University of Groningen
Clinical and spinal radiographic outcome in axial spondyloarthritis
Maas, Fiona
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Maas, F. (2017). Clinical and spinal radiographic outcome in axial spondyloarthritis: Results from the GLAS cohort. Rijksuniversiteit Groningen.
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Clinical and spinal radiographic outcome
in axial spondyloarthritis
Results from the GLAS cohort
ISBN: 978-90-367-9645-3
ISBN: 978-90-367-9644-6 (e-book) Cover design Agnes Schuur
Layout Legatron Electronic Publishing, Rotterdam, The Netherlands Printed by Ipskamp Printing, Enschede, The Netherlands.
© Fiona Maas, Groningen, 2017.
All rights reserved. No part of this publication may be reproduced or transmitted in any form or by any means, without permission of the author.
The GLAS cohort was financially supported by unrestricted grants from Pfizer BV, Abbvie BV, and UCB Pharma BV.
The printing of this thesis was financially supported by the Graduate School of Medical Sciences of the University Medical Center Groningen, University of Groningen, Pfizer BV, Celgene BV, UCB Pharma BV, and Abbvie BV.
Clinical and spinal radiographic outcome
in axial spondyloarthritis
Results from the GLAS cohort
Proefschrift
ter verkrijging van de graad van doctor aan de
Rijksuniversiteit Groningen
op gezag van de
rector magnificus prof. dr. E. Sterken
en volgens besluit van het College voor Promoties.
De openbare verdediging zal plaatsvinden op
woensdag 8 maart 2017 om 14.30 uur
door
Fiona Maas
Promotor Prof. dr. H. Bootsma Copromotores Dr. A. Spoorenberg Dr. S. Arends Beoordelingscommissie
Prof. dr. D.M.F.M. van der Heijde Prof. dr. W.F. Lems
CONTENT
Chapter 1 General introduction 11
PART I Radiographic outcome of excessive bone formation in AS patients
treated with TNF-α inhibitors
Chapter 2 Spinal radiographic progression in patients with ankylosing spondylitis 27 treated with TNF-α blocking therapy: a prospective longitudinal
observational cohort study
Chapter 3 Reduction in spinal radiographic progression in ankylosing spondylitis 47 patients receiving prolonged treatment with TNF-α inhibitors
Chapter 4 Ankylosing spondylitis patients at risk of poor radiographic outcome 73 show diminishing spinal radiographic progression during long-term
treatment with TNF-α inhibitors
Chapter 5 Radiographic damage and progression of the cervical spine in 93 ankylosing spondylitis patients treated with TNF-α inhibitors:
facet joints vs. vertebral bodies
Chapter 6 Incorporating the cervical facet joints in the mSASSS is of additional 115 value in the evaluation of radiographic outcome in ankylosing spondylitis
Part II Radiographic outcome of excessive bone loss in AS patients
Chapter 7 Radiographic vertebral fractures develop in patients with ankylosing 137 spondylitis during 4 years of TNF-α blocking therapy
Chapter 8 Clinical risk factors for the presence and development of vertebral 157 fractures in patients with ankylosing spondylitis
Part III Influence of gender and BMI on disease outcome and the development of a physical activity questionnaire for axial SpA
Chapter 9 Male and female patients with axial spondyloarthritis experience 181 disease activity, physical function, and quality of life differently:
results from the GLAS cohort
Chapter 10 Obesity is common in axial spondyloarthritis and associated with 189 poor clinical outcome
Chapter 11 Disease-specific questionnaire to assess physical activity in patients 203 with axial spondyloarthritis: the axSpA-SQUASH
Chapter 12 Summary and General Discussion 251
Chapter 13 Nederlandse Samenvatting 277
Dankwoord 287
Curriculum Vitae 291
Chapter 1
EPIDEMIOLOGY
Spondyloarthritis (SpA) reflects a group of chronic inflammatory rheumatic diseases with common clinical, genetic, and immunological features [1,2]. Diseases within the SpA family can roughly be divided into axial SpA and peripheral SpA, depending on the predominant location of clinical manifestations (Figure 1) [3].
The overall prevalence of SpA worldwide ranges between 0.20-1.61% [4]. A strong association exists between the prevalence of SpA and the MHC class I molecule human leukocyte antigen (HLA) B27. In countries with a higher prevalence of HLA-B27, the prevalence of SpA is also higher [4,5].
Figure 1. Spectrum of diseases within the family of spondyloathritis. Adapted from Raychaudhuri et
al. [3].
Abbreviations: SpA: Spondyloarthritis; AS: Ankylosing spondylitis; PsA: Psoriatic arthritis; ReA: Reactive arthritis; IBD:
Inflammatory bowel disease.
In axial SpA, the axial skeleton is mainly involved, including the sacroiliac (SI) joints and spine. Axial SpA consists of ankylosing spondylitis (AS) and non-radiographic axial SpA. AS is the best known phenotype of axial SpA characterized by inflammation and radiographic damage of the SI joints and spine. Non-radiographic axial SpA is a phenotype in which radiographic damage of the SI joints is not (yet) present. It can reflect the stage prior to AS (Figure 2) [1].
1
Figure 2. Stages of axial spondyloarthritis. Adapted from Rudwaleit et al. [1].
Most patients with axial SpA experience their first complaints between 15 and 45 years of age. The disease develops gradually and the course is highly variable between patients. It can take up to 10 years from first symptoms to the development of radiographic damage of the SI joints and spine. Some patients never develop radiographic damage and will not progress to AS [6-8].
The overall prevalence of axial SpA worldwide is not exactly known. In a French study, a prevalence of 0.36% was found [9]. In the United States, the prevalence was estimated at 0.70% [10]. Prevalence rates for AS worldwide ranges between 0.02-1.4% [4,5,11]. AS is more prevalent in males than in females. In non-radiographic axial SpA, this gender difference is less pronounced [12-14].
Clinical manifestations
The hallmark features of axial SpA are sacroiliitis and spondylitis referring to inflammation of the SI joints and the spine, respectively. Inflammation can cause severe, chronic low back pain [11]. Symptoms of inflammatory back pain and/or buttock pain are accompanied by stiffness and reduced spinal mobility [15]. These symptoms become worse in rest, e.g. during the night, and improve with physical exercise. Many axial SpA patients also present accessory clinical manifestations in other areas of the body, such as enthesitis especially at the heel (Achilles tendon), peripheral arthritis, uveitis (inflammatory disorder of the eye), psoriasis (skin disease), and inflammatory bowel disease (e.g. Crohn’s disease and ulcerative colitis) (Figure 3) [11,16]. The presence of clinical manifestations can vary over time with episodes of increased pain and stiffness and episodes of quiet disease.
