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O R L
OX F O R D R H E U M ATOLOGY LIB RARY

Sjögren’s Syndrome
O R L
OX F O R D R H EU MATO LO GY LIBRARY

Sjögren’s Syndrome
Edited by

Wan-Fai Ng
Musculoskeletal Research Group, Institute of Cellular Medicine,
Faculty of Medical Sciences, Newcastle University, UK

1
3
Great Clarendon Street, Oxford, OX2 6DP,
United Kingdom
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 Contents

Contributors vii
Symbols and abbreviations ix
 Epidemiology, genetics, and disease burden 1
Simon Bowman
2 Diagnosis and clinical assessment 11
Wan-Fai Ng, Rebecca Batten, and Imna Rahiman
3 Oral features 23
Arjan Vissink, Frederik KL Spijkervet, and Hendrika Bootsma
4 Ocular features 43
Saaeha Rauz
v
5 Fatigue, pain, and quality of life 57
Roald Omdal and Katrine Brække Norheim
6 Systemic (extra-glandular) features 67
Elizabeth Price
7 Evidence-based evaluation and therapies 77
Raphaèle Seror and Divi Cornec
8 Lymphoma: Pathogenesis, prediction, and therapy 89
Francesca Barone and Serena Colafrancesco
9 Case studies 101
Benjamin Fisher

Appendix  ESSDAI 113

Appendix 2 ESSPRI 119
Appendix 3 EULAR sicca score 121
Index 23
 Contributors

Francesca Barone Wan-Fai Ng

Clinician Scientist Professor of Rheumatology
Honorary Consultant Rheumatologist Newcastle University and Honorary
Institute of Inflammation and Ageing Consultant Rheumatologist,
University of Birmingham, UK Newcastle upon Tyne Hospitals NHS
Foundation Trust
Rebecca Batten
Rheumatology Specialty Trainee Katrine Brække Norheim
Newcastle upon Tyne Hospitals NHS
Clinical Scientist
Foundation Trust
Clinical Immunology Unit
Newcastle University, UK
Stavanger University Hospital
Hendrika Bootsma Stavanger, Norway
Professor of Rheumatology vii
Head of Department of Rheumatology Roald Omdal
and Clinical Immunology Professor of Medicine
University Medical Center Groningen, Clinical Immunology Unit
The Netherlands Department of Internal Medicine
Stavanger University Hospital
Simon Bowman Stavanger, Norway
Consultant and Honorary Professor of
Rheumatology Elizabeth Price
Queen Elizabeth Hospital,
Birmingham, UK Consultant Rheumatologist
Great Western Hospitals NHS
Serena Colafrancesco Foundation Trust, UK
Specialist in Rheumatology
Rheumatology Unit Imna Rahiman
Sapienza University of Rome, Italy Specialist Registrar in Rheumatology
Divi Cornec St Helens and Knowsley
NHS Trust, UK
Rheumatologist
Rheumatology Department
Centre Hospitalier Regional Universitaire Saaeha Rauz
de Brest, France Senior Clinical Lecturer
Clinical Ophthalmologist
Benjamin Fisher Institute of Inflammation
Senior Clinical Lecturer and Ageing
Institute of Inflammation and Ageing University of Birmingham, UK
Centre for Translational Inflammation
Research
University of Birmingham, UK
 Raphaèle Seror Arjan Vissink
Contributors

Assistance Publique—Hôpitaux de Paris Professor of Oral Medicine

Hôpitaux Universitaire Paris-Sud Department of Oral and Maxillofacial
IMVA Research Center on Immunology Surgery
of Viral Infections and Autoimmune University Medical Center Groningen,
Diseases The Netherlands
Université Paris-Sud,
Le Kremlin-Bicêtre, France
Frederik KL Spijkervet
Professor and Chairman
Department of Oral and Maxillofacial
Surgery
University Medical Center Groningen,
The Netherlands

