University of Groningen

Clinical and spinal radiographic outcome in axial spondyloarthritisMaas, Fiona

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Chapter 12

Summary and general discussion

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Axial spondyloarthritisAxial spondyloarthritis (SpA), including ankylosing spondylitis (AS) as the most well-known

phenotype, is a chronic rheumatic inflammatory disease in which predominantly the axial

skeleton is involved. The hallmark features of axial SpA are inflammation and structural

changes of the sacroiliac (SI) joints and the spine. Pain, spinal stiffness, and loss of function

limits the ability to perform daily activities [1-3]. Typical structural changes are the formation

of syndesmophytes between vertebrae leading to ankylosis of the spine [1]. In contrast to

this bone formation, axial SpA patients have an increased risk for bone loss, resulting in low

bone mineral density (BMD) and vertebral fractures [4,5].

Axial SpA is an overall slowly progressive and heterogeneous disease with high inter-

patient variability [6,7]. Treatment is given to reduce disease activity and to improve

outcome. Conventional treatment includes non-steroidal anti-inflammatory drugs (NSAIDs)

in combination with adequate patient education, physical exercise, or physical therapy.

Treatment with biologicals, such as tumor necrosis factor-alpha (TNF-α) inhibitors and, very

recently, IL-17 inhibitors, can be prescribed when patients have persistently high disease

activity despite of conventional treatment [8,9].

The overall objective of this thesis was to evaluate disease outcome, especially bone-related

outcome, during long-term follow-up of axial SpA patients treated according to (inter)

national guidelines in daily clinical practice. The following topics are covered in this thesis:

Part I) Long-term radiographic outcome of excessive bone formation in the spine of AS

patients treated with TNF-α inhibitors, Part II) Radiographic outcome of excessive bone loss

in the spine of AS patients, Part III) The influence of gender and BMI on disease outcome and

the development of a physical activity questionnaire for axial SpA patients.

GLAS cohortAll studies described in this thesis were based on patient data from an ongoing, prospective,

longitudinal, observational, cohort study in the North of the Netherlands; the ‘Groningen

Leeuwarden Axial Spondyloarthritis’ (GLAS) cohort. The GLAS cohort started in November

2004 in the Medical Center Leeuwarden (MCL) and the University Medical Center Groningen

(UMCG). The initial aim of the GLAS study was to evaluate clinical aspects of long-term

treatment with TNF-α inhibitors in daily clinical practice, with a focus on bone-related

outcome. Patients with active AS who started TNF-α inhibitor treatment were included in the

cohort. Since the end of 2008, the inclusion criteria were extended to all consecutive axial

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SpA patients, irrespective of disease activity and 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.

The GLAS cohort is embedded in the daily clinical care of axial SpA patients. Consecutive axial

SpA patients who visit the outpatient clinics of the MCL or UMCG are asked to participate in

the cohort. After patients have given written informed consent, they are followed according

to a fixed protocol and seen by specialized and trained rheumatologists, physician assistants,

or rheumatology consultants every 6 to 12 months. The management and assessment of

the disease is conducted according to the latest guidelines established by the Assessment

in SpondyloArthritis International Society (ASAS), the European League against Rheumatism

(EULAR), and the Dutch Society of Rheumatology (NVR) Spondyloarthritis working groups.

[8] The domains and assessment core set for cohort studies as recommended by the ASAS/

Outcome Measures in Rheumatology Clinical Trials (OMERACT) working group are used to

evaluate disease status [10,11]. Disease activity, physical functioning, health-related quality of

life, spinal mobility, presence of extra-articular manifestations (EAMs), radiographic changes,

and bone mineral density are evaluated during follow-up. Patient symposia are organized

every 2 years to inform patients about the disease, study results, and future plans, and to

promote involvement in the cohort.

Currently, more than 600 axial SpA patients are included in the GLAS cohort. The drop-out

rate is relatively low for a long-term cohort study (13% at 8 years of follow-up). The majority

of patients with long-term follow-up have been treated with TNF-α inhibitors due to the

initial inclusion criteria of the GLAS cohort. Therefore, this thesis mainly describes the results

of patients treated with these biologicals.