Figure 3. Example of extra-articular manifestations in axial SpA. A: Enthesitis of right Achilles tendon; B: Uveitis; C: Psoriasis; D: Inflammatory bowel disease (Crohn’s disease). Adapted from the Assessment of SpondyloArthritis international Society (ASAS) website [16].
Figure 4. Structural changes in the spine and scores according to the modified Stoke AS spine score (mSASSS). Reprinted from the Assessment of SpondyloArthritis international Society (ASAS) handbook [17].
1
Sacroiliitis and spondylitis can lead to structural changes and ossification of the SI joints and spine. The most characteristic structural changes are syndemophyte formation and calcification of the anterior and posterior ligaments of the spine (Figure 4) [17]. Syndesmophytes and calcification can lead to complete fusion or ankylosis of the total vertebral column in a fixed, mostly forward-stooped, position, named hyperkyphosis [11]. The process of excessive bone formation varies from person to person. On average, excessive bone formation is a slow process; patients develop approximately one syndesmophyte or two minor structural changes (e.g. sclerosis, erosions, or squaring of vertebral bodies) every 2 years [18,19].
In addition to excessive bone formation, axial SpA patients are at increased risk of bone loss. Osteoporosis and vertebral fractures can already be observed at a relatively young age [20,21]. Vertebral fractures can be complicated by increased back pain and add to the forward-stooped posture of axial SpA patients [22].
Diagnosis and classification
In daily clinical practice, the diagnosis of axial SpA is mainly based on the combination of clinical manifestations, imaging (sacroiliitis), findings of physical examination, levels of acute phase reactants (C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR)), HLA-B27 status, and family history of SpA [23].
The modified New York criteria can be used to classify patients with AS [24]. Patients with radiographic signs of definite sacroiliitis on plain radiographs of the pelvis and presence of ≥1 clinical criterion are classified as having AS (Table 1). Definite sacroiliitis is defined as sclerosis and/or erosions (grade 2) bilaterally or severe sclerosis/erosions with or without ankylosis (grade 3 or 4) unilaterally.
As the development of radiographic damage can take many years, or even not occur in some patients, the Assessment in SpondyloArthritis International Society (ASAS) developed new classification criteria for axial SpA [1]. These criteria are especially developed to classify patients with both early and advanced disease for clinical research. According to the ASAS criteria, patients with back pain for >3 months and age onset <45 years are classified as having axial SpA if they have signs of sacroiliitis on imaging (detected by radiography ór magnetic resonance imaging (MRI)) and ≥1 clinical feature, or if they are HLA-B27 positive and have
≥2 clinical features (Table 1). Based on the presence or absence of definite radiographic sacroiliitis on imaging, patients can be sub classified into AS or non-radiographic axial SpA, respectively (Figure 2). The ASAS criteria may contribute to the reduced delay between symptoms and diagnosis [1].
Table 1. Classification criteria for AS and axial SpA [1,24].
Modified New York criteria for classification of AS ASAS criteria for classification axial SpA
Patients with radiological criterion in combination with ≥1 clinical criterion:
– Low back pain and stiffness for >3 months that improves with exercise, but is not relieved by rest. – Limitation of motion of the lumbar spine in the
sagittal and frontal planes.
– Limitation of chest expansion relative to normal values corrected for age and sex.
Patients with back pain for >3 months, age onset <45 years, and:
– Sacroiliitis on imaging and ≥1 clinical feature or:
– HLA-B27 positive and ≥2 clinical features
Radiological criterion:
– Sacroiliitis grade >2 bilaterally or grade 3-4 unilaterally.
Clinical features: – Inflammatory back pain – Arthritis – Enthesitis (heel) – Uveitis – Dactylitis – Psoriasis – Crohn’s disease/colitis – Good response to NSAIDs – Family history for SpA – HLA-B27 positive – Elevated CRP levels Sacroiliitis on imaging:
– Active (acute) inflammation on MRI highly suggestive of sacroiliitis associated with SpA
– Definite radiographic sacroiliitis according to modified New York criteria
Abbreviations: AS: Ankylosing spondylitis; SpA: Spondyloarthritis; ASAS: Assessment in SpondyloArthritis International
Society; HLA-B27: Human leukocyte antigen-B27; NSAID: Non-steroidal anti-inflammatory drug; CRP: C-reactive protein; MRI: Magnetic resonance imaging.
1
Management
The ASAS/European League against Rheumatism (EULAR) working group has developed management recommendations for axial SpA [25]. The main treatment goals are reducing signs and symptoms, maintaining spinal function, preventing complications and structural damage, and thereby improving the health-related quality of life of axial SpA patients [25]. Treatment of axial SpA consists of a combination of non-pharmacological and pharmacological management. The non-pharmacological management includes adequate patient education, physical exercise or physical therapy, and rehabilitation to improve spinal function and posture. First-line pharmacological treatment comprises treatment with non-steroidal anti-inflammatory drugs (NSAIDs). In patients with peripheral arthritis, conventional disease modifying anti-rheumatic drugs (DMARDs), e.g. sulfasalazine, might be considered. These DMARDs do not improve axial complaints. In patients with persistently high disease activity despite of conventional, first-line treatment, biologicals can be prescribed. Tumor necrosis factor-alpha (TNF-α) inhibitors are currently the most prescribed biological treatment for axial SpA. TNF-α inhibitors inhibits the effect of the pro-inflammatory cytokine TNF-α, a cytokine that plays an important role in the initiation and maintenance of inflammation in axial SpA [26]. Very recently other cytokines such as IL-17 and the IL-12/23 pathway are found to play an important role in axial SpA, creating novel treatment options [27].
