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 Sjögren’s Syndrome

Contributors

CONSULTING EDITOR

RICHARD H. HAUG, DDS

Carolinas Center for Oral Health,
Charlotte, North Carolina

EDITOR

MICHAEL T. BRENNAN, DDS, MHS,

FDS, RCSEd
Professor and Director, Sjögren’s Syndrome
and Salivary Disorders Center, Carolinas
Medical Center, Department of Oral Medicine,
Charlotte, North Carolina

AUTHORS

MICHAEL T. BRENNAN, DDS, MHS, Winthrop University Hospital, Mineola; State

FDS, RCSEd University of New York at Stony Brook School
Professor and Director, Sjögren’s Syndrome of Medicine, Stony Brook, New York
and Salivary Disorders Center, Carolinas
Medical Center, Department of Oral Medicine, SIRI BEIER JENSEN, DDS, PhD
Charlotte, North Carolina Section of Oral Medicine, Clinical Oral
Physiology, Oral Pathology and Anatomy,
STEVEN E. CARSONS, MD Department of Odontology, Faculty of
Professor of Medicine, State University of Health and Medical Sciences, University
New York at Stony Brook School of Medicine, of Copenhagen, Copenhagen, Denmark
Stony Brook; Chief, Division of Rheumatology,
Allergy, and Immunology, Winthrop University MALIN V. JONSSON, DMD, PhD
Hospital, Mineola, New York Broegelmann Research Laboratory,
Department of Clinical Science, Haukeland
KONSTANTINA DELLI, DDS, MSc,
University Hospital; Section for Oral and
Dr med dent
Maxillofacial Radiology, Department of
Department of Oral and Maxillofacial
Clinical Dentistry, University of Bergen,
Surgery, University Medical Center Groningen,
Bergen, Norway
University of Groningen, Groningen,
The Netherlands
RAFAEL MADERO-VISBAL, MD, FACS
ANDREA HERMAN, RDH, BS Research Assistant, MD Anderson Cancer
Oral Medicine Dental Hygienist, Department Center, Orlando, Orlando, Florida
of Oral Medicine, Carolinas Center for Oral
Health, Charlotte, North Carolina ZVONIMIR MILAS, MD, FACS
Director, Head and Neck Cancer Center,
SABATINO IENOPOLI, DO Levine Cancer Institute; Associate Professor,
Division of Rheumatology, Allergy and UNC School of Medicine, Charlotte Campus,
Immunology, Department of Medicine, Charlotte, North Carolina
iv Contributors

JOEL J. NAPEÑAS, DDS, FDS RCS(Ed) VIDYA SANKAR, DMD, MHS, FDS RCSEd
Assistant Professor, Division of Oral Medicine Associate Professor, Director, Oral Medicine
and Radiology, Schulich School of Medicine Clinic, Dental School, University of Texas
and Dentistry, Western University, London, Health Science Center San Antonio,
Ontario, Canada; Department of Oral Medicine, San Antonio, Texas
Carolinas Medical Center, Charlotte,
North Carolina FRED K.L. SPIJKERVET, DMD, PhD
Professor and Chairman, Department of Oral
and Maxillofacial Surgery, University Medical
JENENE L. NOLL, RN, BSN
Center Groningen, University of Groningen,
Clinical Care Coordinator, Department of
Groningen, The Netherlands
Oral Medicine, Sjögren’s Syndrome and
Salivary Disorders Center, Carolinas
STEVEN TAYLOR, MBA, BA
Medical Center, Charlotte, North Carolina
Chief Executive Officer, Sjögren’s Syndrome
Foundation, Bethesda, Maryland
ANDRES PINTO, DMD, MPH, FDS RCSEd
Chairman, Department of Oral and MICHAEL D. TURNER, DDS, MD, FACS
Maxillofacial Medicine and Diagnostic Director, New York Center for Salivary Gland
Sciences, University Hospitals Case Diseases, Head and Neck Institute, Beth Israel
Medical Center and Case Western Reserve Medical Center, New York; Division Chief,
University School of Dental Medicine, Oral and Maxillofacial, Jacobi Medical Center,
Cleveland, Ohio Bronx, New York

ARJAN VISSINK, DDS, MD, PhD

TOVE R. REKSTEN, MPh, PhD
Professor, Department of Oral and
Broegelmann Research Laboratory,
Maxillofacial Surgery, University Medical
Department of Clinical Science, Haukeland
Center Groningen, University of Groningen,
University Hospital, University of Bergen,
Groningen, The Netherlands
Bergen, Norway
JASON J. WU, DO
TANYA S. ROULEAU, DMD, FDS RCS(Ed) Division of Rheumatology, Allergy and
Director, General Practice Residency Immunology, Department of Medicine,
Program, Department of Oral Medicine, Winthrop University Hospital, Mineola;
Carolinas Medical Center, Charlotte, Nassau University Medical Center, East
North Carolina Meadow, New York
 Sjögren’s Syndrome

Contents
Preface: Sjögren’s Syndrome ix
Michael T. Brennan

Sjögren’s Syndrome: An Update on Epidemiology and Current Insights on

Pathophysiology 1
Tove R. Reksten and Malin V. Jonsson
Primary Sjögren’s syndrome (pSS) is an autoimmune chronic inflammatory disorder
affecting 0.2% to 3.0% of the population, with a 9:1 female to male ratio. Features
are oral and ocular dryness, local and systemic autoantibody production, and
progressive focal mononuclear cell infiltration in the affected salivary and lacrimal
glands. Lymphoma is the most severe complication of pSS, occurring in 4% to
5% of patients. Genetic studies identified an association with HLA and susceptibility
genes in cytokine genes and genes involved in B-cell differentiation. Genetic varia-
tions may help explain why disease manifestations differ among patients and sup-
ports the hypothesis of certain distinct disease phenotypes.

Diagnosis of Sjögren’s Syndrome: American-European and the American College

of Rheumatology Classification Criteria 13
Vidya Sankar, Jenene L. Noll, and Michael T. Brennan
Classification criteria provide a formalized approach to studying course and man-
agement of rheumatic disease, as well as a measure of improvement in care. Under-
standing the purposes of classification criteria sets and the differences between
different classification criteria is crucial for understanding rheumatic disease and
for the design and conduct of clinical and epidemiologic investigations. In this
article, the similarities and differences between the American-European Consensus
Group Criteria (AECG) and the newly proposed American College of Rheumatology
(ACR) classification criteria for Sjögren’s syndrome and the clinical implications
of switching to the ACR classification criteria from the AECG are described.

Salivary Gland Biopsy for Sjögren’s Syndrome 23

Konstantina Delli, Arjan Vissink, and Fred K.L. Spijkervet
Salivary gland biopsy is a technique broadly applied for the diagnosis of Sjögren’s
syndrome (SS), lymphoma accompanying SS, sarcoidosis, amyloidosis, and other
connective tissue disorders. SS has characteristic microscopic findings involving
lymphocytic infiltration surrounding the excretory ducts in combination with destruc-
tion of acinar tissue. This article focuses on the main techniques used for taking
labial and parotid salivary gland biopsies in the diagnostic workup of SS with respect
to their advantages, their postoperative complications, and their usefulness for
diagnostic procedures, monitoring disease progression, and treatment evaluation.

Salivary Gland Dysfunction and Xerostomia in Sjögren’s Syndrome 35

Siri Beier Jensen and Arjan Vissink
In this article, salivary gland dysfunction and xerostomia in Sjögren’s syndrome (SS)
are discussed, with a focus on the pathophysiology of salivary dysfunction in SS, the
vi Contents

clinical presentation of dry mouth in SS, how to assess salivary gland hypofunction
and xerostomia in SS, and the impact of salivary gland dysfunction on quality of life
in patients with SS.

Oral Complications of Sjögren’s Syndrome 55

Joel J. Napeñas and Tanya S. Rouleau
Numerous oral manifestations associated with salivary gland dysfunction, and
particularly Sjögren’s syndrome, have been reported in the literature. This article
discusses the evidence on a wide range of oral manifestations associated with
Sjögren’s syndrome.

Management of Xerostomia and Other Complications of Sjögren’s Syndrome 63

Andres Pinto
This article provides an overview of the published literature in English in the past 63
years involving the management of xerostomia and other oral complications of
Sjögren’s syndrome. The evidence supporting studied interventions was evaluated
using published criteria.

Salivary Gland Disease in Sjögren’s Syndrome: Sialoadenitis to Lymphoma 75

Michael D. Turner
Although the cause and molecular pathways of Sjögren’s syndrome are still
unknown, basic, clinical, and translational science have started to identify linkages
to other known processes. With the advent of newer, more sensitive, and more
accurate chemokine, cytokine, and genetic analysis, the molecular progression of
the disease may be understood. The modern technology of sialoendoscopy to treat
obstructive sialoadenitis from mucous plugging, and the addition of rituximab to cur-
rent chemotherapy, have allowed patients with Sjögren’s syndrome to have a better
quality of life and, if they develop lymphomatous changes, a significant increase in
their disease remission and survival rate.

The Role of Parotidectomy in Sjögren’s Syndrome 83

Rafael Madero-Visbal and Zvonimir Milas
Sjögren’s syndrome, a chronic and progressive autoimmune disorder mainly char-
acterized by xerophthalmia, xerostomia, and parotid enlargement, is primarily man-
aged medically, but some patients will require surgical management. Patients with
Sjögren’s syndrome have an increased risk of non-Hodgkin lymphoma. Superficial
parotidectomy is indicated for diagnostic purposes and can be therapeutic in limited
circumstances. Surgical indications for parotidectomy in Sjögren’s syndrome in-
clude recurrent parotitis refractory to medical management; salivary gland malig-
nancy; and severe, refractory pain. Surgical complications include transient or
permanent facial nerve injury, post-operative pain, persistent inflammation of rem-
nant parotid tissue, Frey syndrome, and facial scarring.

Extraglandular Manifestations of Primary Sjögren’s Syndrome 91

Sabatino Ienopoli and Steven E. Carsons
Sjögren’s syndrome is a chronic autoimmune disease that typically affects the sal-
ivary and lacrimal glands. Aside from the common glandular signs and symptoms,
 Contents vii

Sjögren’s syndrome may also cause mononuclear infiltration and immune complex
deposition involving extraglandular sites producing several extraglandular manifes-
tations (EGM). The prevalence of EGMs varies greatly depending on the particular
manifestation. This article examines the ways that EGMs may present in patients
with primary Sjögren’s syndrome. The focus is on the more prevalent and significant
EGMs including involvement of the nervous system, pulmonary manifestations, vas-
culitis associated with primary Sjögren’s syndrome, and arthropathy.

Management of Extraglandular Manifestations of Primary Sjögren’s Syndrome 101

Jason J. Wu and Steven E. Carsons
Primary Sjögren’s syndrome can have multiple extra-glandular manifestations
ranging from mild to severe. Treatment for extra-glandular manifestations is organ
specific and therapies are targeted based on the primary organs involved. Preferred
treatment options used for extra-glandular manifestations of Sjögren’s syndrome
are usually extrapolated from the physician’s experience in treating similar manifes-
tations in other autoimmune conditions such as rheumatoid arthritis and systemic
lupus erythematous. The lack of immunomodulating disease modifying drugs in
Sjögren’s syndrome can be frustrating for patients dealing with extra-glandular man-
ifestations, however recent advances in the field has made the future look promising
for new therapeutic options.

Coping Strategies and Support Networks for Sjögren’s Syndrome Patients 111
Andrea Herman, Steven Taylor, and Jenene Noll
Sjögren’s syndrome is a chronic systemic autoimmune disease that can affect any
organ system in the body. The most common symptoms are dryness of the mouth
and eyes resulting from chronic inflammation and a progressive loss of secretory
function. As with most individuals managing a chronic condition, patients with
Sjögren’s are on a multipronged path to disease and symptom management.
Various coping strategies are presented in this article and the advantages and dis-
advantages discussed. Additionally, how a support group functions and practical
guidance for the initiation of a Sjögren’s support group are discussed.

Index 117
viii Sjögren’s Syndrome

ORAL AND MAXILLOFACIAL SURGERY

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 Sjögren’s Syndrome

P re f a c e
S j ö g re n’s Syn d ro me

Michael T. Brennan, DDS, MHS, FDS, RCSEd

Editor

Sjögren’s syndrome is a systemic autoimmune in- explore the different salivary gland disease and
flammatory condition impacting women more the medical/surgical aspects for managing condi-
frequently than men (9:1) and is often diagnosed tions, ranging from salivary gland infection to
between the ages of 40 and 60, although it is not un- lymphoma. Additional articles provide the latest
common for symptoms to start much earlier than an literature regarding the wide range of extraglandu-
official diagnosis. The most common symptoms of lar manifestations of Sjögren’s and the manage-
Sjögren’s include dry mouth, dry eyes, and fatigue, ment strategies for these conditions. Finally, the
although many other organ systems can be im- last article explores patient coping strategies and
pacted in patients with this condition. the role of the Internet and support groups to
The field of Sjögren’s has made significant ad- assist with patients managing their chronic auto-
vances in recent years, although much work is still immune condition.
needed to understand the many aspects of this The information presented in this issue provides
condition. The overall goal of this issue of Oral the latest regarding the complex issues of Sjög-
and Maxillofacial Surgery Clinics of North America ren’s, as well as points to the many research
is to provide an up-to-date review by international opportunities necessary to enhance our under-
experts of key topics vital to understanding this standing of Sjögren’s.
complex condition.
The articles in the current issue cover a wide Michael T. Brennan, DDS, MHS, FDS, RCSEd
range of topics, including the latest in the epidemi- Sjögren’s Syndrome and
ology and pathophysiology of Sjögren’s; utilization Salivary Disorders Center
and controversies of the different classification Department of Oral Medicine
criterias currently used for Sjögren’s, and consid- Carolinas Medical Center
erations and techniques for salivary gland biopsies 1000 Blythe Boulevard
currently used to establish a Sjögren’s diagnosis. Charlotte, NC 28232, USA
Three articles present the oral signs and symp-
toms of Sjögren’s and the evidence base for man- E-mail address:
aging the oral sequelae of Sjögren’s. Two articles [email protected]
oralmaxsurgery.theclinics.com

Oral Maxillofacial Surg Clin N Am 26 (2014) ix

http://dx.doi.org/10.1016/j.coms.2013.10.001
1042-3699/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
S j ög ren ’s S y n d ro m e
An Update on Epidemiology and Current
Insights on Pathophysiology
Tove R. Reksten, MPh, PhDa, Malin V. Jonsson, DMD, PhDa,b,*

KEYWORDS
 Primary Sjögren’s syndrome  pSS  Autoimmune diseases  Inflammatory disorder
 Epidemiology  Salivary glands  Pathogenesis

KEY POINTS
 Primary Sjögren’s syndrome (pSS) is an autoimmune disease that affects 0.2% to 3.0% of the
population.
 Nine of 10 patients with pSS are female.
 Primary SS is characterized by chronic inflammation of the exocrine glands, dryness symptoms,
secretory dysfunction, and autoantibodies.
 Cytokines, chemokines, and survival factors attract and retain various subsets of chronic inflamma-
tory cells in the target organ of pSS.
 Genetic studies indicate roles for certain cytokine genes and genetic factors regulating B-cell dif-
ferentiation in the pathogenesis of pSS.
 NHL occurs in 4% to 5% of patients with pSS and is associated with certain risk factors.

INTRODUCTION night. Problems with speaking and eating due to

reduced saliva secretion may ultimately lead to
Sjögren’s syndrome is an autoimmune rheumatic isolation of patients with the potential risk for de-
disease characterized by focal mononuclear cell pression and reduced quality of life, as well as se-
infiltration of the salivary and lachrymal glands.1 vere problems linked to poor oral health.5 Changes
Primary Sjögren’s syndrome (pSS) occurs alone, in secretion and composition of saliva, and higher
whereas secondary Sjögren’s syndrome occurs dental caries activity have been suggested as po-
in association with other autoimmune diseases, tential markers to determine the autoimmune sali-
frequently rheumatoid arthritis (RA) and systemic vary gland dysfunction in pSS.6
lupus erythematosus (SLE).2 Signs of systemic Dry eyes (keratoconjunctivitis sicca) are often
autoimmune disease with musculoskeletal, pulmo- described as a sensation of grit or sand in the
nary, gastric, hematological, dermatologic, renal, eyes, redness, itching, and photosensitivity. As
and neurologic manifestations may also be evident with saliva, the tear flow and tear composition is
in patients with SS.1,3 altered in patients with pSS.7 The dryness may
Common complaints are dryness of the mouth also affect the airways, and reduced secretory ca-
(xerostomia), and difficulties with talking, tasting, pacity of sebaceous glands cause to be seen xero-
and swallowing.4 Xerostomia is typically first sis in up to 30% of patients with pSS.8 Other
oralmaxsurgery.theclinics.com

noticed, as it becomes necessary to have chewing cutaneous manifestations include erythemas,

gum or lozenges on hand to stimulate saliva pro- vasculitis, and dermatitis.
duction, and by the urge to drink water during the

a
Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, The Laboratory
Building, 5th Floor, Haukeland University Hospital, Bergen N-5021, Norway; b Section for Oral and Maxillofa-
cial Radiology, Department of Clinical Dentistry, University of Bergen, Årstadveien 19, Bergen N-5009, Norway
* Corresponding author.
E-mail address: [email protected]

Oral Maxillofacial Surg Clin N Am 26 (2014) 1–12

http://dx.doi.org/10.1016/j.coms.2013.09.002
1042-3699/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
2 Reksten & Jonsson

Tiredness and fatigue are other disabling com- PATHOGENESIS OF SS

plaints in pSS, contributing to work disability and Histopathology of the Target Organ
depression,9 and seem to remain mainly un-
The typical histopathological finding in labial minor
changed throughout the disease course.10 Extra-
salivary gland (MSG) biopsies is a progressive
glandular manifestations, such as arthralgia and
focal infiltration of mononuclear lymphoid cells.28
myalgia are reported by up to 75% and 45% of pa-
A typical foci consists, per definition, of at least
tients, respectively,11,12 and Raynaud phenome-
50 mononuclear cells, such as lymphocytes,
non is present in 10% to 15% of the patients,
plasma cells, and macrophages, and is sur-
often preceding the onset of sicca symptoms.13
rounded by otherwise normal-appearing glandular
tissue (Fig. 1). The focus score, the number of foci
PREVALENCE AND INCIDENCE per 4 mm2 of MSG tissue, is associated with the
presence of keratoconjunctivitis sicca and autoan-
SS has been suggested to affect 0.2% to 3.0%
tibodies29,30 and largely correlates with the
of the population.14–16 It predominantly affects
reduced salivary secretion.31 Despite lymphocytic
women between 40 and 60 years of age, with a
infiltration and structural alterations within the
9:1 female:male ratio. Younger individuals and
MSGs, the remaining secretory acini seem to be
children may also be affected.1 Most epidemio-
functional and capable of secreting saliva.6
logic studies are based on hospital registries and
Another pattern of inflammation in labial MSG
research cohorts and then extrapolated to the
biopsies is chronic inflammation, characterized
general population. Regional differences are not
by scattered mononuclear cell infiltration without
extensively known.
focal aggregates and accompanied by degenera-
There is no specific test for pSS, and a range of
tive changes, such as acinar atrophy, ductal hyper-
classification criteria have been applied over the
plasia, fibrosis, and/or adipocyte infiltration.32
years. Differences in items concerning dryness
Adipocytes are a possible source of chemokines33;
symptoms and autoimmune features have resulted
resident adipocytes expressed CXCL12 in the
in variations in prevalence, and depending on
MSGs of patients with pSS, possibly providing sur-
which criteria are used to diagnose the patients,
vival niches for long-lived plasma cells.
the reported prevalence of pSS varies in different
Studies have indicated a role for both the inflam-
populations and with gender. In a Norwegian
matory cells and the salivary gland epithelium.34
population-based study of 2 age groups, the prev-
Salivary gland epithelial cells (SGEC) are them-
alence was determined to be 0.22% in those 40 to
selves suggested to take part in the autoimmune
44 years old and 1.4% in those 71 to 74 years old.17
inflammation seen in pSS MSG, expressing func-
In a local Norwegian population with 93% female
tional Toll-like receptors possibly inducing an
patients, the prevalence was estimated at
innate immune response.35 Furthermore, BAFF
0.05%.18 This is in line with 0.09%19 and 0.15%16
gene expression in SGEC was significantly
in Greece, less than 0.1% to 0.4% in Great Brit-
ain,15 and 0.17% in Brazil,20 whereas a Turkish
study including only women reported a prevalence
of 0.72%.21 A comparison of the recently intro-
duced American College of Rheumatology (ACR)
criteria for SS22 to the American-European Con-
census Group (AECG) criteria2 showed 81%
concordance in classification of pSS in 646 pa-
tients with sicca symptoms; 279 patients received
the diagnosis by the AECG criteria and 268 by the
ACR criteria. Regardless of classification, patients
with pSS had similar gene expression profiles,
which were different from healthy controls.23
The number of incidence studies of pSS is
limited. A Slovenian study using the criteria from
199624 and an American study both suggested a
yearly incidence of 3.9 per 100,000.25,26 Odds ra-
tio for SS was, in an Italian study, found to be 7.4
if the individual had a first-degree relative with Fig. 1. Haematoxylin and eosin (H&E) stained minor
autoimmune disease, and for women the risk salivary gland tissue section with focal mononuclear
was slightly higher in women who had given birth, cell inflammation and surrounded by otherwise
with an odds ratio of 2.1.27 normal-appearing salivary gland tissue.
 Sjögren’s Syndrome - Epidemiology and Pathogenesis 3

increased after both interferon (IFN)-a and IFN-g to the Ro/SSA and La/SSB proteins are included
stimulation,36 with SGEC from patients with pSS in the diagnostic criteria for pSS.2,22 Antibodies to
significantly more susceptible to BAFF expression Ro/SSA are found in approximately 60% of pa-
under stimulation with IFN-a than healthy controls. tients, and antibodies to La/SSB in about 40%.47
The same study found that SGEC from patients Systemic levels are reported to coincide with local
and healthy controls would secrete soluble BAFF autoantibody production.39,48 Virtually all anti–
after IFN-a and IFN-g stimulation, adding a poten- La-positive patients are anti-Ro positive, and rheu-
tial pathogenic role of SGEC in pSS. Costimulatory matoid factor is present in 80% of patients.49
molecules are also shown to be expressed by Autoantibodies are also present in healthy individ-
epithelial cells in pSS, including CD80 and CD86 uals, but at lower titers and of different isotypes,47
by ductal epithelial cells in patients with severe sia- and age, but not disease manifestations, have
ladenitis, as shown by immunohistochemical been found to influence the presence of autoanti-
staining.37,38 These cells may possibly be able bodies.50 Recently, methods for detecting autoanti-
to activate and stimulate T cells, as infiltrating bodies in saliva, in which levels are almost
CD281 T cells were seen in close proximity to 4000-fold lower than in serum, have been devel-
the CD80/CD81 ductal cells.38 SGECs do have oped, promising potential noninvasive diagnostic
the capacity to participate in the local autoimmune procedures.51
response, although how SGECs in pSS differ from Antibodies directed against the Ro/La ribonu-
SGECs in healthy controls remains to be seen. cleoprotein complexes have been correlated with
younger age,29 more inflammation, and GC-like
Clinical Implications of Lymphoid Neogenesis structures31 and a higher prevalence of extragland-
ular manifestations, such as recurrent parotidome-
Lymphoid neogenesis in the form of germinal
galy, cutaneous vasculitis, Raynaud phenomenon,
center (GC)-like structures; well-circumscribed in-
and renal involvement,52 and arthralgia, arthritis,
flammatory foci presenting with a dark and light
peripheral neuropathy, leukopenia, and thrombo-
zone,39 has been described in the MSGs of 20%
cytopenia.53 Anti-Ro/SSA and anti-La/SSB are
to 25% of patients with SS.31,39–44 GC-like struc-
involved in development of neonatal lupus, charac-
tures were characterized by B-cell and T-cell orga-
terized by skin rash, liver and hematological fea-
nization, increased levels of proliferating cells,
tures, and congenital heart block.54
follicular dendritic cell networks, activated endo-
thelial cells, autoantibody producing cells and Other autoantibodies
apoptotic events,39,41,42 and B-cell expression of Quite frequently, patients with pSS present with
activation-induced cytidine deaminase (AICDA).43 other autoantibodies than the hallmarking anti-Ro/
A certain clinical immunologic phenotype has SSA and anti-La/SSB. Indeed, in the ACR criteria,
been indicated in patients with GC-like structures the presence of antinuclear antibodies (ANA) and
(GC1)31 and GC1 patients also exhibit aberrant rheumatoid factor (RF) may be sufficient for diag-
cytokine profiles32 and genetic traits.45 nosis.22 Antimuscarinic 3 receptor (M3R) antibodies
An association of GC development with in- are present in sera of patients with pSS,55 and are
creased risk of B-cell lymphomas, wherein forma- postulated to play a role in long-term loss of M3R
tion of proliferating GCs were thought to contribute function, giving a clue to understand the exocrinop-
to malignant transformation and development of athy in pSS,56 being capable of damaging saliva
mucosa-associated lymphoid tissue (MALT) lym- production.57 Anticentromere antibodies (ACA)
phoma has long been proposed.46 Seven of 175 were found in a small subpopulation of patients
patients in a Swedish study went on to develop with pSS with a distinct disease phenotype.58
non-Hodgkin lymphoma (NHL) in a total of 1855 Various clinical associations have been de-
patient years at risk, with a median onset of 7 years scribed in relation to the diverse autoantibodies
following the initial diagnostic salivary gland bi- found in patients with SS (reviewed in Ref59).
opsy. Six of the 7 patients had GC-like structures
at diagnosis.44 In a Greek study investigating ma- Cytokines and Chemokines
jor infiltrating cells in salivary gland infiltrates of
Cytokines and chemokines attract T cells and
various severity, 3 of 7 cases with lymphoma
monocytes, and also eosinophils, natural killer
also presented with GC-like structures in the minor
(NK) cells, and dendritic cells (DC). Cytokines
salivary glands.40
play a pivotal role in the immune reaction, and pa-
tients with autoimmune diseases like pSS have a
Local and Systemic Autoantibodies
significantly different cytokine profile compared
Involvement of autoantibodies and cytokines are with healthy controls.60 Elevated levels of cyto-
hallmarks of autoimmune disease. Autoantibodies kines and chemokines might be responsible for
4 Reksten & Jonsson

