Inflammatory bowel disease therapeutics

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Inflammatory bowel disease therapeutics

• Michael Beyak
• Assistant Professor
• Division of Gastroenterology,
• Department of Medicine
• beyakm_at_post.queensu.ca

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Objectives

• To recognize common clinical manifestations of
  IBD
• To be able to formulate a plan for initial
  investigations in a patient with suspected IBD
• To be able to initiate treatment in a patient
  with suspected IBD
• To be able to initiate management of disease
  exacerbations in patients with known IBD
• To beable to recognize important serious
  complicaitons of IBD or its treatment

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Case 1

• 19 yo woman, presents to office with diarrhea and
  urgency x 1 month
• Travelled to mexico a month ago
• Past history of recurrent UTIs, otherwise well
• Exam normal apart from small amount of blood on
  glove after rectal exam

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Further history / initial investigations?

• What is diarrhea?
• Stool cultures C.Diff
• CBC, inflammatory markers.
• ?abdominal xray
• Sigmoidoscopy (if available)

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Suspect diagnosis of UC, ?management?

• What choices are available for mild moderate UC
• 5-ASA what dose? Which preparation
• Steroids route?

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Cheat sheet for 5-ASA drugs
Start with dose of 3-4g / day at least for active
disease
Podolsky NEJM 2002
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Disease extent
pancolitis
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What points to distal or left sided disease?

• Frequent small volume stools
• Prominent sx of urgency, tenesmus
• Relative lack of systemic sx, blood test abn
• Why Important?
• Enemas / suppositories are v. effective. (enemas
  for disease up to splenic Flexure, suppositories
  for rectal disease)
• Often combination of topical and oral 5-ASA is
  more effective.

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Case 2

• 35 yo male, longstanding ileal Crohns disease,,
  presents to office with increasing crampy RLQ
  pain, diarrhea (5-6 watery BM /day) and malaise
• Meds Pentasa 2 g / d, vit B12 inj
• O/E
• Fullness and tenderness in RLQ, no peritoneal
  signs

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Investigations?

• Bloodwork plt / wbc count often high, anemia
  common
• Ultrasound often useful to demonstrate bowel
  thickening, inflammatory mass, abscess
• If diagnosis is in question SBFT can
  demonstrate typical features of ileal crohns

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Treatment

• Crohns disease therapies similar to UC
• 5-ASA chose drug that is released in ileum
  (e.g. pentasa, salofalk) 4-5 g/d For all but
  mild disease 5-ASA not very effective
• Better evidence for sulfasalazine in CD (colonic)
• Ileal release budesonide (entocort) 9 mg/d
  (expensive need drug plan / sec 8 approval)
• Antibiotics quality of evidence is poor
• Metronidazole (colonic crohns)
• Ciprofloxiacin (ileocolonic)
• Others e.g. clarithromycin (small studies)

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Case 2 contd

• Pt started on 4 g pentasa / day
• Returns a month later, now 7-10 BM/day, weight
  loss 5 kg, more pain, anorexia, no fever
• Hb 100, WBC 10 Plt 500
• What now?

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When to use systemic steroids

• Moderate to severe disease
• Disease refractory to 5-asa / topical steroids/
  abx
• Systemic symptoms / extraintestinal
  manifestations
• Dose 40mg / day prednisone avoid rapid taper
  will relapse
• Rule out infectious complication
• Corticosteroids double the risk of serious
  infection in CD

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What next?

• Slow taper of steroids reduce dose by 2.5-5mg
  each week
• Steroids are ineffective and toxic as maintenance
  therapy will need other drug (5-ASA may work
  for mild disease but likely will need immune
  modulator)

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Other considerations

• Abdominal imaging if significant pain /
  tenderness / fever
• When to refer
• Probably most patients with first time moderate
  severe disease
• Patients not responding to first line Rx,
  requiring systemic steroids
• requiring multiple courses of steroids

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Case 2 contd

• Pt has been on 2 courses of tapering doses of
  steroids 40mg /d taper to zero, reducing dose
  5mg / week.
• Now on prednisone again, down to 20 mg / day sx
  recurring - What to do now?
• Risks of long term steroid use?

