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233
17 Medical Management of Ulcerative Colitis
oral 5-ASA as monotherapy. A reasonable regime would be 2.4 g oral mesalazine
(or 6.75 g balsalazide) together with 1–2 g rectal 5-ASA foam or liquid enemas.
In moderate attacks of extensive or left-sided UC or mild attacks not responding to
the above therapy, oral steroids are indicated as outlined above. If remission is not
achieved – steroid-dependent disease, frequent relapses (more than two to three courses
of steroids per year), or early relapse (within 6 weeks of a course of steroids) – azathio-
prine 2–2.5 mg/kg/day or mercaptopurine 0.75–1.5 mg/kg/day should be used.
For those unresponsive to thiopurines, further medical therapy with infl iximab
can be considered but is not currently endorsed by NICE. Surgical options should
be discussed. As a general rule, surgery should be discussed early in the course of
medical therapy in those with unresponsive moderately active UC.
17.5.2 Active Proctitis and Proctosigmoiditis
General principles are as for extensive UC. The aim is to gain remission and mini-
mize side effects from systemic drugs. Suppositories are better tolerated in proctitis
and foam or liquid enemas for proctosigmoiditis. Most patients prefer foam enemas,
but some fi nd the pressure release uncomfortable and thus prefer liquid enemas;
however, they are more diffi cult to retain. Initial therapy should be with 5-ASA
1–2 g per day for mild to moderate attacks, usually combined with oral 5-ASA
(2.4 g oral mesalazine or 6.75 g balsalazide). Meta-analysis shows 5-ASA to be
superior to steroid enemas. However, if remission is not achieved with 5-ASA topi-
cally in mild to moderate disease, then topical steroids should be tried. For active
proctitis, initial therapy should be with suppositories (mesalazine suppositories 1 g
nocte) which achieve median remission rates of 67% (31–80%) versus 7–11% given
placebo [ 1 ] and are twice as effective as topical steroids. If rectal 5-ASA fails, then
steroid suppositories should be tried. Combined oral and topical mesalazine is prob-
ably more effective than either one alone for active distal disease.
If the combination of oral and rectal 5-ASA or steroids fails to achieve remission,
then a course of oral steroids is indicated with continuation of oral and rectal 5-ASA.
Thiopurine therapy should be used in resistant or refractory disease.
Resistant proctitis can be diffi cult to treat and there is no evidence-based therapy
pathway. A trial of oral steroids is logical. If this is ineffective, the authors tend to use
initially arsenic suppositories (acetarsol 500 mg) for 2–4 weeks which are often very
effective. If this is ineffective, then there is evidence for rectal lignocaine 800 mg bd
(20 ml of 2% lignocaine gel via a syringe and enema tube), butyrate, bismuth,
ciclosporin, and sucralfate. These depend on local availability, and there is limited trial
evidence on which is more effective or whether they are better used in combination.
It is important to remember, particularly in resistant proctitis, that proximal con-
stipation is common due to hypomotility in the infl amed segment. This proximal
constipation further worsens distal infl ammation, probably because drug delivery to
the distal colon is affected. Clear explanation is needed for patients to understand the
rationale for trying laxatives. Treatment with PEG-based laxatives is the best thera-
peutic option to improve the proximal constipation. For resistant distal disease, it
234
P. Flanagan and K. Leiper
can be diffi cult to determine the contribution of coexisting irritable bowel. Prominent
pain without evidence of proximal constipation is often a clue to this, together with
other typical IBS symptoms. Sigmodoscopic evaluation can help to differentiate.
For distal disease, refractory to the above therapy infl iximab or ciclosporin can be
used, but the remission rates are unimpressive and surgery should be considered.
17.5.3 Maintenance of Remission
5-ASAs are also effective at preventing relapse of UC. Because of the defi nite
effect on reducing fl are-up rates and the probable effect in reducing colon cancer,
long-term maintenance therapy with 5-ASA is recommended for all patients.
Sulphasalazine may be superior to other 5-ASAs, although the newer drugs are
still preferred for their side effect profi le. There is limited evidence for the
optimum dose and therefore a dose of oral mesalazine 1.2–2.4 g daily or bal-
salazide 4.5 g daily should be considered as fi rst-line therapy. For patients with
frequently relapsing distal disease not controlled with oral 5-ASA, a combination
of oral and topical 5-ASAs every night or second night can maintain remission.
Azathioprine is effective in maintaining remission in UC and is usually contin-
ued long term. However, patients who achieve and maintain stable remission for
4–5 years can discontinue therapy. Although there is a small chance of fl are-up, the
risk-benefi t (i.e., risk of lymphoma) suggests stopping at this stage.
