody [
276
,
277
]. The presence of another ANA pattern or the identification
of “atypical” ANAs can allow the identification of a secondary SS, an overlap with another systemic
disease or a specific pSS subgroup [
159
]. The prognostic implication of these antibodies is discussed in
the prognosis section.
5.5. Blood Workup
In addition to ANA testing, the initial blood workup for suspected autoimmune systemic
disease includes a complete blood count; a coagulation profile with antiphospholipid panel;
urea/creatinine dosage and urine sediment and 24-h urine protein or urine protein/creatinine
levels; Na
+
/K
+
/HCO
3−
/Cl
−
/Uric Acid levels to investigate renal tubulopathy; hepatic enzymes levels;
creatine phosphokinase (CPK) to investigate myositis; C3/C4/CH50 levels, Rheumatoid Factor (RF),
Cyclic Citrullinated Peptide (CCP) antibodies, Coombs test; serum protein electrophoresis and total
IgG, IgM and IgA levels to investigate presence of polyclonal hypergammaglobulinemia and/or
monoclonal gammapathy; HCV serology; VDRL/TPHA; free T4 levels, TSH, anti-thyroid peroxidase,
anti-thyroglobulin, anti-mitochondrial, anti-smooth muscle, anti-gastric parietal cell antibodies in
case of associated auto-immune diseases. Hypergammaglobulinemia and lymphopenia are classically
described during pSS. Their presence may be an additional argument, but their diagnostic performance
is not known.
5.6. Sjögren’s Syndrome Differential Diagnosis
Classically all disorders manifested clinically by sicca symptoms, glandular enlargement and/or
rheumatic/systemic manifestations fall under the differential diagnosis of pSS (Table 3). However,
a rational and pragmatic approach often leads to the correct diagnosis [278].
5.7. Primary versus Secondary Sjögren’s Syndrome
It is classic in medical nosology to describe the isolated and idiopathic form of a disorder as
“primary” and to qualify as “secondary” the forms associated with specific causes or entities. SS is no
exception. Historically, this dichotomy differentiated pSS patients from patients suffering from RA
complicated by sicca syndrome. Subsequently, “secondary SS” (sSS) extended to other connective
tissue diseases (e.g., SLE and Systemic Sclerosis (SScl)) and autoimmune diseases (e.g., primary biliary
cirrhosis, thyroiditis and vasculitis) [
279
]. This nomenclature has also been indirectly “ratified” in
AECG Classification Criteria from 2002 [
250
], classifying as “sSS” patients with another well-defined

J. Clin. Med. 2020,9, 2299 22 of 61
major connective tissue disease and at least one dry symptom (ocular or buccal) and 2 out of 3 signs of
exocrine dysfunction (MSGB, SG signs or ocular signs in Table 2).
Table 3. Differential diagnosis of Sjögren’s syndrome (non-exhaustive list).
Sicca Symptoms
Complex
Glandular
Involvement
Articular
Involvement
Systemic
Involvement
Xerogenic medications X _ _ _
Aromatase inhibitors (X) _ X (X) pSS-like
Age-related dryness X _ _ _
Metabolic sialadenosis _ X _ _
Non-SS dry eye diseases X _ _ _
Head and neck irradiation X _ _ _
Sarcoïdosis X X X X
Hyperlipoproteinemia (II, IV, V type) X X (X) _
Chronic Graft vs. Host disease X X X X
Primary lymphoma X X _ (X)
Amyloïdosis X X (X) (X) Renal,
purpura
Viral chronic sialadenitis (HCV, HIV, HTLV-1)
X (X) X X
Other chronic Non-specific sialadenitis X X Usually
unilateral _ _
Diabetes Mellitus X (X)
Sialadenosis
(X)
Cheiroarthropathy
(X)
Neuropathy
Haemochromatosis X (X) X CPPD (X)
Other connective tissue disease X _ X X
Rheumatoid arthritis (X) _ X (X)
Granulomatosis with polyangiitis X (X) X X
IgG4-related disease (Mikulicz syndrome) X X (X) (X)
Anxiety, fibromyalgia X _ (X) _
Checkpoint inhibitors X (X) X X
In light of current data, this dichotomy seems obsolete and should be reviewed. While
polyautoimmunity and overlap syndromes are currently recognized, one can wonder why SS is
still considered a second-class disorder.
Based on the examination of salivary gland biopsies of 34 RA patients with sicca symptoms,
two phenotypes can be differentiated [
280
]. One group of patients presented a phenotype characterized
by mild salivary gland lesions and negative autoantibody. Histologically, minor SG biopsies display
increased prevalence of antigen-presenting cells and CD8+T cells, decreased presence of B cells,
and “non-activated” epithelial cells (based on the expression of HLA-DR and co-stimulation proteins
D80/B7.1). A second group of patients presented a phenotype characterized by glandular manifestations
and/or auto-antibodies positivity. Their minor SG biopsies demonstrated CD80/B7.1 overexpression
and low frequency of S100+cells, correlated with the positivity of anti-Ro/SSA autoantibodies and/or
focus score
≥
1. Both groups had an historical RA-sSS and an RA-pSS overlap, respectively. In this
study, compared to RA patients without sicca symptoms, RA-sicca patients statistically present more
Raynaud’s phenomenon, SG enlargement, palpable purpura and renal, lung and liver involvement.
They displayed more frequent ANA, anti-Ro/SSA autoantibodies and RF positivity. The published
data do not allow us to know if these manifestations are over-represented in the second group.
From a serohistological point of view, there is no difference in terms of anti-Ro/SSA positivity,
anti-La/SSB positivity and SG infiltration between a pSS alone and an sSS associated with a SLE [
281
]
or SScl [
282
]. It therefore seems more like an overlap than a so-called sSS. On the other hand, as for RA

J. Clin. Med. 2020,9, 2299 23 of 61
patients, SS overlap modifies the associated clinical phenotype. Compared with SLE-alone patients,
patients with SLE-SS overlap are older and had a higher frequency of Raynaud’s phenomenon,
anti-Ro/SSA positivity, anti-La/SSB positivity and rheumatoid factor. They also had a significantly
lower frequency of renal involvement, lymphadenopathy and thrombocytopenia [
281
]. Compared
with SScl-alone patients, patients with SScl-SS overlap seem less at risk of serious complications from
SScl namely lung fibrosis, pulmonary artery hypertension and scleroderma renal crisis [282].
To summarize, “secondary SS” is to be banned from our vocabulary [
283
] or—at a pinch—redefined
very restrictively for some exocrine involvement occurring in rheumatoid arthritis not corresponding
to a real SS, if such an entity exists. Moreover, “secondary SS” has disappeared from the classification
criteria of 2012 and 2016. The patient has or does not have (p)SS, which may or not be associated with
other autoimmune diseases, reflecting common etiopathogenic pathways. In this way, the clinician
avoids three pitfalls: (1) minimizing the SS-related symptoms, which decrease the quality of life of
the patients; (2) forgetting that overlap may change the clinical phenotype and (3) forgetting the risk
of lymphoma. Unfortunately, pSS overlap syndromes had been under-recognized, under-researched
and possibly under-treated in the past because of the historical label of “secondary SS” and their
exclusions from the majority of clinical trials [
284
]. Their management is therefore based on the
clinician’s expertise, patient choices, best evidence and practice for the management of all associated
diseases. To better individualize pSS in the future, it would be necessary to be able to move from
a clinical definition to a molecular or even epigenetic signature.
6. Prognosis
Once the pSS diagnosis is made, treatment and medical decisions will be based on the expected
course of the disease and its impact on the patient’s life. This burden can be summarized in “5D”: Death
(mortality), Disease activity, Damage accrual, Discomfort (pain and sicca symptoms) and Disability.
To assess the effect of therapeutic interventions on the natural history and functional repercussions of
the disease, scores that can be used as clinical outcomes in trials have been developed.
6.1. Death
Although overall pSS mortality is low and similar to the general population [
285
], a subgroup
of patients will have a poorer vital prognosis. The excess mortality observed in such subgroup of
patients is generally attributed to the development of lymphoma or to uncommon but severe visceral
involvement. The leading causes of mortality in pSS patients are cardiovascular events, followed by
solid-organ and lymphoid malignancies and infections [
285
]. Risk factors associated with increased
mortality are advanced age at diagnosis, male sex, parotid enlargement, abnormal parotid scintigraphy,
extraglandular involvement, vasculitis, anti-SSB positivity, low C3 and C4 and cryoglobulinaemia [
285
].
pSS is associated with increased risks of overall cancer (pooled RR 1.17 to 1.88), non-Hodgkin
lymphoma (NHL) (pooled RR 8.53 to 18.99) and thyroid cancer (pooled RR 1.14 to 4.03) [
286
,
287
].
Biomarkers associated with the development of lymphoma are mainly signs associated with exuberant
B cell proliferation and immune-complex production [
288
–
290
]: parotid swelling, Focus-Score
≥
3,
germinal centre-like lesions, skin vasculitis or palpable purpura, complement consumption (Low C3,
C4 or CH50), presence of cryoglobulinemia or monoclonal paraproteinemia, rheumatoid factor,
increased
β
-2 microglobulin, lymphocytopenia, hypoglobulinemia, lymphadenopathy or splenomegaly
and head and neck irradiation.
6.2. Disease Activity
Disease activity may be defined as the functional or structural changes in an organ related to
inflammatory burden of the disease and are reversible under treatment. As in other inflammatory
diseases, disease activity can fluctuate over time and progress between relapses and remissions.
A significant proportion of pSS patients—nearly 50–70%—display a systemic manifestation at the
time of glandular onset or within 6 months, mainly lymphadenopathy/splenomegaly, non-erosive

