OTHER AUTOIMMUNE DISORDERS
€gren’s syndrome
Sjo
Simon J Bowman
Vijay Rao
Abstract
€gren’s syndrome is a systemic autoimmune disorder characterized by
Sjo
focal inflammation of the exocrine glands, leading to dry eyes and dry
mouth. Two forms of the syndrome have been defined: primary (pSS),
in which dysfunction of the exocrine glands occurs in the absence of
other autoimmune diseases, and secondary (sSS), in which patients suffer
additional autoimmune processes, especially connective tissue disorders
such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE),
and scleroderma. About 70% of patients with pSS have anti-Ro and/or
anti-La autoantibodies. Hypergammaglobulinaemia is also common and
a proportion of patients have systemic involvement. Better use of symp-
tomatic therapies can make a big difference to patients and there is also
current interest in whether anti-B cell therapy could be effective in treat-
ing pSS.
Keywords Alternative criteria; assessment; biologic therapy; diagnosis;
€gren’s; therapy
histology; pSS; Sjo
€gren’s syndrome (SS) is a systemic autoimmune disorder
Sjo
characterized by focal lymphocytic infiltration of the exocrine
glands, leading to dry eyes and dry mouth.1 It occurs either as a
primary disorder (pSS) or as a (usually late) complication in
patients with other rheumatic disorders, such as rheumatoid
arthritis (RA), systemic lupus erythematosus (SLE) and sclero-
derma (when it is termed ‘secondary’ Sjo€gren’s syndrome).
Anti-Ro and/or anti-La antibodies are found in approximately
70% of pSS patients and are associated with particular human
leucocyte antigen (HLA) types e especially HLA-DR3 and, to a
lesser degree, HLA-DR2. Hypergammaglobulinaemia with raised
immunoglobulin G (IgG) and/or IgM concentrations is also
common. Systemic features also occur in some patients with pSS.
Epidemiology, diagnosis and classification
pSS is a common disease that affects 0.1%e0.6% of the general
adult population with a female to male ratio of at least 9:1 and
mean age at diagnosis of approximately 50 years.1 The revised
AmericaneEuropean Consensus Group (AECG) criteria2 are
now the gold standard for the classification of SS and have
superseded pre-existing criteria sets. They require various
combinations of standardized dryness symptoms, reduction of
lacrimal/salivary flow, an abnormal labial gland biopsy and/or
Simon J Bowman PhD FRCP is a Consultant Rheumatologist at Queen
Elizabeth Hospital, Birmingham and Honorary Professor at the
University of Birmingham, UK. Competing interests: none declared.
Vijay Rao MBBS MRCP (UK) is Senior Registrar in Rheumatology at Queen
Elizabeth Hospital, University Hospitals Birmingham NHS Trust,
Birmingham, UK. Competing interests: none declared.
MEDICINE 42:3
What’s new?
C The Sjo € gren’s syndrome registries e to promote basic science
and clinical research in pSS
C Clinical assessment tools e the ESSDAI and ESSPRI have been
developed
C The use of ultrasound in pSS
C The AmericaneEuropean Consensus Group classification
€ gren’s
criteria continue to be the key diagnostic tool for Sjo
syndrome but the SICCAeACR criteria provide an alternative
C Clinical trials of anti-B cell therapy are being pursued by a
number of research groups as a potential therapy for pSS
C Inhibitors of BAFF, including anti-BAFF monoclonal antibodies
(TACI-Ig or BAFF-R-Ig) are currently being evaluated
anti-Ro/La autoantibodies (Table 1). They are also useful in
clinical diagnosis.
An alternative approach to classification criteria for SS has
recently been proposed by the Sjo €gren’s International Collabo-
rative Clinical Alliance (SICCA) Group3 (Table 2). These criteria
identify a similar cohort of patients to the AECG criteria.
Aetiology and pathogenesis
The aetiology of SS is unknown. A number of viruses, such as the
EpsteineBarr virus and endogenous retroviruses, have been
proposed as possible causative agents without definitive evi-
dence. Parotid gland swelling can also be a feature of HIV
infection although the histological features differ. The finding of
a Sjo€gren-like syndrome associated with hepatitis C virus infec-
tion4 provides some support for the hypothesis that SS could
have a viral aetiology.
