PRIMER

Sjögren syndrome
Pilar Brito-Zerón1–3, Chiara Baldini4, Hendrika Bootsma5, Simon J. Bowman6,
Roland Jonsson7,8, Xavier Mariette9,10, Kathy Sivils11, Elke Theander12,
Athanasios Tzioufas13 and Manuel Ramos-Casals2,3,14
Abstract | Sjögren syndrome (SjS) is a systemic autoimmune disease that primarily affects the exocrine
glands (mainly the salivary and lacrimal glands) and results in the severe dryness of mucosal surfaces,
principally in the mouth and eyes. This disease predominantly affects middle-aged women, but can
also be observed in children, men and the elderly. The clinical presentation of SjS is heterogeneous
and can vary from sicca symptoms to systemic disease (characterized by peri-epithelial lymphocytic
infiltration of the affected tissue or the deposition of the immune complex) and lymphoma.
The mechanism underlying the development of SjS is the destruction of the epithelium of the exocrine
glands, as a consequence of abnormal B cell and T cell responses to the autoantigens Ro/SSA and
La/SSB, among others. Diagnostic criteria for SjS include the detection of autoantibodies in patient
serum and histological analysis of biopsied salivary gland tissue. Therapeutic approaches for SjS
include both topical and systemic treatments to manage the sicca and systemic symptoms of disease.
SjS is a serious disease with excess mortality, mainly related to the systemic involvement of disease
and the development of lymphomas in some patients. Knowledge of SjS has progressed substantially,
but this disease is still characterized by sicca symptoms, the systemic involvement of disease,
lymphocytic infiltration to exocrine glands, the presence of anti-Ro/SSA and anti-La/SSB
autoantibodies and the increased risk of lymphoma in patients with SjS.

Sjögren syndrome (SjS) is a systemic autoimmune dis­
ease with a specific predisposition for causing inflam­
mation of the exocrine glands, predominantly the
salivary and lacrimal glands but also including the nose,
upper respiratory tract, oropharynx and, in women, the
vagina. The main consequence of this inflammation is
the develop­ment of sicca symptoms, such as dryness
of the mucosal surfaces, principally in the mouth and
eyes1. Hendrik Sjögren was the first to establish that
typical sicca symptoms extended beyond glandular
­involvement and termed the sicca syndrome SjS.
The autoimmune aetiopathogenetic basis of SjS was
confirmed in the 1960s and the presence of the auto­
antibodies SjS-related antigen A (SSA; also known
as anti-Ro/SSA antibodies) and SSB (also known as
anti-­La/SSB antibodies), in addition to organ-specific
lymphocyte infiltration (for example, focal lymphocytic
sialadenitis (FLS) or inflammation of the salivary glands)
Correspondence to M.R.‑C. became central for the pathobiology and diagnosis of
Department of Autoimmune this disease (FIG. 1). Since then, knowledge of SjS has pro­
Diseases, ICMiD, Hospital gressed substantially, but the five features of this disease
Clínic, C/Villarroel, 170,
that were initially defined in the early years (the develop­
08036 Barcelona, Spain.
mramos@clinic.ub.es ment of sicca symptoms, systemic involvement of disease,
lymphocytic infiltration to exocrine glands, the presence
Article number: 16047
doi:10.1038/nrdp.2016.47 of autoantibodies and the increased risk of ­lymphoma in
Published online 7 July 2016 patients with SjS) still characterize this disease.
In the past 50 years, the term ‘secondary SjS’ has
been used in the research setting for patients diag­
nosed with SjS in combination with another systemic
autoimmune disease and ‘primary SjS’ for those whom
SjS is the only diagnosis. However, this terminology is
under debate, and standardized guidelines on when or
why they should be used are lacking. ‘Secondary SjS’
is mainly used in patients with concomitant systemic
autoimmune diseases (such as rheumatoid arthritis,
systemic sclerosis or systemic lupus erythematosus
(SLE)) and is rarely used in patients with concomitant
organ-specific autoimmune diseases (for example,
­autoimmune thyroiditis, primary biliary cholangitis
or autoimmune hepatitis). In addition, some authors
have used ‘secondary SjS’ for patients with clinical dry­
ness who do not fulfil the criteria of SjS, whereas others
have proposed the use of different terms, such as ‘associ­
ated SjS’ for patients with SLE and ‘secondary SjS’ for
those with rheumatoid arthritis2. In fact, the distinc­
tion between primary and secondary (or associated) SjS
reflects only the frequently reported clinical situation of
the coexistence or overlap of SjS in patients with other
autoimmune diseases1. With respect to patient manage­
ment, dividing patients into ‘primary’ or ‘secondary’ SjS
makes no sense as the management of SjS is the same in
both patient populations.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 1

© 2016 Macmillan Publishers Limited. All rights reserved
PRIMER
Author addresses
1
Autoimmune Diseases Unit, Department of Medicine, Hospital CIMA- Sanitas,
Barcelona, Spain.
2
Sjögren Syndrome Research Group (AGAUR), Laboratory of Autoimmune Diseases Josep
Font, IDIBAPS-CELLEX, Barcelona, Spain.
3
Department of Autoimmune Diseases, ICMiD, Hospital Clínic, C/Villarroel, 170,
08036 Barcelona, Spain.
4
Rheumatology Unit, University of Pisa, Pisa, Italy.
5
Department of Rheumatology and Clinical Immunology, University of Groningen,
University Medical Center Groningen, Groningen, The Netherlands.
6
Rheumatology Department, University Hospitals Birmingham NHS Foundation Trust,
Birmingham, UK.
7
Broegelmann Research Laboratory, Department of Clinical Science, University of
Bergen, Bergen, Norway.
8
Department of Rheumatology, Haukeland University Hospital, Bergen, Norway.
9
Université Paris Sud, INSERM, Paris, France.
10
Center for Immunology of Viral Infections and Autoimmune Diseases, Assistance
Publique — Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Le Kremlin-Bicêtre,
Paris, France.
11
Oklahoma Sjögren’s syndrome Center of Research Translation, Oklahoma Medical
Research Foundation, Oklahoma City, Oklahoma, USA.
12
Department of Rheumatology, Malmö University Hospital, Lund University, Lund, Sweden.
13
Department of Pathophysiology, School of Medicine, National University of Athens,
Athens, Greece.
14
Department of Medicine, University of Barcelona, Barcelona, Spain.
Scientific reports have mainly focused on primary
disease (thus avoiding the confounding effect of an
additional autoimmune disease) to provide a more
homogeneous characterization of SjS, especially after
the introduction of the first set of worldwide classifica­
tion criteria in 1993 (REF. 3). Thus, the term SjS has been
used throughout this Primer to refer to primary SjS and
the term associated SjS used for studies that included
patients with concomitant autoimmune diseases. This
Primer describes the epidemiology and aetiopatho­
genetic mechanisms of SjS, the global clinical picture
including both glandular and systemic manifestations,
the approaches to diagnosis and treatment, patient qual­
ity of life and concludes by presenting an outlook on the
potential advances in the understanding of SjS.
Epidemiology
The reported incidence and prevalence of SjS varies
according to both the study design and the classifica­
tion criteria used4. The pooled prevalence rates in studies
that used the 1993 European Classification Criteria was
12‑fold higher than the pooled prevalence rates in stud­
ies that used the 2002 American–European Consensus
Group (AECG) criteria, whereas the pooled prevalence
rates reported in population-based epidemiological
studies were slightly lower than that calculated in the
total population4. The incidence of SjS ranges between
3 and 11 cases per 100,000 individuals5,6, whereas the
prevalence ranges between 0.01% and 0.72%7,8. It is also
likely that there are asymptomatic cases, which never
become diagnosed. Only one study has evaluated the
influence of race or ethnicity on the prevalence of SjS.
This study found a significant twofold higher prevalence
among individuals with a non-European background
than in those with a European background in the general
population of the Greater Paris area7.
2 | 2016 | VOLUME 2
© 2016 Macmillan Publishers Limited. All rights reserved
At the presentation of disease, the epidemiological
profile of SjS is very typical, which might aid early diag­
nosis. First, SjS predominantly affects women. In fact, SjS
has the most unbalanced gender ratio out of all systemic
autoimmune diseases; close to a 10/1 female/male ratio
was reported in a big data study of >14,000 patients with
SjS9. Moreover, the phenotypic expression of SjS differs
in men and women; men present with severe ocular
involvement and less-pronounced systemic and immuno­
logical involvement of disease compared with women10,11.
Second, although SjS can occur at all ages, it is mainly
diagnosed between 30 and 50 years of age. SjS is rare in
children and the female/male ratio is less evident in chil­
dren than in adults12. Enlargement of the parotid glands,
which is not one of the typical sicca symptoms, is the
predominant feature observed at presentation in children
with SjS12, although salivary gland biopsy is just as useful
for SjS diagnosis in children as in adults13. Moreover, the
most frequently reported autoantibody is anti-Ro/SSA
antibody, but not antinuclear antibody (ANA), which
is the most common antibody in adults12. By contrast,
parotid gland involvement and anti-Ro/SSA antibodies
are observed less frequently in older patients >70 years
of age than in those <70 years of age, and elderly patients
also have a higher frequency of pulmonary involvement11.
SjS and other autoimmune diseases frequently
­coincide (associated SjS) in daily practice. In patients with
systemic autoimmune diseases, the proportion of patients
with concomitant SjS differs between conditions; 14–18%
of patients with SLE14,15, 7–17% with rheumatoid arthri­
tis16,17 and 12% with systemic sclero­sis also have associ­
ated SjS18. In clinical practice, the manage­ment of
associated SjS should be the same as the ­management
of primary SjS.
SjS can be a serious disease with excess mortality.
The main causes of death traditionally associated with
excess mortality in patients with SjS are B cell lym­
phoma, severe organ-specific features (principally,
interstitial lung disease, renal failure and severe cryo­
globulinaemic v­ asculitis), in addition to infections and
cardiovascular disease19.
Mechanisms/pathophysiology
Multiple environmental factors that interact with an
individual’s genetic susceptibility can influence SjS
develop­ment. Increased levels of cytokines and chemo­
kines as a result of abnormal responses of both T cells
and B cells to autoantigens, such as the ribonucleo­
protein particles Ro/SSA and La/SSB expressed by the
epithelium of the exocrine glands (such as the salivary
and lacrimal glands), lead to chronic inflammation
of the exocrine glands and the eventual loss of their
physio­logical functions20. Salivary gland epithelial cells
(SGECs) in patients with SjS drive and regulate local
autoimmune responses by actively mediating the accu­
mulation, activation and differentiation of immune
cells. Immune cells and the inflammatory micro­
environment further activate epithelial cells or regulate
their survival, thus creating a vicious cycle of epithelial
cell and immune cell interaction that perpetuates the
­autoimmune responses observed in SjS21.
www.nature.com/nrdp
 PRIMER

