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230 F. De Iorio, L. Benini, N. Tacchella, I. Vantini
were no differences for all the endpoints, but there
was a tendency for a greater efficacy and lower side
effects of 5-ASA preparations over sulfasalazine [5].
It was concluded that for their higher cost, 5-ASA
preparations should be reserved for selected groups
such as sulfasalazine-intolerant patients or men con-
cerned about infertility.
The best dosage of mesalazine for inducing remis-
sion remains open to debate. Higher doses seem to
produce better results, doses below 2 g/day did not
show any benefit over placebo [5]. Disease extension
does not influence the response to therapy in that
similar responses are found in pancolitis and distal
colitis [7].
Few data are available on the different outcomes
concerning the efficacy of various 5-ASA formula-
tions. Only a single study suggested that balsalazide
induces more rapid clinical remission with less
adverse effects compared to a pH-dependent formu-
lation of mesalazine [8], but this requires confirma-
tion. On the other hand, olsalazine was not superior
to an enteric-coated mesalazine in inducing endo-
scopic remissions [9].
Maintenance
Four out of six studies demonstrated that 5-ASA is
superior to placebo in remission maintenance at
6–12 months [10–15]. In a meta-analysis of ran-
domised, double-blinded, placebo-controlled trials
with a duration of at least 6 months, 5-ASA was able
to halve the number of relapses compared to placebo,
with a number needed to treat of 6 to prevent one
relapse [6]. Sulfasalazine and 5-ASA have similar effi-
cacy in long-term maintenance remission and the
choice among the drugs should be based on factors
such as cost or tolerance. For maintenance therapy,
doses of 5-ASA ranged between 2 to 4.4 g/day. In the
acute phase, while disease extension did not influ-
ence the efficacy in maintaining remission [16], no
information exists on the different effects of various
ASA formulations.
Topical Therapy
Topical mesalazine is an effective alternative to
steroids enemas during the acute-phases of left-sided
colitis [17–24]. In two recent meta-analyses, rectal 5-
ASA was superior to rectal steroids in inducing clini-
cal, endoscopic and histologic improvement [25, 26].
Mesalazine enemas were as effective as oral sul-
fasalazine but with fewer adverse effects in left-sided
mild/moderate UC [27]. The drug induced remission
in a duration-dependent but not in a dose-dependent
way [26].
In a recent comparison of the use of these old
drugs according to international guidelines in IBD
patients, it was concluded that (1) 64% of patients
received suboptimal dosages of oral 5-ASA, despite
the evidence that their efficacy is dose-related; (2)
topical aminosalicylates were not used in 75% of
patients with distal colitis, despite the evidence that
combined oral and topical therapy is more effective
than systemic therapy alone [28, 29].
Table 1. Expectations expressed by members of the British National Association of Colitis and Crohn’s Disease for their
medical management
Before diagnosis
– Rapid access to hospital investigation
– Referral to a hospital that has a gastroenterologist specialised in IBD
At diagnosis
Availability of suitable written information and audio-visual material
Information about patient support groups and sources of help
Opportunity to meet non-medical members of staff, such as a clinical nurse specialist or medical social worker
familiar with IBD
Hospital management
Sufficient information to make a rational personal choice about treatment options
Close integration of medical and surgical management
Straightforward access to support services, including dieticians, psychological support, and social workers
Clearly stated management plans on discharge with well defined roles and responsibilities
Outpatient management
Continuity of care, both in hospital and in primary care
Patients dislike seeing different individuals at each visit
A system that allows a choice about appropriate long term follow up
Direct telephone access
Attention to physical, emotional, and quality of life issues
Help with problems related to insurance, employment, or social security
Medical Treatment of Ulcerative Colitis 231
Adverse Effects of Aminosalycilates
Mild side effects of sulfasalazine (mainly headache,
nausea, epigastric pain, and diarrhoea) occur in
10–45% of patients, whereas serious idiosyncratic
reactions (including Stevens Johnson syndrome,
pancreatitis, agranulocytosis, or alveolitis) are rare.