viii
 Symbols and abbreviations

ACE angiotensin converting enzyme

ACR American College of Rheumatology
AECG American European Consensus Group
AIHA autoimmune haemolytic anaemia
AIR AutoImmunité et Rituximab
ANA anti-nuclear antibody
BAFF B-cell activating factor
BRAF-MDQ Bristol rheumatic arthritis fatigue multi-dimensional questionnaire
CBT cognitive behavioural therapy
CFS chronic fatigue syndrome
CHB congenital heart block
CK creatine kinase ix
CMV cytomegalovirus
CNS central nervous system
CRP C-reactive protein
CSF cerebrospinal fluid
CT computerized tomography
DLBC diffuse large B-cell
DNMT DNA methyl transferase
dRTA distal renal tubular acidosis
dsDNA double stranded DNA
EBV Epstein-Barr virus
EMG electromyography
ENA extractable nuclear antigen
ESR erythrocyte sedimentation rate
ESSDAI EULAR Sjögren’s Syndrome Disease Activity Index
ESSPRI EULAR Sjögren’s Syndrome Patient Reported Index
EULAR European League Against Rheumatism
FACIT-F functional assessment of chronic illness therapy fatigue subscale
FISH fluorescent in situ hybridization
FNA fine needle aspiration
FLS focal lymphocytic sialadenitis
FSS fatigue severity scale
fVAS fatigue visual analogue scale
 GC germinal centre
Symbols and abbreviations

HGP hypergammaglobulinaemic purpura

HIV human immunodeficiency virus
HLA human lymphocyte antigen
HRCT high resolution computed tomography
HRQoL health-related quality of life
IBS irritable bowel syndrome
ICER incremental cost-effectiveness ratio
IFN interferon
IPI International Prognostic Index
IVIg intravenous immunoglobulins
LDH lactate dehydrogenase
LESA lymphoepithelial sialoadenitis
LIP lymphocytic interstitial pneumonitis
MALT mucosa associated lymphoid tissue
MCII minimal clinically important improvement
MCP metacarpophalangeal
x ME myalgic encephalomyelitis
MFI multidimensional fatigue inventory
MGD meibomian gland dysfunction
MHC major histocompatibility complex
miRNA microRNAs
MRI magnetic resonance imaging
mRNAs messenger RNAs
NHL non-Hodgkin’s lymphoma
NICE National Institute for Health and Care Excellence
NSAID nonsteroidal anti-inflammatory drugs
NSIP non-specific interstitial pneumonia
OSDI Ocular Surface Disease Index
PASS patient satisfactory symptom state
PBC primary biliary cirrhosis
PCR polymerase chain reaction
PET positron emission tomography
PNS peripheral nervous system
PIP proximal interphalangeal
PROFAD profile of fatigue and discomfort
PROMS patient reported outcomes
pSS primary Sjögren’s syndrome
RA rheumatoid arthritis
RF rheumatoid factor
RTA distal renal tubular acidosis

Symbols and abbreviations

SCLE subacute cutaneous lupus erythematosus
SGEC salivary gland epithelial cells
SICCA Sjögren’s International Clinical Collaborative Alliance
SL sublingual glands
SLE systemic lupus erythematosus
SM submandibular glands
SNP single nucleotide polymorphism
SS Sjögren’s syndrome
SSA anti-Ro antibodies
SSB anti-La antibodies
SSCAI SS Clinical Activity Index
SSDAI SS Disease Activity Index
SSI Sicca Symptoms Inventory
SSDDI Sjögren’s Syndrome Disease Damage Index
sSS secondary Sjögren’s syndrome
TAP transporter associated with antigen processing
TCAs tricyclic antidepressants xi

TFBUT tear film break-up time

TNF tumour necrosis factors
TTG tissue transglutaminase
US ultrasound
SGUS salivary gland ultrasound scan
UTI urinary tract infection
UWS unstimulated whole saliva
VAS ‘visual analogue scales’ or ‘visual analogue scale’
WMH white matter hyper-intensities
 Chapter 

Epidemiology, genetics,
and disease burden
Simon Bowman

Key points
• Primary Sjögren’s syndrome (pSS) is a worldwide disease, nine to 3
times more common in women than men, and typically presenting in the
middle years.
• Its prevalence is estimated at 0.04–0.06% of the adult female population.
• The major genetic contribution to pSS is from the human leukocyte
antigen (HLA) region, particularly the HLA-DR3.
• Additional genetic associations have been identified through modern 1
genetic techniques.These include interferon-related genes, B-cell related
genes, and TNIP.
• PSS may also be affected by epigenetic factors such as DNA methylation
and microRNA effects on cell regulation.
• Many studies on pSS have identified negative effects on health-related
quality of life, as well as its impact on direct healthcare and other
indirect costs.

