Recent update on the surgical and medical management of ulcerative colitis, including various controversies regarding IPAA and recent medical management incorporating the role of biologicals

1. RECENT UPDATE ON
MANAGEMENT OF ULCERATIVE
COLITIS
DR AMIT DANGI
DEPARTMENT OF SURGICAL GASTROENTEROLOGY

2. INDICATIONS : ELECTIVE
Intractable disease Concern for malignancy Extraintestinal manifestations
Impaired QOL
Acute: Symptoms not
controlled despite maximal
medical therapy
Chronic: Inability to taper
medications to a tolerable
maintenance dose
Drug induced complications
Long standing colitis
DALM
Dysplasia ( any grade)
Partially obstructing lesion
(stricture)
Controversies:
Timing of surgery for cancer
prophylaxis
Role of biopsy in directing the
timing of colectomy
Growth retardation.
Joint, eye and skin related
Extraintestinal manifestations
Hemolytic anemia
(Colectomy+Splenectomy)
Anorectal complications

3. EMERGENCY INDICATIONS
Acute severe colitis unresponsive
to IV steroids
Toxic megacolon with impending
perforation
Perforation Hemorrhage
(massive, unrelenting)
Total obstruction from
stricture

4. Emergency Procedures
Procedure Indications Contraindications Advantages Disadvantages
Total colectomy
with end
ileostomy
Life-threatening
emergencies.
Acute severe
colitis.
High dose
steroids
Massive
hemorrhage
Allows option for
IPAA; low risk
Requires second
operation; may
develop rectal
recurrence of
disease
Proctocolectomy
with end
ileostomy
Life-threatening
emergencies
Severely toxic or
unstable patient
Definitive
treatment
No option for
IPAA; moderate
risk for perineal
nerve damage
Blow-hole
colostomy with
end ileostomy
Life-threatening
emergencies
Rarely, if ever,
indicated
Short, simple
decompression
procedure
Diseased colon
and rectum
retained

5. ELECTIVE SX Indications Contraindications Advantages Disadvantages
TPC + END
ILEOSTOMY
Avoid risks of IPAA
Elderly
Poor sphincter function
Rectal cancer: Middle and
lower 1/3 or large upper
1/3 tumors
Patient’s aversion to
permanent ileostomy
Obesity
Life-threatening
emergencies
Eliminates all
diseeased mucosa.
Single operation
Nerve injuries
Permanent
ileostomy
Delayed perineal
wound healing
Stoma problems
High risk of SBO
TAC+IRA No rectal involvement
Avoid permanent stoma and
IPAA
Young women of
childbearing age to preserve
fertility
Poor sphincter tone or
dysfunction
Rectal/perianal d/s
Dysplasia or cancer
One-stage operation
Complete continence
with good function
Less nerve injury
Eliminates stoma
30% Recurrence rate
(requiring ileostomy)
20% proctectomy.
Risk of rectal cancer
requiring lifelong
surveillance
KOCK’S
ILEOSTOMY
Alternative to conventional
ileostomy.
Poor sphincter tone
Low rectal cancer
Failed IPAA
Conversion from ileostomy
Possibility of CD
Previous SB resection
Patients > 60 years
Obesity
Coexisting medical
illness
Avoids ileostomy
Patients remain
continent
Good QOL
Improved body image
High reoperation rate
(35%) due to nipple
valve dysfunction or
failure
High fistula rate
Pouchitis

6. Approach
• Open
• Laparoscopic
• HALS
Pouch Design
Anastomosis
• Stapled
(single/double
stapled)
• Hand-sewn

7. TYPES OF IPAA
RECONSTRUCTION
• DOUBLE STAPLED
• DOUBLE PURSE STRING SINGLE STAPLED
• HAND SEWN

8. Hand Sewn or Stapled Anastomosis
• Stapled anastomosis: Better outcomes, particularly with regard to
soiling, faecal leakage and social restriction.
• Risk of cuffitis (rarely pouch dysfunction), and risk of dysplasia (very
rarely cancer, <30 reported) with stapled anastomosis.
• Mandatory that the surgical team can also perform a mucosectomy
and a hand-sewn anastomosis should the stapled anastomosis fail.
• No room for re-stapling.
• In case of neoplasia complicating colitis : Stapled is equally safe.