the increased recruitment and retention of lym-

phocytes to the MSGs and the ectopic GC-like
structures found in the GC1 subgroup. Differ-
ences in cytokine profile in patients with and
without myalgia are demonstrated,61 and IFN-g
and eotaxin have been suggested as potential bio-
markers for GC1 patients with pSS.62 Type I inter-
ferons found in labial salivary gland biopsies,
together with elevated serum levels of these cyto-
kines, indicate a potential etiopathogenic mecha-
nism for interferons.63 The same study evaluated Fig. 2. Chronic inflammation in the MSGs of patients
the capacity of pSS sera to induce IFN-a, and with Sjögren’s syndrome may ultimately induce
concluded that immune complexes of autoanti- lymphoid neogenesis. Activated mononuclear cells
such as T cells, B cells, and DCs are detected in the
bodies and RNA may be the inducers. IFN-a in-
salivary glands as periductal chronic inflammatory
duces B cell differentiation and maintains Th1
cell infiltrates. Local production of cytokines and che-
cells,64 and the type I IFN system has been sug- mokines lead to attraction of T and B cells. Organized
gested as a possible pathogenic mechanism in aggregates composed of T cells, B cells, FDC networks,
pSS.65 A Th1 cytokine signature was seen in activated endothelial cells, and plasma cells form GC-
MSG samples from patients, although could not like structures. Long-term, inappropriate cytokine
be correlated with disease severity.66 Systemic production and chemokine expression may lead to
levels of NCR3/NKp30, an NK cell specific acti- prolonged B-cell survival, possibly promoting neo-
vating receptor mediating cross-talk between NK plastic transformations in the target organ of SS.
cells and dendritic cells and type II IFN secretion,
were increased in pSS and associated with INF-g
(BAFF),42,62 help explain the B-cell drive of the dis-
secretion, and accumulation of NK cells correlated
ease,73 proving a possible target for treatment,74
with severity of exocrinopathy.67
and contradicting the previous dogma that solely
Previous observations in which mRNA expres-
T cells are responsible for the abnormal cytokine
sion of IFN-g only was detected in salivary glands
production. Accumulation of chronic inflammatory
of patients with pSS and not in healthy controls,
cells in the target organ may be due to increased
whereas other cytokines, such as interleukin
migration and/or a consequence of B-cell activa-
(IL)-6 and IL-10, were seen in both,68 along with
tion and differentiation in GC-like structures or by
altered peripheral cytokine profiles,69 led to the
excess BAFF75 favoring B-cell survival by antia-
notion that T cells, and especially Th1 cells, are
poptotic pathways, such as Bcl-2, a protein that
the main conductors of disease development
mediates lymphocyte survival in a mitochondria-
and progression. In a Norwegian cohort of pSS,
dependent way. Plasma cells marked for survival
cytokines IL-17, IL-1RA, IL-15, macrophage in-
are increased in pSS and Bcl-2 seem to be induced
flammatory protein (MIP) 1a, MIP-1b, eotaxin,
by IL-6, which is associated with focus score.33 In
IFN-a, and IL-4 levels were significantly increased
another study, peripheral blood monocytes pro-
in GC1 patients. In addition, minor differences in
duced significantly higher levels of sBAFF and
cytokine levels were found when comparing age
IL-6 compared with monocytes from healthy con-
groups. Increased titers of Th17-associated
trols, both following INF-g stimulation and in
cytokines, IL-17, IL-1b, and the IL-23 subunit IL-
absence of stimulation. Stimulation of monocytes
12p40, were speculated to indicate a higher activ-
by sBAFF induced IL-6 production, and expression
ity of these cells in GC1 patients.32
of BAFF and transcription factors regulating IL-6
Chemokines CXCL13 and CCL21 are produced
were increased in pSS monocytes.76
by epithelial cells in relation to chronic inflam-
matory cells in MSGs from patients with
T Cells in pSS
SS.33,39,70,71 Increased attraction, retention, and
survival of inflammatory cells promote lymphoid Over the years, several studies have investigated
structure formation (Fig. 2). In a murine model for the role of T cells in pSS. For one, T cells constitute
SS, CXCL13 was associated with disease progres- up to 75% of the infiltrating cells, with 45% to 55%
sion and blockade resulted in a slight reduction in shown to be CD41 cells and 15% to 35% being
glandular inflammation. In patients with SS, CD81 cells, including transforming growth factor
CXCL13 was elevated in serum and saliva, and beta (TGF-b1) and Foxp31 cells.77 Furthermore,
saliva CXCL13 was associated with xerostomia.72 T-cell signature cytokines have important effector
The presence of B-cell specific cytokines in functions, including IFN-g, IL-17, IL-21, and IL-4,
pSS, such as upregulated B-cell activating factor and finally, T cells are important in the activation,
 Sjögren’s Syndrome - Epidemiology and Pathogenesis 5

maturation, and differentiation of autoantibody- to the presence of extraglandular manifestations,

producing plasma cells. and were further positively correlated with T-cell
activation markers and negatively correlated with
Cytotoxic T cells IgG and IgM memory B-cell populations.
The role of cytotoxic T cells (CTLs) in pSS patho-
genesis has not been studied in detail, but novel Th17 cells
autoantigen fragments after CTL-induced ap- Th17 cells are the third subset of T helper cells.87
optosis have been reported in which unique Evidence that IL-17 mediates inflammatory auto-
structural autoantigen modifications have been immune diseases is accumulating, with mice
suggested to occur during caspase-independent models describing Th17 and/or IL-17 involvement
death pathways. Both caspase-3 and granzyme in RA,88 psoriasis,89,90 and diabetes.91 Curiously,
B cleaves La/SSB, and granzyme B cleaves so far the IL-17 gene has not been reported as a
the muscarinic 3 receptor (M3R), and if either is susceptibility gene in autoimmune disease.92
inhibited, altered cleavage may result in autoanti- Evidence of systemic involvement of Th17 in
gens. Indeed, antiapoptotic Bcl-2 members, inhib- pSS is scarce, although elevated serum levels of
itors of endogenous caspase-3, are highly Th17-associated cytokines in pSS have been re-
expressed in pSS epithelial cells.78,79 ported.32,93 Local minor salivary gland IL-17 expres-
Autoreactive CTLs are seen in pSS targeting sion has been verified by several groups,93–95
SS56.80 SS56 is structurally related to Ro-52, and but reported distribution patterns vary greatly,
seronegative patients with pSS have been shown possibly due to specificity of immunostaining.96
to have autoantibodies directed against SS56. A recent article rejected the suggestion that
SS56-specific CTLs were identified by IFN-g IL-17 is directly involved in B-cell antibody produc-
enzyme-linked immunosorbent spot (ELISPOT) tion in vivo.97 Nonetheless, Th17 cells enhance
assay, and a later experiment did indeed show B-cell proliferation, at least in mice,98 and one
that SS56-specific CTLs from patients with pSS might speculate whether one of the other Th17-
were capable of lysing SS5655–64 loaded T cells.81 associated cytokines, like IL-21, provide the
NKT cells Th17 help. IL-21R–/– mice have defective immuno-
NKT cells are found in only limited amounts among globulin production, and disorganized GC forma-
circulating lymphocytes, and there is just one re- tion,99 and IL-21 produced by Th17 cells may
ported case of extranodal NKT-cell lymphoma in play a role in formation of the GC-like structures
pSS.82 Other findings with regard to NKT cells seen in some minor salivary gland tissue samples
are contradicting, with reports of elevated levels from patients with pSS, indicated by increased
of NKT cells in peripheral blood and in particular levels of Th17-associated cytokines in serum of
in patients with extraglandular manifestations,83 GC1 patients.32
and reports of reduced levels as compared with Aicda upregulation in GC B cells is associated
healthy controls.84 The latter study postulated with development of pathogenic autoantibodies
that this could be due to abnormality of NKT cells, in BXD2 mice, and activated CD41 T cells are
with nonresponding patients (50%) presenting central regulators of autoreactive B cells.100 The
with cells that would not expand in the presence association of T cells to B cells in GCs was abro-
of APC from responders, and possibly due to over- gated by IL-17 blocking agents,101 and the same
stimulation, as the responders did expand in vitro study showed that the absence of IL-17 resulted
in spite of low numbers in vivo. in a smaller GC response but also an altered
follicular:marginal zone ratio of B cells. If IL-17 is
Follicular helper T cells crucial for the formation and stabilization of
Recently, evidence of follicular helper T (Tfh) cells ectopic GCs, IL-17–positive staining in the GC-
in pSS has emerged. Peripheral CD41CXCR51 like structures in pSS minor salivary gland tissue
CCR61 cells are found in increased amounts in would be expected, but has thus far not been
pSS, and these levels are positively correlated reported.
with ESSDAI, immunoglobulin, Ro/SSA, and La/
SSB.85 Th17 subsets of CD41CXCR51 T cells The Treg/Th17 balance
may differentiate into Tfh and provide cognate The absolute ratio of Tregs in pSS peripheral blood
help to antigen-specific B cells, which again (PB) and the MSGs is disputed. Although most
may lead to differentiation into autoantibody- findings point toward a lower ratio of CD41
producing plasma cells. A higher frequency of CD25high cells in PB compared with healthy con-
this subset may also be a disease activity trols,102,103 there were, however, no significant dif-
biomarker. Szabo and colleagues86 found that ferences in the suppressive abilities of the cells
the elevated ratios of Tfh cells could be attributed from patients and healthy controls. On the other
6 Reksten & Jonsson

hand, Foxp31 cells seemed to correlate with protective against development of Raynaud
inflammation grade in the MSG.104,105 phenomenon.116 The functional consequences
The reciprocal relationship with Th17 cells is in a of these genetic polymorphisms remain to be
fine balance crucial for immune homeostasis. Two elucidated.
important cytokines, namely TGF-b and IL-6, are Nevertheless, disease susceptibility has been
involved in the differentiation of these cells and associated with HLA alleles, and Arnett and col-
the maintenance of the balance, and a skewed leagues117 demonstrated an association with
production of TGF-b and IL-6 is seen in MSG HLA-DQ and strong autoantibody response in
epithelial cells in pSS.106 Increased IL-6 produc- pSS. Some cytokine genes are shown or sug-
tion seen in the MSG may explain the imbalance gested to be associated with pSS and/or anti-
in regulation of Th17, fostering a pathogenic envi- Ro/SSA and/or anti-La/SSB, including the TNF-a
ronment. Furthermore, Tregs represent a type of and IL-10 genes,114,118 a SNP in the Il2–Il21
cells controlling and suppressing improper im- region,119 and Il6.120 We examined possible asso-
mune reactions, sustaining tolerance in the periph- ciations of cytokine genes to the presence of
ery. One might postulate that reduced levels of GC-like structures in patients with pSS, and found
Tregs in pSS opens up for autoimmunity and that one SNP in Ccl11 (eotaxin) and one SNP in the
breach of tolerance, whereas others postulate Ccl7–Ccl11 region were associated with GC sta-
that there is a certain pool of Tregs, and with auto- tus.45 This greatly supports our initial findings in
immune inflammation in exocrine glands, they which GC1 patients had elevated serum levels
migrate from the periphery. The observation of of CCL11, and also supports the conclusions
fewer Treg cells in advanced than in mild salivary from a discriminant function analysis suggesting
gland infiltrates support a view that DC-derived CCL11 as 1 of 3 key discriminant biomarkers for
TGF-b may induce FoxP3 in naı̈ve T cells and GC1.62 The CCL11 allele variant seen in GC1 pa-
switch T-cell differentiation toward Th17 in the tients seems to be protective, although patients
presence of IL-6.107,108 have higher CCL11 serum levels than GC– pa-
tients. Interestingly, this is a phenomenon also
observed in a congenic experimental autoimmune
Genetics
encephalomyelitis rat strain,121 where CCL11
A hereditary link was early suggested in SS, and, apparently is involved in a signaling pathway not
indeed, 35% of patients with pSS have relatives related to eosinophil recruitment.122
with other autoimmune diseases.109 Susceptibility
genes to SS are found in HLA-B8,110 the tumor ne- RISK AND PREDICTION OF LYMPHOMA
crosis factor (TNF) system,111 and in components
of the type I IFN system.112 Genetic polymor- Although mortality is not significantly increased in
phisms in the promoter of NCR3/NKp30 were pSS compared with the general population,123 a
associated with reduced gene transcription and well-documented and severe complication is the
function, and seemed to have a protective role in progression to B-cell lymphoma.124–126 The asso-
pSS.67 ciation between pSS and lymphoma has been
Genetic association studies in pSS have thus far studied over the past 50 years. At first the risk
mainly been candidate gene studies, in which was overestimated due to a selected patient mate-
known gene associations in other autoimmune dis- rial,125 whereas more recent population-based
eases have formed the basis. Susceptibility genes studies in Scandinavia indicate a 9-fold to
have been identified in several genes involved in 16-fold increase in risk127,128 with NHL of the
B-cell differentiation, including EBF1, BLK, and MALT type occurring in 4% to 5% of patients
TNFSF4,113 although these SNPs showed no asso- with pSS.46 Several subtypes of NHL are associ-
ciation to the presence of Ro/La autoantibodies. ated with pSS, the most common being MALT
Another study reported genetic associations of lymphoma and diffuse large B-cell lymphoma
TGF-b and TNF-a gene polymorphisms to the (DLBCL), and a 28 times increased risk of MALT
presence of anti-La antibodies rather than to the lymphoma and 11 times increased risk of DLBCL
disease.114 In a recent genome-wide association was determined.129 In comparison with other
study (GWAS) of patients with pSS, IRF5, STAT4, autoimmune chronic inflammatory diseases, the
and BLK, associations were confirmed and novel risk for NHL in pSS is higher than in SLE and
associations near IL12A, CXCR5, and TNIP1 RA.130 Patients with SS and chronic Helicobacter
established.115 pylori infection are at increased risk for developing
Further proposals of genetic implications for the lymphomas, possibly related to prolonged lym-
pSS etiology and autoantibody expression are phocytic activation in the target organ(s) of these
the CTLA4 haplotypes, which are also possibly patients.131,132
 Sjögren’s Syndrome - Epidemiology and Pathogenesis 7

Recent suggestions for lymphoma prediction in inflammatory connective tissue diseases and con-
SS include CD4 lympocytopenia127 and GC-like trols. Acta Ophthalmol Scand 1999;77(1):1–8.
structures in MSG biopsies.44 Established predic- 8. Bernacchi E, Amato L, Parodi A, et al. Sjögren’s
tors for lymphoma development in SS are recur- syndrome: a retrospective review of the cutaneous
rent or permanent swelling of major salivary features of 93 patients by the Italian Group of Im-
glands, lymphadenopathy, cryoglobulinemia, munodermatology. Clin Exp Rheumatol 2004;
splenomegaly, low complement levels of C4 and 22(1):55–62.
C3, lymphopenia, skin vasculitis or palpable pur- 9. Barendregt PJ, Visser MR, Smets EM, et al. Fatigue
pura, M-component in serum or urine, peripheral in primary Sjögren’s syndrome. Ann Rheum Dis
neuropathy, glomerulonephritis, and elevated 1998;57(5):291–5.
beta2-microglobulin (reviewed in Jonsson and 10. Haldorsen K, Bjelland I, Bolstad AI, et al. A five-
colleagues133). Individuals with several risk factors year prospective study of fatigue in primary
or overlapping autoimmune diseases most likely Sjögren’s syndrome. Arthritis Res Ther 2011;
have an increased risk of pSS-associated lym- 13(5):R167.
phoma.134,135 Other suggested risk factors for 11. Haga HJ, Peen E. A study of the arthritis pattern in
lymphoma may be male gender136 and duration primary Sjögren’s syndrome. Clin Exp Rheumatol
of disease.127,137 2007;25(1):88–91.
In summary, pSS can have manifestations 12. Lindvall B, Bengtsson A, Ernerudh J, et al. Subclin-
ranging from mild to severe, including significant ical myositis is common in primary Sjögren’s syn-
oral and ocular symptoms, disabling fatigue, drome and is not related to muscle pain.
reduced quality of life, and, for some patients, an J Rheumatol 2002;29(4):717–25.
increased risk of developing lymphoma. 13. Garcia-Carrasco M, Siso A, Ramos-Casals M, et al.
Raynaud’s phenomenon in primary Sjögren’s syn-
drome. Prevalence and clinical characteristics in
REFERENCES
a series of 320 patients. J Rheumatol 2002;29(4):
1. Jonsson R, Bowman SJ, Gordon TP. Sjögren’s syn- 726–30.
drome. In: Koopman WJ, editor. Arthritis and allied 14. Birlik M, Akar S, Gurler O, et al. Prevalence of pri-
conditions. 15th edition. Philadelphia: Lippincott mary Sjögren’s syndrome in Turkey: a population-
Williams & Wilkins; 2005. p. 1681–705. based epidemiological study. Int J Clin Pract
2. Vitali C, Bombardieri S, Jonsson R, et al. Classifica- 2009;63(6):954–61.
tion criteria for Sjögren’s syndrome: a revised 15. Bowman SJ, Ibrahim GH, Holmes G, et al. Esti-
version of the European criteria proposed by the mating the prevalence among Caucasian women
American-European Consensus Group. Ann of primary Sjögren’s syndrome in two general prac-
Rheum Dis 2002;61(6):554–8. tices in Birmingham, UK. Scand J Rheumatol 2004;
3. Manthorpe R, Jacobsson LT, Kirtava Z, et al. Epide- 33(1):39–43.
miology of Sjögren’s syndrome, especially its pri- 16. Trontzas PI, Andrianakos AA. Sjögren’s syndrome:
mary form. Ann Med Interne (Paris) 1998;149(1): a population based study of prevalence in Greece.
7–11. The ESORDIG study. Ann Rheum Dis 2005;64(8):
4. Jonsson MV, Delaleu N, Marthinussen MC, et al. 1240–1.
Oral and dental manifestations of Sjögren’s syn- 17. Haugen AJ, Peen E, Hulten B, et al. Estimation of
drome: current approaches to diagnostics and the prevalence of primary Sjögren’s syndrome in
therapy. In: Fox RI, Fox C, editors. Sjögren’s syn- two age-different community-based populations
drome: pathogenesis and therapy. New York, Dor- using two sets of classification criteria: the Horda-
drecht (The Netherlands), Heidelberg (Germany), land Health Study. Scand J Rheumatol 2008;
London: Springer; 2011. p. 221–42. 37(1):30–4.
5. Brosky ME. The role of saliva in oral health: strate- 18. Gøransson LG, Haldorsen K, Brun JG, et al. The
gies for prevention and management of xerosto- point prevalence of clinically relevant primary
mia. J Support Oncol 2007;5(5):215–25. Sjögren’s syndrome in two Norwegian counties.
6. Pedersen AM, Bardow A, Nauntofte B. Salivary Scand J Rheumatol 2011;40(3):221–4.
changes and dental caries as potential oral 19. Alamanos Y, Tsifetaki N, Voulgari PV, et al. Epidemi-
markers of autoimmune salivary gland dysfunction ology of primary Sjögren’s syndrome in north-west
in primary Sjögren’s syndrome. BMC Clin Pathol Greece, 1982-2003. Rheumatology 2006;45(2):
2005;5(1):4. 187–91.
7. Bjerrum KB. Tear fluid analysis in patients with pri- 20. Valim V, Zandonade E, Pereira AM, et al. Primary
mary Sjögren’s syndrome using lectin probes. Sjögren’s syndrome prevalence in a major metro-
A comparative study of patients with primary politan area in Brazil. Rev Bras Reumatol 2013;
Sjögren’s syndrome, patients with other immune 53(1):24–34.
8 Reksten & Jonsson

21. Kabasakal Y, Kitapcioglu G, Turk T, et al. The prev- 34. Manoussakis MN, Kapsogeorgou EK. The role of
alence of Sjögren’s syndrome in adult women. intrinsic epithelial activation in the pathogenesis
Scand J Rheumatol 2006;35(5):379–83. of Sjögren’s syndrome. J Autoimmun 2010;35(3):
22. Shiboski SC, Shiboski CH, Criswell LA, et al. 219–24.
American College of Rheumatology classification 35. Spachidou MP, Bourazopoulou E, Maratheftis CI,
criteria for Sjögren’s syndrome: a data-driven, et al. Expression of functional Toll-like receptors
expert consensus approach in the Sjögren’s Inter- by salivary gland epithelial cells: increased
national Collaborative Clinical Alliance Cohort. mRNA expression in cells derived from patients
Arthritis Care Res 2012;64(4):475–87. with primary Sjögren’s syndrome. Clin Exp Immunol
23. Rasmussen A, Ice JA, Li H, et al. Comparison of the 2007;147(3):497–503.
American-European Consensus Group Sjögren’s 36. Ittah M, Miceli-Richard C, Eric Gottenberg J, et al.
syndrome classification criteria to newly proposed B cell-activating factor of the tumor necrosis factor
American College of Rheumatology criteria in a family (BAFF) is expressed under stimulation by inter-
large, carefully characterized sicca cohort. Ann feron in salivary gland epithelial cells in primary Sjög-
Rheum Dis. [E-pub ahead of print]. ren’s syndrome. Arthritis Res Ther 2006;8(2):R51.
24. Vitali C, Bombardieri S, Moutsopoulos HM, et al. 37. Manoussakis MN, Dimitriou ID, Kapsogeorgou EK,
Assessment of the European classification criteria et al. Expression of B7 costimulatory molecules
for Sjögren’s syndrome in a series of clinically by salivary gland epithelial cells in patients with
defined cases: results of a prospective multicentre Sjögren’s syndrome. Arthritis Rheum 1999;42(2):
study. The European Study Group on Diagnostic 229–39.
Criteria for Sjögren’s Syndrome. Ann Rheum Dis 38. Matsumura R, Umemiya K, Goto T, et al. Glandular
1996;55(2):116–21. and extraglandular expression of costimulatory
25. Plesivcnik Novljan M, Rozman B, Hocevar A, et al. molecules in patients with Sjögren’s syndrome.
Incidence of primary Sjögren’s syndrome in Ann Rheum Dis 2001;60(5):473–82.
Slovenia. Ann Rheum Dis 2004;63(7):874–6. 39. Salomonsson S, Jonsson MV, Skarstein K, et al.
26. Pillemer SR, Matteson EL, Jacobsson LT, et al. Inci- Cellular basis of ectopic germinal center formation
dence of physician-diagnosed primary Sjögren and autoantibody production in the target organ of
syndrome in residents of Olmsted County, Minne- patients with Sjögren’s syndrome. Arthritis Rheum
sota. Mayo Clin Proc 2001;76(6):593–9. 2003;48(11):3187–201.
27. Priori R, Medda E, Conti F, et al. Risk factors for 40. Christodoulou MI, Kapsogeorgou EK,
Sjögren’s syndrome: a case-control study. Clin Moutsopoulos HM. Characteristics of the minor
Exp Rheumatol 2007;25(3):378–84. salivary gland infiltrates in Sjögren’s syndrome.
28. Jonsson R, Kroneld U, Backman K, et al. Progres- J Autoimmun 2010;34(4):400–7.
sion of sialadenitis in Sjögren’s syndrome. Br J 41. Jonsson MV, Skarstein K. Follicular dendritic cells
Rheumatol 1993;32(7):578–81. confirm lymphoid organization in the minor salivary
29. Atkinson JC, Travis WD, Slocum L, et al. Serum glands of primary Sjögren’s syndrome. J Oral
anti-SS-B/La and IgA rheumatoid factor are Pathol Med 2008;37(9):515–21.
markers of salivary gland disease activity in pri- 42. Jonsson MV, Szodoray P, Jellestad S, et al. Associ-
mary Sjögren’s syndrome. Arthritis Rheum 1992; ation between circulating levels of the novel TNF
35(11):1368–72. family members APRIL and BAFF and lymphoid or-
30. Daniels TE, Whitcher JP. Association of patterns of ganization in primary Sjögren’s syndrome. J Clin
labial salivary gland inflammation with keratocon- Immunol 2005;25(3):189–201.
junctivitis sicca. Analysis of 618 patients with sus- 43. Le Pottier L, Devauchelle V, Fautrel A, et al. Ectopic
pected Sjögren’s syndrome. Arthritis Rheum germinal centers are rare in Sjögren’s syndrome
1994;37(6):869–77. salivary glands and do not exclude autoreactive
31. Jonsson MV, Skarstein K, Jonsson R, et al. Serolog- B cells. J Immunol 2009;182(6):3540–7.
ical implications of germinal center-like structures 44. Theander E, Vasaitis L, Baecklund E, et al.
in primary Sjögren’s syndrome. J Rheumatol Lymphoid organisation in labial salivary gland bi-
2007;34(10):2044–9. opsies is a possible predictor for the development
32. Reksten TR, Jonsson MV, Szyszko EA, et al. Cytokine of malignant lymphoma in primary Sjögren’s syn-
and autoantibody profiling related to histopatholog- drome. Ann Rheum Dis 2011;70(8):1363–8.
ical features in primary Sjögren’s syndrome. Rheu- 45. Reksten TR, Johnsen SJ, Jonsson MV, et al. Ge-
matology 2009;48(9):1102–6. netic associations to germinal centre formation in
33. Szyszko EA, Brokstad KA, Øijordsbakken G, et al. primary Sjögren’s syndrome. Ann Rheum Dis
Salivary glands of primary Sjögren’s syndrome pa- 2013. [Epub ahead of print].
tients express factors vital for plasma cell survival. 46. Voulgarelis M, Dafni UG, Isenberg DA, et al. Malig-
Arthritis Res Ther 2011;13(1):R2. nant lymphoma in primary Sjögren’s syndrome: a
 Sjögren’s Syndrome - Epidemiology and Pathogenesis 9

