1. ASAS – recent achievements
General remarks
Improvement Criteria
Anti-TNF Treatment recommendations
Prof.J.Braun
Rheumazentrum Ruhrgebiet
Herne
Free University Berlin
Germany

2. SpA subtypes AS Ankylosing spondylitis (AS) Undifferentiated SpA
EULAR proposal for terminology: Spondyloarthritis (SpA) Francois R, Eulderink F, Bywaters EGL. Ann Rheum Dis 1995; 54:
SpA subtypes
Ankylosing spondylitis (AS)
Undifferentiated SpA
Psoriatic SpA
Reactive SpA
SpA associated with chronic inflammatory bowel diseases
Outcome ! AS

3. Modified New York Criteria 1984 for Diagnosis/Classification of Ankylosing Spondylitis
van der Linden et al. A & R 1984
Clinical Criteria
inflammatory back pain (Calin 1977)
reduced spinal mobility in 2 planes ( < 3 cm)
reduced thoracic excursion (< 3cm)
Radiologic Criterium
sacroiliitis of > grade II bilat, > grade II unilat

4. ESSG Criteria 1991 for Spondyloarthritis
Dougados M et al. A&R 1991
2 major criteria
inflammatory back pain
asymmetric oligoarthritis of the lower limbs
7 minor criteria
enthesitis (heel)
alternating buttock pain
sacroiliitis (radiographic)
family history of SpA
psoriasis
inflammatory bowel disease
symptomatic preceding infection (urogenital, enteral)

5. Undifferentiated Spondyloarthritis
unequivocal SpA symptoms, but no definitive
Spondylitis ankylosans
Psoriatic arthritis
Reactive arthritis
Arthritis associated with CED
covers
early cases
abortive forms
overlaps, transitions
differentiation towards
AS sacroiliitis < grade II
ReA clinical picture, antibodies, PCR
30-50% development of AS

6. Assessments in Spondyloarthritides
Diagnosis
5 subgroups (AS, PSpA, uSpA, RSpA, SpAIBD)
Outcome, Monitoring
Disease activity (BASDAI)
Pain (VAS, NRS scales)
Patient global assessment (VAS, NRS scales)
Inflammation (morning stiffness, CRP, ESR)
Localisation (axial, peripheral, organ manifestations)
Spinal mobility (BASMI)
Function (BASFI)
Damage (mod. SASSS, BASRI, MRI score)
Quality of life (SF-36, AS-Quol)

7. Ankylosing spondylitis - detection of spinal inflammation by MRI
Braun J et al. Rheum Dis Clin North Am 1998; 24:
Brandt J et al. Arthritis Rheum 2000; 43:

8. Scoring active spinal inflammation in ankylosing spondylitis by ASspiMRI-a
Braun J, van der Heijde D. Best Pract Res Clin Rheumatol 2002 Sep;16(4):

9. Relative changes of MRI scores on infliximab (n=9) or placebo (n=11) therapy
Post-Gad STIR T1
%-change
Braun J et al., Arthritis Rheum 2003 April; 48: 1126

10. Assessments in Spondyloarthritides
Inflammatory back pain
(questionnaires, pain scales)
Spinal mobility
BASMI, chest expansion, lat. Schober
Joint counts
(44 J.C.)
Enthesitis scores
(MASES, ..)
Dactylitis
Organ involvement
anterior uveitis (n flares)
psoriasis
colitis
other organ involvement

11. ASAS working group criteria for improvement and remission in AS
(JJ Anderson, D van der Heijde, DT Felson, M Dougados. A&R 2001;)
20% Improvement:
improvement of at least 20% and absolute improvement of
at least 10 on a scale in at least 3 of the following domains:
Patient global
Pain
Function (BASFI)
Inflammation (last 2 questions of the BASDAI on morning stiffness)
and
absence of deterioration of at least 20% and absolute change of
at least 10 on a scale in the potential remaining domain
Partial remission:
a value below 20 on a scale in each of the 4 domains