Historical background and description

Sjögren’s syndrome (SS) was described by Henrik Sjögren, a Swedish ophthalmolo-
gist, in 933 []‌. He used the term ‘keratoconjunctivitis sicca’ to distinguish the ocular
surface features from those seen in vitamin-A deficiency (xerophthalmia). The term
‘xerostomia’ is, however, used to describe oral dryness. Henri Gougerot, a French
­dermatologist, had previously described three patients with sicca syndrome and salivary
gland atrophy in 925 [2]. Jan Mikulicz-Radecki, an Austro/Polish surgeon described
the histological features in 892 [3]. As well as dryness of eyes and mouth, dryness of
the trachea, skin, nose, vagina, and bowel are also common.
The distinction between primary SS (pSS) and secondary SS (sSS) was set out in the
960s [4]‌. The link with mucosa associated lymphoid tissue (MALT) B-cell lymphoma
was also reported [5] and Chisholm and Mason described their scoring system for the
histological features of salivary gland biopsies in pSS [6]. The anti-Ro (SS-A) and anti-La
(SS-B) antibodies were first identified [7] in 969 and subsequently shown to be associ-
ated with pSS, HLA-DR3 and other human lymphocyte antigen (HLA) haplotypes [8]
and the neonatal lupus syndrome [9].
 The glandular features and management of pSS and sSS are generally regarded as being
Epidemiology, genetics, and disease burden

similar although fibrosis, for example, is a more typical feature in scleroderma-related

sSS. Unless otherwise stated, this chapter will focus on pSS.

Epidemiology and prevalence

SS is a worldwide disease with a strong female bias—traditionally reported as 9: but
possibly as high as 3: [0]. Typically, pSS presents in the fifth or sixth decade but can
present at any age including, although rarely, in childhood.
Initial research into the prevalence of pSS came up with widely differing estimates
as low as 0.08% ( in ,250) using the San Diego (California) criteria [] or as high
as 3% of the adult female population in a community-based study in the UK [2]. One
explanation for this variation was the use of different, more permissive, classification
criteria in the latter study.
More recent studies using the American-European Consensus Group (AECG)
­criteria have estimated the prevalence in women in the UK at 0.–0.4% [3]. Other
CHAPTER 

international studies using the AECG criteria have estimated the prevalence at around
0.2% [4] in the community and 0.04–0.06% in the hospital setting [5].

2 Classification criteria
In clinical practice it is up to the clinician to use their judgement in making a diagnosis
of pSS. In research it is essential to have agreed classification criteria so that there is
confidence that participants in a study have the specified condition. During the 980s
a number of classification criteria were proposed with a major debate as to the advan-
tages and disadvantages of each of these criteria [6].
In 988 a working group of 29 experts from 2 European countries initiated a study
to develop consensus criteria and published their initial findings in 993. The preliminary
European criteria [7] included six components: symptoms of oral dryness identified
through the presence of at least one out of three specified dry mouth questions and simi-
larly for dry eyes, objective eye dryness, objective oral dryness, a positive labial salivary
gland biopsy (≥  focus score/4 mm2), and positive anti-Ro/La antibodies. Four out of
the six components were required to make a diagnosis of pSS. Exclusion criteria were also
proposed (head and neck radiotherapy, hepatitis C infection, acquired ­immunodeficiency
syndrome (AIDs), pre-existing lymphoma, sarcoidosis, graft-versus-host disease, and use
of anticholinergic drugs). These criteria were subsequently modified to require the pres-
ence of either positive anti-Ro/La antibodies or positive labial salivary gland biopsy to
form the AECG criteria [8] thus requiring evidence of an immunological basis for the
dryness. The diagnosis of pSS is also fulfilled if three out of the four objective criteria
are present. The criteria also propose that secondary SS is present if at least one oral or
ocular symptom is present and two objective criteria (other than anti-Ro/La antibodies
as these are not associated with sSS in rheumatoid arthritis (RA) or scleroderma).
The AECG criteria are the most widely used ‘gold-standard’ criteria for the classifica-
tion of pSS in research studies. Criteria are never fixed in perpetuity, however, and as
new technology such as ultrasound becomes more widely used or new data becomes
available [9] further revision is likely. For example, one of the differences between
the various criteria is whether to score a focus score of ≥  or >  as positive and
recent data suggests that the former is more closely linked with the clinical phenotype
of pSS [20].
 In 203, an international collaboration, the Sjögren’s International Clinical

Epidemiology, genetics, and disease burden

Collaborative Alliance (SICCA), funded by the National Institutes for Health in the US,
collected data from ,68 participants to devise the American College of Rheumatology
preliminary criteria for SS [2] which requires at least two out of three components to
be present, namely: (i) a positive labial salivary gland biopsy with a focus score of one
or more; (ii) at least one positive antibody/combination out of anti-Ro, anti-La, or, the
presence of both an ANA ≥ in 320 and a positive rheumatoid factor; and (iii) dry eyes
as determined by the presence of a new ocular staining score of ≥3. At the present
time an international group of experts are bringing these criteria together to produce
an American College of Rheumatology/European League Against Rheumatism con-
sensus criteria.

