Pre Meeting Questionnaire Results

1
ASAS recent achievements

• General remarks
• Improvement Criteria
• Anti-TNF Treatment recommendations

Prof.J.Braun Rheumazentrum Ruhrgebiet Herne Free
University Berlin Germany
2
EULAR proposal for terminology Spondyloarthritis
(SpA)Francois R, Eulderink F, Bywaters EGL. Ann
Rheum Dis 1995 54615-625

• 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 ( lt 3 cm)
• reduced thoracic excursion (lt 3cm)
• Radiologic Criterium
• sacroiliitis of gt grade II bilat, gt grade II
  unilat

4
ESSG Criteria 1991 for Spondyloarthritis
Dougados M et al. AR 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 lt 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
697-735 Brandt J et al. Arthritis Rheum 2000 43
1346-52
8
Scoring active spinal inflammation in ankylosing
spondylitis by ASspiMRI-a
Braun J, van der Heijde D. Best Pract Res Clin
Rheumatol 2002 Sep16(4) 573-604
9
Relative changes of MRI scores on infliximab
(n9) or placebo (n11) 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. AR 2001)
20 Improvement

• improvement of at least 20 and absolute
  improvement of
• at least 10 on a 0-100 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 0-100 scale in the potential
  remaining domain

Partial remission

• a value below 20 on a 0-100 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 (n69)
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
? 20 change in any 4 of 5 (incl. BASDAI instead of Morning stiffness) 5,7 67,6 28,6
Reference criteria
? 50 change of the BASDAI 8.6 58.8 19.6
? 40 change of the BASDAI 8.6 64.7 23.5
? 50 ASAS 5.7 52.9 18.7
? 40 ASAS 5.7 64.7 26.5
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
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

• 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
Question 5 (2/3)

• 5b. Chosen cut off
• ? 2 NSAIDs (Refractory to NSAIDs) 2
• VAS ? 40 mm (Patients global assessment) 3
• VAS ? 40 mm (Inflammatory pain) 3
• BASFI ? 40 (Functional impairment ) 2
• ESR gt 28 (Laboratory parameters) 3
• abnormal range CRP (Laboratory parameters) 3

22
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
• Patients global is not relevant enough 1
• BASDAI is more relevant 3
• 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 11
• Somewhat better 30
• Similar 33
• Somewhat worse 22
• Much worse 0
• I dont 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
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

1. Diagnosis
2. Disease activity
3. Failure of conventional Treatment
4. Absence of contraindications
5. Monitoring
6. 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 lt 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)
• Patients 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

• lt 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 ?