J. Clin. Med. 2020,9, 2299 24 of 61
arthritis and neurologic involvement [
291
]. The long-term study of the Antonius Nieuwegein Sjögren
(ANS) cohort revealed that, within 10 years of diagnosis, 30.7% of the 140 patients included in this
study developed an associated extraglandular or autoimmune manifestation such as polyneuropathy,
interstitial lung disease, arthritis, discoid or subacute cutaneous lupus erythematosus (LE) and
Hashimoto’s disease [
292
]. The presence of cryoglobulinemia is associated with an increased risk of
developing a systemic manifestation [
211
,
292
]. On the other hand, presenting widespread pain seems
to be a “protective phenotype” [292].
Currently the European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI)
score has been used to quantify the inflammatory systemic activity of the disease. Within ESSDAI,
clinical or biological manifestations are classified as “low” (1 point), “moderate” (2 points) or
“high activity” (3 points) in 12 domains. To calculate the ESSDAI score, the value of the highest level
of activity for each domain is multiplied by the domain weight (1 to 6) and then added together.
The maximum theoretical ESSDAI score is 123. Minimal clinically important improvement was defined
as an improvement of at least three points. More recently, ClinESSDAI score, a variant of the ESSDAI
score without the biological domain, has also been used [293] (Table 4).
Table 4. Common damage, burden and activity scores for clinical monitoring of pSS patients.
EULAR Sjögren’s
Syndrome Disease
Activity Index
EULAR Sjögren’s
Syndrome Patient
Reported Index
Sjögren’s
Syndrome Disease
Damage Index
Sjögren’s
Syndrome
Damage Index
Abbreviation ESSDAI ESSPRI SSDDI SSDI
First description Seror et al. [294] Seror et al. [295] Vitali et al. [296] Barry et al. [297]
Year 2010 2011 2007 2008
Type Activity index PRO Damage index Damage index
Domains (n) 12 1 6 9
Items (n) 44 3 9 27
Items scoring 0 to 3 VAS (0–10) 1, 2 or 5 1
Domain weight 1 to 6 1 1 1
Calculation Sum Mean Sum Sum
Score range 0–123 0–10 0–16 0–27
Clinically significant
threshold
<5 Low ≥5, ≤13
moderate ≥14 high
≥
5/10 is an unsatisfactory
symptom state - -
Minimal clinically
important difference
≥3 points
improvement
≥1 point or ≥15%
improvement - -
VAS =visual analogue scale, PRO =patient reported outcome.
However, it should be borne in mind that (clin) ESSDAI score does not investigate all of the
possible events related to pSS. Out of 6331 patients included in the international register “The Big
Data Sjögren Project Consortium” [
207
], 1641 patients (26%) had at least one non-ESSDAI systemic
manifestation on a predefined list of 26 organ-specific features not currently included in the ESSDAI
classification. Patients with non-ESSDAI manifestations are patients with higher systemic activity than
patients without non-ESSDAI manifestations (mean ESSDAI 10.3 vs. 5.5, p<0.001).
Patients with significant systemic activity are generally patients with early onset disease,
antinuclear antibodies (ANA) positivity with a higher frequency of anti-Ro/SSA (with or without
anti-La/SSB), low C3, low C4 and cryoglobulinemia [
154
,
276
,
277
,
298
]. Children of anti-Ro/SSA positive
mothers are at risk of specific neonatal complications such as neonatal lupus and congenital heart
block [
277
]. Paradoxically, patients with higher disease activity are less disabled by sicca syndrome
or widespread pain [
276
,
277
]. Conversely, patients with late-onset seronegative disease will mainly
present a more disabling sicca syndrome but fewer systemic manifestations linked to the activity of
the disease [
277
]. Finally, isolated anti-La/SSB positivity occurs in only 3% of pSS patients and is

J. Clin. Med. 2020,9, 2299 25 of 61
associated with an intermediate phenotype between Ro/SSA positive- and seronegative patients [
277
].
Thus, systemic complications could appear many years after initial pSS diagnosis and justify long-term
surveillance, especially in cryoglobulinemia or “high risk” phenotype patients.
The immunological profile of pSS highlights the presence of atypical ANA—12% of cases [
299
]—or
other specific autoantibodies. A subset of pSS patients with anti-centromere positivity develops a
clinical phenotype overlapping between SS and systemic sclerosis with a higher age, more frequent
Raynaud’s phenomenon and keratoconjonctivitis sicca and a lower proportion of anti-Ro/SSA and
anti-La/SSB, rheumatoid factor, leukocytopenia and hypergammaglobulinemia [
159
,
299
]. In most
cases, a minority of these patients appear to progress to an authentic systemic sclerosis. Anti-Cyclic
Citrullinated Peptides (anti-CCP) positivity—present in 3–10% of patients—is associated with a greater
frequency of joint manifestations or with overlap with rheumatoid arthritis (RA) [
159
,
277
]. The presence
of anti-mitochondrial antibodies (1.7–13%) and anti-smooth muscle/anti-liver kidney microsomal
antibodies (30–62%) is associated with overlap with primary biliary cirrhosis and autoimmune
hepatitis [159].
6.3. Damage Accrual
Disease damage may be defined as the addition over time of irreversible functional or structural
changes resulting from disease activity, iatrogenic treatments or co-morbidities.
Two scores exist to quantify damage related to pSS: SS Disease Damage Index (SSDDI) [
296
]
and SS Damage Index (SSDI) [
297
]. SSDDI is composed of a list of 18 irreversible damages affecting
6 organ-domains (oral, ocular, neurologic, pleuropulmonary, renal and lymphoproliferative), divided
into 9 items weighted for severity. SSDI is an unweighted checklist of 27 items divided into 3 lists: ocular
damage, oral damage and systemic damage. Systemic damage is further subclassified into 7 areas:
neurological, renal, pulmonary, cardiovascular, gastrointestinal, musculoskeletal and malignancy
(Table 4).
In a retrospective study using 148 pSS patients attending the UCLH Sjögren’s clinic followed
for 10 years, Krylova et al. revealed that 28.3%, 36.7% and 45% of patients displayed SSDI damage
(excluding oral damage that was not assessed in the study) after 1, 5 and 10 years of disease,
respectively [
300
]. Items most involved are in the ocular domain, parotid swelling and malignancy.
These results suggested that pSS patients accumulate less damage—calculated on different scores—over
time than lupus patients, who have a greater inflammatory burden and use of immunosuppressive
treatments [300].
Another retrospective study using 155 pSS patients showed that the total increase of patients with
damage was 28% after 1 year, 44% after 3 years, 74% after 5 years and 83% at 10 years, with a good
correlation between SSDDI and SSDI [
301
]. More specifically, teeth loss and/or caries, salivary flow
impairment, corneal ulcers and tear flow impairment were reported in 49.5%, 34%, 22.6% and 11% of
patients, respectively. Unsurprisingly, systemic damage—observed in 13.5% of patients—was correlated
with basal ESSDAI, low C4 and lymphopenia. In the same way, persistent SG swelling—detected in
14% of patients—was associated with (bio)markers of systemic activity and B cell proliferation (lower
age at diagnosis, anti-Ro/SSA positivity, cryoglobulinemia, low C4, hypergammaglobulinemia and
lymphopenia). Lymphoproliferative disorders were detected in 4.5% and malignancy in 9% of cases at
10 years post-diagnosis [301].
6.4. Discomfort and Disability
SS can be disabling and associated with significant functional status impairment related to oral
and/or ocular dryness, systemic activity, pain, fatigue and daytime somnolence, anxiety and depression
symptoms [
302
–
304
]. Objective assessments of sicca syndrome correlated poorly with symptoms and
remain generally stable over time [
305
]. Besides the associated symptoms, sicca syndrome also has a
negative impact on smell, taste, pruritus, voice, swallowing and sexual function [
306
,
307
]. Fatigue and
pain are both correlated with reduced quality of life and psychological distress [
307
]. Patients with