Primary versus secondary Sjögren’s syndrome

Both sets of criteria have similar exclusions. Individuals with another connective tissue
disease such as rheumatoid arthritis, systemic lupus erythematosus, or scleroderma are

CHAPTER 
typically described as having ‘secondary’ SS as the development of SS is thought to be
derived from the underlying pathophysiology of the ‘primary’ disease and is not usually
associated with the extra-glandular features seen in patients with pSS. In rheumatoid
arthritis, for example, individuals who develop sSS are more likely to be HLA-DR4
positive rather than the HLA-DR3 linked to pSS nor are they likely to have anti-Ro/La 3
antibodies, but rather to be rheumatoid factor positive. In scleroderma, the salivary
gland biopsies are more likely to demonstrate fibrosis. In other autoimmune or con-
nective tissue diseases such as primary biliary cirrhosis it may be less clear cut whether
SS is primary or secondary and is a matter for clinical judgement. The AECG criteria
formally define secondary SS as the presence of at least one symptom of ocular or oral
dryness plus at least one objective feature, or a positive labial salivary gland biopsy.
Other exclusions for pSS include graft versus host disease, sarcoidosis, previous head
and neck radiation, HIV or hepatitis C virus disease, pre-existing lymphoma, and the
use of anticholinergic drugs accounting for the dryness features. Other conditions such
as diabetes, bulimia, and chronic alcohol excess can lead to generalized swelling of the
glands (sialosis). The preliminary American College of Rheumatology (ACR) criteria
have added a relatively recently described condition ‘IgG4 disease’ among the excluded
conditions [22].
Characteristic features of IgG4 disease include raised serum IgG4, IgG4-positive
plasma cells infiltrating tissues, particularly the pancreas, causing autoimmune pancrea-
titis and the salivary glands resulting in swelling and/or dryness. The condition can also
be associated with fibrosis (e.g. retroperitoneal). There is no female bias, no association
with anti-Ro/La antibodies and generally, but not always, a good response to cortico­
steroid therapy. Some patients have been reported to have benefited from treatment
with Rituximab.

Genetics, genomics, and epigenetics

Genetic risk factors
There have been no large-scale twin studies in pSS. Based on case reports and small
studies the estimated concordance rate for SS is low and the sibling prevalence likewise,
suggesting that the heritability of SS is low and environmental factors play a greater role
 [23]. However, in a recent study by Kuo et al, of the 2,705 pSS patients, 05 (0.8%)
Epidemiology, genetics, and disease burden

had an affected relative. The calculated recurrence risk for a sibling or an offspring hav-
ing pSS is approximately 9-fold and 3-fold higher than the general population.
PSS has been closely linked to the presence of particular genes of the human major
histocompatibility complex (MHC) that encodes HLA proteins. These links are princi-
pally between the HLA types and the anti-Ro/La autoantibodies rather than with the
disease per se. Patients with high levels of both anti-Ro and anti-La antibodies have a
very high (circa 90%) likelihood of being HLA DR3 DQ2 positive (typically associated
with the DRB*03-DQB*02-DQA*050 extended haplotype), whereas pSS patients
who have high levels of the anti-Ro antibody only and are negative for anti-La anti-
bodies have an increased frequency of DR2(5) and DQ6 (typically associated with
the DRB*50-DQA*002-DQB*0602 extended haplotype). Conversely, sSS in
patients with RA is associated with HLA-DR4 [24], emphasizing that the clinical and
histopathological similarities between pSS and sSS do not extend into identical genetic
backgrounds.
Other potential genetic markers identified from candidate gene analyses include
cytokine genes (e.g. for IL0, IL family, IL-6, TNF), MHC-related genes such as trans-
CHAPTER 