These reactions are mainly associated with the
sulphonamidic part of the molecule, which explains
why mesalazine or olsalazine are associated with a
frequency of adverse events (diarrhoea, headache,
nausea, and rash, bloody diarrhoea) similar to place-
bo [30, 31]. No comparison between balsalazide and
placebo has been published, but adverse events are
lower than with sulfasalazine [31]. A population
based study found that renal derangement (intersti-
tial nephritis and nephrotic syndrome) is associated
with disease severity rather than with dosage or type
of mesalazine and that, in any case, the risk is only
marginally increased (OR 1.60 vs. normal) [32].
Patients with pre-existing renal impairment or using
other potentially nephrotoxic drugs, should have
renal function monitored during 5-ASA therapy.
Corticosteroids
Corticosteroids are potent anti-inflammatory agents
for moderate to severe relapses of both UC and CD.
They have no role in maintenance therapy for either
disease. They act through inhibition of several
inflammatory pathways via the suppression of inter-
leukin transcription, induction of IkB (an inhibitor
of the NFkB complex), suppression of the arachidon-
ic acid metabolism and stimulation of apoptosis of
lymphocytes within the lamina propria of the gut.
Many strategies attempt to maximise their topical
effects, while limiting systemic side effects. As for
example, budesonide is a poorly absorbed corticos-
teroid with limited bioavailability and extensive first-
pass metabolism which reduces its systemic toxicity
in ileocecal CD or UC.
Efficacy for Active UC
Trials are all over 30 years old, but results are consis-
tent: oral prednisolone (starting at 40 mg daily)
induced remission in 77% of 118 patients with mild
to moderate disease within 2 weeks, compared with
48% treated with 8 g/day sulfasalazine. A combina-
tion of oral and rectal steroids is better than either
alone. Adverse events are more frequent with a dose
of 60 mg/day compared with 40 mg/day, without
added benefit; doses of prednisolone of 15 mg/day
are ineffective for active disease. The optimal dose
for “outpatient” management of acute UC appears to
be 40 mg.
Efficacy should be balanced against side effects,
but decisive treatment of active disease in conjunc-
tion with a strategy for complete withdrawal of
steroids is often appreciated by patients suffering
miserable symptoms. Regimens of steroid therapy
vary among centres. A standard weaning strategy
helps to identify patients who relapse rapidly or do
not respond and need adjunctive therapy with thiop-
urines or hospital admission [4].
Adverse Effects of Steroids
Three broad groups can be identified, although 50%
of patients report no adverse event. Early effects are
mainly due to high doses and include cosmetic
effects (acne, moon face, oedema), sleep and mood
disturbance, dyspepsia, or glucose intolerance.
Effects associated with prolonged use (usually
12 weeks) include posterior subcapsular cataracts,
osteoporosis, osteonecrosis of the femoral head,
myopathy, and susceptibility to infections. Effects
during withdrawal include acute adrenal insufficien-
cy (from sudden cessation), a syndrome of myalgia,
malaise, and arthralgia (similar to recrudescence of
UC), or raised intracranial pressure. Complete
steroid withdrawal is facilitated by early introduction
of azathioprine, adjuvant nutritional therapy, or
timely surgery.
One of the most frequent mistakes in the therapy
of UC is the prolonged use of steroids (effective only
in inducing clinical remission but not in mainte-
nance). There is no excuse either for using them
repeatedly for either frequent relapses, either for
fruitless attempts at tapering them or for continuing
them at homeopathic doses to maintain remission.
Steroids are neither safe nor effective in any of these
situations. Corticosteroids are often used for an
excessive duration even in patients with mild disease
without a clear “exit” strategy, utilising alternative
drugs to maintain remission. The standard of prac-
tice worldwide is currently to maintain long-term
remissions with either a high-dose of 5-ASAs, anti-
metabolites, anti-TNF drugs, or even surgery, rather
than with long-term or frequently repeated steroids
[29].
Immunomodulators
Purine anti-metabolites inhibit ribonucleotide syn-
thesis, but the mechanism of immunomodulation is
carried out by inducing T-cell apoptosis. Azathio-
232 F. De Iorio, L. Benini, N. Tacchella, I. Vantini
prine (AZA) is metabolised to 6-mercaptopurine (6-
MP) and subsequently to 6-thioguanine nucleotides.
Thioguanine has been used for treatment of IBD, but
caution is appropriate because of potential hepato-
toxicity.