Aetiopathogenetic mechanisms TNF ligand superfamily member 6 (also known as FAS

The current theory explaining the pathogenesis of SjS —
termed ‘autoimmune epithelitis’ in this context — sug­
gests that the epithelium is the inflamed tissue in SjS22.
The exocrinopathy and involvement of functional
parts of an organ (parenchyma) are associated with
the development of lymphocytic infiltrates in epithe­
lial cells surrounding or invading organs. According to
this theory, epithelial cells are thus central regulators of
the auto­immune response by acting as atypical antigen-­
presenting cells and are not just innocent bystanders
affected by infiltrating immune cells (FIG. 2). However,
auto­immune epithelitis is only one explanation for the
immuno­pathology of SjS, although it is the theory with
the most support. Several studies have also suggested a
role for a neuroendocrine mechanism that is related to
the influence of hormones and neuropeptides in the func­
tion of the exocrine glands23 that could explain why some
patients with SjS present with severe sicca symptoms with
no (or limited) inflammatory histopathological features24.
To date, numerous studies have investigated this theory
of autoimmune epithelitis, by examining affected SGECs
and epithelial cells of the lacrimal glands. These studies
have shown that epithelial cells are able to o ­ rchestrate
innate and acquired immune responses in SjS25,26.
Immune activation in epithelia. SGECs have
been shown to constitutively express a plethora of
immune-competent molecules that are implicated in
lymphoid cell recruitment, homing, activation, differ­
entiation and proliferation, and immune cell expansion
and organization20,25 (FIG. 2). These molecules include
human leukocyte antigen (HLA) class I molecules,
tumour necrosis factor (TNF) receptor superfamily
member 5 (also known as CD40; a co-stimulatory pro­
tein involved in antigen presentation), adhesion mol­
ecules, the apoptosis-related molecules TNF receptor
superfamily member 6 (also known as FAS receptor) and
ligand), pro-inflammatory cytokines, cytokines involved
in lymphoid cell differentiation and many chemokines
that attract T cells and form the germinal centre (that
is, sites in secondary lymphoid organs where B cells
mature)20,25. Expression of these molecules in SGECs is
upregulated further by cytokines secreted by immune
cells, which infiltrate tissue lesions, suggesting abnor­
mal interactions between SGECs and immune cells in
SjS. SGECs have been shown to activate CD4+ T cells
in vitro and mediate their differentiation into follicular
helper T cells27, which in turn enhances the survival
of B cells20,25,28. In addition, SGECs have been shown
to directly interact with B cells and can promote their
differentiation towards B cell subtypes, similar to those
observed in salivary gland lesions of patients with SjS29.
The constitutive expression of most immune-­
competent molecules was significantly increased and
stable in SGEC cell lines derived from patients with SjS
compared with cells from healthy controls25. In addition,
in SGECs of patients with SjS, high MYC (a regulatory
gene involved in cell proliferation) expression was found
compared with controls, and translocation of Ro/SSA
and La/SSB autoantigens to the cell membrane was
observed in the cytoplasm via histological examination
by in situ hybridization. These data indicate intrinsic
immune activation in SGECs of patients with SjS25. The
cause of the activation of immune responses in the epi­
thelial cells is currently unknown; epigenetic changes or
latent viral infections might have a role (see below)20.
Histopathological studies have revealed that glandular
epithelial cells express molecules that are indicative of
both a type I interferon (IFN) signature (predominantly
IFNβ) and a type II IFN signature (predominately IFNγ),
whereas immune cells express molecules that are typical
for a type II IFN signature (IFNγ)30,31. The IFN signature
in salivary gland lesions seen in patients with SjS and the
high constitutive Toll-like receptor 3 (TLR3) expression

Discovery of Use of the term ‘sicca syndrome’ Use of antimalarials in SjS Evaluation of Increased Diagnosis
filamentary keratitis for oral, ocular and vaginal dryness xerostomia risk of Clinical
(strands of (dry mouth) lymphoma presentation
degenerated Use of rose bengal dye for Salivary flow by salivary in patients Treatment
epithelial cells on the the assessment of ocular rates used for scintigraphy with SjS
corneal surface) damage in patients with SjS SjS diagnosis

1882 1903 1925 1933 1951 1954 1959 1964 1967 1968 1971 1975 1978 1982

Labial salivary gland

First use of Use of cortisone in SjS biopsy Identification Detection of
lacrimal blotting Association of the SjS- anti-Ro/SSA
paper test for ‘About keratoconjunctivitis sicca’ thesis between Lymphocytic sialadenitis precipitating and anti-La/SSB
detection of showing the association between sicca SjS and observed in oral tissue antibodies antibodies in
dry eyes syndrome and systemic features lymphoma of patients with SjS A, B and C patients with SjS

Figure 1 | Milestones in the history of SjS compressed in 100 years
(1882–1982). Patients affected by isolated sicca symptoms were first
reported at the end of the nineteenth century and symptoms were
integrated into a ‘sicca syndrome’ by Gougerot in 1925. However, the first
to suggest they could be attributed to a systemic disease was the Swedish
ophthalmologist Henrik Sjögren, who, in 1933, established that the disease
spectrum extended beyond glandular involvement. Subsequent studies in
the mid‑twentieth century confirmed the association
Nature Reviewsof| Disease
sicca syndrome
Primers
with other rheumatic and autoimmune diseases and with an unusually high
frequency of haematological malignancies. The autoimmune
aetiopathogenetic basis of Sjögren syndrome (SjS) was confirmed in the
1960s, and the presence of autoantibodies (Ro/SSA and La/SSB) and
organ-specific lymphocytic infiltration (focal lymphocytic sialadenitis)
become central for the pathobiology and diagnosis of the disease.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 3

© 2016 Macmillan Publishers Limited. All rights reserved
PRIMER

in SGECs and responsiveness to TLR3 signalling by
SGECs further support the implication of viral infection
in SjS pathogenesis.
Immune activation in SjS can be triggered by sentinel
cells, such as dendritic cells and plasmacytoid dendritic
cells, as evidenced by experimental models21. The robust
genetic association between HLA class I and class II mol­
ecules and SjS pathogenesis (see below) strongly suggests
the involvement of T cells. In accordance, T cells that
secrete IFNy and IL‑17 have been detected in inflamed
salivary glands of patients with SjS and are associated
with tissue damage32,33.
Cytokines such as IL‑7 that drive effector T cells are
overexpressed by SGECs of patients with SjS33. Innate
immune signalling via TLR activation, such as that
elicited by viral infections, might induce IL‑7 produc­
tion by SGECs, dendritic cells or endothelial cells33,34.
IL‑7 can drive effector T cells to induce sialoadenitis in
mice35. Other cytokines that are overexpressed in the
salivary glands of patients with SjS (such as IL‑7, IL‑17,
IL‑21, IL‑22 and IL‑23) have been shown to contribute
to the abnormal T cell and B cell response and might
play a crucial role in SjS, and can increase the risk of
lymphoid neogenesis21,26,36.

Mucolytics Mucus changes Dry surfaces Increased Eyes: topical

chance of corticosteroids
infection and antibiotics
Epithelial cell
of the salivary or Mouth: good
lacrimal glands Eyes: eye drops and gels oral health
Mouth: saliva substitutes and fluorides
Ro/SSA Secretagogues Gland hypofunction
and La/SSB
autoantigens

Surface
expression of Apoptosis
autoantigens Autoantigen-
containing
vesicle

TLR Tissue damage

Autoantibodies

Cytokines and chemokines CD4+ IL-17

(type I IFN signature) T cell IFNγ

Plasma
IL-7 cell
IL-17

Dendritic
cell IL-6 BAFF
IL-12
IL-21 IL-12 TH1 cell IL-12
IL-6
IL-23 B cell
TFH cell IL-6 B cell depletion
IL-17 therapy
IL-21
TH17 cell IL-22
IL-7
BAFF

BAFF

Germinal centre
formation

BAFF

Figure 2 | The pathogenesis of autoimmune epitelitis as a potential explanation for SjS. Immune-competent
Nature Reviews | Disease Primers
molecules, such as Toll-like receptors (TLRs) are constitutively expressed by salivary gland epithelial cells (SGECs).
Activation of TLR signalling in gland epithelium causes the production of autoantigens, the upregulation of
immune-competent molecules (chemokines and cytokines), apoptosis and epithelial hypofunction. Autoantigens can be
released from SGECs and presented to immune cells. CD4+ T cells differentiate into follicular helper T (TFH) cells, which
increase B cell survival. Interaction between SGECs and B cells promotes B cell differentiation. Potential treatments are
highlighted in green boxes. BAFF, B cell-activating factor; IFN, interferon; TH, T helper.