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PART I: RADIOGRAPHIC OUTCOME OF EXCESSIVE BONE FORMATION DURING TREATMENT WITH TNF-α INHIBITORS

Chapter 2 describes spinal radiographic progression in 176 AS patients treated with TNF-α

inhibitors for up to 6 years (median follow-up duration was 3.8 years). Spinal radiographic

damage was scored by two independent readers on lateral radiographs of the cervical and

lumbar spine according to the modified Stoke AS spine score (mSASSS, range 0-72) [12].

To prevent reader bias regarding the knowledge of the applied therapy, radiographs were

scored with unknown time sequence. Spinal radiographic progression was investigated

using generalized estimating equations (GEE), a statistical method in which longitudinal

associations could be explored taking into account the within-patient correlations. The

mean progression rate was 1.3 mSASSS units per 2 years at the group level. At the individual

patient level, a large variability in spinal radiographic progression was seen. Patients with

baseline syndesmophytes showed a 4-fold higher progression rate than patients without

syndesmophytes. Male patients showed a 2.5-fold higher progression rate than female

patients.

In chapter 3, the course of spinal radiographic progression during treatment with TNF-α

inhibitors was explored in a larger group of patients with up to 8 years of follow-up. In this

study, radiographs were randomized together with radiographs of patients from a Dutch

historical cohort not treated with TNF-α inhibitors and scored in chronological time order

(mSASSS). This methodology was used to prevent reader bias regarding the knowledge

of the applied therapy and to reduce the measurement error related to reading with

unknown time sequence. The course over time was evaluated in patients with complete

data over 4 years, 6 years, and 8 years of follow-up using different GEE time models (linear

and non-linear models). GEE analysis in patients with 4 years of follow-up revealed that

spinal radiographic progression followed a linear course with stable progression rates of

1.7 mSASSS units per 2 years. Patients with 6 and 8 years of follow-up showed a non-linear

course of spinal radiographic progression with reducing progression rates from max. 2.8

mSASSS units during the 0-2 year time interval to min. 0.8 mSASSS units during the 6-8

year time interval. Although the number of patients with 8 years of follow-up was limited,

diminishing radiographic progression was already seen during the 2-4 year and 4-6 year time

interval. Similar results were found with sensitivity analysis after linear imputation of missing

radiographic data at intermediate time points and with sensitivity analysis after adjustment

for potential confounders.

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Chapter 4 describes the influence of patient characteristics on the course of spinal

radiographic progression in 80 AS patients treated with TNF-α inhibitors for 6 years. Spinal

radiographic damage over time was significantly associated with male gender, older age,

longer disease duration, current smoking status, higher BMI, and, most importantly, presence

of baseline syndesmophytes. Patients with these risk factors for poor radiographic outcome

showed the highest but also diminishing spinal radiographic progression over time.

Radiographic progression rates reduced from max. 2.8 units during 0-2 year time interval to

min. 0.9 units during 4-6 year time interval. Patients without risk factors showed stable and

low progression rates of ≤1 mSASSS unit per 2 years.

The mSASSS as used for the assessment of spinal radiographic damage in AS includes

only the anterior corners of the cervical and lumbar vertebral bodies. Previous studies

have shown that other parts of the spine such as the facet (zygapophyseal) joints are also

affected in AS [13,14]. Chapter 5 describes radiographic damage and progression of the

cervical facet joints scored according the method of de Vlam et al. [13]. in 98 AS patients

treated with TNF-α inhibitors for 4 years. Damage and progression of cervical facet joints

were frequently observed; in 25% and 13% of the patients, respectively. Damage of cervical

facet joints was associated with longer disease duration, higher disease activity, higher

mSASSS, larger occiput-to-wall distance, and a history of extra-articular manifestations,

including inflammatory bowel disease (IBD), uveitis, and psoriasis. In comparison, damage

and progression of the cervical vertebral bodies assessed with mSASSS was observed in 52%

and 26% of the patients, respectively. The majority of patients with radiographic progression

of cervical facet joints did not show progression of vertebral bodies.

Based on the results in chapter 5, a composite scoring system, the combined AS spine score

(CASSS) was introduced and its additional value to the mSASSS was evaluated in chapter 6.