Maintenance of Remission
Despite the general acceptance of these drugs in UC,
there are few randomised controlled trials (RCT)
evaluating the efficacy of AZA and 6-MP. This is
mainly due to the fact that researchers must adjust
the dosage of the drugs to their haematological
effects, which makes the maintenance of blindness
difficult. The first trials in the seventies showed a
steroid-sparing effect, but not an improvement in
disease activity [33–34].
In a large and long-term retrospective clinical sur-
vey, AZA was significantly more effective in inducing
remissions in patients with UC compared with CD
(87% vs. 64%) [35]. This was also true in a recent
prospective, randomised, controlled study on the
efficacy and safety of AZA and 5-ASA in inducing
remission in steroid dependent UC [36]. Seventy-two
patients were randomised to receive AZA
2 mg/kg/day or oral 5-ASA 3.2 g/day, for a 6-month
period. At the beginning, all patients were taking 40
mg of prednisolone, which was gradually tapered
according to the clinical improvement. Endoscopic
and clinical remission was achieved in 19 of 36 AZA
patients compared to 7 of 36 in the 5-ASA group.
Four AZA and 35-ASA patients underwent colecto-
my. Significantly more AZA than 5-ASA patients
complained of mild to moderate adverse events.
Patients with UC in whom remission was induced
by AZA benefited from maintenance treatment, since
withdrawal of therapy doubled the relapse rate [37];
moreover, AZA is effective in avoiding colectomy in
steroid-dependent or steroid-resistant UC [38].
Pharmocodynamics
AZA is a prodrug that is rapidly cleaved in the liver
by glutathione-S-transferase to 6-MP. This active
component is metabolised in the liver and in the gut
by one of three enzymes: (1) thiopurin-S-methyl-
transferase (TPMT), (2) xanthine-oxidase, (3) hypox-
anthine-guanine-phosphoryl transferase.
Side Effects of Immunosuppressants
AZA and 6-MP inhibits the proliferation of T and B
lymphocytes, thereby reducing cytotoxic T cells and
plasma cells. During AZA or 6MP, 6-thioguanine
nucleotides accumulate slowly in tissues, probably
accounting for the protracted action of these drugs
upon their suspension. This intracellular accumula-
tion of 6-thioguanine nucleotides is responsible for
the cytotoxic effects of these drugs by the inhibition
of purine synthesis, nucleotide interconversions,
DNA and RNA synthesis and chromosomal replica-
tion. Measurements of erythrocyte 6-thioguanine
may be helpful in optimising the dose of AZA/6-MP
for a clinical response without myelosuppressive
effects.
In has been suggested that leukaemic patients
deficient in TPMT are at increased risk of myelotox-
icity [39], but this does not necessarily apply to IBD.
In one study, 31 of 41 IBD patients with AZA-induced
myelosuppression did not carry a TPMT mutation.
Evidence that TPMT activity predicts other side
effects or outcome is limited, and so far, it cannot be
recommended as a prerequisite to therapy [40].
AZA should be introduced at a low dose,
0.5–1.5 mg/kg daily, and increased gradually within
2 weeks to 2.5 mg/kg daily. Blood monitoring
(haematology and liver function tests) should be per-
formed weekly until the maintenance dose is
reached, and monthly thereafter. The equivalent dose
of 6-MP is initially 0.25–0.5 mg/kg daily, increasing
to 1.0–1.5 mg/kg daily. If white blood cells decrease
below 3 000/mm
3
or platelets below 120 000/mm
3
, the
drug should be discontinued or the dose reduced
until these parameters normalise. Furthermore, if
liver biochemistry (and/or serum amylase) exceeds
more than 50% of the upper normal limit, AZA/6MP
should be discontinued, and then cautiously reintro-
duced.
Both AZA and 6-MP are considered slow-acting
drugs, with an effect expected after 12–17 weeks. A
recent study suggests that AZA works faster than pre-
viously believed, showing effects after 4 weeks [41].
In any case, for their slow onset of action, these drugs
have no place as a monotherapy in acute relapses of
UC. Allopurinol blocks the metabolism of 6-MP by
the inhibition of xanthine-oxidase, so that patients
on allopurinol should receive half doses of AZA/6-
MP.