Disease outcome
In order to evaluate disease status and investigate the effect of treatment in daily clinical practice and in clinical studies, core sets of disease outcomes and measuring instruments have been proposed by the ASAS/Outcome Measures in Rheumatology Clinical Trials (OMERACT) working group [28]. Three core sets are developed, a core set for studies evaluating the effect of disease controlling anti-rheumatic therapy, for studies evaluating physical therapy and symptom modifying anti-rheumatic drugs, and for studies in daily clinical practice such as prospective cohort studies. Overall, the core sets include the following disease outcomes: physical function, pain, morning stiffness, fatigue, patient global assessment of disease activity, spinal mobility, inflammation of the peripheral joints and entheses, acute phase reactants, and structural damage [17,28]. Different instruments have been developed and validated to measure these disease outcomes (Table 2). Bone loss and physical activity are not incorporated in these core sets, although they are very relevant for both outcome and management of this disease.
Table 2. Core set of disease outcomes and measuring instruments for axial SpA studies as proposed by the ASAS/OMERACT working group [16,27].
Domain Measuring instruments
Physical function Bath AS Functional Index (BASFI)
Pain Numeric rating scale/Visual analogue scale (NRS/VAS) Pain questions in Bath AS Disease Activity Index (BASDAI)
Moring stiffness NRS/VAS
Stiffness question in BASDAI
Fatigue NRS/VAS
Fatigue question in BASDAI Patient global assessment of disease activity NRS/VAS
Spinal mobility Occiput-to-wall distance Chest expansion Lateral spinal flexion Modified Schober test Cervical rotation
Bath AS Mobility Index (BASMI)
Inflammation of peripheral joints and entheses Total number of swollen joints (44-joint count) Total number of tender enthesis according to validated enthesitis scores, e.g. 12-point Berlin Index, 17-point University of California San Francisco (UCSF) Index, 13-point Maastricht AS Enthesitis Score (MASES)
Acute phase reactants C-reactive protein (CRP)
Erythrocyte sedimentation rate (ESR) Structural damage Modified Stoke AS Spine Score (mSASSS)
Abbreviations: SpA: Spondyloarthritis; ASAS: Assessment in SpondyloArthritis International Society; OMERACT: Outcome
Measures in Rheumatology Clinical Trials.
GLAS cohort
Prospective cohort studies with standardized longitudinal assessments are very valuable in the field of axial SpA to evaluate the disease course and effects of treatment in daily clinical practice. In 2004, a prospective cohort study started in the daily clinical practice of axial SpA patients in the University Medical Center of Groningen (UMCG) and the Medical Center of Leeuwarden (MCL), named the ‘Groningen Leeuwarden Axial Spondyloarthritis’ (GLAS) cohort. The GLAS cohort is an ongoing, prospective, longitudinal observational cohort study with standardized assessment and management protocols. The initial aim was to carefully monitor and evaluate the course of the disease during treatment with TNF-α inhibitors.
1
Consecutive AS outpatients diagnosed with AS starting treatment with TNF-α inhibitors are included in the GLAS study. These patients fulfil the modified New York criteria for AS and the ASAS criteria to start treatment with TNF-α inhibitors, i.e. persisted active disease according to the Bath AS disease activity index (BASDAI ≥4) and/or according to the expert, despite of treatment with 2 different NSAIDs for 4 weeks [29].
Since the end of 2008, the inclusion of patients has been extended to all consecutive axial SpA outpatients who fulfil the ASAS criteria for axial SpA or the modified New York criteria for AS, irrespective of treatment regimen. The overall objective of the GLAS cohort is to combine up-to-date clinical care for axial SpA patients with clinical research to gain more knowledge about the long-term course of this disease.
Included patients are followed according to a fixed protocol. They are seen by specialized and trained rheumatologists, physician assistants, or rheumatology consultants every 6 to 12 months. If necessary, patients can visit the outpatient clinics more frequently. In line with the ASAS/OMERACT core set of domains and measuring instruments, standardized follow-up visits includes the assessments of physical function, pain, morning stiffness, fatigue, patient global, spinal mobility, inflammation of peripheral joints and entheses, and acute phase reactants. In addition, the health-related quality of life (ASQoL) and vitamin D levels are measured every visit and serum, plasma, urine, and DNA samples are collected and stored for biobanking. Every 2 years, radiographs of the spine and pelvis are taken to evaluate structural damage and bone loss expressed as vertebral fractures. In addition, bone mineral density (BMD) assessments are performed every 2 to 4 years.
The GLAS cohort is approved by the local ethics committees of MCL and UMCG and all participating patients have provided written informed consent according to the Declaration of Helsinki. With more than 600 patients included, the GLAS cohort provides very valuable, clinical data of a large group of axial SpA patients.
OUTLINE OF THIS THESIS
The primary focus of this thesis was on investigating the long-term course of excessive bone formation and bone loss during treatment in daily clinical practice and to explore the relationships with patient characteristics in axial SpA.
The first part (Part I) of this thesis focuses on spinal radiographic outcome of excessive bone formation in AS patients treated with TNF-α inhibitors. Results from previous studies investigating the effect of TNF-α inhibitors on spinal radiographic progression showed inconclusive results. Short-term studies could not find an effect of TNF-α inhibitors on spinal radiographic progression whereas long-term studies showed a possible relationship between the use of TNF-α inhibitors and less spinal radiographic progression [30]. Methodological issues and problems related to the overall slow and heterogeneous process of excessive bone formation should be taken into account. Therefore, the aim of the first part of this thesis was to investigate the long-term course of spinal radiographic progression and relationships with patient characteristics during treatment with TNF-α inhibitors.
In chapter 2, spinal radiographic progression was evaluated in AS patients who were treated with TNF-α inhibitors for up to 6 years (median follow-up duration was 3.8 years). Spinal radiographs were scored with unknown time sequence according to the mSASSS. Advanced statistical techniques (generalized estimating equations (GEE)) were used for longitudinal data analyses and to estimate mean progression rates. In chapter 3, a subsequent study was conducted in which a larger group of patients with longer follow-up was included. The aim of this study was to evaluate the course of spinal radiographic progression up to 8 years of follow-up in AS patients treated with TNF-α inhibitors. In contrast to the previous study, spinal radiographs were scored with known time sequence after randomization together with radiographs of AS patients not treated with TNF-α inhibitors from a historical cohort study. GEE with different longitudinal time models were used to explore whether spinal radiographic progression followed a linear or non-linear course over time. Chapter 4 presents a sub analysis of this study in which the influence of patient characteristics on spinal radiographic progression was explored. Chapter 5 describes radiographic damage and 4-year progression of cervical facet joints in AS patients treated with TNF-α inhibitors. Damage of cervical facet joints was scored according to the method of de Vlam et al. [31] and compared to damage of cervical vertebral bodies as scored according to the mSASSS. In addition, associations with patient characteristics and clinical outcome were investigated. Chapter 6 introduces a new scoring method in which the cervical facet joint scores were added to the mSASSS. This combined score, named CASSS, was compared to the mSASSS using three aspects of the OMERACT filter: feasibility, discrimination, and truth [32].