In CASSS, the cervical facet joint scores of the method of de Vlam et al. (range 0-15) were

incorporated in the mSASSS (range 0-72), leading to a score range of 0-87. CASSS was

compared to the original mSASSS according to the three aspects of the OMERACT filter,

i.e. feasibility, discrimination, and truth [15]. Feasibility of CASSS was very good; total scores

could be calculated in >90% of the patients, no additional radiographs were necessary, and

the assessment of cervical facet joints took only a few extra minutes. Inter-observer reliability

was excellent for both scoring methods without an increase in the measurement error for

CASSS. CASSS resulted in a few more patients classified as having ‘definite damage’ (61%

versus 57%) and ‘definite progression’ (55% versus 48%). With regard to truth, the construct

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validity of CASSS was better since 46% of the patients had higher baseline scores, 25% had

higher progression scores, and cervical rotation correlated better with CASSS than with

mSASSS.

PART II: RADIOGRAPHIC OUTCOME OF EXCESSIVE BONE LOSS

Chapter 7 describes the prevalence and incidence of radiographic vertebral fractures in

the thoracic and lumbar spine of 105 AS patients with active disease who were treated with

TNF-α inhibitors for 4 years. Vertebral fractures were assessed by two readers according

to the method of Genant et al. [16]. A reduction in vertebral height of ≥20% was defined

as a radiographic vertebral fracture. At baseline, 27 (26%) patients had one or more

radiographic vertebral fractures. New vertebral fractures were observed in 21 (20%) patients.

Most prevalent and new developed fractures were mild (72% and 80%, respectively). The

remaining fractures were moderate and one was severe. The 21 patients with new vertebral

fractures were older, had longer smoking duration, worse physical function, lower lumbar

spine BMD, and more frequently pre-existing vertebral fractures of moderate degree (≥25%

height reduction). Lumbar spine BMD as well as hip BMD improved significantly during 4

years of TNF-α blocking therapy. However, patients with new vertebral fractures showed

significantly less improvement in lumbar spine BMD than patients without new vertebral

fractures.

Chapter 8 describes the prevalence and 2-year incidence of vertebral fractures in 292 AS

patients treated with TNF-α inhibitors or conventional therapy. The same scoring method was

used as described in chapter 7. At baseline, a total of 89 radiographic vertebral fractures were

found in 59 (20%) patients. Only 2 fractures were symptomatic of which one received clinical

attention. The majority of the fractures were mild, wedge shaped and located in the mid and

low thoracic spine. During 2 years of follow-up, 15 (6%) patients developed 18 new fractures.

Only one fracture was symptomatic and received clinical attention. In addition to patients

with new fractures, 7 (2%) patients showed an increase in severity of existing fractures. In

these 7 patients, mild fractures deteriorated to moderate fractures. The prevalence and

incidence of new vertebral fractures was comparable between 184 AS patients with active

disease who started TNF-α inhibitors and 108 AS patients with inactive disease who stayed

on conventional treatment (21% versus 19% and 5% versus 6%, resp.). Clinical risk factors for

vertebral fractures were: older age, higher BMI, longer smoking duration, larger occiput-to-

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wall distance, more spinal radiographic damage, and low hip BMD. Occiput-to-wall distance

was identified as an independent risk factor for having radiographic vertebral fractures. The

use of NSAIDs at baseline was independently associated with a reduced risk of having and

developing vertebral fractures.

PART III: INFLUENCE OF GENDER AND BMI ON DISEASE OUTCOME AND THE DEVELOPMENT OF A PHYSICAL ACTIVITY QUESTIONNAIRE FOR AXIAL SPA

In chapter 9, gender differences with regard to subjective and objective clinical outcome

measures as used in daily clinical practice were explored in a cross-sectional study of 466

axial SpA patients who visited the outpatient clinic between 2011 and 2012. Female patients

scored worse on all patient-reported outcome measures than male patients, i.e. women

had higher Bath AS disease activity index (BASDAI), patient’s global score of disease activity,

tender joint count, Bath AS functional index (BASFI), and AS quality of life questionnaire

(ASQoL). Women also had higher AS disease activity score (ASDAS), a measure that combines

subjective aspects (patient questions) and an objective aspect of disease activity, C-reactive

protein (CRP). Objective, univariable measures of disease activity, i.e. CRP levels and swollen

joint count, were comparable between female and male patients.

