Download Treatment of ibd

Treatment of inflammatory bowel
disease
Goals of treatment
Induction of
remission
Maintenance
of remission
Goals of Treatment
Prevent
complication
Improve QOL
Avoid
hospitalization
and surgery
Reduce or
eliminate
steroid use
Mucosal
healing
Aminosalicylates
5-ASA
Bacterial cleavage:
Sulfasalazine
Time release:
Pentasa
PH dependent:
Asacol
Salofalk
Oral 5-ASA Release Sites
Pentasa®
Asacol®
AZOCOMPOUNDS
Stomach
Small
Intestine
Large
Intestine
Mesalamine in
microgranules
Mesalamine
w/ eudragit-S
Azo bond
Aminosalicylate
• Well established role in induction and maintaining
remission in UC
• Dose –related effect in UC
• Long term safety established
• Efficacy in crohn’s disease is controversial due to
absence of rigorous evidence and preponderance of
negative studies
Steroids
Corticosteroids are potent antiinflammatory agents for the
acute treatment of patients with
moderate to severe relapses of
IBD.
Steroids
Topical
Oral
Prednisone
Prednisolone
Budesonide
Parentral
Hydrocortisone
Methylprednisolone
Steroids
Budesonide is a poorly absorbed
corticosteroid with limited bioavailability
due to extensive first-pass metabolism
(degraded by the liver and red blood
cells) that can produce therapeutic
benefit with reduced systemic toxicity
Definitions
• Corticosteroid refractory disease
– Patients who have active disease despite prednisolone up
to 0.75 mg/kg/day over a period of four weeks.
• Corticosteroid dependent disease; Patients who are
either
– (a) unable to reduce corticosteroids below the equivalent of
prednisolone 10 mg/day (or budesonide below 3 mg/day)
within three months of starting corticosteroids, without
recurrent active disease, or
– (b) who have a relapse within three months of stopping
corticosteroids.
The aim should be to withdraw corticosteroids completely.
E F Stange, S P L Travis; ECCO Consensus on the diag&Mang of CD”Gut 2006;55(Suppl
Steroids
• Crohn’s disease: 50% of patients will require
treatment with steroids.
• Of those 28% will become steroid dependent
• Ulcerative colitis: 34% of patients will require
treatment with steroids.
• Of those 22% will become steroid dependent
Steroid
• Effective for the short-term control of
symptoms of Crohn's disease but are neither
effective nor safe for long-term maintenance
of response.
• In patients with disease that is refractory to or
dependent on glucocorticoids, steroid-sparing
strategies should be considered, including
immune modulators or surgery.
Principles of steroid use in IBD
1. Use an effective dose—Underdosing at the start of therapy typically leads to dose escalation and
prolonged dosing to achieve a response.
2. Do not overdose—Patients who do not benefit from 40 to 60 mg are unlikely to benefit from
increased or prolonged oral dosing. Such patients require intravenous dosing or treatment with
another rapidly acting agent, such as infliximab
3. Do not treat for excessively short periods—Doses should not be tapered too quickly once
symptoms have been controlled. Very brief courses of gluco-corticoids (≤3 weeks) are likely to result
in a rebound flare.
4. Do not treat for excessively long periods—Patients in whom a second glucocorticoid taper fails
shortly after a first should be considered candidates for glucocorticoid-sparing immune modulators.
Glucocorticoids should not be begun without a strategy in mind for terminating treatment.
5. Anticipate side effects—Bone loss in particular may be anticipated with even short-term use.
Strategies to preserve bone density should be undertaken early).
Steroid adverse effects
Hypertension
Hyperglycemia
Cataract
Adrenal
suppression
Osteoporosis
Osteonecrosis
Neuropsychiatric
effects
Immunomodulators: azathioprine and 6 mercaptopurine
AZA and 6-MP are chemically related immunomodulators.
AZA is nonenzymatically converted to 6-MP.
Their onset of full activity is slow and may take 3 months.