Side-effects of immunosuppressants can be cate-
gorised as (1) bone-marrow suppression, 2) short-
term effects and 3) long-term effects. The side-effects
occur in about 10–15% of patients with IBD and are
either dose-dependent (bone marrow suppression)
or idiosyncrasic (pancreatitis, allergic reactions or
hepatitis).
Severe leukopenia, although rare (around 3%),
may develop suddenly and unpredictably in between
blood tests, even during long-term treatment. Side
effects detected with short-term use often occur with-
Medical Treatment of Ulcerative Colitis 233
in the first week of treatment and include pancreati-
tis (3.3% of patients), allergic reactions including
rash, idiosyncratic hepatitis with cytonecrosis,
cholestasis or insidious onset of liver dysfunction
(3.3%) and infections (7.4%). Pancreatitis resolves
upon drug withdrawal but recurs on retreatment,
which precludes the use of either AZA or 6MP.
Some 5–10% of patients stop treatment on their
own mainly during the first month. Nausea, vomiting
and malaise are the most common problems espe-
cially if the dose is increased too fast. Infections are
the theoretical risk of the long-term use of these
agents, but their incidence is not higher than with
high-dose prednisolone.
In patients on long-term immunosuppressants
one may expect an increase incidence of neoplastic
diseases. Actually, a prospective study of 1 349 non-
transplant patients receiving AZA, including 280
patients with IBD, showed a significant increase in
non-Hodgkin’s lymphoma, squamous cell carcinoma
and other tumours (overall risk increased by a factor
of 1.6) [42]. In contrast, reports from St Mark’s Hos-
pital (755 patients) and Oxford (2 205 patients)
showed a risk of neoplasia comparable with the gen-
eral population, but after a treatment of only 1 year
[43, 44].
A recent meta-analysis found a fourfold increase
risk of lymphoma in IBD patients on azathioprine/6-
MP possibly as a result of the drugs, the severity of
the disease, or a combination of the two [45]. In any
case, decision analysis suggests that in IBD, the ben-
efits of AZA outweigh the risk of lymphoma [46, 47].
The main mistake in the use of anti-metabolites is
probably undertreatment [29]. Three forms of
undertreatment are still rampant. The first is waiting
too long to introduce these agents. One relapse noted
during or soon after an attempted steroid withdraw-
al is an indication for the introduction of anti-
metabolites. Likewise, neither cyclosporine nor
infliximab should be used without a previous intro-
duction of anti-metabolites in the expectation that
they will be needed over the long-term.
The second mistake is underdosing. The habit of
administering 6-MP or azathioprine at a fixed dosage
of 50 mg/day should have long been abandoned. A
reasonable starting dose of 6-MP is 1.5 mg/kg/day
and of azathioprine 2.5–3 mg/kg/day. Even more
important, is not giving up with these drugs until
being sure that they have been administered at the
maximal doses. By definition, the dose has been
pushed up enough either when success is achieved
or when mild leukopenia has occurred (WBC in the
3 000–4 000/mm
3
range). If there is uncertainty about
efficacy, adsorption, or adherence, additional infor-
mation can be gained by looking for a substantial
increase in MCV or by measuring drug metabolites.
The last mistake is an early suspension of the drug.
No “safe” number of years has been established after
which these medications can be withdrawn without
the risk of relapse. Moreover, it is of critical impor-
tance not to suspend 6-MP or azathioprine during
pregnancy. Safety in pregnancy has been unequivo-
cally established via published experience [48].
Indeed, the risk to pregnancy is infinitely greater
from relapse of disease than from adverse effect of
treatment.
Methotrexate (MTX)
Conflicting results are available on the efficacy of
MTX in UC. In an early RCT, no significant differ-
ences were found between oral MTX (12.5 mg/week)
and placebo at 9 months in 67 UC patients [49]. In
another RCT, MTX (15 mg/week) was as effective as
6-MP (1.5 mg/kg/day) and 5-ASA (3 g/day), but less
effective in maintaining remission in steroid-
dependent UC patients. A dose of subcutaneous MTX
at 15 and 25 mg/week showed a similar efficacy in
inducing remission [50].