9. Meta-analysis :
• 21 studies
• N=4183 pts
• Hand-sewn: 2699
• Stapled IPAA: 1484 pts
• No significant difference in postoperative complications
• Bowel frequency similar
• Incontinence to liquid stool, seepage at night higher with hand-
sewn IPAA; significantly lower resting and squeeze pressure
• Sexual dysfunction, quality of life, and rate of ATZ dysplasia similar
Lovegrove RE, Constantinides VA, Heriot AG, et al. A comparison of hand-sewn versus stapled ileal pouch anal
anastomosis (IPAA) following proctocolectomy: a meta-analysis of 4183 patients. Ann Surg 2006;244(1):18–26

10. Double stapled or double purse string
• Double stapled : 2 staple lines across each other, creating stapled dog ears
and potentially ischemic areas.
• Single stapled double purse string: Eliminate intersection staple lines and
stapled corners.
• Double staples also avoided in taTME approach.
• Slowamis and Marerick (AJS 2006): 160 non diverted/ non irradiated
patients underwent double purse string anastomosis:
96% : No pelvic sepsis
2.5%: Pelvic sepsis with no anastomotic defect
Leak : 1 patient
Ta-TME approach: Single stapled

11. Managing the rectal remnant in Emergency Colectomy
• The whole rectum and the IMA should be preserved.
“facilitates subsequent pouch surgery”
• Ways to deal with stump:
Leave additional sigmoid colon
Closure of stump at fascia level (subcutaneous stoma)
Mucus fistula
Rectal decompression with per rectal drain

12. Site of Anastomosis for restorative proctocolectomy
• Distance between dentate line and anastomosis should
not exceed 2 cm.
Comparison
• At dentate line: More seepage and soilage
• At the top of anal columns: Function better preserved
but diseased mucosa left
• Above anal columns (1 cm): Disease recurrence
¥Martin LW et al. The critical level for preservation of continence in ileoanal anastomosis. J Pediatric
Surg 20:664-667, 1985.

13. Defunction or Not: Role of covering ileostomy
• Two vs One stage
• Financial benefits
• If complicated: High price?
• Emerging evidence:
Defunctioning the distal
anastomosis reduce the
incidence of a leak.
• No difference in complication rates in
selected groups
No long term steroids
Absolutely no tension
anastomosis
Otherwise healthy patients
• Single stage IPAA: highly select cases
Thick or fatty abdominal wall
Short small bowel
mesentery.
Sugarman HJ, Newsome HH. Stapled ileoanal anastomosis without a temporary ileostomy. Am J Surg
1994;167:58–66

14. Single or Two stage: Covering loop Ileostomy?
• No RCT’s of sufficient power
Disadvantages of ileostomy:
• Stoma related complications
• Higher incidence of SBO
Concern for pelvic sepsis: One would
rather deal with these complications
Acutely unwell malnourished colitis
patient taking high-dose steroids—
No other choice
Single stage IPAA:
Precautions
• Irrigate distal ileum with
antibiotics
• Irrigate anorectum before
rectal division
• Place catheter for
drainage

15. One, two or three stage IPAA?
• Pouch failure rates from St Marks higher in patients without a covering stoma; (15% vs
8%)
Tulchinsky H et al Ann Surg 2003; 238: 229-234
• Anastomotic separation occurs in approximately 5%-15% of patients
• Complication rates for ileostomy closure in 10%- 30%
• Another report published contrasting figures with less than 1% of one stage pouches
failing
MacRae HM et al Dis Colon Rectum 1997; 40: 257-262
Most reports favour a two stage procedure.

