Infliximab Maintenance Therapy for Fistulating Crohn`s Disease

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Infliximab Maintenance Therapy for Fistulating
Crohns Disease

• New England journal of Medicine
• Feb. 26,2004
• Directed by Dr. A. HAMAM
• Presented ByDr.Y.Abu-Zanouna

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Crohns Disease

• It is an idiopathic ,chronic ,transmural
  inflammatory process of the bowel ,that can
  affect any part of the GI tract ,most cases
  involve terminal ileum.
• It is believed to be a result of an imbalance
  between pro inflammatory and anti-inflammatory
  mediators.
• Unpredictable flares remissions.

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Pathophysiology

• The exact cause remains unknown
• Theories genetic microbial,immunologic,
  environmental, dietary, vascular ,psychosocial.
• Microscopically inflammation around the crypts,
  ulceration ,granuloma , mesentery lymph nodes.
• Macroscopically Hyperemia edema , ulcers
  cobble stone ,segmental lesions

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Genetics

• 1st degree relatives have a 5-25 higher risk
  than normal population.
• Family members of patients with Crohns Disease
  have increased risk for both CD UC.
• Offspring have an 8.9 siblings an 8.6 risk
  for developing IBD
• Susceptibility regions detected on different
  chromosomes (6 ,12 , 16 )

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Epidemiology

• Incidence rate in children 3.5/100,000 in NA 10
  19 yr olds.
• More than 1/3 of patients present in childhood or
  adolescence.
• Family history is present in 30 ,younger than
  30.
• Males Females in adulthood, Males gt females in
  childhood.
• Highest incidence in Caucasians.

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Clinical Presentation

• Weight loss 85
• Diarrhea 80
• Abdominal pain 85
• Rectal bleeding 50
• Growth failure 35
• Fever 40

• Rectal disease 25
• Extraintestinal signs 25
• Perianal disease 25
• Nausea vomiting25

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Clinical presentation

• Physical examination
• Growth Delay , wt loss , delayed puberty
• RLQ mass tenderness
• Palpable thickened loop of intestine
• Hyperactive bowel sounds
• Perianal rectal examination skin tag ,fissure
  ,fistula, hemorrhoids or abscess.

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Laboratory Aids

• Anemia
• Chronic inflammation
• Malabsorption ( B 12 folate )
• Chronic blood loss
• Leukocytosis
• Chronic inflammation
• Abscess
• Steroid treatment

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Labs

• Hypoalbuminemia
• Hypocholestrolemia
• Hypocalcaemia
• Hypomagnesaemia
• High CRP ESR
• P-ANCA CD 19 vs. UC 80
• ASCA Anti Saccharomyces Crevisiae Antibdy
• CD 60

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Imaging Studies

• Plain Abdominal radiograph
• Barium contrast studies
• CT scan
• MRI
• U/S
• Radionucleotide Scans

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Procedures

• Colonoscopy
• Obtaining multiple biopsies diagnostic
• Dilatation of fibrotic strictures
• Upper endoscopy
• Differentiating Crohns from other disease
• ERCP diagnostic therapeutic

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Differential Diagnosis

• UC
• Appendicitis
• Infection
• HUS
• HSP
• Irritable Bowel Syndrome

• Immune deficiency
• PUD
• TB
• Lactose intolerance
• SI Lymphoma
• Psychosocial disturbance

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Complications

• Obstruction( 8-40 )
• Transient stricture formation
• Fistulization
• Enteroenteral ,entervesical ,enterovaginal
  ,enterocutaneos
• Abscess formation
• Perianal Disease (25-50)
• Adhesions
• Malabsorption
• Growth Failure

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Treatment

• Medical Care
• Diarrhea
• Abdominal pain
• Diet nutritional therapy
• Balanced , high Fiber
• Low fat , MCTG
• Enteral therapy ,elemental diet in acute disease
• TPN

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Medical Treatment

• 5 ASA preparations
• Steroids
• Immunosuppressants Azathioprine , 6 MP.
• Antibiotics
• If medical treatment fails, surgical resection of
  the involved part of bowel is resected .

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Fistulae

• Fistulae between Bowel loops are usually benign
  may not produce major problems
• Enterovesical, enterocutaneous , cologastric ,
  coloduedenal are more serious .
• Surgery progressive obstruction,abscess,
  malabsorption.
• Medically Metronidazole, Ciprofloxacin

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New Medical Therapies

• Immunosupressive agents Tacrolimus
• Mycophenolate mofetil
• Anti inflammatory Cytokines IL 10, IL11

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INFLIXIMAB

• Monoclonal Antibody against TNF
• It blocks TNF in the serum at the cell surface,
  leading to lysis of TNF-producing macrophages
  T-cells.
• In one study 65 of refractory cases of CD
  responded well to Rx with infliximab 1/3 went
  into remission.
• Patients who relapsed , responded again to
  further infusions.
• Effective in patients with Fistulae ,median
  duration of response 12 wks.

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INFLIXIMAB

• Before starting treatment
• Allergies Infliximab , rodents
• Pregnancy Studies have not been conducted.
• Breast FeedingNot known whether it is excreted
  in breast milk or not
• Medical problems
• Congestive Heart Failure
• Active infections
• Tuberculosis infection ( PPD)

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Infliximab in Children?!

• Studies on this medicine have been done ONLY in
  adult patients there is no specific information
  comparing use of infliximab in children with use
  in other age groups.

