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VU Research Portal The evolving treatment of ankylosing spondylitis van Denderen, J.C. 2015 document version Publisher's PDF, also known as Version of record Link to publication in VU Research Portal citation for published version (APA) van Denderen, J. C. (2015). The evolving treatment of ankylosing spondylitis. General rights Copyright and moral rights for the publications made accessible in the public portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognise and abide by the legal requirements associated with these rights. • Users may download and print one copy of any publication from the public portal for the purpose of private study or research. • You may not further distribute the material or use it for any profit-making activity or commercial gain • You may freely distribute the URL identifying the publication in the public portal ? Take down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim. E-mail address: [email protected] Download date: 10. Oct. 2021 THE EVOLVING TREATMENT OF ANKYLOSING SPONDYLITIS VRIJE UNIVERSITEIT THE EVOLVING TREATMENT OF ANKYLOSING SPONDYLITIS ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. F.A. van der Duyn Schouten, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op woensdag 6 mei 2015 om 11.45 uur in de aula van de universiteit, De Boelelaan 1105 ISBN: 978-94-6259-628-3 Copyright © 2015 JC van Denderen Cover: Ellen van Diek Layout: Persoonlijkproefschrift.nl, Matthijs Ariëns Printing: Ispkamp Drukkers, Enschede door Printing of thesis was financially supported by: Pfizer BV, Janssen-Cilag BV, AbbVie Johannes Christiaan van Denderen BV, Mundipharma BV, UCB Pharma BV, Will-Pharma BV. geboren te Kampen All rights reserved. No part of this book may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, without permission of the author. promotor: prof.dr. J.W.J. Bijlsma CONTENTS copromotoren: dr. I.E. van der Horst-Bruinsma dr. M.T. Nurmohamed Chapter 1 Introduction: 1. General introduction. 8 2. History of the disease ankylosing spondylitis. 11 3. History of therapy in ankylosing spondylitis. 21 4. Objectives and outline of this thesis. 29 Chapter 2 Efficacy and safety of mesalazine (Salofalk®) in an open study 41 of 20 patients with ankylosing spondylitis. Chapter 3 Statin therapy might be beneficial for treating patients with 51 ankylosing spondylitis. Chapter 4 Double blind, randomised, placebo controlled study of 57 leflunomide in the treatment of active ankylosing spondylitis. Chapter 5 Decreased clinical response to infliximab in ankylosing 71 spondylitis is correlated with anti-infliximab formation. Chapter 6 Elevated liver enzymes in patients with ankylosing 81 spondylitis treated with etanercept. Chapter 7 What do we miss? ASAS non-responders on anti-TNF 95 therapy show improvement in performance-based physical function. Chapter 8 Adalimumab significantly reduces the recurrence rate of 107 anterior uveitis in patients with ankylosing spondylitis. Chapter 9 Etanercept increases bone mineral density in ankylosing 121 spondylitis, but does not prevent the increase of vertebral fractures. Chapter 10 1. General discussion and summary. 138 2. Nederlandse samenvatting. 162 3. Dankwoord. 168 4. Curriculum vitae. 169 5. List of publications. 170 6. List of abbreviations and illustrations. 173 CHAPTER 1 Introduction 1. General introduction. 2. History of the disease ankylosing spondylitis. 3. History of therapy in ankylosing spondylitis. 4. Objectives and outline of this thesis. Chapter 1 Introduction 1 GENERAL INTRODUCTION. limitation of mobility of the spine and thorax. After many years flattening of the lumbar lordosis and increase of the thoracic kyphosis can occur; which produce The subject of this thesis is the disease ankylosing spondylitis (AS) and particularly the characteristic curved and immobile posture. In addition, this posture becomes various aspects of drug therapy in AS. aggravated by flexion contractures in the hips in case of hip arthritis. Some AS AS is the prototype of a group of diseases, called spondyloarthritides, which have patients can not stand erect, nor see well straight forward (figure 1). The severity of 1 inflammation of the spine and sacroiliac joints as common features. Other diseases AS can range from mild disease and limited radiological changes to a severe disease belonging to spondyloarthritis (SpA) are psoriatic arthritis, reactive arthritis, arthritis with persisting disease activity and disability. Pain and structural damage can associated with inflammatory bowel disease and a subgroup of juvenile idiopathic cause limitation of mobility, functional impairment, reduction in well being and can arthritis. In the Netherlands AS is often called “ziekte van Bechterew”. lead to absence and disability at work [8]. Predictors of functional impairment are: 2 AS is characterised by a chronic sterile inflammation of joints and entheses worse