It is often accepted that MTX is more effective in
Crohn’s disease than in UC. However, in a recent ret-
rospective study on 22 UC and 48 CD patients treat-
ed with MTX (orally or i.m.) with a mean mainte-
nance dose of 20 mg/week, remission was achieved in
34 of 55 patients who completed more than 3 months
of treatment. Treatment was equally effective for
Crohn’s disease and UC. Life-table analysis showed
that the chances of remaining in remission at 12, 24
and 36 months of treatment were 90, 73 and 51%,
respectively [51].
Side Effects
Measurement of full blood count and liver function
tests are advisable before and within 4 weeks of start-
ing therapy, then monthly thereafter. Early toxicity
from methotrexate is primarily gastrointestinal (nau-
sea, vomiting, diarrhoea, and stomatitis) and may be
limited by 5 mg of folic acid the day following MTX
injection. Treatment is discontinued in 10–18% of
patients because of side effects. The principal con-
cerns are hepatotoxicity and pneumonitis. A study of
liver biopsies in IBD patients taking MTX showed
mild histological abnormalities despite cumulative
doses of up to 5.4 grams. Surveillance liver biopsy is
not warranted, but if the transaminases increase to
more than twice the upper normal limit, it is sensible
to withhold MTX until it returns to normal before a
retrial of the drug [52]. The prevalence of pneumoni-
tis has been estimated at 2–3 cases per 100 patient
234 F. De Iorio, L. Benini, N. Tacchella, I. Vantini
years of exposure, but even large series have not
reported any case. The main concern with this drug
is its teratogenicity, which limits its use in fertile
patients.
Cyclosporin
Cyclosporin (CyA) is an inhibitor of calcineurin, pre-
venting clonal expansion of T-cell subsets. It has a
rapid onset of action and is effective in the manage-
ment of severe UC which failed to improve from the
intensive steroidal therapy. Several uncontrolled
studies and a few controlled studies of intravenous
cyclosporine in patients with severe UC are available.
Lichtiger et al. reported on 20 patients, 9 randomized
to placebo and 11 to CyA, in continuous infusion, in
addition to steroids for up to 14 days. Nine out of 11
patients on CyA responded after a mean period of
7 days compared with none on placebo. Responders
continued on oral CyA 8 mg/kg/day and, at 6 months,
5 out of 11 maintained remission [53].
When used as a monotherapy (continuous infu-
sion of either CyA 4 mg/kg/day or methylpred-
nisolone 40 mg/day), a response at 8 days was
obtained in 9 out of 14 of CyA vs. 8 out of 15 of
methylprednisolone. Responders were slowly
switched to AZA maintenance. At 12 months, 7 out of
9 patients initially treated with CyA maintained
remission compared with 3 out of 8 with steroids.
[54].
In a further study, 30 patients were randomised to
monotherapy with CyA 4 mg/kg/day i.v. or CyA i.v in
combination with methylprednisolone 1 mg/kg/day.
At 7 days, a complete remission was obtained in 10
out of 15 on CyA vs. 14 out of 15 on the combination
therapy [55]. While 2 and 4 mg of the drug show the
same efficacy, topical treatment is not effective [56,
57].
Intravenous CyA is rapidly effective as a salvage
therapy for patients with refractory colitis, who
would otherwise face colectomy, but its use is con-
troversial because of toxicity and its high long-term
failure rate. There is now a trend to use CyA earlier to
improve outcome. To do so, early predictors of
steroid failure are needed [58–59]. For its rapid onset
of action, CyA can be considered as a “bridge” to
maintenance therapy with immunomodulators and
only rarely should be continued for more than
3–6 months.
In a recent Cochrane Review, it was concluded
that there is limited evidence that CyA is more effec-
tive than standard treatment alone in preventing
colectomy in severe UC, even if its beneficial effect
cannot be excluded due to the small sample size [60].
The possible efficacy of CyA in these severe cases has
to be weighed against possible side effects. Minor
side effects occur in 31–51%, including tremor,
paresthesias, malaise, headache, abnormal liver func-
tion, gingival hyperplasia, and hirsutism. Major com-
plications are renal insufficiency (23%), infections
(20%), seizures (3%), death (2%) and anaphylaxis
(1%) [61].
The risk of seizures is increased in patients on
intravenous CyA with serum cholesterol less than
120 mg/dl and serum magnesium less than 1.5 mg/dl.