12. Improvement criteria for treatment with biologics in AS – a data driven analysis based on the RCT with Infliximab (n=69)
Domains: 1. Metrology (BASMI) 4. Patients global (VAS)
2. CRP 5. Function (BASFI)
3. Pain on VAS 6. Morning stiffness/BASDAI
Improvement definition
% improving in the placebo-treated group
% improving in the infliximab-treated group 2
 20% change in any 5 of 6
2.9
67.7
31.9
 20% change in any 4 of 5
(without CRP)
8.6
76.5
32.6
 30% change in any 4 of 6
5.7
64.7
26.5
(incl. BASDAI instead of Morning stiffness)
5,7
67,6
28,6
Reference criteria
 50% change of the BASDAI
58.8
19.6
 40% change of the BASDAI
23.5
 50% ASAS
52.9
18.7
 40% ASAS

13. Development of a consensus on anti-TNF
Therapy in ankylosing spondylitis
1st Meeting in Berlin in January 2002
First Questionnaire Results
ASAS Delphi Exercise (M.Dougados)
ASAS Meeting Stockholm: decision
Preparation of 2nd Berlin Meeting
ASAS Delphi exercise
2nd Meeting in Berlin in January 2003
Publication of two papers in Ann Rheum Dis 9/2003
ASAS consensus
Results of Delphi exercise

14. ASAS members participation
First questionnaire
Full ASAS members participation : 61% (36/59)
Second questionnaire
Full ASAS members participation : 56% (33/59)

15. Question 1 ASAS members estimation
Percentage of patients potentially candidate for biologics

16. Question 3
Do you consider that the sensitivity and specificity of the future practice guidelines for biologics in AS should be assessed ? (gold standard = rheumatologists’ opinion)
Yes : 89%
If yes, do you consider that sensitivity and specificity should be assessed before publishing the ASAS recommendations?
Yes : 52% No : 48%

17. EBM and/or Experts’ opinion: 88%
Question 1
Should we go for strict guidelines (high thresholds) or for flexible guidelines (low thresholds)?
Strict : 40%
Flexible : 60%
Must the guidelines and proposed cut-offs always evidence based, or experts agreed, where evidence is lacking?
Strict EBM : 12%
EBM and/or Experts’ opinion: 88%
Question 2

18. When can biologics initiation can be considered, in daily practice?
Topic 1
When can biologics initiation can be considered, in daily practice?

19. Question 4
Do you agree with the separation into 3 categories : isolated axial involvement, peripheral arthritis, enthesitis?
Yes : 71%
Disagreement was mainly because :
artificial separation
frequent association of the 3 categories, especially enthesitis with the 2 others  “enthesitis should not be considered as a distinct entity”
does not take into account the “weight” of the different categories (one swollen joint or one painful enthesis doesn't seem strong enough as convincing indication)

20. Question 5 (1/3)
Are the criteria selected by the Delphi exercise for axial involvement acceptable for you?
Yes : 75%

21. Number of ASAS members who selected the item
Question 5 (2/3)
Disagreement was because :
5a. Chosen variables
Refractory to NSAIDs 0
Patient’s global assessment 0
Inflammatory pain 0
Functional impairment 1
Laboratory parameters (ESR, CRP) 3
Number of ASAS members who selected the item
5b. Chosen cut off
 2 NSAIDs (Refractory to NSAIDs) 2
VAS  40 mm (Patient’s global assessment) 3
VAS  40 mm (Inflammatory pain) 3
BASFI  40 (Functional impairment ) 2
ESR > 28 (Laboratory parameters) 3
abnormal range CRP (Laboratory parameters) 3

22. Number of ASAS members who selected the item
Question 5 (3/3)
Disagreement was because :
Number of ASAS members who selected the item
5c. 3 of 4 rule
Biologics initiation can be based on patient derived variables only 5
Biologics initiation can be considered for patient without pain 3
Function is not relevant to consider biologics initiation 2
Pain is not relevant enough to consider biologics initiation 0
Patient’s global is not relevant enough 1
BASDAI is more relevant
Other propositions
Objective parameters needed 3
Lacking past history and severity of the disease 1
Should treat patients equally irrespective of ESR or CRP 1
3 months duration NSAIDs period too long 1

23. Question 7 (1/3)
Are the criteria selected by the Delphi exercise for enthesitis presentation acceptable for you?
Yes : 69%

24. Question 8
How do you rate the view considering 3 groups of variables (patient derived variables, physician derived variables, technical) compared to the results of the Delphi exercise?
Much better %
Somewhat better %
Similar %
Somewhat worse %
Much worse 0%
I don’t know 3%
41%
22%

25. Question 4
Concerning the initiation of biologics in AS, which of the following do you feel should be considered?

26. Question 10 (1/3)
Concerning the objective assessments, what is your opinion concerning the definition of an active disease?

