IBD Therapy

1
IBD Therapy

• October 27, 2008

2
Case Presentation

• 23 year old female with 3- 4 month history of
  weight loss, abdominal pain and diarrhea
• Stool studies negative
• Labs Hgb 10.1 Hct 33 Plts 544, ESR 44, Albumin
  3.0
• Colonoscopy- normal but could not enter the
  terminal ileum

3
Other Studies
4
Crohns Disease Therapy
Tysabri
Severity
Surgery
Infliximab, Adalimumab, Certilizumab
Corticosteroids, Immunomodulators
5-ASAs, Budesonide, Antibiotics
5
Factors that affect therapy

• How sick is the patient?
• What is the disease distribution?
• Are there complications ? abscess, fistula,
  obstuction
• Has the patient had prior surgery for Crohns
  disease?

6
Budesonide in Crohns Disease

• Budesonide - Entocort

• Budesonide vs. Mesalamine

• 3 mg capsules
• Ileal release based on pH dependent mechanism
• Steroid with rapid 1st pass metabolism ? less
  systemic effects

Patients in remission
Thomsen et al 339 (6) 370
7
Less adrenal suppression but still some

• Indicated in mild to moderate ileal Crohns
  disease
• Prescribing information ? for 9 week course of
  therapy 3 weeks at each dose 9 mg, 6 mg, 3 mg
• We do use it more long term in some patients
• Still need to follow bone density

8
5-Aminosalicylates

• What are the drugs?

• What are the issues?

• Sulfasalazine
• Mesalamine
• Pentasa 250 mg or 500 mg
• Asacol 400 mg
• Rowasa 4 gram enema
• Canasa 1,000 mg supp
• Lialda 1.2 gram tablet
• Balsalazide (Colazal)
• Osalazine (Dipentum)

• Differ in release characteristics
• Evidence based medicine ?greater role in UC than
  CD
• Sulfasalazine has some data to suggest efficacy
  in colonic CD
• Use in mild disease
• Adverse events worsening of disease activity,
  increased creatinine, pancreatitis, allergic
  reaction (rash)

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Location of Oral Mesalamine Release
Stomach
Jejunum
Ileum
Colon
Sulfasalazine
Colazal (balsalazide)
Dipentum (olsalazine)
Asacol (mesalamine)delayed-release tablets
Lialda (mesalamine)MMX technology mixed release
Pentasa (mesalamine) controlled-release capsules
10
5-Aminosalicylates for induction of remission in
active Crohns Disease

• 5 ASAs in Crohns

• Singleton et al study

• Singleton study 16 weeks
• 2 subsequent studies did not show significant
  difference
• May have mild efficacy
• Currently use of 5-ASAs in CD not considered
  primary therapy

Singleton et al. Gastroenterology.
19931041293-1301.
11
Mesalamine for Maintenance of Remission in
Crohns Disease
Meta-Analysis of Clinical Trials
Risk Difference, 95 CI
0.5
0.4
0.3
0.2
0.1
0
0.1
0.2
0.3
0.4
0.5
Overall
Favors Control
Favors Treatment
Pooled estimate of treatment effect was
significant (P .0028)
Camma C et al. Gastroenterology.
19971131465-1473.
12
Case continued

• Patient started on 4 grams of Pentasa per day and
  9 mg of Entocort
• Partial response initially but then develops
  worse abdominal pain and diarrhea.
• Prednisone is initiated

13
Steroids and IBD

• Role

• Side effects

• Historically important role in the management of
  acute disease
• No maintenance role
• No beneficial role for doses greater than 40 60
  mg/day
• For acute disease 40 mg/day x 3 weeks then start
  taper at 5 mg q 1-2 weeks
• IV steroids for hospitalized, severely ill patient

• Osteoporosis
• Cataracts
• Poor tissue healing
• Increased complications
• Infections

14
Induction of Remission in IBD with
Azathioprine/6MP

• 425 patients (209 AZA/6-MP, 216 placebo)
• End-points steroid sparing effect, clinical
  response
• Time to respond average 3.1 months

Sandborn et al, Cochrane Library, Issue 4, 2000
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Azathioprine/6MP in IBD

• Efficacy/Issues

• Intolerance/Risks

• Effective in 50 70 of patients with IBD
• 30 failure due to intolerance (15) or no
  response (15)
• Metabolism issues TPMT
• Uses
• Steroid sparing
• Post operative prophylaxis