J. Clin. Med. 2020,9, 2299 26 of 61
widespread pain—34.9% of the cohort—were more frequently negativefor anti-La/SSB, more frequently
seronegative for all autoantibodies (ANA/SSA/SSB/RF) and had statistically fewer extraglandular
manifestations in a Dutch study including 83 patients [
308
]. Another Italian study on 100 pSS patients
demonstrated a prevalence of widespread pain of 22%, a phenotype statistically associated with
fewer systemic and immunological manifestations (hypergammaglobulinemia, rheumatoid factor,
focus-score
≥
1) [
309
]. A subset of pSS patients therefore seem to develop a clinical phenotype with
lower visceral involvement but with significant morbidity linked to glandular manifestations and
a significant psychosomatic burden [
302
,
310
], bringing them closer to the notion of “Sicca Asthenia
Polyalgia (SAP) Syndrome” [
311
–
313
]. At diagnosis, one in 4 patients is unable to work. This figure
increases to more than 1 in 3 at 1 year. Work disability at 2 years is 40% and is related to fibromyalgia
pattern, age and incapacity for work at diagnosis [
314
]. pSS has a high individual and societal cost,
especially due to dental cost, symptomatic therapies and disease compensation [307].
EULAR SS Patient Reported Index (ESSPRI) is a consensus index calculated as the mean of 3 visual
analogue scales (VAS)—self-assessment of dryness, (limb) pain and fatigue—allowing easy measurement
of patients’ symptoms in pSS [
295
]. By convention, patient-acceptable symptom state was defined by an
ESSPRI <5/10 and the minimal clinically important improvement by a decrease of at least one point or
15%. The ESSPRI score is correlated with the Patient Global Assessment [PGA] [
295
] and with more
complex and time-consuming scores such as the Profile of Fatigue and Discomfort [PROFAD] [
295
],
Sicca Symptoms Inventory [SSI] [
295
], Health Assessment Questionnaire [HAQ] [
315
], Short Form 36
health survey [SF-36] [
302
], time trade-off values [TTO] and EuroQol5D VAS [
316
,
317
]. Very interestingly,
a study using baseline data from 120 patients included in the TEARS study revealed that—even if
there is a small correlation between ESSPRI and ESSDAI—ESSPRI is the only determinant associated
with the quality of life score SF-36 in a multivariate model [
318
]. The ESSPRI score is therefore a good
clinical screening and monitoring tool as well as a good surrogate endpoint to study the effectiveness of
therapeutic interventions on pSS associated “Sicca Asthenia Polyalgia” Syndrome (Table 4).
It is therefore important, a fortiori in mild cases with low activity score but disabling sicca
syndrome, to focus on improving the quality of life of patients through attentive and multimodal
symptomatic management and to offer a multidisciplinary management program for the most disabled.
7. Therapeutic
Despite a better understanding of its pathophysiology, treatment of SS remains disappointing
and essentially palliative. Systemic activity is treated by immunosuppressant drugs, based on
scarce evidence. Manifestations linked to damage caused by local or systemic activity of pSS
should be identified because they are by definition irreversible and cannot therefore be improved
by immunosuppressive treatments. In the last 5 years, pSS management has been addressed by
guidelines from EULAR [
210
], British Society of Rheumatology and National Institute for Health
and Care Excellence (NICE) [
319
], Brazilian Society of Rheumatology [
320
], Research Team for
Autoimmune Diseases [
321
] and Sjögren’s Syndrome Foundation [
322
]. The main principles for care
are summarized below.
7.1. Sicca Syndrome and Non-Visceral Manifestations
Despite the dysimmune origin of the disease, no immunosuppressive treatment has demonstrated
sufficient efficacy associated with a satisfactory risk–benefit balance in the treatment of sicca syndrome
and non-visceral aspecific manifestations (non-inflammatory widespread chronic pain, fatigue).
Treatment is mainly focused on symptom management and prevention or treatment of complications
resulting from exocrinopathy (Table 5).
Therapeutic approach to oral dryness must be driven by baseline objective and subjective severity
of hyposialia and xerostomia. To this end, current guidelines recommend evaluating baseline SG
function by measuring unstimulated (UWSF) and stimulated salivary flow (SWSF) or using salivary
scintigraphy. Subjective xerostomia impact is captured by a simple Visual Analogue Scale, as part

J. Clin. Med. 2020,9, 2299 27 of 61
of the ESSPRI score. EULAR guidelines propose an algorithmic approach to the management of
dry mouth: patients with an UWSF <0.1 mL/min are categorized based on their SWSF as mild
(>0.7 mL/min), moderate (0.1–0.7 mL/min) or severe dysfunction (<0.1 mL/min). Self-care advice and
non-pharmacological stimulation are proposed to mild cases as first line therapy [
210
]. Pharmacological
stimulation (pilocarpine per os or as a mouthwash, cevimeline per os) is the treatment of choice in
moderate cases (with residual SG function) or in mild dysfunction patients who failed to respond to
basic recommendations, in addition to first line therapy. Saliva substitutes are reserved for patients
with no residual function or as a third line treatment in non-responding patients.
Table 5. Current treatment for sicca-related manifestations.
Salivary Gland Involvement Lachrymal Gland Involvement Skin and Vaginal Mucosa
Involvement
Self-Care
- Environment humidification
-
Elimination of offending drugs
- Avoidance of caffeine, alcohol
- Avoidance of tobacco
- Excellent oral hygiene
- Limit acidic and sugar intake
- Limit eating between meals
- Chew xylitol-containing gum
- Environment humidification
- Elimination of offending drugs
- Excellent ocular hygiene
Conserve - Scleral contact lenses
Replace - Salivary substitutes
- Artificial tears
- Liposomal spray
- Autologous serum drops
- Vaginal lubricants
- Topical oestrogen
Stimulate
- Mechanical stimulants (gums)
- Pilocarpine PO
- Pilocarpine mouthwash
- Cevimeline PO
- Choleretic (anetholtrithione)
- Mucolytic (NAC, bromhexine)
- Electrostimulation
- Pilocarpine 5 mg q6h PO
- Pilocarpine eye drops
- Cevimeline 30 mg q8h
- Lid hygiene with hot pad
- Diquafosol eye drops (Japan)
- Rebamipide eye drops (Japan)
-
Pilocarpine 5 mg q6h PO
- Cevimeline 30 mg q8h
Complications
Prevention and
Management
- Fluoride mouthwash
- Chlorhexidine mouth bath
In case of candida infection
- Oral nystatin
- Fluco-/Itraconazole
In case of glands swelling
- Exclude stone or infection
- Massaging major glands
- NSAID or glucocorticoid drops
- Calcineurin inhibitors drops
- Lifitegrast eye drops
- Botulinium toxin treatment
- Corneal grafting
- Doxycycline PO
The stomatological complications of exocrinopathy affecting the SG are cavities formation,
periodontal disease, candida infections and glandular swellings linked to abscess or to a lithiasic
disease. It is therefore strongly recommended that patient adopts impeccable dental hygiene and be
evaluated at least 2 times per year by a dental professional. Local fluoride-based treatments can be
administrated. Candida simple infection (visible white plaques) are treated with Nystatin mouthwash
for 7 days. One-week prophylactic treatment may be repeated every 8 weeks in the event of recurrence.
Erythematous infection of tongue or oral cavity is treated with Fluconazole 50 mg for 10 days. Angular
cheilitis is treated with Miconazole topically on each side of the mouth for 2 weeks. Presence of
abscess or lithiasic involvement can be treated with antibiotic treatment and stomatologist involvement
is indicated. If no infectious or mechanical cause is found in case of gland swelling, a distinction
must be made between primary neoplasia, systemic activity of the disease (as scored in ESSDAI,
treated by glucocorticoid in loco by sialendoscopy, per os or intra-muscular) and the appearance of a
lymphomatous complication.
The management of dry eyes must also be guided by the objective and subjective severity
of keratoconjunctivitis sicca (KCS), resulting from damage to corneal and conjunctival epithelium
secondary to accelerated tear-film break-up and hyperosmolar tear composition. EULAR guidelines

