Crohns Disease Revisited DDW 2005

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Crohns Disease RevisitedDDW 2005

• Philippe Saniour, MD
• St Joseph Hospital, Beirut

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New Therapeutic Goals in Crohns Disease

• Induction of rapid response and
• maintenance of remission without steroids
• Complete mucosal healing of all involved
• segments and maintenance of healing
• Complete and permanent closure of fistulas
• Avoidance of complications, hospitalisations,
• surgeries and mortality

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What Factors Predict Individuals Prognosis

• 1/Clinically Smoking, the need to use steroids
  within the first 6 months after diagnosis, and
  possibly ileal location, with colonic location
  having a better outcome
• 2/Biologically Higher p-ANCA associated with a
  later age of onset and a UC-like behaviour, and
  high ASCA levels with earlier age of onset and a
  fibrostenoting behaviour
• 3/Genetically NOD 2 status, with some mutations
• (L1007FsinsC) leading to a higher risk of
  surgeries

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Therapeutic StrategiesEpisodic

• Symptoms based treatment (on flare)
• Advantages minimize risk of adverse
• drug effects and cost
• Disadvantages repeated exposure to
• steroids, impractical for immune modulators
• with a slow onset, loss of response because
• of antigenicity with the new biologic therapies

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Therapeutic StrategiesStep up

• Sequential escalation based upon symptoms,
  usually
• starting with the safest medication but with the
  least
• efficacy.
• Most prevalent strategy
• Advantages minimize risks of adverse drugs
  effects
• Disadvantages risk of inadequate treatment, not
  targeting
• the underlying process, i.e. the inflammation and
  the
• potential complications

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Therapeutic StrategiesStep on

• Therapy with a potent agent since the beginning
• Advantages strong suppression of inflammation
• from diagnosis
• Disadvantages Expensive, treats all patients as
  if
• they have identical risk and lead to unnecessary
• exposure to adverse drug effects

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Therapeutic StrategiesStep down

• Therapy with a potent agent at diagnosis and
  de-escalation
• of therapy after initial response
• Advantages robust initial suppression of disease
  and less
• expensive than step up / step on
• Disadvantages loss of response to biologics like
• Infliximab when re-used, and safety concerns
• about exposing all patients to potent agents

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Therapeutic StrategiesRisk Stratified

• Identifies patients at highest risk for worse
• outcome and treat them with potent agents
• Advantages appropriate treatment,
• minimum cost and risk of drugs adverse
• events
• Disadvantages prognosis is imperfect

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Crohns Disease RevisitedSelected Abstracts
Diagnosis, Prognosis and Genetics

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New Diagnostic Tools

• Etat des lieux
• Clinical and lab assessment of activity in CD
  correlate poorly with
• endoscopic findings, thus the need for markers of
  intestinal
• inflammation
• Recently, fecal Calprotectin and Lactoferrin are
  being evaluated as
• surrogate markers for neutrophil influx in the
  bowel lumen
• Antimicrobial antibodies like ASCA (Anti
  Saccharomyces Cervisiiae
• Antibodies) and Omp-C (E Coli protein) are also
  used as diagnostic
• and prognostic indicators of disease activity and
  behaviour

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New Diagnostic Tools

• 1/ Gaya et al Fecal Calprotectin on a spot stool
  sample to
• asses CD activity significant correlation with a
  White Cell
• Scan with a FC level gt 100 mcg/g 80 sensitive
  and
• 67 specific.
• 2/ Sparow et al Fecal ASCA in CD
• Serum ASCA is present in 50-60 of patients with
  CD.
• In this study, 11/23 pts with active CD had
  stool ASCA
• (by ELISA), and none of the 39 controls
• ? High specificity of fecal ASCA

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New Diagnostic Tools

• 3/ JH Boone et al Measurement of Fecal
  Lactoferrin, ASCA and ANCA
• in non IBD patients and healthy controls ASCA
  100 specific
• (previous studies ? 92).
• Borderline elevation of Lactoferrin in lt 6 of
  non IBD and healthy
• controls
• 4/ Marceletti et al Antimicrobial antibodies as
  prognostic indicators
• for CD course
• 188 pts , using logistic regression analysis,
• Significant correlation between ASCA (Ig G, IgA),
  Omp C
• and small bowel localisation, fibrostenotic and
  fistulising disease,
• as well as requirement for surgery

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Imaging in Crohns Disease

• CT Enterography
• Solem et al Comparison of sensitivity,
  specificity and accuracy of
• SBFT, Capsule Endoscopy, CT Enterography and
  Ileoscopy in the
• diagnosis of small bowel CD
• Ileoscopy and CT have the best accuracy of 85-87
• Higgins et al CT enterography changed clinical
  management in 67
• of studied patients (51 pts), regarding addition
  or withdrawal of steroids,
• despite poor correlation with traditional
  radiology and clinical
• presentation

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Crohns Disease and Genetics

• NOD 2 /CARD 15 gene (Chr 12) ?
• Intracellular bacterial recognition
• Toll-like Receptors (TLR 1?9) ?
• Membrane bound receptors to microbial adjuvents
• activating innate immune cells
• Mutations in the NOD 2 / CARD 15 gene (3) more
• common in CD and confer different phenotypes

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Genetics

• Brand et al The role of TLR 4 Asp299Gly
  Mutation and
• NOD 2 / CARD 15 mutations in susceptibility and
  phenotyping of CD
• 299 pts and 199 unrelated controls
• Results
• 1- TLR 4 mutation in CD v/s controls 14.2 v/s
  7.5
• 2- TLR 4 mutation confer a stricturing phenotype
  34 v/s 17
• 3- TLR 4 and NOD 2 - 47 strictures
• 4- TLR 4 and NOD 2 71 fistulas
• 5- NOD 2 28 ileal disease ( 15 if NOD 2 -)
  