multicenter, retrospective, clinical study by the a multiplex cytokine array system. Scand J Immu-
European Concerted Action on Sjögren’s Syn- nol 2004;59(6):592–9.
drome. Arthritis Rheum 1999;42(8):1765–72. 61. Eriksson P, Andersson C, Ekerfelt C, et al. Sjögren’s
47. Garberg H, Jonsson R, Brokstad KA. The serolog- syndrome with myalgia is associated with subnormal
ical pattern of autoantibodies to the Ro52, Ro60, secretion of cytokines by peripheral blood mononu-
and La48 autoantigens in primary Sjögren’s syn- clear cells. J Rheumatol 2004;31(4):729–35.
drome patients and healthy controls. Scand J 62. Szodoray P, Alex P, Jonsson MV, et al. Distinct pro-
Rheumatol 2005;34(1):49–55. files of Sjögren’s syndrome patients with ectopic
48. Salomonsson S, Wahren-Herlenius M. Local pro- salivary gland germinal centers revealed by serum
duction of Ro/SSA and La/SSB autoantibodies in cytokines and BAFF. Clin Immunol 2005;117(2):
the target organ coincides with high levels of 168–76.
circulating antibodies in sera of patients with 63. Båve U, Nordmark G, Lövgren T, et al. Activation of
Sjögren’s syndrome. Scand J Rheumatol 2003; the type I interferon system in primary Sjögren’s
32(2):79–82. syndrome: a possible etiopathogenic mechanism.
49. Elkon KB, Gharavi AE, Hughes GR, et al. Autoanti- Arthritis Rheum 2005;52(4):1185–95.
bodies in the sicca syndrome (primary Sjögren’s 64. Theofilopoulos AN, Baccala R, Beutler B, et al.
syndrome). Ann Rheum Dis 1984;43(2):243–5. Type I interferons (alpha/beta) in immunity and
50. Haga HJ, Jonsson R. The influence of age on dis- autoimmunity. Annu Rev Immunol 2005;23:307–36.
ease manifestations and serological characteristics 65. Akdis M, Palomares O, van de Veen W, et al.
in primary Sjögren’s syndrome. Scand J Rheumatol TH17 and TH22 cells: a confusion of antimicro-
1999;28(4):227–32. bial response with tissue inflammation versus
51. Ching KH, Burbelo PD, Gonzalez-Begne M, et al. protection. J Allergy Clin Immunol 2012;129(6):
Salivary anti-Ro60 and anti-Ro52 antibody profiles 1438–49.
to diagnose Sjögren’s syndrome. J Dent Res 66. Kolkowski EC, Reth P, Pelusa F, et al. Th1 predom-
2011;90(4):445–9. inance and perforin expression in minor salivary
52. Martel C, Gondran G, Launay D, et al. Active glands from patients with primary Sjögren’s syn-
immunological profile is associated with systemic drome. J Autoimmun 1999;13(1):155–62.
Sjögren’s syndrome. J Clin Immunol 2011;31(5): 67. Rusakiewicz S, Nocturne G, Lazure T, et al. NCR3/
840–7. NKp30 contributes to pathogenesis in primary
53. Ramos-Casals M, Solans R, Rosas J, et al. Primary Sjögren’s syndrome. Sci Transl Med 2013;5(195):
Sjögren syndrome in Spain: clinical and immuno- 195ra96.
logic expression in 1010 patients. Medicine 2008; 68. Sun D, Emmert-Buck MR, Fox PC. Differential cyto-
87(4):210–9. kine mRNA expression in human labial minor salivary
54. Buyon JP. Neonatal lupus. Curr Opin Rheumatol glands in primary Sjögren’s syndrome. Autoimmu-
1996;8(5):485–90. nity 1998;28(3):125–37.
55. Marczinovits I, Kovacs L, Gyorgy A, et al. 69. Hagiwara E, Pando J, Ishigatsubo Y, et al. Altered
A peptide of human muscarinic acetylcholine re- frequency of type 1 cytokine secreting cells in the
ceptor 3 is antigenic in primary Sjögren’s syn- peripheral blood of patients with primary Sjögren’s
drome. J Autoimmun 2005;24(1):47–54. syndrome. J Rheumatol 1998;25(1):89–93.
56. Jin M, Hwang SM, Davies AJ, et al. Autoantibodies 70. Salomonsson S, Larsson P, Tengner P, et al.
in primary Sjögren’s syndrome patients induce Expression of the B cell-attracting chemokine
internalization of muscarinic type 3 receptors. Bio- CXCL13 in the target organ and autoantibody pro-
chim Biophys Acta 2012;1822(2):161–7. duction in ectopic lymphoid tissue in the chronic in-
57. Dawson LJ, Stanbury J, Venn N, et al. Antimuscar- flammatory disease Sjögren’s syndrome. Scand J
inic antibodies in primary Sjögren’s syndrome Immunol 2002;55(4):336–42.
reversibly inhibit the mechanism of fluid secretion 71. Xanthou G, Polihronis M, Tzioufas AG, et al.
by human submandibular salivary acinar cells. “Lymphoid” chemokine messenger RNA expres-
Arthritis Rheum 2006;54(4):1165–73. sion by epithelial cells in the chronic inflammatory
58. Bournia VK, Diamanti KD, Vlachoyiannopoulos PG, lesion of the salivary glands of Sjögren’s syndrome
et al. Anticentromere antibody positive Sjögren’s patients: possible participation in lymphoid struc-
syndrome: a retrospective descriptive analysis. ture formation. Arthritis Rheum 2001;44(2):408–18.
Arthritis Res Ther 2010;12(2):R47. 72. Kramer JM, Klimatcheva E, Rothstein TL. CXCL13
59. Bournia VK, Vlachoyiannopoulos PG. Subgroups of is elevated in Sjögren’s syndrome in mice and hu-
Sjögren syndrome patients according to serolog- mans and is implicated in disease pathogenesis.
ical profiles. J Autoimmun 2012;39(1–2):15–26. J Leukoc Biol 2013. [Epub ahead of print].
60. Szodoray P, Alex P, Brun JG, et al. Circulating cyto- 73. Cornec D, Devauchelle-Pensec V, Tobon GJ, et al.
kines in primary Sjögren’s syndrome determined by B cells in Sjögren’s syndrome: from pathophysiology
10 Reksten & Jonsson

to diagnosis and treatment. J Autoimmun 2012; producing interleukin 17. Nat Immunol 2005;
39(3):161–7. 6(11):1133–41.
74. Abdulahad WH, Kroese FG, Vissink A, et al. Immune 88. Nakae S, Nambu A, Sudo K, et al. Suppression of
regulation and B-cell depletion therapy in patients immune induction of collagen-induced arthritis in
with primary Sjögren’s syndrome. J Autoimmun IL-17-deficient mice. J Immunol 2003;171(11):
2012;39(1–2):103–11. 6173–7.
75. Mackay F, Browning JL. BAFF: a fundamental sur- 89. Nakajima K, Kanda T, Takaishi M, et al. Distinct roles
vival factor for B cells. Nat Rev Immunol 2002; of IL-23 and IL-17 in the development of psoriasis-
2(7):465–75. like lesions in a mouse model. J Immunol 2011;
76. Yoshimoto K, Tanaka M, Kojima M, et al. Regulatory 186(7):4481–9.
mechanisms for the production of BAFF and IL-6 90. Nakajima K, Kanda T, Takaishi M, et al. Correction:
are impaired in monocytes of patients of primary distinct roles of IL-23 and IL-17 in the development
Sjögren’s syndrome. Arthritis Res Ther 2011; of psoriasis-like lesions in a mouse model.
13(5):R170. J Immunol 2011;187(11):6157–8.
77. Katsifis GE, Moutsopoulos NM, Wahl SM. 91. Emamaullee JA, Davis J, Merani S, et al. Inhibition
T lymphocytes in Sjögren’s syndrome: contributors of Th17 cells regulates autoimmune diabetes in
to and regulators of pathophysiology. Clin Rev Al- NOD mice. Diabetes 2009;58(6):1302–11.
lergy Immunol 2007;32(3):252–64. 92. Ghoreschi K, Laurence A, Yang XP, et al. T helper 17
78. Ayukawa K, Taniguchi S, Masumoto J, et al. La auto- cell heterogeneity and pathogenicity in autoimmune
antigen is cleaved in the COOH terminus and loses disease. Trends Immunol 2011;32(9):395–401.
the nuclear localization signal during apoptosis. 93. Katsifis GE, Rekka S, Moutsopoulos NM, et al.
J Biol Chem 2000;275(44):34465–70. Systemic and local interleukin-17 and linked cy-
79. Rosen A, Casciola-Rosen L. Altered autoantigen tokines associated with Sjögren’s syndrome im-
structure in Sjögren’s syndrome: implications for munopathogenesis. Am J Pathol 2009;175(3):
the pathogenesis of autoimmune tissue damage. 1167–77.
Crit Rev Oral Biol Med 2004;15(3):156–64. 94. Mieliauskaite D, Dumalakiene I, Rugiene R, et al.
80. Billaut-Mulot O, Cocude C, Kolesnitchenko V, et al. Expression of IL-17, IL-23 and their receptors in
SS-56, a novel cellular target of autoantibody re- minor salivary glands of patients with primary
sponses in Sjögren syndrome and systemic lupus Sjögren’s syndrome. Clin Dev Immunol 2012;
erythematosus. J Clin Invest 2001;108(6):861–9. 2012:187258.
81. Baek Sorensen R, Faurschou M, Troelsen L, et al. 95. Sakai A, Sugawara Y, Kuroishi T, et al. Identification
Melanoma inhibitor of apoptosis protein (ML-IAP) of IL-18 and Th17 cells in salivary glands of
specific cytotoxic T lymphocytes cross-react with patients with Sjögren’s syndrome, and amplifica-
an epitope from the auto-antigen SS56. J Invest tion of IL-17-mediated secretion of inflammatory
Dermatol 2009;129(8):1992–9. cytokines from salivary gland cells by IL-18.
82. Yan B, Liu Y, Hu D, et al. A rare case of extranasal J Immunol 2008;181(4):2898–906.
NK/T cell lymphoma presenting as autoimmune 96. Yapici U, Roelofs JJ, Florquin S. The importance of
rheumatic manifestations associated with Sjögren’s testing anti-IL-17 antibodies from different sup-
syndrome. Ann Hematol 2010;89(4):423–4. pliers. Am J Transplant 2012;12(2):504–5 [author
83. Szodoray P, Papp G, Horvath IF, et al. Cells with reply: 6].
regulatory function of the innate and adaptive im- 97. Shibui A, Shimura E, Nambu A, et al. Th17 cell-
mune system in primary Sjögren’s syndrome. Clin derived IL-17 is dispensable for B cell antibody
Exp Immunol 2009;157(3):343–9. production. Cytokine 2012;59(1):108–14.
84. Kojo S, Adachi Y, Keino H, et al. Dysfunction of T cell 98. Mitsdoerffer M, Lee Y, Jager A, et al. Proinflamma-
receptor AV24AJ181, BV111 double-negative reg- tory T helper type 17 cells are effective B-cell
ulatory natural killer T cells in autoimmune diseases. helpers. Proc Natl Acad Sci U S A 2010;107(32):
Arthritis Rheum 2001;44(5):1127–38. 14292–7.
85. Li XY, Wu ZB, Ding J, et al. Role of the frequency of 99. Ozaki K, Spolski R, Feng CG, et al. A critical role for
blood CD4(1) CXCR5(1) CCR6(1) T cells in auto- IL-21 in regulating immunoglobulin production. Sci-
immunity in patients with Sjögren’s syndrome. Bio- ence 2002;298(5598):1630–4.
chem Biophys Res Commun 2012;422(2):238–44. 100. Hsu HC, Wu Y, Yang P, et al. Overexpression of
86. Szabo K, Papp G, Barath S, et al. Follicular helper activation-induced cytidine deaminase in B cells
T cells may play an important role in the severity of is associated with production of highly patho-
primary Sjögren’s syndrome. Clin Immunol 2013; genic autoantibodies. J Immunol 2007;178(8):
147(2):95–104. 5357–65.
87. Park H, Li Z, Yang XO, et al. A distinct lineage 101. Hsu HC, Yang P, Wang J, et al. Interleukin 17-produc-
of CD4 T cells regulates tissue inflammation by ing T helper cells and interleukin 17 orchestrate
 Sjögren’s Syndrome - Epidemiology and Pathogenesis 11

autoreactive germinal center development in autoim- 115. Lessard CJ, Li H, Adrianto I, et al. Identification of
mune BXD2 mice. Nat Immunol 2008;9(2):166–75. multiple genetic variants associated with Sjögren’s
102. Li X, Li X, Qian L, et al. T regulatory cells are syndrome involved in both the innate and adaptive
markedly diminished in diseased salivary glands immune responses. Nature genetics, in press, the
of patients with primary Sjögren’s syndrome. paper is accepted for publication but not e-pub
J Rheumatol 2007;34(12):2438–45. yet; hence in press.
103. Liu MF, Lin LH, Weng CT, et al. Decreased 116. Downie-Doyle S, Bayat N, Rischmueller M, et al.
CD41CD251bright T cells in peripheral blood of Influence of CTLA4 haplotypes on susceptibility
patients with primary Sjögren’s syndrome. Lupus and some extraglandular manifestations in primary
2008;17(1):34–9. Sjögren’s syndrome. Arthritis Rheum 2006;54(8):
104. Christodoulou MI, Kapsogeorgou EK, 2434–40.
Moutsopoulos NM, et al. Foxp31 T-regulatory cells 117. Arnett FC, Bias WB, Reveille JD. Genetic studies in
in Sjögren’s syndrome: correlation with the grade of Sjögren’s syndrome and systemic lupus erythema-
the autoimmune lesion and certain adverse prog- tosus. J Autoimmun 1989;2(4):403–13.
nostic factors. Am J Pathol 2008;173(5):1389–96. 118. Hulkkonen J, Pertovaara M, Antonen J, et al. Ge-
105. Sarigul M, Yazisiz V, Bassorgun CI, et al. The netic association between interleukin-10 promoter
numbers of Foxp3 1 Treg cells are positively corre- region polymorphisms and primary Sjögren’s syn-
lated with higher grade of infiltration at the salivary drome. Arthritis Rheum 2001;44(1):176–9.
glands in primary Sjögren’s syndrome. Lupus 119. Maiti AK, Kim-Howard X, Viswanathan P, et al. Confir-
2010;19(2):138–45. mation of an association between rs6822844 at the
106. Kawanami T, Sawaki T, Sakai T, et al. Skewed pro- Il2-Il21 region and multiple autoimmune diseases:
duction of IL-6 and TGFbeta by cultured salivary evidence of a general susceptibility locus. Arthritis
gland epithelial cells from patients with Sjögren’s Rheum 2010;62(2):323–9.
syndrome. PLoS One 2012;7(10):e45689. 120. Hulkkonen J, Pertovaara M, Antonen J, et al.
107. Romagnani S. Human Th17 cells. Arthritis Res Ther Elevated interleukin-6 plasma levels are regulated
2008;10(2):206. by the promoter region polymorphism of the IL6
108. Youinou P, Pers JO. Disturbance of cytokine net- gene in primary Sjögren’s syndrome and correlate
works in Sjögren’s syndrome. Arthritis Res Ther with the clinical manifestations of the disease.
2011;13(4):227. Rheumatology 2001;40(6):656–61.
109. Reveille JD, Wilson RW, Provost TT, et al. Primary 121. Öckinger J, Stridh P, Beyeen AD, et al. Genetic var-
Sjögren’s syndrome and other autoimmune dis- iants of CC chemokine genes in experimental auto-
eases in families. Prevalence and immunogenetic immune encephalomyelitis, multiple sclerosis and
studies in six kindreds. Ann Intern Med 1984; rheumatoid arthritis. Genes Immun 2010;11(2):
101(6):748–56. 142–54.
110. Fye KH, Terasaki PI, Moutsopoulos H, et al. Associ- 122. Adzemovic MZ, Ockinger J, Zeitelhofer M, et al.
ation of Sjögren’s syndrome with HLA-B8. Arthritis Expression of Ccl11 associates with immune
Rheum 1976;19(5):883–6. response modulation and protection against neu-
111. Bolstad AI, Le Hellard S, Kristjansdottir G, et al. As- roinflammation in rats. PLoS One 2012;7(7):
sociation between genetic variants in the tumour e39794.
necrosis factor/lymphotoxin alpha/lymphotoxin 123. Theander E, Manthorpe R, Jacobsson LT. Mortality
beta locus and primary Sjögren’s syndrome in and causes of death in primary Sjögren’s syn-
Scandinavian samples. Ann Rheum Dis 2012; drome: a prospective cohort study. Arthritis Rheum
71(6):981–8. 2004;50(4):1262–9.
112. Nordmark G, Kristjansdottir G, Theander E, et al. 124. Anderson LG, Talal N. The spectrum of
Additive effects of the major risk alleles of IRF5 benign to malignant lymphoproliferation in Sjög-
and STAT4 in primary Sjögren’s syndrome. Genes ren’s syndrome. Clin Exp Immunol 1972;10(2):
Immun 2009;10(1):68–76. 199–221.
113. Nordmark G, Kristjansdottir G, Theander E, et al. 125. Kassan SS, Thomas TL, Moutsopoulos HM, et al.
Association of EBF1, FAM167A(C8orf13)-BLK and Increased risk of lymphoma in sicca syndrome.
TNFSF4 gene variants with primary Sjögren’s syn- Ann Intern Med 1978;89(6):888–92.
drome. Genes Immun 2011;12(2):100–9. 126. Zulman J, Jaffe R, Talal N. Evidence that the malig-
114. Gottenberg JE, Busson M, Loiseau P, et al. Associ- nant lymphoma of Sjögren’s syndrome is a mono-
ation of transforming growth factor beta1 and tu- clonal B-cell neoplasm. N Engl J Med 1978;
mor necrosis factor alpha polymorphisms with 299(22):1215–20.
anti-SSB/La antibody secretion in patients with pri- 127. Theander E, Henriksson G, Ljungberg O, et al.
mary Sjögren’s syndrome. Arthritis Rheum 2004; Lymphoma and other malignancies in primary
50(2):570–80. Sjögren’s syndrome: a cohort study on cancer
12 Reksten & Jonsson

incidence and lymphoma predictors. Ann Rheum patients with Sjögren’s syndrome. Clin Cancer
Dis 2006;65(6):796–803. Res 2004;10(2):476–80.
128. Johnsen SJ, Brun JG, Goransson LG, et al. Risk 133. Jonsson MV, Theander E, Jonsson R. Predictors for
of non-Hodgkin’s lymphoma in primary Sjögren’s the development of non-Hodgkin lymphoma in pri-
syndrome: a population-based study. Arthritis mary Sjögren’s syndrome. Presse Med 2012;41(9
Care Res 2013;65(5):816–21. Pt 2):e511–6.
129. Smedby KE, Hjalgrim H, Askling J, et al. Autoim- 134. Baimpa E, Dahabreh IJ, Voulgarelis M, et al. Hema-
mune and chronic inflammatory disorders and tologic manifestations and predictors of lymphoma
risk of non-Hodgkin lymphoma by subtype. J Natl development in primary Sjögren syndrome: clinical
Cancer Inst 2006;98(1):51–60. and pathophysiologic aspects. Medicine 2009;
130. Zintzaras E, Voulgarelis M, Moutsopoulos HM. The 88(5):284–93.
risk of lymphoma development in autoimmune dis- 135. Zhang W, Feng S, Yan S, et al. Incidence of malig-
eases: a meta-analysis. Arch Intern Med 2005; nancy in primary Sjögren’s syndrome in a Chinese
165(20):2337–44. cohort. Rheumatology 2010;49(3):571–7.
131. Raderer M, Osterreicher C, Machold K, et al. 136. Ansell P, Simpson J, Lightfoot T, et al. Non-Hodgkin
Impaired response of gastric MALT-lymphoma to lymphoma and autoimmunity: does gender matter?
Helicobacter pylori eradication in patients with Int J Cancer 2011;129(2):460–6.
autoimmune disease. Ann Oncol 2001;12(7): 137. Ioannidis JP, Vassiliou VA, Moutsopoulos HM.
937–9. Long-term risk of mortality and lymphoproliferative
132. Streubel B, Huber D, Wohrer S, et al. Frequency of disease and predictive classification of primary
chromosomal aberrations involving MALT1 in Sjögren’s syndrome. Arthritis Rheum 2002;46(3):
mucosa-associated lymphoid tissue lymphoma in 741–7.
Diagnosis of Sjögren’s Syndrome
American-European and the American
College of Rheumatology Classification
Criteria
Vidya Sankar, DMD, MHS, FDS RCSEda,*,
Jenene L. Noll, RN, BSNb,
Michael T. Brennan, DDS, MHS, FDS RCSEdb

KEYWORDS
 Sjögren’s syndrome  Diagnosis  Classification

KEY POINTS
 The terms diagnostic criteria and classification criteria for Sjögren’s syndrome (SS) are frequently
used interchangeably, although they represent different concepts; therefore, the differences are
highlighted.
 Advances in the understanding of SS create the need for refinement of classification criteria.
 The major differences between and the strengths and weaknesses of the American European
Consensus Group Criteria and the American College of Rheumatology (ACR) criteria for SS are
addressed.
 Application of the more stringent ACR classification criteria in clinical practice may have an effect
on reported prevalence of the disease.

