DETERMINANTS OF DISEASE SEVERITY IN PRIMARY SJöGREN'S SYNDROME Anna Paulien ...

164 Pages·2014·7.43 MB·English

Determinants of Disease severity in
primary sjögren’s synDrome

anna paulien risselada
© A.P Risselada, 2014
The copyright of the articles that have been published or accepted for publication
has been transferred to the respective journals.
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Cover: based on painting ‘transverse line’, by Kandinsky
ISBN: 978-94-6182-475-2
Printing of this thesis was financially supported by Pfizer BV, Roche Nederland BV,
Dutch Arthritis Foundation
Determinants of Disease severity in
primary sjögren’s synDrome
Determinanten van ziekte-ernst
in primair sjögren’s synDroom
(met een samenvatting in het Nederlands)
proefsCHrift
ter verkrijging van de graad van doctor aan de Universtiteit Utrecht
op gezag van de rector magnificus, prof.dr. G.J. van der Zwaan,
ingevolge het besluit van het college voor promoties
in het openbaar te verdedigen
op dinsdag 11 november 2014 des middags te 12.45 uur
door
anna paulien risselada
geboren op 27 januari 1981 te Leeuwarden
Promotoren: Prof.dr. J.W.J. Bijlsma
Prof.dr. F.P.J.G. Lafeber
Copromotoren: Dr. A.A. Kruize
Dr. J.A.G van Roon
taBLe of Contents
Chapter 1 General introduction 7
Chapter 2 Relation of systemic autoantibodies to the number of
extraglandular manifestations in primary Sjögren's syndrome:
a retrospective analysis of 65 patients in the Netherlands 21
Chapter 3 Clinical applicability of the EULAR Sjögren’s Syndrome
disease activity index (ESSDAI) – a cumulative ESSDAI
score adds in describing disease severity 33
Chapter 4 Disease expression of primary Sjögren’s syndrome in women
with pre- versus postmenopausal onset of disease 41
Chapter 5 Clinical features distinguishing lymphoma development in
primary Sjögren’s syndrome – a retrospective cohort study 53
Chapter 6 Aggravating vasculitis in untreated non-Hodgkin lymphoma
associated with primary Sjögren’s syndrome 71
Chapter 7 The prognostic value of routinely performed minor
salivary gland assessments in primary Sjögren’s Syndrome 79
Chapter 8 The role of ectopic germinal centers in the immunopathology
of primary Sjögren’s syndrome: a systematic review 89
Chapter 9 Soluble IL-7 receptor as a novel marker for long-term
disease outcome in primary Sjögren’s syndrome 107
Chapter 10 Summary and general discussion 115
Chapter 11 Dutch summary / Nederlandse samenvatting 141
Chapter 12 Appendix 151
List of abbreviations 156
List of publications 159
Dankwoord 161
Curriculum vitae 163

1
generaL introDuCtion

sjögren’s synDrome
1
Named after the Swedish ophthalmologist Hendrik Sjögren, Sjögren’s syndrome is a
chronic systemic autoimmune disease primarily targeting exocrine glands. Salivary and
lacrimal glands are mostly affected, leading to symptoms of oral and ocular dryness G
e
n
(xerostomia and keratoconjunctivitis sicca). The disease can stand on its own, termed e
r
a
primary Sjögren’s syndrome, but can also be seen in adjunction to other connective l In
tissue diseases, like rheumatoid arthritis or systemic lupus erythematosus, and is than tr
o
named secondary Sjögren’s syndrome (Table 1) (1). d
u
c
Primary Sjögren’s syndrome (pSS) is the second most common systemic autoimmune t
Io
disease, only rheumatoid arthritis being more prevalent, and is estimated to affect n

