1. Ankylosing spondylitis
Dr Chris Edwards

2. Prevalence

3. Worldwide prevalence up to 0.9%1
Prevalence varies by population and is closely correlated to prevalence of HLA-B272
Prevalence also varies among ethnic groups
Male:Female – 5:1
Peak age of onset: 15 – 35 years
1. Braun et al. Arthritis Rheum 1998; 41: Sieper J et al. Ann Rheum Dis 2002; 61 (Suppl. III): iii8-18.

4. Co-morbidity & co-mortality

5. There may also be extra-articular manifestations of AS.
Spinal fracture - most serious complication encountered in AS
Prostatitis is prevalent among men with AS
Long-term disease increases risk of cardiovascular complications
Acute anterior uveitis occurs in 20% to 40% of cases. Other extra-articular manifestations include aortic regurgitation, pulmonary fibrosis, and, among male patients, prostatitis
Sieper J et al. Ann Rheum Dis 2002; 61 (Suppl. III): iii8-18.

6. Disease burden – cost impact

7. Etanercept provides a rapid reduction in:
disease activity
Objective functional measures
Work instability
This suggests that therapy may be cost effective in terms of work disability
Barkham N et al Ann Rheum Dis 2008; 67 (suppl II) : 382

8. Productivity Costs of ankylosing spondylitis in the USA, The Netherlands, France and Belgium
USA (n=241)
Netherlands (n=130)
France (n= 53)
Belgium (n= 26)
Work disability (%) 12
41*
23* 9*
Days sick leave pt/y; † mean (range)
Not stated
19 (0–130)
6 (0–77)
9 (0–60)
Friction costs/pt/y: † mean (range)
Not applied
€1257 (0–7356)
€428 (0–5979)
€476 (0–2354)
Human capital costs/pt/y; mean (range)
US $4945 (0–45800)
€4227 (0–39145)‡
€8862 (0–46818)
€3188 (0–43550)
€3609 (0–34320)
*Adjusted for age and sex. Includes patients with partial work disability who continue in a part-time paid job in The Netherlands and France † in those with a paid job ‡ converted to Euros using 1998 purchasing power parities
Sieper J et al. Ann Rheum Dis 2002; 61 (Suppl. III): iii8-18.

9. Disease burden – quality of life impact

10. Understanding the burden of disease
Quality of Life
An individuals’ perception of their position in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards and concerns
World Health Organisation (1995)
Health:
is a complete state of physical, mental, and social well-being and not merely the absence of disease or infirmity
World Health Organisation (1947)
BoD in AS – less well understood than RA – but in recent years increase in our understanding
To measure health we need to define it.
Quality of Life – no consensus on definition
- generally an inclusive approach to health is recommended – including physical, emotional and social well-being.
Most widely cited definition – recently developed further with the International Classification of Disease – provides a comprehensive framework for considering the consequences of health and disease.
Definition recognises health as multi-dimensional; recognises the positive and negative aspects of health.
The definition has informed a number of instruments.

11. Quality of Life Physical function Symptoms Global health
ADL, mobility, physical activity
Symptoms
Pain, sleep, stiffness, fatigue
Global health
Social well-being
Relationships, opportunities, sexual activity and satisfaction
Role activities
Employment, household management
Emotional well-being
Anxiety, control, self-esteem
Cognitive function
Cognition, concentration, memory
Personal constructs
Life satisfaction, stigma,
Bodily appearance, spirituality
QoL influenced by main disease disability pathways and factors external to this pathway – eg educatin and psychosocial characteristics
List: domains of health most commonly identified in the literature as relevant to PROMs.
Range from those most obviously related to a patient’s health status – global view, symptoms, emotional wb to tose reflecting a broader view of health / life – social function, role activity.
Some domains poorly explored in literature – such as body impact, sense of embarrassment or stigma associated with some health problems.
When list from UK survey grouped:
Role activities – 1
Symptoms – 4
Personal construct – 2
Physical function – 7
Emotional wb – 3
Social wb - 7