A number of cytokines, including interleukin-1 (IL-1), tumour
necrosis factor-a (TNF-a), IL-6, IL-10, interferon-a (IFN-a), IFN-g
and IL-18, are up-regulated in the salivary glands in pSS.4 Che-
mokines such as CXCL13 and CCL21 are also expressed and may
be potential therapeutic targets.5e7 The common finding of
hypergammaglobulinaemia in pSS, and the presence of autoan-
tibodies and of B cell-containing germinal centres in salivary
glands, imply a role for B cells in pSS and this is further sup-
ported by the presence of a raised serum concentration of the B
cell-activating factor (BAFF), otherwise known as B cell
lymphocyte stimulator (BLyS).8,9
IFN type I has been shown to induce BAFF expression in
cultured monocytes and salivary gland epithelial cells of patients
with pSS.10 This cytokine can induce polyclonal B cell stimula-
tion, which results in higher autoantibody production and
enhanced autoantigeneautoantibody reaction with complement
consumption.10 The formation and organization of lymphocytic
foci suggest an important and dynamic role for helper T cells
(TH), specifically TH1, TH2 and TH17, in development of SS.11
Based on the findings of the genome-wide association study
(GWAS) in SLE and RA, pSS is associated with a variant haplo-
type of STAT4.12 STAT4 transduces IL-12, IL-23, and IFN type I in
T cells and monocytes, leading to TH1 and TH17 differentiation,
monocyte activation, and production of IFN-g.12 There is also
evidence of a strong additive effect of the major risk alleles of
162 Ó 2014 Elsevier Ltd. All rights reserved.
 OTHER AUTOIMMUNE DISORDERS
€gren’s syndrome e AmericaneEuropean Consensus
Sjo
Group criteria
C Ocular symptoms e dryness >3/12; sensation of grit; need to
use tear drops
C Oral symptoms e dryness >3/12; salivary gland swelling; need
for liquids to help swallowing
C Ocular signs e Schirmer 5 mm/5 min; Rose Bengal staining
C Histology* e labial salivary gland biopsy
C Salivary gland involvement e flow rate 1.5 ml/15 min; sia-
lography; scintigraphy
C Autoantibodies* anti-Ro (SSA) &/or anti-La (SSB)
Primary SS ¼ four out of the above six criteria with at least one of
these* criteria positive or three out of the four objective criteria
(3e6 above) and no exclusion criteria (sarcoid, lymphoma, hepatitis
C, HIV, GvHD, head and neck radiotherapy, medications)
Secondary SS ¼ RA/SLE, etc.: with criteria 1 and/or 2 above posi-
tive, plus two of criteria 3, 4 or 6 above
GvHD, graft-versus-host disease; HIV, human immunodeficiency virus; RA,
rheumatoid arthritis; SLE, systemic lupus erythematosus.
See: Vitali C, Bombardieri S, Jonsson R, et al. Classification criteria for
Sj€
ogren’s syndrome: a revised version of the European criteria published by
the AmericaneEuropean consensus group. Ann Rheum Dis 2002; 61: 554e8.
Table 1
IRF5 and STAT4 in pSS.13 Another gene locus in pSS is MECP2,
which is critical in DNA methylation-induced transcription
silencing.14
Although gland destruction can occur as the disease pro-
gresses, in early disease, many patients with low basal tear/
saliva production remain able to produce tears/saliva on stimu-
lation. This implies that the secretory mechanisms are intact but
inhibited and antimuscarinic antibodies have been implicated.15
Histological features
There are three main groups of salivary glands e the parotid in
front of the ears, the submandibular below the angles of the jaw and
the numerous labial (lip) glands. Diagnostic labial gland biopsy is
best done by an experienced specialist as there is a small chance of
permanent numbness or dysaesthesia. The classical histological
SICCA Group/American College of Rheumatology
€gren’s
provisional classification criteria for Sjo
syndrome: a data-driven, expert consensus approach
in the SICCA cohort
At least two of the following three are needed:
C Positive serum anti-Ro and/or anti-La antibodies, or positive
rheumatoid factor and antinuclear antibody (titre 1:320)
C Presence of keratoconjunctivitis sicca (KCS) defined by an
ocular staining score 3
C Presence of focal lymphocytic sialadenitis defined by a focus
score 1 focus/4 mm2 in labial salivary gland biopsy samples.