4 | 2016 | VOLUME 2 www.nature.com/nrdp

© 2016 Macmillan Publishers Limited. All rights reserved

TLR signalling. SGECs, via TLRs, can also sense innate
immunity signals, leading to the upregulation of the
previously mentioned immune-competent molecules
(including HLA class I molecules, FAS receptor, FAS
ligand and pro-inflammatory cytokines) in SGECs
(FIG. 2); this mechanism links the innate and adaptive
immune responses 20,25. Furthermore, TLR3 signal­
ling in SGECs leads to hypofunction of the salivary
glands, SGEC apoptosis and upregulation of Ro/SSA
and La/SSB autoantigens; the increase in the levels of
autoantigens suggests that TLR3 signalling in SGECs
might also be implicated in autoantigen presenta­
tion20,25,30. Finally, SGECs might also mediate the expo­
sure and presentation of intracellular ribonucleoproteins
(such as Ro/SSA and La/SSB) to the immune system by
the release of autoantigen-containing vesicles, such as
exosomes from healthy SGECs or apoptotic blebs from
apoptotic SGECs20,25.
Apoptosis. Apoptosis of SGECs has been proposed as a
potential aetiopathogenetic mechanism that is associ­
ated with the impairment of secretory glandular func­
tion37. The importance of epithelial cell apoptosis in
the pathogenesis of SjS is supported by data obtained
from an experimental mouse model. In these mice,
silencing the expression of nuclear factor-κB (NF‑κB)
inhibitor-ζ in epithelial cells of the lacrimal gland of
the eye led to increased apoptosis of epithelial cells and
SjS-like inflammatory lesion in the lacrimal glands.
These features were associated with high titres of serum
anti-Ro/SSA and anti-La/SSB antibodies and could be
reversed by treating the mice with apoptosis-blocking
caspase inhibitors38.
Environmental factors
Viral infections. Viral infections are considered one of
the key aetiological factors involved in SjS, as tissue of
the salivary glands are sites of latent viral infections39.
The list of viruses that can be involved in SjS is long and
includes members of the Herpesviridae family, such as
Epstein–Barr virus (EBV) and human herpesvirus 6
(HHV6). The potential causative role of EBV and HHV6
infections in SjS has been studied, but establishing a
causative relationship is difficult because of the high
prevalence of these viruses in the healthy population40.
Immune responses to EBV (EBV-specific IgG) have been
demonstrated in patients with SjS41. A higher prevalence
of HHV6‑specific antibodies has been detected in the
serum of patients with SjS (in 36% of patients) than in
control individuals (in 10% of controls)42. However,
other studies could not confirm this finding 43,44.
Retroviruses can infect cells of the immune sys­
tem and can cause aberrant antiretroviral responses
that could lead to autoimmunity. High serum titres of
human T cell lymphotropic virus 1 (HTLV1)-specific
antibodies and the presence of salivary IgA antibodies
against HTLV1 was reported in patients with SjS in
areas of Japan that are endemic for HTLV1, more so
than in individuals who do not have SjS45. In addition
to its effect in autoimmunity, HTLV1 might directly
infect SGECs46.
NATURE REVIEWS | DISEASE PRIMERS
© 2016 Macmillan Publishers Limited. All rights reserved
PRIMER
In Mediterranean countries, patients with SjS have
been reported to have a higher frequency (14%) of
chronic hepatitis C virus (HCV) infections than healthy
individuals47. Histological analysis of salivary gland
biopsies revealed a higher frequency of FLS in patients
with SjS who are infected with HCV (57%) than in
patients with SjS who are not infected with HCV (5%)48.
In a separate study, HCV infection was identified in
13% of a cohort of Spanish patients with SjS. In these
patients, the autoimmune response was characterized
by an abnormal predominance of anti-La/SSB, over
anti-Ro/SSA, autoantibodies compared with patients
with SjS in the absence of HCV infection49.
Lymphotropic viruses have also been associated with
the development of autoimmune diseases. Some viral
domains of EBV, HHV6 and human immunodeficiency
virus 1 have molecular similarities to some antigenic
epitopes on the La/SSB protein50. These viral domains
are referred to as ‘self-determinants’, and viral infections
can induce the translocation of these viral domains to
the cell surface and could promote the induction of
autoantibodies. Owing to the increased understand­
ing of the genetic complexity and the central role of
type I and type II IFNs in systemic autoimmunity 51, the
emphasis is now on how viruses trigger autoimmunity
and specifically on the role of interactions of viruses
with pattern-recognition receptors, such as TLRs. This
concept is also highly relevant to the emerging impor­
tance of gene–environment inter­actions in systemic
auto­immunity. However, viruses might trigger auto­
immunity long before the manifestation of disease, and
auto­antibodies have been found in patients for up to
decades before the diagnosis of SjS52,53.
Smoking. Among other environmental factors, ­smoking
has emerged as a risk factor for SjS and other auto­
immune disorders, such as SLE and myositis54. Some
studies have reported a lower frequency of smoking
among patients with SjS than control individuals55,56, and
other studies have linked cigarette smoking with a higher
­frequency of ANAs57 and a lower frequency of FLS58.
Genetic factors
The genetic basis of SjS is expected to be as complex as
that of other autoimmune diseases including SLE and
rheumatoid arthritis, each of which have >100 estab­
lished genetic associations. However, compared with
SLE and rheumatoid arthritis, the genetic architecture
of SjS remains relatively unexplored. Familial clustering
studies show that approximately 35% of patients with
SjS have relatives with SjS or a related auto­immune
disease59. Moreover, having a twin sibling with SjS is
associated with a 662‑fold higher risk of develop­
ing this disease than individuals without an affected
twin sibling60.
Genome-wide association studies have shown
strong associations between SjS and the HLA class I,
class II and class III regions, with multiple associations
observed for HLA class II molecules, HLA-antigen D
related (HLA‑DR) and HLA‑DQ loci61–63. Some HLA
class II alleles are associated with the production of
VOLUME 2 | 2016 | 5
PRIMER
autoantibodies in SjS but not with other clinical features
of the disease63. By integrating genetic and transcrip­
tional data, associations expression quantitative trait
loci were identified, for example, five HLA class I and
class II loci (HLA‑A, HLA‑C, HLA‑DRB6, HLA‑DPB1
and HLA‑DQA1)64. These results suggest that HLA risk
alleles could not only affect HLA function (including
peptide binding and antigen presentation) but could
also influence the expression levels of HLA class I and
class II molecules.
Other loci involved in a wide variety of innate and
adaptive immune processes have also been shown to be
substantially associated with SjS. Examples are genes
encoding molecules involved in type I and type II IFN
signalling and target processes (such as IRF5, IL12A
and STAT4), NF-κB signalling (for example, TNIP1 and
TNFAIP3), lymphocyte trafficking (such as CXCR5),
and activation and differentiation of antibody-producing
cells (such as BLK)61.
Very little is known about how these SjS-associated
genetic variants change normal biological activity or
how they are involved in disease. However, expression
quantitative trait loci were also identified in IL12A, BLK
and TNIP1 alleles, suggesting that these variants might
act by influencing the expression levels of the associated
proteins61. In addition, the precise subsets of immune
cells in which these variants cause pathogenetic effects
are unclear. The expression of BLK is relatively limited
to B cells, but the expression of all the other associated
genes have been shown in multiple subtypes, such as
natural killer cells, monocytes, dendritic cells, as well as
T cells and B cells61. Understanding these genetic effects
and the consequences of these genetic risk variants in
the function of the immune system are important for
determining causal disease mechanisms in SjS.
Lymphoma development
Patients with SjS are at increased risk of developing lym­
phoma65. Compared with other autoimmune diseases,
SjS has the highest risk of lymphoma development than
the general population, with a standardized incidence
ratio of 9–44 in studies before 2000 and 5–15 in stud­
ies after 2000 (REF. 65). Marginal zone lymphomas and
especially mucosa-associated lymphoid tissue (MALT)
lymphomas are the most common histological subtype
of lymphoma observed in patients with SjS.
In patients with SjS, lymphomagenesis is a multi­
step aetiopathogenetic process65. The first step is the
chronic stimulation of polyclonal B cells, especially in
patients in whom the autoantibody rheumatoid factor
is detected. Activation of polyclonal B cells might be
associated with an increased risk of oncogenic muta­
tions and mono­clonal selection. A dysfunction in one of
the checkpoints of the activation of autoimmune B cells
could speed up the development of a haematological
malignancy as the last step in the process. It was recently
found that functional germinal mutations in TNFAIP3,
which controls NF‑κB activation, were associated with
SjS-related lymphomas66.
Two of the main features of SjS — chronic expo­
sure to autoantigens and immune activation — might
6 | 2016 | VOLUME 2
© 2016 Macmillan Publishers Limited. All rights reserved
promote lymphomagenesis. For example, in patients
with SjS, a predictive risk factor for the development of
lymphoma is the presence of germinal centre-like struc­
tures within the mucosal sites of exocrine glands (where
they usually are not present)67. Interestingly, the levels
of CXC-chemokine ligand 13 (CXCL13), a chemokine
that attracts memory B cells within germinal centres,
have been found to be increased in patients with SjS and
lymphoma compared with patients with SjS who do not
have lymphoma68. Two recent studies have demonstrated
that the levels of TNF ligand superfamily member 13B
(also called B cell-activating factor (BAFF); a protein
involved in B cell survival, activation and differenti­
ation) are increased in patients with SjS with lymphoma
compared with those without 69,70. Polymorphisms in
TNFSF13B and TNFRSF13C have been found to be
associated with lymphoma develop­ment in patients with
SjS71. FMS-like tyrosine kinase 3 (FLT3) is a cytokine
related to the differentiation and proliferation of early
B cell progenitors, and increased serum levels of FLT3
have been found in patients with SjS and lymphoma
compared with healthy individuals72.
Diagnosis, screening, and prevention
Clinical presentation
SjS is a slowly progressing chronic autoimmune disease.
Clinical manifestations are extremely variable; the pres­
entation of this disease can range from an organ-specific
autoimmune disease to a systemic autoimmune disease
and a lymphoproliferative condition.
Sicca symptoms. Dryness of the eyes and mouth are
the classic symptoms associated with SjS and are
present in the vast majority of patients. Patients with
dry mouth usually complain of the inability to swal­
low dry food without fluid intake, changes in their
sense of taste, burning mouth, difficulties in speak­
ing continuously and the need for waking during the
night to have a drink of water 73. Physical examination
­usually reveals a dry, erythematous (red skin), sticky
oral mucosa, a dry fissured tongue and an accelerated
­dental caries73. Dental caries in SjS is usually found in
a specific pattern, with damage commonly observed to
the cervical region and/or smooth surface of the teeth
(regions that are usually rather resistant to caries owing
to the continuous flow of saliva over these surfaces)73.
Approximately one-third of patients complain of fre­
quent swelling of the parotid glands74. Parotid swell­
ing is commonly seen in relatively young patients75.
Eye symptoms include eyes that feel sandy and itchy,
and that might be red in appearance and might pres­
ent with dilatation of the bulbar conjunctival vessels.
Furthermore, patients with SjS report an inability to
wear contact lenses and the need for use of tear sub­
stitutes. In addition to the salivary and lacrimal glands,
other exocrine glands might be affected in patients
with SjS. Dryness can also affect the nose, the upper
respir­atory tract and the oro­pharynx, which can cause
rhinitis sicca, persistent cough and hoarseness1. Many
patients also experience xerosis cutis (abnormally dry
skin) and, in women, vaginal dryness76,77.
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General symptoms and organ-specific complications.
SjS can also be associated with systemic symptoms
(BOX 1), which can be seen in approximately 50–60% of
patients19,69. Severe clinical manifestations have been
described in 15–20% of patients with SjS, whereas the
prevalence of lymphoma has been estimated at around
5% 78. Low levels of complement C3 and comple­
ment C4, hypergammaglobulinaemia or the presence
of cryo­globulins, rheumatoid factor or anti-Ro/SSA
auto­antibodes can be used to identify patients with a
potentially more-severe clinical expression of SjS that
might merit closer follow‑up over time. Several of these
markers (such as complement C4, rheumatoid factor and
cryoglobulins) are included in the current classification
criteria of cryoglobulinaemic vasculitis79, and one study
found that patients with SjS who fulfilled these criteria
at diagnosis are at higher risk of death80.
Systemic symptoms might develop either at the
presen­tation of SjS or later. When systemic symptoms
appear before the onset of the characteristic symptoms of
SjS or when the typical symptoms are mild, this disease
is referred to as occult SjS or non-sicca onset of SjS74.
According to the European League Against Rheumatism
(EULAR) SjS Disease Activity Index (ESSDAI; disease
score ranging from 0 to 123)81, systemic features of SjS
can be described by recognizing various organ domains
at different levels of disease activity.
General symptoms of SjS include fever, weight
loss and fatigue, and are common presenting features
of this disease and are observed in seropositive and
sero­negative patients for both anti-Ro/SSA and anti-
La/SSB antibodies. However, functional impairment
related to general symptoms seems to be greater in
seronegative patients82,83.
The systemic symptoms and complications of SjS
can be widespread, involving most systems of the body,
including the cutaneous, articular, pulmonary, cardio­
vascular, nephro-urological, nervous and haematological
systems, among others (BOX 1; FIG. 3).
Synovitis or arthritis is common in patients with
SjS84 (FIG. 3a), but causes less joint erosion and is more
relapsing and remitting than in rheumatoid arthri­
tis84. Subclinical synovitis is frequently observed by
­musculoskeletal ultrasonography in patients with SjS85.
Skin involvements of disease include cutaneous
vasculitis84, which can include various lesion subtypes,
predominantly flat purpura, observed in patients
with hypergammaglobulinaemia and palpable pur­
pura, which are associated with cryoglobulinaemic
v­ asculitis86 (FIG. 3b).
Involvement of the pulmonary system is c­ ommon
in SjS and is observed in 16% of patients 84, but is
rarely clinically relevant. Patients with SjS are at risk
of develop­ing interstitial lung diseases (FIG. 3d) and are
more likely to have rheumatoid factor, anti-Ro/SSA and
anti-La/SSB autoantibodies and lymphopaenia than
patients with SjS with no lung involvement of disease87.
The kidneys are potentially targeted by two dis­
tinct immunopathological pathways in patients with
SjS: infiltration of the tubular epithelium by activated
lymphocytes, resulting in interstitial nephritis, and
NATURE REVIEWS | DISEASE PRIMERS
© 2016 Macmillan Publishers Limited. All rights reserved
PRIMER
immune complex-mediated membranous or mem­
branoproliferative glomerulonephritis88. Some renal
complications of SjS, such as distal renal tubular acido­
sis might ­compromise renal function, but might also be
clinically silent.
Complications of SjS can affect both the peripheral
and the central nervous systems (CNS). Approximately
10% of patients with SjS are also diagnosed with periph­
eral neuropathies89, of which sensory neuropathy is the
most commonly reported. The frequency of CNS involve­
ment in patients with SjS is approximated at 3% of causes
using the ESSDAI definitions84 and can include myelitis,
aseptic meningitis and cerebral lesions that might mimic
those observed in multiple sclerosis90 (FIG. 3e).
Other complications of SjS include cytopaenia
(in approximately one-third of patients with SjS), Raynaud
phenomenon (FIG. 3c) , serositis and p ­ rotein-losing
enteropathy, among others90.
Lymphoma. Diffuse large B cell lymphoma is often
formed as a consequence of the progression of a low-
grade lymphoma65. The salivary glands, primarily the
parotid glands, are the most frequent site of MALT lym­
phomas in patients with SjS (FIG. 3f), but lymphomas can
also occur in other mucosal sites, such as the stomach,
the lungs and the eyes. The most frequent presentation
of lymphoma is persistent parotid enlargement, which
can be difficult to differentiate from benign parotid
enlargement. Some clinical findings might be useful in
differentiating between parotid enlargement and lym­
phoma, for example, benign parotid enlargement is
often bilateral and the swelling fluctuates in size, whereas
lymphoma is more often unilateral, swelling is fixed
and sometimes hard. Ultrasonography of the salivary
glands (including Doppler ultrasonography) and MRI
might also aid the differentiation between benign and
m
­ alignant parotid enlargement
The main clinical predictors of lymphoma are per­
sistent swelling of the salivary glands, lymphadenopathy
and palpable purpura (overwhelmingly related to cryo­
globulinaemia) (BOX 2). These predisposing factors are
easily checked in clinical practice and should be included
in the management of patients with SjS. Moderate
(an ESSDAI score of 5–14) and, especially, high dis­
ease activity (an ESSDAI score of ≥14) is predictive of
­lymphoma development in patients with SjS91,92.
Diagnostic tests
Sicca symptoms. Diagnostic tests to determine sicca
symptoms try to measure glandular dysfunction and
quantify the degree of involvement of the main glands
affected (that is, the major salivary and lacrimal
glands) (TABLE 1). The two main oral tests to assess
­salivary gland function are the measurement of salivary
flow rates and salivary gland scintigraphy 93. The main
ocular tests include Schirmer’s tests and analysis of the
corneal surface using dyes (fluorescein and lissamine
green) that stain degenerated or dead cells (­corneal
stainings)94. Ultrasonography and MRI are mainly used
to evalu­ate the most common complications of SjS,
such as i­ nfections and lymphoma95.
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PRIMER