Chapter 10 describes the prevalence of overweight and obesity in relation to clinical

outcome in 461 axial SpA patients from the GLAS cohort. BMI data were compared with

gender-matched data from a population-based cohort study in the same geographical

region with comparable age distribution, the LifeLines cohort (n=136,577). In our axial SpA

population, overweight (BMI ≥25-<30kg/m2) was present in 37% of the patients and obesity

(BMI ≥30kg/m2) in 22% of the patients. In the general LifeLines population, overweight and

obesity were present in 43% and 15% of the participants, respectively. In axial SpA, overweight

and obese patients were significantly older, had longer symptom duration, and more often

comorbidity, especially hypertension, than patients with normal BMI. Interestingly, presence

of obesity was significantly associated with worse clinical outcome measures, including

worse score on BASDAI, ASDAS, CRP, ESR, BASFI, and ASQoL.

In chapter 11, a disease-specific, patient-reported questionnaire was introduced for the

assessment of physical activity in axial SpA. A qualitative study with a stepwise approach

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was used to modify an existing, validated physical activity questionnaire for the general

population, the Short QUestionnaire to Assess Health-enhancing physical activity (SQUASH).

This questionnaire measures the duration, frequency, and intensity of physical activities

during transport, work, household, and leisure time, including sports. Semi-structured in-

depth interview were performed with 9 experts in the field of axial SpA and a focus group

was organized with 8 axial SpA patients. Multiple requirements for adaptations were

proposed and discussed. In total, 15 adaptations were implemented and the SQUASH was

modified into a more standardized, disease-specific questionnaire, the axSpA-SQUASH. The

most important adaptations concerned: explanation, rewording, and standardization of

response options throughout the questionnaire and addition of more response possibilities

and clarification of examples related to the domains of the SQUASH (e.g. inclusion of exercise

therapy, other transportation activities, and childcare).

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GENERAL DISCUSSION

Bone formation in axial SpARadiographic progression in relation to pathophysiology

Excessive bone formation in axial SpA is a complex and multifactorial process that varies

greatly between patients, also during treatment with TNF-α inhibitors as shown in chapters

2 and 3. In the past century, knowledge about axial SpA is extremely increased, but the

underlying pathophysiological mechanisms are not yet completely understood. Genetics,

the immune system, biomechanical stress, and environmental factors are considered as

factors that contribute to new bone formation [17-19].

In the historical Outcomes in AS International Study (OASIS) with a follow-up duration up to

12 years, spinal radiographic progression followed a linear course at the group level with a

mean progression rate of 2 mSASSS units per 2 years [7]. Spinal radiographic progression was

found to be longitudinally associated with assessments of disease activity. A higher BASDAI,

ASDAS, or CRP at the start of a 2-year time interval was associated with more radiographic

progression during the next 2 years of follow-up [20]. These findings suggest that inhibition

of inflammation and, thereby, reducing disease activity seems beneficial to reduce spinal

radiographic progression in axial SpA.

Shortly after the discovery that TNF-α inhibitors are very effective in reducing disease activity

and improving clinical outcome in AS, open-label extension studies were performed to

investigate the effect of TNF-α inhibitors on spinal radiographic outcome. These 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 [21-

24]. Prospective and retrospective studies with up to 8 years of follow-up reported about a

possible relationship between TNF-α inhibitors and less spinal radiographic progression in

AS over time [25,26]. In our prospective cohort of AS patients treated with TNF-α inhibitors,

a deflection of spinal radiographic progression was found after more than 4 years of follow-

up (chapter 3). This deflection was especially seen in patients with an increased risk of poor

radiographic outcome, e.g. baseline syndesmophytes and male gender. Patients without risk

factors showed very slow, linear spinal radiographic progression (chapter 4). These results

show that TNF-α inhibitors cannot stop radiographic progression immediately. However,

long-term inhibition of inflammation with these agents diminishes and may even prevent

spinal radiographic progression over time [27].