See: Shiboski SC et al. Arthritis Care Res (Hoboken). 2012 April; 64(4):
475e487.
Table 2
MEDICINE 42:3
feature is of at least one ‘focus’ of 50 or more (predominantly CD4
þve) T lymphocytes per high-powered field, clustered around a
salivary duct (periductal focal lymphocytic infiltrates).
Histology reports sometimes describe a generalized scattering
of inflammatory cells, including plasma cells, across the gland,
described as a ‘chronic sialadenitis’; this can be found in normal
individuals and should be classed as a negative biopsy.
Clinical features
Dryness
An insidious onset of dry eyes and dry mouth is the most common
presentation. Other patients may present with vaginal dryness, a
dry cough or, occasionally, swollen salivary glands.
Dry eyes
Patients with mild dry eyes may self-medicate with over-the-
counter lubricating eye drops. If they are referred to a hospital
ophthalmology department, a slit-lamp examination of the ocular
surface (including the use of vital dye eye drops) can be per-
formed. One simple test that can be carried out in a routine clinic
is Schirmer’s test, using standardized blotting paper strips to
measure tear flow over a 5-minute period; 5 mm or less of wet-
ting is classed as objectively dry.
Although many patients with SS are still able to produce tears
with stimulation, it is inhibition of basal tear production that
makes the eyes feel dry. Some patients even complain of watery
eyes resulting from chronic irritation/inflammation of the eyelid
margins (blepharitis).
Not all patients with dry eyes have SS. Other causes include
dysfunction of the oil-producing meibomian glands, and
blockage of the lacrimal gland ductules due to mucus-producing
goblet-cell injury. Hot, dry environments, air-conditioned offices,
working with computers and tiredness can all cause ocular dry-
ness symptoms. Medications such as antihistamines with anti-
cholinergic effects reduce the neural activation of the glands and
have the potential to aggravate dry eyes.
Dry mouth
The most common cause of dry mouth is medication (e.g. anti-
depressants, antihistamines, diuretics or beta-blockers). Head and
neck radiotherapy can result in rapid and sometimes irreversible
dry mouth. Diabetes mellitus or renal failure or other conditions
associated with dehydration may also present with oral dryness
symptoms. Some older patients have xerostomia in combination
with osteoarthritis.
A number of patients who complain of oral dryness do not
actually have reduced salivary flow. They perceive an alteration
in oral lubrication that is often part of an oral dysaesthesia
(‘burning mouth syndrome’). Mouth breathing and anxiety can
also cause oral dryness.
Clinical features include a lack of obvious saliva in the mouth
and absence of a normal ‘pool’ of saliva underneath the tongue.
The mucosa is dry and sticks to the gloved finger on examina-
tion. In long-standing cases, there is an increase in the incidence
of dental caries and oral candidiasis may be present. In more
severe cases the tongue is atrophic, fissured or even ulcerated.
Unstimulated salivary flow can be measured formally by asking
the patient to ‘drool’ into a pot for 15 min; a salivary volume of
1.5 ml or less is classed as objectively dry.
163 Ó 2014 Elsevier Ltd. All rights reserved.
 OTHER AUTOIMMUNE DISORDERS
Musculoskeletal and other systemic features
Another common presentation of pSS is with arthralgia, fatigue
and malaise, which may lead to a diagnosis of fibromyalgia or
chronic fatigue syndrome. A new symptom questionnaire (Eu-
ropean League Against Rheumatism [EULAR] Sjo €gren’s syn-
drome patient reported index, ESSPRI) has been developed to
measure the severity of fatigue and pain in pSS along with dry-
ness.16 A positive rheumatoid factor and/or antinuclear antibody
are often found in pSS. Some patients present with a true in-
flammatory arthritis and RA is sometimes misdiagnosed.