6-MP and AZA are members of the thiopurine class of medications and are commonly used
to treat patients with CD and UC who are corticosteroid dependent in an attempt to
withdraw corticosteroids and maintain patients in remission off corticosteroids.
AZA and 6-MP have also been shown in some studies to reduce clinical and endoscopic
postoperative recurrence of CD.
Indications of immunosuppressant
Maintenance of
steroid-induced
remission
Steroid
resistant cases
Perianal fistula
? Post-op
recurrence
Safety and tolerability
• Flu like symptoms occuring after 2-3 weeks
and resolve on discontinuation of RX (20%)
• Hepatotoxicity and pancreatitis(<5%)
• Leukopenia(<3%)
• Good long term tolerance
• Can be given during pregnancy
• ? ↑ risk of neoplasm
Methotrexate
induces clinical response more rapidly than 6-MP or AZA in patients with IBD.
Indicated for induction and maintenance of remission in patients with crohn’s disease
Methotrexate is absolutely contraindicated in pregnancy.
The currently available evidence is insufficient to support the use of methotrexate for the induction or
maintenance of remission in patients with active UC.
Routine monitoring of laboratory parameters, including complete blood counts and liver-associated
laboratory chemistries, is recommended in patients who are treated with methotrexate.
Cyclosporine
• Competetively binds to and inhibit calmodulin
dependent calcineurin, leading to suppression of Tcell and IG E receptor signaling pathways.
• IV Cyclosporine has a rapid onset of action
• Neither intravenous nor oral low-dose cyclosporine
has proven efficacy in patients with luminal CD.
• High toxicity limiting its use
Biologic treatment
Drug
Route of
Interval
administration between
injection
indication
Infliximab
Anti TNF monoclonal
AB
IV
8 weeks
CD and Ulcerative colitis
Adalimumab
Humanized anti TNF
AB
S/C
2 weeks
CD
S/C
4 weeks
CD
Certolizumab Pegylated anti TNF
Natalizumab
Anti-alpha4 integrin AB IV
CD refractory to anti
TNF
Treatment
Presence of
extraintestinal SXS
Disease
location
Therapeutic
options
Therapy
induced
complications
Disease
severity
Treatment of ulcerative colitis
Disease location
Distal
(below the splenic
flexure)
Topical treatment
Disease extent
Extensive
(proximal to splenic
flexure)
Systemic
medication
Topical treatment
5-ASA
Enema
(SPLENIC FLEXURE)
Steroid
Topical RX
Suppository
(Distal 10 cm)
5-ASA
Advantage of topical therapy
Quicker
response
Less
frequent
dosing
Mild to moderate distal colitis:
induction of remission
• Topical 5 –ASA is more effective than topical
steroid and oral 5-ASA
• Combination of oral and topical 5-ASA is more
effective than either alone
• Patient unresponsive to topical therapy: po
steroids
Mild to moderate distal colitis:
maintenance of remission
• Topical and oral 5-ASA :Effective in
maintainaing remission
• Combination of oral and topical 5-ASA is more
effective than oral 5-ASA alone
• Topical and oral steroid: no role
Mild to moderate extensive colitis:
induction of remission
• Oral 5-ASA is the first line of therapy
• Oral steroids are reserved for:
- refractory patients to PO +/- topical 5-ASA
- troubling sxs requiring rapid improvement
Mild to moderate extensive colitis:
maintenance of remission
• All 5 –ASA are effective in preventing relapse
• Azathioprine or 6-MP may be used:
-steroid sparing agent in steroid dependent patients
-steroid refractory patients who are not acutely ill
-remission not adequately maintained on 5-ASA
Management of severe colitis
• Patients with severe colitis refractory to maximal
oral prednisone, oral 5-ASA and topical RX, or
presents with toxicity should be hospitalized for
IV steroids
• Patients not responding within 7-10 days of
maximal medical therapy should be offered
alternative treatment:
-biologic treatment
-cyclosporin
- surgery
Cyclosporine
• Cyclosporine has a rapid onset of action (more rapid
than AZA, 6-MP, or methotrexate) and when
administered intravenously has been shown to be
effective in the management of patients with severe
UC.