The second part (Part II) of this thesis focuses on spinal radiographic outcome of bone loss in AS patients. In daily clinical practice, vertebral fractures are frequently not recognized [33].
1
In addition, longitudinal data about the development of vertebral fractures are limited in AS. Therefore, the aim of the second part was to investigate the prevalence and incidence of radiographic vertebral fractures in relation to patient characteristics, disease outcome, medication use, and clinical symptoms.
Chapter 7 describes the prevalence and 4-year incidence of radiographic vertebral fractures and relationships with patient characteristics, clinical assessments, radiographic damage, and BMD in AS patients with active disease who were treated with TNF-α inhibitors. In Chapter 8, the prevalence and 2-year incidence of radiographic vertebral fractures and the relation to patient characteristics, clinical assessments, and medication use was investigated in the total GLAS cohort, including patients treated with TNF-α inhibitors or with conventional treatment. Additionally, this study describes whether radiographic vertebral fractures were symptomatic and received clinical attention.
The last part (Part III) of this thesis focuses on the influence of gender and body mass index (BMI) on disease outcome and on the development of a disease-specific physical activity questionnaire in axial SpA.
The aim of the cross-sectional study presented in chapter 9 was to investigate whether there were differences between male and female axial SpA patients in patient-reported outcome measures of disease activity, physical function, and quality of life. In chapter 10, the prevalence of overweight and obesity in axial SpA patients was investigated and compared to the general population. The association of BMI with disease activity, physical function, and quality of life was explored in axial SpA patients.
Physical exercise is very important in the management of axial SpA. However, a disease-specific instrument to assess physical activity is lacking. Therefore, the aim of the study described in chapter 11 was to develop a disease-specific questionnaire for the assessment of physical activity in axial SpA. This questionnaire was developed in collaboration with axial SpA patients and experts using a qualitative study design.
The last two chapters of this thesis, chapter 12 and chapter 13, provide a summary and general discussion on the findings of this thesis in English and Dutch, respectively.
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PART I
Radiographic outcome of
excessive bone formation in AS patients
treated with TNF-α inhibitors
Chapter 2
Spinal radiographic progression in patients
with ankylosing spondylitis treated with TNF-α
blocking therapy: a prospective longitudinal
observational cohort study
Fiona Maas Anneke Spoorenberg Elisabeth Brouwer Reinhard Bos Monique Efde Rizwana Chaudhry Nic Veeger Peter van Ooijen Rinze Wolf Hendrika Bootsma Eveline van der Veer Suzanne Arends
ABSTRACT
Objectives: To evaluate spinal radiographic damage over time and to explore the associations of radiographic progression with patient characteristics and clinical assessments including disease activity in ankylosing spondylitis (AS) patients treated with tumor necrosis factor-alpha (TNF-α) blocking therapy in daily clinical practice.
Methods: Consecutive outpatients from the Groningen Leeuwarden AS (GLAS) cohort were included based on the availability of cervical and lumbar radiographs before start of TNF-α blocking therapy and after 2, 4, and/or 6 years of follow-up. Clinical data were assessed at the same time points. Radiographs were scored by two independent readers using the modified Stoke AS Spine Score (mSASSS). Spinal radiographic progression in relation to clinical assessments was analyzed using generalized estimating equations.
Results: 176 AS patients were included, 58% had syndesmophytes at baseline. Median mSASSS increased significantly from 10.7 (IQR: 4.6-24.0) at baseline to 14.8 (IQR: 7.9-32.8) at 6 years. At the group level, spinal radiographic progression was linear with a mean progression rate of 1.3 mSASSS units per 2 years. Both spinal radiographic damage at baseline and radiographic progression were highly variable between AS patients. Male gender, older age, longer disease duration, higher BMI, longer smoking duration, high CRP, and high ASDAS were significantly associated with syndesmophytes at baseline. Significantly more radiographic progression was seen in patients with versus without syndesmophytes (2.0 vs. 0.5 mSASSS units per 2 years) and in patients >40 versus ≤40 years of age (1.8 vs. 0.7 mSASSS units per 2 years). No longitudinal associations between radiographic progression and clinical assessments were found.
Conclusions: This prospective longitudinal observational cohort study in daily clinical practice shows overall slow and linear spinal radiographic progression in AS patients treated with TNF-α blocking therapy. At the individual level, progression was highly variable. Patients with syndesmophytes at baseline showed a 4-fold higher radiographic progression rate than patients without syndesmophytes.
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INTRODUCTION
Ankylosing spondylitis (AS) is a chronic rheumatic inflammatory disorder which usually begins before the fourth decade of life. AS is characterized by inflammation in combination with new bone formation and bone loss. The disease mainly affects the axial skeleton and causes pain, stiffness, and impaired functioning of the spine. The disease course is found to be highly variable between AS patients. Excessive bone formation is an important disease outcome of AS. In the spine, this comprises the formation of syndesmophytes which may lead to complete fusion of the spine, resulting in a so-called ‘bamboo spine’. In most AS patients, it takes years from the first disease symptoms to manifestations of bone formation on radiographs [1]. Therefore, long-term follow-up is needed to investigate radiographic progression.
Tumor necrosis factor-alpha (TNF-α) blocking therapy leads to a clear improvement in disease activity, functional outcome measures, and quality of life in the majority of AS patients who do not respond to conventional treatment [1]. However, variable results have been reported regarding the effect of TNF-α blocking therapy on the development of spinal radiographic damage in AS. Multiple open-label extension studies did not show a significant difference in spinal radiographic progression after 2 years of TNF-α blocking therapy compared to TNF-α blocker naive AS patients from historical cohorts [2-5]. Two other open-label extension studies could not demonstrate an inhibition of spinal radiographic progression during 4 years of TNF-α blocking therapy [6,7]. However, in a retrospective study in only 22 AS patients, diminished radiographic progression was found after 4 to 8 years of TNF-α blocking therapy compared to AS patients from a historical cohort [8]. Furthermore, a large prospective longitudinal observational study with 1.5 to 9 years of follow-up reported that TNF-α blocker exposure (2.5 ± 2.8 years) was associated with less spinal radiographic progression [9].