J. Clin. Med. 2020,9, 2299 28 of 61
propose an algorithmic approach based on Ocular Staining Score (OSS) score and Ocular Surface
Disease Index (OSDI) questionnaire to classify patients as non-severe or severe KCS [
210
]. The British
Society of Rheumatology recommended a classification into 3 categories (mild, moderate and severe
dry eyes) based on the Schirmer’s test, Break Up Time (BUT) and ocular staining [
319
]. First line
therapy for all patients with dry eyes is the instillation of preservative-free artificial tears containing
methylcellulose or hyaluronate, and ointment at night. In DREAM studies, use of supplements of n-3
fatty acids for 12 month and beyond does not improve OSDI, staining scores, BUT or Schirmer test
compared to olive oil in dry eyes patients [
323
,
324
]. Although these treatments are not associated with
an improvement in objective parameters, substantial subjective improvement in both groups suggests
that daily olive oil teaspoon should be used in dry eye management [
325
]. Although the origin of the
dryness is the decrease in the production of tears, a dysfunction of the Meibomian glands can also be
associated and must be treated by daily eyelid massage with hot pad or liposomal spray to reconstitute
the lipid layer preventing the evaporation of the tear film. In patients with persistent Meibomian
inflammation and blepharitis, doxycycline 50 mg once daily for a minimum of 3 months is effective as
a metallomatrix proteinase inhibitor. In case of refractory case of severe KCS, local treatment using
NSAID-, glucocorticoid- or cyclosporin-containing eyedrops can be used under the strict supervision
of an ophthalmologist. Rescue therapies by serum eye drops, oral or topical muscarinic agonists,
lifitegrast-containing eyedrops or lacrimal plugs insertion must be evaluated in specialized settings.
Only two Disease Modifying Anti-Rheumatic Drug (DMARDs) have demonstrated a significant
effect on sicca syndrome: Methotrexate in a small uncontrolled trial [
326
], and Mizoribine (a Japanese
DMARD) in 2 cohort studies [
327
,
328
]. With regard to biological therapies, infliximab, etanercept,
belimumab and tocilizumab have failed to demonstrate a favourable effect on exocrine glandular
function in their respective RCTs. “Abatacept Sjögren Active Patients” (ASAP) proof-of-concept trial
on abatacept showed a significant improvement in ESSPRI and BUT, but not on SWSF while another
trial showed no effect on ESSPRI and SWSF. Some randomized trials, but not all, find an improvement
in exocrine function and dryness with rituximab. In TEARS study, a study using 120 patients, aims for
a>30% improvement in at least 2 VAS in 4 (fatigue, pain, dryness and PGA) at 6–16–24 weeks, primary
endpoint is only reached at week 6, and this effect is no longer found thereafter. Dryness VAS is
statistically different from the placebo group from week 6 to 24, but no group achieved a clinically
significant decrease. The other large trial, TRACTISS, studying the effect of rituximab on 133 patients
with a primary endpoint of >30% improvement oral dryness and fatigue VAS at 48w, did not show
significant improvements in any outcome measure, except unstimulated salivary flow. However,
this intervention does not seem cost-effective. The clinical significance of those differences remains to
be determined and is interpreted according to the various guidelines. Only the Sjögren’s Syndrome
Foundation proposes to use rituximab as rescue therapy for sicca syndrome [322].
In pSS patients, complaints regarding general non-specific symptoms (non-inflammatory
musculoskeletal pain and fatigue) mimicking a fibromyalgia picture are common and can be challenging
for the clinician. In this context, differential diagnosis is important. Non-specific manifestation of
another condition (e.g., hypothyroidism, hypocortisolism, osteoarthritis, depression, neoplasia) or
resulting from a misleading manifestation linked to the systemic activity of the disease (e.g., myositis,
inflammatory arthralgia or arthritis, hypokalaemia or osteomalacia due to tubular involvement,
small fibre neuropathy or lymphoma) must be ruled out. When no secondary cause is identified,
this fibromyalgia-like presentation can be treated as such [
329
]. These can be quantified and monitored
using the ESSPRI score or standardized scores such as the Profileof Fatigue and the Brief Pain Inventory.
Education and management according to the biopsychosocial model of chronic pain, lifestyle adaptation,
sleep management strategies and the practice of moderate physical activity are the cornerstones of
the management of fatigue and pain. Many patients report benefit from joining a SS support group.
If drug treatment is necessary, it will consist of the prescription of conventional painkillers (short-term
acetaminophen or NSAID). Antidepressants and anticonvulsants may be considered as co-analgesic
medications in chronic musculoskeletal or neuropathic pain, keeping in mind the anticholinergic effect

J. Clin. Med. 2020,9, 2299 29 of 61
of these drugs, which can worsen sicca syndrome. Opioids are not suitable treatments for chronic pain
patients. DHEA supplementation is not recommended.
As a rule of thumb, systemic immunomodulatory drugs should not be used to treat non-specific
systemic manifestations because evidence is scarce. In currently available biotherapies, abatacept and
belimumab failed to demonstrate an effect on fatigue and pain VAS. Data on rituximab are conflicting:
3 RCTs showed an improvement in fatigue VAS, results not found in the large TRACTISS trial. A phase
2 RCT on a total of 17 patients failed to demonstrate >20% improvement of fatigue VAS at 24 weeks,
fatigue VAS improvement at 24w or >30% improvement of fatigue VAS at 24w. The authors only
report a statistically significant improvement in fatigue VAS in treated group compared to baseline,
while the placebo group did not reach a statistically significant difference [
330
]. In two other studies,
patients with early pSS and active disease treated with RTX displayed a significant improvement
in fatigue VAS compared to placebo from different time points post-treatment [
331
,
332
]. All RCTs
have shown that rituximab is not associated with an improvement in pain VAS. An RCT investigating
the effect of anakinra on fatigue, although not reaching its primary endpoint, shows a significant
improvement in VAS fatigue [
333
]. Off-label use of DMARD or biological treatments, even as a rescue
therapy, is currently not mainstream recommendation in this indication. However, some guidelines
suggest a trial of hydroxychloroquine in patients with recurrent musculoskeletal complaints or fatigue,
mainly based on “experience-based medicine”. In its 2015 guidelines, Sjögren’s Syndrome Committee
of Brazilian Society of Rheumatology highlighted the possibility of using rituximab as rescue therapy
for fatigue (but not sicca syndrome) management [320].
7.2. Systemic Manifestations
Management of visceral manifestations linked to disease systemic activity is currently based
only on rare randomized controlled trials, cohort studies or case-reports [
334
]. Treatment regimens
are often borrowed from systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), mixed
cryoglobulinemia or idiopathic organ-specific autoimmune disease management.
Therapeutic regimen must be tailored to organ specific involvement and severity of the disorder.
This approach requires organ-by-organ examination of disease activity and pre-existing damage.
To this end, ESSDAI score may be used as a guide but does not take into count all the systemic
manifestations of pSS [
210
]. As a rule of thumb, systemic immunosuppressive therapy will only be
offered to patients with moderate or severe organ activity (as define in ESSDAI score) or moderate
overall systemic activity (ESSDAI
≥
5) [
210
]. Organ manifestation classified as mild usually requires
only self-care advice, local treatment or pain relief medication (NSAID for inflammatory arthralgia
or co-analgesic for neuropathic pain). In case of treatment failure, low-dose corticosteroid treatment
and/or conventional DMARD may be considered depending on clinical manifestation.
In cases requiring immunosuppressive therapy, an induction/remission biphasic regimen is
recommendedfortherapidcontroloforgan damageandthepreservationofitsfunction[
210
]. Corticosteroid
therapy is an almost essential treatment for moderate to severe systemic manifestations. To date,
no steroid-free regimen has been studied in pSS and 95% of the published regimens include corticosteroid
therapy, alone or in combination with an immunosuppressant [
210
]. When immunosuppressive therapy is
prescribed, it is usually a conventionalbroad-spectrum immunosuppressant usedas a cortisone-sparing or as
a remission-inducing agent: hydroxychloroquine, methotrexate, other conventional DMARDs (leflunomide,
salazopirine), mycophenolate mofetil or cyclosporine. As there are no head-to-head comparisons, the choice
of immunosuppressant is mainly based on the clinician’s experience and on the therapeutic regimens
used in idiopathic or lupus-related disorders (HCQ and MTX in skin and articular involvement, AZA,
CyA or MMF in pulmonary or renal involvement). Severe life- or organ-threatening manifestations (central
nervous system involvement, glomerulonephritis), generally require an aggressive regimen including
methylprednisolone pulse-therapy combined with an alkylating agent (usually cyclophosphamide IV
or PO, more rarely chlorambucil) as remission-inducing agents. IVIG at immunomodulatory doses are
used in neuropathies or myositis. Biological therapies (mainly rituximab) generally come only in the

J. Clin. Med. 2020,9, 2299 30 of 61
third line as rescue therapies. The exception to this rule concerns the manifestations associated with
cryoglobulinemia where rituximab is proposed as an immunosuppressant of choice, in combination with
corticosteroid therapy or even plasmapheresis in life-threatening cases. As with other autoimmune diseases,
corticosteroid therapy should be reasoned with a tapering regimen guaranteeing the shortest possible
exposure to supraphysiological doses while maintaining remission. Complications of chronic corticosteroid
therapy must be addressed proactively.
Hydroxychloroquine is commonly used as first line DMARD for moderate systemic manifestations
mainly affecting the skin and joints. Its use is mainly based on the similarities between pSS and SLE,
as pSS is sometimes considered as “lupus of mucous membranes”. As opposed to SLE, the evidence
for its use in systemic manifestations of pSS does not actually exist, and its use is completely empirical.
The first—JOQUER trial—attempting to demonstrate the effect of hydroxychloroquine over 24 weeks
failed to reach the primary endpoint (30% or greater reduction between weeks 0 and 24 in scores on 2
of 3 VAS (dryness, pain, and fatigue)) [
335
]. In a more recent RCT performed over 2 weeks, no effect of
hydroxychloroquine was seen on BUT test, Schirmer test, corneal staining score or OSDI score [
336
].
While those RCT have not been designed to investigate the effect of the drug on systemic manifestations
of the disease, and the number of patients was small, hypergammaglobulinemia statistically improved
significantly [335,336].
7.3. pSS-Associated Lymphoma
The occurrence of lymphoma is a complication that must be screened clinically, especially in
patients at risk (see above). Any appearance of a firm, painless glandular swelling must be investigated
if it does not disappear spontaneously. The exams of choice to detect lymphoma are an MRI of the
major SG and a CT of chest, abdomen and pelvis for staging or a PET scan to investigate the entire
body in a single examination. pSS patients with lymphoma require personalized treatment provided
by an oncohematologist according to the histological type, the extent of the involvement and the
systemic manifestations.
7.4. Obstetrical Considerations
Ideally, pSS patients of childbearing age should benefit from a preconception consultation aimed at
reviewing their treatment and their serological profile (anti-Ro/SSA, anti-La/SSB and antiphospholipid
panel). Low-dose aspirin can be considered to promote placental implantation [
319
]. Anti-Ro/SSA
positive mothers should be followed regularly by foetal ultrasound in a specialized centre [
210
,
319
].
Prophylactic treatment of neonatal atrioventricular block with hydroxychloroquine may be offered,
since this drug is compatible with pregnancy [
210
]. If a conduction disorder appears on a follow-up
ultrasound, rescue therapy with glucocorticoid with or without IVIG may be attempted [
210
]. In the
event of atrioventricular block at birth, a pacemaker must be quickly implanted.
7.5. Targeted Therapies: Revolution or Disillusion?
Targeted therapies have revolutionized Rheumatology in recent years, especially in chronic
inflammatory rheumatism—such as in RA—and, to a lesser extent, systemic diseases such as SLE and
vasculitis. In terms of pSS, many targeted therapies have been tested or are currently in the pipeline.
Unfortunately, a revolution like the one known in the field of RA has not yet occurred. These targeted
drugs are shown in Figure 4and summarized in Tables 6–12.
Given their predominant role in the production of autoantibodies, germinal centres and the
evolution towards lymphoma, B cell depletion is one of the therapeutic mechanisms studied in pSS
(Tables 6–8). In addition to the mixed results of the anti-CD20 Rituximab RCTs, other targeted drugs
have been studied. Epratuzumab, an anti-CD22 B cell depleting therapy studied in SLE patients had a
positive effect on the systemic activity of SLE patients with Sjögren syndrome in a post-hoc analysis of
EMBODY trial [
337
]. However, an RCT should be designed to assess the effect of the therapy on both
ESSDAI and ESSPRI in pSS patients. Other B cell depletion strategies aiming at blocking the BAFF