16. Meta-analysis comparing results in patients with
or without ileostomy.
Weston-Petrides GK, et al Arch Surg 2016

17. Another meta-analysis
Remzi FH, Fazio VW, et al. Dis Colon Rectum 2006.

18. • Retrospective analysis: John Hopkins (2000-2011)
• Patient cohort: Patients who underwent 2-stage or 3-stage IPAA surgery for refractory active UC
• N=144 patients
• 3 stage: Only 19.4%.
• Decision to perform a 3-stage vs 2-stage procedure was affected by emergent status (P < .001) and
hemodynamic instability (P = .04) but not by age, sex, BMI, use of steroids, or use of anti TNF agents
• 2-stage procedures (multivariate regression): Incidence of perioperative complications was affected
by surgeon experience (P = .02) but not by emergent status, use of steroids, or use of anti–tumor
necrosis factor agents.
• Similar outcome in patients with acute UC undergoing 2 stage or 3 stage procedure.
• Use of steroids and anti–TNF agents alone do not appear to justify the decision to avoid IPAA creation
at the first operation provided that it is performed by a high-volume IBD surgeon.
JAMA Surgery July 2013 Volume 148, Number 7

19. Urgent sx: n=580 Elective sx: n= 599
Urgent sx: Younger ,malnourished, more severe active disease, higher steroid use (P < 0.05).
Hemodynamic stability was similar in both gp .
More subtotal colectomies in urgent pts (5.1% vs 29%, P , .0001)
Fewer laparoscopic procedures (8.8% vs 18%, P < 0.07) in urgent pts.
Multivariate regression: Short-term complications were increased with higher BMI and
urgency status (P =0.05).
Similar anastomotic leaks and long-term complications.
Surgeon inexperience and use of immunomodulators other than infliximab : Increased odds
of long-term fistula/abscess (OR, 5.56; P = .05] and pouch failure (OR, 13.3; P = .01).

20. • Better fecal continence with intramesocolic excision.
• Similar overall bowel or sexual functions.
Hicks CW et al. AJS.2014
Intramucosal or Total mesorectal Excision

21. Laparoscopic/SIL IPAA
• Laparoscopic colonic mobilisation
• Extra corporial bowel division and pouch construction
• May help to reduce pelvic adhesions
• Have value in fertile women
• Early return of bowel function
• Reduced hospital stay
Geisler DP, Condon ET, Remzi FH. Colorectal Dis. 2010;12:941-943
Young-Fadok TM, etal. Gastroenterology 2001;A-452:2302

22. Lengthening Procedures

23. Lengthening Procedures
1. Ligation of the IC, distal SMA or, less commonly, individual ileal
mesenteric vessels : 3-6 cm gain in length
2. Complete mobilization of the small bowel mesentery to the root of
the SMA at the pancreatic head
3. Step-wise ‘‘relaxing’’ incisions of the peritoneum over tension lines
along the pouch mesentery
4. Orienting the ileal pouch anteriorly within the pelvis
5. Using an S-pouch configuration.
6. Leave pouch in pelvis with proximal loop ileostomy

24. Techniques for ensuring
adequate length include
Preserving ileocolic
artery during initial
stage of right
colectomy
Mobilizing the
posterior attachment
of entire small bowel
mesentery up to D3
Assessing most inferior
point of terminal
ileum, generally
located 15 to 20 cm
from ICJ
• Assess vascular pedicle in
ileal mesentery
(ileocolic/ileal branch)
• Dividing the peritoneum
of the mesentery on
both anterior and
posterior sides
• If necessary, divide 1 to 3
distal ileal branches-->
additional 2 to 4 cm of
length
Burnstein et al, Technique of
mesenteric lengthening in ileal
reservoir-anal anast+ mosis. Dis
Colon Rectum. 1987;30:863-866
• SMA pedicle can be
divided at the point
of origin of last
jejunal branch - safe
if ileocolic pedicle
preserved
• Vary apex of
pouch
Thirlby, Am J S, 1995