These findings triggered the debate about the effect of TNF-α blocking therapy and the relationship between disease activity and spinal radiographic progression in AS. In previous cross-sectional and longitudinal studies in AS patients with a large variability in disease duration, disease activity, and treatment regimens, disease activity at baseline and over time were associated with spinal radiographic damage and progression [10-12]. Also, elevated inflammatory markers at baseline were found to be associated with the presence of syndesmophytes at baseline and with radiographic progression in AS patients and in
early axial spondyloarthritis (SpA) [10,11]. Very recently, a longitudinal association between the AS Disease Activity Score (ASDAS) and radiographic progression was observed during 12 years of follow-up in a large cohort of AS patients mainly treated with non-steroidal anti-inflammatory drugs (NSAIDs) [12].
The aim of this prospective longitudinal cohort study was to evaluate spinal radiographic damage over time and to explore the associations of radiographic progression with patient characteristics and clinical assessments including disease activity in AS patients treated with TNF-α blocking therapy in daily clinical practice.
METHODS
The present analysis was based on data from the Groningen Leeuwarden Ankylosing Spondylitis (GLAS) cohort. GLAS is an ongoing prospective longitudinal observational cohort study in the northern part of the Netherlands. Since November 2004, this cohort included consecutive AS outpatients who started TNF-α blocking therapy at the University Medical Center Groningen (UMCG) or the Medical Center Leeuwarden (MCL) because of active disease [13]. All patients were over 18 years of age, fulfilled the modified New York criteria for AS [14], and the ASAS criteria to start TNF-α blocking therapy (active disease defined as Bath AS Disease Activity Index (BASDAI) ≥4 and/or based on expert opinion) [15].
The choice of the TNF-α blocking agent (infliximab, etanercept, or adalimumab) was based on the judgment of the treating rheumatologist and/or the specific preference of the patient. As described previously, the standard regimen for infliximab was 5 mg/kg intravenously at 0, 2, 6 weeks and then every 8 weeks, for etanercept 50 mg (once) or 25 mg (twice) subcutaneous injection every week, and for adalimumab 40 mg subcutaneous injection every two weeks [16].
Patients were clinically evaluated at baseline, after 3 months, and then every 6 months according to a fixed protocol. Disease activity was measured at each follow-up visit and treatment continuation was based on BASDAI improvement (≥50% or two units compared with baseline) and/or expert opinion. Patients were allowed to switch between different TNF-α blocking agents and to receive concomitant medication as usual in daily clinical practice. Type, dose, and frequency of TNF-α blocking therapy were recorded at all follow-up
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visits. Temporary stop was registered and the total duration of exposure to TNF-α blocking therapy was expressed as the percentage of follow-up time.
Patients included in the analysis started with TNF-α blocking therapy between 2004 and October 2011 and had lateral radiographs of the cervical and lumbar spine available at baseline and after at least 1 follow-up visit at 2, 4 and/or 6 years.
The GLAS cohort was approved by the local ethics committees of the MCL and the UMCG. All patients provided written informed consent according to the Declaration of Helsinki.
Data collection
Baseline characteristics included: gender, age, symptom duration, time since diagnosis, HLA-B27 status, history of smoking (duration in years), and history of extra-articular manifestations. At baseline and at each follow-up visit, disease activity was assessed with BASDAI [18], ASDASCRP[19,20], physician’s and patient’s global assessment (GDA), C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). Since all patients had high disease activity at baseline and in order to analyze whether baseline disease activity status was associated with spinal radiographic progression, cut-off values for very high disease activity as defined in previous studies were used to stratify patients: BASDAI >6 [12], ASDAS >3.5 [21], physician’s and patient’s GDA >6 [21], CRP >10 mg/L, and ESR >20 mm/hr [11]. Furthermore, body weight and height were assessed to calculate body mass index (BMI), NSAID use was recorded, and ASAS-NSAID index was calculated [17].
Assessments of spinal radiographic damage
Lateral radiographs of the cervical and lumbar spine were independently scored by two trained readers (FM and RC). In order to blind readers for patient characteristics and time sequence, all identifying information including exam dates were removed from the radiographs. Radiographs were scored using the modified Stoke AS Spine Score (mSASSS). The anterior corners of lower C2 until upper Th1 and lower Th12 until upper S1 were scored for the presence of erosions, sclerosis, and/or squaring (1 point per vertebral site), non-bridging syndesmophytes (2 points per site), and non-bridging syndesmophytes (complete bridging of vertebrae; 3 points per site). The mSASSS was calculated as the sum of the scores of all individual sites (range 0-72). Patients with complete spinal ankylosis (mSASSS of 72) at baseline were excluded since no radiographic progression could occur in these patients. If ≤3 scores of vertebral sites were missing, the scores of these sites were substituted by the
mean score of the vertebrae of the corresponding spinal segment, as proposed by Wanders
et al. [22,23]. If >3 scores of vertebral sites were missing, the radiograph was excluded from the analysis. Radiographs were reassessed if the mSASSS total score of both readers differed by >5 units. When the discrepancy of >5 units persisted after reassessment, consensus was reached. The average mSASSS total score of both readers was used for the analysis.
Inter-observer reliability between readers for baseline mSASSS was very good, with an intraclass correlation coefficient (ICC; two-way mixed effects model, single measures, absolute agreement; before reassessment) of 0.987 (95% confidence interval (CI): 0.982-0.991). Inter-observer reliability for mSASSS change scores was moderate to good with ICC’s of 0.690 (95% CI: 0.596-0.765) for 0-2 year interval, 0.690 (95% CI: 0.545-0.794) for 2-4 year interval, and 0.400 (95% CI: 0.110-0.626) for 4-6 years interval. Bland-Altman plots revealed no systematic error. The mean difference in progression scores between the two readers was 0.1 (95% CI: -3.2-3.4) for all 2-years intervals (Supplementary Figure S1).