• Bone marrow suppression
• Pancreatitis
• Hepatotoxicity
• Nausea
• Myalgias flu like symptoms
• Other Risks
• Lymphoma 4 fold
• Abnormal PAP / HPV
• Infection

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AZA/6MP Metabolism
DNA RNA
6-TG nucleotides
6-TU
XO
HPRT
6-TImP
AZA
6-MP
TPMT
TPMT
6-MMP ribonucleotides
6-MMP
Purine synthesis
Circulation
Intracellular
17
6-TG Level Correlates WithClinical Response
Dubinsky M. et al, Gastroenterology
2000118705-13
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TPMT (thiopurine methyltransferase)
Allelic polymorphism
Low Risk ? efficacy
Severe Marrow Suppression
High Risk for Marrow Suppression
Low Risk

-
19
How to use TPMT activity in initiation of therapy.
20
Monitoring Azathioprine/6MP therapy

• TPMT phenotype at baseline
• CBC/LFTs at baseline and 1-2 weeks after
  initiation
• Q month the first 3 months
• If dose stable then q 3 months and if acute
  illness develops

21
Case continued

• Patient unable to taper completely off of
  steroids despite the addition of 6-MP six months
  ago
• Metabolites checked
• 6 TG 124 pmol
• 6 MMP 12,178 pmol
• With these levels it is unlikely that we will be
  able to get to a point where patient will have
  therapeutic 6 TG levels without toxicity.
• Theoretic alternative is 6-TG (unfortunately
  associated with liver toxicity)

22
Methotrexate

• Methotrexate

• Pivotal Induction Study

• Immunomodulatory vs. Immunosuppressant
• Active both in induction and maintenance of
  remission
• 25 mg sc/week x 16 weeks then dosage reduce to 15
  mg sc/week
• Give folate on off days
• Monitor LFTs, CBC,

Feagan BG et al. N Engl J Med. 1995332292
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Adverse effects of Methotrexate

• Serious Adverse Events

• Common Adverse Events

• Hepatotoxicity
• Hypersensitivity pneumonitis
• Myelosuppression
• Birth defects in offspring

• Nausea and vomiting (42)
• Diarrhea (7)
• Headache (17)
• Abdominal pain (18)
• Joint pain (16)
• Elevated AST, ALT
• Stomatitis

Feagan BG, et al. (1995) N Engl J Med. 332292-297
24
Anti-TNF Antibodies
Humanized Fab fragment
Human recombinant antibody
Chimeric monoclonal antibody
VL
VH
CH1
No Fc
Mouse Human
PEG
IgG1
IgG1
PEG
Certolizumab pegol
Infliximab
Adalimumab
PEG Polyethylene glycol
25
Induction of Remission at 4 weeks
5, 10, 20 mg/kg
100, 200, 400 mg
40/20, 80/40, 160/80
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Long Term Maintenance of Clinical Response to
Anti-TNF therapy
CDAI 70
CDAI 70
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How do they differ?

• Route of administration
• Infliximab IV
• Certilizumab and Adalimumab SC
• Amount of Mouse protein
• Apoptosis yes for Infliximab and Adalimumab, no
  for certilizumab

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Anti-TNF therapy

• Infliximab (infusion)
• Induction 5mg/kg IV at weeks 0, 2 and 6
• Maintenance 5mg/k IV at 8 weeks
• LOR Escalate dose or shorten interval
• Cetolizumab pegol ( SC , nurse administered)
• Loading dose 400 mg sc at weeks 0, 2 and 4
• Maintenance 400 mg sc at 4 weeks
• LOR ? Attempt re-induction
• Adalimumab ( SC, prefilled syringe)
• Loading dose 160 mg at week 0, 80 mg at week 2
• Maintenance 40 mg sc EOW or weekly
• LOR Shorten dosing interval

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Case 2

• 24 year old male presents with 2 months of bloody
  diarrhea
• Travel to Tanzania at the end of the trip
  developed acute diarrhea
• Toxic symptoms resolved but continued progressive
  bloody diarrhea

30
Ulcerative Colitis
Contiguous disease Mucosal involvement Crypt
abscesses/chronicity Cultures negative
31
Ulcerative Colitis Treatment Pyramid
Severe
Infliximab
Mild
32
Treatment of UC

• Induction vs. Maintenance
• Left-sided vs. pan-colonic
• Fulminate disease
• Steroid dependent disease
• Chemoprevention of colon cancer

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What do we know?