26. DI Chiu et al. Tech Coloproctol2016

27. History of pouches
• Parks and Nicholls (1978) S pouch
• 1980, Utsunomiya et al described J pouch.
• 1980, Fonkalsrud introduced a side-to-side
pouch.
• 1985, Nicholls and Pezim described W pouch.
• Functional outcome not dependant on
configuration of the pouch
• Presently the J pouch is the reservoir that most
surgeons use.
POUCHES IN UC
• J pouch
• S pouch
• W pouch
• H pouch
• B pouch

28. W AND J POUCH
J W
Easy construction.
Benefits from staplers
Needs only 30-40cm of
ileum.
If long enough, function
well
Time consuming to
construct.
Difficult to do with
staplers.
Uses 50cm of ileum.
Only marginally better
than J pouch in stools
frequency

29. J POUCH
(Utsunomiya)
• Easiest to create
• Most common
• Terminal 30-40 cm
of small intestine
• Folded into two 15
or 20 cm
segments
• 1.5cm enterotomy
made
longitudinally at
pouch apex
¥ Johnston et al, Gut,
1996
S POUCH (Parks
& Nicholls)
• Reaches upto 2-
4 cm further
than J-pouch.
• Usually created if
excessive tension
• Constructed
using 3 limbs of
12- 15 cm of
terminal small
bowel with a 2-
cm exit conduit

30. Pouches - comparison
• Recent meta-analysis : 18 studies with 1519 patients
• No significant differences in postop complications including leak, stricture,
pelvic sepsis, pouchitis, SBO , and pouch failure
• Bowel frequency/use of anti-diarrhoeals higher in J-pouch patients
• S- or W-pouch had more difficulty in pouch evacuation
• Seepage and incontinence equal in all
Lovegrove RE, et al. Meta- analysis of short-term and long-term outcomes of J, W and S ileal reservoirs for restorative
proctocolectomy. Colorectal Dis 2007
• Good outcomes: Compliant ileal reservoiR, Strong anal sphincter, Intact anal
reflexes
• Pouch design does not affect outcome
Lewis WG et al Gut 1995; 37: 552-6
McHugh SM et al Dis Colon Rect 1987; 30: 671-77
Oresland T et al Scand J Gastroenterol 1990; 25: 986-996

31. IPAA: Points of controversy
Role of IRA:
• Preservation of postoperative fertility in
the female.
• Better functional results.
• QOL is not necessarily improved.
• Indications:
Technical difficulties for creation of
IPAA
Doubt persists between UC and CD
Altered sphincter function, in
particular, patients older than 70.
Young females (fertility).
• Pre-requisites:
Non fibrotic rectum
No extra-intestinal manifestations
No dysplasia or colorectal malignancy
Duration of disease is less than 10 yrs.
• The patient must adhere to a strict
surveillance program for the remnant
rectum (level of evidence 3).
• At 10 years, the risk of secondary
proctectomy is estimated to be around
20%.
Ileal pouch-anal anastomosis: Points of controversy
Journal of Visceral Surgery (2017)

32. • No age limit to performance of IPAA, as long as preoperative
sphincter function is preserved.
• Similar functional results and failure rates in Indeterminate colitis.
• Acceptable long term outcome of IPAA for CD (well- selected pts
when the reservoir can be left in situ), although with higher failure
rate.
• Fazio et al: Functional outcome and QOL good to excellent in 95%
cases (n=150 IPAA for CD).
• Laparoscopic approach preferred esp in fertile woman.
• Postoperative morbidity and QOL equivalent to those after
laparotomy
• Earlier return of transit, less postoperative pain and shorter hospital
stay
Ileal pouch-anal anastomosis: Points of controversy
Journal of Visceral Surgery (2017)