Oral therapy is an alternative in these circumstances
[62]. Using prophylaxis against Pneumocystis carinii
pneumonia is an individual decision dependent on
nutritional state, concomitant immunomodulator
therapy, and duration of therapy, but other oppor-
tunistic infections (for example, Aspergillus sp.) may
be as common.
Tacrolimus
Tacrolimus (FK 506), a macrolide immunosuppres-
sant, acts by blocking the enzyme calcineurin which
interrupts the signal transduction pathway in the T-
cell. It is 10 to 100-fold more potent in inhibiting
lymphocyte activation in vitro than CyA, and its
intestinal absorption is more reliable even in the
presence of gastrointestinal disease. This drug, which
is expensive and rather toxic, may be effective in a
subset of patients with severe disease, steroid resist-
ant or intolerant [63–65].
Infliximab
Infliximab (IFX) (Remicade) is a chimeric anti-TNF
monoclonal antibody with potent anti-inflammatory
effects, possibly dependent on apoptosis of inflam-
matory cells, which has become the best choice in
both active and fistulising CD unresponsive to stan-
dard therapy.
Additionally, TNA-α plays a crucial role in the
inflammatory process in UC. In this disease, high
levels of TNF-α are mainly found in the superficial
colonic layers, as opposed to CD, where it is found
deeper in the mucosa or submucosa. Normally the
inflammatory response to TNF-α is counterbalanced
by inhibitors, and there is evidence that the produc-
tion of TNF-α inhibitors is down-regulated in IBD.
It has been shown that TNF-α blocking agents
probably do not act by binding and inactivating TNF-
α, but rather by inducing the apoptosis of TNF-
expressing inflammatory cells, as proven by the inef-
ficacy of etanercept. Resistance to apoptosis has been
shown in both CD and UC, but with different mecha-
nisms. The defect in CD occurs in the mitochondrial
Medical Treatment of Ulcerative Colitis 235
pathway of apoptosis (imbalance of mitochondrial
bcl-2 bax), whereas in UC it derives from the overex-
pression of FLICE-inhibitory protein (FLIP) and
impairment of the caspase mediated apoptosis.
These data support the use of IFX in UC, mainly in
steroid-refractory or severely ill patients. Open trials
on such patients suggested an effect in 50–75% of
cases, which was maintained long-term in 25% of
cases [66–68]. Concomitant use of anti-metabolites
was associated with a lower rate of relapse.
Recently, two large multicentre placebo-con-
trolled studies—Active Ulcerative Colitis 1 and 2
(ACT 1 and 2)—evaluated the efficacy of IFX for
induction and maintenance of remission in UC
patients [69]. Three hundred and sixty-four patients
with moderate to severe active UC according to the
Mayo Index despite concurrent medications (corti-
costeroids alone or in combination with AZA/6-MP,
in ACT 1, or with AZA/6-MP and 5-ASA in ACT 2),
were randomised to receive placebo or IFX 5 mg/kg
or 10 mg/kg intravenously at weeks 0, 2 and then
every 8 weeks through week 46 (in ACT 1) or week 22
(in ACT2). In both studies, a clinical response was
obtained in 69% of IFX 5 mg and 61–69% IFX 10 mg,
compared to 29–37% in the placebo group, with no
difference between patients who are or are not
steroid-refractory. At week 30 in both studies, IFX
patients were more likely to have a clinical response
than controls, and showed a clear steroid-sparing
effect. In fact, while at baseline, 56% of patients were
on steroids, by week 30, 22% of them discontinued
steroids while maintaining remission. Long-term
studies will clarify whether these promising results
and the cost-effectiveness of this medical approach in
avoiding colectomy will be maintained over the
years.
Other Approaches
Interferon-β
Immunomodulatory therapy with interferon-beta
(IFN-β) might represent a new strategy in UC due to
the divergent effects of this cytokine on the immuno-
logical and inflammatory process. IFN-β produces an
anti-inflammatory effect by inhibiting the produc-
tion of IFN-γ and TNF-α and by antagonising early
events in the IFN-γ signalling pathway. In addition,
IFN-β increases the expression of anti-inflammatory
cytokine IL-10 and enhances T suppressor and NK
cell activity.