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IBD Therapy
Anti-TNF
Anti-TNF
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Paradigm of IBD therapies

• 2 goals in IBD
• Induction
• Maintenance
• Who is a candidate for maintenance therapy?
• First time severe disease?
• gt/2 flares moderate severe
• Post operative?
• Frequent requirement for steroids
• There is a move to introduce more potent agents
  earlier in disease course to hopefully alter the
  natural history of disease and prevent
  complications

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Induction therapies

• 5-asa (CD/UC) 4g/d
• Steroids (CD / UC)
• Antibiotics (CD)
• Immunomodulators
• Imuran / 6-MP (CD/UC work very slowly)
• MTX (CD)
• Biologics
• Infliximab / adalimumab (CD/UC)

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Maintenance therapies

• 5-ASA (1-2g/d, though many say that induction
  dose should be maintenance dose)
• Adherence is particularly important in this class
  of drugs
• Steroids no evidence according to big meta
  analyses, budesonide some benefit in a few trials
• Immunomodulators
• Infliximab (q 8wk infusions), adalimumab
  s.c.injection q2weeks

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Case 3

• 54 yo male, longstanding UC, multiple courses of
  steroids, presents to ER with 10-15 bloody BM / x
  2 -3 weeks,
• Has tried to self medicate with prednisone 20mg /
  d, immodium
• Lost 5kg, fatigued, increasing abdo pain
• O/E fever, tachy, tender distended abdo

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Initial investigations

• AXR
• Labs WBC 20, HB 85,
• CRP150
• Diagnosis
• Potential complication?

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Management

• Hospitalize, IV hydration
• Avoid antiperistaltics
• IV steroids antibiotics, serial clinical exam
  and AXR
• Refer to GI and Gen Surg
• Severe UC / toxic megacolon has a significant
  mortaility associated with it.
• In the pre- steroid days severe colitis carried
  a25 mortality rate
• If no response to steroids in 3 days or
  worsening Surgery.

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Case 4

• 36 yo woman
• Longstanding ileal crohns disease
• Just had 3rd resection for ileal stricture
• Feels well, no symptoms
• Bloodwork shows Plt 425, CRP 22
• What now?

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Post operative maintenance

• Of pts with crohns that need surgery, at least
  2/3 will have another OR
• Many therapies have been tried
• There is debate in literature, but most experts
  are looking at risk stratifying and at least
  starting maintenance therapy in those at high
  risk (more than 1 surgery, aggressive disease,
  smokers)
• In the others suggest endoscopic assessment at
  1 yr then if active disease start Rx

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Evidence based post op maintenance

• 5-ASA mixed results, some trials show a benefit
• Antibiotics perhaps the best quality evidence,
  trials showing benefit have looked at metro /
  ornidazole at 1 year, but differences lose stat
  significance later on
• Dropouts very high
• AZA / 6-MP Only 1 rct, but lots of problems,
  several retrospective trials suggesting benefit
  and its use in mantenance in uonperated pts make
  it the most popular
• Biologics recent trial shown that incidence of
  endoscopic recurrence is much reduced (84 vs 9)
  but clinical remission non significant

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Quick cases Primary care problems in IBD pts on
tertiary care drugs

• 22 yo F, Hx of Crohns, recently started Imuran,
  presents with
• Severe sore throat, fever
• Can cause severe leukopenia
• Epigastric pain
• Can cause drug induced pancreatitis
• 34 yo M, UC, on prednisone 40 mg, hip pain
• Think of AVN of hip
• 28 yo F started on Pentasa for CD- Increasing
  diarrhea
• some get a secretory diarrhea

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Quick cases contd

• 56 yo F with CD, on metronidazole
• Burning fingers toes
• Long term Metro can cause peripheral neuropathy
• 44 yo M inmate, CD, on infliximab
• cough, SOB, fever
• Be aware of the risk of severe TB reactivation in
  patients on anti-TNF drugs

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Conclusions

• Mild IBD 5-ASA
• Consider topical therapies for distal disease
• Mild - Mod IBD
• 5-ASA, budesonide (CD), antibiotics (CD)
• Prednisone
• Topical Steroids for distal disease
• Severe IBD
• Systemic steroids
• Hospitalization
• Consider infliximab

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Conclusions Contd

• Refer when
• Uncertain Dx
• Inadequate response to first line rx
• Severe enough to need systemic steroids
• Need for immunomodulator maintenance

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References

• Ulcerative colitis diagnosis and management
  Collins BMJ  2006333340-343 (12 August)
• Guidelines for the management of inflammatory
  bowel disease in adultsM J Carter, A J Lobo, and
  S P L TravisGut 2004 53 (Suppl 5) v1-v16