J. Clin. Med. 2020,9, 2299 31 of 61
pathway showed a positive effect on the ESSDAI and ESSPRI scores at 28–52 weeks [
338
,
339
]. However,
the confirmation of these promising results against a placebo is necessary. Other strategies targeting
BAFF pathway are also under investigation: a TACI-antibody fusion protein called RC18, rituximab
+belimumab combo therapy, Tibulizumab—a dual anti-BAFF (belimumab) and anti-IL-17 antibody
(Ixekizumab)—and Ianalumab (anti-BAFF receptor). The results of these different studies are expected
during 2020. B cell targeting drugs by Bruton tyrosine kinase inhibitor (4 molecules), LTßR fusion
protein, PI3K
δ
inhibitor (3 molecules) and Cathepsin S inhibitor are currently being evaluated with
inconclusive results to date. Bortezomib, a proteasome inhibitor used for the treatment of multiple
myeloma, has been successfully used in 2 cases of refractory pSS reports but has never been studied on
a larger scale [236,340].
J. Clin. Med. 2020, 9, x FOR PEER REVIEW 31 of 63
specialized centre [210,319]. Prophylactic treatment of neonatal atrioventricular block with
hydroxychloroquine may be offered, since this drug is compatible with pregnancy [210]. If a
conduction disorder appears on a follow-up ultrasound, rescue therapy with glucocorticoid with or
without IVIG may be attempted [210]. In the event of atrioventricular block at birth, a pacemaker
must be quickly implanted.
7.5. Targeted Therapies: Revolution or Disillusion?
Targeted therapies have revolutionized Rheumatology in recent years, especially in chronic
inflammatory rheumatism—such as in RA—and, to a lesser extent, systemic diseases such as SLE and
vasculitis. In terms of pSS, many targeted therapies have been tested or are currently in the pipeline.
Unfortunately, a revolution like the one known in the field of RA has not yet occurred. These targeted
drugs are shown in Figure 4 and summarized in Tables 6–12.
Figure 4. Synoptic view of targeted drugs (being) studied in pSS. Therapeutic classes are in bold.
Biotherapies and small molecules are in black if they have been the subject of one or more trials in
pSS or in grey if they exist but have not been tested in pSS. Names in strikethrough are drugs whose
development has been stopped because of unacceptable side effects or because of portfolio
prioritization.
Given their predominant role in the production of autoantibodies, germinal centres and the
evolution towards lymphoma, B cell depletion is one of the therapeutic mechanisms studied in pSS
(Tables 6–8). In addition to the mixed results of the anti-CD20 Rituximab RCTs, other targeted drugs
have been studied. Epratuzumab, an anti-CD22 B cell depleting therapy studied in SLE patients had
a positive effect on the systemic activity of SLE patients with Sjögren syndrome in a post-hoc analysis
of EMBODY trial [337]. However, an RCT should be designed to assess the effect of the therapy on
both ESSDAI and ESSPRI in pSS patients. Other B cell depletion strategies aiming at blocking the
BAFF pathway showed a positive effect on the ESSDAI and ESSPRI scores at 28–52 weeks [338,339].
However, the confirmation of these promising results against a placebo is necessary. Other strategies
targeting BAFF pathway are also under investigation: a TACI-antibody fusion protein called RC18,
rituximab + belimumab combo therapy, Tibulizumab—a dual anti-BAFF (belimumab) and anti-IL-17
antibody (Ixekizumab)—and Ianalumab (anti-BAFF receptor). The results of these different studies
are expected during 2020. B cell targeting drugs by Bruton tyrosine kinase inhibitor (4 molecules),
LTßR fusion protein, PI3Kδ inhibitor (3 molecules) and Cathepsin S inhibitor are currently being
evaluated with inconclusive results to date. Bortezomib, a proteasome inhibitor used for the
treatment of multiple myeloma, has been successfully used in 2 cases of refractory pSS reports but
has never been studied on a larger scale [236,340].
Figure 4.
Synoptic view of targeted drugs (being) studied in pSS. Therapeutic classes are in bold.
Biotherapies and small molecules are in black if they have been the subject of one or more trials in
pSS or in grey if they exist but have not been tested in pSS. Names in strikethrough are drugs whose
development has been stopped because of unacceptable side effects or because of portfolio prioritization.
T-cells play a central role in the modulation and polarization of the local autoimmune reaction
within lymphocyte infiltrates in the exocrine glands. They are also used as therapeutic target by
biotherapies interfering with the T-cell co-stimulation (Table 9). To date, there is no convincing result
to recommend these treatments in pSS, but most studies targeting the CD40-ligand (CD154)/CD40
pathway are in progress. Therapies targeting T-cell trafficking, such as Fingolimod or Natalizumab,
have not been studied in pSS.
With regard to anti-cytokine targeted therapies, RCTs using anti-TNF (infliximab and etanercept)
and anti-IL6 receptor (tocilizumab) are negative (Table 11). Anakinra demonstrated a statistically
significant decrease in fatigue VAS, without however reaching its primary clinical endpoint.
The development of GSK2618960—an anti-IL-7R
α
biotherapy—was stopped by the company due
to the prioritization of their portfolio. So far, only one RCT studying the effect of Ustekinumab—an
anti-IL-12/IL-23 antibody—on ESSDAI score at week 24 as primary endpoint is expected to give results
in 2022 [341].
In a phase II trial, Filgotinib—a Jak1 inhibitor—and Lanraplenib—a SIK inhibitor—failed to
demonstrate a significant effect on the ESSDAI and ESSPRI scores [
342
]. Finally, innovative therapies
targeting plasmacytoid dendritic cells, immune complexes by RNase1-Fc fusion protein or the induction
of T-reg cells by low-dose IL-2 injections are being evaluated. These various therapies are reviewed in
Table 12.

J. Clin. Med. 2020,9, 2299 32 of 61
Table 6. B cell targeted drugs in pSS part 1: monoclonal antibodies directed against B cell specific Cluster of Differentiation (CD).
DRUG TRIAL (Reference) Inclusion Criteria
Number of Subjects Age
(Years)
Disease
Duration
(Years)
Mean
ESSDAI
Primary
Outcome Results
Effects (Statistically Significant)
Drg Ctrl Sicca
Syndrome Fibro-Like Systemic
Rituximab
Anti-CD20
NCT00363350
Phase I/II
[343]
AECG criteria
RF+and SSa and/or SSb+
SWS >0.15 mL/min
20 10 43
±11
5.25
±4.17
8
(4–13) SWS

at 48w met
SWS/UWS

LG test

Schirmer =
BUT =
SF36

MFI

Vasculitis

Phase III
[330]
AECG criteria
SSa and/or SSb+
F-VAS ≥5/10
8 9 51
(22–64)
7.25
(1–18) na

>20% of F-VAS
at 24w;

F-VAS at 24w;

>30% of F-VAS
at 24w
not met
not met
not met
UWS =
Schirmer =
F-VAS

PROFAD

P-VAS =
Soc-SF36

Glandular

Phase III
[332]
AECG criteria
SSa and/or SSb+
Disease duration ≤2y
2/5 of [PhGA >50 mm or
ESSDAI ≥6 or
subESSPRI ≥5]
19 22 40
(27–53)
1
(1–2)
20
(6–41)
∆ESSDAI until
120W
met
from 24w
to 120w
D-VAS

Schirmer

UWS

P-VAS =
F-VAS

ESSDAI

NCT00740948 Phase III
TEARS
[331]
AECG criteria with 2/4
VAS ≥5/10 for PhGA,
pain, fatigue and dryness
AND biologically active
OR 1 extra-glandular
manifestation or parotid
gland enlargement.
63 57 52.9
±13.3
4.6
±4.8
10
±6.9