Box 1 | Organ‑by‑organ systemic manifestations

Oral symptoms Pancreatic complications
• Hyposalivation • Recurrent acute pancreatitis
• Soreness
Nephro-urological complications
• Adherence of food to the mucosa
• Renal tubular acidosis (9% of patients)
• Dysphagia
• Glomerulonephritis (4% of patients)*
• Difficulties in speaking or eating
• Interstitial cystitis (in the absence of bacterial
• Dental caries infection)
• Oral candidiasis • Osteomalacia
Ocular symptoms • Recurrent renal colic due to renal stones
• Insufficient tears • Hypokalaemic paralysis*
• Inability to tear
Peripheral nervous system complications
• Foreign-body sensation
• Mixed polyneuropathy
• Conjunctival inflammation (keratoconjunctivitis sicca)
• Axon sensory polyneuropathy
• Eye fatigue
• Sensory ataxic neuronopathy*
• Decreased visual acuity
• Blepharitis • Axon sensorimotor polyneuropathy
• Bacterial keratitis • Trigeminal or other cranial neuropathies
• Demyelinating polyradiculoneuropathy
General symptoms
• Autonomic neuropathy
• Fatigue
• Pure sensory neuronopathy
• Chronic pain
• Low-grade fever • Mononeuritis multiplex*
• Weight loss • Small-fibre neuropathy (painful paresthesias)

Lymph node complications Central nervous system complications

• Reactive multiple lymphadenopathy (swelling of the • White matter lesions
lymph nodes) (multiple sclerosis‑like disease)*
• Lymphoproliferative complications • Neuromyelitis optica spectrum disorder*
Cutaneous complications • Recurrent aseptic meningitis
• Cutaneous vasculitis (10% of patients) Haematological complications
• Purpura • Haemolytic anaemia*,‡
• Cutaneous ulcers* • Unexplained leukopaenia (lymphopaenia and
• Annular erythema (9% of patients) neutropaenia)
• Xerosis cutis (abnormally dry skin; 23–68% of patients) • Unexplained thrombocytopaenia*
Articular and muscle complications • Evans syndrome‡
• Arthralgias (joint pain; 60–70% of patients) • Unexplained monoclonal gammopathy
• Non-erosive symmetric arthritis • Thrombotic thrombocytopaenic purpura*,‡
• Subclinical synovitis (20–30% of patients) • B cell lymphoma*
• Jaccoud arthropathy (non-erosive joint disorder)‡
Obstetrics
• Myalgias (20–40% of patients)
• Autoimmune congenital heart block*
• Myositis‡
• Cardiac fibroelastosis
Pulmonary complications • Unexplained fetal valvular disease
• Chronic obstructive lung disease
• Neonatal lupus
• Bronchiectasis
• Interstitial lung diseases* Ear, nose and throat complications
• Pleuritis‡ • Recurrent parotid enlargement
• Bilateral multicystic parotid masses
Cardiovascular complications
• Sensorineural hearing loss
• Raynaud phenomenon (13% of patients)
• Parotid lymphoma*
• Pericarditis‡
• Pulmonary arterial hypertension*,‡ *Denotes severe systemic manifestations74,84,90. ‡Denotes rarely
reported manifestations (<1% of patients) or suggesting
• Dysautonomia polyautoimmunity (that is, the coexistence of other systemic
• Cryoglobulinaemic vasculitis* autoimmune diseases).

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 PRIMER

a b c

d e f

Figure 3 | Systemic involvement in patients with SjS. a | Synovitis (swelling of the extensor tendon sheath; black arrows)
Nature Reviews | Disease Primers
and arthritis (fusiform swelling of the proximal interphalangeal joints; white arrows). b | Cutaneous vasculitis or raised
reddish-purple spots on the legs. c | Raynaud phenomenon: white fingers (inadequate blood flow; white arrows) and red
fingers (return of blood flow; black arrows). d | Biopsy-proven lymphocytic interstitial pneumonia: multiple areas of
ground-glass attenuation on pulmonary CT (arrows). e | Cerebral multiple sclerosis‑like involvement: bright spots (arrows)
represent demyelinating lesions on cerebral MRI. f | Parotid mucosa-associated lymphoid tissue (MALT) lymphoma:
enlarged right parotid gland with diffuse cystic replacement (arrows). SjS, Sjögren syndrome.