INTRODUCTION of rheumatic diseases and provide a conceptual

base for measuring future improvements in clinical
Sjögren’s syndrome (SS) is a chronic, systemic care. They usually focus on clinical objectives
autoimmune disorder with multiple organ system to improve clinical research activities.1 They are
involvement, which lacks 1 single objective diag- dynamic and continually evolve, as our under-
nostic gold standard, making diagnosis challenging. standing of the disease increases. Diagnosis dif-
This situation is also true in other rheumatic dis- fers from classification criteria in that the latter
eases, such as systemic lupus erythematosus attempts to categorize a more homogeneous pop-
(SLE) and rheumatoid arthritis (RA). Each of these ulation in an attempt to better assess response to
diseases has its own unique combination of clinical treatments.
and laboratory manifestations, which are relied on Since 1965, there have been 11 sets of classifi-
when making a diagnosis. The clinician’s judgment cation criteria for SS.2–12 Past classification criteria
is the closest thing there is to a gold standard for contain a combination of subjective and objective
diagnosis.
oralmaxsurgery.theclinics.com

findings in 3 areas of specialty practice: rheuma-

Classification criteria are used as a formalized tology, ophthalmology, and oral medicine. Criteria
approach to studying the course and management

a
Oral Medicine Clinic, Dental School, University of Texas Health Science Center San Antonio, 7703 Floyd Curl
Drive, MC 7914, San Antonio, TX 78229, USA; b Sjögren’s Syndrome and Salivary Disorders Center, Carolinas
Medical Center, Department of Oral Medicine, 1000 Blythe Boulevard, Charlotte, NC 28203, USA
* Corresponding author.
E-mail address: [email protected]

Oral Maxillofacial Surg Clin N Am 26 (2014) 13–22

http://dx.doi.org/10.1016/j.coms.2013.09.001
1042-3699/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
14 Sankar et al

sets generally include the presence of serologic tear film layers, or damage or deficits of the ocular
markers, objective oral and ocular findings surface.
assessing either function or changes in gland ar- Most of the previous classification criteria sets
chitecture or degree of damage, and subjective also included the presence of subjective symp-
oral and ocular complaints. toms of oral and ocular dryness in addition to these
Criteria sets have assessed glandular changes objective measures. The most commonly used
by the presence of focal lymphocytic infiltration or symptom assessment criteria involve a positive
focus score (FS). This pathologic process occurs response to at least 1 of the following 3 questions
within the lacrimal glands, all 4 of the major sali- related to ocular symptoms: “Have you had daily,
vary glands as well as the labial minor salivary persistent, troublesome dry eyes for more than
glands (LSGs). Biopsy of the labial minor salivary 3 months?”; “Do you have a recurrent sensation
gland is a less invasive procedure compared with of sand or gravel in the eyes?”; and “Do you use
biopsy of one of the major salivary glands or the tear substitutes more than 3 times a day?” Assess-
lacrimal glands and is therefore the procedure of ment of oral symptoms involves a positive
choice. One limitation associated with the LSG response to at least 1 of the following: “Have you
biopsy is that the sensitivity and specificity of this had a daily feeling of dry mouth for more than
test vary widely (63%–93% and 61%–100%, 3 months?”; “Have you had recurrently or persis-
respectively).13 To complicate matters, the preva- tently swollen salivary glands as an adult?”; and
lence of focal lymphocytic infiltration in postmor- “Do you frequently drink liquids to aid in swallow-
tem LSG studies ranges from 0% to 22.4% in ing dry food?” The problem with assessing subjec-
males and 0% to 35.7% in females.14 In addition, tive complaints when determining SS classification
recent studies have shown that there are signifi- is that dry eye and dry mouth symptoms are com-
cant discrepancies in the evaluation of LSG mon and nonspecific.
biopsies among different pathologists, different According to the Dry Eye Workshop 2007 report,
specialties, and different specialty centers.15,16 prevalence of dry eye ranges from 5% to 30% in
For this reason, classification criteria sets varied people aged 50 years and older.18 The prevalence
in what was considered a positive FS, ranging of dry eye syndrome in the United States is esti-
from an FS of more than 1 to 1 or more. Other mated to be 3.2 million women and 1.7 million
objective tests of salivary gland function include men, for a total of 4.9 million patients 50 years
salivary flow rates, scintigraphy, and sialography. and older.19 Prevalence estimates of xerostomia
These tests are associated with a variety of limita- fluctuate depending on the population being stud-
tions, which are covered in more detail later. ied but have been reported as high as 24.8%.20
Autoantibodies are another common compo- Classification criteria are intended to provide a
nent of classification criterion. Anti-Ro/SSA and formalized approach to studying course and
anti-La/SSB antibodies are among the most fre- management of rheumatic disease, as well as a
quently detected autoantibodies against extract- measure of improvement in clinical care. Under-
able nuclear antigens associated with SS. standing the purposes of specific criteria sets and
Problematically, SSA has also been associated the differences between different criteria cate-
with SLE, systemic sclerosis, polymyositis, primary gories is crucial for understanding the rheumatic
biliary cirrhosis, dermatomyositis, mixed connec- disease literature and for the design and conduct
tive tissue disease (CTD), and RA. The pathologic of clinical and epidemiologic investigations.1 In
role of these antibodies is still poorly understood. this article, the similarities and differences between
Higher titers of SSA and SSB are associated with the American-European Consensus Group Criteria
greater incidence of extraglandular manifestations (AECG)9 and the newly proposed American Col-
of SS such as purpura, leukopenia, and lymphope- lege of Rheumatology (ACR) classification criteria
nia.17 Other less specific markers of inflammation for SS are described.21 The clinical implications
such as IgG, antinuclear antibody (ANA), erythro- of switching to the ACR classification criteria from
cyte sedimentation rate, and rheumatoid factor the AECG are also explored.
(RF) have been included in past criteria.
Several ocular tests have been proposed for use AECG CRITERIA
in the classification of SS. Tests include tear
breakup time, Schirmer tests with and without The AECG criteria (Box 1) published in 2002 were
anesthesia, clearance tests, corneal esthesiome- developed after criticisms were raised about the
try, corneal and conjunctival staining with differing European Study Group on Classification Criteria
scoring and staining methods, and imprint (ESGCC) for SS,8 which were developed and vali-
cytology. These tests assess the ability of the dated between 1989 and 1996 and were subject to
lacrimal glands to function, the integrity of the certain bias based on a combination of ocular
 Diagnosis of Sjögren’s Syndrome 15

Box 1
AECG criteria for SS

I. Ocular symptoms: a positive response to at least 1 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 1 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
1 of the following 2 tests:
1. Schirmer I test, performed without anesthesia (<5 mm in 5 minutes)
2. Rose bengal score or other ocular dye score (>4 according to van Bijsterveld scoring system)
IV. Histopathology: in minor salivary glands (obtained through normal-appearing mucosa), focal lym-
phocytic sialoadenitis, evaluated by an expert histopathologist, with an FS greater than 1, defined
as several lymphocytic foci (which are adjacent to normal-appearing mucous acini and contain >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 1 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 according to the scoring system of
Rubin and Holt36
3. Salivary scintigraphy showing reduced concentration or delayed excretion of tracer according to
the method proposed by Schall and colleagues37
VI. Autoantibodies: presence in the serum of the following autoantibodies:
1. Antibodies to Ro(SSA) or La(SSB) antigens, or both

symptoms, oral symptoms, and salivary gland to the total number of cases included in the study
dysfunction without the need for focal lymphocytic group.
infiltrates or anti-Ro/La antibodies.9 The AECG The ROC analyses showed that using 4 of 6 pos-
criteria modified this classification to include at itive elements to meet criteria, combinations that
least one objective finding, thus redefining the included only symptoms yielded greater sensiti-
rules of the ESGCC. vities and lower specificities, whereas criteria
When developing the 2002 AECG criteria, sets that included only objective findings yielded
receiver operating characteristic (ROC) curves lower sensitivities and higher specificities. The
were constructed based on an analysis of 180 AECG agreed that combinations of subjective
cases selected from a patient group provided by and objective parameters from the ROC curves
16 centers from 10 European countries. The study should replace the previously proposed any 4 of
group included 76 patients classified as having 6 combination in classifying patients with pSS.
primary SS (pSS) by the judgment of the clinician, The AECG subsequently decided that certain
41 patients with different CTDs without clinical specifications must be added to the criteria sets
evidence of secondary SS, and 63 patients with in order to make the item definitions more precise
sicca complaints but no SS. The ROC analysis and the tests more generally applicable (Box 2).
allowed for determination of the accuracy of dif- The AECG criteria set represents a combination
ferent combinations of positive items to correctly of subjective assessments, objective salivary and
classify patients (true positive patient cases) plus ocular function tests, histopathology, and auto-
controls (true negative control cases) with respect antibodies. Because some components of the
16 Sankar et al

Box 2 group used for comparison in classifying second-

Revised rules for classification for pSS ary SS comprised 72 patients clinically classified
as having SS associated with another well-
In patients without any potentially associated defined disease CTD, and 41 patients with
disease, pSS may be defined as follows: CTDs but clinically classified as not having sec-
a. The presence of any 4 of the 6 items indicates ondary SS.
pSS, if either item IV (histopathology) or VI
(serology) is positive
CRITIQUE OF THE AECG CRITERIA
b. The presence of any 3 of the 4 objective
criteria items (ie, items III, IV, V, and VI) The low numbers of patients used for this criteria
c. The classification tree procedure represents development and the lack of geographic variety
a valid alternative method for classification, were a few of the overall criticisms of the AECG
although it should be more properly used criteria. In the following list are other reported
in clinical-epidemiologic surveys weaknesses, some of which were considered by
the Sjögren’s International Collaborative Clinical
Alliance (SICCA) group in developing new criteria
classification criteria could be met using multiple specific to the measures used.21
different tests (ie, item V, salivary gland involve- (Items 1 and 2) Ocular/oral symptoms*:
ment could be met by either unstimulated whole
salivary flow rates, sialography changes, or scin-  Scales for scoring subjective measures vary
tigraphy), patients could meet classification of and are not unique
pSS having met 4 of the following 6 criteria:  Subjective tests lack specificity for SS and do
not correlate with objective measures
1. Ocular symptoms  The use of subjective tests potentially creates
2. Oral symptoms a heterogeneous pool of patients with SS,
3. Ocular signs assessed by Schirmer I test or making it difficult to diagnose, assess efficacy
ocular dye scores of treatment, and determine the prognosis of
4. Histopathology patients with SS
5. Salivary signs assessed by unstimulated whole
salivary flow, positive parotid sialography, or *One strength was that symptoms are the usual
positive salivary scintigraphy prompts that drive patients to seek out a
6. Antibodies to Ro(SSA) or La(SSB) antigens, or diagnosis.
both (3) Ocular signs assessed by Schirmer I test

The AECG also reached a consensus on a list  The test does not correlate with disease
of exclusion criteria (see Box 2) and criteria to  The test lacks specificity for SS
classify cases of secondary SS (Box 3). The (4) Ocular signs assessed by ocular dye scores

 This is a time-consuming grading system that

Box 3
is difficult to apply in clinical practice
Revised rules for classification for secondary SS
In patients with a potentially associated disease (5) Histopathology: none found
(eg, another well-defined CTD), the presence (6) Salivary signs assessed by salivary flow rates
of item I or item II plus any 2 from among items
III, IV, and V may be considered to indicate  Types of saliva (whole vs individual gland) and
secondary SS collection techniques (spitting, drooling, suc-
tion devices, absorption, use of wafers, use
Exclusion criteria:
of iodine starch) vary
Past head and neck radiation treatment  Other factors such as circadian variation,
Hepatitis C infection patient hydration, fasting state, medication,
and possibly age and sex affect saliva pro-
AIDS
duction rates
Preexisting lymphoma  Measures lack specificity for SS
Sarcoidosis
(7) Salivary signs assessed by sialography
Graft-versus-host disease
Use of anticholinergic drugs (since a time  Technique is becoming obsolete
<4-fold the half-life of the drug)  Technique cannot distinguish between var-
ious causes of glandular inflammation
 Diagnosis of Sjögren’s Syndrome 17

(8) Salivary signs assessed by scintigraphy States; the rest were from 4 countries on 3 conti-
nents) to review evidence-based literature and to
 Test scores correlate with flow rates but not generate items. There was a consensus that panel
FSs members would use objective tests (eg, specific
 The test may not provide sufficient diagnostic serum measures of autoimmunity, ocular staining
specificity to offset monetary expenses reflecting lacrimal hypofunction, and LSG biopsy
 The test lacks specificity for SS reflecting focal lymphocytic sialadenitis) that
 The test requires referral to a tertiary-care would likely be part of the new classification
facility and placement of intravenous access criteria. It was agreed that no diagnostic labels
for radiographic dye isotope placement would be used for enrollment and that all partici-
(9) Autoantibodies pants would undergo the same set of standardized
objective tests and questionnaires capturing
 Found in only 60% of patients with SS various signs and symptoms. The final list of
 Found in other CTDs potential criteria items is available at http://sicca.
 The presence of these autoantibodies corre- ucsf.edu/.
lates with earlier onset of the disease, longer Data analysis summaries were presented to the
duration of SS, and is associated with extra- group by the epidemiologist. Cutoff values for
glandular features (parotid gland enlarge- tests were set, and possible surrogates were dis-
ment, vasculitis, splenomegaly)22 cussed. Frequency tables, binary regression, clas-
sification trees, and Venn diagrams were
ACR CRITERIA generated. Results from a statistical classification
based on latent class analysis were presented to
SICCA was funded by the National Institutes of the panel of experts and represented a subset of
Health to develop new classification criteria for participants (n 5 1107). Classification criteria
SS, citing “The need for new classification criteria target individuals with signs and symptoms that
is clear considering the current lack of standardi- may be suggestive of SS such as previous sus-
zation inherent to the use of multiple older criteria picion or diagnosis of SS, increased serum auto-
in the field, and the emergence of biological agents antibody levels; bilateral parotid enlargement, a
as potential treatments,”21 and that “considering recent increase in dental caries; or have diagnoses
the potentially serious adverse effects and comor- of RA or SLE. The rationale for these eligibility
bidities of these agents, criteria used for enroll- criteria was that only patients with such character-
ment into clinical trials will need to be clear, easy istics would be evaluated for SS or considered for
to apply, and have high specificity. They also enrollment in a clinical trial designed to evaluate a
must rely upon well-established objective tests potential therapeutic agent for SS.
that are clearly associated with the systemic/auto- The final criteria were selected (Box 4) and
immune, oral, and ocular characteristics of the dis- criteria validation was made by comparison with
ease, and include alternate tests only when they a gold standard diagnosis derived from a statisti-
are diagnostically equivalent.” The SICCA group cal model fitted to data from a range of diagnostic
also states that it would be desirable for new clas- tests rather than comparisons with patients diag-
sification criteria for SS to be endorsed by profes- nosed with the disease by clinical judgment.
sional rheumatology organizations across the External validation was performed on approxi-
world (such as the ACR or European League mately 300 participants not included in the original
Against Rheumatism [EULAR]) to increase their data set. Controls were selected among partici-
credibility and maximize standardization when pants observed to be negative according to the
enrolling participants into clinical trials. AECG criteria (participants with RA, SLE, sclero-
The SICCA group used consensus methodology derma, or other CTD were excluded from these
derived from the nominal group technique.23 This analyses).
included defining the target population, identifying
an initial list of criteria components and selection ACR CRITERIA CRITIQUE
of preliminary classification criteria. Validation ex-
ercises were then performed. Criticisms of the ACR criteria start with the method
These criteria were developed in 4 phases. An with which patients were identified, because no
expert panel was convened in 2004 made up of preliminary definition of the disease was provided.
members the relevant clinical specialties (7 rheu- In addition, there are a few examples of classifica-
matologists, 6 ophthalmologists, and 7 experts in tion criteria for rheumatic diseases derived by
oral medicine) from a heterogeneous geographic applying the methodology used to derive this
area (9 members [45%] were from the United criteria.24 As more validation exercises are
18 Sankar et al

Box 4 systemic autoimmune disorder (secondary SS)

ACR classification criteria for SSa were excluded from the analyses. Nevertheless,
the preliminary criteria were proposed as a valid
The classification of SS, which applies to individ-
tool to classify secondary SS even although it is
uals with signs/symptoms that may be sugges-
tive of SS, is met in patients who have at least established that patients with secondary SS
2 of the following 3 objective features: tend to manifest different patterns of clinical
presentation.24
1 Positive serum anti-SSA (Ro) or anti-SSB (La) Although in theory, the ACR criteria claim to be a
or (positive RF and ANA 1:320) simple criteria set because they include only 3
2 Labial salivary gland biopsy showing focal objective items, they may be more difficult for
lymphocytic sialadenitis with an FS of 1 the general practitioner to apply. Research centers
focus/4 mm2 or greaterb may have a readily available network of easily
3 Keratoconjunctivitis sicca with ocular stain- accessible rheumatologists, oral medicine spe-
ing score of 3 or greater (assuming that indi- cialists, and ophthalmologists, but this may not
vidual is not using daily eye drops for be feasible in the private practice setting. The
glaucoma and has not had corneal surgery Schirmer I test could be easily administered in
or cosmetic eyelid surgery in the last 5 years)c the rheumatology or dental office setting. Under
Previous diagnosis of any of the following con- the new criteria, patients need to be referred to
ditions excludes participation in SS studies or an ophthalmologist who is familiar with the scoring
therapeutic trials because of overlapping clin- system, resulting in possible delay or inaccuracies
ical features or interference with criteria tests: in assessment.
 History of head and neck radiation treatment Another concern regarding the criteria selected
by the ACR was that patients with low ocular
 Hepatitis C infection
flow who have may not yet have progressed to
 AIDS surface abrasion as well as patients with low sali-
 Sarcoidosis vary flow without lymphocytic infiltrates (possibly
 Amyloidosis because of error in sampling or errors in scoring
inflammation, for example) or those patients with
 Graft-versus-host disease
subclinical immunologic processes may be mis-
 IgG4-related disease classified. It is possible that these patients are at
a
Exclusion: participants with RA, SLE, scleroderma, an earlier stage of the disease or may have sub-
or other CTD from the analyses, because there were clinical immunologic processes and may have a
only 87 (6%) such participants. higher likelihood of response to treatments.24
b
Using histopathologic definitions and FS assess- Daniels reports that within the SICCA population
ment methods previously described and OSS previ-
ously described.30
with keratoconjunctivitis sicca (KCS) only at base-
c
Using ocular staining score as previously described.27 line, a few people developed features of SS 2 years
later.25 In addition, it has been postulated that
abnormal FS and presence of anti-SSA/SSB auto-
performed using the ACR criteria, more informa- antibodies might not be independent variables,
tion will be brought forth to determine the perfor- that there is some interdependency of the classifi-
mance of this methodology. cation criteria, which increases the probability of
Usually, when developing new criteria sets, pro- not classifying cases of SS with a negative biopsy
posed criteria sets are compared with a gold stan- or autoantibodies.26
dard. The practice of defining a gold standard is With regards to the ocular stain scoring (OSS)
based on a series of cases (those with the disease) method used in the ACR criteria, a new method
and controls (those without the disease) identified was developed by Whitcher and colleagues,27
by expert clinicians. The investigators of the ACR which is a modification of the Oxford scoring sys-
criteria acknowledge that although this is the sys- tem developed by Bron and colleagues28 for as-
tem that is generally used, it was not practical for sessing KCS. This new method was tested on
them to apply this to their methodology “because the same population with SICCA used for develop-
diagnosis must rely on three clinical specialties.” ment of the ACR criteria. This new scoring system
In this case, comparisons were made to alternative also gives equal weight of corneal (0–6) staining to
versions of the preliminary criteria, derived from a conjunctiva staining (nasal 0–3; temporal 0–3).
statistical model fitted to data rather than to There was no explanation of how the OSS cutoff
patients with diagnosed pSS. of 3 or higher was determined or why corneal
Another criticism of the ACR criteria was staining could now account for half of the maximal
that patients with SS and another associated score (6), whereas in previous ocular scoring
 Diagnosis of Sjögren’s Syndrome 19

methods, corneal staining accounted for one-third caused by a therapeutic intervention, many inno-
of the total score. Although this scoring system vative tests or other such candidate markers for
was compared with tear breakup time and SS such as a-fodrin autoantibodies, M3 receptor
Schirmer I scores, it was not compared with antibody, ultrasonography, magnetic resonance
Oxford scores28 or van Bjisterveld scores.29 It is imaging (MRI), and MRI sialography may have
therefore impossible to compare this scoring sys- been better candidates for consideration.30
tem with previously established systems and Following these markers or imaging may be more
results. Also, exclusion criteria in the Witcher study reflective of response to biologics in clinical trials
did not mention those individuals who had punc- than the ones selected.
tual occlusion, those already on medications
such as cyclosporine eye drops or other eye lubri- COMPARISON OF AECG WITH ACR CRITERIA
cants, or those taking parasympathomimetics. IN CLINICAL PRACTICE
The scoring system proposed by Witcher used
Venn diagrams to visualize the interrelationships In order to determine the usefulness of the ACR
between an abnormal OSS and the other 2 main criteria in a clinical practice, we examined 100
phenotypic characteristics of SS (FS and sero- consecutive patients who met the AECG at the
logy), the investigators used an FS of greater Sjögren’s Syndrome and Salivary Disorders Cen-
than 1 rather than FS 1 or greater to classify ter, Carolinas Center for Oral Health, Carolinas
patients. Health Care System, Charlotte, NC. As shown in
With regards to the laboratory items selected Table 1, the specific criteria used in the ACR clas-
by SICCA, criteria included a combination of alter- sification criteria (ie, serology, ocular staining, and
native, less specific measures (ANA and RF) in labial salivary gland biopsy) were documented
place of more specific measures (SSA and SSB based on the available data of 100 patients with
autoantibodies) derived by a consensus decision pSS based on the AECG criteria. Of the 100
rather than the stated purposes for establishment patients with pSS based on the AECG criteria,
of new classification criteria, and eliminated the only 5 patients had sufficient data available to
Schirmer test from the objective eye criteria meet the ACR criteria (Table 1).
because of its lower specificity compared with There are a numerous reasons that only 5 of 100
ocular staining.24 patients with pSS by the AECG criteria would
In diagnosing SS, there are potentially many also meet the ACR criteria with the data available
subclinical immunologic processes that precede in this particular clinical practice. First, this oral
clinical disease, potentially delaying diagnosis by medicine practice receives many referrals from
several years or preventing patients from entry in rheumatologists in the community to further
clinical trials while at an early disease stage evaluate for pSS, when patients have negative
when they have a greater potential for response laboratory test results but still have symptoms
to biologics. If establishing classification criteria and extraglandular manifestations suggestive of
is intended to allow monitoring for changes pSS. Only 24 of 100 patients had either a positive

Table 1
Number (%) of patients with pSS meeting or diagnosed by the A–E criteria who met specific ACR
criteria and classified by the ACR criteria as SS

Completed but not Not Completed

Sjögren Criteria Positive Negative Scored by Criteria or not Available
Meets A-Ea criteria 100 0 — —
Meets ACR criteria 5 95 — —
Specific ACR criteria
Serum
Anti-SSA or anti-SSB positive 24 72 — 4
ANA 1:320 and 1RF 3 86 — 11
OSS: lissamine green on the conjunctiva 2 2 3 93
and fluorescein on the cornea
Labial salivary gland biopsy: focal 75 1 0 24
lymphocytic sialadenitis/FS 1/4 mm2
a
A-E, American-European criteria.
20 Sankar et al

anti-SSA or anti-SSB, therefore a minor salivary autoimmune conditions. According to Tsuboi and
gland biopsy was completed in these patients colleagues,31 the ACR revised criteria for the clas-
with negative autoimmune serology. Approxi- sification of SLE (1997) have been adopted for
mately 60% of pSS have positive laboratory test establishing diagnosis in daily clinical practice as
results, therefore there is a referral bias with this well as for classification purposes in clinical
present sample with only 24% having a positive studies. Tsuboi and colleagues also assert that
laboratory test result. In addition, the 24 patients the 2010 RA classification criteria (an ACR/EULAR
with positive laboratory test results did not have collaborative initiative) is used not only in clinical
the minor salivary gland biopsy completed, studies of RA but also in daily clinical practice for
because these patients met the AECG criteria the diagnosis of RA. Therefore, these diagnostic
without this additional invasive test. Theoretically, systems for SLE and RA could be regarded as
if the rate of positive laboratory test results was the gold standard for both clinical studies and daily
higher (eg, 60%) in this patient population, most clinical practice.
of these patients would likely meet the AECG If ACR classification criteria are adopted as
criteria and would not require a salivary gland diagnostic criteria, this may have a great impact
biopsy to meet the classification criteria. on the reported prevalence of the disease. As Bal-
The lower rate of positive autoimmune serology dini and colleagues reported,26 when criteria sets
is not the main reason for the lower rate of AECG switch to the use of more objective measures,
positive patients with pSS also meeting the ACR the overall prevalence of pSS estimated according
criteria. The primary factor is the challenges of to the preliminary European criteria varied from a
obtaining ocular staining scores, as proposed in minimum of 0.35 (95% confidence interval [CI],
the ACR criteria. Only 4 of 100 patients had stain- 0.17–0.65) to a maximum of 3.59 (95% CI, 2.43–
ing scored in a manner consistent with the ACR 5.08). Classified using the AECG criteria, the prev-
criteria, whereas another 3 of 100 had staining alence estimates decreased to 0.05 (95% CI,
but it was not scored in a way that could be 0.048–0.052) to 0.6 (95% CI, 0.24–1.39).32–35 The
used by the ACR criteria. The remaining 93 higher stringency allowed the AECG criteria to
patients did not have ocular staining completed, identify more homogeneous patients, but the
or no eye examination was available for assess- higher specificity was extensively criticized. There
ment. All 100 patients did have a Schirmer I test have been no published prevalence estimates
available, but this is not used in the ACR criteria. using the ACR criteria, but with the increased
strictness of the ACR criteria, it will be interesting
DISCUSSION to see the overall prevalence estimates of SS
with this newer classification criteria.
The purpose of classification criteria is to separate If the ACR criteria are used to estimate preva-
patients with a disease both from patients without lence rates of SS and the prevalence is greatly
the disease and from normal individuals. Concep- reduced, this may have an impact on the willing-
tually, classification criteria become, in practice, ness of drug companies to pursue SS as a new
the same as diagnostic criteria. There are exam- indication for existing drugs or the development
ples in the scientific literature in which some have of novel therapies.
attempted to determine if a certain classification Decreased prevalence rates may also have an
criteria set is the best way to diagnose SS.30 In a impact on insurance coverage, both medical and
perfect world, if sensitivity and specificity were dental, for patients.
both 100%, they would be termed diagnostic In addition, the use of ocular staining alone in the
criteria. However, classification criteria sets are ocular assessment may cause delays in classifying
not perfect, and a certain proportion of patients those with SS. With AECG criteria, ocular involve-
are always misclassified. Thus, criteria committees ment could be assessed by the Schirmer I test
should be careful to emphasize that meeting (or without anesthesia. This procedure could be per-
not meeting) classification criteria does not equate formed in the clinical setting of the rheumatologist
to a diagnosis and that the physician, considering or the oral medicine specialist. The ACR criteria
features of an individual patient beyond those rep- would require patients to be referred to an ophthal-
resented in the criteria, is the only one who can mologist, specifically one with knowledge of the
establish a diagnosis for an individual patient.1 scoring system developed by the SICCA group.
One potential source of confusion that the ACR Because this scoring system is new, it will be an
criteria present is that because they are endorsed additional challenge to find ophthalmologists
by the ACR, these classification criteria have the who are familiar with this scoring system for indi-
potential to be more frequently confused with viduals or group practices not affiliated with a clin-
diagnostic criteria, which has occurred with other ical trial consortium.
 Diagnosis of Sjögren’s Syndrome 21