Presence of syndesmophytes at baseline was defined when both readers scored a non-bridging or non-bridging syndesmophyte (≥2 points) at one or more vertebral sites. Inter-observer reliability for presence of syndesmophytes was very good with Cohen’s kappa of 0.89 (95% CI 0.83-0.96) and absolute agreement of 95%.
Definitions of spinal radiographic progression according to Baraliakos et al. were used to distinguish between slow progression (<2 mSASSS units within 2 years), moderate progression (2 to 5 mSASSS units within 2 years), and fast progression (>5 mSASSS units within 2 years) [24].
Statistical analysis
Results were expressed as mean ± SD or median (interquartile range (IQR)) for normally distributed and non-normally distributed data, respectively. Independent samples T-test, Mann-Whitney U test, Chi-Square test, and Fisher Exact test were used to compare differences in baseline characteristics between groups.
Generalized estimating equations (GEE) was used to analyze spinal radiographic progression over time within subjects and to calculate mean radiographic progression rate at the group level. Because correlations of spinal radiographic damage were approximately equal at different time points, the exchangeable correlation structure was used. Different models of
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time (linear, quadratic, cubic, square, logarithmic, and exponential) were used to investigate whether time was linear or non-linear associated with radiographic progression. In case residuals were non-normally distributed, parameters were transformed (log or square root) before entered into the equation.
In the baseline analysis, interactions between time and the following patient characteristics and baseline clinical assessments were tested: gender, age, symptom duration, time since diagnosis, HLA-B27 status, BMI, duration of smoking, NSAID use, disease activity (BASDAI, ASDAS, physician’s and patient’s GDA, CRP, ESR), and presence of syndesmophytes. If interaction effects with time were found (p-values ≤0.05), the mean radiographic progression rate was calculated after stratification into subgroups based on clinically relevant or median values.
In the longitudinal analysis, the relationship between radiographic progression and disease activity, BMI, and NSAID use over time was investigated with an autoregressive marginal time-lag model. This model investigates the influence of disease activity at the start of a 2-year interval (eg. BASDAIt), BMI at the start of a 2-year interval (BMIt), or mean cumulative NSAID use during a 2-year period (ASAS-NSAIDt−t+1) on the radiographic score at the end of a 2-year interval (mSASSSt+1), adjusted for the radiographic score at the start of this interval (mSASSSt) so radiographic progression was modeled. The following models were tested: mSASSSt+1 modeled by mSASSSt and BASDAIt, ASDASt, physician’s GDAt, patient’s GDAt, CRPt, ESRt. BMIt, and ASAS-NSAIDt−t+1.
Statistical analysis was performed with IBM SPSS Statistics 22 (SPSS, Chicago, IL, USA). P-values ≤0.05 were considered statistically significant.
RESULTS
In total, 176 of the 267 AS patients who started with TNF-α blocking therapy between November 2004 and October 2011 were included in the analysis (Figure 1). Baseline characteristics of included patients were comparable to those who were excluded because of missing radiographs (n=78) or >3 missing vertebral edges (n=5) at baseline or at follow-up, except for symptom duration (median 14 vs. 17 years, p<0.05). Eight patients were excluded
because of complete spinal ankylosis at baseline. These patients were older (mean 55 vs. 42 years, p<0.01) and had longer symptom duration (median 38 vs. 14 years, p<0.01).
Of the 176 included patients, 69% were male, mean age was 42 ± 11 years, median symptom duration 14 years (IQR: 7-24), and 77% were HLA-B27 positive (Table 1). History of inflammatory bowel disease, uveitis, psoriasis, and peripheral arthritis were seen in 11%, 32%, 7%, and 34% of the patients, respectively.
All patients had high disease activity at baseline (91% BASDAI ≥4, 99% ASDAS ≥2.1, and 68% CRP ≥6mg/L). Twenty-seven (15%) patients started with infliximab, 110 (63%) with etanercept, and 39 (22%) with adalimumab. During follow-up, 45 (26%) switched to another TNF-α blocking agent. Patients were exposed to TNF-α blocking therapy for 97% of the follow-up time (IQR: 83%-100%).
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Spinal radiographic damage and clinical assessments before the start of TNF-α blocking therapy
At baseline, median mSASSS was 11 (IQR: 5-24) and 102 (58%) patients had at least one syndesmophyte according to both readers. Patients with syndesmophytes at baseline were more frequently male, older, had longer symptom and diagnosis duration, higher BMI, longer duration of smoking, and had more often very high disease activity based on ASDAS (>3.5) and CRP (>10 mg/L) (Table 1).
Spinal radiographic progression during TNF-α blocking therapy
Mean clinical follow-up time was 3.8 ± 1.8 years (range 1-7). During this period, 176, 151, 98, and 50 patients had mSASSS data available at baseline and after 2, 4, and 6 years of follow-up, respectively. Baseline characteristics were comparable in all these groups, only a significantly longer symptom duration and higher ASAS-NSAID index were seen in patients with 6 years data (Table 1 and Supplementary Table S1).
Median mSASSS increased significantly from 10.7 (IQR: 4.6-24.0) at baseline to 14.8 (IQR: 7.9-32.8) at 6 years (Table 2). At the group level, a linear time model revealed the best fit for the data. Mean progression rate was estimated at 1.3 mSASSS units per 2 years.
At the individual level, both spinal radiographic damage at baseline and radiographic progression over time were highly variable between AS patients (Figure 2). During the 2-years intervals, no or slow progression was found in 59-70%, moderate progression in 18-33%, and fast progression in 5-12% of the patients (Table 2).
The presence of syndesmophytes and older age were significantly associated with spinal radiographic progression. Patients with syndesmophytes at baseline had a 4-fold higher radiographic progression rate than patients without syndesmophytes (2.0 vs. 0.5 mSASSS units per 2 years). This increased progression rate also applies for patients with only 1 syndesmophyte compared to patients without syndesmophytes (1.8 vs. 0.5 mSASSS units per 2 years). Patients >40 years of age showed a 2.5-fold higher radiographic progression rate than patients ≤40 years (1.8 vs. 0.7 mSASSS units per 2 years) (Table 3).
Table 1. Baseline characteristics of the total AS study population and stratified by the presence or absence of syndesmophytes at baseline.
