Updates on AS

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Updates on AS Powered By Docstoc
					Updates on the use of
biologic therapies in AS

     Dr. Millicent Stone
   Noon Rounds,2/9/2003
    St. Michael’s Hospital
OBJECTIVES
 Rationale for TNF blockade in AS
     Background
 Evidence for TNF blockade in AS
     Recent updates from EULAR, 2003
 Burden of need for TNF blockade in AS
     ISSAS
 Patient selection for therapy
     GRAB
Ankylosing Spondylitis

 Common inflammatory disease of the spine
 Spinal deformity and disability

 Progressive with symptoms beginning in the
  2nd or 3rd and continuing into the 5th and 6th
  decade

 Prior to the advent of biologics no effective
  treatments
Delay in diagnosis from symptom onset




                           Calin et al J Rheumatol 2002
  Sacroilitis by MRI




Normal SI - SE T1      Fused SI - SE T1
TNF mRNA In Sacroiliac Biopsy In AS
                                           Inflamed
                                            sacroiliac joint of
                                            a young, female
                                            patient with AS
                                           3 years disease
                                            duration
                                           In situ
                                            hybridization



  Braun J et al. Arthritis Rheum. 1995.
   Sacroiliac Biopsy In Ankylosing
   Spondylitis




Bollow M, Braun J. Ann Rheum Dis. 2000.
Rationale for TNF blockade
 TNF- in AS
    Over-expression of TNF in mouse model produces
     AS like disease
    Serum compared to NILBP
    Abundant TNF- mRna in Sacroiliac joint biopsy
     specimens
 TNF promoter polymorphisms with functional
  significance
 Good therapeutic effect in other autoimmune
  disease, IBD, RA
      60% AS patients have sub clinical colitis
TNF receptor blockers
 Etanercept (embryl)
 Humira (adalimumab)
 Infliximab (remicade)
CASE REPORTS
 Case reports
     Early in disease course
     Advanced disease
 Case Report #1 Early disease

 Mr. DG, 34yr old male sports reporter, East
  Indian/Caribbean origin

 1998 AS   (modified New York criteria)


 2000 Spondylitis clinic, (for NASC study)
    Early am stiffness- several hours
    Pain throughout axial spine- constant
    Failed 2 NSAIDS
    BASDAI=8
BASDAI: INFLAMMATION
    BASDAI

    Please tick the box that indicates your answer to each question.
    All questions refer to last week.

    1. How would you describe the overall level of fatigue/tiredness you have experienced?
            0       1        2        3         4        5           6       7       8       9         10
    none                                                                                             very severe

    2. How would you describe the overall level of AS neck, back or hip pain you have had?

            0       1        2        3         4        5           6       7       8       9         10
    none                                                                                          very severe
    3. How would you describe the overall level of pain/swelling in the joints other than neck, back or hips you
    have had? (ie: peripheral joints)

            0       1        2        3         4        5           6       7               9         10
    none                                                                                      very severe
    4. How would you describe the overall level of discomfort you have had from any areas tender to touch or
    pressure?

           0       1        2        3        4         5           6       7       8       9        10
    none                                                                                       very severe
    5. How would you describe the overall level of mourning stiffness you have had from the time you wake
    up?

               0       1        2        3          4       5           6       7       8        9        10
    none                                                                                             very severe
    6. How long does your morning stiffness last from the time you wake up?

           0       1        2        3        4         5           6       7       8       9        10
    0 hr                                                     1 hr                                           2 or
                                                                                                          more hours
Examination
   Looked very healthy!
   General physical normal
   No extra-articular features
   Locomotor
       O-W=0, C-E=4.5, Schober’s=5, F-F=0
       C-Spine rotation by 10º all directions
       T-Spine rotation  by 40° right and left
       No peripheral joints involved,
       No enthesitis

       CRP mildly elevated/ESR Normal
       Progress
 05/2000: c/o TNF-blocker
       Excellent clinical response, except headaches++ few
        days after infusion
       BASDI=0 after one infusion

       Promotion at work




 12/2001:d/c (planning a family)
Progress
 04/2002: Recurrence of symptoms
 03/2003: Returned to Spondylitis Clinic
        BASDAI=9
        0-W=0, C-E=2.8, Schober’s=4.8, F-F=13
        C-spine rotation  20° (R&L),
        T-spine rotation 95°(R),40°(L)


 07/2003: Recommenced TNF-blocker,
  allergic reaction infusion stopped
Case#2 Advanced disease
 42 yr old male from Philippines (twin)
 1989: AS (modified New York criteria)
    Symptoms for 2 years prior to diagnosis
 1997-1999:
    Bilateral THR
 2000:
    Failed 3 NSAIDSs & Sulphasalazine
    C/o severe axial stiffness and pain
    No extra-articular manifestations, peripheral
     disease, or enthesopathy
Investigations
  X-ray- Bamboo spine

