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. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system or transmitted in any form or by any means without prior permission of the author. Lay-out & printing: Off page, www.offpage.nl 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