33. • Stapled anastomosis preferred but the surgeon should have mastery of both
anastomotic techniques (ECCO 2012 recommendations).
• IPAA is feasible without a protective ileostomy with no increase in morbidity,
particularly in patients with FAP and selected cases of UC.
• Single stage:
No tension on anastomosis
Adequate hemostasis
Air-tightness leak test
Absence of malnutrition (albumin<3.5mg/dL)
Absence of anemia (Hb < 13.5 mg/dL) and
Absence of prolonged consumption of high doses of steroid (≥ 20 mg
prednisone for more than 3 months).
Remzi FH, Fazio VW, et al. Dis Colon Rectum 2006
Grobler SP, et al. Br J Surg 1992.

34. Pregnant females
• No consensus as to which delivery route is best after IPAA
• Functional outcome does not seem to be altered at medium term
after vaginal delivery.
• Caution is therefore warranted.
• 2009 INCA recommendations :
‘‘reasonable to propose a C-section in the light of the risk that vaginal
delivery might alter sphincter function and pelvic floor status’’.
Hahnloser D, et al. Dis Colon Rectum 2015
Remzi FH, et al. Dis Colon Rectum 2005

35. Low dose vs High dose peri-operative steroids
• Zaghiyan et al (Retrospective review Surgery 2012, Am Surgery 2011) : No
significant improvement in postoperative hemodynamic stability with the use
of high-dose perioperative corticosteroids compared with low-dose or no
• Zaghiyan et al then conducted a RCT (Annals of Surgery 2014) investigating the
use of the
High-dose (IV hydrocortisone 100 mg tds, followed by taper) versus
Low-dose (IV hydrocortisone equivalent to preoperative dosing or no
corticosteroid dosing
for patients who were not taking steroids at the time of surgery)
perioperative steroids
for 92 corticosteroid-treated patients with IBD undergoing colorectal
surgery.
• No differences in the incidence of postoperative postural hypotension
between groups but a trend toward more infectious complications in the high-
dose treated patients (16% versus 4%; P = 0.11).

36. • Aytac et al (DCR 2014) : 235 corticosteroid treated patients:
Use of stress-dose corticosteroids did not negatively impact early
postoperative outcomes
No cases of intraoperative adrenal crises even if no stress-dose
steroids were given.
• However, no objective measures to document potential AI, such as
pre- or post- operative ACTH or cortisol measurements were
performed in any of these studies.

38. 1. Patients without adrenal
suppression:
Do not require extra
corticosteroid
supplementation in the
perio- perative period.
2. Patients with adrenal suppression:
Patients taking supraphysiologic (>20
mg prednisone per day)
corticosteroids dosing for at least 3
weeks preoperatively
• These patients should be treated
with higher doses than their
preoperative regimen peri-op.
• Patients with presumed adrenal
suppression undergoing minor
surgery (e.g., local excision, exam-
ination under anesthesia, ileostomy
reversal) should not require
additional treatment aside from
preoperative steroid dosing.
3. Patients with
intermediate or
unclear adrenal
suppression:
(prednisone 5–20 mg
daily) should be
considered for pre-
operative HPA axis
testing to determine
whether they fall
under the guidelines
for group 1 or 2.
Inflamm Bowel Dis Volume 21, Number 1, January 2016

39. Early Complications
• Acute pelvic sepsis 5-24%
• Anastomotic leaks 5-18%
• SBO 15-44% (5-20%)
• Pouch bleeding
• Pouch–rectostomy ( stapled
anastomosis)
• PVT
Sagar PM, Pemberton JH.
Intraoperative, postoperative and
reoperative problems with ileoanal
pouches. Br J Surg. 2012;99:454–
68.
Complications
• Leak from IPAA :7 - 18%
• Anastomotic sinus : 2–8 %
• Chronic pelvic sepsis 6 %
• Symptomatic stricture : 16 %
• Pouch–cutaneous fistula: 5 %
• Pouch–vaginal fistula : 3–15%
• SBO requiring operation : 5-20%
• Cuffitis 5-16%
• Symptomatic pouchitis (cumulative incidence at
10 years) 40%
• Ultimate failure of pouch: 4 %
• Permanent diversion: 1 %
• Pouch excision : 3 %
• Symptomatic portal vein thrombosis : 6%