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An explanation of this possible delayed effect is given by the TNF-brake hypothesis

[28,29]. TNF-α is a key pro-inflammatory cytokine in axial SpA that upregulates Dickkopf-

related protein-1 (Dkk-1), an antagonist of the Wingless (Wnt) signaling pathway for new

bone formation. Processes of new bone formation are downregulated at sites of active

inflammation whereas processes of bone resorption are upregulated. When inflammatory

lesions resolve, the levels of TNF-α reduce. As a result, repair processes can be activated

and less Dkk-1 expression allows Wnt signaling to stimulate new bone formation at sites of

resolved inflammation. This may explain the (ongoing) formation of new bone in axial SpA,

also after start of TNF-α inhibitor treatment [28]. The TNF-brake hypothesis also assumes that

persistent reduction of inflammation will prevent the development of new inflammatory

lesions resulting in less activated repair processes and a reduction of spinal radiographic

progression over time [29].

More recently, novel insights into the pathophysiology of bone formation of axial SpA have

been described. Influences of biomechanical stress and other pro-inflammatory cytokines in

addition to TNF-α, such as interleukin (IL)-23, IL-17 and IL-22, have been found to play a role

in the excessive bone formation in axial SpA [30-32]. Treatment with IL-17 is now available for

axial SpA and studies with IL-12/23 inhibitors are under way. The future will learn us whether

these new treatments can reduce new bone formation in axial SpA.

Assessing spinal radiographic progression; pitfalls in the methodology

Due to the overall slow and very heterogeneous process of bone formation in axial SpA,

the evaluation of spinal radiographic progression brings along multiple methodological

challenges. The EULAR working group recommends radiography of the spine, not repeated

more frequently than every 2 years, and use of the mSASSS for the assessment of spinal

radiographic progression in axial SpA patients [12,33]. The reliability of the mSASSS is very

good but the ability to discriminate between small changes is limited, especially over a short

period of time [34]. The smallest detectable change (SDC), the change that can be detected

without a measurement error, over a 2 years period is often larger than the mean progression

rate (chapter 3) [7]. Therefore, longer follow-up or very large study populations are needed to

detect ‘true’ changes beyond the measurement error.

A scoring method in which more elements of the spine are included may help to improve

the sensitivity to change. In chapter 5, we have shown that cervical facet joints are frequently

affected in AS. Incorporating the cervical facet joint scores of de Vlam et al. in the mSASSS

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resulted in a broader range of scores without an increase in the measurement error

(chapter 6). With this composite scoring method named CASSS, more patients with spinal

radiographic progression were captured. In combination with the high feasibility and the

possibility to extract mSASSS scores from CASSS, this scoring method would be relevant in

this slowly progressive disease.

The sensitivity to change of the scoring method will also improve when radiographs are

scored in chronological time order (chapter 3) [35,36]. Scoring with known time sequence

reduces the measurement error as negative progression will not be scored. However,

reader bias concerning the applied therapy should be taken into account, for example by

randomizing the radiographs with radiographs of patients on conventional therapy or from

a historical cohort study.

Finally, it is important to take into account patient selection and completion bias. As known

from literature and also demonstrated in chapter 2-4, different patient characteristics can

affect the course of spinal radiographic progression [6,7,25,37-39]. An accurate description

of patient selection, patient characteristics, and number of patients over time is important.

When patient numbers differ over time due to drop-outs or incomplete data, complete

case analysis, analysis in different sub groups, sensitivity analysis after imputation of missing

data, and/or adjustments for patient characteristics with known influence on radiographic

outcome should be performed using advanced, repeated measures statistics.

Bone loss in axial SpAVertebral fractures and pathophysiology

Although the focus in axial SpA outcome research is mainly on excessive bone formation, we

have shown that radiographic vertebral fractures are common in axial SpA (chapter 7 and

8). In line with bone formation, the etiology of vertebral fractures is probably multifactorial.

Genetic and hormonal factors, immobility due to pain or spinal stiffness, inflammation, and

presumably also biomechanical stress, may play a role in the development of vertebral

fractures in axial SpA [40-42].