Baseline syndemophytes All patients
(n=176) Present (n=102) Absent (n=74) p-value
Male gender 121 (69) 78 (77) 43 (58) 0.009
Age (yrs) 42.3 ± 11.1 46.8 ± 10.1 36.2 ± 9.4 <0.001
Symptom duration (yrs) 14 (7-23) 18 (10-25) 10 (5-17) <0.001 Time since diagnosis (yrs) 5 (1-14) 8 (1-19) 3 (1-11) 0.011
HLA-B27+ 134 (77) 77 (76) 57 (77) 0.903 BMI (kg/m2) 26.4 ± 4.1 27.2 ± 4.1 25.2 ± 3.7 0.004 Smoking (yrs) 12 (0-22) 16 (0-25) 7 (0-16) 0.020 NSAID use 130 (74) 79 (78) 51 (69) 0.203 ASAS-NSAID index (0-100) 50 (0-100) 50 (0-100) 40 (0-100) 0.602 BASDAI (0-10) 6.1 ± 1.6 6.1 ± 1.5 6.0 ± 1.7 0.929 BASDAI >6 84 (48) 52 (51) 32 (43) 0.310 ASDASCRP 3.7 ± 0.8 3.8 ± 0.7 3.6 ± 0.8 0.150 ASDAS >3.5 104 (60) 68 (68) 36 (49) 0.013 Physician’s GDA (0-10) 4 (3-6) 4 (3-6) 4 (3-6) 0.701 Physician’s GDA >6 34 (20) 23 (23) 11 (16) 0.238 Patient’s GDA (0-10) 7 (5-8) 7 (5-8) 7 (6-8) 0.280 Patient’s GDA >6 105 (60) 56 (55) 49 (66) 0.151 CRP (mg/L) 12 (4-22) 14 (6-22) 9 (4-21) 0.141 CRP >10 mg/L 97 (56) 63 (62) 34 (47) 0.038 ESR (mm/hr) 21 (10-34) 20 (10-34) 21 (9-34) 0.832 ESR >20 mm/hr 87 (50) 49 (49) 38 (52) 0.691 mSASSS (range 0-72) 11 (5-24) 21 (12-38) 4 (2-7) <0.001 Values are presented as number of patients (%), mean ± SD, or median (IQR).
Abbreviations: AS: ankylosing spondylitis; HLA: human leukocyte antigen; BMI: body mass index; NSAID: non-steroidal
anti-inflammatory drug; ASAS: Assessment of SpondyloArthritis international Society; BASDAI: Bath AS Disease Activity Index; ASDAS: AS Disease Activity Score; GDA: global disease activity; CRP: C-reactive protein; ESR: erythrocyte sedimentation rate; mSASSS: modified Stoke AS Spine Score.
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Figure 2. Spinal radiographic progression at patient level of AS patients with 6 years of follow-up (n=50).
Table 2. mSASSS status and progression scores of AS patients who started with TNF-α blocking therapy.
Status scores Baseline
(n=176) 2 year (n=151) 4 year (n=98) 6 year (n=50)
Mean mSASSS 16.9 ± 16.7 17.5 ± 17.2 21.4 ± 18.5 21.4 ± 18.7 Median mSASSS 10.7 (4.6-24.0) 10.9 (4.6-25.5) 15.0 (5.6-32.1) 14.8 (7.9-32.8)
Progression scores 0-2 year
(n=151) 2-4 year (n=75) 4-6 year (n=42)
Mean change mSASSS 1.3 ± 3.2 1.4 ± 2.8 1.3 ± 2.0
Median change mSASSS 0.8 (-0.5-2.1) 1.2 (-0.6-2.8) 1.0 (-0.1-2.8) <2 mSASSS units/2 years (slow) 106 (70) 44 (59) 27 (64) 2-5 mSASSS units/2 years (moderate) 27 (18) 25 (33) 13 (31) >5 mSASSS units/2 years (fast) 18 (12) 6 (8) 2 (5) Values are presented as number of patients (%), mean ± SD or median (IQR).
Table 3. Effect of time and time interactions with baseline characteristics on spinal radiographic progression.
β (95% CI) p-value Intervals n
Time 1.25 (1.10-1.40) <0.001 475 176 Time*gender 0.104 475 176 Time*age 0.045 475 176 Age ≤40 years 0.68 (0.49-0.90) 206 75 Age >40 years 1.78 (1.64-1.93) 269 101 Time*symptom duration 0.565 448 166
Time*time since diagnosis 0.516 465 171
Time*HLA-B27 0.855 473 175 Time*BMI 0.221 360 141 Time*smoking 0.117 362 133 Time*NSAID use 0.246 475 176 Time*ASAS-NSAID index 0.668 381 130 Time*BASDAI 0.526 475 176 Time*ASDAS 0.764 467 173 Time*Physician’s GDA 0.123 466 172 Time*Patient’s GDA 0.506 473 175 Time*CRP 0.375 469 174 Time*ESR 0.339 466 173 Time*syndesmophytes 0.022 475 176 Without syndesmophytes 0.52 (0.39-0.66) 203 74 With syndesmophytes 2.02 (1.88-2.17) 272 102
See Table 1 for abbreviations.
Table 4. Longitudinal analysis of the relationship between spinal radiographic progression and disease activity, BMI, and NSAID use.
β (95% CI) p-value Intervals n
Previous mSASSS 1.02 (1.00-1.04) <0.001 268 159 BASDAI -0.02 (-0.15-0.10) 0.737 259 159 ASDAS 0.24 (-0.08-0.55) 0.143 255 158 Physician’s GDA -0.05 (-0.19-0.09) 0.497 264 156 Patient’s GDA -0.03 (-0.16-0.10) 0.637 267 159 CRP 0.03 (0.00-0.06) 0.071 255 158 ESR 0.03 (0.00-0.06) 0.056 252 158 BMI -0.02 (-0.09-0.05) 0.596 266 181 ASAS-NSAID index 0.00 (-0.01-0.01) 0.905 196 87
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Longitudinal association between spinal radiographic progression and clinical assessments
Disease activity improved significantly during TNF-α blocking therapy. From baseline to 3 months, mean BASDAI improved from 6.1 to 3.2, mean ASDAS from 3.7 to 2.1, median physician’s GDA from 4 to 2, median patient’s GDA from 7 to 3, median CRP from 12 to 3 mg/L, and median ESR from 21 to 6 mm/hr (all p<0.001). These improvements remained stable during long-term follow-up (data not shown). Mean BMI showed a small increase during follow-up, from 26.4 at baseline to 26.6 kg/m2 at 6 years (p<0.05). NSAID use decreased significantly from 74% at baseline to 41%, 37%, and 25% at 2, 4, and 6 years, respectively (p<0.001). Mean cumulative NSAID intake according to the ASAS-NSAID index decreased from 24.3 during the first 2 years to 14.4 and 9.2 during the 2-4 and 4-6 years time intervals, respectively (p<0.001).
