Updates on the use of biologic therapies in AS

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Updates on the use of biologic therapies in AS

• Dr. Millicent Stone
• Noon Rounds,2/9/2003
• St. Michaels Hospital

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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

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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

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Delay in diagnosis from symptom onset
Calin et al J Rheumatol 2002
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Sacroilitis by MRI
Normal SI - SE T1
Fused SI - SE T1
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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.
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Sacroiliac Biopsy In Ankylosing Spondylitis
Bollow M, Braun J. Ann Rheum Dis. 2000.
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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

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TNF receptor blockers

• Etanercept (embryl)
• Humira (adalimumab)
• Infliximab (remicade)

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CASE REPORTS

• Case reports
• Early in disease course
• Advanced disease

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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
• BASDAI8

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BASDAI INFLAMMATION
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Examination

• Looked very healthy!
• General physical normal
• No extra-articular features
• Locomotor
• O-W0, C-E4.5, Schobers5, F-F0
• 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

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Progress

• 05/2000 c/o TNF-blocker
• Excellent clinical response, except headaches
  few days after infusion
• BASDI0 after one infusion
• Promotion at work
• 12/2001d/c (planning a family)

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Progress

• 04/2002 Recurrence of symptoms
• 03/2003 Returned to Spondylitis Clinic
• BASDAI9
• 0-W0, C-E2.8, Schobers4.8, F-F13
• C-spine rotation ? 20 (RL),
• T-spine rotation 95(R),40(L)
• 07/2003 Recommenced TNF-blocker, allergic
  reaction infusion stopped

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Case2 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

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Investigations

• X-ray- Bamboo spine
• Normal CRP ESR
• Enhancement on C-spine, MRI

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SPINAL INFLAMMATION
BASELINE
2 DAYS
2 WEEKS
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Progress

• 08/2000 c/o TNF-blocker
• Good clinical response (BASDAI from 8-5)
• Improvement noted on MRI, however abnormal LFTs
• 2003
• Still doing well on Remicade
• But no structural change

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Uncontrolled studies
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Randomized Controlled Studies in AS
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• Early studies difficult to draw comparisons
  across studies due to lack of common outcome
  measures

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DEFINITION OF RESPONSE TO TREATMENT IN AS TRIALS

• ASAS Response criteria
• 20 relative improvement and gt10 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
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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

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BASFI
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Global Assessment PTGA
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BASMISPINAL MOBILITY

• Lateral bending
• Intermalleolar distance
• Occiput to wall
• Modified schober index

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ASAS shortcomings

• Relative vs nominal
• No acute phase reactants
• No spinal assessment
• Validated in short term trials using NSAIDS

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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

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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)

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OP 0005 Davis et al Ann Rheum Dis 200362(1) 65

• Randomized double-blind placebo-controlled
  multi-centre (30) trial of etanercept (n138) vs
  placebo (n139) in AS by modified New York
  criteria
• 11 allocation
• Inclusion active disease (patient global pain
  scores and BASDAIgt4)
• Exclusion ankylosis prior anti-TNF
• Other stable NSAIDS/DMARDS and prednisone
  lt10mg/day

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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
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Demographics of cohort
Davis et al 2003
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Response to treatment
Davis et al 2003
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Secondary outcomes
Davis et al 2003
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Adverse events
Davis et al 2003
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OP0097 Calin et al Ann Rheum Dis 62(1) 2003

• A multi-centre placebo-controlled trial of Enbrel
  in Ankylosing Spondylitis

Calin et al 2003
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Primary outcome
Calin et al 2003
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Adverse events

• No difference in SAEs
• No difference in infection rates
• Only 1 SAE
• Note entry criteria was BASDAI gt3 so were a lot
  of patients less active and were they going to
  get better anyway???

Calin et al 2003
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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.
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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

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Infliximab Monotherapy Study In Active
Ankylosing Spondylitis
Values are means
Braun J. Lancet. 2002.
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Infliximab Monotherapy Study In Active
Ankylosing Spondylitis
Baseline BATH Ankylosing Spondylitis Indices
Values are mean
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Primary outcome
Braun et al Lancet 2002
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Should all patients receive a TNF receptor
blocker?

• Impressive response rates
• BUT..
• Cost
• Availability
• Adverse events

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OP 0104 van der Heijde, Ann Rheum Dis 2003 62(1)
97

• ASAS international consensus guidelines
• ASAS WORKSHOP BERLIN 2003

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ASAS Consensus

• Initiation of therapy
• Ankylosing Spondylitis
• (usually meet modified New York criteria)
• Failed conventional therapy
• Active disease for at least 4 weeks
• BASDAI gt 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

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ASAS consensus guidelines

• Response
• at 6-12 weeks
• BASDAI gt50 improvement and absolute improvement
  gt2 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

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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

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ISSAS Study Current Report
12 Rheumatologists have withdrawn from the study
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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
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What are the risks??

• For
• Patient

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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
• Crohns disease experience

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What are the risks??

• For the Doctor

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Patient selection for therapy

• Low risk
• Patient who are likely to respond
• Good documentation

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

• Principal Investigators
• Dr. Millicent Stone
• Dr. Robert D Inman

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Learning points CASE 1Early 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

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Learning points Case2Advanced 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 LFTs following biologic therapy
• Predictors of response to treatment (?? CRP)