porter associated with antigen processing (TAP) and tumour necrosis factors (TNF)
and the Ro/La autoantigens themselves [25] (see Box .).
Microarray technology can be used to genotype large numbers of single nucleotide
polymorphisms whose frequency can be compared in thousands of cases and controls
4 to identify novel associations between genes and disease for further study. In a study by
Lessard et al in 203 [26] using Illumina microarray technology of four datasets totalling
4,337 patient samples and 2,459 control samples the HLA region at 6p2 demon-
strated the strongest association with the peak at HLA-DQB. Other risk loci included
IRF5, STAT4, IL-2A, BLK, CXCR5, and TNIP (Figure .).
IRF5 is a transcription factor mediating type  interferon responses, STAT4 is a
transcription factor for cellular responses initiated by type  interferons, and can be
induced by IL-2 in some circumstances. BLK is a non-receptor Src family tyrosine
kinase involved in B-cell receptor signalling and B-cell development whereas CXCR5
is a chemokine receptor for B-lymphocyte chemoattractant (BLC). IL-2 can induce
CXCR5 expression potentially linking the two themes of type  interferons and B-cell
activation. The function of TNIP is not fully described but is involved in NFkB regula-
tion. In a study of single nucleotide polymorphisms in ,05 patients and 4,460 controls
an association was found between antibody-positive primary SS and two single nucleo-
tide polymorphisms (SNPs) in TNIP [27].
Gene expression profiling using microarray technology can be used to identify genes
that are over or under expressed in particular circumstances, which may be relevant
to disease pathogenesis. In pSS (and systemic lupus erythematosus (SLE) and some
other autoimmune disorders), one current theme, across a range of studies, is of over-
expression of interferon (IFN) inducible genes, including Toll-like receptors, STAT4,
IRF5, BAFF, and MECP2 [28, 29]. IFN is typically upregulated by viruses and this may

Box . Genetic risk factors in pSS

HLA
IRF-TNPO3
STAT4
IL-2A
FAM67A-BLK
 Epidemiology, genetics, and disease burden
115 HLA
85
55
IRF5

16 STAT4
12 IL12A BLK
TNIP1 CXCR5
8

0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 1516 17 19 21
18 20 22
Chromosome

CHAPTER 
Figure . Summary of genome-wide association results for 27,50 variants overlapping between DS and
DS2 after imputation and meta-analysis. The −log0(P) for each variant is plotted according to chromosome
and base pair position. A total of seven loci exceeded the GWS of Pmeta < 5×0−8 (light grey dashed line).
Suggestive threshold (Pmeta < 5×0−5) is indicated by a dark grey dashed line.
Reproduced with kind permission from Lessard et al 203; reference 26.
5

provide a link between the ‘disease trigger’ in these disorders and subsequent patho-
genic processes.
Epigenetics
Another area that is currently of interest is that of ‘epigenetics’ which refers to pro-
cesses such as DNA methylation or histone acetylation of DNA [30]. Such DNA modi-
fications are potentially inheritable but do not alter the DNA sequence itself [3], can
modulate gene expression patterns during cell development, the cell cycle, and biologi-
cal/environmental changes. Disease-associated epigenetic alterations of gene expres-
sion could therefore theoretically contribute to pathogenesis of inflammatory diseases
such as pSS. In general, DNA demethylation is associated with gene activation whereas
DNA methylation is associated with gene inactivation (see Box .2).
Thabet et al 203 [32] evaluated global DNA methylation within salivary gland epithe-
lial cells (SGEC), peripheral T cells, and B cells from SS patients. Global DNA methyla-
tion was reduced in SGEC from SS patients, while no difference was observed in T and
B cells. SGEC demethylation in SS patients was associated with a seven-fold decrease in
DNA methyl transferase (DNMT)  and a two-fold increase in Gadd45-alpha expres-
sion. SGEC demethylation appeared to be at least partly related to the infiltrating
B cells as it is reduced in patients treated with anti-CD20 antibodies to deplete B cells.
Consistently, co-culture of human salivary gland cells and B cells led to an alteration of
the PKC delta/ERK/DNMT pathway.
Altorok et al 204 [33] performed a genome-wide analysis of DNA methylation in
T-cells in pSS identified 3 demethylated genes including lymphotoxin-alpha, type-I inter-
feron pathway genes, and genes encoding for water channel proteins and 5 hypermeth-
ylated gene regions including RUNX which may have a role in lymphoma predisposition.
In a study by Gestermann et al 202 [34] there was no change in the methylation
profile of the IRF5 promoter region, despite the known genetic polymorphisms.
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