Classification criteria will continue to change as for Sjogren’s syndrome: a systematic review. Auto-
technology advances and knowledge of SS in- immun Rev 2013;12(3):416–20.
creases. This progress will make a more homoge- 14. Takeda Y, Komori A. Focal lymphocytic infiltration in
neous patient population and it is hoped lead to the human labial salivary glands: a postmortem
earlier diagnosis and development of more effec- study. J Oral Pathol 1986;15(2):83–6.
tive therapeutics. However, it is possible that 15. Stewart CM, Bhattacharyya I, Berg K, et al. Labial
newly established criteria sets may not allow for salivary gland biopsies in Sjogren’s syndrome: still
direct comparison between new studies and previ- the gold standard? Oral Surg Oral Med Oral Pathol
ous ones. Oral Radiol Endod 2008;106(3):392–402.
16. Tavoni AG, Baldini C, Bencivelli W, et al. Minor sali-
vary gland biopsy and Sjogren’s syndrome: compar-
REFERENCES
ative analysis of biopsies among different Italian
1. Fries JF, Hochberg MC, Medsger TA Jr, et al. Criteria rheumatologic centers. Clin Exp Rheumatol 2012;
for rheumatic disease. Different types and different 30(6):929–33.
functions. The American College of Rheumatology 17. Harley JB, Alexander EL, Bias WB, et al. Anti-Ro
Diagnostic and Therapeutic Criteria Committee. (SS-A) and anti-La (SS-B) in patients with Sjogren’s
Arthritis Rheum 1994;37(4):454–62. syndrome. Arthritis Rheum 1986;29(2):196–206.
2. Bloch KJ, Buchanan WW, Wohl MJ, et al. Sjoeg- 18. Research in dry eye: report of the Research Sub-
ren’s syndrome. A clinical, pathologic, and sero- committee of the International Dry Eye Workshop
logic study of sixty-2 cases. Medicine 1965;44: (2007). Ocul Surf 2007;5(2):179–93.
187–231. 19. Yavuz B, Bozdag Pehlivan S, Unlu N. An overview
3. Daniels TE, Silverman S Jr, Michalski JP, et al. The on dry eye treatment: approaches for cyclosporin
oral component of Sjogren’s syndrome. Oral Surg a delivery. TheScientificWorldJournal 2012;2012:
Oral Med Oral Pathol 1975;39(6):875–85. 194848.
4. Homma M, Tojo T, Akizuki M, et al. Criteria for Sjog- 20. Murray Thomson W, Chalmers JM, John Spencer A,
ren’s syndrome in Japan. Scand J Rheumatol Suppl et al. A longitudinal study of medication exposure
1986;61:26–7. and xerostomia among older people. Gerodontology
5. Manthorpe R, Frost-Larsen K, Isager H, et al. Sjog- 2006;23(4):205–13.
ren’s syndrome. A review with emphasis on immuno- 21. Shiboski SC, Shiboski CH, Criswell L, et al. Amer-
logic features. Allergy 1981;36(3):139–53. ican College of Rheumatology classification criteria
6. Skopouli FN, Drosos AA, Papaioannou T, et al. Pre- for Sjogren’s syndrome: a data-driven, expert
liminary diagnostic criteria for Sjogren’s syndrome. consensus approach in the Sjogren’s International
Scand J Rheumatol Suppl 1986;61:22–5. Collaborative Clinical Alliance cohort. Arthritis Care
7. Fox RI, Robinson CA, Curd JG, et al. Sjogren’s syn- Res (Hoboken) 2012;64(4):475–87.
drome. Proposed criteria for classification. Arthritis 22. Tzioufas AG, Voulgarelis M. Update on Sjogren’s
Rheum 1986;29(5):577–85. syndrome autoimmune epithelitis: from classification
8. Vitali C, Bombardieri S, Moutsopoulos HM, et al. Pre- to increased neoplasias. Best Pract Res Clin Rheu-
liminary criteria for the classification of Sjogren’s matol 2007;21(6):989–1010.
syndrome. Results of a prospective concerted ac- 23. Fink A, Kosecoff J, Chassin M, et al. Consensus
tion supported by the European Community. Arthritis methods: characteristics and guidelines for use.
Rheum 1993;36(3):340–7. Am J Public Health 1984;74(9):979–83.
9. Vitali C, Bombardieri S, Jonsson R, et al. Classifica- 24. Vitali C, Bootsma H, Bowman SJ, et al. Classifi-
tion criteria for Sjogren’s syndrome: a revised cation criteria for Sjogren’s syndrome: the authors
version of the European criteria proposed by the actually need to definitively resolve the long
American-European Consensus Group. Ann Rheum debate on the issue. Ann Rheum Dis 2013;72(4):
Dis 2002;61(6):554–8. 476–8.
10. Shearn MA. Major problems in internal medicine. 25. Daniels TE. Do the authors need new diagnostic
Sjogren’s syndrome, vol. 2. Philadelphia: WB Saun- criteria for Sjogren’s syndrome? Presse Med 2012;
ders; 1971. 41(9 Pt 2):e441–9.
11. Ohfuji T. Sjogren’s Disease Research Committee. 26. Baldini C, Talarico R, Tzioufas AG, et al. Classifica-
Review on research reports: annual report of the tion criteria for Sjogren’s syndrome: a critical review.
Ministry of Health and Welfare. Japan: Japanese J Autoimmun 2012;39(1–2):9–14.
Ministry of Health; 1977. 27. Whitcher JP, Shiboski CH, Shiboski SC, et al. A
12. Fujibayashi T. Revised diagnostic criteria for Sjog- simplified quantitative method for assessing kerato-
ren’s Syndrome. Rheumatology: Oxford; 2000. conjunctivitis sicca from the Sjogren’s Syndrome
13. Guellec D, Cornec D, Jousse-Joulin S, et al. Diag- International Registry. Am J Ophthalmol 2010;
nostic value of labial minor salivary gland biopsy 149(3):405–15.
22 Sankar et al

28. Bron AJ, Evans VE, Smith JA. Grading of corneal Sjogren’s syndrome in 2 Norwegian counties. Scand
and conjunctival staining in the context of other dry J Rheumatol 2011;40(3):221–4.
eye tests. Cornea 2003;22(7):640–50. 34. Haugen AJ, Peen E, Hulten B, et al. Estimation of the
29. van Bijsterveld OP. Diagnostic tests in the Sicca syn- prevalence of primary Sjogren’s syndrome in 2 age-
drome. Arch Ophthalmol 1969;82(1):10–4. different community-based populations using 2 sets
30. Aframian DJ, Konttinen YT, Carrozzo M, et al. Urban of classification criteria: the Hordaland Health Study.
legends series: Sjogren’s syndrome. Oral Dis 2013; Scand J Rheumatol 2008;37(1):30–4.
19(1):46–58. 35. Mavragani CP, Moutsopoulos HM. The geoepidemi-
31. Tsuboi H, Hagiwara S, Asashima H, et al. Validation ology of Sjogren’s syndrome. Autoimmun Rev 2010;
of different sets of criteria for the diagnosis of Sjog- 9(5):A305–10.
ren’s syndrome in Japanese patients. Mod Rheuma- 36. Rubin P, Holt JF. Secretory sialography in diseases
tol 2013;23(2):219–25. of the major salivary glands. American Journal of
32. Binard A, Devauchelle-Pensec V, Fautrel B, et al. Roentgenology, Radium Therapy, and Nuclear Med-
Epidemiology of Sjogren’s syndrome: where are the icine 1957;77(4):575–98.
authors now? Clin Exp Rheumatol 2007;25(1):1–4. 37. Schall GL, Anderson LG, Wolf RO, et al. Xerostomia
33. Goransson LG, Haldorsen K, Brun JG, et al. The in Sjogren’s syndrome. Evaluation by sequential sali-
point prevalence of clinically relevant primary vary scintigraphy. JAMA 1971;216(13):2109–16.
S a l i v a r y Gl a n d B i o p s y
f o r Sj ög re n ’s S y n d ro m e
Konstantina Delli, DDS, MSc, Dr med dent,
Arjan Vissink, DDS, MD, PhD, Fred K.L. Spijkervet, DMD, PhD*

KEYWORDS
 Salivary gland  Biopsy  Labial gland  Parotid gland  Sjögren’s syndrome

KEY POINTS
 Lymphocytic sialadenitis in labial salivary glands is a widely accepted criterion for histologic confir-
mation of Sjögren’s syndrome (SS).
 Sensitivity and specificity of parotid and labial biopsies for diagnosing SS are comparable.
 Parotid gland incision biopsy can overcome most of the disadvantages of labial gland excision
biopsy.
 In contrast to labial salivary glands, lymphoepithelial lesions and early stage lymphomas can often
be observed in parotid gland tissue of patients with SS.
 Parotid tissue can be harvested easily; repeated biopsies from the same parotid gland are possible;
histopathologic results can be compared with other diagnostic results derived from the same gland.
 Parotid biopsies, in contrast to labial salivary gland biopsy, allow the clinician to prospectively monitor
disease progression and to assess the effects of the intervention treatment at a glandular level.

INTRODUCTION biopsy when applying the AECG’s classification

criteria, it has yet to be validated in regard to the
Salivary gland biopsy is a technique broadly ACR’s classification criteria.1
applied for the diagnosis of Sjögren’s syndrome This article focuses on the main techniques
(SS), lymphoma accompanying SS, sarcoidosis, used for taking labial and parotid salivary gland
amyloidosis, and other connective tissue disor- biopsies in the diagnostic workup of SS with
ders. SS has characteristic microscopic findings respect to their advantages, their postoperative
involving lymphocytic infiltration surrounding the complications, and their usefulness for diagnostic
excretory ducts in combination with the destruc- procedures, monitoring disease progression, and
tion of acinar tissue (Fig. 1). In affected parotid treatment evaluation.
glands, epimyoepithelial islands in a background
of lymphoid stroma can be additionally seen, and LABIAL SALIVARY GLAND BIOPSY
lymphoepithelial lesions (LELs) are a common
phenomenon (Fig. 2). Minor salivary glands are widely distributed in the
Biopsy of the labial salivary glands is considered labial, buccal, and palatal mucosa of the oral cav-
one of the 4 objective American-European Con- ity.2 Because pathognomonic changes are seen in
sensus Group’s (AECG) classification criteria and minor salivary glands, the minor salivary gland bi-
one of the 3 objective American College of Rheu- opsy is largely used for assisting the diagnosis of
oralmaxsurgery.theclinics.com

matology’s (ACR) classification criteria for SS SS. Labial salivary glands, in particular, are easily
(Table 1). Although the parotid biopsy has been accessible, lie above the muscle layer, and are
shown to be an alternative for labial salivary gland separated from the oral mucous membrane by a

Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, University of Groningen,
Groningen, the Netherlands
* Corresponding author. Department of Oral and Maxillofacial Surgery, University Medical Center Groningen,
PO Box 30.001, 9700 RB Groningen, The Netherlands.
E-mail address: [email protected]

Oral Maxillofacial Surg Clin N Am 26 (2014) 23–33

http://dx.doi.org/10.1016/j.coms.2013.09.005
1042-3699/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
24 Delli et al

Marx and colleagues7 modified Greenspan’s

technique with a mucosal excision of 3.0 
0.75 cm. Delgado and Mosqueda8 preferred a
longitudinal incision of 1 cm in the labial mucosa
in front of the mandibular cuspids. Guevara-
Gutierrez and coworkers9 proposed the punch bi-
opsy technique performed with a 4-mm punch
just penetrating the epithelium of the lower lip.
Mahlsted and colleagues10 recommended a
1.0- to 1.5-cm wedge-shaped excision of
mucosa between the midline and commissure.
Gorson and Ropper11 reported a 1-cm vertical
incision just behind the wet line through the mu-
cosa and submucosa. An oblique incision, start-
ing 1.5 cm from the midline and proceeding
Fig. 1. Lymphocytic infiltration (*) surrounding excre- latero-inferiorly, avoiding the glandular-free zone
tory ducts and destruction of acini (Hematoxylin and in the center of the lower lip was advocated
Eosin stain (H&E)). by Berquin and colleagues.12 Caporali and
colleagues13 reported a small incision of 2 to
thin layer of fibrous connective tissue. Although 3 mm on the inner surface of the lower lip. In
the chance of excessive bleeding is minimal, view of the lack of sufficient evidence to support
because the arterial supply to the lip lies deep,3 the superiority of one technique over the others,
there is a risk of sensible nerve injury because especially in respect to short- and long-term
the branches of the mental nerve in the lower lip morbidity, the shape and the size of the incision
are closely associated to the minor salivary glands can be considered a matter of preference. The
(Fig. 3).4 incision shape has included elliptical, horizontal,
Labial salivary gland biopsies in the diagnosis of vertical, and wedge shapes; the incision length
SS were introduced by Chisholm and Mason5 in has varied from a few millimeters to 2 cm. The
1968 and involved oral preparation of patients authors of the present article, based on their clin-
with local anesthetic infiltration followed by ical experience, suggest a horizontal incision of
excising an ellipse of oral mucous membrane approximately 2 cm, which is in agreement with
down to the muscle layer.5 The wound was closed the technique proposed by Greenspan and
with 4-0 silk sutures, which were removed after 4 colleagues6 whereby the surgeon uses loupe
to 5 days. Ideally, 6 to 8 minor glands must be har- operation glasses (magnification  2.5) to pre-
vested and sent for histopathologic examination. cisely excise the salivary glands without disturb-
Several technicians have revised this technique ing the direct underlying sensible nerves (Fig. 4).
(Table 2). Greenspan and colleagues6 described The first grading system for salivary gland
a 1.5- to 2.0-cm linear incision of mucosa, parallel biopsies was used by Chisholm and Mason5 in
to the vermillion border and lateral to the midline. an attempt to standardize the examined area and
record the degree of histopathologic change. At
present, according to the revised AECG’s classifi-
cation criteria and the ACR’s classification criteria
for SS, a labial salivary gland biopsy is considered
positive if minor salivary glands (obtained through
normal-appearing mucosa) demonstrate focal
lymphocytic sialadenitis, evaluated by an expert
histopathologist, with a focus score of 1 or more
(defined as several lymphocytic foci, containing
more than 50 lymphocytes per 4 mm2 of glandular
tissue) (see Table 1).

Complications
The most commonly reported complications of
Fig. 2. Lymphoepithelial lesions (*) form as the result labial gland biopsy are the following1,6–8,10,12–17:
of atrophy of the columnar ductal epithelium and pro-
liferation of basal epithelial cells, associated with intra- 1. Localized sensory alteration (frequently de-
epithelial infiltration. (Courtesy of Dr EA Haacke) scribed with the terms anesthesia, reduced or
 Salivary Gland Biopsy for Sjögren’s Syndrome 25

Table 1
Histologic criteria for diagnosing SS on salivary gland biopsies

Type of Biopsy Positivity

Labial gland If minor salivary glands (obtained through normal-appearing mucosa)
demonstrate focal lymphocytic sialadenitis, evaluated by an expert
histopathologist, with a focus score 1 or more, defined as several lymphocytic
foci (which are adjacent to normal appearing mucous acini and contain more
than 50 lymphocytes) per 4 mm2 of glandular tissue
Parotid gland If one of the 2 following criteria is fulfilled:
1. A focus score of 1 or more, defined as the number of lymphocytic foci (which are
adjacent to normal-appearing acini and contain >50 lymphocytes) per 4 mm2 of
glandular parotid tissue (including fat tissue), regardless of the presence of
benign LELs
2. Small lymphocytic infiltrates, not fulfilling the criterion of a focus score of more
than 1, in combination with the presence of benign LELs
Sublingual Not determined

Abbreviation: LELs, lymphoepithelial lesions.

Data from Refs.1,18,19

partial loss of sensation, transitory numbness, not for treatment and disease activity evaluation20;
and hypoesthesia); may last for a few months although very rare, B-cell mucosa-associated
or can be permanent lymphoid tissue (MALT) lymphomas can be found
2. External hematoma in labial biopsies of patients with SS.21,22
3. Local swelling
4. Formation of granulomas
PAROTID GLAND BIOPSY
5. Internal scarring and cheloid formation
6. Failing sutures The parotid gland is the largest salivary gland and is
7. Local pain positioned on the lateral aspect of the face over-
lying the posterior surface of the mandible and an-
Suitability for Diagnostic and Treatment teroinferior to the auricle.23 Traditionally, the gland
Evaluation Purposes is divided into a superficial and deep lobe based
on the course of the facial nerve as it passes
A widely accepted criterion for histologic confir-
through. When the facial nerve enters the parotid
mation of SS is focal lymphocytic sialadenitis in
gland, it forms a characteristic branching pattern
labial salivary glands.18,19 Labial biopsies are
that resembles a goosefoot and is known as the
mainly well suited for the diagnostic workup but
pes anserinus, giving 2 main divisions of the facial
nerve (Fig. 5). Surgically, the facial nerve can be
located in approximately 2 to 4 mm deep to the infe-
rior end of the tympanomastoid suture line and 1 cm
deep and slightly anteroinferior to the tragal pointer.
Kraaijenhagen24 initially described the parotid
gland biopsy technique: the area is anesthetized
with local infiltration anesthesia after the standard
preparation. With a No. 15 blade, a small 1- to
2-cm incision is made just below the earlobe
near the posterior angle of the mandible. The
skin is incised, and the parotid capsule is exposed
by blunt dissection. The capsule of the gland is
carefully opened, and a small amount of superficial
parotid tissue is removed. The procedure is
Fig. 3. The branch of the mental nerve (*) that sup-
plies the mucous membrane of the lower lip usually completed with a 2- to 3-layered closure. The
divides into 2 sub-branches (a horizontal and a verti- capsule must be cautiously closed to avoid future
cal), which have an ascending course toward the leakage or the development of sialocele (Fig. 6).
vermillion border and are in close relation to the The technique was slightly modified by the pre-
labial salivary glands (**). sent authors with an incision below and slightly
26
Table 2
Comparison of techniques

Technique Advantages Complications

Labial gland
Chisholm & Ellipse of oral mucous 1. Widely distributed 1. Temporary or
Mason,5 1968 membrane down to glands permanent alteration
the muscle layer; 2. Easily accessible in sensation in the
harvest of 6 to 8 glands area of the incision
glands; wound closure 3. Minimal chance of 2. External hematoma
with 04-gauge silk bleeding 3. Local swelling
sutures, which must be 4. Granulomas
removed after 4 to formation
5 days 5. Internal scarring and
Greenspan 1.5- to 2.0-cm linear cheloid formation
et al,6 1974 incision of mucosa, 6. Suture failing
parallel to the 7. Local pain
vermillion border and
lateral to the midline
Marx Mucosal incision of 3.0 
et al,7 1988 0.75 cm
Delgado & Longitudinal incision of
Moscueda,8 1 cm in the labial
1989 mucosa in front of the
mandibular cuspids
Guevara- Punch biopsy
Gutierrez
et al,9 2001
Mahlsted 1.0- to 1.5-cm wedge-
et al,10 2002 shaped incision
between the midline
and commissure
Gorson & 1-cm vertical incision just
Ropper,11 2003 behind the wet line
through the mucosa
and submucosa
Berquin Oblique incision, starting
et al,12 2006 1.5 cm from the midline
and proceeding latero-
inferiorly, avoiding the
glandular-free zone in
the center of the lower
lip
Caporali Small incision of 2 to
et al,13 2007 3 mm on the inner
surface of the lower lip
Parotid gland
Kraaijenhagen,24 1- to 2-cm incision just 1. Presence of LELs 1. Temporary alteration
1975 below and behind the 2. Identification of in sensation in the
Marx earlobe near the MALT area of the incision
et al,7 1988 posterior angle of the 3. Possibility of repeated 2. Facial nerve damage
McGuirt mandible; the skin is biopsy from the same 3. Sialoceles
et al,43 2002 incised and the parotid gland 4. Salivary fistulae
Baurmash capsule is exposed by 4. Comparison with 5. Risk of harvesting
et al,44 2005 blunt dissection; other diagnostic re- only fat tissue
Pijpe capsule of the gland is sults derived from the 6. Demanding surgical
et al,1 2007 opened and adequate same gland (eg, expertise
amount of superficial secretory function,
parotid tissue is sialographic
removed; the appearance)
procedure is
completed with a 2- to
3-layered closure
(continued on next page)
 Salivary Gland Biopsy for Sjögren’s Syndrome 27

Table 2
(continued)

Technique Advantages Complications

Sublingual salivary gland
Pennec Incision between the first 1. Collection of sufficient 1. Uncomfortable scars
et al,27 1990 premolar and the amount of tissue 2. Bleeding
Adam lateral cutting tooth 3. Swelling in the floor of
et al,28 1992 the mouth
Berquin 4. Risk of ligaturing
et al,12 2006 Wharton duct
5. Not established
histopathologic criteria
Data from Refs.5–13,24,27,28,43

behind the earlobe (Fig. 7). The capsule of the pa- (including fat tissue), regardless of the pres-
rotid gland and subcutaneous tissue is closed with ence of benign LELs
4-0 Vicryl (Johnson & Johnson Inc, Belgium) su- 2. Small lymphocytic infiltrates, not fulfilling the
tures, whereas the skin is closed with 5-0 Ethilon criterion of a focus score of 1 or more, in com-
sutures (Johnson & Johnson Inc, Belgium). In this bination with the presence of benign LELs
way, the aesthetic results are excellent and future
scar is invisible to the eye from an anterior/lateral
point of view.
Complications
Pijpe and coworkers1 established a new set of Despite the potential risk of facial nerve damage
validated histopathologic criteria for diagnosing and the development of sialoceles and salivary
SS according to the AECG’s classification criteria fistulae, a temporary change in sensation in the
based on the biopsy of the parotid gland (see skin area of the incision is the only well-
Table 1). A parotid biopsy was considered positive documented complication described to date.1,7
if one of the 2 following criteria was fulfilled:
Suitability for Diagnostic and Treatment
1. A focus score of 1 or more (defined as the num-
Evaluation Purposes
ber of lymphocytic foci, which are adjacent to
normal-appearing acini and contain >50 lym- Parotid biopsies allow the clinician to monitor the
phocytes) per 4 mm2 of glandular parotid tissue disease progression and to assess the effect of

Fig. 4. Harvesting labial salivary glands. (A) Horizontal incision of approximately 1.5 cm. (B) Harvest of 6 to 8 mi-
nor salivary glands. (C) Closure of the wound with 5-0 Vicryl (Johnson & Johnson Inc, Belgium) rapide (resorbable)
inverted, buried notch sutures.
28 Delli et al

be compared with other diagnostic results derived

from the same gland (eg, secretory function,
sialographic appearance, and ultrasound).25 Addi-
tionally, by performing parotid biopsies as a
routine diagnostic procedure for SS, LELs and
lymphomas located in the parotid gland can
identified.7,26

SUBLINGUAL SALIVARY GLAND BIOPSY

The sublingual salivary gland is the smallest of
the major salivary glands. It lies in the floor of
the mouth on both sides of the tongue and is
covered only by oral mucosa. There are a few re-
ports about taking a biopsy of the sublingual
salivary gland for the diagnosis of SS.12,27,28
The technique is performed with a 1-cm linear
Fig. 5. The facial nerve enters the parotid gland form- mucosal incision in the floor of the mouth, 1 cm
ing a characteristic branching pattern that resembles
anterolaterally from the Wharton duct to 1 cm
a goosefoot and is known as the pes anserinus, giving
anteroposteriorly.12,27,28
2 main divisions of the facial nerve. The parotid gland
is divided into a superficial and deep lobe based on
the course of the facial nerve as it passes through. In Complications
the area of the incisional biopsy of the parotid gland,
the distance between the gland surface and the facial The postoperative complications of sublingual
nerve is approximately 1.5 cm. salivary gland biopsy are the following12,27:
an intervention treatment in SS. This is feasible 1. Ligaturing the Wharton duct, resulting from the
because parotid tissue can be harvested easily, placement of sutures
repeated biopsies from the same parotid gland 2. Bleeding
are possible, and the histopathologic results can 3. Swelling in the floor of the mouth

Fig. 6. Incisional biopsy of the parotid gland. (A) The area is anesthetized with local infiltration anesthesia. (B)
With a No. 15 blade, a small 1- to 2-cm incision is made just below and behind the earlobe near the posterior
angle of the mandible. (C) The skin is incised, and the parotid capsule is exposed by blunt dissection. The capsule
of the gland is carefully opened, and a small amount of superficial parotid tissue is removed. (D) The procedure is
completed with a 2- to 3-layered closure with 4-0 absorbable sutures (polyglycolic acid), and the skin layer is
closed with 5-0 nylon sutures.
 Salivary Gland Biopsy for Sjögren’s Syndrome 29

Table 3
Sensitivity and specificity of biopsy techniques

Sensitivity Specificity
Technique (%) (%)
Labial gland biopsy 60–82 91–94
Parotid gland biopsy 78 86
Sublingual gland 66 52
biopsy
Data from Pijpe J, Kalk WW, van der Wal JE, et al. Parotid
gland biopsy compared with labial biopsy in the diag-
nosis of patients with primary Sjögren’s syndrome. Rheu-
matology 2007;46:335–41; and Pennec YL, Leroy JP,
Jouquan J, et al. Comparison of labial and sublingual sali-
vary gland biopsies in the diagnosis of Sjögren’s syn-
drome. Ann Rheum Dis 1990;49:37–9.