30% of at least
2/4 VAS at
6-16-24w
met at 6w
not met
at 16-24w
D-VAS

Schirmer =
P-VAS =
F-VAS

ESSDAI =
Glandular =
Articular =
Phase III
TRACTISS
[344]
pSS with SSa+
UWS >0 mL/min
F-VAS and D-VAS >5/10
67 66 54
±11.5
5.7
±5.4
5.7
±4.5

30% D-VAS and
F-VAS at 48w not met
UWS

ESSPRI =
D-VAS =
F-VAS =
SF36 =
PROFAD =
ESSDAI

Epratuzumab
Anti-CD22
Post-hoc
Phase I/II
EMBODY
[337]
SLE with SSa+and
SS diagnosis
31
+41 40 46.4
±12.3
5.1
(0–34) na
BICLA at 48w
∆BILAG at 48w
∆SLEDAI at 48w
∆PhGA at 48w
met
met
not met
not met
na na BILAG

AECG =American European Consensus Group, Drg =drug/treatment group, Ctrl =control group, Fibro-like =fibromyalgia-like symptoms such as fatigue and widespread pain, FR+ =
presence of rheumatoid factor, SSa/SSb =anti-Ro/SSa and anti-La/SSb, SWS =stimulated whole saliva flow, UWS =unstimulated whole saliva flow, LG test =lissamine green test, BUT =
break-up time, SF36 =Short Form 36 health survey score, Soc-SF36 =social component of SF36 score, Phys-SF36 =physical component of SF36 score, MFI =Multidimensional Fatigue
Inventory score, F-VAS =fatigue visual analogue scale, Schirmer =Schirmer test, P-VAS =Pain visual analogue scale, PROFAD =Profile of Fatigue and Discomfort, DSST =Digit Symbol
Substitution Test, ESSDAI =EULAR SS disease activity index, D-VAS =dryness visual analogue scale, PhGA =physician global activity visual analogue scale, subESSPRI =P-VAS, D-VAS
or F-VAS, BILAG =British Isles Lupus Assessment Group index, BICLA =BILAG-based Combined Lupus Assessment, ESSPRI =EULAR SS Patient Reported Index, SAEs =serious
adverse effects, SGUS =salivary gland ultrasound, Ig =immunoglobulin,


=decrease/increase, ∆=difference.

J. Clin. Med. 2020,9, 2299 33 of 61
Table 7. B cell targeted drugs in pSS part 2: BAFF/APRIL system targeted therapies.
DRUG TRIAL
(References) Inclusion Criteria
Number of Subjects Age
(Years)
Disease
Duration
(Years)
Mean
ESSDAI Primary Outcome Results
Effects (Statistically Significant)
Drg Ctrl Sicca
Syndrome Fibro-Like Systemic
Belimumab
Anti-BAFF
NCT01160666
NCT01008982
Phase II
BELISS
[338,339]
AECG criteria
SSa and/or SSb+
AND systemic
complication OR B cell
activation OR early
disease (≤5 years)
30 - 49.5
±6.5
5.7
±5.6
8.8
±7.4

of 2/5 VAS at 28w
-≥30% D-VAS;
-≥30% F-VAS;
-≥30% P-VAS;
-≥30% PhGA;
-≥25% B cell markers
60% response
ESSPRI

D-VAS

UWS =
Schirmer =
ESSPRI

P-VAS =
F-VAS =
SF36 =
ESSDAI

Glandular

Follow-up of previous
study 15 - 40.2
±11.8
5.9
±5.7
3.8
±3.1
Idem
between 28–52w
86.7%
Stable response
ESSPRI

D-VAS

UWS =
Schirmer =
ESSPRI

P-VAS =
F-VAS =
Phys-SF36

ESSDAI

Glandular

Articular

Biologic

RC18
TACI-Igfusion
protein
NCT04078386
Phase II
[345]
AECG criteria
SSa+
ESSDAI ≥5
30 ? ? ? ∆ESSDAI at 24w December 2020 Secondary
endpoint
Secondary
endpoint
Primary
endpoint
Rituximab
Anti-CD20 +
Belimumab
Anti-BAFF
NCT02631538
Phase II
[346]
AECG criteria
SSa and/or SSb+ESSDAI
≥5
UWS >0 mL/min
D-VAS ≥5/10
70 ? ? ? SAEs at 104w
AESIs at 104w
Study
completed on
June 2020
Secondary
endpoint na Secondary
endpoint
Tibulizumab
(LY3090106)
Anti-BAFF +
Anti-IL-17
NCT02614716
Phase I
[347]
AECG criteria
SSa and/or SSb+32 ? ? ? SAEs at 197d Not
published na na na
Ianalumab
(VAY736)
Anti-BAFFR
NCT02149420
Phase II
[348]
AECG criteria
ANA ≥1:160
SSa and/or SSb+
ESSDAI ≥6
UWS >0 mL/min
6+12 9 50.5
±12.16 ?12.5
(6, 31) ∆ESSDAI at 12w not met D-VAS

SF-36 =
MFI

F-VAS

ESSDAI =
Articular

NCT02962895
Phase II
[349]
AECG criteria
SSa+
ESSDAI ≥6 (from 7
domains only)
195 ? ? ?
Change in
multi-dimensional disease
activity at 24w
Study
completed on
June 2020
Secondary
endpoint
Secondary
endpoint
Primary
endpoint

J. Clin. Med. 2020,9, 2299 34 of 61
Table 8. B cell targeted drugs in pSS part 3: drugs targeting other B cells survival and function pathways.
DRUG TRIAL (Reference) Inclusion Criteria
Number of Subjects Age
(Years)
Disease
Duration
(Years)
Mean
ESSDAI
Primary
Outcome Results
Effects (Statistically Significant)
Drg Ctrl Sicca
Syndrome Fibro-Like Systemic
LOU064
BTK inhibitor
NCT04035668
Phase II
LOUISSe
[350]
2016 ACR/EULAR
criteria
SSa and/or SSb+
ESSDAI ≥6
UWS >0 mL/min
252 ? ? ? ∆ESSDAI at 24w
Estimated Study
Completion on
January 2023
Secondary
endpoint
Secondary
endpoint
Secondary
endpoint
Tirabrutinib
(GS-4059)
BTK inhibitor
NCT03100942
Phase II
[342]
AECG criteria
SSa and/or SSb+
ESSDAI ≥4
38 37 55.8
±10.06 ?10.4
±5.36
Protocol-Specified
Response Criteria
at 12w
not met ESSPRI =ESSPRI =ESSDAI =
BMS-986142
BTK inhibitor
NCT02843659
Phase II
[351]
2016 ACR/EULAR
criteria
SSa and/or SSb+
ESSDAI ≥6
UWS >0 mL/min
5+6 7 51.2
±11.41 ? ? ∆ESSDAI at 12w Not published Secondary
endpoint
Secondary
endpoint
Secondary
endpoint
Branebrutinib
BTK inhibitor
NCT04186871
Phase II
[352]
2016 ACR/EULAR
criteria
Moderate to severe pSS
? ? ? ? ?
Protocol-Specified
Response Criteria
at 24w
Estimated Study
Completion on
June 2022
na na Primary
endpoint
Baminercept
LTβ-R
fusion protein
NCT01552681
Phase II
[353]
2016 ACR/EULAR
criteria
UWS >0.1 mL/min
≥1 non-life-threatening
systemic manifestation(s)
33 19 52.0
±11.0 ?3.1
±3.4 ∆SWS at 24w not met
D-VAS =
Schirmer

UWS =
F-VAS =ESSDAI =
Parsaclisib
(INCB050465)
PI3Kδinhibitor
NCT03627065
Phase II
[354]
AECG criteria
SGUS score >2
SSa and/or SSb+
ESSDAI ≥6
Oral dryness score ≥5.
10 ? ? ? ∆SGUS score at
12w Not published na na na
Seletalisib
(UCB5857)
PI3Kδinhibitor
NCT02610543
Phase II
[355]
AECG criteria
FAN ≥1:160
SSa and/or SSb+
ESSDAI ≥6
13 14 ? ? ? ∆ESSDAI at 12w not met
ESSPRI =
SWSF =
Schirmer =
na ESSDAI =
Leniolisib
(CDZ173)
PI3Kδinhibitor
NCT02775916
Phase II
[356]
pSS diagnosis
SSa and/or SSb+
ESSDAI ≥6, ESSPRI ≥5
SWS >0.1 mL/min
20 10 47.3
±13.07 ? ? ∆ESSDAI at 12w
SAEs at 12w not met ESSPRI =SF-36 =
MFI =na

J. Clin. Med. 2020,9, 2299 35 of 61
Table 9. T-cell targeted drugs in pSS: co-stimulation receptors or ligands inhibition.
DRUG TRIAL Inclusion Criteria
Number of Subjects Age
(Years)
Disease
Duration
(Years)
Mean
ESSDAI
Primary
Outcome Results
Effects (Statistically Significant)
Drg Ctrl Sicca
Syndrome Fibro-Like Systemic
Abatacept
CTLA-4 Ig
fusion protein
NCT02915159
Phase III
[357]
2016 ACR/EULAR criteria
SSa+
ESSDAI ≥5
92 95 52
±12.9 ?9.4
±4.3 ∆ESSDAI at 169d Not met ESSPRI =
SWS =ESSPRI =ESSDAI =
DAS28