Autoantibodies and immunological abnormalities.
Autoantibodies are the key serological markers of auto­
immune diseases and can be present up to 20 years before
the diagnosis of SjS52,55.
ANAs are a range of autoantibodies that are specific
for nuclear and cytoplasmic components of human cells.
ANAs are the most frequently detected autoantibodies
in patients with SjS (found in >80% of patients) and, as
such, are one of the better ways to identify SjS in patients
presenting with sicca features in non-specialized clinical
settings, such as in primary care.
Rheumatoid factor antibodies are specific for the Fc
fragment of IgG. Rheumatoid factor is present in 50% of
patients with SjS and has been associated with the main
clinical, histopathological and laboratory features of
this disease90.
The detection of ANA and rheumatoid factor auto­
antibodies is useful in patients who are referred for fur­
ther diagnostic assessment from primary care centres to
indicate the presence of autoimmune disease. However,
the detection of ANA and rheumatoid factor antibodies
is not included in the current classification criteria for SjS,
as they are common in a range of autoimmune diseases
(as such, they have low specificity for SjS).
Anti-Ro/SSA antibodies are ANAs that target two pro­
teins — Ro52 and Ro60 — that are associated with small
molecules of RNA96. Anti-Ro/SSA antibodies are detected
in up to 70% of patients with SjS, although the proportion
of patients with these antibodies might vary according to
the detection method; 12–20% of patients who were found
to be negative for anti-Ro/SSA antibodies might still have
specific antibodies against Ro52 and Ro60 (REF. 97). Recent
studies suggest that anti-Ro52 and anti-Ro60 autoantibod­
ies might be associated with different clinical phenotypes
of SjS and that separate detection is desirable when a
diagnosis of SjS is suspected98. Anti‑Ro52 antibodies are
closely associated with the main clinical, immunological
and histopathological features of SjS99. In addition, Ro52
has been detected on the surface of apoptotic cardiac
cells from patients with congenital heart block100, which
is an acquired heart disease that can develop in the fetus
of mothers with SjS and is associated with the transfer of
maternal Ro52 antibodies across the placenta to the fetus.
Anti-La/SSB antibodies target the La/SSB protein,
which is involved in variable aspects of RNA metabolism,
including the binding of viral-related RNAs. Anti-La/SSB
antibodies are detected in up to 50% of patients with SjS
and are frequently associated with the presence of anti-Ro/
SSA antibodies. The detection of both anti-La/SSB and
anti-Ro/SSA autoantibodies is associated with a higher
chance of testing positive for ANAs101 and with systemic
activity of SjS82,102. Only between 2.3% and 7% of patients
with SjS have isolated anti-La/SSB antibodies without con­
comitant anti-Ro/SSA antibodies49,103,104. Patients with SjS
and anti-Ro/SSA antibodies reportedly have a higher fre­
quency of the main clinical and immunological features
of SjS than patients with SjS and anti-La/SSB antibodies
only 103. However, patients with SjS and anti-La/SSB anti­
bodies have a higher frequency of some clinical features of
SjS, such as dry mouth and the presence of ANA-specific
antibodies, than patients who are ­negative for both
anti-Ro/SSA and anti-La/SSB antibodies103.

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PRIMER
Cryoglobulins are immunoglobulins that precipi­
tate at <37 °C in vitro105. Nearly 10% of patients with SjS
present with circulating cryoglobulins, which are over­
whelmingly mixed (that is, they consist of both IgG and
IgM components)105. Cryoglobulins are the principal
immunological markers that are suggestive of a poor
prognosis in SjS, including a higher prevalence of sys­
temic disease, increased risk of B cell lymphoma and
poor survival19,78,89,106. The detection of cryoglobulins in
patients with SjS is essential, both at initial diagnosis of
the disease and during the follow‑up; some data obtained
from laboratory analysis can point to the presence of an
underlying mixed cryoglobulinaemia, such as low levels
of complement C4, increased levels of rheumatoid factor
and serum monoclonal IgM gammopathy 105.
Hypocomplementaemia, which is characterized by
low levels of complement C3 and/or complement C4,
are found in 10–25% of patients with SjS. Like cryo­
globulins, hypocomplementaemia is associated with the
adverse outcomes of SjS, such as lymphoma and death19.
Circulating monoclonal immunoglobulins (also
known as monoclonal gammopathy of undetermined
significance) are found in up to 20% of patients with
SjS107, with mIgGκ being the most frequent type19,108.
Monoclonal gammopathy is related to a high preva­
lence of parotid gland enlargement and extraglandular
features of SjS, among others, and is associated with a
poor prognosis, owing to the development of neoplasia
and eventual death107,108.
Box 2 | Risk indicators for lymphoma development in SjS
Clinical, laboratory, immunological, histopathological and genetic findings associated
with increased risk for the development of lymphoma.
Clinical features
• Persistent parotid gland enlargement
• Purpura
• European League Against Rheumatism Sjögren syndrome (SjS) Disease Activity Index
(ESSDAI) score of ≥5
Laboratory abnormalities
• CD4+ lymphopaenia
Immunological findings
• Low complement C3 or C4 levels
• Mixed cryoglobulinaemia
• Monoclonal gammopathy of undetermined significance
• Increased lymphocyte-related cytokine levels (including B cell-activating factor,
FMS-like tyrosine kinase 3 ligand, CXC-chemokine ligand 13 and CXC-chemokine
ligand 11)
• Increased β2‑microglobulin levels
• Presence of rheumatoid factor
Histopathological features
• Presence of germinal centres in the lymph nodes
• Focus score of >3
Genetic polymorphisms
• TNFSF13B
• TNFRSF13C
• TNFAIP3
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Salivary biopsy. Histopathological analysis of minor
salivary gland biopsy is a very specific test for the diag­
nosis of SjS, together with the detection of anti-Ro/SSA
antibodies109. The biopsy technique with the best ­balance
between efficacy in removing the salivary glands and
safety is using a linear incision of the buccal side of
the lower lip, rather than the use of a punch biopsy 110;
parotid gland biopsy has also been used by some111. The
key requirements for an accurate histological evaluation
are an adequate number of glands (3–5 in total), with
the evaluation of a sufficient glandular surface and the
determination of an average focus score (the n ­ umber
of lymphocytic aggregates per 4 mm 2 of glandular
surface analysed)110.
FLS detection is considered the gold-standard diag­
nostic test for SjS, but results should be interpreted with
caution in the absence of a suggestive clinical manifesta­
tions. The presence of FLS has been reported in individ­
uals without any signs of SjS, for example, in 2.5% of
autopsy subjects112 and 17% of young volunteers113, FLS
is defined as one or more dense aggregate (or focus)
of ≥50 lymphocytes in the perivascular or periductal
areas of the salivary glands and is considered the key
histopathological feature of SjS110 (FIG. 4). The finding
of one or more germinal centre-like structure in the
­salivary glands has been associated with a higher risk of
­developing lymphoma114.
Laboratory abnormalities. Patients with SjS often
have a triad of abnormalities that can be determined
using routine laboratory testing. Approximately one-
third of patients with SjS have cytopaenia19,115, includ­
ing normocytic anaemia, leukopaenia (related to
lymphopaenia and/or neutropaenia) and thrombocyto­
paenia, especially in patients carrying anti-Ro/SSA or
anti-La/SSB antibodies. Cytopaenias are predominantly
asymptomatic but might be clinically overt in some
cases74, and are closely associated with systemic disease
and poor outcomes19,89,116,117. The detection of polyclonal
hypergammaglobulinaemia points to polyclonal B cell
activation, and the erythrocyte sedimentation rate
often correlates with the quantity of circulating gamma
immunoglobulins. Serum levels of C‑reactive protein are
usually normal in patients with SjS, so increased ­levels
indicate the presence of an infection. Raised serum
­levels of β2‑microglobulin have been reported in one-
third of patients with SjS69. Other laboratory abnormal­
ities might suggest SjS-related renal involvement (such
as increased levels of creatinine, proteinuria, hypokal­
aemia and a urine pH of >5.5 despite severe acidaemia)
or associated liver disease (indicated by increased levels
of ­transaminases or alkaline phosphatases).
Classification criteria
The AECG classification criteria118 have been used
worldwide for the past 10 years and are still the criteria
used in clinical practice for the diagnosis of SjS. This
criteria require evidence of a SjS-specific autoimmune
process (either the detection of anti-Ro/SSA and/or
anti-La/SSB antibodies or the presence of FLS in ­salivary
gland biopsy), and has a sensitivity of 93.5% and a
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 PRIMER

Table 1 | Diagnostic tests to evaluate sicca symptoms in patients with SjS

Diagnostic Technical details Comments Refs
test
Evaluating the main salivary glands (parotid and submandibular glands)
Unstimulated Quantification of salivary volume (weight) produced Results can be influenced by age, 1
salivary flow in a defined time length of disease, comorbidities,
rates temperature or medications
Stimulated Measurement of the salivary flow rate after Better correlation with 1
salivary flow stimulation with chewing gum or lemon juice histopathological results or structural
rates glandular damage compared with the
unstimulated salivary flow rate test
Salivary Non-invasive quantification of uptake and secretion Severe involvement (grade IV) at 93
scintigraphy of technetium 99 by the salivary glands diagnosis associated with higher
systemic activity and poor outcomes
Evaluating the lacrimal glands
Schirmer’s test I Measurement of lacrimal gland output (measured on Evaluates baseline secretion 94
filter paper under local anaesthesia)
Schirmer’s test II Measurement of lacrimal gland output (measured on Measures baseline plus reflex 94
filter paper without anaesthesia) secretion
Corneal Evaluation of corneal damage (degenerated or dead Nowadays, rose bengal (a non-vital 94
stainings cells) through the use of dyes (such as fluorescein, dye) has been substituted by
rose bengal and lissamine green) and a slit lamp lissamine green (a vital dye)
SjS, Sjögren syndrome.

specificity of 94%. In 2012, Shiboski et al.119 proposed a Screening and prevention

new set of classification criteria for SjS, on behalf of the
American College of Rheumatology (known as the ACR
criteria), which is similar to the AECG classification in
both sensitivity (92.5%) and specificity (95.4%).
Differential diagnosis
The most frequent cause of sicca symptoms is the
chronic use of drugs that can cause dryness of mucosal
surfaces, mainly antihypertensive, antihistamine and
anti­depressant medications, and these medications are
commonly used in the elderly. In addition, sicca symp­
toms can be caused by a range of external or environ­
mental factors that might cause mucosal dryness: for
example, allergy and/or atopy, local infections, dehydra­
tion or irradiation, chronic viral infections such as
HCV, human immunodeficiency virus or HTLV1, and
systemic diseases that mimic the symptomology of SjS
through the infiltration of the exocrine glands by granu­
lomas (sarcoidosis and tuberculosis), amyloid proteins
(amyloidosis) or malignant cells (haematological neo­
plasia). A more recently recognized cause of s­ alivary
gland infiltration by immune cells is IgG4‑related
disease (IgG4‑RD). The involvement of organs infre­
quently affected by SjS (such as the pancreas, biliary
tract, gallbladder, mediastinum, retroperitoneum,
hypophysis and gonads) can be the first clinical sign of
IgG4‑RD120. Raised levels of IgG4 have been reported
in 7% of patients with SjS121, and IgG4‑RD should be
confirmed in these patients by histopathological and
­immunohistochemical study of the salivary glands
and other organs120.
As SjS affects men less often than women, other dis­
eases with similar symptoms to SjS, such as HCV infec­
tion, IgG4‑RD and sarcoidosis, should be specifically
investigated in men who present with sicca syndrome49,122.
SjS is a chronic disease that cannot be prevented.
However, screening approaches that target specific sub­
sets of patients with SjS might either prevent or ensure
timely treatment of the main complications. Oral and
ocular dryness are the principal symptoms, together with
episodic parotid gland swelling, that are indicative of SjS.
However, current evidence suggests that the diagnosis of
SjS should not be delayed until the development of sicca
symptoms. A large number of non-sicca features might
appear up to 20 years before the development of sicca
symptoms52,53, including the development of annular
erythema, autoimmune cytopaenias, or congential heart
block or neonatal lupus erythematosus in babies carried
by mothers with anti‑Ro/SSA antibodies123. The presence
of autoantibodies (especially anti-Ro/SSA antibodies) can
be used for the early diagnosis of SjS in these patients.
By contrast, the frequency of anti-Ro/SSA or anti-La/SSB
autoantibodies is often lower in patients with SjS who
only have neurological involvement than in patients with
SjS who have no neurological involvement, and these
patients often require a salivary gland biopsy showing
the presence of FLS for the early diagnosis of SjS74. Some
studies suggest that SjS is now being diagnosed earlier
in life; in a Spanish cohort, the mean age at SjS diagno­
sis was 62 years in 1997 (REF. 124) and was reported as
54 years in 2015 (REF. 19).
Management
Monitoring and follow‑up
Given the heterogeneity of SjS, the frequency and tools
used for monitoring and follow‑up will differ from
patient to patient. Studies have shown that, in many
cases, the progression of the disease can be successfully
determined from diagnosis, whereas the disease might
follow an unexpected path in others. Thus, a general