Incisional biopsy of the parotid gland can over-

come most of the disadvantages of the labial bi-
opsy (see Table 2). When evaluating the parotid
Fig. 7. The technique of the biopsy of the parotid and the labial biopsy, sensitivity and specificity
gland was slightly modified by the present authors are comparable (see Table 3), estimated to be
with an incision below and slightly behind the earlobe 78% and 86%, respectively.1 Parotid gland tissue
(blue line). can be harvested easily; repeated biopsies from
the same parotid gland are possible (an important
asset in studies assessing the efficacy of a treat-
COMPARISON OF TECHNIQUES ment in patients with SS or monitoring disease
progression); the histopathologic results can be
Although focal lymphocytic sialadenitis in the labial compared with other diagnostic results derived
salivary gland is a widely accepted criterion for his- from the same gland (secretory function, sialo-
tologic confirmation of SS, biopsies of the labial graphic appearance, ultrasound). In contrast to
salivary glands may have several disadvantages labial salivary glands, LELs are often observed in
(Table 2). The sensitivity and specificity of labial the parotid gland tissue of patients with SS. These
salivary gland biopsies vary in the literature. Data LELs, a characteristic histologic feature of the ma-
from different studies are often difficult to compare jor salivary glands in SS,33 develop as a result of
because different sets of criteria for diagnosing SS hyperplasia of ductal basal cells within a lympho-
have been used and the outcome of the labial bi- cytic infiltrate. In addition, well-formed lymphoid
opsy is a strong determinant for the final diagnosis. follicles or germinal centers, often adjacent to
In a normal population, the labial biopsy resulted in ductal epithelium, can be found in the major sali-
a 6% to 9% false-positive diagnoses; 18% to 40% vary glands.34 Because both LELs and reactive
of the patients with a clinical diagnosis of SS have lymphoid follicles also indicate malignant lym-
a negative labial biopsy, resulting in a sensitivity of phoma, benign LELs must be discriminated from
60% to 82% and a specificity of 91% to 94% premalignant lesions using strict criteria.35,36
(Table 3).14,29–33 According to the ACR’s classifi- Four percent to 7% of patients with SS develop
cation criteria, the labial biopsy has a sensitivity malignant B cell lymphoma,37,38 48% to 75% of
of 89.8% (95% confidence interval [CI] 87.2– which are of the MALT type. These B-cell lym-
92.0) but a lower specificity of 74.3% (95% CI phomas are most frequently located in the parotid
71.0–77.5).19 Moreover, it may be difficult to har- gland.39–41 The assessment of patients with SS
vest a sufficient number of labial salivary glands who may have developed a MALT lymphoma is
in atrophic submucosa of patients with longstand- not always easy, but an incisional biopsy of the pa-
ing SS.30 In addition, permanent sensory loss of rotid gland can be safely performed under local
the mucosa of the lower lip, occurring in 1% to anesthesia4 and can help toward this diagnosis.
10% of the patients, is a known complication of Pollard and coworkers26 have established an algo-
a labial biopsy7,14,15 Pijpe and coworkers1 report rithm for the management of MALT-type lym-
sensory loss in 6% of patients after labial biopsy, phoma of parotid gland and associated SS
whereas no permanent sensory loss was observed (MALT-SS), showing the importance of a parotid
after a parotid biopsy. gland biopsy for controlling the disease (Fig. 8).
30 Delli et al

DIAGNOSIS

A B C
SS diagnostic
Patient with SS Patient with parotid gland
work-up (Vitali)
suspected for lymphoma swelling
1. Ocular symptoms
Persistent parotid gland FNA/ incision biopsy
2. Oral symptoms
swelling parotid gland/ superficial
3. Salivary gland tests
Low C4, M-protein, parotidectomy
4. Full examination by
cryoglobulins Lymphoma
rheumatologist/ internist
Vasculitis
5. Serology, autoantibodies
6. Histopathology: based on
parotid gland biopsy

MALT-SS

Staging of MALT lymphoma

Imaging: MRI/CT-head/neck
Debatable: CT-thorax/abdomen, bone marrow

L (localized) LD (locally disseminated) DD (disseminated disease)

Only salivary gland(s) Regional lymph nodes Distant lymph nodes or
bone marrow

Determine SS-activity
Complete physical exam, laboratory tests (blood count, IgM-Rf,
immunoglobulins, complement C3/C4, cryoglobulines and M-protein

TREATMENT

SS with major disease activity SS with minor disease activity

Severe extraglandular disease* No severe extraglandular disease

MALT lymphoma MALT lymphoma MALT lymphoma

All stages Asymptomatic; all stages Symptomatic

R-CP x 6-8** No lymphoma treatment, L: Low dose involved field

only symptomatic treatment radiotherapy, 2x2 Gy
SS (NSAID, low-dose
prednisone, LD/DD: R-CP x 6-8**
hydroxychloroquine 200-400
mg /day)

Fig. 8. Management of MALT-type lymphoma of parotid gland associated with SS (MALT-SS). *Severe extra-
glandular disease: polyarthritis/myositis, glomerulonephritis, nervous system involvement, cryoglobulinemic
vasculitis, other severe organ involvement, serologic abnormalities: cryoglobulinemia, C4 less than 0.10 g/L.
**Six intravenous infusions of 375 mg/m2 of rituximab and 6 to 8 cycles of cyclophosphamide, given every
3 weeks. FNA, fine-needle aspiration; IgM, immunoglobulin M; NSAID, nonsteroidal antiinflammatory drugs;
R-CP, rituximab with cyclophosphamide and prednisone. (Adapted from Pollard RP, Pijpe J, Bootsma H, et al.
Treatment of mucosa-associated lymphoid tissue lymphoma in Sjogren’s syndrome: a retrospective clinical study.
J Rheumatol 2011;38:2205; with permission.)
 Salivary Gland Biopsy for Sjögren’s Syndrome 31

Additionally, in pediatric patients with clinical REFERENCES

suspicion of SS and a negative minor salivary
gland biopsy result, a parotid gland biopsy could 1. Pijpe J, Kalk WW, van der Wal JE, et al. Parotid
be safe and effective in order to establish histo- gland biopsy compared with labial biopsy in the
pathologic evidence for the diagnosis of SS.42 diagnosis of patients with primary Sjögren’s syn-
Finally, it is noteworthy that the pain following drome. Rheumatology 2007;46:335–41.
labial and parotid biopsies is comparable in 2. Geerling G, Raus P. Minor salivary gland transplan-
severity and disappears within 1 month.1 tation. Dev Ophthalmol 2008;41:243–54.
Notwithstanding these aforementioned advan- 3. Meskin LH, Bernard B, Warwick WJ. Biopsy of the
tages, biopsies of the parotid gland have not labial mucous salivary glands in cystic fibrosis.
become commonplace because of the concern JAMA 1964;188:82–3.
for damage to the facial nerve and the develop- 4. Alsaad K, Lee TC, McCartan B. An anatomical study
ment of sialoceles and salivary fistulae (see of the cutaneous branches of the mental nerve. Int J
Table 2). In addition, parotid gland biopsies are Oral Maxillofac Surg 2003;32:325–33.
not part of the established criteria for diagnosing 5. Chisholm DM, Mason DK. Labial salivary gland bi-
SS and demand higher surgical expertise. They opsy in Sjögren’s disease. J Clin Pathol 1968;21:
are validated for the AECG’s classification criteria 656–60.
but not yet for the ACR’s classification criteria. 6. Greenspan JS, Daniels TE, Talal N, et al. The histo-
A comparison of sublingual gland biopsy with pathology of Sjögren’s syndrome in labial salivary
labial gland biopsy has shown that the sensitivity gland biopsies. Oral Surg Oral Med Oral Pathol
of sublingual gland biopsy is better than that of 1974;37:217–29.
the labial gland biopsy, whereas the specificity of 7. Marx RE, Hartman KS, Rethman KV. A prospective
the latter is better than that of the former (see study comparing incisional labial to incisional pa-
Table 3).27 As far as the postoperative complica- rotid biopsies in the detection and confirmation of
tions are concerned, researchers claim that sublin- sarcoidosis, Sjögren’s disease, sialosis and lym-
gual gland biopsy is a relatively safe procedure phoma. J Rheumatol 1988;15:621–9.
(see Table 2). Because placing a suture might in- 8. Delgado WA, Mosqueda A. A highly sensitive
crease the risk of ligaturing the Wharton duct and method for diagnosis of secondary amyloidosis by
lead to swelling of the floor of the mouth, no su- labial salivary gland biopsy. J Oral Pathol Med
ture28 or careful placement of 1 to 2 sutures could 1989;18:310–4.
be an alternative.29 Damage to the mental nerve is 9. Guevara-Gutierrez E, Tlacuilo-Parra A, Minjares-
obviously not feasible because of the operation Padilla LM. Minor salivary gland punch biopsy for
site, whereas damage to the lingual nerve related evaluation of Sjögren’s syndrome. J Clin Rheumatol
to this biopsy technique has never been reported 2001;7:401–2.
in the literature. An advanced risk of bleeding is 10. Mahlsted K, Ussmüller J, Donath K. Value of minor
encountered in cases when a more posterior inci- salivary gland biopsy in diagnosing Sjögren’s syn-
sion is made, which, however, resolves spontane- drome. J Otolaryngol 2002;31:299–303.
ously.12 To date, specialized histopathologic 11. Gorson KC, Ropper AH. Positive salivary gland
criteria have not been established for the diag- biopsy, Sjögren syndrome, and neuropathy: clinical
nosis of SS after a sublingual gland biopsy, and re- implications. Muscle Nerve 2003;28:553–60.
searchers merely used the criteria for labial gland 12. Berquin K, Mahy P, Weynand B, et al. Accessory or
biopsies.12,27,29 sublingual salivary gland biopsy to assess systemic
disease: a comparative retrospective study. Eur
Arch Otorhinolaryngol 2006;263:233–6.
SUMMARY 13. Caporali R, Bonacci E, Epis O, et al. Comment on:
Early diagnosis and treatment are of high impor- parotid gland biopsy compared with labial biopsy
tance for preventing the complications associated in the diagnosis of patients with primary Sjögren’s
with SS. Unfortunately, so far there is not a single syndrome [author reply]. Rheumatology 2007;46:
test capable of confirming the diagnosis of SS. A 1625.
positive salivary gland biopsy provides strong evi- 14. Daniels TE. Labial salivary gland biopsy in Sjögren’s
dence, which, in correlation with additional diag- syndrome. Assessment as a diagnostic criterion in
nostic tests, can establish the classification of 362 suspected cases. Arthritis Rheum 1984;27:
SS. Parotid gland biopsy is a relatively simple 147–56.
technique, has the potential to overcome most of 15. Richards A, Mutlu S, Scully C, et al. Complications
the disadvantages of the labial biopsy, and can associated with labial salivary gland biopsy in the
additionally aid in monitoring disease progression investigation of connective tissue disorders. Ann
and the effect of an intervention treatment in SS. Rheum Dis 1992;51:996–7.
32 Delli et al

16. Friedman H, Kilmar V, Galletta VP, et al. Lip biopsy in syndrome. Scand J Rheumatol Suppl 1986;61:
connective tissue diseases. A review and study of 52–5.
seventy cases. Oral Surg Oral Med Oral Pathol 30. Vitali C, Tavoni A, Simi U, et al. Parotid sialography
1979;47:256–62. and minor salivary gland biopsy in the diagnosis of
17. Teppo H, Revonta M. A follow-up study of minimally Sjögren’s syndrome. A comparative study of 84 pa-
invasive lip biopsy in the diagnosis of Sjögren’s syn- tients. J Rheumatol 1988;15:262–7.
drome. Clin Rheumatol 2007;26:1099–103. 31. De Wilde PC, Kater L, Baak JP, et al. A new and
18. Vitali C, Bombardieri S, Jonsson R, et al, European highly sensitive immunohistologic diagnostic crite-
Study Group on Classification Criteria for Sjögren’s rion for Sjögren’s syndrome. Arthritis Rheum 1989;
Syndrome. Classification criteria for Sjögren’s syn- 32:1214–20.
drome: a revised version of the European criteria 32. Vitali C, Moutsopoulos HM, Bombardieri S. The
proposed by the American-European Consensus European Community Study Group on diagnostic
Group. Ann Rheum Dis 2002;61:554–8. criteria for Sjögren’s syndrome. Sensitivity and spec-
19. Shiboski SC, Shiboski CH, Criswell L, et al, Sjögren’s ificity of tests for ocular and oral involvement in Sjög-
International Collaborative Clinical Alliance (SICCA) ren’s syndrome. Ann Rheum Dis 1994;53:637–47.
Research Groups. American College of Rheuma- 33. Ihrler S, Zietz C, Sendelhofert A, et al. Lymphoepi-
tology classification criteria for Sjögren’s syndrome: thelial duct lesions in Sjögren-type sialadenitis.
a data-driven, expert consensus approach in the Virchows Arch 1999;434:315–23.
Sjögren’s International Collaborative Clinical Alli- 34. Jordan RC, Speight PM. Lymphoma in Sjögren’s
ance cohort. Arthritis Care Res (Hoboken) 2012; syndrome. From histopathology to molecular pathol-
64:475–87. ogy. Oral Surg Oral Med Oral Pathol Oral Radiol En-
20. Vissink A, Bootsma H, Kroese FG, et al. How to dod 1996;81:308–20.
assess treatment efficacy in Sjögren’s syndrome? 35. Quintana PG, Kapadia SB, Bahler DW, et al. Salivary
Curr Opin Rheumatol 2012;24:281–9. gland lymphoid infiltrates associated with lymphoe-
21. Van Mello NM, Pillemer SR, Tak PP, et al. B cell MALT pithelial lesions: a clinicopathologic, immunopheno-
lymphoma diagnosed by labial minor salivary gland typic, and genotypic study. Hum Pathol 1997;28:
biopsy in patients screened for Sjögren’s syndrome. 850–61.
Ann Rheum Dis 2005;64:471–3. 36. De Vita S, De Marchi G, Sacco S, et al. Preliminary
22. Theander E, Vasaitis L, Baecklund E, et al. classification of nonmalignant B cell proliferation
Lymphoid organisation in labial salivary gland bi- in Sjögren’s syndrome: perspectives on pathobi-
opsies is a possible predictor for the development ology and treatment based on an integrated
of malignant lymphoma in primary Sjögren’s syn- clinico-pathologic and molecular study approach.
drome. Ann Rheum Dis 2011;70:1363–8. Blood Cells Mol Dis 2001;27:757–66.
23. Witt RL. Salivary gland anatomy. In: Salivary gland dis- 37. Sutcliffe N, Inanc M, Speight P, et al. Predictors of
eases. Surgical and medical management. New York: lymphoma development in primary Sjögren’s syn-
Thieme Medical Publishers; 2005. p. 1–7. drome. Semin Arthritis Rheum 1998;28:80–7.
24. Kraaijenhagen HA. Letter: technique for parotid 38. Theander E, Henriksson G, Ljungberg O, et al. Lym-
biopsy. J Oral Surg 1975;33:328. phoma and other malignancies in primary Sjögren’s
25. Pijpe J, Meijer JM, Bootsma H, et al. Clinical and syndrome: a cohort study on cancer incidence and
histologic evidence of salivary gland restoration lymphoma predictors. Ann Rheum Dis 2006;65:
supports the efficacy of rituximab treatment in 796–803.
Sjögren’s syndrome. Arthritis Rheum 2009;60: 39. Kassan SS, Thomas TL, Moutsopoulos HM, et al.
3251–6. Increased risk of lymphoma in sicca syndrome.
26. Pollard RP, Pijpe J, Bootsma H, et al. Treatment of Ann Intern Med 1978;89:888–92.
mucosa-associated lymphoid tissue lymphoma in 40. Tzioufas AG, Boumba DS, Skopouli FN, et al.
Sjögren’s syndrome: a retrospective clinical study. Mixed monoclonal cryoglobulinemia and mono-
J Rheumatol 2011;38:2198–208. clonal rheumatoid factor cross-reactive idiotypes
27. Pennec YL, Leroy JP, Jouquan J, et al. Comparison as predictive factors for the development of lym-
of labial and sublingual salivary gland biopsies in phoma in primary Sjögren’s syndrome. Arthritis
the diagnosis of Sjögren’s syndrome. Ann Rheum Rheum 1996;39:767–72.
Dis 1990;49:37–9. 41. Voulgarelis M, Dafni UG, Isenberg DA, et al. Malig-
28. Adam P, Haroun A, Billet J, et al. Biopsy of the sali- nant lymphoma in primary Sjögren’s syndrome: a
vary glands. The importance and technic of biopsy multicenter, retrospective, clinical study by the
of the sublingual gland on its anterio-lateral side. European Concerted Action on Sjögren’s syndrome.
Rev Stomatol Chir Maxillofac 1992;93:337–40. Arthritis Rheum 1999;42:1765–72.
29. Lindahl G, Hedfors E. Focal lymphocytic infiltrates 42. Radfar L, Kleiner DE, Fox PC, et al. Prevalence and
of salivary glands are not confined to Sjögren’s clinical significance of lymphocytic foci in minor
 Salivary Gland Biopsy for Sjögren’s Syndrome 33

salivary glands of healthy volunteers. Arthritis syndrome. Arch Otolaryngol Head Neck Surg
Rheum 2002;47:520–4. 2002;128:1279–81.
43. McGuirt WF Jr, Whang C, Moreland W. The role of 44. Baurmash H. Parotid biopsy technique. J Oral
parotid biopsy in the diagnosis of pediatric Sjögren Maxillofac Surg 2005;63:1556–7.
Sa livary Gland Dy s f un c t ion and
X e ros t o m i a i n S j ögren’s
S y n d ro m e
Siri Beier Jensen, DDS, PhDa,*, Arjan Vissink, DMD, MD, PhDb

KEYWORDS
 Sjögren’s syndrome  Salivary gland dysfunction  Hyposalivation  Sialometry  Xerostomia
 Subjective assessment

KEY POINTS
 Unstimulated whole saliva sialometry is a major criterion for evaluation of salivary gland dysfunction
in Sjögren’s syndrome according to the American-European Consensus Group classification
criteria.
 Stimulated whole saliva sialometry and gland specific sialometry are of importance for diagnosing
patients with SS. Unstimulated and stimulated sialometry are essential in identifying patients who
may benefit from intervention therapy.
 Xerostomia should be assessed regularly by validated tools to evaluate impact on oral health-
related quality of life and monitor alleviation/treatment efficacy or disease progression.

INTRODUCTION the clinical presentation of dry mouth in SS, how to

assess salivary gland hypofunction and xerosto-
It is generally accepted that the secretions of the mia in SS, and the impact of salivary gland
salivary glands are of paramount importance for dysfunction on quality of life in patients with SS.
the maintenance of oral health. A reduced salivary
flow induces symptoms that include the subjective
SALIVARY GLAND PHYSIOLOGY
feeling of dry mouth (xerostomia), difficulty with
What is Saliva?
the swallowing of food, and an increased suscep-
tibility to dental caries and opportunistic infec- The mixed fluid in the mouth is called whole saliva
tions. These symptoms reflect the impact of or oral fluid. Whole saliva is for the greater part
reduced salivary flow on the maintenance of the composed of secretions from 3 pairs of major sali-
health of the oral tissues, because salivary vary glands (parotid, submandibular [SM], and
dysfunction negatively affects several main func- sublingual [SL]) and from numerous minor glands
tions of saliva, such as (1) protecting the mineral- (labial, buccal, lingual, palatal, retromolar). Each
ized tissues against wear and demineralization, type of gland secretes a fluid with a characteristic
(2) wetting the oral mucosa, thereby forestalling protein composition.1 In addition, whole saliva
oral desiccation and infection, and (3) promoting contains gingival crevicular fluid, microorganisms,
speech and the digestion of food. In this article, food debris, and shed mucosal cells. Saliva is a hy-
salivary gland dysfunction and xerostomia in Sjög- potonic fluid relative to plasma, and it is composed
oralmaxsurgery.theclinics.com

ren’s syndrome (SS) is discussed, with a focus on of more than 99% water and less than 1% of dry
the pathophysiology of salivary dysfunction in SS, matter, such as proteins and salts. The normal

a
Section of Oral Medicine, Clinical Oral Physiology, Oral Pathology and Anatomy, Department of Odontology,
Faculty of Health and Medical Sciences, University of Copenhagen, Nørre Allé 20, 2200 Copenhagen N,
Denmark; b Department of Oral and Maxillofacial Surgery, Universeity of Groningen and University Hospital
Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands
* Corresponding author.
E-mail address: [email protected]

Oral Maxillofacial Surg Clin N Am 26 (2014) 35–53

http://dx.doi.org/10.1016/j.coms.2013.09.003
1042-3699/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
36 Jensen & Vissink

daily production of whole saliva ranges between system, in particular during its transport in the stri-
0.5 and 1.5 L. ated ducts. Similar to the fluid secreted by most
At night and in resting state during daytime, the exocrine organs (eg, sweat and lacrimal glands),
SM and SL glands are the main contributors saliva formation involves 2 stages. The primary
to whole saliva (Table 1). Together with the fluid secreted by salivary acinar cells resembles
numerous minor salivary glands, they secrete plasma in ionic composition, which is rich in so-
most of the salivary mucins.2 The large salivary dium, chloride, and bicarbonate (see Fig. 1). As
mucins are responsible for the viscoelastic proper- this primary secretion passes through the ductal
ties of mucous saliva. These large glycoproteins system, sodium, chloride, and bicarbonate are
are the backbone of the lubricating layers that reabsorbed, whereas potassium is excreted, re-
cover all oral surfaces, acting as diffusion barriers sulting in a fluid hypotonic to plasma, although
impeding the entry of noxious agents, including rich in potassium. When saliva secretion rate is
acids, microorganisms, and viruses. This mucous increased, as a result of the combination of a
layer helps in reducing the friction between antag- maximum reabsorption capacity in the duct
onistic tooth surfaces. The low-molecular-weight epithelium and the shorter passage time in the
mucins have broad-spectrum bacteria-binding duct, the stimulated saliva secretion is less hypo-
properties and play an important role in the oral tonic than the resting saliva. This situation results
clearance of bacteria, yeasts, and viruses. Without in apparently increased sodium, chloride, and bi-
mucins, the oral mucosa and the dental surfaces carbonate concentrations and decreased potas-
become highly vulnerable to infection, inflamma- sium concentration.
tion, and mechanical wear.3 Stimulation of salivary secretions thus influ-
ences both the quantity of saliva and its ionic
Saliva Secretion: The Two-Step Model and protein composition. In addition, large differ-
ences exist between individuals, both in the vol-
Basically, saliva is formed in 2 steps. The secretory
ume and the protein composition of saliva.
end pieces (acini) produce primary saliva, which is
Altogether this situation makes it difficult, in partic-
isotonic, having an ionic composition similar to
ular for whole saliva, to define normal reference
that of plasma (Fig. 1). The primary fluid is then
values for salivary parameters with which to
modified in the ductal system by selective reab-
compare patient data.
sorption of sodium and chloride, and by a certain
secretion of potassium and bicarbonate, although
Salivary Secretion and Composition in SS
the duct is impermeable to water. Thus the secre-
tion rate and thereby the volume of final saliva are When discussing whole saliva, one should be
determined directly by the formation rate of pri- aware that saliva enters the mouth at several loca-
mary saliva by the acinar cells. tions, but the different glandular secretions are not
The ionic composition of saliva is strongly well mixed. For example, the contribution of pa-
dependent on the secretion rate. When the salivary rotid saliva to (un)stimulated whole saliva varies
secretion rate is low (eg, at rest), the mouth fluid is from site to site, ranging from being the major
rich in potassium and chloride and low in sodium contributor to whole saliva collected buccally
and bicarbonate. On stimulation of the flow rate, from the maxillary molars to being almost noncon-
sodium, chloride, and bicarbonate concentrations tributing to whole saliva collected in the incisor re-
increase, and potassium decreases (Fig. 2). This gion. This site-specific variation in composition of
situation can be explained by the ion exchange whole saliva seems to account for the site speci-
mechanism during saliva transport in the ductal ficity of smooth surface caries and supragingival

Table 1
Relative (%) contribution of different gland types to whole saliva under various conditions

Stimulated Stimulated
Salivary Unstimulated (Mechanical) (Acid)
Gland Sleep Whole Saliva Whole Saliva Whole Saliva
Parotid 0 21 58 45
SM 72 70 33 45
SL 14 2 2 2
Minor glands 14 7 7 8
Data from Refs.39–41
 Salivary Gland Dysfunction and Xerostomia 37

Fig. 1. Ionic and protein composition of tissue fluid, acinar secretion, and oral fluid. (From Bardow A, Pedersen AM,
Nauntofte B. Saliva. In: Miles TS, Nauntofte B, Svensson P, editors. Clinical oral physiology. 1st edition. Copenhagen
(Denmark): Quintessence; 2004. p. 25; with permission.)

calculus deposition. The wide variation in local

contribution of the various salivary glands to whole
saliva is also obvious when assessing mucosal
wetness, because the thickness of the salivary
layer on the oral mucosa is thinner in the labial
and anterior hard palatal region than on the buccal
mucosa and anterior tongue.4 This finding may
explain the site-specific differences in oral dryness
as reported by some patients.
In many studies, whole saliva is used, which has
potential value in estimating which treatment
might be effective in a particular patient with SS
or for the use of saliva as a diagnostic tool in
point-of-care diagnostics, because constituents
from nonsaliva sources to whole saliva might
be an asset in distinguishing patients with SS
from patients with a salivary gland dysfunction
mimicking SS. For understanding what is really
happening regarding the salivary component of
SS, analysis of glandular secretions, directly re-
flecting what is ongoing in a particular type of sali-
Fig. 2. Composition of saliva changes when salivary vary gland, is preferred. Thus, in the assessment of
flow rate increases. the secretory capacity of a patient, a first glance
38 Jensen & Vissink

measurement of the total secretions accumulating than patients with pSS. Also unstimulated parotid
in the mouth (oral fluid) seems to be the most and SM/SL flow rates are significantly lower in pa-
appropriate method, reflecting the overall capacity tients with SS compared with patients with non-SS
of all salivary glands. Collection of whole saliva is sicca and healthy controls. Moreover, with regard
the method most often used, because it is easy to salivary composition, differences exist between
to perform, taking only a few minutes, without patients with SS, patients with non-SS sicca, and
the need for a specialized collecting device. How- healthy controls to include higher mean sodium
ever, for analytical purposes, whole saliva is of and chloride concentrations and lower phosphate
limited value, because it detects neither dysfunc- concentrations in parotid and SM/SL saliva of pa-
tion of any of the separate salivary glands nor tients with SS (Table 3). Compared with healthy
gland specific sialochemical changes. Another controls, patients with non-SS sicca showed in-
argument against its use in understanding SS at creases in potassium and amylase concentration
a glandular level is that whole saliva does not and a decrease in sodium concentration, both in
necessarily represent the sum of individual gland parotid and SM/SL saliva.
secretions but may include contamination with
sputum, serum, food debris, and other nonsalivary Early manifestations
components. Nevertheless, only a reduced rate of In about a fifth of the patients with pSS, sialometry
secretion of unstimulated whole saliva is consid- showed normal flow rates, accompanied by
ered to be of diagnostic value in SS. considerably changed salivary composition,
Collection of selective glandular saliva may including increased sodium and chloride concen-
show preferential involvement of salivary glands, trations. This combination of normal flow rates
such as hyposalivation of the SM/SL salivary and changed salivary composition was not
glands, which often is observed in SS. In addition, observed in patients with non-SS sicca and
when compared with healthy individuals, sialo- healthy controls. About a fifth of the patients with
chemistry of the glandular saliva may show several pSS showed low stimulated flow rate from the
characteristic changes in electrolytes and proteins SM/SL glands accompanied by a (sub)normal
(enzymes) in SS, reflecting the effect of autoim- flow rate from the parotid glands. These profiles
mune attack on the secretory cells in individual are characteristic of early salivary manifestation
salivary glands. However, in clinical practice, SS of SS, because both occurred almost exclusively
needs to be differentiated from other salivary in the patients with SS and are related to short
gland diseases and conditions mimicking SS. duration (<1 year) of oral symptoms.5
When compared with healthy controls, salivary
flow rate of patients with primary SS (pSS), pa- Late manifestations
tients with secondary SS (sSS), and patients with Extremely low stimulated flow rate for exclusively
sicca complaints mimicking SS (non-SS sicca) is the SM/SL glands was found in about a tenth of
significantly lower (Table 2). Furthermore, patients the patients with SS, whereas extremely low flow
with sSS have on average higher parotid flow rates rates for all major salivary glands were found in a

