Joint destruction in RA: pathogenic mechanisms and future therapies

1
2002 Rheumatology International Roundtable
Co-chairs Peter E Lipsky MD Scientific
Director National Institute of Arthritis and
Musculoskeletal and Skin Diseases Bethesda, MD,
USA   Professor Ravinder N Maini Head,
Kennedy Institute of Rheumatology Imperial
College Faculty of Medicine London, England

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2002 Rheumatology International Roundtable
faculty (i)
Jürgen Braun MD  Rheumazentrum RuhrgebietHerne,
GermanyRoy Fleischmann MD  University of
Texas Southwestern Medical Center at
DallasDallas, TX, USA
Professor Marc Feldmann Kennedy Institute of
RheumatologyImperial College Faculty of
MedicineLondon, EnglandMarc C Hochberg
MD University of Maryland Baltimore, MD,
USA
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2002 Rheumatology InternationalRoundtable
faculty (ii)
Theodore Pincus MD  Vanderbilt University
Medical CenterNashville, TN, USAJosef S Smolen
MD  University of ViennaDivision of
RheumatologyVienna, AustriaFrederick Wolfe MD 
University of KansasSchool of MedicineWichita,
KS, USA
Michael Schiff MD Denver Arthritis ClinicDenver,
CO, USADésirée van der Heijde MD University
Hospital MaastrichtDepartment of Rheumatic
DiseasesMaastricht, The Netherlands David E
Yocum MD University of Arizona Health Sciences
CenterTucson, AZ, USA
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Introduction
In the past 3 years, biologic response modifiers
(BRMs) have become an important part of the
armamentarium of drugs used to treat RA
patients In September 2002, a panel of
international experts met to discuss the use of
anti-TNF agents in RA
Satellite program / Nov 2002 / Biologics come of
age
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Anti-TNFs safer, more effective than traditional
DMARDs in RA (i)

• Compared to traditional DMARDS, COBRA, ATTRACT,
  and STAR results show that etanercept,
  infliximab, and anakinra
• are safer
• are more effective
• have higher retention rates (gt2 y)

there are possible hematologic effects
anti-TNF therapy should be stopped in the
event of serious infection
R Fleischmann MD
Satellite program / Nov 2002 / Biologics come of
age
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Time to efficacy and 50 retention time of
traditional DMARDs
R Fleischmann MD
Satellite program / Nov 2002 / Biologics come of
age
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Anti-TNFs safer, more effective than traditional
DMARDs in RA (ii)

• Compared to methotrexate and placebo, anti-TNFs
  also
• slow radiographic progression
• improve HAQ scores
• maintain long-term response rates

R Fleischmann MD
Satellite program / Nov 2002 / Biologics come of
age
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Anti-TNFs not everyone is convinced
Many of us here in the room believe the
hypothesis that you have been putting forward,
but we need more data to really be convinced. -
Josef S Smolen MD You have given us a great
summary here, but we are struggling to compare
these drugs across trials, and this is very
difficult to do. - Claire Bombardier MD
Satellite program / Nov 2002 / Biologics come of
age
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Issues in comparing clinical trials

• Different patient populations
• age
• severity of disease
• co-morbidities
• medications
• Different statistical analyses
• Different outcome measures
• Need head-to-head randomized trials and more
  observational registries

C Bombardier MD
Satellite program / Nov 2002 / Biologics come of
age
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Patient questionnaires

• The RADAI questionnaire
• measures activity, joint counts, and pain
• when used with the HAQ, also offers significant
  prognostic value
• Patient questionnaires provide the most
  effective currently available clinical measure to
  predict the two indisputable outcomes of RA
  mortality and work disability than lab tests,
  x-rays, or joint exams.
• -Theodore Pincus MD

Satellite program / Nov 2002 / Biologics come of
age
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Risk management and anti-TNFs

• Potential risks of anti-TNFs
• infusion or injection site reactions
• infections (eg, TB)
• autoimmune reactions
• malignancy
• congestive heart failure
• death
• Professor Ravinder Maini outlined strategies,
  including proper vigilance and screening, for
  managing these risks

Professor R Maini
Satellite program / Nov 2002 / Biologics come of
age
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TB screening in Spain (i)

• Before screening began in January 2002, Spain
  recorded 21 cases of TB out of 1800 RA patients
  on anti-TNFs. Since screening began, 1 new case
  of TB has been reported.
• Screening guidelines
• PPT test and chest x-ray
• reactions gt0.5 cm positive for TB
• if test negative, test is repeated 1 week later
  (1015 of patients test positive at this second
  text)