27. Variables to collect in order to evaluate biologics efficacy
Question 12 (1/2)
Variables to collect in order to evaluate biologics efficacy
Acute phase reactants
Function
Spinal mobility

28. International ASAS consensus statement for the clinical use of anti-TNFa-treatment in patients with Ankylosing Spondylitis in daily practice
Jürgen Braun, Thao Pham, Jochen Sieper, John Davis, Sjef van der Linden, Maxime Dougados and Désirée van der Heijde for the ASAS Working Group
Berlin, Herne, Marseille, San Francisco, Paris, Maastricht

29. List of ASAS members/ participants/questionnaire co-workers
1.   Adebajo A O, UK
2.   Amor B, France
3.   Boers M, NL
4.   Boonen A, NL
5.   Bosch van den, F, Belgium
6.   Brandt J, Germany
7.   Braun J, Germany *
8.   Burgos Vargas R, Mexico
9.   Calin A, UK
10. Clegg D, USA
11. Collantes Estevez E, Spain
12. Darmawan J, Indonesia
13. Davis J, USA *
14. Dougados M, France *
15. Dijkmans B A C, NL
16. Edmonds J, Australia
17. Emery P, UK
18. Feltelius N, Sweden
19. Géher P, Hungary
20. Guillemin F, France
21. Heijde van der D, NL*
22. Horst v.d.-Bruinsma I, NL
23. Khan MA, USA
24. Kirazli J, Turkey
25. Kuipers J, Germany
26. Landewé R, NL
27. Leirisalo-Repo M, Finland
28. Linden v. d. S, NL *
29. Linssen A., NL
30. Listing J, Germany
31. Maetzel A, Canada
32. Maksymowych W, Canada
33. Mielants H, Belgium
34. Olivieri I., Italy
35. Peloso P, USA
36. Pham T, France
37. Reveille J, USA
38. Riel van, NL
39. Rudwaleit M, Germany
40. Russell A S, Canada
41. Salvarani, C., Italy
42. Sieper J., Germany *
43. Stone M A, Canada
44. Sturrock R, UK
45. Yu, D, USA
46. Zeidler H, Germany
* Steering Committee
Members of ASAS

30. Why are guidelines for the use of anti-TNFa treatment in AS needed?
Introduction of anti-TNF agents has led to new therapeutic opportunities in the spondyloarthritides
Efficacy of infliximab and etanercept in AS
Approval of infliximab and etanercept for AS
Uncertainty regarding the optimal use and potential side effects on anti-TNF agents
Considerable costs of anti -TNF therapy

31. Methodology employed to develop the guidelines
Review of the current literature
Expert opinion
Delphi exercise
Consensus meeting of the international assessment in AS (ASAS) working group

32. Questions concerning the use of anti-TNFa therapy in AS
What patients are appropriate candidates to consider for anti-TNF therapy ?
How should response to anti-TNF therapy be measured ?
When should anti-TNF therapy be continued and discontinued ?

33. What patients are candidates to consider for anti-TNFa therapy?
Persistence of active disease
Threat of severe disease (damage)
Likelihood of response to therapy

34. International consensus on anti-TNFa therapy in ankylosing spondylitis
Diagnosis
Disease activity
Failure of conventional Treatment
Absence of contraindications
Monitoring
Discontinuation
Initiation
Monitoring
Discontinuation
ASAS Meeting in Berlin January 2003
Braun J et al. Ann Rheum Dis 9/2003

35. 1. Diagnosis of ankylosing spondylitis
Patients ‘normally’ fulfilling the modified New York Criteria for definitive AS (1984 van der Linden et al.)
Radiological criterion
Sacroiliitis, grade  II bilaterally
or grade III to IV unilaterally