Phase I/II
ASAP
[358]
AECG criteria and ESSDAI
≥
6
Disease duration ≤5 years
SWS ≥0.10 mL/min
SSa and/or SSb+or FR+
Proven by parotid gland
biopsy.
15 - 43
(32–51)
11
(7–36)
11
(8–14)
∆ESSDAI at
24-48w met
ESSPRI

SWS/UWS =
Schirmer =
BUT

ESSPRI

ESSDAI

NCT02067910
Phase III
ASAPIII
[359]
AECG criteria and ESSDAI
≥
5
Time from diagnosis ≤7 years 40 39 49
±16
8
(4–14) ?∆ESSDAI at 24w Not met
ESSPRI

FSFI

DVAS =
UWS =
Schirmer =
Fatigue =ESSDAI =
Articular

Iscalimab
(CFZ533)
Anti-CD40
NCT02291029
Phase IIa
[360]
AECG criteria and ESSDAI
≥
6
SSA+OR FR+and FAN ≥
1:320
SWS ≥0 mL/min
8+21 4+11 51.3
±13.5 ?10.7
±4.6 SAEs at 12w safe
ESSPRI

UWS =
Schirmer =
MFI =
SF-36 =ESSDAI

Articular

NCT03905525 Phase II
TWINSS
[361]
2016 ACR/EULAR criteria
SSa+
SWS >0.01 mL/min,
P1: ESSDAI ≥5 or P2 ESSPRI
≥5.
260 ? ? ?
∆ESSDAI at 24w
in P1
∆ESSPRI at 24w
in P2
Estimated
Study
Completion
on June 2022
Included
endpoint
Included
endpoint
Included
endpoint
VIB4920
MEDI4920
Anti-CD40L
NCT04129164
Phase II
[362]
P1: ESSDAI ≥5
P2: ESSDAI <5 et ESSPRI ≥5174 ? ? ?
∆ESSDAI at 169d
in P1
∆ESSPRI at 169d
in P2
Estimated
Study
Completion
on April 2022
Included
endpoint
Included
endpoint
Included
endpoint
Prezalumab
(AMG557)
(MEDI5872)
Anti-B7RP1
NCT02334306
Phase IIa
[363]
AECG criteria and ESSDAI
≥
5
SSa and/or SSb+
FR+, cryoglobulinemia or
hypergammaglobulinemia
16 16 50.7
±13 ? ? ∆ESSDAI at 99d Not met ESSPRI =ESSPRI =ESSDAI =
Lulizumab
(BMS-931699)
Anti-CD28
NCT02843659
Phase II
[351]
2016 ACR/EULAR criteria
SSa and/or SSb+
ESSDAI ≥5
USW >0.01 mL/min
5+6 7 51.2
±11.41 ? ? ∆ESSDAI at 12w Not
published
Secondary
endpoint
Secondary
endpoint
Primary
endpoint

J. Clin. Med. 2020,9, 2299 36 of 61
Table 10. T-cell targeted drugs in pSS: therapies preventing autoantigen presentation.
DRUG TRIAL
(Reference) Inclusion Criteria
Number of Subjects Age
(Years)
Disease
Duration
(Years)
Mean
ESSDAI Primary Outcome Results
Effects (Statistically Significant)
Drg Ctrl Sicca
Syndrome Fibro-Like Systemic
Petesicatib
RO5459072
Cathepsin S
Inhibitor
NCT02701985
Phase IIa [364]
AECG criteria
SSa and/or SSb+
ESSDAI ≥5
ESSPRI ≥5
USW >0.0 mL/min
Oral D-VAS ≥5/10
38 37 52.2
±12.5 ? ? ∆ESSDAI ≥3 at 12w Not met ESSPRI =ESSPRI =
SF36 =ESSDAI =
Efalizumab
Anti-LFA-1
NCT00344448
Phase II [365]
AECG criteria
SSa and/or SSb+6 3 53
±11.2 ? ? Protocol-specified
composite score at 12w
Early termination due to serious side effect in other trial
Table 11. Anti-cytokine targeted drugs in pSS.
DRUG TRIAL Inclusion Criteria
Number of Subjects Age
(Years)
Disease
Duration
(Years)
Mean
ESSDAI Primary Outcome Results
Effects (Statistically Significant)
Drg Ctrl Sicca
Syndrome Fibro-Like Systemic
Anakinra
IL1R antagonist
protein
NCT00683345
Phase II
[333]
AECG criteria
18–80 years
Western European descent
No depression or comorbidity
13 13 55
(36–80)
5
(1–17) ?
Group-wise
comparison of the
fatigue scores at 4w
not met na F-VAS

na
Tocilizumab
Anti-IL-6R
NCT01782235
Phase I/II
ETAP
[366]
AECG criteria
ESSDAI ≥555 55 50.9
(26–76) ?11.5
(5–25)
∆ESSDAI ≥3 at 12W
without new item
without

≥
1/10 PGA
not met ESSPRI =
Schirmer =ESSPRI =ESSDAI =
Articular

Infliximab
Anti-TNF
Phase III
TRIPSS
[367]
AECG criteria
2/3 D-VAS, F-VAS, P-VAS ≥5/10 54 49 54.4
±10.4
4.0
±5.5 na

30% in 2/3 D-VAS,
F-VAS, P-VAS at
10–22w
not met SWS =
Schirmer =SF-36 =SJC =
TJC =
Etanercept
TNFR-Ig fusion
protein
NCT00001954
Phase II
[368]
1986 and AECG criteria
Elevated ESR or IgG levels 14 14 55.5
(46, 59) ? na

20% in 2/3 pSS
domains
(protocol-specified)
not met
D-VAS =
Schirmer =
VB =
SWS =
na na
Ustekinumab
Anti-IL-12/IL-23
(p40 subunit)
NCT04093531
Phase I
[341]
2016 ACR/EULAR criteria 15 - ? ? ? ∆ESSDAI at 24W
Estimated Study
Completion on
December 2021
na Secondary
endpoint
Primary
endpoint
GSK2618960
anti–IL-7Rα
NCT03239600
Phase II
[369]
AECG criteria
SWS >0.1 mL/min

Ig or FR+or ANA ≥1:320
D-VAS ≥5/10 or Schirmer <10 mm
0 - - - SAEs at 27w Withdraw
The study is stopped for Portfolio prioritization

J. Clin. Med. 2020,9, 2299 37 of 61
Table 12. Miscellaneous targeted drugs in pSS.
DRUG TRIAL (Reference) Inclusion Criteria
Number of Subjects Age
(years)
Disease
Duration
(Years)
Mean
ESSDAI Primary Outcome Results
Effects (Statistically Significant)
Drg Ctrl Sicca
Syndrome Fibro-Like Systemic
Daxdilimab
VIB7734
Anti-ILT7
NCT03817424
Phase I
[370]
Unspecified ? ? ? ? SAEs at 169d
AESIs at 169d June 2020 na na na na
Filgotinib
Jak1 inhibitor
NCT03100942
Phase II
[342]
AECG criteria
SSa and/or SSb+
ESSDAI ≥4
38 37 52.2
±10.54 ?10.2
±6.23
Protocol-Specified
Response Criteria at 12w not met ESSPRI =ESSPRI =ESSDAI =
Lanraplenib
(GS-9876)
SIK inhibitor
NCT03100942
Phase II
[342]
AECG criteria
SSa and/or SSb+
ESSDAI ≥4
38 37 56.2
±9.72 ?10.5
±4.89
Protocol-Specified
Response Criteria at 12w not met ESSPRI =ESSPRI =ESSDAI =
RSLV-132
RNase1-Fc
fusion protein
NCT03247686
Phase II
[371]
AECG criteria
SSA+
Interferon signature
22 8 ? ? ? Interferon gene
expression at day99 Not published ESSPRI =
mPRO-F

DSST

FACIT-F =
ESSPRI =
ESSDAI =
Low-dose
IL-2
T-reg induction
NCT01988506
Phase II
Transreg
[372]
pSS diagnosis 84-132 ? ? ? T-reg percentage
Estimated Study
Completion on
February 2022
na na na