17.5.4 Colorectal Cancer (CRC)
Although there are no RCT data, meta-analysis suggests a protective effect of
mesalazine in the prevention of CRC (OR, 0.51; 95% CI, 0.37–0.69) and for
Chemoprophylaxis for CRC plus dysplasia (OR, 0.51; 95% CI, 0.38–0.69) [ 13 ] .
The benefi t is associated with regular mesalazine use and a dose of at least 1.2 g/
day. Curiously, there seems to be no effect on the occurrence of dysplasia alone.
The risk of CRC is highest in UC patients with coexisting primary sclerosing
cholangitis, and in this patient group, there is strong evidence that ursodeoxy-
cholic acid has a chemoprotective effect against CRC [ 14 ] .
17.6 Management of Acute Severe Colitis
(see Chaps. 18 and 19 )
17.6.1 Recognition
Acute severe colitis is the index presentation of IBD in 40% with the remainder
representing a severe fl are known as UC. The differential diagnoses are outlined in
235
17 Medical Management of Ulcerative Colitis
Table 17.2 . A short history with sudden onset of symptoms is more suggestive of
infection. Severity is assessed using Truelove and Witts’ criteria.
17.6.2 Initial Assessment
Initial assessment includes full blood count, U&Es, LFTs, CRP, and stool culture –
together with a plain abdominal x-ray and unprepared sigmoidoscopy and biopsies.
In patients with an established diagnosis, sigmoidoscopy need not be performed if
there is good clinical evidence of active disease, but it may be useful for the diagno-
sis of CMV infection. CMV is often found in severely active UC though its signifi -
cance is unclear.
17.6.3 Prognostic Features
Plain abdominal x-ray evidence of three or more small bowel loops or mucosal
islands is associated with a high risk of colectomy. Likewise, toxic megacolon
(>5.5 cm), low albumin (<30 g/dl), and extensive deep ulceration at endoscopy are
associated with >75% risk of colectomy. Overall, about 30% of presentations with
acute severe colitis will require colectomy.
17.6.4 The Role of Infection
It is important to exclude infection as the cause of acute severe colitis or a factor in
fl aring up existing colitis. C . diffi cile infection is signifi cantly higher in patients with
ulcerative colitis (37.3 per 1,000) compared with general medical patients (4.5 per
1,000) and has doubled over the last 7 years. The combination of C . diffi cile infec-
tion and ulcerative colitis has higher colectomy rates and increased mortality (odds
ratio 3.79, CI 2.84–5.06) [ 13 ] . All patients should be assessed for C . diffi cile and
treated according to local protocol. CMV infection is seen in 10% of active UC and
up to 36% of steroid refractory disease, but its role is unclear, and it may simply be
a marker of disease severity rather than a pathogen.
17.7 General Guidelines
All patients should be seen by a consultant gastroenterologists and IBD specialist
nurse. If there are signs of high risk of colectomy on admission (see above), the
patient should be seen by a consultant colorectal surgeon and stoma-therapist. All
patients should be advised on the day of admission of the risk of nonresponse to
medical therapy and subsequent surgery.
236
P. Flanagan and K. Leiper
Routine management points are as follows:
Joint medical and surgical management is appropriate. •
Patients should be weighed. If the patient is malnourished, dietetic review and •
supplementary enteral nutrition is required.
Intravenous fl uid and electrolyte replacement to correct and prevent dehydration •
or electrolyte imbalance.
Blood transfusion to maintain a hemoglobin >10 g/dl. •
Avoid anticholinergic, antidiarrheal agents, and opiates. •
Prophylactic low molecular weight heparin (3.4 times increased risk of DVT). •
Intravenous hydrocortisone 100 mg qds or methylprednisolone 60 mg/day (67% •
remission rate, 30% colectomy rate, and 1% mortality).
Rectal 5-ASA 1–2 g nocte. •
There is no evidence that oral 5-ASAs affect outcome in severe colitis and there-•
fore should not be used.
If initial attack of UC and duration less than 2 weeks, oral ciprofl oxacin •
to cover for infectious colitis. Otherwise routine antibiotics are not
recommended.
Evidence of toxic megacolon (diameter >5.5 cm, or cecum >9 cm), requires •
urgent joint review by medical and surgical teams. If there is no evidence of
severe systemic upset, then a trial of medical therapy can be attempted for 24 h.
If there is any deterioration, then surgery is indicated. It must be remembered
that steroid therapy can mask the symptoms and signs of perforation.