• It often demonstrates clinical efficacy within 1 week
when administered intravenously.
• Oral cyclosporine has a possible role in the induction of
a clinical response in UC and short term in the
maintenance of an intravenous cyclosporine-induced
response, allowing time for the slow-acting purine
analogues to become effective.
Biologic treatment
• Infliximab is the only FDA approved treatment
for patients with moderate-severe ulcerative
colitis
• ACT 1 study: treatment with infliximab can
prevent hospitalizations and surgery for UC
patients in the first year of treatment
Ulcerative Colitis: Mild to Moderate
Acute flare
Exclude enteric
pathogen
Patient unwilling
to take rectal
therapy
Left side
Extensive
Patient willing to
take rectal therapy
Oral 5-ASA
Consider rectal therapy
(5-ASA and/or steroid)
Oral 5-ASA
Response
adequate
Maintain
Response
adequate
Maintain
oral 5-ASA
Response
inadequate
Response
adequate
Consider
increased dose
Response
inadequate
Response
inadequate
Response
inadequate
Oral steroid
Ulcerative Colitis: Moderate to Severe
Moderate
Severe
Inadequate response
Inadequate response
Oral steroid
IV Steroid
Consider
CyA
Adequate response
Response
Taper
Unsuccessful
6MP/AZA
Failure
Successful
Maintain on
5-ASA and
observe
Success
Maintain
6-MP/AZA
Infliximab
Response
Maintain
infliximab
No
response
No
response
Colectomy
Therapeutic Pyramid for
Active UC
Severe
Surgery
Cyclosporine
Moderate
Infliximab
Systemic Corticosteroids
AZA/6-MP
Oral Steroids
Mild
Aminosalicylates
Indication for surgery
• Total colectomy with ileoanal pouch anastomosis is
the procedure of choice for patients with UC:
Severe
hemmorrhage
Perforation
Toxic megacolon
unresponsive to
maximal medical
therapy
Carcinoma/ High
grade dysplasia
Medically
intractable
symptoms
Indications for surgery in UC
Perforation
6%
Perforation Toxic uc
6%
Toxic
10% UC
10%
Colorectal
Analysis of 917 UC patients at
Heidelberg University between
1982 and 2001
ca 7%
Colorectal
Carcinoma
Dysplasia 3%
7%
Failure of
medical therapy
74%Failure of
Dysplasia
2%
medical
therapy
75%
Hoffmann et al. Chronisch-Entzündliche Darmerkrankungen. Thieme 2004
Potential Complications of UC Surgery
•
•
•
•
•
•
•
•
3-10 stools/24 hrs 1
Decrease in female fertility (38-54%)3-5
Pouchitis (10-60%)1
Small bowel obstruction (20%)1
Abscesses & fistulae (5-12%)6
Pouch-vaginal fistula (4%)1
Long-term continence problems (15%)6
Impotence (1.5%)2
1Sagar
3Olsen,
PM, Pemberton JH. In Satsangi J, Sutherland L, et al, eds. Inflammatory Bowel Diseases. Spain: Elsevier Limited; 2003:491 511.
2Pemberton
KO, et al. Gastroenterology. 2002;122:15-19.
5Gorgun
4Johnson
E, et al. Surgery. 2004;136(4):795–803.
6Stange
JH, et al. Ann. Surg. 1987;206(4):504-513.
P, et al. Dis Colon Rectum. 2004;47;1119–1126.
et al. Colitis ulcerosa – Morbus Crohn.Uni-Med Verlag AG 1999.
Pouchitis
• Idiopathic inflammation of “pouch” after ileoanal
pouch anastomosis
Stool
frequency
Rectal
bleeding
Tenesmus
incontinence
urgency
Abdominal
pain
Fever
Treatment of crohn’s disease
Mild to moderate luminal active disease
• Despite the use of oral mesalamine treatment in
the past, new evidence suggests that this
approach is minimally effective as compared with
placebo and less effective than budesonide or
conventional corticosteroids
5-ASA in crohn’s disease
• No mesalamine product has been FDA
approved for either induction or maintenance
of remission
• Not effective in maintaining post-operative
remission.