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© 2016 Macmillan Publishers Limited. All rights reserved
PRIMER
a b
c d
Figure 4 | Histopathological features of the salivary gland inReviews
Nature SjS scenarios. Although
| Disease Primers
focal lymphocytic sialadenitis (FLS) is the key histopathological feature of Sjögren
syndrome (SjS), salivary glands within normal limits (meaning the glandular tissue is
non-pathological but is different to that observed in healthy individuals), in addition to
other morphological patterns of chronic inflammation can be observed in salivary gland
tissue from patients with SjS. a | Salivary glands within normal limits showing the general
architecture with scattered plasma cells (circles), without acinar atrophy. b | Nonspecific
chronic sialadenitis showing scattered or focal infiltration of lymphocytes, macrophages
and plasma cells (circles) into the salivary gland, and are not adjacent to normal looking
acini that are located in the gland lobules. c | FLS is distinguished by one or more dense
aggregate of ≥50 lymphocytes (circles; usually more than several hundred), generally
located in perivascular or periductal locations. The aggregates are adjacent to
normal-appearing acini, found in gland lobes or lobules without duct dilation or
interstitial fibrosis and only contain low numbers of plasma cells. d | Sclerosing chronic
sialadenitis characterized by interstitial fibrosis (black arrows), in addition to several
patterns of chronic inflammation (circles) and acinar atrophy (yellow arrows). Daniels
et al.110 suggest that sclerosing chronic sialadenitis could be an advanced stage of
nonspecific chronic sialadenitis. Images courtesy of L. A. Hernández, Hospital Clinic,
Barcelona, Spain.
monitoring and follow‑up plan that is suitable for all
patients cannot be provided and will depend on the risk
of complications.
The ESSDAI125 is a very important tool for evaluating
systemic disease activity in patients with SjS and includes
the evaluation of a range of laboratory tests (BOX 3), which
should all be fully assessed at diagnosis of SjS and yearly
during the first 5–10 years thereafter 19. The EULAR SjS
Patient-Reported Index (ESSPRI) instrument seems less
useful than the ESSDAI for evaluating systemic activity,
although fatigue might be bothersome from early on126.
Patients with SjS should be subdivided into two
groups: those with risk factors for systemic complications
or lymphoma and those with little risk of these compli­
cations. Between 25% and 30% of patients with SjS are at
high risk for the development of systemic complications
and merit closer follow‑up; in these patients, a clinical
assessment every 3–6 months should be mandatory.
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© 2016 Macmillan Publishers Limited. All rights reserved
However, with sufficient self-monitoring, patients can
be seen yearly or when required, for example, when
pre-defined symptoms or situations that mirror potential
lymphoma development appear. The physician in charge
should monitor the ESSDAI score. Two important risk
factors not included in the ESSDAI are high focus scores
(≥3) or the presence of germinal centres in the salivary
glands67,127. The more of these factors that are present, the
higher the risk of development of systemic complications
or lymphoma, so more-frequent follow-ups are required.
If prevailing lymphoma is suspected, further steps should
be determined in collaboration with onco­logists128.
With regard to eye and mouth dryness, monitor­ing and
­follow‑­up of SjS aim to prevent irreversible tooth dam­
age, which is mainly caused by the lack of saliva. At least
bi‑annual dental visits for prophylactic treatment and
for the early recognition of tooth damage are necessary
for patients with SjS129. The ocular surface is rarely sub­
jected to irreversible damage as a consequence of SjS, and
regu­lar ophthalmologist visits are mandatory in the most
severe and treatment-resistant cases.
Age at disease onset or diagnosis can be important
for patient monitoring 11. Younger patients (<40 years
of age), who become positive for anti-Ro/SSA or
anti-La/SSB autoantibodies, less often develop sicca
symptoms but are prone to more-severe and systemic
disease than older patients (>40 years of age) with
these autoantibodies53. The presence of well-preserved
­g landular ­t issue with a high functional capacity in
younger patients might provide an explanation.
A subgroup of patients with SjS (almost 25% of
patients) who fulfil the 2002 AECG criteria118 (BOX 4)
present without detectable levels of anti-Ro/SSA or
anti-La/SSB antibodies 19. These patients are often
middle-­aged or older and have a milder disease course
in terms of systemic complications and disease-related
lymphomas. However, sicca symptoms and fatigue are
frequent and severe, which makes the use of the ESSPRI
tool to capture the disease burden ideal126. The ESSDAI
would typically be very low (<3). After an initial assess­
ment, ESSDAI measurements should be repeated after
1 or 2 years, which can be done by a well-informed
general practitioner. Management will generally focus
on supportive measures for fatigue and arthralgias and
monitoring of unexpected organ complications.
Management of sicca symptoms
Symptomatic treatment of SjS is usually limited to the
treatment of sicca symptoms (FIG. 2). For the treatment
of dry eyes, tear substitution therapy consisting of
high-viscosity eye drops and gels, in combination with
oral mucolytic agents to dissolve mucus, is the mainstay
treatment. Patients with SjS-associated severe or refrac­
tory keratoconjunctivitis sicca might require a short-
term course of topical anti-inflammatory agents (for
example, twice daily topical cyclosporine). Autologous
serum eye drops (eye drops containing biochemical
components that mimic natural tears more closely
than regular eye drops) and temporary occlusion of the
puncta (a procedure to reduce the rate of tear drainage
from the eye) have been used in most refractory cases130.
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Local management of the oral component of SjS is
focused on moistening of oral surfaces, in addition to
the use of preventive measures to preserve or obtain
optimal oral health. Correct oral hygiene combined with
frequent application of fluorides in patients with dental
complications are important to prevent the occurrence of
new dental caries and to slow the progression of existing
caries129. Several saliva substitutes are available but are not
used over time by many patients.
Drugs with a systemic effect, for example, secreta­
gogues, such as pilocarpine and cevimeline, can also be
used for the symptomatic management of sicca symp­
toms. Both drugs are muscarinic receptor agonists and
induce a transient increase in salivary and lacrimal gland
outputs in patients with some residual functional
­glandular tissue. Both drugs are approved by the US FDA
in the United States for the treatment of dry eyes and
mouth in patients with SjS, but cevimeline is not avail­
able worldwide. Common adverse effects of these drugs
include sweating, flushing, the urgent need for urination
and gastrointestinal discomfort, which might limit their
clinical application130,131.
Management of systemic disease
Only a few clinical trials have investigated the effect of
systemic treatments for the extraglandular manifesta­
tions of SjS for numerous reasons. First, extraglandular
symptoms are heterogeneous (BOX 1). Second, clinical
­trials generally include patients with low systemic disease
activity, for example, thereby excluding several patient
subgroups in SjS. Third, there was previously a lack of
validated outcome measures to evaluate the systemic
manifestations in patients with SjS130. However, treat­
ments for ­extraglandular manifestations of SjS need to
be developed.
Non-biological therapies. Non-biological therapies are
still used for SjS treatment, even though strong evidence
is lacking. The main non-biological drugs that are used
for the treatment of SjS are corticosteroids and hydroxy­
chloroquine. The use of prednisone (a corticosteroid) to
treat SjS is based on its effectiveness in the management
of other autoimmune diseases. Based on clinical experi­
ence, low-dose prednisone is used for the treatment of
arthritis and cutaneous symptoms. High doses of predni­
sone have shown efficacy for the treatment of kidney,
lung and CNS features in uncontrolled studies on SjS130.
The long-term use of corticosteroids is associated with
adverse effects, including osteoporosis, diabetes, weight
gain and dyslipidaemia130.
The therapeutic effect of hydroxychloroquine is
based on the inhibition of TLR signalling, which affects
the innate immune response by reducing the production
of pro-inflammatory cytokines, such as type I IFNs, and
other serological parameters, such as IL‑6, IgG, erythro­
cyte sedimentation rate and rheumatoid factor 132,133.
Hydroxychloroquine is used as maintenance therapy in
SjS, based on the reduction of symptoms and improved
serological parameters in patients with SLE and rheuma­
toid arthritis133. However, a randomized controlled trial
(RCT) found that hydroxychloroquine treatment was
NATURE REVIEWS | DISEASE PRIMERS
© 2016 Macmillan Publishers Limited. All rights reserved
PRIMER
not superior to placebo in patients with SjS132, although
the low disease activity of patients who were enrolled in
this study (a mean ESSDAI score of 2) does not allow
ap­ otential benefit of the drug in systemic disease to
be excluded.
The usefulness of other immunosuppressive agents
(such as cyclosporine A, azathioprine, methotrexate,
leflunomide and mycophenolic acid) has been evalu­
ated in a small cohort of patients with SjS130. The results
from these studies are homogeneous, and limited benefit
was seen on the sicca symptoms of SjS; the benefits on
systemic disease were not evaluated. In addition, high
rates of adverse events were observed (seen in 41–100%
of patients)130.
Biological therapies. Promising results have been
reported with several biological agents, especially those
targeting B cells. B cell depletion therapy with rituximab
(a CD20‑specific antibody) reduced some symptoms
of SjS, including fatigue, and improved salivary flow in
two small RCTs and also in uncontrolled studies134–139.
Serological and histological analysis showed complete
depletion of B cells in serum, a partial depletion of B cells
in the s­ alivary glands140 and a reduction in the absolute
numbers of follicular helper T cells and their hallmark
cytokine IL‑21. Despite pretreatment with corticosteroids,
antihistamines and paracetamol, some patients developed
a serum sickness-like syndrome, which can be associ­
ated with hypergammaglobulinaemia, making patients
with SjS prone to the formation of antichimeric anti­
bodies against rituximab135. A multicentre RCT recruited
122 patients in a consecutive manner and assigned them to
rituximab infusions (1 g) or placebo treatments at week 0
and week 2. This trial did not show significant differences
in the primary outcome (a composite score that evalu­
ated dryness, pain, fatigue and general health at 24 weeks),
objective diagnostic tests (for example, Schirmer’s test and
salivary gland biopsy) or the ESSDAI score. Significant
differences were found for some other end points (that is,
sicca symptoms, fatigue, visual analogue scale and salivary
flow rate)136. Post hoc analysis applying the SjS response
index also showed a significant difference in response rate
between rituximab and placebo groups141. Despite the
findings of this trial, rituximab is prescribed off-label for
the management of severe ­extraglandular manifestations
of SjS, including lymphoma131.
Box 3 | The ESSDAI
The European League Against Rheumatism Sjögren
syndrome (SjS) Disease Activity Index (ESSDAI) is used to
assess the severity of SjS and includes assessments of the
following laboratory parameters.
• Complement levels
• Blood cell counts
• Cryoglobulin levels
• Serum gammaglobulin levels
• IgG levels
• Serum monoclonal components
• Muscle enzyme levels
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PRIMER
Other biological therapies that target B cells include
epratuzumab and belimumab. Epratuzumab is a B cell
receptor CD22‑specific monoclonal antibody that acts
via B cell antigen receptor signalling and leads to partial
B cell depletion. A small prospective study in patients
with SjS showed a beneficial effect of epratuzumab on
fatigue, but the effect on extraglandular manifestations
Box 4 | 2002 AECG criteria for the diagnosis of SjS
Revised international classification criteria for SjS*
I. Ocular symptoms: a positive response to at least one of the following questions:
1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
2. Do you have a recurrent sensation of sand or gravel in the eyes?
3. Do you use tear substitutes more than 3 times a day?
II. Oral symptoms: a positive response to at least one of the following questions:
1. Have you had a daily feeling of dry mouth for more than 3 months?
2. Have you had recurrently or persistently swollen salivary glands as an adult?
3. Do you frequently drink liquids to aid in swallowing dry food?
III. Ocular signs — that is, objective evidence of ocular involvement defined as a
positive result for at least one of the following two tests:
1. Schirmer’s test I, performed without anaesthesia (≤5 mm in 5 minutes)
2. Rose bengal score or other ocular dye score (≥4 according to van Bijsterveld’s
scoring system)
IV. Histopathology: in minor salivary glands (obtained through normal-appearing mucosa)
focal lymphocytic sialoadenitis, evaluated by an expert histopathologist, with a focus score
>1, defined as a number of lymphocytic foci (which are adjacent to normal-appearing
mucous acini and contain more than 50 lymphocytes) per 4 mm2 of glandular tissue
V. Salivary gland involvement: objective evidence of salivary gland involvement defined
by a positive result for at least one of the following diagnostic tests:
1. Unstimulated whole salivary flow (≤1.5 ml in 15 minutes)
2. Parotid sialography showing the presence of diffuse sialectasias (punctate, cavitary
or destructive pattern), without evidence of obstruction in the major ducts
3. Salivary scintigraphy showing delayed uptake, reduced concentration and/or
delayed excretion of tracer
VI. Autoantibodies: presence in the serum of the following autoantibodies:
1. Antibodies to Ro/SSA or La/SSB antigens, or both
Revised rules for classification
For primary SjS. In patients without any potentially associated disease, primary SjS may
be defined as follows:
• a. The presence of any four of the six items is indicative of primary SjS, as long as
either item IV (histopathology) or VI (serology) is positive
• b. The presence of any three of the four objective criteria items (that is, items III, IV,
V and VI)
• c. The classification tree procedure represents a valid alternative method for
classification, although it should be more properly used in clinical–epidemiological
surveys
For secondary SjS. In patients with a potentially associated disease (for instance,
another well-defined connective tissue disease), the presence of item I or item II plus
any two from among items III, IV and V may be considered as indicative of secondary
SjS. Exclusion criteria:
• Past head and neck radiation treatment
• Hepatitis C virus infection
• Acquired immunodeficiency syndrome (AIDS)
• Pre-existing lymphoma
• Sarcoidosis
• Graft-versus-host disease
• Use of anticholinergic drugs (as a time shorter than fourfold the half-life of the drug)
AECG, American–European Consensus Group; SjS, Sjögren syndrome. *See REF. 118.
Reproduced from Classification criteria for Sjögren’s syndrome: a revised version of the
European criteria proposed by the American–European Consensus Group, Vitali, C. et al., 61,
554–558, © 2002, with permission from BMJ Publishing Group Ltd.
14 | 2016 | VOLUME 2
© 2016 Macmillan Publishers Limited. All rights reserved
was not evaluated142. An open-label trial of belimumab
(a BAFF-blocking drug) showed a decrease in ESSDAI
scores in 60% of patients treated with this drug 143.
With respect to T cell targeting, abatacept (a fusion
molecule) prevents CD28 co‑stimulation between
antigen-presenting cells, including B cells and T cells.
Abatacept is also presumed to inhibit the full activa­
tion of T cells and T cell-dependent B cell activation.
In two open-label trials, abatacept reduced the glandular
and extraglandular manifestations of SjS, reflected by a
signifi­cant improvement in ESSDAI scores, and a reduc­
tion in the levels of IgG and rheumatoid factor and in the
number of follicular helper T cells144,145. A phase III RCT
(ASAP III trial) is ongoing 146 (TABLE 2).
Management of lymphomas
Following the diagnosis of lymphoma, the therapeutic
approach must be planned according to the subtype of
lymphoma present. Some clinicians recommend a watch­
ful waiting approach in patients with low-grade lympho­
mas that affects the exocrine glands only 65. By contrast,
patients with disseminated MALT lymphoma or those
with concomitant high disease activity have an increased
risk of lymphoma progression, so could benefit from
early treatment to stop progression into more-aggressive
types of lymphomas65. The best therapeutic regimen for
the treatment of lymphoma is the combination of rituxi­
mab with alkylating agents, such as cyclophosphamide,
chlorambucil, fludarabine and/or bendamustine128,147.
The combination of rituximab and bendamustine has
been shown to be effective and safe for marginal zone
and MALT lymphomas147. In patients with diffuse large
B cell lymphoma, treatment should be adapted according
to the histological grade of the lymphoma and is based
on the association of rituximab with cyclophosphamide,
doxorubicin, vincristine and prednisone148.
Quality of life
The main symptoms associated with SjS are unpleasant
and can be debilitating. Thus, many patients report a
reduction in their quality of life (QOL) or, more specifi­
cally, a reduction in their health-related QOL (HRQOL).
QOL is defined as the overall well-being of individuals
and societies and covers a broad range of concepts, includ­
ing personal well-being, the environment, happiness levels
and personal freedom, some of which are not necessarily
relevant to SjS. In a study evaluating QOL and HRQOL in
SjS, patients demonstrated reduced QOL and HRQOL to
a comparable level as patients with rheumatoid arthri­
tis or SLE149. Other studies have found similar results
with reduced QOL measured by the WHOQOL-BREF,
which is linked to psychological disorders such as anxiety
and somatization150,151. In addition, the 36‑Item Short-
Form Health Survey (SF‑36) shows a reduced HRQOL
in patients with SjS similar to that seen in patients with
rheumatoid arthritis or SLE; compared with SjS, the physi­
cal and pain domains of patients are more profoundly
reduced in rheumatoid arthritis149,152–154. Generally, a
reduction in the HRQOL-assessed SF‑36 scores is more
dependent on fatigue, pain and low mood than on the
severity of dryness symptoms in patients with SjS154,155.
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Table 2 | Ongoing diagnostic and therapeutic studies in primary SjS