• 5-Aminosalicylates
• Steroids
• Immunomodulators
• Anti-TNF
• Antibiotics
• Nicotine
• Probiotics

34
Types of 5-ASA Trials

• Topical vs. systemic therapy
• Different preparations, different release
  characteristics
• Combination therapy (oral topical, oral AZA)
• Dose ranging studies

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Ulcerative ColitisOral mesalamine
patients in remission or improved
Placebo
1.6 g/d
4.8 g/d
Schroeder K, Tremaine, W. NEJM 1987. 3171625-29.
36
Oral vs Oral Rectal Mesalamine
Comparable results at the same 5-ASA dose
P0.56
P 0.36
P0.29
Endoscopic Remission
Remission
Days to Remission
Vecchi M, et al. Aliment Pharm Ther. 2001.
15(2)251-6.
37
Corticosteroids

• Rapid clinical benefit
• Treatment related side effects
• Preparations
• Route of administration
• IV vs. Oral vs. topical
• Steroid dependence

38
Preparations and Potency

• Hydrocortisone 1x
• Prednisone 4x
• Methylprednisolone 5x
• Dexamethasone 10x
• Budesonide 16x

39
Steroids in UC Landmark Study
Truelove and Witts BMJ (1955)21041-8 Hospitalized
UC 100 mg Cortisone vs. Placebo
40
Azathioprine

• Thiopruine analogue that modulates the immune
  response
• AZA ? 6-mercaptopurine
• Mixed results in controlled trials in UC
• Indications
• Induction of remission in moderate to severe
  disease (takes time)
• Maintenance of remission
• Steroid sparing

41
UC maintenance of remission with AZA ? 1 year
remission

• Jewell (Gut 1974)
• AZA 1.5 - 2.5 mg/kg (n40) Placebo (n40) 11
  months
• Hawthorne (BMJ, 1992)
• AZA (x 100mg) (n33) Placebo (n34) 12 months
  withdrawal trial

p 0.04
ns
42
Other AZA trials

• AZA vs. MTX (Paoluzi et al Aliment Pharmacol Ther
  2003 17479-80) (MTX good alternative to AZA in
  AZA intolerant patients)
• AZA vs. AZA/Osalazine (Mantzaris et al Am J
  Gastro 2004 991122-8) (Dont need 5-ASA to
  maintain remission)
• AZA vs. Mycophenolate mofetil (Orth, Am J Gastro
  2000 951201-7) (AZA/Prednisonlone better than
  Mycophenolate/Prednisolone)
• AZA steroid sparing trials (4 controlled trials/3
  positive)

43
Infliximab in UC
ACT 1
ACT 2
Rutgeerts et al (2005) NEJM 3532462-2476
44
Infliximab for steroid refractory UC Oxford
outcome data (2000 2006)

• 30 patients treated with infliximab for
  refractory ulcerative colitis
• 16 (53) went on to colectomy
• 5 (17) steroid free remission after a median
  follow-up of 13 months (2 72)
• No difference in colectomy rate for acute severe
  UC failing IV steroids (8/14) and steroid
  refractory (8/16)

Jacobovitz et al (2007) Aliment Pharm Ther 261055
45
Cyclosporin in Severe UC

• Inhibition of immune responses initiated by T
  lymphocytes
• Randomized, double blind controlled trial
• N 20
• Severe UC, still active despite 7 days of IV
  steroids
• 4mg/kg cyclosporin in continuous IV infusion for
  up to 14 days vs. placebo

46
Cyclosporin in Severe UC
Response Rate 82 in CYA and 0 in placebo
treated group P lt .001
Lichtiger et al NEJM 1994 3301841-1845
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E Coli Nissle 1917 vs. Mesalazine

• Probiotic
• Double blind, double dummy trial Maintenance of
  remission
• n 327
• UC in remission
• 12 month treatment trial of probiotic 200 mg/day
  or mesalazine 500 mg tid

48
E Coli Nissle 1917 vs. Mesalazine
Relapse percentage similar between groups
Kruis et al Gut 2004 531617-1623
49
Transdermal Nicotine in UC
Randomized-double blind placebo controlled
trial N 64 4 weeks of Rx
Sandborn et al,( 1997) 126 364-371
50
Surgical Therapy
Total Abdominal Colectomy with ileal pouch anal
anastomosis