41. TAMIS/TATME
• Hybrid of TEM & SILS with conventional lap instruments
• Benefits of TEM at a fraction of the cost
• In patients with a narrow pelvis, the TAMIS approach with its ability to
increase the mobilization of the rectum and improve visibility, may be
valuable

42. LEAKS
• Believed to be associated
with peri-pouch sepsis and
subsequent poor pouch
function
• Double stapled anastomosis
leak rate: 3-4%

43. TAMIS
• No need to transect rectum through abdominal approach
• Single stapled anastomosis
• No stapler-on-stapler line
• No side pockets
• Can expect higher anastomosis integrity hence less leaks
Atallah S, Albert M, Larach S. Transanal minimally invasive surgery: a giant leap forward. Surg Endosc. 2010;24(9):2200–2205

44. Evaluation and treatment algorithm of IPAA
complications after IPAA for U

45. THERAPEUTIC AGENTS IN UC
CONVENTIONAL AGENTS
• AMINOSALICYLATES (Oral + Topical)
• CORTICOSTEROIDS (Oral + Topical)
• THIOPURINES
• CYCLOSPORINE
• BUDESONIDE MMX (Topical)
EFFECTIVE IN MOST CASES
WHERE THE DISEASE IS REFRACTORY OR
INTOLERANT TO CONVENTIONAL
THERAPEUTIC AGENTS

46. BIOLOGICALS
Drug Class Trials Dosage Efficacy
INFLIXIMAB ANTI TNF -α
chimeric mouse-
human recombinant
monoclonal antibody
(25% murine and 75%
human
ACT 1 & 2
UN SUCCESS
IV (5mg/10mg 2
weekly)
21% Steroid free remission at 30
wks
26% steroid free remission at 1 yr
INFLIXIMAB + AZA : 40%
ADALIMUBAB anti- TNF-α IgG1
Completely human
anti- TNF-α IgG1
ULTRA 1 AND 2 SC (40 mg s/c
every 2 week)
16.5% remission at 8 week
22% at 52 week
9-10% remission in pts with
previous use of anti TNF pts
40-50% reduction in UC related
hospitalisation
GOLIMUBAB human IgG1 anti-
TNF-α antagonist
PURSUIT SC 17.8% remission at week 6
(200/100 mg)
23.8% remission at wh 54 (50
mg)
27.8% remission at wk 54
(100mg)

47. Drug Class Trials Dosage Efficacy
Tofacitinib JAK1/JAK3
INHIBITOR
CLINICAL RESPONSE AND
REMISSION AT 8 WEEKS
0.5 mg bd : 32% and 13%
3 mg bd : 48% and 33%
10 mg bd : 61% and 48%
15 mg bd : 78% and 41%
Placebo : 42% and 10%
VEDOLOZUMAB INTEGRIN
BLOCKING
ANTIBODY
α4β7 INTEGRIN
INHIBITOR
GEMINI 47.1% clinical response at 6
weeks
16.9% remission at 6 week
44% remission at week 52.
ETROLIZUMAB α4β7 and αEβ7
integrin INHIBITOR
3 monthly doses
of etrolizumab
at 100 mg
20.5% clinical remission at
week 10

48. Drug Class Efficacy
VISILIXIMAB ANTI CD 3 NO BENEFIT IN PATIENTS WITH IV STEROIDS
BASILIXIMAB IL-2 (CD 25) INHIBITOR SHOWN POTENTIAL
DACLIZUMAB CD 25 INHIBITOR INEFFECTIVE
ABATACEPT CTLA4-Ig: a co-stimulatory
receptor inhibitor
NO BENEFIT
OZANIMOD oral antagonist of the
sphingosine 1 receptor
subtypes 1 and 5
21-26% REMISSION RATE AT 32 WEEKS