  Normal CRP & ESR

  Enhancement on C-
    spine, MRI
           SPINAL INFLAMMATION




BASELINE


           2 DAYS


                        2 WEEKS
Progress

    08/2000: c/o TNF-blocker
       Good clinical response (BASDAI from 8-5)
       Improvement noted on MRI, however
        abnormal LFT’s

    2003:
       Still doing well on Remicade
       But no structural change
        Uncontrolled studies
Study                  Patients      Trial duration MRI
                                     (weeks)
Infliximab
Van den Bosch 2000     21SpA         12

Brandt et al 2000      11            12           Yes(3)

Stone et al 2001       21            22           Yes(10)

Breban 2001 Abstract   50 AS axial   12

Maksymowytch 2002      21            12           Yes(6)

Etanercept
Marzo-Ortega           10 AS (E)     12        Yes(10)
        Randomized Controlled Studies in AS


Trial                     Patients   Trial duration   Px % Tx %

Infliximab

Braun et al 2002             75       12              8    53*
*50% improvement in BASDAI



Etanercept

Gorman et al 2002            40       16              30   80#
#
 20% improvement in 5/6
parameters
 Early studies difficult to draw comparisons
  across studies due to lack of common
  outcome measures
  DEFINITION OF RESPONSE TO
  TREATMENT IN AS TRIALS

              ASAS Response criteria

 20% relative improvement and >10 units of
  absolute improvement in 3 of 4 domains with no
  worsening in the third
     Function, inflammation, pain and patient global
      assessment


                               Anderson et al Arthritis Rheum 2001
Bath Ankylosing Spondylitis
Functional Index (BASFI)
  Used to evaluate functional ability

  BASFI is comprised and scored as follows:
     8 VAS regarding function scored:
      Easy 0 1 2 3 4 5 6 7 8 9 10 Impossible
     2 questions regarding ability to cope with daily
      life scored:
      Easy 0 1 2 3 4 5 6 7 8 9 10 Impossible
BASFI
        Please indicate your level of ability with each of the following activities during the last week.
        (An aid is a piece of equipment which helps you perform an action or movement)

        1. Putting on your socks or tights without help or aids (e.g. sock aid).

               0         1        2        3         4        5         6          7      8        9        10
        easy                                                                                             impossible

        2. Bending forward from the wait to pick up a pen from the floor without an aid.


        easy   0         1        2        3         4        5         6          7      8        9       10
                                                                                                         impossible

        3. Reaching up to a high shelf without help or aids (e.g. helping hand).

               0         1        2        3         4        5         6          7      8        9        10
        easy                                                                                             impossible

        4. Getting up out of an armless dining room chair without using your hands or any other help.

               0         1        2        3         4        5         6          7      8        9        10
        easy                                                                                             impossible

        5. Getting up off the floor without help from lying on your back.

               0         1        2        3         4        5         6          7      8        9        10
        easy                                                                                             impossible

        6. Standing unsupported for 10 minutes without discomfort.

               0         1        2        3         4        5         6          7      8        9        10
        easy                                                                                             impossible

        7. Climbing 12-15 steps without using a handrail or walking aid. One foot at each step.

               0         1        2        3         4        5         6          7      8        9        10
        easy                                                                                             impossible

        8. Looking over our shoulder without turning your body.

               0         1        2         3        4         5        6          7       8         9      10
        easy                                                                                             impossible

        9. Doing physically demanding activities (e.g. physiotherapy exercises, gardening or sports).

               0         1        2        3         4        5         6          7      8        9        10
        easy                                                                                             impossible

        10. Doing a full days activities, whether it be at home or at work.
               0         1        2        3         4        5         6          7      8        9        10
        easy                                                                                             impossible
Global Assessment: PTGA


       1. Please tick a box to indicate the effect your disease has had on your well-being over
       the last week.

              0     1       2       3       4      5       6       7      8       9     10
       none                                                                           very severe

       2. Please indicate the effect your disease has had on your well-being over the last six
       months.

              0     1       2       3      4       5       6       7      8       9     10
       none                                                                           very severe




                                                    Source:
                                                    Jones, SD., Steiner, A., Garrett, SL., and Calin A.. The Bath Ankylosing Spondylitis
                                                    Patient Global Score (BAS-G). British Journal of Rheumatology 1996;35:66-71.
BASMI:SPINAL MOBILITY
 Lateral bending
 Intermalleolar distance
 Occiput to wall
 Modified schober index
ASAS shortcomings
 Relative vs nominal
 No acute phase reactants
 No spinal assessment
 Validated in short term trials using NSAIDS
Abstract SP0111
van der Heijde Ann Rheum Dis 62(1) 35

 Assessing the efficacy of anti-TNF treatment
  AS disease modifying or disease controlling
  therapy for patients with AS