36. 1. Diagnosis of ankylosing spondylitis
Clinical criteria (1 out of the following 3)
Low back pain and stiffness for more than 3 months that improves with exercise but is not relieved by rest
Limitation of motion of the lumbar spine in both the sagittal and frontal planes
Limitation of chest expansion relative to normal values correlated for age and sex

37. 2. Disease activity before anti-TNFa therapy
I. active disease for at least 4 weeks
II. BASDAI  4 (0-10) and an expert* opinion**
  * The expert is a physician, usually a rheumatologist, with expertise in inflammatory back pain and the use of biologics. The expert should be locally defined.
** An expert opinion is comprised of both clinical features (history and examination) and either serum acute phase reactant levels or imaging results, such as radiographs demonstrating rapid progression or MRI scans indicating inflammation.

38. 3. Treatment failure before anti-TNFa therapy
Different for patients with predominantly
Axial disease
Peripheral disease
Entheseal disease

39. 3. Treatment failure before anti-TNFa therapy
All patients must have had adequate therapeutic trials of at least 2 NSAIDs.
An adequate therapeutic trial is defined as :
Treatment for at least 3 months at maximal recommended or tolerated anti-inflammatory dose unless contraindicated
Treatment for < 3 months where treatment was withdrawn because of intolerance, toxicity, or contraindications.

40. 3. Treatment failure before anti-TNFa therapy
Patients with symptomatic peripheral arthritis (normally having or failing local steroid injection for those with oligoarticular involvement) must have had adequate therapeutic trial of both NSAIDs and salazopyrine*
Salazopyrine:
Treatment for at least 4 months at standard target dose or maximally tolerated dose unless contraindicated or not tolerated.
Treatment for less than 4 months, where treatment was withdrawn because of intolerance or toxicity or contraindicated.

41. 3. Treatment failure before anti-TNFa therapy
Patients with symptomatic enthesitis must have had an adequate therapeutic trial of at least two local steroid injections unless contraindicated.

42. 4. Contraindications for anti-TNFa therapy
active infection
patients at high risk of infection including:
chronic leg ulcer
previous tuberculosis (note: please follow local recommendations for prevention or treatment)
septic arthritis of a native joint within the last 12 months
sepsis of a prosthetic joint within the last 12 months, or indefinitely if the joint remains in situ
persistent or recurrent chest infections
Indwelling urinary catheter

43. 4. Contraindications for anti-TNFa therapy
women who are pregnant or breastfeeding;
effective contraception must be practiced
history of Lupus or Multiple Sclerosis
malignancy or pre-malignancy states excluding
basal cell carcinoma
malignancies diagnosed and treated more than 10 years previously (where the probability of total cure is very high)

44. 5. Monitoring of anti-TNFa therapy
BASDAI
ASAS core set

45. BASDAI (0 – 10) [past week, VAS, NRS]
fatigue/tiredness
neck, back, or hip pain
pain/swelling in joints other than neck, back or hips
discomfort from any areas tender to touch or pressure
duration and intensity of morning stiffness from time of awakening (up to 120 minutes)

46. ASAS core set of assessments for daily practice
Physical function (BASFI or Dougados functional index)
Pain (VAS, last week, spine at night, due to AS and VAS, last week, spine due to AS)
Spinal mobility (chest expansion and modified Schober and occiput to wall distance and lateral lumbar flexion)
Patient’s global assessment (VAS, last week)
Stiffness (duration of morning stiffness, spine, last week)
Peripheral joints and entheses (number of swollen joints [44 joints count], enthesitis score such as developed in Maastricht, Berlin or San Francisco)
Acute phase reactants (ESR or CRP)
Fatigue (VAS)
van der Heijde et al. J Rheumatol 1997

47. 6. Discontinuation of anti-TNFa therapy
< 50% relative change or absolute change of 20 mm of BASDAI and Expert Opinion : Continuation yes/no
after 6 to 12 weeks of treatment

48. Further development Implementation in clinical practice
Regular update (2005)
Recommendations will be published in the Annals of Rheumatic Diseases and become available on the website of the ARD and ASAS
(publication of U.S.- specific Comments)

49. Personal proposal:
link PsA working group to ASAS
Future:
Assessments in SpA working group ?