A pilot-study investigated whether IFN-β could
induce clinical remission in 25 patients with steroid-
refractory UC. Patients were treated with 0.5 MIU
human IFN-β i.v. (n=18) or 1MIU recombinant IFN-
β s.c. (n=7). Maintenance treatment was carried out
for 52±78.8 weeks, 3 times a week. Twenty-two
patients entered remission with a mean time to
response of 3 weeks and a mean duration of remis-
sion of 13 weeks [70]. However, in two subsequent
larger trials, no differences were observed between
IFN-β and placebo [71–72].
Antibodies Anti-Integrin
A therapeutic approach in UC could be the inhibition
of migration of leukocytes into the inflamed intestine
by blocking cellular adhesion molecules. The α4β7
integrin is primarily involved in the recruitment of
leukocytes in the gut; it is present on the cell surface
of a small population of circulating T lymphocytes.
Its major ligand is mucosal-addressin-cell adhesion
molecule 1, selectively expressed on the endothelium
of the intestinal vasculature especially in the
inflamed bowel. MLN02 is a monoclonal antibody
that specifically recognises the α4β7 heterodimer.
Its efficacy in UC was recently assessed in a multi-
centre double-blind placebo-controlled trial [73]. A
clinical improvement was observed in 66% of
patients on 0.5 mg/kg/day of MLN02, in 53% on
2 mg/kg/day of MLN02 and in 33% on placebo. The
role of MLN02 in clinical practice needs to be care-
fully evaluated to define its safety profile. In fact,
natalizumab, a similar drug that interrupts leukocyte
homing through the blockade of the α4β1 integrin,
reduced immune surveillance in the brain with sub-
sequent reactivation of the JC virus. This led to pro-
gressive multifocal leuko-encephalopathy, invariably
fatal, in three patients and the drug was withdrawn
from the market [74].
Leukocytapheresis
Accumulating evidence suggests that an abnormal T-
cell-specific immune response to host flora may be a
driving force in abnormal inflammation in UC. There
is also reasonable consensus that the intestinal
epithelium in patients with UC is dominated by
leukocytes, macrophages and CD4+ lymphocytes
with a T-helper 2 phenotype. Recruitment of these
inflammatory cells from the systemic circulation into
the intestinal epithelium may be a critical step in the
amplification of the inflammatory response. Each
cell can generate pro-inflammatory mediators such
as cytokines, chemokines, growth factors and nitric
oxide radicals which will deteriorate inflamed epithe-
lium. Leukocytapheresis (LCAP) is a therapy based
on a selective removal of leukocytes from systemic
circulation, obtained by the passage of blood either
236 F. De Iorio, L. Benini, N. Tacchella, I. Vantini
through a column or through a filter. So far, this form
of therapy has mainly been studied in Japan. Recent
studies demonstrated that LCAP might be useful for
active Crohn’s disease and UC after failure of con-
ventional drug treatments.
In an early study, the effect of LCAP on maintain-
ing remission was evaluated in steroid-refractory UC
after induction of remission with the same therapeu-
tic procedure. Via induction-LCAP, six patients
reached complete remission and one reached partial
remission and was then treated with maintenance-
LCAP. Four of them were maintained in remission
without steroid treatment over 12 months. Recur-
rence was observed in three patients 3–6 months
after the beginning of maintenance, and two of them
re-entered remission by re-induction. One patient
then presented a second recurrence and underwent a
total colectomy [75].
Sakata et al. evaluated 51 UC patients with severe
or moderate disease, who failed to respond to con-
ventional therapy. Thirty-three patients went into
complete remission after the first induction therapy
with significant improvement of the activity score.
Ten of them relapsed, but 21 maintained remission
with LCAP maintenance [76].
In another study [77], 60 UC patients on sul-
fasalazine for at least 8 weeks prior to the treatment
received a total of 10 sessions of LCAP therapy (once
or twice a week). Most patients were also on pred-
nisolone at entry, and had steroids tapered or dis-
continued during the study depending on the level of
improvement. Fifty patients responded to therapy, 14
by achieving a complete remission, with no serious
adverse effects.