Other systemic features include Raynaud’s phenomenon, fe-
vers, photosensitivity, leucocytoclastic vasculitis, interstitial lung
disease, paraproteinaemia or cryoglobulinaemia, renal tubular
acidosis, interstitial nephritis, peripheral neuropathy and facial
nerve palsies. A diagnosis of SLE may be considered if a patient
with apparent pSS presents with these features, particularly if
they have a low serum complement C4 (about 10% of pSS pa-
tients), positive anti-double-stranded DNA (dsDNA) antibodies
or clinical features such as mouth ulcers. However, true pSS and
SLE can co-exist.
Younger female patients with pSS and anti-Ro/La antibodies
who are planning a family should be counselled about
the neonatal ‘lupus’ syndrome (the occurrence of SLE-like
symptoms e most commonly a rash resembling discoid lupus
erythematosus and sometimes with other abnormalities such as
heart block or hepatosplenomegaly in an infant born to a
mother usually with SLE or primary Sjo €gren’s syndrome who
carries the anti-Ro/La antibodies) associated with maternale
fetal transmission of these antibodies.
A systemic activity index to evaluate systemic complications
(EULAR Sjo €gren’s syndrome disease activity index, ESSDAI)17 is
now available for use in clinical practice and therapeutic trials
in pSS.
€gren’s syndrome
Ultrasound diagnosis of Sjo
The characteristic ultrasound appearance of the parotid salivary
gland of a patient with advanced SS shows black areas and white
lines instead of the normal plain grey appearance throughout,
and resembles ‘Swiss cheese’ (Figure 1).
Salivary gland swelling and lymphoma
Patients with pSS have a 44-fold increased risk of mucosa-
associated lymphoid tissue (MALT)-type B cell lymphoma.18 A
low serum complement C4 concentration, leucopenia and
hypergammaglobulinaemia are all associated with lymphoma
development.19 Any patient with SS and persistent salivary gland
swelling should be investigated further, usually with ultrasound
or magnetic resonance imaging, and possible biopsy.
Occasionally, persistent salivary gland swelling can be the
first presentation of pSS. Sarcoidosis and HIV disease (diffuse
infiltrative lymphocytosis syndrome) must also be considered.
Diabetes, chronic alcoholism and anorexia can also cause non-
inflammatory salivary gland swelling (sialosis). Some patients
with a low-grade, localized asymptomatic lymphoma can be
treated expectantly. For most patients with progressive salivary
gland enlargement, lymph node involvement or systemic symp-
toms, it is likely that they will be treated with a chemotherapeutic
MEDICINE 42:3
Figure 1 Ultrasound of the parotid salivary gland of a patient with
advanced Sjo €gren’s syndrome showing the characteristic ‘Swiss cheese’
appearance of black areas and white lines instead of the normal plain
grey appearance throughout (with thanks to Dr John Rout for kindly
providing this picture).
regimen, such as CHOP (cyclophosphamide, doxorubicin,
vincristine and prednisolone). More recently this has been
combined routinely with rituximab.
IgG4-related sialadenitis
IgG4-related disease is a recently identified condition character-
ized by a male to female ratio of 1:1, significantly higher total
IgG, IgG2, IgG4 and IgE and lower IgG1, IgG3, IgA and IgM
concentrations,20 and characteristic histopathological findings in
salivary and/or lacrymal glands. IgG4-related sialadenitis should
be considered in the differential diagnosis of Sjo €gren’s patients,
especially in a male patient with enlargement with salivary/
lacrimal glands and the absence of anti-Ro/SAA and/or anti-La/
SSB autoantibodies. Given that IgG4-related disease is highly
responsive to corticosteroids, early identification of the diagnosis
has important implications on therapeutic grounds.