12. Work disability: AS-specific
Employment rates range 55–85%
50% of studies report < 70%
Work disability rates range 3–41%
50% of studies report > 20%
Risk factors:
Age
Disease duration
Physical function**
Pain
Physically demanding jobs
Lower education level
WD in AS can often be masked – but increasing evidence that AS influences career decisions.
AS-specific
Employment rates range 55-85%
50% of studies report rates < 70%
Work disability
rates range 3-41%
50% of studies report rates > 20%
Higher employment rates for AS v RA. – see also compared to other rheum conditions
But much lower than general pop (but not for women?)
Workforce Withdrawal (Boonen 2001)
Yearly increase: 5% first year
13% 5yrs
21% 10yrs
23% 15yrs
31% 20yrs
Age and sex adjusted risk of withdrawal 3.1x higher than general Dutch pop.
ick
Risk factor – include: older age at diagnosis; manual work; coping strategies
Psychosocial impact of Work Disability
Majority –ve views
Frustration, inadequacy, reduced choice,
dependency, reduced self-esteem
Few +ve views
Positive mood, less pressured,
‘life has new meaning’
Sieper et al, 2002; Boonen et al, 2001

13. Work disability: AS-specific
Workforce withdrawal
1st year 5%
5 years 13%
10 years 21%
15 years 23%
20 years 31%
3.1x higher than general population
WD in AS can often be masked – but increasing evidence that AS influences career decisions.
AS-specific
Employment rates range 55-85%
50% of studies report rates < 70%
Work disability
rates range 3-41%
50% of studies report rates > 20%
Higher employment rates for AS v RA. – see also compared to other rheum conditions
But much lower than general pop (but not for women?)
Workforce Withdrawal (Boonen 2001)
Yearly increase: 5% first year
13% 5yrs
21% 10yrs
23% 15yrs
31% 20yrs
Age and sex adjusted risk of withdrawal 3.1x higher than general Dutch pop.
ick
Risk factor – include: older age at diagnosis; manual work; coping strategies
Psychosocial impact of Work Disability
Majority –ve views
Frustration, inadequacy, reduced choice,
dependency, reduced self-esteem
Few +ve views
Positive mood, less pressured,
‘life has new meaning’
Sieper et al, 2002; Boonen et al, 2001

14. Social well-being Older studies suggest few problems
Intimate relationships
Men no problems; women less enjoyment (Elst et al, 1984)
Few report marital strain / avoidance (Dalyan et al, 1999)
27% mild discomfort; 7% severe discomfort (Wordsworth et al, 1986)
Impact on daily life (n 129) - % reporting limitations:
1% social interactions
2% communication
3% normal role activities
6% leisure activities
Little research
Bakker – impact on daily routine activities (n= 129) – few reported difficulties with social function: 6% leisure, 3% role activities, 2% communication, 1% social interaction.
Sexual health
Wordsworth (survey of n=100)
(Bakker et al, 1995)

15. Social well-being: AS and RA
Health status comparison: SF-36 generic health status
AS better Physical health
RA better Mental health
No group differences for:
SF-36: Pain, Physical or Emotional-Role functioning, Social Function, Vitality or General Health
Fatigue (MFI) or Behavioural Coping (CORS)
Work: +ve association with physical health in both groups
No studies comparing impact of AS directly to general population??? – but numerous comparing RA and GP
Norm based scoring of SF-36 – supports interpretation
MFI Multidimensional Fatigue Inventory
CORS Coping with Rheumatic Stressors
Chorus et al, 2003

16. SF-36 scores for patients with RA and patients with AS
100 80
RA male 60
AS male 40
RA female
Comparison between RA and AS patients
SF-36 generic health status
AS better Physical health
RA better Mental health
No group differences for:
Pain, Physical or Emotional-Role functioning, Social Function, Vitality or General Health (all SF-36)
Fatigue (MFI) or Behavioural Coping (CORS)
Work: +ve association with physical health in both groups 20
AS female
Physical Component
Mental Component
Summary
Summary
Chorus et al, 2003

17. Immunology and pathogenesis

18. Pathogenesis Immune-mediated, involving: HLA-B27
Inflammatory cellular infiltrates
Cytokines such as TNFα and IL-10
Genetic and environmental factors
Sieper J et al. Ann Rheum Dis 2002; 61 (Suppl. III): iii8-18.