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Side Effects

• Common chest pain, fever , flushing, S.O.B ,
  Abdominal pain, N/V , headache , fainting, muscle
  pain , sore throat , nasal congestion
• Less common Back pain, hematuria
  ,dysuria,urgency, stomatitis.
• RareWeight loss ,thrombocytopenia

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Other uses

• Ankylosing Spondylitis
• Psoriasis
• Reactive arthritis
• Rheumatoid Arthritis
• Inflammatory bowel disease arthritis.

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Infliximab Maintenance Therapy for Fistulizing
Crohns Disease

• Background
• Infliximab , is effective in maintenance therapy
  for CD with no fistulae It is not known whether
  it is effective as maintenance therapy for
  patients with fistulae.
• Methods
• Multicenter , double blind , randomized ,
  placebo-controlled trial to evaluate the efficacy
  of infliximab maintenance therapy in 306 adult
  patients with CD 1 or gt draining abdominal or
  perianal fistulas of at least 3 months duration.

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Cont

• Patients received 5mg/kg, IV on weeks 0 ,2 6.
• A total of 195 patients who had a response at
  weeks 10 14 , and 87 patients who had no
  response were then randomly assigned to receive
  placebo or infliximab 5mg/kg every 8 weeks to
  be followed to week 54.
• The primary analysis was the time to loss of
  response among patients who had a response at
  week 14 and underwent randomization.

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Results

• The time to loss of response was significantly
  longer for patients who received infliximab
  maintenance therapy than for those who received
  placebo ( more than 0 wks vs. 14 wks ) P 0.001
• At week 54 , 19 of patients in the placebo group
  had a complete absence of draining fistulas , as
  compared with with 36 of patients in the
  infliximab maintenance group. P 0.009

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Conclusion

• Patients with fistulizing CD who have a response
  at induction therapy with infliximab have an
  increased likelihood of a sustained response over
  54-week period if infliximab treatment is
  continued every 8 weeks.

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Methods

• Patients
• Men women gt18 yrs , with CD,1 or gt fistula.
• Concurrent therapies for CD were permitted .
• Excluded
• abscess or stricture requiring surgery
• Previously received infliximab

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Methods

• Study design
• Patients were screened for eligibility 2 weeks
  before enrollment.
• All eligible patients received Iv infusions 0,2
  6 weeks
• Response reduction of at least 50 from
  baseline number of draining fistulas at
  consecutive visits 4 or gt Wks apart.
• Patient had a response if it was observed at both
  10 14 wks.

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Cont

• Loss of response
• Recrudescence of draining fistulas.
• Need to change medications for CD
• Need for additional therapy for persistent or
  worsening luminal disease activity.
• Discontinuation of study medication due to lack
  of efficacy .
• Complete response absence of fistulas

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(No Transcript)
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Follow up safety efficacy evaluation

• Physical examination at 0, 2, 6, 10, 14, 22, 30
  ,38 ,46 54 wks.
• CD Activity Index ( 0- 600 )
• Inflammatory Bowel Disease Questionnaire health
  related quality of life ( 32-224)
• Adverse events were ascertained lab tests
  obtained

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Efficacy Patients with response

• Time to loss of response 14 wks vs. 40 wks
• Loss of response 62 vs. 40
• Disease Activity 6 vs. 36
• IBD questionnaire at 30 54 wks
• 45 vs. 14 10

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Efficacy

• Patients with No Response
• Subsequent response 16 vs. 21
• Crossover treatment
• Among randomized patients with a response during
  induction therapy who subsequently lost their
  response 61 who were allowed to crossover from
  placebo to infliximab ,reestablished a response ,
  57 reestablished a response after crossing over
  from infliximab dose of 5mg/kg to 10 mg/ kg .

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Antibodies against Infliximab

• Response rates among patients with antibodies
  against Infliximab (32) , those without
  antibodies (31) those with inconclusive
  results (29) were similar.
• Those with antibodies were 2-3 X more likely to
  have infusion reactions.
• Administration of steroids immunomodulators at
  base line appeared to prevent development of AB
  against infliximab.

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Safety

• Adverse events occurred in 92 of pts in placebo
  group vs. 89 in infliximab group.
• Discontinuation due to S/E 8 vs. 4
• Most common worsening of CD 6.
• No deaths or cancers occurred during the study.
• Infections requiring antimicrobial therapy 1/3
  of pts .
• Serious infections 5 ( Abscess)
• Opportunistic infections CMV , cutaneous
  nocardia.

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Safety

• Infusion reactions more with infliximab 1 vs.
  4.
• The reactions were not severe enough to warrant
  discontinuation of infusion , only one reaction
  was severe.
• Patients assigned to infliximab twice as likely
  to have ANA , 4 times to have anti ds-DNA abs.
• One patient developed Lupus like syndrome yet he
  had ve ANA anti ds-DNA.

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Discussion

• Fistulas remain a common yet challenging
  complication of CD.
• The results indicate that maintenance treatment
  with infliximab every 8 weeks is superior to
  placebo infusion in patients who had a response
  to induction infliximab.Compared with placebo ,
  twice as many patients from the infliximab group
  had durable complete closure of fistulas over
  th54 wks of study.
• Superior control of disease activity quality of
  life were associated with infliximab maintenance
  therapy.

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Discussion

• The findings confirm that the onset of fistula
  response to infliximab is rapid.
• Patients with fistulas tolerated infliximab well.
• The proportion of patients who developed
  antibodies is similar to other studies of this
  agent.

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Conclusion

• Among patients with fistulizing Crohns Disease
  whose fistulas closed after infliximab induction
  therapy , continued infliximab infusion at fixed
  intervals maintained closure for longer period
  than did placebo infusions.

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