Treatment with TNF-α inhibitors can improve BMD of the lumbar spine and, to a lesser

extent, at the hip in axial SpA, (chapter 7) [4]. However, new vertebral fractures are still

observed during treatment with these drugs (chapter 7) and no differences were found

between patients on TNF-α inhibitor treatment or conventional treatment during 2 years

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of follow-up (chapter 8). An increase in the number of patients with radiographic vertebral

fractures during 2 years of TNF-α inhibitor treatment was also found in a small prospective

observational cohort study in 49 axial SpA patients [43]. Previous analysis of bone turnover

markers in 72 AS patients from the GLAS cohort showed that especially bone-specific

alkaline phosphatase (BALP), a marker that plays a central role in the mineralization process

of bone, increases during 3 years of TNF-α inhibitor treatment [44]. A mineralization does not

necessarily represent good bone quality. Since our data were derived from an observational

cohort study, no conclusions could be drawn about the effect of TNF-α inhibitors on the

development of radiographic vertebral fractures.

In line with previous axial SpA studies and studies in postmenopausal women from

the general population, vertebral fractures do not occur along the whole spine [45-49].

Vertebral fractures occurred most often in the mid- and low thoracic spine (chapter 7 and

8). Mechanical stress of vertebral bodies in these parts of the spine in combination with the

already weakened bone structure in axial SpA can result in radiographic vertebral fractures

without major trauma, even at a relatively young age (chapter 8) [50]. Patients with vertebral

fractures had a larger occiput-to-wall distance and more spinal radiographic damage

(chapter 7 and 8). Fusion of the spine in a fixed, forward-stooped posture with larger occiput-

to-wall distance increases the mechanical stress on the vertebrae which may result in an

increased risk of more radiographic vertebral fractures. Since occiput-to-wall distance was

an independent risk factor for the presence of vertebral fractures, this measurement can act

as an indicator for the presence of vertebral fractures in axial SpA.

Assessing vertebral fractures: pitfalls in the methodology

Bone loss is often evaluated using BMD assessment in the daily clinical practice of axial SpA.

However, BMD of the lumbar spine (AP view) might not be a reliable representation of real

bone loss of the vertebral bodies, especially in patients with advanced disease [41]. BMD

measured by dual-energy X-ray absorptiometry (DXA) can be overestimated by the presence

of syndesmophytes, ligament calcifications, and fusion of facet joints [41]. Furthermore,

two-dimensional DXA images do not reflect the microarchitecture and composition of the

vertebral bodies, two important properties of bone quality [51]. Data about radiographic

vertebral fractures, the final outcome of poor bone quality and bone loss of the vertebral

body, is therefore very relevant.

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The diagnosis of vertebral fractures in axial SpA is complicated by the lack of symptoms and

difficulties in the discrimination between back pain complaints caused by inflammation and

spinal stiffness or by vertebral fractures [52]. As a consequence, the vast majority of fractures

do not receive clinical attention (chapter 8). Routinely screening for radiographic vertebral

fractures is desirable in axial SpA, especially in patients with large and progressing occiput-to-

wall distance. Lateral radiographs of the thoracic and lumbar spine are appropriate options

to screen for vertebral fractures. Most fractures are found in the thoracic spine. Therefore, this

region should definitely be included.

For the assessment of vertebral fractures on spinal radiographs, the semi-quantitative

method of Genant is the best available scoring method [16]. This method allows readers to

judge whether a deformity demonstrates a vertebral fracture, natural variation, or is caused

by degenerative changes. Subsequently, the vertebral heights are measured and the relative

height reduction can be calculated. In axial SpA, the discrimination between radiographic

vertebral fractures and non-fracture deformities can be difficult, especially regarding mild

fractures. Structural changes such as erosions, blurring of joint margins, syndesmophytes,

spondylophytes, and calcification of the ligaments can limit the interpretability. Furthermore,

a small difference in the angle of the radiograph in combination with the arbitrary cut-off

values of the method of Genant (≥20% height reduction) can limit the reproducibility of

assessing mild fractures. Some studies have used a different cut-off value (≥25% height

reduction) to define vertebral fractures [49,53]. However, several studies in postmenopausal

osteoporotic women and the results of our two studies showed that mild fractures can

deteriorate to moderate vertebral fractures within 2 years of follow-up. Furthermore, mild

fractures can act as a risk factor for the development of new vertebral fractures [54-56].