51. TRADITIONAL AND REAL LIFE NNT

52. Fecal microbiome transfer : Role of microbiota
• Administration of a heterologous fecal microbiome from healthy donors to UC patients through
duodenal/jejunal intubation, colonoscopy, or enemas.
• Overall, most but not all controlled trials and a meta-analysis were positive,
• More remission rates above controls.
• In a remarkable course, a negative trial turned positive when a “super-donor” returned to the study.
• The vast majority of those patients receiving his feces (rather than from the other donors) experienced
benefit, although the peculiarities of his fecal microbiome are still enigmatic.
• Antagonizes the reduced diversity in a patient’s microbiome by increasing bacterial species.
• However, quite surprisingly, a sterile fecal filtrate was also effective in pseudomembranous colitis, suggesting
that the relevant effector is rather the virome including bacteriophages.
• Accordingly, there is much to be learned before a “messy” procedure proven to be a cure in many
Clostridium difficile relapsers becomes standard in ulcerative colitis.
Fecal Microbiota Transplantation Induces Remission in Patients With Active Ulcerative Colitis in a
Randomized Controlled Trial. Gastroenterology. 2017

53. Primary and secondary failure rate
• Primary failure : 40% in IBD clinical trials;
• Switching to another anti-TNF agent, the treatment becomes effective
at 50%.
• -
• A secondary loss of response can also occur at 1 year after anti- TNF
initiation in IBD patients
• Solutions for the issues in anti-TNF-α treatment of UC are expected to
be elucidated in the future.
• Ben-Horin S, Autoimmun Rev 2014

54. RESCUE THERAPY
• TO AVOID COLECTOMY
• Intravenous corticosteroids: mainstay therapy for
severe UC
Alternatives (steroid-refractory disease) :
Ciclosporin, tacrolimus, or infliximab
These should be considered early (on or around
day 3 of steroid therapy)
Decision making process not delayed (extending
therapy beyond 7 to 10 days carries no additional
benefit)
• Systematic review of 32
trials (1974-2206) of
steroid therapy for acute
severe colitis
• n= 1991 patients
• Overall response to
steroids : 67% (95% CI 65–
69%)
• Need of colectomy : 29%
(95% CI 28–31%)
• Mortality was 1%
• Turner D et al. Clin
Gastroenterol Hepatol
2016.

55. SALVAGE THERAPY
• 1) Can one predict who will fail to respond to iv corticosteroids early,
so that appropriate salvage therapy can be started in a timely
fashion?
• 2) Are the available salvage therapies (calcineurin inhibitors or
infliximab) equally effective? Are there subgroups of patients in
whom one strategy is preferred over another?
• 3) When should the response to salvage therapy be assessed, and if a
patient fails to respond to one salvage therapy should a second
therapy be commenced?

56. • Factors that predict the need for colectomy in acute severe colitis
• 1. Clinical : OXFORD CRITERIA AND SWEDEN INDEX
• 2. Biochemical : HIGH CRP, LOW ALBUMIN AND pH, RAISED ESR
• 3. Radiological markers : COLONIC DILATATION > 5.5 CM, MUCOSAL
ISLANDS ON AXR, ILEUS, DEEP ULCERS predict need for colectomy
• Second European evidence-based consensus on the diagnosis and
management of ulcerative colitis. 2012

57. • Infliximab as a single dose (5 mg/kg) has also been shown to be an
effective salvage therapy in patients with severe UC refractory to iv
steroids.
• A small RCT included 45 patients (24 infliximab and 21 placebo)
• Colectomy rates at 3 months: Infliximab vs placebo 7/24 vs 14/21: p =
0.017;
• Järnerot G, et al. Gastroenterology 2005;