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Genetics

• Hungarian Survey NOD 2 / CARD 15 Mutations and
  CD
• Ileal involvement, stricturing behaviour, need
  for resection
• and younger age of onset
• European Cooperative IBD study
• CARD 15 mutations and ASCA on longitudinal
  changes
• in disease phenotypes
• Associated with a change from inflammation to
  stricturing
• and fistulizing (OR 3,2)
• Conclusion both genetic factors and abnormal
  immune
• response to bacterial stimuli may play a role in
  the
• pathogenesis and the behaviour of Crohns Disease
  

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Crohns Disease Revisited

• Selected Abstracts
• Treatment

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Treatment Strategy

• Management of recent onset Crohns disease a
  controlled randomized
• trial comparing step up and top down therapy
  (Hommes et al)
• 26 Belgian and Dutch centres, 129 pts with CDAI
  gt 200
• Initial open label therapy with
• 1- Infliximab 5 mg/kg on week 0, 2, 6 combined
  with azathioprine 2.5 mg/kg ( top down )
• 2- Prednisone ( step up)
• Study end points
• a- Remission ( CDAI lt 150 ) at 6 and 12 months
• b- Remission at 6 and 12 months AND no steroids
• Disease recurrence
• Td Re-treatment with Infliximab and/or
  Metothrexate
• Su Re-treatment with steroids or start AZA or
  Methotrexate

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Treatment StrategyRemission
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Treatment Strategy

• Top Down 0 steroids at 6 and 12 months,
• 25 failed at 6 months and needed
• additional Infliximab
• Step up at 6 months, 52 failed and
• needed more steroids, and at 12 months,
• 62 were on Azathioprine or Metothrexate
• Colonoscopy at 1 year (subgroup)
• Td 75 complete mucosal healing
• Su 21 complete mucosal healing

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Infliximab and Immunosuppressors

• Assess the clinical benefit of continuing
• immunosuppressive treatment concomitant to
• Infliximab. (Van Assche)
• Previous studies have demonstrated the benefit
• of concomitant therapy in order to decrease
• immunogenicity and improve outcome.
• Alternative approach, discontinue
• immunosuppressant after induction of early
• immune tolerance to Infliximab over 6 months

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Infliximab and Immunosuppressors

• 57 patients
• Group I 30 pts continued on AZA or Metothrexate
• Group II 27 pts discontinued treatment
• All were maintained on Infliximab Q 8 weeks
• Endpoint flare before next scheduled injection
• Results 6/29 (Gr I) and 10/27 (Gr II) had a
  flare
• (P .24 NS) after a mean follow up of 7 months
• Results suggest that continuing immunosuppressors
• with Infliximab beyond 6 months may not add any
  benefit

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Safety of Crohns Therapy

• TREAT registry data Study the long term safety
  of
• treatment in CD
• Patients prospectively followed since 8/2004
• 6290 pts with more than 10 000 pts year f/u
• 3179received Infliximab, 87 2 infusions
• INFX patients had more mod-severe disease (30.8
  v/s
• 10.3) and more sev-fulminant disease (2.5 v/s
  0.6)

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Safety of Crohns Therapy

• Results
• Mortality INFX v/s others ? .53 py v/s .43 py
• Incidence of neoplasms including lymphoma .43 py
  v/s .51
• Serious infection 1.33 py v/s .70 py ( inc.)
• Multivariable regression analysis, increase in
  relation
• with severity of disease and prednisone use
• INFX injection reaction 4.6 of 20309 inj. ,
• severe reaction in 0.12
• Conclusion INFX has a similar safety profile to
  other CD
• therapies despite its use in more severe cases

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CLASSIC II Open Label CohortConclusion

• Clinical remission and response increased
• with long term Adalimumab treatment
• At 6 months, 71 (156/220 pts) were still
• taking the treatment with 2/3 of them (98)
• on Qow schedule
• Long term administration of Adalimumab
• is well tolerated with no new safety concerns

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Natalizumab

• Humanised monoclonal IgG4 antibody
• to a4 integrin
• Phase II study (Ghosh et al, NEJM 2003)
• Phase III study ENACT-1 (Sandborn et al, AGA
  2004)
• ENACT-2 (Sandborn et al, AGA 2004, abstract)
• Followup on ENACT-2 and subgroup analysis
• (Sandborn et al, AGA 2005)

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NatalizumabENACT-2

• A comparison of
• sustained v/s point-in
• time response and
• remission rates
• following 12 months of
• infusions

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NatalizumabENACT-2

• Subgroup analysis
• 1/ Previous exposure to INFX
• (108 pts 48 Nat, 60 Pla) 48 v/s 10 CR
• 2/ Failure to INFX (57 pts 24 Nat, 33 Pla)
• 42 v/s 18 CR
• 3/ Pts on steroids (143 pts, 67 Nat, 76 Pla)
• 45 Cr off steroids v/s 17
• 4/ Pts on Immunosupressors (122pts 62 Nat, 60
  Pla)
• 52 v/s 23 CR

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Interleukin-10

• IL-10 is a cytokine that down-regulates
• TH1 Inflammatory response
• When administered as an infusion, it failed
• to work
• Postulation it might act locally and need to
• be delivered locally in high concentrations

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Interleukin-10

• Braat et al (Amsterdam)
• Lactococcus Lactis genetically modified to
  produce IL-10,
• administered orally to 10 pts with active CD for
  7 consecutive days
• Bacteria present in feces during administration
• and was absent within 2 days of terminating the
  treatment
• No dissemination of the transgene observed in
  other bacteria
• CDAI score decreased by an average of 72
• during the 1 week treatment
• 
  ?
• Lactococcus Lactis IL-10
  Super Probiotic