Mild to moderate luminal active disease
• Oral budesonide is more effective than placebo,
or 5-ASA and have similar efficacy to conventional
po steroids for the treatment of mild-moderate
active CD involving distal ileum and/or right
colon.
• Budesonide is recommended for use as primary
therapy for patients with mild to moderate active
CD localized to ileum and/or right colon
Moderate to severe luminal disease
• Prednisone (40 -60 mg/day) until resolution of
symptoms
• Infection or abscess requires antibiotic therapy
or drainage
• Azathioprine and 6-MP are effective in
maintaining a steroid-induced remission
• Parenteral methotrexate (25 mg/week) :effective
for steroid-dependent and steroid-refractory CD
Biologic treatment
• Anti TNF monoclonal Ab : infliximab, adalimunab
and cetrolizumab are effective for:
-moderate- severely active CD not responding
despite complete and adequate therapy with a
steroids or immunosuppressive agent
-as alternative to steroid therapy in selected
patients in whom steroid is contraindicated
• The anti-alpha 4 integrin Ab : natalizumab, is
effective for patients with moderate to severely
active disease who had an inadequate response to
anti TNF AB or unable to tolerate it
Drug
Mild-moderate active CD
Induction
Maintenance
Oral
sulfasalzine
YES
Oral
mesalamine
NO
NO
Oral steroid
YES
NO
Refractory and severely
active CD
Induction
Maintenance
Perianal fistula
Induction
Maintenance
NO
NO
NO
NO
NO
YES
NO
YES
Methotrexate
YES
YES
Infliximab
YES
YES
YES
YES
Adalimunab
YES
YES
YES in
subgroup
analysis
YES in
subgroup
analysis
centrolizumab
YES
YES
No data
No data
IV steroid
Azathioprine/
6MP
Post-op
recurrence
YES
NO
YES
NO
NO
YES
Therapeutic Strategies:
Step 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
Therapeutic pyramid for treatment of
luminal non fistulizing crohn’s disease
Severe
Surgery
Biologic RX
Methotrexate
Azathioprine/6MP
Mild
Steroids
Antibiotics
5-ASA
Budesonide
Therapeutic Strategies:
Top down
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
Treatment of perianal fistula
• Mesalamine:
• No clinical trial has demonstrated any beneficial
effect of mesalazine on fistula healing.
• Steroids:
• Not effective
Treatment of perianal fistula
• Antibiotics: widely used first-line treatment for fistulas in patients with
Crohn’s disease
• Dual role in the treatment of fistulas: as a primary therapy and as an
adjuvant therapy for abscesses and infections caused by the fistula.
• Metronidazole:
• Most studied antibiotic
• Fistulas generally respond to administration of this antibiotic after 6–8
weeks, but therapy is typically continued for 3–4 months.
• Ciprofloxacin:
• The beneficial effects of the fluoroquinolone antibiotic, ciprofloxacin, have
demonstrated in various studies.
• combination treatment with metronidazole and ciprofloxacin has shown
beneficial effects
Treatment of perianal fistula
• Immunosuppressives:
• Azathioprine and 6-mercaptopurine: seem to
be effective treatments for perianal fistulas
• Methotrexate: Not recommended
• Cyclosporin: Not recommended
Treatment of perianal fistula
• Biologic: In contrast to azathioprine and 6- MP, the
clinical effects of biologics begin to be seen soon after
initiation of therapy
• Surgery:
• The reported incidence of perianal fistulas that require
surgery in patients with Crohn’s disease varies from 25–
30%.
• The goals of surgery in these patients are to cure the
fistula(s) while preserving anal sphincter function.