58. Predictors of response to infliximab
Increased short term response is seen in patients with :
High disease activity at baseline and
Seronegative for ANCA
Homozygous for the IBD risk increasing variants in the IL23R gene
Jürgens M, et al. Am J Gastroenterol 2010

59. Selection between calcineurin inhibitors and
infliximab.
• A retrospective review of two cohorts of patients receiving salvage
therapy for steroid-refractory severe UC (49 treated with infliximab
and 43 with ciclosporin) suggests
• Lower immediate colectomy rate in the ciclosporin group.
• Hazard ratios for risk of colectomy in infliximab-treated patients in
comparison with ciclosporin treated pts
• HR 11.2 (95% CI 2.4–53.1, p=0.002) at 3 months
• HR 3.0 (95% CI 1.1–8.2, p = 0.030) at 12 months
• Sjöberg M, et al. Inflamm Bowel Dis 2011

60. CYSIF trial
Randomised 111 thiopurine-naive patients with steroid refractory severe colitis
into
• 1. IV ciclosporin 2 mg/kg/day for 8 days (levels 150–250 ng/mL) followed by 4
mg/kg/day oral therapy,
• 2. Infliximab 5 mg/kg at weeks 0, 2 and 6.
• Treatment failure at day 98 (the primary endpoint):
• 60% vs 54% of patients in the ciclosporin vs infiliximab (p – 0.49)
• The colectomy rates (day 98) in ciclosporin vs infliximab (18% and 21% ;p = 0.66)
• Serious adverse events were numerically more common in the infliximab group
Laharie D, et al: a randomized study (CYSIF). J Crohns Colitis 2011
• A large UK based pragmatic clinical trial (CONSTRUCT) using quality of life and
health economic endpoints is still recruiting (2012).

61. • Another potential advantage of cyclosporine is the short half life of
ciclosporin .
• In the event that salvage therapy fails and colectomy is required,
Ciclosporin will clear from the circulation far quicker than infliximab.
This may have advantages given that septic complications are the major
cause of post-operative morbidity and mortality.
One small series reported that ciclosporin did not increase the risk of
complications after colectomy.
• Lees CW, et al. Pharmacol Ther 2007
• Hyde GM, et al. Dis Colon Rectum 2001

62. Third line medical therapy.
• In general only a single attempt at rescue therapy with a CNI or infliximab
should be considered before referral for colectomy.
• However, treatment success has been reported for sequential use of
calcineurin inhibitors and infliximab after iv corticosteroids.
A Recent cohort from France assessed outcome after third line medical
therapy in 86 patients, The probability of colectomy-free survival was 61.3 ±
5.3% at 3 months and 41.3±5.6% at 12 months.
Clinical remission was achieved in only 30% and three year colectomy rates
were 63%.
Leblanc S, Am J Gastroenterol 2011
Herrlinger KR, Aliment Pharmacol Ther 2010

63. REFRACTORY PROCTITIS AND DISTAL COLITIS
• Refractory proctitis and distal colitis :
• IV steroid therapy
• Salvage medical therapies such as oral or rectal ciclosporin, oral or rectal
tacrolimus, or infliximab.
Järnerot G, Gastroenterology 1985
Sandborn WJ, ET AL. Gastroenterology 1994;106:1429–35.
• MODERATELY ACTIVE STEROID REFRACTORY DISEASE SHOULD BE
TREATED WITH ANTI TNF THERAPY OR TACROLIMUS
• STEROID DEPENDANT ACTIVE UC : THIOGUANINS ARE FIRST CHOICE
• ECCO STATEMENT 2012

64. TOP DOWN THERAPY
Well established in CD
Patients who have an accelerated disease course and
would likely benefit from an earlier intervention
Current tools do not allow reliable advance
identification of these patients.
Patients that can benefit from top down therapy
Pancolitis
Requiring steroid therapy
G.R. Lichtenstein (ed.), Medical Therapy of Ulcerative
Colitis,
Biological agents induce mucosal healing : alter the
natural history of UC in severe UC early in Step Down
approach