Daily Monitoring
Recording of pulse, temperature, blood pressure, and BMs at least four times •
a day
Daily recording of stool frequency •
Physical examination daily to evaluate abdominal tenderness and rebound •
tenderness
Recording of vital signs four times daily and more often if deterioration noted •
Daily FBC, CRP, serum electrolytes, and serum albumin •
AXR (or CT scan) if signs of deterioration or initial AXR shows dilatation •
Assessment of Response:
A stool frequency of >8 /day or CRP >45 mg/l after 3 days intravenous hydro-•
cortisone predicts the need for surgery in 85% of cases.
Intravenous steroids are generally given for 5 days. There is no benefi t beyond •
7–10 days.
Patients who enter remission should be considered for maintenance therapy with •
a thiopurine.
On discharge, oral steroids should be tapered over 8 weeks. Supplementation •
with calcium and vitamin D is recommended.
237
17 Medical Management of Ulcerative Colitis
17.8 Steroid Nonresponders
Patients who are steroid refractory can be considered for medical rescue therapy
with Infl iximab or Ciclosporin A (CiA) or for surgery. However, it should be
remembered that 50% of patients who do not enter complete remission with ste-
roids will require colectomy within a year. The effectiveness of CiA was fi rst
described in 1994 where a dose of 4 mg/kg given as a continuous infusion for
1 week and titrated to trough levels was associated with an 82% response rate [
1 ] .
Subsequent trials show an equivalent effi cacy of 2 mg/kg. Of those who respond,
53% will subsequently relapse and come to colectomy. CiA has the advantage of
rapid onset of action, median 4 days, but can cause seizures, hypertension, and
anaphylaxis.
Infl iximab has gained favor as rescue therapy due to its ease of administration and
possible lower risk of side effects. A single dose of infl iximab 5 mg/kg in patients
with steroid refractory colitis demonstrated a 29.1% colectomy rate compared to a
67% in the placebo group. There is a lack of data on long-term follow-up of patients
given infl iximab, but colectomy free rates are probably around 50% [ 16 ] .
There has been concern that the use of infl iximab or CiA may adversely affect
outcome from surgery, but to date there has been no strong evidence to support this.
A further concern is that continuing medical therapy may worsen the short-term or
medium-term mortality (“saving colons risking lives”). Recent data from the
national IBD audit suggests that mortality may be increased with use of CiA com-
pared with surgery or infl iximab in steroid nonresponders. However, two ongoing
randomized trials (CYSIF and CONSTRUCT) are comparing the two drugs in this
situation.
Recommendation:
There is no published direct comparison of CiA and infl iximab. Consideration of •
colectomy or rescue therapy with either intravenous ciclosporin 2 mg/kg/day or
infl iximab if there is no improvement by day 3 or there is subsequent deteriora-
tion. NICE recommends ciclosporin as fi rst line (and IFX use only if ciclosporin
is contraindicated) based on health economic analyses and the paucity of data to
support the use of IFX over ciclosporin.
For patients already on immunosuppressive therapy such as azathioprine/6-mer-•
captopurine at the time of presentation, infl iximab or surgery should be consid-
ered as options.
Rescue with i.v. 2 mg/kg/day ciclosporin (contraindications serum Mg < 0.5 mM •
or cholesterol <3.0 mM). If remission induced, start oral ciclosporin for
3–6 months is appropriate.
Rescue with infl iximab 3-dose induction of 5 mg/kg (0, 2, and 6 weeks). •
Infl iximab should be given as a “bridge” to longer term immunosuppressive ther-
apy such as azathioprine/6-mercaptopurine.
238
P. Flanagan and K. Leiper
If no response to rescue therapy is seen within 4–7 days, colectomy is •
recommended.
Ciclosporin after infl iximab or vice versa is not recommended. •
• Colectomy should always be considered and offered if there is any clinical
deterioration .
17.9 Emerging Therapy for UC
Unfortunately, there has not been a great increase in the number of new therapies
available to treat ulcerative colitis. A recent study of triple antibiotic therapy of
amoxicillin, tetracyline, and metronidazole showed some promise. The rationale
is that there is an increase in Fusobacterium varium in UC, and this triple antibi-
otic combination is effective in reducing counts of F . varium . The effect is mod-
est in improving symptoms and no increase in inducing remission [ 17 ] . Probiotics
have disappointingly shown little effect with only E . coli Nissle showing limited
effect. The only convincing evidence for probiotics is the effect of VSL#3 in
pouchitis.
Adacolumn apheresis is a technology which may be effective in UC particularly
severely active UC. In this technique peripheral blood is passed through a column
of plastic beads, which adsorb activated neutrophils and moncytes/macrophages.
The treatment has few side effects and is usually performed one to two times a week
for 4–5 weeks. Although a randomized controlled trial of sham versus nonsham
treatment was negative, there is some evidence that it may be signifi cantly benefi cial
in severely active disease [ 18 ] .