Therefore, the identification of mild fractures, in addition to moderate and severe fractures,

seems relevant in axial SpA. Current research is now focusing on the development of new

algorithms to improve the diagnosis of vertebral fractures in axial SpA [57,58].

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Patient characteristics in relation to bone-related outcomeMultiple patient characteristics are associated with excessive bone formation and bone loss

in axial SpA. Some are associated with both aspects of bone-related outcome (Figure 1).

Figure 1. Schematic overview of associations of patient characteristics with bone loss and bone formation in the GLAS-cohort.

Abbreviations: mSASSS: Modified Stoke AS spine score; EAMs: Extra-articular manifestations; IBD: Inflammatory bowel disease; ASDAS: AS disease activity scale; CRP: C-reactive protein; BASFI: Bath AS functional index; OWD: Occiput-to-wall distance; BMD: Bone mineral density; NSAID: Non-steroidal anti-inflammatory drugs; BMI: Body mass index.

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Gender

As known from literature and confirmed in our cohort, males are more prone to develop spinal

radiographic damage than females [59,60]. Female patients, on the other hand, scored higher

on patient-reported outcome measures of disease status (chapter 9). Objective measures of

disease activity such as CRP levels and swollen joints were not significantly different between

female and male patients. Pooled analysis of data from clinical control studies in 1,283 AS

patients treated with etanercept, sulfasalazine or placebo, also showed that female patients

scorer higher on BASDAI and patient’s global disease activity assessment than male patients

[61]. These results suggest that female patients may experience their symptoms worse than

males. From previous studies, it is known that women tend to differ in their health approach

and how they communicate their health problems [61]. This should be taken into account

when interpreting patient-reported outcome measures in both daily clinical practice and

clinical studies, especially when subjective measures such as the BASDAI are used for clinical

decision making. Other cut-off values for different stages of disease activity (e.g. high versus

low) might be needed for male and female axial SpA patients.

Age, disease duration, and disease severity

The results of this thesis confirmed that older AS patients with longer and more severe

disease, e.g. higher disease activity, worse physical functioning, and worse spinal mobility

had more spinal radiographic damage and/or radiographic vertebral fractures (Figure 1)

[38,41]. A history of EAMs, including inflammatory bowel disease (IBD), uveitis, and psoriasis,

was only significantly associated with radiographic damage of the cervical facet joints, not

with damage of vertebral bodies. The association with uveitis has also been found in a small

cross-sectional study of 50 AS patients in which 37% of patients with facet ankylosis had a

history of uveitis [13]. Facet joint damage is further frequently present in psoriatic arthritis

[63,64]. So far, the exact underlying pathophysiology of facet joint involvement and extra

articular manifestations is not known.

In line with previous studies, the presence of baseline syndesmophytes is the most

important, independent predictor for radiographic progression of the vertebral bodies

[38,65]. Our results showed that the presence of (partial) ankylosis of cervical facet joints was

the independent predictor for radiographic progression of facet joints (chapter 5). For the

development of new vertebral fractures, the presence of (moderate) radiographic vertebral

fractures may act as a predictor, as confirmed by other studies [54,55].

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NSAID use

Previous studies have described a possible positive effect of NSAID use on spinal radiographic

progression [66,67]. However, the Effects of NSAIDs on RAdiographic Damage in Ankylosing

Spondylitis (ENRADAS) trial investigated primarily the effect of continuous versus on

demand use of NSAIDS on 2-year radiographic progression and did not demonstrate any

differences [68]. In our cohort, we could also not found any association between NSAID use

and spinal radiographic progression, possibly because NSAID use decreased rapidly over

time due to the good clinical effect of TNF-α inhibitors. However, patients using NSAIDs

at baseline had a reduced risk of the presence and development of radiographic vertebral

fractures. A comparable association has been found in previous AS studies [69,70]. Literature

describes contradictory theories about the underlying mechanism regarding the influence

of NSAIDs on bone. Some studies suggested that NSAIDs interfere with bone healing while

other studies declared that NSAID use can have a protective effect on bone loss since pain

relief may result in more physical activity which helps in maintaining bone mass [40].