19. Diagnosis

20. AS/SpA: Characteristic Parameters Used for Early Diagnosis
Symptoms
Inflammatory
Back Pain
Imaging
Lab
HLA-B27
ESR/CRP
Patient’s
history
Good response
to NSAIDs
Family history
Rudwaleit M, et al. Ann Rheum Dis. 2004;63:535-43

21. AS/Axial SpA: Typical Manifestations/Features
Sensitivity
Specificity
LR+
LR-
Inflammatory back pain
75%
76%
3.1
0.33
Enthesitis (heel pain)
37%
89%
3.4
Peripheral arthritis
40%
90%
4.0
Dactylitis
18%
96%
4.5
Anterior uveitis
22%
97%
7.3
Positive family history for SpA
32%
95%
6.4
0.29
Psoriasis
10%
3.3
Inflammatory bowel disease 4%
99%
Good response to NSAIDs
77%
85%
5.1
0.27
Elevated acute phase reactants
50%
80%
2.5
HLA-B27 (axial involvement)
9.0
0.11
MRI (STIR)
Positive likelihood ratio (LR+) = sensitivity/(100-specificity)
Negative likelihood ratio (LR-) = (100-sensitivity/specificity)
Rudwaleit M, et al. Ann Rheum Dis. 2004;63:535-43
Rudwaleit M, Feldtkeller E. and Sieper J. Ann Rheum Dis 2007;. In press.

22. Spondyloarthritis - main manifestations
Axial involvement/spinal inflammation
Peripheral arthritis
Peripheral enthesitis
Axial SpA
SpA subtypes
Ankylosing spondylitis (AS)
Undifferentiated SpA
Psoriatic SpA
Reactive SpA
SpA associated with chronic inflammatory bowel diseases AS

23. Ankylosing Spondylitis: a chronic inflammatory rheumatic disease with debilitating potential
24 years
main affection of the spine, entheses, peripheral joints and the eye
main symptom: inflammatory back pain
1/3 of patients with severe disease
overall prevalence high (0.5%)
etiology unknown
definite genetic load (new genes !)
strong HLA B27 association
late diagnosis (5-7 years)
reduced quality of life
increased risk of unemployment
direct/indirect costs AS
49 years
Zink A et al, J Rheum 2000, 2001; Boonen A et al., Ann Rheum Dis 2001, 2002, Ward M et al. J Rheum 2001, A&R 2002

24. Possible Outcomes of Ankylosing Spondylitis

25. Age at Onset of Symptoms and Age at Diagnosis in AS (DVMB)
Time from first symptoms to diagnosis: 5–10 yrs
100
Age at onset of
symptoms 80
Age at diagnosis 60
Patients (%) 40
n=1396 20
920 males
476 females
Age (yrs) 10 20 30 40 50 60 70
Feldtkeller E, et al. Z Rheumatol. 1999;58:21-30.
Feldtkeller E, et al. Rheumatol Int. 2003;23:61-6.

26. Diagnosis of IBP if 2 / 4 criteria are fulfilled
Differentiating clinical features of IBP in patients < 45 years with chronic back pain
( > 3 months )
Morning stiffness > 30 min
Improvement with exercise, not with rest
Awakening at 2. half of the night because of pain
Alternating buttock pain * * * *
Diagnosis of IBP if 2 / 4 criteria are fulfilled
sensitivity %
specificity %
(AS n = 101; non-AS back pain n = 112)
Rudwaleit M et al. A&R 2006

27. Use of the new IBP criteria as diagnostic criteria in individual patients
Morning stifness > 30 min
Improvement by movement, but not rest
Wakening up in the 2nd half of the night because of pain
Alternating buttock pain
≥ 2 out of 4 positive
Sensitivity 70.3%
Specificity 81.2%
LR+ 3.7
≥ 3 out of 4 positive
Sensitivity 33.6%
Specificity 97.3%
LR+ 12.4
Rudwaleit et al. Arthritis Rheum 2006;54:678-81

28. X-ray evidence of sacroiliitis: a prerequisite for diagnosing AS (modified NY criteria 1984)
van der Linden Arthritis Rheum 1984

29. A role for magnetic resonance imaging in the diagnosis of early sacroiliitis in pondyloarthritides
Active sacroiliac inflammation
Braun J et al. A&R 1994

30. The diagnostic value of scintigraphy in assessing sacroiliitis in AS - a systematic literature research
Out of a total of 99 articles about scintigraphy found, 25 were included into the analysis.
Overall sensitivity for scintigraphy to detect sacroiliitis was 52 % for patients with established AS (N= 361) and 49 % for patients with probable sacroiliitis (N= 255).
Sensitivity of scintigraphy in AS patients with inflammatory back pain (indicating ongoing inflammation) was 53 % (N= 112) and in patients with AS and suspected sacroiliitis with magnetic resonance imaging showing acute sacroiliitis (as a gold standard) was 53 % (N=62).
In controls with MLBP specificity was 78 % (N= 60), resulting in LRs not higher than
The data suggest that scintigraphy of the sacroiliac joints is at the most of limited diagnostic value for the diagnosis of established AS including the early diagnosis of probable / suspected sacroiliitis.
Song I et al. Ann Rheum Dis Jan 29 [Epub ahead of print]