During TNF-α blocking therapy, no significant longitudinal associations were found between spinal radiographic progression and disease activity, BMI, or NSAID use over time (Table 4). Also the change in disease activity during the first 3 to 6 months, remission at 6 months (e.g. ASDAS <1.3), prolonged remission (ASDAS <1.3 for at least 2 consecutive visits), and change in NSAID use during the first 2 years were not significantly associated with spinal radiographic progression (data not shown). Only a trend was observed for the longitudinal association of CRP and ESR levels with radiographic progression (Table 4).
DISCUSSION
This observational longitudinal cohort study prospectively investigated spinal radiographic damage over time and the associations of radiographic progression with patient characteristics and clinical assessments including disease activity in 176 AS patients treated with TNF-α blocking therapy in daily clinical practice. Spinal radiographic progression was linear at the group level with a mean progression rate of 1.3 mSASSS units per 2 years. This indicates that, on average, AS patients treated with TNF-α blocking therapy showed slow radiographic progression according to the definitions of Baraliakos et al. (<2 mSASSS units per 2 years) [24]. Radiographic progression was also linear during 12 years of follow-up in a large cohort of AS patients mainly treated with NSAIDs. In this cohort, the mean progression rate was estimated at 2.0 mSASSS units per 2 years [12,25]. Although the mean 2-year progression rate found in our patients treated with TNF-α blocking agents was lower, no conclusions
can be made since a direct comparison between the two cohorts is lacking. Other studies in AS patients treated with TNF-α blocking therapy for 2-8 years showed variable mSASSS progression scores with a minimum of 0.4 and a maximum of 1.8 mSASSS units per 2 years [2-8].
Before start of TNF-α blocking therapy, all AS patients had high disease activity and more than half (58%) had syndesmophytes, which is comparable to the results of previous studies. In these previous studies, the proportion of patients with syndesmophytes at baseline varied from 30% in ‘early’ AS (≤10 years symptom duration) [11], 47-58% in AS patients with a variable disease activity status [25] to 55-61% in AS patients with active disease before start of TNF-α blocking therapy [7,8]. In accordance with earlier findings, we found that male gender, older age, elevated CRP levels, but also longer symptom and diagnosis duration, longer smoking duration, and ASDAS >3.5 were significantly associated with the presence of syndesmophytes at baseline [10,26]. Additionally, we found that patients with high disease activity and syndesmophytes at baseline had significantly higher BMI which suggests an association between disease activity, BMI, and radiographic damage. However, this could not be confirmed in the longitudinal analyses.
At the individual level, spinal radiographic progression was highly variable. The mean mSASSS progression rate was 4-fold higher in patients with syndesmophytes at baseline and 2.5-fold higher in patients >40 years of age. These findings indicate that radiographic progression during the treatment of TNF-α blocking therapy mainly occurs in older AS patients and in patients with more advanced disease. Previous studies with different treatment regimens also identified the presence of syndesmophytes at baseline as the most important predictor for the development of more radiographic damage in both ‘early’ axial SpA [11] and longstanding AS [2,10,24,27].
In our analyses, none of the disease activity assessments at baseline and over time were significantly associated with spinal radiographic progression. This is probably due to the low variability in disease activity since all patients had high disease activity before start of TNF-α blocking therapy and stable low disease activity during treatment. Moreover, the mean change in mSASSS at the group level was small, which makes it difficult to observe significant differences. This was also confirmed by the low observed regression coefficients of the time-lagged autoregressive GEE models. Historical longitudinal observational cohort studies in AS patients that have found significant relationships between disease activity and
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radiographic progression included patients with a high variability in disease activity status and treatment regimens [11,12]. In the Outcome in AS International Study (OASIS), patients with very high disease activity (ASDAS >3.5) over time showed an additional increase of 2.3 mSASSS unts per 2 years compared to patients with inactive disease (ASDAS <1.3) [12]. In another analysis of the same cohort, ESR was significantly associated with the development of new syndesmophytes after 4 years of follow-up (OR 1.03, 95% CI: 1.00-1.07, p<0.05) [10]. In 210 early axial SpA patients from the German Spondyloarthritis Inception Cohort (GESPIC), elevated ESR levels at baseline (>20 mm/hr) and time-averaged elevated CRP levels over 2 years (>6 mg/L) were significantly associated with spinal radiographic progression during 2 years of follow-up [11].
Previous studies in AS reported a positive effect of continuous use of NSAIDs on the reduction of radiographic progression [28,29]. In our study, NSAID use decreased rapidly over time resulting in very low ASAS-NSAID index scores, as expected in patients starting TNF-α blocking agents. Only 10% of the patients had a cumulative NSAID intake of ≥50 according to the ASAS-NSAID index and no effect on radiographic progression could be found. Furthermore, follow-up data on smoking was not available in this study and therefore we could not include smoking in the longitudinal model to investigate this influence on spinal radiographic progression.
In the present study the reading of the radiographs was done without known time sequence which may lead to negative and smaller progression rates than when the reading was done in chronological time order [30]. Furthermore, it was not possible to draw conclusions about the effect of TNF-α blocking therapy on spinal radiographic progression, since AS patients without TNF-α blocking therapy were not included.
CONCLUSIONS
This large prospective observational cohort study in AS patients treated with TNF-α blocking therapy in daily clinical practice showed that spinal radiographic progression was overall slow and linear at the group level. At the individual level, radiographic progression was highly variable. Patients with syndesmophytes at baseline had a 4-fold increased radiographic progression rate and patients >40 years of age had a 2.5-fold increased radiographic progression rate. No longitudinal associations between radiographic progression and clinical
assessments were found. A direct longitudinal comparison between cohorts with long-term follow-up and large study populations of AS patients treated with and without long-term TNF-α blocking therapy is required to evaluate the effect of this treatment and to further investigate the relationship between clinical assessment (e.g. disease activity) and spinal radiographic progression.
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