Management of SS
Conventional disease-modifying therapies do not appear to be
effective in pSS, although low-dose prednisolone and hydroxy-
chloroquine are often used empirically to treat arthralgia and
fatigue. A randomized controlled trial of infliximab versus pla-
cebo in 103 patients demonstrated the absence of efficacy of
infliximab in pSS.21 Similar lack of efficacy was shown in a
controlled trial of etanercept.22
Treatment of dry eyes includes careful lid hygiene. Tear
substitutes should be used as needed, starting with watery
drops, such as hypromellose, and moving on, if necessary, to
thicker, more viscous drops, such as polyacrylic acid. If pa-
tients are using drops more than six times a day, preservative-
free drops, such as carmellose 0.5%, should be used. Paraffin-
based gels, such as Lacri-LubeÒ, can be used at night. In pa-
tients with severe dry eyes, the tear drainage ducts, through
which tears drain from the eyes into the nose, can be deliber-
ately blocked, temporarily by plugs or permanently by cautery.
Dry eye can lead to secondary inflammation and require use,
under specialist care, of hyaluronic acid preparations,
164 Ó 2014 Elsevier Ltd. All rights reserved.
 OTHER AUTOIMMUNE DISORDERS
autologous serum, weak corticosteroid eye drops and/or long-
term oral tetracycline-based antibiotics.
Treatment of dry mouth starts with avoidance of dehydration
and attention to oral hygiene e regular brushing and flossing,
use of alcohol-free fluoride and/or diluted chlorhexidine
mouthwashes (to reduce dental caries) and regular dental check-
ups. Many patients will carry a bottle of water with them and, if
they have some residual salivary gland function, use sugar-free
gum, pastilles or lozenges. Saliva-substitute sprays are not pre-
dictably effective as they may not remain on the oral surface for
long enough; saliva replacement gels may be preferred. Pilocar-
pine, is a muscarinic agonist licensed for use in SS.
€gren’s syndrome
Biologic therapies in primary Sjo
Rituximab, a monoclonal antibody directed against CD20 and
leading to transient blood B cell depletion, has shown partial
improvements in subjective and objective sicca symptoms in
small studies.23 However, the results of two large controlled
trials are awaited before considering its use in large populations
of patients. Several other therapeutic strategies are being studied,
targeting other B-cell surface proteins (epratuzumab anti-CD22)
or major cytokines of B cell homeostasis (e.g., BAFF, IL-6 and
lymphotoxin-b).
As well as BAFF/BLyS, TNF-alpha, IL-1 and IL-6, a number of
other conventional cytokines have been shown to be up-regulated
in the salivary glands in PSS. These include IL-2, IL-3, IL-4, IL-10,
IL-15, IL-21, IL-22, TNF-R1 and TNF-R2, TGFb, IFNa, IFNg,
GM-CSF, epidermal growth factor and cytokines of the TH17
system.24
A number of studies have suggested increased expression of
TLRs on salivary epithelial cells in pSS.24 Up-regulation of TLRs
may in turn increase expression of adhesion molecules, such as
ICAM-1, or cytokines such as IFN type 1, IL-6, IL-17, and IL-23.24
In theory, therefore, up-regulation of TLRs (e.g. by viruses) may
trigger glandular inflammation and damage in pSS. Inhibitors of
TLRs may be useful therapeutic agents in pSS.
The increasing recording of patient data into registries such as
the UK Primary Sjo €gren’s Syndrome Registry (UKPSSR)25 will
also facilitate clinical trials of new therapies for pSS. A 15 Dawson L, Stanbury J, Venn N, Hasdimir B, Rogers SN, Smith PM.
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 OTHER AUTOIMMUNE DISORDERS
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MEDICINE 42:3
Practice points
C Not everyone with dry eyes or dry mouth has Sjo €gren’s
syndrome
C A labial gland biopsy showing ‘chronic sialadenitis’ is a
negative biopsy and should not be reported as ‘compatible
with Sjo€gren’s syndrome’
C Saliva replacement gels and/or sugar-free pastilles are usually
more effective for dry mouth than artificial saliva sprays that
stay on the oral surface for only a short period; pilocarpine is
also available in the UK to stimulate residual saliva production
C Patients with pSS who develop persistent salivary gland
swelling must be assessed for the presence of lymphoma (44-
fold increased risk of MALT lymphoma in pSS) and open biopsy
may be needed in some cases
166 Ó 2014 Elsevier Ltd. All rights reserved.