31. Early back pain cohort: clinical items vs
Early back pain cohort: clinical items vs. imaging for the diagnosis of spondyloarthritis
n = 69 with IBP < 2 years
Heuft-Dorenbosch L et al. Ann Rheum Dis Jun;65(6): Epub 2005 Oct 11

32. What is helpful for an early diagnosis of AS ?
Screen young patients ( < 45 y) with back pain > 3 months
Ask for inflammatory back pain
Ask for other signs of spondyloarthritis (uveitis, enthesitis)
Do the HLA B27 test
Add imaging when necessary (MRI, X-rays)

33. AS assessment tools

34. AS Measures of Disease Outcome
Bath Ankylosing Spondylitis (BAS) scales
BASDAI – Disease Activity Index
BASFI – Functional Index
BASGI – Global Index
BASMI – Metrology Index
BASRI – Radiographic Index
Other measurement indexes
SF-36 – 36-Item Medical Outcomes Study Short-Form Health Survey
ASAS – Assessments in Ankylosing Spondylitis Working Group Improvement Criteria

35. Disease Activity Assessment
Index
Metric
BASFI
Disability Level
BASDAI
Disease Activity Level
BASMI
Spinal Mobility
ASAS - IC
Composite Sum of Disease Activity
BASFI = Bath Ankylosing Spondylitis Functional Index
BASDAI = Bath Ankylosing Spondylitis Disease Activity Index
BASMI = Bath Ankylosing Spondylitis Metrology Index
ASAS - IC = ASsessment in Ankylosing Spondylitis Improvement Criteria

36. Bath Ankylosing Spondylitis Functional Index (BASFI)
Visual analogue scale
Easy (1) – impossible (10)
Mean (VAS) of 10 questions:
Putting on your socks or tights without help or aids
Bending forward from the waist to pick up a pen from the floor without an aid
Reaching up to a high shelf without help or aids (e.g helping hand)
Getting up out of an armless dining room chair without using your hands or other help
Getting up off the floor without help from lying on your back
Standing unsupported for ten minutes without discomfort?
Climbing steps without using a handrail or walking aid (one foot on each step)?
Looking over your shoulder without turning your body?
Doing physically demanding activities (eg physio exercises, gardening, sport)?
Doing a full day’s activities at home or at work?
relate to the functional anatomy of subjects
relate to a subject’s ability to cope with everyday life
Calin, J Rheumatol 1994;21:

37. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)
Visual analogue scale (0 – 10 cm)
None (1) – Very severe (10)
Fatigue - How would you describe the overall level of fatigue/tiredness you have experienced?
Spinal pain - How would you describe the overall level of AS neck, back or hip pain you have had?
Joint pain - How would you describe the overall level of pain/swelling in joints other than neck, back or hips you have had?
Enthesitis - How would you describe the overall level of discomfort you have had from any areas tender to touch or pressure?
Inflammation:
Duration morning stiffness - How would you describe the overall level of morning stiffness you have had from the time you wake up?
Severity morning stiffness - How long does your morning stiffness last from the time you wake up? (scale of 0 to >2 hrs)
BASDAI =
0.2 [F + S + J + E (Duration + Severity Morning Stiffness)]
Range 0 – 10
Garrett, J Rheumatol 1994;21:

38. Bath Ankylosing Spondylitis Metrology Index (BASMI)
Represented as aggregate score (ranging from 0 to 10) using the variables below
Score
Measurement 1 2
Tragus-to-wall
< 15 cm
15 to 30 cm
>30 cm
Lumbar flexion (modified Schober test)
> 4 cm
2 to 4 cm
< 4 cm
Cervical rotation
> 70º
20 to 70º
< 20º
Lumbar side flexion
> 10 cm
5 to 10 cm
< 5 cm
Intermalleolar distance
> 100 cm
70 to 100 cm
< 70 cm
Jenkinson, J Rheumatol 1994;21:

39. Objectives of disease management
Reduce and/or prevent deleterious effects of:
Inflammation
Ankylosis
Abnormal posture
Aim for:
No or low disease activity (pain, stiffness, MRI, CRP)
Good function, no disability
No structural damage (no growth of syndesmophytes)
Good quality of life
No increased cardiovascular morbidity
Normal life expectancy
Dougados M et al. J.Rheumatol 2001;28-62:16-20