17.10 Conclusion
Diagnosis of UC is fairly easy. Medical therapy on fl are-up is based on symptoms
to estimate extent of disease. Maintenance therapy is with oral 5-ASA; rectal 5-ASA
is used for active distal disease with the addition of oral steroids for active extensive
disease. Steroid-refractory or frequently relapsing patients should consider thiopu-
rine therapy. Infl iximab has limited effect in chronically active UC.
Acute severe UC is a medical emergency and requires joint management by
medical and surgical teams. Initial therapy is with high-dose IV steroids; if response/
remission is not achieved within 3–5 days, then the team and patient need to discuss
surgery versus “rescue” medical therapy with either ciclosporin or infl iximab. In
most cases, “rescue” medical therapy will be initiated. However, colectomy is a
highly effective therapy, and delay should not occur in continuing medical therapy
when objective response is not achieved.
239
17 Medical Management of Ulcerative Colitis
Key Points
Proctitis
Rectum to rectosigmoid
Rectal 5-ASA; suppositories, foam, enema. Topical steroids if fails•
Consider simultaneous Oral & Rectal 5-ASA•
Resistant proctitis – oral steroids, thiopurine•
Acute left sided Colitis
Disease beyond the rectosigmoid
Mild disease relapse oral 5-ASA together with rectal 5-ASA•
Moderate/ non-responsive disease, use oral steroids; azathioprine for •
frequent/ early relapse
Unresponsive – consider infl iximab discuss surgery early if remains •
unresponsive
Acute Severe Colitis
30% require colectomy (low albumin, deep ulceration on endoscopy, AXR •
3 or more small bowel loops, mucosal islands)
Joint Management
LMW heparin•
IV hydrocortisone 100mg qds plus Rectal 5-ASA•
Steroid non-responders - medical rescue therapy with Infl iximab or •
Ciclosporin A (CiA)
Subtotal Colectomy if no response to rescue therapy is seen within •
4-7 days
Case Scenario Answers
(a) CRP is a useful test to monitor infl ammation – TRUE
[ For any fl are-up, stool should be sent for microbiology including CDT
and blood to check U&Es, FBC, CRP, and albumin .]
(b) Appendicectomy before 20 years protects against ulcerative colitis –
TRUE
[ The effect is strongest for those with appendicectomy for appendicitis below
the age of 20, with no apparent effect on reducing the chance of developing
UC after this age. The reason for this effect is likely to be that genes which
increase the risk of early appendicitis in some way reduce the risk of UC or
vice versa . However, it is not known which genes these may be .]
(c) Rectal ASA might be considered as fi rst-line therapy – TRUE
[ Meta-analysis shows rectal 5-ASAs to be superior to placebo in active
distal colitis. Remission was achieved in around two-thirds of patients
treated with rectal 5-ASA. Combination with oral 5-ASAs achieves higher
240
P. Flanagan and K. Leiper
References
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(d) An isolated patch of infl ammation in the cecum strongly suggests Crohn’s
disease – FALSE
[ A patch of infl ammation in cecum or around appendiceal orifi ce is seen
in about 30% of patients with left-sided UC ]
(e) CMV inclusions may be found in CUC biopsies – TRUE
[ CMV is often found in severely active UC, though its signifi cance is
unclear . ]
241
17 Medical Management of Ulcerative Colitis
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243
S.R. Brown et al. (eds.), Contemporary Coloproctology,
DOI 10.1007/978-0-85729-889-8_18, © Springer-Verlag London Limited 2012
18.1 Introduction
The lifetime incidence of colectomy in patients with ulcerative colitis (UC) is
traditionally quoted as being in the region of 30%. However, recent population-
based cohort evidence from Europe suggests that the colectomy rate after 10 years
of disease may be 10% or lower [ 1, 2 ] . The surgical options are governed by the
indication for the surgery as well as patient-related factors including general
condition, level of immunosuppression, age, and comorbidities, as well as
psychological factors and patient preferences.
18.2 Indications for Surgery
The indications for surgery in UC are broadly divided into emergency and elective
categories, and these are shown in Table 18.1 .
D. L. Beral , M.B.Ch.B., M.D., FRCS (Eng.)
The John Goligher Colorectal Unit ,
St James University Hospital ,
Leeds , LS9 7TF , UK
J. E. Hartley, B.Sc. (Hons), M.D., FRCS (
*)
The University of Hull Academic Surgical Unit ,
Castle Hill Hospital ,
Hull , HU16 5JQ , UK
e-mail: j.e.hartley@hull.ac.uk
Chapter 18
Surgical Options in Ulcerative Colitis
Daniel L. Beral and John E. Hartley
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