Table 2
Salivary flow rate of SS-positive patients (groups A and B: pSS and sSS, respectively), SS-negative
patients (patients suspected of having SS at referral, but not fulfilling the criteria for SS diagnosis,
group C), and healthy controls (group D)

Group A Group B Group C Group D

(n 5 33) (n 5 25) (n 5 42) (n 5 36)
Unstimulated
Parotid flow rate (mL/min/gland) 0.02 (0.04)a 0.02 (0.04)a 0.04 (0.06) 0.05 (0.06)
SM/SL flow rate (mL/min/gland) 0.05 (0.09)a,b 0.02 (0.03)a,b 0.12 (0.13) 0.12 (0.12)
Stimulated
Parotid flow rate (mL/min/gland) 0.12 (0.13)a 0.24 (0.25)a 0.19 (0.15)a 0.52 (0.42)
SM/SL flow rate (mL/min/gland) 0.24 (0.28)a,b 0.26 (0.35)a 0.42 (0.28) 0.46 (0.24)

Values are mean (standard deviation).

a
Significant difference between patients and healthy controls. Statistical test used: analysis of variance.
b
Significant difference between SS-positive and SS-negative patients.
Adapted from Kalk WW, Vissink A, Spijkervet FK, et al. Sialometry and sialochemistry: diagnostic tools for Sjögren’s syn-
drome. Ann Rheum Dis 2001;60:1110–6; with permission.
 Salivary Gland Dysfunction and Xerostomia 39

Table 3
Composition of stimulated glandular saliva from SS-positive patients (groups A and B: pSS and sSS,
respectively), SS-negative patients (patients suspected of having SS at referral, but not fulfilling the
criteria for SS diagnosis, group C), and healthy controls (group D)

Parotid Glands (Mean of Two Sides) SM/SL Glands

Group A Group B Group C Group D Group A Group B Group C Group D
(n 5 33) (n 5 25) (n 5 42) (n 5 36) (n 5 33) (n 5 25) (n 5 42) (n 5 36)
Sodium 26 (23)a,b 23 (22)a 4 (4)b 14 (12) 20 (15)a,b 16 (11)a,b 6 (6)b 11 (6)
(mmol/L)
Potassium 23 (6) 23 (9) 30 (21)b 24 (6) 21 (21) 18 (7) 20 (6)b 17 (6)
(mmol/L)
Chloride 30 (14)b 37 (28)a,b 18 (6) 16 (12) 27 (15)b 34 (35)a,b 16 (5) 16 (6)
(mmol/L)
Calcium 1.3 (1.0) 1.0 (0.2) 1.3 (0.8) 0.8 (0.6) 1.9 (0.9) 1.9 (0.5) 2.2 (1.6) 1.7 (0.6)
(mmol/L)
Phosphate 4.5 (2.4) 4.2 (1.6) 5.8 (2.9) ND 2.3 (1.2)a 2.5 (1.2)a 3.9 (1.7) ND
(mmol/L)
Urea (mmol/L) 5.6 (2.0) 4.9 (2.4) 6.1 (2.5) 3.8 (1.2) 2.9 (1.8) 3.8 (2.3) 4.0 (1.9) 2.5 (0.6)
Total protein 1.2 (0.5)b 1.6 (1.3)b 1.2 (0.6)b 0.6 (0.6) 0.6 (0.3) 0.8 (0.5) 0.7 (0.4) 0.8 (0.6)
(g/L)
Total protein 0.1 (0.1) 0.3 (0.5) 0.2 (0.2) 0.3 (0.3) 0.2 (0.2) 0.3 (0.6) 0.3 (0.3) 0.4 (0.3)
(g/min)
Amylase 519 (344) 618 (474) 842 (486)b 590 (510) 117 (97) 162 (293) 138 (121) ND
(103 U/L)
Amylase 59 (65) 180 (295) 152 (142) 307 (264) 45 (60) 27 (60) 58 (70) ND
(103 U/min)

Data are expressed as mean (standard deviation) and are based on the number of patients with available information.
Abbreviation: ND, not determined.
a
Significant difference between SS-positive and SS-negative patients.
b
Significant difference between patients and healthy controls. Statistical test used: analysis of variance (multicompar-
ison according to Scheffé).
Adapted from Kalk WW, Vissink A, Spijkervet FK, et al. Sialometry and sialochemistry: diagnostic tools for Sjögren’s syn-
drome. Ann Rheum Dis 2001;60:1110–6; with permission.

quarter (pSS, 30%; sSS, 16%). Extremely low flow saliva can reveal sequential involvement of partic-
rates for all salivary glands were rarely observed in ular glands, reflecting the ongoing autoimmune
patients with non-SS sicca and not in healthy con- process in individual major salivary glands. By us-
trols. These profiles were related significantly to ing glandular saliva, patients with SS may
long duration (>2 years) of oral symptoms.5 frequently be diagnosed at an earlier stage, and
progression or effects of therapeutic intervention
What can saliva tell about the progression can be measured in a noninvasive way (Fig. 3).
of SS? This finding is also in agreement with studies
As mentioned earlier, sialometry and sialochemis- showing progressive destruction of salivary gland
try can be used as a diagnostic tool either by col- tissue in patients with longer disease duration.7
lecting whole saliva (the combined secretions of all Determination of glandular flow rates is not only
salivary glands) or by collecting glandular saliva important in the diagnostic workup of SS but it is,
(gland specific saliva). Although unstimulated possibly, a parameter for assessing the potential
whole saliva is a major criterion for evaluation of for intervention.7 Furthermore, patients with early
salivary gland dysfunction in SS, when SS de- SS have the highest sodium concentrations, which
velops, not all major salivary glands may yet man- are related to more severe disease manifesta-
ifest dysfunction, rendering whole saliva less tions.8 This finding argues for early diagnosis and
valuable as a diagnostic tool or as a parameter immediate treatment of patients with early-onset
for evaluating progression of the disease or thera- pSS, who often have residual salivary gland func-
peutic intervention than glandular saliva.6,7 In tion and high degrees of fatigue. An intervention
contrast to whole saliva, analysis of gland specific study with B-cell depletion in patients with SS
40 Jensen & Vissink

Fig. 3. Mean (standard error of the mean) salivary flow rates of patients with pSS (A), sSS (B), and healthy controls
at baseline and 3.6  2.3 (mean  standard deviation) years follow-up. UWS, unstimulated whole saliva. *P<.05
versus baseline, by Wilcoxon signed rank. (From Pijpe J, Kalk WW, Bootsma H, et al. Progression of salivary gland
dysfunction in patients with Sjögren’s syndrome. Ann Rheum Dis 2007;66:107–12; with permission.)

showed that only patients with sufficient residual with HLA-DR3/B8, the association with other sys-
gland function (ie, patients with early SS) re- temic and organ-specific autoantibodies, and the
sponded well to treatment.9 It seems that some re- histopathologic findings in the affected glands.
sidual salivary gland tissue is necessary for either As for the etiopathogenesis of SS, no definite
recovery or regeneration of secretory gland tissue answers are as yet available, comparable with
after intervention therapy. Therefore, gland spe- other autoimmune diseases. Various findings
cific sialometry is not only of paramount impor- have suggested that viruses may be involved, in
tance for diagnosing patients with early-onset SS particular the Epstein-Barr virus, the Coxsackie vi-
but also crucial in identifying patients who may rus, and retroviruses such as human T-lympho-
benefit highly from intervention therapy. tropic virus 1. However, these findings have not
been convincingly confirmed. Some virus infec-
PATHOPHYSIOLOGY OF SALIVARY GLAND tions, in particular hepatitis C virus and human im-
DYSFUNCTION AND XEROSTOMIA IN SS munodeficiency virus infection, can produce
symptoms and pathologic findings similar to that
SS is considered to be an autoimmune disorder. in SS. However, the presence of these latter infec-
Arguments for the autoimmune pathogenesis are tions is an exclusion criterion for SS. Besides these
the presence of characteristic autoantibodies, exogenous factors, various endogenous factors
the strong female preponderance, the association may be involved, in particular, hormonal factors,
 Salivary Gland Dysfunction and Xerostomia 41

apparent from the strong female preponderance CLINICAL PRESENTATION OF DRY MOUTH
and genetic factors. The extended haplotype
HLA-DR3/B8/DQ-2, in combination with the C4A Dry mouth is rarely an isolated symptom. Usually, it
null gene, is present in around 50% of patients is accompanied by other oral, as well as systemic,
with SS compared with 20% to 25% of controls. complaints. The oral symptoms primarily accrue
Thus, both exogenous and endogenous factors from chronic salivary gland hypofunction, which
could be involved in the cause of SS, but no single induces, over time, a decrease in the amount and
factor is apparent.10 composition of the oral fluids that bathe and
The pathologic findings in the affected glands protect the oral tissues and contribute to the
may give a clue to the pathogenetic pathways alimentary and masticatory functions of saliva. Pa-
involved in the development of the characteristic tients may complain of dryness that is present
inflammatory SS lesion. T cells (80%), particularly throughout their oral cavity or of dryness that it is
CD4-positive T cells, predominate in the infiltrates, localized to select areas of the mouth (eg, the
and recent data, as in other autoimmune diseases, lips, cheeks, tongue, palate, floor of the mouth,
suggest that CD4-positive Th-17 cells secreting and throat). They may also complain of difficulty
interleukin 17 are major effector cells in the with chewing, swallowing, and speaking. The gen-
glands.11 In addition, clusters of B cells, consti- eral complaint as well as the severity of oral dry-
tuting 10% to 20% of the infiltrate, as well as ness is not proportionally related to a decrease in
plasma cells are present. Like all cells that belong the flow rate of saliva.14 In about a quarter of the
to the mucosal immune system, the salivary patients complaining of moderate to severe oral
glands of healthy individuals contain mostly IgA- dryness, the mouth might even appear moist on
producing B cells and plasma cells. However, clinical inspection. However, salivary flow may
the B cells and plasma cells in the glands of pa- sometimes be directly associated with other oral
tients with SS produce predominantly IgG, with a complaints. For example, the complaints of oral
local production of autoantibodies. Depletion of dryness while eating, the need to sip liquids to
B lymphocytes using a CD20-specific monoclonal swallow food, or difficulties in swallowing have all
antibody (rituximab) resulted in improvement of been highly correlated with measurable decreases
salivary function in patients with recent-onset in the rate of flow of stimulated whole saliva. It is
pSS, as well as restoration, at least in part, of the the stimulated saliva that is directly related to
architecture of the ductal system in the parotid alimentation, mastication, and deglutition.
gland.9,12 This finding suggests that B cells play Dry mouth is also frequently associated with
a major pathogenic role in disease development. generalized desiccation. Patients should, there-
The precise mechanisms leading to glandular fore, be systematically queried about the pres-
destruction in SS have not been fully elucidated. ence of dryness in other body sites, especially
The pathogenetic pathways operative in the sali- the eyes, but also the throat, the nose, the skin,
vary glands could also be operative in other organs and the vaginal area. Most patients carry bottles
affected in SS, such as the lungs and kidneys, in of water or other fluids with them at all times to
which CD4-positive interstitial infiltrates may aid speaking and swallowing and for their overall
occur. Besides, small-vessel vasculitis can be pre- oral comfort. The mucosa may be sensitive to
sent in SS. This feature is clinically manifest as spicy or coarse foods. This sensitivity limits the
purpura in the skin, mononeuritis multiplex, and patient’s enjoyment of meals and may compro-
glomerulonephritis. Here, deposition of immune mise their nutrition. Other complaints that might
complexes consisting of mixed cryoglobulins is be relevant in diagnosing the symptoms underly-
considered a major pathogenic factor. ing the patients’ perception of oral dryness are
As mentioned earlier, SS is a lymphoproliferative dry, tickling coughs, recurrent swelling of the ma-
disease, in which B cells play a dominant role. Se- jor salivary glands, chronic fatigue, and painful
vere hypergammaglobulinemia and the presence joints.
of various autoantibodies are serologic hallmarks Most patients with advanced salivary gland
of the disease. Monoclonal components are hypofunction have obvious signs of mucosal dry-
frequently present, both as circulating monoclonal ness. The lips often appear cracked, peeling, and
antibodies in plasma and in the glandular tissues, atrophic. The buccal mucosa may appear pale
as shown by molecular analysis of B cells. In- and corrugated; the tongue may be smooth and
creased production of B-cell activation factor by, reddened, with loss of some of the dorsal
among others, T cells may underlie B-cell proli- papillae, or may have, as commonly seen in pa-
feration.13 This situation may lead to the develop- tients with SS, a fissured appearance (Fig. 4).
ment of B-cell lymphoma within the salivary glands There is often a marked increase in erosion and
as well as in other locations. dental caries, particularly recurrent lesions and
42 Jensen & Vissink

ASSESSMENT OF SALIVARY GLAND

HYPOFUNCTION AND XEROSTOMIA
Along with assessing salivary gland hypofunction
and xerostomia to establish an SS diagnosis, as-
sessing the level of salivary gland hypofunction is
also an asset in the treatment of xerostomia and
salivary gland hypofunction. This treatment should
be based on answers to the following:
 To determine the cause of the dry mouth. If
the cause can be determined, eliminate it.
This may abate the problem. It also may
diminish the symptoms that are consequen-
tially associated with it.
 To determine, if the cause cannot be as-
sessed or if treating the cause only partially
relieves the oral dryness, whether it is
Fig. 4. The tongue often has a fissured appearance in
possible to stimulate the flow of saliva. This
patients with SS.
strategy, per se, may readily diminish the
oral desiccation.
decay on root surfaces and even cusp tip involve-  To determine, if the saliva cannot be
ment (Fig. 5). The decay may be progressive, adequately stimulated, whether one can com-
even in the presence of vigilant oral hygiene. bat the arid feeling by coating the surfaces of
With diminished salivary output, there is a ten- the oral mucosa.
dency for greater accumulations of food debris  To determine what else can be done to pre-
in the interproximal regions, especially where serve and protect the teeth and the oral soft
recession has occurred. tissues and provide relief to the patient.
Candidiasis is frequent. It may appear as red,
erythematous patches on the oral mucosa (eg, The most important issue that can be learned from
beneath dentures) or it may appear as white, curd- this approach is that subjective and objective eval-
like mucocutaneous lesions on any surface uation of both the pattern of complaints and the
(thrush). Fungal lesions of the corners of the mouth level of residual flow is of utmost important in
(angular cheilitis) are more likely to occur in pa- both diagnosing the underlying cause of salivary
tients with dry mouth who wear dentures and gland dysfunction and selecting the most effective
have a posterior bite collapse. treatment option to prevent or reduce the causes
The patient should be examined for facial and consequences of the dysfunction.
asymmetry. Enlargement of the salivary glands
is frequently seen. The major salivary glands How to Measure Salivary Gland
should be palpated to detect masses (eg, Hypofunction?
mucosal-associated lymphoid tissue lymphomas,
non-Hodgkin lymphomas). The single, most constant feature of saliva is its
variability. Its volume, its composition, and its vis-
cosity fluctuate throughout the day. Its normal
values vary widely among individuals. The unsti-
mulated secretion is significantly influenced by
the time of day and year (circadian rhythms), by
previous stimulation, by the position of the body,
and by exposure to light and temperature. These
are important, controllable variables, which should
be standardized for each patient when conducting
sialometric tests. Uncontrollable variables that
affect flow include the gender, age, and weight
of the patient, the size of the salivary glands, the
patient’s physical and mental health, and their
intake of medications.15
Fig. 5. Carious destruction of teeth in patients with SS As discussed earlier, the criteria used for the
often starts at the cervical region of teeth. collection of saliva should be standardized for
 Salivary Gland Dysfunction and Xerostomia 43

every patient. Regardless of the test used, the reliable. In the draining method, saliva is allowed
most critical of these factors is the time of day to passively drain from the mouth into a collecting
that the saliva sample is obtained and the length vessel (see Fig. 6). The spitting technique is similar
of the collection procedure. It is best if the sample to the draining method, but the accumulated saliva
can be obtained from a patient after an overnight is periodically expectorated into a tube. The suc-
fast. This is a readily duplicable event. The next tion method involves the use of the standard, plas-
best and more comfortable time for both the pa- tic, dental saliva ejector, and the swab method is
tients and clinician to routinely collect saliva is in conducted by placing preweighed cotton rolls or
the morning, between 8 and 11 AM. The patient gauze sponges into the mouth, leaving them for
must refrain from eating, drinking, smoking, or a fixed period, and then reweighing them after
oral hygiene procedures for at least 90 minutes the test. The swab method is an effective way to
before the test session. Whatever the time set, estimate the degree of salivation in patients with
whether after a fast or in the morning or even in severe xerostomia. However, again, regardless of
the afternoon, the test should be performed as the method used, the conditions of the test should
constantly as possible for each patient every be the same for each patient each time that saliva
time. Furthermore, the more time is taken to is collected. The objective should be patient
collect a sample of saliva, the more reliable it is. standardization.15
The minimum time is 5 minutes, but recent studies
advocate 10 minutes for diagnostic and research Collection of Stimulated Whole Saliva
purposes.16 In the European Union–US criteria
for SS, a collection time of 15 minutes for unstimu- Whole saliva is generally stimulated by either
lated whole saliva is required; the cutoff value is mastication or taste (see Fig. 6). One method
less than 1.5 mL/15 min (Fig. 6).6 uses chewing to stimulate saliva; the other, citric
acid. Both methods are reliable. Flow rates using
citric acid are generally greater than those induced
Collection of Resting Whole Saliva
by wax. When applying the masticatory method,
The flow rate of resting whole saliva can be per- the patient is either given a piece of paraffin wax
formed by 4 techniques: the draining method, the (weight w1–2 g; melting point 42 C–44 C), a piece
spitting method, the suction method, and the of gum base, or a piece of Parafilm (ParafilmÒ M,
swab technique. All of them provide roughly Bemis Company, Inc, Neenah, Wisconsin, USA)
similar results; the swab technique is the least to chew for 5 minutes. The accumulated saliva is

Fig. 6. Collection of whole saliva. (A) Sialometry requires a balance with 2 digits precision, a clock or timer, and a
plastic cup. (B) The patient is seated comfortably in a chair and is instructed to keep the head tilted slightly for-
ward, the mouth slightly open, the eyes open, and to minimize orofacial movements and to avoid swallowing of
saliva during the collection process. The procedure should take place in a quiet room, where the patient can sit
alone. The resting whole saliva flow rate is measured over a 15-minute period, during which the patient allows
the saliva to accumulate in the floor of the mouth and then lets it drain into the preweighed plastic cup. The
stimulated whole saliva flow rate is measured over a 5-minute period, during which the patient chews a piece
of paraffin wax (neutral taste) with their own normal chewing frequency or stimulated by a 2% citric acid solu-
tion applied to the lateral borders of the tongue with a cotton applicator every 30 seconds, and spits the saliva
into a preweighed plastic cup with a regular interval of 1 minute. (C) After the saliva collection, the plastic cup is
weighed, including the collected saliva, and the weight of the plastic cup is subtracted, and divided by the collec-
tion time (ie, 15 minutes for the unstimulated and 5 minutes for the stimulated sialometry, respectively). Because
1 g is considered equivalent to 1 mL saliva, the flow rate is given in mL/min.17
Other documents randomly have
different content
 Yo vi sobre un tomillo
quexarse un paxarillo
viendo su nido amado,
de quien era caudillo,
de un labrador robado.
Vìle tan congojado
por tal atrevimiento
dar mil quexas al viento
para que al cielo santo
lleve su tierno llanto,
lleve su triste acento,
yà con triste harmonia
esforçando al intento
mil quexas repitia:
ya cansando callava:
y al nuevo sentimiento
ya sonòro volvia.
Ya circular volaba:
ya rastrero corria:
ya pues de rama en rama
al rùstico seguia,
i saltando en la grama,
parece que decia:
dame, rùstico fiero,
mi dulce compañìa!
Yoì qué respondia
el rùstico: No quiero.

507 The subjoined passage presents a specimen of the

affectation of the Estilo Culto:—

Los ciento, que dio passòs, bella dama,

los mil, que dio suspiros, tierno rio,
 siendo ella esquiva, mas que al Sol su rama,
i el, mas que el Sol, amante a su desvio:
yo cantarè, que amor mi pecho inflama,
i no de Marte el plomo, cuyo brio
en el vaciado bronce, resonante
vengança es ya de Jupiter tonante.

508 See the first volume of the History of Italian Poetry and
Eloquence, p. 50.

509 Villegas has thus translated one of Virgil’s idyls into

Spanish hexameters:—

Lycidas, Corydon, i Corydon el amante de Philis,

Pastor el uno de cabras, el otro de blancas ovejas,
ambos a dos tiernos, moços ambos, Arcades ambos,
viendo que los rayos del sol fatigaban el orbe,
i que bibrando fuego feroz la canicula ladra,
al puro christal, que cria la fuente sonóra,
llevados del son alegre de su blando susurro,
las plantas veloces mueven, los passos animan,
i al tronce de un verde enebro se sientan amigos, &c.

510 The following are intended for hexameters and

pentameters:—

Como el monte sigues a Diana, dixo Cytherea,

Dictyna hermosa, siendo la caça fea?
No me la desprecias Cyprida, responde Diana,
Tu tambien fuiste caça, la red lo diga.

511 It is an ode to Zephyr:—

 Dulce vecino de la verde selva,
huesped eterno del Abril florido,
vital aliento de la madre Venus,
Zephyro blando,
Si de mis ansias el amor supiste,
tù, que las quejas de mi voz llevaste,
oye, no temas, i a mi Nympha dile,
dile que muero.
Philis un tiempo mi dolor sabia,
Philis un tiempo mi dolor lloraba,
quisome un tiempo, mas agora temo,
temo sus iras; &c.

512 The stanzas, in which the arrival of Orpheus at the

Acheron is related, may serve as a specimen of Jauregui’s
talent for poetic description:—

Llega á Aqueronte, y en su orilla espera,

Las cuerdas requiriendo y consultando:
Vè la grosera barca, à la ribera
Opuesta conducir copioso bando:
Del instrumento, y de la voz esmera
De nuevo entonces el acento blando;
Gime la cuerda al rebatir del arco,
Y su gemido es remora del barco.
Resonò en la ribera tiempo escaso
El canto que humanar las piedras suele;
Quando atrás vuelve, y obedece el vaso
Mas á la voz, que al remo que le impele;
La conducida turba, al nuevo caso,
Se admira, se regala, se conduele,
Y las réprobas almas, con aliento,
Se juzgan revocadas del tormento.
 Orfeo, Cant. II.

513 The following is a sonnet of Jauregui addressed to the

rising sun:—

Rubio Planeta, cuya lumbre pura

del tiempo mide cada punto, i ora,
si el bello objeto, que mi pecho adora
solo le gozo entre la noche oscura;
Por què ya se adelanta, i se apresura
tu luz injusta, i el Oriente dora?
las sonbras alexando de la Aurora,
i con las sonbras mi feliz ventura?
Diràs que el dulce espacio defraudado
ya de la noche, me daràs el dia,
tal que de vida un punto no me devas.
Sì deves (causa del ausencia mia)
que es vida solo el tiempo que me llevas;
i el que me ofreces un mortal cuidado.

514 Jauregui’s translation of Lucan was published, together

with his Orfeo, under the title of Pharsalia de D. Juan de
Jauregui, por D. Ramon Fernandez, Madrid, 1789, in 2
vols. 8vo. The other poetic works of this author, including
his translation of the Amynta, are collected in the Rimas
de D. Juan de Jauregui, Sevilla, 1618, in quarto.

515 The name of this poet is of Italian origin. He was

descended from a branch of the Italian house of Borgia,
and married the heiress of the principality of Squillace in
Naples. Both names were, according to Spanish custom,
hispanized, first in the pronunciation, and subsequently in
the orthography.
516 I have seen only the second edition of the Obras in verso
de D. Francisco de Borja, Principe de Esquillache,
Amberes, 1654, 692 pages, quarto. Some of his poems
are contained in the Parnaso Español.

517 He thus addresses his poems:—

A manos de muchos vais,

Versos mios, sin defensa,
Y sujetos a la ofensa
De quien menos la esperais.
Y si en tal peligro estais,
Injustamente me animan
Los que piden que os impriman;
Pues quando luzir pretenden,
Si oscuros son, no se entienden,
Y si claros, no se estiman.
El que sabe, estimarà,
Si algun estudio teneis:
A mas gloria no aspireis;
Ni mas el tiempo os darà.
Quien defenderos podrà,
Serà quando mas, alguno;
Y si es Platon, basta èl uno.
Que en las frases y en los modos
Querer contentar a todos,
Es no agradar a ninguno.