 Alternative definitions of Response
     ASAS 40
     5 out of 6 domains acute phase reactants and
      spinal mobility
Why not ask the patient??
 ASAS are valid criteria and compare well with
  Patient global assessment

 Pt GA may be a simpler more reliable for
  assessing improvement in individual patients

     Stone et al (under review ACR,2003)
OP 0005
Davis et al Ann Rheum Dis 2003;62(1): 65

 Randomized double-blind placebo-controlled multi-
  centre (30) trial of etanercept (n=138) vs placebo
  (n=139) in AS by modified New York criteria
      1:1 allocation


 Inclusion: active disease (patient global pain scores
  and BASDAI>4)
 Exclusion: ankylosis prior anti-TNF


 Other: stable NSAIDS/DMARDS and prednisone
  <10mg/day
 Outcomes

 Primary outcomes measure
     ASAS 20 at week 12
 Secondary outcomes
     ASAS 50, ASAS 70, partial remission

 Treatment: Etanercept 25mg sc twice weekly



                                     Davis et al 2003
Demographics of cohort
   Parameters             Placebo   Etanercept
                          (n=138)   (n=139)
   AGE                    41        42
   MALE (%)               75        76
   CAUCASIAN (%)          91        94
   Disease duration (yrs) 10.5      10.1
   (mean)
   HLA B27 +              84        84
   TJC                    8.7       8.0
   SJC                    3.7       3.0
   Schober’s index (SI) 2.97        3.09
   Chest expansion (CE) 3.21        3.26
   Occiput to wall (OW) 5.33        5.59
   NSAID (%)              92        91
   STEROIDS (%)           14        13
   DMARD (%)              31        31
   SSZ (%)                22        21

                                                 Davis et al 2003
Response to treatment

     Outcome Week            Week 12       Week 24        Week 24
     (%)       12
               Placebo       Etanercept    Placebo        Etanercept
     ASAS 20 27              60            23             58
     ASAS 50 15              45            9              43
     ASAS 70 6               27            5              28
     BASDAI 15               48            14             41
     50
     BASDAI 6                30            5              30
     70
     Partial   8             21            8              21
     remission
     ASAS      12            37            7              33
     DCART
     ASAS 40 15              43            13             41
     RESPONSE PLATEAUED AT WEEK 8 MAINTAINED TO WEEK 24

                                                               Davis et al 2003
Secondary outcomes

   (%             Placebo   Etanercept
   improvement
   at 24 weeks)
   Spinal
   mobility
   C-E            0         16.7
   Schober        0         9
   O--W           0         25
   Acute phase
   reactants
   ESR            0         60
   CRP            0         72




                                         Davis et al 2003
Adverse events

                     Placebo   Etanercept
    Injection site   9         30
    rxn*
    URTI             12        20
    Serious          2         3
    adverse events
    Iritis           8         3
    Colitis          1         2
    Death            1         1
    Convulsion       0         1




                                            Davis et al 2003
OP0097
Calin et al Ann Rheum Dis 62(1) 2003
 A multi-centre placebo-controlled trial of
  Enbrel in Ankylosing Spondylitis

       BASELINE         PLACEBO ETANERCEPT
       Number           45      39
       Disease          9.7     15*        0.0006
       duration (yrs)
       BASFI            57      60          ns
       BASDAI           58      61          ns
       AGE              40.7    45          ns




                                                 Calin et al 2003
Primary outcome


 12 weeks   Placebo   Etanercept
 ASAS 20    23        60*



                              Calin et al 2003
Adverse events
 No difference in SAE’s
 No difference in infection rates
 Only 1 SAE


 Note entry criteria was BASDAI >3 so were a lot of
  patients less active and were they going to get better
  anyway???



                                          Calin et al 2003
  Infliximab Monotherapy Study
  In Active Ankylosing Spondylitis
Randomized, double-blind, placebo-controlled
 12-week monotherapy study

 National, multicenter

 48-Week Open-label Follow-up

 Infliximab 5 mg/kg induction (0,2,6 weeks)
  maintenance every 6 weeks

Braun J. Lancet. 2002.
Infliximab Monotherapy Study
In Active Ankylosing Spondylitis

 Primary Endpoint
   Regression of disease activity  50%

 Secondary Endpoints
   Improvement in visual analogue score for spinal
    pain
   BASFI, BASMI, SF-36
   Working group response criteria, C-reactive protein,
    ESR
Infliximab Monotherapy Study
In Active Ankylosing Spondylitis
                         Infliximab,n=34 Placebo,(n=35)
 Male/Female                 23/11           22/13
 Age*                         40.6           39.0
 Disease duration*            16.4           14.9
 (yrs)
 HLA-B27                      31              27
 # Swollen Joints*            0.9             2.0
 Anterior uveitis            50%             43%