Treatment of external fistulas (perianal or enterocutaneous)
Antibiotic therapy (metronidazole
and ciprofloxacin) for 3 months
plus long-term immunosuppressant
drugs (azathioprine 6MP)
Biologics for 2–3 months
followed by long-term
immunosuppressant therapy
Administration of biologics
Surgery ,resection of the diseased bowel segment if no improvement
Treatment of internal fistula
• If asymptomatic: no need for tratment
• Symptomatic :surgical resection of diseased
bowel segment
Factors predicting prognosis
smoking
clinical
Use of steroid
within 6 month
after dx
?ileal location
prognosis
High ASCA
biological
Genetic
NOD2 STATUS
Earlier age of
onset
Fibrostenoting
Indication of surgery in crohn’s disease
• Surgical resection, stricturoplasty, or drainage of
abscesses is indicated to treat complications or
medically refractory disease
• Surgical resection rarely “ cures ” CD
• Nevertheless, surgical intervention is required in up
to two thirds of patients
• The most common indications for surgical resection
are refractory disease despite medical therapy or
side effects of medication (steroid dependence)
Indications for surgery
obstructing
stenoses
cancerous or
precancerous
lesions
suppurative
complications
medically
refractory
disease.
Preventing post-op recurrence
Azathioprine/6MP
Stop smoking
? Biologic therapy
?Metronidazole
Stricturoplasty
• Stricturoplasty has been advocated as an
important alternative to resection in the
treatment of selected fibrotic strictures of the
small bowel and should be attempted when
possible to help avoid:
- impaired nutrient absorption
-steatorrhea
-bacterial overgrowth
-short bowel syndrome
Cancer in IBD
Cancer in crohn’s disease
• When Crohn's disease involves the large bowel, the
excess risk of colorectal cancer appears to be similar
to that in ulcerative colitis of similar extent.
• The characteristics and prognosis of colorectal
cancer in Crohn's disease also are similar to those
for colorectal cancer in ulcerative colitis.
• surveillance colonoscopy has been recommended
as a means of early detection.
COLORECTAL CANCER RISK IN
ULCERATIVE AND CROHN’S
COLITIS
Colorectal cancer in ulcerative colitis
• Patients with UC have an increased risk of colorectal
cancer.
• This risk is dependent on several factors
• the most important
-duration
-extent of disease
• Other risk factors :
-PSC
-family history of colon cancer
-age at diagnosis of disease
-severity of inflammation
Risk Factors for Colon Cancer in Ulcerative
Colitis and Crohn’s colitis
Risk Factor
Importance
Extent of disease
++++
Duration of disease
++++
Primary Sclerosing Cholangitis
Young age at onset
+++
+
Positive family history
+
Severity of Inflammation
?
Choi PM, et al. Gastroenterol Clin North Am 1995;24:671-87.
Eaden J. Am J Gastroenterol 2000;95:2710-2719.
Cumulative Incidence for Colorectal Cancer Based
on Extent of Disease at Time of Diagnosis
40
pancolitis
left-sided colitis
30
Cumulative
CRC (%) 20
10
0
0
10
20
30
Years follow-up
40
Ekbom, et al NEJM, 1990
Colorectal cancer in ulcerative colitis
• The incidence of colon cancer in UC has been estimated at
approximately 7% to 10% at 20 years of disease and as high
as 30% after 35 years of disease.
• in general, the risk of CRC may be estimated to increase
within the range of 0.5% to 1.0% per year after 8 to 10 years
of disease in patients with extensive UC
Colorectal cancer in ulcerative colitis
annual colonoscopy with biopsies in patients with UC
extending beyond the splenic flexure who have disease
for 8 to 10 years
Examinations should be performed during periods of
inactive disease so as not to allow inflammation and
reactive change to obscure the picture.
Four-quadrant biopsies should be obtained every 10
cm and from any potentially dysplastic lesion
Protective factors
5-ASA
Tight
medical
control
Folate
Future of IBD treatment
• 5 ASA will be administered once daily in ulcerative
colitis , and decrease in crohn’s disaease
• Treatment of IBD with steroids will decrease due to
lack of long term efficacy and side effects
• The use of anti-TNF therapy will most likely
increase
• They will be used earlier in the course of CD with
more rigorous treatment goal: mucosal healing