E Martín-Mola MD and J Gómez-Reino MD
Satellite program / Nov 2002 / Biologics come of
age
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TB screening in Spain (ii)
Patients who test positive for TB are not started
on Remicade until they have been on prophylactic
anti-TB therapy for 1 month Anti-TB therapy
continues for a full 9 months I think we have
to wait until the end of the year to really see
the impact of these recommendations, but we are
quite happy with the results and I think we are
moving in the right direction. - Juan
Gómez-Reino MD
E Martín-Mola MD and J Gómez-Reino MD
Satellite program / Nov 2002 / Biologics come of
age
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Cooperative on Quality of Life Survey in
Rheumatic Diseases (COP-QoL)
Goal to define the health and functional status
of patients with RA and ankylosing spondylitis
(AS) and assess if physicians' evaluations
corresponded with those of their patients
Self-assessments used RADAI rheumatoid arthritis
disease activity index HAQ health assessment
questionnaireFDI functional disability
indexSF-36 Short-Form 36
JS Smolen MD
Satellite program / Nov 2002 / Biologics come of
age
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COP-QoL results

• 6050 patient questionnaires were returned
• Many patients needed more aggressive treatment of
  their disease
• Discordance between patient and physician
  perceptions
• patients rated their health status lower than did
  their physicians
• patients reported being more severely affected by
  their disease than their physicians perceived

JS Smolen MD
Satellite program / Nov 2002 / Biologics come of
age
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Consensus workshop I RA trial design (i)

• Placebo-controlled trials play a role in dose
  finding and registration
• should be limited in duration
• should include an opt-out period after 12-16
  weeks that would be determined by protocol (not
  by investigator)
• Active comparator trials should have similar
  regimens, doses, and co-therapies
• Need head-to-head trials of anti-TNF therapies

Marc C Hochberg MD
Satellite program / Nov 2002 / Biologics come of
age
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Consensus workshop I RA trial design (ii)

• Trial design
• 1 year (minimum) to establish signs, symptoms,
  and radiographs
• 2 years (minimum) to establish a functional
  indication
• measure CRP, x-ray, QoL, and pharmacoeconomic
  endpoints, plus time patients remain on a therapy

Marc C Hochberg MD
Satellite program / Nov 2002 / Biologics come of
age
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Consensus workshop I RA trial design (iii)
Ultrasound and MRI are still experimentaland
need to be validated Registries and observational
studies may be best for assessing long-term
outcomes
Marc C Hochberg MD
Satellite program / Nov 2002 / Biologics come of
age
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Consensus workshop II differences between
infliximab and etanercept
No significant difference in efficacy or
safety Half-life makes a difference, but not to
clinicians who choose which one to prescribe Cost
and access very important to clinicians None of
the adverse effects reported are of major
concern, except for TB. Screening can reduce the
risk of TB
Michael Schiff MD
Satellite program / Nov 2002 / Biologics come of
age
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Consensus workshop III evaluating radiographic
information (i)
Radiographic evaluation is important for
diagnosis and to aid in prognosis however,it is
not applicable to all clinical trials For the
investigation of structural claims,x-rays should
be obtained at baseline,6 months, 1 year, and 2
years
Désirée van der Heijde MD
Satellite program / Nov 2002 / Biologics come of
age
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Consensus workshop III evaluating radiographic
information (ii)

• Trials 2 observers are sufficient
• average of the 2 and not a consensus score should
  be used
• presentation of the data should be in absolute
  numbers and not as a percentage of the maximum
  score
• scoring of hands and feet should be included in
  all clinical trials
• Observational studies 1 observer is sufficient

Désirée van der Heijde MD
Satellite program / Nov 2002 / Biologics come of
age
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Consensus workshop IV radiographic damage
disability (i)

• More research and more funding needed to explore
  if a relationship exists between radiographic
  damage and disability
• no evidence of a cross-sectional correlation
• some evidence of a correlation if longitudinal
  data are used, with estimates of the area under
  the curve. More sub-studies needed to reveal the
  extent of the correlation.

Frederick Wolfe MD
Satellite program / Nov 2002 / Biologics come of
age
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Consensus workshop IV radiographic damage
disability (ii)

• More studies needed to
• determine how to treat a patient whose
  radiographic progression is faster than expected
• evaluate if a relationship between radiographic
  damage and small and large joints exists
• evaluate if radiologic benefit in the absence of
  clinical benefit is possible

Frederick Wolfe MD
Satellite program / Nov 2002 / Biologics come of
age
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Conclusions biologics represent a significant
advance (i)
In the past 3 years, biologic therapy has met the
high expectations that its initial appearance
generated Concerns about safety of anti-TNFs have
decreased as experience with them has
increased Clinicians have become more confident
in prescribing anti-TNFs for their patients
Panel
Satellite program / Nov 2002 / Biologics come of
age
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Conclusions biologics represent a significant
advance (ii)
Long-term studies are needed to give more
definitive answers regarding the safety and
enduring efficacy of these agents Overall,
anti-TNF agents are remarkably safe and effective
compared to the other drugs currently on the
market to treat RA
Panel
Satellite program / Nov 2002 / Biologics come of
age