* Values are means

Braun J. Lancet. 2002.
Infliximab Monotherapy Study
In Active Ankylosing Spondylitis
                  Baseline BATH Ankylosing Spondylitis Indices



                                 Infliximab        Placebo
Patients                              34              35
Activity                            6.5               6.3
Function                            5.4               5.1
Metrology                           3.7               3.7
Radiography                         6.5               6.6
Pain (VAS)                          7.2               7.3
Values are mean
Primary outcome


   OUTCOME       Infliximab   Placebo
   BASDAI 50%    53           9
   BASDAI 20 %   58           16
   BASDAI 70 %   30           4
   ASAS 20       68           23
   ASAS 50       48           8




                                    Braun et al Lancet 2002
Should all patients receive a TNF
receptor blocker?
 Impressive response rates
BUT…..
     Cost
     Availability
     Adverse events
OP 0104
van der Heijde, Ann Rheum Dis 2003 62(1) 97




 ASAS international consensus guidelines
      ASAS WORKSHOP BERLIN 2003
ASAS Consensus
 Initiation of therapy
    Ankylosing Spondylitis
         (usually meet modified New York criteria)

    Failed conventional therapy
    Active disease for at least 4 weeks
         BASDAI > 4 and Physician global (specialist) yes/no

    Refractory disease
         Failed at least 2 NSAIDS at max tolerated doses

          during 3 month period and I/A steroids/SSZ if
          indicated
                                  ASAS workshop, Berlin January 2003
ASAS consensus guidelines
 Response
         at 6-12 weeks
         BASDAI >50% improvement and absolute
          improvement >2 units and Physician global
          assessment of response to treatment

 Infusions every 6-8 weeks
 ASAS core domains, function, inflammation, patient
  pain and patient global assessment, spinal mobility
  and BASDAI assessed in follow up on all patients
Do you AGREE??
 AGREE STATEMENT FOR ASSESSEING
  VALIDITY OF GUIDELINES

 ISSAS study International Start TNF blockers
  Study
     4 Centres Canada, Berlin, Maastrict, Mexico,
      California
     Aim –To assess the burden of need for TNF
      blockers applying these guidelines
ISSAS Study Current Report

                 Province             # of participating   # of patients recruited
                                      Rheumatologists
      Ontario                                 28                     67


      BC                                      1                      0


      Alberta                                 2                      0


      Manitoba                                1                      0


      Nova Scotia                             1                      0


      Saskatchewan                            1                      0


      Newfoundland                            1                      38


      Quebec                                  1                      0
                    Total                     36*                    67


    *12 Rheumatologists have withdrawn from the study
OSA
Mission of the OSA

   To provide an Association
    for people with Ankylosing
    Spondylitis and Related
    Diseases that supports
    and promotes continuous
    education, improved
    health and wellness for all
    family members and a
    dedicated commitment to
    raising funds for AS
    research
                                  www.spondylitis.ca
What are the risks??
 For
     Patient
Adverse events
 Precautions TB and infection generic for all diseases
    treated with biologics
   Headaches
   Abnormal liver function tests
   Demyelination
   Sepsis
   Injection site reactions, infusion reactions
       Crohn’s disease experience
What are the risks??
 For the Doctor
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 professionals FDA notifies health professionals that tuberculosis and other
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Patient selection for therapy
 Low risk
 Patient who are likely to respond
 Good documentation
Discriminating features of responders


                    Responders     Non responders   p-value

                       N=18             N=4

    Sex M:F            15:3             3:1          0.78

       Age           39.7  8.5      40.3  6.5       0.9

 Disease duration     9 7.2          16  5.7       0.08

  NSAID therapy         14               3           0.14

 DMARD therapy           7               2            0.7

    BASDAI           5.8  1.15       5.6  2.2      0.39

     BASFI            6  2.4          6 2.2         0.9

      CRP           30.72  35.9    6.25  4.99      0.01

     TNF-           4797.8        2607  546      0.006
                       2793


                                                    Stone et al Ann Rheum Dis 2003
GRAB/eAS Project
  Genetics of Response in Ankylosing Spondylitis to Biologic Agents




                 Principal Investigators:
                   Dr. Millicent Stone
                  Dr. Robert D Inman
Learning points CASE #1
Early onset disease
    Pregnancy and conception on/off biologics

    Are biologics a cure, how long does the effect last after
     discontinuation?

    Appropriate dosing intervals

    DMARD effect or not

    Effect on axial vs peripheral disease

    How to manage headaches after treatment
Learning points Case#2
Advanced disease
     Late disease, patients with advanced disease respond
      (maybe not as well)

     Effect of biologics on established ankylosis/ and on
      disease progression

     ?Early intervention in patients with poor prognostic
      indicators (I.e hip disease)

     Abnormal LFT’s following biologic therapy

     Predictors of response to treatment (?? CRP)

				
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