0.9-6 per 1000 individuals. The disease has a high preponderance of women, with a
female: male ratio of 9: 1, and is diagnosed most often in the fourth and fifth decade
of life, although pediatric cases do also occur (2-6).
The inflammation of the exocrine glands contributes to the diminished glandular
function (and/or destruction), inducing symptoms of dryness. Frequently, not only
dryness of eyes and mouth are observed, but also of skin, airways, and vagina.
Extensive inflammation of parotid glands may cause parotid gland swelling, seen
as evident swelling of the cheeks before the ears resembling mumps. In addition
to dryness, patients commonly experience fatigue and musculoskeletal pains. The
inflammation in Sjögren’s syndrome, being a systemic autoimmune disease, may
extend beyond exocrine glands and thus involve other organ systems. Extraglandular
manifestations, like arthritis, myositis, skin lesions, renal involvement, lung disease and
blood cell abnormalities, are seen in a substantial number of patients. In addition, risk
of malignant lymphoma is increased, affecting 5-10% of patients during their disease
course (7). In most patients however, pSS disease expression is relatively stable over
time without major events occurring (8, 9).
Treatment of Sjögren’s syndrome is limited to symptomatic relieve of dryness
symptoms using topical therapies (salivary substitutes and artificial tears) (10).
Systemic therapies using Disease-Modifying Anti-Rheumatic Drugs (DMARD) such
as hydroxychloroquine and leflunomide have shown little effects on burdensome
symptoms like dryness, fatigue and musculoskeletal pains (8, 11, 12). For extraglandular
manifestations DMARDs and prednisone may be effective, however (10, 12). Of
biologics, TNF-α inhibition showed no efficacy, B-cell depleting therapy (Rituximab)
might be effective for extraglandular manifestations (12-14), and other biologics
targeting specific cells or cytokines are currently being tested in clinical trials.
The European League Against Rheumatism (EULAR) developed a Sjögren’s
Syndrome Disease Activity Index (ESSDAI), to enable universal and systematic
description of disease expression as an aid for therapeutic trials. The ESSDAI consists
of 12 organ domains with an assigned weight factor [n], namely constitutional [3],
lymphadenopathy [4], glandular [2], articular [2], cutaneous [3], pulmonary [5], renal [5],
9
muscular [6], peripheral nervous system [5], central nervous system [5], haematological
1
[2], and biological [1] domain. For each domain, the severity of the manifestation is
scored as absent (=0), low (=1), moderate (=2), or high (=3). These counts are then
multiplied by the assigned weight factor. Total disease activity scores can range
G
e between 0 and 123 points (Appendix A) (15).
n
e
r
a
l
In
tr Table 1: American-European Classification Criteria for Sjögren’s syndrome (2002) (1)
o
d
uc I. Ocular symptoms: a positive response to at least one of the following questions:
tIo 1. Have you had daily, persistent, troublesome dry eyes for more than 3 months?
n 2. Do you have a recurrent sensation of sand or gravel in the eyes?

3. Do you use tear substitutes more than 3 times a day?
II. Oral symptoms: a positive response to at least one of the following questions:
1. Have you had daily feeling of dry mouth for more than 3 months?
2. Have you had recurrently or persistently swollen salivary glands as an adult?
3. Do you frequently drink liquids to aid in swallowing dry food?
III. Ocular signs – that is, objective evidence of ocular involvement defined as a positive result for
at least one of the following two tests:
1. Schirmer’s I test, performed without anesthesia (≤5 mm in 5 minutes)
2. Rose Bengal score or other ocular dye score (≥4 according to van Bijsterveld’s scoring system)
IV. Histopathology: in minor salivary glands (obtained through normal-appearing mucosa) focal
lymphocytic sialoadenitis, evaluated by an expert pathologist, with a focus score ≥1, defined as
a number of lymphocytic foci (which are adjacent to normal-appearing mucous acini and contain
more than 50 lymphocytes) per 4 mm2 of glandular tissue
V. Salivary gland involvement: objective evidence of salivary gland involvement defined by a
positive result for at least one of the following diagnostic tests:
1. Unstimulated whole salivary flow (≤1.5 ml in 15 minutes)
2. Sialectasia on parotid sialography
3. Abnormal salivary scintigraphy
VI. Autoantibodies in serum: antibodies to SSA (Ro) or SSB (La), or both
For primary SS:
a. Presence of any 4 of the 6 items, as long as IV or VI is positive
b. Presence of any 3 of the 4 objective criteria items (III, IV, V, VI)
For secondary SS:
In patients with a potentially associated connective tissue disease, presence of item I or II plus
any 2 items from among items III, IV and V may be indicative of secondary SS
Exclusion criteria:
past head and neck radiation treatment, Hepatitis C infection, Acquired immunodeficiency
disease (AIDS)
pre-existing lymphoma, sarcoidosis, graft versus host disease, use of anticholinergic drugs (since
a time shorter than 4-fold the half-life of the drug).
patHogenesis of primary sjögren’s synDrome
In Sjögren’s syndrome, two major autoimmune phenomena are observed: [1] focal
peri-epithelial infiltration of the affected tissue by lymphocytes (predominantly CD4+
10