J. Clin. Med. 2020,9, 2299 38 of 61
8. Conclusions
pSS is a multifaceted disease combining pleiomorphic systemic autoimmune manifestations,
glandular manifestations, a frequently added psychosomatic component and the possible progression
to non-Hodgkin lymphoma. Its management has two complementary facets: improving the quality of
life of patients by tackling dryness, fatigue and chronic pain symptomatically in a multidisciplinary way
and treating systemic manifestations to prevent damage, which will worsen the vital and functional
prognosis. Although we understand more and more its pathophysiology, many questions remain
unanswered, and its treatment remains disappointing compared to other autoimmune diseases.
pSS therefore remains a vast field of investigation where much fundamental and clinical research
remains to be done. Ten take-home messages:
1.
SS is characterized by lymphoplasmacytic infiltration of exocrine glands. The cause of SS is complex
and influenced by a combination of genetic, epigenetic, hormonal and environmental factors.
2.
The pathogenic mechanisms remain unclear. However, the immune system-mediated loss of
glands function, specifically of salivary and lacrimal glands, certainly explains the common
symptoms of dry mouth and dry eyes. In this inflammatory environment, T-cells mediate a direct
destruction of glandular tissue and B-cell activation, leading to the production of autoantibodies.
More than 20 autoantibodies could be involved in SS, but the most commonly used for SS
diagnosis are anti-Ro/SSA and anti-La/SSB.
3.
Although often reduced to its sicca syndrome due to its tropism for glandular tissue, pSS remains
a systemic disease that can affect virtually all organs. These clinical manifestations can be due to
various mechanisms: dryness secondary to exocrinopathy, autoimmune epithelitis with periepithelial
lymphocytic infiltration of target organs, autoimmunity and clonal lymphocytic expansion.
4.
Due to its protean and willingly insidious presentation, pSS is sometimes difficult to recognize
and may delay diagnosis by more than 10 years. Classification criteria are used to create cohorts
for study purposes and should not be used blindly as diagnostic criteria but as a guide in clinical
practice. For these various reasons, the gold standard for individual diagnosis of pSS remains the
opinion of an expert clinician.
5.
From a serohistological point of view, so-called “secondary Sjögren’s syndrome” in SLE and SScl
patients does not differ from pSS. It is therefore preferable to forget this historical dichotomy.
In this way, the clinician avoids three pitfalls: (1) minimizing the SS-related symptoms, which
decrease the quality of life of the patients; (2) forget that overlap may change the clinical phenotype
and (3) forget the risk of lymphoma.
6.
Although overall pSS mortality is low and similar to the general population, a subgroup of patients
will have a poorer vital prognosis linked to cardiovascular events, solid-organ and lymphoid
malignancies and infections. Biomarkers associated with the development of MALT lymphoma
are mainly signs associated with exuberant B cell proliferation and immune-complex production.
7.
The impact of pSS can be assessed according to three clinical dimensions: “sicca asthenia polyalgia”
complex, inflammatory disease activity and structural damage. They are assessed by the ESSPRI,
ESSDAI and SSD(D)I scores, respectively. Even in the absence of florid systemic manifestations,
pSS can be disabling and associated with significant functional status impairment related to oral
and/or ocular dryness, systemic activity, pain, fatigue and daytime somnolence, anxiety and
depression symptoms.
8.
The treatment of manifestations linked to the “sicca asthenia polyalgia” complex mainly involves
symptomatic measures and rehabilitation. To date, no immunosuppressant has demonstrated a
favourable risk–benefit balance in this indication.
9.
The treatment of manifestations related to inflammatory disease activity is currently based
on scarce evidence. Therapeutic regimen must be tailored to organ specific involvement and
severity of the disorder. Mild manifestations will be treated with hydroxychloroquine or local
corticosteroids while moderate to severe systemic involvement will require the use of systemic

J. Clin. Med. 2020,9, 2299 39 of 61
corticosteroid therapy, combined or not with a broad-spectrum immunosuppressant. Rituximab
will only be used as a third line, except in cases of cryoglobulinemia where it is the treatment
of choice.
10. Despite targeted therapies having revolutionized rheumatology in recent years and the impressive
number of molecules tested so far in pSS, a revolution like the one known in the field of RA has
not yet occurred.
Author Contributions:
D.P., C.C., J.P., M.S.S. and C.D. contributed to the writing of the review. All authors have
read and agreed to the published version of the manuscript.
Funding:
This research was funded the EU H2020 contract HarmonicSS (H2020-SC1-2016-RTD/731944), Fonds
Erasme, Fonds de la Recherche Scientifique—FNRS (grant J.0053.20). DP is a Research Fellow of the Fonds de la
Recherche Scientifique—FNRS.
Acknowledgments: The authors thank Bahija Jellouli for her secretarial help.
Conflicts of Interest: The authors declare no conflicts of interest.
Abbreviations
ACA Anti-centromere antibodies
ACPA Anti-citrullinated protein antibodies
ACR American College of Rheumatology
AECG American European Consensus Group
AH Autoimmune Hepatitis
ANA Antinuclear antibodies
anti-M3R Anti-muscarinic receptor 3
APRIL A proliferation-inducing ligand
ASAP “Abatacept Sjögren Active Patients” study
AZA Azathioprine
BAFF B cell Activating Factor
BCR B cell receptor
BUT Break-up Time
CCP Cyclic Citrullinated Peptide
circRNA Circular RNA
ciRNAs Intronic circRNAs
ClinESSDAI Clinical ESSDAI variant
CPK Creatine phosphokinase
CRISP-3 Cysteine-Rich Secretory Protein 3 ()
CT-scan Computerized tomography
CyA Ciclosporin A
DAMPS Danger-associated molecular patterns
DAP-kinase Pro-apoptotic death associated protein kinase
DHEA Dehydroepiandrosterone
DHT Dihydrotestosterone
DLBCL Diffuse large B cell lymphoma
DMARD Disease Modifying Anti-Rheumatic Drug
DNMTs DNA methyltransferases
DREAM “Dry Eye Assessment and Management” study
EBV Epstein-Barr virus
ecircRNAs Exonic circRNAs
EIciRNAs Exon-intron circRNAs
ELISA Enzyme-linked immunosorbent assay
ENT Ear-Nose-Throat
ESSDAI EULAR Sjögren’s syndrome disease activity index
ESSPRI EULAR Sjögren’s Syndrome Patient Reported Index
EULAR European League Against Rheumatism
FASl Fas ligand

J. Clin. Med. 2020,9, 2299 40 of 61
FDC Follicular dendritic cells
GCs Germinal centres
HCQ Hydroxychloroquine
HCV Hepatitis C virus
HLH Hemophagocytic lymphohistiocytosis
HTLV1 Human T-lymphotropic virus type I
ICAM-1 InterCellular Adhesion Molecule 1
IF Immunofluorescence
IFN Interferon
IgG,A,M Immunoglobulin G, A and M
IL- Interleukin
ILD Interstitial lung disease(s)
IRF Interferon Regulatory Factor
IV Intravenous therapy
IVIG Intravenous Immunoglobulin
KCS Keratoconjunctivitis sicca
LEMA Myoepithelial sialadenitis
LESA lymphoepithelial sialadenitis
LIP Lymphocytic interstitial pneumonitis
LMP1 Latent membrane protein 1
lncRNA Long non-coding RNAs
LPR Laryngopharyngeal reflux
LSG Labial SG
MALT mucosa-associated lymphoid tissue
MHC Major histocompatibility genes
MMF Mycophenolate mofetil
MMP Matrix metalloproteinases
MPGN Mesangioproliferative glomerulonephritis
MRI Magnetic Resonance Imaging
MS Multiple Sclerosis
MSGB Minor salivary gland biopsy
MTX Methotrexate
NAC N-acetylcystein
NFkB Nuclear factor kappa-light-chain-enhancer of activated B cells
NHL Non-Hodgkin’s lymphoma
NICE National Institute for Health and Care Excellence
NMOSD Neuromyelitis optica spectrum disorder
NOD Non-obese diabetic
NSAID Nonsteroidal anti-inflammatory drugs
NSIP Nonspecific interstitial pneumonia
OMERACT Outcome Measures in Rheumatology group
OSDI Ocular Surface Disease Index
OSS Ocular Staining Score
PAMPs Pathogen-associated molecular patterns
PBC Primary Biliary Cirrhosis
PDC Plasmacytoid dendritic cells
PDL1 Programmed death ligand 1
PET scan Positron emission tomography
PGA Patient Global Assessment
PIP Prolactin inducible protein
PO per os
PSP Parotid secretory protein
pSS Primary Sjögren’s Syndrome
pSS-ILD pSS-related interstitial lung disease
q6h, q8h Every 6 h, every 8 h
RA Rheumatoid Arthritis

J. Clin. Med. 2020,9, 2299 41 of 61
RCT Randomized controlled trial
RF Rheumatoid Factor
RTA Renal tubular acidosis
RTX Rituximab
RX1 Runt-related transcription factor
SAM Methyl donor S-adenosylmethionine
SAP Sicca Asthenia Polyalgia
SF-36 Short Form 36 health survey
SG Salivary Gland
SGS Salivary glands scintigraphy
SGUS Salivary glands ultrasound
SICCA Sjögren’s International Collaborative Clinical Alliance
SLE Systemic lupus erythematosus
SNP Single nucleotide polymorphism
SP-1 Salivary protein 1
SSDDI Sjögren’s Syndrome Disease Damage Index
SSDI Sjögren’s Syndrome Damage Index
sSS Secondary Sjögren’s Syndrome
SWSF Stimulated Whole Salivary Flow rate
TACI Transmembrane Activator and CAML Interactor
TEARS “Tolerance and efficacy of rituximab in primary Sjögren syndrome” trial
Tfh Follicular helper T cells
TLRs Toll Like Receptors
TNF-αTumour necrosis factor-α
TPHA Treponema Pallidum Hemagglutinations Assay
TRACTISS “TRial of Anti-B-Cell Therapy In patients with primary Sjögren’s Syndrome” trial
TSH Thyroid-stimulating hormone
TTP Thrombotic Thrombocytopenic Purpura
UCLH University College London Hospitals
UIP Usual interstitial pneumonia
UWSF Unstimulated Whole Saliva Flow rate
VAS Visual analogue scales
VDRL Venereal Disease Research Laboratory
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