Life style factors: Smoking and high BMI

An important finding of the studies in this thesis was that lifestyle factors such as smoking

and high BMI were associated with the presence and development of both spinal

radiographic damage and radiographic vertebral fractures (Figure 1). In addition, our cross-

sectional analysis showed that a higher BMI was associated with more comorbidities and

worse clinical outcome, including higher disease activity and worse physical functioning

and quality of life, despite of treatment with NSAIDs or TNF-α inhibitors (chapter 10). Previous

studies showed less treatment response to TNF-α inhibitors in obese AS patients [71,72].

An unhealthy lifestyle, components of tobacco smoke, and adipose tissue in overweight

and obese patients may activate immune responses leading to higher secretion of pro-

inflammatory cytokines [39,73]. In addition, other factors such as physical inactivity can lead

to worse bone-related and clinical outcome. Therefore, clinicians and patients should be

aware of the negative consequences of an unhealthy lifestyle on disease outcome in axial

SpA.

Physical activity

Although physical activity is considered to be a cornerstone in the management of axSpA that

can affect disease outcome, the assessment of physical activity is not included in the core set

of disease outcomes and measuring instruments as recommended by the ASAS/Outcome

Measures in Rheumatology Clinical Trials (OMERACT) working group [10]. Therefore, we

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have developed a disease-specific physical activity questionnaire in collaboration with axial

SpA patients and experts (chapter 11). Data obtained from the axSpA-SQUASH will provide

insight into the performed activities and perceived intensity of axial SpA patients during

transport, work, household, and leisure time, including sports. Data can be used to develop

physical activity guidelines and to investigate the relationships with disease outcome and

other lifestyle factors. According to axial SpA patients and experts, this disease-specific

physical activity questionnaire would be a relevant addition to other measuring instruments

proposed by the ASAS/OMERACT working group for axial SpA. The next step will be further

validation of the axSpA-SQUASH, which was beyond the scope of this thesis.

CONCLUSIONS

The studies in this thesis provided an overview of bone-related outcome and its associations

with patient characteristics in a large, prospective, observational cohort study of axial SpA

patients in the daily clinical practice.

The deflection in spinal radiographic progression with reducing progression rates during

treatment with TNF-α inhibitors may suggest that long-term treatment with these drugs

can reduce radiographic progression. However, the assessment of spinal radiographic

progression is challenging in axial SpA because of the overall slow process of bone formation

and large variation between individual patients. The composite scoring method CASSS, in

which the cervical facet joints are incorporated in the mSASSS, seems a promising scoring

method that can detect more patients with spinal radiographic damage and progression.

Radiographic vertebral fractures were frequently observed in axial SpA. In daily clinical

practice, a stepwise approach with routinely assessing the occiput-to-wall distance in

combination with radiography of the thoracic and lumbar spine will help clinicians to detect

these fractures in axial SpA.

The expression of the disease can differ between axial SpA patients. Male patients were more

prone to develop spinal radiographic damage whereas female patients experienced their

symptoms as more severe than male patients. These gender differences should be taken

into account in clinical decision making. Also the influence of lifestyle factors on disease

outcome should be taken into account. Smoking and higher BMI were associated with poor

268

bone-related and clinical outcome. Promoting a healthy lifestyle, including cessation of

smoking, weight reduction in case of obesity, and supporting physical activity are important

goals in the management of axial SpA.

The axSpA-SQUASH is a disease-specific, self-reported questionnaire that can easily be used

in clinical studies, daily clinical practice, and for self-management. The axSpA-SQUASH will

give better insight into the level of daily physical activity of individual patients. This will help

us to develop more tailored advice in future concerning physical activity in axial SpA.

In addition to radiographic and clinical data as presented in this thesis, more data are

collected in the GLAS cohort. For example, serum, plasma, urine, and DNA samples are

collected every visit and bone turnover markers are measured. With all these data collected,

the GLAS cohort provides very valuable data of axial SpA patients in the daily clinical practice.

Combining these data with other axial SpA cohorts will increase the current knowledge

about the disease course during treatment in daily clinical practice. Furthermore, the GLAS

cohort provides data to further investigate the underlying pathophysiological mechanisms

of excessive bone formation and bone loss in axial SpA.

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