The endoscopic severity scores were markedly
improved in 22 of 46 patients and 68% of steroid-
dependent cases could stop steroids. The average
dose of steroid after 10 sessions decreased from 15.3
to 3.6 mg/day. In terms of symptom activity, LCAP is
more effective in patients who during the course of
their disease had received a low cumulative dosage of
steroids. There was a highly significant association
between symptomatic improvement of diarrhoea,
abdominal pain and rectal bleeding and duration of
apheresis or number of sessions per week. Five of the
non-responders to LCAP improved with convention-
al therapy, the other five underwent elective colecto-
my. No additional maintenance therapy was provid-
ed. The improvement continued for a mean duration
of 199 days (range: 21–614). The time to relapse was
negatively correlated with endoscopic and histologic
findings and the cumulative dosage of steroids. Fur-
ther studies will clarify whether this approach will
also prove cost-effective in Western populations.
Conclusions
Many different and evolving approaches are available
for the treatment of ulcerative colitis. A comprehen-
sive treatment that includes not just the disease but
also the patient (often severely debilitated by a life-
long disease, in a proportion of cases refractory to
standard treatments) and an effective patient-doctor
alliance may improve the overall results.
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Introduction
Surgery continues to play a major role in the man-
agement of ulcerative colitis because it may save the
patient’s life, eliminate the long-term risk of cancer,
and most importantly, eradicate the disease. Surgical
treatment of ulcerative colitis still remains a chal-
lenge for the surgeon despite growing knowledge
about the disease and advanced surgical techniques.
Optimal timing for surgery is the mainstay of a good
outcome and is as important as the quality of sur-
gery. Although as many as one third of patients with
ulcerative colitis require at least one surgical proce-
dure to address complications derived from their dis-
ease, the decision in favour of a surgical approach
and its timing is rarely an easy one. It is estimated
that approximately 30% of patients with ulcerative
colitis will undergo colectomy during the course of
the disease [1]. All indications for surgical treatment
of ulcerative colitis can be divided into two major
types: those requiring emergency surgery and those
requiring elective operation.
Indications for Emergency Surgery
Emergency surgery in ulcerative colitis is indicated in
cases when life-treating complications occur during
the course of the disease. It is of paramount signifi-
cance to stress the value of well-timed surgical treat-
ment since in many cases appropriate indications
(Table 1) and timely operation can save the patient’s
life.
Massive Haemorrhage
Massive haemorrhage is rarely an indication for
emergency colectomy. Severe, life-treating haemor-
rhage occurs in 0–4.5% of patients with ulcerative
colitis and it accounts for approximately 10% of all
emergency colectomies performed due to ulcerative
colitis [2]. The clinician should recognise potentially
severe, massive bleeding and undertake appropriate
measures in a timely fashion because a haemorrhage
is one of the indications of the disease and can be eas-
ily underestimated. It is of paramount importance to
distinguish a slow but persistent haemorrhage from
severe bleeding with rapidly circulating volume loss.
Haemorrhage with anaemia <6 g/dl, requiring 4–6
units of packed red cells, or haemorrhage with shock
resistant to resuscitation should prompt emergency
colectomy.
Since the bleeding is a marker of the severity of the
disease, the clinician should be aware that the
patient’s life is not jeopardised only by the bleeding
itself but by the severe underlying disease. Massive
haemorrhage is often associated with concomitant
toxic megacolon [2]. Many of these patients are or
were using an immunosuppressive therapy that
could further increase the risk. Sometimes paramed-
ical reasons like reserves of blood in the blood bank,
surgical facilities, etc., can also influence the decision
for operative treatment. In any case, the clinician,
erroneously believing that the bleeding will sponta-
neously cease, should not prolong medical treatment
indefinitely. There are some reports of successfully
managed severe bleeding in ulcerative colitis using a
highly selective transcatheter embolisation [3]. This
procedure is suggested as an alternative therapeutic
approach in selected cases. Despite this successful
but sporadic attempt, emergency proctocolectomy is
currently advocated as the only reliable treatment.
The alternative approach could be emergency colec-
tomy without proctectomy. This alternative has the
advantages of being a more simple procedure that
can be performed in emergency settings by a less
Indications for Surgical Treatment of Ulcerative Colitis
Zoran V. Krivokapic, Goran I. Barisic
Table 1. Indications for emergency surgery in ulcerative
colitis
• Massive haemorrhage
• Fulminant colitis
• Toxic megacolon
• Perforation
• Obstruction
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