ClinicalTrials.gov Patients Diagnostic approach or procedure Type of study Study phase Funding
identifier
Diagnosis
NCT02132585 SjS Speckle-tracking echocardiography Observational N/A Other
NCT01470638 SjS FLT3 ligand levels Observational N/A Other
NCT01807689 SjS Salivary biomarkers Observational N/A Other
NCT00074373 Congenital heart block Research registry Observational N/A Other
New drug interventions
NCT02004067 SjS Ocular cyclosporine Interventional Phase IV Industry
NCT01316770 SjS Dexamethasone irrigation Interventional Phase II US NIH
NCT00543166 SjS Dehydroepiandrosterone Interventional Phase IV Other
NCT01759108 SjS Rebamipide Interventional NP Other
NCT01782235 SjS Tocilizumab Interventional Phase II/III Other
NCT02067910 SjS Abatacept Interventional Phase III Industry
NCT02464319 SjS Human IL‑2 Interventional Phase II Other
NCT01552681 SjS Baminercept Interventional Phase II NIH
NCT02610543 SjS UCB5857 Interventional Phase II Industry
NCT02334306 SjS AMG 557 or MEDI5872 Interventional Phase II Industry
NCT02149420 SjS VAY736 Interventional Phase II Industry
NCT02291029 SjS CFZ533 Interventional Phase II Industry
NCT01379573 Congenital heart block Hydroxychloroquine Interventional Phase II Other
NCT02503163 Dry eyes with SjS KCT‑0809 ophthalmic solution Interventional Phase III Industry
NCT02503176 Dry eyes with SjS KCT‑0809 ophthalmic solution Interventional Phase III Industry
NCT02503189 Dry eyes with SjS KCT‑0809 ophthalmic solution Interventional Phase III Industry
Other therapeutic approaches
NCT02370225 SjS Aerobic exercise Interventional NP Other
NCT01501019 SjS Exercise training Interventional NP Other
NCT02031172 SjS Effects of sustained reading on the ocular surface Observational NP Other
NCT02110446 SjS Chinese herbal formula SS1 Interventional Phase II Other
NCT00953485 SjS Allogeneic mesenchymal stem cells Interventional Phase I/II Other
NCT02112019 SjS Sialoendoscopy Interventional NP Other
NCT01174329 SjS Automatic neuro-electrostimulation Interventional Phase II/III Other
NCT02153515 Dry eyes Fingerprick autologous blood Interventional Phase III Other
NCT02193490 Dry eyes DNase Interventional Phase I/II Industry
NCT02148497 Dry eyes Multicoloured Placido disk imaging Interventional NP Other
NCT02066896 Keratoconjunctivitis sicca Laser 3R 790 nm infrared GaAIAs Interventional Phase II Other
Data from ClinicalTrials.gov, accessed December 16 2015. FLT3, FMS-like tyrosine kinase 3; GaAIA, gallium-aluminium-arsenide; N/A, not applicable;
NP, not provided; SjS, Sjögren syndrome; SS1, Strengthen Earth 1 oz.