518 He characterizes his own style as follows:—

Sigo un medio en la jornada,

Y de mis versos despido,
O palabras de ruido,
O llaneza demasiada;
 Y oscuridad afectada.
Es camino de atajar
No saberse declarar;
Ya quien se deve admitir,
Estudie para escrivir,
No escrive para estudiar.

519 For example, the following, which may be styled the

Disenchantment, (Desengaño.)

Dichosa soledad, mudo silencio,

Secretos passos de dormidas fuentes,
Que por el verde prado sus corrientes,
Jamas, si van ò vienen diferencio:
Vuestra quietud estimo, y reverencio
Con ojos, y deseos diferentes;
Pues ya, ni el ciego aplauso de las gentes
Con ambiciosa pluma diligencio.
Desde la luz, que viste la mañana,
Los passos cuento al trabajado dia,
Hasta que pisa el Sol la espuma cana.
De quanto fue mi engaño, y compañia,
De quanto amè, con ignorancia vana,
En vuestra soledad perdì la mia.

520 Even the commencement of this poem, except in so far as

regards the diction, encourages no favourable
expectation:—

Canto a Jacob, y de su Esposa canto

La peregrina angelica hermosura:
Siete años de fineza, amor y llanto,
Sin premio, sin verdad, y sin ventura:
 El engañoso Suegro, que entretanto
Con fingida esperanza le assegura,
Y al burlado pastor, que le servia,
Promesas de Raquel cumple con Lia.
Tu, Musa celestial, que en las estrellas
Segura pones invisibles plantas,
Y en dulce paz de sus legiones bellas,
Sobre las altas fuentes te lebantas:
Si es tuyo el mando, si obedecen ellas
De essas puras esquadras sacrosantas,
Presto descienda de su rayo ardiente
Fuego, que el pecho y su temor aliente.

521 Part of one of these poems may be transcribed here:—

Llamavan los pajarillos

Con dulces voces al Sol,
Que por aver quien le llama,
Mal dormido recordò.
Escuchava entre las aves
De un arroyuelo la voz,
Que agradecido a su lumbre,
La bien venida le diò.
Entre las ramas de un olmo
Le acompaña un ruiseñor,
Enamorado testigo
De quantas vezes saliò.
Yo sola triste al son
De todos lloro soledad, y amor.
En el valle de mi aldea
Zelosa aguardando estoy,
Que salga un Sol a mis ojos,
Que en otros braços dormiò.
Montes dezidle, que siento
 De los males el mayor,
Si como al padra del dia
Le veis primero que yo; &c.

522 It is only necessary to refer to Velasquez and Dieze.

523 It is not now necessary to refer to the old and desultory

collections of the works of Count Rebolledo. They may be
found collected altogether under their respective titles in
the edition of the Obras Poeticas de Conde Bernardino de
Rebolledo, Madrid, 1778, in 4 vols. octavo. In this
collection the interesting letter in prose, (Part I. in the
Ocios p. 261), in which Rebolledo gives a detailed account
of his residence in Copenhagen, is deserving of particular
attention.

524 The three following afford fair specimens of his talent in

this species of composition:—

I.

Dichoso quien te mira

y mas dichoso quien por tì suspira,
y en extremo dichoso,
quien un suspiro te debió amoroso.

II.

Lisi, yo te vì en sueños tan piadosa,

como despierta el alma le desea,
pero menos hermosa.
Quién habrá que tal crea?
dos imposibles me fingió la idéa,
 y con ser su ilusion tan engañosa
la temo misteriosa,
y que inmortal en mì el tormento sea,
si no has de ser piadosa hasta ser fea.

III.

Lisis, este diamante

de mi firmeza simbolo brillante
en que quiso incluir naturaleza
un rayo de la luz de tu belleza,
bien constante, y helado,
a nuestros corazones retratado,
mas puede la experiencia persuadirme,
que es el tuyo mas duro, el mio mas firme.

525 See vol. 2. of the Obras.

526 For example:—

Los Estados, de aquel vinculo libres,

eligieron concordes a Christiano,
hijo de Teodorico
de Oldemburg y Delmenhorste Conde
(progenio del famoso Witekindo,
sucesor de los Reyes de Saxonia,
con titulo de Duque)
casó con Dorotéa,
viuda de Christoval,
y coronóse luego en Copenhaguen.
En tanto los Suecos eligieron
a Carlos, y tuvieron
los dos dudosa guerra;
 pero siendo vencido y desterrado,
y Christiano en Suecia coronado,
llevó a Dania el tesoro de aquel Reyno:
a que añadió la herencia
de Sleswic y de Holsacia,
por la muerte de Adolfo,
su director y tio.
Selvas Danicas 1. cap. ii.

527 The commencement, for instance:—

La selva mas pomposa,

que a su deidad consagra Dinamarca,
tiene por centro un christalino lago,
que de un ameno isleo,
que visten flores y coronan plantas,
es fragrante y lucida competencia,
es hundosa tambien circumferencia:
y él a las bellas Ninfas,
de la deidad al culto dedicadas,
apacible teatro,
donde lazos y redes
suelen tender en las estivas calmas,
a los peces, las fieras y las almas.
Aqui yo fatigado
de un infinito número de penas,
de procelosas iras agitado,
del destino arrastrando las cadenas,
cierto de sus injurias,
y del progreso de mi vida incierto,
no esperado tomé traquilo puerto;
y entre sus verdes y floridas greñas
de la deidad reverencié las señas.
528 For example:—

Hasta el cordon vestido de ladrillo

de tierra solo el parapeto aprueba,
a quantos en su fábrica molestan
pagan con lo que duran lo que cuestan:
la linea de defensa
al tiro de mosquete no aventage,
ni excedan de noventa,
ni tengan menos de sesenta grados
los ángulos franqueados;
capaces los traveses,
y las golas no estrechas,
entre sí guarden proporciones tales,
que por perfecionar algunas cosas
no queden las demás defectuosas.
Selva militar y polit. Distincion,
(that is to say, Section,) vi. § 2.

529 For example:—

La antigüedad llamó advertidamiente

los consejeros ojos,
son del cuerpo politico y humano
adalides forzosos,
que han de haber visto mucho,
verlo de lejos y de cerca todo,
y recibir especies diferentes,
y por los nervios opticos
comunicarlas al comun sentido,
representando fieles los obgetos,
sin ocultar virtudes ni defetos;
el Reyno que no admite compañia
anda a ciegas sin ellos,
 la prudencia Real está librada
en saber escogellos,
y a cuidadoso examen obligada.
1. c. Distincion xxiii. § 2.

530 The Duke of Veragua’s letter, together with Calderon’s

answer, and the catalogue to which the correspondence
bears reference, are printed in La Huerta’s Teatro
Hespañol, vol. iii. part ii.

531 Satisfactory accounts of the various collections and

editions of the dramas, and other less important works of
Calderon, are contained in Dieze’s Remarks on Velasquez,
p. 242 and p. 341. The dramas of Calderon, which La
Huerta has published in his Teatro Hespañol, afford but a
partial idea of the poet’s talent; for those he has selected
are all Comedias de Capa y Espada, two only excepted;
and of these two, one, which is styled a Comedia heroyca,
belongs to the mythological class.

532 See the definition of the various classes of the Spanish

comedy, p. 364, 5, 6, 7.

533 According to the testimony of travellers, even the most

unlettered Spaniard is so accustomed to follow without
effort a complicated dramatic plot, that after witnessing
the representation of a piece, he will describe all the
minute details of the romantic story, while a well informed
foreigner, familiar with the Spanish language, can with
difficulty comprehend a few of the scenes.

534 A very superficial criticism on Calderon’s dramatic works,

written by Blas Nasarre, who was prepossessed in favour
of French literature, is contained in the History of Spanish
Poetry, by Velasquez. See Dieze’s edition, p. 341.
535

Ines. Qué ayrosa te has levantado?

Esta vez sola, señora,
no hiciera falta la aurora,
quando en su cristal nevado
dormida hubiera quedado;
pues tu luz correr pudiera
la cortina lisonjera
al sol, siendo sumillér
de uno y otro rosiclér,
deydad de una y otra esfera.
Bien el concepto Hespañol
dixera, viendote ahora....

D. Ana. Qué?

Ines. Que en tus ojos, señora,

madrugaba el claro sol:
dixera, al ver tu arreból
quien à tu rigor se ofrece,
quien sus desdenas padece,
Don Luis....
Bien vengas Mal si vengas Solo. Jorn. i.

536 For example, in a tender conversation which occurs in the

comedy, entitled, “A House with two Doors is ill to Watch.”

Lisardo. Dificilmente pudiera

conseguir, señora, el Sol,
que la flor de girasol
su resplandor seguiera.
Dificilmente quisiera
el Norte, fixa luz clara,
 que el Imán no le mirára;
y el Imán deficilmente
intentára, que obediente
el acero le dexára.
Si Sol es vuestro explendor,
girasol la dicha mia:
si Norte vuestra porfia,
piedra Imán es mi dolor:
si es Imán vuestro rigor,
acero mi ardor severo;
pues cómo quedarme espero;
quando veo, que se ván,
mi Sol, mi Norte, y mi Imán,
siendo flor, piedra y acero?
Casa con dos Puertas, mala
es de Guardar. Jorn. i.

The lady replies to this compliment in a similar strain.

537 In the Casa con dos Puertas, &c. the valet thus jokes with
the lady’s maid, who is on the stage with her mistress, but
both veiled:—

Calabazas. Mui malditísimas caras

debeis de tener las dos.

Silvia. Mucho mejores, que vos.

Calabaz. Y està bien encarecido;

porque yo soy un Cupido.

Silvia. Cupido somos yo y tú.

Calabaz. Cómo?
 Silvia. Yo el pido, y tù el cu.

Calabaz. No me estâ bien el partido.

538 An incident of this occurs in the first scene of the piece,

entitled, Dar Tiempo al Tiempo, (Give Time to Time).

Voz. Agua va!

Chacon. Mientas, picaña;

que esto no es agua.

D. Juan. Que ha sido?

Chacon. Que ha de ser, pese oi mi alma;

cosas de Madrid precisas,
que antes fueron necessarias.
Vive Christo....

D. Juan. No des voces.

Chacon. Cómo no! Puerca, berganta,

si eres hombre, sal aqui.

D. Juan. No el barrio alborotes: calla.

Chacon. Calle un limpio.

Dar Tiempo al Tiempo. Jorn. i.

539 These stories are sometimes related in the most elegant

octaves; for example, in the play, entitled, Con quien
Vengo, Vengo, (I Come with whom I Come), there is one
which commences in the following way:—
 Yo vì en Milan una mujer tan bella.
No digo bien mujer. Yo vì una Diosa,
en los cielos de Abril fragante estrella,
en los campos del sol luciente rosa
tan entendida, tan sagaz, que en ella,
como demas estaba, el ser hermosa,
que parece formó naturaleza
Tal fue, que habiendo, á mi desvelo dado
mas de alguna ocasion, y habiendo sido
agradecido iman de mi cuidado
y no ingrata prision de mi sentido:
habiendo pues á mi temor librado
necios favores, que borró el olbido,
con nueva voluntad, con nuevo empeño,
mudable me dexó por otro dueño.
Con quien Vengo, Vengo. Jorn. ii.

540 For example, in the play, entitled, Bien vengas Mal, si

vengas Solo, (Misfortune comes Well, if it comes Alone), a
lady resolutely refuses to betray a secret, which her lover
endeavours to extort from her.

D. Diego. Mujer eres: poco importa,

que descubras un secreto.
No aspires, Doña Ana, à ser
el prodigio de estos tiempos.

D. Ana. Quien fue prodigio de amor,

sabrá, serlo del silencio.

D. Diego. No quiere, la que à su amante

no descubre todo el pecho.

D. Ana. No es noble, quien le descubre,

 quando vá una vida en ello.

D. Diego. En fin no lo has de decir?

D. Ana. No.

D. Diego. Pues en nada te creo.

D. Ana. Valgate Dios por retrato,

en qué confusion me has puesto.
Bien vengas Mal, si vengas Solo. Jorn. i.

541 In Los Empeños de un Acaso, (the Consequences of an

Accident), a lover resolves, for his mistress’s sake, to
assist his rival in a case of difficulty:—

Qué noble, honrado y valiente,

viendo humilde á su enemigo,
no le ampara y favorece?
No solo pues la licencia
que me pide, le concede
mi valor; mas la palabra,
de ayudarle, y de valerle,
hasta que á su dama libre.
El caso, Don Diego, es este.
Mirad, como faltar puedo
á su amparo, quando tiene
privelegios de enemigo,
y de amigo en mì Don Felix?
Los Empeños de un Acaso. Jorn. iii.

542 Thus, a father points out the levity of another lady, as an

example for his daughter to avoid:—
 Ya ves, hija, lo que pasa,
á quien dá necios oidos
á pensamientos perdidos.
Mira fuera de su casa
una mujer, que ha venido
buscandonos por sagrado.
Mira un amante empeñado,
mira un hermano ofendido,
y mirala à ella en efecto
á riesgo, por un error,
de perder vida y honor.
Dar Tiempo al Tiempo. Jorn. i.

543 The piece, entitled, Tambien hay duelo en las Damas,

(Ladies also have their Troubles), terminates in the
following manner:—

Con cuyo raro suceso,

sacando la moraleja,
quede al mundo por exemplo,
que hubo una vez en el mundo
mujer, amor y secreto,
porque hubo duelo en las damas.
Perdonad sus muchos yerros.

544 For example, the double soliloquies, which run in concert,

and of which the following is a specimen:—

D. Diego. Habrá hombre mas infeliz!

D. Pedro. Habrá hombre mas desdichado!

 D. Diego. Qué no haya una ingrata hallado!

D. Pedro. Que no haya hallado à Beatriz!

D. Diego. Sin duda que la siguió,

el que su vida guardaba.

D. Pedro. Sin duda en la calla estaba,

él que á su rexa llamó.
Dar Tiempo al Tiempo. Jorn. ii.

545 The Spanish title which Calderon has given to this comedy,
is, Darlo todo, y no dar Nada, (To give all, and give
Nothing).

546 Called by Calderon, Las Armas de la Hermosura, (The

Arms of Beauty.)

547 The effect cannot be conceived without the necessary

connection; but the words spoken by the ghost of the
prince, when about to head the army, may be quoted
here:—

Alf. Pues a embestir Enrique, que no hay duda

que el cielo nos ayuda. F. Si os ayuda
Sale Don Fernando.
porque obligando al cielo,
que vió tu Fe, tu Religion, tu zelo,
oy tu causa defiende,
librarme a mi esclavitud pretende,
porque por raro exemplo
por tantos Templos, Dios me ofrece un Templo,
antorcha desafida del Oriente,
tu exercito arrogante
alumbrando he de ir siempre delante;
 para que oy en trofeos,
iguales, gran Alfonso, en tu deseos,
llegues a Fez, no a coronarte agora
sino a librar mi Ocaso en el Aurora.
Jornada iii.

548 Comparisons of heaven with the earth, and of water with

the earth, through the idea of a flower, were dwelt on
with a particular fondness by other Spanish poets of
Calderon’s age. The following is a conversation between
the Moorish Princess Phœnix, (Fenix was formerly a name
for women in Spain), and her female slaves in a garden on
the sea shore:—

Zar. Pues puedente divertir

tu tristeza estos jardines,
qual la primavera hermosa
labra en estatuas de rosa
sobre temples de jazmines,
hazle al már, un barco sea
dorado carro del Sol.

Ros. Y quando tanto arrebol

errar por sus ondas vea,
con grande melancolia
el jardin al már dirà:
ya el Sol en su centro està,
muy breve ha sido este dia.

Fen. Pues no me puedo alegrar,

formando sombras y lexos
la emulacion que en reflexos
tienen la tierra, y el már,
quando con grandezas sumas
compiten entre esplandores
 las espumas a las flores,
las flores a las espumas.

549 With all their faults these two sonnets are so beautiful and
so perfectly in Calderon’s style, that they may properly be
included in the collection of examples quoted here.—
Prince Fernando brings flowers to the Princess Phœnix.
After all sorts of handsome things have been uttered,
Fernando says:—

Estas que fueron pompa, y alegria,

despertando al Albor de la mañana,
a la tarde seràn lastima vana,
durmiendo en braços de la noche fria.
Este matiz, que al cielo desafia,
Iris listado de oro, nieve y grana,
serà escarmiento de la vida humana,
tanto se emprende en termino de un dia.
A florecer las rosas madrugaron,
y para envejecerse florecieron,
cuna, y sepulcro en un boton hallaron.
Tales los hombres sus fortunas vieron,
en un dia nacieron, y espiraron,
que passados los siglos horas fueron.

To this Phœnix replies in a strain somewhat over poetic

even for a Moorish Princess:—

Fen. Essos rasgos de luz, essas centellas,

que cobran con amagos superiores
alimentos del Sol en resplandores,
aquello viven que se duelen dellas.
Flores nocturnas son, aunque tan bellas,
 efimeras padecen sus ardores;
pues si un dia es el siglo de las flores,
una noche es la edad de las estrellas.
De essa pues Primavera fugitiva,
ya nuestro mal, ya nuestro bien se infiere,
registro es nuestro, ò muera el Sol, ò viva.
Que duracion avrá que el hombre espere,
ò que mudança avrá que no reciba
de Astro, que cada noche nace, y muere?
550

Fer. Valiente Moro, y galan,

si adoras como refieres,
si idolatras como dizes,
si amas como encareces,
si zelas como suspiras,
si como rezelas temes,
y si como sientes amas,
dichosamente padeces,
no quiero por tu rescate
más precio, de que le acetes.
Buelvete, y dile a tu dama,
que por su esclavo te ofrece
un Portugues Cavallero,
i si obligada pretendo
pagarme el precio por ti;
yo de doy lo que me deves,
cobra la deuda en amor,
y logra tus interesses.

551 The list is given in the appendix to his Theatro Hespañol,

under the title:—Catalogo Alphabetico de las Comedias
Tragedias, &c. Madrid, 1785.

552 The Alcazar del Secreto, and the Gitanilla de Madrid, and
several other pieces of merit, by Antonio de Solis, may be
found in La Huerta’s Theatro Hespañol. Accounts of the
editions of the dramas and other works of this ingenious
writer, are given by Dieze in his edition of Velasquez.

553 This piece is printed with several others by Moreto, in the

Theatro Hespañol.
554 It belongs to the class of comedias de figuron. (See p.
367.) La Huerta places this comedy at the commencement
of his Theatro Hespañol.

555 Blankenburg, in his literary appendix to Sulzer’s Dictionary,

expresses a doubt whether there ever was a particular
collection of the comedies of Maestro Tirso de Molina. I
can at least state that I have seen a fifth volume of his
comedies, (Madrid, 1636, in quarto), which contains
eleven dramas, chiefly historical and spiritual.

556 This is the only drama by Rojas given in La Huerta’s

Theatre; and in the older collections the works of Rojas
seldom appear.

557 Many of his dramas may be found in various collections.

They are included along with his other poems in the
Cithara de Apolo by D. Agust. de Salazar y Torres, Madrid,
1692, in two volumes, published by one of the author’s
friends, who on his part was a perfect Gongorist, as the
title of the collection sufficiently proves.

558 Nicolas Antonio, a very incompetent judge in matters of

taste, lauds Antonio de Mescua to the skies. But he is
seldom mentioned by other authors.

559 A historical comedy by Guillen de Castro, entitled, Las

Mocedades del Cid, furnished Corneille with the idea of his
tragedy of the Cid.

560 An elegant edition of the Historia de la Conquista de

Mexico, por D. Antonio de Solis, in 2 vols. quarto, was
published at Madrid in 1776.

561 The following are the historiographic rules of Antonio de

Solis, in his own words:—
 Los Adornos de la Eloquencia son accidentes en la
Historia, cuya substancia es la Verdad, que dicha como
fue, se dize bien: siendo la puntualidad de la noticia la
mejor elegancia de la Narracion. Con este conocimiento
he puesto en la certidumbre de lo que refiero, mi principal
cuydado. Examen, que algunas vezes me bolviò à la tarea
de los Libros, y Papeles: porque hallando en los Sucessos,
ò en sus circunstancias, discordantes, con notable
oposicion, à nuestros mismos Escritores, me ha sido
necessario buscar la Verdad con poca luz, ò congeturarla
de lo mas verisimil; pero digo entonces mi reparo: y si
llego á formar opinion, conozco la flaqueza de mi
dictamen, y dexo, lo que afirmo, al arbitrio de la razon.—
Prologo.

562 They are all collected under the title of Obras de Lorenzo
Gracian, &c. Amberes, 1725, in 2 vols. quarto.

563 Of this the following fragment of a conversation between

Fortune and a dissatisfied person, affords a specimen:—

Tampoco será el llamarte hijo de tu madre. Menos, antes

me glorio yo de esso, que ni yo sin ella, ni ella sin mi: ni
Venus sin Cupido, ni Cupido sin Venus. Ya se lo que es,
dixo la Fortuna. Que? Que sientes mucho el hazerte
heredero de tu abuelo el mar, en la inconstancia, y
engaños? No por cierto, que essas son niñerias; pues si
estas son burlas, que seràn las veras? Lo que à mi me
irrita, es, que me levanten testimonies. Aguarda, que ya
te entiendo, sin duda es aquello que dizen, que trocaste el
arco con la muerte, y que desde entonces no te llaman ya
amor de amar, sino de morir, amor á muerte; de modo,
que amor, y muerte todo es uno. Crisi iv.

564 He reduces all mental talents and faculties to two kinds,

Genio and Ingenio. But the distinctions he draws between
 them, are as difficult to translate as the different
applications of the French word Esprit. On this subject he
says, among other things:—

Estos dos son los dos Exes del lucimiento discreto, la

naturaleza los alterna, y el arte los realça. Es el hombre
aquel celebre Microcosmos, y el Alma su firmamento.
Hermanados el Genio, y el Ingenio, en verificacion de
Athlante, y de Alcides; asseguran el brillar, por lo dichoso,
y lo lucido, á todo el resto de prendas.

El uno sin el otro, fue en muchos felicidad à medias,

acusando la embidia, ò el descuido de la suerte.

El discreto, Opp. T. i. p. 389.

565 For example, in the treatise last quoted, he says:—

Ay hombres tan desiguales en las materias, tan diferentes

de si mismos en las ocasiones, que desmienten su propio
credito, y deslumbran nuestro concepto; en unos puntos
discurren, que buelan, en otros, ni perciben, ni se
mueven. Oy todo les sale bien, mañana todo mal, que aun
el entendimiento, y la ventura tienen desiguales. Donde
no ay disculpa, es en la voluntad, que es crimen del
alvedrio, y su variar no està lexos del desvariar. Lo que oy
ponen sobre su cabeça, mañana lo llevan entre pies, por
no tener pies, ni cabeça.

566 The Spanish title of this work is, Agudeza y Arte de

Ingenio.

567 Si el percibir la agudeza acredita de Aguila, el produzirla

empeñara en Angel: empleo de Cherubines y elevacion de
hombres, que nos remonta à extravagante Gerarquia.
568 Es este ser uno de aquellos, que son mas conocidos à
bulto y menos à precision: dexase percibir, no definir, y en
tan remoto assunto estimese qualquiera descripcion, lo
que es para los ojos la hermosura, y para los oidos la
consonancia, esso es para el entendimiento el concepto.

Agudeza y Arte de Ingenio. Discurso ii.

569 These letters are contained in the collection of Mayans y

Siscar.

570 The Real Academia Española, founded on the plan of the

Académie Française.

571 It is singular that over all Europe, the Portuguese phrase,

Auto da Fe, has become current in preference to the
Spanish Auto de Fe.

572 La Huerta includes this play among the four Comedias

Heroycas of his Theatro Hespañol, probably for the sake
of its elegant language; for in other respects it would not
have been difficult to have selected a better drama in the
class to which it belongs.

573 This comedy, which may be found in many collections, is

also included in La Huerta’s Theatro Hespañol.

574 This piece is also contained in the Theatro Hespañol.

575 For example, the word Madamisela from the French

Mademoiselle. In like manner Cervantes introduced the
word Madama, but it is employed only in a comic sense.

576 I have seen the third edition of the poetic writings of this
lady. The following is the title:—Poemas de la unica
poetisa Americana, Musa decima, Soror Juana Inez de la
Cruz, &c. Sacolas a luz D. Juan Camacho Gayna, Cavallero
 del orden de Santiago, &c. Barcelona 1691, in quarto.—It
certainly would not be fair to pass by unnoticed a book of
this kind which went through three editions.

577 The following is one of three sonnets, in which the

authoress rings changes on the theme, “whether it is
better to be beloved without loving, or to love without
being beloved.”

Feliciano me adora, y le aborrezco;

Lisardo me aborrece, y le adoro;
por quien no me apetece ingrato, lloro;
y al que me llora tierno, no apetezco:
A quien mas me desdora, el alma ofrezco,
à quien me ofrece victimas, desdoro;
desprecio al que enrriqueze mi decoro;
y al que le haze desprecios, enrriquezco:
Si con mi ofensa al uno reconvengo,
me reconviene el otro à mi ofendido
y à padecer de todos modos vengo;
Pues ambos atormentan mi sentido;
aqueste con pedir lo que no tengo,
y aqueste con no tener lo que le pido.

578 For example, the following, in which, however, the play of

the Antitheses becomes at last frigid.

En persiguirme, Mundo, que interessas?

en que te ofendo? quando solo intento
poner bellezas en mi entendimiento,
y no mi entendimiento en las bellezas?
Yo no estimo thesoros, ni riquezas;
y assi, siempre me causa mas contento,
poner riquezas en mi entendimiento;
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