initial features of the disease, older age, smoking, uveitis and peripheral joint (entheses are the sites of attachment of tendons, ligaments and joint capsules). disease, especially hip involvement [6, 9-12]. The inflammation in AS is localised primarily in the sacroiliac joints and spine, Patients with AS have an increased risk of mortality [10]. In a review the standardized 3 but peripheral joints can be involved as well. The peripheral arthritis is usually an mortality ratio was approximately 1.7 (range 1.5-1.9), which for the most part could asymmetric oligoarthritis of the lower extremities, including the hips. In contrast to be ascribed to cardiovascular diseases [13]. rheumatoid arthritis the inflammation does in a lesser degree lead to destruction (erosions) of bone, but can lead to local ossification. This hyperostosis can lead In AS extra-spinal and extra-articular manifestations are observed. AS is associated 4 to ankylosis and in some cases to the characteristic bamboo spine. This has given with skin disease (psoriasis), inflammatory bowel disease (ulcerative colitis and the disease its name: the Greek ankylos means stiff/curved and spondylos means Crohn’s disease) and preceding enteral or genitor-urinal infections (reactive vertebra/spine. arthritis). One third of the patients with AS experience attacks of inflammation of the eye (acute anterior uveitis) [14]. Problems of the heart (conduction disturbance 5 In mid-Europe AS affects 0.3-0.5 % of the population and the prevalence for SpA is and aortic root anomaly) and sometimes apical pulmonary fibrosis do occur. 1-2% [1]. The Human Leukocyte Antigen (HLA) B27 is the most important genetic The incidence of osteoporosis and vertebral fractures is increased, as well as the factor linked to the disease. In more than 90% of Caucasian AS patients HLA-B27 is incidence of cardiovascular disease [15-18]. 6 present. This explains the familial aggregation of AS and the higher prevalence of AS in the northern countries, where HLA-B27 is more prevalent [2]. Men are affected In the next paragraph, the historical context of the disease AS will be discussed, more often than women (ratio 2-3 to 1) [1, 3]. including the evolution towards the recognition as a separate disease. In the third The pathophysiology of the disease is not fully clarified. Probably, in subjects with paragraph of the introduction the therapy of AS in the past and present will be 7 genetic susceptibility, auto-inflammatory processes are triggered by environmental discussed. At the end of the introduction an outline of this thesis is given. factors (for example enteral or urogenital microbes and smoking), mechanical stress and/or HLA-B27 binding peptides [4-6]. 8 Laboratory investigation can show raised acute phase reactants (erythrocyte sedimentation rate (ESR) and C-reactive protein), but often does not [7]. Diagnostic for AS are radiological changes of the sacroiliac joints: sclerosis, erosions and ankylosis. Later in the disease process similar changes can be seen in the rest of the 9 spine at the corners of the spinal corpora, in the intervertebral and costovertebral joints. 10 In most cases the disease starts in young adults (<30 years), but is diagnosed several years later. General symptoms, like anaemia and tiredness, often occur. The inflammation causes pain and stiffness in the buttocks, the lower back and other parts of the spine. The complaints are worst in the late night and early morning and improve with moving and not with rest. Inflammation and ankylosis can cause 8 9 Chapter 1 Introduction 2 HISTORY OF THE DISEASE ANKYLOSING SPONDYLITIS. The evolution of ankylosing spondylitis (AS) towards a separate disease entity is described in this paragraph, based on old descriptions, pathophysiological findings in animal and human skeletons and new scientific developments like the 1 invention of X-rays and DNA-sequencing, that unravelled the HLA-B27 association. Classification criteria for AS were developed and later AS was embedded in the broader spectrum of axial spondyloarthritis (SpA). 2 Old literature and art Luke, one of the four evangelists, was a Greek physician who wrote around Anno Domini 75 in verse 13 of the Gospel ascribed to him: “Ende siet / daer was eene 3 vrouwe / die hadde eenen geest der kranckheyt achtien jaren / ende sy was krom / ende en konde niet wel op-sien” [19]. Caelius Aurelianus, a Roman physician in the fifth century, described a patient in Figure 1. Progression of ankylosing spondylitis in a patient with severe disease. By 1957, 10 “De Ischiadicis et Psoadicis”: The patient is seized by pain in the nates, moves years after the onset of disease, he has very limited extension of his spine as evidenced by the 4 loss of lordosis and exaggeration of thoracic kyphosis (spine is fusing in flexion). By 1967, he slowly, and can only bend or stand erect with difficulty [20].

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