The EuroQol EQ‑5D tool has also confirmed a reduced Outlook

HRQOL in patients with SjS, and linked this to more-­
severe symptoms (particularly pain levels) and the pres­
ence of systemic disease156. Although there are some
differences between these studies regarding the worst-­
affected domains of HRQOL in SjS and the associations
of HRQOL with other features of disease, they consistently
show the reduction of HRQOL in patients with SjS and the
association between systemic features of disease, such as
fatigue, pain and low mood. The presence of dryness was
less closely associated with a reduced HRQOL, if at all.
The clinical knowledge of SjS has rapidly evolved over
recent years, but not enough to permit considerable
changes in the daily management of patients. The areas
with the biggest changes are discussed below.
Novel aetiopathogenetic pathways
Some studies are investigating mechanisms previously
identified in other diseases, such as IFN-related mech­
anisms that involve the expression of microRNA and IFN-
inducible proteins, such as IFNγ-inducible protein 16, and

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© 2016 Macmillan Publishers Limited. All rights reserved
PRIMER
cytokines, for example, IL‑17 and IL‑21 (REFS 157,158).
Other aetiopathogenetic pathways under investigation
include autophagy, the role of aromatase and, especially,
epigenetic dysregulation, which might be restricted to the
main cellular components involved in the aetiopatho­
genesis of SjS, such as epithelial cells and lymphocytes159,160.
Epigenetic mechanisms including histone modifications,
non-coding RNAs and, particularly, DNA methylation,
could have an aetiopathogenetic role in SjS161. With
respect to novel antigens, some new molecules have also
been proposed, for example, the poly(U)-­binding-splicing
factor PUF60 and carbamylated proteins162,163. Cell types
under investigation include ­natural killer cells; in one
study, patients with SjS with low numbers of n ­ atural killer
cells in salivary gland tissue and blood responded better to
belimumab treatment than patients with higher numbers
of natural killer cells164.
Environmental factors
The classic debate on the influence of genetics versus
environment factors on the pathogenesis of human dis­
ease also exists for SjS. One study has estimated the herit­
ability of SjS to be around 54%60, but other studies have
focused on the effect of environmental factors. Examples
of novel environmental factors include the human o ­ cular
and oral microbiota in SjS165,166. Other aetiopathogenetic
investigations include the potential effect of exposure to
environmental toxins, including a high risk of developing
SjS in people with occupational exposure to solvents167,
in rescue and recovery workers exposed to aerosol­
ized dust in the 2001 World Trade Center site168 or an
increased risk of SjS associated with airborne pollution
(fine particulates)169.
Diagnosing sicca symptoms
For ocular tests, studies are now using double staining
(the use of both lissamine green and fluorescein), to cal­
culate the ocular staining score170 and have investigated
specific damage in some corneal areas, such as the central
optical zone171 or the influence of a desiccating environ­
ment on corneal staining 172. Technical developments
are promoting more-accurate quantitative evaluation
in salivary gland scintigraphic studies with enhanced
accuracy, although there remains no clear consensus on
their use in clinical practice93. With respect to salivary
gland biopsy, an international consensus on updating
the histopathological classification that has been used
with minimal variations for >40 years is needed. A close
cooperation between clinicians and pathologists should
also be promoted to facilitate the integration of patho­
logical results with clinical manifestations of each patient.
Histopathological findings that do not fit the current
criteria, such as focal aggregates of <50 lymphocytes,
chronic atrophic sialadenitis and the presence of germi­
nal centre-like structures, could have some diagnostic
value if integrated into the appropriate clinical scenario.
Diagnosing systemic disease
The increasing use of the ESSDAI and the recent pub­
lication of data from large European cohorts using the
ESSDAI19,78 have confirmed SjS as a systemic disease.
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© 2016 Macmillan Publishers Limited. All rights reserved
Unfortunately, the heterogeneous diagnostic approaches
used to confirm SjS have halted the field. The need for
consensus is clear, and the EULAR-SjS Task Force Group
is working on developing organ-specific recommenda­
tions84 and new scores for better characterization and
measurement of systemic disease173,174. The scoring of sys­
temic disease might provide better patient stratification,
as patients with the greatest systemic activity at diagnosis
of SjS have been shown to have a poorer prognosis19,89.
New diagnostic tests
Some imaging techniques, such as three-dimensional
MRI and 18F-fluorodeoxyglucose PET, are increasingly
used to improve the non-invasive diagnosis of SjS,
including parotid and dorsal root involvement of the
disease, in addition to lymphadenopathy or interstitial
lung disease175–177.
Ultrasonography is increasingly used for the diagno­
sis of SjS. Several studies have found a potential role for
ultrasonography in the early diagnosis of SjS, with a high
diagnostic accuracy 178,179.
Classification criteria
The existence of two sets of classification criteria (the
AECG and the ACR criteria), both of which have simi­
lar diagnostic accuracies, has induced some confusion
among the clinical community. An international ACR–
EULAR study group is trying to identify a consensual
set of criteria that maintains the same standards as pre­
vious sets, namely, the mandatory presence of either
anti-Ro/SSA antibodies (anti-La/SSB antibodies are over­
whelmingly associated with anti-Ro/SSA antibodies) or
FLS. Future efforts should explore the usefulness of incor­
porating features other than the presence of anti-Ro/SSA
autoantibodies and the glandular involvement of disease,
including organ-specific ESSDAI involvements (clinical,
laboratory and immunological) and the use of novel
imaging techniques (especially ultrasonography, but also
CT or MRI) into the diagnostic criteria for SjS.
Complexity and chronicity
SjS is associated with a considerable number of comorbid­
ities, principally, the higher risk of lymphomas, but also
other systemic or organ-specific autoimmune diseases180,
non-haematological cancer 181 and cardio­vascular 56,182 and
infectious19 complications. This constellation of associ­
ated disorders often provokes considerable concern and
doubt in both patients and physicians, and is respon­
sible for the high degree of complexity and chronicity
of SjS, which leads to increased hospitaliza­tion and out­
patient visits183. Studies focusing on the complexity and
chronicity of SjS are required for better understanding of
disease outcomes.
Drug-free management
Drug-free therapeutic interventions often receive little
attention and resources, and data from a systematic
review showed that all drug-free therapeutic studies
in SjS were of low quality and had a high risk of bias,
measured according to the Cochrane Risk of Bias Tool184.
Future studies should evaluate the disease from a holistic
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 PRIMER

perspective, focusing on the influence of determinants Disruptive innovations

involving personal life and work on the phenotypic
expression of SjS. This should include the effects of diet
(Mediterranean, Japanese, high-sugar and processed
food), regular aerobic exercise (principally for the
manage­ment of non-sicca general symptoms) and stress
(which acts not only to worsen the intensity of sicca
­features but also as a potential trigger of systemic flares).
Biological therapies
Direct and indirect B cell blockade seems to be the
most-promising approach in terms of biological thera­
pies for the management of SjS, although other therapeu­
tic targets are under investigation (TABLE 2). IL‑6 blockade
is another promising option, as IL‑6 induces the polar­
ization of follicular helper T cells and is also important
for the induction of IL‑21 production185. IL‑6 blockade is
currently being investigated in a phase III RCT186. Other
co‑stimulatory pathways, such as blocking CD40–CD40
ligand, which crosslinks innate and adaptive immune
cells and pathways, are also promising therapeutic
options187. Isolated studies are exploring other drugs,
such as fingolimod (an immunomodulatory drug) in
patients with multiple sclerosis-like CNS involvement
and bortezomib188,189. However, the disappointing results
of the two largest RCTs carried out in SjS, which both
evaluated drugs that were considered to be effective in
daily practice (hydroxychloroquine and rituximab), have
opened a debate about RCTs in SjS132,136. These trials used
a composite outcome based on the subjective evaluation
of dryness, fatigue and pain. The strong influence of per­
sonal and environmental factors on the intensity of this
triad of symptoms could explain the lack of significant
differences. In addition, inadequate patient selection, the
influence of concomitant drugs and the hetero­geneity
of diagnostic tests could have contributed to the lack of
significant differences between placebo and therapeutic
groups. The EULAR-SjS Task Force and other inter­
national groups are working on finding more solid,
­objective outcomes for future RCTs in SjS173,190,191.
Disruptive innovations that displace earlier technologies
or working methods are rapidly emerging in this cen­
tury, including health-related areas, which are among
the areas with the greatest potential for dramatic change.
In SjS, the most innovative therapeutic approaches are
those investigating the use of gene therapy to modulate
aquaporin or IL‑17 expression192, the role of robotic or
bioartificial techniques, including tissue engineering-­
based organ regeneration of lacrimal or salivary
glands193, and the proteomic and genomic analysis of
saliva to search for SjS-specific diagnostic soluble bio­
markers194,195. Enhanced understanding of the influence
of the disease on factors external to the patient and the
aetiopathogenetic mechanisms of extraglandular dam­
age could lead to the generation of new treatments for
SjS. In addition, a more holistic approach to individual
patient management, the formation of active inter­
national collaborations promoting multicentre patient
registries and a consensus on diagnostic and therapeutic
approaches, and application of new disruptive technolo­
gies have the potential to be gamechangers in our under­
standing of the disease and provide solid improvements
in the QOL and the prognosis of patients with SjS.
Quality of life
Most studies have reported nonspecific general com­
plaints as the main contributors to the poor HRQOL
in patients with SjS. Ongoing studies are investigating
other features that could contribute to poor HRQOL,
for example, inadequate dental and periodontal health196,
the effect of gynaecological involvement on the sex lives
of women197,198 and the effect of voice disorders and
other ear, nose and throat symptoms on occupational
and social activities199. In terms of moving forwards,
one key question that remains unanswered is whether
therapeutic interventions can lead to improved HRQOL.
Whether therapies that lead to clinical and symptomatic
improvements are also associated with an enhanced
HRQOL is of considerable interest 145,200.

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Acknowledgements
The authors thank L. Alós, Pathology Department, Hospital
Clínic, IDIBAPS, Barcelona, Spain, for her assistance in
preparing the histopathological images.
Author contributions
Introduction (P.B.‑Z.); Epidemiology (M.R.‑C.); Mechanisms/
pathophysiology (A.T., K.S. and R.J.); Diagnosis, screening
and prevention (C.B. and P.B.‑Z.); Management (E.T., H.B. and
X.M.); Quality of life (S.J.B.); Outlook (M.R.‑C.); Overview of
Primer (M.R.‑C.).
Competing interests statement
The authors declare no competing interests.
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